Epididymitis was diagnosed in three rams in a commercial sheep flock in southern Ontario. The affected rams had palpably enlarged epididymides and two rams had semen which contained inflammatory cells and was of poor quality. Serum compliment fixation titers for Brucella ovis were 1:20, 1:80 and 1:90. Five other rams in the flock were clinically normal and without titers. Two of the affected rams had lesions similar to those produced by experimental infection with B. ovis. The infection in the rams had no apparent affect on ewe performance. The source of the infection remains unknown, but the rams were purchased from a flock which had imported ewes from the western U.S.A.

Use of a cell culture model of a specific epithelium requires documentation of its differentiation. This study reports permeability of mannitol concurrent with a profile of differentiation markers of filter-grown TR146 cells, a cell line originating from a human buccal carcinoma, cultivated submerged or at the air-liquid interface for 23 to 31 d. A multilayered squamous epithelial-like tissue was found. The maximal permeability barrier and the most distinct stratification were obtained at day 23, when cultured submerged (apparent permeability coefficient 4.08 +/- 0.15 (x 10(-6)) cm/s; transepithelial electrical resistance 102 +/- 5 omega x cm2). The profile of differentiation markers demonstrated similarities to normal human buccal epithelium by expression of K4, K10, K13, K16, and K19 keratins, plasma membrane-associated transglutaminase, involucrin, and epidermal growth factor receptor. Uniform expression of K5, K8 and K18 was consistent with the carcinogenic origin of TR146 cells. Identical profiles of differentiation markers were obtained irrespective of method or time of culture. Karyotyping proved the human origin of TR146 cells. Three different passages had near triploid (3n+-) chromosome compliments and consistent occurrence of four marker chromosomes [mar4, mar5, mar9, and add(5)(p)], while differences between them defined them as subclones. The results indicate that a submerged filter-grown TR146 cell culture at day 23 of culture has the potential to model the human buccal epithelial barrier for permeation of drugs.

Complement-dependent cytotoxicity (CDC) mediated by a chimeric anti-Lewis Y monoclonal antibody (cH18A; human IgG1) was investigated in this study. Human lung adenocarcinoma cell lines (PC7, PC9, and PC14) were used as the target cells. PC7 and PC9 cells, expressed Lewis Y antigen and were lysed by cH18A as effectively as by the parent mouse anti-Lewis Y antibodies (mH18A) in a concentration-dependent manner. PC14 cells did not express Lewis Y antigen and were not lysed by either cH18A or mH18A. cH18A mediated CDC activity against PC7 and PC9 cells was enhanced by the combined use of monoclonal antibodies directed against CD46(MCP), CD55(DAF), and CD59. These molecules are complement-regulatory proteins which protect host cells from CDC. PC7 and PC9 cells, showed high levels of surface expression of these proteins, PC7 cells were more susceptible to cH18A-mediated CDC than PC9 cells. Use of multiple blocking antibodies to the complement-regulatory proteins produced more enhancement of cH18A-mediated CDC than a single antibody. Moreover, expression of CD55 and CD59 by PC7 and PC9 cells was decreased after treatment with PI-PLC, resulting in increased susceptibility to cH18A-mediated CDC. Although the reason is unknown, PC7 cells became more susceptible to CDC than PC9 cells after PI-PLC treatment even in the absence of cH18A. These data suggest that chimeric monoclonal antibodies can be used to induce CDC against lung adenocarcinoma, and that such CDC is potentiated by a variety of antibodies blocking compliment-regulatory proteins on the tumour cell surface.

BACKGROUND

Identifying previously unrecognized adverse drug reactions (signals) is an important part of post-marketing surveillance. Automated signal generation now forms part of routine surveillance of spontaneous adverse drug reactions reported to the UK Yellow Card system. The Drug Safety Research Unit (DRSU) provides an additional post-marketing drug surveillance scheme in the UK, using the non-interventional observational cohort technique of Prescription-Event Monitoring (PEM), and systematically collects data on patients who were prescribed selected newly licensed drugs in primary care clinical practice. The introduction of a new computer system in January 2000 enabled the development of an automated signal generation system to compliment the process of identification of possible safety signals in drug data collected using PEM.

OBJECTIVE

To use incidence rate ratios (IRRs) as a form of signal generation in the DSRU database, with particular interest in rofecoxib, plus further evaluation of any signal(s) of interest by requesting additional information from the general practioner (GP) of each relevant case.

