[Endocrine disruptors : Evidence from epidemiological studies necessitates a critical review of model systems]. / Endokrine Modulatoren : Hinweise aus epidemiologischen Studien bedürfen einer kritischen Überprüfung in Modellsystemen.

Endocrine disruptive chemicals (EDCs) cause adverse health effects through interaction with endocrine systems. They are classified by chemical structure, effects on specific endocrine systems, bioaccumulation, persistence in the environment, or clinically observable effects. For research of the complex mechanisms of action in the human body, only in vitro model systems have so far been available, that have insufficient high-throughput capacity, which makes risk evaluation more difficult. In addition, in industrial nations, living people are often exposed to mixtures of substances, with various effects. The clinical importance of epigenetic changes caused by the action of EDCs during vulnerable phases of development is currently unclear. Epidemiological studies are criticized because reproducibility is not always guaranteed. Nevertheless, they remain the method of choice for the development and analysis of suitable model systems. Positive associations, in spite of sometimes conflicting results, are key in the selection of factors that can then be analysed in model systems in an unbiased way. This article depicts the mainly positive epidemiological findings for EDC-caused effects in the fields of growth and metabolism, neurocognitive development and sexual development and reproduction. As a result, there is a need for closer linkage between epidemiological studies and mechanistic research into model systems, especially focusing on the interaction of different EDCs and the consequences of prenatal and early life exposure.

Disability and disability benefit seeking in chronic low back pain.

BACKGROUND: Numerous studies suggest psychosocial factors contribute to functional disability in patients with chronic low back pain (CLBP). However, less is known about the association of psychosocial factors, such as depression, with seeking medical disability benefits and their prevalence in benefit seekers compared with patients already receiving such payments. AIMS: To determine if characteristics of disability benefit seekers differ from patients receiving disability benefits and if both differ from patients not dependent on such payments. METHODS: Questionnaire data on pain, health-related quality of life, depression, social support, substance abuse, adverse childhood experiences and disability seeking were obtained from CLBP respondents recruited at 10 primary care clinics throughout Texas. A multinomial logistic regression model was computed using variables significantly associated with disability status and pain severity in univariate models. RESULTS: There were 213 participants. In full models, compared with those not on disability benefits, only depression symptoms were significantly associated with seeking disability benefits (odds ratio [OR] = 1.13; 95% confidence interval [CI] 1.01-1.26) and only duration of pain was significantly associated with being on such benefits (OR = 1.05; 95% CI 1.01-1.09). CONCLUSIONS: Patient characteristics differ between disability benefit seekers and those established on disability benefit payments. Depression may be a modifiable correlate of disability benefit seeking that if treated may reduce the number of patients who eventually come to depend on disability benefits. Additional data collection involving other pain syndromes is warranted to determine if these results are unique to CLBP or apply to other painful conditions.

Seizures in Children with HIV infection in South Africa: A retrospective case control study.

PURPOSE: Data relating to the role that Human immunodeficiency virus (HIV) contributes towards seizures in HIV-infected children is limited. The management of seizures in this group is complex due to potential interactions between antiseizure medication and antiretroviral therapies. This study explores the seizure semiology and course of a population of affected children based on questions raised from a previous epidemiological study. METHODS: A retrospective case-control study of all patients presenting to an HIV neurology clinic between 2008-2015 was conducted. A multinomial logistic regression model was used to identify risk factors for seizure occurrence in HIV-infected children, as well as factors associated with seizure control. RESULTS: Of 227 HIV-infected children (median 82 months, interquartile range 41-109), 52 (23%) reported a past or present history of seizures. Prior bacterial meningitis (p = 0.03, OR 12.5, 95% CI 1.2-136.1), cerebrovascular accident (CVA, p = 0. 005, OR 8.1, 95% CI 1.9-34.9) and or tuberculous meningitis (TBM, p = 0.0004) was associated with an increased risk of seizures in HIV-infected children. Generalised tonic-clonic seizures were the predominant seizure type (64%) with the majority caused by an infectious aetiology (62%). Thirty-two (62%) of these patients had epilepsy in-line with the latest diagnostic criteria. HIV-infected children with epilepsy who were treated with efavirenz were more likely to have poor seizure control (OR 23.1 95% CI 3.4-159.6, p = 0.0001). CONCLUSIONS: This study provides new data highlighting the complex clinical presentation and management challenges of HIV-infected children with seizures.

