Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems.
It is increasingly appreciated that altered neuroimmune mechanisms might play a role in the development of schizophrenia and related psychotic illnesses. On the basis of human epidemiological findings, a number of translational rodent models have been established to explore the consequences of prenatal immune activation on brain and behavioral development. The currently existing models are based on maternal gestational exposure to human influenza virus, the viral mimic polyriboinosinic-polyribocytidilic acid [Poly(I:C)], the bacterial endotoxin lipopolysaccharide, the locally acting inflammatory agent turpentine, or selected inflammatory cytokines. These models are pivotal for establishing causal relationships and for identifying cellular and molecular mechanisms that affect normal brain development in the event of early-life immune exposures. An important aspect of developmental immune activation models is that they allow a multi-faceted, longitudinal monitoring of the disease process as it unfolds during the course of neurodevelopment from prenatal to adult stages of life. An important recent refinement of these models is the incorporation of multiple etiologically relevant risk factors by combining prenatal immune challenges with specific genetic manipulations or additional environmental adversities. Converging findings from such recent experimental attempts suggest that prenatal infection can act as a "neurodevelopmental disease primer" that is likely relevant for a number of chronic mental illnesses. Hence, the adverse effects induced by prenatal infection might reflect an early entry into the neuropsychiatric route, but the specificity of subsequent disease or symptoms is likely to be strongly influenced by the genetic and environmental context in which the prenatal infectious process occurs.


Glial regulation of neuronal function: from synapse to systems physiology.
Classically, glia have been regarded as non-excitable cells that provide nourishment and physical scaffolding for neurones. However, it is now generally accepted that glia are active participants in brain function that can modulate neuronal communication via several mechanisms. Investigations of anatomical plasticity in the magnocellular neuroendocrine system of the hypothalamic paraventricular and supraoptic nuclei led the way in the development of much of our understanding of glial regulation of neuronal activity. In this review, we provide an overview of glial regulation of magnocellular neurone activity from a historical perspective of the development of our knowledge of the morphological changes that are evident in the paraventricular and supraoptic nuclei. We also focus on recent data from the authors' laboratories presented at the 9th World Congress on Neurohypophysial Hormones that have contributed to our understanding of the multiple mechanisms by which glia modulate the activity of neurones, including: gliotransmitter modulation of synaptic transmission; trans-synaptic modulation by glial neurotransmitter transporter regulation of neurotransmitter spillover; and glial neurotransmitter transporter modulation of excitability by regulation of ambient neurotransmitter levels and their action on extrasynaptic receptors. The magnocellular neuroendocrine system secretes oxytocin and vasopressin from the posterior pituitary gland to control birth, lactation and body fluid balance, and we finally speculate as to whether glial regulation of individual magnocellular neurones might co-ordinate population activity to respond appropriately to altered physiological circumstances.


Temperature and cell-type dependency of sulfide effects on mitochondrial respiration.
Previous studies suggest that sulfide-induced inhibition of cytochrome c oxidase (cCox) and, consequently, the metabolic and toxic effects of sulfide are less pronounced at low body temperature. Because the temperature-dependent effects of sulfide on the inflammatory response are still a matter of debate, we investigated the impact of varying temperature on the cCox excess capacity and the mitochondrial sulfide oxidation by the sulfide-ubiquinone oxidoreductase in macrophage-derived cell lines (AMJ2-C11 and RAW 264.7). Using an oxygraph chamber, the inhibition of mitochondrial respiration was measured by stepwise titrations with sulfide and the nonmetabolizable cCox inhibitor sodium azide at 25°C and 37°C. Using the latter of the two inhibitors, the excess capacity of the cCox was obtained. Furthermore, we quantified the capacity of these cells to withstand sulfide inhibition by measuring the amount required to inhibit respiration by 50% and 90% and the viability of the cells after 24-h exposure to 100 ppm of hydrogen sulfide. At low titration rates, the AMJ2-C11 cells, but not the RAW 264.7 cells, increased their capacity to withstand exogenously added sulfide. This effect was even greater at 25°C than at 37°C. Furthermore, only the AMJ2-C11 cells remained viable after sulfide exposure for 24 h. In contrast, only in the RAW 264.7 cells that an increase in cCox excess capacity was found at low temperatures. In macrophage-derived cell lines, both the excess capacity of cCox and the efficiency of sulfide elimination may increase at low temperatures. These properties may modify the effects of sulfide in immune cells and, potentially, the inflammatory response during sulfide exposure at different body temperatures.


Isolation and characterization of charge-tagged phenylperoxyl radicals in the gas phase: direct evidence for products and pathways in low temperature benzene oxidation.
The phenylperoxyl radical has long been accepted as a critical intermediate in the oxidation of benzene and an archetype for arylperoxyl radicals in combustion and atmospheric chemistry. Despite being central to many contemporary mechanisms underpinning these chemistries, reports of the direct detection or isolation of phenylperoxyl radicals are rare and there is little experimental evidence connecting this intermediate with expected product channels. We have prepared and isolated two charge-tagged phenyl radical models in the gas phase [i.e., 4-(N,N,N-trimethylammonium)phenyl radical cation and 4-carboxylatophenyl radical anion] and observed their reactions with dioxygen by ion-trap mass spectrometry. Measured reaction rates show good agreement with prior reports for the neutral system (k(2)[(Me(3)N(+))C(6)H(4)˙ + O(2)] = 2.8 × 10(-11) cm(3) molecule(-1) s(-1), Φ = 4.9%; k(2)[((-)O(2)C)C(6)H(4)˙ + O(2)] = 5.4 × 10(-11) cm(3) molecule(-1) s(-1), Φ = 9.2%) and the resulting mass spectra provide unequivocal evidence for the formation of phenylperoxyl radicals. Collisional activation of isolated phenylperoxyl radicals reveals unimolecular decomposition by three pathways: (i) loss of dioxygen to reform the initial phenyl radical; (ii) loss of atomic oxygen yielding a phenoxyl radical; and (iii) ejection of the formyl radical to give cyclopentadienone. Stable isotope labeling confirms these assignments. Quantum chemical calculations for both charge-tagged and neutral phenylperoxyl radicals confirm that loss of formyl radical is accessible both thermodynamically and entropically and competitive with direct loss of both hydrogen atom and carbon dioxide.


A simplified model of screening questionnaire and home monitoring for obstructive sleep apnoea in primary care.
To address the growing burden of disease and long waiting lists for sleep services, a simplified two-stage model was developed and validated for identifying obstructive sleep apnoea (OSA) in primary care using a screening questionnaire followed by home sleep monitoring. 157 patients aged 25-70 years attending their primary care physician for any reason at six primary care clinics in rural and metropolitan regions of South Australia participated. The first 79 patients formed the development group and the next 78 patients the validation group. A screening questionnaire was developed from factors identified from sleep surveys, demographic and anthropometric data to be predictive of moderate to severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the two-channel ApneaLink device against full polysomnography. The diagnostic accuracy of the overall two-stage model was then evaluated. Snoring, waist circumference, witnessed apnoeas and age were predictive of OSA and incorporated into a screening questionnaire (ROC area under curve (AUC) 0.84, 95% CI 0.75 to 0.94, p<0.001). ApneaLink oximetry with a 3% dip rate was highly predictive of OSA (AUC 0.96, 95% CI 0.91 to 1.0, p<0.001). The two-stage diagnostic model showed a sensitivity of 0.97 (95% CI 0.81 to 1.00) and specificity of 0.87 (95% CI 0.74 to 0.95) in the development group, and a sensitivity of 0.88 (95% CI 0.60 to 0.98) and specificity of 0.82 (95% CI 0.70 to 0.90) in the validation group. A two-stage model of screening questionnaire followed by home oximetry can accurately identify patients with OSA in primary care and has the potential to expedite care for patients with this common sleep disorder.


Defective ENaC processing and function in tissue kallikrein-deficient mice.
An inverse relationship exists between urinary tissue kallikrein (TK) excretion and blood pressure in humans and rodents. In the kidney TK is synthesized in large amounts in the connecting tubule and is mainly released into the urinary fluid where its function remains unknown. In the present study mice with no functional gene coding for TK (TK-/-) were used to test whether the enzyme regulates apically expressed sodium transporters. Semiquantitative immunoblotting of the renal cortex revealed an absence of the 70-kDa form of gamma-ENaC in TK-/- mice. Urinary Na+ excretion after amiloride injection was blunted in TK-/- mice, consistent with reduced renal ENaC activity. Amiloride-sensitive transepithelial potential difference in the colon, where TK is also expressed, was decreased in TK-/- mice, whereas amiloride-sensitive alveolar fluid clearance in the lung, where TK is not expressed, was unchanged. In mice lacking the B2 receptor for kinins, the abundance of the 70-kDa form of gamma-ENaC was increased, indicating that its absence in TK-/- mice is not kinin-mediated. Incubation of membrane proteins from renal cortex of TK-/- mice with TK resulted in the appearance of the 70-kDa band of the gamma-ENaC, indicating that TK was able to promote gamma-ENaC cleavage in vitro. Finally, in mouse cortical collecting ducts isolated and microperfused in vitro, the addition of TK in the luminal fluid increased significantly intracellular Na+ concentration, consistent with an activation of the luminal entry of the cation. The results demonstrate that TK, like several other proteases, can activate ENaC in the kidney and the colon.


