We report the case of a 78-year-old female who was found to have a mycotic thoracic aortic arch aneurysm caused by Clostridium septicum. Subsequent investigations demonstrated adenocarcinoma of the caecum with two liver metastases. The patient underwent a hybrid procedure involving endovascular repair of the aneurysm with a right-to-left carotid crossover bypass and a left carotid to left subclavian bypass to protect the cerebral and left subclavian blood flow. The caecal tumour was later completely excised by laparoscopic right hemicolectomy. The patient then underwent resection for the liver metastases. There was no evidence of tumour recurrence 2 years after her right hemicolectomy. This case emphasizes the importance of the association of C. septicum infection with colorectal malignancy. To our knowledge, this is the first case of a mycotic aortic arch aneurysm caused by C. septicum being successfully treated with a hybrid endovascular repair procedure.
Due to its long half-life (78 h) and decay properties (77% electron capture, 23% ?(+), Emax = 897 keV, Eav = 397 keV, E? = 909 keV, I? = 100%) (89)Zr is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H3DFO) are the most widely used bifunctional chelators for coordination of (89)Zr(4+) because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. (89)Zr-DFO complexes are reportedly stable in vitro but there is evidence that (89)Zr(4+) is released in vivo, and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H3CP256 and its bifunctional maleimide derivative, H3YM103, for coordination of Zr(4+) and compared the NMR spectra, and the (89)Zr(4+) radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H3DFO and its analogues. H3CP256 coordinates (89)Zr(4+) at carrier-free concentrations forming [(89)Zr(CP256)](+). Both H3DFO and H3CP256 were efficiently radiolabelled using [(89)Zr(C2O4)4](4-) at ambient temperature in quantitative yield at pH 6-7 at millimolar concentrations of chelator. Competition experiments demonstrate that (89)Zr(4+) dissociates from [(89)Zr(DFO)](+) in the presence of one equivalent of H3CP256 (relative to H3DFO) at pH 6-7, resulting largely in [(89)Zr(CP256)](+). To assess the stability of H3DFO and H3YM103 immunoconjugates radiolabelled with (89)Zr, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with (89)Zr(4+) in >98% yield at high specific activities and the labeled immunoconjugates were stable in serum with respect to dissociation of the radiometal. In vivo studies in mice indicate that (89)Zr(4+) dissociates from YM103-trastuzumab with significant amounts of activity becoming associated with bones and joints (25.88 ± 0.58% ID g(-1) 7 days post-injection). In contrast, <8% ID g(-1) of (89)Zr activity becomes associated with bone in animals administered (89)Zr-DFO-trastuzumab over the course of 7 days. The tris(hydroxypyridinone) chelator, H3CP256, coordinates (89)Zr(4+) rapidly under mild conditions, but the (89)Zr-labelled immunoconjugate, (89)Zr-YM103-trastuzumab was observed to release appreciable amounts of (89)Zr(4+)in vivo, demonstrating inferior stability when compared with (89)Zr-DFO-trastuzumab. The significantly lower in vivo stability is likely to be a result of lower kinetic stability of the Zr(4+) tris(hydroxypyridinone complex) relative to that of DFO and its derivatives.
United States Veterans of the Iraqi (Operation Iraqi Freedom (OIF)) and Afghanistan (Operation Enduring Freedom (OEF)) conflicts have frequently returned from deployment after sustaining mild traumatic brain injury (mTBI) and enduring stressful events resulting in posttraumatic stress disorder (PTSD). A large number of returning servicemembers have been diagnosed with both a history of mTBI and current PTSD. Substantial literature exists on the neuropsychological factors associated with mTBI and PTSD occurring separately; far less research has explored the combined effects of PTSD and mTBI. The current study employed neuropsychological and psychological measures in a sample of 251 OIF/OEF Veterans to determine whether participants with a history of mTBI and concurrent PTSD (mTBI+PTSD) have poorer cognitive and psychological outcomes than participants with mTBI only (mTBI-o), PTSD only (PTSD-o), or Veteran controls (VC), when groups are comparable on IQ, education, and age. The mTBI+PTSD group performed more poorly than VC, mTBI-o, and PTSD-o groups on several neuropsychological measures. Effect size comparisons suggest small deleterious effects for mTBI-o on measures of processing speed and visual attention and small effects for PTSD-o on measures of verbal memory, with moderate effects for mTBI+PTSD on the same variables. Additionally, the mTBI+PTSD group was significantly more psychologically distressed than the PTSD-o group, and PTSD-o group was more distressed than VC and mTBI-o groups. These findings suggest Veterans with mTBI+PTSD perform significantly lower on neuropsychological and psychiatric measures than Veterans with mTBI-o or PTSD-o. The results also raise the possibility of persisting cognitive changes following mTBI sustained during deployment.
The interactions of the intrinsic laryngeal muscles (ILMs) in controlling fundamental frequency (F0) and glottal posture remain unclear. In an in vivo canine model, three sets of intrinsic laryngeal muscles-the thyroarytenoid (TA), cricothyroid (CT), and lateral cricoarytenoid plus interarytenoid (LCA/IA) muscle complex-were independently and accurately stimulated in a graded manner using distal laryngeal nerve stimulation. Graded neuromuscular stimulation was used to independently activate these paired intrinsic laryngeal muscles over a range from threshold to maximal activation, to produce 320 distinct laryngeal phonatory postures. At phonation onset these activation conditions were evaluated in terms of their vocal fold strain, glottal width at the vocal processes, fundamental frequency (F0), subglottic pressure, and airflow. F0 ranged from 69 to 772?Hz and clustered into chest-like and falsetto-like groups. CT activation was always required to raise F0, but could also lower F0 at low TA and LCA/IA activation levels. Increasing TA activation first increased then decreased F0 in all CT and LCA/IA activation conditions. Increasing TA activation also facilitated production of high F0 at a lower onset pressure. Independent control of membranous (TA) and cartilaginous (LCA/IA) glottal closure enabled multiple pathways for F0 control via changes in glottal posture.
Since the early 2000s concern has increased that college students might feign ADHD in pursuit of academic accommodations and stimulant medication. In response, several studies have validated tests for use in differentiating feigned from genuine ADHD. Although results have generally been positive, relatively few publications have addressed the possible impact of the presence of psychological disorders comorbid with ADHD. Because ADHD is thought to have accompanying conditions at rates of 50% and higher, it is important to determine if the additional psychological disorders might compromise the accuracy of feigning detection measures. The present study extended the findings of Jasinski et al. (2011) to examine the efficacy of various measures in the context of feigned versus genuine ADHD with comorbid psychological disorders in undergraduate students. Two clinical groups (ADHD only and ADHD + comorbid psychological disorder) were contrasted with two non-clinical groups (normal controls answering honestly and normal participants feigning ADHD). Extending previous research to individuals with ADHD and either an anxiety or learning disorder, performance validity tests such as the Test of Memory Malingering (TOMM), the Letter Memory Test (LMT), and the Nonverbal Medical Symptom Validity Test (NV-MSVT) were effective in differentiating both ADHD groups from normal participants feigning ADHD. However, the Digit Memory Test (DMT) underperformed in this study, as did embedded validity indices from the Wechsler Adult Intelligence Scale-IV (WAIS-IV) and Woodcock Johnson Tests of Achievement-III (WJ-III).
The contribution of the innate immune system to inflammatory bowel disease (IBD) is under intensive investigation. Research in animal models has demonstrated that type I interferons (IFN-Is) protect from IBD. In contrast, studies of patients with IBD have produced conflicting results concerning the therapeutic potential of IFN-Is. Here, we present data suggesting that IFN-Is play dual roles as regulators of intestinal inflammation in dextran sodium sulfate (DSS)-treated C57BL/6 mice. Though IFN-Is reduced acute intestinal damage and the abundance of colitis-associated intestinal bacteria caused by treatment with a high dose of DSS, they also inhibited the resolution of inflammation after DSS treatment. IFN-Is played an anti-inflammatory role by suppressing the release of IL-1? from the colon MHC class II(+) cells. Consistently, IL-1 receptor blockade reduced the severity of inflammation in IFN-I receptor-deficient mice and myeloid cell-restricted ablation of the IFN-I receptor was detrimental. The proinflammatory role of IFN-Is during recovery from DSS treatment was caused by IFN-I-dependent cell apoptosis as well as an increase in chemokine production and infiltrating inflammatory monocytes and neutrophils. Thus, IFN-Is play opposing roles in specific phases of intestinal injury and inflammation, which may be important for guiding treatment strategies in patients.
