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Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 με at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 με at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Background: Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene., Methods: Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1., Results: Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants., Conclusions: S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.

As the initial part in the development of osteoarthritis (OA), subchondral bone sclerosis has been considered to be initiated by excess mechanical loading and proven to be correlated to other pathological changes. Sclerostin, which is an essential mechanical stress response protein, is encoded by the SOST gene. It is expressed in osteocytes and mature chondrocytes and has been proven to be closely correlated to OA. However, the relationship and mechanism between the SOST gene and the development of OA remain unclear. The aim of the present study was to investigate the role of the SOST gene in OA pathogenesis in the subchondral bone. A knee anterior cruciate ligament transection (ACLT) mouse osteoarthritis (OA) model on SOST-knockout (SOST KO) and wild-type (WT) mice was established. The pathogenic and phenotypic changes in the subchondral bone were investigated by histology, micro-CT, immunohistochemistry, TRAP staining, Masson staining, and Toluidine blue staining. It was found that sclerostin expression decreased in both the calcified cartilage and mineralized subchondral structures during the development of OA. Joint instability induced a severe cartilage degradation phenotype, with higher OARSI scores in SOST KO mice, when compared to WT mice. SOST KO mice with OA exhibited a higher BMD and BV/TV ratio, as well as a higher rate of bone remodeling and TRAP-positive cell number, when compared to the WT counterparts, but the difference was not significant between the sham-operation groups. It was concluded that loss of sclerostin aggravates knee OA in mice by promoting subchondral bone sclerosis and increasing catabolic activity of cartilage., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Jingyu Li et al.)

Introduction: Although the nose and lungs are separate organs, numerous studies have reported that the entire respiratory system can be considered as a single anatomical and functional unit. The upper and lower airways affect each other either directly or through reflex mechanisms., Objective: In this study, we aimed to evaluate the effects of the radiofrequency ablation of persistent inferior turbinate hypertrophy on nasal and pulmonary function., Methods: Twenty-seven patients with bilateral persistent inferior turbinate hypertrophy without septal deviation were included in this study. All of the patients were evaluated using anterior rhinoscopy, nasal endoscopy, acoustic rhinometry, a visual analogue scale, and flow-sensitive spirometry on the day before and 4 months after the radiofrequency ablation procedure., Results: The post-ablation measurements revealed that the inferior turbinate ablation caused an increase in the mean cross-sectional area and volume of the nose, as well as in the forced expiratory volume in 1s, forced vital capacity, and peak expiratory flow of the patients. These differences between the pre- and post-ablation results were statistically significant. The post-ablation visual analogue scale scores were lower when compared with the pre-ablation scores, and this difference was also statistically significant., Conclusion: This study demonstrated that the widening of the nasal passage after the reduction of the inferior turbinate size had a favorable effect on the pulmonary function tests., (Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Objective and Importance: Camurati-Engelmann disease (CED) is a rare, autosomal-dominant genetic disorder resulting in hyperostosis of the long bones and skull. Patients often develop cranial nerve dysfunction and increased intracranial pressure secondary to stenosis of nerve foramina and hyperostosis. Surgical decompression may provide symptomatic relief in select patients; however, a small number of reports document the recurrence of symptoms due to bony regrowth. We present a patient who had been treated previously with bilateral frontal and parietal craniotomy who experienced recurrence of symptoms due to reossification of her cranial bones. This report underscores the progressive nature of CED and its influence on surgical management. Furthermore, we propose a novel surgical approach with multiple craniectomies and titanium mesh cranioplasties that could potentially offer long-term symptomatic relief., Clinical Presentation: A 46-year-old female patient with CED who was treated with ventriculoperitoneal shunting, posterior fossa decompression, and multiple craniotomies 2 decades prior presented with signs and symptoms of increased intracranial pressure. Studies of the skull at presentation demonstrated rethickening of cranial bones that resulted in severely decreased intracranial volume., Intervention: A radical craniectomy, requiring 4 separate bone flaps made up of bilateral frontal and parietal bones, was performed. The remaining coronal and sagittal bony struts were drilled to approximately 1 cm thick. Cranioplasties with 4 separate titanium meshes were performed to preserve the natural contour of the patient's skull., Conclusions: Although surgical decompression could provide some patients with CED symptomatic relief, clinicians should consider managing CED as a chronic condition. To the authors' knowledge, this is one of few case reports documenting the recurrence of symptoms in a patient with CED treated by surgical intervention. Furthermore, we propose that multiple craniectomies with titanium mesh cranioplasties confer more permanent symptomatic control, and, more importantly, lower the risk of recurrence secondary to cranial hyperostosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose of Review: Discovery of the Wnt signaling pathway and understanding the central role of osteocyte in skeletal homeostasis have been the major advances in skeletal biology over the past decade. Sclerostin, secreted mainly (but not exclusively) by osteocytes, has emerged as a key player in skeletal homeostasis. This review highlights the most relevant recent advances., Recent Findings: Sclerostin by inhibiting Wnt signaling pathway decreases bone formation and osteoblast differentiation and promotes osteoblast apoptosis. Ability to measure serum sclerostin levels better clarified the role of sclerostin in various physiologic and pathologic states. Early clinical trials with antibodies to sclerostin have produced robust increases in bone mineral density, and fracture prevention trials are underway., Summary: Since the discovery of Wnt signaling pathway and sclerostin's association with high bone mass, there has been a remarkable progress. Clinical trials with fracture endpoints, already underway, should expand osteoanabolic therapeutic horizon in the very near future. Measurement of sclerostin levels in a number of conditions has advanced our knowledge about pathophysiology of skeletal and nonskeletal disorders in an altogether new light.

