Spinal cord injury as a result of Staphylococcus aureus pyogenic spinal infection complicating infected atopic eczema: two case reports.

INTRODUCTION: Pyogenic spinal infections (PSI) are a rare cause of spinal cord injury (SCI). These most often affect the lumbar spine, followed by the thoracic spine and least commonly the cervical spine, with Staphylococcus aureus being the most common causative organism. Atopic eczema is a dermatological condition which can lead to a breakdown of the skin's natural barrier function, allowing bacterial colonisation and infection. Haematological seeding of bacteria from a distant source of infection, including the skin and soft tissues, is a recognised aetiology of PSI. CASE PRESENTATION: We present two patients who sustained a SCI as a result of PSI secondary to infected atopic eczema. Methicillin-sensitive Staphylococcus aureus (MSSA) was identified as the causative organism in both patients. The two patients required prolonged courses of intravenous followed by oral antibiotics. Neurological outcomes varied between the two patients. One patient had incomplete tetraplegia (C3 AIS C), and upon discharge required hoisting from their bed to a power chair, had an indwelling urethral catheter and required bowel care. The other patient had incomplete paraplegia (L3 AIS D), and at discharge was independent with activities of daily living and was mobile with two elbow crutches. DISCUSSION: We believe that the two cases presented here represent the only examples of secondarily infected atopic eczema causing PSI and resultant SCI in the published literature. As SCI is a serious and potentially life-altering complication, medical professionals treating patients with atopic eczema should be aware of this risk.

Artificial Intelligence for Radiotherapy Auto-Contouring: Current Use, Perceptions of and Barriers to Implementation.

AIMS: Artificial intelligence has the potential to transform the radiotherapy workflow, resulting in improved quality, safety, accuracy and timeliness of radiotherapy delivery. Several commercially available artificial intelligence-based auto-contouring tools have emerged in recent years. Their clinical deployment raises important considerations for clinical oncologists, including quality assurance and validation, education, training and job planning. Despite this, there is little in the literature capturing the views of clinical oncologists with respect to these factors. MATERIALS AND METHODS: The Royal College of Radiologists realises the transformational impact artificial intelligence is set to have on our specialty and has appointed the Artificial Intelligence for Clinical Oncology working group. The aim of this work was to survey clinical oncologists with regards to perceptions, current use of and barriers to using artificial intelligence-based auto-contouring for radiotherapy. Here we share our findings with the wider clinical and radiation oncology communities. We hope to use these insights in developing support, guidance and educational resources for the deployment of auto-contouring for clinical use, to help develop the case for wider access to artificial intelligence-based auto-contouring across the UK and to share practice from early-adopters. RESULTS: In total, 78% of clinical oncologists surveyed felt that artificial intelligence would have a positive impact on radiotherapy. Attitudes to risk were more varied, but 49% felt that artificial intelligence will decrease risk for patients. There is a marked appetite for urgent guidance, education and training on the safe use of such tools in clinical practice. Furthermore, there is a concern that the adoption and implementation of such tools is not equitable, which risks exacerbating existing inequalities across the country. CONCLUSION: Careful coordination is required to ensure that all radiotherapy departments, and the patients they serve, may enjoy the benefits of artificial intelligence in radiotherapy. Professional organisations, such as the Royal College of Radiologists, have a key role to play in delivering this.

A Review of the Metrics Used to Assess Auto-Contouring Systems in Radiotherapy.

Auto-contouring could revolutionise future planning of radiotherapy treatment. The lack of consensus on how to assess and validate auto-contouring systems currently limits clinical use. This review formally quantifies the assessment metrics used in studies published during one calendar year and assesses the need for standardised practice. A PubMed literature search was undertaken for papers evaluating radiotherapy auto-contouring published during 2021. Papers were assessed for types of metric and the methodology used to generate ground-truth comparators. Our PubMed search identified 212 studies, of which 117 met the criteria for clinical review. Geometric assessment metrics were used in 116 of 117 studies (99.1%). This includes the Dice Similarity Coefficient used in 113 (96.6%) studies. Clinically relevant metrics, such as qualitative, dosimetric and time-saving metrics, were less frequently used in 22 (18.8%), 27 (23.1%) and 18 (15.4%) of 117 studies, respectively. There was heterogeneity within each category of metric. Over 90 different names for geometric measures were used. Methods for qualitative assessment were different in all but two papers. Variation existed in the methods used to generate radiotherapy plans for dosimetric assessment. Consideration of editing time was only given in 11 (9.4%) papers. A single manual contour as a ground-truth comparator was used in 65 (55.6%) studies. Only 31 (26.5%) studies compared auto-contours to usual inter- and/or intra-observer variation. In conclusion, significant variation exists in how research papers currently assess the accuracy of automatically generated contours. Geometric measures are the most popular, however their clinical utility is unknown. There is heterogeneity in the methods used to perform clinical assessment. Considering the different stages of system implementation may provide a framework to decide the most appropriate metrics. This analysis supports the need for a consensus on the clinical implementation of auto-contouring.

