AI implementation in the UK landscape: Knowledge of AI governance, perceived challenges and opportunities, and ways forward for radiographers.

INTRODUCTION: Despite the rapid increase of AI-enabled applications deployed in clinical practice, many challenges exist around AI implementation, including the clarity of governance frameworks, usability of validation of AI models, and customisation of training for radiographers. This study aimed to explore the perceptions of diagnostic and therapeutic radiographers, with existing theoretical and/or practical knowledge of AI, on issues of relevance to the field, such as AI implementation, including knowledge of AI governance and procurement, perceptions about enablers and challenges and future priorities for AI adoption. METHODS: An online survey was designed and distributed to UK-based qualified radiographers who work in medical imaging and/or radiotherapy and have some previous theoretical and/or practical knowledge of working with AI. Participants were recruited through the researchers' professional networks on social media with support from the AI advisory group of the Society and College of Radiographers. Survey questions related to AI training/education, knowledge of AI governance frameworks, data privacy procedures, AI implementation considerations, and priorities for AI adoption. Descriptive statistics were employed to analyse the data, and chi-square tests were used to explore significant relationships between variables. RESULTS: In total, 88 valid responses were received. Most radiographers (56.6 %) had not received any AI-related training. Also, although approximately 63 % of them used an evaluation framework to assess AI models' performance before implementation, many (36.9 %) were still unsure about suitable evaluation methods. Radiographers requested clearer guidance on AI governance, ample time to implement AI in their practice safely, adequate funding, effective leadership, and targeted support from AI champions. AI training, robust governance frameworks, and patient and public involvement were seen as priorities for the successful implementation of AI by radiographers. CONCLUSION: AI implementation is progressing within radiography, but without customised training, clearer governance, key stakeholder engagement and suitable new roles created, it will be hard to harness its benefits and minimise related risks. IMPLICATIONS FOR PRACTICE: The results of this study highlight some of the priorities and challenges for radiographers in relation to AI adoption, namely the need for developing robust AI governance frameworks and providing optimal AI training.

Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC.

Identification of anti-alpha toxin monoclonal antibodies that reduce the severity of Staphylococcus aureus dermonecrosis and exhibit a correlation between affinity and potency.

Staphylococcus aureus alpha toxin (AT) is an important virulence determinant and may be a valid target for immunoprophylaxis against staphylococcal disease. Here we report the identification of potent inhibitory anti-AT monoclonal antibodies (MAbs) derived using B-cell hybridoma technology from VelocImmune mice engineered to produce IgG with a human variable domain. A small panel of inhibitory MAbs blocked AT-mediated lysis of rabbit red blood cells, A549 human lung epithelial cells, and THP-1 human monocytic cells, in a dose-dependent manner. Binding studies indicated that these MAbs recognize a similar epitope on AT and exhibit dissociation constants (K(D)) ranging from 0.50 to 15 nM. In an S. aureus dermonecrosis model, mice passively immunized with anti-AT inhibitory MAbs exhibited significant reductions of lesion size relative to mice treated with an irrelevant IgG control. Interestingly, there was a correlation between MAb affinity for a single epitope, the 50% inhibitory concentration (IC(50)) in the AT hemolytic assay, and lesion size reduction in the dermonecrosis model. A representative high-affinity MAb, 2A3.1, was demonstrated to significantly reduce lesion size following infection with three different clinical isolates (USA300, CC30, and CC5). Taken together, these results indicate that in vitro potency of anti-AT MAbs predicts in vivo potency in this model, supporting their continued preclinical evaluation as molecules for immunoprophylaxis against staphylococcal skin and soft tissue infections caused by diverse clinical isolates.

Demonstration of ignition radiation temperatures in indirect-drive inertial confinement fusion hohlraums.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 µm diameter hot core.

Assessment of the functionality of genome-wide canine SNP arrays and implications for canine disease association studies.

