Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

Primary school mobile dental program in New South Wales, Australia: protocol for the evaluation of a state government oral health initiative.

BACKGROUND: Socioeconomically disadvantaged children are disproportionately affected by oral disease. Mobile dental services help underserved communities overcome barriers to accessing health care, including time, geography, and trust. The NSW Health Primary School Mobile Dental Program (PSMDP) is designed to provide diagnostic and preventive dental services to children at their schools. The PSMDP is mainly targeted toward high-risk children and priority populations. This study aims to evaluate the program's performance across five local health districts (LHDs) where the program is being implemented. METHODS: The evaluation will use routinely collected administrative data, along with other program-specific data sources, from the district public oral health services to conduct a statistical analysis that determines the reach and uptake of the program, its effectiveness, and the associated costs and cost-consequences. The PSMDP evaluation program utilises data from Electronic Dental Records (EDRs) and other data sources, including patient demographics, service mix, general health, oral health clinical data and risk factor information. The overall design includes cross-sectional and longitudinal components. The design combines comprehensive output monitoring across the five participating LHDs and investigates the associations between socio-demographic factors, service patterns and health outcomes. Time series analysis using difference-in-difference estimation will be conducted across the four years of the program, involving services, risk factors, and health outcomes. Comparison groups will be identified via propensity matching across the five participating LHDs. An economic analysis will estimate the costs and cost-consequences for children who participate in the program versus the comparison group. DISCUSSION: The use of EDRs for oral health services evaluation research is a relatively new approach, and the evaluation works within the limitations and strengths of utilising administrative datasets. The study will also provide avenues to improve the quality of data collected and system-level improvements to better enable future services to be aligned with disease prevalence and population needs.

Diabetic mitochondria are resistant to palmitoyl CoA inhibition of respiration, which is detrimental during ischemia.

The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischemia provides a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial, and secondly, whether the chronically elevated lipid content within the diabetic heart could make mitochondria less sensitive to the effects of PCoA. PCoA acutely decreased ADP-stimulated state 3 respiration and increased the apparent Km for ADP twofold. The half maximal inhibitory concentration (IC50 ) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in diabetic mitochondria, with no significant difference in the Km for ADP in the presence of PCoA, and an increase in the IC50 to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, regenerating the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischemia, however, this beneficial effect was blunted in diabetic mitochondria. Finally, using 31 P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischemia, with a threefold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism seen during myocardial ischemia in the diabetic heart.

Differential drivers of intraspecific and interspecific competition during malaria-helminth co-infection.

Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in mice: initial infectious dose and co-infection with a helminth that limits the availability of red blood cells (RBCs). Using a statistical, time-series approach to model the within-host 'epidemiology' of malaria, we found that increasing initial dose reduced the time to peak cell-to-cell parasite propagation, but also reduced its magnitude, while helminth co-infection delayed peak cell-to-cell propagation, except at the highest malaria doses. Using a mechanistic model of within-host infection dynamics, we identified dose-dependence in parameters describing host responses to malaria infection and uncovered a plausible explanation of the observed differences in single vs co-infections. Specifically, in co-infections, our model predicted a higher background death rate of RBCs. However, at the highest dose, when intraspecific competition between malaria parasites would be highest, these effects of co-infection were not observed. Such interactions between initial dose and co-infection, although difficult to predict a priori, are key to understanding variation in the severity of disease experienced by hosts and could inform studies of malaria transmission dynamics in nature, where co-infection and low doses are the norm.

Side-grooved Charpy impact testing: Assessment of splitting and fracture properties of high-toughness plate steels.

The fracture properties and susceptibility to crack-divider delamination (or splitting) of three commercially produced high-toughness X70 pipeline steels are evaluated with Charpy impact test samples modified to incorporate side grooves. Temperature-dependent impact data are compared with standard Charpy V-notch (CVN) and drop weight tear test data (DWTT). It is shown that the modified geometry prevents the accumulation of plastic deformation at upper shelf energy temperatures and improves the accuracy of impact properties measurements. It also promotes splitting, mirroring the splitting behavior assessed with DWTT samples. To demonstrate the effects of splitting on fracture characteristics and impact energies, steels with similar tensile properties but different splitting susceptibilities are considered. Splitting severity is maximum close to the ductile-brittle transition temperature. However, the effect of splitting on impact energy is minimum at such temperature, as this type of delamination increases energy absorption at lower temperatures and decreases it by a similar extent at higher temperatures. This finding is discussed by examination of force-displacement curves from the instrumented impact tests.

