Os autores declaram não haver conflito de interesses “
“In

Os autores declaram não haver conflito de interesses. “
“In populations with high incidence of tuberculosis (TB), there have been an increased number of TB cases reported in patients treated with tumor necrosis factor

antagonists (anti-TNF).1 In fact, the relative risk (RR) of developing TB is 1.6–25.2 times higher in Rheumatoid Arthritis (RA) patients under anti-TNF therapy than in RA patients treated with conventional immunosuppressive therapy, depending on the clinical setting and the anti-TNF used.1, 2, 3, 4, 5, 6 and 7 Active TB in the context of check details anti-TNF therapy usually results from the reactivation of a latent infection, shortly after the beginning of the treatment.5 and 8 TB often presents an atypical behavior, which may pose difficulties to the diagnosis.9 In countries with high incidence of TB, cases caused by new infection are also particularly frequent. TNF is fundamental for the immunological defence against Mycobacterium tuberculosis, especially in the formation and maintenance of granulomas. Animal models confirmed that it is possible to reactivate TB after administering anti-TNF antibodies. 10 Besides anti-TNFs,

SD-208 solubility dmso other biological agents were approved for immune mediated inflammatory disease’s treatment. Data about the risk of developing TB infection in patients treated with these other agents are scarce. Even though this risk might be lower for some of the biological agents that do not interfere with TNF until more data is available this group assumed that this position paper should be applied to all biological treatments. Preventive chemotherapy can significantly reduce the incidence of active TB in individuals with latent infection, identified by positive tuberculin skin test (TST) or interferon-γ release assay (IGRA).11

The currently available evidence about the best management to prevent TB in patients receiving biological therapy is limited. In this position paper on the screening and prevention of TB in patients treated with biological therapy, delegates from Rutecarpine the Tuberculosis Committee (TC) of the Portuguese Pulmonology Society (SPP), the Rheumatoid Arthritis Study Group (GEAR) of the Portuguese Society of Rheumatology (SPR), the Portuguese Society of Dermatology and Venereology (SPDV) and the Portuguese Society of Gastroenterology (SPG), have revised and updated recommendations that had been previously developed by the GEAR – SPR and by the TC – SPP, first published in 200612 and latter updated in 2008.13 The main objective of this position paper is to contribute for the reduction of the number of cases of reactivated TB and new TB infections in patients with immune mediated inflammatory diseases who are candidates for treatment with biological therapy in Portugal.

The highest value of TSS was 247 mg l− 1 recorded at stn MB9, wh

The highest value of TSS was 247 mg l− 1 recorded at stn. MB9, which

was located at the centre of the bloom patch ( Figure 3). The surface chlorophyll a concentration varied widely, between 1.4 μg l− 1 at stn. MB1 near the bay mouth and 521 μg l− 1 at stn. MB9 in the middle of the bloom patch ( Figure 4). The surface Chl a values of EW transect stations were high (> 3 μg l− 1). RG7204 purchase Similarly, the northern part of the bay (stn. MB3) also had comparatively high levels of TChl a at the surface. Accessory pigments like peridinin, fucoxanthin, zeaxanthin, lutein, violaxanthin, neoxanthin and antheraxanthin, when normalised to TChl a, displayed considerable variation among stations as a function of depth. The TChl b/TChl a ratios were high (81%) towards the northern part of the bay (stn. MB5) – an indication of a high chlorophyte abundance (

Figure 5). The photosynthetic pigment peridinin/TChl a and fucoxanthin/TChl a ratios were also higher in the mid part of the bay, with mean values of 0.05 and 0.13 μg l− 1 respectively. Zeaxanthin and lutein were the most dominant accessory non-photosynthetic pigments. The peridinin/TChl a ratio was exceptionally high (60%) in the surface waters at stn. MB7 and outweighed all other pigments, showing a clear dominance of dinoflagellates. On the EW transect at stns. MB12, MB13 and MB9 the fucoxanthin/TChl a ratio increased markedly below 15 m, owing to the aggregation of the diatoms Haslea gigantea and Chaetoceros spp. (unpublished data). Lutein, a marker pigment for chlorophytes and prasinophytes, was also ascribed to chlorophytes this website since microscopic observations revealed the absence of prasinophytes in the samples (see Furuya et al. 2006). On the NS transect at stns. MB2, 4 and 5 the high zeaxanthin/TChl a ratios of > 0.18 μg l− 1

