Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Genomics of ankylosing spondylitis

Ankylosing spondylitis (AS) is the prototypic and most prevalent and debilitating spondyloarthropathy, a group of arthritides where the spine and pelvis are specifically targeted. Unlike many other forms of arthritis in which joint damage is mediated through tissue destruction, in AS uncontrolled bone formation occurs, frequently resulting in joint fusion and consequently significant disability. It is estimated that there are 2.4 million spondyloarthritis sufferers in the U.S., twice as many as rheumatoid arthritis. The pathogenesis of AS is very poorly understood and both genetics and gene expression profiling approaches have been utilized to elucidate the underlying mechanisms and pathways that drive the disease. Using powerful genome-wide association study approaches a number of candidate genes have been found to be associated with AS. However, although such approaches can identify genes that can contribute to the disease process, they do not inform us of the actual changes in gene/cell activity at any point in the disease process. Expression profiling allows us to take a "snapshot" of cellular activity and what gene activity changes are underlying those changes. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. The results to date have been somewhat disappointing with little consensus on gene activity changes due to the low power of the studies undertaken. Some more recent better powered studies have identified diagnostic expression profiles that do point to a possible role for expression profiling in early AS diagnosis. Future studies will require collaborative approaches to target specific disease stages and sites with larger numbers of samples.

Evidence-based recommendations for the diagnosis of ankylosing spondylitis: Results from the Australian 3E initiative in rheumatology

• As part of the 3E program, we conducted a systematic literature review and gathered consensus from 23 practising Australian rheumatologists to develop guidelines for early identification of ankylosing spondylitis and specialist referral. • In three rounds of break-out sessions followed by discussion and voting, the specialist panel addressed three questions related to diagnosis of ankylosing spondylitis: In individuals with back pain, what are the early clinical features that suggest ankylosing spondylitis? How useful is imaging in identifying early ankylosing spondylitis? Based on which clinical features should a general practitioner refer a patient to a rheumatologist for further evaluation? • The panel agreed on six recommendations related to the three questions: 1a. Early clinical features to suggest ankylosing spondylitis include inflammatory back pain and age at symptom onset < 45 years. 1b. The absence of symptomatic response to an appropriate course of non-steroidal anti-inflammatory drugs makes the diagnosis of ankylosing spondylitis less likely. 1c. Raised inflammatory markers are supportive, but their absence does not rule out the diagnosis of ankylosing spondylitis. 2a. Despite low sensitivity to detect changes of early ankylosing spondylitis, plain radiographs of the pelvis and spine are appropriate initial imaging techniques. 2b. Magnetic resonance imaging is a useful imaging modality for detecting early changes of ankylosing spondylitis. 3. Individuals with inflammatory back pain should be referred to a rheumatologist for further evaluation. • Effective dissemination and implementation of these recommendations are important to standardise the approach to early diagnosis of ankylosing spondylitis.

The effects of +Gz force on the bone mineral density of fighter pilots

HYPOTHESIS Bone is a metabolically active tissue which responds to high strain loading. The purpose of this study was to examine the bone response to high +Gz force loading generated during high performance flying. METHODS The bone response to +Gz force loading was monitored in 10 high performance RAAF pilots and 10 gender-, age-, height-, weight-matched control subjects. The pilots were stationed at the RAAF base at Pearce, Western Australia, all completing the 1-yr flight training course. The pilots flew the Pilatus PC-9 aircraft, routinely sustaining between 2.0 and 6.0 +Gz. Bone mineral density (BMD) and bone mineral content (BMC) were measured at baseline and 12 mo, using the Hologic QDR 2000+ bone densitometer. RESULTS After controlling for change in total body weight and fat mass, the pilots experienced a significant increase in BMD and BMC for thoracic spine, pelvis, and total body, in the magnitude of 11.0%, 4.9%, and 3.7%, respectively. However, no significant changes in bone mineral were observed in the pilots lumbar spine, arms or legs. The control group experienced a significant decrease in pelvic BMC, with no other bone mineral changes observed at any site. CONCLUSIONS These findings suggest that site specific BMD is increased in response to high +Gz forces generated during high performance flying in a PC-9.

Myelodysplasia as a cause of hindlimb ataxia in two beef calves.

Myelodysplasia is a general term referring to abnormal development of the spinal cord. Unless associated with vertebral malformations, it can be difficult to distinguish clinically from other causes of spinal cord disease. These case reports describe the clinical and pathological findings in two calves with a distinctive non-progressive pelvic limb ataxia. The syndrome was observed in two calves on a large, extensively managed beef cattle property near Richmond, north Queensland. Both calves had similar clinical signs, including hindlimb ataxia with swaying of the pelvis and a well-coordinated bilateral hopping-like action. The differential diagnoses are discussed. A focal or diffuse myelodysplasia should be suspected in calves that have exhibited a non-progressive hindlimb ataxia from birth.

