Life course longitudinal growth and risk of knee osteoarthritis at age 53 years: evidence from the 1946 British birth cohort study.

OBJECTIVE: To examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD). MATERIALS AND METHODS: Data are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 years. Associations between (1) height at each age (2) height gain during specific life periods (3) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested. RESULTS: In sex-adjusted models, estimated associations between taller height and decreased odds of knee osteoarthritis at age 53 years were small at all ages - the largest associations were an OR of knee osteoarthritis of 0.9 per 5 cm increase in height at age 4, (95% CI 0.7-1.1) and an OR of 0.9 per 5 cm increase in height, (95% CI 0.8-1.0) at age 6. No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis. CONCLUSIONS: There was limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this.

Oral Medicine for undergraduate dental students in the United Kingdom and Ireland-A curriculum.

INTRODUCTION: Oral Medicine focuses on care for patients with chronic, recurrent and medically related disorders of the orofacial region that are distinct from diseases of the periodontal and tooth tissues, with an emphasis on non-surgical management. At present, there are no shared outcomes for Oral Medicine to define the standards to be achieved before new graduates become registered dentists engaged with ongoing professional development. CURRICULUM: We present a consensus undergraduate curriculum in Oral Medicine agreed by representatives from 18 Dental Schools in the United Kingdom and Republic of Ireland. The scope of Oral Medicine practice includes conditions involving the oral mucosa, salivary glands, neurological system or musculoskeletal tissues that are not directly attributable to dental (tooth and periodontium) pathology. Account is taken of the priorities for practice and learning opportunities needed to support development of relevance to independent clinical practice. The outcomes triangulate with the requirements set out by the respective regulatory bodies in the UK and Republic of Ireland prior to first registration and are consistent with the framework for European undergraduate dental education and greater harmonisation of dental education. CONCLUSIONS: This curriculum will act as a foundation for an increasingly shared approach between centres with respect to the outcomes to be achieved in Oral Medicine. The curriculum may also be of interest to others, such as those responsible for the training of dental hygienists and dental therapists. It provides a platform for future collective developments with the overarching goal of raising the quality of patient care.

The STR/ort mouse model of spontaneous osteoarthritis - an update.

Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes.

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing.

SULF1/SULF2 enzymes regulate cell signalling that impacts the growth and differentiation of many tissues. To determine their possible role in cartilage and bone growth or repair, their expression was examined during development and bone fracture healing using RT-PCR and immunochemical analyses. Examination of epiphyseal growth plates revealed differential, inverse patterns of SULF1 and SULF2 expressions, with the former enriched in quiescent and the latter in hypertrophic chondrocyte zones. Markedly higher levels of both SULFs, however, were expressed in osteoblasts actively forming bone when compared with proliferating pre-osteoblasts in the periosteum or the entombed osteocytes which express the lowest levels. The increased expression of Sulf1 and Sulf2 in differentiating osteoblasts was further confirmed by RT-PCR analysis of mRNA levels in rat calvarial osteoblast cultures. SULF1 and SULF2 were expressed in most foetal articular chondrocytes but down-regulated in a larger subset of cells in the post-natal articular cartilage. Unlike adult articular chondrocytes, SULF1/SULF2 expression varied markedly in post-natal hypertrophic chondrocytes in the growth plate, with very high SULF2 expression compared with SULF1 apparent during neonatal growth in both primary and secondary centres of ossification. Similarly, hypertrophic chondrocytes expressed greatly higher levels of SULF2 but not SULF1 during bone fracture healing. SULF2 expression unlike SULF1 also spread to the calcifying matrix around the hypertrophic chondrocytes indicating its possible ligand inhibiting role through HSPG desulphation. Higher levels of SULF2 in both developing and healing bone closely correlated with parallel increases in hedgehog signalling analysed by ptc1 receptor expression.

The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures.

