Lumbar disc disease: the effect of inversion on clinical symptoms and a comparison of the rate of surgery after inversion therapy with the rate of surgery in neurosurgery controls.
[Purpose] We have previously shown inversion therapy to be effective in a small prospective randomised controlled trial of patients with lumbar disc protrusions. Our purpose now was to measure symptoms and to compare the surgery rate following inversion for 85 participants with the surgery rate in 3 control groups. [Participants and Methods] Each of the 85 inverted participants acted as their own control for the "symptomatic" part of the study. In the "Need for surgery" part of the study, one control group was made up of similar patients with leg pain and sciatica who were referred to the same clinic in the same year. Two additional control groups were examined: the original control group from the pilot trial and the lumbar disc surgery waiting list patients. [Results] Inversion therapy relieved symptoms: there were improvements in the Visual Analogue Score, Roland Morris and Oswestry Disease indices and Health Utility Score compared with their pre-treatment status. Also, the 2 year surgery rate in the inversion participants in the registry (21%) was significantly lower than in the matched control group (39% at two years and 43% at four years). It was also lower than the surgery rate in the other 2 control groups. [Conclusion] Inversion therapy relieved symptoms and avoided surgery.


[The end of food: dietary supplementation and diet among avid members of workout and fitness centers in Rio de Janeiro].
The article addresses the particular diet of a group of avid members of workout and fitness centers in Rio de Janeiro. It shows how diet is related to keeping in shape and to the prevailing type of sociability. Using direct and participatory ethnographic observation and open interviews, research was conducted at 12 fitness clubs on the North and South sides of Rio for three years. For the group under study, eating is about relying on a system of knowledge related to the science of nutrition for the benefit of managing one's physical shape and athletic performance. This movement produces the notion of food as a powerful chemical artifice that enhances the aesthetics of the body.


Hedgehog Activation for Enhanced Rotator Cuff Tendon-to-Bone Healing.
Rotator cuff repair is a common orthopaedic procedure, yet the rate of failure to heal after surgery is high. Repair site rupture is due to poor tendon-to-bone healing and lack of regeneration of the native fibrocartilaginous enthesis. During development, the enthesis is formed and mineralized by a pool of progenitors activated by hedgehog signaling. Furthermore, hedgehog signaling drives regenerative enthesis healing in young animals, in contrast to older animals, in which enthesis injuries heal via fibrovascular scar and without participation of hedgehog signaling. Hedgehog activation improves tendon-to-bone healing in an animal model of rotator cuff repair. Controlled laboratory study. A total of 78 adult Sprague-Dawley rats were used. Supraspinatus tendon injury and repair were completed bilaterally, with microsphere-encapsulated hedgehog agonist administered to right shoulders and control microspheres administered to left shoulders. Animals were sacrificed after 3, 14, 28, or 56 days. Gene expression and histological, biomechanical, and bone morphometric analyses were conducted. At 3 days, hedgehog signaling pathway genes Gli1 (1.70; P = .029) and Smo (2.06; P = .0173), as well as Runx2 (1.69; P = .0386), a transcription factor of osteogenesis, were upregulated in treated relative to control repairs. At 14 days, transcription factors of tenogenesis, Scx (4.00; P = .041), and chondrogenesis, Sox9 (2.95; P = .010), and mineralized fibrocartilage genes Col2 (3.18; P = .031) and Colx (1.85; P = .006), were upregulated in treated relative to control repairs. Treatment promoted fibrocartilage formation at the healing interface by 28 days, with improvements in tendon-bone maturity, organization, and continuity. Treatment led to improved biomechanical properties. The material property strength (2.43 vs 1.89 N/m2; P = .046) and the structural property work to failure (29.01 vs 18.09 mJ; P = .030) were increased in treated relative to control repairs at 28 days and 56 days, respectively. Treatment had a marginal effect on bone morphometry underlying the repair. Trabecular thickness (0.08 vs 0.07 mm; P = .035) was increased at 28 days. Hedgehog agonist treatment activated hedgehog signaling at the tendon-to-bone repair site and prompted increased mineralized fibrocartilage production. This extracellular matrix production and mineralization resulted in improved biomechanical properties, demonstrating the therapeutic potential of hedgehog agonism for improving tendon-to-bone healing after rotator cuff repair. This study demonstrates the therapeutic potential of hedgehog agonist treatment for improving tendon-to-bone healing after rotator cuff injury and repair.


Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury.
The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.


Toward Understanding the Formation Mechanism and OER Catalytic Mechanism of Hydroxides by In Situ and Operando Techniques.
Developing efficient and affordable electrocatalysts for the sluggish oxygen evolution reaction (OER) remains a significant barrier that needs to be overcome for the practical applications of hydrogen production via water electrolysis, transforming CO2 to value-added chemicals, and metal-air batteries. Recently, hydroxides have shown promise as electrocatalysts for OER. In situ or operando techniques are particularly indispensable for monitoring the key intermediates together with understanding the reaction process, which is extremely important for revealing the formation/OER catalytic mechanism of hydroxides and preparing cost-effective electrocatalysts for OER. However, there is a lack of comprehensive discussion on the current status and challenges of studying these mechanisms using in situ or operando techniques, which hinders our ability to identify and address the obstacles present in this field. This review offers an overview of in situ or operando techniques, outlining their capabilities, advantages, and disadvantages. Recent findings related to the formation mechanism and OER catalytic mechanism of hydroxides revealed by in situ or operando techniques are also discussed in detail. Additionally, some current challenges in this field are concluded and appropriate solution strategies are provided.


Ceramides mediate cigarette smoke-induced metabolic disruption in mice.
Cigarette smoke exposure increases lung ceramide biosynthesis and alters metabolic function. We hypothesized that ceramides are released from the lung during cigarette smoke exposure and result in elevated skeletal muscle ceramide levels, resulting in insulin resistance and altered mitochondrial respiration. Employing cell and animal models, we explored the effect of cigarette smoke on muscle cell insulin signaling and mitochondrial respiration. Muscle cells were treated with conditioned medium from cigarette smoke extract (CSE)-exposed lung cells, followed by analysis of ceramides and assessment of insulin signaling and mitochondrial function. Mice were exposed to daily cigarette smoke and a high-fat, high-sugar (HFHS) diet with myriocin injections to inhibit ceramide synthesis. Comparisons were conducted between these mice and control animals on standard diets in the absence of smoke exposure and myriocin injections. Muscle cells treated with CSE-exposed conditioned medium were completely unresponsive to insulin stimulation, and mitochondrial respiration was severely blunted. These effects were mitigated when lung cells were treated with the ceramide inhibitor myriocin prior to and during CSE exposure. In mice, daily cigarette smoke exposure and HFHS diet resulted in insulin resistance, which correlated with elevated ceramides. Although myriocin injection was protective against insulin resistance with either smoke or HFHS, it was insufficient to prevent insulin resistance with combined CS and HFHS. However, myriocin injection restored muscle mitochondrial respiration in all treatments. Ceramide inhibition prevents metabolic disruption in muscle cells with smoke exposure and may explain whole body insulin resistance and mitochondrial dysfunction in vivo.


Long-term advantages of permanent expandable implants in breast aesthetic surgery.
Permanent expandable implants are widely used in breast reconstructive surgery, but their use in aesthetic surgery is still uncommon. Previous reports on breast expansion-augmentation using permanent expandable implants focused on immediate and early advantages but failed to evaluate long-term benefits, because the reservoir was removed a few months after implantation and the ability to adjust the implant size was lost. Since 1986, we have used permanent expandable implants in 129 women for unilateral or bilateral breast augmentation using the following approach: implants were positioned submuscularly through a transaxillary incision; the filling port was placed a few centimeters below the incision and permanently retained; the implants were positioned underinflated and then overexpanded starting 2 weeks after implantation; after a period of overinflation, deflation to the preoperatively planned volume was scheduled; patients' suggestions regarding final volume adjustments were followed; the effects of repeated overinflations and deflations were investigated in several different conditions. Permanent expandable implants offer unique long-term technical and psychological advantages in the management of highly demanding patients and in the following clinical situations: pregnancy, impending capsular contracture, contralateral progressive ptosis, tubular breasts(s), difficult mammographic examination, spontaneous deflation, and rippling. Disadvantages include economical cost, port-related problems, and repeated requests by patients for volume changes. Saline permanent expandable implants allowed less flexibility in adjusting the breast size and caused discomfort when overexpanded. Permanent expandable implants in breast aesthetic surgery offer several advantages, and because patients can play an active role in deciding volume adjustments, compliance is very high.