Domestic dogs share a wide range of important disease conditions with humans, including cancers, diabetes and epilepsy. Many of these conditions have similar or identical underlying pathologies to their human counterparts and thus dogs represent physiologically relevant natural models of human disorders. Comparative genomic approaches whereby disease genes can be identified in dog diseases and then mapped onto the human genome are now recognized as a valid method and are increasing in popularity. The majority of dog breeds have been created over the past few hundred years and, as a consequence, the dog genome is characterized by extensive linkage disequilibrium (LD), extending usually from hundreds of kilobases to several megabases within a breed, rather than tens of kilobases observed in the human genome. Genome-wide canine SNP arrays have been developed, and increasing success of using these arrays to map disease loci in dogs is emerging. No equivalent of the human HapMap currently exists for different canine breeds, and the LD structure for such breeds is far less understood than for humans. This study is a dedicated large-scale assessment of the functionalities (LD and SNP tagging performance) of canine genome-wide SNP arrays in multiple domestic dog breeds. We have used genotype data from 18 breeds as well as wolves and coyotes genotyped by the Illumina 22K canine SNP array and Affymetrix 50K canine SNP array. As expected, high tagging performance was observed with most of the breeds using both Illumina and Affymetrix arrays when multi-marker tagging was applied. In contrast, however, large differences in population structure, LD coverage and pairwise tagging performance were found between breeds, suggesting that study designs should be carefully assessed for individual breeds before undertaking genome-wide association studies (GWAS).

Clinical validation of an autoantibody test for lung cancer.

BACKGROUND: Autoantibodies may be present in a variety of underlying cancers several years before tumours can be detected and testing for their presence may allow earlier diagnosis. We report the clinical validation of an autoantibody panel in newly diagnosed patients with lung cancer (LC). PATIENTS AND METHODS: Three cohorts of patients with newly diagnosed LC were identified: group 1 (n = 145), group 2 (n = 241) and group 3 (n = 269). Patients were individually matched by gender, age and smoking history to a control individual with no history of malignant disease. Serum samples were obtained after diagnosis but before any anticancer treatment. Autoantibody levels were measured against a panel of six tumour-related antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1 and SOX2). Assay sensitivity was tested in relation to demographic variables and cancer type/stage. RESULTS: The autoantibody panel demonstrated a sensitivity/specificity of 36%/91%, 39%/89% and 37%/90% in groups 1, 2 and 3, respectively, with good reproducibility. There was no significant difference between different LC stages, indicating that the antigens included covered the different types of LC well. CONCLUSION: This assay confirms the value of an autoantibody panel as a diagnostic tool and offers a potential system for monitoring patients at high risk of LC.

Technical validation of an autoantibody test for lung cancer.

BACKGROUND: Publications on autoantibodies to tumour-associated antigens (TAAs) have failed to show either calibration or reproducibility data. The validation of a panel of six TAAs to which autoantibodies have been described is reported here. MATERIALS AND METHODS: Three separate groups of patients with newly diagnosed lung cancer were identified, along with control individuals, and their samples used to validate an enzyme-linked immunosorbant assay. Precision, linearity, assay reproducibility and antigen batch reproducibility were all assessed. RESULTS: For between-replicate error, samples with higher signals gave coefficients of variation (CVs) in the range 7%-15%. CVs for between-plate variation were only 1%-2% higher. For between-run error, CVs were in the range 15%-28%. In linearity studies, the slope was close to 1.0 and correlation coefficient values were generally >0.8. The sensitivity and specificity of individual batches of antigen varied slightly between groups of patients; however, the sensitivity and specificity of the panel of antigens as a whole remained constant. The validity of the calibration system was demonstrated. CONCLUSIONS: A calibrated six-panel assay of TAAs has been validated for identifying nearly 40% of primary lung cancers via a peripheral blood test. Levels of reproducibility, precision and linearity would be acceptable for an assay used in a regulated clinical setting.

Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*.

