Origin of the spectral shifts among the early intermediates of the rhodopsin photocycle.

A combined strategy based on the computation of absorption energies, using the ZINDO/S semiempirical method, for a statistically relevant number of thermally sampled configurations extracted from QM/MM trajectories is used to establish a one-to-one correspondence between the structures of the different early intermediates (dark, batho, BSI, lumi) involved in the initial steps of the rhodopsin photoactivation mechanism and their optical spectra. A systematic analysis of the results based on a correlation-based feature selection algorithm shows that the origin of the color shifts among these intermediates can be mainly ascribed to alterations in intrinsic properties of the chromophore structure, which are tuned by several residues located in the protein binding pocket. In addition to the expected electrostatic and dipolar effects caused by the charged residues (Glu113, Glu181) and to strong hydrogen bonding with Glu113, other interactions such as π-stacking with Ala117 and Thr118 backbone atoms, van der Waals contacts with Gly114 and Ala292, and CH/π weak interactions with Tyr268, Ala117, Thr118, and Ser186 side chains are found to make non-negligible contributions to the modulation of the color tuning among the different rhodopsin photointermediates.

Early blood exchange transfusion in malignant pertussis: A case report.

OBJECTIVE:: To report early blood exchange transfusion in malignant pertussis and a favorable clinical outcome. SETTING:: A pediatric intensive care unit in a tertiary hospital in Geneva, Switzerland. DESIGN:: A descriptive case report. PATIENT:: An 8-wk-old girl was diagnosed with malignant pertussis (extreme leukocytosis, seizures, pneumonia, and secondary severe hypoxic respiratory failure associated with pulmonary hypertension). After administration of a one-volume blood exchange transfusion, a rapid decrease in white blood cell count (from 119,000/mm to 36,500/mm) was observed and followed by clinical improvement and favorable outcome despite the initial presence of all described risk factors associated with a high mortality. CONCLUSION:: The use of exchange blood transfusion early in the course of the disease might help to prevent a fatal outcome of malignant pertussis.

Non-functioning pituitary macro-incidentalomas benefit from early surgery before becoming symptomatic.

OBJECTIVE: Pituitary incidentalomas (PIs) constitute an increasingly clinical problem. While the therapeutic management is well defined for symptomatic non-functioning PIs (NFPIs), a controversy still exists for asymptomatic macro-NFPIs between surgery and a "wait and see" approach. The aim of this study is to compare surgical results between symptomatic and asymptomatic macro-NFPIs. METHODS: We conducted a retrospective study on 76 patients with newly diagnosed symptomatic and asymptomatic macro-NFPIs operated on between 2001 and 2010. We compared age, tumor size and surgical results between these two patient groups. RESULTS: After the initial evaluation, 48 patients were found to be symptomatic. Gross total removal (GTR) rate was significantly higher in asymptomatic (82%) than in symptomatic patients (58%; p=0.03). Gross total removal was strongly associated with Knosp's classification (p=0.01). Postoperative endocrinological impairment was significantly associated with the existence of preoperative symptoms (p=0.03). It was 10 times less frequent in the asymptomatic group. In symptomatic patients, postoperative visual and endocrinological impairment were present in 49% and 78% versus 0% and 14% in asymptomatic patients respectively. CONCLUSIONS: The endocrinological and visual outcome was better in those patients who underwent surgery for asymptomatic tumors. The extent of tumor resection was also significantly greater in smaller tumors. It would therefore be appropriate to offer surgery to patients with asymptomatic macro-NFPIs.