METHODS

Crude IRRs were calculated for each event term of interest by comparing the incidence rate for each lower term event reported in rofecoxib users with the comparable incidence rate for the whole PEM database (77 drugs of various therapeutic classes) from the total person-exposure time up to 180 days after starting the drug. To investigate a possible class effect, IRRs were also calculated using a second comparator cohort including only those PEM study drugs within the same therapeutic class (non-steroidal anti-inflammatory drugs, NSAIDs) and used for similar indications. Cases arising out of potential signals were followed up for additional information.

RESULTS

A potential signal of 'colitis' was identified when rofecoxib was compared with the rest of the database, IRR 5.8 (95% CI 2.7,11.3; z statistic 5.6), and when the comparator group was changed to include only the other four NSAIDs, IRR 4.3 (95% CI 1.4,14.5; z statistic 2.8). Other possible signals, compared with the rest of the database, included events deemed to be related to the underlying condition, labelled adverse events and events describing effectiveness of treatment. Further evaluation of this signal revealed that there were 11 reports of colitis (two reports for one patient) that occurred while taking rofecoxib and within 180 days of exposure. A causality assessment for these 10 patients did not confirm an association with newly developing colitis, but showed that the events were 'possible' exacerbations of pre-existing colitis during treatment with rofecoxib.

CONCLUSIONS

The use of IRRs for signal generation using PEM data is worthwhile and enables time to be taken into account. Previously unrecognized adverse events require further evaluation to confirm that a possible safety signal exists. In this study, the number of patients reported to have colitis was small but compared with other drugs on the database, the incidence rate was relatively high. Follow-up revealed a possible relationship between exacerbation of pre-existing colitis and treatment with rofecoxib. Hypotheses arising from signal generation require evaluation and cannot be taken as a conclusive evidence for clinical differences in the safety profiles of drugs.

To investigate Brucella infection in cattle, sheep, goat, reindeer and yak in Mongolia, serological reactions of Brucella-infected and -vaccinated domestic animals were compared by the agar gel immunodiffusion (AGID) test with a polysaccharide (poly-B) of the B. Abortus strain S-19. The sensitivity and specificity were compared with conventional serological tests that are commonly used in Mongolia, such as the rose Bengal test, the tube agglutination test and the compliment fixation test. A total of 73.3, 100, 100, 95.8 and 61.9% of the sera from suspected cattle, yak, goat, sheep and reindeer, respectively, that were positive in the compliment fixation test, were also positive in the AGID test. Sera from vaccinated cattle, sheep and goat were positive over 90% by conventional tests 3 months after vaccination, but were negative by the AGID. These results suggest that the AGID test may be useful to differentiate infected and vaccinated animals in the field.

Nineteen patients with symptoms of chronic venous insufficiency (CVI) were treated with 13-week cycles of intermittent pneumatic compression (IPC) during 2 h sessions twice weekly, with most treatments at home. At study completion, quantitative subjective scores for total symptomatology were improved in 16/19 patients (84%). Enhancement of fibrinolytic potential in vivo was detected in 86% of observations on specimens from CVI patients over 2 h of IPC, with accelerated euglobulin clot lysis times (ELT) noted within 15 min of initiating compression. The enhanced fibrinolytic potential was attributed to increased urokinase plasminogen activator (u-PA), probably released from perturbed endothelial cells by IPC. Significant decreases in total t-PA antigen (mass concentration) but not t-PA activity, were produced by IPC in CVI patients only (P = 0.0001), with greater effects noted in the non-anticoagulated versus the anticoagulated cohort. Plasminogen activator inhibitor type 1 (PAI-1) levels rose rapidly after IPC only in the controls and non-anticoagulated CVI patients. PAI-1 decreased in those receiving anticoagulation. No platelet perturbation was detected during IPC by measuring levels of beta-thromboglobulin or the thromboxane A2 metabolite, 11-dehydrothromboxane B2; however, significant (P < 0.003) decreases in plasma prostacyclin (PGI2) levels (measured as the stable 6-ketoprostaglandin F-1-alpha-metabolite) were observed after 15 min of IPC in non-anticoagulated CVI patients only. There was no evidence of increased thrombin generation by IPC, determined by urinary excretion of fibrinopeptide A and prothrombin fragment 1. Concurrent anticoagulation appears to mediate more favorable biochemical alterations in CVI, although subjective improvement did not correlate with anticoagulation. The mechanism(s) by which these physiologic changes compliment the mechanical effects of IPC remain to be elucidated and will require adequately controlled and powered studies.