Breast Infection: A Review of Diagnosis and Management Practices.
Mastitis is a common condition that predominates during the puerperium. Breast abscesses are less common, however when they do develop, delays in specialist referral may occur due to lack of clear protocols. In secondary care abscesses can be diagnosed by ultrasound scan and in the past the management has been dependent on the receiving surgeon. Management options include aspiration under local anesthetic or more invasive incision and drainage (I&D). Over recent years the availability of bedside/clinic based ultrasound scan has made diagnosis easier and minimally invasive procedures have become the cornerstone of breast abscess management. We review the diagnosis and management of breast infection in the primary and secondary care setting, highlighting the importance of early referral for severe infection/breast abscesses. As a clear guideline on the management of breast infection is lacking, this review provides useful guidance for those who rarely see breast infection to help avoid long-term morbidity.


Ecological impacts of water-based recreational activities on freshwater ecosystems: a global meta-analysis.
Human presence at water bodies can have a range of ecological impacts, creating trade-offs between recreation as an ecosystem service and conservation. Conservation policies could be improved by relying on robust knowledge about the relative ecological impacts of water-based recreation. We present the first global synthesis on recreation ecology in aquatic ecosystems, differentiating the ecological impacts of shore use, (shoreline) angling, swimming and boating. Impacts were assessed at three levels of biological organization (individuals, populations and communities) for several taxa. We screened over 13 000 articles and identified 94 suitable studies that met the inclusion criteria, providing 701 effect sizes. Impacts of boating and shore use resulted in consistently negative, significant ecological impacts across all levels of biological organization. The results were less consistent for angling and swimming. The strongest negative effects were observed in invertebrates and plants. Recreational impacts on birds were most pronounced at the individual level, but not significant at the community level. Due to publication bias and knowledge gaps, generalizations of the ecological impacts of aquatic recreation are challenging. Impacts depend less on the form of recreation. Thus, selectively constraining specific types of recreation may have little conservation value, as long as other forms of water-based recreation continue.


The development of emotion-related neural circuitry in health and psychopathology.
Disturbances in the detection of, response to, and interpretation of emotion are common in many forms of psychopathology. The amygdala, striatum, and structures within the prefrontal cortex are highly involved in mediating these stages of emotion processing, and evidence indicates that these regions show structural and functional alterations in different types of psychopathology, including anxiety, depression, and autism spectrum disorders. However, we do not know how genes and the environment interact to alter development of these brain regions in ways that give rise to emotion-related psychopathology. This review discusses the current understanding of brain regions that are involved in emotional functioning, how they develop, and how they are altered in three forms of psychopathology: anxiety, depression, and autism spectrum disorders. Following this, a framework is described that may facilitate the integration of investigations of genetic variation and brain function with symptom and diagnostic measures. The framework involves three components: (a) a greater emphasis on simultaneously analyzing multiple levels (genes, brain function, behavior, symptoms, and diagnoses); (b) further integration of developmental considerations, including timing of environmental events, adaptations (or maladaptations), and disorder-related trajectories that guide some children toward atypical experiences; and (c) greater cross-talk between animal and human investigations to take advantage of biological measures that cannot be acquired in humans.


Immediate rather than delayed memory impairment in older adults with latent toxoplasmosis.
The neurotropic parasite Toxoplasma gondii infects one third of the world population, but its effect on memory remains ambiguous. To examine a potential relationship of the infection with immediate and delayed memory, a population-based study was conducted in 4485 participants of the Third National Health and Nutrition Examination Survey aged 60years and older. Serum anti-Toxoplasma IgG antibodies were measured by enzyme immune assay and verbal memory was assessed using the Mini-Mental State Examination and the East Boston Memory Test. The prevalence of latent toxoplasmosis was 41%; in one way analysis of variance, anti-Toxoplasma IgG antibody levels significantly differed across tertiles for immediate (P=0.006) but not delayed memory scores (P=0.22). In multinomial logistic regression adjusting for covariates, Toxoplasma seropositivity was associated with lower immediate memory performance (OR: 0.65, 95% CI: 0.44, 0.97 for medium tertile and OR: 0.61, 95% CI: 0.37, 0.98 for highest tertile in reference to the lowest tertile), especially in non-Hispanic Whites (OR: 0.56, 95% CI: 0.36, 0.88 for medium tertile and OR: 0.51, 95% CI: 0.30, 0.87 for highest tertile in reference to the lowest tertile). However, no relationship with delayed memory was observed. In conclusion, latent toxoplasmosis is widespread in older adults and may primarily affect immediate rather than delayed memory, particularly in White Americans.


Interneuronal correlations at longer time scales predict decision signals for bistable structure-from-motion perception.
Perceptual decisions are thought to depend on the activation of task-relevant neurons, whose activity is often correlated in time. Here, we examined how the temporal structure of shared variability in neuronal firing relates to perceptual choices. We recorded stimulus-selective neurons from visual area V5/MT while two monkeys (Macaca mulatta) made perceptual decisions about the rotation direction of structure-from-motion cylinders. Interneuronal correlations for a perceptually ambiguous cylinder stimulus were significantly higher than those for unambiguous cylinders or for random 2D motion during passive viewing. Much of the difference arose from correlations at relatively long timescales (hundreds of milliseconds). Choice-related neural activity (quantified as choice probability; CP) for ambiguous cylinders was positively correlated with interneuronal correlations and was specifically associated with their long timescale component. Furthermore, the slope of the long timescale - but not the instantaneous - component of the correlation predicted higher CPs towards the end of the trial i.e. close to the decision. Our results suggest that the perceptual stability of structure-from-motion cylinders may be controlled by enhanced interneuronal correlations on longer timescales. We propose this as a potential signature of top-down influences onto V5/MT processing that shape and stabilize the appearance of 3D-motion percepts.


Duplications in ADHD patients harbour neurobehavioural genes that are co-expressed with genes associated with hyperactivity in the mouse.
Attention deficit/hyperactivity disorder (ADHD) is a childhood onset disorder, prevalent in 5.3% of children and 1-4% of adults. ADHD is highly heritable, with a burden of large (>500 Kb) copy number variants (CNVs) identified among individuals with ADHD. However, how such CNVs exert their effects is poorly understood. We examined the genes affected by 71 large, rare, and predominantly inherited CNVs identified among 902 individuals with ADHD. We applied both mouse-knockout functional enrichment analyses, exploiting behavioral phenotypes arising from the determined disruption of 1:1 mouse orthologues, and human brain-specific spatio-temporal expression data to uncover molecular pathways common among genes contributing to enriched phenotypes. Twenty-two percent of genes duplicated in individuals with ADHD that had mouse phenotypic information were associated with abnormal learning/memory/conditioning ("l/m/c") phenotypes. Although not observed in a second ADHD-cohort, we identified a similar enrichment among genes duplicated by eight de novo CNVs present in eight individuals with Hyperactivity and/or Short attention span ("Hyperactivity/SAS", the ontologically-derived phenotypic components of ADHD). In the brain, genes duplicated in patients with ADHD and Hyperactivity/SAS and whose orthologues' disruption yields l/m/c phenotypes in mouse ("candidate-genes"), were co-expressed with one another and with genes whose orthologues' mouse models exhibit hyperactivity. Moreover, genes associated with hyperactivity in the mouse were significantly more co-expressed with ADHD candidate-genes than with similarly identified genes from individuals with intellectual disability. Our findings support an etiology for ADHD distinct from intellectual disability, and mechanistically related to genes associated with hyperactivity phenotypes in other mammalian species.


Air Pollution and Preterm Birth: Do Air Pollution Changes over Time Influence Risk in Consecutive Pregnancies among Low-Risk Women?
Since the 2000s, air pollution has generally continued to decrease in the U.S. To investigate preterm birth (PTB) risk associated with air pollutants in two consecutive pregnancies, we estimated exposures using modified Community Multiscale Air Quality models linked to the NICHD Consecutive Pregnancy Study. Electronic medical records for delivery admissions were available for 50,005 women with singleton births in 20 Utah-based hospitals between 2002-2010. We categorized whole pregnancy average exposures as high (>75th percentile), moderate (25-75) and low (<25). Modified Poisson regression estimated second pregnancy PTB risk associated with persistent high and moderate exposure, and increasing or decreasing exposure, compared to persistent low exposure. Analyses were adjusted for prior PTB, interpregnancy interval and demographic and clinical characteristics. Second pregnancy PTB risk was increased when exposure stayed high for sulfur dioxide (32%), ozone (17%), nitrogen oxides (24%), nitrogen dioxide (43%), carbon monoxide (31%) and for particles < 10 microns (29%) versus consistently low exposure. PTB risk tended to increase to a lesser extent for repeated PTB (19-21%) than for women without a prior PTB (22-79%) when exposure increased or stayed high. Area-level changes in air pollution exposure appear to have important consequences in consecutive pregnancies with increasing exposure associated with higher risk.