Dislocation after total hip replacement: there is no such thing as a safe zone for socket placement with the posterior approach

Introduction Malorientation of the socket contributes to instability after hip arthroplasty but the optimal orientation of the cup in relation to the pelvis has not been unequivocally described. Large radiological studies are few and problems occur with film standardisation, measurement methodology used and alternative definitions of describing acetabular orientation. Methods A cohort of 1,578 patients from a single institution is studied where all patient data was collected prospectively. Risk factors for patients undergoing surgery are analysed. Radiological data was compared between a series of non-dislocating hips and dislocating cases matched 2:1 by operation type, age and diagnosis. Results The overall dislocation rate for all 1,578 cases was 3.23% but the rate varied according to the type of surgery performed. The rate in uncomplicated primary cases was 2.4% which increased to 9.3% for second stage implantation for a two stage procedure for infection. There was no significant difference in the variability of the dislocating and non-dislocating groups for either inclination (p = 0.393) or anteversion (p = 0.661). Conclusions A “safe zone” for socket orientation to avoid dislocation could not be defined. The cause of dislocation is multifactorial, re-establishing the anatomic centre of rotation, balancing soft tissues and avoidance of impingement around the hip are important considerations.

Inflammation-driven bone formation in a mouse model of ankylosing spondylitis: Sequential not parallel processes

Background Ankylosing spondylitis (AS) is an immune-mediated arthritis particularly targeting the spine and pelvis and is characterised by inflammation, osteoproliferation and frequently ankylosis. Current treatments that predominately target inflammatory pathways have disappointing efficacy in slowing disease progression. Thus, a better understanding of the causal association and pathological progression from inflammation to bone formation, particularly whether inflammation directly initiates osteoproliferation, is required. Methods The proteoglycan-induced spondylitis (PGISp) mouse model of AS was used to histopathologically map the progressive axial disease events, assess molecular changes during disease progression and define disease progression using unbiased clustering of semi-quantitative histology. PGISp mice were followed over a 24-week time course. Spinal disease was assessed using a novel semi-quantitative histological scoring system that independently evaluated the breadth of pathological features associated with PGISp axial disease, including inflammation, joint destruction and excessive tissue formation (osteoproliferation). Matrix components were identified using immunohistochemistry. Results Disease initiated with inflammation at the periphery of the intervertebral disc (IVD) adjacent to the longitudinal ligament, reminiscent of enthesitis, and was associated with upregulated tumor necrosis factor and metalloproteinases. After a lag phase, established inflammation was temporospatially associated with destruction of IVDs, cartilage and bone. At later time points, advanced disease was characterised by substantially reduced inflammation, excessive tissue formation and ectopic chondrocyte expansion. These distinct features differentiated affected mice into early, intermediate and advanced disease stages. Excessive tissue formation was observed in vertebral joints only if the IVD was destroyed as a consequence of the early inflammation. Ectopic excessive tissue was predominantly chondroidal with chondrocyte-like cells embedded within collagen type II- and X-rich matrix. This corresponded with upregulation of mRNA for cartilage markers Col2a1, sox9 and Comp. Osteophytes, though infrequent, were more prevalent in later disease. Conclusions The inflammation-driven IVD destruction was shown to be a prerequisite for axial disease progression to osteoproliferation in the PGISp mouse. Osteoproliferation led to vertebral body deformity and fusion but was never seen concurrent with persistent inflammation, suggesting a sequential process. The findings support that early intervention with anti-inflammatory therapies will be needed to limit destructive processes and consequently prevent progression of AS.

Estudio de caso de los efectos toxicológicos de las hojas de la planta 5 negritos (Lantana camara L.) en ovinos

