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"J. R. Adams"
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LTBP-2 Has a Single High-Affinity Binding Site for FGF-2 and Blocks FGF-2-Induced Cell Proliferation
Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) belongs to the fibrillin-LTBP superfamily of extracellular matrix proteins. LTBPs and fibrillins are involved in the sequestration and storage of latent growth factors, particularly transforming growth factor β (TGF-β), in tissues. Unlike other LTBPs, LTBP-2 does not covalently bind TGF-β, and its molecular functions remain unclear. We are screening LTBP-2 for binding to other growth factors and have found very strong saturable binding to fibroblast growth factor-2 (FGF-2) (Kd = 1.1 nM). Using a series of recombinant LTBP-2 fragments a single binding site for FGF-2 was identified in a central region of LTBP-2 consisting of six tandem epidermal growth factor-like (EGF-like) motifs (EGFs 9-14). This region was also shown to contain a heparin/heparan sulphate-binding site. FGF-2 stimulation of fibroblast proliferation was completely negated by the addition of 5-fold molar excess of LTBP-2 to the assay. Confocal microscopy showed strong co-localisation of LTBP-2 and FGF-2 in fibrotic keloid tissue suggesting that the two proteins may interact in vivo. Overall the study indicates that LTBP-2 is a potent inhibitor of FGF-2 that may influence FGF-2 bioactivity during wound repair particularly in fibrotic tissues.
Journal Article
Field guide to the spiders of California and the Pacific coast states
With over 40,000 described species, spiders have adapted to nearly every terrestrial environment across the globe. Over half of the world’s spider families live within the three contiguous Pacific Coast states—not surprising considering the wide variety of habitats, from mountain meadows and desert dunes to redwood forests and massive urban centers. This beautifully illustrated, accessible guide covers all of the families and many of the genera found along the Pacific Coast, including introduced species and common garden spiders. The author provides readers with tools for identifying many of the region’s spiders to family, and when possible, genus and species. He discusses taxonomy, distribution, and natural history as well as what is known of the habits of the spiders, the characters of families, and references to taxonomic revisions of the pertinent genera. Full-color plates for each family bring to life the incredible diversity of this ancient arachnid order.
eBook
Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients
Aim
The pathophysiology of delirium remains elusive though neurotransmitters and their precursor large neutral amino acids (LNAAs) may play a role. This pilot study investigated whether alterations of tryptophan (Trp), phenylalanine (Phe), and tyrosine (Tyr) plasma levels were associated with a higher risk of transitioning to delirium in critically ill patients.
Methods
Plasma LNAA concentrations were determined on days 1 and 3 in mechanically ventilated (MV) patients from the MENDS randomized controlled trial (dexmedetomidine vs. lorazepam sedation). Three independent variables were calculated by dividing plasma concentrations of Trp, Phe, and Tyr by the sum of all other LNAA concentrations. Delirium was assessed daily using the confusion assessment method for the intensive care unit (CAM-ICU). Markov regression models were used to analyze independent associations between plasma LNAA ratios and transition to delirium after adjusting for covariates.
Results
The 97 patients included in the analysis had a high severity of illness (median APACHE II, 28; IQR, 24–32). After adjusting for confounders, only high or very low tryptophan/LNAA ratios (
p
= 0.0003), and tyrosine/LNAA ratios (
p
= 0.02) were associated with increased risk of transitioning to delirium, while phenylalanine levels were not (
p
= 0.27). Older age, higher APACHE II scores and increasing fentanyl exposure were also associated with higher probabilities of transitioning to delirium.
Conclusions
In this pilot study, plasma tryptophan/LNAA and tyrosine/LNAA ratios were associated with transition to delirium in MV patients, suggesting that alterations of amino acids may be important in the pathogenesis of ICU delirium. Future studies evaluating the role of amino acid precursors of neurotransmitters are warranted in critically ill patients.
Journal Article
An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity
We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c+ major histocompatibility complex (MHC) class IIhi) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal TH17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple TH1, TH2, and TH17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4+ T lymphocytes. Loss of T and B lymphocytes in Rag1-/- × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1-/-, indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/TH17 response, similar to that of human ulcerative colitis.
Journal Article
Psychological factors and asthma quality of life: a population based study
Background: Reports of psychological conditions in asthmatic subjects have been limited to certain population groups or convenience samples. A study was undertaken of the prevalence of psychological distress in asthma in the general population and its associations with quality of life. Methods: The WANTS Health and Well-being Survey is a population household interview survey of adults (age ⩾18) in Western Australia, the Northern Territory, and South Australia. Data obtained were weighted to the closest census data to provide population representative estimates. Positive answers to two questions: “Have you ever been told by a doctor that you have asthma?” and “Do you still have asthma?” determined current doctor-diagnosed asthma. Other items included the SF-12, the Kessler-10 index of psychological distress, questions on feelings of lack of control in different areas of life, and on mental health conditions. Results: From the available sample of 10 080, 7619 interviews were completed (participation rate 74.8%), with 834 people reporting current doctor-diagnosed asthma (11.2%). Psychological distress was more frequent in those with asthma (17.9% v 12.2%, p<0.01) and a higher proportion with asthma were at higher risk for anxiety or depression (40.5% v 31.2%, p<0.01). Mental health conditions were also more common (16.2% v 10.8%, p<0.01), as was the frequency of those who sometimes or always felt a lack of control over their health (33.5% v 24.3%, p<0.01). People with both asthma and psychological distress had significantly lower scores on the SF-12 physical component summary (PCS) than those with either asthma or distress alone. Among those with psychological distress, mental component summary (MCS) scores did not differ between asthmatic and non-asthmatic respondents. In a multiple regression model the frequency of a feeling of lack of control over health—together with age, family’s financial situation, education level, and number of days partially unable to work or perform usual duties—was significantly associated with scores on the PCS (r = 0.73, adjusted r2 = 0.54). Conclusion: These results, from a representative population sample, show that psychological distress and decreased feelings of control are common in asthma and are significantly associated with physical health status.
