Health economic evaluation: cost-effective strategies in humanitarian and disaster relief medicine.

The health economic evaluation is a tool used in disaster relief medicine to generate a cost-benefit analysis. Like all areas of healthcare, disaster relief operations must use finite financial resources, much of which comes from charitable donations and foreign aid. Interventions can be assessed using cost-effectiveness tools and equity assessments. Through these tools, interventions that maximise benefit for a given cost are highlighted in the immediate rapid response phase where food, clean water and shelter are prioritised, often with military support. Beyond this, applications of technology and pre-response training are discussed as cost-effective investments made in anticipation of a disaster. In particular, novel technology-based approaches are being explored to deliver medical advice remotely through telemedicine and remote consulting. This strategy allows medical specialists to operate remotely without the logistical and financial challenges of forward basing at the disaster site. Interventions in disaster relief medicine are often expensive. A specific and regularly reviewed health economic assessment ensures that healthcare interventions yield a maximal impact while limiting waste and working within the budgetary constraints of a disaster medicine response. This is a paper commissioned as part of the humanitarian and disaster relief operations special issue of BMJ Military Health.

Characterization of the Sheep Round Window Membrane.

Intratympanic injection is a clinically used approach to locally deliver therapeutic molecules to the inner ear. Drug diffusion, at least in part, is presumed to occur through the round window membrane (RWM), one of the two openings to the inner ear. Previous studies in human temporal bones have identified a three-layered structure of the RWM with a thickness of 70-100 µm. This is considerably thicker than the RWM in rodents, which are mostly used to model RWM permeability and assess drug uptake. The sheep has been suggested as a large animal model for inner ear research given the similarities in structure and frequency range for hearing. Here, we report the structure of the sheep RWM. The RWM is anchored within the round window niche (average vertical diameter of 2.1 ± 0.3 mm and horizontal diameter of 2.3 ± 0.4 mm) and has a curvature that leans towards the scala tympani. The centre of the RWM is the thinnest (55-71 µm), with increasing thickness towards the edges (< 171 µm), where the RWM forms tight attachments to the surrounding bony niche. The layered RWM structure, including an outer epithelial layer, middle connective tissue and inner epithelial layer, was identified with cellular features such as wavy fibre bundles, melanocytes and blood vessels. An attached "meshwork structure" which extends over the cochlear aqueduct was seen, as in humans. The striking anatomical similarities between sheep and human RWM suggest that sheep may be evaluated as a more appropriate system to predict RWM permeability and drug delivery in humans than rodent models.

Periodontal disease in free-ranging koalas (Phascolarctos cinereus) from the Mount Lofty Ranges, South Australia, and its association with koala retrovirus infection.

BACKGROUND: In northern Australian koala populations (Queensland and New South Wales), periodontal disease (gingivitis and periodontitis) is common while koala retrovirus subtype A is endogenous, with other subtypes transmitted exogenously. Koala retrovirus has been hypothesised to cause immune suppression and may predispose koalas to diseases caused by concurrent infections. In southern Australia populations (Victoria and South Australia) periodontal disease has not been investigated, and koala retrovirus is presumably exogenously transmitted. This study described oral health in South Australian koalas and investigated if an association between periodontal disease and koala retrovirus exists. METHODS: Oral health was examined for wild-caught koalas from the Mount Lofty Ranges (n = 75). Koala retrovirus provirus was detected in whole blood using nested PCR and proviral load determined with qPCR. Periodontal disease severity was recorded and used to calculate the Final Oral Health Index (0-normal, 24-severe).Results Periodontal disease was observed in 84% (63/75) of koalas; 77% had gingivitis (58/75) and 65% (49/75) had periodontitis. The average Final Oral Health Index was 5.47 (s.d 3.13). Most cases of periodontal disease were associated with the incisors. Koala retrovirus-infected koalas were more likely to present with periodontitis (p = 0.042) and the Final Oral Health Index was negatively correlated with proviral load (ρ = -0.353, p = 0.017). CONCLUSION: South Australian koalas had a high prevalence of gingivitis and periodontitis. Periodontal disease was more prevalent in the incisors. Exogenous koala retrovirus infection may also facilitate the development of periodontitis by modulation of the immune response to concurrent oral bacterial infections.