Comparative effectiveness of upfront treatment strategies in elderly women with ovarian cancer.
Observational studies comparing neoadjuvant chemotherapy to primary surgery for advanced-stage ovarian cancer are limited by strong selection bias. Multiple methods were used to control for confounding and selection bias to estimate the effect of primary treatment on survival for ovarian cancer. The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify women ≥ 65 years of age with stage II-IV epithelial ovarian cancer who survived > 6 months from the date of diagnosis and received treatment from 1991 through 2007. Traditional regression analysis, propensity score-based analysis, and an instrumental variable analysis (IVA) using geographic location as an instrument were used to compare survival between neoadjuvant chemotherapy and primary surgery. A total of 9587 patients with stage II-IV ovarian cancer were identified. Use of primary surgery decreased from 63.2% in 1991 to 49.5% by 2007, whereas primary chemotherapy increased from 19.7% in 1991 to 31.8% in 2007 (P < .0001). In the observational cohort survival (hazard ratio [HR] = 1.27; 95% confidence interval [CI] = 1.19-1.35) was inferior for patients treated with neoadjuvant chemotherapy; both median survival (15.8 versus 28.8 months) and 2-year survival (36% versus 56%) were lower in the neoadjuvant chemotherapy group compared to those who underwent surgery. In the IVA, primary treatment had minimal effect on overall survival (HR = 1.04; 95% CI = 0.67-1.60). The median survival for patients with a value of the instrument less than the median (24.0 months, 95% CI = 23.0-25.0) and greater than or equal to median value of the IV (24.0 months, 95% CI = 23.0-26.0) were similar. Use of neoadjuvant therapy has increased over time. Survival with neoadjuvant chemotherapy did not differ significantly from primary surgery in elderly women in the United States.


The efficiency of Viscum album ssp. album and Hypericum perforatum on human immune cells in vitro.
Viscum album L. ssp. album and Hypericum perforatum L. are used for the treatment of different diseases. In this study, the effects of these herbals on immune cells were assessed in vitro. The phagocytosis, candidacidal activity of neutrophils and adhesion function of epithelial cells were investigated. Also, the expression of the surface markers of lymphocytes was analyzed by flow cytometry. It was observed that V. album ssp. album increased phagocytic activity and candidacidal activity of neutrophils and decreased adhesion function of epithelial cells. We also observed that in human peripheral blood mononuclear cells stimulated by Viscum album L. ssp. album the levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells, CD69 expressions in the activated T lymphocytes and CD3(-)CD16(+)CD56(+) NK cells increased compared to the cells that were not stimulated by this herbal. Whereas CD4(+)CD25(+), CD8(+)CD25(+) T cells, CD 69 expression and CD3(-)CD16(+)CD56(+) Natural killer cells did not show any significant differences with the presence of Hypericum perforatum L. compared to the control group. Hypericum perforatum L. increased candidacidal activity of neutrophils and decreased adhesion function of epithelial cells. In the light of these findings, it is considered that these extracts may be used as an adjuvant treatment option for immune activation in immunosuppressed patients.


The touchscreen operant platform for assessing executive function in rats and mice.
This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents. Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies.


Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure.
Background Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods and Results We enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra-abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH-related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH-specific therapy escalation) and all-cause mortality for 1-year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (P<0.0001) and was significantly associated with right heart and renal function, intra-abdominal pressure, and neurohormonal and hydration status. During follow-up, the morbidity/mortality end point occurred in 91 patients and was independently predicted by RVSI (RVSI in the third tertile versus referent: hazard ratio: 4.72 [95% CI, 2.10-10.59; P<0.0001]). Receiver operating characteristic curves suggested superiority of RVSI to individual intrarenal venous flow patterns in predicting outcome (areas under the curve: 0.789 and 0.761, respectively; P=0.038). Conclusions We propose RVSI as a conceptually new and integrative Doppler index of renal congestion. RVSI provides additional prognostic information to stratify PH for the propensity to develop right heart failure. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03039959.


[Effect of artificial NaCl and KCl gradients on the active transport of organic acids in energy-depleted proximal kidney tubules. I. The NaCl gradient].
The present work has been undertaken to obtain a direct evidence of the involvement of chemical gradient of Na+ in organic acid transport in the renal tubules. Superficial tubules of rat and turtle kidneys were depleted of Na and K during cold preincubation to be then incubated in the presence of ouabain under anoxic conditions at 30 degrees C. Uptake of an organic acid, fluorescein, was detected in proximal tubules of the essential surface of kidneys by means of contact microfluorometry. The creation of artificial gradient of NaCl (medium to cells) stimulated the uphill uptake of fluorescein in the tubules. The dissipation of Na gradient was accompanied with the efflux of fluorescein from tubules. The presence in the medium of harmaline, an inhibitor of Na-dependent transport systems, as well as the replacement of Cl- for SO2- or SCN- resulted in the disappearance of the stimulatory effect of Na gradient on the fluorescein transport. It is concluded that the fluorescein transfer across the baso-lateral membrane of tubular cells may be energized by Na chemical gradient, and this process significantly depends on the anionic environment.


Optical Communications Experiments at 6328 A and 10.6 micro.
Diagnostic optical communication experiments were performed comparing noncoherent and coherent detection techniques. Three different receiver-transmitter configurations with variable apertures were used during the experiments that were performed over a 1-km real atmospheric path. In every case, it was found that the coherent system fading, due to atmospheric turbulence, was considerably greater than the noncoherent system fading. This result shows the greater sensitivity of the coherent system to the time-varying wavefront breakup produced by atmospheric turbulence. A coherent homodyne experiment at 10.6 micro over a 2-km round-trip path was also performed. Its results indicated that a coherent system at 10.6 micro is less susceptible to atmospheric turbulence than a coherent system at 6328 A.


Antiarrhythmic effects of azimilide in paroxysmal supraventricular tachycardia: efficacy and dose-response.
Azimilide is a novel classification III antiarrhythmic agent that blocks both I(Kr)and I(Ks)and shows evidence of efficacy in patients with atrial fibrillation or flutter. Its effect on paroxysmal supraventricular tachycardia (PSVT) has not been reported. One hundred ninety-three patients with symptomatic PSVT were enrolled in 4 double-blind, randomized, placebo-controlled clinical trials with almost identical trial design (supraventricular arrhythmia-1 [SVA-1], SVA-2, SVA-3, and SVA-4), performed as a separate stratum of studies that also included a stratum of patients with atrial fibrillation or flutter. Patients received oral azimilide (100 mg in SVA-1 and SVA-3, 35 or 75 mg in SVA-2, and 125 mg in SVA-4) or matching placebo twice daily for 3 days (loading period), followed by once-daily dosing (maintenance period). The primary outcome variable was the first recording of a symptomatic supraventricular arrhythmia (either PSVT, atrial fibrillation, or atrial flutter) recorded on a transtelephonic electrocardiographic event recorder. The duration of study was 270 days in SVA-1 and SVA-2 and 180 days in SVA-3 and SVA-4. Combined analysis results of the PSVT stratum from the 4 studies showed a dose-response relationship in prolongation of time to recurrence (P =.02). In the combined 100-mg daily dose, the hazard ratio (placebo:azimilide) was 2.35 (P =.023). The hazard ratio for the 125-mg daily dose measured 1.28 (P = not significant). However, the time to recurrence was prolonged when the patients receiving 100 and 125 mg daily were combined and compared with placebo (P =.02). There were no deaths and 1 case of torsades de pointes. These trial results suggest a significant dose-related suppression of PSVT with azimilide, with a low risk of serious adverse events.


HIV Malaria Co-Infection Is Associated with Atypical Memory B Cell Expansion and a Reduced Antibody Response to a Broad Array of Plasmodium falciparum Antigens in Rwandan Adults.
HIV infected individuals in malaria endemic areas experience more frequent and severe malaria episodes compared to non HIV infected. This clinical observation has been linked to a deficiency in antibody responses to Plasmodium falciparum antigens; however, prior studies have only focused on the antibody response to <0.5% of P. falciparum proteins. To obtain a broader and less-biased view of the effect of HIV on antibody responses to malaria we compared antibody profiles of HIV positive (HIV+) and negative (HIV-) Rwandan adults with symptomatic malaria using a microarray containing 824 P. falciparum proteins. We also investigated the cellular basis of the antibody response in the two groups by analyzing B and T cell subsets by flow cytometry. Although HIV malaria co-infected individuals generated antibodies to a large number of P. falciparum antigens, including potential vaccine candidates, the breadth and magnitude of their response was reduced compared to HIV- individuals. HIV malaria co-infection was also associated with a higher percentage of atypical memory B cells (MBC) (CD19+CD10-CD21-CD27-) compared to malaria infection alone. Among HIV+ individuals the CD4+ T cell count and HIV viral load only partially explained variability in the breadth of P. falciparum-specific antibody responses. Taken together, these data indicate that HIV malaria co-infection is associated with an expansion of atypical MBCs and a diminished antibody response to a diverse array of P. falciparum antigens, thus offering mechanistic insight into the higher risk of malaria in HIV+ individuals.


High-resolution broadband (>100 cm-1) infrared heterodyne spectro-radiometry using an external cavity quantum cascade laser.
Broadband thermal infrared heterodyne spectro-radiometry using an external cavity quantum cascade laser as a tunable local oscillator has been performed over a frequency range of more than 100 cm(-1) at a central frequency of 1190 cm(-1). Heterodyne spectro-radiometry is demonstrated for two local oscillator tuning modes: broadband tuning for transmission and emission spectroscopy of broadband absorbers (Freon 12), and broadband frequency selection in combination with fine continuous frequency tuning for high-resolution (0.021 cm(-1)) transmission spectroscopy (N(2)O). In each case concentration retrievals are performed and analyzed. The spectroradiometer noise level is demonstrated to be twenty two and eight times the fundamental shot-noise limit in the two scanning modes respectively.