Journal Article
Factors associated with hospital admissions and repeat emergency department visits for adults with asthma
BACKGROUND A small proportion of patients with asthma account for a disproportionate number of acute health service events. To identify whether factors other than severity and low socioeconomic status were associated with this disproportionate use, a prospective study was undertaken to examine management and psychosocial factors associated with increased risk for admission to hospital with asthma and repeat visits to the emergency department over a 12 month period. METHODS A total of 293 patients with moderate or severe asthma managed at least in part at two teaching hospitals completed surveys of clinical status, acute events, sociodemographic, and psychological variables. RESULTS Twenty three percent had a single admission to hospital and 16% had two or more hospital admissions. Twenty six percent had one emergency department visit and 32% had two or more visits to the emergency department. In a multiple logistic regression model, adjusted for age, sex, education and income, odds ratios (95% CI) for baseline factors associated with hospital admissions over the next 12 months were: moderate severity compared with severe asthma 0.6 (0.2 to 0.9); no hospital admissions in the past 12 months 0.1 (0.01 to 0.2); not possessing a written asthma action plan 4.0 (1.5 to 10.7); less use of an avoidance coping style 0.4 (0.3 to 0.7); lower preferences for autonomy in asthma management decisions 1.4 (0.96 to 2.0). Adjusted odds ratios (95% CI) for repeat emergency department visits were: moderate asthma severity 0.3 (0.1 to 0.8); current regular use of oral corticosteroids 10.0 (3.1 to 32.4); a hospital admission in the past 12 months 2.9 (1.8 to 4.8); not possessing a written asthma action plan 2.2 (1.1 to 5.6); less dislike of asthma medications 0.7 (0.5 to 0.9). CONCLUSIONS In addition to factors relating to severity, not possessing a written asthma action plan, avoidance coping, and attitudes to self-management were related to acute use of health services in this at risk group. Interventions need to address or take these factors into account to reduce asthma morbidity.
Journal Article
Evidence of Mass Ordering of Charm and Bottom Quark Energy Loss in Au+Au Collisions at RHIC
Partons traversing the strongly interacting medium produced in heavy-ion collisions are expected to lose energy depending on their color charge and mass. We measure the nuclear modification factors for charm- and bottom-decay electrons, defined as the ratio of yields, divided by the number of binary nucleon–nucleon collisions, in sNN=200 GeV Au+Au collisions to p+p collisions (RAA), or in central to peripheral Au+Au collisions (RCP). We find the bottom-decay electron RAA and RCP to be significantly higher than those of charm-decay electrons. Model calculations including mass-dependent parton energy loss in a strongly coupled medium are consistent with the measured data. These observations provide evidence of mass ordering of charm and bottom quark energy loss when traversing through the strongly coupled medium created in heavy-ion collisions.
Journal Article
Underdiagnosed asthma in South Australia
Background: The prevalence of undiagnosed asthma in the general population and the clinical and demographic characteristics of these patients compared with those with diagnosed asthma are unclear. Methods: The North West Adelaide Health Survey (NWAHS) is a population household interview survey of adults (age >18 years) in the north western suburbs of Adelaide, South Australia (regional population 0.6 million). Data obtained were weighted to the closest census data to provide population representative estimates. Positive answers to: “Have you ever had asthma?”; “Has it been confirmed by a doctor?”; ”Do you still have asthma?” determined current physician diagnosed asthma. A positive bronchodilator response on spirometric testing according to ATS criteria without a physician’s diagnosis determined undiagnosed asthma. Other measures included the SF-12 health survey questionnaire, the Selim index of severity of chronic lung disease, skin allergy tests, and demographic data. Results: Of the 3422 individuals interviewed, 2523 (74%) agreed to participate in the clinical assessment. Of these, 292 (11.6%) had asthma, 236 (9.3%) with a doctor’s diagnosis of asthma and 56 (2.3%) with undiagnosed asthma defined on spirometric criteria; thus, 19.2% of the total asthma group were undiagnosed. Those undiagnosed were more likely (p<0.05) to be >40 years old, on government benefits, with an income 65 years. Health service use over the previous year was similar for both asthma groups. Conclusion: Undiagnosed asthma is common among the Australian population, with a similar clinical spectrum to those with diagnosed asthma.
Journal Article
Compressed Fast Multipole Representations for Homogeneous 3-D Kernels
For homogeneous kernels, the memory requirements associated with H2 representations of integral equation matrices can be reduced by incorporating translational invariance. Starting with a non-translationally invariant H2 representation, this can be accomplished using a left/right iterative algorithm. In this paper, it is shown that a similar algorithm can also be used to compress an existing fast multipole method (FMM). It is observed that the iterative compression converges faster when used to compress an FMM than when it is applied to an H2 representation. Resulting savings in floating-point operations are indicated, and extensions of the reported method are discussed.
Journal Article