PURPOSE Previous studies have confirmed the influence of dehydration and an altered mucus (e.g., due to pathologies) on phonation. However, the underlying reasons for these influences are not fully understood. This study was a preliminary inquiry into the influences of mucus architecture and concentration on vocal fold oscillation. METHOD Two excised human larynges were investigated in an in vitro setup. The oscillations of the vocal folds at various airflow volume rates were recorded through the use of high-speed imaging. Engineered mucus containing polymers (interconnected polymers and linear polymers) was applied to the vocal folds. From the high-speed footage, glottal parameters were extracted through the use of objective methods and were compared to a gold standard (physiological saline solution). RESULTS Variations were found for all applications of mucus. Fundamental frequency dropped and the oscillatory behavior (speed quotient [SQ], closing quotient [CQ]) changed for both larynges. The 2 applied mucus architectures displayed different effects on the larynges. The interconnected polymer displayed clear low-pass filter characteristics not found for the linear polymer. Increase of polymer concentration affected parameters to a certain point. CONCLUSION The data confirm results found in previous studies. Furthermore, the different effects-comparing architecture and concentration-suggest that, in the future, synthetic mucus can be designed to improve phonation.
Many pharmaceuticals and personal care products (PPCPs) have been shown to be biotransformed in water treatment systems. However, little research exists on the effect of initial PPCP concentration on PPCP biotransformation or on the microbial communities treating impacted water. In this study, biological PPCP removal at various concentrations was assessed using laboratory columns inoculated with wastewater treatment plant effluent. Pyrosequencing was used to examine microbial communities in the columns and in soil from a soil aquifer treatment (SAT; a method of water treatment prior to reuse) site. Laboratory columns were supplied with different concentrations (0.25, 10, 100, or 1,000 ?g liter(-1)) of each of 15 PPCPs. Five PPCPs (4-isopropyl-3-methylphenol [biosol], p-chloro-m-xylenol, gemfibrozil, ketoprofen, and phenytoin) were not removed at any tested concentrations. Two PPCPs (naproxen and triclosan) exhibited removals independent of PPCP concentration. PPCP removal efficiencies were dependent on initial concentrations for biphenylol, p-chloro-m-cresol, chlorophene, diclofenac, 5-fluorouracil, ibuprofen, and valproic acid, showing that PPCP concentration can affect biotransformation. Biofilms from sand samples collected from the 0.25- and 10-?g liter(-1) PPCP columns were pyrosequenced along with SAT soil samples collected on three consecutive days of a wetting and drying cycle to enable comparison of these two communities exposed to PPCPs. SAT communities were similar to column communities in taxonomy and phylotype composition, and both were found to contain close relatives of known PPCP degraders. The efficiency of biological removal of PPCPs was found to be dependent on the concentration at which the contamination occurs for some, but not all, PPCPs.
Although alterations in gut microbiota composition during acute colitis have been repeatedly observed, associated functional changes and the recovery from dysbiosis received little attention. In this study, we investigated structure and function of the gut microbiota during acute inflammation and recovery in a dextran sodium sulfate (DSS)-colitis mouse model using metatranscriptomics, bacterial 16S rRNA gene amplicon sequencing and monitoring of selected host markers. Parallel to an increase of host markers of inflammation during acute colitis, we observed relative abundance shifts and alterations in phylotype composition of the dominant bacterial orders Clostridiales and Bacteroidales, and an increase of the low abundant Enterobacteriales, Deferribacterales, Verrucomicrobiales and Erysipelotrichales. During recovery, the microbiota began to resume, but did not reach its original composition until the end of the experiment. Microbial gene expression was more resilient to disturbance, with pre-perturbation-type transcript profiles appearing quickly after acute colitis. The decrease of Clostridiales during inflammation correlated with a reduction of transcripts related to butyrate formation, suggesting a disturbance in host-microbe signalling and mucosal nutrient provision. The impact of acute inflammation on the Clostridiales was also characterized by a significant downregulation of their flagellin-encoding genes. In contrast, the abundance of members of the Bacteroidales increased along with an increase in transcripts related to mucin degradation. We propose that acute inflammation triggered a selective reaction of the immune system against flagella of commensals and temporarily altered murine microbiota composition and functions relevant for the host. Despite changes in specific interactions, the host-microbiota homeostasis revealed a remarkable ability for recovery.
Ionizing space radiation causes oxidative DNA damage and triggers oxidative stress responses, and compromised DNA repair mechanisms can lead to increased risk of carcinogenesis. Young adult mice with developed innate and adaptive immune systems that harbored either a conventional intestinal microbiota (CM) or an intestinal microbiota with a restricted microbial composition (RM) were irradiated with a total dose of 1 Gy delivered by high-energy protons (2.5 GeV/n, LET = 0.2-2 keV/?m) or silicon or iron ions (850 MeV/n, LET ? 50 keV/?m and 1 GeV/n, LET = 150 keV/?m, respectively). Six hours after whole-body irradiation, acute chromosomal DNA lesions were observed for RM mice but not CM mice. High-throughput rRNA gene sequencing of intestinal mucosal bacteria showed that Barnesiella intestinihominis and unclassified Bacterodiales were significantly more abundant in male RM mice than CM mice, and phylotype densities changed in irradiated mice. In addition, Helicobacter hepaticus and Bacteroides stercoris were higher in CM than RM mice. Elevated levels of persistently phosphorylated ?-H2AX were observed in RM mice exposed to high-energy protons compared to nonirradiated RM mice, and they also were associated with a decrease of the antioxidant glutathione in peripheral blood measured at four weeks after irradiation. After radiation exposure, CM mice showed lower levels of ?-H2AX phosphorylation than RM mice and an increase in specific RM-associated phylotypes, indicating a down-regulating force on DNA repair by differentially abundant phylotypes in RM versus a radiation-sensitive complex CM.
Co-occurrence networks produced from microbial survey sequencing data are frequently used to identify interactions between community members. While this approach has potential to reveal ecological processes, it has been insufficiently validated due to the technical limitations inherent in studying complex microbial ecosystems. Here, we simulate multi-species microbial communities with known interaction patterns using generalized Lotka-Volterra dynamics. We then construct co-occurrence networks and evaluate how well networks reveal the underlying interactions and how experimental and ecological parameters can affect network inference and interpretation. We find that co-occurrence networks can recapitulate interaction networks under certain conditions, but that they lose interpretability when the effects of habitat filtering become significant. We demonstrate that networks suffer from local hot spots of spurious correlation in the neighborhood of hub species that engage in many interactions. We also identify topological features associated with keystone species in co-occurrence networks. This study provides a substantiated framework to guide environmental microbiologists in the construction and interpretation of co-occurrence networks from microbial survey datasets.
