A Jovian analogue orbiting a white dwarf star.

Studies1,2 have shown that the remnants of destroyed planets and debris-disk planetesimals can survive the volatile evolution of their host stars into white dwarfs3,4, but few intact planetary bodies around white dwarfs have been detected5-8. Simulations predict9-11 that planets in Jupiter-like orbits around stars of ≲8 M☉ (solar mass) avoid being destroyed by the strong tidal forces of their stellar host, but as yet, there has been no observational confirmation of such a survivor. Here we report the non-detection of a main-sequence lens star in the microlensing event MOA-2010-BLG-477Lb12 using near-infrared observations from the Keck Observatory. We determine that this system contains a 0.53 ± 0.11 M☉ white-dwarf host orbited by a 1.4 ± 0.3 Jupiter-mass planet with a separation on the plane of the sky of 2.8 ± 0.5 astronomical units, which implies a semi-major axis larger than this. This system is evidence that planets around white dwarfs can survive the giant and asymptotic giant phases of their host's evolution, and supports the prediction that more than half of white dwarfs have Jovian planetary companions13. Located at approximately 2.0 kiloparsecs towards the centre of our Galaxy, it is likely to represent an analogue to the end stages of the Sun and Jupiter in our own Solar System.

Do we have the right PROMs for measuring outcomes in lumbar spinal surgery?

PURPOSE: Patient-reported outcome measures (PROMs) have become an important part of routine auditing of outcomes in spinal surgery in the UK. PROMs can be used to help assess the quality of care provided by surgical units by determining the comparative health status of patients, before and after surgery. This study was designed to review the PROMs used to assess outcomes in spinal surgery and to determine if they are fit for the purpose. METHODS: A systematic literature search was undertaken to identify studies that reported PROMs data following lumbar spinal surgery. The PROMs that were used in each study were recorded and a separate search was undertaken to determine the evidence regarding the validity of each measure. RESULTS: The initial search identified 1142 abstracts, which were reduced through de-duplication, filtering and review to 58 articles, which were retrieved and reviewed in full. The search identified that the majority of studies used either the Oswestry Disability Index (ODI), SF-36, Roland-Morris Disability Questionnaire (RMDQ) and EQ-5D along with visual analogue scales or numeric rating scales for back and leg pain. CONCLUSIONS: The consistent use of PROMs supports the comparison of outcomes from different studies, although there was minimal evidence regarding the specificity and sensitivity of these measures for use with lumbar spinal patients. Our review highlights the need to determine a consensus regarding the use and reporting of outcome measures within the lumbar spine literature.

Potential roles of cytokines and chemokines in human intervertebral disc degeneration: interleukin-1 is a master regulator of catabolic processes.

OBJECTIVE: These studies investigated cytokine and chemokine receptor profiles in nucleus pulposus (NP) cells, and the effects of receptor stimulation on mRNA levels of extracellular matrix (ECM) components, degrading enzymes and cytokine and chemokine expression. METHOD: Immunohistochemistry (IHC) was performed to localise expression of CD4, CCR1, CXCR1 and CXCR2 in human NP tissue samples. Effects of cytokine and chemokine stimulation was performed to investigate effects related to ECM remodelling and modulation of cytokine and chemokine mRNA expression. RESULTS: IHC identified CD4, CCR1, CXCR1 and CXCR2 expression by NP cells. Differential expression profiles were observed for CD4 and CXCR2 in tissue samples from degenerate and infiltrated IVDs. In vitro stimulations of primary human NP cultures with IL-16, CCL2, CCL3, CCL7 or CXCL8 did not identify any modulatory effects on parameters associated with ECM remodelling or expression of other cytokines and chemokines. Conversely, IL-1 was seen to modulate ECM remodelling and expression of all other cytokines and chemokines investigated. CONCLUSION: This study demonstrates for the first time that NP cells express a number of cytokine and chemokine receptors and thus could respond in an autocrine or paracrine manner to cytokines and chemokines produced by NP cells, particularly during tissue degeneration. However, this study failed to demonstrate regulatory effects on ECM genes and degradative enzymes or other cytokines and chemokines for any target investigated, with the exception of IL-1. This suggests that IL-1 is a master regulator within the IVD and may exert regulatory potential over a plethora of other cytokines and chemokines.

