To derive and validate a clinical rule that stratifies the risk of cardiac complications in patients hospitalized for community-acquired pneumonia (CAP) and compare its performance to the pneumonia severity index (PSI) score.
Various plant factors are co-opted by virus elements (RNA, proteins) and have been shown to act in pathways affecting virus accumulation and plant defence. Here, an interaction between Pepino mosaic virus (PepMV) triple gene block protein 1 (TGBp1; p26) and tomato catalase 1 (CAT1), a crucial enzyme in the decomposition of toxic hydrogen peroxide (H?O?), was identified using the yeast two-hybrid assay, and confirmed via an in?vitro pull-down assay and bimolecular fluorescent complementation (BiFC) in?planta. Each protein was independently localized within loci in the cytoplasm and nuclei, sites at which their interaction had been visualized by BiFC. Following PepMV inoculation, CAT mRNA and protein levels in leaves were unaltered at 0, 3 and 6 days (locally) and 8 days (systemically) post-inoculation; however, leaf extracts from the last two time points contained increased CAT activity and lower H?O? evels. Overexpression of PepMV p26 in?vitro and in?planta conferred the same effect, suggesting an additional involvement of TGBp1 in potexvirus pathogenesis. The accumulation of PepMV genomic and subgenomic RNAs and the expression of viral coat protein in noninoculated (systemic) leaves were reduced significantly in CAT-silenced plants. It is postulated that, during PepMV infection, a p26-CAT1 interaction increases H?O? cavenging, thus acting as a negative regulator of plant defence mechanisms to promote PepMV infections.
Recently it has been hypothesized that perforation of colorectal cancer (CRC) itself is not a predictor of poor prognosis. The aim of this study was to analyze the prognostic impact, of the spontaneous perforation of the tumour, metastatic lymph nodes and lymph node ratio (LNR) after potentially curative surgery.
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis by its role in DNA methylation, repair, and synthesis. We analyzed the impact of MTHFR C677T polymorphism in colorectal cancer in a region of the Tenerife Island whose population has a history of genetic isolation and a low genetic variability. This allows analyzing the effects of the polymorphism that are not due to interactions with different genetic variants.
Although traditionally regarded as a disease confined to the lungs, acute pneumonia has important effects on the cardiovascular system at all severities of infection. Pneumonia tends to affect individuals who are also at high cardiovascular risk. Results of recent studies show that about a quarter of adults admitted to hospital with pneumonia develop a major acute cardiac complication during their hospital stay, which is associated with a 60% increase in short-term mortality. These findings suggest that outcomes of patients with pneumonia can be improved by prevention of the development and progression of associated cardiac complications. Before this hypothesis can be tested, however, an adequate mechanistic understanding of the cardiovascular changes that occur during pneumonia, and their role in the trigger of various cardiac complications, is needed. In this Review, we summarise knowledge about the burden of cardiac complications in adults with acute pneumonia, the cardiovascular response to this infection, the potential effects of commonly used cardiovascular and anti-infective drugs on these associations, and possible directions for future research.
Gallstone ileus is an uncommon type of mechanical intestinal obstruction caused by an intraluminal gallstone, and preoperative diagnosis is difficult in the Emergency department. This study is a retrospective analysis of the clinical presentation of 5 patients with gallstone ileus treated between 2000-2010. Clinical features, diagnostic testing, and surgical treatment were analyzed. Five patients were included: 2 cases showed bowel obstruction; 2 patients presented a recurrent gallstone ileus with prior surgical intervention; and one patient presented acute peritonitis due to perforation of an ileal diverticula. In all cases CT confirmed the preoperative diagnosis. In our experience, gallstone ileus may present with clinical features other than intestinal obstruction. In suspicious cases CT may be useful to decrease diagnostic delay, which is associated with more complications.