Pyrosequencing of the bacterial community associated with a cosmopolitan marine diatom during enrichment with crude oil revealed several Arenibacter phylotypes, of which one (OTU-202) had become significantly enriched by the oil. Since members of the genus Arenibacter have not been previously shown to degrade hydrocarbons, we attempted to isolate a representative strain of this genus in order to directly investigate its hydrocarbon-degrading potential. Based on 16S rRNA sequencing, one isolate (designated strain TG409(T)) exhibited >99% sequence identity to three type strains of this genus. On the basis of phenotypic and genotypic characteristics, strain TG409(T) represents a novel species in the genus Arenibacter, for which the name Arenibacter algicola sp. nov. is proposed. We reveal for the first time that polycyclic aromatic hydrocarbon (PAH) degradation is a shared phenotype among members of this genus, indicating that it could be used as a taxonomic marker for this genus. Kinetic data for PAH mineralization rates showed that naphthalene was preferred to phenanthrene, and its mineralization was significantly enhanced in the presence of glass wool (a surrogate for diatom cell surfaces). During enrichment on hydrocarbons, strain TG409(T) emulsified n-tetradecane and crude oil, and cells were found to be preferentially attached to oil droplets, indicating an ability by the strain to express cell surface amphiphilic substances (biosurfactants or bioemulsifiers) as a possible strategy to increase the bioavailability of hydrocarbons. This work adds to our growing knowledge on the diversity of bacterial genera in the ocean contributing to the degradation of oil contaminants and of hydrocarbon-degrading bacteria found living in association with marine eukaryotic phytoplankton.
There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt-Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt-Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.
Microbial biogeography is influenced by the combined effects of passive dispersal and environmental selection, but the contribution of either factor can be difficult to discern. As thermophilic bacteria cannot grow in the cold seabed, their inactive spores are not subject to environmental selection. We therefore conducted a global experimental survey using thermophilic endospores that are passively deposited by sedimentation to the cold seafloor as tracers to study the effect of dispersal by ocean currents on the biogeography of marine microorganisms. Our analysis of 81 different marine sediments from around the world identified 146 species-level 16S rRNA phylotypes of endospore-forming, thermophilic Firmicutes. Phylotypes showed various patterns of spatial distribution in the world oceans and were dispersal-limited to different degrees. Co-occurrence of several phylotypes in locations separated by great distances (west of Svalbard, the Baltic Sea and the Gulf of California) demonstrated a widespread but not ubiquitous distribution. In contrast, Arctic regions with water masses that are relatively isolated from global ocean circulation (Baffin Bay and east of Svalbard) were characterized by low phylotype richness and different compositions of phylotypes. The observed distribution pattern of thermophilic endospores in marine sediments suggests that the impact of passive dispersal on marine microbial biogeography is controlled by the connectivity of local water masses to ocean circulation.
Intra- and inter-specimen variations in trabecular anisotropy are often ignored in quantitative computed tomography (QCT)-based finite element (FE) models of the vertebra. The material properties are typically estimated solely from local variations in bone mineral density (BMD), and a fixed representation of elastic anisotropy ("generic anisotropy") is assumed. This study evaluated the effect of incorporating specimen-specific, trabecular anisotropy on QCT-based FE predictions of vertebral stiffness and deformation patterns. Orthotropic material properties estimated from microcomputed tomography data ("specimen-specific anisotropy"), were assigned to a large, columnar region of the L1 centrum (n?=?12), and generic-anisotropic material properties were assigned to the remainder of the vertebral body. Results were compared to FE analyses in which generic-anisotropic properties were used throughout. FE analyses were also performed on only the columnar regions. For the columnar regions, the axial stiffnesses obtained from the two categories of material properties were uncorrelated with each other (p?=?0.604), and the distributions of minimum principal strain were distinctly different (p???0.022). In contrast, for the whole vertebral bodies in both axial and flexural loading, the stiffnesses obtained using the two categories of material properties were highly correlated (R2?>?0.82, p?<?0.001) with, and were no different (p?>?0.359) from, each other. Only moderate variations in strain distributions were observed between the two categories of material properties. The contrasting results for the columns versus vertebrae indicate a large contribution of the peripheral regions of the vertebral body to the mechanical behavior of this bone. In companion analyses on the effect of the degree of anisotropy (DA), the axial stiffnesses of the trabecular column (p?<?0.001) and vertebra (p?=?0.007) increased with increasing DA. These findings demonstrate the need for accurate modeling of the peripheral regions of the vertebral body in analyses of the mechanical behavior of the vertebra.
The Minnesota Multiphasic Personality Inventory-2-RF (MMPI-2-RF) validity scales were evaluated to determine accuracy when differentiating honest responding, random responding, genuine posttraumatic stress disorder (PTSD), and feigned PTSD. Undergraduate students (n = 109), screened for PTSD, were randomly assigned to 1 of 4 instructional groups: honest, feign PTSD, half random, and full random. Archival data provided clinical MMPI-2-RF profiles consisting of 31 veterans diagnosed with PTSD. Veterans were diagnosed with PTSD using a structured interview and had passed a structured interview for malingering. Validity scales working as a group had correct classification rates of honest (96.6%), full random (88.9%), genuine PTSD (80.7%), fake PTSD (73.1%), and half random (44.4%). Results were fairly supportive of the scales ability to discriminate feigning and full random responding from honest responding of normal students as well as veterans with PTSD. However, the RF validity scales do not appear to be as effective in detecting partially random responding.
Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress.
Nitrospira are the most widespread and diverse known nitrite-oxidizing bacteria and key nitrifiers in natural and engineered ecosystems. Nevertheless, their ecophysiology and environmental distribution are understudied due to the recalcitrance of Nitrospira to cultivation and the lack of a molecular functional marker, which would allow the detection of Nitrospira in the environment. Here we introduce nxrB, the gene encoding subunit beta of nitrite oxidoreductase, as a functional and phylogenetic marker for Nitrospira. Phylogenetic trees based on nxrB of Nitrospira were largely congruent to 16S rRNA-based phylogenies. By using new nxrB-selective PCR primers, we obtained almost full-length nxrB sequences from Nitrospira cultures, two activated sludge samples, and several geographically and climatically distinct soils. Amplicon pyrosequencing of nxrB fragments from 16 soils revealed a previously unrecognized diversity of terrestrial Nitrospira with 1,801 detected species-level OTUs (using an inferred species threshold of 95% nxrB identity). Richness estimates ranged from 10 to 946 co-existing Nitrospira species per soil. Comparison to an archaeal amoA dataset obtained from the same soils [Environ. Microbiol. 14: 525-539 (2012)] uncovered that ammonia-oxidizing archaea and Nitrospira communities were highly correlated across the soil samples, possibly indicating shared habitat preferences or specific biological interactions among members of these nitrifier groups.
The intestinal microbiota is known to regulate host energy homeostasis and can be influenced by high-calorie diets. However, changes affecting the ecosystem at the functional level are still not well characterized. We measured shifts in cecal bacterial communities in mice fed a carbohydrate or high-fat (HF) diet for 12 weeks at the level of the following: (i) diversity and taxa distribution by high-throughput 16S ribosomal RNA gene sequencing; (ii) bulk and single-cell chemical composition by Fourier-transform infrared- (FT-IR) and Raman micro-spectroscopy and (iii) metaproteome and metabolome via high-resolution mass spectrometry. High-fat diet caused shifts in the diversity of dominant gut bacteria and altered the proportion of Ruminococcaceae (decrease) and Rikenellaceae (increase). FT-IR spectroscopy revealed that the impact of the diet on cecal chemical fingerprints is greater than the impact of microbiota composition. Diet-driven changes in biochemical fingerprints of members of the Bacteroidales and Lachnospiraceae were also observed at the level of single cells, indicating that there were distinct differences in cellular composition of dominant phylotypes under different diets. Metaproteome and metabolome analyses based on the occurrence of 1760 bacterial proteins and 86 annotated metabolites revealed distinct HF diet-specific profiles. Alteration of hormonal and anti-microbial networks, bile acid and bilirubin metabolism and shifts towards amino acid and simple sugars metabolism were observed. We conclude that a HF diet markedly affects the gut bacterial ecosystem at the functional level.The ISME Journal advance online publication, 12 September 2013; doi:10.1038/ismej.2013.155.
