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Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis

Tue, 08 May 2012 23:00:00 GMT

Title: Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis Authors: Burr, Marian L; Viatte, Sebastien; Bukhari, Marwan; Plant, Darren; Symmons, Deborah P.M.; Thomson, Wendy; Barton, Anne Abstract: Abstract Introduction The utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeated testing in subjects with early inflammatory polyarthritis (IP). Methods Anti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care-based inception cohort. The relation between change in anti-CCP status/titer and the presence of radiologic erosions, the extent of the Larsen score, and Health Assessment Questionnaire (HAQ) score by 5 years was investigated. Results With a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF, and 21% for both at baseline. Nine (2%) anti-CCP-negative patients seroconverted to positive, and nine (4.6%) anti-CCP-positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared with baseline status alone (accuracy, 75% versus 74%). A higher baseline anti-CCP titer (but not change in anti-CCP titer) predicted worse radiologic damage at 5 years (P < 0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titer of 2 to 5 U/ml was strongly associated with erosions by 5 years (odds ratio, 3.6 (1.5 to 8.3); P = 0.003). Conclusions Repeated testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Post-prandial reactive hypoglycaemia and diarrhea caused by idiopathic accelerated gastric emptying: a case report

Thu, 12 May 2011 23:00:00 GMT

Title: Post-prandial reactive hypoglycaemia and diarrhea caused by idiopathic accelerated gastric emptying: a case report Authors: Middleton, Stephen J; Balan, Kottekkattu Abstract: Abstract Introduction The majority of cases of post-prandial reactive hypoglycemia are considered idiopathic. Abnormalities of B-cell function and glucose regulation by insulin and glucagon have been postulated as causes but associated gastrointestinal dysfunction has not been reported. We report the first case of accelerated gastric emptying associated with post-prandial reactive hypoglycemia, abdominal bloating and diarrhea. We consider that gastric dysmotility is an important cause of this condition as treatment of the underlying abnormal gastric emptying allows effective control of symptoms. Case presentation A 20-year-old Caucasian woman presented with post-prandial fatigue, sweating, nausea, faintness and intermittent confusion, which had led to pre-syncope and syncope on occasions. She also experienced marked abdominal bloating and diarrhea over the same period. These episodes responded to oral administration of sweet drinks. Her symptoms were ameliorated by modification of her diet. Conclusion This is an original case report of the association of idiopathic accelerated gastric emptying with post-prandial reactive hypoglycemia and diarrhea. Family physicians, endocrinologists and gastroenterologists often consult patients with a constellation of post-prandial symptoms, which are considered to be idiopathic in most cases. This case indicates that gastric dysmotility might be the primary cause of these symptoms in some patients and, if found, offers a therapeutic target which in our case was successful. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

A new RNASeq-based reference transcriptome for sugar beet and its application in transcriptome-scale analysis of vernalization and gibberellin responses

Mon, 19 Mar 2012 00:00:00 GMT

Title: A new RNASeq-based reference transcriptome for sugar beet and its application in transcriptome-scale analysis of vernalization and gibberellin responses Authors: Mutasa-Gottgens, Effie S; Joshi, Anagha; Holmes, Helen F; Hedden, Peter; Gottgens, Berthold Abstract: Abstract Background Sugar beet (Beta vulgaris sp. vulgaris) crops account for about 30% of world sugar. Sugar yield is compromised by reproductive growth hence crops must remain vegetative until harvest. Prolonged exposure to cold temperature (vernalization) in the range 6°C to 12°C induces reproductive growth, leading to bolting (rapid elongation of the main stem) and flowering. Spring cultivation of crops in cool temperate climates makes them vulnerable to vernalization and hence bolting, which is initiated in the apical shoot meristem in processes involving interaction between gibberellin (GA) hormones and vernalization. The underlying mechanisms are unknown and genome scale next generation sequencing approaches now offer comprehensive strategies to investigate them; enabling the identification of novel targets for bolting control in sugar beet crops. In this study, we demonstrate the application of an mRNA-Seq based strategy for this purpose. Results There is no sugar beet reference genome, or public expression array platforms. We therefore used RNA-Seq to generate the first reference transcriptome. We next performed digital gene expression profiling using shoot apex mRNA from two sugar beet cultivars with and without applied GA, and also a vernalized cultivar with and without applied GA. Subsequent bioinformatics analyses identified transcriptional changes associated with genotypic difference and experimental treatments. Analysis of expression profiles in response to vernalization and GA treatment suggested previously unsuspected roles for a RAV1-like AP2/B3 domain protein in vernalization and efflux transporters in the GA response. Conclusions Next generation RNA-Seq enabled the generation of the first reference transcriptome for sugar beet and the study of global transcriptional responses in the shoot apex to vernalization and GA treatment, without the need for a reference genome or established array platforms. Comprehensive bioinformatic analysis identified transcriptional programmes associated with different sugar beet genotypes as well as biological treatments; thus providing important new opportunities for basic scientists and sugar beet breeders. Transcriptome-scale identification of agronomically important traits as used in this study should be widely applicable to all crop plants where genomic resources are limiting. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

