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Objective: To evaluate the efficacy on physical functioning and safety of tailored exercise therapy in patients with knee osteoarthritis (OA) and comorbidities. Methods: In a randomized controlled trial, 126 participants were included with a clinical diagnosis of knee OA and at least 1 of the following target comorbidities: coronary disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease, or obesity (body mass index ≥30 kg/m2), with severity score ≥2 on the Cumulative Illness Rating Scale. The intervention group received a 20-week, individualized, comorbidity-adapted exercise program consisting of aerobic and strength training and training of daily activities. The control group received their current medical care for knee OA and were placed on a waiting list for exercise therapy. Primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index, subscale physical functioning (WOMAC-pf), and the 6-minute walk test (6MWT). Measurements were performed at baseline, after 20 weeks (directly posttreatment), and at 3 months posttreatment. Results: Statistically significant physical functioning differences over time were found between the intervention and control group (WOMAC: B = −7.43 [95% confidence interval (95% CI) −9.99, −4.87], P < 0.001; and 6MWT: B = 34.16 [95% CI 17.68, 50.64], P < 0.001) in favor of the intervention group. At 3 months followup, the mean improvements in the intervention group were 33% on the WOMAC scale and 15% on the 6MWT. These improvements are of clinical relevance. No serious adverse events occurred during the intervention. Conclusion: This is the first study showing that tailored exercise therapy is efficacious in improving physical functioning and safe in patients with knee OA and severe comorbidities.

Objective Severe pain in patients with knee osteoarthritis (OA) hampers the ability to exercise. A protocol for the standardized optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol was to reduce pain, thereby allowing the patient to participate in exercise therapy. The objective of the present study was to evaluate the feasibility and outcome of the protocol. Methods Forty-nine patients with knee OA and severe knee pain (numerical rating scale for pain ≥7) were included. Analgesics were prescribed following an incremental protocol. After 6 weeks, a 12-week exercise therapy program was added. Information about analgesic use and exercise therapy content was recorded. Knee pain and activity limitations were assessed at baseline, after 6 weeks, and after 18 weeks. Results Statistically significant improvements in pain and activity limitations were found in intent-to-treat analysis after 6 weeks of analgesic use and after the intervention was completed. Mean improvements from baseline were 30% (P < 0.001) for pain and 17% (P < 0.001) for activity limitations after the intervention was completed. Seventy-eight percent of the patients were able to exercise according to the protocol. In these patients, exercise therapy following 6 weeks of analgesic use resulted in a further improvement of activity limitations of 10% (P = 0.004). Conclusion The combined intervention of standardized analgesic prescription and exercise therapy allows most patients with knee OA and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial.

This hypothesis explores Alzheimer’s Disease (AD) from a new perspective. It has been widely observed that AD patients present initially with “recent” memory loss. Recent memories are constantly created and updated, in contrast to “archived” memories, which do not require updating and which AD patients retain longer. Notably, memory creation and updating require the production and synthesis of proteins in neurons; and in AD patients, neurodegeneration is relative to the number of new proteins that the patient has synthesized. In neuronal protein synthesis, DNA transcribes mRNA, which is then translated into proteins in the cytoplasm. During this process, the unzipped DNA double helix is vulnerable to assault and can subsequently enter apoptosis if it is unable to repair itself. A healthy individual can create and update memories without neurodegeneration, and even among dementia patients, not every protein synthesis is subject to assault or neuronal damage. However, the more proteins are synthesized, the greater the probability of assault. I propose here that, consistent with AD being an agerelated disease, AD patients’ immune systems have declined to the point where they are unable to eradicate assault agents and to repair DNA damage sustained from assaults during neuronal protein synthesis.