Current combat veterans are exposed to many incidents that may result in mild traumatic brain injury (mTBI) and/or posttraumatic stress disorder (PTSD). While there is literature on the neuropsychological consequences of PTSD only (PTSD-o) and mTBI alone (mTBI-o), less has been done to explore their combined (mTBI+PTSD) effect. The goal of this study was to determine whether Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) veterans with mTBI+PTSD have poorer cognitive and psychological outcomes than veterans with PTSD-o, mTBI-o, or combat exposure-only. The final sample included 20 OIF/OEF veterans with histories of self-reported deployment mTBI (mTBI-o), 19 with current PTSD (PTSD-o), 21 with PTSD and self-reported mTBI (mTBI+PTSD), and 21 combat controls (CC) (no PTSD and no reported mTBI). Groups were formed using structured interviews for mTBI and PTSD. All participants underwent comprehensive neuropsychological testing, including neurocognitive and psychiatric feigning tests. Results of cognitive tests revealed significant differences in performance in the mTBI+PTSD and PTSD-o groups relative to mTBI-o and CC. Consistent with previous PTSD literature, significant differences were found on executive (switching) tasks, verbal fluency, and verbal memory. Effect sizes tended to be large in both groups with PTSD. Thus, PTSD seems to be an important variable affecting neuropsychological profiles in the post-deployment time period. Consistent with literature on civilian mTBI, the current study did not find evidence that combat-related mTBI in and of itself contributes to objective cognitive impairment in the late stage of injury.
Fecal microbiota transplantation (FMT) from healthy donors, which is an effective alternative for treatment of Clostridium difficile-associated disease, is being considered for several disorders such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. Disease remission upon FMT is thought to be facilitated by an efficient colonization of healthy donor microbiota, but knowledge of the composition and temporal stability of patient microbiota after FMT is lacking.
The animal and human intestinal mucosa secretes an assortment of compounds to establish a physical barrier between the host tissue and intestinal contents, a separation that is vital for health. Some pathogenic microorganisms as well as members of the commensal intestinal microbiota have been shown to be able to break down these secreted compounds. Our understanding of host-compound degradation by the commensal microbiota has been limited to knowledge about simplified model systems because of the difficulty in studying the complex intestinal ecosystem in vivo. In this study, we introduce an approach that overcomes previous technical limitations and allows us to observe which microbial cells in the intestine use host-derived compounds. We added stable isotope-labeled threonine i.v. to mice and combined fluorescence in situ hybridization with high-resolution secondary ion mass spectrometry imaging to characterize utilization of host proteins by individual bacterial cells. We show that two bacterial species, Bacteroides acidifaciens and Akkermansia muciniphila, are important host-protein foragers in vivo. Using gnotobiotic mice we show that microbiota composition determines the magnitude and pattern of foraging by these organisms, demonstrating that a complex microbiota is necessary in order for this niche to be fully exploited. These results underscore the importance of in vivo studies of intestinal microbiota, and the approach presented in this study will be a powerful tool to address many other key questions in animal and human microbiome research.
The human intestine harbours a complex microbial ecosystem that performs manifold functions important to the nutrition and health of its host. Extensive study has revealed that the composition of the intestinal microbiota is altered in individuals with inflammatory bowel disease (IBD). The IBD associated intestinal microbiota generally has reduced species richness and diversity, lower temporal stability, and disruption of the secreted mucus layer structure. Multiple studies have identified certain bacterial taxa that are enriched or depleted in IBD including Enterobacteriaceae, Ruminococcus gnavus, and Desulfovibrio (enriched) and Faecalibacterium prausnitzii, Lachnospiraceae, and Akkermansia (depleted). Additionally, the relative abundance of some taxa appears to correlate with established markers of disease activity such as Enterobacteriaceae (enriched) and Lachnospiraceae (depleted). Signature shifts in fecal microbial community composition may therefore prove to be valuable as diagnostic biomarkers, particularly for longitudinal monitoring of disease activity and response to treatments.
The massive influx of crude oil into the Gulf of Mexico during the Deepwater Horizon (DWH) disaster triggered dramatic microbial community shifts in surface oil slick and deep plume waters. Previous work had shown several taxa, notably DWH Oceanospirillales, Cycloclasticus and Colwellia, were found to be enriched in these waters based on their dominance in conventional clone and pyrosequencing libraries and were thought to have had a significant role in the degradation of the oil. However, this type of community analysis data failed to provide direct evidence on the functional properties, such as hydrocarbon degradation of organisms. Using DNA-based stable-isotope probing with uniformly (13)C-labelled hydrocarbons, we identified several aliphatic (Alcanivorax, Marinobacter)- and polycyclic aromatic hydrocarbon (Alteromonas, Cycloclasticus, Colwellia)-degrading bacteria. We also isolated several strains (Alcanivorax, Alteromonas, Cycloclasticus, Halomonas, Marinobacter and Pseudoalteromonas) with demonstrable hydrocarbon-degrading qualities from surface slick and plume water samples collected during the active phase of the spill. Some of these organisms accounted for the majority of sequence reads representing their respective taxa in a pyrosequencing data set constructed from the same and additional water column samples. Hitherto, Alcanivorax was not identified in any of the previous water column studies analysing the microbial response to the spill and we discuss its failure to respond to the oil. Collectively, our data provide unequivocal evidence on the hydrocarbon-degrading qualities for some of the dominant taxa enriched in surface and plume waters during the DWH oil spill, and a more complete understanding of their role in the fate of the oil.
Despite the widespread use of monochloramine in drinking water treatment, there is surprisingly little information about its mode of action. In this study, DNA microarrays were used to investigate the global gene expression of Escherichia coli cells exposed to sub-lethal concentrations of monochloramine, with a focus on temporal dynamics. Genes induced by monochloramine were associated with several stress response functions, including oxidative stress, DNA repair, multidrug efflux, biofilm formation, antibiotic resistance, and cell wall repair. The diversity of functional associations supports a model of monochloramine action involving multiple cellular targets including cell membranes, nucleic acids, and proteins. These data suggest that E. coli responds to monochloramine exposure by activating diverse defense responses rather than a single antioxidant system and the exposure may also induce biofilm formation. The induction of multidrug efflux pumps and specific antibiotic resistance genes further suggests that exposure to monochloramine may contribute to reduced susceptibility to some antibiotics.
The highly diverse intestinal microbiota forms a structured community engaged in constant communication with itself and its host and is characterized by extensive ecological interactions. A key benefit that the microbiota affords its host is its ability to protect against infections in a process termed colonization resistance (CR), which remains insufficiently understood. In this review, we connect basic concepts of CR with new insights from recent years and highlight key technological advances in the field of microbial ecology. We present a selection of statistical and bioinformatics tools used to generate hypotheses about synergistic and antagonistic interactions in microbial ecosystems from metagenomic datasets. We emphasize the importance of experimentally testing these hypotheses and discuss the value of gnotobiotic mouse models for investigating specific aspects related to microbiota-host-pathogen interactions in a well-defined experimental system. We further introduce new developments in the area of single-cell analysis using fluorescence in situ hybridization in combination with metabolic stable isotope labeling technologies for studying the in vivo activities of complex community members. These approaches promise to yield novel insights into the mechanisms of CR and intestinal ecophysiology in general, and give researchers the means to experimentally test hypotheses in vivo at varying levels of biological and ecological complexity.
Halomonas species are recognized for producing exopolysaccharides (EPS) exhibiting amphiphilic properties that allow these macromolecules to interface with hydrophobic substrates, such as hydrocarbons. There remains a paucity of knowledge, however, on the potential of Halomonas EPS to influence the biodegradation of hydrocarbons. In this study, the well-characterized amphiphilic EPS produced by Halomonas species strain TG39 was shown to effectively increase the solubilization of aromatic hydrocarbons and enhance their biodegradation by an indigenous microbial community from oil-contaminated surface waters collected during the active phase of the Deepwater Horizon oil spill. Three Halomonas strains were isolated from the Deepwater Horizon site, all of which produced EPS with excellent emulsifying qualities and shared high (97-100%) 16S rRNA sequence identity with strain TG39 and other EPS-producing Halomonas strains. Analysis of pyrosequence data from surface water samples collected during the spill revealed several distinct Halomonas phylotypes, of which some shared a high sequence identity (?97%) to strain TG39 and the Gulf spill isolates. Other bacterial groups comprising members with well-characterized EPS-producing qualities, such as Alteromonas, Colwellia and Pseudoalteromonas, were also found enriched in surface waters, suggesting that the total pool of EPS in the Gulf during the spill may have been supplemented by these organisms. Roller bottle incubations with one of the Halomonas isolates from the Deepwater Horizon spill site demonstrated its ability to effectively produce oil aggregates and emulsify the oil. The enrichment of EPS-producing bacteria during the spill coupled with their capacity to produce amphiphilic EPS is likely to have contributed to the ultimate removal of the oil and to the formation of oil aggregates, which were a dominant feature observed in contaminated surface waters.