Las intoxicaciones en los animales de producción, constituyen un problema que el productor se enfrenta día a día. Con el presente estudio de caso se valoró los efectos tóxicos de las hojas de la planta Lantana cámara L. conocido como cuasquito o cinco negritos,que provoca lesiones en hígado, riñones y foto dermatitis en rumiantes, para el presente ensayo se tomaron 6 ovinos hembras de una año de edad aproximadamente y con un peso promedio de 30 kg y se organizaron en tres grupos de dos individuos cada uno a los cuales se les suministró pasto jaragua a razón de 3kg/pv/día, el primer grupo de control solamente con pasto, al segundo grupo se le suministró 8g de hojas de la planta / kg p.v. y al tercer grupo se le suministró 12g de hojas de la planta / kg de p.v. y su respectiva cantidad de pasto por día, durante 21 días para finalizar con la necropsia, dando como resultado en el examen de BHC (Biometría Hemática completa) en los grupos tratados que no existe alteración significativa en los valores hemáticos, los síntomas y signos clínicos predominantes fueron hipernea, postración, conjuntiva con enrojecimiento marcado, diarrea, búsqueda de sombra, disminución del consumo del alimento, pelo opaco y piel seca, micción frecuente con orina amarilla oscuray las principales lesiones observadas a través de la necropsia revelóque en el grupo número 2, los hígados presentaron adherencias, bordes irregulares y petequias hemorrágicas, en la región de la pelvis y médula renal se observó ictericia, petequias hemorrágicas y en vesícula biliar formación de residuos en bilis y en el grupo número 3 se observó una marcada ictericia en la región de la pelvis y médula renal, también se observaron adherencias en hígados, petequias en riñón e hígado y abundante residuo biliar.

MRI features of cellular angiomyofibroma with pathologic correlation.

Within the spectrum of extratesticular mesenchymal tumors in the scrotum and perineum lies cellular angiofibroma, also known as angiomyofibroblastoma-like tumor, a rare lesion originally described to almost exclusively occur in the vulva, perineum, and pelvis of women. We report a case of this tumor, with an adjacent scrotal lipoma, occurring in a 60-year-old male who presented to our department with a firm palpable scrotal mass. To our knowledge, the MRI findings of this entity have yet to be described in the radiological literature. We present the MRI features of cellular angiofibroma that are consistent with the pathological characteristics of this entity-a benign cellular and fibrous tumor with prominent vascularity.

Optimization of treatment strategy used during shockwave lithotripsy to maximize stone fragmentation efficiency.

BACKGROUND AND PURPOSE: Previous studies have demonstrated that treatment strategy plays a critical role in ensuring maximum stone fragmentation during shockwave lithotripsy (SWL). We aimed to develop an optimal treatment strategy in SWL to produce maximum stone fragmentation. MATERIALS AND METHODS: Four treatment strategies were evaluated using an in-vitro experimental setup that mimics stone fragmentation in the renal pelvis. Spherical stone phantoms were exposed to 2100 shocks using the Siemens Modularis (electromagnetic) lithotripter. The treatment strategies included increasing output voltage with 100 shocks at 12.3 kV, 400 shocks at 14.8 kV, and 1600 shocks at 15.8 kV, and decreasing output voltage with 1600 shocks at 15.8 kV, 400 shocks at 14.8 kV, and 100 shocks at 12.3 kV. Both increasing and decreasing voltages models were run at a pulse repetition frequency (PRF) of 1 and 2 Hz. Fragmentation efficiency was determined using a sequential sieving method to isolate fragments less than 2 mm. A fiberoptic probe hydrophone was used to characterize the pressure waveforms at different output voltage and frequency settings. In addition, a high-speed camera was used to assess cavitation activity in the lithotripter field that was produced by different treatment strategies. RESULTS: The increasing output voltage strategy at 1 Hz PRF produced the best stone fragmentation efficiency. This result was significantly better than the decreasing voltage strategy at 1 Hz PFR (85.8% vs 80.8%, P=0.017) and over the same strategy at 2 Hz PRF (85.8% vs 79.59%, P=0.0078). CONCLUSIONS: A pretreatment dose of 100 low-voltage output shockwaves (SWs) at 60 SWs/min before increasing to a higher voltage output produces the best overall stone fragmentation in vitro. These findings could lead to increased fragmentation efficiency in vivo and higher success rates clinically.

Optimising the use of virtual and conventional simulation: a clinical and economic analysis

Background and purpose: Currently, optimal use of virtual simulation for all treatment sites is not entirely clear. This study presents data to identify specific patient groups for whom conventional simulation may be completely eliminated and replaced by virtual simulation. Sampling and method: Two hundred and sixty patients were recruited from four treatment sites (head and neck, breast, pelvis, and thorax). Patients were randomly assigned to be treated using the usual treatment process involving conventional simulation, or a treatment process differing only in the replacement of conventional plan verification with virtual verification. Data were collected on set-up accuracy at verification, and the number of unsatisfactory verifications requiring a return to the conventional simulator. A micro-economic costing analysis was also undertaken, whereby data for each treatment process episode were also collected: number and grade of staff present, and the time for each treatment episode. Results: The study shows no statistically significant difference in the number of returns to the conventional simulator for each site and study arm. Image registration data show similar quality of verification for each study arm. The micro-costing data show no statistical difference between the virtual and conventional simulation processes. Conclusions: At our institution, virtual simulation including virtual verification for the sites investigated presents no disadvantage compared to conventional simulation.