Shared cytogenetic abnormalities in lung-tumors and corresponding peripheral-blood lymphocytes.
We analyzed chromosomal alterations in primary lung tumours and peripheral blood lymphocytes (PBLs) from 10 lung cancer patients (nine with non-small cell lung carcinoma and one with small cell lung carcinoma) to determine whether there were shared chromosomal changes in the normal and diseased tissue of these cases. This study revealed that each paired sample had at least three chromosomes and two chromosomal regions in common for structural rearrangements. The chromosomes most frequently found structurally altered in paired analysis were 1 and 3 (60% each), 5 (50%), 6, 7, and 9 (40% each), and 14 (30%). Chromosome region 3p13-3p21 was structurally rearranged in both the normal and tumour tissues of three patients. Chromosome 3 was structurally rearranged in all ten tumours. The chromosome arms most commonly affected in the tumours were 3p (nine times), 9p and 5q (eight times each), Ip and 7q (six times each), 10q and 11q (five times each), 14q and 6q (four times each). The most frequently affected chromosomal regions in these tumours were (in decreasing order) 9p23-p24, 3p21-3p13, 5q11, 1p34, 7q22, and 11q13. Frequent polysomy of 7 and 12 and loss of D-group chromosomes were also observed in the tumours analyzed. Comparing the changes found only in tumours with those found in both PBLs and tumours was helpful in shedding some light on the probable sequence of genetic events leading to lung cancer. This investigation also offered compelling evidence that genomic instability at the chromosomal level in PBLs corresponds with the genetic changes observed in tumours indicating that PBL analysis can help identify the early chromosomal changes in lung cancer. PBL chromosomal analysis thus has a promising future in the genetic analysis of lung cancers.


Integration of an abdominal Hox complex with Pax2 yields cell-specific EGF secretion from Drosophila sensory precursor cells.
Cis-regulatory modules (CRMs) ensure specific developmental outcomes by mediating both proper spatiotemporal gene expression patterns and appropriate transcriptional levels. In Drosophila, the precise transcriptional control of the serine protease rhomboid regulates EGF signaling to specify distinct cell types. Recently, we identified a CRM that activates rhomboid expression and thereby EGF secretion from a subset of abdominal sensory organ precursor cells (SOPs) to induce an appropriate number of lipid-processing cells called oenocytes. Here, we use scanning mutagenesis coupled with reporter assays, biochemistry and genetics to dissect the transcriptional mechanisms regulating SOP-specific rhomboid activation. Our results show that proper spatial activity of the rhomboid CRM is dependent upon direct integration of the abdomen-specific Hox factor Abdominal-A and the SOP-restricted Pax2 factor. In addition, we show that the Extradenticle and Homothorax Hox co-factors are differentially integrated on the rhomboid CRM by abdominal versus thoracic Hox proteins in the presence of Pax2. Last, we show that Abdominal-A uses both Pax2-dependent and Pax2-independent mechanisms to stimulate rhomboid CRM activity to induce proper oenocyte numbers. Thus, these data demonstrate how a CRM integrates Hox and neural transcriptional inputs to regulate the appropriate spatial pattern and levels of EGF secretion to specify an essential cell fate.


Progression of normotensive adolescents to hypertensive adults: a study of 26,980 teenagers.
Although prehypertension at adolescence is accepted to indicate increased future risk of hypertension, large-scale/long follow-up studies are required to better understand how adolescent blood pressure (BP) tracks into young adulthood. We studied 23 191 male and 3789 female adolescents from the Metabolic Lifestyle and Nutrition Assessment in Young Adults cohort (mean age: 17.4 years) with BP <140/90 mm Hg at enrollment or categorized by current criteria for pediatric BP and body mass index (BMI) values. Participants were prospectively followed up with repeated BP measurements between ages 25 and 42 years and retrospectively between ages 17 and 25 years for the incidence of hypertension. We identified 3810 new cases of hypertension between ages 17 and 42 years. In survival analyses, the cumulative risk of hypertension between ages 17 and 42 years was 3 to 4 times higher in men than in women. Using Cox regression models adjusted for age, BMI, and stratified by baseline BP, the hazard ratio of hypertension increased gradually across BP groups within the normotensive range at age 17 years, without a discernible threshold effect, reaching a hazard ratio of 2.50 (95% CI: 1.75 to 3.57) for boys and 2.31 (95% CI: 0.71 to 7.60) for girls in the group with BP at 130 to 139/85 to 89 mm Hg. BMI at age 17 years was strongly associated with future risk of hypertension even when adjusted to BP at age 17 years, particularly in boys. Yet, BMI at age 30 years attenuated this association, more evidently in girls. In conclusion, BP at adolescence, even in the low-normotensive range, linearly predicts progression to hypertension in young adulthood. This progression and the apparent interaction between BP at age 17 years and BMI at adolescence and at adulthood are sex dependent.