Recently there has been growing concern that college students may feign symptoms of ADHD in order to obtain academic accommodations and stimulant medication. Unfortunately research has only begun to validate detection tools for malingered ADHD. The present study cross-validated the results of Sollman, Ranseen, and Berry (2010) on the efficacy of several symptom validity tests for detection of simulated ADHD among college students. Undergraduates with a history of diagnosed ADHD were randomly assigned either to respond honestly or exaggerate symptoms, and were compared to undergraduates with no history of ADHD or other psychiatric disorders who were also randomly assigned to respond honestly or feign symptoms of ADHD. Similar to Sollman et al. (2010) and other recent research on feigned ADHD, several symptom validity tests, including the Test of Memory Malingering (TOMM), Letter Memory Test (LMT), Digit Memory Test (DMT), Nonverbal Medical Symptom Validity Test (NV-MSVT), and the b Test were reasonably successful at discriminating feigned and genuine ADHD. When considered as a group, the criterion of failure of 2 or more of these SVTs had a sensitivity of. 475 and a specificity of 1.00.
"Barcode-tagged" PCR primers used for multiplex amplicon sequencing generate a thus-far-overlooked amplification bias that produces variable terminal restriction fragment length polymorphism (T-RFLP) and pyrosequencing data from the same environmental DNA template. We propose a simple two-step PCR approach that increases reproducibility and consistently recovers higher genetic diversity in pyrosequencing libraries.
With the use of an endoscopic, high-speed camera, vocal fold dynamics may be observed clinically during phonation. However, observation and subjective judgment alone may be insufficient for clinical diagnosis and documentation of improved vocal function, especially when the laryngeal disease lacks any clear morphological presentation. In this study, biomechanical parameters of the vocal folds are computed by adjusting the corresponding parameters of a three-dimensional model until the dynamics of both systems are similar. First, a mathematical optimization method is presented. Next, model parameters (such as pressure, tension and masses) are adjusted to reproduce vocal fold dynamics, and the deduced parameters are physiologically interpreted. Various combinations of global and local optimization techniques are attempted. Evaluation of the optimization procedure is performed using 50 synthetically generated data sets. The results show sufficient reliability, including 0.07 normalized error, 96% correlation, and 91% accuracy. The technique is also demonstrated on data from human hemilarynx experiments, in which a low normalized error (0.16) and high correlation (84%) values were achieved. In the future, this technique may be applied to clinical high-speed images, yielding objective measures with which to document improved vocal function of patients with voice disorders.
The present meta-analysis provides the first meta-analysis of research on stand-alone neurocognitive feigning tests since publication of the preceding paper by Vickery, Berry, Inman, Harris & Orey (2001). Studies of dedicated neurocognitive feigning test performances in adults appearing in published or unpublished (theses and dissertations) sources through October 2010 were reviewed and subjected to stringent inclusion criteria to maximize the validity of results. Neurocognitive feigning tests were included only if at least three contrasts of criterion-supported honest patient groups and feigners were available. Tests that met criteria for review included the Victoria Symptom Validity Test, used as an anchor to compare Vickery and colleagues results; Test of Memory Malingering, Word Memory Test, Letter Memory Test, and Medical Symptom Validity Test. Effect sizes and test parameters at published cut scores were compiled and compared. Results reflected large effect sizes for all measures (mean d = 1.55, 95% confidence interval [CI] = 1.48-1.63). Mean specificity was 0.90 (95% CI = 0.85-0.94). Mean sensitivity was 0.69 (95% CI = 0.63-0.75). Several moderators of effect size were identified, with certain manipulations resulting in a weakening of effect size. Unexpectedly, warning simulators to feign believably increased effect sizes.
Curcumin is a naturally occurring phytochemical and an extract of turmeric. Extensive in vitro and in vivo data have paved the way for curcumin to become the subject of clinical trials. Curcumin modulates key signalling pathways important in cellular processes. Numerous mechanisms of action have been elucidated. The potential for clinical efficacy is apparent from benign and malignant disease models. Curcumin has potent anti-inflammatory and anti-neoplastic properties used alone and in combination with standard therapies. Early-phase trials have ascertained pharmacological properties and consistently demonstrate it to be safe and well tolerated. However, bioavailability is limited and efficacious doses have not yet been determined. Evidence of efficacy has been derived from animal models or small clinical trials. There is only finite data supporting the use of curcumin in phase III trials with specific diseases (e.g. ulcerative colitis). However, for the vast majority of conditions additional early-phase studies are required to justify larger trials determining efficacy.
A new tripodal tris(hydroxypyridinone) bifunctional chelator for gallium allows easy production of (68)Ga-labelled proteins rapidly under mild conditions in high yields at exceptionally high specific activity and low concentration.
Differentiating between benign and malignant causes of obstructive jaundice can be challenging, even with the advanced imaging and endoscopic techniques currently available. In patients with obstructive jaundice, the predictive accuracy of bilirubin levels at presentation was examined in order to determine whether such data could be used to differentiate between malignant and benign disease.
Postoperative complications are associated with a poor long-term prognosis after resection of colorectal liver metastases via an undetermined mechanism. The preoperative systemic inflammatory response, itself a predictor of poor survival, was recently shown to independently predict postoperative infectious complications after primary colorectal cancer resection.
Today, the prevention and treatment of voice disorders is an ever-increasing health concern. Since many occupations rely on verbal communication, vocal health is necessary just to maintain ones livelihood. Commonly applied models to study vocal fold vibrations and air flow distributions are self sustained physical models of the larynx composed of artificial silicone vocal folds. Choosing appropriate mechanical parameters for these vocal fold models while considering simplifications due to manufacturing restrictions is difficult but crucial for achieving realistic behavior. In the present work, a combination of experimental and numerical approaches to compute material parameters for synthetic vocal fold models is presented. The material parameters are derived from deformation behaviors of excised human larynges. The resulting deformations are used as reference displacements for a tracking functional to be optimized. Material optimization was applied to three-dimensional vocal fold models based on isotropic and transverse-isotropic material laws, considering both a layered model with homogeneous material properties on each layer and an inhomogeneous model. The best results exhibited a transversal-isotropic inhomogeneous (i.e., not producible) model. For the homogeneous model (three layers), the transversal-isotropic material parameters were also computed for each layer yielding deformations similar to the measured human vocal fold deformations.
Differentiating between chronic pancreatitis and pancreatic adenocarcinoma can be difficult due to considerable overlap in disease presentation and radiological signs and the frequent co-existence of the two conditions. In this situation, surgeons may have to proceed to "blind" pancreaticoduodenectomy or attempt to confirm malignancy intraoperatively with frozen section (FS) histology.
In nature, stressful environments often occur in combination or close succession, and thus the ability to prepare for impending stress likely provides a significant fitness advantage. Organisms exposed to a mild dose of stress can become tolerant to what would otherwise be a lethal dose of subsequent stress; however, the mechanism of this acquired stress tolerance is poorly understood. To explore this, we exposed the yeast gene-deletion libraries, which interrogate all essential and non-essential genes, to successive stress treatments and identified genes necessary for acquiring subsequent stress resistance. Cells were exposed to one of three different mild stress pretreatments (salt, DTT, or heat shock) and then challenged with a severe dose of hydrogen peroxide (H(2)O(2)). Surprisingly, there was little overlap in the genes required for acquisition of H(2)O(2) tolerance after different mild-stress pretreatments, revealing distinct mechanisms of surviving H(2)O(2) in each case. Integrative network analysis of these results with respect to protein-protein interactions, synthetic-genetic interactions, and functional annotations identified many processes not previously linked to H(2)O(2) tolerance. We tested and present several models that explain the lack of overlap in genes required for H(2)O(2) tolerance after each of the three pretreatments. Together, this work shows that acquired tolerance to the same severe stress occurs by different mechanisms depending on prior cellular experiences, underscoring the context-dependent nature of stress tolerance.