Experimental Observations of Laser-Driven Tin Ejecta Microjet Interactions.

The study of high-velocity particle-laden flow interactions is of importance for the understanding of a wide range of natural phenomena, ranging from planetary formation to cloud interactions. Experimental observations of particle dynamics are sparse given the difficulty of generating high-velocity flows of many particles. Ejecta microjets are micron-scale jets formed by strong shocks interacting with imprinted surfaces to generate particle plumes traveling at several kilometers per second. As such, the interaction of two ejecta microjets provides a novel experimental methodology to study interacting particle streams. In this Letter, we report the first time sequences of x-ray radiography images of two interacting tin ejecta microjets taken on a platform designed for the OMEGA Extended Performance (OMEGA EP) laser. We observe that the microjets pass through each other unattenuated for the case of 11.7±3.2 GPa shock pressures and jet velocities of 2.2±0.5 km/s but show strong interaction dynamics for 116.0±6.1 GPa shock pressures and jet velocities of 6.5±0.5 km/s. We find that radiation-hydrodynamic simulations of the experiments are able to capture many aspects of the collisional behavior, such as the attenuation of jet velocity in the direction of propagation, but are unable to match the full spread of the strongly interacting cloud.

A Randomized Controlled Study of a Cognitive Behavioral Planning Intervention for College Students With ADHD: An Effectiveness Study in Student Counseling Services in Flanders.

Objective: The effectiveness of a short (six session) individual cognitive behavioral planning intervention for college students with attention-deficit/hyperactivity disorder (ADHD) was tested. Method: In three student counseling services in Flanders, individuals with ADHD (N = 58) were randomized to the intervention or waitlist condition. Pre- and posttreatment assessments were conducted, and within the intervention group, a 4-month follow-up was conducted. Primary outcomes were ADHD symptoms and study skills; secondary outcomes were comorbid symptoms and planning skills on a neuropsychological task. Results: Intent-to-treat analyses showed a significant interaction on one outcome: inattention symptoms. The treatment condition improved from pretest to posttest, whereas the waitlist did not. Other measures showed large significant time effects (improved skills, reduction of symptoms in both groups) but no interactions. Stability analyses were not possible due to substantial dropout at follow-up. Conclusion: Specific treatment effects are on one outcome (inattention) and modest; for further implementation, the treatment needs adaptation.

El consumo de leche posterior al ejercicio disminuye la excreción de electrolitos / Milk consumption after exercise decreases electrolyte excretion

La rehidratación es fundamental para la correcta recuperación posterior al ejercicio físico y el deporte. Las bebidas lácteas parecen ser una buena opción como bebidas rehidratantes después del ejercicio, pero aún los mecanismos no están completamente dilucidados. El presente estudio tiene por objetivo medir los efectos en la excreción de electrolitos en la orina al rehidratar con una bebida láctea baja en grasa o una bebida isotónica tras la realización de una sesión de ejercicio intermitente. 14 sujetos físicamente activos (23 ± 4 años), se dividieron en dos grupos: 1) rehidratación con bebida isotónica (ISO) y 2) rehidratación con bebida láctea baja en grasa (LBG). Se evaluó la gravedad específica de la orina (GEO), electrolitos (Na+ y K+) en orina y retención de fluidos, después del ejercicio y 4 horas posterior a la rehidratación. Se encontraron diferencias significativas en la GEO y en la excreción de K+ en el grupo LBG (p<0.005), ambos grupos muestran diferencias significativas en la excreción de Na+. Los resultados muestran que la rehidratación con bebida láctea mejora la GEO y disminuyen la excreción de K+ de forma más eficiente que la bebida isotónica posterior al ejercicio (AU)