Ultrastructural localization of lectin-binding sites on the zonae pellucidae and plasma membranes of mammalian eggs.
Receptors for Ricinus communis agglutinin I (RCAI), concanavalin A (Con A), and wheat germ agglutinin (WGA) were localized on the zonae pellucidae and plasma membranes of hamster, mouse, and rat eggs with ferritin-lectin conjugates. Intact eggs labeled with the ferritin conjugates showed dense concentrations of RCAI and WGA receptors in the outermost regions of their zonae pellucidae and sparse distributions of Con A receptors throughout the zonae. Ferritin-lectin labeling was specific, since inhibitory saccharides effectively blocked labeling. The asymmetric density of RCAI receptors across the zona was confirmed by ferritin-RCAI and fluorescein-RCAI labeling of mechanically isolated zonae pellucidae, indicating that the RCAI-binding sites are more densely distributed in the exterior zona regions. Plasma membranes of rodent eggs contained RCAI, WGA, and Con A receptors. These receptors were found to be more or less randomly distributed on surfaces of aldehyde-fixed eggs or on eggs labeled near 0 degrees C. However, eggs incubated at 25 degrees C showed aggregated WGA- and Con A-binding site distributions on their plasma membranes. This indicates that lectin-induced receptor redistribution occurs at this temperature. The possibility that plasma membrane receptor mobility is a requirement for sperm-egg fusion is discussed.


Robust output feedback control of nonlinear stochastic systems using neural networks.
We present an adaptive output feedback controller for a class of uncertain stochastic nonlinear systems. The plant dynamics is represented as a nominal linear system plus nonlinearities. In turn, these nonlinearities are decomposed into a part, obtained as the best approximation given by neural networks, plus a remaining part which is treated as uncertainties, modeling approximation errors, and neglected dynamics. The weights of the neural network are tuned adaptively by a Lyapunov design. The proposed controller is obtained through robust optimal design and combines together parameter projection, control saturation, and high-gain observers. High performances are obtained in terms of large errors tolerance as shown through simulations.


CC family chemokines directly regulate myoblast responses to skeletal muscle injury.
Chemokines have been implicated in the promotion of leucocyte trafficking to diseased muscle. The purpose of this study was to determine whether a subset of inflammatory chemokines are able to directly drive myoblast proliferation, an essential early component of muscle regeneration, in a manner which is entirely independent of leucocytes. Cultured myoblasts (C2C12) were exposed to monocyte chemoattractant protein-1 (MCP-1; CCL2), macrophage inflammatory protein-1alpha (MIP-1alpha; CCL3) or MIP-1beta (CCL4). All chemokines induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and greatly increased myoblast proliferative responses. Chemokine-induced myoblast proliferation was abolished by pertussis toxin and the MEK1/2 inhibitor U0126, implicating both Galphai-coupled receptors and ERK1/2-dependent signalling. Myoblasts expressed receptors for all of the chemokines tested, and mitogenic responses were specifically inhibited by antibodies directed against CC family chemokine receptors 2 and 5 (CCR2 and CCR5). Within an in vitro myogenic wound healing assay devoid of leucocytes, all chemokines significantly accelerated the time course of myoblast wound closure after mechanical injury. Injections of MCP-1 into cardiotoxin-injured skeletal muscles in vivo also suppressed expression of the differentiation marker myogenin, consistent with a mitogenic effect. Taken together, our results indicate that CC chemokines have potent and direct effects on myoblast behaviour, thus indicating a novel role in muscle repair beyond leucocyte chemoattraction. Therefore, interventions aimed at modulating the balance between myoblast and leucocyte effects of CC chemokines in injured muscle could represent a novel strategy for the treatment of destructive muscle pathologies.