Evolution of Earth-like Planetary Atmospheres around M Dwarf Stars: Assessing the Atmospheres and Biospheres with a Coupled Atmosphere Biogeochemical Model.

Earth-like planets orbiting M dwarfs are prominent targets when searching for life outside the Solar System. We apply our Coupled Atmosphere Biogeochemical model to investigate the coupling between the biosphere, geosphere, and atmosphere in order to gain insight into the atmospheric evolution of Earth-like planets orbiting M dwarfs and to understand the processes affecting biosignatures and climate on such worlds. This is the first study applying an automated chemical pathway analysis quantifying the production and destruction pathways of molecular oxygen (O2) for an Earth-like planet with an Archean O2 concentration orbiting in the habitable zone of the M dwarf star AD Leonis, which we take as a type-case of an active M dwarf. The main production arises in the upper atmosphere from carbon dioxide photolysis followed by catalytic hydrogen oxide radical (HOx) reactions. The strongest destruction does not take place in the troposphere, as was the case in Gebauer et al. ( 2017 ) for an early Earth analog planet around the Sun, but instead in the middle atmosphere where water photolysis is the strongest. Results further suggest that these atmospheres are in absolute terms less destructive for O2 than for early Earth analog planets around the Sun despite higher concentrations of reduced gases such as molecular hydrogen, methane, and carbon monoxide. Hence smaller amounts of net primary productivity are required to oxygenate the atmosphere due to a change in the atmospheric oxidative capacity, driven by the input stellar spectrum resulting in shifts in the intrafamily HOx partitioning. Under the assumption that an atmosphere of an Earth-like planet survived and evolved during the early high-activity phase of an M dwarf to an Archean-type composition, a possible "Great Oxidation Event," analogous to that on Early Earth, would have occurred earlier in time after the atmospheric composition was reached, assuming the same atmospheric O2 sources and sinks as on early Earth. Key Words: Earth-like-Oxygen-M dwarf stars-Atmosphere-Biogeochemistry-Photochemistry-Biosignatures-Earth-like planets. Astrobiology 18, 856-872.

Evolution of Earth-like Extrasolar Planetary Atmospheres: Assessing the Atmospheres and Biospheres of Early Earth Analog Planets with a Coupled Atmosphere Biogeochemical Model.

Understanding the evolution of Earth and potentially habitable Earth-like worlds is essential to fathom our origin in the Universe. The search for Earth-like planets in the habitable zone and investigation of their atmospheres with climate and photochemical models is a central focus in exoplanetary science. Taking the evolution of Earth as a reference for Earth-like planets, a central scientific goal is to understand what the interactions were between atmosphere, geology, and biology on early Earth. The Great Oxidation Event in Earth's history was certainly caused by their interplay, but the origin and controlling processes of this occurrence are not well understood, the study of which will require interdisciplinary, coupled models. In this work, we present results from our newly developed Coupled Atmosphere Biogeochemistry model in which atmospheric O2 concentrations are fixed to values inferred by geological evidence. Applying a unique tool (Pathway Analysis Program), ours is the first quantitative analysis of catalytic cycles that governed O2 in early Earth's atmosphere near the Great Oxidation Event. Complicated oxidation pathways play a key role in destroying O2, whereas in the upper atmosphere, most O2 is formed abiotically via CO2 photolysis. The O2 bistability found by Goldblatt et al. ( 2006 ) is not observed in our calculations likely due to our detailed CH4 oxidation scheme. We calculate increased CH4 with increasing O2 during the Great Oxidation Event. For a given atmospheric surface flux, different atmospheric states are possible; however, the net primary productivity of the biosphere that produces O2 is unique. Mixing, CH4 fluxes, ocean solubility, and mantle/crust properties strongly affect net primary productivity and surface O2 fluxes. Regarding exoplanets, different "states" of O2 could exist for similar biomass output. Strong geological activity could lead to false negatives for life (since our analysis suggests that reducing gases remove O2 that masks its biosphere over a wide range of conditions). Key Words: Early Earth-Proterozoic-Archean-Oxygen-Atmosphere-Biogeochemistry-Photochemistry-Biosignatures-Earth-like planets. Astrobiology 16, 27-54.

Cyclosporine A delays wound healing and apoptosis and suppresses activin beta-A expression in rats.