BarraCUDA - a fast short read sequence aligner using graphics processing units

Fri, 13 Jan 2012 00:00:00 GMT

Title: BarraCUDA - a fast short read sequence aligner using graphics processing units Authors: Klus, Petr; Lam, Simon; Lyberg, Dag; Cheung, Ming Sin; Pullan, Graham; McFarlane, Ian; Yeo, Giles S H; Lam, Brian Y H Abstract: Abstract Background With the maturation of next-generation DNA sequencing (NGS) technologies, the throughput of DNA sequencing reads has soared to over 600 gigabases from a single instrument run. General purpose computing on graphics processing units (GPGPU), extracts the computing power from hundreds of parallel stream processors within graphics processing cores and provides a cost-effective and energy efficient alternative to traditional high-performance computing (HPC) clusters. In this article, we describe the implementation of BarraCUDA, a GPGPU sequence alignment software that is based on BWA, to accelerate the alignment of sequencing reads generated by these instruments to a reference DNA sequence. Findings Using the NVIDIA Compute Unified Device Architecture (CUDA) software development environment, we ported the most computational-intensive alignment component of BWA to GPU to take advantage of the massive parallelism. As a result, BarraCUDA offers a magnitude of performance boost in alignment throughput when compared to a CPU core while delivering the same level of alignment fidelity. The software is also capable of supporting multiple CUDA devices in parallel to further accelerate the alignment throughput. Conclusions BarraCUDA is designed to take advantage of the parallelism of GPU to accelerate the alignment of millions of sequencing reads generated by NGS instruments. By doing this, we could, at least in part streamline the current bioinformatics pipeline such that the wider scientific community could benefit from the sequencing technology. BarraCUDA is currently available from http://seqbarracuda.sf.net Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India

Thu, 15 Dec 2011 00:00:00 GMT

Title: Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India Authors: Mehrotra, Sanjana; Fakiola, Michaela; Oommen, Joyce; Jamieson, Sarra E; Mishra, Anshuman; Sudarshan, Medhavi; Tiwary, Puja; Rani, Deepa SELVI; Thangaraj, Kumarasamy; Rai, Madhukar; Sundar, Shyam; Blackwell, Jenefer M Abstract: Abstract Background IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India. Methods Three single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients. Results Family-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021). Conclusions This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

A difficult diagnosis - constrictive pericarditis and its treatment: a case report

Sat, 28 Nov 2009 00:00:00 GMT

Title: A difficult diagnosis - constrictive pericarditis and its treatment: a case report Authors: Altemimi, Harith A; Altaf, Syed Y; James, Rhian K; Nata, Rajah; Kumar, Eshwar B; Codispoti, Max Abstract: Abstract The diagnosis of constrictive pericarditis requires a high degree of clinical suspicion, for the signs and symptoms of this disease can be falsely attributed to other causes. Herein, we present a case of a 70-year old retired farmer whose symptoms of right heart failure were initially attributed to co-existing pneumonia and pulmonary embolism. He was discharged. Three weeks later he presented with worsening breathlessness and ascites. Echocardiography, computed tomography and cardiac catheterization revealed the diagnosis of constrictive pericarditis. He underwent complete pericardectomy and to date has made a good recovery. This case exemplifies the difficulty in diagnosing this condition, the investigation required, and provides a discussion of the benefit and outcomes of prompt treatment. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Evaluation of bleach-sedimentation for sterilising and concentrating Mycobacterium tuberculosis in sputum specimens

