The Norwich Osteoarthritis of the Ankle MRI Score (NOAMS): a reliability study.

AIM: To define and test the inter- and intra-rater reliability of a grading system for staging osteoarthritis (OA) of the ankle with magnetic resonance imaging (MRI) (Norwich Osteoarthritis of the Ankle MRI Score, NOAMS). MATERIALS AND METHODS: The MRI features to be included in the score were defined by a multidisciplinary expert panel through a Delphi process. An anonymised randomised dataset of 50 MRI studies was created from patients with concurrent plain radiographs to include 10 ankles of each of the Kellgren-Lawrence grades 0 to 4. Two experienced musculoskeletal radiologists and two trainees scored each ankle MRI twice independently and blinded to the plain radiographs. RESULTS: The inter-rater kappa coefficient of agreement for cartilage disease was 0.88 (95% confidence interval [CI]: 0.85, 0.91) for experienced raters and 0.71 (95% CI: 0.67, 0.76) for trainees. Inter-rater agreement for subchondral bone marrow oedema and cysts varied from 0.73 to 0.82 for experienced raters and from 0.63 to 0.75 for trainees with lowest 95% CI of 0.48 and 0.63. When bone marrow lesions were combined into a total joint score the level of agreement increased to between 0.88 and 0.97 with lowest 95% CI of 0.86. Combining cartilage zone scores did not increase the reliability coefficients. CONCLUSION: An expert panel considered that cartilage degradation and subchondral bone marrow lesions were the most important features for staging the severity of ankle OA on MRI. Experienced observers can grade the severity of ankle OA on MRI with a clinically useful high degree of reproducibility.

Establishing the reliability of a novel battery of range of motion tests to enable evidence-based classification in Para Swimming.

OBJECTIVES: To evaluate the reliability of swimming-specific range of movement tests developed in order to permit evidenced-based classification in the sport of para swimming. DESIGN: Test-retest intra- and inter-examiner reliability. SETTING: International Swimming training camps and university exercise science departments. PARTICIPANTS: 42 non-disabled participants (mean age 23.2 years) and 24 Para swimmers (mean age 28.5 years). MAIN OUTCOME MEASURES: Intra- and inter-examiner reliability of a battery of novel active range of motion tests. RESULTS: Good to excellent intra-examiner reliability was found for the majority (32/34) of tests in non-disabled participants (ICC = 0.85-0.98). SEM values ranged from 1.18° to 6.11°. Similarly, good to excellent inter-examiner reliability was found for the majority (35/42) of tests in non-disabled participants (ICC = 0.85-0.98). SEM values range from 0.73° to 6.52°. Para swimmers exhibited significantly reduced range of motion compared to non-disabled participants. CONCLUSIONS: The large majority of ROM tests included in this novel battery were reliable both within and between examiners in non-disabled participants. The tests were found to differentiate between non-disabled participants and Para swimmers with hypertonia or impaired muscle power.

Can a single session of motor imagery promote motor learning of locomotion in older adults? A randomized controlled trial.

PURPOSE: To investigate the influence of a single session of locomotor-based motor imagery training on motor learning and physical performance. PATIENTS AND METHODS: Thirty independent adults aged >65 years took part in the randomized controlled trial. The study was conducted within an exercise science laboratory. Participants were randomly divided into three groups following baseline locomotor testing: motor imagery training, physical training, and control groups. The motor imagery training group completed 20 imagined repetitions of a locomotor task, the physical training group completed 20 physical repetitions of a locomotor task, and the control group spent 25 minutes playing mentally stimulating games on an iPad. Imagined and physical performance times were measured for each training repetition. Gait speed (preferred and fast), timed-up-and-go, gait variability and the time to complete an obstacle course were completed before and after the single training session. RESULTS: Motor learning occurred in both the motor imagery training and physical training groups. Motor imagery training led to refinements in motor planning resulting in imagined movements better matching the physically performed movement at the end of training. Motor imagery and physical training also promoted improvements in some locomotion outcomes as demonstrated by medium to large effect size improvements after training for fast gait speed and timed-up-and-go. There were no training effects on gait variability. CONCLUSION: A single session of motor imagery training promoted motor learning of locomotion in independent older adults. Motor imagery training of a specific locomotor task also had a positive transfer effect on related physical locomotor performance outcomes.

Low-Load Very High-Repetition Resistance Training Attenuates Bone Loss at the Lumbar Spine in Active Post-menopausal Women.