Cyclosporine A is a powerful immunosuppressive agent which is widely used for the prevention of allograft rejection and for the treatment of autoimmune diseases. Clinical and experimental data show that it may also act on connective tissue. We investigated the influence of cyclosporine A on granulation tissue formation and wound healing. Using an in vitro approach, we followed the time course of rat dermal fibroblasts during wound repair. Granulation fibroblasts were compared to dermal fibroblasts flow cytometrically and by mRNA analysis with respect to the expression of procollagen alpha1(I), integrin beta1, interleukin-6, transforming growth factor beta1, keratinocyte growth factor and activin betaA. The most pronounced effect in cyclosporine-treated rats was the strong down-regulation of activin beta expression. In cryo-sections of granulation tissue from the same rats, the distribution and expression intensity of intercellular adhesion molecule and its receptors were investigated by immunohistology. Clearly, a time course was detectable. Tissue from CsA-treated animals showed a delay of three days compared to untreated animals. Apoptosis was also delayed in CsA-treated rats by around three days. Furthermore, we investigated the effect of CsA on the expression of collagen alpha1(I), fibronectin and matrix metalloprotease 1 genes in dermal fibroblasts from untreated donors. No changes in the mRNA steady state levels of these genes were revealed after direct addition of different doses of CsA to fibroblast cultures. Our data suggest that CsA may interfere with the complicated net of interactions between connective tissue and the immune system by down-regulation of the inflammatory phase by modulation of cytokines and a subsequent delay of tissue repair.

[Acupuncture massage vs Swedish massage and individual exercise vs group exercise in low back pain sufferers--a randomized controlled clinical trial in a 2 x 2 factorial design]. / Akupunktmassage nach Penzel versus klassische Teilmassage und Einzel- versus Gruppenkrankengymnastik bei chronischen Rückenschmerzen--eine randomisierte, kontrollierte klinische Studie in 2 x 2-faktoriellem Design.

OBJECTIVE: Rehabilitation programs for low back pain (LBP) almost always contain massage and exercise therapy in one form or another. AIM: This study aimed to quantify the effectiveness of therapeutic 'Acupuncture' massage (APM; i.e. tonic stimulation of entire meridians) according to Penzel versus Swedish massage (SM) and individual medical exercises (IE) versus group exercises (GE) in LBP sufferers. PATIENTS AND METHODS: 109 patients participating in a complex in-patient rehabilitation program were randomised to four groups in a 2 x 2 factorial design. Main outcome measures were functional ability/disability (Functional Questionnaire Hanover, FFbH) and pain intensity (10 cm visual analogue scale, VAS). Pre/post changes were evaluated by means of 2-way analysis of variance (ANOVA). Additionally, lumbar motility was measured by a 2-inclinometer technique. RESULTS: Baseline mean FFbH score was 66 (SD = 18)%, mean pain intensity on VAS was 4.5 (SD = 2.4) cm. Lumbar flexion and extension were 49 (13) and 13 (7). Because of some differences between groups at baseline, group-standardized outcomes were used for analysis. APM showed beneficial effects for both disability and pain compared with SM (group differences: delta FFbH 7.0% [95% confidence interval (CI) 2.5-11.6], p = 0.003; delta VAS 0.8 cm [95% CI: 2-15], p = 0.024). Standardized response means were SRMFFbH = 0.5 and SRMVAS = 0.8 for APM, as opposed to SRMFFbH = -0.01 and SRMVAS = 0.4 for SM. Neither significant group differences between both exercise groups [delta FFbH -0.5% (95% CI -5.2 to 4.2); delta Vas 0.4 cm (95% CI 0.3 to 1.1)] nor significant interactions between medical exercise and massage were found. CONCLUSIONS: Given the fact that even the treatments considered to be the best available achieve at best moderate effects, the observed effect sizes with APM are promising and warrant further investigation in replication studies. In contrast to common view, no superiority of individual versus group exercises could be found in the present study.

Impact of stearic acid and oleic acid on hemostatic factors in the context of controlled diets consumed by healthy men.