Anal furunculosis (AF) is a chronic inflammatory disease of perianal tissues that particularly affects German Shepherd dogs (GSD). An immune-mediated aetiopathogenesis is suggested by T-cell infiltration, upregulated cytokine gene expression, clinical response to ciclosporin therapy and a strong genetic association with the DLA-DRB1*00101 allele. Given the close proximity of TNFA and DLA-DRB1 in the canine major histocompatibility complex (MHC), together with the strong linkage disequilibrium (LD) observed across this region, the primary disease association could be with either locus. We have investigated whether there may be an association of AF with TNFA gene polymorphism in GSDs. Cohorts of AF-affected and AF-unaffected GSDs of known dog leucocyte antigen (DLA) class II profile were genotyped for 10 single nucleotide polymorphisms (SNPs) in the canine TNFA locus using Sequenom iPLEX technology. Seven discrete TNFA haplotypes were identified in GSDs for combinations of these SNPs. TNFA haplotype frequencies were compared in cases and controls. The TNFA haplotype 3 (ATCGTTACGG), was at significantly increased frequency in cases (29% vs 15%, OR 2.5, 95% CI 1.4-4.8; P = 0.003). All seven discrete TNFA SNP haplotypes were examined for their association with DLA-DRB1/DQA1/DQB1 established haplotypes. TNFA haplotype 3 was preferentially associated with both DLA-DRB1*00101(3A)- and DLA-DRB1*00102(3B)-positive haplotypes. The DLA-DRB1* 00101/TNFA-3A haplotype was significantly associated with AF (19.3% vs 5.8%; OR 3.7, 95% CI: 1.5-8.9; P = 0.003), whereas the DLA-DRB1*00102/TNFA-3B haplotype was not (P = NS). These findings suggest that susceptibility to AF in GSDs is primarily associated with DLA-DRB1*00101 and any association with the TNFA locus is secondary and is likely to be because of LD.

Autoantibodies in lung cancer: possibilities for early detection and subsequent cure.

BACKGROUND: People with lung cancer usually present at a late stage in the course of their disease when their chances of long-term survival are low. At present there is little to offer for early diagnosis, even in those at high risk of developing the disease. Autoantibodies have been shown to be present in the circulation of people with various forms of solid tumour before cancer-associated antigens can be detected, and these molecules can be measured up to 5 years before symptomatic disease. OBJECTIVE: To assess the potential of a panel of tumour-associated autoantibody profiles as an aid to other lung cancer screening modalities. METHODS: Plasma from normal controls (n = 50), patients with non-small cell lung cancer (n = 82) and patients with small cell lung cancer (n = 22) were investigated for the presence of autoantibodies to p53, c-myc, HER2, NY-ESO-1, CAGE, MUC1 and GBU4-5 by enzyme-linked immunosorbent assay. RESULTS: Raised levels of autoantibodies were seen to at least 1/7 antigens in 76% of all the patients with lung cancer plasma tested, and 89% of node-negative patients, with a specificity of 92%. There was no significant difference between the detection rates in the lung cancer subgroups, although more patients with squamous cell carcinomas (92%) could be identified. CONCLUSION: Measurement of an autoantibody response to one or more tumour-associated antigens in an optimised panel assay may provide a sensitive and specific blood test to aid the early detection of lung cancer.

Wildlife as reservoirs for parasites infecting commercial species: host specificity and a redescription of Kudoa amamiensis from teleost fish in Australia.

Parasites of the genus Kudoa (Phylum Myxozoa) have long been known to cause considerable losses to finfish aquaculture. One such parasite species, Kudoa amamiensis, causes unsightly white cysts in the skeletal muscle of yellowtail kingfish, Seriola quinqueradiata, in Japan rendering the fillets unmarketable. The authors who characterized K. amamiensis, Egusa & Nakajima, 1980, hypothesized that yellowtail kingfish, as non-natives to the area, were accidental hosts of the parasite and that it normally infects native reef fish (damselfish, Family Pomacentridae). Since then, we have found parasites that are consistent with the description of K. amamiensis in two species of damselfish and one species of carangid fish in Australia, and it has been recorded previously in another species of reef-associated fish. Our morphometric, histological and DNA results suggest that these specimens are K. amamiensis, and are new host records for that species. Furthermore, our observations show that reef fish may act as a reservoir of myxozoan infection for commercial species, and as such should be considered an infection pathway for species in aquaculture.