Sustained exposure to high levels of parathyroid hormone (PTH), as observed in hyperparathyroidism, is catabolic to bone. The increase in the RANKL/OPG ratio in response to continuous PTH, resulting in increased osteoclastogenesis, is well established. However, the effects of prolonged PTH exposure on key regulators of skeletal mineralisation have yet to be investigated. This study sought to examine the temporal expression of PHOSPHO1, TNAP and nSMase2 in mineralising osteoblast-like cell cultures and to investigate the effects of continuous PTH exposure on the expression of these enzymes in vitro. PHOSPHO1, nSMase2 and TNAP expression in cultured MC3T3-C14 cells significantly increased from day 0 to day 10. PTH induced a rapid downregulation of Phospho1 and Smpd3 gene expression in MC3T3-C14 cells and cultured hemi-calvariae. Alpl was differentially regulated by PTH, displaying upregulation in cultured MC3T3-C14 cells and downregulation in hemi-calvariae. PTH was also able to abolish the stimulatory effects of bone morphogenic protein 2 (BMP-2) on Smpd3 and Phospho1 expression. The effects of PTH on Phospho1 expression were mimicked with the cAMP agonist forskolin and blocked by the PKA inhibitor PKI (5-24), highlighting a role for the cAMP/PKA pathway in this regulation. The potent down-regulation of Phospho1 and Smpd3 in osteoblasts in response to continuous PTH may provide a novel explanation for the catabolic effects on the skeleton of such an exposure. Furthermore, our findings support the hypothesis that PHOSPHO1, nSMase2 and TNAP function cooperatively in the initiation of skeletal mineralisation.

miRNA-221 and miRNA-222 synergistically function to promote vascular calcification.

Vascular calcification shares many similarities with skeletal mineralisation and involves the phenotypic trans-differentiation of vascular smooth muscle cells (VSMCs) to osteoblastic cells within a calcified environment. Various microRNAs (miRs) are known to regulate cell differentiation; however, their role in mediating VSMC calcification is not fully understood. miR-microarray analysis revealed the significant down-regulation of a range of miRs following nine days in culture, including miR-199b, miR-29a, miR-221, miR-222 and miR-31 (p < 0.05). Subsequent studies investigated the specific role of the miR-221/222 family in VSMC calcification. Real-time quantitative polymerase chain reaction data confirmed the down-regulation of miR-221 (32.4%; p < 0.01) and miR-222 (15.7%; p < 0.05). VSMCs were transfected with mimics of miR-221 and miR-222, individually and in combination. Increased calcium deposition was observed in the combined treatment (two-fold; p < 0.05) but not in individual treatments. Runx2 and Msx2 expression was increased during calcification, but no difference in expression was observed following transfection with miR mimics. Interestingly, miR-221 and miR-222 mimics induced significant changes in ectonucleotide phosphodiesterase 1 (Enpp1) and Pit-1 expression, suggesting that these miRs may modulate VSMC calcification through cellular inorganic phosphate and pyrophosphate levels.

Reducing the cost of lower limb wound management through industry partnership and staff education.

Following an audit of practice in North East London Foundation Trust (NELFT), obstacles in the management of lower limb conditions were identified. An appraisal of needs in terms of skills and theory updates for staff led to a fixed-term 'honorary contract' between the trust and a wound-care company to facilitate a rolling programme of education, to upskill staff in terms of assessment and treatment, and develop standardised care pathways. After 3 months, a repeated practice audit revealed a reduction in nurse contact hours of 1156 hours. The partnership with industry proved to be beneficial and did not compromise care, and trust staff were not obligated to use their product.

Energetic Charged-Particle Phenomena in the Jovian Magnetosphere: First Results from the Ulysses COSPIN Collaboration.

The Ulysses spacecraft made the first exploration of the region of Jupiter's magnetosphere at high Jovigraphic latitudes ( approximately 37 degrees south) on the dusk side and reached higher magnetic latitudes ( approximately 49 degrees north) on the day side than any previous mission to Jupiter. The cosmic and solar particle investigations (COSPIN) instrumentation achieved a remarkably well integrated set of observations of energetic charged particles in the energy ranges of approximately 1 to 170 megaelectron volts for electrons and 0.3 to 20 megaelectron volts for protons and heavier nuclei. The new findings include (i) an apparent polar cap region in the northern hemisphere in which energetic charged particles following Jovian magnetic field lines may have direct access to the interplanetary medium, (ii) high-energy electron bursts (rise times approximately 17 megaelectron volts) on the dusk side that are apparently associated with field-aligned currents and radio burst emissions, (iii) persistence of the global 10-hour relativistic electron "clock" phenomenon throughout Jupiter's magnetosphere, (iv) on the basis of charged-particle measurements, apparent dragging of magnetic field lines at large radii in the dusk sector toward the tail, and (v) consistent outflow of megaelectron volt electrons and large-scale departures from corotation for nucleons.