High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n = 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n = 4 and adults [24 and 43 years], n = 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced -1.9% (p < 0.0001, younger tissue age) and -1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice-a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency., (© 2014 American Society for Bone and Mineral Research.)

Objective: This study was designed to investigate the pathogenic contributions of fibroblast-like synoviocytes (FLS) to juvenile idiopathic arthritis (JIA) by identifying pathways with dysregulated gene expression in FLS from patients with oligoarticular JIA., Methods: FLS were derived from synovial fluid obtained by arthrocentesis from patients with JIA undergoing intraarticular steroid injections and from orthopedic control patients. Gene expression profiles of the JIA and control FLS were obtained using the Affymetrix platform, with application of Ingenuity Pathway Analysis and Gene Set Enrichment Analysis software to define gene sets in dysregulated pathways and networks of potential pathologic relevance in this disease. Biologically relevant differentially expressed genes were confirmed by RNA and protein analysis., Results: Exploration of global gene expression profiles of the JIA FLS revealed important dysregulated pathways, including the transforming growth factor β (TGFβ) signaling, as well as endochondral bone formation, cartilage formation, and β-catenin networks. Importantly, bone morphogenetic protein 4 (BMP-4) was significantly overexpressed in the JIA FLS. FLS from patients with oligoarticular JIA exhibit a chondrocyte phenotype, as evidenced by expression of type II collagen and aggrecan., Conclusion: Dysregulation of the pathways involved in the pathogenesis of oligoarticular JIA were revealed through gene expression profiling. JIA FLS displayed dysregulated TGFβ signaling and exhibited a hypertrophic chondrocyte phenotype. These characteristics, along with contributions from the β-catenin network may have implications for endochondral bone formation and local growth disturbances in oligoarticular JIA. Overexpression of BMP-4 in FLS from patients with oligoarticular JIA in particular may play an important role in disease pathogenesis, with a direct effect on functional outcome and with implications for future treatment., (© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: Hyperostosis cranialis interna (HCI) is an autosomal dominant sclerosing bone dysplasia affecting the skull base and the calvaria, characterized by cranial nerve deficits due to stenosis of neuroforamina. The aim of this study is to describe the value of several neurophysiological, audiometric and vestibular tests related to the clinical course of the disorder., Methods: Ten affected subjects and 13 unaffected family members were recruited and tested with visual evoked potentials, masseter reflex, blink reflex, pure tone and speech audiometry, stapedial reflexes, otoacoustic emissions, brainstem evoked response audiometry and electronystagmography., Results: Due to the symmetrical bilateral nature of this disease, the sensitivity of visual evoked potentials (VEPs), masseter reflex and blink reflex is decreased (25-37.5%), therefore reducing the value of single registration. Increased hearing thresholds and increased BERA latency times were found in 60-70%. The inter-peak latency I-V parameter in BERA has the ability to determine nerve encroachment reliably. 50% of the patients had vestibular abnormalities. No patient had disease-related absence of otoacoustic emissions, because the cochlea is not affected., Conclusion: In patients with HCI and similar craniofacial sclerosing bone dysplasias we advise monitoring of vestibulocochlear nerve function with tone and speech audiometry, BERA and vestibular tests. VEPs are important to monitor optic nerve function in combination with radiological and ophthalmologic examination. We do not advise the routine use of blink and masseter reflex., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The article covers results of studies concerning time of fluorosis development in patients with signs of connective tissue dysplasia syndrome (CTDS). if compared with patients without CTDS, and of studies concerning hyperostosis coefficient in accordance with presence or absence of CTDS. Efficiency of physical therapy and balneotherapy for these patients are also reported by the authors.

Object: Although bone invasion and hyperostosis are common phenomena in patients with intracranial meningiomas, the basic pathomechanism is not fully understood. Based on an immunohistochemical study of surgically resected samples with hyperostosis, we postulate a possible mechanism of hyperostosis in patients with intracranial meningiomas., Materials and Methods: Forty-six meningiomas were evaluated in this study. Twenty-six meningiomas associated with hyperostosis specimens served as the study group, and 20 meningiomas without any bony changes served as controls. An immunohistochemical staining technique was used to detect the expression of matrix metalloproteinase (MMP)-2, -9, and -13, membrane type (MT)1-MMP, estrogen receptor (ER), and progesterone receptor (PR) in the main tumor and hyperostotic portions of the studied samples., Results: In the non-hyperostosis group, expression of MMP-13, MT1-MMP, and ER was significantly less than in the main tumor portion of hyperostotic meningiomas, while there was no difference in the expression of MMP-2 and -9 and PR in the main tumor between the two groups. In the hyperostosis group, the immunoreactivity of MMP-2 in the hyperostotic portion revealed a higher pattern of expression than the main tumor (p < 0.002). The expression of MMP-9, MT1-MMP, ER, and PR had relatively positive immunoreactivity in the main tumor portion (P < 0.05)., Conclusions: Increased expression of MMP-13 and MT1-MMP in the tumor portion of hyperostosis of meningiomas might contribute to the initiation of osteolysis. Activated MMP-2 in hyperostotic lesions may change the physiological metabolism of the skull bone, thus playing an important role in hyperostosis formation.