Mon, 10 Oct 2011 23:00:00 GMT

Title: Evaluation of bleach-sedimentation for sterilising and concentrating Mycobacterium tuberculosis in sputum specimens Authors: Chew, Rusheng; Calderon, Carmen; Schumacher, Samuel G.; Sherman, Jonathan M.; Caviedes, Luz; Fuentes, Patricia; Coronel, Jorge; Valencia, Teresa; Hererra, Beatriz; Zimic, Mirko; Huaroto, Lucy; Sabogal, Ivan; Escombe, A. Rod; Gilman, Robert H.; Evans, Carlton A. Abstract: Abstract Background Bleach-sedimentation may improve microscopy for diagnosing tuberculosis by sterilising sputum and concentrating Mycobacterium tuberculosis. We studied gravity bleach-sedimentation effects on safety, sensitivity, speed and reliability of smear-microscopy. Methods This blinded, controlled study used sputum specimens (n = 72) from tuberculosis patients. Bleach concentrations and exposure times required to sterilise sputum (n = 31) were determined. In the light of these results, the performance of 5 gravity bleach-sedimentation techniques that sterilise sputum specimens (n = 16) were compared. The best-performing of these bleach-sedimentation techniques involved adding 1 volume of 5% bleach to 1 volume of sputum, shaking for 10-minutes, diluting in 8 volumes distilled water and sedimenting overnight before microscopy. This technique was further evaluated by comparing numbers of visible acid-fast bacilli, slide-reading speed and reliability for triplicate smears before versus after bleach-sedimentation of sputum specimens (n = 25). Triplicate smears were made to increase precision and were stained using the Ziehl-Neelsen method. Results M. tuberculosis in sputum was successfully sterilised by adding equal volumes of 15% bleach for 1-minute, 6% for 5-minutes or 3% for 20-minutes. Bleach-sedimentation significantly decreased the number of acid-fast bacilli visualised compared with conventional smears (geometric mean of acid-fast bacilli per 100 microscopy fields 166, 95%CI 68-406, versus 346, 95%CI 139-862, respectively; p = 0.02). Bleach-sedimentation diluted paucibacillary specimens less than specimens with higher concentrations of visible acid-fast bacilli (p = 0.02). Smears made from bleach-sedimented sputum were read more rapidly than conventional smears (9.6 versus 11.2 minutes, respectively, p = 0.03). Counting conventional acid-fast bacilli had high reliability (inter-observer agreement, r = 0.991) that was significantly reduced (p = 0.03) by bleach-sedimentation (to r = 0.707) because occasional strongly positive bleach-sedimented smears were misread as negative. Conclusions Gravity bleach-sedimentation improved laboratory safety by sterilising sputum but decreased the concentration of acid-fast bacilli visible on microscopy, especially for sputum specimens containing high concentrations of M. tuberculosis. Bleach-sedimentation allowed examination of more of each specimen in the time available but decreased the inter-observer reliability with which slides were read. Thus bleach-sedimentation effects vary depending upon specimen characteristics and whether microscopy was done for a specified time, or until a specified number of microscopy fields had been read. These findings provide an explanation for the contradictory results of previous studies. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Vocation and avocation: Leisure activities correlate with professional engagement, but not burnout, in a cross-sectional survey of UK doctors