ASTRONOMY: The Distance to the Large Magellanic Cloud.

The Large Magellanic Cloud (LMC), a satellite of the Milky Way, is an important yardstick by which most intergalactic distances are measured. But as Cole explains in this Perspective, how far away the LMC is remains a matter of dispute, with far reaching implications in cosmology. But observations of Cepheids and of eclipsing binaries, two types of stars that allow absolute luminosity and thus absolute distances to be determined, are promising to resolve this important issue in the not too distant future.

Potent inhibition of cartilage biosynthesis by coincubation with joint capsule through an IL-1-independent pathway.

The reason for the increased risk for development of osteoarthritis (OA) after acute joint trauma is not well understood, but the mechanically injured cartilage may be more susceptible to degradative mediators secreted by other tissues in the joint. To establish a model for such interactions, we coincubated bovine cartilage tissue explants together with normal joint capsule and found a profound ( approximately 70%) reduction in cartilage proteoglycan biosynthesis. This reduction is due to release by the joint capsule of a heat-labile and non-toxic factor. Surprisingly, while cultured synovium is a canonical source of interleukin-1 (IL-1), blockade either by soluble IL-1 type II receptor (sIL-1r) or IL-1 receptor antagonist (IL-1RA) had no effect. Combined blockade of IL-1 and tumor necrosis factor alpha (TNF-alpha) also had no effect. To support the clinical relevance of the findings, we harvested joint capsule from post-mortem human knees. Human joint capsule from a normal adult knee also released a substance that caused an approximately 40% decrease in cartilage proteoglycan biosynthesis. Furthermore, this inhibition was not affected by IL-1 blockade with either sIL-1r or IL-1RA. These results suggest that joint capsule tissue from a normal knee joint can release an uncharacterized cytokine that potently inhibits cartilage biosynthetic activity by an IL-1- and TNF-independent pathway.

Experimental haemophilic arthropathy in a mouse model of a massive haemarthrosis: gross, radiological and histological changes.

Recurrent haemarthrosis results in chronic synovitis and destructive arthropathy. The long-term effect of a single haemorrhage is not known. To investigate the histopathological changes following a single, but major joint haemorrhage, an animal model of massive haemarthrosis without mechanical trauma was developed and is described in this manuscript. The knee joint capsule of mice deficient in coagulation factor VIII or IX and non-haemophilic wild type mice was punctured to induce a one time, but massive haemorrhage. The single joint puncture resulted in acute haemarthrosis in both types of haemophilic mice but not in wild type mice. Subsequent to injury, the changes in the knee joints were analysed using gross, histological and radiographic assessments and compared with the uninjured knee. In addition, a novel imaging modality, micro-computed tomography, was used to document the structural damage to the joint. Our results indicate that the long-term changes classically observed in patients with advanced haemophilic arthropathy are evident following a single massive haemarthrosis. This model will allow a thorough investigation of the pathobiology of blood-induced joint disease and will be useful to test the efficacy of innovative therapeutic strategies to prevent haemophilic synovitis and arthropathy.

Body mass index of girls in health influences menarche and skeletal maturation: a leptin-sympathetic nervous system focus on the trunk with hypothalamic asymmetric dysfunction in the pathogenesis of adolescent idiopathic scoliosis?

Lower body mass index (BMI) and lower circulating leptin levels have been reported in girls with AIS. In this paper we evaluate skeletal sizes and asymmetries by higher and lower BMI subsets about the means for each of three groups of girls age 11-18 years: 1) normals, 2) school screening referrals, and 3) preoperative girls. Higher and lower BMI subsets, likely to have separated subjects with higher from those with lower circulating leptin levels, identify: 1) girls with relatively earlier and later menarche; 2) trunk width size greater in the higher than in the lower BMI subset, of all three groups; 3) abnormal upper arm length (UAL) asymmetries (right minus left) in the lower BMI subset of the preoperative girls; and 4) in thoracic AIS of screened and preoperative girls, Cobb angle and apical vertebral rotation each significantly and positively correlate with UAL asymmetry in the lower BMI subset but not in the higher BMI subset. In preoperative girls, the lower BMI subset shows the combination of relatively reduced pelvic width and abnormal UAL asymmetry, suggesting that both are linked to lower circulating leptin levels. An earlier puberty with hormonal changes provides a plausible explanation for the larger trunk width at the shoulders and pelvis especially at the younger ages in the higher BMI subsets. At the shoulders, this widening is driven by the ribcage which, in human evolution was acquired with decoupling of head and trunk movements required for efficient bipedal gait. The UAL asymmetry patterns within the groups and BMI subsets are not explained by hormonal mechanisms. It is hypothesized that 1) normal trunk widening of the thoracic cage by hormones in human adolescence is supplemented via the sympathetic nervous system under leptin-hypothalamic control influenced by energy stores (metabolic fuel); and 2) hypothalamic dysfunction with altered hypothalamic sensitivity to leptin through a SNS-driven asymmetric effect may create skeletal length asymmetries in upper arms, ribs, ilia and vertebrae, and initiate AIS. Additional mechanisms acting in the spine and trunk may be required for AIS to progress including 1) somatic nervous system dysfunction, 2) biomechanical spinal growth modulation, and 3) osteopenia.