Analysis of spontaneous, user-generated data about gestational diabetes on online forums: implications for diabetes prevention.

AIMS: To explore the experiences and perceptions of gestational diabetes mellitus reported by women within online parental-support forums and, specifically, to analyse what women say about a diagnosis of gestational diabetes, their future risk of type 2 diabetes, and lifestyle behaviour for management of gestational diabetes and prevention of type 2 diabetes. METHODS: The discussion boards of two parenting websites (Mumsnet and Netmums) were searched using the search term 'gestational diabetes or GD' in February 2019. Relevant posts made by users with gestational diabetes on or after 1 January 2017 were retained for analysis. Framework analysis using pre-existing framework from a previous study was used to organize and analyse the data. RESULTS: A total of 646 posts generated by 282 unique users were included in the analysis. Analysis of the online content identified three important implicit messages that may be being conveyed to readers. The first is that gestational diabetes is not a serious diagnosis that warrants undue concern. Secondly, few users recognized the importance of their own behaviours or lifestyle, with others minimizing personal responsibility or attributing gestational diabetes to non-modifiable factors. Finally, there was a lack of acknowledgment of heightened risk of type 2 diabetes. These three messages will all directly mitigate against the efforts of clinicians (and others) to encourage women with gestational diabetes to improve their lifestyle behaviours in the longer term. CONCLUSIONS: These findings highlight messages that are being widely disseminated and that are unlikely to support prevention of type 2 diabetes.

Opioid Analgesics Do Not Improve Abdominal Pain or Quality of Life in Crohn's Disease.

BACKGROUND: Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). AIMS: We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. METHODS: We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1 year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. RESULTS: Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. CONCLUSIONS: Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.

Transfusion requirement and length of stay of anaemic surgical patients associated with a patient blood management service: a single-Centre retrospective study.

OBJECTIVE: To assess the value of patient blood management (PBM) in the detection and management of preoperative anaemia before elective surgery. BACKGROUND: PBM is recognised as the standard of care, with diagnosis and management of preoperative anaemia being the key components of PBM. No formal assessment of the value of PBM anaemia screening and correction before scheduled surgery had been made at our hospital. METHODS: We conducted a retrospective study in a tertiary-care, academic hospital of consecutive records of elective surgery (n = 25 641). We excluded minor surgeries. We identified anaemic patients who had been assessed by PBM or not (non-PBM). We calculated transfusion incidence and hospital length of stay (LOS) across all surgical specialities. RESULTS: During the 1-year study period, 15 245 patients were eligible for inclusion; 311 patients (2·0%) were transfused, and 83·3% of transfusions were in anaemic patients. Transfusion incidence was 9·2% in anaemic PBM-assessed patients and 17·4% in non-PBM patients. For haemoglobin (Hb) <100 g L-1 , the transfusion incidence was 22·1% [95% confidence interval (CI) 15·5-30·6%] in PBM and 40·0% (95% CI 35·1-45·0%) in non-PBM patients, and for Hb 100-119 g L-1 , it was 4·7% (95% CI 2·8-7·5%) and 7·9% (95% CI 6·3-9·8%), respectively. Overall mean LOS was 2·1 days [standard deviation (SD) 6·0]. Mean LOS with Hb <100 g L-1 was 6·7 days (SD 14·8) in PBM-assessed patients and 12·4 days (SD 19·5) in non-PBM patients and was 3·1 (SD 5·2) and 6·2 (SD 9·5) days, respectively, for Hb 100-119 g L-1 . CONCLUSION: Anaemic elective surgery patients assessed by patient blood management (PBM) had a markedly lower transfusion risk and shorter LOS than anaemic patients not assessed by PBM.

Optimization of foraging and diet by the piscivorous Othos dentex (Serranidae).