coincided with comparatively high temperatures (> 28.1 °C). The NPP index, a measure of the relative importance of non-photosynthetic pigments with respect to total pigment concentration, showed high values Orotidine 5′-phosphate decarboxylase at the surface (> 0.6) at most of the stations ( Figure 6). On the EW transect NPP values ranged from 0.54 to 0.68, whereas on the NS transect NPP ranged from 0.60 to 0.67. Surface NPP values also varied considerably on the EW transect: 0.67 at stn. MB9 and 0.63 at the nearby stn. MB13. The chlorophyll specific absorption coefficients varied widely in the bay, within and outside the bloom patch. The lower a*ph(λ) values recorded in this study are typical of eutrophic waters containing larger phytoplankton species, thus demonstrating greater pigment packaging. The spectrally averaged chlorophyll-specific absorption coefficients (ā*ph(λ)) showed a decreasing trend with depth. Apart from the major absorption peaks (blue absorption maximum at 440 nm and red absorption maximum near 676 nm), marked absorption peaks at 475 nm and 653 nm were seen at almost all stations.

The authors declare that no experiments were performed on humans

The authors declare that no experiments were performed on humans or animals for this investigation. The authors declare that they have followed the protocols of their work centre on the publication

of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study. The authors declare that no patient data appear in this article. The authors have no conflicts of interest to declare. “
“Mulher de 66 anos, leucodérmica, seguida em consulta por anemia ferropénica e referenciada por suspeita de doença linfoproliferativa. Medicada com propranolol, ranitidina, sinvastatina, loflazepato de etilo, bromazepam, IDO inhibitor diclofenac e sulfato ferroso oral. A endoscopia Proteasome structure digestiva alta era normal. A tomografia computorizada revelou exuberante componente adenomegálico mediastínico, abdominal e retroperitoneal, bem como neoformação sólida com 9 cm de extensão, envolvendo o cólon transverso. Foi submetida a colonoscopia tendo sido detetada, no cólon transverso, uma extensa lesão ulcerada com coloração negra e de bordos elevados (Figura 1, Figura 2 and Figura

3). A análise histológica das biopsias colhidas revelou adenocarcinoma pouco diferenciado com extensa ulceração e depósitos de material negro positivo na coloração de Perls. Procedeu-se ainda a estudo dirigido das linfadenopatias que se revelaram lesões metastáticas do adenocarcinoma cólico. O óbito ocorreu cerca de 5 meses após o diagnóstico. Os autores apresentam este caso pela raridade do aspeto endoscópico do tumor do cólon. A coloração negra em lesão endoscópica pode ser devida à produção de melanina – o que não se verificou nesta doente – ou à presença de pigmentos exógenos. Nesta doente, o pigmento depositado na mucosa ulcerada era positivo para a coloração de Perls, identificando iões de ferro na forma férrica. Várias espécies de bactérias pertencentes à flora do cólon produzem sulfureto de hidrogénio, que ao reagir com iões

ferro, provenientes não só da hemorragia local como Thymidine kinase também da medicação da doente, origina sulfato férrico, apresentando-se como um precipitado negro1. Será provavelmente esta a razão para a coloração encontrada2. Os autores declaram não haver conflito de interesses. “
“Homem de 50 anos, raça branca, submetido a endoscopia digestiva alta por queixas dispépticas. Observou-se um pólipo séssil com 10 mm de diâmetro no 1/3 inferior do esófago, de aparente origem subepitelial (fig. 1), que se removeu com ansa diatérmica. A histologia foi compatível com tumor de células granulares, com margens livres (Figura 2 and Figura 3). A endoscopia de controlo, realizada após 12 meses, não mostrou evidência de recidiva tumoral. O tumor de células granulares foi descrito pela primeira vez em 1926 por Abrikossoff.

