Updating the epidemiological transition model.

The main feature of the epidemiological transition is a shift in the recorded causes of death from infectious diseases to other morbid conditions. This paper outlines modifications made to Omran's original model and stages of transition, and suggests that without a focus on aetiology and morbidity, these have been basically descriptive rather than explanatory, and potentially misleading because infections have been confirmed as causes of various chronic diseases. Common infections and related immune responses or inflammatory processes contribute to the multifactorial aetiology of morbid conditions that together make a substantial contribution to overall mortality, and infectious causation is suspected for many others because of strong evidence of association. Investigation into possible infectious causes of conditions frequently recorded as the underlying cause of death can be integrated into a framework for comparative research on patterns of disease and mortality in support of public health and prevention. A theory of epidemiological transition aimed at understanding changes in disease patterns can encompass the role in different conditions and chronic diseases of infections contracted over the life course, and their contribution to disability, morbidity and mortality relative to other causes and determinants.

Selecting for a sustainable workforce to meet the future healthcare needs of rural communities in Australia.

An undersupply of generalists doctors in rural communities globally led to widening participation (WP) initiatives to increase the proportion of rural origin medical students. In 2002 the Australian Government mandated that 25% of commencing Australian medical students be of rural origin. Meeting this target has largely been achieved through reduced standards of entry for rural relative to urban applicants. This initiative is based on the assumption that rural origin students will succeed during training, and return to practice in rural locations. One aim of this study was to determine the relationships between student geographical origin (rural or urban), selection scores, and future practice intentions of medical students at course entry and course exit. Two multicentre databases containing selection and future practice preferences (location and specialisation) were combined (5862), representing 54% of undergraduate medical students commencing from 2006 to 2013 across nine Australian medical schools. A second aim was to determine course performance of rural origin students selected on lower scores than their urban peers. Selection and course performance data for rural (461) and urban (1431) origin students commencing 2006-2014 from one medical school was used. For Aim 1, a third (33.7%) of rural origin students indicated a preference for future rural practice at course exit, and even fewer (6.7%) urban origin students made this preference. Results from logistic regression analyses showed significant independent predictors were rural origin (OR 4.0), lower Australian Tertiary Admissions Rank (ATAR) (OR 2.1), or lower Undergraduate Medical and Health Sciences Admissions Test Section 3 (non-verbal reasoning) (OR 1.3). Less than a fifth (17.6%) of rural origin students indicated a preference for future generalist practice at course exit. Significant predictors were female gender (OR 1.7) or lower ATAR (OR 1.2), but not rural origin. Fewer (10.5%) urban origin students indicated a preference for generalist practice at course exit. For Aim 2, results of Mann-Whitney U tests confirmed that slightly reducing selection scores does not result in increased failure, or meaningfully impaired performance during training relative to urban origin students. Our multicentre analysis supports success of the rural origin WP pathway to increase rural student participation in medical training. However, our findings confirm that current selection initiatives are insufficient to address the continuing problem of doctor maldistribution in Australia. We argue for further reform to current medical student selection, which remains largely determined by academic meritocracy. Our findings have relevance to the selection of students into health professions globally.

Use of the Atlantic nut clam (Nucula proxima) and catworm (Nephtys incisa) in a sentinel species approach for monitoring the health of Bay of Fundy estuaries.

Designing an effective environmental monitoring system for population responses requires knowledge of the biology of appropriate sentinel species and baseline information on the area's physical and chemical characteristics. This study collected information in Saint John Harbor, NB, Canada, for two abundant marine benthic invertebrates, the Atlantic nut clam (Nucula proxima) and the catworm (Nephtys incisa) to characterize their seasonal and spatial variability, determine the ideal sampling time and methods, and develop baseline data for future studies. We also evaluated whether contamination is impacting invertebrates by comparing sediment metal concentrations to responses of benthic infauna. Metals were generally below sediment quality guidelines except for nickel and arsenic. Clam densities were variable between sites but not seasons, whereas catworm densities were not significantly different between sites or seasons. Overall, these species show potential for environmental monitoring, although investigation at more contaminated sites is warranted to assess their sensitivity.

Long-term trends in cardiovascular disease mortality and association with respiratory disease.