Ultrasound femoral anteversion (FAV) relative to tibial torsion (TT) is abnormal after school screening for adolescent idiopathic scoliosis (AIS): evaluation by two methods.

In the scoliotic spine, torsion is generally evaluated in relation to axial rotation of the apical vertebra. In the lower limbs, the changes in torsion by age of femoral anteversion (FAV) relative to tibial torsion (TT) have been studied in dried bones, normal growing subjects and adults and subjects with osteoarthritis of the hip or the knee. This paper reports the application of real-time ultrasound to FAV and TT in normal children age 11-18 years and in scoliosis screening referrals with particular reference to how FAV relates to TT as 1) ratios, and 2) tibio-femoral index (TFI) of torsion, calculated as TT minus femoral FAV. The FAV/TT ratio findings show an abnormal normal relationship of FAV to TT both proximo-distally and in left-right asymmetry. These may express torsional abnormalities in femoral and/or tibial growth plates with left-right asynchrony suggesting the possibility of similar torsional abnormalities in vertebral end-plates and/or rib growth plates initiating the deformity of AIS. TFI of the right limb in the scoliosis girls is greater than in the normals that is interpreted as resulting from earlier skeletal maturation of FAV. FAV/TT ratios and TFI are unrelated to the spinal deformity (Cobb angle and apical vertebral rotation) except for boys where TFI is associated with apical vertebral rotation. FAV/TT ratios may be a more accurate method estimating the relationship of FAV to TT. than TFIs.

Leg-arm length ratios correlate with severity of apical vertebral rotation in girls after school screening for adolescent idiopathic scoliosis (AIS): a dynamic pathomechanism in the initiation of the deformity?

There is increasing support for the view that the unique human bipedalism and the erect posture are prerequisites for the pathogenesis of adolescent idiopathic scoliosis (AIS). How human bipedalism may contribute to the pathogenesis of AIS is not clear. In normal humans, axial rotations and counter-rotations of the trunk are carried out frequently and forcibly in activities that are not performed by quadrupeds. Some workers have analysed gait in AIS subjects, others have studied torsions in lower limb bones, but there are only two reports on leg-arm ratios in relation to AIS. In this paper, leg-arm ratios studied in relation to the spinal deformity in scoliosis screening referrals, reveal a highly significant correlation with the apical vertebral rotation but not the Cobb angle of the scoliosis curves. We suggest that leg-arm proportions and movements during gait involving pelvi-spinal axial rotations and thoracic counter-rotations contribute a dynamic pathomechanism to early AIS from whatever cause and involving the thoracic cage. Curve progression needs other mechanisms that may include a central nervous system failure to control structural asymmetry of vertebral axial rotation, and biomechanical spinal growth modulation.

Ultrasound femoral anteversion (FAV) and tibial torsion (TT) after school screening for adolescent idiopathic scoliosis (AIS).