, 2013) The gammaproteobacterial SAR92 clade were initially rega

, 2013). The gammaproteobacterial SAR92 clade were initially regarded to constitute a monophyletic clade of species with NVP-BKM120 order adaptations to oligotrophic conditions ( Stingl et al., 2007). However, in comparison with the outcome of the 16S pyrotag and 16S metagenome analysis ( Fig. 2b-c) we observed higher amount of expressed 16S rRNA sequences for the SAR92 clade on 31/03/2009

( Fig. 2a), suggesting an active role in the breakdown of algae-derived compounds as anticipated in the previous study ( Teeling et al., 2012). 16S cDNA estimates for the SAR11 clade were notably depleted in the earlier sample (Fig. 2a) suggesting that SAR11 members cannot profit from abound substrates during algal blooms and thus were outcompeted by other clades AZD2281 (Fig. 1). Pyrotag sequencing identified many SAR11 to consist of ‘Candidatus Pelagibacter’ species. The well-studied representative ‘Ca. P.

ubique’ HTCC1062 has a rather small genome (1.3 Mbp) with a single rRNA operon ( Giovannoni et al., 2005), and in terms of its genetic repertoire is perfectly adapted for the oligotrophic open ocean but not for coastal algae blooms. We compared two 454 metatranscriptome datasets from two different time points (Table 1). The 454 metatranscriptomes provided sufficient resolution down to class level when combined with the taxonomically classified metagenome. The most abundant transcripts with known functions were assigned to genes that are indicative of proliferating cells, such as elongation factors, DNA gyrases, sigma factors and chaperonins. For example, a total of 643 cDNA reads encoding for GTP-binding elongation factors (Pfam: GTP_EFTU) could be detected in the later sample (14/04/2009), which account for 2% of all Pfam annotations. With a 145-fold larger dataset, the Illumina metatranscriptome complemented the 454 data and allowed us to assign more reads on family and genus level; hence it allows us to make a clearer statement when combined with the metagenome data. In addition, the omission of mRNA enrichment provided a

less selleck screening library biased picture. The previously described pronounced peak in the abundance of carbohydrate-active enzymes [CAZymes (Cantarel et al., 2009)] during the bacterial succession (Teeling et al., 2012) was also detected in this study. The majority of CAZymes constituted glycoside hydrolases (GHs) and were expressed by Flavobacteria (mainly genera Formosa, and Polaribacter) which are known to harbor high proportions of GHs ( Fernández-Gómez et al., 2013). However, transcripts for the degradation of complex polysaccharides were also detected to a lesser extent in Gammaproteobacteria — mostly in the SAR92-clade and some in Reinekea. The Illumina data provided additional results and revealed CAZyme expression of the α-glucan-degrading families GH13 and GH31 in Reinekea also on the 31/03/2009. While on 14/04/2009 454-data showed no expression of GH31, expression of GH13 was detected.

As a secondary objective we aimed to assess the prevalence of gas

As a secondary objective we aimed to assess the prevalence of gastric precursor lesions at a population basis by means of a national multicentre cross-sectional study. All 43 National Health Service Portuguese hospitals with Gastroenterology Departments registered with the Portuguese Society

of Digestive Endoscopy were invited to participate in this study by sending all their UGI endoscopy reports from a randomly assigned day. If biopsies were performed, the results of the relevant histopathology diagnosis were also requested. Invitation letters were sent several months before the date chosen for the study and all Departments were invited to report all UGI endoscopies performed on a single day (November 17th, 2011). Inclusion criteria were the completion of an already scheduled UGI endoscopy in a National TGF-beta inhibitor Service Hospital and a signed informed consent, specific to the study. Exclusion criteria were emergency exams, failure to provide informed consent or any contraindication to performing

a UGI endoscopy. The confidentiality of all records was ensured by removing the names of patients, doctors and nurses from the EX 527 cost reports before they were sent to the main investigator. Also, permission for compilation of multicenter national data was requested from and granted by the Portuguese Data Protection Authority (Authorisation 4639/2010). As the study involved the performance of only already-scheduled endoscopic exams, with no additional exams or measures, no Ethics Committee approval was required but prior approval was obtained from the Portuguese Society of Digestive 4��8C Endoscopy. Reports included information on the patient’s gender and age, exam indications, main endoscopic findings and conclusions, procedures performed (including sedation, biopsies and therapy) and histopathological results, if applicable. Selection bias was minimised by informing the Departments of the study date only a week beforehand, to prevent major changes

in the daily schedule and all Departments were instructed to proceed as usual in their daily practice. No exclusion criteria were defined for gastroenterologist experience, type of endoscope used, indication for exam (but emergency cases were excluded), performance or not of biopsies or minimum number of cases needed to participate. No sample size was predefined for this study and the results reported for the continuous variables are the means and standard deviations while proportions are reported as percentages with 95% confidence intervals (CI). Comparative statistical analysis used Student’s t-test for the continuous variables and Pearson’s Chi-square test or Fisher’s Exact test for the dichotomous variables, as appropriate, with p = 0.05 representing statistical significance. Of all 43 Portuguese National Health Service hospitals with a Gastroenterology Department, 12 (28%) participated in the study.