Estimation of fetal and effective dose for CT examinations

Doses from CT examinations are difficult to estimate. However, they are requested more frequently due to the increase in CT examinations. In particular, fetal dose estimations are frequently required for patients who have discovered, subsequent to the examination, that they were pregnant when the examination was conducted. A computer model has been developed to facilitate such dose calculations. This model combines empirical beam data with anatomical information. The model has been verified using thermoluminescent dosemeter (TLD) readings of internal and surface dose from both phantoms and patients, including intrauterine doses for patients undergoing afterloading gynaecological intracavitary treatment. Although only limited experimental data were available, the results indicate that the model accurately predicts uterine doses within acceptable errors. This approach has been validated for fetal dose estimation. The model was also used in a comparison with the nationally available CT dose data from the National Radiological Protection Board (NRPB). The two models were found to be in agreement for fetal dose estimations.

Análise do padrão motor em pessoas com diagnóstico de esquizofrenia: uma abordagem em tempo real

A esquizofrenia é uma perturbação mental grave caracterizada pela coexistência de sintomas positivos, negativos e de desorganização do pensamento e do comportamento. As alterações motoras são consistentemente observadas mas, ainda pouco estudadas na esquizofrenia, sendo relevantes para o seu diagnóstico. Neste quadro, o presente estudo tem como objetivo verificar se os indivíduos com esquizofrenia apresentam alterações na coordenação motora, comparativamente com o grupo sem esquizofrenia, bem como analisar se as disfunções dos sinais neurológicos subtis (SNS) motores se encontram correlacionadas com o funcionamento executivo e com os domínios psicopatológicos da perturbação. No total participaram 29 indivíduos (13 com diagnóstico de esquizofrenia e 16 sem diagnóstico) equivalentes em termos de idade, género, escolaridade e índice de massa corporal. Para avaliar o desempenho motor recorreu-se ao sistema Biostage de parametrização do movimento em tempo real, com a tarefa de lançameto ao alvo; a presença de SNS foi examinada através da Brief Motor Scale; o funcionamento executivo pela aplicação do subteste do Vocabulário e da fluência verbal e a sintomatologia clínica através da Positive and Negative Sindrome Scale. Pela análise cinemática do movimento constatou-se que os indivíduos com esquizofrenia recrutam um padrão motor menos desenvolvido e imaturo de movimento, com menor individualização das componentes (principalmente do tronco e pélvis), necessitando de mais tempo para executar a tarefa, comparativamente com os sujeitos sem a perturbação que evidenciaram um movimento mais avançado de movimento. Os indivíduos com esquizofrenia mostraram índices elevados de disfunção dos SNS (média =6,01) estabelecendo este domínio uma relação boa e negativa com o desempenho verbal (rho Spearman=-0,62) e uma relação forte e positiva com todos os domínios psicopatológicos (rho Spearman=0,74). O estudo da existência de alterações motoras como parte intrínseca da esquizofrenia revela-se pertinente uma vez que possibilita uma compreensão mais aprofundada da sua fisiopatologia e permite que se desenvolvam práticas mais efetivas na área da saúde e reabilitação.

Mutilations Due to Medical Disorders in Children

Soft-tissue and bone necrosis, although rare in childhood, occasionally occur in the course of infectious diseases, either viral or bacterial, and seem to be the result of hypoperfusion on a background of disseminated intravascular coagulation. Treatment consists in correction of septic shock and control of necrosis. Necrosis, once started, shows extraordinarily rapid evolution, leading to soft-tissue and bone destruction and resulting in anatomic, functional, psychological, and social handicaps. Ten mutilated children were treated from January 1986 to January 1999 in Hospital de Dona Estefaˆ nia, Lisbon, Portugal. One was recovering from hemolytic-uremic syndrome with a severe combined immunodeficiency, another malnourished, anemic child had malaria, and three had chicken pox (in one case complicated by meningococcal septicemia). There were three cases of meningococcal and two of pyocyanic septicemia (one in a burned child and one in a patient with infectious mononucleosis). The lower limbs (knee,leg, foot) were involved in five cases, the face (ear, nose, lip) in four, the perineum in three, the pelvis (inguinal region, iliac crest) in two, the axilla in one, and the upper limb (radius, hand) in two. Primary prevention is based on early recognition of risk factors and timely correction. Secondary prevention consists of immediate etiologic and thrombolytic treatment to restrict the area of necrosis. Tertiary prevention relies on adequate rehabilitation with physiotherapy and secondary operations to obtain the best possible functional and esthetic result.