The aim of this study was to determine the dietary characteristics and mouth morphology of Othos dentex and to use these data, together with in situ observations of feeding behaviour, to elucidate how foraging and diet are optimized by this piscivorous serranid. Seasonal spear and line fishing over reefs in south-western Australia yielded 426 O. dentex (total length, LT , 183-605 mm), among which the stomachs of 95 contained food. The food in the stomachs of 76 fish was sufficiently undigested to be seen to contain, almost invariably, a single fish prey, which was typically identifiable to family and often to species. The prey of O. dentex, which were measured (LT ), represented 10 families, of which the Labridae and Pempheridae constituted nearly two-thirds of the prey volume. Two-way crossed analysis of similarities of volumetric data for stomach contents showed that the dietary compositions of the different length classes of O. dentex in the various seasons were significantly related to length class of prey, but not to prey family, length class within the various prey families or season. Furthermore, an inverse (Q-mode) analysis, including one-way analysis of similarities, showed that the patterns in the prey consumed by the different length classes of O. dentex in the various seasons were related more strongly to length class than prey family. The former trend is exemplified in a shade plot, by a marked diagonality of the length classes of prey with increasing predator size. The ingestion of typically a single teleost prey, whose body size increases as that of O. dentex increases, reduces the frequency required for seeking prey, thus saving energy and reducing the potential for intraspecific competition for food. The ability of O. dentex to ingest large prey is facilitated by its possession of a very large gape, prominent recurved teeth, dorsal and independently-moveable eyes, cryptic colouration and effective ambush behaviour. Othos dentex has thus evolved very cost-effective mechanisms for optimizing its foraging and diet.

Interdecadal changes in the community, population and individual levels of the fish fauna of an extensively modified estuary.

This study examined inter-period changes over two to three decades in the fish fauna of an urbanized estuary experiencing rapid population growth and a drying climate (Swan-Canning Estuary, Western Australia). Responses were compared at the fish community level (species composition; 1978-2009 in the shallows and 1993-2009 in deeper waters) and at the population and individual levels of an estuarine indicator species, black bream Acanthopagrus butcheri (biomass-abundance and per capita mass at age, respectively; 1993-2009). All three levels showed distinct shifts from earlier to later periods, but their patterns, sensitivity and breadth differed. Community composition changed markedly in the shallows of the lower-middle estuary between the late 1970s and all later periods and moderately between more disparate periods from 1995 to 2009. Several species trends could be linked to the increasing salinity of the estuary or declining dissolved oxygen levels in its middle-upper reaches. Community changes were, however, small or insignificant in the shallow and deeper waters of the upper estuary and deeper waters of the middle estuary, where environmental perturbations are often most pronounced. This may reflect the resilience of the limited suite of species that typify those reaches and thus their lack of sensitivity in reflecting longer-term change at the coarser level of mean abundance. One such species, the selected indicator, A. butcheri, did, however, show marked temporal changes at both the population and individual levels. Biomass decreased markedly in deeper waters while increasing in the shallows from earlier to later periods, presumably reflecting an onshore movement of fish, and per capita body mass in the 2+, 3+ and 4+ year classes fell steadily over time. Such changes probably indicate deteriorating habitat quality in the deeper waters. The study outcomes provide support for a multifaceted approach to the biomonitoring of estuaries using fishes and highlight the need for complementary monitoring of relevant stressors to better disentangle cause-effect pathways.

Emergence of Zika Virus Epidemic and the National Response in Jamaica.