Autoantibodies in breast cancer: their use as an aid to early diagnosis.

BACKGROUND: There is increasing evidence that the immune system produces a humoral response to cancer-derived antigens. This study assessed the diagnostic potential of autoantibodies to multiple known tumour-associated proteins. PATIENTS AND METHODS: Sera from normal controls (n = 94), primary breast cancer patients (n = 97) and patients with ductal carcinoma in situ (DCIS) (n = 40) were investigated for the presence of autoantibodies to p53, c-myc, HER2, NY-ESO-1, BRCA1, BRCA2 and MUC1 antigens by enzyme-linked immunosorbent assay. RESULTS: Reproducibly elevated levels of autoantibodies were seen in at least one of the six antigens in 64% of primary breast cancer patient sera and 45% of patients with DCIS at a specificity of 85%. No significant differences were seen when patients were subdivided by age, tumour size, histological grade, lymph node status or detection methodology. CONCLUSIONS: Autoantibodies against one or more of these tumour-associated antigens appears to indicate the presence of early-stage breast cancers. Autoantibody assays against a panel of antigens could be used as an aid to mammography in the detection and diagnosis of early primary breast cancer, especially in younger women at increased risk of breast cancer where mammography is known to have reduced sensitivity and specificity.

Iron acquisition mechanisms of Flavobacterium psychrophilum.

Forty strains of Flavobacterium psychrophilum were tested for the production of siderophores using the universal Chrome Azurol S (CAS) assay. The majority of the strains (85%) were CAS positive (CAS+) and some (15%) were CAS negative (CAS-). The cryptic plasmid pCP1 was carried by all positive strains and was lacking from negative strains. While a weak catechol reaction was detectable in CAS+ culture supernatants, the CAS reaction was, to some extent, heat sensitive, questioning whether the positive reaction was caused only by siderophores. The ability to grow in vitro under iron-restricted conditions did not correlate with the CAS reactivity, as growth of both CAS+ and CAS- strains was similarly impaired under iron restriction induced by 2,2 dipyridyl. Suppressed growth under these conditions was restored by addition of FeCl3, haemoglobin and transferrin for both CAS+ and CAS- strains.

Frecuencia de tuberculosis pulmonar y extrapulmonar en un hospital de referencia de la provincia de Córdoba, 1991-2003 / [Frequency of pulmonary and extrapulmonary tuberculosis in a reference hospital in Córdoba province, 1991-2003]

Tuberculosis continues to be a serious problem of public health causing nearly three million deaths per year all over the world. Despite technologic improvements in the diagnostic methods, it is not possible to control the disease in the absence of surveillance and treatment follow-up programs supervising the ending of treatments, and definitive cure of patients. The frequency of pulmonary and extrapulmonary tuberculosis, and simultaneous pulmonary and extrapulmonary tuberculosis localization among patients assisted at Tránsito Cáceres de Allende Hospital during thirteen years (1991-2003), was determined. The benefit of inoculating the specimens on Stonebrink medium for the best recuperation of Mycobacterium bovis was herein observed, and the contribution of Ziehl Neelsen staining in extrapulmonary materials was tested as well. Out of 790 cases of tuberculosis diagnosed, 723 were pulmonary, and 48 were extrapulmonary localization (pleural 31, renal 7, ganglionar 5, meningeal 2, genital 1, pericardial 1 and digestive 1), and 19 patients presented both, pulmonary and extrapulmonary tuberculosis. Out of the 723 pulmonary cases, 9 were caused by M. bovis. All M. bovis isolates grew on Stonebrink medium, and only one grew also on Lowenstein Jensen. Smear microscopy using Ziehl Neelsen staining resulted positive in 4 extrapulmonary specimens.