Purpose To investigate the effect of anti-inflammatory therapy on selective laser trabeculoplasty (SLT) outcomes. Design Randomized, double-masked, placebo-controlled trial. Participants Patients with primary open-angle or pseudo-exfoliation glaucoma. Methods Patients undergoing SLT were randomized to receive placebo (artificial tears), prednisolone acetate 1%, or ketorolac tromethamine 0.5% eye drops 4 times per day for 5 days commencing immediately after SLT. Main Outcome Measures Change in intraocular pressure (IOP) from baseline to the 1-month post-SLT visit. Results Mean change in IOP at the 1-month primary outcome time point, as well as all other time points, was not significantly different among groups ( P = 0.99). Likewise, a repeated-measures, mixed-effects model did not find significant differences in IOP outcome at the 1-month time point ( P = 0.95). The IOP was reduced in all groups at the 1-month post-SLT time point and all other time points, and no significant differences were found between groups using separate unadjusted cross-sectional analyses of variance ( P > 0.15 for analyses at all time points). Treatment failure rates were not different among groups ( P = 0.75), and at 1 year after SLT, the percentage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups. Conclusions Anti-inflammatory therapy after SLT does not seem to substantially influence the IOP-lowering effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efficacy in achieving a sustained reduction in IOP.

A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy-neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL-associated copy number regions were revealed including losses of 1p32-36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy-neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2-q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high-resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single-gene somatic aberrations in FL tumorigenesis.

We present the outcome of an independent prospective series of phase-3 Oxford medial mobile-bearing unicompartmental knee replacement surgery. Eight surgeons performed the 154 procedures in a community-based hospital between 1998 and 2003 for patients aged 60 and above. Seventeen knees were revised; in 14 cases a total knee replacement was performed, in 3 cases a component of the unicompartmental knee prosthesis was revised, resulting in a survival rate of 89% during these 2-7 years follow-up interval. This study shows that mobile-bearing unicompartmental knee replacement using a minimally invasive technique is a demanding procedure. The study emphasises the importance of routine in surgical management and strict adherence to indications and operation technique used to reduce outcome failure.

Item does not contain fulltext BACKGROUND: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) has been extensively evaluated in groups of patients with osteoarthritis, yet not in patients with a femoral neck fracture. This study aimed to determine the reliability, construct validity, and responsiveness of the WOMAC compared with the Short Form-12 (SF-12) and the EuroQol 5D (EQ-5D) questionnaires for the assessment of elderly patients with a femoral neck fracture. METHODS: Reliability was tested by assessing the Cronbach alpha. Construct validity was determined with the Pearson correlation coefficient. Change scores were calculated from ten weeks to twelve months of follow-up. Standardized response means and floor and ceiling effects were determined. Analyses were performed to compare the results for patients less than eighty years old with those for patients eighty years of age or older. RESULTS: The mean WOMAC total score was 89 points before the fracture in the younger patients and increased from 70 points at ten weeks to 81 points at two years postoperatively. In the older age group, these scores were 86, 75, and 78 points. The mean WOMAC pain scores before the fracture and at ten weeks and two years postoperatively were 92, 76, and 87 points, respectively, in the younger age group and 92, 84, and 93 points in the older age group. Function scores were 89, 68, and 79 points for the younger age group and 84, 71, and 73 points for the older age group. The Cronbach alpha for pain, stiffness, function, and the total scale ranged from 0.83 to 0.98 for the younger age group and from 0.79 to 0.97 for the older age group. Construct validity was good, with 82% and 79% of predefined hypotheses confirmed in the younger and older age groups, respectively. Responsiveness was moderate. No floor effects were found. Moderate to large ceiling effects were found for pain and stiffness scales at ten weeks and twelve months in younger patients (18% to 36%) and in the older age group (38% to 53%). CONCLUSIONS: The WOMAC showed good reliability, construct validity, and responsiveness in both age groups of elderly patients with a femoral neck fracture who had been physically and mentally fit before the fracture. The instrument is suitable for use in future clinical studies in these populations. CLINICAL RELEVANCE: The results are based on two clinical trials. The questionnaires used concern pure, clinically relevant issues (ability to walk, climb stairs, etc.). Moreover, the results can be used for future research comparing clinical outcomes (or treatments) for populations with a femoral neck fracture.