Rehydration is essential for post-exercise and sport recovery. Milk seems to be a good option like sport drinks after exercise, yet the rehydration mechanisms are still not fully understood. The aim of this study was to measure the effect of drinking low-fat milk and an isotonic beverage after intermittent exercise on urine electrolytes. 14 physically active men (23 ± 4 y) were split into two groups: 1) rehydration with isotonic drink (ISO), and 2) rehydration with low-fat milk (LBG). Specific gravity (GEO) and electrolytes (Na+ and K+) were measured in urine before and after exercise with rehydration. Significant differences were found for the GEO and in K+ excretion in the LBG group (p <0.05). Both groups showed significant differences for Na+ excretion concentrations. We conclude that drinking low fat milk after exercise when compared to an isotonic drink, improves GEO and K excretion (AU)

Validity and reliability of aortic pulse wave velocity and augmentation index determined by the new cuff-based SphygmoCor Xcel.

Aortic pulse wave velocity (AoPWV) and augmentation index (AIx) are commonly used measures of large elastic artery stiffness and wave reflection, respectively. Recently, a new cuff-based SphygmoCor device (Xcel) has been developed to measure both AoPWV and AIx. We sought to examine the following: (1) the validity of Xcel compared with the well-validated tonometry-based SphygmoCor device (MM3); (2) the intratest and day-to-day reliability of Xcel; (3) the influence of body side (right or left) on Xcel measurements; and (4) the relation of Xcel measurements to carotid artery compliance, distensibility and ß-stiffness index. We found that measurements of AoPWV and AIx between Xcel and MM3 were not different (P=0.26 and P=0.43, N=22 and 26, respectively) and were strongly related (r=0.85 and 0.75, P<0.0001), and based on Bland-Altman plots there was good agreement between them. Intra-test (intraclass correlation=0.996 and 0.983, P<0.0001; AoPWV and AIx, N=24 and 26, respectively) and day-to-day reliability (intraclass correlation=0.979 and 0.939, P<0.0001) were high. Xcel AoPWV and AIx on the left versus right body side were not different (P=0.19 and P=0.58, N=14 and 15, respectively) and were highly correlated (r=0.99 and 0.94, P<0.0001). AoPWV and AIx measured with Xcel were positively related with ß-stiffness index (r=0.62 and 0.51, P< or = 0.005, N=23 and 24, respectively) and negatively related with distensibility (r = -0.58 and -0.44, P < or = 0.02, N=23 and 24, respectively). In conclusion, Xcel measures of AIx and AoPWV are valid, highly reliable and not affected by body side. Xcel is a useful tool for use in research and the clinic.

Whole grain wheat sourdough bread does not affect plasminogen activator inhibitor-1 in adults with normal or impaired carbohydrate metabolism.

BACKGROUND AND AIMS: Epidemiological studies suggest whole grain consumption is associated with a reduced risk of cardiovascular disease (CVD), possibly through alterations in glucose metabolism and subsequent effects on plasminogen activator inhibitor (PAI)-1, a novel biomarker for CVD. Our aim was to investigate the effect of 6 wk of whole grain wheat sourdough bread consumption versus refined white bread on PAI-1. METHODS AND RESULTS: Normoglycemic/normoinsulinemic (NGI; n = 14; age 53 ± 6 y; BMI 26.5 ± 2.9 kg/m(2)) and hyperglycemic/hyperinsulinemic (HGI; n = 14; age 57 ± 7 y; BMI 35.7 ± 5.7 kg/m(2)) adults incorporated whole grain wheat sourdough (162.5 g) or white (168.8 g) bread into their diet, for 6 wk in a randomized crossover study. Pre- and post-intervention, fasting blood samples were analyzed for PAI-1 (primary outcome), as well as glucose, insulin and glucagon (secondary outcomes) at fasting and postprandially after an oral glucose tolerance test (OGTT). Anthropometric measures, fasting glucose, insulin, glucagon and PAI-1 antigen and activity were not different between treatments in either NGI or HGI adults. Glucose incremental area under the curve (iAUC) was lower (19%, P = 0.02) after 6 wk consumption of whole grain wheat sourdough bread compared to white bread in the HGI group, with no differences in insulin or glucagon iAUC in either group. CONCLUSION: Our data showed decreased glucose iAUC after an OGTT following 6 wk whole grain wheat bread consumption in adults with differing glycemic/insulinemic status, but no improvements in PAI-1 or fasting glycemic parameters.