The recent decline in cardiovascular disease mortality in Western countries has been linked with changes in life style and treatment. This study considers periods of decline before effective medical interventions or knowledge about risk factors. Trends in annual age-standardized death rates from cerebrovascular disease, heart disease and circulatory disease, and all cardiovascular disease are reviewed for three phases, 1881-1916, 1920-1939, and 1940-2000. There was a consistent decline in the cerebrovascular disease death rate between 1891 and 2000, apart from brief increases after the two world wars. The heart disease and circulatory disease death rate was declining between 1891 and 1910 before cigarette smoking became prevalent. The early peak in cardiovascular mortality in 1891 coincided with an influenza pandemic and a peak in the death rate from bronchitis, pneumonia and influenza. There is also correspondence between short-term fluctuations in the death rates from these respiratory diseases and cardiovascular disease. This evidence of ecological association is consistent with the findings of many studies that seasonal influenza can trigger acute myocardial infarction and episodes of respiratory infection are followed by increased risk of cardiovascular events. Vaccination studies could provide more definitive evidence of the role in cardiovascular disease and mortality of influenza, other viruses, and common bacterial agents of respiratory infection.

Infrared lidar observations of stratospheric aerosols.

We observed the stratospheric aerosol layer at 34° north latitude with a photon-counting 1574 nm lidar on three occasions in 2011. During all of the observations, we also operated a nearby 523.5 nm micropulse lidar and acquired National Weather Service upper air data. We analyzed the lidar data to find scattering ratio profiles and the integrated aerosol backscatter at both wavelengths and then calculated the color ratio and wavelength exponent for lidar backscattering from the stratospheric aerosols. The visible-light integrated backscatter values of the layer were in the range 2.8-3.5×10⁻4 sr⁻¹ and the infrared integrated backscatter values ranged from 2.4 to 3.7×10⁻5 sr⁻¹. The wavelength exponent was determined to be 1.9±0.2.

Relationship of selection criteria to subsequent academic performance in an Australian undergraduate dental school.

In 1998, in addition to previous academic achievement, an aptitude test (UMAT) and a structured interview were introduced into selection for the Bachelor of Dental Science (BDSc), the undergraduate dental course at the University of Western Australia. The aim of this study was to determine the relationship between the combination of school-leaver dental students' entry scores, some demographic characteristics and subsequent student performance in the undergraduate course. Three hundred and ninety-eight school-leavers who enrolled in the BDSc from 1999 through 2011 were studied. Regression models were constructed comprising entry scores, gender and age as predictors in relation to subsequent academic performance. The main outcome measure was the weighted average mark (WAM) for each of five academic year levels as well as results in specific units, defined as either 'knowledge' based or 'clinically' based. Of the variables studied, previous academic performance and female gender had the strongest relationship with yearly WAM for Years 1 through 4 and for both 'knowledge' based and 'clinically' based units. The interview score showed a strong relationship in the major clinical years and in a range of 'clinically' based units. UMAT scores were less consistent in relationship to WAM. These results support assessment through a highly structured interview together with prior academic achievement as an evidence-based approach to selection of students for this undergraduate dental course.

Therapeutic immunomodulation using a virus--the potential of inactivated orf virus.

Viruses can manipulate the immune response against them by various strategies to influence immune cells, i.e. by over-activation leading to functional inactivation, bypassing antigen presentation or even suppression of effector functions. Little is known, however, about how these features of immune regulation and modulation could be used for therapeutic purposes. Reasons for this include the complexity of immune regulatory mechanisms under certain disease conditions and the risks that infections with viruses pose to human beings. The orf virus (ORFV), a member of the Parapoxvirus genus of the poxvirus family, is known as a common pathogen in sheep and goats worldwide. The inactivated ORFV, however, has been used as a preventative as well as therapeutic immunomodulator in veterinary medicine in different species. Here, we review the key results obtained in pre-clinical studies or clinical studies in veterinary medicine to characterise the therapeutic potential of inactivated ORFV. Inactivated ORFV has strong effects on cytokine secretion in mice and human immune cells, leading to an auto-regulated loop of initial up-regulation of inflammatory and Th1-related cytokines, followed by Th2-related cytokines that attenuate immunopathology. The therapeutic potential of inactivated ORFV has been recognised in several difficult-to-treat disease areas, such as chronic viral diseases, liver fibrosis or various forms of cancer. Further research will be required in order to evaluate the full beneficial potential of inactivated ORFV for therapeutic immunomodulation.

Delivery of Echinococcus granulosus antigen EG95 to mice and sheep using recombinant vaccinia virus.

The tapeworm Echinococcus granulosus is the causative agent of hydatid disease and affects sheep, cattle, dogs and humans worldwide. It has a two-stage life cycle existing as worms in the gut of infected dogs (definitive host) and as cysts in herbivores and humans (intermediate host). The disease is debilitating and can be life threatening where the cysts interfere with organ function. Interruption of the hydatid life cycle in the intermediate host by vaccination may be a way to control the disease, and a protective oncosphere antigen EG95 has been shown to protect animals against challenge with E. granulosus eggs. We explored the use of recombinant vaccinia virus as a delivery vehicle for EG95. Mice and sheep were immunized with the recombinant vector, and the result monitored at the circulating antibody level. In addition, sera from immunized mice were assayed for the ability to kill E. granulosus oncospheres in vitro. Mice immunized once intranasally developed effective oncosphere-killing antibody by day 42 post-infection. Antibody responses and oncosphere killing were correlated and were significantly enhanced by boosting mice with either EG95 protein or recombinant vector. Sheep antibody responses to the recombinant vector or to EG95 protein mirrored those in mice.