The aim of this paper is to review the main aspects related to high bone density (HBD) as well as to discuss the physiologic mechanisms involved in bone health. There are still no well-defined criteria for identification of individuals with HBD and there are few studies on the topic. Most studies demonstrate that overweight, male gender, black ethnic background, physical activity, calcium and fluoride intake and use of medications such as statins and thiazide diuretics play a relevant and positive role on bone mineral density. Moreover, it is known that individuals with certain diseases such as obesity, diabetes, estrogen receptor-positive breast or endometrial cancer have greater bone density than healthy individuals, as well as athletes having higher bone density than non-athletes does not necessarily mean that they have healthy bones. A better understanding of risk and protective factors may help in the management of patients with bone frailty and have applicability in the treatment and in the prevention of osteoporosis, especially intervening on non-modifiable risk factors., (Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.)

Inactivating mutations of the SOST gene cause a reduction in sclerostin levels and are associated with high bone mass. The clinical phenotypes, sclerosteosis and van Buchem's disease, were described in 1950s. Much later, it was learned that both diseases are due to loss-of-function mutations in the SOST gene. As a regulator of an important osteoanabolic pathway, Wnt, inactivation of SOST leads to a stimulation of the pathway it regulates. The high bone mass in patients with either sclerosteosis or van Buchem's disease is associated with unusual skeletal strength; they do not fracture. Knowledge of this molecule and its actions led rather quickly to the development of anti-sclerostin antibodies that lead to marked increases in bone mass in both animals and human subjects. Blocking sclerostin action with anti-sclerostin antibodies is a promising new therapeutic approach to osteoanabolic therapy of osteoporosis.

Summary: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder., Introduction: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia., Methods: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex., Results: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001)., Conclusion: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Sclerosteosis is a rare bone sclerosing dysplasia, caused by loss-of-function mutations in the SOST gene, encoding sclerostin, a negative regulator of bone formation. The purpose of this study was to determine how the lack of sclerostin affects bone turnover in patients with sclerosteosis and to assess whether sclerostin synthesis is decreased in carriers of the SOST mutation and, if so, to what extent this would affect their phenotype and bone formation. We measured sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked C-telopeptide (CTX) in serum of 19 patients with sclerosteosis, 26 heterozygous carriers of the C69T SOST mutation, and 77 healthy controls. Chips of compact bone discarded during routine surgery were also examined from 6 patients and 4 controls. Sclerostin was undetectable in serum of patients but was measurable in all carriers (mean 15.5 pg/mL; 95% confidence interval [CI] 13.7 to 17.2 pg/mL), in whom it was significantly lower than in healthy controls (mean 40.0 pg/mL; 95% CI 36.9 to 42.7 pg/mL; p < 0.001). P1NP levels were highest in patients (mean 153.7 ng/mL; 95% CI 100.5 to 206.9 ng/mL; p = 0.01 versus carriers, p = 0.002 versus controls), but carriers also had significantly higher P1NP levels (mean 58.3 ng/mL; 95% CI 47.0 to 69.6 ng/mL) than controls (mean 37.8 ng/mL; 95% CI 34.9 to 42.0 ng/mL; p = 0.006). In patients and carriers, P1NP levels declined with age, reaching a plateau after the age of 20 years. Serum sclerostin and P1NP were negatively correlated in carriers and age- and gender-matched controls (r = 0.40, p = 0.008). Mean CTX levels were well within the normal range and did not differ between patients and disease carriers after adjusting for age (p = 0.22). Our results provide in vivo evidence of increased bone formation caused by the absence or decreased synthesis of sclerostin in humans. They also suggest that inhibition of sclerostin can be titrated because the decreased sclerostin levels in disease carriers did not lead to any of the symptoms or complications of the disease but had a positive effect on bone mass. Further studies are needed to clarify the role of sclerostin on bone resorption., (Copyright © 2011 American Society for Bone and Mineral Research.)