Prevalencia de micobacteriosis y de tuberculosis en pacientes de un hospital de referencia de la provincia de Córdoba / Prevalence of mycobacteriosis and tuberculosis in a reference hospital, Cordoba province

Las micobacterias ambientales (MA) constituyen un importante grupo de especies bacterianas que se encuentran en el medio ambiente, pueden colonizar y ocasionalmente producir enfermedad enel hombre. En este trabajo se investigó la frecuencia de casos de micobacteriosis en relación con los de tuberculosis durante un período de diez años (1.991-2.000). Se estudiaron 16.700 muestras de 9.300 pacientes adultos de ambos sexos asistidos en el Hospital Regional de Tuberculosis de la Provincia de Córdoba, por consulta espontánea. Los aislamientos se realizaron por cultivo en los medios de Lowenstein Jensen y Stonebrink. Las colonias de bacilos ácidoalcohol resistentes (BAAR) se identificaron por pruebas bioquímicas y moleculares. El total de casos diagnosticados fue de 716, de los cuales 684 (95,5%) correspondieron a al complejo Mycobacterium tuberculosis y a micobacterias ambientales 32 (4,5%). Los casos de micobacteriosis se definieron por reiterados aislamientos con desarrollo representativo de una micobacteria ambiental, sospecha clínica y radiológica. De los 32 casos de micobacteriosis, el 75% del total correspondió aMycobacterium avium-intracellulare,15,6% a Mycobacterium fortuitum, 3,1% a Mycobacterium kansasii y 6,3% a Mycobacterium chelonae.Los casos de tuberculosis fueron 94,5% de localización pulmonar y 5,5% extrapulmonar.

Environmental mycobacteria (EM) constitute an important group of bacteria species found in the environment. They can colonize and occasionally produce disease in man. Sixteen thousand three hundred samples from 9300 adult symptomatic patients from the Hospital Regional of Tuberculosis in Cordoba were bacteriolocally investigated. The isolations were performed by culture on Lowenstein Jensen and Stonebrink culture media. The colonies of acid fast bacilli (AFB) were identified by biochemical and molecular tests. Among 716 culture positive cases, 684 (95.5%) were due to Mycobacterium tuberculosis complex and 32 to environmental mycobacteria.Serial samples allowed the confirmation of the etiologicalagent in culture and correlated with consistent clinical and radiological abnormalities. Seventy-five percente of these patients were affected by M. avium complex, 15.6% by M. fortuitum, 3.1% Mycobacterium kansasii and 6.3% Mycobacterium chelonae. Among tuberculosis cases, 94.5% and 5.5% had pulmonary and extrapulmonary disease respectively.

Expression of p27kip1 in breast cancer and its prognostic significance.

p27kip1 is a member of the KIP/CIP family of cyclin-dependent kinase inhibitors and is a negative cell-cycle regulator that is thought to play a role in tumour suppression. Reduced levels of this protein have been observed in a number of human cancers. However, evidence is conflicting as to whether p27kip1 has a role to play in breast cancer, including predicting behaviour and prognosis. The present investigation aimed to provide a definitive study of 830 breast cancer cases with median patient follow-up of 104 months to determine the true prognostic significance, if any. Immunohistochemical analysis of tissue microarrays and three scoring methods were used to assess p27kip1 expression. Univariate analysis showed a significant relationship between reduced p27kip1 expression and increasing tumour grade, nuclear pleomorphism, mitosis, and decreasing tubule formation (all p<0.001). Significant associations between reduced p27, negative oestrogen receptor status, and ductal/no special type tumours were also observed. Survival analysis demonstrated that patients with tumours with high p27kip1 levels had an improved survival compared with those with cancers with low expression. On multivariate analysis, when compared with existing factors, p27kip1 was not, however, an independent prognostic factor. It is concluded that the inverse relationship between p27kip1 levels and histological grade and individual grade components suggests a role for p27kip1 in both cell proliferation and differentiation, but is not clinically useful.