Escherichia coli avoids high dissolved oxygen stress by activation of SoxRS and manganese-superoxide dismutase.
High concentrations of reactive oxygen species (ROS) were reported to cause oxidative stress to E. coli cells associated with reduced or inhibited growth. The high ROS concentrations described in these reports were generated by exposing the bacteria to H2O2 and superoxide-generating chemicals which are non-physiological growth conditions. However, the effect of molecular oxygen on oxidative stress response has not been evaluated. Since the use of oxygen-enriched air is a common strategy to support high density growth of E. coli, it was important to investigate the effect of high dissolved oxygen concentrations on the physiology and growth of E. coli and the way it responds to oxidative stress. To determine the effect of elevated oxygen concentrations on the growth characteristics, specific gene expression and enzyme activity in E. coli, the parental and SOD-deficient strain were evaluated when the dissolved oxygen (dO2) level was increased from 30% to 300%. No significant differences in the growth parameters were observed in the parental strain except for a temporary decrease of the respiration and acetate accumulation profile. By performing transcriptional analysis, it was determined that the parental strain responded to the oxidative stress by activating the SoxRS regulon. However, following the dO2 switch, the SOD-deficient strain activated both the SoxRS and OxyR regulons but it was unable to resume its initial growth rate. The transcriptional analysis and enzyme activity results indicated that when E. coli is exposed to dO2 shift, the superoxide stress regulator SoxRS is activated and causes the stimulation of the superoxide dismutase system. This enables the E. coli to protect itself from the poisoning effects of oxygen. The OxyR protecting system was not activated, indicating that H2O2 did not increase to stressing levels.


Sensitivity to change of the Beach Questionnaire to behaviour, attitudes and knowledge related to sun exposure: quasi-experimental before-after study.
Health questionnaires must present accredited measurement properties such as validity, reliability and sensitivity to change, the latter being essential for interventions to be planned and for evaluating their effectiveness. The aim of this study was to evaluate the sensitivity to change of a Beach Questionnaire. Quasi-experimental before-after study carried out in 2011, for a study population of adolescents attending schools in the Costa del Sol. First, the questionnaire was administered to the adolescents, after which a multicomponent educational intervention was carried out; finally, three months later, the same questionnaire was re-administered to the same adolescents. Changes were assessed in the categories of each item, using the McNemar test, and the changes in the scores, standardised to a range of 0-100, using the Student t test for paired samples, and including the mean of the differences and the 95% confidence interval. The level of statistical significance was set at p < 0.05. 228 adolescents, aged 14-17 years, and 55.3% were girls. Statistically significant changes were observed in sunburn experiences, exposure to the sun at mid-day and attitudes to sun exposure and suncreams. For the seven items related to knowledge about sun exposure, a higher rate of correct answers was observed. The analysis of changes, within the standardised range, revealed a significant improvement in the scores for sun exposure habits (MD 4.33; CI 95% 2.2-6.5), attitudes to sun exposure (MD 2.22; CI 95% 1.2-3.2) and knowledge (MD 9.10; CI 95% 7.1-11.1), but not in those for sun-protection practices (MD 0.23; CI 95% -1.2-1.7). The Beach Questionnaire on behaviour, attitudes and knowledge related to sun exposure is the first such instrument in Spanish language to provide sufficient sensitivity to change. It constitutes a useful tool for epidemiologic research into photoprotection and for skin cancer prevention programmes.


Effect of Cr(III) Adsorption on the Dissolution of Boehmite Nanoparticles in Caustic Solution.
The incorporation of relatively minor impurity metals onto metal (oxy)hydroxides can strongly impact solubility. In complex highly alkaline multicomponent radioactive tank wastes such as those at the Hanford Nuclear Reservation, tests indicate that the surface area-normalized dissolution rate of boehmite (γ-AlOOH) nanomaterials is at least an order of magnitude lower than that predicted for the pure phase. Here, we examine the dissolution kinetics of boehmite coated by adsorbed Cr(III), which adheres at saturation coverages as sparse chemisorbed monolayer clusters. Using 40 nm boehmite nanoplates as a model system, temperature-dependent dissolution rates of pure versus Cr(III)-adsorbed boehmite showed that the initial rate for the latter is consistently several times lower, with an apparent activation energy 16 kJ·mol-1 higher. Although the surface coverage is only around 50%, solution analysis coupled to multimethod solids characterization reveal a phyicochemical armoring effect by adsorbed Cr(III) that substantially reduces the number of dissolution-active sites on particle surfaces. Such findings could help improve kinetics models of boehmite and/or metal ion adsorbed boehmite nanomaterials, ultimately providing a stronger foundation for the development of more robust complex radioactive liquid waste processing strategies.


[Stabilizing action of heavy water (D20) on the cell].
Literature data and our own findings show convincingly that heavy water (D2O) stabilizing proteins against denaturants and proteinases increases cell thermostability in plants and animals and that of microorganisms. In Drosophila, along with cell and organism thermostabilities, it enhances thermophilia. Evidence is given in favour of the suggestion that the protein stabilization is responsible for the above biological effects of D2O, although heavy water may increase the melting temperature of nucleic acids and, but slightly, of lipids.