This research was supported in part by a grant from the CSIR 12th

This research was supported in part by a grant from the CSIR 12th five year project (BSC-0205). “
“Bisphenol A (BPA), is an industrial chemical that has been present in many hard plastic bottles, including baby bottles, food storage containers

and dental sealants ([1] and [2]). Trace amount of BPA released from these products gets into food and consumed by humans. Thus, in humans, BPA is detected not only in serum and urine Trametinib price but also in the placenta and amniotic fluid ([3] and [4]). Studies employing standardized toxicity have thus far supported the safety of current low levels of human exposure to BPA [5], [6] and [7]. However, considering that human exposure is abundant and prolonged, there are controversies about this criteria

based on single dose exposure Lumacaftor clinical trial in animal studies. Recently, several studies have been being carried and found that a low dose of BPA below the no observed adverse effect level (NOAEL) have significant effects ([8] and [9]). The adverse effects of BPA are largely related to its estrogenic activity (Hirori et al., 1999; [10]) and result in disturbances to reproductive function [11], steroidogenesis [12] and adipogenesis [13]. However, BPA is reported to induce inflammatory cytokines [13] associated with increased oxidative stress which is detrimental to cell viability ([14] and [15]). The liver is the major organ for the metabolism and detoxification of xenobiotics, including BPA [16]. Therefore, the liver could be largely PD184352 (CI-1040) exposed to BPA, and could be susceptible to regular doses, than other organs. In humans, the urinary concentration of BPA

was associated with abnormal liver function [17]. There are some reports that high doses of BPA altered liver weights in mice or rats [6] and [7] and decreased the viability of rat hepatocytes [14]. Human hepatocarcinoma HepG2 cells are widely studied cell lines to understand the xenobiotic metabolism. It contains the entire battery of detoxification enzymes to metabolize BPA to sulfate and glucuronide conjugates [18] and [19] and certainly qualifies as an in vitro model to study the BPA toxicity and serves as a platform to identify pharmacologically active compounds which acts as an antidote. Ashwagandha (Withania somnifera) is a popular herb used in traditional medicine and remedies that have been in practice in India from time immemorial. Although trusted for its wide health benefits, the active principles of Ashwagandha for its pharmacological effects have not been understood to large extent. Recently, few studies using cell and animal models have demonstrated anti-inflammatory, anti-cancer, anti-diabetic, anti-stress, anti-oxidant, neuroprotective and immune-modulatory potentials of Ashwagandha and its derivatives ( [20] and [21]). Thus, it is postulated that supercritical CO2 extract (SCFE) of Ashwagandha principally containing withanolides may rescue liver from BPA induced toxicity.

, 2009) In this context, dietary restriction and the consequent

, 2009). In this context, dietary restriction and the consequent lack of available endogenous resources have been shown to cause reduced immune reactivity in Rhodnius prolixus ( Feder et al., 1997), Tenebrio molitor ( Siva-Jothy and Thompson, 2002) and tsetse flies ( Kubi et al., 2006 and Akoda

et al., 2009). Our research interest has been focused on whether and how much the nutritionally dependent processes of protein storage and reproduction are KU-57788 affected by infection in the honey bee. Insect storage proteins are synthesized in the fat body and secreted into the hemolymph, where they accumulate in large quantities. These proteins are known as vitellogenin (Vg) (Wyatt, 1999 and Raikhel et al., 2005), hexamerins (Hex) (Telfer and Kunkel, 1991)

