Two new species of Pseudohalonectria from palms

Two new species, Pseudohalonectria eubenangeensis and I? palmicola, are described from palms in rainforests in north Queensland, Australia. The new species are compared with the known species in the genus, all of which occur in freshwater habitats. This is the first record of species in this genus from terrestrial habitats and from monocotyledonous hosts.published_or_final_versio

Impact of high-cost drugs for individual patient use

To document and describe the individual patient use (IPU) scheme at St Vincent's Hospital, Sydney in terms of submissions and approvals and assess the financial impact of the scheme on the hospital drug expenditure. Method: All submissions for IPU approvals received between January 1997 and December 2001 were reviewed. Submissions were collected on a calendar year basis. Data collection and analysis included identification of approved medication and indication, off- label or approved indication, prescriber, ward, outcome of therapy, person deciding the approval, approval date duration and expiry, amount of medication dispensed and the cost of therapy. The annual cost and proportion of overall drug expenditure for each approval was calculated. Results: The number of approvals had a trend to increase each year. 67.1% of the IPU approvals were for off-label indications. Requested feedback on clinical outcomes was provided only in 18% of cases. The drug acquisition cost of the IPU scheme more than doubled in the period between 1999 and 2001. Similarly the proportion of the drug expenditure on IPU drugs increased significantly (p<0.001) from 1.6% in 1999 to 3.6% in 2001. Conclusion: The results indicated that the number of approvals and submissions for IPU had a tendency to increase. The financial impact of the IPU scheme increased over the years reviewed

Physiological and clinical consequences of relief of right ventricular outflow tract obstruction late after repair of congenital heart defects.

BACKGROUND: Right ventricular outflow tract obstruction (RVOTO) is a common problem after repair of congenital heart disease. Percutaneous pulmonary valve implantation (PPVI) can treat this condition without consequent pulmonary regurgitation or cardiopulmonary bypass. Our aim was to investigate the clinical and physiological response to relieving RVOTO. METHODS AND RESULTS: We studied 18 patients who underwent PPVI for RVOTO (72% male, median age 20 years) from a total of 93 who had this procedure for various indications. All had a right ventricular outflow tract (RVOT) gradient >50 mm Hg on echocardiography without important pulmonary regurgitation (less than mild or regurgitant fraction <10% on magnetic resonance imaging [MRI]). Cardiopulmonary exercise testing, tissue Doppler echocardiography, and MRI were performed before and within 50 days of PPVI. PPVI reduced RVOT gradient (51.4 to 21.7 mm Hg, P<0.001) and right ventricular systolic pressure (72.8 to 47.3 mm Hg, P<0.001) at catheterization. Symptoms and aerobic (25.7 to 28.9 mL.kg(-1).min(-1), P=0.002) and anaerobic (14.4 to 16.2 mL.kg(-1).min(-1), P=0.002) exercise capacity improved. Myocardial systolic velocity improved acutely (tricuspid 4.8 to 5.3 cm/s, P=0.05; mitral 4.7 to 5.5 cm/s, P=0.01), whereas isovolumic acceleration was unchanged. The tricuspid annular velocity was not maintained on intermediate follow-up. Right ventricular end-diastolic volume (99.9 to 89.7 mL/m2, P<0.001) fell, whereas effective stroke volume (43.7 to 48.3 mL/m2, P=0.06) and ejection fraction (48.0% to 56.8%, P=0.01) increased. Left ventricular end-diastolic volume (72.5 to 77.4 mL/m2, P=0.145), stroke volume (45.3 to 50.6 mL/m2, P=0.02), and ejection fraction (62.6% to 65.8%, P=0.03) increased. CONCLUSIONS: PPVI relieves RVOTO, which leads to an early improvement in biventricular performance. Furthermore, it reduces symptoms and improves exercise tolerance. These findings have important implications for the management of this increasingly common condition

Transcriptome-wide analysis reveals different categories of response to a standardised immune challenge in a wild rodent

Individuals vary in their immune response and, as a result, some are more susceptible to infectious disease than others. Little is known about the nature of this individual variation in natural populations, or which components of immune pathways are most responsible, but defining this underlying landscape of variation is an essential first step to understanding the drivers of this variation and, ultimately, predicting the outcome of infection. We describe transcriptome-wide variation in response to a standardised immune challenge in wild field voles. We find that markers can be categorised into a limited number of types. For the majority of markers, the response of an individual is dependent on its baseline expression level, with significant enrichment in this category for conventional immune pathways. Another, moderately sized, category contains markers for which the responses of different individuals are also variable but independent of their baseline expression levels. This category lacks any enrichment for conventional immune pathways. We further identify markers which display particularly high individual variability in response, and could be used as markers of immune response in larger studies. Our work shows how a standardised challenge performed on a natural population can reveal the patterns of natural variation in immune response

Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P&lt;0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P&lt;0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA

Adiposity is associated with blunted cardiovascular, neuroendocrine and cognitive responses to acute mental stress