Mon, 29 Aug 2011 23:00:00 GMT

Title: Vocation and avocation: Leisure activities correlate with professional engagement, but not burnout, in a cross-sectional survey of UK doctors Authors: McManus, I C; Jonvik, Hallgeir; Richards, Peter; Paice, Elisabeth Abstract: Abstract Background Sir William Osler suggested in 1899 that avocations (leisure activities) in doctors are related to an increased sense of vocation (professional engagement) and a decreased level of burnout. This study evaluated those claims in a large group of doctors practicing in the UK while taking into account a wide range of background variables. Methods A follow-up questionnaire was sent to 4,457 UK-qualified doctors who had been included in four previous studies of medical school selection and training, beginning in 1980, 1985, 1990 and 1989/1991. A total of 2,845 (63.8%) doctors returned the questionnaire. Questions particularly asked about work engagement, satisfaction with medicine as a career, and personal achievement (Vocation/engagement), stress, emotional exhaustion, and depersonalization (BurnedOut), and 29 different leisure activities (Avocation/Leisure), as well as questions on personality, empathy, work experience, and demography. Results Doctors reporting more Avocation/Leisure activities tended to be women, to have older children, to be less surface-rational, more extravert, more open to experience, less agreeable, and to fantasize more. Doctors who were more BurnedOut tended to be men, to be more sleep-deprived, to report a greater workload and less choice and independence in their work, to have higher neuroticism, lower extraversion and lower agreeableness scores, and to have lower self-esteem. In contrast, doctors with a greater sense of Vocation/engagement, tended to see more patients, to have greater choice and independence at work, to have a deep approach to work, to have a more supportive-receptive work environment, to be more extravert and more conscientious, and to report greater self-esteem. Avocation/Leisure activities correlated significantly with Vocation/engagement, even after taking into account 25 background variables describing demography, work, and personality, whereas BurnedOut showed no significant correlation with Avocation/Leisure activities. Popular Culture and High Culture did not differ in their influence on Vocation/engagement, although there was a suggestion that Depersonalization was correlated with more interest in Popular Culture and less interest in High Culture. Conclusion In this cross-sectional study there is evidence, even after taking into account a wide range of individual difference measures, that doctors with greater Avocation/Leisure activities also have a greater sense of Vocation/Engagement. In contrast, being BurnedOut did not relate to Avocation/Leisure activities (but did relate to many other measures). Osler was probably correct in recommending to doctors that, 'While medicine is to be your vocation, or calling, see to it that you also have an avocation'. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

Mon, 08 Aug 2011 23:00:00 GMT

Title: Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1 Authors: Gregor, Anne; Albrecht, Beate; Bader, Ingrid; Bijlsma, Emilia K; Ekici, Arif B; Engels, Hartmut; Hackmann, Karl; Horn, Denise; Hoyer, Juliane; Klapecki, Jakub; Kohlhase, Jurgen; Maystadt, Isabelle; Nagl, Sandra; Prott, Eva; Tinschert, Sigrid; Ullmann, Reinhard; Wohlleber, Eva; Woods, Geoffrey; Reis, Andre; Rauch, Anita; Zweier, Christiane Abstract: Abstract Background Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. Methods 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. Results By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. Conclusions We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Harnessing the self-harvesting capability of benthic cyanobacteria for use in benthic photobioreactors

Sun, 17 Jul 2011 23:00:00 GMT

Title: Harnessing the self-harvesting capability of benthic cyanobacteria for use in benthic photobioreactors Authors: Esson, Diane; Wood, Susanna A; Packer, Michael A Abstract: Abstract Benthic species of algae and cyanobacteria (i.e., those that grow on surfaces), may provide potential advantages over planktonic species for some commercial-scale biotechnological applications. A multitude of different designs of photobioreactor (PBR) are available for growing planktonic species but to date there has been little research on PBR for benthic algae or cyanobacteria. One notable advantage of some benthic cyanobacterial species is that during their growth cycle they become positively buoyant, detach from the growth surface and form floating mats. This 'self-harvesting' capability could be advantageous in commercial PBRs as it would greatly reduce dewatering costs. In this study we compared the growth rates and efficiency of 'self-harvesting' among three species of benthic cyanobacteria; Phormidium autumnale; Phormidium murrayi and Planktothrix sp.. Phormidium autumnale produced the greatest biomass and formed cohesive mats once detached. Using this strain and an optimised MLA media, a variety of geometries of benthic PBRs (bPBRs) were trialed. The geometry and composition of growth surface had a marked effect on cyanobacterial growth. The highest biomass was achieved in a bPBR comprising of a vertical polyethylene bag with loops of silicone tubing to provide additional growth surfaces. The productivity achieved in this bPBR was a similar order of magnitude as planktonic species, with the additional advantage that towards the end of the exponential phase the bulk of the biomass detached forming a dense mat at the surface of the medium. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Centrosome polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems.