and lipophorins (Lp) (Soulages and Wells, 1994). Vg, the yolk vitellin precursor, is the major protein in the hemolymph of adult honey bee queens. It is continuously sequestered by the growing oocytes and incorporated into the yolk during vitellogenesis (Engels et al., CX 5461 1990), thus serving as a nutrient reserve for the eggs and embryos. Except for the workers from the capensis subspecies, which regularly produce diploid female offspring without mating (throughout thelytokous parthenogenesis, Anderson, 1963), even in the presence of the queen ( Moritz et al., 1999 and Beekman et al., 2002), and for a described anarchistic mutant phenotype ( Montague and Oldroyd, 1998), worker reproduction is low in Apis mellifera queenright colonies ( Pirk et al., 2004) where most workers do not reproduce ( Visscher, 1989). Nevertheless, a proportion of them can have functional ovaries and lay haploid male eggs (throughout arrhenotokous parthenogenesis) if separated from the queen ( Jay, 1968 and Visscher, 1996). Like queens, the worker bees

also accumulate Vg in their hemolymph, although at lower Fludarabine levels. Ovary activation in workers entail increased Vg synthesis for incorporation in the growing oocyte ( Engels et al., 1990 and Hartfelder and Engels, 1998). In addition to its essential function in reproduction, Vg has other important physiological roles in the honey bee. It is a zinc carrier protein that is important for hemocyte integrity (Amdam et al., 2004), it regulates the endocrine systems via regulating the juvenile hormone titer (Guidugli et al., 2005), it protects the honey bee against oxidative stress (Seehuus et al., 2006), it is involved in worker longevity (Nelson et al., 2007) and pollen or nectar foraging choice (Ihle et al., 2010). Hexamerins are primarily storage proteins in the insect larvae hemolymph, where they constitute a source of amino acids and energy for metamorphosis (Telfer and Kunkel, 1991).

, 1999)

suggests manual therapists viewed practice as pro

, 1999)

suggests manual therapists viewed practice as professional artistry; this is also suggested by an Australian study of ‘expert’ manual therapists (Edwards et al., 2004). In this research, Edwards also highlighted the relationship between different types of knowledge used in practice and a broad range of clinical reasoning approaches employed by the physiotherapists. In addition, therapists completing Masters level study in manual therapy became more patient-centred, creatively adapting to individual patients (Stathopoulos and Harrison, 2003, Rushton and Lindsay, 2010, Petty et al., 2011a and Petty et al., 2011b) also suggested a professional artistry view of practice. This emerging evidence of professional artistry is perhaps unsurprising given the widespread acknowledgement of the biopsychosocial CYC202 manufacturer model (Engel, 1977) and Mature Organism Model (Gifford, 1998) that highlight the social, psychological and behavioural dimensions of health and disability; they emphasise the need for manual therapists to understand the patient’s unique experience (Jones et al., 2002). One major aim of clinical reasoning

is that practitioners take ‘wise’ action; that is, they take the ‘best judged action Antiinfection Compound Library clinical trial in a specific context’ (Higgs and Jones, 2008, p. 4). Given the complexity surrounding patients’ problems, this is likely to involve a diverse mix of knowledge types such as that suggested in Table 3. We suggest that contemporary manual

therapy, that embraces a biopsychosocial approach, needs to use a variety of different types of knowledge to underpin practice. Enhancing manual therapy practice would require building this eclectic knowledge base; that is all aspects of our practice knowledge Sitaxentan (all types of knowledge used in practice, not just technical rational) need to be explicated, critically reviewed and developed. This has also been argued be others (Richardson, 1993, Malterud, 2001, Titchen and Ersser, 2001b and Higgs et al., 2004). A major way to develop and create this new knowledge is, of course, through research. Research can be broadly categorised into quantitative and qualitative approaches; the approach used is largely determined by the research question. Quantitative research helps to explain phenomena by collecting numerical data. It tests hypotheses, controls variables, measures, identifies cause and effect, and through statistical analysis, aims to generalize findings to predict future events. A major strength of quantitative research is therefore to determine the efficacy and effectiveness of manual therapy interventions.

Most importantly,

however, we also observed that alpha po

Most importantly,

however, we also observed that alpha power is significantly larger over ipsi- as compared to contralateral recordings. In contrast to the P1 which is interpreted as evoked alpha activity (that is short and transient), alpha power can be monitored over the entire time course of a trial. According to our hypothesis that alpha reflects (functional) inhibition, we expected significant differences during the poststimulus period that are due to the side where the target is presented. In general, BMS-907351 clinical trial ipsilateral alpha power should be larger than contralateral alpha power. For the prestimulus period, we expect differences in alpha power that are induced by the cue. In invalid trials subjects will expect the target at the ‘wrong’ location. Thus, for invalid trials, the target is expected in the ipsilateral hemisphere (with respect to actual target presentation) and hence the power in the contralateral hemisphere will be larger. As an example, if in the invalid condition the cue points to the Alectinib chemical structure left hemifield, we expect larger prestimulus alpha power over the left hemisphere which is contralateral to the actual target presentation. Thus, for the prestimulus period, we expected larger power over ipsilateral

sites in the valid condition but larger power over contralateral sites in the invalid condition. This expected pattern of results could be confirmed statistically and is illustrated in Fig. 7. It should be noted that around 100 ms poststimulus (cf. the black vertical line in Fig. 7) there is the