BACKGROUND

The proteins of the complement cascade play an important role in inflammation and the immune response. They have been shown to be activated during cardiopulmonary bypass (CPB), and may be responsible for the inflammatory response to CPB. We looked at the effect of APT070, an anti-complement agent, on human blood during in vitro CPB.

METHODS

Four hundred millilitres of blood was venesected from healthy human volunteers and heparinised. To the blood was added either APT070 to a concentration of 50 microg/ml (n=5) or vehicle control (n=4). The blood was entered into an in vitro CPB circuit and circulated for 90 min.

RESULTS

Our results showed that after 90 min of in vitro bypass APT070 significantly inhibited the activation of compliment as demonstrated by C3a (p=0.03) and sC5b-9 (p=0.01) levels, and reduced neutrophil stimulation as measured by CD11b expression (p=0.04 at 90 min).

CONCLUSIONS

APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.

OBJECTIVE

Q-switched laser therapy is commonly used for the removal of tattoos. However, despite ever increasing demand for this intervention, a better understanding of the mechanisms that result in pigment reduction is required in order to optimise outcomes and reduce the number of treatment episodes.

METHODS

A finite element analysis computer simulation was developed to model the fragmentation response of ink granules during irradiation of a professional black tattoo using a Q-switched Nd:YAG laser. Thermal and acoustic mechanisms were considered, allowing the optimal laser settings to be predicted throughout the course of treatment. Changes in the thermal properties of the ink during heating were taken into account to improve the reliability of the results obtained.

RESULTS

The simulated results are in close agreement with clinical observations. Thermal fragmentation was shown to be the dominant mechanism in pigment reduction when using a 6 nanoseconds pulse at 1,064 nm. In order to provide maximum clearance whilst maintaining acceptable levels of tissue thermal damage, later treatments were shown to benefit from higher fluence levels than initial treatments. Larger spot diameters were also preferable throughout the course of treatment.

CONCLUSIONS

The results from the simulation build upon previous work carried out in the field, applying ink thermal coefficients which vary with temperature for the first time. These results compliment clinical knowledge, suggesting that a proactive increase in fluence during a course of treatments is likely to improve the response to laser therapy.

This qualitative study explored how young people (16- to 24-year olds), both smokers and non-smokers, talk about the social role of smoking in their everyday lives. In 22 focus group interviews, 47 high school children and 40 university undergraduates participated. On the basis of analyses, it is proposed that the perceived need to smoke cannot be reduced to addiction; cigarettes appear to play a complex social role in young people's lives. In order to resist smoking, participants highlighted the need to provide an excuse to peers, and some reasons (e.g. an interest in sport for boys) were considered more legitimate than others. Cigarettes (certain brands) were also claimed to be used as a way of controlling other people's perception of smokers, and also to serve as a social tool (for instance, to fill in awkward gaps in conversation). Additionally, smoking was argued to be subject to context (e.g. some schools possess a pro-smoking ethic, while others and universities are anti-smoking). Finally, it was claimed that stopping smoking is difficult since all of the foregoing social factors cannot easily be avoided. The findings of this study compliment and enrich existing social psychological approaches to smoking in young people, and lay the basis for anti-smoking campaigns which take into account the complex social role cigarettes play in the lives of young people.

beta-Secondary deuterium isotope effects have been measured for equine serum butyrylcholinesterase-catalyzed hydrolysis of acetyl-L(3)-thiocholine (L=H or (2)H). The dependencies of initial rates on isotopic substrate concentrations show close adherence to Michaelis-Menten kinetics, and yield the following isotope effects: (D3)k(cat)/K(m)=0.98+/-0.02 and (D3)k(cat)=1.10+/-0.02. The modestly inverse isotope effect on k(cat)/K(m) is consistent with partial rate limitation by a step that converts the sp(2)-hybridized ester carbonyl of the E+A reactant state into a quasi-tetrahedral transition state in the acylation stage of catalysis. On the other hand, the markedly normal isotope effect on k(cat) indicates that the Michaelis complex that accumulates at substrate saturation of the active site during catalytic turnover is a tetrahedral intermediate, whose decomposition is the rate-limiting step. These results compliment a previous report [J.R. Tormos et al., J. Am. Chem. Soc. 127 (2005) 14538-14539] that showed that substrate-activated hydrolysis of acetylthiocholine (ATCh), catalyzed by recombinant human butyrylcholinesterase, is also rate limited by decomposition of an accumulating tetrahedral intermediate.

