A novel role for the TIR domain in association with pathogen-derived elicitors

Plant innate immunity is mediated by Resistance (R) proteins, which bear a striking resemblance to animal molecules of similar function. Tobacco N is a TIR-NB-LRR R gene that confers resistance to Tobacco mosaic virus, specifically the p50 helicase domain. An intriguing question is how plant R proteins recognize the presence of pathogen-derived Avirulence (Avr) elicitor proteins. We have used biochemical cell fraction and immunoprecipitation in addition to confocal fluorescence microscopy of living tissue to examine the association between N and p50. Surprisingly, both N and p50 are cytoplasmic and nuclear proteins, and N's nuclear localization is required for its function. We also demonstrate an in planta association between N and p50. Further, we show that N's TIR domain is critical for this association, and indeed, it alone can associate with p50. Our results differ from current models for plant innate immunity that propose detection is mediated solely through the LRR domains of these molecules. The data we present support an intricate process of pathogen elicitor recognition by R proteins involving multiple subcellular compartments and the formation of multiple protein complexes. © 2007 Burch-Smith et al

Evidence-based decision support for pediatric rheumatology reduces diagnostic errors.

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ( unaided ), versus after use of the DDSS ( aided ). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p \u3c 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an open book approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists\u27 ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086

Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestational-age and appropriate-for-gestational-age premature infants

BACKGROUND: There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth. OBJECTIVE: To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants. DESIGN/METHODS: A retrospective study was done of the 2,487 infants born without congenital anomalies at ≤36 weeks of gestation and admitted to the neonatal intensive care unit (NICU) at John Dempsey Hospital, between Jan. 1992 and Dec. 1999. Recent (1994–96) U.S. birth weight percentiles for gestational age (GA), race and gender were used to classify neonates as SGA (<10th percentile for GA) or AGA (10(th)–90th percentile for GA). Using multivariate logistic regression and survival analyses to control for GA, SGA and AGA infants were compared for mortality and respiratory morbidity. RESULTS: Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA ≤ 32 wk (OR = 1.27, 95% CI 0.32 – 1.98) but significantly decreased risk for RDS at GA > 32 wk (OR = 0.41, 95% CI 0.27 – 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 – 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26–36 wks GA than AGA infants. CONCLUSIONS: Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at ≥32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Effect of valdecoxib pretreatment on pain and secondary hyperalgesia: a randomized controlled trial in healthy volunteers [ISRCTN05282752, NCT00260325]

BACKGROUND: Induction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers. METHODS: The study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped. RESULTS: The area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation. CONCLUSION: We demonstrated that a single, oral dose of valdecoxib when does not attenuate secondary hyperalgesia induced by heat/capsaicin in a cutaneous sensitization pain model in healthy volunteers

Relationship between knee and ankle degeneration in a population of organ donors

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a progressive degenerative condition of synovial joints in response to both internal and external factors. The relationship of OA in one joint of an extremity to another joint within the same extremity, or between extremities, has been a topic of interest in reference to the etiology and/or progression of the disease.</p> <p>Methods</p> <p>The prevalence of articular cartilage lesions and osteophytes, characteristic of OA, was evaluated through visual inspection and grading in 1060 adult knee/tali pairs from 545 cadaveric joint donors.</p> <p>Results</p> <p>Joint degeneration increased more rapidly with age for the knee joint, and significantly more knee joints displayed more severe degeneration than ankle joints from as early as the third decade. Women displayed more severe knee degeneration than did men. Severe ankle degeneration did not exist in the absence of severe knee degeneration. The effect of weight on joint degeneration was joint-specific whereby weight had a significantly greater effect on the knee. Ankle grades increasingly did not match within a donor as the grade of degeneration in either the left or the right knee increased.</p> <p>Conclusions</p> <p>Gender and body type have a greater effect on knee joint integrity as compared to the ankle, suggesting that knees are more prone to internal causative effects of degeneration. We hypothesize that the greater variability in joint health between joints within an individual as disease progresses from normal to early signs of degeneration may be a result of mismatched limb kinetics, which in turn might lead to joint disease progression.</p

Severe male infertility after failed ICSI treatment-a phenomenological study of men's experiences

<p>Abstract</p> <p>Background</p> <p>Male-factor infertility underlies approximately 30% of infertility in couples seeking treatment; of which 10% is due to azoospermia. The development of assisted reproductive technology (ART), enabling the use of epididymal or testicular sperm for fertilization of the partner's oocytes, has made biological fatherhood possible for men with obstructive azoospermia. There is limited knowledge of men's experience of their own infertility. The aim of this study was to describe men's experiences of obstructive azoospermia infertility.</p> <p>Methods</p> <p>Eight men with obstructive azoospermia, who had terminated Swedish public health system ART treatment two years previously without subsequent childbirth, were interviewed using a descriptive phenomenological method.</p> <p>Results</p> <p>The essence of the phenomenon is expressed with a metaphor: climbing a mountain step by step with the aim of reaching the top, i.e. having a child and thus a family with a child. Four constituents are included (1) inadequacy followed by a feeling of redress (2) marginalisation, (3) chivalry (4) extension of life and starting a family as driving forces.</p> <p>Conclusions</p> <p>Knowledge of men's experiences of their own infertility is important as a supporting measure to increase the quality of care of infertile couples. By adopting this facet of gender perspective in fertility treatment guidelines, care can hopefully be optimized.</p