Twenty-four studies utilizing the Wechsler Adult Intelligence Scale (WAIS) Digit Span subtest--either the Reliable Digit Span (RDS) or Age-Corrected Scaled Score (DS-ACSS) variant--for malingering detection were meta-analytically reviewed to evaluate their effectiveness in detecting malingered neurocognitive dysfunction. RDS and DS-ACSS effectively discriminated between honest responders and dissimulators, with average weighted effect sizes of 1.34 and 1.08, respectively. No significant differences were found between RDS and DS-ACSS. Similarly, no differences were found between the Digit Span subtest from the WAIS or Wechsler Memory Scale (WMS). Strong specificity and moderate sensitivity were observed, and optimal cutting scores are recommended.
Deliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following the introduction of a new formulation with an increased emetic concentration, an alginate and a purgative in Sri Lanka. Further, formulation changes were introduced in October 2006; this study was designed to assess the impact of these changes on 6-week mortality following paraquat ingestion.
The hybridization of nucleic acid targets with surface-immobilized probes is a widely used assay for the parallel detection of multiple targets in medical and biological research. Despite its widespread application, DNA microarray technology still suffers from several biases and lack of reproducibility, stemming in part from an incomplete understanding of the processes governing surface hybridization. In particular, non-random spatial variations within individual microarray hybridizations are often observed, but the mechanisms underpinning this positional bias remain incompletely explained.
For the analysis of vocal fold dynamics, sub- and supraglottal influences must be taken into account, as recent studies have shown. In this work, we analyze the influence of changes in the epilaryngeal area on vocal fold dynamics. We investigate two excised female larynges in a hemilarynx setup combined with a synthetic vocal tract consisting of hard plastic and simulating the vowel /a/. Eigenmodes, amplitudes, and velocities of the oscillations, the subglottal pressures (P(sub)), and sound pressure levels (SPLs) of the generated signal are investigated as a function of three distinctive epilaryngeal areas (28.4 mm(2), 71.0 mm(2), and 205.9 mm(2)). The results showed that the SPL is independent of the epilarynx cross section and exhibits a nonlinear relation to the insufflated airflow. The P(sub) decreased with an increase in the epilaryngeal area and displayed linear relations to the airflow. The principal eigenfunctions (EEFs) from the vocal fold dynamics exhibited lateral movement for the first EEF and rotational motion for the second EEF. In total, the first two EEFs covered a minimum of 60% of the energy, with an average of more than 50% for the first EEF. Correlations to the epilarynx areas were not found. Maximal values for amplitudes (up to 2.5 mm) and velocities (up to 1.57 mm/ms) changed with varying epilaryngeal area but did not show consistent behavior for both larynges. We conclude that the size of the epilaryngeal area has significant influence on vocal fold dynamics but does not significantly affect the resultant SPL.
Several emerging technologies are aiming to meet renewable fuel standards, mitigate greenhouse gas emissions, and provide viable alternatives to fossil fuels. Direct conversion of solar energy into fungible liquid fuel is a particularly attractive option, though conversion of that energy on an industrial scale depends on the efficiency of its capture and conversion. Large-scale programs have been undertaken in the recent past that used solar energy to grow innately oil-producing algae for biomass processing to biodiesel fuel. These efforts were ultimately deemed to be uneconomical because the costs of culturing, harvesting, and processing of algal biomass were not balanced by the process efficiencies for solar photon capture and conversion. This analysis addresses solar capture and conversion efficiencies and introduces a unique systems approach, enabled by advances in strain engineering, photobioreactor design, and a process that contradicts prejudicial opinions about the viability of industrial photosynthesis. We calculate efficiencies for this direct, continuous solar process based on common boundary conditions, empirical measurements and validated assumptions wherein genetically engineered cyanobacteria convert industrially sourced, high-concentration CO(2) into secreted, fungible hydrocarbon products in a continuous process. These innovations are projected to operate at areal productivities far exceeding those based on accumulation and refining of plant or algal biomass or on prior assumptions of photosynthetic productivity. This concept, currently enabled for production of ethanol and alkane diesel fuel molecules, and operating at pilot scale, establishes a new paradigm for high productivity manufacturing of nonfossil-derived fuels and chemicals.
Neurons that respond selectively to the orientation of visual stimuli were discovered in V1 more than 50 years ago, but it is still not fully understood how or why this is brought about. We report experiments planned to show whether human observers use cross-correlation or auto-correlation to detect oriented streaks in arrays of randomly positioned dots, expecting that this would help us to understand what David Marr called the computational goal of V1. The streaks were generated by two different methods: either by sinusoidal spatial modulation of the local mean dot density, or by introducing coherent pairs of dots to create moiré patterns, as Leon Glass did. A wide range of dot numbers was used in the randomly positioned arrays, because dot density affects cross- and auto-correlation differently, enabling us to infer which method was used. This difference stems from the fact that the cross-correlation task is limited by random fluctuations in the local mean density of individual dots in the noisy array, whereas the auto-correlation task is limited by fluctuations in the numbers of randomly occurring spurious pairs having the same separation and orientation as the deliberately introduced coherent pairs. After developing a new method using graded dot luminances, we were able to extend the range of dot densities that could be used by a large factor, and convincing results were obtained indicating that the streaks generated by amplitude modulation were discriminated by cross-correlation, while those generated as moiré patterns were discriminated by auto-correlation. Though our current results only apply to orientation selectivity, it is important to know that early vision can do more than simple filtering, for evaluating auto-correlations opens the way to more interesting possibilities, such as the detection of symmetries and suspicious coincidences.
A number of methods are available for the drainage of pancreatic pseudocysts, including percutaneous, endoscopic and open approaches. In Leicester, we developed a combined radiological and endoscopic technique (predating the use of endoscopic/ultrasound) to allow drainage of pancreatic pseudocysts into the stomach. The aim of the study was to evaluate the long-term results of this approach.
Stable Mycobacterium avium infections of several Acanthamoeba strains were characterized by increased infection resistance of recent environmental isolates and reduced infectivity in the presence of other bacteria. Exposure of M. avium in coculture with Acanthamoeba castellanii to monochloramine yielded inactivation kinetics markedly similar to those observed for A. castellanii alone.
In the context of comparisons of surgical outcomes, risk adjustment is the retrospective adjustment of a providers or a surgeons results for case mix and/or hospital volume. It allows accurate, meaningful inter-provider comparison. It is therefore an essential component of any audit and quality improvement process. The aim of this study was to review the literature to identify those factors known to affect prognosis in hepatobiliary and pancreatic cancer surgery.
Volatile fuel costs, the need to reduce greenhouse gas emissions and fuel security concerns are driving efforts to produce sustainable renewable fuels and chemicals. Petroleum comes from sunlight, CO(2) and water converted via a biological intermediate into fuel over a several million year timescale. It stands to reason that using biology to short-circuit this time cycle offers an attractive alternative--but only with relevant products at or below market prices. The state of the art of biological engineering over the past five years has progressed to allow for market needs to drive innovation rather than trying to adapt existing approaches to the market. This report describes two innovations using synthetic biology to dis-intermediate fuel production. LS9 is developing a means to convert biological intermediates such as cellulosic hydrolysates into drop-in hydrocarbon product replacements such as diesel. Joule Unlimited is pioneering approaches to eliminate feedstock dependency by efficiently capturing sunlight, CO(2) and water to produce fuels and chemicals. The innovations behind these companies are built with the market in mind, focused on low cost biosynthesis of existing products of the petroleum industry. Through successful deployment of technologies such as those behind LS9 and Joule Unlimited, alternative sources of petroleum products will mitigate many of the issues faced with our petroleum-based economy.
Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.
The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle-treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit.
Significant motivations and incentives exist for young-adult students to seek a diagnosis of attention-deficit/hyperactivity disorder (ADHD). With ADHD information readily accessible on the Internet, todays students are likely to be symptom educated prior to evaluation. This may result in false-positive diagnoses, particularly when students are motivated to convey symptoms. We evaluated the utility of ADHD symptom checklists, neurocognitive tests, and measures initially developed to detect feigned neurocognitive or psychiatric dysfunction (symptom validity tests [SVTs]). The performance of 31 undergraduates financially motivated and coached about ADHD via Internet-derived information was compared to that of 29 ADHD undergraduates following medication washout and 14 students not endorsing symptomatology. Results indicated malingerers readily produced ADHD-consistent profiles. Symptom checklists, including the ADHD Rating Scale and Connerss Adult ADHD Rating Scale-Self-Rating Form: Long, were particularly susceptible to faking. Connerss Continuous Performance Test-II findings appeared more related to motivation than condition. Promising results were seen with all cognitive SVTs (Test of Memory Malingering [TOMM], Digit Memory Test, Letter Memory Test, and Nonverbal-Medical Symptom Validity Test), particularly TOMM Trial 1 when scored using Trial 2 criteria. All SVTs demonstrated very high specificity for the ADHD condition and moderate sensitivity to faking, which translated into high positive predictive values at rising base rates of feigning. Combining 2 or more failures resulted in only modest declines in sensitivity but robust specificity. Results point to the need for a thorough evaluation of history, cognitive and emotional functioning, and the consideration of exaggerated symptomatology in the diagnosis of ADHD.
There are two previously reported cases describing the management of pregabalin self-poisoning and one further case of management of therapeutic pregabalin accumulation. The peak reported pregabalin concentrations in these cases ranged from 13 mg/L to approximately 60 mg/L. Previous case reports have suggested that both supportive care and enhanced elimination are appropriate managements for pregabalin toxicity. A 54-year-old male presented following ingestion of 8.4 g of pregabalin. Initially, he had no clinical features of toxicity, although he developed significant neurological depression and coma approximately 3 h post-ingestion. He was managed with supportive care (including endotracheal intubation and mechanical ventilation) until his level of consciousness improved. Subsequent toxicological screening confirmed isolated pregabalin ingestion, with a serum pregabalin concentration of 66.5 mg/L at the time he clinically deteriorated. The pharmacokinetic properties of pregabalin indicate the potential value of extra-corporeal elimination methods such as haemodialysis. Clinical toxicologists should be aware that whilst there is a pharmacokinetic basis for the use of extra-corporeal methods in those with severe toxicity arising from excessive plasma pregabalin concentrations, there are case reports, including this one, where patients have been managed with supportive measures only.
Previous investigations using in vivo models to study the role of intrinsic laryngeal muscles in phonation have used neuromuscular stimulation to study voice parameters. However, these studies used coarse stimulation techniques using limited levels of neuromuscular stimulation. In the current investigation, a technique for fine control of laryngeal posturing was developed using graded stimulation of the laryngeal nerves. Vocal fold strain history to graded stimulation and a methodology for establishing symmetric laryngeal activation is presented. This methodology has immediate applications for the study of laryngeal paralysis and paresis, as well as general questions of neuromuscular control of the larynx.
Escherichia coli growth in biofilms and growth at a suboptimal temperature of 20 °C have been shown to decrease sensitivity to monochloramine (Berry, D., C. Xi, L. Raskin. 2009. Environ. Sci. Technol. 43, 884-889). In order to better understand why growth conditions affect sensitivity to monochloramine, a comparative transcriptomic approach was used to identify common patterns of differentially-expressed genes under these growth conditions and during monochloramine exposure. This approach revealed a set of differentially-expressed genes shared under multiple conditions (planktonic growth at 20 °C, biofilm growth, and exposure of planktonic cells to monochloramine), with nine genes shared under all three conditions. Functional gene categories enriched in the shared gene sets included: general metabolic inhibition, redox and oxidoreductase response, cell envelope integrity response, control of iron and sulfur transport metabolism and several genes of unknown function. Single gene deletion mutant analyses verified that loss of 15 of the 24 genes up-regulated during monochloramine exposure as well as during other tested conditions increased E. coli sensitivity to monochloramine up to two fold. Constitutive expression of down-regulated genes in single gene mutants yielded mixed results, indicating that the expression of some down-regulated genes actually decreases sensitivity to monochloramine. These results contribute to the understanding of the bacterial response to disinfectants by characterizing the overlap between growth condition associated stress responses and monochloramine-associated stress responses. This characterization highlights the bacterial responses responsible for decreased sensitivity to monochloramine under different growth conditions.
In a cross-validation of results from L. O. Graue et al. (2007), standard psychological assessment instruments, as well as tests of neurocognitive and psychiatric feigning, were administered under standard instructions to 24 participants diagnosed with mild mental retardation (MR) and 10 demographically matched community volunteers (CVH). A 2nd group of 25 community volunteers was instructed to malinger MR (CVM) during testing. CVM participants obtained Wechsler Adult Intelligence Scale (3rd ed.; D. Wechsler, 1997) Full Scale Intelligence Quotient scores that were significantly lower than the demographically similar CVH group but comparable to the MR group, suggesting that CVM subjects feigned cognitive impairment. On the basis of standard cutting scores from test manuals or published articles, of the 11 feigning measures administered, only the Test of Memory Malingering (TOMM; T. N. Tombaugh, 1996) retention trial had a specificity rate >.90 in the MR group. However, the 2nd learning trial of the TOMM, as well as a short form of the Digit Memory Test (T. J. Guilmette, K. J. Hart, A. J. Guiliano, & B. E. Leininger, 1994), approached this level of specificity, with both at .88. These results raise concerns about the specificity rates at recommended cutting scores of commonly used feigning tests in defendants with MR.
Human voice originates from the three-dimensional (3D) oscillations of the vocal folds. In previous studies, biomechanical properties of vocal fold tissues have been predicted by optimizing the parameters of simple two-mass-models to fit its dynamics to the high-speed imaging data from the clinic. However, only lateral and longitudinal displacements of the vocal folds were considered. To extend previous studies, a 3D mass-spring, cover-model is developed, which predicts the 3D vibrations of the entire medial surface of the vocal fold. The model consists of five mass planes arranged in vertical direction. Each plane contains five longitudinal, mass-spring, coupled oscillators. Feasibility of the model is assessed using a large body of dynamical data previously obtained from excised human larynx experiments, in vivo canine larynx experiments, physical models, and numerical models. Typical model output was found to be similar to existing findings. The resulting model enables visualization of the 3D dynamics of the human vocal folds during phonation for both symmetric and asymmetric vibrations.
The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters (123)I-iodide, (131)I-iodide and (99m)Tc-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate (18)F-labelled tetrafluoroborate ([(18)F]TFB) for PET imaging of hNIS.
Radiology reports provide specialist interpretation of images and relate these findings to the patients symptoms and signs. This study compared ultrasound (USS) reports generated by radiologists and sonographers to determine if any significant or clinically relevant differences existed.
The majority of patients with advanced colorectal cancer die from hepatic metastases caused by disease progression; therefore, several novel technologies are in clinical development to potentially improve local control of liver disease. Radioembolization is a technique for administering radiotherapy internally to unresectable primary or secondary hepatic malignancies in a single procedure. This technique involves the injection of resin or glass microspheres that contain (90)Y into the arterial supply of the liver. Clinical trials of radioembolization used with concomitant radiosensitizing chemotherapy have shown promising results in patients with metastatic colorectal cancer. Several reports suggest that radioembolization is associated with significant downsizing of liver metastases to permit subsequent surgical resection. In this article, the rationale for combining radioembolization with the cytotoxic and molecularly targeted agents licensed for the systemic treatment of colorectal cancer is outlined. Clinical data from trials of radioembolization with concomitant systemic treatment are reviewed, with an emphasis on the appropriateness of primary end points in large-scale trials and the practical aspects of surgical resection in patients whose tumors are successfully downsized by this chemoradiation approach.
