Backward bifurcation, equilibrium and stability phenomena in a three-stage extended BRSV epidemic model

In this paper we consider the phenomenon of backward bifurcation in epidemic modelling illustrated by an extended model for Bovine Respiratory Syncytial Virus (BRSV) amongst cattle. In its simplest form, backward bifurcation in epidemic models usually implies the existence of two subcritical endemic equilibria for R 0 < 1, where R 0 is the basic reproductive number, and a unique supercritical endemic equilibrium for R 0 > 1. In our three-stage extended model we find that more complex bifurcation diagrams are possible. The paper starts with a review of some of the previous work on backward bifurcation then describes our three-stage model. We give equilibrium and stability results, and also provide some biological motivation for the model being studied. It is shown that backward bifurcation can occur in the three-stage model for small b, where b is the common per capita birth and death rate. We are able to classify the possible bifurcation diagrams. Some realistic numerical examples are discussed at the end of the paper, both for b small and for larger values of b

CorNet : assigning function to networks of co-evolving residues by automated literature mining

CorNet is a web-based tool for the analysis of co-evolving residue positions in protein superfamily sequence alignments. CorNet projects external information such as mutation data extracted from literature on interactively displayed groups of co-evolving residue positions to shed light on the functions associated with these groups and the residues in them. We used CorNet to analyse six enzyme super-families and found that groups of strongly co-evolving residues tend to consist of residues involved in a same function such as activity, specificity, co-factor binding, or enantioselectivity. This finding allows to assign a function to residues for which no data is available yet in the literature. A mutant library was designed to mutate residues observed in a group of co-evolving residues predicted to be involved in enantioselectivity, but for which no literature data is available yet. The resulting set of mutations indeed showed many instances of increased enantioselectivity

GP-initiated preconception counselling in a randomised controlled trial does not induce anxiety

BACKGROUND: Preconception counselling (PCC) can reduce adverse pregnancy outcome by addressing risk factors prior to pregnancy. This study explores whether anxiety is induced in women either by the offer of PCC or by participation with GP-initiated PCC. METHODS: Randomised trial of usual care versus GP-initiated PCC for women aged 18–40, in 54 GP practices in the Netherlands. Women completed the six-item Spielberger State Trait Anxiety Inventory (STAI) before PCC (STAI-1) and after (STAI-2). After pregnancy women completed a STAI focusing on the first trimester of pregnancy (STAI-3). RESULTS: The mean STAI-1-score (n = 466) was 36.4 (95% CI 35.4 – 37.3). Following PCC there was an average decrease of 3.6 points in anxiety-levels (95% CI, 2.4 – 4.8). Mean scores of the STAI-3 were 38.5 (95% CI 37.7 – 39.3) in the control group (n = 1090) and 38.7 (95% CI 37.9 – 39.5) in the intervention group (n = 1186). CONCLUSION: PCC from one's own GP reduced anxiety after participation, without leading to an increase in anxiety among the intervention group during pregnancy. We therefore conclude that GPs can offer PCC to the general population without fear of causing anxiety. Trial Registration: ISRCTN5394291

Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers

Contains fulltext : 73592.pdf (publisher's version ) (Open Access)RATIONALE: In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. OBJECTIVE: The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. MATERIALS AND METHODS: We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime. RESULTS: Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. CONCLUSIONS: Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function

Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.</p> <p>Methods</p> <p>Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.</p> <p>Results</p> <p>Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.</p> <p>Conclusions</p> <p>In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.</p

Differential effects of Atomoxetine on executive functioning and lexical decision in Attention-Deficit/Hyperactivity Disorder and Reading Disorder

Objective: The effects of a promising pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), atomoxetine, were studied on executive functions in both ADHD and reading disorder (RD) because earlier research demonstrated an overlap in executive functioning deficits in both disorders. In addition, the effects of atomoxetine were explored on lexical decision. Methods: Sixteen children with ADHD, 20 children with ADHD + RD, 21 children with RD, and 26 normal controls were enrolled in a randomized placebo-controlled crossover study. Children were measured on visuospatial working memory, inhibition, and lexical decision on the day of randomization and following two 28-day medication periods. Results: Children with ADHD + RD showed improved visuospatial working memory performance and, to a lesser extent, improved inhibition following atomoxetine treatment compared to placebo. No differential effects of atomoxetine were found for lexical decision in comparison to placebo. In addition, no effects of atomoxetine were demonstrated in the ADHD and RD groups. Conclusion: Atomoxetine improved visuospatial working memory and to a lesser degree inhibition in children with ADHD + RD, which suggests differential developmental pathways for co-morbid ADHD + RD as compared to ADHD and RD alone

Total 18F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour

Positron emission tomography (PET) using 6-[(18)F]fluoro-L-dihydroxyphenylalanine ((18)F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. (18)F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total (18)F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. Seventy-seven consecutive carcinoid patients who underwent an (18)F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on (18)F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. (18)F-dopa PET detected 979 lesions. SUV(max) on (18)F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. Tumour load per patient measured with (18)F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity

Enhanced diagnostic immunofluorescence using biopsies transported in saline

BACKGROUND: The demonstration of tissue-bound immunoreactants by direct immunofluorescence microscopy (DIF) is a valuable parameter in the diagnosis of various autoimmune and immunecomplex-mediated skin diseases. For preservation of tissue-bound immunoreactants, biopsies are usually fresh-frozen in liquid nitrogen or transported in Michel's fixative. But even optimally preserved tissue specimens are no guarantee for the correct diagnosis by DIF, especially when weak to moderate IgG fluorescence of the epidermal basement membrane zone is involved. In such cases false negative results are easily obtained due to the relatively high dermal "background" fluorescence produced by polyclonal anti-human IgG fluorescein conjugates. METHODS: In the present study we have compared the use of normal saline (0.9% NaCl) with liquid nitrogen and Michel's fixative as transport medium for skin biopsies. From 25 patients with an autoimmune skin disease (pemphigus, pemphigoid, lupus erythematosus and vasculitis) four matched skin biopsies were obtained and transported in either saline for 24 and 48 hours, liquid nitrogen, or Michel's fixative for 48 hours. RESULTS: Direct IF microscopy showed significant reduction of background fluorescence (p < 0.01) and relatively enhanced desired specific (IgG, IgA) staining in biopsies transported in saline. A conclusive or tentative IF diagnosis was reached in 92% after 24 h saline, 83% after 48 h saline, 68% after freezing in liquid nitrogen, and 62% after 48 h Michel's medium (n = 25). CONCLUSIONS: We conclude that transporting biopsies without freezing in normal saline for 24 hours is an adequate and attractive method for routine IF diagnosis in autoimmune and immune complex-mediated dermatoses. The superior results with saline incubation are explained by washing away of IgG background in dermis and epidermis

Brugia malayi Antigen (BmA) inhibits HIV-1 trans-infection but neither BmA nor ES-62 alter HIV-1 infectivity of DC induced CD4+ Th-cells

One of the hallmarks of HIV-1 disease is the association of heightened CD4+ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4+ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4+ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4+ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4+ Th-cells induced by exposed DCs