This study determined the effect of 6 months of low-load very high-repetition resistance training on bone mineral density (BMD) and body composition in nonosteoporotic middle-aged and older women. Fifty healthy, active community-dwelling women aged 56-75 years took part in the two-group, repeated-measures randomized controlled trial. Participants either undertook 6 months of low-load very high-repetition resistance training in the form of BodyPump™ or served as control participants. Outcome measures included BMD at the lumbar spine, hip, and total body; total fat mass; fat-free soft tissue mass and maximal isotonic strength. Significant group-by-time interactions were found for lumbar spine BMD and maximal strength in favor of the BodyPump™ group. No favorable effects were found for hip BMD, total body BMD, total fat mass, or fat-free soft tissue mass. Three participants withdrew from the intervention group due to injury or fear of injury associated with training. Under the conditions used in this research, low-load very high-repetition resistance training is effective at attenuating losses in lumbar spine BMD compared to controls in healthy, active women aged over 55 years but did not influence hip and total body BMD or fat mass and fat-free soft tissue mass.

Low-load high-repetition resistance training improves strength and gait speed in middle-aged and older adults.

OBJECTIVES: To determine the effect of 26 weeks of low-load high-repetition resistance training (BodyPump™) on maximal strength, gait speed, balance and self-reported health status in healthy, active middle-aged and older adults. DESIGN: Two-group randomised control trial. METHODS: Sixty-eight apparently healthy, active adults aged over 55 years completed either 26 weeks of BodyPump™ training (PUMP) or served as control participants (CON). The BodyPump™ group (n = 32, age = 66 ± 4 years) trained twice per week for 26 weeks while the control group (n = 36, age = 66 ± 5 years) continued with their normal activities. Leg-press and Smith-machine bench-press one repetition maximum (1RM), gait speed, balance, and self-reported health status were all assessed at baseline and follow-up. RESULTS: Significant group-by-time interactions in favour of the BodyPump™ group were found for leg-press 1RM (PUMP + 13%, CON + 3%, p = 0.007, partial eta(2) = 0.11), Smith-machine bench-press 1RM (PUMP + 14%, CON +5%, p = 0.001, partial eta(2) = 0.18), normal gait speed (PUMP + 23%, CON +9 %, p = 0.028, partial eta(2) = 0.08) and single leg balance right (PUMP + 24%, CON - 7%, p = 0.006, partial eta(2) = 0.12). There were no group-by-time interactions for health status measures. Three participants in the BodyPump™ group withdrew from training due to injury or fear of injury related to training. CONCLUSIONS: Low-load high-repetition resistance training in the form of BodyPump™ is effective at improving maximal strength, gait speed and some aspects of standing balance in adults over 55 years. The training was well tolerated by the majority of participants.

Twelve weeks of BodyBalance® training improved balance and functional task performance in middle-aged and older adults.

PURPOSE: The purpose of the study was to evaluate the effect of BodyBalance(®) training on balance, functional task performance, fear of falling, and health-related quality of life in adults aged over 55 years. PARTICIPANTS AND METHODS: A total of 28 healthy, active adults aged 66±5 years completed the randomized controlled trial. Balance, functional task performance, fear of falling, and self-reported quality of life were assessed at baseline and after 12 weeks. Participants either undertook two sessions of BodyBalance per week for 12 weeks (n=15) or continued with their normal activities (n=13). RESULTS: Significant group-by-time interactions were found for the timed up and go (P=0.038), 30-second chair stand (P=0.037), and mediolateral center-of-pressure range in narrow stance with eyes closed (P=0.017). There were no significant effects on fear of falling or self-reported quality of life. CONCLUSION: Twelve weeks of BodyBalance training is effective at improving certain balance and functional based tasks in healthy older adults.

Outcome of limited forefoot amputation with primary closure in patients with diabetes.

Limited forefoot amputation in diabetic patients with osteomyelitis is frequently required. We retrospectively reviewed diabetic patients with osteomyelitis, an unhealed ulcer and blood pressure in the toe of > 45 mmHg who underwent limited amputation of the foot with primary wound closure. Between 2006 and 2012, 74 consecutive patients with a mean age of 67 years (29 to 93), and a median follow-up of 31 months, were included. All the wounds healed primarily at a median of 37 days (13 to 210; mean 48). At a median of 6 months (1.5 to 18; mean 353 days), 23 patients (31%) suffered a further ulceration. Of these, 12 patients (16% of the total) required a further amputation. We conclude that primary wound closure following limited amputation of the foot in patients with diabetes is a safe and effective technique when associated with appropriate antibiotic treatment.

Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema.

We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.

Bilateral pneumothoraces treated with a single chest drain.

Resolution of bilateral pneumothoraces with a single chest drain is seldom seen in clinical practice. A 76-year-old man underwent coronary artery bypass grafting following which he developed bilateral pneumothoraces.

Effects of gender and age on paediatric headache.

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.

Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer.