The biological functions of the tumor suppressor ING1 have been studied extensively in the past few years since it was cloned. It shares many biological functions with p53 and has been reported to mediate growth arrest, senescence, apoptosis, anchorage-dependent growth, chemosensitivity, and DNA repair. Some of these functions, such as cell cycle arrest and apoptosis, have been shown to be dependent on the activity of both ING1 and p53 proteins. Two recent reports by Scott and colleagues demonstrate that p33(ING1) (one of the ING1 isoforms) translocates to the nucleus and binds to PCNA upon UV irradiation. Here we report that p33(ING1) mediates UV-induced cell death in melanoma cells. We found that overexpression of p33(ING1) increased while the introduction of an antisense p33(ING1) plasmid reduced the apoptosis rate in melanoma cells after UVB irradiation. We also demonstrated that enhancement of UV-induced apoptosis by p33(ING1) required the presence of p53. Moreover, we found that p33(ING1) enhanced the expression of endogenous Bax and altered the mitochondrial membrane potential. Taken together, these observations strongly suggest that p33(ING1) cooperates with p53 in UVB-induced apoptosis via the mitochondrial cell death pathway in melanoma cells.

To determine whether the perception of body posture is altered in idiopathic scoliosis, a simple neurophysiologic experiment through laser line projection was conducted to test this hypothesis in three groups of individuals: 89 children with idiopathic scoliosis (IS). 50 children with congenital scoliosis (CS) and 45 controls without scoliosis. The subjects were instructed to adjust a laser line projection to the direction of gravity in vertical and in horizontal projections in a dark environment. The performance, expressed as the deviation from the earth vertical (measured in degrees). was calculated by a computer. The three groups fulfilled the vertical and horizontal adjustments within the same accuracy. No relation with age. sex or severity of scoliotic deformity was found. Yet, the angle between vertical and horizontal laser lines was significantly related with the severity of scoliosis, both in IS and CS. In contrast to our hypothesis, it A as concluded that perception Of Postural control in IS is not altered. Therefore, this study indicates that IS is not likely to be caused by a dysfunction of postural control. (C) 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Approximately 2.7 billion years ago, cyanobacteria began producing oxygen by photosynthesis. Any free oxygen they produced was chemically captured by dissolved iron or organic matter. There was no ozone layer to protect living species against the radiation from space. Eukaryotic cells lived in water, under hypoxic environments, and metabolized glucose by fermentation. The Great Oxygenation Event (GOE) describes the point when oxygen sinks became saturated. This massive oxygenation of the Earth occurred approximately half a billion years ago. Species that evolved after the GOE are characterized by aerobic metabolism. Mammals evolved approximately a few hundred million years ago, with the ancient eukaryotic genes deeply embedded in their genome. Many genes have been exchanged by horizontal gene transfer (HGT) throughout the history of cellular evolution. Mammals have been invaded by viruses, and while viral genetic relics are embedded in mammalian junk genes, not all junk genes are genetic relics of viruses. These viral relics have been inactivated through evolution and have little impact on mammalian life. However, there is evidence to suggest that these viral genetic relics are linked to cancer. This hypothesis states that cancer develops when cell reproduction becomes defective because of the active involvement of viral genes, in a process similar to genetic engineering. Cancer cells are amalgamations of genetically modified organisms (GMOs). There are two main groups in cancer development. One group of cells arises by genetic engineering of a viral genetic relic, such as endogenous retroviruses (ERVs), which evolved after oxygenation of the atmosphere. This group is referred to here as genetically modified organisms from viral genes (GMOV). GMOVs may be inhibited by anticancer drugs. The second group arises by engineering of the genes of ancient eukaryotes, which existed prior to the oxygenation of the Earth. This second group is referred to as genetically modified organisms from ancient eukaryotic genes (GMOE). The GMOE group lives in hypoxic environments and metabolizes glucose by fermentation. GMOEs represent advanced cancer, which proliferate aggressively and are resistant to DNA damage. It has been demonstrated that as an ERV becomes more prevalent in a mammalian genome, the possibility that the mammal will develop cancer increases. The hypothesis also states that most cancers have their origins in GMOV by the incorporation of viral genes from junk genes. As the cancer progresses, further subgroups of cancer GMOs will develop. If the cancer advances even further, the GMOE could eventually develop prior to late-stage cancer. Because the genes of ancient eukaryotes have enhanced innate immunity, GMOE will eventually prevail over the weaker GMOV during cancer subgroup competition. Hence, cancer development is mainly determined by genes in the mammalian genome. An inherent weakness of cancer cells is their dependence on glucose and iron. Furthermore, they cannot tolerate physical disturbance. Ancient gene GMOs can be treated with a combination of mechanical vibration using glucose-coated magnetic nanoparticles and strengthening of the immune system. Herein, I suggest trials for verifying this hypothesis.