A patient with dry mouth.

INTRODUCTION: Xerostomia is a common symptom among patients referred to ENT clinics. We present an evidence-based approach in a patient complaining of xerostomia who has not been exposed to radiotherapy. METHOD (search strategy): This review was based on a literature search last performed on 1 July 2008. MEDLINE and EMBASE databases and the Cochrane Library were searched using the subject headings dry mouth, hyposalivation and xerostomia in combination with diagnosis, therapy and surgery. Results were limited to English language articles including clinical trials, randomised controlled trials, meta-analyses, systematic reviews, review articles and human studies. Relevant references from selected articles were reviewed. RESULTS: Xerostomia is not synonymous with hyposalivation. Effective management covers symptomatic relief with selected saliva substitutes, sialogogic agents, addressing underlying dental complications and oral infections, and review of prescribed medication. CONCLUSION: Xerostomia is a common symptom for a wide range of triggering factors, but the treatment is largely palliative and preventative in nature.

Oral leukoplakia and proliferative verrucous leukoplakia: a review for dental practitioners.

Objectives To provide an overview of the current thinking in terms of the diagnosis and management of oral leukoplakia and proliferative verrucous leukoplakia as relevant to general dental practitioners.Data sources, data selection, data extraction, data synthesis We searched the MEDLINE Ovid, EMBASE databases and the Cochrane Library, (1990 to 16 April 2017), restricting our search to English language with the following key words: leukoplakia, white patch, proliferative verrucous leukoplakia, precancerous lesion, premalignant lesions, potentially malignant oral conditions and potentially malignant oral disorders. The two authors selected key papers and engaged in collaborative data extraction and synthesis of the selected reference material.Conclusions General dental practitioners (GDPs) are likely to encounter patients with a known or yet undiagnosed oral leukoplakia in their clinical practice. The diagnosis is clinically based as there are no pathognomonic histopathological features. The definition of leukoplakia has evolved over the years. The importance of recognition and appropriate management relating to this condition is described particularly as it is one of the oral potentially malignant lesions. The inferred increased risk of malignant transformation is well documented however controversy still persists in terms of the appropriate management for these lesions. Proliferative verrucous leukoplakia is a recalcitrant, often widespread and multifocal distinct type of leukoplakia. It is considered to have a high rate of malignant transformation with implications in terms of lifelong monitoring both clinically and histopathologically. A high index of suspicion is important for general dental practitioners in order to identify such lesions that would require onward referral for further investigation and management.

Coeliac disease in children - an update for general dental practitioners.

Coeliac disease (CD) is an immune-mediated systemic disorder caused by ingestion of gluten found in wheat, rye and barley. It affects around 1% of children, but 90% of cases are considered to remain undiagnosed. CD classically presents with gastrointestinal manifestations including diarrhoea, bloating, weight loss and abdominal pain, but extra-intestinal features (including oral and dental manifestations) are increasingly being reported. Dental and oral manifestations such as dental enamel defects, delayed eruption of teeth, recurrent aphthous ulcers are well-recognised manifestations of CD. In patients with yet undiagnosed CD, these can sometimes be the only presenting features. Dentists have regular contact with well children, and therefore the visit to the dentist is an opportunity to suspect CD. When CD is suspected, Dental practitioners can liaise with the general medical practitioner to organise screening for coeliac disease. Positive serology will prompt onward referral to a paediatric gastroenterologist to confirm the diagnosis. The recent European Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines revised in 2012 have streamlined the diagnostic pathway for faster diagnosis of CD. Management involves strict adherence to a gluten free diet, which should lead to resolution of symptoms, recovery of intestinal mucosa and prevention of long-term complications associated with it. This article aims to describe CD, inform of recent changes to the diagnostic pathway and highlight the dental manifestations of the condition to equip dental practitioners to aid early diagnosis and initiation of treatment for children with CD.

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model.