Torsion and counter-torsion in the spine are features of the three-dimensional deformity of adolescent idiopathic scoliosis, Vertebral axial rotation has recently been found in the normal adult thoracic spine. Torsion in the lower limbs, femora and tibiae is a feature of normal human skeletal postnatal development. In recent years, femoral anteversion (FAV) and tibial torsion (TT) have been studied in normal children by imaging techniques, especially ultrasound. This paper reports summaries of the application of real-time ultrasound to FAV and TT of normal children and scoliosis school screening referrals. In the scoliosis girls and boys, the FAV decrease and FAV asymmetry compared with normals may result from abnormally increased femoral detorsion maturationally earlier with left-right asynchrony which, if repeated as a growth plate anomaly in the trunk (spine and/or periapical ribs), might initiate the AIS deformity, given other requirements. In scoliosis boys relative to girls, the TT decrease without asymmetry may result from sexually dimorphic maturation at knee tibial growth plates ? maturationally delayed TT with left-right synchrony.

The posterior skeletal thorax: rib-vertebral angle and axial vertebral rotation asymmetries in adolescent idiopathic scoliosis.

The deformity of the ribcage in thoracic adolescent idiopathic scoliosis (AIS) is viewed by most as being secondary to the spinal deformity, though a few consider it primary or involved in curve aggravation. Those who consider it primary ascribe pathogenetic significance to rib-vertebra angle asymmetry. In thoracic AIS, supra-apical rib-vertebra angle differences (RVADs) are reported to be associated with the severity of the Cobb angle. In this paper we attempt to evaluate rib and spinal pathomechanisms in thoracic and thnoracolumbar AIS using spinal radiographs and real-time ultrasound. On the radiographs by costo-vertebral angle asymmetries (rib-vertebral angle differences RVADs, and rib-spinal angle differences RSADs), apical vertebral rotation (AV) and apical vertebral translation (AVT) were measured; and by ultrasound, spine-rib rotation differences (SRRDs) were estimated. RVADs are largest at two and three vertebral levels above the apex where they correlate significantly and positively with Cobb angle and AVT but not AVR. In right thoracic AIS, the cause(s) of the RVA asymmetries is unknown: it may result from trunk muscle imbalance, or from ribs adjusting passively within the constraint of the fourth column of the spine to increasing spinal curvature from whatever cause. Several possible mechanisms may drive axial vertebral rotation including, biplanar spinal asymmetry, relative anterior spinal overgrowth, dorsal shear forces in the presence of normal vertebral axial rotation, asymmetry of rib linear growth, trunk muscle imbalance causing rib-vertebra angle asymmetry weakening the spinal rotation-defending system of bipedal gait, and CNS mechanisms.

Collagen degradation products modulate matrix metalloproteinase expression in cultured articular chondrocytes.

Destruction of collagen within osteoarthritic cartilage depends in part on collagen-degrading matrix metalloproteases (MMP). Degradative fragments of type II collagen (Col II) occur in normal and in osteoarthritic cartilage, and may contribute to regulation of matrix turnover by interfering with normal cell-matrix communication pathways. Therefore, the effects of different types of collagen fragments on mRNA and protein levels of MMP-2, MMP-3, MMP-9, and MMP-13 in cultured bovine articular knee chondrocytes and explants were examined. Primary chondrocytes and explants were incubated with fragments from whole cartilage collagen matrix (Colf) and from purified type II collagen (Col2f), or with a synthetic 29-mer peptide representing the amino-terminal domain of type II collagen (Ntelo). Gelatin zymography revealed increases of proMMP-2, a shift towards active MMP-2 and increases in proMMP-9, depending on the type of fragment. In situ hybridization of cartilage sections displayed MMP-3 mRNA in virtually all cells. Moderate to strong increases in MMP-2, MMP-3, MMP-9, and MMP-13 mRNA levels were detected by quantitative PCR. The results demonstrate stimulating effects of collagen fragments on both mRNA and/or protein from MMP -2, -3, -9, and -13, and suggest a novel mechanism of MMP induction and activation that includes a particular role for N-telo in controlling catabolic pathways of matrix turnover.

Patterns of extra-spinal left-right skeletal asymmetries in adolescent girls with lower spine scoliosis: relative lengthening of the ilium on the curve concavity & of right lower limb segments.

Extra-spinal skeletal length asymmetry have been reported for the upper limbs and periapical ribs of patients with thoracic adolescent idiopathic scoliosis. This paper reports (1) a third pattern with relative lengthening of the ilium on the concavity of lower spine scolioses, and (2) a fourth pattern of relative lengthening of the right total leg and right tibia unrelated statistically to the severity or side of lower spinal scolioses. The findings pose the question: are these anomalous extra-spinal left-right skeletal length asymmetries unconnected with the pathogenesis of AIS. Or, are they indicative of what may also be happening to some vertebral physes as an initiating pathogenic mechanism for the scoliosis?