Single particle adsorbing transfer system.
Here we present a novel approach for horizontal transfer of single particles after laser microdissection. The developed technique is a single particle adsorbing system for highly selective and gentle horizontal transfer of microdissected fixed and living material. As mediated via low-pressure technology, the transfer process can be precisely controlled, thus facilitating horizontal particle transfer of any isolated material, e.g. tissue material, single cells or chromosomes, in addition to precise positioning for sample release. This collection method allows one to predefine target positions and enables material transfer without contamination to any planar microchip device. This contamination free transfer is indispensable for novel lab-on-a-chip systems performing nanoscale polymerase chain reaction analyses. Using virtual reaction chamber microdevices, small amounts of microdissected material--as little as one single cell--can be directly transmitted and immediately used for single cell analysis.


Prevention and repair of circulatory shock and cerebral ischemia/injury by various agents in experimental heatstroke.
The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4 degrees C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.


Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats.
Suberoylanilide hydroxamic acid (SAHA), or vorinostat, is a histone deacetylase inhibitor approved for use as chemotherapy for lymphoma in humans. The goal of this study was to establish pharmacological parameters of SAHA in cats. Our interest in treating cats with SAHA is twofold: as an anticancer chemotherapeutic and as antilatency therapy for feline retroviral infections. Relying solely on data from studies in other animals would be inappropriate as SAHA is partially metabolized by glucuronidation, which is absent in feline metabolism. SAHA was administered to cats intravenously (2 mg/kg) or orally (250 mg/m², ~17 mg/kg) in a cross-over study design. Clinically, SAHA was well tolerated at these dosages as no abnormalities were noted following administration. The pharmacokinetics of SAHA in cats was found to be similar to that of dogs, but the overall serum drug exposure was much less than that of humans at an equivalent dose. The pharmacodynamic effect of an increase in acetylated histone proteins in blood was detected after both routes of administration. An increased oral dose of 60 mg SAHA/kg administered to one animal resulted in a surprisingly modest increase in peak drug concentration, suggesting possible saturation of absorption kinetics. This study provides a foundation for future studies of the clinical efficacy of SAHA in treating feline disease.


Frequency-Dependent Representation of Reinforcement-Related Information in the Human Medial and Lateral Prefrontal Cortex.
The feedback-related negativity (FRN) is a commonly observed potential in scalp electroencephalography (EEG) studies related to the valence of feedback about a subject's performance. This potential classically manifests as a negative deflection in medial frontocentral EEG contacts following negative feedback. Recent work has shown prominence of theta power in the spectral composition of the FRN, placing it within the larger class of "frontal midline theta" cognitive control signals. Although the dorsal anterior cingulate cortex (dACC) is thought to be the cortical generator of the FRN, conclusive data regarding its origin and propagation are lacking. Here we examine intracranial electrophysiology from the human medial and lateral prefrontal cortex (PFC) to better understand the anatomical localization and communication patterns of the FRN. We show that the FRN is evident in both low- and high-frequency local field potentials (LFPs) recorded on electrocorticography. The FRN is larger in medial compared with lateral PFC, and coupling between theta band phase and high-frequency LFP power is also greater in medial PFC. Using Granger causality and conditional mutual information analyses, we provide evidence that feedback-related information propagates from medial to lateral PFC, and that this information transfer oscillates with theta-range periodicity. These results provide evidence for the dACC as the cortical source of the FRN, provide insight into the local computation of frontal midline theta, and have implications for reinforcement learning models of cognitive control.


Genome BLAST distance phylogenies inferred from whole plastid and whole mitochondrion genome sequences.
Phylogenetic methods which do not rely on multiple sequence alignments are important tools in inferring trees directly from completely sequenced genomes. Here, we extend the recently described Genome BLAST Distance Phylogeny (GBDP) strategy to compute phylogenetic trees from all completely sequenced plastid genomes currently available and from a selection of mitochondrial genomes representing the major eukaryotic lineages. BLASTN, TBLASTX, or combinations of both are used to locate high-scoring segment pairs (HSPs) between two sequences from which pairwise similarities and distances are computed in different ways resulting in a total of 96 GBDP variants. The suitability of these distance formulae for phylogeny reconstruction is directly estimated by computing a recently described measure of "treelikeness", the so-called delta value, from the respective distance matrices. Additionally, we compare the trees inferred from these matrices using UPGMA, NJ, BIONJ, FastME, or STC, respectively, with the NCBI taxonomy tree of the taxa under study. Our results indicate that, at this taxonomic level, plastid genomes are much more valuable for inferring phylogenies than are mitochondrial genomes, and that distances based on breakpoints are of little use. Distances based on the proportion of "matched" HSP length to average genome length were best for tree estimation. Additionally we found that using TBLASTX instead of BLASTN and, particularly, combining TBLASTX and BLASTN leads to a small but significant increase in accuracy. Other factors do not significantly affect the phylogenetic outcome. The BIONJ algorithm results in phylogenies most in accordance with the current NCBI taxonomy, with NJ and FastME performing insignificantly worse, and STC performing as well if applied to high quality distance matrices. delta values are found to be a reliable predictor of phylogenetic accuracy. Using the most treelike distance matrices, as judged by their delta values, distance methods are able to recover all major plant lineages, and are more in accordance with Apicomplexa organelles being derived from "green" plastids than from plastids of the "red" type. GBDP-like methods can be used to reliably infer phylogenies from different kinds of genomic data. A framework is established to further develop and improve such methods. delta values are a topology-independent tool of general use for the development and assessment of distance methods for phylogenetic inference.


A numerical simulation of the flow in a T-type bifurcation and its application to an "end to side" fistula.
Some recent surgical procedures such as arteriovenous fistula, or coronary and cerebral by-passes were observed to yield counterdirectional branching blood flows. There is a lack of knowledge about the role of the counterdirectional flow ratio, the angle of anastomosis and the shear stresses in the process of thrombogenesis that leads to shunt occlusion. The program developed to simulate these hemodynamic conditions uses an efficient numerical scheme for the solution of the 2-D Navier-Stokes equations and can be easily adapted to flows in other geometrical configurations.


Chimpanzee (Pan troglodytes) and orangutan (Pongo abelii) forethought: self-control and pre-experience in the face of future tool use.
Planning for future needs has traditionally been considered to be restricted to human cognition. Although recent studies on great ape and corvid cognition challenge this belief, the phylogenesis of human planning remains largely unknown. The complex skill for future planning has not yet been satisfactorily established in any other extant primate species than our own. In humans, planning for future needs rely heavily on two overarching capacities, both of which lie at the heart of our cognition: self-control, often defined as the suppression of immediate drives in favor of delayed rewards, and mental time travel, which could be described as a detached mental experience of a past or future event. Future planning is linked to additional high complexity cognition such as metacognition and a consciousness usually not attributed to animals. In a series of four experiments based on tool use, we demonstrate that chimpanzees (Pan troglodytes) and orangutans (Pongo abelii) override immediate drives in favor of future needs, and they do not merely rely on associative learning or semantic prospection when confronted with a planning task. These results suggest that great apes engage in planning for the future by out competing current drives and mentally pre-experiencing an upcoming event. This suggests that the advanced mental capacities utilized in human future planning are shared by phylogenetically more ancient species than previously believed.


Reloadable multidrug capturing delivery system for targeted ischemic disease treatment.
Human clinical trials of protein therapy for ischemic diseases have shown disappointing outcomes so far, mainly because of the poor circulatory half-life of growth factors in circulation and their low uptake and retention by the targeted injury site. The attachment of polyethylene glycol (PEG) extends the circulatory half-lives of protein drugs but reduces their extravasation and retention at the target site. To address this issue, we have developed a drug capture system using a mixture of hyaluronic acid (HA) hydrogel and anti-PEG immunoglobulin M antibodies, which, when injected at a target body site, can capture and retain a variety of systemically injected PEGylated therapeutics at that site. Furthermore, repeated systemic injections permit "reloading" of the capture depot, allowing the use of complex multistage therapies. This study demonstrates this capture system in both murine and porcine models of critical limb ischemia. The results show that the reloadable HA/anti-PEG system has the potential to be clinically applied to patients with ischemic diseases, who require sequential administration of protein drugs for optimal outcomes.


Collett's snake (Pseudechis colletti) envenoming in snake handlers.
Collett's snake (Pseudechis colletti) is a member of the black snake genus and occurs in a warm temperate to sub-tropical region of central Queensland, Australia. There are no reports of bites occurring in the wild, and bites were previously thought to cause only minor effects. They are a popular snake among zoos and exotic snake keepers. To investigate the clinical effects of severe envenoming by Collett's snake, and possible treatment options. Case series. Clinical and laboratory features are described for six bites, all in snake handlers. All six bites were from captive snakes, resulting in severe envenoming in four. Two patients were treated early with black snake antivenom, and only developed an anticoagulant coagulopathy and mild myolysis. Two developed anticoagulant coagulopathy and severe rhabdomyolysis associated with acute renal failure, requiring haemodialysis; both received antivenom >10 h after the bite, and initially received minimal fluid replacement. Other effects included thrombocytopenia, non-immune haemolytic anaemia and a marked leukocytosis. Collett's snake envenoming is characterized by early generalized systemic effects (nausea, vomiting, abdominal pain, diarrhoea and headache) and an anticoagulant coagulopathy, followed in some cases by rhabdomyolysis and acute renal failure in untreated patients within 24 h. Early initiation of fluid therapy and treatment with black snake antivenom should be undertaken in all envenomed patients.