BACKGROUND: Jamaica, along with the Americas, experienced major epidemics of arboviral diseases transmitted by the Aedes aegypti mosquito in recent years. These include dengue fever in 2012, Chikungunya fever in 2014 and Zika virus infection (ZIKV) in 2016. We present the emergence of the ZIKV epidemic in Jamaica and outline the national response. METHODS: The Ministry of Health's preparedness included: heightened surveillance, clinical management guidance, vector control and management, laboratory capacity strengthening, training and staffing, risk communication and public education, social mobilization, inter-sectoral collaboration, resource mobilization and international cooperation. RESULTS: The first case of ZIKV was confirmed on January 29, 2016 with date of onset of January 17, 2016. From January 3 to July 30, 2016 (Epidemiological Week (EW) 1-30), 4648 cases of ZIKV were recorded (4576 suspected, 72 laboratory-confirmed). Leading symptoms were similar among suspected and confirmed cases: rash (71% and 88%), fever (65% and 53%) and joint pains (47% and 38%). There were 17 suspected cases of Guillain Barre syndrome; 383 were reported in pregnant women, with no reports of microcephaly to date. Zika and dengue viruses were circulating predominantly in 2016. At EW30, 1744 cases of dengue were recorded (1661 suspected and 83 confirmed). Dengue serotypes 3 and 4 were circulating with 121 reports of dengue haemorrhagic fever. CONCLUSION: The possibility exists for endemicity of ZIKV similar to dengue and chikungunya in Jamaica. A ZIKV vaccine, similar to the dengue and chikungunya vaccines, is needed to be fast-tracked into clinical trials to mitigate the effects of this disease.

Audit and review for evidence-based red cell wastage reduction measures.

Stocks of red blood cells (RBC) are held to ideally match supply and demand; hold too great a stock and unnecessary wastage occurs; too low a stock results in delay or lack of blood for the patient. Blood is a precious resource and its supply needs to be managed effectively. The aim was to identify how RBC units are wasted and propose laboratory-based reduction measures that would not compromise the clinical requirements of the patient. Wastage of RBC was investigated using a 'dashboard' query of a laboratory information management system. By employing service improvement tools, proposals were made to reduce unnecessary RBC waste while ensuring an adequate supply to the patient. The efficacy of those proposals was examined using the same dashboard to compare similar periods before and after their introduction. The reduction in RBC wastage for all groups during an eight month period (December to July) was from 6.4% (5.3% non-AB or B RhD-positive) pre-implementation to 4.4% (2.5% non-AB/B RhD-positive) post-implementation. Group O RhD-negative wastage reduced from 10.4% to 4.4% after introduction of waste-saving proposals. However, there was an increase in staff time required to introduce the changes and in associated Group and Screen testing (3.4 to 3.8 per unit issued). RBC wastage was significantly reduced (P<0.0001) by 32.8% (52%, non-AB/B RhD-positive), saving approximately 225 RBC units per annum. Financially, increased associated costs did not negate the savings made by the measures introduced.

Dietary variations within a family of ambush predators (Platycephalidae) occupying different habitats and environments in the same geographical region.

This study has determined the extents and basis for variations in the composition of the prey ingested by the abundant species of a family highly adapted for ambush predation, i.e. Platycephalidae, in a region (south-western Australia) where that family is found in different habitats and environments. Dietary data were thus collected for Leviprora inops and Platycephalus laevigatus from seagrass in marine embayments and for Platycephalus westraliae from over sand in an estuary. These were then collated with those recorded previously for Platycephalus speculator from over sand and in seagrass in an estuary and for Platycephalus longispinis from over sand in coastal marine waters. While crustaceans and teleosts together dominated the diet of all five species, their percentage volumetric dietary contributions varied greatly, with those of crustaceans ranging from 7% for L. inops to 65% for P. speculator and those of teleosts ranging from 29% for P. longispinis to 91% for L. inops. For analyses, the data were separated into two sets. The first comprised the 17 dietary categories of invertebrates and all identified and unidentified teleosts collectively, while the second consisted of the 23 identified teleost families, both of which were subjected to permutational analysis of variance (PERMANOVA), analysis of similarities (ANOSIM) and a new (two-way) version of the RELATE procedure. The diets of three species changed seasonally, when using invertebrate dietary categories and teleosts collectively, but with only one species, when employing identified teleost families, probably reflecting a greater tendency for invertebrate than teleost prey abundance to change during the year. On the basis of dietary data for invertebrate taxa + teleosts collectively, the diets of three of the five species changed serially with body size, with a fourth species feeding, throughout life, predominantly on the carid Palaemonetes australis. Based on identified teleost families, the diets of the three species that fed predominantly on teleosts underwent serial size-related changes. Although L. inops and the co-occurring P. laevigatus both consume large volumes of teleosts, the former ingests larger, less demersal and more mobile prey, e.g. the labrids Haletta semifasciata and Neoodax balteatus, than the latter, e.g. the scorpaenid Gymnapistes marmoratus, reflecting the possession by L. inops of a far longer head and larger buccal cavity. Circumstantial evidence suggests that the large differences in the volumes of crustaceans and teleosts consumed by each platycephalid species are related to differences in the relative availability of these prey in the different habitats or environments of each species.