In this article we develop an extension to the signal detection theory framework to separately estimate internal noise arising from representational and decision processes. Our approach constrains signal detection theory models with decision noise by combining a multipass external noise paradigm with confidence rating responses. In a simulation study we present evidence that representation and decision noise can be separately estimated over a range of representative underlying representational and decision noise level configurations. These results also hold across a number of decision rules and show resilience to rule miss-specification. The new theoretical framework is applied to a visual detection confidence-rating task with 3 and 5 response categories. This study compliments and extends the recent efforts of researchers (Benjamin, Diaz, & Wee, 2009; Mueller & Weidemann, 2008; Rosner & Kochanski, 2009; Kellen, Klauer, & Singmann, 2012) to separate and quantify underlying sources of response variability in signal detection tasks.

Existent rigid unit mode (RUM) models based on rotating squares, which may explain the phenomenon of negative thermal expansion (NTE), are generalized so as to assess the NTE potential for novel systems made from rectangular or rhombic rigid units. Analytical models for the area coefficients of thermal expansion (CTE) of these innovative networks are derived in an attempt to determine the optimal geometrical parameters and connectivity for maximum NTE. It was found that all systems exhibit NTE, the extent of which is determined by the shape and connectivity of the elemental rigid units (side lengths ratio or internal angle). It was also found that some of the networks proposed here should exhibit significantly superior NTE properties when compared with the well-known network of squares, and that for optimal NTE characteristics, pencil-like rigid units should be used rather than square-shaped ones, as these permit larger pore sizes that are more conducive to NTE. All this compliments earlier work on the negative Poisson's ratio (auxetic) potential of such systems and may provide a route for the design of new materials exhibiting superior thermo-mechanical characteristics including specifically tailored CTEs or giant NTE characteristics.

OBJECTIVE

Peer feedback is well placed to play a key role in satisfying educational and governance standards in general practice. Although the participation of general practitioners (GPs) as reviewers of evidence will be crucial to the process, the professional, practical and emotional issues associated with peer review are largely unknown. This study explored the experiences of GP reviewers who make educational judgements on colleagues' significant event analyses (SEAs) in an established peer feedback system.

METHODS

Focus groups of trained GP peer reviewers in the west of Scotland. Interviews were taped, transcribed and analysed for content.

RESULTS

Consensus on the value of feedback in improving SEA attempts by colleagues was apparent, but there was disagreement and discomfort about making a dichotomous 'satisfactory' or 'unsatisfactory' judgement. Differing views on how peer feedback should be used to compliment the appraisal process were described. Some concern was expressed about professional and legal obligations to colleagues and to patients seriously harmed as a result of significant events. Regular training of peer reviewers using several different educational methods was thought essential in enhancing or maintaining their skills. Involvement of the participants in the development of the feedback instrument and the peer review system was highly valued and motivating.

CONCLUSIONS

Acting as a peer reviewer is perceived by this group of GPs to be an important professional duty. However, the difficulties, emotions and tensions they experience when making professional judgements on aspects of colleagues' work need to be considered when developing a feasible and rigorous system of educational feedback. This is especially important if peer review is to facilitate the 'external verification' of evidence for appraisal and governance.

Age-related macular degeneration (AMD) is a major cause of visual impairment that affects the central retina. Genome wide association studies and candidate gene screens have identified members of the complement pathway as contributing to the risk of AMD. In this review, we discuss the complement system, its importance in retinal development and normal physiology, how its dysregulation may contribute to disease, and how it might be targeted to prevent damage to the aging choriocapillaris in AMD.

Several studies suggest that activation of compliment cascade contributes to the development of the inflammatory immune response in ischemic stroke and results in tissue injury by initiating apoptosis and necrosis. It is proposed that suppression of the compliment activation may have positive effect on stroke severity and outcome. However, the majority of data relevant to involvement of the compliment in the pathogenethic mechanisms of stroke have been obtained in animal models of stroke that does not allow to extrapolate these data to humans. Our previous studies were the first ones demonstrated the involvement of both the classical and the alternative complement activation pathways in the pathogenetic mechanisms of generation and development of stroke in humans. In the present work, using immunoblotting, we determined the levels of key components of the classical and alternative pathways of complement activation, C3 and factor B, in the blood of patients with ischemic stroke. Comparing to healthy controls, patients with ischemic stroke are characterized by the increased level of C3 and decreased level of factor B.