Aim: The IMAGE prosthesis was developed with the objective of proximal load induction to avoid stress shielding and proximal bone resorption. In this study patients were followed clinically and radiologically with a special emphasis on osteointegration of the shaft in the proximal and distal regions. In addition, the reconstruction of the bony geometry of the proximal humerus was investigated., Method: 95 consecutive patients (mean age: 61.1 years) with an IMAGE shaft were followed up prospectively over five years after primary hip arthroplasty. Radiologically, the osteointegration was appraised on the basis of the parameters cortical bone hypertrophy, radiolucent lines, shaft sintering and the position of the rotational centre. The clinical parameters assessed were the Harris hip score (HSS) and the WOMAC score., Results: In Dorr C configuration no distal cortical bone hypertrophy was visible, in contrast to 19% in types A and B. By means of this criterion in 81% of the cases, a metaphyseal anchoring can be assumed. In 20% of the cases proximal and in 11.1% distal radiolucent lines were found. In only 3.3 % of the patients were the radiolucent lines due to unwanted distal osteointegration. In most cases the reasons were PE wear and metallosis. In 18.8% a distal anchoring was visible. Sintering (in total 18 prostheses) was greatest in Dorr C configuration and high-grade osteoporosis. The difference in offset reconstruction was 4.23 mm on average. In reconstruction of the rotational centre the variability was between 2.0 and 6.9 mm. 94.13 points were attained in the HHS and 10.13 points in the WOMAC score. Specific complications related to the implantation were not observed., Conclusions: Proximal stress transmission can be supported and the danger of stress shielding can be reduced by means of an appropriate design of a prosthetic stem. Distal corticoid hypertrophy was found in only 19% of the patients with the prosthesis model investigated as compared to 60% having prostheses with distal femoral anchoring. The medium-term clinical results are excellent, so that the shaft appears suitable for primary as well as secondary osteoarthritis of the hip joint., (Georg Thieme Verlag KG Stuttgart, New York.)

Introduction: The aim of this study was to investigate the effects of nasal obstruction with enlargement of inferior turbinates on the aerodynamic flow pattern using Computational Fluid Dynamics (CFD) tools including the effects of turbulence., Methods: A high-resolution 3-dimensional model of the nasal cavity was constructed from MRI scans of a healthy human subject using MIMICS 12.0 software. Nasal cavities corresponding to healthy, moderate and severe nasal obstructions were simulated by enlarging the inferior turbinate geometrically. Numerical simulations with turbulent flow models were implemented using FLUENTS for CFD simulations., Results: In the healthy nose, the main respiratory air stream occurs mainly in the middle of the airway, accompanied by a diffused pattern of turbulent flow on the surface of the nasal mucosa. The peak value of turbulent flow is found in the functional nasal valve region. However, this aerodynamic flow pattern has partially or completely changed in the models with enlarged inferior turbinate. An inhalation flow rate of 34.8 L/min with a maximum velocity of 5.69 m/s, 7.39 m/s and 11.01 m/s are detected, respectively, in the healthy, moderately and severely obstructed noses. Both total negative pressure and maximum shear stress have increased by more than three and two times, respectively, in severely blocked noses compared to the healthy one., Conclusion: Data of this study provide quantitative and quantitative information of the impact of inferior turbinate hypertrophy on the aerodynamic pattern and physiological functions of nasal airflow. By including the model of turbulent airflow, the results of this experimental study will be more meaningful and useful in predicting the aerodynamic effects of surgical correction of inferior turbinate hypertrophy.

Background: Nasal congestion is one of the most common complaints dealt with in otorhinolaryngology. Side effects of decongestants are frequently seen in patients with chronic nasal congestion. This leads to an increasing demand of alternative treatments such as acupuncture. Future studies on acupuncture should aim at objectifying effects by both physical measuring and double blinding. Therefore, we were interested in whether these effects can potentially be measured as increase in nasal airflow (NAF) in ventus ("wind") disease of traditional Chinese medicine (TCM)., Methods: Twenty-four patients with a history of nasal congestion due to hypertrophic inferior turbinates or chronic sinusitis without polyposis were additionally diagnosed according to the Heidelberg model of TCM. They were asked to score the severity of their nasal congestion on a visual analog scale (VAS). The acupuncturist was blinded according to the Heidelberg blinding assay. NAF was measured by using active anterior rhinomanometry (ARM). Specific verum acupoints according to the Chinese medical diagnosis were tested against nonspecific control acupoints. VAS and NAF were scored and measured before and 15 and 30 minutes after acupuncture., Results: Control acupuncture showed a significant improvement in VAS and a deterioration of NAF. Verum acupuncture showed highly significant improvements in VAS and NAF. In addition, verum acupuncture improved NAF and VAS significantly over time., Conclusion: Our control and verum acupoints fulfill the condition of a control and verum treatment, respectively. Measuring NAF by RRM and scoring VAS are possible and reflect acupuncture effects in vivo.

Unlabelled: Vertebral hyperostosis typically predominates at the thoracic spine and causes only minor symptoms. Involvement of the cervical spine may cause dysphagia due to pressure on the esophagus. We report three cases of dysphagia revealing cervical hyperostosis., Case Reports: The patients were 3 men aged 54-73 years. Dysphagia was moderate in 2 patients and severe in 1 patient who had lost 4 kg over 6 months. Stiffness of the neck with mild pain was present. One patient reported a neck injury in childhood and another had a brother and father with similar symptoms. Radiographs showed exuberant anterior cervical hyperostosis. Two patients also had hyperostotic changes at the thoracic spine and pelvis. The skin and neurological evaluation were normal. Findings were normal from standard blood tests (C-reactive protein, calcium, and vitamin D). Tests were negative for the HLA-B27 antigen in all 3 patients. Serum vitamin A levels were high, ranging from 894 to 1123 microg/L (normal, 489-720). None of the patients reported taking retinoids or having unusual eating habits., Discussion: Dysphagia can result from anterior cervical hyperostosis. A role for hypervitaminosis A in the genesis of hyperostosis has long been suspected. In our patients, the absence of vitamin A supplementation suggests an abnormality in vitamin A metabolism.