Mon, 27 Jun 2011 23:00:00 GMT

Title: Centrosome polarisation to the immunological synapse directs secretion from cytolytic cells of both the innate and adaptive immune systems. Authors: Stinchcombe, Jane C; Salio, Mariolina; Cerundolo, Vincenzo; Pende, Daniela; Arico, Maurizio; Griffiths, Gillian M Abstract: Abstract Background Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs), this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK) and invariant NKT (iNKT) cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. Results NK cells were conjugated with B-cell targets lacking major histocompatibility complex class I 721.221 cells, and iNKT cells were conjugated with glycolipid-pulsed CD1-bearing targets, then prepared for thin-section electron microscopy. High-resolution electron micrographs of the immunological synapse formed between NK and iNKT cytolytic cells with their targets revealed that in both NK and iNKT cells, the centrioles could be found associated (or 'docked') with the plasma membrane within the immunological synapse. Secretory clefts were visible within the synapses formed by both NK and iNKT cells, and secretory lysosomes were polarised along microtubules leading towards the docked centrosome. The Golgi apparatus and recycling endosomes were also polarised towards the centrosome at the plasma membrane within the synapse. Conclusions These results reveal that, like CTLs of the adaptive immune system, the centrosomes of NK and iNKT cells (cytolytic cells of the innate immune system) direct secretory lysosomes to the immunological synapse. Morphologically, the overall structure of the immunological synapses formed by NK and iNKT cells are very similar to those formed by CTLs, with both exocytic and endocytic organelles polarised towards the centrosome at the plasma membrane, which forms a focal point for exocytosis and endocytosis within the immunological synapse. We conclude that centrosomal polarisation provides a rapid, responsive and precise mechanism for secretory lysosome delivery to the immunological synapse in CTLs, NK cells and iNKT cells. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Can Improving Working Memory Prevent Academic Difficulties? A School Based Randomised Controlled Trial

Sun, 19 Jun 2011 23:00:00 GMT

Title: Can Improving Working Memory Prevent Academic Difficulties? A School Based Randomised Controlled Trial Authors: Roberts, Gehan; Quach, Jon; Gold, Lisa; Anderson, Peter; Rickards, Field; Mensah, Fiona; Ainley, John; Gathercole, Susan; Wake, Melissa Abstract: Abstract Background Low academic achievement is common and is associated with adverse outcomes such as grade repetition, behavioural disorders and unemployment. The ability to accurately identify these children and intervene before they experience academic failure would be a major advance over the current 'wait to fail' model. Recent research suggests that a possible modifiable factor for low academic achievement is working memory, the ability to temporarily store and manipulate information in a 'mental workspace'. Children with working memory difficulties are at high risk of academic failure. It has recently been demonstrated that working memory can be improved with adaptive training tasks that encourage improvements in working memory capacity. Our trial will determine whether the intervention is efficacious as a selective prevention strategy for young children at risk of academic difficulties and is cost-effective. Methods/Design This randomised controlled trial aims to recruit 440 children with low working memory after a school-based screening of 2880 children in Grade one. We will approach caregivers of all children from 48 participating primary schools in metropolitan Melbourne for consent. Children with low working memory will be randomised to usual care or the intervention. The intervention will consist of 25 computerised working memory training sessions, which take approximately 35 minutes each to complete. Follow-up of children will be conducted at 6, 12 and 24 months post-randomisation through child face-to-face assessment, parent and teacher surveys and data from government authorities. The primary outcome is academic achievement at 12 and 24 months, and other outcomes include child behaviour, attention, health-related quality of life, working memory, and health and educational service utilisation. Discussion A successful start to formal learning in school sets the stage for future academic, psychological and economic well-being. If this preventive intervention can be shown to be efficacious, then we will have the potential to prevent academic underachievement in large numbers of at-risk children, to offer a ready-to-use intervention to the Australian school system and to build international research partnerships along the health-education interface, in order to carry our further studies of effectiveness and generalisability. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

No evidence for association between SLC11A1 and visceral leishmaniasis in India

Thu, 19 May 2011 23:00:00 GMT

Title: No evidence for association between SLC11A1 and visceral leishmaniasis in India Authors: Mehrotra, Sanjana; Oommen, Joyce; Mishra, Anshuman; Sudharshan, Medhavi; Tiwary, Puja; Jamieson, Sarra E; Fakiola, Michaela; Rani, Deepa Selvi; Thangaraj, Kumarasamy; Rai, Madhukar; Sundar, Shyam; Blackwell, Jenefer M Abstract: AbstractBackgroundSLC11A1 has pleiotropic effects on macrophage function and remains a strong candidate for infectious disease susceptibility. 5' and/or 3' polymorphisms have been associated with tuberculosis, leprosy, and visceral leishmaniasis (VL). Most studies undertaken to date were under-powered, and none has been replicated within a population. Association with tuberculosis has replicated variably across populations. Here we investigate SLC11A1 and VL in India. MethodsNine polymorphisms (rs34448891, rs7573065, rs2276631, rs3731865, rs17221959, rs2279015, rs17235409, rs17235416, rs17229009) that tag linkage disequilibrium blocks across SLC11A1 were genotyped in primary family-based (313 cases; 176 families) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between SLC11A1 variants and VL. Quantitative RT/PCR was used to compare SLC11A1 expression in mRNA from paired splenic aspirates taken before and after treatment from 24 VL patients carrying different genotypes at the functional promoter GTn polymorphism (rs34448891). ResultsNo associations were observed between VL and polymorphisms at SLC11A1 that were either robust to correction for multiple testing or replicated across primary and replication samples. No differences in expression of SLC11A1 were observed when comparing pre- and post-treatment samples, or between individuals carrying different genotypes at the GTn repeat.ConclusionsThis is the first well-powered study of SLC11A1 as a candidate for VL, which we conclude does not have a major role in regulating VL susceptibility in India. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Relationship between the tissue-specificity of mouse gene expression and the evolutionary origin and function of the proteins

Tue, 28 Jun 2005 23:00:00 GMT

Title: Relationship between the tissue-specificity of mouse gene expression and the evolutionary origin and function of the proteins Authors: Freilich, Shiri; Massingham, Tim; Bhattacharyya, Sumit; Ponstingl, Hannes; Lyons, Paul A; Freeman, Tom C; Thornton, Janet M Abstract: Abstract Background The combination of complete genome sequence information with expression data enables us to characterize the relationship between a protein's evolutionary origin or functional category and its expression pattern. In this study, mouse proteins were assigned into functional and phyletic groups and the gene expression patterns of the different protein groupings were examined by microarray analysis in various mouse tissues. Results Our results suggest that the proteins that are universally distributed in all tissues are predominantly enzymes and transporters. In contrast, the tissue-specific set is dominated by regulatory proteins (signal transduction and transcription factors). An increased tendency to tissue-specificity is observed for metazoan-specific proteins. As the composition of the phyletic groups highly correlates with that of the functional groups, the data were tested in order to determine which of the two factors - function or phyletic age - is dominant in shaping the expression profile of a protein. The observed differences in expression patterns of genes between functional groups were found mainly to reflect their different phyletic origin. The connection between tissue specificity and phyletic age cannot be explained by the recent rate of evolution. Finally, although metazoan-specific proteins tend to be tissue-specific compared with phyletically conserved proteins present in all domains of life, many such 'universal' proteins are also tissue-specific. Conclusion The minimal cellular transcriptome of the metazoan cell differs from that of the ancestral unicellular eukaryote: new functions were added (metazoan-specific proteins), whilst other functions became specialized and no longer took place in all cells (tissue-specific pre-metazoan proteins). Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure

Wed, 10 Sep 2008 23:00:00 GMT

Title: Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure Authors: Geeraerts, Thomas; Newcombe, Virginia F J; Coles, Jonathan P; Abate, Maria Giulia; Perkes, Iain E; Hutchinson, Peter J A; Outtrim, Jo G; Chatfield, Dot A; Menon, David K Abstract: Abstract Introduction The dural sheath surrounding the optic nerve communicates with the subarachnoid space, and distends when intracranial pressure is elevated. Magnetic resonance imaging (MRI) is often performed in patients at risk for raised intracranial pressure (ICP) and can be used to measure precisely the diameter of optic nerve and its sheath. The objective of this study was to assess the relationship between optic nerve sheath diameter (ONSD), as measured using MRI, and ICP. Methods We conducted a retrospective blinded analysis of brain MRI images in a prospective cohort of 38 patients requiring ICP monitoring after severe traumatic brain injury (TBI), and in 36 healthy volunteers. ONSD was measured on T2-weighted turbo spin-echo fat-suppressed sequence obtained at 3 Tesla MRI. ICP was measured invasively during the MRI scan via a parenchymal sensor in the TBI patients. Results Measurement of ONSD was possible in 95% of cases. The ONSD was significantly greater in TBI patients with raised ICP (>20 mmHg; 6.31 ± 0.50 mm, 19 measures) than in those with ICP of 20 mmHg or less (5.29 ± 0.48 mm, 26 measures; P < 0.0001) or in healthy volunteers (5.08 ± 0.52 mm; P < 0.0001). There was a significant relationship between ONSD and ICP (r = 0.71, P < 0.0001). Enlarged ONSD was a robust predictor of raised ICP (area under the receiver operating characteristic curve = 0.94), with a best cut-off of 5.82 mm, corresponding to a negative predictive value of 92%, and to a value of 100% when ONSD was less than 5.30 mm. Conclusions When brain MRI is indicated, ONSD measurement on images obtained using routine sequences can provide a quantitative estimate of the likelihood of significant intracranial hypertension.

Gdt2 regulates the transition of Dictyosteliumcells from growth to differentiation

Sun, 04 Jul 2004 23:00:00 GMT

Title: Gdt2 regulates the transition of Dictyosteliumcells from growth to differentiation Authors: Chibalina, Margarita V; Anjard, Christophe; Insall, Robert H Abstract: Abstract Background Dictyostelium life cycle consists of two distinct phases – growth and development. The control of growth-differentiation transition in Dictyostelium is not completely understood, and only few genes involved in this process are known. Results We have isolated a REMI (restriction enzyme-mediated integration) mutant, which prematurely initiates multicellular development. When grown on a bacterial lawn, these cells aggregate before the bacteria are completely cleared. In bacterial suspension, mutant cells express the developmental marker discoidin Iγ even at low cell densities and high concentrations of bacteria. In the absence of nutrients, mutant cells aggregate more rapidly than wild type, but the rest of development is unaffected and normal fruiting bodies are formed. The disrupted gene shows substantial homology to the recently described gdt1 gene, and therefore was named gdt2. While GDT1 and GDT2 are similar in many ways, there are intriguing differences. GDT2 contains a well conserved protein kinase domain, unlike GDT1, whose kinase domain is probably non-functional. The gdt2 and gdt1 mRNAs are regulated differently, with gdt2 but not gdt1 expressed throughout development. The phenotypes of gdt2- and gdt1- mutants are related but not identical. While both initiate development early, gdt2- cells grow at a normal rate, unlike gdt1- mutants. Protein kinase A levels and activity are essentially normal in growing gdt2- mutants, implying that GDT2 regulates a pathway that acts separately from PKA. Gdt1 and gdt2 are the first identified members of a family containing at least eight closely related genes. Conclusions We have isolated and characterised a new gene, gdt2, which acts to restrain development until conditions are appropriate. We also described a family of related genes in the Dictyostelium genome. We hypothesise that different family members might control similar cellular processes, but respond to different environmental cues. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Information and shared decision-making are top patients' priorities