Displaying compassion, benevolence and respect, and preserving the dignity of patients are important for any healthcare professional to ensure the provision of high quality care and patient outcomes. This paper presents a structured search and thematic review of the research evidence relating to values-based recruitment within healthcare. Several different databases, journals and government reports were searched to retrieve studies relating to values-based recruitment published between 1998 and 2013, both in healthcare settings and other occupational contexts. There is limited published research related to values-based recruitment directly, so the available theoretical context of values is explored alongside an analysis of the impact of value congruence. The implications for the design of selection methods to measure values is explored beyond the scope of the initial literature search. Research suggests some selection methods may be appropriate for values-based recruitment, such as situational judgment tests (SJTs), structured interviews and multiple-mini interviews (MMIs). Personality tests were also identified as having the potential to compliment other methods (e.g. structured interviews), as part of a values-based recruitment agenda. Methods including personal statements, references and unstructured/'traditional' interviews were identified as inappropriate for values-based recruitment. Practical implications are discussed in the context of values-based recruitment in the healthcare context. Theoretical implications of our findings imply that prosocial implicit trait policies, which could be measured by selection tools such as SJTs and MMIs, may be linked to individuals' values via the behaviours individuals consider to be effective in given situations. Further research is required to state this conclusively however, and methods for values-based recruitment represent an exciting and relatively unchartered territory for further research.

The educational and research implications of defining mental retardation as a self-regulatory disorder were explored. Behavioral, social-learning, and cognitive conceptualizations regarding the structure and development of self-regulation were examined. Emphasis was placed on showing how these conceptualizations compliment each other. Several perspectives were presented, specifically, that both the essential components of the self-regulatory system along with the environments that promote self-regulated behavior must be isolated. Self-regulation was described as a complex skill that develops like other skills and can be taught through behavioral techniques. Self-regulation was suggested to basically be a linguistically guided process. The assertion was made that individuals with retardation, because of their extensive language deficiencies, are delayed in developing self-regulatory control. The role of life experience and motivational processes in the development of self-regulation was also stressed.

Recent advances in medical imaging are beginning to allow us to quantify brain tissue maturation in the growing human brain prior to normal term age, and are beginning to shed new light on early human brain growth. These advances compliment the work already done in cellular level imaging in animal and post mortem studies of brain development. The opportunities for collaborative research that bridges the gap between macroscopic and microscopic windows on the developing brain are significant. The aim of this paper is to provide a review of the current research into MR imaging of the living fetal brain with the aim of motivating improved interfaces between the two fields. The review begins with a description of faster MRI techniques that are capable of freezing motion of the fetal head during the acquisition of a slice, and how these have been combined with advanced post-processing algorithms to build 3D images from motion scattered slices. Such rich data has motivated the development of techniques to automatically label developing tissue zones within MRI data allowing their quantification in 3D and 4D within the normally growing fetal brain. These methods have provided the basis for later work that has created the first maps of tissue growth rate and cortical folding in normally developing brains in-utero. These measurements provide valuable findings that compliment those derived from post-mortem anatomy, and additionally allow for the possibility of larger population studies of the influence of maternal environmental and genes on early brain development.

BACKGROUND

In Aotearoa/New Zealand cervical screening programmes have reduced cervical cancer; however, half of cervical cancer cases among Pacific women are found among clients who had not attended cervical screening. Hence, we set out to determine health provider perspectives on barriers that prevent their services reaching Pacific women within Aotearoa/New Zealand.

METHODS

Twenty semi-structured interviews were conducted with health care providers, Pap smear takers and community workers in the Wellington region. Participants were asked their views on factors that enabled and/or constrained the participation of Pacific women in their cervical screening services.

RESULTS

Six interrelated themes influencing participation in cervical screening among Pacific women in the Wellington region were apparent: the funding and practice of service delivery; family always coming first; the cost of screening services; type of employment; the appropriateness of information; and attitudes to self and screening.

CONCLUSIONS

Determining specific ethnic group actual health needs and meeting them contributes to overall improvement in New Zealand's health status. The results identified the need for improvements to the delivery of screening services including adapting cervical screening services to the requirements of Pacific women through more outreach services at alternate clinic hours; culturally appropriate practitioners; the ability to take up opportunities for health checks and foster long-term relationships; as well as appropriate monitoring and evaluation of approaches. Funding and reporting relationships also need to be compatible with the goal of improving outcomes for Pacific women. Further research into client voices for their particular needs to compliment the service provider perspective as well as minority groups is called for.