Wild-type and mutant forms of the pyruvate dehydrogenase multienzyme complex from Bacillus subtilis.
A simple procedure is described for the purification of the pyruvate dehydrogenase complex and dihydrolipoamide dehydrogenase from Bacillus subtilis. The method is rapid and applicable to small quantities of bacterial cells. The purified pyruvate dehydrogenase complex (s0(20),w = 73S) comprises multiple copies of four different types of polypeptide chain, with apparent Mr values of 59 500, 55 000, 42 500 and 36 000: these were identified as the polypeptide chains of the lipoate acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3) and the two types of subunit of the pyruvate decarboxylase (E1) components respectively. Pyruvate dehydrogenase complexes were also purified from two ace (acetate-requiring) mutants of B. subtilis. That from mutant 61142 was found to be inactive, owing to an inactive E1 component, which was bound less tightly than wild-type E1 and was gradually lost from the E2E3 subcomplex during purification. Subunit-exchange experiments demonstrated that the E2E3 subcomplex retained full enzymic activity, suggesting that the lesion was limited to the E1 component. Mutant 61141R elaborated a functional pyruvate dehydrogenase complex, but this also contained a defective E1 component, the Km for pyruvate being raised from 0.4 mM to 4.3 mM. The E1 component rapidly dissociated from the E2E3 subcomplex at low temperature (0-4 degrees C), leaving an E2E3 subcomplex which by subunit-exchange experiments was judged to retain full enzymic activity. These ace mutants provide interesting opportunities to analyse defects in the self-assembly and catalytic activity of the pyruvate dehydrogenase complex.


Modification of the mechanical cardiac performance during end-expiratory voluntary apnea recorded with ballistocardiography and seismocardiography.
To assess if micro-accelerometers and gyroscopes may provide useful information for the detection of breathing disturbances in further studies. Forty-three healthy volunteers performed a 10 s end-expiratory breath-hold, while ballistocardiograph (BCG) and seismocardiograph (SCG) determined changes in kinetic energy and its integral over time (iK, J · s). BCG measures overall body accelerations in response to blood mass ejection into the main vasculature at each cardiac cycle, while SCG records local chest wall vibrations generated beat-by-beat by myocardial activity. This minimally intrusive technology assesses linear accelerations and angular velocities in 12 degrees of freedom to calculate iK during the whole cardiac cycle. iK produced during systole and diastole were also computed. The iK during normal breathing was 87.1 [63.3; 132.8] µJ · s for the SCG and 4.5 [3.3; 6.2] µJ · s for the BCG. Both increased to 107.1 [69.0; 162.0] µJ · s and 6.1 [4.4; 9.0] µJ · s, respectively, during breath-holding (p = 0.003 and p < 0.0001, respectively). The iK of the SCG further increased during spontaneous respiration following apnea (from 107.1 [69.0; 162.0] µJ · s to 160.0 [96.3; 207.3] µJ · s, p < 0.0001). The ratio between the iK of diastole and systole increased from 0.35 [0.24; 0.45] during apnea to 0.49 [0.31; 0.80] (p < 0.0001) during the restoration of respiration. A brief voluntary apnea generates large and distinct increases in SCG and BCG waveforms. iK monitoring during sleep may prove useful for the detection of respiratory disturbances. ClinicalTrials.gov number: NCT03760159.


Enhancing a cancer prevention and control curriculum through interactive group discussions.
The Principles and Practice of Cancer Prevention and Control course (Principles course) is offered annually by the National Cancer Institute Cancer Prevention Fellowship Program. This 4-week postgraduate course covers the spectrum of cancer prevention and control research (e.g., epidemiology, laboratory, clinical, social, and behavioral sciences) and is open to attendees from medical, academic, government, and related institutions across the world. In this report, we describe a new addition to the Principles course syllabus, which was exclusively a lecture-based format for over 20 years. In 2011, cancer prevention fellows and staff designed and implemented small group discussion sessions as part of the curriculum. The goals of these sessions were to foster an interactive environment, discuss concepts presented during the Principles course, exchange ideas, and enhance networking among the course participants and provide a teaching and leadership opportunity to current cancer prevention fellows. Overall, both the participants and facilitators who returned the evaluation forms (n=61/87 and 8/10, respectively) reported a high satisfaction with the experience for providing both an opportunity to explore course concepts in a greater detail and to network with colleagues. Participants (93%) and facilitators (100%) stated that they would like to see this component remain a part of the Principles course curriculum, and both groups provided recommendations for the 2012 program. The design, implementation, and evaluation of this initial discussion group component of the Principles course are described herein. The findings in this report will not only inform future discussion group sessions in the Principles course but may also be useful to others planning to incorporate group learning into large primarily lecture-based courses.