Rheumatoid arthritis susceptibility and interleukin 10: a study of two ethnically diverse populations.

INTRODUCTION: IL-10 is an immunoregulatory cytokine which may modulate disease expression in rheumatoid arthritis (RA). The IL-10 gene is highly polymorphic with a number of single nucleotide polymorphisms in the promoter region and two microsatellite loci, IL10.R and IL10.G, 4 kb and 1.1 kb 5' of the transcription initiation site. It has been reported that allele 2 of the IL10.R microsatellite (IL10.R2) is associated with increased IL-10 secretion and IL10.R3 with reduced secretion. Subsequently, over-representation of IL10.R2 and under-representation of IL10.R3 in three independent RA groups has been reported. The aim of the current study is to determine whether there is an association between the IL10.R2 allele and RA in two ethnically distinct populations. METHODS: IL10.R genotypes were determined by semi-automated DNA sequencing technology in 186 UK Caucasians and 138 South Africans of Zulu or Sotho origin, fulfilling the 1987 American College of Rheumatology (ACR) criteria for RA. The Caucasian patients had relatively severe disease and comprised 75 patients with RA vasculitis, 22 with Felty's syndrome and 89 who had undergone a joint replacement (hip or knee) within 15 years of the onset of disease. Allele frequencies were compared with 296 Caucasians and/or 73 South Africans. RESULTS: The frequency of the IL10.R2 allele was significantly greater in the South Africans (RA and controls) than in the Caucasians (0.78 vs 0.66, P=1 x 10(-6)), while the frequency of IL10.R3 was less common (0.16 vs 0.3, P=1 x 10(-8)). No differences were observed in either IL10.R2 or IL10.R3 frequencies between patients and controls in either population. CONCLUSIONS: We were unable to confirm any association between IL10.R alleles and RA in this study. However, significant differences were demonstrated in the frequency of IL10.R2 and IL10.R3 between the two ethnic groups. The relatively high frequency of IL10.R2 in the South African population (0.78) would have reduced the power to detect an association with RA.

Needs assessment of women with urinary incontinence in a district health authority.

BACKGROUND: The prevalence of urinary incontinence in women is difficult to estimate because definitions vary between researchers and among women, for whom thresholds of complaint differ. However, studies have also shown that only about a quarter of women affected by urinary incontinence consult a doctor for their symptoms, despite evidence of effective treatments and better management of the condition in primary care. AIM: To assess the perceived needs of women with urinary incontinence living at home. DESIGN: Cross-sectional community survey. SETTING: A 1% stratified random sample of women living at home, registered with a local GP, and aged 45 years and over (n = 720) in a north London district health authority with a total population of 308,000. RESULTS: Out of 720 questionnaires, 489 were returned completed (68%). A total of 227 (46%) women had symptoms of significant urinary incontinence. Seventy-eight (16%) had significant symptoms which they said were not a problem, and 149 (30%) of the total number of responders acknowledged that they had significant symptoms and that these symptoms were a problem for them; of these, 48 (32%) sought help from their GP; 16 out of the 48 consulting their GP were happy with the treatment given, and the remaining 101 women who considered their incontinence to be a problem had not consulted their GP and 76 of those had also not told anyone else that they had a problem. The commonest reasons given by the 101 women who admitted having a problem and who had not consulted their GPs were that they thought that they should cope on their own (43 [42.6%]), that incontinence was inevitable with age (26 [25.7%]) or that it was embarrassing to talk about the problem to their GP (14 [13.8%]). CONCLUSIONS: Despite the existence of effective interventions for urinary incontinence, many women who are incontinent do not seek help even when they perceive their incontinence to be a problem. Half of the women who did consult their GP did not find the treatment offered helpful. Achieving health gain for women with urinary incontinence will require a more active approach than currently exists to inform people that better care is available, to help counteract the stigma attached to the problem, and to ensure that primary care professionals are able to provide effective services.

Neuroprotective effects of the CRF1 antagonist R121920 after permanent focal ischemia in the rat.

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.

BMS-204352 (Bristol Myers Squibb).