Defining critical habitats of threatened and endemic reef fishes with a multivariate approach.

Understanding critical habitats of threatened and endemic animals is essential for mitigating extinction risks, developing recovery plans, and siting reserves, but assessment methods are generally lacking. We evaluated critical habitats of 8 threatened or endemic fish species on coral and rocky reefs of subtropical eastern Australia, by measuring physical and substratum-type variables of habitats at fish sightings. We used nonmetric and metric multidimensional scaling (nMDS, mMDS), Analysis of similarities (ANOSIM), similarity percentages analysis (SIMPER), permutational analysis of multivariate dispersions (PERMDISP), and other multivariate tools to distinguish critical habitats. Niche breadth was widest for 2 endemic wrasses, and reef inclination was important for several species, often found in relatively deep microhabitats. Critical habitats of mainland reef species included small caves or habitat-forming hosts such as gorgonian corals and black coral trees. Hard corals appeared important for reef fishes at Lord Howe Island, and red algae for mainland reef fishes. A wide range of habitat variables are required to assess critical habitats owing to varied affinities of species to different habitat features. We advocate assessments of critical habitats matched to the spatial scale used by the animals and a combination of multivariate methods. Our multivariate approach furnishes a general template for assessing the critical habitats of species, understanding how these vary among species, and determining differences in the degree of habitat specificity.

Characteristics of the ichthyofauna of a temperate microtidal estuary with a reverse salinity gradient, including inter-decadal comparisons.

Data on the fish fauna of the Leschenault Estuary on the lower west coast of Australia were collected and used as a model to elucidate the characteristics of permanently open estuaries with a reverse salinity gradient, which undergo seasonal changes similar to many other estuaries with Mediterranean climate. Focus was placed on determining (1) the relationships of the number of species, density, life cycle category and species composition of fishes with region (within estuary), season and year and salinity, (2) whether species are partitioned along the lengths of such systems and (3) the extent and significance of any inter-decadal changes in species composition. The analyses and interpretation involved using multi-factorial permutational multivariate analysis of variance (PERMANOVA) and analysis of similarity (ANOSIM) designs, and three new or recently published visualization tools, i.e. modified non-metric multidimensional scaling (nMDS) plots, coherent species curves and segmented bubble plots. The base, lower, upper and apex regions of the Leschenault Estuary, along which the salinity increased in each season except in winter when most rainfall occurs, were sampled seasonally for the 2 years between winter 2008 and autumn 2010. Estuarine residents contributed twice as many individuals, but less than half the number of species as marine taxa. While the numbers of marine species and estuarine residents declined between the base or lower and apex regions, the individuals of marine species dominated the catches in the base region and estuarine residents in the other three regions. Ichthyofaunal composition in each region underwent conspicuous annual cyclical changes, due to time-staggered differences in recruitment among species, and changed sequentially along the estuary, both paralleling salinity trends. Different groups of species characterized the fauna in the different regions and seasons, thereby partitioning resources among species. The ichthyofauna of the apex region, in which salinities reached 54 and temperatures 36° C, recorded the highest maximum density and, in terms of abundance, was dominated (90%) by three atherinid species, emphasizing the ability of this family to tolerate extreme conditions. Comparisons between the data for 2008-2010 and 1994 demonstrate that the spotted hardyhead Craterocephalus mugiloides and the common hardyhead Atherinomorus vaigiensis had colonized and become abundant in the Leschenault Estuary in the intervening period. This represents a southwards extension of the distribution of these essentially tropical species during a period of increasing coastal water temperatures as a result of climate change. The abundance of weed-associated species, e.g. the western gobbleguts Ostorhinchus rueppellii and the soldier Gymnapistes marmoratus, increased, whereas that of the longfinned goby Favonigobius lateralis decreased, probably reflecting increases in eutrophication and siltation, respectively.