The B cell antigen receptor (BCR) efficiently facilitates the capture and processing of a specific antigen for presentation on MHC class II molecules to antigen-specific CD4(+) T cells (1). Despite this, the majority of B cells are thought to play only a limited role in CD4(+) T cell activation because BCRs are clonotypically expressed. Here, we show, however, that activated B cells can, both in vitro and in vivo, rapidly donate their BCR to bystander B cells, a process that is mediated by direct membrane transfer between adjacent B cells and is amplified by the interaction of the BCR with a specific antigen. This results in a dramatic expansion in the number of antigen-binding B cells in vivo, with the transferred BCR endowing recipient B cells with the ability to present a specific antigen to antigen-specific CD4(+) T cells.

Femoral stem tip orientation and surgical approach in total hip arthroplasty.

INTRODUCTION: A posterior entry point, a neutral tip position and neutral stem alignment are recommended to avoid a thin cement mantle and ensure an optimal outcome in total hip arthroplasty (THA). Our aim was to highlight any influence of surgical approach in obtaining an optimal stem orientation. METHODS: We examined the post-operative, digitised radiographs of 100 (50 each group) polished, tapered Exeter THA, inserted via the antero-lateral or posterior approaches. Stem tip position was assessed in both coronal and sagittal planes and stem alignment was assessed in the coronal plane. RESULTS: There was a significant difference between the two approaches in the sagittal stem tip position only (p=0.01). DISCUSSION: Our results illustrate that a neutral stem tip position in THA is significantly more difficult to obtain with an antero-lateral approach, when compared to the posterior approach. A posterior approach to the hip avoids the cuff of glutei that can lever the proximal stem anteriorly causing an anterior entry point and a posterior stem tip position. We also illustrate how the anatomy of the proximal femur in the sagittal plane makes a neutral stem alignment difficult to achieve with either approach.

Antibody targeting to a class I MHC-peptide epitope promotes tumor cell death.

Therapeutic mAbs that target tumor-associated Ags on the surface of malignant cells have proven to be an effective and specific option for the treatment of certain cancers. However, many of these protein markers of carcinogenesis are not expressed on the cells' surface. Instead these tumor-associated Ags are processed into peptides that are presented at the cell surface, in the context of MHC class I molecules, where they become targets for T cells. To tap this vast source of tumor Ags, we generated a murine IgG2a mAb, 3.2G1, endowed with TCR-like binding specificity for peptide-HLA-A*0201 (HLA-A2) complex and designated this class of Ab as TCR mimics (TCRm). The 3.2G1 TCRm recognizes the GVL peptide (GVLPALPQV) from human chorionic gonadotropin beta presented by the peptide-HLA-A*0201 complex. When used in immunofluorescent staining reactions using GVL peptide-loaded T2 cells, the 3.2G1 TCRm specifically stained the cells in a peptide and Ab concentration-dependent manner. Staining intensity correlated with the extent of cell lysis by complement-dependent cytotoxicity (CDC), and a peptide concentration-dependent threshold level existed for the CDC reaction. Staining of human tumor lines demonstrated that 3.2G1 TCRm was able to recognize endogenously processed peptide and that the breast cancer cell line MDA-MB-231 highly expressed the target epitope. The 3.2G1 TCRm-mediated CDC and Ab-dependent cellular cytotoxicity of a human breast carcinoma line in vitro and inhibited in vivo tumor implantation and growth in nude mice. These results provide validation for the development of novel TCRm therapeutic reagents that specifically target and kill tumors via recognition and binding to MHC-peptide epitopes.

Ca(2+) stores and capacitative Ca(2+) entry in human neuroblastoma (SH-SY5Y) cells expressing a familial Alzheimer's disease presenilin-1 mutation.

Presenilins are involved in the proteolytic production of Alzheimer's amyloid peptides, but are also known to regulate Ca(2+) homeostasis in various cells types. In the present study, we examined intracellular Ca(2+) stores coupled to muscarinic receptors and capacitative Ca(2+) entry (CCE) in the human neuroblastoma SH-SY5Y cell line, and how these were modulated by over-expression of either wild-type presenilin 1 (PS1wt) or a mutant form of presenilin 1 (PS1 deltaE9) which predisposes to early-onset Alzheimer's disease. Ca(2+) stores discharged by application of 100 microM muscarine (in Ca(2+)-free perfusate) in PS1wt and PS1 DeltaE9 cells were significantly larger than those in control cells, as determined using Fura-2 microfluorimetry. Subsequent CCE, observed in the absence of muscarine when Ca(2+) was re-admitted to the perfusate, was unaffected in PS1wt cells, but significantly suppressed in PS1 deltaE9 cells. However, when Ca(2+) stores were fully depleted with thapsigargin, CCE was similar in all three cell groups. Western blots confirmed increased levels of PS1 in the transfected cells, but also demonstrated that the proportion of intact PS1 in the PS1 deltaE9 cells was far greater than in the other two cell groups. This study represents the first report of modulation of both Ca(2+) stores and CCE in a human, neurone-derived cell line, and indicates a distinct effect of the PS1 mutation deltaE9 over wild-type PS1.