BMS-204352 is a fluoro-oxindole potassium channel opener being developed by Bristol-Myers Squibb as a potential neuroprotectant for the treatment of acute ischemic stroke. Phase I trials were underway in Japan in 1998 [288541]. By July 1999, it was in phase II trials in the US [331682] and by October 2000, phase II trials had also begun in Japan [384751]. At the 219th American Chemical Society meeting in March 2000, it was reported that BMS-204352 had entered worldwide phase III trials involving patients with suspected acute stroke [362077], [361291]. In February 2001, Credit Suisse First Boston predicted sales of $111 million in 2005 [399484]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2004. The analysts predicted peak sales would occur in 2008, with sales of $500 million in the US at that time [319225].

Effect of melting point of chiral terpenes on human stratum corneum uptake.

The effect of melting point of chiral penetration enhancers on their stratum corneum uptake was investigated. The pure enantiomers of a chiral compound often possess different melting points, and therefore dissimilar solubilities, to the racemate because of variations in their crystal structure. Two terpenes, menthol and neomenthol, saturated in propylene glycol/water, were applied to stratum corneum. Racemic menthol melts at approximately 33 degrees C, some 9 degrees C lower than the pure enantiomers, whereas racemic neomenthol melts at 26 degrees C higher than the study temperature, considered as the theoretical melting point of its enantiomers, which are both liquids. Terpene solubility increased with the propylene glycol content of the vehicle. The lower melting forms of both penetration enhancers possessed the highest solubility in every vehicle. Maximum stratum corneum uptake was obtained from formulations containing the lower melting forms of each enhancer in 60% w/w propylene glycol systems (highest concentration used). Compared with menthol, the larger melting point difference between optical forms of neomenthol produced bigger differences in their uptake. Thus melting point depression of menthol and neomenthol, by selection of the appropriate optical form, increased the amount of terpene delivered to the stratum corneum, in agreement with theoretical predictions.

Dispersion and toxicity to non-target aquatic organisms of pesticides used to treat sea lice on salmon in net pen enclosures.

Pesticides are used extensively in the finfish aquaculture industry to control sea lice infestations on farmed salmon. The most prevalent method of use is to enclose a net pen with an impervious tarpaulin and mix a pesticide solution within that enclosure. After treatment for short periods (1 h) the pesticide solution is released to the environment. Concerns have been raised that there is a potential risk to non-target aquatic organisms from those releases. The fate of dispersing pesticide solutions was measured after six simulated treatments in the Lower Bay of Fundy, New Brunswick. Three simulated treatments were done with azamethiphos and three with cypermethrin. Rhodamine dye was added to all pesticide solutions in order to facilitate tracking of the dispersing plume through real-time measurements of dye concentrations by a flow-through fluorometer coupled with a differential global positioning system (DGPS). Water samples were obtained from within the plumes at various times after release and analysed for pesticide content and toxicity to a benthic amphipod Eohaustorius estuaris. Dye concentrations were detectable for time periods after release which varied from 2 to 5.5 h. Distances travelled by the dye patches ranged from 900 to 3000 m and the dye concentrations at the final sampling period were generally 1/200-1/3000 the pre-release concentrations and cypermethrin concentrations were generally 1/1000-1/2000 the pre-release concentrations. Cypermethrin concentrations in water samples were closely correlated with dye concentrations, indicating that dye analyses were an accurate surrogate for cypermethrin concentrations. Most samples taken after the releases of azamethiphos were not toxic to test organisms in 48 h exposures and none were beyond 20 min post-release. By contrast, almost all samples taken after the release of cypermethrin, even up to 5-h post-release, were toxic. Data indicate the potential to cause toxic effects over areas of hectares from a single release of cypermethrin.

Localization, anchoring, and functions of protein kinase C isozymes in the heart.

Although protein kinase C (PKC) was identified more than 20 years ago, and is involved in a wide variety of essential cellular processes, assigning specific roles to each PKC isozyme has proved difficult. Results over the last few years have suggested that much of the specificity of activated PKC isozymes is attributed to their subcellular localization bringing them into close proximity to a subset of substrates. Our laboratory has taken advantage of the importance of PKC localization and studied the way in which PKC isozymes are anchored. We have identified PKC anchoring proteins (RACKs or Receptors for Activated C Kinase) and used information about interaction sites between PKC isozymes and their respective RACKs to design peptides which modulate translocation of specific PKC isozymes to the functional site. These isozyme-specific peptides can be delivered into isolated or cultured cells or expressed in transgenic mice to determine the role of specific PKC isozymes in particular functions. Here we will describe the isozymes-specific peptide activators and inhibitors that we have developed and the specific functions of each isozyme in cardiac ventricular tissue.