A phosphatidylinositol/phosphatidylcholine transfer protein is required for differentiation of the dimorphic yeast Yarrowia lipolytica from the yeast to the mycelial form.
The SEC14SC gene encodes the phosphatidylinositol/phosphatidylcholine transfer protein (PI/PC-TP) of Saccharomyces cerevisiae. The SEC14SC gene product (SEC14pSC) is associated with the Golgi complex as a peripheral membrane protein and plays an essential role in stimulating Golgi secretory function. We report the characterization of SEC14YL, the structural gene for the PI/PC-TP of the dimorphic yeast Yarrowia lipolytica. SEC14YL encodes a primary translation product (SEC14YL) that is predicted to be a 497-residue polypeptide of which the amino-terminal 300 residues are highly homologous to the entire SEC14pSC, and the carboxyl-terminal 197 residues define a dispensible domain that is not homologous to any known protein. In a manner analogous to the case for SEC14pSC, SEC14pYL localizes to punctate cytoplasmic structures in Y. lipolytica that likely represent Golgi bodies. However, SEC14pYL is neither required for the viability of Y. lipolytica nor is it required for secretory pathway function in this organism. This nonessentiality of SEC14pYL for growth and secretion is probably not the consequence of a second PI/PC-TP activity in Y. lipolytica as cell-free lysates prepared from delta sec14YL strains are devoid of measurable PI/PC-TP activity in vitro. Phenotypic analyses demonstrate that SEC14pYL dysfunction results in the inability of Y. lipolytica to undergo the characteristic dimorphic transition from the yeast to the mycelial form that typifies this species. Rather, delta sec14YL mutants form aberrant pseudomycelial structures as cells enter stationary growth phase. The collective data indicate a role for SEC14pYL in promoting the differentiation of Y. lipolytica cells from yeast to mycelia, and demonstrate that PI/PC-TP function is utilized in diverse ways by different organisms.


Considering sampling bias in close-kin mark-recapture abundance estimates of Atlantic salmon.
Genetic methods for the estimation of population size can be powerful alternatives to conventional methods. Close-kin mark-recapture (CKMR) is based on the principles of conventional mark-recapture, but instead of being physically marked, individuals are marked through their close kin. The aim of this study was to evaluate the potential of CKMR for the estimation of spawner abundance in Atlantic salmon and how age, sex, spatial, and temporal sampling bias may affect CKMR estimates. Spawner abundance in a wild population was estimated from genetic samples of adults returning in 2018 and of their potential offspring collected in 2019. Adult samples were obtained in two ways. First, adults were sampled and released alive in the breeding habitat during spawning surveys. Second, genetic samples were collected from out-migrating smolts PIT-tagged in 2017 and registered when returning as adults in 2018. CKMR estimates based on adult samples collected during spawning surveys were somewhat higher than conventional counts. Uncertainty was small (CV < 0.15), due to the detection of a high number of parent-offspring pairs. Sampling of adults was age- and size-biased and correction for those biases resulted in moderate changes in the CKMR estimate. Juvenile dispersal was limited, but spatially balanced sampling of adults rendered CKMR estimates robust to spatially biased sampling of juveniles. CKMR estimates based on returning PIT-tagged adults were approximately twice as high as estimates based on samples collected during spawning surveys. We suggest that estimates based on PIT-tagged fish reflect the total abundance of adults entering the river, while estimates based on samples collected during spawning surveys reflect the abundance of adults present in the breeding habitat at the time of spawning. Our study showed that CKMR can be used to estimate spawner abundance in Atlantic salmon, with a moderate sampling effort, but a carefully designed sampling regime is required.


Characterization of bovine kappa-casein fractions and the kinetics of chymosin-induced macropeptide release from carbohydrate-free and carbohydrate-containing fractions determined by high-performance gel-permeation chromatography.
Bovine kappa-casein was fractionated at pH 8.0 on DEAE-Sepharose with an NaCl gradient, followed by DEAE-cellulose chromatography using a decreasing pH gradient from pH 6.0 to 4.5. At least ten components could be identified, each differing in N-acetylneuraminic acid (NeuAc) and/or phosphorus content. Two components appeared to be multiply-phosphorylated, but did not contain NeuAc. The possible significance of this finding in relation to the mode of phosphorylation and glycosylation in vivo is discussed. A carbohydrate-free fraction as well as two NeuAc-containing fractions were compared in their substrate behaviour towards the action of the milk-clotting enzyme chymosin at pH 6.6 and 30 degrees C. To this end the trichloroacetic acid-soluble reaction products were analysed by high-performance gel-permeation chromatography. In order of increasing carbohydrate content the kcat. values found ranged from 40 to 25 s-1 and the Km values from 9 to 3 microM; the overall substrate properties of these components as reflected by the kinetic parameter kcat./Km ranged from 5 to 8 microM-1 X S-1. Irreversible polymerization of the carbohydrate-free fraction brought about a more-than-2-fold increase in Km, the kcat. value remaining virtually constant. The kcat./Km found for the cleavage of whole kappa-casein at pH 6.6 was of the same magnitude as the kcat./Km found for the polymerized carbohydrate-free fraction (i.e. about 3 microM-1 X S-1). No indication of substrate inhibition was found for the carbohydrate-free fraction.


The journey of positioning self as both mental health nurse and qualitative researcher: a critical reflection.
This paper discusses the development of a mental health nurse clinician to a mental health nurse researcher. Understanding the theoretical and professional drives that shape mental health nurses clinical practice and how that links to becoming a researcher is discussed. Mental health nurses who conduct research have to often move between their clinical roles and that of the researcher, doing this safely using a reflective supervision approach enables the nurse to conduct the research from a stronger professional and ethical standpoint. The intention of the paper is to encourage mental health nurses to engage in research and development. Shifting between the positions of a mental health nurse clinician and a qualitative researcher has some parallels to the processes in the nurse-service user relationship. This paper addresses this development from practitioner to researcher in one mental health nurse's journey through a PhD study using constructivist grounded theory. The paper examines theoretical and professional drives that have shaped my clinical practice and the role of the researcher in constructivist grounded theory, the notion of the researcher shifting between insider and outsider status, and the importance of reflexivity in conducting research. These influences will be discussed in the context of the development of a constructivist grounded theory study of the delivery of health care to service users with a mental illness in general hospital wards.


A limited and useful approach to determine proximal periodontal health.
Previous researchers have shown that there exists an interaction between gingival blood flow and gingival health. The purpose of this study was to compare the papillary blood flow at sites treated by a bridge with the blood flow at untreated sites. Twenty persons with resin-bonded fixed partial dentures were included in the study. The contralateral natural teeth of the site symmetrical to that of the restorations were used as controls. Blood flow was measured from the middle point of the papillae from both test and control sites by Laser Doppler Flowmetry (LDF). The plaque index, papillary bleeding index and probing depth measurements were recorded. There was a statistically significant difference between the test and control sites in papillary blood flow measurements and clinical indices (p < 0.05). Moreover there was statistical significance between gingival blood flow measurements and papillary bleeding index in the experimental group (p < 0.05). In short, there exists an important relationship between resin-bonded fixed partial dentures and papillary blood flow. Although there were no correlations between LDF values and clinical parameters, it can be emphasized, within the limits of the study, that LDF readings have limited diagnostic value, at least when it comes to clinical performance of fixed prosthesis.


Aerial exposure to the bacterial volatile compound trimethylamine modifies antibiotic resistance of physically separated bacteria by raising culture medium pH.
Bacteria release a wide diversity of small bioactive molecules that often correspond to secondary metabolites. Among them, volatile molecules produced under various growth conditions were shown to mediate cross-kingdom interactions with plants, nematodes, and fungi. Although the role of volatile compounds in bacterial biology is not well understood, recent reports indicated that they could play a role in airborne interactions between bacteria and influence antibiotic resistance, biofilm formation, and virulence. In this study, we investigated long-distance effects of 14 previously described Escherichia coli volatile compounds upon the bacteria E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis. We show that several of these molecules constitute chemical cues influencing growth, adhesion, and motility in exposed bacteria. Moreover, we show that aerial exposure to trimethylamine (TMA), a volatile compound produced in animal intestines and tissues upon biogenic reduction of trimethylamine oxide (TMAO), modifies the antibiotic resistance profiles of all tested Gram-positive and Gram-negative bacteria. We demonstrate that the TMA mode of action is distinct from that previously described for ammonia and results from nonspecific transient alteration of antibiotic uptake due to pH increase in the environment of bacteria aerially exposed to TMA. Our study therefore presents a new way by which volatile compounds can affect community behavior and structure in physically separated bacteria. It further demonstrates that bacterial gases and volatile compounds mediate chemical interactions, triggering functional responses that play an important role in the development of bacterial communities. Bacteria release many different volatile compounds during food transformation and fermentation. Here we sought to investigate the role of several bacterial volatile molecules released by Escherichia coli during long-distance airborne interactions with other bacteria. While several tested volatiles affect bacterial motility and surface adhesion, we show that aerial exposure to trimethylamine, a molecule produced by E. coli and many other Gram-negative bacteria in animal intestines and infected tissues, also modulates antibiotic resistance in all tested bacteria. We demonstrate that exposure to trimethylamine increases the pH of the growth medium of exposed bacteria, resulting in modifications in antibiotic uptake and transient alteration of antibiotic resistance. Our study therefore presents a new mechanism by which volatile compounds can affect community behavior and structure in physically separated bacteria, and it illustrates how airborne chemical interactions between bacteria contribute to the development of bacterial communities.