Location of release sites and calcium-activated chloride channels relative to calcium channels at the photoreceptor ribbon synapse.

Vesicle release from photoreceptor ribbon synapses is regulated by L-type Ca(2+) channels, which are in turn regulated by Cl(-) moving through calcium-activated chloride [Cl(Ca)] channels. We assessed the proximity of Ca(2+) channels to release sites and Cl(Ca) channels in synaptic terminals of salamander photoreceptors by comparing fast (BAPTA) and slow (EGTA) intracellular Ca(2+) buffers. BAPTA did not fully block synaptic release, indicating some release sites are <100 nm from Ca(2+) channels. Comparing Cl(Ca) currents with predicted Ca(2+) diffusion profiles suggested that Cl(Ca) and Ca(2+) channels average a few hundred nanometers apart, but the inability of BAPTA to block Cl(Ca) currents completely suggested some channels are much closer together. Diffuse immunolabeling of terminals with an antibody to the putative Cl(Ca) channel TMEM16A supports the idea that Cl(Ca) channels are dispersed throughout the presynaptic terminal, in contrast with clustering of Ca(2+) channels near ribbons. Cl(Ca) currents evoked by intracellular calcium ion concentration ([Ca(2+)](i)) elevation through flash photolysis of DM-nitrophen exhibited EC(50) values of 556 and 377 nM with Hill slopes of 1.8 and 2.4 in rods and cones, respectively. These relationships were used to estimate average submembrane [Ca(2+)](i) in photoreceptor terminals. Consistent with control of exocytosis by [Ca(2+)] nanodomains near Ca(2+) channels, average submembrane [Ca(2+)](i) remained below the vesicle release threshold (∼ 400 nM) over much of the physiological voltage range for cones. Positioning Ca(2+) channels near release sites may improve fidelity in converting voltage changes to synaptic release. A diffuse distribution of Cl(Ca) channels may allow Ca(2+) influx at one site to influence relatively distant Ca(2+) channels.

Mechanism-based bioanalysis and biomarkers for hepatic chemical stress.

Adverse drug reactions, in particular drug-induced hepatotoxicity, represent a major challenge for clinicians and an impediment to safe drug development. Novel blood or urinary biomarkers of chemically-induced hepatic stress also hold great potential to provide information about pathways leading to cell death within tissues. The earlier pre-clinical identification of potential hepatotoxins and non-invasive diagnosis of susceptible patients, prior to overt liver disease is an important goal. Moreover, the identification, validation and qualification of biomarkers that have in vitro, in vivo and clinical transferability can assist bridging studies and accelerate the pace of drug development. Drug-induced chemical stress is a multi-factorial process, the kinetics of the interaction between the hepatotoxin and the cellular macromolecules are crucially important as different biomarkers will appear over time. The sensitivity of the bioanalytical techniques used to detect biological and chemical biomarkers underpins the usefulness of the marker in question. An integrated analysis of the biochemical, molecular and cellular events provides an understanding of biological (host) factors which ultimately determine the balance between xenobiotic detoxification, adaptation and liver injury. The aim of this review is to summarise the potential of novel mechanism-based biomarkers of hepatic stress which provide information to connect the intracellular events (drug metabolism, organelle, cell and whole organ) ultimately leading to tissue damage (apoptosis, necrosis and inflammation). These biomarkers can provide both the means to inform the pharmacologist and chemist with respect to safe drug design, and provide clinicians with valuable tools for patient monitoring.

Conservation and variation of the parapoxvirus GM-CSF-inhibitory factor (GIF) proteins.

The GIF protein of orf virus (ORFV) binds and inhibits the ovine cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). An equivalent protein has so far not been found in any of the other poxvirus genera and we therefore investigated whether it was conserved in the parapoxviruses. The corresponding genes from both the bovine-specific pseudocowpox virus (PCPV) and bovine papular stomatitis virus (BPSV) were cloned and sequenced. The predicted amino acid sequences of the PCPV and BPSV proteins shared 88 and 37 % identity, respectively, with the ORFV protein. Both retained the six cysteine residues and the WSXWS-like motif that are required for biological activity of the ORFV protein. However, an analysis of the biological activity of the two recombinant proteins revealed that, whilst the PCPV GIF protein bound to both ovine and bovine GM-CSF and IL-2 with very similar binding affinities to the ORFV GIF protein, no GM-CSF- or IL-2-binding activity was found for the BPSV protein.