Criniviruses comprise one of the genera within the family Closteroviridae. Members in this family are restricted to the phloem and rely on whitefly vectors of the genera Bemisia and/or Trialeurodes for plant-to-plant transmission. All criniviruses have bipartite, positive-sense single-stranded RNA genomes, although there is an unconfirmed report of one having a tripartite genome. Lettuce infectious yellows virus (LIYV) is the type species of the genus, the best studied so far of the criniviruses and the first for which a reverse genetics system was developed. LIYV RNA 1 encodes for proteins predicted to be involved in replication, and alone is competent for replication in protoplasts. Replication results in accumulation of cytoplasmic vesiculated membranous structures which are characteristic of most studied members of the Closteroviridae. These membranous structures, often referred to as Beet yellows virus (BYV)-type vesicles, are likely sites of RNA replication. LIYV RNA 2 is replicated in trans when co-infecting cells with RNA 1, but is temporally delayed relative to RNA 1. Efficient RNA 2 replication also is dependent on the RNA 1-encoded RNA-binding protein, P34. No LIYV RNA 2-encoded proteins have been shown to affect RNA replication, but at least four, CP (major coat protein), CPm (minor coat protein), Hsp70h, and P59 are virion structural components and CPm is a determinant of whitefly transmissibility. Roles of other LIYV RNA 2-encoded proteins are largely as yet unknown, but P26 is a non-virion protein that accumulates in cells as characteristic plasmalemma deposits which in plants are localized within phloem parenchyma and companion cells over plasmodesmata connections to sieve elements. The two remaining crinivirus-conserved RNA 2-encoded proteins are P5 and P9. P5 is 39 amino acid protein and is encoded at the 5 end of RNA 2 as ORF 1 and is part of the hallmark closterovirus gene array. The orthologous gene in BYV has been shown to play a role in cell-to-cell movement and indicated to be localized to the endoplasmic reticulum as a Type III integral membrane protein. The other small protein, P9, is encoded by ORF 4 overlaps with ORF 3 that encodes the structural protein, P59. P9 seems to be unique to viruses in the genus Crinivirus, as no similar protein has been detected in viruses of the other two genera of the Closteroviridae.
Cognitive impairment in Parkinsons disease (PD) has received little attention to date and as such, there are currently very few treatment options available. The aim of the present study was to determine whether cognitive training might alleviate these cognitive symptoms and if so, whether such changes might be correlated with altered brain patterns. The performance of 10 PD patients and 10 paired healthy controls was assessed in a modified version of the Stroop task performed in association with functional magnetic resonance imaging, and half of the PD patients were given 6?months of cognitive daily training based on Sudoku exercises. Results showed that the training program improved the cognitive performance in the Stroop test of the trained Parkinsons patients during MRI, specifically in terms of reaction time, and of correct and missing answers. Moreover, training provoked reduced cortical activation patterns with respect to untrained patients that were comparable to the patterns of activation observed in controls. Based on these findings, we propose that cognitive training can contribute significantly to save brain resources in PD patients, maybe by readdressing the imbalance caused by the alterations to inhibitory circuitry. Furthermore, these data strongly support the development and use of standardized cognitive training programs in PD patients.
Plant viral capsid proteins (CP) can be involved in virus movement, replication and symptom development as a result of their interaction with host factors. The identification of such interactions may thus provide information about viral pathogenesis. In this study, Pepino mosaic virus (PepMV) CP was used as bait to screen a tomato (Solanum lycopersicum) cDNA library for potential interactors in yeast. Of seven independent interacting clones, six were predicted to encode the C-termini of the heat shock cognate 70 (Hsc70) proteins. Three full length tomato Hsc70s (named Hsc70.1, .2, .3) were used to confirm the interaction in the yeast two hybrid assay and bimolecular fluorescent complementation (BiFC) in planta. The PepMV CP-Hsc70 interaction was confirmed only in the case of Hsc70.3 for both assays. In BiFC, the interaction was visualized in the cytoplasm and nucleus of agroinfiltrated Nicotiana benthamiana epidermal cells. During PepMV infection, Hsc70.3 mRNA levels were induced and protein accumulation increased at 48 and 72 h post inoculation. In transmission electron microscopy using immunogold labelling techniques, Hsc70 was detected to co-localize with virions in the phloem of PepMV-infected tomato leaves. These observations, together with the co-purification of Hsc70 with PepMV virions further support the notion of a PepMV CP/Hsc70 interaction during virus infection.
Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem.
Despite the availability of excellent antibiotics, the mortality from community-acquired pneumonia (CAP) remains substantial. Most deaths occur during the first week of hospitalization. Because antibiotics rapidly eradicate bacteria from pulmonary secretions, an ongoing inflammatory response may be responsible for the poor outcome, and treatment with immunomodulatory drugs might be beneficial in this setting. Macrolides and statins exert a broad range of anti-inflammatory effects. Although randomized control trials have not been done, clinical evidence favors the addition of a macrolide to a beta-lactam for the treatment of pneumococcal pneumonia and supports a role for macrolides in the treatment of all-cause CAP without regard to their anti-microbial activity. The weight of several retrospective studies suggests that statins be considered in treating acute CAP. Further support for the use of statins derives from the high association between pneumonia and acute myocardial infarction. Aspirin might also be of benefit in treating patients hospitalized for pneumonia because of its anti-inflammatory activity as well as its benefits in acute myocardial infarction. Treatment of CAP with corticosteroids has yielded mixed results and the value of this approach is not well established, although further research is currently underway. Ibuprofen is not of benefit in treating sepsis in humans and glitazones may increase the risk of severe pneumonia.
The Lettuce infectious yellows virus (LIYV) RNA 2 mutant p1-5b was previously isolated from Bemisia tabaci-transmitted virus maintained in Chenopodium murale plants. p1-5b RNA 2 contains a single-nucleotide deletion in the minor coat protein (CPm) open reading frame (ORF) that is predicted to result in a frameshift and premature termination of the protein. Using the recently developed agroinoculation system for LIYV, we tested RNA 2 containing the p1-5b CPm mutant genotype (agro-pR6-5b) in Nicotiana benthamiana plants. We showed that plant infection triggered by agro-pR6-5b spread systemically and resulted in the formation of virions similar to those produced in p1-5b-inoculated protoplasts. However, virions derived from these mutant CPm genotypes were not transmitted by whiteflies, even though virion concentrations were above the typical transmission thresholds. In contrast, and as demonstrated for the first time, an engineered restoration mutant (agro-pR6-5bM1) was capable of both systemic movement in plants and whitefly transmission. These results provide strong molecular evidence that the full-length LIYV-encoded CPm is dispensable for systemic plant movement but is required for whitefly transmission.
A Brain Computer Interface (BCI) provides direct communication from the brain to a computer or electronic device. In order for BCIs to become practical assistive devices it is necessary to develop robust systems, which can be used outside of the laboratory. This paper appraises the technical challenges, and outlines the design of an intuitive user interface, which can be used for smart device control and entertainment applications, of specific interest to users. We adopted a user-centred approach, surveying two groups of participants: fifteen volunteers who could use BCI as an additional technology and six users with complex communication and assistive technology needs. Interaction is based on a four way choice, parsing a hierarchical menu structure which allows selection of room location and then device (e.g. light, television) within a smart home. The interface promotes ease of use which aim to improve the BCI communication rate.
Acute coronary syndromes are a leading cause of morbidity and mortality worldwide. The mechanisms underlying the triggering of these events are diverse and include increased coronary and systemic inflammatory activity, dominant prothrombotic conditions, increased biomechanical stress on coronary arteries, variations in the coronary arterial tone, disturbed haemodynamic homoeostasis, and altered myocardial metabolic balance. There is experimental evidence that acute infections can promote the development of acute coronary syndromes, and clinical data strongly support a role for acute infections in triggering these events. In our Review, we summarise the pathogenesis of coronary artery disease and present the evidence linking acute infections with the development of acute coronary syndromes. Greater awareness of this association is likely to encourage research into ways of protecting patients who are at high risk.
The aim of this study was to detect and quantify Vibrio parahaemolyticus using flow cytometry (FCM) in combination with a polyclonal antibody developed in our laboratory. Experiments were carried out using V. parahaemolyticus cells in pure and mixed bacteria culture suspensions in either artificial or natural seawater. Using FCM, V. parahaemolyticus cells labelled with the polyclonal antibody and a secondary fluorescein isothiocyanate-conjugated antibody were detected and rapidly quantified at low cell densities (10(3) cells?ml(-1) ) in both the pure and mixed cultures. To determine the specificity of our antibody, its cross-reactivity with other ATCC bacterial strains and some environmental Vibrio spp. and Gram-positive isolates was also assessed. Significant immunoreactivity levels above background were obtained for V. harvey 64, V. parahaemolyticus 704 and V. alginolyticus 1407, although the intensities were significantly less than for V. parahaemolyticus Conero. The experiments carried out in natural seawater confirmed the antibody specificity towards V. parahaemolyticus Conero even if a lower proportion of labelled cells was observed. The application of FCM in combination with a primary polyclonal antibody appears to be a promising technique for the detection and quantification of V. parahaemolyticus cells in aquatic environments.
The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient outcome after treatment with 5-FU-based chemotherapy to determine the contribution of MTHFR genotypes in the risk of colorectal cancer (CRC) and in the response to therapy.
A link between acute infections and the development of acute coronary syndromes (ACS) has been proposed. We used retrospective cohort and self-controlled case series analyses to define the closeness of the association between acute bacterial pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae and ACS. For the retrospective cohort analysis we included a control group of patients with admission diagnoses other than pneumonia or ACS. For the self-controlled case series analysis, we made within-person comparisons of the risk for ACS during the 15 days after admission for pneumonia with that of 365 days before and after that event. In 206 pneumonia patients (144 S. pneumoniae, 62 H. influenzae) we identified 22 (10.7%) cases of ACS, which compared to 6 (1.5%) among 395 controls resulted in an odds ratio (OR) of 7.8 (95% confidence interval [CI], 3.1-19.4). With multivariate logistic regression analysis, the OR for ACS in the pneumonia group remained elevated (OR, 8.5; 95% CI, 3.4-22.2). By the self-controlled case series method, the risk of ACS remarkably increased during the first 15 days after the diagnosis of pneumonia (incidence rate ratio, 47.6; 95% CI, 24.5-92.5). The characteristics and strength of these associations suggest a causal role for the acute infection in this relationship.
We evaluated a possible association between S. aureus bacteremia (SAB) and the occurrence of myocardial infarction (MI) in 588 patients using the self-controlled case series method. SAB increased the risk for MI 35-fold in the 2 d after recognition of this infection (IRR = 35.3; CI 16.7-74.7).
The capsid protein (CP) of the monopartite begomovirus Tomato yellow leaf curl Sardinia virus (TYLCSV), family Geminiviridae, is indispensable for plant infection and vector transmission. A region between amino acids 129 and 152 is critical for virion assembly and insect transmissibility. Two previously described mutants, one with a double Q129P Q134H mutation (PNHD) and another with a further D152E change (PNHE), were found nontransmissible (NT). Another NT mutant with a single N130D change (QDQD) was retrieved from a new mutational analysis. In this study, these three NT mutants and the wild-type (wt) virus were compared in their relationships with the whitefly vector Bemisia tabaci and the nonvector Trialeurodes vaporariorum. Retention kinetics of NT mutants were analyzed by quantitative dot blot hybridization in whiteflies fed on infected plants. The QDQD mutant, whose virions appeared nongeminate following purification, was hardly detectable in either whitefly species at any sampling time. The PNHD mutant was acquired and circulated in both whitefly species for up to 10 days, like the wt virus, while PNHE circulated in B. tabaci only. Using immunogold labeling, both PNHD and PNHE CPs were detected in B. tabaci salivary glands (SGs) like the wt virus, while no labeling was found in any whitefly tissue with the QDQD mutant. Significant inhibition of transmission of the wt virus was observed after prior feeding of the insects on plants infected with the PNHE mutant, but not on plants infected with the other mutants. Virion stability and ability to cross the SG barrier are necessary for TYLCSV transmission, but interactions with molecular components inside the SGs are also critical for transmissibility.
Germline mutations or the malfunctioning of postreplicative mismatch repair genes (MMR) are responsible of hereditary nonpolyposis colorectal cancer (HNPCC), and are also implied in some sporadic colorectal cancer (CRC) forms without any familial history of this disease. Besides germinal mutations and methylation, single-nucleotide polymorphisms (SNP) can predispose to nonfamilial CRC with low to moderate penetrance. In this case-control study, we analyzed three MLH1 single-nucleotide polymorphisms (exon 5: 415G-->C, rs28930073; exon 8: 655A-->G, rs1799977 and exon 16: 1852-1853AA-->GC) in 140 sporadic colorectal cancer cases and 125 healthy individuals to evaluate the relationship among CRC risk and clinicopathologic and genetic characteristics of the tumors. In our study, no 415G-->C variant carrier was found among all analyzed samples. The 1852-1853AA-->GC is a rare variant detected in heterozygoses in five controls and one case. In relation to the more frequent 655A-->G polymorphism, association analyses revealed that G carriers (AG or GG genotype) displayed a higher risk of CRC compared with AA homozygous [odds ratio (OR) AG=2.55, 95% confidence interval (CI)=1.48-4.39; P=0.01 and OR GG=2.48, 95% CI=1.20-5.11; P=0.01, respectively]. G-carrier males showed high CRC risk compared with homozygous AA wild-type individuals (OR: AG=3.05; 95% CI=1.49-6.26, P=0.002; OR: GG=3.60; 95% CI=1.29-10.03). Nevertheless, patients carrying the G allele displayed a better outcome than wild-type genotype carriers (log rank=7.26; P=0.007) and did not present vascular invasion (P=0.03), distant metastasis (P=0.004), or recurrence (P=0.01). MLH1 655A-->G change is associated with an increased risk, although it seems to have a favorable effect on patients, providing a better outcome. Moreover, our results suggest that for genomic profiling to predict the clinical outcome of patients with colorectal cancer, gender must also be considered.
Lettuce infectious yellows virus (LIYV) encodes a 26 kDa protein (P26) previously shown to associate with plasmalemma deposits (PLDs), unique LIYV-induced cytopathologies located at the plasmalemma over plasmodesmata pit fields in companion cells and phloem parenchyma. To further characterize the relationship of P26 and PLDs, we assessed localization and cytopathology induction of P26 expressed from either LIYV or a heterologous Tobacco mosaic virus (TMV) vector using green fluorescent protein (GFP) fusions, immunofluorescence microscopy, biochemical fractionation, and transmission electron microscopy (TEM). TEM analyses demonstrated that P26 not only associated with, but induced formation of PLDs in the absence of other LIYV proteins. Interestingly, PLDs induced by P26-expressing TMV were no longer confined to phloem cells. Putative P26 orthologs from two other members of the genus Crinivirus which do not induce conspicuous PLDs exhibited fractionation properties similar to LIYV P26 but were not associated with any PLD-like cytopathology.
Several viruses in the genus Closterovirus including Grapevine leafroll-associated virus-2 (GLRaV-2), encode a tandem of papain-like leader proteases (L1 and L2) whose functional profiles remained largely uncharacterized. We generated a series of the full-length, reporter-tagged, clones of GLRaV-2 and demonstrated that they are systemically infectious upon agroinfection of an experimental host plant Nicotiana benthamiana. These clones and corresponding minireplicon derivatives were used to address L1 and L2 functions in GLRaV-2 infection cycle. It was found that the deletion of genome region encoding the entire L1-L2 tandem resulted in a ~100-fold reduction in minireplicon RNA accumulation. Five-fold reduction in RNA level was observed upon deletion of L1 coding region. In contrast, deletion of L2 coding region did not affect RNA accumulation. It was also found that the autocatalytic cleavage by L2 but not by L1 is essential for genome replication. Analysis of the corresponding mutants in the context of N. benthamiana infection launched by the full-length GLRaV-2 clone revealed that L1 or its coding region is essential for virus ability to establish infection, while L2 plays an accessory role in the viral systemic transport. Strikingly, when tagged minireplicon variants were used for the leaf agroinfiltration of the GLRaV-2 natural host, Vitis vinifera, deletion of either L1 or L2 resulted in a dramatic reduction of minireplicon ability to establish infection attesting to a host-specific requirement for tandem proteases in the virus infection cycle.
Lettuce infectious yellows virus (LIYV), the type member of the genus Crinivirus in the family Closteroviridae, is specifically transmitted by the sweet potato whitefly (Bemisia tabaci) in a semipersistent manner. LIYV infections result in a low virus titer in plants and protoplasts, impeding reverse genetic efforts to analyze LIYV gene/protein functions. We found that synergistic interactions occurred in mixed infections of LIYV and Turnip mosaic virus (TuMV) in Nicotiana benthamiana plants, and these resulted in enhanced accumulation of LIYV. Furthermore, we examined the ability of transgenic plants and protoplasts expressing only the TuMV P1/HC-Pro sequence to enhance the accumulation of LIYV. LIYV RNA and protein titers increased by as much as 8-fold in these plants and protoplasts relative to control plants. LIYV infections remained phloem-limited in P1/HC-Pro transgenic plants, suggesting that enhanced accumulation of LIYV in these plants was due primarily to increased replication efficiency, not to greater spread.
The hMSH2(M688R) mismatch repair (MMR) gene mutation has been found in five large families from Tenerife, Spain, suggesting it is a Lynch syndrome or hereditary non-polyposis colorectal cancer (LS/HNPCC) founder mutation. In addition to classical LS/HNPCC tumors, these families present with a high incidence of central nervous system (CNS) tumors normally associated with Turcot or constitutional mismatch repair deficiency (CMMR-D) syndromes. Turcot and CMMR-D mutations may be biallelic, knocking out both copies of the MMR gene. The hMSH2(M688R) mutation is located in the ATP hydrolysis (ATPase) domain. We show that the hMSH2(M688R)-hMSH6 heterodimer binds to mismatched nucleotides but lacks normal ATP functions and inhibits MMR in vitro when mixed with the wild-type (WT) heterodimer. Another alteration that has been associated with LS/HNPCC, hMSH2(M688I)-hMSH6, displays no identifiable differences with the WT heterodimer. Interestingly, some extracolonic tumors from hMSH2(M688R) carriers may express hMSH2-hMSH6, yet display microsatellite instability (MSI). The functional analysis along with variability in tumor expression and the high incidence of CNS tumors suggests that hMSH2(M688R) may act as a dominant negative in some tissues, while the hMSH2(M688I) is most likely a benign polymorphism.
Inactivation of Mismatch Repair genes in Lynch Syndrome, caused by inherited mutations, decreases the ability to repair DNA errors throughout life. This deficit may allow the development of any tumor type. Nevertheless, the Syndrome develops a specific tumor spectrum associated with the disease. We think that such spectrum of tumors would be related to the action of certain endogenous carcinogens such as bile acids and estrogens that aggravate the inherited defect.
Community-acquired pneumonia (CAP) affects >5 million adults each year in the United States. Although incident cardiac complications occur in patients with community-acquired pneumonia, their incidence, timing, risk factors, and associations with short-term mortality are not well understood.
We have developed an assay based on rice embryogenic callus for the rapid functional characterization of metabolic genes. We validated the assay using a selection of well-characterized genes with known functions in the carotenoid biosynthesis pathway, allowing the rapid visual screening of callus phenotypes based on tissue color. We were then able to use the system to identify the functions of two uncharacterized genes: a chemically-synthesized ?-carotene ketolase gene optimized for maize codon usage; and a wild-type Arabidopsis thaliana ortholog of the cauliflower Orange gene. In contrast to previous reports, we found that the wild-type Orange allele was sufficient to induce chromoplast differentiation. We also found that chromoplast differentiation could be induced by increasing the availability of precursors and thus driving flux through the pathway, even in the absence of Orange. Remarkably, we found that diverse endosperm-specific promoters were highly active in rice callus despite their restricted activity in mature plants. Our callus system provides a unique opportunity to predict the impact of metabolic engineering in complex pathways and provides a starting point for quantitative modeling and the rational design of engineering strategies using synthetic biology. We discuss the impact of our data on the analysis and engineering of the carotenoid biosynthesis pathway. This article is protected by copyright. All rights reserved.
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