Could targeting immunometabolism be a way to control the burden of COVID-19 infection?
This review portrays the metabolic consequences of Covid-19 infection at different stages of the clinical syndrome. It also describes how events can change when patients with metabolic problems are infected and the effects that diet and nutrition might play to influence the outcome of infection. We also discuss the types of maneuvers that could be used to reshape metabolic events and question if this approach could be a practical therapy used alone or in combination with other approaches to reduce the burden of Covid-19 infection.


Pulse exposure of haematopoietic grafts to prostaglandin E2 in vitro facilitates engraftment and recovery.
The aim of this study was to evaluate the effects of prostaglandin E(2) (PGE(2) ) on haematopoietic stem cell (HSC) function and determine its mechanism of action. HSC were exposed to PGE(2) for 2 h and effects on their homing, engraftment and self-renewal evaluated in vivo. Effects of PGE(2) on HSC cell cycle, CXCR4 expression and migration to SDF-1α were analysed in vitro. Apoptosis was evaluated by examination of survivin expression and active caspase-3 levels. Equivalent haematopoietic reconstitution was demonstrated using 4-fold fewer PGE(2) -treated cells compared to controls. Multilineage reconstitution was stable on secondary transplantation, indicating that PGE(2) affects long-term repopulating HSC (LT-HSC) and that enhanced chimaerism of PGE(2) -pulsed cells results from their initial treatment. PGE(2) increased CXCR4 expression on mouse and human HSC, increased their migration to SDF-1αin vitro and enhanced in vivo marrow homing 2-fold, which was blocked by a CXCR4 receptor antagonist. PGE(2) pulse exposure reduced apoptosis of mouse and human HSC, with increase in endogenous caspase inhibitor survivin, and concomitant decrease in active caspase-3. Two-fold more HSC entered the cell cycle and proliferated within 24 h after PGE(2) pulse exposure. These studies demonstrate that short-term PGE(2) exposure enhances HSC function and supports the concept of utility of PGE(2) as an ex vivo strategy to improve function of haematopoietic grafts, particularly those where HSC numbers are limited.


Mobile phone technology in the management of asthma.
Peak flow monitoring is widely recommended as part of a self-management plan for asthma. We conducted an observational study using electronic peak flow monitoring and mobile phone technology in a UK general practice population over a nine-month period. Patients between 12 and 55 years of age who required treatment with regular inhaled steroids and (as needed) bronchodilators were recruited from nine general practices. Patients were included if their asthma was considered stable (i.e. no exacerbation in the previous three months). No therapeutic intervention was proposed. The primary outcome measure was compliance. In all, 69% of the 46 participants who filled in the post-study questionnaire were 'satisfied' or 'very satisfied' by the study, citing the ease of use and the increased autonomy and understanding of asthma as the main advantages. In total, 74% indicated that the system had helped to improve their ability to manage their symptoms. The most positive features of the telemedicine system were described as follows: increased awareness and information about asthma, improved ability to monitor/manage the condition with the feedback screens on the mobile phone and ease of use.


Depression, healthcare utilization, and comorbid psychiatric disorders after spinal cord injury.
Depression is often comorbid with other psychiatric conditions in the general population, with resultant impact on severity of conditions and healthcare utilization. It is unclear to what degree this is also true among persons with spinal cord injury (SCI). This study examined rates at which psychiatric conditions were comorbid with depression after SCI, and the association between a depression diagnosis and healthcare and pharmaceutical drug use. Retrospective analysis of data (N = 41 213) abstracted from Veterans Health Administration administrative databases between fiscal years (FYs) 1997 and 2007 to examine overall rates of depression. Administrative data from FY 2007 was used to examine rates of psychiatric disorders comorbid with depression, and to compare veterans with SCI and depression to veterans with SCI but no depression on healthcare and pharmaceutical use. Twenty-eight percent (n = 11 506) of 41 213 veterans who received SCI care between FY 1997 and FY 2007 were diagnosed with depressive disorders. Among the veterans with SCI and depression diagnoses in 2007 (n = 2615), 70% were also diagnosed with another psychiatric illness, with posttraumatic stress disorder and other anxiety disorders being the most common. Veterans with SCI and depression had more healthcare visits and received more pharmaceutical prescriptions than their counterparts without depression. Persons with SCI and depression are likely to experience comorbid psychiatric illnesses, with associated increased healthcare visits and medication use. Research and theory on depression after SCI should develop toward describing and addressing psychiatric and medical co-morbidities that are normative in this population.


Acute glucose elevation is highly predictive of infection and outcome in critically injured trauma patients.
To evaluate whether acute glucose elevation (AGE) is predictive of infection and outcome in critically injured trauma patients during the first 14 days of ICU admission. A prospective study was conducted on 2200 patients admitted to the ICU over a 2 1/2 year period. The diagnosis of infection was made via a multidisciplinary fashion utilizing CDC criteria. After early glucose stabilization occurred (no significant change for 48 hours after admission) monitoring for AGE was performed utilizing a computational and graded algorithmic model. Iatrogenic causes of AGE were excluded. Stepwise regression models were performed controlling for age, gender, mechanism of injury, diabetes, injury severity, and APACHE 2 score. ROC curves were used to evaluate the positive predictive value of the test. Seventy-seven percent of the patients in the cohort were males, and were admitted for blunt injuries (n = 1870 or 85%). The mean age, Injury Severity Score, and APACHE score were 44 ± 20 years, 29 ± 13, and 13 ± 7, respectively. The mean admission serum glucose value was 141 ± 36 mg/dL (range, 64-418 mg/dL). A total of 616 (28%) patients were diagnosed with an infection during the first 14 days of admission. AGE had a 91% positive predictive value for infection diagnosis. In addition, AGE was associated with a significant increase in ventilator, ICU, and hospital days as well as mortality even when adjusted for age, injury severity, APACHE score, and diabetes (P < 0.001). AGE is a highly accurate predictor of infection and should stimulate clinicians to identify a new source of infection.


Optic neuropathy diagnosis in the emergency room - retrospective observational study of the last 18 years.
Optic neuropathies (ON), a broad spectrum of disorders of the optic nerve, are a frequent cause of visual loss, presenting either in isolation or associated to neurological or systemic disorders. They are often first evaluated in the Emergency Room (ER) and a rapid determination of the etiology is imperative for implementing timely and appropriate treatment. We aim to describe ER demographic data and clinical characteristics, as well as the performed imaging exams, of patients subsequently hospitalized and diagnosed with ON. Furthermore, we seek to explore the accuracy of ER discharge diagnosis and evaluate possible predictive factors that may influence it. We retrospectively reviewed the medical records of 192 patients admitted to the ward of the Neurology Department of Centro Hospitalar Universitário São João (CHUSJ), with a discharge diagnosis of ON. Subsequently, we selected those admitted from the ER, with clinical, laboratory and imaging data, between January 2004 and December 2021. We included 171 patients. All participants were discharged from the ER and admitted in the ward with a main diagnostic suspicion of ON. Patients were stratified according to suspected etiology at the time of discharge: 99 inflammatory (57.9%), 38 ischemic (22.2%), 27 unspecified (15.8%) and 7 other (4.1%). By comparing with current follow-up diagnosis, 125 patients had an accurate ER diagnosis category (73.1%), 27 had an ON diagnosis of unspecified etiology that was defined only during follow-up (15.8%) and 19 had an inaccurate diagnosis category (11.1%). Diagnostic change was more common with ER ischemic diagnosis (21.1%) compared to inflammatory diagnosis (8.1%) (p = 0.034). Our study reveals that most patients with ON can be accurately diagnosed in the ER through clinical history neurological and ophthalmological evaluation.


Similarities in transcription factor IIIC subunits that bind to the posterior regions of internal promoters for RNA polymerase III.
In eukaryotes, RNA polymerase III (RNAP III) transcribes the genes for small RNAs like tRNAs, 5S rRNA, and several viral RNAs, and short interspersed repetitive elements (SINEs). The genes for these RNAs and SINEs have internal promoters that consist of two regions. These two regions are called the A and B blocks. The multisubunit transcription factor TFIIIC is required for transcription initiation of RNAP III; in transcription of tRNAs, the B-block binding subunit of TFIIIC recognizes a promoter. Although internal promoter sequences are conserved in eukaryotes, no evidence of homology between the B-block binding subunits of vertebrates and yeasts has been reported previously. Here, I reported the results of PSI-BLAST searches using the B-block binding subunits of human and Shizosacchromyces pombe as queries, showing that the same Arabidopsis proteins were hit with low E-values in both searches. Comparison of the convergent iterative alignments obtained by these PSI-BLAST searches revealed that the vertebrate, yeast, and Arabidopsis proteins have similarities in their N-terminal one-third regions. In these regions, there were three domains with conserved sequence similarities, one located in the N-terminal end region. The N-terminal end region of the B-block binding subunit of Saccharomyces cerevisiae is tentatively identified as a HMG box, which is the DNA binding motif. Although I compared the alignment of the N-terminal end regions of the B-block binding subunits, and their homologs, with that of the HMG boxes, it is not clear whether they are related. Molecular phylogenetic analyses using the small subunit rRNA and ubiquitous proteins like actin and alpha-tubulin, show that fungi are more closely related to animals than either is to plants. Interestingly, the results obtained in this study show that, with respect to the B-block binding subunits of TFIIICs, animals appear to be evolutionarily closer to plants than to fungi.