Arachidonic acid protects neonatal rat cardiac myocytes from ischaemic injury through epsilon protein kinase C.

OBJECTIVES: Arachidonic acid is a second messenger which activates protein kinase C (PKC) and is released from the heart during ischaemic preconditioning. The purpose of this study was to examine the effect of arachidonic acid on activation of PKC in cardiac myocytes and the cellular consequences. METHODS: Neonatal rat cardiac myocytes were isolated and maintained in culture. Arachidonic acid-induced activation of PKC was examined by cell fractionation and western blot analysis. Contraction frequency was measured by visual inspection under a microscope. Ischaemia was simulated by subjecting cells to an atmosphere of lower than 0.5% oxygen in the absence of glucose and cell damage determined by release of cytosolic lactate dehydrogenase or direct cell viability assay. RESULTS: Arachidonic acid resulted in translocation of delta and epsilonPKC but not alpha, betaII, eta or zetaPKC isozymes, indicating activation of only delta and epsilonPKC. Arachidonic acid induced a dose-dependent decrease in spontaneous contraction rate of cardiac myocytes which was blocked by a selective peptide translocation inhibitor of epsilonPKC. Pretreatment with arachidonic acid partially protected cardiac myocytes against ischaemia. Down-regulation of PKC with 24 h 4beta-phorbol,12-myristate,13-acetate treatment, inhibition of PKC by chelerythrine and selective inhibition of epsilonPKC translocation all decreased the protective effect of arachidonic acid. Pretreatment with eicosapentaenoic acid or oleic acid also protected cardiac myocytes against ischaemia. CONCLUSIONS: These results demonstrate that arachidonic acid selectively activates delta and epsilonPKC in neonatal rat cardiac myocytes, leading to protection from ischaemia. We suggest this is a potential mechanism of PKC activation during PC. In addition, our results suggest that different classes of free fatty acid directly exert cardioprotection from ischaemic injury in cardiac myocytes.

The development and validation of a radiographic grading system for the hip in ankylosing spondylitis: the bath ankylosing spondylitis radiology hip index.

OBJECTIVE: To develop a simple but reproducible radiological scoring system for the hip in ankylosing spondylitis (AS). METHODS: A consensus approach was used to develop a grading system whereby hip radiographs of 470 patients with AS were scored from 0 to 4 (normal, suspicious, mild, moderate, and severe), producing the Bath Ankylosing Spondylitis Radiology Hip Index ( BASRI-hip or BASRI-h). The system was designed to be specific for AS radiographic change at the hip and includes circumferential joint space narrowing, osteophytes, erosions, and protrusio acetabulae. This score can then be added to the BASRI-spine, forming the grading system BASRI-total, scored 2-16. Radiographs of 134 patients were used to test reproducibility. Blinded radiographs of 100 non-AS patients were included randomly to assess disease specificity. Sensitivity to change was determined using 438 radiographs from 122 patients, over 219 time intervals. RESULTS: Inter and intraobserver variation for the right and left hip showed 83-84% and 94-96% complete agreement, respectively. Disease specificity was 0.76. If non-AS patients with a total hip replacement were excluded, disease specificity was 0.83. Sensitivity to change became apparent at one year (p < 0.001). Grading the hips using a single radiograph takes seconds. CONCLUSION: BASRI-h is a reliable method for grading hip radiographic change in AS. It is disease-specific, sensitive to change, simple to use, and rapid to perform.

Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.

Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia.

Our recent results showed that extended p38 mitogen-activated protein kinase (p38) activation during ischemia leads to cell death, at least partly through apoptosis, in neonatal rat cardiomyocytes. However, other studies have shown that p38 activation during a short preconditioning treatment protects cardiomyocytes from ischemic cell death. This suggests that the duration of p38 activation determines its cellular function and therefore inactivation of p38 by phosphatases may play an important role. In neonatal rat cardiomyocytes, we used the tyrosine phosphatase inhibitor, vanadate, to prevent p38 inactivation, thus extending the strength and length of p38 activation during ischemia. This resulted in higher susceptibility to cell death from ischemia in a dose-dependent manner and over time; the additional damage induced by vanadate was inhibited by SB203580, a selective inhibitor of p38. We conclude that a tyrosine phosphatase is inactivated during ischemia, resulting in prolonged p38 activation which causes cell death.