Background: Nasal obstruction (NO) is a very common symptom, but its effect on nasal physiology has not been fully understood. We performed this study to determine the effect of severity of NO due to inferior turbinate hypertrophy on airflow pattern using the computational fluid dynamics simulations., Methods: A three-dimensional nasal cavity model was constructed from the MRI scans of a healthy human subject. Nasal cavities corresponding to healthy, moderate, and severe NO was simulated by enlarging the inferior turbinate geometrically, which can be documented by approximately one-third reduction of the minimum cross-sectional area (1.453 cm(2) in the healthy nose) for the moderate (0.873 cm(2)) and two-thirds (0.527 cm(2)) for the severe obstruction., Results: Total negative pressure through the nasal cavity increased during the inspiratory phase by almost twofold (-19 Pa) and threefold (-33 Pa) for moderate and severe blockage, respectively, compared with the increase of total negative pressure of -10 Pa in a healthy nose. In cases of moderate and severe blockage, a higher velocity and shear stress was observed at the nasopharynx and dorsal region of the nasal cavity. Moreover, nasal valve function will not exist in severe NO because of the changes of airflow pattern at the original nasal valve location., Conclusion: Impairment of nasal airflow and physiology is evidenced in NO caused by inferior turbinate hypertrophy. Data of this study may help in predicting the aerodynamic effects of surgical correction of the inferior turbinate hypertrophy.

We analysed the functional adaptation of the first and second metatarsal bones to altered strain in flexible flatfoot. Fifty consecutive women (20-40 years of age) were enrolled: 31 patients with a flexible flatfoot and metatarsalgia (59 feet) and 19 controls with asymptomatic feet (37 feet). They were compared for cortical thickness (medial, lateral, dorsal and plantar) of the two bones. The null hypothesis of no overall difference between the deformed and healthy feet with regard to cortical thicknesses of the two bones was rejected in a multivariate test (p = 0.046). The groups differed significantly only regarding dorsal cortical thickness of the second metatarsal, which was around 18.1% greater in the deformed feet (95% confidence interval: 7.7-28.4%, p < 0.001). Hypertrophy of the dorsal corticalis of the second metatarsal bone appears to be the main metatarsal adaptive reaction to altered strain in the flexible flatfoot.

Purpose of Review: This review summarizes recent advances in the field of diabetes and rheumatic disease. These conditions exert a significant healthcare burden on our society and much remains to be learned regarding their pathophysiology and treatment., Recent Findings: We summarize new insights into diabetes and its association with osteoarthritis, rheumatoid arthritis, carpal tunnel syndrome, osteoporosis, diffuse idiopathic skeletal hyperostosis, crystalline arthropathy, neuropathic arthropathy, and tendinopathy. Diabetes has major effects on connective tissues, which have significant impact on both the development and outcome of these diseases of cartilage, bone, ligament, and tendon. An improved understanding of the mechanisms through which diabetes alters connective tissue metabolism should lead to better preventive and therapeutic interventions., Summary: Incremental progress has been made in understanding the interactions between diabetes and common musculoskeletal syndromes. Although this review highlights exciting areas of future interest, more work in this field is certainly warranted.

The authors present two cases of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome with rapidly progressing destructive spondylitis treated surgically. The spinal lesions in SAPHO syndrome generally have a good prognosis and rarely cause the structural destruction or neurological deterioration. Case 1: a 63-year-old female had palmoplantar pustulosis for 2 years. At first, she only felt a pain in the nape with no inducing factor. Two months later, she had incomplete quadriplegia (ASIA scale C). Magnetic resonance imaging showed destruction of C4-C7, kyphotic deformity, and severe compression of the spinal cord. Decompression and reconstruction surgery using anterior and posterior approach improved her paralysis. Case 2: a 69-year-old female complained of persistent back pain. Magnetic resonance imaging revealed spondylitis of T7-T9. Although there were no typical skin lesions, we diagnosed SAPHO syndrome by hyperostosis of the sternocostoclavicular joint and sacral joint. Destruction with kyphotic deformity of the spine progressed gradually for 3 months. Curettage and reconstruction surgery using thoracic endoscope relieved her pain and prevented the destruction of the spine. The histopathology of the specimen obtained surgically showed non-specific inflammation in both cases. Spondylitis in SAPHO syndrome may cause severe destruction and kyphotic deformity followed by paralysis.