BACKGROUND Two staging systems for oral leukoplakias have been proposed to better predict prognosis. Although one system includes site as an independent determinant, its use is controversial. METHODS Recent studies have shown that loss of heterozygosity (LOH) in oral premalignancies is associated with risk of progression. The authors analyzed 127 oral dysplasias for LOH on 3 chromosome arms (3p, 9p, and 17p). The lesions included 71 from the floor of mouth, ventrolateral tongue, and soft palate complex (designated high risk [HR] sites) and 56 from the rest of the oral cavity (low risk [LR] sites). RESULTS Dysplasias from HR sites contained significantly higher LOH frequencies than LR sites (percentage with any loss, P = 0.0004; percentage with multiple losses, P = 0.0001; percentage loss on each of the arms, P < 0.05). Loss on 3p and/or 9p, a pattern associated with a 24-fold increased risk of progression (Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357–62) was more frequent among HR lesions (P = 0.0005). Loss of heterozygosity frequencies were elevated at HR sites among both genders and among smokers and nonsmokers. For different histologic groups, LOH frequencies were elevated for HR sites in mild dysplasias (P < 0.05) and moderate dysplasias (marginal significance, P = 0.06), but not in severe dysplasias/carcinoma in situ. CONCLUSIONS Anatomic location of mild and moderate oral dysplasias in Western populations may be an important diagnostic indicator because lesions at HR sites have a greater tendency to include genetic alterations associated with elevated risk of progression. Cancer 2001;91:2148–55. © 2001 American Cancer Society.

The objective of this study was to determine the impact of a community based model of care for diabetes patients in general practice settings. Using a quasi-experimental study design the effects of two interventions, individual dietetic counselling and group counselling, were assessed using glycosylated haemoglobin (HbA1c) as the outcome measure. Clients were referred by 78 of the 136 members of a Division of General Practice in New South Wales, Australia. This project was designed to replicate decision making in the practice setting rather than follow strict protocols and criteria for interventions associated with controlled trials. When the intervention groups were compared, there was no significant difference with respect to age, gender, diagnosis, exercise level, therapy or initial level of HbA1c .A significant difference in the pre- and post-intervention level of HbA1c was found for those patients who attended individual education ( p=0.03), which was in contrast to those provided a group intervention, where there was no significant difference ( p=0.84). The ‘best fit’ model for the individual intervention explained 60% of the variance. The analysis of variance indicates that initial HbA1c ( p

Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism–detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35–9.878, P = 0.011) and 3.19 (95% confidence interval, 1.06–9.57, P = 0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. Cancer Res; 70(22); 9166–74. ©2010 AACR.

The tumour suppressor TP53 (previously termed p53) mediates a pathway that is considered to be one of the most important mechanisms in the maintenance of genomic stability. The function of TP53 can be abrogated by genomic deletion, mutation, or deregulation of upstream and downstream participants in the TP53 pathway. While aberrations of TP53 are widely prevalent in non-haematological malignancies (over 60%), they are present in much lower frequency in haematological malignancies (

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model–based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q−, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.

