Dissecting a wildlife disease hotspot: the impact of multiple host species, environmental transmission and seasonality in migration, breeding and mortality.

Avian influenza viruses (AIVs) have been implicated in all human influenza pandemics in recent history. Despite this, surprisingly little is known about the mechanisms underlying the maintenance and spread of these viruses in their natural bird reservoirs. Surveillance has identified an AIV 'hotspot' in shorebirds at Delaware Bay, in which prevalence is estimated to exceed other monitored sites by an order of magnitude. To better understand the factors that create an AIV hotspot, we developed and parametrized a mechanistic transmission model to study the simultaneous epizootiological impacts of multi-species transmission, seasonal breeding, host migration and mixed transmission routes. We scrutinized our model to examine the potential for an AIV hotspot to serve as a 'gateway' for the spread of novel viruses into North America. Our findings identify the conditions under which a novel influenza virus, if introduced into the system, could successfully invade and proliferate.

The consequences of climate change at an avian influenza 'hotspot'.

Avian influenza viruses (AIVs) pose significant danger to human health. A key step in managing this threat is understanding the maintenance of AIVs in wild birds, their natural reservoir. Ruddy turnstones (Arenaria interpres) are an atypical bird species in this regard, annually experiencing high AIV prevalence in only one location-Delaware Bay, USA, during their spring migration. While there, they congregate on beaches, attracted by the super-abundance of horseshoe crab eggs. A relationship between ruddy turnstone and horseshoe crab (Limulus polyphemus) population sizes has been established, with a declining horseshoe crab population linked to a corresponding drop in ruddy turnstone population sizes. The effect of this interaction on AIV prevalence in ruddy turnstones has also been addressed. Here, we employ a transmission model to investigate how the interaction between these two species is likely to be altered by climate change. We explore the consequences of this modified interaction on both ruddy turnstone population size and AIV prevalence and show that, if climate change leads to a large enough mismatch in species phenology, AIV prevalence in ruddy turnstones will increase even as their population size decreases.

Mathematical Modeling of Viral Zoonoses in Wildlife.

Zoonoses are a worldwide public health concern, accounting for approximately 75% of human infectious diseases. In addition, zoonoses adversely affect agricultural production and wildlife. We review some mathematical models developed for the study of viral zoonoses in wildlife and identify areas where further modeling efforts are needed.

The role of optimal control in assessing the most cost-effective implementation of a vaccination programme: HPV as a case study.

Vaccination against the human papillomavirus (HPV) is a recent development in the UK. This paper uses an optimal control model to explore how best to target vaccination. We find that the vaccination of sexually active individuals has a greater impact on disease control than the vaccination of sexually non-active individuals. Extending the model to include male vaccination, we find that including males in a vaccination strategy is cost-effective. We compare the optimal control solution to that from a constant control model and show that the optimal control model is more efficient at forcing the system to a disease-controlled steady state.

Multiple aggressive squamous skin cancers in association with nonbullous congenital ichthyosiform erythroderma.

Nonbullous congenital ichthyosiform erythroderma (NBCIE) is one of the autosomal recessive inherited non-syndromic ichthyoses and is currently diagnosed on clinical grounds alone. Skin cancer is not a recognized complication of NBCIE. We report here two NBCIE patients who have developed multiple aggressive nonmelanoma skin cancers, predominantly cutaneous squamous cell carcinoma. NBCIE may be a risk factor for skin cancer development.

Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals.

BACKGROUND: Viral warts may cause significant morbidity in individuals unable to mount an adequate T-helper 1 cell-mediated immune response to human papillomavirus. Imiquimod is a potent inducer of antiviral cytokine activity which has shown significant efficacy in the treatment of genital warts. Similar efficacy in cutaneous warts is not yet established. OBJECTIVES: To assess the response of persistent cutaneous warts to 5% imiquimod cream in immunosuppressed individuals. METHODS: Fifteen immunosuppressed patients with warts on the hands and/or feet present for more than 18 months, which had failed to respond to a minimum of 12 weeks of topical salicylic acid and four cycles of cryotherapy, were recruited. Imiquimod 5% cream was applied in an open label, right vs. left comparison study for 24 weeks (three times weekly for 8 weeks, daily for 8 weeks, then daily with occlusion for 8 weeks). RESULTS: Twelve (80%) patients completed the study protocol. Benefit was seen in five patients [36% in the intent-to-treat analysis (14 patients)], including more than 30% clearance of warts in three patients and reduction in overall size of warts in two further cases. Local skin reactions occurred in four (29%) patients and were usually mild. A transient rise in creatinine (11-29% above baseline) was measured in three renal transplant recipients, but we did not consider that this was related to imiquimod exposure. CONCLUSIONS: This is the first controlled study to assess therapeutic efficacy of topical 5% imiquimod cream in persistent warts associated with immunosuppression. It provides preliminary evidence that topical imiquimod may benefit a subgroup of immunosuppressed patients with recalcitrant cutaneous warts.

Lack of mutations within ST7 gene in tumour-derived cell lines and primary epithelial tumours.

ST7 is a candidate tumour suppressor gene at human chromosome locus 7q31.1. We have performed mutational analysis of ST7 in a wide-range of cell lines and primary epithelial cancers and detected only one missense change in a breast cancer cell line. Other mutations previously found in cell lines and primary tumours were not evident in our analysis. These results imply that another tumour suppressor gene at this locus may be more important than ST7 in carcinogenesis.

Reinforcement by orally delivered methadone, cocaine, and methadone-cocaine combinations in rhesus monkeys: are the combinations better reinforcers?