Early Entry Sawed Portland Cement Concrete Transverse Joint Ends, MLR-97-5, 2003

Experiments with early entry light sawing of Portland cement concrete (PCC) contraction joints began in Iowa in 1989. Since that time, changes in early sawing equipment have occurred as well as changes in specifications for sawing. The option to use early sawing for transverse contraction joints was specified in 1992. A problem happening occasionally with early sawing was the break out of some of the concrete around the end of the joint as the saw blade approached the edge of the slab. To prevent this, it was proposed that the sawing would terminate approximately 1/2" to 3/4" before the edge of the slab, creating a "short joint". This procedure would also leave a concrete "dam" to prevent the run-out and waste of the hot liquid joint sealant onto the shoulder. It would also eliminate the need for the labor and material for applying a duct tape dam at the open ends of each sawed joint to stop hot liquid sealant run-out Agreements were made with the contractor to apply the "short joint" technique for 1 day of paving. The evaluation and results are compared with an adjoining control section. The research found no negative aspects from sawing the "short joint". Three specific findings were noted. They are the following: 1) No joint end "blow-out" spalls of concrete occurred. 2) The need for the duct tape dam to stop liquid sealant overflow was eliminated. 3) Joint end corner spalls appear to be caused mainly by construction shouldering operations equipment. The "short joint" sawing technique can be routinely applied to early entry sawed transverse contraction joints with expectations of only positive results.

Lipoxygenase 2 and the early steps of jasmonic acid biosynthesis in "Arabidopsis thaliana"

Résumé Les oxylipines, telles que l'acide jasmonique (AJ ou jasmonate), jouent un rôle central en réponse à la blessure et à la pathogenèse. De nombreuses études ont montré l'importance de la voie canonique du jasmonate lors de la défense des plantes. De plus, un précurseur cyclopentenone de l'AJ, l'acide oxo-phyto-dienoic (OPDA), a été impliqué comme jouant le rôle d'une molécule signal lors de la défense contre certains pathogènes. En utilisant des mutants bloqués dans la biosynthèse de l'acide jasmonique (aos) ou dans sa perception (coi1-1), nous avons cherché à définir dans quelle mesure l'OPDA joue un rôle de signal induisant l'expression génétique en réponse à la blessure chez Arabidopsis. A l'aide de puces à ADN (microarray), nous avons montré que les transcriptomes d'aos et de coi1-1 sont très semblables après blessure, ce qui suggère que les produits d'AOS sont tous perçus via COI1. Pourtant, lorsqu'on analyse les métabolites présents chez ces mutants, une différence est visible, puisque aos n'accumule pas d'AJ, alors que coi1-1 en accumule encore rapidement après blessure. Nous avons étudié la possibilité qu'un mécanisme de régulation post-traductionnelle sur la voie de biosynthèse du jasmonate explique l'accumulation d'AJ chez coi1-1 après blessure. La lipoxygenase 2 (LOX2) est la première enzyme impliquée dans la biosynthèse de l'AJ et est donc une cible potentielle d'un tel mécanisme. Un indice sur la manière dont l'activité LOX pourrait être régulée vient du mutant fou2 (pour fatty acid oxygenation upregcilated 2) dans lequel l'activité LOX ainsi que le niveau d'AJ sont constitutivement élevés. Cette mutation implique un flux de cation dans la régulation de la production de l'AJ. De plus, il a été montré que plusieurs LOXs, dans des organismes autres que des plantes, peuvent lier le calcium. Nous montrons que l'activité LOX requiert l'addition de cations divalents pour être maximale in vitro, et que non seulement le calcium mais aussi le magnésium joue ce rôle. De plus, nous caractérisons un mutant récessif de LOX2 chez Arabidopsis (lox2-1). Ces plantes sont fertiles, et une analyse quantitative montre qu'elles accumulent toujours un peu d'AJ après blessure. Ceci suggère que LOX2 n'est pas la seule LOX impliquée dans la synthèse d'AJ. Aussi les plantes lox2-1 ne sont pas plus sensibles que les plantes de type sauvage lorsqu'elles sont infectées par la moisissure Botrytis cinerea ou lorsqu'elles sont exposées à un détritivore, néanmoins elles sont plus sensibles lorsqu'elles sont offertes en nourriture à un insecte herbivore. Les insectes et les plantes ont co-évolué conjointement, ainsi une plante ne contenant qu'un niveau réduit d'AJ favorise l'insecte. La disponibilité d'un mutant avec un niveau intermédiaire d'AJ va permettre de mieux comprendre pourquoi les plantes produisent autant de jasmonate. Abstract Oxylipins such as jasmonic acid (JA) play central roles in the wound response and during pathogenesis and many studies have confirmed the important role of the canonical jasmonate pathway in plant defense. Moreover, the cyclopentenone precursor of JA, oxo-phytodienoic acid (OPDA), is also thought to function as a signaling molecule in defense towards some pathogens. Its action was reported to depend on a different signal pathway to JA. By using mutants blocked in the biosynthesis (aos) or perception (coil-1) of JA, we investigated to which extend OPDA works as signaling molecule to trigger gene expression in the wound response of Arabidopsis. Using microarrays, we showed that aos and coil-1 transcriptome are similar in response to wounding, suggesting that products of AOS are all perceived by COI1. However, we found a difference between the two mutants at the metobolomic level, since aos is devoid of JA, but coil-1 can still rapidly accumulate JA upon wounding. We investigated the possibility that the post-translational activation of JA biosynthesis could explain the fast accumulation of JA in coil-1 plants upon wounding. Lipoxygenase (LOX) 2 is the first enzyme implicated in JA synthesis and was thus chosen as a potential target for posttranslational regulation. A clue as to how LOX activity might be regulated came from the fatty acid oxygenation upregulated 2 (foul) mutant in which LOX activity and JA levels are elevated. The foul mutant implicates cations flux in the regulation of JA production, and several LOXs in organisms other than plants have been shown to bind calcium. We showed that Arabidopsis LOX requires divalent cations for full activity in vitro, and that not only calcium but also magnesium can play this role. Moreover, a single recessive mutant of AtLOX2 was characterized. These plants are fully fertile. Quantitative oxylipin analysis showed that lox2-1 can still accumulate some JA after wounding, which suggests that LOX2 is not the only LOX involved in JA biosynthesis. lox2-1 plants do not show altered susceptibility to the fungus Botrytis cinerea or to a detritivore, however, they are more susceptible to an insect herbivore. The insect and plants are closely co-evolved and a reduced ability to synthesize JA favors the insect. The availability of a lox2-1 mutant with intermediate JA levels will further help understanding why plants produce elevated JA levels.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Impaired metabolic reactivity to oxidative stress in early psychosis patients.