Background Prescription of analgesics is complex in patients with knee OA and severe pain. We developed a protocol for the standardized prescription of analgesics based on the World Health Organization analgesic ladder (1) and the Beating osteoARTritis (BART) strategy for stepped care in hip and knee OA (2). Objectives The aim of this study was to evaluate the feasibility and outcome of the analgesic protocol. Methods Forty-nine patients with knee OA and severe knee pain (NRS≥7; range 0-10) were included. Analgesics were prescribed following an incremental protocol (Figure 1) for a period of six weeks. Pain intensity was evaluated every two weeks. When there was insufficient pain reduction (NRS-pain>5), a consultation at the rheumatologist was planned to offer an analgesic of the next step. Analgesics of the next step were added to analgesics of the previous step(s). Analgesic use was recorded. Knee pain (NRS-pain) and activity limitations (WOMAC-PF) were measured. Data were collected at baseline and after six weeks. Subsequently, patients started with exercise therapy. Results At baseline 84% of the patients used analgesics. Of all patients, 77% used acetaminophen, 36% used NSAIDs and 16% used weak opioids. At baseline, analgesics were used irregularly and at an suboptimal dose. Analgesic use after six weeks is described in Figure 1. The maximal daily dosage was used in 93% of the patients that used acetaminophen, in 66% of the patients that used NSAIDs, and in 44% of the patients that used weak opioids. Combinations of analgesics were common. No serious adverse events occurred. In 39% of the patients NRS-pain was ≤5 after six weeks. Despite NRS-pain>5, a further step in the analgesic protocol was not accepted by the patient (n=14) or not prescribed by the rheumatologist (n=13), the latter mostly due to contra-indications or side effects. Statistically significant and clinically relevant mean improvements from baseline were 19% (p Conclusions After six weeks, patients used analgesics regularly and often at a preferential dose. Prescription of analgesics following an incremental protocol reduces pain and activity limitations in patients with knee OA and severe pain. References World Health Organization. Cancer pain relief: with a guide to opioid availability. Available at: http://whqlibdoc.who.int/publications/9241544821.pdf (accessed 14 January 2014). Smink AJ, et al. Clin Rheumatol 2011;30:1623-9. Disclosure of Interest None declared

Background Severe pain in patients with knee OA hampers the ability to exercise. A protocol for the optimization of analgesics in combination with exercise therapy was developed. The purpose of this protocol is to reduce pain and thereby allowing the patient to participate in exercise therapy. Objectives The objective of the present study was to evaluate the feasibility and outcome of the protocol. Methods Forty-nine patients with knee OA and severe knee pain (NRS-pain≥7, range 0-10) were included in this study. Analgesics were prescribed following an incremental protocol. The incremental steps were (1) acetaminophen, (2) NSAIDs, (3) weak opioids and (4) intra-articular steroid injections. After six weeks of analgesic use a supervised exercise therapy program for 12 weeks was added, consisting of muscle strengthening exercises and training of daily activities. Knee pain was assessed with NRS-pain and activity limitations were assessed with WOMAC-PF. Data were collected at baseline, after six weeks, and after 18 weeks. Results In intention-to-treat analyses statistically significant improvements in pain and activity limitations were found after six weeks of analgesic use and after the complete intervention. Mean improvements from baseline were 30% (p Conclusions The combined intervention of analgesics and exercise therapy allows most patients with knee osteoarthritis and severe pain to participate in exercise therapy, leading to reduction of pain and activity limitations. These promising results need to be confirmed in a randomized controlled trial. Disclosure of Interest None declared

As modern day society takes an increasing interest in outdoor activities, its exposure to sunlight has never been greater. As a consequence, countries throughout the world are experiencing a dramatic increase in the incidences of skin carcinomas and melanomas. From DNA photolesions to mutations, skin cancer and cell death provides an authoritative source of information for photobiologists interested in the series of genetic events that occur in the skin, and eventually lead to cancer. With contributions from eminent scientists in the field, this book includes the latest information on DNA photolesions and repair, as well as the key mechanisms of solar UV in skin cancer initiation and development. Significant information relating to UV-induced photolesions and mechanisms of skin tumour occurrence is also included. By providing the basic phenomena underlying the science and an overview of the biological events that take place when cells are exposed to solar UV radiation, From DNA photolesions to mutations, skin cancer and cell death is suitable to all researchers interested in the process of photocarcinogenesis.