The utility of extracellular microstimulation as an ancillary tool to compliment cross-correlation analyses is explored. This technique aims at demonstrating the "sufficiency' of the spike train generated by the "reference' neuron in eliciting spikes in the "target' neuron. It involves activating the reference neuron with very low-intensity current pulses (1-10 microA) delivered through the recording microelectrode. Microstimulation can provide independent evidence that can either support or refute notions of synaptic connectivity generated by correlation analyses. Data are presented from antidromically identified descending corticofugal neurons and putative inhibitory interneurons of S1 "barrel' cortex of the rabbit and from simultaneously recorded neurons in the topographically aligned "barreloid' of ventroposterior medial thalamus (VPM). A very strong relationship was seen between brief, statistically significant peaks in the cross-correlograms (CCGs) suggestive of monosynaptic excitatory input and the responses of cortical neurons to VPM microstimulation. Thus, 18/19 cortical neurons that responded to microstimulation pulses of < 6 microA showed a significant CCG with the VPM neuron. Conversely, each of 16 cortical neurons that failed to respond at 10 microA also failed to show a significant CCG. CCGs compiled from independent data sets collected before and after hundreds of microstimulation pulses were very similar, showing that such stimulation can be relatively benign. The method has many limitations, which are discussed. The most serious problem is that the effects of extracellular current pulses cannot be limited to the reference neuron. Nevertheless, microstimulation can provide independent experimental support or refutation of hypotheses of synaptic connectivity that are generated by cross-correlation analyses. In addition, since the technique is rapidly implemented and has considerable power to predict significant cross-correlations, it can be useful in deciding which neuron pairs to study when limited time is available for data collection.

BACKGROUND

Clinical trials of the RTS,S malaria vaccine have completed Phase III and the vaccine is on track for registration. Before making decisions about implementation, it is essential to prepare the ground for introducing the vaccine by assessing awareness and willingness to use malaria vaccines and to provide policy makers with evidence-based information on the best strategies to engage communities to manage the introduction of malaria vaccine in Tanzania.

METHODS

In November 2011, as part of a large cross-sectional study of all 23 regions of Tanzania (mainland Tanzania and Zanzibar) was conducted during Tanzanian Integrated Measles Campaign (IMC) survey. In this study, the variables of interests were awareness and willingness to use a malaria vaccine. The main outcome measure was willingness to use a malaria vaccine. Logistic regression was used to examine the influence of predictive factors.

RESULTS

A representative sample of 5502 (out of 6210) women, aged 18 years or older and with children under 11 months old, was selected to participate, using random sampling probability. Awareness of the forthcoming malaria vaccine, 11.8 % of participants in mainland Tanzania responded affirmatively, compared to 3.4 % in Zanzibar (p value <0.0001). 94.5 % of all respondents were willing to vaccinate their children against malaria, with a slight difference between mainland Tanzania (94.3 %) and Zanzibar (96.8 %) (p value = 0.0167).

CONCLUSIONS

Although mothers had low awareness and high willingness to use malaria vaccine, still availability of malaria vaccine RTS,S will compliment other existing malaria interventions and it will be implemented through the Immunization, Vaccines and Biologicals (IVB) programme (formerly EPI). The information generated from this study can aid policy makers in planning and setting priorities for introducing and implementing the malaria vaccine.

Accelerometry provides information on habitual physical capability that may be of value in the assessment of function in Duchenne muscular dystrophy. This preliminary investigation describes the relationship between community ambulation measured by the StepWatch activity monitor and the current standard of functional assessment, the 6-minute walk test, in ambulatory boys with Duchenne muscular dystrophy (n = 16) and healthy controls (n = 13). All participants completed a 6-minute walk test and wore the StepWatch™ monitor for 5 consecutive days. Both the 6-minute walk test and StepWatch accelerometry identified a decreased capacity for ambulation in boys with Duchenne compared to healthy controls. There were strong, significant correlations between 6-minute walk distance and all StepWatch parameters in affected boys only (r = 0.701-0.804). These data proffer intriguing observations that warrant further exploration. Specifically, accelerometry outcomes may compliment the 6-minute walk test in assessment of therapeutic interventions for Duchenne muscular dystrophy.