Because increasing evidence point to the convergence of environmental and genetic risk factors to drive redox dysregulation in schizophrenia, we aim to clarify whether the metabolic anomalies associated with early psychosis reflect an adaptation to oxidative stress. Metabolomic profiling was performed to characterize the response to oxidative stress in fibroblasts from control individuals (n = 20) and early psychosis patients (n = 30), and in all, 282 metabolites were identified. In addition to the expected redox/antioxidant response, oxidative stress induced a decrease of lysolipid levels in fibroblasts from healthy controls that were largely muted in fibroblasts from patients. Most notably, fibroblasts from patients showed disrupted extracellular matrix- and arginine-related metabolism after oxidative stress, indicating impairments beyond the redox system. Plasma membrane and extracellular matrix, 2 regulators of neuronal activity and plasticity, appeared as particularly susceptible to oxidative stress and thus provide novel mechanistic insights for pathophysiological understanding of early stages of psychosis. Statistically, antipsychotic medication at the time of biopsy was not accounting for these anomalies in the metabolism of patients' fibroblasts, indicating that they might be intrinsic to the disease. Although these results are preliminary and should be confirmed in a larger group of patients, they nevertheless indicate that the metabolic signature of reactivity to oxidative stress may provide reliable early markers of psychosis. Developing protective measures aimed at normalizing the disrupted pathways should prevent the pathological consequences of environmental stressors.