Study Design. A prospective study in which patients with idiopathic scoliosis were examined longitudinally by radiographic and electromyographic measurements according to a protocol. Objectives. To measure the growth velocity of the spine and the electromyographic ratio of the paraspinal muscles to determine their relation to progression of the scoliotic curve. Summary of Background Data. Several factors have been reported to be involved in the progression of idiopathic scoliosis. Possible factors may be growth disturbances and muscular abnormality. Methods. Thirty patients with idiopathic scoliosis were examined over periods of 4 to 5 months. The periods were scored for progression, defined as an increase in Cobb angle of >10degrees. Spinal growth velocity was measured as the length difference of the scoliotic spine between two consecutive radiographs. The electromyographic activity on both sides of the spine expressed as an electromyographic ratio was measured during relaxed upright standing using bipolar surface electrodes. Predictability of progression was evaluated with regression analysis and receiver operating characteristic analysis. Results. There was an independent association between both spinal growth velocity and electromyographic ratio and progression of the scoliotic curve. An equal sensitivity and specificity of spinal growth velocity for progression of 79.1% was observed at a growth velocity cutoff point of 11 mm/year. Similarly, a cutoff point of 1.25 for the electromyographic ratio could be determined with a predictive value for progression of 68.9%. In the presented nomogram, a spinal growth velocity >15 mm/year combined with an electromyographic ratio >2 gave an 89% probability of progression of the scoliotic deformity. Growth velocities Conclusions. The combined measurement of spinal growth velocity and electromyographic ratio has significant predictive potential and may be valuable in the evaluation and treatment of idiopathic scoliosis.

The tumour suppressor ING1 shares many biological functions with p53, such as cell cycle arrest, DNA repair, apoptosis, and chemosensitivity. Since p53 inhibits invasion and angiogenesis of melanoma cells, we sought to investigate if p33ING1 (one of ING1 isoforms) is also involved in these biological processes. We first overexpressed p33ING1 in melanoma cells and assessed the protein levels in MMP-1, MMP-2, and MMP-9. Results from Western blot analysis showed no significant difference in these matrix metalloproteinase levels between cells transfected with vector, p33ING1, and antisense p33ING1. Wound healing assay was performed to examine if p33ING1 plays a role in migration and invasion. Results showed that there was no difference between vector, p33ING1, and antisense p33ING1 groups in melanoma cell migration across the wound. Western blot analysis also indicated that there is no difference in the levels of proteins which are directly involved in angiogenesis, such as VEGF, Flt-1, and Flk-1, between cells transfected with vector, p33ING1, and antisense p33ING1. Furthermore, functional studies indicated that cultured medium derived from p33ING1-transfected melanoma cells did not stimulate the growth of HUVEC cells, compared to controls, providing support to the lack of functional role of p33ING1 in angiogenesis. In conclusion, we demonstrate in vitro that p33ING1, unlike p53, does not play a role in angiogenesis and migration in melanoma cells.

A transverse force system, consisting of an anterior progression force counteracted by a posterior force and torque, acts on the vertebrae of a scoliotic spine. The aim of the newly introduced TriaC brace is to reverse this transverse force pattern by externally applied and constantly present orthotic forces. In the frontal plane the force system in the TriaC brace is in accordance with the force system of the conventional braces. However, in the sagittal plane the force system acts only in the thoracic region. As a result, there is no pelvic tilt, and it provides flexibility without affecting the correction forces during body motion. In the current preliminary study it is demonstrated that the brace prevents further progression of the Cobb angle and axial rotation in idiopathic scoliosis. The new brace has the added advantage of comfort for the wearer, and it offers a better cosmetic appearance, as well as, potentially, a better compliance. (C) 2002 IPEM. Published by Elsevier Science Ltd. All rights reserved.

Although analysis of scoliotic deformity is still studied extensively by means of conventional roentgenograms, computer-assisted digital analysis may allow a faster, more accurate and more complete evaluation of the scoliotic spine. In this study, a new computer-assisted measurement method was evaluated. This method uses digital reconstruction images for quantitative analysis of the scoliotic spine. The aim of the current study was to determine the reliability of the computer-assisted measuring method, which was done by establishing coefficients of repeatability for a variety of measurements. Measurements were carried out by five observers on 30 frontal and 10 lateral scoliotic digital reconstruction images. Each image was measured on three separate occasions by placing anatomical vertebral landmarks and drawing lines with a computer pointing device. The computer then calculated a number of geometrical shape parameters from scale calibration, landmarks and lines. The intra- and interobserver results were subjected to an analysis of variance to assess the level of agreement, and the means and standard deviations were calculated. The coefficient of repeatability (CR) was taken to be equal to two standard deviations. The mean intraobserver CR was found to be 3.1degrees for the Cobb angle on the frontal digital image and 3.3degrees for the kyphosis Cobb angle on the lateral overview. The mean difference in the intraobserver CR of the Cobb angle between measurements made by placing landmarks and those made by drawing lines was not statistically significant (P>0.05). The mean intraobserver CR for the other parameters can be summarized as follows: for lateral deviation it was 0.8 mm, for axial rotation 4.0degrees and for length of the spine 3.3 mm. The interobserver bias was negligible. It can be concluded that the reliability of our new method for quantifying geometrical variables on digital reconstruction images is better than measurements on conventional roentgenograms in previously published reports. The presented method is therefore considered to be more accurate for research of spinal deformities and more adequate for clinical management of scoliosis.