OBJECTIVE: To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect. METHODS: Knee joints from STR/Ort mice with advanced OA and age-matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro-computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x-ray computed microtomography was developed and applied. RESULTS: Meta-analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP-13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase-PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP-13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age-matched CBA mice. CONCLUSION: Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA.

MMP and TIMP temporal gene expression during osteocytogenesis.

Osteocytes within bone differentiate from osteoblast precursors which reside in a mineralised extracellular matrix (ECM). Fully differentiated osteocytes are critical for bone development and function but the factors that regulate this differentiation process are unknown. The enzymes primarily responsible for ECM remodelling are matrix metalloproteinases (MMP); however, the expression and role of MMPs during osteocytogenesis is undefined. Here we used MLO-A5 cells to determine the temporal gene expressions of the MMP family and their endogenous inhibitors--tissue inhibitors of metalloproteinases (TIMPs) during osteocytogenesis. RT-qPCR revealed expression of 14 Mmps and 3 Timps in MLO-A5 cells. Mmp2, Mmp23 and Mmp28 were decreased concurrent with mineralisation onset (P < 0.05*). Mmp14 and Mmp19 mRNAs were also significantly increased at day 3 (P < 0.05*) before returning to baseline levels at day 6. Decreased expressions of Timp1, Timp2 and Timp3 mRNA were observed by day 6 compared to day 0 (P < 0.05*). To examine whether these changes are linked to osteocytogenesis, we determined Mmp/Timp mRNA expressions in mineralisation-limited conditions. RT-qPCR revealed that the previously observed decreases in Mmp2, Mmp23 and Mmp28 were not observed in these mineralisation-limited cultures, therefore closely linking these MMPs with osteocyte differentiation. Similarly, we found differential expression of Timp1, Timp2 and Timp3 mRNA in mineralisation-restricted cultures (P < 0.05*). In conclusion, we have identified several members of the MMP/TIMP families as regulators of ECM remodelling necessary for the acquisition of the osteocyte phenotype.

Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing.

PHOSPHO1 is one of principal proteins involved in initiating bone matrix mineralisation. Recent studies have found that Phospho1 KO mice (Phospho1-R74X) display multiple skeletal abnormalities with spontaneous fractures, bowed long bones, osteomalacia and scoliosis. These analyses have however been limited to young mice and it remains unclear whether the role of PHOSPHO1 is conserved in the mature murine skeleton where bone turnover is limited. In this study, we have used ex-vivo computerised tomography to examine the effect of Phospho1 deletion on tibial bone architecture in mice at a range of ages (5, 7, 16 and 34 weeks of age) to establish whether its role is conserved during skeletal growth and maturation. Matrix mineralisation has also been reported to influence terminal osteoblast differentiation into osteocytes and we have also explored whether hypomineralised bones in Phospho1 KO mice exhibit modified osteocyte lacunar and vascular porosity. Our data reveal that Phospho1 deficiency generates age-related defects in trabecular architecture and compromised cortical microarchitecture with greater porosity accompanied by marked alterations in osteocyte shape, significant increases in osteocytic lacuna and vessel number. Our in vitro studies examining the behaviour of osteoblast derived from Phospho1 KO and wild-type mice reveal reduced levels of matrix mineralisation and modified osteocytogenic programming in cells deficient in PHOSPHO1. Together our data suggest that deficiency in PHOSPHO1 exerts modifications in bone architecture that are transient and depend upon age, yet produces consistent modification in lacunar and vascular porosity. It is possible that the inhibitory role of PHOSPHO1 on osteocyte differentiation leads to these age-related changes in bone architecture. It is also intriguing to note that this apparent acceleration in osteocyte differentiation evident in the hypomineralised bones of Phospho1 KO mice suggests an uncoupling of the interplay between osteocytogenesis and biomineralisation. Further studies are required to dissect the molecular processes underlying the regulatory influences exerted by PHOSPHO1 on the skeleton with ageing.