The effects of stearic acid (STA) on cardiovascular disease risk beyond lipid and lipoprotein risk factors, including hemostasis, are unclear, particularly when compared with unsaturated fatty acids. The aim of the present study is to compare the effects of STA with those of oleic acid (OL) on markers of hemostasis. In a randomized crossover study, 50 men consumed six controlled diets for 5 weeks each (39% energy from fat, 15% energy from protein, 46% energy from carbohydrate (CHO)). Fat (8% energy) was replaced across diets by: STA, OL, CHO (control), trans fatty acids (TFAs), TFA/STA and 12:0-16:0 saturated fatty acids. Factor VIIc, plasminogen activator inhibitor-1 (PAI-1) and plasmin alpha-2-antiplasmin complex concentrations were not different between OL and STA (P>0.05). Compared with control, OL increased factor VIIc and PAI-1 (P≤0.05), whereas there were no differences with STA (P>0.05). STA and OL similarly affect markers of hemostasis in healthy men, within the context of a highly controlled diet.

Potential biosignatures in super-Earth atmospheres II. Photochemical responses.

Spectral characterization of super-Earth atmospheres for planets orbiting in the habitable zone of M dwarf stars is a key focus in exoplanet science. A central challenge is to understand and predict the expected spectral signals of atmospheric biosignatures (species associated with life). Our work applies a global-mean radiative-convective-photochemical column model assuming a planet with an Earth-like biomass and planetary development. We investigated planets with gravities of 1g and 3g and a surface pressure of 1 bar around central stars with spectral classes from M0 to M7. The spectral signals of the calculated planetary scenarios have been presented by in an earlier work by Rauer and colleagues. The main motivation of the present work is to perform a deeper analysis of the chemical processes in the planetary atmospheres. We apply a diagnostic tool, the Pathway Analysis Program, to shed light on the photochemical pathways that form and destroy biosignature species. Ozone is a potential biosignature for complex life. An important result of our analysis is a shift in the ozone photochemistry from mainly Chapman production (which dominates in Earth's stratosphere) to smog-dominated ozone production for planets in the habitable zone of cooler (M5-M7)-class dwarf stars. This result is associated with a lower energy flux in the UVB wavelength range from the central star, hence slower planetary atmospheric photolysis of molecular oxygen, which slows the Chapman ozone production. This is important for future atmospheric characterization missions because it provides an indication of different chemical environments that can lead to very different responses of ozone, for example, cosmic rays. Nitrous oxide, a biosignature for simple bacterial life, is favored for low stratospheric UV conditions, that is, on planets orbiting cooler stars. Transport of this species from its surface source to the stratosphere where it is destroyed can also be a key process. Comparing 1g with 3g scenarios, our analysis suggests it is important to include the effects of interactive chemistry.

The renal type H+/peptide symporter PEPT2: structure-affinity relationships.

The H(+)/peptide cotransporter PEPT2 is expressed in a variety of organs including kidney, lung, brain, mammary gland, and eye. PEPT2 substrates are di- and tripeptides as well as peptidomimetics, such as beta-lactam antibiotics. Due to the presence of PEPT2 at the bronchial epithelium, the aerosolic administration of peptide-like drugs might play a major role in future treatment of various pulmonary and systemic diseases. Moreover, PEPT2 has a significant influence on the in vivo disposition and half-life time of peptide-like drugs within the body, particularly in kidney and brain. PEPT2 is known to have similar but not identical structural requirements for substrate recognition and transport compared to PEPT1, its intestinal counterpart. In this review we compiled available affinity constants of 352 compounds, measured at different mammalian tissues and expression systems and compare the data whenever possible with those of PEPT1.

Study of structure and function of recombinant pea root plastid porin by biophysical methods.

Pea root plastid porin (Fischer et al. (1994) J. Biol. Chem. 269, 25754-25760), which belongs to the family of mitochondrial (eukaryotic) porins, was expressed in Escherichia coli in high amounts using the pQE expression system. The recombinant protein was reconstituted into lipid bilayer membranes, and its characteristic properties were compared to those of the native porin isolated from pea root plastids. No significant difference was found between the native and the recombinant form when the protein was preincubated in detergent and sterol. The recombinant porin seems to be a valuable model system for the study of eukaryotic porins by spectroscopic methods, in which high amounts of protein are needed. CD spectroscopy was performed to determine the secondary structure of the porin under different conditions. It was found to have a high degree of beta-sheet structure in the nonionic detergent Genapol X-80 and in lipid vesicles. The more polar detergent sodium dodecyl sulfate (SDS) induced a large amount of alpha-helix structure in the protein. Addition of sterol to the porin in Genapol buffer did not influence its secondary structure to any measurable extent, whereas it had a strong influence on channel forming activity in black lipid bilayers. First refolding experiments performed in decreasing urea concentrations are discussed together with the results of the other measurements with regard to protein folding and channel formation.