RATIONALE: Polydrug abuse is a problem that has been infrequently examined. In the present study, drug self-administration procedures were used to investigate the reinforcing effects of drug combinations. OBJECTIVES: To determine the absolute and relative response rates maintained by orally delivered methadone, cocaine, and their combinations under sequential and concurrent access. Choice between drug combinations containing different concentrations of cocaine was also determined. METHODS: Oral intake of methadone, cocaine, and their combinations was studied with rhesus monkeys during daily 3-h sessions. Lip contact (the operant response) was reinforced by delivery of liquid contingent upon completion of a fixed-ratio schedule. In one series, the drugs and drug combinations were studied sequentially with the water vehicle concurrently available. In the next series, the drugs and drug combinations were concurrently available. In the third series, pairs of drug combinations containing different concentrations of cocaine were also concurrently available. RESULTS: Methadone, cocaine and their combinations functioned as reinforcers. Under sequential access, response rates for the drug combinations and the component drugs were often similar. However, under concurrent access, response rates for the drug combinations were greater than response rates for the component drugs at the highest FR size for each condition. Also, drug combinations containing higher cocaine concentrations were preferred to combinations containing lower cocaine concentrations. CONCLUSIONS: Combinations of methadone and cocaine have relatively greater reinforcing effects than the component drugs, and these greater reinforcing effects are better detected with concurrent measures than with sequential measures.

Sertraline in children and adolescents with social anxiety disorder: an open trial.

OBJECTIVE: The aim of this open-label study was to assess the therapeutic benefits, response pattern, and safety of sertraline in children with social anxiety disorder. METHOD: Fourteen outpatient subjects with a primary Axis I diagnosis of social anxiety disorder were treated in an 8-week open trial of sertraline. Diagnostic and primary outcome measures included the Anxiety Disorders Interview Schedule for Children, Clinical Global Impressions scale (CGI), Social Phobia and Anxiety Inventory for Children, and a standardized behavioral avoidance test. RESULTS: As measured by the CGI (Improvement subscale), 36% (5/14) of subjects were classified as treatment responders and 29% (4/14) as partial responders by the end of the 8-week trial. A significant clinical response appeared by week 6. Self-report and behavioral measures showed significant clinical improvement into normal range across all domains measured. The mean dose of sertraline was 123.21+/-37.29 mg per day. Sertraline was generally well tolerated. CONCLUSION: In open treatment, sertraline resulted in significant improvement in symptoms of childhood social anxiety disorder. Absolute response rates varied depending on rating scales used. Findings from this study are sufficiently strong to warrant a future multisite, randomized, double-blind, placebo-controlled trial of sertraline for treatment of childhood social anxiety disorder.

Species- and brain region-specific dopamine transporters: immunological and glycosylation characteristics.

Dopamine transporters (DATs) from the caudate nucleus of four species (rat, mouse, dog, and human) and four regions of rat brain (striatum, nucleus accumbens, prefrontal cortex, and midbrain) were photoaffinity labeled and analyzed by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis for cross-reactivity to four epitope-specific rat antipeptide antibodies. Each of these antibodies varied in its efficiency at recognizing DAT. The DATs from the rat brain regions exhibited the same degree of recognition by each of the four sera, a result compatible with these proteins being the product of a single gene. The DATs from the different species were recognized by all four sera but with different efficiencies, possibly relating to amino acid sequence differences within the immunizing epitope. All of the photolabeled, immunoprecipitated DATs migrated with a molecular mass of approximately 80 kDa, and no lower molecular mass forms were found. The DATs from all species and brain regions tested were shown by enzymatic deglycosylation to contain N-linked carbohydrates and sialic acids in amounts comparable with rat striatal DATs. The finding that no photolabeled DAT forms < 80 kDa were isolated from membranes indicates that partially or incompletely glycosylated forms are not present, even in the midbrain cell bodies where immature forms might be expected to be found. These findings verify the utility of these anti-rat antibodies as biochemical tools for studying DATs from other species and extend our knowledge of biochemical characteristics of DATs from these species and brain regions.

Effects of non-right-handedness on risk for sudden death associated with coronary artery disease.

The hypothesis that non-right-handedness is associated with sudden cardiac death was tested based on evidence that sympathetic imbalance may contribute to ventricular arrhythmogenesis and evidence that left-handers may have a shorter lifespan than right-handers. The study included 26 patients with coronary artery disease (CAD), a history of ventricular tachycardia-ventricular fibrillation (VT-VF), and implanted defibrillators, and 26 patients with CAD and no history of serious arrhythmias who were matched for age, sex, and New York Heart Association functional class. Patients with any history of neurologic disorders were excluded. Left-handers either wrote with the left hand or were converted from left- to right-handedness in childhood. Non-right-handers used the left hand for writing, drawing, or throwing. Handedness rates in patients with VT-VF and case-control subjects were compared with published norms in the general population to take expected rates into account. The rates of left-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with VT-VF were significantly higher (p < 0.003 and p < 0.0001, 2-tailed, respectively) than those of similarly aged adults in the general population (left-handedness, 5%; non-right-handedness, 10.2%). The rates of left-handedness (2 of 26 or 7.7%) and non-right-handedness (4 of 26 or 15.4%) observed in the case-control group correspond closely to the expected values for that group (left-handedness, 1.3 of 26 or 5%; non-right-handedness, 2.65 of 26 or 10.2%) derived from the general population rates and were not significantly different from them.(ABSTRACT TRUNCATED AT 250 WORDS)