Rheumatological manifestations of Diabetes Mellitus may be classified in: non articular, articular and bone conditions. Among non articular conditions, diabetic cheiroarthropathy, frequent in type I diabetes, the most important disorder related to limited joint mobility, results in stiff skin and joint contractures. Adhesive capsulitis of the shoulder, flexor tenosynovitis, and Duputryen's and Peyronie's diseases are also linked to limited joint mobility. Diffuse skeletal hyperostosis, due to calcification at entheses, is frequent and early, particularly in type 2 diabetes. Neuropathies cause some non articular conditions, mainly neuropathic arthritis, a destructive bone and joint condition more common in type I diabetes. Algodistrophy, shoulder-hand and entrapment syndromes are also frequent. Mononeuropathy causes diabetic amyotrophy, characterised by painless muscle weakness. Among muscle conditions, diabetic muscle infarction is a rare, sometimes severe, condition. Among articular conditions, osteoarthritis is frequent and early in diabetes, in which also chondrocalcinosis and gout occur. Rheumatoid arthritis (RA) and diabetes I have a common genetic background and the presence of diabetes gives to RA an unfavourable prognosis. Among bone conditions, osteopenia and osteoporosis may occur early in type 1 diabetes. Contrarily, in type 2 diabetes, bone mineral density is similar or, sometimes, higher than in non diabetic subjects, probably due to hyperinsulinemia.

Two bullmastiffs with calvarial hyperostosis syndrome are described and are the first documented examples in females. The clinical and radiologic features were similar to those previously reported in males. Magnetic resonance (MR) imaging findings have not previously been reported. One dog underwent MR imaging and abnormalities included thickening of the frontal bones with loss of normal fat signal and changes in the overlying soft tissues. In one of the dogs, long bone changes were seen in the femora and resembled those seen with craniomandibular osteopathy.

Sclerosteosis and Van Buchem disease are two closely related bone disorders characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is associated with mutations in the SOST gene and Van Buchem disease with a 52 kb deletion downstream of the SOST gene that probably affects transcription of the gene. Expression of the gene product sclerostin in bone is restricted to osteocytes and it is a negative regulator of bone formation. It inhibits BMP-stimulated bone formation, but cannot antagonize all BMP responses. The exclusive bone phenotype of good quality of patients with sclerosteosis and Van Buchem disease and the specific localization of sclerostin make it an attractive target for the development of bone forming therapeutics.

Longitudinal bone growth results from coordination of proliferation and hypertrophy of chondrocytes, calcification of the matrix, vascular invasion, and completion of endochondral bone formation in the growth plate. Although proliferative and hypertrophic chondrocytes are well characterized histomorphologically, the understanding of factors governing this transition is not fully explained. Our hypothesis was that significant differential gene expression exists between proliferative and hypertrophic chondrocytes that may provide clues to the regulation of this transition at the transcriptional level. Normal Sprague-Dawley rat growth plate chondrocytes from the proliferative zone (PZ) and hypertrophic zone (HZ) were isolated by laser capture microdissection and then subjected to microarray analysis. Confirmation of the differential expression of selected genes was done by in situ hybridization and quantitative reverse transcription (RT) polymerase chain reaction (PCR). A total of 40 transcripts showed at least twofold greater expression in the PZ compared to HZ at both 6 and 7 weeks of age, while 52 transcripts showed twofold greater expression in the HZ compared to PZ at these time points. Many of the differentially expressed genes in each zone had very high levels of expression and thus were classified as "enriched transcripts" for that zone. The PZ-enriched transcripts included fibromodulin, proline arginine-rich end leucine-rich repeat protein, lactate dehydrogenase, and enolase 1 alpha. In contrast, HZ-enriched transcripts included collagen I, protein kinase (lysine deficient 4), proteasome (prosome, macropain) activator subunit 4, prostaglandin I2 synthase, and integrin-binding sialoprotein, matrix metalloproteinase 13 (MMP13), and collagen X. Other genes were highly expressed in cells from both zones, including collagen II, aggrecan, cartilage oligomeric protein, cartilage link protein, laminin receptor, and eukaryotic translocation elongation factor. Functional classification of the PZ-enriched transcripts showed an increased percentage of genes expressed in nuclear cell cycle and transcription functions. In contrast, the HZ-enriched transcripts were more involved in extracellular structure and membrane receptor and transporter functions. Pathway analysis indicated that transforming growth factor beta and parathyroid hormone-related protein (PTHrP) pathways were important in both zones, and bone morphogenic protein pathway played a role in the HZ. It is likely that these differentially expressed genes are involved in regulation of the transition from proliferation to differentiation functions in the growth plate.

Chronic nasal obstruction is a common disorder, mostly caused by hypertrophic inferior turbinates. In cases of nonresponse to conservative medical management, the surgical reduction of the inferior turbinates is often required. Surgical techniques for the reduction of hyperplastic nasal turbinates include monopolar or bipolar coagulation, partial or total reduction of the turbinates with a conchotome or scissors and laser surgery with Nd:YAG, CO(2) or KTP. Argon plasma coagulation (APC) is a new, innovative technique in otorhinolaryngology which is based on high-frequency electrocoagulation with an argon gas source. The fast and short surgery times, the absence of hemorrhagic complications and, in rhinosurgery, the complete abstention from any kind of nasal packing are remarkable. Between March and November 2000, a group of 157 patients with symptoms of nasal obstruction due to hypertrophic inferior turbinates were treated using APC, at the Otorhinolaryngology Surgery Department of the Hospital of Dolo (Venice). The follow-up period was 24 months. Rhinomanometry was performed to objectively measure the nasal obstruction and to verify the postoperative improvement. The Student t test was used for statistical data. After 24 months, 87% (p < 0.001) of the patients reported to have a better nasal airflow than before the operation. None of the patients needed a nasal packing after APC surgery. The indication, advantages, complications, controversies and long-term results of the treatment with APC in rhinosurgery are reviewed and discussed., (Copyright 2003 S. Karger AG, Basel)