Identification of potential CTL epitopes of bovine RSV using allele-specific peptide motifs from bovine MHC class I molecules.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young infants and housed calves. Depletion of CD8+ lymphocytes from calves inhibited their ability to clear the virus from the nasopharynx and lungs. To study these cells further, a cytotoxic T lymphocyte (CTL) assay was established. CTL could be demonstrated in the peripheral blood of gnotobiotic calves 7-10 days post infection (p.i.) with RSV and in lungs 10 days p.i. This response was both MHC-restricted and virus-specific. Following separation of the lung lymphocytes by magnetic activated cell sorting, it was shown that the cytolytic activity was mediated by cells of the CD8+ phenotype. To identify epitopes recognised by bovine CTL, the consensus motifs from MHC class I alleles found in the herd at Compton were identified. cDNA libraries were constructed and screened for full length class I sequences. The isolated cDNA clones were then transfected into mouse P815 cells and the expressed product immunoprecipitated and matched with a serological specificity. The bovine MHC class I molecules were isolated from lysed transfected cells by affinity chromatography, using a monoclonal antibody specific for bovine MHC class I, and bound peptides were separated by reverse-phase HPLC. Analysis of the protein sequences of bovine RSV for the defined motifs has identified potential CTL epitopes.

Hepatitis C virus and oral lichen planus/lichenoid reactions: lack of evidence for an association.

Some studies have suggested an association between the mucocutaneous disorder lichen planus and chronic infection with hepatitis C virus. Most of these studies have been based purely on serological markers. The present study sought to detect hepatitis C virus RNA in both peripheral blood and in biopsy material collected from oral mucosal lesions. Twenty-seven patients were studied, six with classical lichen planus and 21 with oral lichenoid reactions. The diagnoses were confirmed by histopathological examination. Reverse transcription PCR was employed to detect hepatitis C virus RNA in the blood specimens. The same method was used to detect hepatitis C virus RNA in lesional tissue, following RNA extraction from sections of the biopsies. The virus was not detected in any of the paired blood and tissue specimens examined. It is concluded that hepatitis C virus is not commonly associated with oral lichen planus or lichenoid reactions in Scotland.

Diagnosis of acromegaly in orofacial pain: two case reports.

Acromegaly is an uncommon condition, with an annual incidence in the UK of three per million. The gradual onset of the clinical features mean that often friends and relatives are unaware of the underlying pathology. In view of the morbidity, and indeed mortality, arising from undiagnosed cases, general dental practitioners and other healthcare workers should routinely take note of systemic as well as intra-oral changes occurring in their patients when seen on review. The association of paraesthesia, anaesthesia and pain with acromegaly is well documented. However, there appear to be few reports linking acromegaly with orofacial pain or dysaesthesia. This paper describes two such cases.

Cartilage to bone transitions in health and disease.

Aberrant redeployment of the 'transient' events responsible for bone development and postnatal longitudinal growth has been reported in some diseases in what is otherwise inherently 'stable' cartilage. Lessons may be learnt from the molecular mechanisms underpinning transient chondrocyte differentiation and function, and their application may better identify disease aetiology. Here, we review the current evidence supporting this possibility. We firstly outline endochondral ossification and the cellular and physiological mechanisms by which it is controlled in the postnatal growth plate. We then compare the biology of these transient cartilaginous structures to the inherently stable articular cartilage. Finally, we highlight specific scenarios in which the redeployment of these embryonic processes may contribute to disease development, with the foresight that deciphering those mechanisms regulating pathological changes and loss of cartilage stability will aid future research into effective disease-modifying therapies.

Internal carotid artery aneurysm presenting as orofacial pain.

OBJECTIVES: We report a case of an internal carotid artery aneurysm presenting as orofacial pain. METHOD: Case report and discussion. RESULTS: A 59-year-old patient presented with a four-year history of chronic oral pain accompanied by a right-sided occipital headache. No local organic pathology was detected, and a provisional diagnosis of persistent idiopathic facial pain was made. A neurosurgery referral was made to exclude neurovascular pathology, which resulted in the detection of an aneurysm originating from the right posterior communicating artery. This was successfully treated by coil embolisation, with subsequent resolution of symptoms. CONCLUSION: In this patient, an atypical history of pain with no other neurological signs or symptoms, other than accompanying occipital headache, led to the discovery of an intracranial aneurysm. This case highlights the need for appropriate referral and imaging in cases in which the clinical history and findings are not classical, and also emphasises the need for interdisciplinary management.