The current study examined the effectiveness of the MMPI-2 Restructured Form (MMPI-2-RF; Ben-Porath and Tellegen, 2008) over-reporting indicators in civil forensic settings. The MMPI-2-RF includes three revised MMPI-2 over-reporting validity scales and a new scale to detect over-reported somatic complaints. Participants dissimulated medical and neuropsychological complaints in two simulation samples, and a known-groups sample used symptom validity tests as a response bias criterion. Results indicated large effect sizes for the MMPI-2-RF validity scales, including a Cohens d of .90 for Fs in a head injury simulation sample, 2.31 for FBS-r, 2.01 for F-r, and 1.97 for Fs in a medical simulation sample, and 1.45 for FBS-r and 1.30 for F-r in identifying poor effort on SVTs. Classification results indicated good sensitivity and specificity for the scales across the samples. This study indicates that the MMPI-2-RF over-reporting validity scales are effective at detecting symptom over-reporting in civil forensic settings.
Previous research has been equivocal on personality trait and psychopathology differences between temporal lobe and other types of epilepsy, as well as between patients with right and left temporal lobe seizure foci. In this study, personality differences between patients with right temporal (n=23), left temporal (n=21), and extratemporal (n=24) epilepsy were investigated using the NEO Personality Inventory-Revised (NEO-PI-R). No statistically significant differences were found on any of the NEO-PI-R domains or facet trait scales. There were also no significant differences between groups on the Minnesota Multiphasic Personality Inventory 2 (MMPI-2), a measure of psychopathology. However, mild elevations were seen in all groups on clinical scales related to physical symptoms, health concern, and depression. These data suggest there are no consistent personality or psychopathology differences, as measured by the NEO-PI-R and the MMPI-2, between patients with left temporal, right temporal, and extratemporal epilepsy whose seizures are localized using video/EEG monitoring.
The Structured Interview of Reported Symptoms (SIRS; Rogers et al., Structured interview of reported symptoms (SIRS) and professional manual, 1992) is a well-validated psychological measure for the assessment of feigned mental disorders (FMD) in clinical, forensic, and correctional settings. Comparatively little work has evaluated its usefulness in compensation and disability contexts. The present study examined SIRS data from 569 individuals undergoing forensic neuropsychiatric examinations for the purposes of workers compensation, personal injury, or disability proceedings. Using bootstrapping comparisons, three primary groups were identified: FMD, feigned cognitive impairment (FCI), genuine-both (GEN-Both) that encompasses both genuine disorders (GEN-D) and genuine-cognitive presentation (GEN-C). Consistent with the SIRS main objective, very large effect sizes (M Cohens d = 1.94) were observed between FMD and GEN-Both groups. Although not intended for this purpose, moderate to large effect sizes (M d = 1.13) were found between FCI and GEN-Both groups. An important consideration is whether SIRS results are unduly affected by common diagnoses or clinical conditions. Systematic comparisons were performed based on common disorders (major depressive disorder, PTSD, and other anxiety disorders), presence of a cognitive disorder (dementia, amnestic disorder, or cognitive disorder NOS), or intellectual deficits (FSIQ < 80). Generally, the magnitude of differences on the SIRS primary scales was small and nonsignificant, providing evidence of the SIRS generalizability across these diagnostic categories. Finally, the usefulness of the SIRS improbable failure-revised (IF-R) scale was tested as a FCI screen. Although it has potential in ruling out genuine cases, the IF-R should not be used as a feigning screen.
The flow-induced vibrations of a single-layer vocal fold model were investigated as a function of vocal fold stiffness, and subglottal and supraglottal acoustic loading. Previously, it was reported that the single-layer vocal fold model failed to vibrate when short, clinically-relevant tracheal tubes were used. Moreover, it was reported that the model had a propensity to be acoustically driven, and aerodynamically driven vibration was observed only when a vertical restraint was applied superiorly to the vocal folds. However, in this study involving a wider range of source/tract conditions, the previous conclusions were shown to apply only for the special case of a stiff vocal fold model, for which self-oscillation occurred only when the vocal fold vibration synchronized to either a subglottal or supraglottal resonance. For a more general case, when vocal fold stiffness was decreased, the model did exhibit self-oscillation at short tracheal tubes, and no vertical restraint was needed to induce aerodynamically driven phonation. Nevertheless, the vocal fold vibration transitioned from aerodynamically-driven to acoustically-driven vibration when one of the subglottal resonance frequencies approximated one of the natural frequencies of the vocal folds. In this region, strong superior-inferior vibrations were observed, the phonation threshold pressure was significantly reduced, and the phonation onset frequency was heavily influenced by the dominant acoustic resonance. For acoustically-driven phonation, a compliant subglottal system always lowered phonation threshold. However, an inertive vocal tract could either increase or decrease phonation threshold pressure, depending on the phonation frequency.
The purpose of this study was to explore the latent structure of feigned neurocognitive deficit. Scores on the Test of Memory Malingering (TOMM), Letter Memory Test (LMT), and Victoria Symptom Validity Test (VSVT) served as indicators in a taxometric investigation of 527 compensation-seeking adults using three taxometric procedures -- mean above minus below a cut (MAMBAC), maximum covariance (MAXCOV), and latent-mode factor analysis (L-Mode). All three procedures showed evidence of dimensional latent structure. The fact that feigned neurocognitive symptomatology is ordered along a continuum rather than bifurcating into distinct categories has important implications for theory, research, and clinical practice.
The majority of patients with pancreatic cancer are non-resectable and jaundiced at presentation. Methods of palliation in such patients with locally advanced disease comprise endoscopic placement of a biliary endoprosthesis or surgical bypass.
Naturally occurring anthocyanins possess colorectal cancer chemopreventive properties in rodent models. We investigated whether mirtocyan, an anthocyanin-rich standardized bilberry extract, causes pharmacodynamic changes consistent with chemopreventive efficacy and generates measurable levels of anthocyanins in blood, urine, and target tissue. Twenty-five colorectal cancer patients scheduled to undergo resection of primary tumor or liver metastases received mirtocyan 1.4, 2.8, or 5.6 grams (containing 0.5-2.0 grams anthocyanins) daily for 7 days before surgery. Bilberry anthocyanins were analyzed by high performance liquid chromatography (HPLC) with visible or mass spectrometric detection. Proliferation was determined by immunohistochemistry of Ki-67 in colorectal tumor. Concentrations of insulin-like growth factor (IGF)-I were measured in plasma. Mirtocyan anthocyanins and methyl and glucuronide metabolites were identified in plasma, colorectal tissue, and urine, but not in liver. Anthocyanin concentrations in plasma and urine were roughly dose-dependent, reaching approximately 179 ng/gram in tumor tissue at the highest dose. In tumor tissue from all patients on mirtocyan, proliferation was decreased by 7% compared with preintervention values. The low dose caused a small but nonsignificant reduction in circulating IGF-I concentrations. In conclusion, repeated administration of bilberry anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in humans resembling those seen in Apc(Min) mice, a model of FAP adenomas sensitive to the chemopreventive properties of anthocyanins. Studies of doses containing <0.5 gram bilberry anthocyanins are necessary to adjudge whether they may be appropriate for development as colorectal cancer chemopreventive agents.
Although endoscopic treatment of jaundice is increasingly used in the palliation of unresectable malignant disease, surgical bypass still has a role to play in this setting. This study aimed to reappraise the short-term and long-term results of combined biliary/gastric bypass (hepaticojejunostomy and gastrojejunostomy) as palliation for unresectable malignant disease.
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