Recurrent localised cutaneous parapoxvirus infection in three cats.

CASE HISTORY: Three cats were presented with single proliferative lesions affecting one foot, which failed to heal after medical treatment, and recurred despite surgical resection. PATHOLOGICAL FINDINGS: Histologically, the lesions were proliferative and papillary. There was marked acanthosis, rete peg formation, and compact orthokeratosis, with large numbers of bacteria in the orthokeratotic scale. Some biopsies had multifocal keratinocyte swelling of the stratum granulosum, and amphophilic intracytoplasmic inclusions were present in some of the swollen cells. The dermis consisted of a light fibrous stroma with marked capillary proliferation. Parapoxviruses were detected in the lesions of all cats by electron microscopic examination. PCR analysis detected orf virus (contagious ecthyma virus) in two cats, and orf virus was cultured from one cat. DIAGNOSIS: Parapoxvirus infection in cats. CLINICAL RELEVANCE: Parapoxvirus infection should be considered as a differential diagnosis when dealing with proliferative, non-healing lesions on the feet of cats, especially cats in rural areas. The recovery of orf virus from a cat with typical poxvirus lesions extends the range of species affected by this virus.

PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity.

Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular monoamine transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage.

Plateau potentials in developing antennal-lobe neurons of the moth, Manduca sexta.

Using whole cell recordings from antennal-lobe (AL) neurons in vitro and in situ, in semi-intact brain preparations, we examined membrane properties that contribute to electrical activity exhibited by developing neurons in primary olfactory centers of the brain of the sphinx moth, Manduca sexta. This activity is characterized by prolonged periods of membrane depolarization that resemble plateau potentials. The presence of plateau potential-generating mechanisms was confirmed using a series of tests established earlier. Brief depolarizing current pulses could be used to trigger a plateau state. Once triggered, plateau potentials could be terminated by brief pulses of hyperpolarizing current. Both triggering and terminating of firing states were threshold phenomena, and both conditions resulted in all-or-none responses. Rebound excitation from prolonged hyperpolarizing pulses could also be used to generate plateau potentials in some cells. These neurons were found to express a hyperpolarization-activated inward current. Neither the generation nor the maintenance of plateau potentials was affected by removal of Na+ ions from the extracellular medium or by blockade of Na+ currents with TTX. However, blocking of Ca2+ currents with Cd2+ (5 x 10(-4) M) inhibited the generation of plateau potentials, indicating that, in Manduca AL neurons, plateau potentials depend on Ca2+. Examining Ca2+ currents in isolation revealed that activation of these currents occurs in the absence of experimentally applied depolarizing stimuli. Our results suggest that this activity underlies the generation of plateau potentials and characteristic bursts of electrical activity in developing AL neurons of M. sexta.

Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation.

The antiepileptic drug lamotrigine (LTG) is known to reduce cortical excitability evaluated by transcranial magnetic stimulation (TMS). We investigated the relationship between LTG oral dosages, serum levels and inhibitory effects on resting motor threshold (RMT), a parameter of motor system excitability assessed by TMS. In a randomized, placebo-controlled crossover study 16 male volunteers received 325 mg LTG as a single dose, as bi-hourly graded cumulative dose, or placebo. RMT and serum levels were measured before and after 2-8 h. With single dose, RMT elevation showed a poor but significant correlation to serum levels. With graded dose, serum levels as well as RMT increased dose-dependently with significant (P<0.0001) linear correlation. However, detailed comparison showed a high inter-individual variability in the relationship resembling a sigmoid correlation. Different mechanisms besides the sodium-channel blockage as the main mode of action of LTG are discussed to explain the diversity of individual dose-response relationships. Provided that the RMT elevation reflects the antiepileptic potential of LTG, TMS may be developed as a tool to monitor interindividual response of epilepsy patients to LTG treatment as well as to explore efficacy of other antiepileptic drugs with similar mode of action.

Construction of a recombinant orf virus that expresses an Echinococcus granulosus vaccine antigen from a novel genomic insertion site.

The potential of recombinant poxviruses as expression vectors has been extensively studied using Vaccinia virus but there has been only limited transfer of this technology to the Parapoxvirus genus. We detail here the construction of a recombinant Orf virus that expresses an antigenic peptide (EG95) of the causative agent of cystic hydatid disease, Echinococcus granulosus. Expression of this foreign antigen was regulated by a synthetic early/late poxvirus transcriptional promoter and levels of expression comparable to that achieved by a similar vaccinia virus recombinant were observed. The expression cassette was inserted into a unique orf virus gene (G1L) thereby confirming the non-essential nature of that gene and identifying a novel genomic insertion site. This recombinant will be a valuable tool with which to assess the potential of recombinant orf viruses to deliver vaccine antigens to sheep.