Cancer in Indigenous Australians: a review.

OBJECTIVES: To summarize for the first time evidence of the impact of cancer on Indigenous Australians. METHODS: Medline search of peer-reviewed scientific journals, and extensive search of reports of government agencies, publications of cancer registries and non-government organizations, and other non-peer-reviewed sources. RESULTS: Indigenous Australians have much higher incidence rates than other Australians of cancers of the lung, liver, and cervix; but much lower rates of cancers of the breast, colon and rectum, prostate, melanoma of skin, and lymphoma. Some of these differences can be explained, in part at least, by differences in risk factor prevalence. Indigenous Australians also have higher mortality and lower survival from cancer as a whole than other Australians. More advanced disease at diagnosis, and possibly poorer treatment, are partly responsible for these differences, but other factors may also be involved. CONCLUSIONS: Less accessible and less effective health programs are as great a problem for cancer control as for other aspects of Indigenous health in Australia. Major improvements in preventive services, screening, primary care, and specialist treatment services are required to reduce cancer incidence and improve cancer outcomes for Australia's Indigenous people.

Decreased lung ischemia-reperfusion injury in rats after preoperative administration of cyclosporine and tacrolimus.

OBJECTIVES: Calcineurin inhibitors reduce experimental reperfusion injury in the liver, brain, heart, kidney, and small bowel. These studies were undertaken to determine whether these agents are similarly protective against lung ischemia-reperfusion injury. METHODS: Left lungs of male rats were rendered ischemic for 90 minutes and reperfused for as long as 4 hours. Treated animals received cyclosporine A (INN: ciclosporin; 1 or 5 mg/kg) or tacrolimus (0.2 mg/kg) 6 hours before ischemia, at reperfusion, or 2 hours after reperfusion. Injury was quantitated in terms of tissue polymorphonuclear leukocyte accumulation (myeloperoxidase content), vascular permeability (iodine 125-labeled bovine serum albumin extravasation), and bronchoalveolar lavage leukocyte content. Separate tissue samples were processed for nuclear protein and cytokine messenger RNA. RESULTS: Treatment with cyclosporine (5 mg/kg) or tacrolimus (0.2 mg/kg) 6 hours before reperfusion reduced lung vascular permeability by 54% and 56% relative to control animals (P <.03). The protective effects of cyclosporine and tacrolimus treatment before reperfusion correlated with 42% and 43% reductions in tissue polymorphonuclear leukocyte (myeloperoxidase) content (P <.008) and marked reductions in bronchoalveolar lavage leukocyte accumulation (P <.01). Administration of cyclosporine or tacrolimus at the time of reperfusion or 2 hours into the reperfusion period offered little or no protection. Animals treated before reperfusion also demonstrated marked reductions in nuclear factor kappaB activation and expression of proinflammatory cytokine messenger RNA. CONCLUSION: Cyclosporine and tacrolimus treatment before reperfusion was protective against lung ischemia-reperfusion injury in rats. The mechanism of these protective effects may involve the inhibition of nuclear factor kappaB, a central transcription factor mediating inflammatory injury. The decreased expression of cytokine messenger RNA indicates that both cyclosporine and tacrolimus may exert their protective effects at the pretranscriptional level.

Non-albicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance.