Left-right upper arm length asymmetry associated with apical vertebral rotation in subjects with thoracic scoliosis: anomaly of bilateral symmetry affecting vertebral, costal and upper arm physes?

Left-right skeletal length asymmetries in upper limbs related to curve side and severity have been detected with adolescent idiopathic scoliosis (AIS). This paper reports upper arm length asymmetry in thoracic scoliosis related significantly to apical vertebral rotation in school screening referrals. The reason(s) for the association of upper arm length asymmetry with apical vertebral rotation is unknown and three factors are considered: (1) neuromuscular mechanisms from primary or secondary causes, (2) relative concave neurocentral synchondrosis overgrowth, and (3) relative concave periapical rib length overgrowth, A putative anomaly of growth plates (physes) of ribs, neurocentral synchondroses and upper arms, would account for the findings. A solution to this dilemma may emerge from the results of surgery should concave periapical rib resections become evaluated further for right thoracic AIS in girls.

Patterns of extra-spinal left-right skeletal asymmetries and proximo-distal disproportion in adolescent girls with lower spine scoliosis: ilio-femoral length asymmetry & bilateral tibial/foot length disproportion.

Anomalous extra-spinal left-right skeletal length asymmetries have been detected in girls with adolescent idiopathic (AIS) in four sites (1) upper limbs, (2) periapical ribs, (3) ilium, and (4) right leg and right tibia. This paper on adolescent girls with lower spine scoliosis reports (1) a fifth pattern of left-right ilio-femoral length asymmetry associated with sacral alar height asymmetry, and (2) bilateral anomalous lengthening of the tibia relative to the foot. The findings are consistent with the hypothesis that at the time of diagnosis of AIS in girls there are anomalies of skeletal proportions associated with a predisposition to curve progression; these proportions are in three dimensions--left-right, cephalo-caudal in the trunk (proximo-distal in the lower limbs), and front-back in the trunk. The origin of these anomalies is unknown but possible causes, and of the associated AIS, are genetic and environmental factors acting in embryonic life not expressed phenotypically until years after birth.

Etiologic theories of idiopathic scoliosis: the breaking of bilateral symmetry in relation to left-right asymmetry of internal organs, right thoracic adolescent idiopathic scoliosis (AIS) and vertebrate evolution.

In the search to understand the etiology and pathogenesis of adolescent idiopathic scoliosis (AIS) some workers have focused on mechanisms initiated in embryonic life including a disturbance of bilateral (left-right or mirror-image) symmetry highly conserved in vertebrates. The normal external bilateral symmetry of vertebrates results from a default process involving mesodermal somites. The normal internal asymmetry of the heart, major blood vessels, lungs and gut with its glands is also highly conserved among vertebrates. It results from the breaking of the initial bilateral symmetry by a binary asymmetry switch mechanism producing asymmetric gene expression around the embryonic node and/or in the lateral plate mesoderm. In the mouse this switch occurs during gastrulation by cilia driving a leftward flow of fluid and morphogen(s) at the embryonic node (nodal flow) that favors precursors of the heart, great vessels and viscera on the left. Based on the non-random laterality of thoracic AIS curves, the hypothesis is suggested that an anomaly of the binary asymmetry switch explains the excess of right/left thoracic AIS. Some support for this hypothesis is the prevalence of right and left scoliosis curve laterality associated with situs inversus. There is recent evidence that vertebrates within their bilateralised shell retain an archaic left-right asymmetric visceral body organization evident in thoracic and abdominal organs.

Etiologic theories of idiopathic scoliosis: enantiomorph disorder concept of bilateral symmetry, physeally-created growth conflicts and possible prevention.