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited - Copyright @ 2012 Jones et al.Obesity and mental stress are potent risk factors for cardiovascular disease but their relationship with each other is unclear. Resilience to stress may differ according to adiposity. Early studies that addressed this are difficult to interpret due to conflicting findings and limited methods. Recent advances in assessment of cardiovascular stress responses and of fat distribution allow accurate assessment of associations between adiposity and stress responsiveness. We measured responses to the Montreal Imaging Stress Task in healthy men (N=43) and women (N=45) with a wide range of BMIs. Heart rate (HR) and blood pressure (BP) measures were used with novel magnetic resonance measures of stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR) and arterial compliance to assess cardiovascular responses. Salivary cortisol and the number and speed of answers to mathematics problems in the task were used to assess neuroendocrine and cognitive responses, respectively. Visceral and subcutaneous fat was measured using T2*-IDEAL. Greater BMI was associated with generalised blunting of cardiovascular (HR:β=−0.50 bpm.unit−1, P=0.009; SV:β=−0.33 mL.unit−1, P=0.01; CO:β=−61 mL.min−1.unit−1, P=0.002; systolic BP:β=−0.41 mmHg.unit−1, P=0.01; TPR:β=0.11 WU.unit−1, P=0.02), cognitive (correct answers: r=−0.28, P=0.01; time to answer: r=0.26, P=0.02) and endocrine responses (cortisol: r=−0.25, P=0.04) to stress. These associations were largely determined by visceral adiposity except for those related to cognitive performance, which were determined by both visceral and subcutaneous adiposity. Our findings suggest that adiposity is associated with centrally reduced stress responsiveness. Although this may mitigate some long-term health risks of stress responsiveness, reduced performance under stress may be a more immediate negative consequence.This work is funded by the UK National Institute of Health Research (NIHR), Siemens Medical Systems, British Heart Foundation (BHF), NIHR Senior Research Fellowship & The Fondation Leducq, BHF Intermediate Fellowship

Muscle fiber and motor unit behavior in the longest human skeletal muscle

The sartorius muscle is the longest muscle in the human body. It is strap-like, up to 600 mm in length, and contains five to seven neurovascular compartments, each with a neuromuscular endplate zone. Some of its fibers terminate intrafascicularly, whereas others may run the full length of the muscle. To assess the location and timing of activation within motor units of this long muscle, we recorded electromyographic potentials from multiple intramuscular electrodes along sartorius muscle during steady voluntary contraction and analyzed their activity with spike-triggered averaging from a needle electrode inserted near the proximal end of the muscle. Approximately 30% of sartorius motor units included muscle fibers that ran the full length of the muscle, conducting action potentials at 3.9 +/- 0.1 m/s. Most motor units were innervated within a single muscle endplate zone that was not necessarily near the midpoint of the fiber. As a consequence, action potentials reached the distal end of a unit as late as 100 ms after initiation at an endplate zone. Thus, contractile activity is not synchronized along the length of single sartorius fibers. We postulate that lateral transmission of force from fiber to endomysium and a wide distribution of motor unit endplates along the muscle are critical for the efficient transmission of force from sarcomere to tendon and for the prevention of muscle injury caused by overextension of inactive regions of muscle fibers

Substrate-dependent activation of the Vibrio cholerae vexAB RND efflux system requires vexR

Vibrio cholerae encodes six resistance-nodulation-division (RND) efflux systems which function in antimicrobial resistance, virulence factor production, and intestinal colonization. Among the six RND efflux systems, VexAB exhibited broad substrate specificity and played a predominant role in intrinsic antimicrobial resistance. The VexAB system was encoded in an apparent three gene operon that included vexR; which encodes an uncharacterized TetR family regulator. In this work we examined the role of vexR in vexRAB expression. We found that VexR bound to the vexRAB promoter and vexR deletion resulted in decreased vexRAB expression and increased susceptibility to VexAB antimicrobial substrates. Sub-strate-dependent induction of vexRAB was dependent on vexR and episomal vexR expression provided a growth advantage in the presence of the VexAB substrate deoxycholate. The expression of vexRAB increased, in a vexR-dependent manner, in response to the loss of RND efflux activity. This suggested that VexAB may function to export intracellular metabolites. Support for this hypothesis was provided by data showing that vexRAB was upregulated in several metabolic mutants including tryptophan biosynthetic mutants that were predicted to accumulate indole. In addition, vexRAB was found to be upregulated in response to exogenous indole and to contribute to indole resistance. The collective results indicate that vexR is required for vexRAB expression in response to VexAB substrates and that the VexAB RND efflux system modulates the intracellular levels of metabolites that could otherwise accumulate to toxic levels

Effects of ecstasy/polydrug use on memory for associative information

Rationale. Associative learning underpins behaviours that are fundamental to the everyday functioning of the individual. Evidence pointing to learning deficits in recreational drug users merits further examination. Objectives. A word pair learning task was administered to examine associative learning processes in ecstasy/polydrug users. Methods. After assignment to either single or divided attention conditions, 44 ecstasy/polydrug users, and 48 nonusers were presented with 80 word pairs at encoding. Following this, four types of stimuli were presented at the recognition phase; the words as originally paired (old pairs), previously presented words in different pairings (conjunction pairs), old words paired with new words, and pairs of new words (not presented previously). The task was to identify which of the stimuli were intact old pairs. Results. Ecstasy/ploydrug users produced significantly more false positive responses overall compared to nonusers. Increased long-term frequency of ecstasy use was positively associated with the propensity to produce false positive responses. It was also associated with a more liberal signal detection theory (SDT) decision criterion value. Measures of long term and recent cannabis use were also associated with these same word pair learning outcome measures. Conjunction word pairs, irrespective of drug use, generated the highest level of false positive responses and significantly more false positive responses were made in the DA condition compared to the SA condition. Conclusions. Overall, the results suggest that long-term ecstasy exposure may induce a deficit in associative learning and this may be in part a consequence of users adopting a more liberal decision criterion value. Key Words: Ecstasy, Drug Use, Cognition, Memory, Associative Learning, Word Pair

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt