bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized comparison of etanercept with usual therapy in an Asian population with active rheumatoid arthritis: the APPEAL trial
Authors: KIM Ho‐Youn , HSU Ping‐Ning , BARBA Merle , SULAIMAN Wahinnuddin , ROBERTSON Debbie , VLAHOS Bonnie , KHANDKER Rezaul , NAB Henk , FREUNDLICH Bruce , KOENIG Andrew
Published: October 2011

Aim:  Rheumatoid arthritis (RA) is an important rheumatologic disease in Asia‐Pacific countries, as in other parts of the world. However, limited information is available regarding RA therapy in this region. The Asia‐Pacific Study in Patients to be Treated With Etanercept or an Alternative Listed DMARD (APPEAL) compared efficacy and safety of etanercept (ETN) + methotrexate (MTX) versus usual disease‐modifying anti‐rheumatic drugs (DMARDs) + MTX (reflecting regional practice) in subjects with moderate to severe RA from multiple Asia‐Pacific countries.

Method:  In this open‐label, active‐comparator, parallel‐design, multicenter study, subjects (n = 300) in the Asia‐Pacific region were randomized to ETN + MTX (n = 197) or DMARD + MTX (n = 103). The primary efficacy endpoint was the American College of Rheumatology (ACR) response (ACR‐N) area under the curve (AUC) over 16 weeks.

Results:  Baseline characteristics were similar between groups. At Week 16, ACR‐N AUC indicated a significantly greater response with ETN + MTX compared with DMARD + MTX (mean difference –145.3; P < 0.001). Significantly greater proportions of subjects achieved ACR 20, 50 and 70 responses with ETN + MTX versus DMARD + MTX at Week 16 (P < 0.05). Low Disease Activity Score based on a 28‐joint count (DAS28 < 3.2) was also achieved by significantly more subjects in the ETN + MTX group versus the DMARD + MTX group (P < 0.001). Greater improvements were shown for DAS28, pain visual analogue scale, health assessment questionnaire, and physician and patient global assessments (P < 0.05) for ETN + MTX versus DMARD + MTX. No new safety signals were found.

Conclusion:  In this Asia‐Pacific population of subjects with moderate to severe RA, ETN + MTX showed superior efficacy versus usual DMARD + MTX regimens, with similar safety profiles.
Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design
Authors: Diskin Ron , Scheid Johannes F. , Marcovecchio Paola M. , West Anthony P. , Klein Florian , Gao Han , Gnanapragasam Priyanthi N. P. , Abadir Alexander , Seaman Michael S. , Nussenzweig Michel C. , Bjorkman Pamela J.
Published: October 2011

Structural analysis of an HIV antibody reveals residues important for neutralization breadth and potency.
A Novel Metabolite of Antituberculosis Therapy Demonstrates Host Activation of Isoniazid and Formation of the Isoniazid-NAD
+
Adduct
Authors: Mahapatra Sebabrata , Woolhiser Lisa K. , Lenaerts Anne J. , Johnson John L. , Eisenach Kathleen D. , Joloba Moses L. , Boom W. Henry , Belisle John T.
Published: October 2011

One of the most effective and widely used antituberculosis (anti-TB) drugs is isoniazid (INH), a prodrug activated via oxidation that forms an adduct with NAD
+
to inhibit NADH-dependent targets of
Mycobacterium tuberculosis
, such as enoyl-acyl carrier protein reductase (InhA). The metabolic by-products and potentially toxic intermediates resulting from INH therapy have been identified through a large body of work. However, an INH-NAD adduct or structures related to this adduct have not been identified in specimens from human TB patients or animal models of TB. Analyses by mass spectrometry of urine collected from TB patients in a study conducted by the NIAID-funded Tuberculosis Research Unit identified 4-isonicotinoylnicotinamide (C
12
H
9
N
3
O
2
) as a novel metabolite of INH therapy. This compound was formed by
M. tuberculosis
strains in a KatG-dependent manner but could also be produced by mice treated with INH independent of an
M. tuberculosis
infection. Thus, the 4-isonicotinoylnicotinamide observed in human urine samples is likely derived from the degradation of oxidized INH-NAD adducts and provides direct evidence of host INH activation.
F18, a Novel Small-Molecule Nonnucleoside Reverse Transcriptase Inhibitor, Inhibits HIV-1 Replication Using Distinct Binding Motifs as Demonstrated by Resistance Selection and Docking Analysis
Authors: Lu Xiaofan , Liu Li , Zhang Xu , Lau Terrence Chi Kong , Tsui Stephen Kwok Wing , Kang Yuanxi , Zheng Purong , Zheng Bojian , Liu Gang , Chen Zhiwei
Published: October 2011

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type 1 (HIV-1) replication. We previously described a newly synthesized small molecule, 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a (+)-calanolide A analog, as a novel anti-HIV-1 NNRTI (H. Xue et al., J. Med. Chem. 53:1397–1401, 2010). Here, we further investigated its antiviral range, drug resistance profile, and underlying mechanism of action. F18 consistently displayed potent activity against primary HIV-1 isolates, including various subtypes of group M, circulating recombinant form (CRF) 01_AE, and laboratory-adapted drug-resistant viruses. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (50% effective concentration, 1.0 nM), which was in stark contrast to the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses byin vitroserial passages and found that the mutation L100I appeared to be the dominant contributor to F18 resistance, further suggesting a binding motif different from that of nevirapine and efavirenz. F18 was nonantagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected peripheral blood mononuclear cells. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore,in silicodocking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase differently from other NNRTIs. This study presents F18 as a new potential drug for clinical use and also presents a new mechanism-based design for future NNRTI.
Macrophyte Species Drive the Variation of Bacterioplankton Community Composition in a Shallow Freshwater Lake
Authors: Zeng Jin , Bian Yuanqi , Xing Peng , Wu Qinglong L.
Published: October 2011

Macrophytes play an important role in structuring aquatic ecosystems. In this study, we explored whether macrophyte species are involved in determining the bacterioplankton community composition (BCC) in shallow freshwater lakes. The BCC in field areas dominated by different macrophyte species in Taihu Lake, a large, shallow freshwater lake, was investigated over a 1-year period. Subsequently, microcosm experiments were conducted to determine if single species of different types of macrophytes in an isolated environment would alter the BCC. Denaturing gradient gel electrophoresis (DGGE), followed by cloning and sequence analysis of selected samples, was employed to analyze the BCC. The DGGE results of the field investigations indicated that the BCC changed significantly from season to season and that the presence of different macrophyte species resulted in lower BCC similarities in the summer and fall. LIBSHUFF analysis of selected clone libraries from the summer demonstrated different BCCs in the water column surrounding different macrophytes. Relative to the field observations, the microcosm studies indicated that the BCC differed more pronouncedly when associated with different species of macrophytes, which was also supported by LIBSHUFF analysis of the selected clone libraries. Overall, this study suggested that macrophyte species might be an important factor in determining the composition of bacterial communities in this shallow freshwater lake and that the species-specific influence of macrophytes on BCC is variable with the season and distance.
Effect of Honey on Streptococcus mutans Growth and Biofilm Formation
Authors: Nassar Hani M. , Li Mingyun , Gregory Richard L.
Published: October 2011

Because of the tradition of using honey as an antimicrobial medicament, we investigated the effect of natural honey (NH) on
Streptococcus mutans
growth, viability, and biofilm formation compared to that of an artificial honey (AH). AH contained the sugars at the concentrations reported for NH. NH and AH concentrations were obtained by serial dilution with tryptic soy broth (TSB). Several concentrations of NH and AH were tested for inhibition of bacterial growth, viability, and biofilm formation after inoculation with
S. mutans
UA159 in 96-well microtiter plates to obtain absorbance and CFU values. Overall, NH supported significantly less (
P
< 0.05) bacterial growth than AH at 25 and 12.5% concentrations. At 50 and 25% concentrations, both honey groups provided significantly less bacterial growth and biofilm formation than the TSB control. For bacterial viability, the results for all honey concentrations except 50% NH were not significantly different from those for the TSB control. NH was able to decrease the maximum velocity of
S. mutans
growth compared to AH. In summary, NH demonstrated more inhibition of bacterial growth, viability, and biofilm formation than AH. This study highlights the potential antibacterial properties of NH and could suggest that the antimicrobial mechanism of NH is not solely due to its high sugar content.
Heme-Biosynthetic Porphobilinogen Deaminase Protects Aspergillus nidulans from Nitrosative Stress
Authors: Zhou Shengmin , Narukami Toshiaki , Nameki Misuzu , Ozawa Tomoko , Kamimura Yosuke , Hoshino Takayuki , Takaya Naoki
Published: October 2011

Microorganisms have developed mechanisms to combat reactive nitrogen species (RNS); however, only a few of the fungal genes involved have been characterized. Here we screened RNS-resistant
Aspergillus nidulans
strains from fungal transformants obtained by introducing a genomic DNA library constructed in a multicopy vector. We found that the
AN0121.3
gene (
hemC
) encodes a protein similar to the heme biosynthesis enzyme porphobilinogen deaminase (PBG-D) and facilitates RNS-tolerant fungal growth. The overproduction of PBG-D in
A. nidulans
promoted RNS tolerance, whereas PBG-D repression caused growth that was hypersensitive to RNS. PBG-D levels were comparable to those of cellular protoheme synthesis as well as flavohemoglobin (FHb; encoded by
fhbA
and
fhbB
) and nitrite reductase (NiR; encoded by
niiA
) activities. Both FHb and NiR are hemoproteins that consume nitric oxide and nitrite, respectively, and we found that they are required for maximal growth in the presence of RNS. The transcription of
hemC
was upregulated by RNS. These results demonstrated that PBG-D is a novel NO-tolerant protein that modulates the reduction of environmental NO and nitrite levels by FHb and NiR.
Roles of Diet and the Acid Tolerance Response in Survival of Common Salmonella Serotypes in Feces of Finishing Pigs
Authors: Rajtak Ursula , Boland Fiona , Leonard Nola , Bolton Declan , Fanning Séamus
Published: October 2011

The persistence ofSalmonellain the environment is an important factor influencing the transmission of infection in pig production. This study evaluated the effects of acid tolerance response (ATR), organic acid supplementation, and physical properties of feed on the survival of a five-strainSalmonellamixture in porcine feces held at 4 and 22°C for 88 days. Acid-adapted or non-acid-adapted nalidixic acid-resistantSalmonellastrains were used to inoculate feces of pigs fed four different diets, which consisted of a nonpelleted, finely ground meal feed or a finely ground, pelleted feed that was left unsupplemented or was supplemented with K-diformate. Organic acid supplementation and physical properties of feed markedly influencedSalmonellasurvival, but the effects were highly dependent on storage temperature; survival was unaffected by ATR. The most pronounced effects were observed at 22°C, a temperature similar to that of finishing pig houses. The supplementation of meal diets with K-diformate significantly reduced the duration of survival (P< 0.1) and increased rates of decline (P< 0.0001) of salmonellae in feces compared to survival in feces of pigs fed unsupplemented meal. The pelleting of feed, compared to feeding meal, significantly reduced (P< 0.1) the duration of survival in feces held at 22°C. Only minor effects of feed form and acid supplementation on survivor numbers were observed at 4°C. Differences in the fecal survival ofSalmonellacould not be related to diet-induced changes in fecal physiochemical parameters. The predominant survival ofS. entericaserovar Typhimurium DT193 and serotype 4,[5],12:i:- in porcine feces demonstrates the superior ability of these serotypes to survive in this environment. Fecal survival and transmission ofSalmonellain pig herds may be reduced by dietary approaches, but effects are highly dependent on environmental temperature.
When Second Best Is Good Enough: Another Probabilistic Look at Saturation Mutagenesis
Authors: Nov Yuval
Published: October 2011

We developed new criteria for determining the library size in a saturation mutagenesis experiment. When the number of all possible distinct variants is large, any of the top-performing variants (e.g., any of the top three) is likely to meet the design requirements, so the probability that the library contains at least one of them is a sensible criterion for determining the library size. By using a criterion of this type, one may significantly reduce the library size and thus save costs and labor while minimally compromising the quality of the best variant discovered. We present the probabilistic tools underlying these criteria and use them to compare the efficiencies of four randomization schemes: NNN, which uses all 64 codons; NNB, which uses 48 codons; NNK, which uses 32 codons; and MAX, which assigns equal probabilities to each of the 20 amino acids. MAX was found to be the most efficient randomization scheme and NNN the least efficient. TopLib, a computer program for carrying out the related calculations, is available through a user-friendly Web server.
Growth Rate-Dependent Control in Enterococcus faecalis: Effects on the Transcriptome and Proteome, and Strong Regulation of Lactate Dehydrogenase
Authors: Mehmeti Ibrahim , Faergestad Ellen M. , Bekker Martijn , Snipen Lars , Nes Ingolf F. , Holo Helge
Published: October 2011

Enterococcus faecalis
V583 was grown in a glucose-limited chemostat at three different growth rates (0.05, 0.15, and 0.4 h
−1
). The fermentation pattern changed with growth rate, from a mostly homolactic profile at a high growth rate to a fermentation dominated by formate, acetate, and ethanol production at a low growth rate. A number of amino acids were consumed at the lower growth rates but not by fast-growing cells. The change in metabolic profile was caused mainly by decreased flux through lactate dehydrogenase. The transcription of
ldh
-
1
, encoding the principal lactate dehydrogenase, showed very strong growth rate dependence and differed by three orders of magnitude between the highest and the lowest growth rates. Despite the increase in
ldh
-1 transcript, the content of the Ldh-1 protein was the same under all conditions. Using microarrays and quantitative PCR, the levels of 227 gene transcripts were found to be affected by the growth rate, and 56 differentially expressed proteins were found by proteomic analyses. Few genes or proteins showed a growth rate-dependent increase or decrease in expression across the whole range of conditions, and many showed a maximum or minimum at the middle growth rate (i.e., 0.15 h
−1
). For many gene products, a discrepancy between transcriptomic and proteomic data were seen, indicating posttranscriptional regulation of expression.
Bacterial Cell Surface Damage Due to Centrifugal Compaction
Authors: Peterson Brandon W. , Sharma Prashant K. , van der Mei Henny C. , Busscher Henk J.
Published: October 2011

Centrifugal damage has been known to alter bacterial cell surface properties and interior structures, including DNA. Very few studies exist on bacterial damage caused by centrifugation because of the difficulty in relating centrifugation speed and container geometry to the damage caused. Here, we provide a simple, versatile method of analysis for describing the compaction of bacteria during centrifugation based on a proposed centrifugation coefficient,
C
. Values of
C
can be related to different bacterial cell surface properties. Changing the geometry of the centrifugation container or centrifugation speeds changed the value of
C
significantly. Initial deposition rates of
Staphylococcus aureus
ATCC 12600 to a glass surface decayed exponentially from 4,217 to 1,478 cm
−2
s
−1
with increasing
C
, while the proportion of staphylococci with a zeta potential of around −15 mV decreased from 97 to 58%. These surface-sensitive parameters were used independently to derive a critical centrifugation coefficient (0.040), above which centrifugation was considered to impact the outcome of surface-sensitive experiments due to cell surface damage. The critical centrifugation coefficient could successfully predict staphylococcal cell surface damage, i.e., a significant change in initial deposition rate or zeta potential distribution, in 84% of all cases included here, whereas the centrifugation speed could predict damage in only 58% of all cases. Moreover, controlling the centrifugation coefficient within narrow limits over a series of experiments yielded 43% smaller standard deviations in initial staphylococcal deposition rates than with centrifugation at fixed speeds for replicate experiments.
Increased Frequency of Regulatory T Cells and T Lymphocyte Activation in Persons with Previously Treated Extrapulmonary Tuberculosis
Authors: de Almeida Alexandre S. , Fiske Christina T. , Sterling Timothy R. , Kalams Spyros A.
Published: October 2011

Extrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4+T lymphocytes in general, are important in the host immune response toMycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions beforeM. tuberculosisinfection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts withM. tuberculosisinfection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4+CD25hiCD127lowFoxP3+cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls withM. tuberculosisinfection, and 18 controls withoutM. tuberculosisinfection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.20%) (P= 0.001). The median proportion of CD4+T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4+T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.32%) (P= 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4+T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.
Efg1 Controls Caspofungin-Induced Cell Aggregation of Candida albicans through the Adhesin Als1
Authors: Gregori Christa , Glaser Walter , Frohner Ingrid E. , Reinoso-Martín Cristina , Rupp Steffen , Schüller Christoph , Kuchler Karl
Published: October 2011

Echinocandin drugs such as caspofungin (CASP), micafungin, and anidulafungin inhibit fungal cell wall biogenesis by blocking Fks1-mediated β-glucan deposition into the cell surface. Candins have become suitable drugs to treat life-threatening diseases caused by several fungal species, including
Candida albicans
, that are pathogenic for humans
.
Here, we present the discovery of a novel CASP-induced flocculation phenotype of
C. albicans
, which formed large cell aggregates in the presence of CASP. High concentrations of sugars such as mannose or glucose inhibit CASP-induced flocculation and improve survival of
C. albicans
cells exposed to CASP. Notably, exposure of
C. albicans
cells to CASP triggers Efg1-dependent expression of the adhesin
ALS1
and induces invasive growth on agar plates. Indeed, cells lacking either Efg1 or Als1 show strongly diminished CASP-induced flocculation, and the absence of Efg1 leads to marked CASP hypersensitivity. On the other hand, CASP-induced invasive growth is enhanced in cells lacking Efg1. Hence, CASP stress drives an Efg1-dependent response, indicating that this multifunctional transcriptional regulator, which is otherwise involved in filamentation, white-to-opaque switching, and virulence, also modulates cell wall remodeling upon CASP challenge. Taken together, our data suggest that CASP-induced cell wall damage activates Efg1 in parallel with the known cell integrity stress signaling pathway to coordinate cell wall remodeling.
Cell Cycle Regulators Interact with Pathways That Modulate Microtubule Stability in Saccharomyces cerevisiae
Authors: Shohat-Tal Aya , Eshel Dan
Published: October 2011

The integrity of mitosis is dependent upon strict regulation of microtubule stability and dynamics. Although much information has been accumulated on regulators of the microtubule cytoskeleton, our knowledge of the specific pathways involved is still limited. Here we designed genetic screens to identify regulators of microtubule stability that are dispensable in the wild type yet become essential under microtubule-disrupting conditions. We found that the transcriptional cofactor Swi6p and activator Swi4p, as well as the G
2
/M-specific cyclin Clb2p, are required in a microtubule-destabilizing environment. Swi6p and Swi4p can combine as a transcriptional complex, called the SBF complex (SBF for Swi4/6 cell cycle box [SCB]-binding factor) that is functionally homologous to the metazoan DP1/2-E2F complex and that controls the G
1
/S transition through the genes it regulates. We show that Swi6p's contribution to microtubule stability can be either dependent or independent of the SBF complex. The SBF-dependent pathway requires downregulation of SBF complex levels and may thereby reroute the transcriptional program in favor of greater microtubule stability. This pathway can be triggered by overexpression of Fcp1p, a phosphatase in the general transcription machinery, or by expression of an allele of
SWI6
that is associated with reduced transcription from SBF-controlled promoters. The SBF-independent pathway is activated by a constitutively nuclear allele of Swi6p. Our results introduce novel roles in microtubule stability for genes whose participation in the process may be masked under normal conditions yet nonetheless acquire a dominant role when microtubule stability is compromised.
PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence
Authors: Dong Dandan , Wang Decheng , Li Ming , Wang Hui , Yu Jia , Wang Chuan , Liu Jun , Gao Qian
Published: October 2011

The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) family proteins are prevalent in pathogenic mycobacteria and play a diverse role in mycobacterial pathogenesis. While some members have been studied, the function of most PE/PPE proteins remains unknown. In this study, we isolated a transposon-inactivatedPPE38mutant ofMycobacterium marinumand characterized its phenotype. We found that the PPE38 protein is associated with the cell wall and exposed on the cell surface. The inactivation ofPPE38altered the bacterial cell surface properties and led to deficiencies in cord formation, sliding motility, and biofilm formation. ThePPE38mutant was defective in phagocytosis by macrophages and exhibited reduced virulence in adult zebrafish. We also found that PPE38 is involved in the induction of proinflammatory cytokines in infected macrophages. Together, our results indicate that PPE38, a previously uncharacterized protein, plays a role in mycobacterial virulence, presumably by modulating the host innate immune response.
Interleukin-4 (IL-4) and IL-13 Suppress Excessive Neutrophil Infiltration and Hepatocyte Damage during Acute Murine Schistosomiasis Japonica
Authors: Seki Takenori , Kumagai Takashi , Kwansa-Bentum Bethel , Furushima-Shimogawara Rieko , Anyan William K. , Miyazawa Yuuki , Iwakura Yoichiro , Ohta Nobuo
Published: October 2011

Due to the importance of neutrophils and proinflammatory cytokines in schistosomal liver damage, we analyzed the mechanisms underlying neutrophil and proinflammatory responses in murine schistosomiasis japonica. We found that granulomatous inflammation around parasite eggs in the liver was greater inSchistosoma japonicum-infected IL-4−/−IL-13−/−(double-knockout [DKO]) mice than in infected wild-type (WT) mice at 6 weeks, but not at 8 weeks, postinfection, suggesting the importance of Th2 responses in these typical hepatic lesions. Infected DKO mice also showed increased neutrophil infiltration accompanying more severe pathology, as shown by the enhanced necrosis of hepatocytes. This was not likely due to a Th1/Th2 imbalance, because there was no detectable increase in gamma interferon (IFN-γ) production in these DKO mice. mRNA expression of interleukin-17A (IL-17A), proinflammatory cytokines, and the neutrophil chemoattractant CXCL2 in liver was higher in infected DKO mice than in WT mice. However, in IL-4−/−IL-13−/−IL-17A−/−(triple-knockout [TKO]) mice, the absence of IL-17A was associated with only marginal differences in schistosomal liver damage, suggesting that IL-17A is only partially responsible for neutrophil-driven hepatic damage. Furthermore, the expression of mRNAs encoding proinflammatory cytokines was not under the control of IL-17A in TKO mice. These findings indicate that IL-4 and IL-13 suppress excessive neutrophil recruitment, proinflammatory cytokine production, and hepatic damage during the acute stage ofS. japonicuminfection, suggesting that neutrophils and proinflammatory cytokines are mainly responsible for hepatocyte damage during acute murine schistosomiasis japonica. However, neutrophil induction and the production of proinflammatory cytokines were not due solely to IL-17A.
Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus
Authors: Gessner Melissa A. , Werner Jessica L. , Lilly Lauren M. , Nelson Michael P. , Metz Allison E. , Dunaway Chad W. , Chan Yvonne R. , Ouyang Wenjun , Brown Gordon D. , Weaver Casey T. , Steele Chad
Published: October 2011

We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility toAspergillus fumigatuslung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense againstA. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early afterA. fumigatuschallenge. Culturing cells from enzymatic lung digestsex vivofurther demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice.In vivoneutralization of IL-22 in the lungs of WT mice resulted in impairedA. fumigatuslung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden afterA. fumigatuschallenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from bothA. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity againstA. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impairedA. fumigatusclearance. Moreover, lungS100a8,S100a9, andReg3gmRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense againstA. fumigatusis mediated by Dectin-1-dependent IL-22 production.
Draft Genome Sequence of Escherichia coli XH001, a Producer of
l
-Threonine in Industry
Authors: Yang Huilin , Liao Yuling , Wang Bin , Lin Ying , Pan Li
Published: October 2011

l
-Threonine has been widely used as a supplement in the food, pharmaceutical, and cosmetic industries. Here, we present a high-quality draft annotated genome sequence of
Escherichia coli
XH001, a producer of
l
-threonine in industry. Its genome and plasmid sequence will provide clues about the molecular mechanisms underlying its beneficial properties.
Genome Sequence of Serinicoccus profundi, a Novel Actinomycete Isolated from Deep-Sea Sediment
Authors: Xiao Jing , Luo Yingxue , Xu Jun
Published: October 2011

Serinicoccus profundi
MCCC 1A05965
T
was isolated from deep-sea sediment collected from the Indian Ocean. It was a Gram-positive, moderately halophilic, aerobic bacterium. Here, we describe the 3.4-Mbp draft genome sequence of
S. profundi
MCCC 1A05965
T
.
Emergency departments in The Netherlands
Authors: Thijssen Wendy A M H , Giesen Paul H J , Wensing Michel
Published: October 2011

Emergency medicine in The Netherlands is faced with an increasing interest by politicians and stakeholders in health care. This is due to crowding, increasing costs, criticism of the quality of emergency care, restructuring of out-of-hours services in primary care and the introduction of a training programme for emergency physicians in 2000. A comprehensive search was conducted of published research, policy reports and updated Dutch websites on acute care. Publications were included in this review if these referred to emergency care, including emergency departments (ED), general practitioner (GP) cooperatives and emergency medical services in The Netherlands and were written in English or Dutch. The literature search identified 14 eligible papers. The manual search identified 11 additional papers. Seven reports and two PhD theses were also included. Given the lack of relevant empirical research the review was liberal in its inclusion, but the analysis focused on research when available. ED in The Netherlands are in different stages of development. However, it is obvious that the presence of emergency physicians is increasing and more ED will be staffed by emergency physicians. Although this seems an important step, it does not necessarily imply a good position of the emergency physician in the ED. What the characteristics of the future patient of the Dutch ED will be is dependent on the development of different ED levels of care and GP cooperatives. The lack of empirical research also points out the need for research on quality of care in Dutch ED.
The prevalence and correlates of psychological outcomes in patients with acute non-cardiac chest pain: a systematic review
Authors: Webster Rosemary , Norman Paul , Goodacre Steve , Thompson Andrew
Published: October 2011

Over 40% of patients admitted to emergency departments (ED) with chest pain receive a non-cardiac diagnosis. Patients with non-cardiac chest pain (NCCP) have a good prognosis in terms of cardiac adverse events and mortality; however, they tend to have poor outcomes in terms of psychological morbidity, quality of life (QoL), further chest pain and the use of health services. In recent years there has been an increase in the use of ED-based ‘rapid rule-out’ protocols and the provision of dedicated chest pain units. This review sought to chart the psychological outcomes of NCCP patients who access ED-based care, and identify the correlates of poorer psychological outcomes. Twelve papers were identified reporting 10 studies. NCCP patients had similar levels of anxiety, depression, and QoL to patients who received a cardiac diagnosis for their pain, but worse levels than healthy controls. Factors associated with poorer psychological outcomes included gender, age, previous psychiatric history and certain symptoms such as fear of dying and light headedness. However, the studies were heterogeneous, with a variety of outcome measures, designs and settings. In summary, the review identifies poor psychological outcomes in NCCP patients accessing ED-based care; however, there is a need for longitudinal studies using reliable and valid measures to define further the predictors of these poor outcomes.
Remote specialist assessment for intravenous thrombolysis of acute ischaemic stroke by telephone
Authors: Rudd Matthew , Rodgers Helen , Curless Richard , Sudlow Mark , Huntley Stuart , Madhava Badanahatti , Garside Mark , Price Christopher I
Published: October 2011

Objective

To describe the process, efficacy and safety of intravenous thrombolysis for acute ischaemic stroke in an emergency department (ED) setting with remote specialist support through structured telephone consultation.

Design

Retrospective case series.

Setting

Three EDs within a single stroke service in northern England.

Participants

Patients with acute stroke given intravenous thrombolytic therapy between 6 September 2007 and 1 October 2010.

Outcome measures

Combined death and dependency at 90 days (0–2 on the modified Rankin Scale for a good outcome vs 3–6 for a poor outcome), door-to-needle time, neurological impairment and presence of treatment related haemorrhage.

Results

192 patients received intravenous thrombolysis. 94/178 (53%) were treated after remote specialist assessment. Data available from 178 patients showed similar proportions with a good outcome after each mode of assessment (56% in person and 48% by telephone). The median door-to-needle time was 8 min faster in the group assessed in person (65 vs 73 min by telephone) but there was no difference in neurological outcome or symptomatic haemorrhage. After review in person, the stroke specialist tended to treat patients with a higher median modified Rankin Scale (1 vs 0 by telephone).

Conclusion

In a single stroke service the clinical outcomes of treatment with intravenous thrombolysis were similar whether assessment was performed after specialist review in person or via a telemedicine service consisting of ED staff training, telephone consultation and remote review of brain imaging by a stroke specialist.
Attitudes of ED staff to the presence of family during cardiopulmonary resuscitation: a Trinidad and Tobago perspective
Authors: Mahabir Dhiyan , Sammy Ian
Published: October 2011

Introduction

Patients' relatives have been allowed in the resuscitation room during active resuscitation in the UK since at least 1994. Several studies have indicated that relatives value the opportunity to observe the care provided, and this has been shown to help the grieving process. However, this enthusiasm has not always been shared by emergency department staff. In Trinidad and Tobago the concept of family presence in the resuscitation room is still a novel one. This study seeks to identify the attitudes of staff towards relatives in the resuscitation room in this setting.

Methods

A cross-sectional survey of attitudes of staff towards family presence in the resuscitation room was undertaken. All full-time doctors and nurses practising in emergency departments in the public sector in Trinidad and Tobago were surveyed, and the responses of doctors and nurses were compared.

Results

214 individuals responded to the questionnaire (108 nurses and 106 doctors). 81.4% of respondents felt that relatives would be traumatised by witnessing resuscitation. 64% felt that staff performance would be inhibited by the presence of a family member during resuscitation. 71.1% believed that allowing a family member to witness resuscitation would prolong the resuscitation. 72% believed that witnessed resuscitation would increase the stress for the staff.

Conclusion

Strong feelings against the presence of family members in the resuscitation room were expressed by physicians and nurses. Implementation of such a policy will require careful preparation and education of staff as to the benefits of this intervention.
The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion
Authors: Chin A. , Svejda B. , Gustafsson B. I. , Granlund A. B. , Sandvik A. K. , Timberlake A. , Sumpio B. , Pfragner R. , Modlin I. M. , Kidd M.
Published: October 2011

Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98–99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50= 1.8 × 10−6M; IC50= 3.7 × 10−8M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT1(vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT1transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.
Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism
Authors: Riehl Terrence E. , Foster Lynne , Stenson William F.
Published: October 2011

The intestinal epithelium is sensitive to radiation injury. Damage to the intestinal epithelium is dose limiting in radiation therapy of abdominal cancers. There is a need for agents that can be given before radiation therapy to protect the intestinal epithelium. C57BL6 mice were subjected to 12 Gy of total body radiation. Some mice received intraperitoneal hyaluronic acid (HA) before radiation. Mice were killed 6 h after radiation to assess radiation-induced apoptosis in the intestine; other mice were killed at 84 h to assess crypt survival. Total body radiation (12 Gy) resulted in increased expression of HA synthases and HA in the intestine and increased plasma HA (5-fold). Intraperitoneal injection of HA (30 mg/kg) before radiation resulted in a 1.8-fold increase in intestinal crypt survival and a decrease in radiation-induced apoptosis. The radioprotective effects of HA were not seen in Toll-like receptor 4 (TLR4)- or cyclooxygenase-2 (COX-2)-deficient mice. Intraperitoneal injection of HA induced a 1.5-fold increase in intestinal COX-2 expression, a 1.5-fold increase in intestinal PGE2, and the migration of COX-2-expressing mesenchymal stem cells from the lamina propria in the villi to the lamina propria near the crypt. We conclude that 1) radiation induces increased HA expression through inducing HA synthases, 2) intraperitoneal HA given before radiation reduces radiation-induced apoptosis and increases crypt survival, and 3) these radioprotective effects are mediated through TLR4, COX-2, and the migration of COX-2-expressing mesenchymal stem cells.
Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE2 and EP receptors
Authors: Lin You-Min , Sarna Sushil K. , Shi Xuan-Zheng
Published: October 2011

We reported previously that mechanical stretch in rat colonic obstruction induces cyclooxygenase (COX)-2 expression in smooth muscle cells. The aims of the present study were to investigate whether in vivo treatment with COX-2 inhibitor has prophylactic and therapeutic effects on motility dysfunction in colon obstruction, and if so what are the underlying mechanisms. Partial colon obstruction was induced with a silicon band in the distal colon of 6–8-wk-old Sprague-Dawley rats; obstruction was maintained for 3 days or 7 days. Daily administration of COX-2 inhibitor NS-398 (5 mg/kg) or vehicle was started before or after the induction of obstruction to study its prophylactic and therapeutic effects, respectively. The smooth muscle contractility was significantly suppressed, and colonic transit rate was slower in colonic obstruction. Prophylactic treatment with NS-398 significantly prevented the impairments of colonic transit and smooth muscle contractility and attenuated fecal collection in the occluded colons. When NS-398 was administered therapeutically 3 days after the initiation of obstruction, the muscle contractility and colonic transit still improved on day 7. Obstruction led to marked increase of COX-2 expression and prostaglandin E2 (PGE2) synthesis. Exogenous PGE2 decreased colonic smooth muscle contractility. All four PGE2 E-prostanoid receptor types (EP1 to EP4) were detected in rat colonic muscularis externa. Treatments with EP1 and EP3 antagonists suppressed muscle contractility in control tissue but did not improve contractility in obstruction tissue. On the contrary, the EP2 and EP4 antagonists did not affect control tissue but significantly restored muscle contractility in obstruction. We concluded that our study shows that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in bowel obstruction. PGE2 and its receptors EP2 and EP4 are involved in the motility dysfunction in obstruction, whereas EP1 and EP3 mediate PGE2 regulation of colonic smooth muscle contractile function in normal state.
Contribution of myocardium overlying the anterolateral papillary muscle to left ventricular deformation
Authors: Itoh Akinobu , Stephens Elizabeth H. , Ennis Daniel B. , Carlhall Carl-Johan , Bothe Wolfgang , Nguyen Tom C. , Swanson Julia C. , Miller D. Craig , Ingels Neil B.
Published: October 2011

Previous studies of transmural left ventricular (LV) strains suggested that the myocardium overlying the papillary muscle displays decreased deformation relative to the anterior LV free wall or significant regional heterogeneity. These comparisons, however, were made using different hearts. We sought to extend these studies by examining three equatorial LV regions in the same heart during the same heartbeat. Therefore, deformation was analyzed from transmural beadsets placed in the equatorial LV myocardium overlying the anterolateral papillary muscle (PAP), as well as adjacent equatorial LV regions located more anteriorly (ANT) and laterally (LAT). We found that the magnitudes of LAT normal longitudinal and radial strains, as well as major principal strains, were less than ANT, while those of PAP were intermediate. Subepicardial and midwall myofiber angles of LAT, PAP, and ANT were not significantly different, but PAP subendocardial myofiber angles were significantly higher (more longitudinal as opposed to circumferential orientation). Subepicardial and midwall myofiber strains of ANT, PAP, and LAT were not significantly different, but PAP subendocardial myofiber strains were less. Transmural gradients in circumferential and radial normal strains, and major principal strains, were observed in each region. The two main findings of this study were as follows: 1) PAP strains are largely consistent with adjacent LV equatorial free wall regions, and 2) there is a gradient of strains across the anterolateral equatorial left ventricle despite similarities in myofiber angles and strains. These findings point to graduated equatorial LV heterogeneity and suggest that regional differences in myofiber coupling may constitute the basis for such heterogeneity.
The role of dynamic instability and wavelength in arrhythmia maintenance as revealed by panoramic imaging with blebbistatin vs. 2,3-butanedione monoxime
Authors: Lou Qing , Li Wenwen , Efimov Igor R.
Published: October 2011

Unlike other excitation-contraction uncouplers, blebbistatin has few electrophysiological side effects and has gained increasing acceptance as an excitation-contraction uncoupler in optical mapping experiments. However, the possible role of blebbistatin in ventricular arrhythmia has hitherto been unknown. Furthermore, experiments with blebbistatin and 2,3-butanedione monoxime (BDM) offer an opportunity to assess the contribution of dynamic instability and wavelength of impulse propagation to the induction and maintenance of ventricular arrhythmia. Recordings of monophasic action potentials were used to assess effects of blebbistatin in Langendorff-perfused rabbit hearts ( n = 5). Additionally, panoramic optical mapping experiments were conducted in rabbit hearts ( n = 7) that were sequentially perfused with BDM, then washed out, and subsequently perfused with blebbistatin. The susceptibility to arrhythmia was investigated using a shock-on-T protocol. We found that 1) application of blebbistatin did not change action potential duration (APD) restitution; 2) in contrast to blebbistatin, BDM flattened APD restitution curve and reduced the wavelength; and 3) incidence of sustained arrhythmia was much lower under blebbistatin than under BDM (2/123 vs. 23/99). While arrhythmias under BDM were able to stabilize, the arrhythmias under blebbistatin were unstable and terminated spontaneously. In conclusion, the lower susceptibility to arrhythmia under blebbistatin than under BDM indicates that blebbistatin has less effects on arrhythmia dynamics. A steep restitution slope under blebbistatin is associated with higher dynamic instability, manifested by the higher incidence of not only wave breaks but also wave extinctions. This relatively high dynamic instability leads to the self-termination of arrhythmia because of the sufficiently long wavelength under blebbistatin.