The detection of anomalous extra-spinal left-right skeletal length asymmetries in the upper limbs, periapical ribs, ilia and lower limbs of subjects with adolescent idiopathic scoliosis (AIS) raises questions about skeletal bilateral symmetry of vertebrates in health and disorder, its origin and control. The vertebrate body plan externally has mirror-image bilateral symmetries that are highly conserved culminating in the adult form. The normal human body can be viewed as containing paired skeletal structures in the axial and appendicular skeleton as 1) separate left and right paired forms (eg long limb bones, ribs, ilia), and 2) united in paired forms (eg vertebrae, sternum, skull, mandible). Each of these separate and united pairs are mirror-image forms--enantiomorphs. Left-right asymmetries of growth plates (physes) may cause (1) in long bones length asymmetries, (2) within one or more vertebral physes putative growth conflict with distortion as deformity, and (3) between ribs and vertebrae putative growth conflict that triggers thoracic AIS suggesting preventive surgery on spine and ribs. There is evidence of a possible role for environmental factors in AIS development. Genes and the environment (nature/nurture) may interact pre- and/or post-natally to explain both the deformity of AIS and its association with widespread anomalous skeletal length asymmetries. If substantiated there may ultimately be a place for the prevention of AIS in some subjects.

Etiologic theories of idiopathic scoliosis: neurodevelopmental concept of maturational delay of the CNS body schema ("body-in-the-brain").

Several workers consider that the etiology of adolescent idiopathic scoliosis (AIS) involves undetected neuromuscular dysfunction. During normal development the central nervous system (CNS) has to adapt to the rapidly growing skeleton of adolescence, and in AIS to developing spinal asymmetry from whatever cause. Examination of evidence from (1) anomalous extra-spinal left-right skeletal length asymmetries, (2) growth velocity and curve progression, and (3) the CNS body schema, parietal lobe and temporoparietal junction, led us to propose a new etiologic concept namely of delay in maturation of the CNS body schema during adolescence. In particular, the development of an early AIS deformity at a time of rapid spinal growth the association of CNS maturational delay results in the CNS attempting to balance a lateral spinal deformity in a moving upright trunk that is larger than the information on personal space (self) already established in the brain by that time of development. It is postulated that the CNS maturational delay allows scoliosis curve progression to occur - unless the delay is temporary when curve progression would cease. The putative maturational delay in the CNS body schema may arise (1) from impaired sensory input: (2) primarily in the brain; and/or (3) from impaired motor output. Oxidative stress with lipid peroxidation in the nervous system may be involved in some patients. The concept brings together many findings relating AIS to the nervous and musculo-skeletal systems and suggests brain morphometric studies in subjects with progressive AIS.

Should we all go to the PROM? The first two years of the British Spine Registry.

The effective capture of outcome measures in the healthcare setting can be traced back to Florence Nightingale's investigation of the in-patient mortality of soldiers wounded in the Crimean war in the 1850s. Only relatively recently has the formalised collection of outcomes data into Registries been recognised as valuable in itself. With the advent of surgeon league tables and a move towards value based health care, individuals are being driven to collect, store and interpret data. Following the success of the National Joint Registry, the British Association of Spine Surgeons instituted the British Spine Registry. Since its launch in 2012, over 650 users representing the whole surgical team have registered and during this time, more than 27 000 patients have been entered onto the database. There has been significant publicity regarding the collection of outcome measures after surgery, including patient-reported scores. Over 12 000 forms have been directly entered by patients themselves, with many more entered by the surgical teams. Questions abound: who should have access to the data produced by the Registry and how should they use it? How should the results be reported and in what forum?

Tartrate-resistant acid phosphatase in bone and cartilage following decalcification and cold-embedding in plastic.

Tartrate-resistant acid phosphatase (TRAP) has been proposed as a cytochemical marker for osteoclasts. We have developed an improved technique for the localization of TRAP in rat and mouse bone and cartilage. This procedure employs JB-4 plastic as the embedding medium, permits decalcification, and results in improved morphology compared with frozen sections. Peritoneal lavage cells were used to determine the appropriate isomer and concentration of tartrate necessary for inhibition of tartrate-sensitive acid phosphatase. After incubation in medium containing 50 mM L(+)-tartaric acid, osteoclasts and chondroclasts were heavily stained with reaction product. On the basis of their relative sensitivity to tartrate inhibition, three populations of mononuclear cells could also be distinguished. These three populations may represent: heavily stained osteoclast/chondroclast precursors; sparsely stained osteoblast-like cells lining the bone surface; and unstained cells of monocyte-macrophage lineage. Our results are consistent with the use of TRAP as a histochemical marker for study of the osteoclast.