Breast cancer risk assessments comparing Gail and CARE models in African-American women.
The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African-American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African-American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5-year breast cancer risk was 0.88% (Range: 0.18-6.60%) for the Gail model and 1.29% (Range: 0.20-4.50%) for the CARE model. Using the usual cutoff-point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar's test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African-Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African-Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk.


Early packed red blood cell transfusion and acute respiratory distress syndrome after trauma.
Transfusion of packed red blood cells (PRBCs) is a risk factor for acute respiratory distress syndrome (ARDS) in trauma patients. Yet, there is a paucity of information regarding the risk of ARDS with incremental PRBCs exposure. For this retrospective analysis, eligible patients from National Study on Costs and Outcomes of Trauma were included. Our main exposure was defined as units of PRBCs transfused during the first 24 h after admission. The main outcome was ARDS. A total of 521 (4.6%) of 14070 patients developed ARDS, and 331 patients (63.5%) who developed ARDS received PRBCs transfusion. Injury severity, thoracic injury, polytrauma, and pneumonia receiving more than 5 units of fresh frozen plasma and 6-10 units of PRBCs were independent predictors of ARDS. Patients receiving more than 5 units of PRBCs had higher risk of developing ARDS (patients who received 6-10 units: adjusted odds ratio 2.5, 95% CI 1.12-5.3; patients who received more than 10 units: odds ratio 2.6, 95% CI 1.1-6.4). Each additional unit of PRBCs transfused conferred a 6% higher risk of ARDS (adjusted odds ratio 1.06; 95% CI 1.03-1.10). Early transfusion of PRBCs is an independent predictor of ARDS in adult trauma patients. Conservative transfusion strategies that decrease PRBC exposure by even 1 unit may be warranted to reduce the risk of ARDS in injured patients.


Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. Ultragenyx Pharmaceutical and Kyowa Kirin International.


Quality of care for coronary heart disease in two countries.
Coronary heart disease is the leading cause of death in the United States and England, and each country devotes substantial resources to its prevention and treatment. We review recent strategies for improving quality of care for coronary heart disease in each country, including clinical guidelines; national standards; performance reports; benchmarking, feedback, and professional leadership; and market-oriented approaches. These strategies highlight the importance of information systems, organizational culture, and incentives to improve the quality of care in both the decentralized health care system of the United States and England's more centralized system.


Accelerated telomere shortening and telomere abnormalities in radiosensitive cell lines.
We examined telomere maintenance in cells of 11 primary fibroblast cell lines with differing genetic defects that confer sensitivity to ionizing radiation. These included cell lines derived from patients with ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, defective Artemis, DNA ligase I and DNA ligase IV, an immunodeficient patient with a defect in DNA double-strand break repair, and a patient diagnosed with xeroderma pigmentosum who, in addition, showed severe clinical sensitivity to ionizing radiation. Our results, based on Southern blot, flow-FISH and Q-FISH (quantitative FISH) measurements, revealed an accelerated rate of telomere shortening in most cell lines derived from the above patients compared to cell lines from normal individuals or a cell line isolated from a heterozygotic parent of one radiosensitive patient. This accelerated telomere shortening was accompanied by the formation of chromatin bridges in anaphase cells, indicative of the early loss of telomere capping function and in some cases low levels of chromosome abnormalities in metaphase cells. We also analyzed telomere maintenance in mouse embryonic stem cells deficient in Brca1, another defect that confers radiosensitivity. Similarly, these cells showed accelerated telomere shortening and mild telomere dysfunction in comparison to control cells. Our results suggest that mechanisms that confer sensitivity to ionizing radiation may be linked with mechanisms that cause telomere dysfunction.


Multiple conformational states of proteins: a molecular dynamics analysis of myoglobin.
A molecular dynamics simulation of myoglobin provides the first direct demonstration that the potential energy surface of a protein is characterized by a large number of thermally accessible minima in the neighborhood of the native structure (for example, approximately 2000 minima were sampled in a 300-picosecond trajectory). This is expected to have important consequences for the interpretation of the activity of transport proteins and enzymes. Different minima correspond to changes in the relative orientation of the helices coupled with side-chain rearrangements that preserve the close packing of the protein interior. The conformational space sampled by the simulation is similar to that found in the evolutionary development of the globins. Glasslike behavior is expected at low temperatures. The minima obtained from the trajectory do not satisfy certain criteria for ultrametricity.


Beta-Cell Fragility As a Common Underlying Risk Factor in Type 1 and Type 2 Diabetes.
Type 1 and type 2 diabetes are distinct clinical entities primarily driven by autoimmunity and metabolic dysfunction, respectively. However, there is a growing appreciation that they may share an etiopathological factor, namely the role of variation in beta-cell sensitivity to stress factors. Increased sensitivity increases the risk of beta-cell death or insulin secretion dysfunction. The beta-cell fragility model proposes that this variation contributes to the risk of developing either type 1 or type 2 diabetes, in the presence of immunological and/or metabolic stress factors. Therapeutics that increase the resistance of beta cells to these factors and decreasing fragility may constitute a new class of anti-diabetogenics, with potential use across both diseases.


Isotretinoin Monitoring Trends: A National Survey of Dermatologists.

BACKGROUND: Isotretinoin is an effective treatment for nodulocystic acne. Outside of required pregnancy testing, laboratory monitoring suggested by the manufacturers is vague. Dermatologists, therefore, monitor a variety of tests with variable frequency. Despite intense monitoring, the majority of patients do not have gross laboratory abnormalities that warrant changes in management.

OBJECTIVE: To survey US dermatologists regarding laboratory monitoring practices while prescribing isotretinoin.

METHODS: An online survey sent via e-mail to members of the American Academy of Dermatology.

RESULTS: 12,396 surveys were sent with a response rate of ~19%. At baseline >60% of responders check a CBC, LFTs, and a lipid panel. 74% check a monthly lipid panel and LFTs, while 57% check a monthly CBC. 75% report stopping isotretinoin when AST or ALT values reach 3 times normal; 89% report stopping at 4 times normal. When triglycerides reach 4 times normal, 72% stop the medication.

CONCLUSIONS: There is no consensus on isotretinoin monitoring tests and frequency, though the majority of dermatologists surveyed monitor a lipid panel and LFTs.

J Drugs Dermatol. 2017;16(6):557-564.
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Development of a catadioptric endoscope objective with forward and side views.
Autofluorescence endoscopy is a promising functional imaging technique to improve screening of pre-cancerous or early cancer lesions in the gastrointestinal (GI) tract. Tissue autofluorescence signal is weak compared to white light reflectance imaging. Conventional forward-viewing endoscopes are inefficient in the collection of light from objects of interest along on the GI luminal wall. A key component of a complete autofluorescence endoscope is the light collection module. In this paper, we report the design, optimization, prototype development, and testing of an endoscope objective that is capable of acquiring simultaneous forward and radial views. The radial-view optical design was optimized for a balance between image quality and light collection. Modulation transfer function (MTF), entrance pupil radius, manufacturability, and field-of-view were parameters used in the lens optimization. In comparison with the typical forward-viewing endoscopes, our nonsequential ray trace simulations suggest the proposed radial-view design is more practical in the light collection. To validate the proposed simulation methods, a 3:1 scaled-up prototype was fabricated. Contrast measurements were taken with the prototype, and then compared with the simulated MTF.


Severity in Plasmodium vivax malaria claiming global vigilance and exploration--a tertiary care centre-based cohort study.
Mounting reports on severe Plasmodium vivax malaria from across the globe have raised concerns among the scientific community. However, the risk of P. vivax resulting in complicated malaria and mortality is not as firmly established as it is with Plasmodium falciparum. This study was conducted to determine the severity proportion and factors associated with severity in cases of vivax and falciparum malaria. Adult patients microscopically diagnosed to have P. vivax/P. falciparum infections from the year 2007-2011 were evaluated based on their hospital records. Severe malaria was defined as per the World Health Organization's guidelines. Comparison was made across species and binary logistic regression was used to determine risk factors of severity. Of 922 malaria cases included in the study, P. vivax was the largest (63.4%, 95% confidence interval (CI) 60.3-66.5%) infecting species, followed by P. falciparum (34.4%, 95% CI 31.3-37.5%) and their mixed infection (2.2%, 95% CI 1.3-3.2%). Severity in P. vivax and P. falciparum was noted to be 16.9% (95% CI 13.9-19.9%) and 36.3% (95% CI 31.0-41.6%) respectively. Plasmodium falciparum had significantly higher odds [adjusted odds ratio (95% CI), 2.80 (2.04-3.83)] of severe malaria than P. vivax. Rising respiratory rate [1.29 (1.15-1.46)], falling systolic blood pressure [0.96 (0.93-0.99)], leucocytosis [12.87 (1.43-115.93)] and haematuria [59.36 (13.51-260.81)] were the independent predictors of severity in P. vivax. Increasing parasite index [2.97 (1.11-7.98)] alone was the independent predictor of severity in P. falciparum. Mortality in vivax and falciparum malaria was 0.34% (95% CI -0.13-0.81%) and 2.21% (95% CI 0.59-3.83%), respectively. Except hyperparasitaemia and shock, other complications were associated (P < 0.05) with mortality in falciparum malaria. Pulmonary oedema/acute respiratory distress syndrome was associated (P = 0.003) with mortality in vivax malaria. Retrospective design of this study possesses inherent limitations. Plasmodium vivax does cause severe malaria and mortality in substantial proportion but results in much lesser amalgamations of multi-organ involvements than P. falciparum. Pulmonary oedema/acute respiratory distress syndrome in P. vivax infection could lead to mortality and therefore should be diagnosed and treated promptly. Mounting complications and its broadening spectrum in 'not so benign' P. vivax warrants global vigilance for any probable impositions.