Delayed xenograft rejection (DXR) remains a major obstacle in discordant xenotransplantation. As strategies of complement inhibition and xenogeneic natural antibody (Ab) removal have been shown to give prolonged xenograft survival, we endeavored to determine whether combining these two strategies would lead to an additive effect in terms of graft survival. The study was initiated with two groups, A and B, where group A received normal kidneys and group B received hCD55 transgenic kidneys. Both groups underwent pre-transplant (day-1) total immunoglobulin (Ig) immunoadsorption (IA) and received an immunosuppression of cyclophosphamide, cyclosporine A, mycophenolate mofetil and corticosteroids. Two subsequent groups (C and D) receiving hCD55 transgenic pig kidneys were then performed with an 'optimized' immunosuppression (Cyclophosphamide starting 1 day earlier) but only group D recipients were immunoadsorbed. Biopsies taken during the post-transplantation period were analyzed for Ab deposition, compliment activation and cellular infiltration. No hyperacute rejection was observed. In the initial immunoadsorbed groups A and B, all baboons underwent DXR, which started surprisingly early (day 5 in most cases. In the subsequent two groups, the immunoadsorbed group D baboons also underwent DXR, again as early as day 5. In contrast, group C baboons did not show any signs of DXR on their day 6 biopsy or at their time of death. Analysis of graft biopsies from the kidneys undergoing rejection or with stable function showed strong deposition of anti-Gal IgM in all cases whereas strong complement C5b-9 deposits were only observed in biopsies at rejection. Cellular infiltration consisted mostly of monocytes/macrophages, was more pronounced in biopsies taken at rejection and was associated with a pro-inflammatory environment involving interleukins 1alpha, 6 and 8. Our findings suggest non-specific Ig (anti-Gal and non-Gal Ig of all isotypes) IA or even incomplete IA in immunosuppressed baboon recipients of transgenic pig kidneys is detrimental to graft survival by being associated with an Ab and compliment driven rejection. We speculate that the IA were insufficient in terms of Ig depletion or frequency inducing an Ab rebound or that this total Ig depletion also removed components facilitating graft survival.

OBJECTIVE

Computed tomography (CT) scanning continues to be an important modality for the diagnosis of injury and disease, most notably for indications of the head and abdomen. (1) According to a recent report published by the Canadian Institutes of Health Information, (1) there were about 10.3 scanners per million people in Canada as of January 2004. Ontario had the fewest number of CT scanners per million compared to the other provinces (8 CT scanners per million). The wait time for CT in Ontario of 5 weeks approaches the Canadian median of 6 weeks. This health technology and policy appraisal systematically reviews the published literature on multidetector CT (MDCT) angiography as a diagnostic tool for the newest indication for CT, coronary artery disease (CAD), and will apply the results of the review to current health care practices in Ontario. This review does not evaluate MDCT to detect coronary calcification without contrast medium for CAD screening purposes.

METHODS

Compared with conventional CT scanning, MDCT can provide smaller pieces of information and can cover a larger area faster. (2) Advancing MDCT technology (8, 16, 32, 64 slice systems) is capable of producing more images in less time. For general CT scanning, this faster capability can reduce the time that patients must stay still during the procedure, thereby reducing potential movement artefact. However, the additional clinical utility of images obtained from faster scanners compared to the images obtained from conventional CT scanners for current CT indications (i.e., non-moving body parts) is not known. There are suggestions that the new fast scanners can reduce wait times for general CT. MDCT angiography that utilizes a contrast medium, has been proposed as a minimally invasive replacement to coronary angiography to detect coronary artery disease. MDCT may take between 15 to 45 minutes; coronary angiography may take up to 1 hour. Although 16-slice and 32-slice CT scanners have been available for a few years, 64-slice CT scanners were released only at the end of 2004.

METHODS

There are many proven, evidence-based indications for conventional CT. It is not clear how MDCT will add to the clinical utility and management of patients for established CT indications. Therefore, because cardiac imaging, specifically MDCT angiography, is a new indication for CT, this literature review focused on the safety, effectiveness, and cost-effectiveness of MDCT angiography compared with coronary angiography in the diagnosis and management of people with CAD. This review asked the following questions: Is the most recent MDCT angiography effective in the imaging of the coronary arteries compared with conventional angiography to correctly diagnose of significant >> 50% lumen reduction) CAD?What is the utility of MDCT angiography in the management and treatment of patients with CAD?How does MDCT angiography in the management and treatment of patients with CAD affect longterm outcomes?The published literature from January 2003 to January 31, 2005 was searched for articles that focused on the detection of coronary artery disease using 16-slice CT or faster, compared with coronary angiography. The search yielded 138 articles; however, 125 were excluded because they did not meet the inclusion criteria (comparison with coronary angiography, diagnostic accuracy measures calculated, and a sample size of 20 or more). As screening for CAD is not advised, studies that utilized MDCT for this purpose or studies that utilized MDCT without contrast media were also excluded. Overall, 13 studies were included in this review.