Malocclusions in the koala (Phascolarctos cinereus).

Malocclusions are a misalignment or incorrect positioning of the teeth when the upper and lower jaws close. These are poorly described in the koala and can result in irregular mastication which can have lifelong effects on body condition and oral health. A total of 370 koalas from two populations in Queensland (295) and one in South Australia (75) were examined for malocclusions. The prevalence of malocclusions in South Australian free-ranging koalas, captive Queensland koalas and Queensland free-ranging koalas was 39% (44), 30% (29) and 22% (29) respectively. Four types of malocclusion were identified based on severity of misalignment of the incisor/canine region, types 1, 2, 3 and 4. Maxillary overbite measurements of the molariform teeth were determined and these anisognathic values were then used to describe malocclusions within familial relationships in captive colonies. Captive koalas with a malocclusion had narrower mandibular width that ranged between 0.5 and 1% less than the normal measurements. The specific malocclusions reported in this study affected individuals by leading to tooth rotation, mobility and erosion with inefficient mastication of food and vegetation compaction. These changes increased the oral cavity pathology, by placing animals at risk of periodontal disease. There was evidence of familial links to malocclusion types in captive animals. Therefore captive breeding recommendations should consider known koala malocclusion traits to minimise their effect on future generations.

A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis - the HUMOR trial.

OBJECTIVE: To assess the efficacy of adalimumab in patients with erosive hand osteoarthritis (OA). METHOD: Patients >50 years old, meeting the American College of Rheumatology (ACR) criteria for hand OA, with pain >50 on 100 mm visual analogue scale (VAS), morning stiffness >30 min and ≥1 erosive joint on X-ray with synovitis present on magnetic resonance imaging (MRI) were included in a randomised double-blind placebo-controlled crossover trial. Patients were randomised to adalimumab (40 mg subcutaneous injections every other week) or identical placebo injections for 12 weeks followed by an 8-week washout and then crossed over treatment groups for another 12 weeks. The primary outcome was change in VAS hand pain over 12 weeks. Secondary outcomes included change in Australian/Canadian Hand OA Index (AUSCAN) pain, function and stiffness subscales from baseline to 4, 8 and 12 weeks, change in MRI-detected synovitis and bone marrow lesions (BMLs) from baseline to 12 weeks and change in VAS from baseline to 4 and 8 weeks. RESULTS: We recruited 51 patients and 43 were randomised to either Group 1 (N = 18, active then placebo) or Group 2 (N = 25, placebo then active). At 12 weeks there was no difference between the groups on the primary outcome measure (mean decrease in VAS pain of 3.2 mm standard deviation (SD 16.7) for adalimumab vs 0.8 mm (SD 29.6) for placebo). The adjusted treatment effect was -0.7 mm (95% confidence interval (CI) -9.3 to 8.0), P = 0.87. No statistically significant differences were found for any secondary outcomes. CONCLUSION: Adalimumab did not show any effect on pain, synovitis or BMLs in patients with erosive hand OA with MRI-detected synovitis as compared to placebo after 12 weeks. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000791831.

Optimal control of diffuser shapes for non-uniform flow.

A simplified model is used to identify the diffuser shape that maximises pressure recovery for several classes of non-uniform inflow. We find that optimal diffuser shapes strike a balance between not widening too soon, as this accentuates the non-uniform flow, and not staying narrow for too long, which is detrimental for wall drag. Three classes of non-uniform inflow are considered, with the axial velocity varying across the width of the diffuser entrance. The first case has inner and outer streams of different speeds, with a velocity jump between them that evolves into a shear layer downstream. The second case is a limiting case when these streams are of similar speed. The third case is a pure shear profile with linear velocity variation between the centre and outer edge of the diffuser. We describe the evolution of the time-averaged flow profile using a reduced mathematical model that has been previously tested against experiments and computational fluid dynamics models. The model consists of integrated mass and momentum equations, where wall drag is treated with a friction factor parameterisation. The governing equations of this model form the dynamics of an optimal control problem where the control is the diffuser channel shape. A numerical optimisation approach is used to solve the optimal control problem and Pontryagin's maximum principle is used to find analytical solutions in the second and third cases. We show that some of the optimal diffuser shapes can be well approximated by piecewise linear sections. This suggests a low-dimensional parameterisation of the shapes, providing a structure in which more detailed and computationally expensive turbulence models can be used to find optimal shapes for more realistic flow behaviour.

Hazard perception skills of young drivers with Attention Deficit Hyperactivity Disorder (ADHD) can be improved with computer based driver training: An exploratory randomised controlled trial.

BACKGROUND: Young drivers with Attention Deficit Hyperactivity Disorder (ADHD) are at higher risk of road traffic injuries than their peers. Increased risk correlates with poor hazard perception skill. Few studies have investigated hazard perception training using computer technology with this group of drivers. OBJECTIVES: *Determine the presence and magnitude of the between-group and within- subject change in hazard perception skills in young drivers with ADHD who receive Drive Smart training. *Determine whether training-facilitated change in hazard perception is maintained over time. METHODS: This was a feasibility study, randomised control trial conducted in Australia. The design included a delayed treatment for the control group. Twenty-five drivers with a diagnosis of ADHD were randomised to the Immediate Intervention or Delayed Intervention group.The Immediate Intervention group received a training session using a computer application entitled Drive Smart. The Delayed Intervention group watched a documentary video initially (control condition), followed by the Drive Smart computer training session. The participant's hazard perception skill was measured using the Hazard Perception Test (HPT). FINDINGS: After adjusting for baseline scores, there was a significant betweengroup difference in post-intervention HPT change scores in favour of the Immediate Intervention group. The magnitude of the effect was large. There was no significant within-group delayed intervention effect. A significant maintenance effect was found at 6-week follow-up for the Immediate Intervention group. CONCLUSIONS: The hazard perception skills of participants improved following training with large effect size and some maintenance of gain. A multimodal approach to training is indicated to facilitate maintenance. A full-scale trial is feasible.

Serpinb9 is a marker of antigen cross-presenting dendritic cells.

Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (grB) that protects cytotoxic lymphocytes from grB-mediated death. In addition, Sb9 is also expressed in accessory immune cells, including dendritic cells (DCs), although its role is debated. Recently, we have demonstrated that Sb9 plays a grB-independent role in cross-presentation of antigens by CD8+ DCs. Here, using a mouse line expressing green fluorescent protein knocked in under the control of the Sb9 promoter, we demonstrate that Sb9 expression is highest in those tissue-resident and migratory DC subsets capable of cross-presentation. Further, we show that CD8+ DCs can be divided into two subsets based on Sb9 expression, and that only the subset expressing higher levels of Sb9 is capable of cross-presentation. These findings add support for role for Sb9 cross-presentation, and indicate that high Sb9 expression is a novel marker of cross-presentation capable DCs.

High frequency bone conduction auditory evoked potentials in the guinea pig: Assessing cochlear injury after ossicular chain manipulation.

Permanent high frequency (>4 kHz) sensorineural hearing loss following middle ear surgery occurs in up to 25% of patients. The aetiology of this loss is poorly understood and may involve transmission of supra-physiological forces down the ossicular chain to the cochlea. Investigating the mechanisms of this injury using animal models is challenging, as evaluating cochlear function with evoked potentials is confounded when ossicular manipulation disrupts the normal air conduction (AC) pathway. Bone conduction (BC) using clinical bone vibrators in small animals is limited by poor transducer output at high frequencies sensitive to trauma. The objectives of the present study were firstly to evaluate a novel high frequency bone conduction transducer with evoked auditory potentials in a guinea pig model, and secondly to use this model to investigate the impact of middle ear surgical manipulation on cochlear function. We modified a magnetostrictive device as a high frequency BC transducer and evaluated its performance by comparison with a calibrated AC transducer at frequencies up to 32 kHz using the auditory brainstem response (ABR), compound action potential (CAP) and summating potential (SP). To mimic a middle ear traumatising stimulus, a rotating bur was brought in to contact with the incudomalleal complex and the effect on evoked cochlear potentials was observed. BC-evoked potentials followed the same input-output function pattern as AC potentials for all ABR frequencies. Deterioration in CAP and SP thresholds was observed after ossicular manipulation. It is possible to use high frequency BC to evoke responses from the injury sensitive basal region of the cochlea and so not rely on AC with the potential confounder of conductive hearing loss. Ongoing research explores how these findings evolve over time, and ways in which injury may be reduced and the cochlea protected during middle ear surgery.

An abattoir survey of equine dental abnormalities in Queensland, Australia.

OBJECTIVE: A cadaver study to estimate the prevalence of dental disorders in horses presented at an abattoir in Queensland, Australia. METHODS: Cadaver heads at a Queensland abattoir were examined for the presence of dental abnormalities and categorised into age groups. The prevalence of abnormalities was analysed by binomial observation of observed proportion, Pearson's Chi-square test or Fisher's exact correlation test. Strength of association was evaluated using Cramer's V test. RESULTS: Heads from horses (n=400) estimated to be between 1 and 30 years of age were placed into four age groups. The most common abnormalities were sharp enamel points (55.3%) and hooks (43%). The highest frequency of dental diseases and abnormalities were in horses 11-15 years old (97.5%). CONCLUSIONS: Common abnormalities were found in all groups and the prevalence increased with age. This study suggests that all horses should have regular complete dental examinations to detect and treat dental disorders in order to limit more severe dental pathologies later in life.

Consensus statement on the investigation and management of non­radiographic axial spondyloarthritis (nr­axSpA)

"AIM: Non-radiographic axial spondyloarthritis (nr-axSpA) is axial inflammatory arthritis where plain radiographic damage is not evident. An unknown proportion of these patients will progress to ankylosing spondylitis (AS). The increasing recognition of nr-axSpA has been greatly assisted by the widespread use of magnetic resonance imaging. The aim of this article was to construct a set of consensus statements based on a literature review to guide investigation and promote best management of nr-axSpA. METHODS: A literature review using Medline was conducted covering the major investigation modalities and treatment options available. A group of rheumatologists and a radiologist with expertise in investigation and management of SpA reviewed the literature and formulated a set of consensus statements. The Grade system encompassing the level of evidence and strength of recommendation was used. The opinion of a patient with nr-axSpA and a nurse experienced in the care of SpA patients was also sought and included. RESULTS: The literature review found few studies specifically addressing nr-axSpA, or if these patients were included, their results were often not separately reported. Fourteen consensus statements covering investigation and management of nr-axSpA were formulated. The level of agreement was high and ranged from 8.1 to 9.8. Treatment recommendations vary little with established AS, but this is primarily due to the lack of available evidence on the specific treatment of nr-axSpA. CONCLUSION: The consensus statements aim to improve the diagnosis and management of nr-axSpA. We aim to raise awareness of this condition by the public and doctors and promote appropriate investigation and management."

NK cell intrinsic regulation of MIP-1α by granzyme M.

Granzymes are generally recognized for their capacity to induce various pathways of perforin-dependent target cell death. Within this serine protease family, Granzyme M (GrzM) is unique owing to its preferential expression in innate effectors such as natural killer (NK) cells. During Listeria monocytogenes infection, we observed markedly reduced secretion of macrophage inflammatory protein-1 alpha (MIP-1α) in livers of GrzM-deficient mice, which resulted in significantly impaired NK cell recruitment. Direct stimulation with IL-12 and IL-15 demonstrated that GrzM was required for maximal secretion of active MIP-1α. This effect was not due to reduced protein induction but resulted from heightened intracellular accumulation of MIP-1α, with reduced release. These results demonstrate that GrzM is a critical mediator of innate immunity that can regulate chemotactic networks and has an important role in the initiation of immune responses and pathogen control.

The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress.