Bone mineral density is a quantitative trait influenced by both genetic and environmental factors. Epidemiological and twin studies have shown heritability for the variance of bone density of up to 80%. The role of genetic factors in bone homeostasis also is clearly illustrated by the existence of an extended group of genetic conditions associated with an abnormal bone density. These conditions are mainly monogenic in that they are caused by mutations in one gene. Recent developments in molecular genetics and genomics have resulted in a dramatically increased power to identify such disease-causing genes. The group of conditions with increased bone density has been poorly studied and understood at the molecular genetic level but recently for some of them, major breakthroughs have been made. These findings will make the molecular analysis of such patients an additional tool in diagnostics and in genetic counseling.

A 76-yr-old man with bilateral total hip arthroplasties was referred for a baseline bone mineral density (BMD) measurement. The L1-L4 lumbar bone density revealed a density above the upper expected value for a young individual (i.e., T-score > 2.5) with large intervertebral variation, while the forearm study revealed an osteoporotic measurement. Lumbar spine radiographs demonstrated abundant, flowing ossification of the anterior spinal ligament, predominantly at L3, consistent with diffuse idiopathic skeletal hyperostosis, which accounted for the increased BMD.

Objective: To establish the pathophysiology of retinoid induced hyperostosis., Methods: Radiographical, histological, ultrastructural, and immunohistochemical features of retinoid induced hyperostosis were evaluated using C3H-Heston mice and Balb mice., Results: Dose dependent and progressive ossification was noted at extraosseous sites of both mouse strains. New bone formation was seen not only in the extraosseous tissues, but subchondral bone showed prominent proliferation. Major histopathological abnormalities appeared to take place in the chondrocytes near the osteochondral junctions, and some of the metaplastic chondrocytes near the osteochondral junction expressed osteocalcin and type I collagen, extracellular molecules normally present in bone. Species dependent responsiveness was also noted., Conclusion: Longterm administration of retinoids may induce an aberrant differentiation of the articular and entheseal chondrocytes near the osteochondral junctions, and the affected cells appeared to produce extracellular components including osteocalcin and type I collagen.

Connective tissue is ubiquitous and subject to alterations that result in changes in the extracellular matrix of vessels and tissues leading to the long-term complications of diabetes. This article reviews only those abnormalities of interstitial connective tissue involving skeleton, joints, skin, and periarticular tissues. Abnormalities in the skin and periarticular tissues result in syndromes limiting joint movement, including limited joint mobility, Dupuytren disease, flexor tenosynovitis, carpal tunnel syndrome, stiff-hand syndrome, and shoulder-hand reflex dystrophy. Of these, only limited joint mobility and stiff-hand syndrome occur exclusively in patients with diabetes. In all of these conditions, advanced glycation end products are thought to form as a result of nonenzymatic reaction of glucose with proteins, causing stiffening.

A characteristic manifestation of SAPHO syndrome is hyperostosis, which most typically affects the sternoclavicular joints. Two cases of SAPHO syndrome with painful hyperostosis of the femur are reported. This misleading localization can lead to delays in the diagnosis and treatment.

There are several hyperostosis diseases of the skull that are accompanied by hearing impairment. In this article a case of Engelmann disease is presented. Currently > 130 cases of Engelmann disease are reported in literature. About 18% of these cases reported hearing impairment, but it is possible that this figure may be higher, because many of the authors concentrated on other aspects of the disease and made no reference to hearing loss in their reports. The etiology of deafness is the narrowing of the internal auditory canals cause by bony encroachment on nerves and vessels. This lends to progressive perceptive hearing loss and narrowing of the tympanic cavities. The result is fixation or adhesion of ossicle to tympanic walls, and narrowing of the bony part of auditory tubes, which causes serous otitis media.

The skeleton provides more than only a framework for the body. Bone is a calcified conjunctive tissue sensitive to various mechanical stimuli, mainly to those resulting from gravity and muscular contractions. Numerous animal and human studies demonstrate the importance of weight-bearing physical activity as well as mechanical loading for maintaining skeletal integrity. Lack of weight-bearing activity is dangerous for the skeleton: a decrease in bone mineral density (BMD) has been demonstrated in animals and humans under conditions of weightlessness or immobilization. Other studies have also reported a lower vertebral BMD among young amenorrheic athletes than among athletes with regular cycles and/or non athletes. The main factor responsible for this lower BMD in the amenorrheic athletes is the persistent low level of endogenous estrogen observed among these women. However this does not represent a premature and irreversible loss of bone mass since the resumption of menses following a decrease in training is the primary factor for a significant increase in vertebral BMD in these formerly amenorrheic athletes. A weight-bearing exercise is likely to be more beneficial at weight-bearing than at non weight-bearing sites, and hypogonadism resulting from very intensive training and exercise is more detrimental to trabecular than cortical bone. Bone deficit at non weight-bearing sites may be attenuated by maintenance of body weight. Nevertheless the etiology of "stress fractures" among athletes remains poorly understood, and the exact relationship between soft tissue mass and BMD is not clear. Osteoporosis, the most common bone disorder in France, is a pathological condition associated with increased loss of bone mass, resulting in a greater risk of fracture. Although symptoms of osteoporosis do not generally occur until after menopause, recent evidence suggests that bone loss starts much earlier in life. Therefore osteoporosis might be prevented by increasing peak bone mass and/or by slowering bone loss after menopause. Exercise such as resistance training or weight-bearing activities like running or walking have an osteogenic effect on increasing BMD in young people, and the decrease in BMD is slower in exercised than in non-exercised post-menopausal women. Nevertheless the influence of the length and of the intensity of such physical activities remain to be determined.