RESULTS

The published literature focused on 16-slice CT angiography for the detection of CAD. Two abstracts that were presented at the 2005 European Congress of Radiology meeting in Vienna compared 64-slice CT angiography with coronary angiography. The 13 studies focussing on 16-slice CT angiography were stratified into 2 groups: Group 1 included 9 studies that focused on the detection of CAD in symptomatic patients, and Group 2 included 4 studies that examined the use of 16-slice CT angiography to detect disease progression after cardiac interventions. The 2 abstracts on 64-slice CT angiography were presented separately, but were not critically appraised due to the lack of information provided in the abstracts. 16-SLICE COMPUTED TOMOGRAPHY ANGIOGRAPHY: The STARD initiative to evaluate the reporting quality of studies that focus on diagnostic tests was used. Overall the studies were relatively small (fewer than 100 people), and only about one-half recruited consecutive patients. Most studies reported inclusion criteria, but 5 did not report exclusion criteria. In these 5, the patients were highly selected; therefore, how representative they are of the general population of people with suspicion if CAD or those with disease progression after cardiac intervention is questionable. In most studies, patients were either already taking, or were given, β-blockers to reduce their heart rates to improve image quality sufficiently. Only 6 of the 13 studies reported interobserver reliability quantitatively. The studies typically assessed the quality of the images obtained from 16-slice CT angiography, excluded those of poor quality, and compared the rest with the gold standard, coronary angiography. This practice necessarily inflated the diagnostic accuracy measures. Only 3 studies reported confidence intervals around their measures. Evaluation of the studies in Group 1 reported variable sensitivity, from just over 60% to 96%, but a more stable specificity, at more than 95%. The false positive rate ranged from 5% to 8%, but the false negative rate was at best under 10% and at worst about 30%. This means that up to one-third of patients who have disease may be missed. These patients may therefore progress to a more severe level of disease and require more invasive procedures. The calculated positive and negative likelihood ratios across the studies suggested that 16-slice CT angiography may be useful to detect disease, but it is not useful to rule out disease. The prevalence of disease, measured by conventional coronoary angiography, was from 50% to 80% across the studies in this review. Overall, 16-slice CT angiography may be useful, but there is no conclusive evidence to suggest that it is equivalent to or better than coronary angiography to detect CAD in symptomatic patients. In the 4 studies in Group 2, sensitivity and specificity were both reported at more than 95% (except for 1 that reported sensitivity of about 80%). The positive and negative likelihood ratios suggested that the test might be useful to detect disease progression in patients who had cardiac interventions. However, 2 of the 4 studies recruited patients who had been asymptomatic since their intervention. As many of the patients studied were not symptomatic, the relevance of performing MDCT angiography in the patient population may be in question. 64-SLICE COMPUTED TOMOGRAPHY ANGIOGRAPHY: An analysis from the interim results based on 2 abstracts revealed that 64-slice CT angiography was insufficient compared to coronary angiography and may not be better than 16-slice CT angiography to detect CAD.

CONCLUSIONS

Cardiac imaging is a relatively new indication for CT. A systematic review of the literature was performed from 2003 to January 2005 to determine the effectiveness of MDCT angiography (16-slice and 64-slice) compared to coronary angiography to detect CAD. At the time of this report, there was no published literature on 64-slice CT for any indications. Based on this review, the Medical Advisory Secretariat concluded that there is insufficient evidence to suggest that 16-slice or 64-slice CT angiography is equal to or better than coronary angiography to diagnose CAD in people with symptoms or to detect disease progression in patients who had previous cardiac interventions. An analysis of the evidence suggested that in investigating suspicion of CAD, a substantial number of patients would be missed. This means that these people would not be appropriately treated. These patients might progress to more severe disease and possibly more adverse events. Overall, the clinical utility of MDCT in patient management and long-term outcomes is unknown. Based on the current evidence, it is unlikely that CT angiography will replace coronary angiography completely, but will probably be used adjunctively with other cardiac diagnostic tests until more definitive evidence is published. If multi-slice CT scanners are used for coronary angiography in Ontario, access to the current compliment of CT scanners will necessarily increase wait times for general CT scanning. It is unlikely that these newer-generation scanners will improve patient throughput, despite the claim that they are faster. Screening for CAD in asymptomatic patients and who have no history of ischemic heart disease using any modality is not advised, based on the World Health Organization criteria for screening. Therefore, this review did not examine the use of multi-slice CT for this purpose.