Tue, 28 Feb 2006 00:00:00 GMT

Title: Information and shared decision-making are top patients' priorities Authors: Schattner, Ami; Bronstein, Alexander; Jellin, Navah Abstract: Abstract Background The profound changes in medical care and the recent stress on a patient-centered approach mandate evaluation of current patient priorities. Methods Hospitalized and ambulatory patients at an academic medical center in central Israel were investigated. Consecutive patients (n = 274) indicated their first and second priority for a change or improvement in their medical care out of a mixed shortlist of 6 issues, 3 related to patient-physician relationship (being better informed and taking part in decisions; being seen by the same doctor each time; a longer consultation time) and 3 issues related to the organizational aspect of care (easier access to specialists/hospital; shorter queue for tests; less charges for drugs). Results Getting more information from the physician and taking part in decisions was the most desirable patient choice, selected by 27.4% as their first priority. The next choices – access and queue – also relate to more patient autonomy and control over that of managed care regulations. Patients studied were least interested in continuity of care, consultation time or cost of drugs. Demographic or clinical variables were not significantly related to patients' choices. Conclusion Beyond its many benefits, being informed by their doctor and shared decision making is a top patient priority. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Molecular mechanisms of traumatic brain injury; the missing link in management

Mon, 02 Feb 2009 00:00:00 GMT

Title: Molecular mechanisms of traumatic brain injury; the missing link in management Authors: Veenith, Tonny; Goon, Serena H; Burnstein, Rowan M Abstract: Abstract Head injury is common, sometimes requires intensive care unit admission, and is associated with significant mortality and morbidity. A gap still remains in the understanding of the molecular mechanism of this condition. This review is aimed at providing a general overview of the molecular mechanisms involved in traumatic brain injury to a busy clinician. It will encompass the pathophysiology in traumatic brain injury including apoptosis, the role of molecules and genes, and a brief mention of possible pharmacological therapies. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

Cost-effectiveness of multidisciplinary management of Tinnitus at a specialized Tinnitus centre

Wed, 11 Feb 2009 00:00:00 GMT

Title: Cost-effectiveness of multidisciplinary management of Tinnitus at a specialized Tinnitus centre Authors: Cima, Rilana; Joore, Manuela; Maes, Iris; Scheyen, Dyon; El Refaie, Amr El; Baguley, David M; Vlaeyen, Johan W S; Anteunis, Lucien Abstract: Abstract Background Tinnitus is a common chronic health condition that affects 10% to 20% of the general population. Among severe sufferers it causes disability in various areas. As a result of the tinnitus, quality of life is often impaired. At present there is no cure or uniformly effective treatment, leading to fragmentized and costly tinnitus care. Evidence suggests that a comprehensive multidisciplinary approach in treating tinnitus is effective. The main objective of this study is to examine the effectiveness, costs, and cost-effectiveness of a comprehensive treatment provided by a specialized tinnitus center versus usual care. This paper describes the study protocol. Methods/Design In a randomized controlled clinical trial 198 tinnitus patients will be randomly assigned to a specialized tinnitus care group or a usual care group. Adult tinnitus sufferers referred to the audiological centre are eligible. Included patients will be followed for 12 months. Primary outcome measure is generic quality of life (measured with the Health Utilities Index Mark III). Secondary outcomes are severity of tinnitus, general distress, tinnitus cognitions, tinnitus specific fear, and costs. Based on health state utility outcome data the number of patients to include is 198. Economic evaluation will be performed from a societal perspective. Discussion This is, to our knowledge, the first randomized controlled trial that evaluates a comprehensive treatment of tinnitus and includes a full economic evaluation from a societal perspective. If this intervention proves to be effective and cost-effective, implementation of this intervention is considered and anticipated. Trial Registration The trial has been registered at ClinicalTrial.gov. The trial registration number is NCT00733044 Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT

Thu, 23 Jul 2009 23:00:00 GMT

Title: DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT Authors: Jones, Rob; Sheehan, Bart; Phillips, Patrick; Juszczak, Ed; Adams, Jessica; Baldwin, Ashley; Ballard, Clive; Banerjee, Sube; Barber, Bob; Bentham, Peter; Brown, Richard; Burns, Alistair; Dening, Tom; Findlay, David; Gray, Richard; Griffin, Mary; Holmes, Clive; Hughes, Alan; Jacoby, Robin; Johnson, Tony; Jones, Roy; Knapp, Martin; Lindesay, James; McKeith, Ian; McShane, Rupert; Macharouthu, Ajay; O'Brien, John; Onions, Caroline; Passmore, Peter; Raftery, James; Ritchie, Craig; Howard, Rob; Domino-ad Team Abstract: Abstract Background Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. Method DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. Discussion There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. Trial registration Current controlled trials ISRCTN49545035 Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.