Osteophyte formation in the vertebral column is a well documented phenomenon that is poorly understood. The most commonly identified etiologic factors are degeneration and altered mechanics of the spine, either of which in turn have been considered to be a result of the natural aging process or the pathogenesis of spinal disease. In Part I [Contemporary Orthopaedics, 29(1): 31-37, 1994], the process of osteophyte formation was reviewed. In Part II, the sequential and consequential changes from the finely interwoven events of aging, degeneration, mechanical instability, and disease are described.

Nine patients (age 8.9, range 6.5 to 9.5 years) with idiopathic haemihypertrophy were followed at six month intervals for two years. The isometric voluntary contraction strength of the elbow flexors and knee extensors was measured bilaterally, and expressed per unit of muscle and bone cross sectional area of the upper arm (elbow flexors) and of the mid thigh (knee extensors). In absolute terms, the hypertrophic side was always stronger, and the increase in strength was strongly correlated with the increase in limb size bilaterally (P less than 0.01). The hypertrophic limb always exerted greater isometric strength, but if strength was standardized for an anthropometric estimate of upper arm and mid thigh cross sectional area, the normal and hypertrophic side were not significantly different. The limb length discrepancy, when expressed in percentage, remained constant at approximately 3%.

Hyperostosis cranialis interna is a recently described autosomal dominant bone disorder characterised by hyperostosis and osteosclerosis confined to the skull, especially the calvarium and the skull base. In the affected family members, we found variable simultaneous involvement of cranial nerves I, II, VII and VIII from late childhood onwards, most likely due to nerve entrapment. Auditory and vestibular functions were followed in 3 young family members for 8 years. At the first examination, pure tone audiograms were normal in all 3 cases and case 1 showed no caloric response in the right ear. During follow-up, this ear developed severe hearing loss progressing to deafness. The left ear showed transient sensorineural hearing loss and a temporarily diminished caloric response. Similar observations were made in case 2. Both cases showed abnormal brain stem auditory-evoked responses during and after the sudden hearing loss, in which initially only wave I was preserved and later on wave V returned with significantly prolonged I-V interval. The latter phenomenon was also observed in case 3 on both sides in the presence of normal audiograms during and after transient unilateral facial nerve paralysis, which was accompanied by bilateral diminished caloric responses.

The occurrence of ossifying enthesopathy during treatment with synthetic retinoids (etretinate, isotretinoin and acitretin) is a side-effect more and more frequently recorded. The authors report here a new case in a patient with a severe psoriatic arthritis. This observation is characterized by the size of ossifications on hips and lumbar spine which appeared after two years of etretinate therapy. The interest of this observation lies in the fact that ossifications occurred while the patient was treated with long-term corticotherapy. The disease for which retinoids are prescribed does not seem to influence the occurrence of those lesions and it is likely that the responsibility of these molecules is entire. Lesions are enthesitis ossification. They are frequent during these treatments (average of 70%) after an average time of 24 to 36 months for etretinate and of 10 months for isotretinoin. Lesions are asymptomatic in about 50% of the cases. After discontinuation of treatment, lesions become quiescent and does not disappear. Growth hormone or abnormalities in vitamin A metabolism could play a role in the physiopathology of lesions.

A total of 19 hyperostoses underlying mandibular posterior fixed partial dentures were observed in 16 patients. In three patients the lesions were bilateral. Histologic examination of hyperostoses from eight patients showed that they were composed essentially of hyperplastic lamellar bone. Radiographic and clinical evidence suggested that subpontic hyperostoses are chronic, slow growing lesions with an exclusive predilection for the mandibular molar-premolar site. They appear to have variable growth rates and attain widely variable maximum size. The etiology of subpontic hyperostoses is unknown, but it is possible that inflammation, trauma, mandibular and occlusal function, and genetic factors, either individually or in combination, play a role in the initiation and development of these lesions. Subpontic hyperostoses have potential periodontal and restorative implications that may require their surgical removal.

This work is devoted to the haemodynamic pathogenesis of congenital vascular-bone syndromes. It is based on our studies of 209 patients suffering from angio-osteohypertrophic and angio-osteohypotrophic syndromes as regards the species and anatomopathological forms of the vascular defects, the haemodynamics, tissue metabolism and changes in the tubular bones. Establishing the haemodynamic pathogenesis of congenital vascular-bone syndromes in vascular defects is very important in determining the principles of their surgical treatment. It offers the possibility of a correct choice of operative tactics and techniques in these severe vascular diseases, which in many cases lead to disability and cardiovascular insufficiency.