Abstract 1919 Poster Board I-942 The secondary genetic events associated with follicular lymphoma (FL) development are obscure as to the identification of critical driver genes. Clinical correlative studies have implicated chromosome band 1p36 deletions and linked them to a propensity for transformation and poor outcome. This region also showed a high frequency of copy-neutral loss of heterozygosity as demonstrated by SNP array analysis. In this study, we applied BAC array comparative genomic hybridization (array CGH) to 141 FL specimens and detected deletion of 1p36 in 20% of the cases with a minimum region of deletion (MRD) of ∼100 kb within the band 1p36.32. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The MRD encompassed five genes: HES5, LOC115110, TNFRSF14, C1orf93 and MMEL1. Methylation status of CpG in the promoter region of genes in the MRD revealed no difference among samples differing in 1p36 status. However, exonic sequencing of the MRD genes identified somatic base mutations only in the TNFRSF14 gene in four of five selected cases with 1p36 deletion. Lower expression of TNFRSF14 was also found in 1p36 deleted cases. Validation of TNFRSF14 mutations was undertaken in an expanded cohort of 251 FL patients which showed that 45 cases (18%) displayed a total of 50 mutations and that inferior prognosis was significantly associated with TNFRSF14 mutation status. We propose that TNFRSF14, a gene previously implicated in growth inhibition and Fas-induced apoptosis, is a candidate tumor suppressor gene in FL. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: Clinical decision making in Hodgkin lymphoma (HL) is primarily based on clinical variables in part because the scarcity of the malignant Hodgkin Reed Sternberg cells (HRS cells) hampers their molecular characterization. However, more recently investigation using laser capture microdissection has allowed a more detailed analysis of these cells. The objective of this study was to detect genomic alterations in HRS cells and correlate these changes with treatment outcome. PATIENTS AND METHODS: We studied 53 patients with classical HL who were primarily treated at the BC Cancer Agency in Vancouver between 1984 and 2006. All received at least 4 cycles of polychemotherapy and stage-dependent radiotherapy if indicated. The cohort included 43 pretreatment samples and 10 biopsies taken at relapse. Treatment failure was defined as disease progression or relapse at any time (n=23), treatment success as absence of progression (n=30). Whole genome amplification (GenomePlex, Sigma) of pools from 500–1000 individually picked, microdissected HRS cells (Molecular Machines & Industries Cellcut with Nikon Eclipse TE2000-S microscope) was performed. 200 ng of amplified DNA was hybridized to 32k submegabase resolution BAC tiling arrays (SMRT) against sex-matched control-DNA. Scoring of array CGH data was performed by computational analysis using CNA-HMMer v0.1 (available at http://www.cs.ubc.ca/~sshah/acgh/) based on a Hidden Markov Model (HMM). Clustering of the 53 cases was performed using the K-medoids algorithm. Areas of amplification bias and known copy number polymorphisms were excluded. RESULTS: On average whole genome amplification generated 500-fold amplification of genomic DNA. The most frequent copy number alterations (>20% of cases) included gains of 2p14–24.3, 9p12–24.3, 12p11.21–13.33, 16p11.2–13.3, 17p11.2–13.3, 17q11.1–25.1, 19p12–13.3, 19q12–13.43, 20q11.21–13.32, 21q22.11–22.2 and losses of 1p36.31–36.33, 6q11.1–27, 7q22.1–36.3, 8p23.1–23.3, 11q22.3–25, 13q33.3–34 and Xq11.2–28. We also identified several small changes ( DISCUSSION: The combination of laser microdissection with subsequent WGA and high resolution array CGH provides a robust and sensitive platform for detecting chromosomal imbalances in microdissected HRS cells. We identified at high-resolution new and recurrent changes defining chromosomal regions that potentially harbor oncogenes and tumor suppressor genes crucial to the pathogenesis of HL. Furthermore, we found copy number alterations that are significantly associated with disease progression which, therefore, could serve as predictive factors for treatment outcome.

Background: The initial genetic event in ∼85% of follicular lymphomas (FL), the most common B-cell lymphoma in North America, is the t(14;18)(q32;q21) resulting in over-expression of the anti-apoptotic protein Bcl-2. The secondary events associated with disease progression are not well understood. Alterations affecting the p arm of chromosome 1 are evident by standard karyotype analysis in ∼20% of FL. We have further examined the relationship between 1p deletion and FL using high resolution genomic analyses. Methods: The prevalence of 1p alterations was investigated in 139 cases of indolent and transformed FL using whole genome tiling path BAC array Comparative Genomic Hybridization (array CGH). Array-based single nucleotide polymorphism analysis was performed on a subset of cases using Affymetrix 500K SNP arrays. Results: Array CGH identified a minimum region of deletion spanning ∼0.5MB within 1p36.32 in 51 cases (37%). In 38 cases (27%) this loss was exhibited in the transformed sample but not the pre-transformation sample. The majority of cases displayed heterozygous deletion, while two cases showed homozygous deletion. The mechanisms of loss included simple deletions, unbalanced translocations with various partner chromosomes and eleven cases with an unbalanced t(1;1)(p36;q12). The Affymetrix 500 SNP array analyses showed copy neutral loss of heterozygosity or acquired uniparental disomy (aUPD) in three of ten cases that were negative for loss by aCGH. Contained within the 1p36.32 minimally deleted region are only a few candidate genes including tumor necrosis factor receptor superfamily 14 (TNFRS14), which has been implicated in growth inhibition of HT-29 human colon adenocarcinoma cells and induction of Fas-mediated apoptosis in non-Hodgkin’s lymphoma. Conclusions: Our data indicate that loss of heterozygosity at 1p36.32 through deletion or aUPD constitutes the most common secondary cytogenetic event in FL. LOH at 1p36 may represent an important step in the progression of indolent to transformed FL. Further studies have been initiated to investigate other possible gene inactivation events such as methylation and mutation.