Differential effects of unaggregated and aggregated amyloid beta protein (1-40) on K(+) channel currents in primary cultures of rat cerebellar granule and cortical neurones.

The effects of amyloid beta protein on voltage-gated K(+) channel currents were studied using the whole-cell patch-clamp technique. The 1-40 amino acid form of amyloid beta protein was applied to primary cultures of rat cerebellar granule and cortical neurones for 24 h. Both the unaggregated and aggregated forms of the peptide, which have differing biological activities, were used. In cerebellar granule neurones, 24-h pre-incubation with 1 microM unaggregated amyloid beta protein resulted in a 60% increase in the 'A'-type component of K(+) current. Increased delayed rectifier activity was Cd(2+)-sensitive and was presumed to be secondary to an increase in voltage-gated Ca(2+) channel current activity. Unaggregated amyloid beta protein had no effect on any component of the K(+) channel current in cortical neurones. One micromolar of aggregated amyloid beta protein had no effect on K(+) channel current in either cell type but reduced cell survival within 24 h as measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays. The unaggregated form of amyloid beta protein had no neurotoxic effects when applied to either neurone type for up to 72 h. These data indicate that the unaggregated, non-pathological form of amyloid beta protein causes changes in the ion channel function of neurones, possibly reflecting a physiological role for the peptide.

Effects of chronic hypoxia on Ca(2+) stores and capacitative Ca(2+) entry in human neuroblastoma (SH-SY5Y) cells.

Microfluorimetric measurements of intracellular calcium ion concentration [Ca(2+)](i) were employed to examine the effects of chronic hypoxia (2.5% O(2), 24 h) on Ca(2+) stores and capacitative Ca(2+) entry in human neuroblastoma (SH-SY5Y) cells. Activation of muscarinic receptors evoked rises in [Ca(2+)](i) which were enhanced in chronically hypoxic cells. Transient rises of [Ca(2+)](i) evoked in Ca(2+)-free solutions were greater and decayed more slowly following exposure to chronic hypoxia. In control cells, these transient rises of [Ca(2+)](i) were also enhanced and slowed by removal of external Na(+), whereas the same manoeuvre did not affect responses in chronically hypoxic cells. Capacitative Ca(2+) entry, observed when re-applying Ca(2+) following depletion of intracellular stores, was suppressed in chronically hypoxic cells. Western blots revealed that presenilin-1 levels were unaffected by chronic hypoxia. Exposure of cells to amyloid beta peptide (1-40) also increased transient [Ca(2+)](i) rises, but did not mimic any other effects of chronic hypoxia. Our results indicate that chronic hypoxia causes increased filling of intracellular Ca(2+) stores, suppressed expression or activity of Na(+)/Ca(2+) exchange and reduced capacitative Ca(2+) entry. These effects are not attributable to increased amyloid beta peptide or presenilin-1 levels, but are likely to be important in adaptive cellular remodelling in response to prolonged hypoxic or ischemic episodes.

A magnetic resonance study of complicated early childhood convulsion.

OBJECTIVES: The relation between complicated early childhood convulsion (ECC) and adult epilepsy is unclear, although a history of complicated ECC is obtainable in half of adults with epilepsy associated with hippocampal sclerosis. It is not known if the ECC is a marker of pre-existing brain damage or is itself harmful to the developing brain. The objective of the study was to assess the extent of structural brain abnormality present soon after a first complicated early childhood convulsion with a view to obtaining data which might contribute to an understanding of whether such abnormalities were likely to be pre-existing or caused by the convulsion. METHODS: Children under the age of 5 years were recruited into the study after their first complicated febrile or non-febrile ECC. None had previously experienced an epileptic seizure. All underwent MRI of the brain within 14 days. Hippocampal volumes and T2 relaxation times were measured. The results were compared with a neurological control group of children without gross structural abnormalities of the neocortex undergoing MRI of the brain for reasons other than epilepsy. RESULTS: Eighteen patients and 10 control subjects were recruited into the study. One patient was subsequently excluded because of EEG and clinical evidence of benign childhood epilepsy. Nine patients had volumetric evidence of significant hippocampal volume asymmetry (3 SD from the mean of the control group), although in only three of these was the asymmetry apparent on visual inspection of the MRI. Three patients had extrahippocampal neuropathology. None of the control subjects had significant hippocampal volume asymmetry (p<0.001). T2 relaxometry showed no evidence that postictal hippocampal oedema contributed to the asymmetry. CONCLUSIONS: There is a high prevalence of structural brain abnormalities in children within 2 weeks of the first complicated early childhood convulsion, including significant hippocampal asymmetry unrelated to oedema. This does not exclude a damaging effect of complicated ECC on the brain, but suggests that in at least some patients the complicated ECC is the result of pre-existing brain abnormalities.