Cytotoxic lymphocytes (CLs) contain lysosome-related organelles (LROs) that perform the normal degradative functions of the lysosome, in addition to storage and release of powerful cytotoxins employed to kill virally infected or abnormal cells. Among these cytotoxins is granzyme B (GrB), a protease that has also been implicated in activation (restimulation)-induced cell death of natural killer (NK) and T cells, but the underlying mechanism and its regulation are unclear. Here we show that restimulation of previously activated human or mouse lymphocytes induces lysosomal membrane permeabilisation (LMP), followed by GrB release from LROs into the CL cytosol. The model lysosomal stressors sphingosine and Leu-Leu-methyl-ester, and CLs from gene-targeted mice were used to show that LMP releases GrB in both a time- and concentration-dependent manner, and that the liberated GrB is responsible for cell death. The endogenous GrB inhibitor Serpinb9 (Sb9) protects CLs against LMP-induced death but is decreasingly effective as the extent of LMP increases. We also used these model stressors to show that GrB is the major effector of LMP-mediated death in T cells, but that in NK cells additional effectors are released, making GrB redundant. We found that limited LMP and GrB release occurs constitutively in proliferating lymphocytes and in NK cells engaged with targets in vitro. In Ectromelia virus-infected lymph nodes, working NK cells lacking Sb9 are more susceptible to GrB-mediated death. Taken together, these data show that a basal level of LMP occurs in proliferating and activated lymphocytes, and is increased on restimulation. LMP releases GrB from LROs into the lymphocyte cytoplasm and its ensuing interaction with Sb9 dictates whether or not the cell survives. The GrB-Sb9 nexus may therefore represent an additional mechanism of limiting lymphocyte lifespan and populations.

A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage.

The human lymphocyte toxins granzyme B (hGrzB) and perforin cooperatively induce apoptosis of virus-infected or transformed cells: perforin pores enable entry of the serine protease hGrzB into the cytosol, where it processes Bid to selectively activate the intrinsic apoptosis pathway. Truncated Bid (tBid) induces Bax/Bak-dependent mitochondrial outer membrane permeability and the release of cytochrome c and Smac/Diablo. To identify cellular proteins that regulate perforin/hGrzB-mediated Bid cleavage and subsequent apoptosis, we performed a gene-knockdown (KD) screen using a lentiviral pool of short hairpin RNAs embedded within a miR30 backbone (shRNAmiR). We transduced HeLa cells with a lentiviral pool expressing shRNAmiRs that target 1213 genes known to be involved in cell death signaling and selected cells with acquired resistance to perforin/hGrzB-mediated apoptosis. Twenty-two shRNAmiRs were identified in the positive-selection screen including two, PCAF and ADA3, whose gene products are known to reside in the same epigenetic regulatory complexes. Small interfering (si)RNA-mediated gene-KD of PCAF or ADA3 also conferred resistance to perforin/hGrzB-mediated apoptosis providing independent validation of the screen results. Mechanistically, PCAF and ADA3 exerted their pro-apoptotic effect upstream of mitochondrial membrane permeabilization, as indicated by reduced cytochrome c release in PCAF-KD cells exposed to perforin/hGrzB. While overall levels of Bid were unaltered, perforin/hGrzB-mediated cleavage of Bid was reduced in PCAF-KD or ADA3-KD cells. We discovered that PCAF-KD or ADA3-KD resulted in reduced expression of PACS2, a protein implicated in Bid trafficking to mitochondria and importantly, targeted PACS2-KD phenocopied the effect of PCAF-KD or ADA3-KD. We conclude that PCAF and ADA3 regulate Bid processing via PACS2, to modulate the mitochondrial cell death pathway in response to hGrzB.

No evidence of triclosan-resistant bacteria following long-term use of triclosan-containing toothpaste.

BACKGROUND AND OBJECTIVE: There is a paucity of data in relation to the possible emergence of triclosan (TCS)-resistant bacteria following long-term exposure to TCS toothpaste. Therefore, this study investigated whether long-term continuous exposure to TCS in toothpaste selects for TCS-resistant bacteria within the oral biofilm. MATERIAL AND METHODS: Dental plaque samples were collected from 40 individuals during year 5 of a randomised controlled trial. Participants had been randomly assigned to use TCS (3000 µg/mL TCS) (n = 18) or placebo toothpaste (n = 22). Diluted plaque samples were plated on to Wilkins-Chalgren agar plates containing 5% (v/v) laked sheep red blood cells and TCS (concentrations ranging from 25 to 150 µg/mL) and incubated at 37 °C under microaerophilic and anaerobic conditions for 2-10 d. Selected bacterial isolates were identified by partial 16S rDNA sequencing and TCS minimum inhibitory concentration (MIC) determined for each isolate. RESULTS: At 3000 µg/mL TCS no growth was observed under microaerophilic or anaerobic conditions in either group. The MICs of TCS for all isolates ranged from 125 to 1000 µg/mL in both groups. Species common to both groups had similar MICs. Veillonella parvula and Campylobacter gracilis were the most frequent isolates from both groups, with similar MICs in both groups. CONCLUSION: The use of TCS-containing toothpaste did not appear to lead to an increase in MIC of TCS of oral bacterial isolates.

Pattern of bone erosion and bone proliferation in psoriatic arthritis hands: a high-resolution computed tomography and radiography follow-up study during adalimumab therapy.

OBJECTIVES: To investigate the pattern and development of bone erosion and proliferation in patients with psoriatic arthritis (PsA) during treatment with adalimumab, using high-resolution computed tomography (CT) and conventional radiography. METHOD: Forty-one biologic-naïve PsA patients were initiated with adalimumab 40 mg subcutaneously every other week. CT and radiography of the 2nd-5th metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints were conducted at baseline (n = 41) and after 24 weeks (n = 32). Changes in bone erosion and proliferation are described and the imaging modalities compared. RESULTS: Ninety percent of bone erosions detected by CT were located in the metacarpal heads, and most frequently in the 2nd-3rd MCP joints. Radial (37%) and ulnar (31%) surfaces were more frequently eroded than dorsal (10%) and palmar (22%) sites. Using CT, bone proliferations were located primarily on the sides of the distal part of the DIP joints (43% of all proliferations), but also proximally in DIP (17%) and MCP joints (27%). For bone erosions and proliferations, respectively, radiography showed a low sensitivity (17% and 26%), but a high specificity (98% and 95%) and accuracy (93% and 87%), with CT as the gold standard reference. Neither CT nor radiography revealed statistically significant changes in bone erosion or proliferation scores between baseline and follow-up. CONCLUSIONS: Patterns of bone erosion and proliferation in PsA hands were revealed in more detail by CT than by radiography. No overall progression or repair could be detected during adalimumab treatment with either of the methods.

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis.

Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, 'worm-like' morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death 'athetosis'. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes.

Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737.

Overexpression of Bcl-2 contributes to resistance of cancer cells to human cytotoxic lymphocytes (CL) by blocking granzyme B (GraB)-induced mitochondrial outer membrane permeabilization (MOMP). Drugs that neutralise Bcl-2 (e.g., ABT-737) may therefore be effective adjuvants for immunotherapeutic strategies that use CL to kill cancer cells. Consistent with this we found that ABT-737 effectively restored MOMP in Bcl-2 overexpressing cells treated with GraB or natural killer cells. This effect was observed even if ABT-737 was added up to 16 h after GraB, after which the cells reset their resistant phenotype. Sensitivity to ABT-737 required initial cleavage of Bid by GraB (gctBid) but did not require ongoing GraB activity once Bid had been cleaved. This gctBid remained detectable in cells that were sensitive to ABT-737, but Bax and Bak were only activated if ABT-737 was added to the cells. These studies demonstrate that GraB generates a prolonged pro-apoptotic signal that must remain active for ABT-737 to be effective. The duration of this signal is determined by the longevity of gctBid but not activation of Bax or Bak. This defines a therapeutic window in which ABT-737 and CL synergise to cause maximum death of cancer cells that are resistant to either treatment alone, which will be essential in defining optimum treatment regimens.

Magnetic resonance imaging for Ménière's disease: correlation with tone burst electrocochleography.

The newly developed use of magnetic resonance imaging of the human inner ear, on a 3 Tesla scanner with intratympanically administered gadolinium, can now reliably distinguish perilymph from endolymph and visually confirm the presence or absence of endolymphatic hydrops. Transtympanic tone burst electrocochleography is an established, and under-utilised evoked response electrophysiological test for hydrops, but it relies on a symptom score to indicate the likelihood of hydrops being present. The current diagnostic criteria for Ménière's disease make no allowance for any in vivo test, making diagnostic errors likely. In this small pilot study of three patients undergoing tone burst electrocochleography, subsequent magnetic resonance imaging confirmed or excluded the hydrops that the electrocochleography predicted. Magnetic resonance imaging of the inner ear is a safe technique that can be performed in conjunction with imaging of the VIIIth cranial nerves. As this report comprised only three patients in a pilot study, rigorous clinical studies are required to define the possible role of magnetic resonance imaging in the diagnosis of Ménière's disease.