Audit report on the AIM - Jefferson, Keokuk Early Childhood Iowa (ECI) Area Board, d/b/a Jefferson/Keokuk Early Childhood Iowa Area for the year ended June 30, 2013

Audit report on the AIM - Jefferson, Keokuk Early Childhood Iowa (ECI) Area Board, d/b/a Jefferson/Keokuk Early Childhood Iowa Area for the year ended June 30, 2013

Biological embedding of early-life exposures and disease risk in humans : a role for DNA methylation

BACKGROUND: Following wider acceptance of 'the thrifty phenotype' hypothesis and the convincing evidence that early-life exposures can influence adult health even decades after the exposure, much interest has been placed on the mechanisms through which early-life exposures become biologically embedded. MATERIALS AND METHODS: In this review, we summarize the current literature regarding biological embedding of early-life experiences. To this end, we conducted a literature search to identify studies investigating early-life exposures in relation to DNA methylation changes. In addition, we summarize the challenges faced in investigations of epigenetic effects, stemming from the peculiarities of this emergent and complex field. A proper systematic review and meta-analyses were not feasible given the nature of the evidence. RESULTS: We identified seven studies on early-life socio-economic circumstances, 10 studies on childhood obesity and six studies on early-life nutrition all relating to DNA methylation changes that met the stipulated inclusion criteria. The pool of evidence gathered, albeit small, favours a role of epigenetics and DNA methylation in biological embedding, but replication of findings, multiple comparison corrections, publication bias and causality are concerns remaining to be addressed in future investigations. CONCLUSIONS: Based on these results, we hypothesize that epigenetics, in particular DNA methylation, is a plausible mechanism through which early-life exposures are biologically embedded. This review describes the current status of the field and acts as a stepping stone for future, better designed investigations on how early-life exposures might become biologically embedded through epigenetic effects.

Stressful life events and neuroticism as predictors of late-life versus early-life depression.

BACKGROUND: The occurrence of depression in younger adults is related to the combination of long-standing factors such as personality traits (neuroticism) and more acute factors such as the subjective impact of stressful life events. Whether an increase in physical illnesses changes these associations in old age depression remains a matter of debate. METHODS: We compared 79 outpatients with major depression and 102 never-depressed controls; subjects included both young (mean age: 35 years) and older (mean age: 70 years) adults. Assessments included the Social Readjustment Rating Scale, NEO Personality Inventory and Cumulative Illness Rating Scale. Logistic regression models analyzed the association between depression and subjective impact of stressful life events while controlling for neuroticism and physical illness. RESULTS: Patients and controls experienced the same number of stressful life events in the past 12 months. However, in contrast to the controls, patients associated the events with a subjective negative emotional impact. Negative stress impact and levels of neuroticism, but not physical illness, significantly predicted depression in young age. In old age, negative stress impact was weakly associated with depression. In this age group, depressive illness was also determined by physical illness burden and neuroticism. CONCLUSIONS: Our data suggest that the subjective impact of life stressors, although rated as of the same magnitude, plays a less important role in accounting for depression in older age compared to young age. They also indicate an increasing weight of physical illness burden in the prediction of depression occurrence in old age.

Blanket Curing to Promote Early Strength Concrete, MLR-87-7, 1989

Fast Track concrete has proven to be successful in obtaining high early strengths. This benefit does not come without cost. Special Type III cement and insulating blankets to accelerate the cure add to its expense when compared to conventional paving. This research was intended to determine the benefit derived from the use of insulating blankets to accelerate strength gain in three concrete mixes using Type I cement. The goal was to determine mixes and curing procedures that would result in a range of opening times. This determination would allow the most economical design for a particular project by tailoring it to a specific time restraint. Three mixes of various cement content were tested in the field. Flexural beams were cast for each mix and tested at various ages. Two test sections were placed for each mix, one section being cured with the addition of insulating blankets and the other being cured with only conventional curing compound. Iowa Department of Transportation specifications require 500 psi flexural strength before a pavement can be opened to traffic. Concrete with Fast Track proportions (nominal 7 1/2 bag), Type I cement, and insulating blankets reached that strength in approximately 36 hr, a standard mix (nominal 6 1/2 bag) using the blankets in approximately 48 hr, and the Fast Track proportions with Type I cement without blankets in about 60 hr. The results showed a significant improvement in early strength gain with the use of insulating blankets.

Audit report on the Ringgold County Early Childhood Iowa Area for the year ended June 30, 2013

Audit report on the Ringgold County Early Childhood Iowa Area for the year ended June 30, 2013