‘crossing point’ (and, thus, no power difference) between invalid ipsi- and contralateral upper alpha Docetaxel power. Beyond that time, ipsilateral alpha power increases, whereas contralateral power decreases, indicating most likely the (delayed) reorientation of attention to the hemifield where the target appeared. Indirect evidence for a positive relationship between alpha power and P1 amplitude comes from research about schizophrenia and frontal lobe dysfunction. The prefrontal cortex is considered to play an important role for the inhibition of irrelevant information and the modulation of the P1–N1 complex in attentional cuing paradigms. Studies with schizophrenic patients have shown reliably that resting EEG is characterized by diminished alpha power and increased theta and delta power (e.g., Itil et al., 1972, Itil et al., 1974, Miyauchi et al., 1990, Sponheim et al., 1994 and Sponheim et al., 2000). Sponheim et al. (2000) have demonstrated that even within a group of schizophrenic patients, diminished alpha power is related to increased negative symptomatology and deviant brain morphology. Haenschel et al. (2007) observed that during the encoding of items in a memory scanning task, the P1 is decreased in schizophrenic patients, but increases with load in healthy control subjects.

Although a switch from short-lived apoptosis prone B cells to lon

Although a switch from short-lived apoptosis prone B cells to longer-lived naïve and resting memory B cells was seen relatively early after initiation of ART, there were no significant changes observed in the

percentages and absolute numbers of total CD19+ B cells during ART in this cohort during the 12 months of observation. Some previous studies in children have shown no changes KU-60019 cost in total CD19+ B cells during ART37 while other studies in both adults and children have shown rises.18, 38, 39 and 40 There are numerous factors that may differ between these samples which could have contributed to these discordant findings but the most immediate apparent need is to follow these trends over a longer observation period. We have previously demonstrated acquisition of pneumococcal protein-specific T cell and B cell immunity in both low carriage and high carriage populations.10, 41, 42, 43,

44 and 45 This naturally acquired immunity may occur as a result of multiple immunizing carriage events to a range of pneumococcal proteins expressed at the mucosal surface.46 In African children, pneumococcal nasopharyngeal carriage occurs very early in life and reaches very high rates47 and, as in this study, carriage rates may be higher among those with HIV infection.48 In this context, we have recently shown that even in minimally symptomatic HIV-infected children, pneumococcal protein antigen-specific memory B-cell numbers are low compared with HIV-uninfected children.10 The delayed recovery in pneumococcal antigen ZVADFMK specific B cell memory after institution of ART that we describe here may indicate that these HIV-infected children remain both more vulnerable to invasive pneumococcal disease and to prolonged or higher density carriage. Understanding more clearly how B cell immune reconstitution relates to pneumococcal colonization will be important in countries such as Malawi

with high HIV prevalence and where Metalloexopeptidase pneumococcal conjugate vaccine (PCV) has recently been introduced into the routine infant immunization schedule, particularly since the effectiveness of these vaccines is to a great extent mediated by effects on carriage and transmission.49 Many of the children reported here were commenced on ART with a low percentage CD4 nadir (Fig. 1A). It is possible that the delayed and incomplete restoration of antigen-specific B cell function we observed would have been ameliorated by earlier initiation of ART.18, 50 and 51 This question has begun to be tackled programmatically as the thresholds for initiating ART are lowered but merits further investigation if vaccines are to be targeted effectively. This work was supported by the Joan Franklin-Adams Trust (scholarship to O.H.I), David Baum Memorial Appeal (grant to A.F and R.S.H.), MLW Core Programme Grant from the Wellcome Trust (funding to R.S.H. – grant number 084679/Z/08/Z) and a Wellcome Trust project grant (funding to R.S.H.