Astaxanthin attenuates neuroinflammation contributed to the neuropathic pain and motor dysfunction following compression spinal cord injury.
Spinal cord injury (SCI) is a debilitating condition in which inflammatory responses in the secondary phase of injury leads to long lasting sensory-motor dysfunction. The medicinal therapy of SCI complications is still a clinical challenge. Understanding the molecular pathways underlying the progress of damage will help to find new therapeutic candidates. Astaxanthin (AST) is a ketocarotenoid which has shown anti-inflammatory effects in models of traumatic brain injury. In the present study, we examined its potential in the elimination of SCI damage through glutamatergic-phospo p38 mitogen-activated protein kinase (p-p38MAPK) signaling pathway. Inflammatory response, histopathological changes and sensory-motor function were also investigated in a severe compression model of SCI in male rats. The results of acetone drop and inclined plane tests indicated the promising role of AST in improving sensory and motor function of SCI rats. AST decreased the expression of n-methyl-d-aspartate receptor subunit 2B (NR2B) and p-p38MAPK as inflammatory signaling mediators as well as tumor necrosis factor-α (TNF-α) as an inflammatory cytokine, following compression SCI. The histopathological study culminated in preserved white mater and motor neurons beyond the injury level in rostral and caudal parts. The results show the potential of AST to inhibit glutamate-initiated signaling pathway and inflammatory reactions in the secondary phase of SCI, and suggest it as a promising candidate to enhance functional recovery after SCI.


Determining the inhibition constants in the HCH-1 model of cellulose hydrolysis.
The products of cellulose hydrolysis, glucose and cellobiose, caused noncompetitive inhibition patterns to be exhibited when Thermomonospora sp. YX cellulase hydrolyzed dyed cellulose. The glucose binding constant, beta(1), was 0.00683 +/- 0.00031 L/g and the cellobiose binding constant, beta(2), was 0.095 +/- 0.0058 L/g. Thus, cellobiose was about 14 times more inhibitory than glucose.


Changes in murine respiratory dynamics induced by aerosolized carfentanil inhalation: Efficacy of naloxone and naltrexone.
Carfentanil (CRF) is an extremely potent opioid capable of inducing fatal respiratory depression. Naloxone (NX) and naltrexone (NTX) are opioid antagonists for which the efficacy against CRF remains largely unexplored. In this study, the effects of aerosolized CRF on respiratory function were investigated using adult male CD-1 mice. Mice were exposed to 0.4 mg/m3 of CRF for 15 min using custom whole-body plethysmograph units. Minute volume (MV), respiratory frequency (f), duty cycle (DC), and tidal volume (TV) were monitored and compared to control animals exposed to aerosolized H2O. CRF exposure induced respiratory depression, characterized by a marked decrease in MV, which was sustained throughout 24 h post-exposure. Prophylactic and therapeutic treatment with intramuscular (i.m.) NX marginally improved MV, with slight dose-dependent effects. Analogous treatment with i.m. NTX returned MV to baseline levels, with all doses and intervention times performing similarly. Despite improvements in MV, treatment administration did not reverse changes in DC, a measure of respiratory timing. Overall, NX and NTX administration alleviated volumetric aspects of opioid-induced respiratory toxicity, while changes in respiratory timing remained unresolved throughout post-exposure observation. These sustained changes and differences in recovery between two aspects of respiratory dynamics may provide insights for further exploration into the underlying mechanism of action of opioids and opioid antagonists.


Methylene blue localizations of pulmonary nodules under CT-guidance: a new procedure used before thoracoscopic resections.
With the expending use of video-assisted thoracoscopy for a wide range of indications, we present our experience of CT-guided localizations of pulmonary nodules with methylene blue injections before their thoracoscopic resections. This technique was developed for deep non-palpable nodules of small size. Forty seven nodules in 44 patients were preoperatively localized under CT guidance and marked with methylene blue injections. The localizations under CT guidance of the 47 nodules were successful in all cases. The surgeon confirmed accurate localization of 46 nodules. In one case, the injected methylene blue could not be identified during thoracoscopy. Complications of this technique included 7 cases of asymptomatic pneumothorax, 5 cases of local and asymptomatic pulmonary hemorrhage, and 2 cases of fits of coughing. Because of this technique, 46 diagnostic thoracotomies could be avoided. CT guided localization with methylene blue injection is a simple and rapid technique enabling good thoracoscopic surgery results.