Non-albicans Candida (NAC) species cause 35-65% of all candidaemias in the general patient population. They occur more frequently in cancer patients, mainly in those with haematological malignancies and bone marrow transplant (BMT) recipients (40-70%), but are less common among intensive care unit (ITU) and surgical patients (35-55%), children (1-35%) or HIV-positive patients (0-33%). The proportion of NAC species among Candida species is increasing: over the two decades to 1990, NAC represented 10-40% of all candidaemias. In contrast, in 1991-1998, they represented 35-65% of all candidaemias. The most common NAC species are C. parapsilosis (20-40% of all Candida species), C. tropicalis (10-30%), C. krusei (10-35%) and C. glabrata (5-40%). Although these four are the most common, at least two other species are emerging: C. lusitaniae causing 2-8% of infections, and C. guilliermondii causing 1-5%. Other NAC species, such as C. rugosa, C. kefyr, C. stellatoidea, C. norvegensis and C. famata are rare, accounting for less than 1% of fungaemias in man. In terms of virulence and pathogenicity, some NAC species appear to be of lower virulence in animal models, yet behave with equal or greater virulence in man, when comparison is made with C. albicans. Mortality due to NAC species is similar to C. albicans, ranging from 15% to 35%. However, there are differences in both overall and attributable mortality among species: the lowest mortality is associated with C. parapsilosis, the highest with C. tropicalis and C. glabrata (40-70%). Other NAC species including C. krusei are associated with similar overall mortality to C. albicans (20-40%). Mortality in NAC species appears to be highest in ITU and surgical patients, and somewhat lower in cancer patients, children and HIV-positive patients. There is no difference between overall and attributable mortality, with the exception of C. glabrata which tends to infect immunocompromised individuals. While the crude mortality is low, attributable mortality (fungaemia-associated mortality) is higher than with C. albicans. There are several specific risk factors for particular NAC species: C. parapsilosis is related to foreign body insertion, neonates and hyperalimentation; C. krusei to azole prophylaxis and along with C. tropicalis to neutropenia and BMT; C. glabrata to azole prophylaxis, surgery and urinary or vascular catheters; C. lusitaniae and C. guilliermondii to previous polyene (amphotericin B or nystatin) use; and C. rugosa to burns. Antifungal susceptibility varies significantly in contrast to C. albicans: some NAC species are inherently or secondarily resistant to fluconazole; for example, 75% of C. krusei isolates, 35% of C. glabrata, 10-25% of C. tropicalis and C. lusitaniae. Amphotericin B resistance is also seen in a small proportion: 5-20% of C. lusitaniae and C. rugosa, 10-15% of C. krusei and 5-10% of C. guilliermondii. Other NAC species are akin to C. albicans-susceptible to both azoles and polyenes (C. parapsilosis, the majority of C. guilliermondii strains and C. tropicalis). Therefore, 'species directed' therapy should be administered for fungaemia according to the species identified-amphotericin B for C. krusei and C. glabrata, fluconazole for other species, including polyene-resistant or tolerant Candida species (C. lusitaniae, C. guilliermondii). In vitro susceptibility testing should be performed for most species of NAC in addition to removal of any foreign body to optimize management.

Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells.

The selectivities of the diadenosine polyphosphates (Ap(n)As, n=2-6) at the human P2Y(1), P2Y(2), P2Y(4), P2Y(6) and P2Y(11) receptors stably expressed in 1321N1 human astrocytoma cells was determined using a Fluorescence Imaging Plate Reader (FLIPR) to measure intracellular Ca(2+) mobilisation. The rank order of agonist potencies at P2Y(1) were: ADP>P(1),P(3)-diadenosine triphosphate (Ap(3)A)>P(1),P(3)-diadenosine hexaphosphate (Ap(6)A)=P(1),P(3)-diadenosine diphosphate (Ap(2)A)>>P(1),P(3)-diadenosine pentaphosphate (Ap(5)A). P(1),P(3)-diadenosine tetraphosphate (Ap(4)A) was inactive up to 1 mM. The rank order of agonist potencies at P2Y(2) were: UTP>Ap(4)A>>Ap(6)A>Ap(5)A>Ap(3)A>>Ap(2)A. The Ap(4)A concentration response curve appeared to be bi-phasic. At P2Y(4) all the Ap(n)As tested were inactive as agonists. At P2Y(6), only Ap(3)A and Ap(5)A showed significant agonist activity. At P2Y(11), only Ap(4)A showed significant agonist activity. Ap(n)As were inactive as antagonists of the P2Y(1), P2Y(2), P2Y(4), P2Y(6) and P2Y(11) receptors. At P2Y(4), however, the Ap(n)As potentiated the UTP response.