Diagnostic findings in sinonasal aspergillosis in dogs in the United Kingdom: 475 cases (2011-2021).

OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.

Myocardial substrate metabolism in obesity.

Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure.

Comparative evaluation of the potency and antigenicity of two distinct BoNT/A-derived formulations.

IncobotulinumtoxinA (Xeomin®) and onabotulinumtoxinA (BOTOX®) are unique botulinum neurotoxin type A (BoNT/A)-derived drugs. IncobotulinumtoxinA utilizes the naked 150 kDa holotoxin portion of BoNT/A, whereas onabotulinumtoxinA uses the complete native 900 kDa complex as drug substance. On the basis of purportedly similar pharmacological characteristics, these formulations were evaluated for potency by LD50 and mouse Digit Abduction Score (DAS) bioassays. DAS was also used to assess antigenicity. Full-range DAS dose-response profiles were achieved with four lots of each product, with similar observations between lots for a given product. Between products, however, the mean DAS potency of incobotulinumtoxinA (ED50 range 7.0-10.2 U/kg) was significantly lower than that of onabotulinumtoxinA (ED50 range 4.4-6.4 U/kg), consistent with lower measured potencies in the LD50 assay for incobotulinumtoxinA (potency range 62-82 U). In assessments of DAS duration of effect at similar unit doses, the observed lower potency of incobotulinumtoxinA translated into decreased peak efficacy and dose effect over time (i.e. shorter duration). In contrast, at equi-efficacious doses yielding near-maximal DAS responses, both toxin formulations were uniformly inhibited in a statistically significant manner when preincubated with rabbit-derived, onabotulinumtoxinA-neutralizing antibodies, supporting the position that inhibition of 150 kDa holotoxin serves as the common basis for neutralization and, therefore, incobotulinumtoxinA would not be expected to be effective in onabotulinumtoxinA-immunoresistant subjects (and vice versa). Further, with lower lot-to-lot relative potency, incobotulinumtoxinA is not dose-equivalent or interchangeable with onabotulinumtoxinA, suggesting that various aspects of drug product formulation may influence observed pharmacology.

Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.

Although the link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established, the role, if any, of BRCA1 in non-familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non-familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear, to conditionally nuclear, to the ER/golgi, to cytoplasmic invaginations into the nucleus. In an attempt to resolve this issue, we have comprehensively characterized 19 anti-BRCA1 antibodies. These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.

Perinatal autopsy rates at the University Hospital of the West Indies: 2002-2008.

OBJECTIVES: High perinatal autopsy rates are necessary for institutional management protocols and national policy-making. This study reviews perinatal autopsy rates and factors affecting these rates at the University Hospital of the West Indies. METHOD: All perinatal deaths (stillborn infants > or = 24 weeks gestation or 500 g; early neonatal deaths ie 0-7 days old) at the University Hospital of the West Indies, between January 2002 and December 2008, were reviewed retrospectively, using the annual perinatal audit records. The annual autopsy rates were calculated and the reasons why autopsies were not done examined. RESULTS: The average stillbirth (SB) autopsy rate was 59.6% (range 51.9 - 76.7%), while that for early neonatal deaths (ENDs) was 47.9% (range 34.4 - 63.2), with an overall average perinatal autopsy rate of 54.0% (range 42.2 - 62.2). Autopsies were requested in 79.3% and 51.7% of SBs and ENDs, respectively. Of those requested, 81.7% were done (75.2% stillbirths; 92.5% ENDs). In the ENDs, failure to request an autopsy was predominantly noted in premature infants weighing < 1000 g (75.2% of those not requested). In stillbirths, the reasons for failure to request were largely unknown with failure to gain permission accounting for only 20.3% of these cases. CONCLUSIONS: The average annual perinatal autopsy rate at the University Hospital of the West Indies between 2002 and 2008 was 54.0%. This is below the internationally recommended rate of 75%. Failure to request an autopsy was the most significant factor contributing to this. The reasons for this are not entirely clear and require further study.