Automated prediction of domain boundaries in CASP6 targets using Ginzu and RosettaDOM.
Domain boundary prediction is an important step in both experimental and computational protein structure characterization. We have developed two fully automated domain parsing methods: the first, Ginzu, which we have described previously, utilizes information from homologous sequences and structures, while the second, RosettaDOM, which has not been described previously, uses only information in the query sequence. Ginzu iteratively assigns domains by homology to structures and sequence families using successively less confident methods. RosettaDOM uses the Rosetta de novo structure prediction method to build three-dimensional models, and then applies Taylor's structure based domain assignment method to parse the models into domains. Domain boundaries observed repeatedly in the models are predicted to be domain boundaries for the protein. Interestingly, RosettaDOM produced quite good domain predictions for proteins of a size typically considered to be beyond the reach of de novo structure prediction methods. For remote fold recognition targets and new folds, both Ginzu and RosettaDOM produced promising results, and in some cases where one method failed to detect the correct domain boundary, it was correctly identified by the other method. We describe here the successes and failures using both methods, and address the possibility of incorporating both protocols into an improved hybrid method.


Sarcoidosis: an update for the primary care physician.
Sarcoidosis is a systemic inflammatory disorder of unknown etiology, characterized by the formation of noncaseating granulomas, multisystem involvement, intrathoracic (pulmonary and lymph node) involvement in more than 90% of cases, and activation of T cells and macrophages at sites of granulomatous inflammation with the release of various chemokines and cytokines including tumor necrosis factor (TNF)-alpha. Despite the fact that sarcoidosis is seen all over the world, the study of its epidemiology has been a challenge for several reasons, including the lack of consistency in case definition, variability in disease presentation, the lack of sensitive and specific diagnostic tests, underrecognition and misdiagnosis of the disease, and a dearth of systematic epidemiologic studies. The ACCESS (A Case Control Etiologic Study of Sarcoidosis) study, a multicenter study done at 10 centers in the United States, is an attempt to better characterize the disease. A study of a subset of patients in the ACCESS study showed there was a delay in making the diagnosis of sarcoidosis, even when patients presented with pulmonary symptoms. The role of the primary care physician includes the establishment of a supportive physician-patient relationship. The morbidity and psychosocial problems associated with this condition necessitate educating patients about the disease because of the overwhelming concerns about its etiology, prognosis, and potential adverse effects of medication. This supportive role enhances patients' roles in the process of shared decision making during testing and treatment decisions.


Precision of actuarial risk assessment instruments: evaluating the 'margins of error' of group v. individual predictions of violence.
Actuarial risk assessment instruments (ARAIs) estimate the probability that individuals will engage in future violence. To evaluate the ;margins of error' at the group and individual level for risk estimates made using ARAIs. An established statistical method was used to construct 95% CI for group and individual risk estimates made using two popular ARAIs. The 95% CI were large for risk estimates at the group level; at the individual level, they were so high as to render risk estimates virtually meaningless. The ARAIs cannot be used to estimate an individual's risk for future violence with any reasonable degree of certainty and should be used with great caution or not at all. In theory, reasonably precise group estimates could be made using ARAIs if developers used very large construction samples and if the tests included few score categories with extreme risk estimates.


Cord blood IgG and the risk of severe Plasmodium falciparum malaria in the first year of life.
Young infants are less susceptible to severe episodes of malaria but the targets and mechanisms of protection are not clear. Cord blood antibodies may play an important role in mediating protection but many studies have examined their association with the outcome of infection or non-severe malaria. Here, we investigated whether cord blood IgG to Plasmodium falciparum merozoite antigens and antibody-mediated effector functions were associated with reduced odds of developing severe malaria at different time points during the first year of life. We conducted a case-control study of well-defined severe falciparum malaria nested within a longitudinal birth cohort of Kenyan children. We measured cord blood total IgG levels against five recombinant merozoite antigens and antibody function in the growth inhibition activity and neutrophil antibody-dependent respiratory burst assays. We also assessed the decay of maternal antibodies during the first 6months of life. The mean antibody half-life range was 2.51months (95% confidence interval (CI): 2.19-2.92) to 4.91months (95% CI: 4.47-6.07). The rate of decline of maternal antibodies was inversely proportional to the starting concentration. The functional assay of antibody-dependent respiratory burst activity predicted significantly reduced odds of developing severe malaria during the first 6months of life (Odds ratio (OR) 0.07, 95% CI: 0.007-0.74, P=0.007). Identification of the targets of antibodies mediating antibody-dependent respiratory burst activity could contribute to the development of malaria vaccines that protect against severe episodes of malaria in early infancy.


A taxonomic signature of obesity in a large study of American adults.
Animal models suggest that gut microbiota contribute to obesity; however, a consistent taxonomic signature of obesity has yet to be identified in humans. We examined whether a taxonomic signature of obesity is present across two independent study populations. We assessed gut microbiome from stool for 599 adults, by 16S rRNA gene sequencing. We compared gut microbiome diversity, overall composition, and individual taxon abundance for obese (BMI ≥ 30 kg/m2), overweight (25 ≤ BMI < 30), and healthy-weight participants (18.5 ≤ BMI < 25). We found that gut species richness was reduced (p = 0.04), and overall composition altered (p = 0.04), in obese (but not overweight) compared to healthy-weight participants. Obesity was characterized by increased abundance of class Bacilli and its families Streptococcaceae and Lactobacillaceae, and decreased abundance of several groups within class Clostridia, including Christensenellaceae, Clostridiaceae, and Dehalobacteriaceae (q < 0.05). These findings were consistent across two independent study populations. When random forest models were trained on one population and tested on the other as well as a previously published dataset, accuracy of obesity prediction was good (~70%). Our large study identified a strong and consistent taxonomic signature of obesity. Though our study is cross-sectional and causality cannot be determined, identification of microbes associated with obesity can potentially provide targets for obesity prevention and treatment.


[Study protocol on the effect of the economic crisis on mortality and reproductive health and health inequalities in Spain].
The aim is to present the protocol of the two sub-studies on the effect of the economic crisis on mortality and reproductive health and health inequalities in Spain. Substudy 1: describe the evolution of mortality and reproductive health between 1990 and 2013 through a longitudinal ecological study in the Autonomous Communities. This study will identify changes caused by the economic crisis in trends or reproductive health and mortality indicators using panel data (17 Autonomous Communities per study year) and adjusting Poisson models with random effects variance. Substudy 2: analyse inequalities by socioeconomic deprivation in mortality and reproductive health in several areas of Spain. An ecological study analysing trends in the pre-crisis (1999-2003 and 2004-2008) and crisis (2009-2013) periods will be performed. Random effects models Besag York and Mollié will be adjusted to estimate mortality indicators softened in reproductive health and census tracts.


Dietary sources of nutrients among US adults, 1989 to 1991.
To identify major food sources of 27 nutrients and dietary constituents for US adults. Single 24-hour dietary recalls were used to assess intakes. From 3,970 individual foods reported, 112 groups were created on the basis of similarities in nutrient content or use. Food mixtures were disaggregated using the US Department of Agriculture (USDA) food grouping system. A nationally representative sample of adults aged 19 years or older (n = 10,638) from USDA's 1989-91 Continuing Survey of Food Intakes by Individuals. ANALYSES PERFORMED: For each of 27 dietary components, the contribution of each food group to intake was obtained by summing the amount provided by the food group for all respondents and dividing by total intake from all food groups for all respondents. This article updates previous work and is, to the authors' knowledge the first to provide such data for carotenes, vitamin B-12, magnesium, and copper. Beef, yeast bread, poultry, cheese, and milk were among the top 10 sources of energy, fat, and protein. The following other major sources also contributed more than 2% to energy intakes: carbohydrate: yeast bread, soft drinks/soda, cakes/cookies/ quick breads/doughnuts, sugars/syrups/jams, potatoes (white), ready-to-eat cereal, and pasta; protein: pasta; and fat: margarine, salad dressings/mayonnaise, and cakes/ cookies/quick breads/doughnuts. Ready-to-eat cereals, primarily because of fortification, were among the top 10 food sources for 18 of 27 nutrients. These analyses are the most current regarding food sources of nutrients and, because of disaggregation of mixtures, provide a truer picture of contributions of each food group.