The Spatiotemporal Limits of Developmental Erk Signaling.
Animal development is characterized by signaling events that occur at precise locations and times within the embryo, but determining when and where such precision is needed for proper embryogenesis has been a long-standing challenge. Here we address this question for extracellular signal regulated kinase (Erk) signaling, a key developmental patterning cue. We describe an optogenetic system for activating Erk with high spatiotemporal precision in vivo. Implementing this system in Drosophila, we find that embryogenesis is remarkably robust to ectopic Erk signaling, except from 1 to 4 hr post-fertilization, when perturbing the spatial extent of Erk pathway activation leads to dramatic disruptions of patterning and morphogenesis. Later in development, the effects of ectopic signaling are buffered, at least in part, by combinatorial mechanisms. Our approach can be used to systematically probe the differential contributions of the Ras/Erk pathway and concurrent signals, leading to a more quantitative understanding of developmental signaling.


Deregulated MAPK activity prevents adipocyte differentiation of fibroblasts lacking the retinoblastoma protein.
A functional retinoblastoma protein (pRB) is required for adipose conversion of preadipocyte cell lines and primary mouse embryo fibroblasts (MEFs) in response to treatment with standard adipogenic inducers. Interestingly, lack of functional pRB in MEFs was recently linked to elevated Ras activity. Ras-dependent signaling plays a significant, although incompletely understood, role in adipocyte differentiation, because activated Ras has been reported to either promote or inhibit adipogenesis depending on the cellular context. In various cell types activation of Ras leads to activation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (PKB)/Akt, which exert opposing effects on adipogenesis, with ERK1/2 inhibiting and PKB/Akt promoting terminal differentiation. Here we report that the levels of activated ERK1/2 and PKB/Akt are significantly increased in pRB-deficient MEFs both before and after the addition of adipogenic inducers. Consistently, we detected higher levels of activated Ras in MEFs lacking pRB. Suppression of ERK1/2 activation by the MEK inhibitor UO126 restored the ability of pRB-deficient MEFs to undergo adipocyte differentiation, as manifested by expression of adipocyte marker genes and lipid accumulation. Furthermore and reflecting the elevated levels of activated PKB/Akt in the pRB-deficient MEFs, differentiation proceeded in an insulin-independent manner. In conclusion, we suggest that pRB plays a pivotal role in adipogenesis by suppressing MAPK activity.


CEP-1347/KT7515, a JNK pathway inhibitor, supports the in vitro survival of chick embryonic neurons.
Developing neurons depend on target-derived trophic factors for survival in vivo and in vitro, which also decrease the activity of c-Jun N-terminal kinase (JNK). We have recently described a survival-promoting effect of inhibitors of cyclin-dependent kinases and JNK on chick peripheral embryonic neurons. Here, we report that the small trophic molecule CEP-1347/KT7515, which has been shown to inhibit the JNK signalling pathway, can promote long term-survival of cultured chick embryonic dorsal root ganglion, sympathetic, ciliary and motor neurons. Because of their pharmacological properties, small trophic molecules such as CEP-1347/KT7515 might be of interest for the treatment of neurodegenerative disorders.


Outcomes of early delirium diagnosis after general anesthesia in the elderly.
Postoperative delirium in the elderly, measured days after surgery, is associated with significant negative clinical outcomes. In this study, we evaluated the prevalence and in-hospital outcomes of delirium diagnosed immediately after general anesthesia and surgery in elderly patients. Consecutive English-speaking surgical candidates, aged 70 years or older, were prospectively enrolled during July to August 2010. After surgery, each participant was evaluated for a Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of delirium in the postanesthesia care unit (PACU) and repeatedly thereafter while hospitalized. Delirium in the PACU was evaluated for an independent association with change in cognitive function from preoperative baseline testing and discharge disposition. Ninety-one (58% female) patients, 78% of whom were living independently before surgery, were found to have a prevalence of delirium in the PACU of 45% (41/91); 74% (14/19) of all delirium episodes detected during subsequent hospitalization started in the PACU. Early delirium was independently associated with impaired cognition (i.e., decreased category word fluency) relative to presurgery baseline testing (adjusted difference [95% confidence interval] for change in T-score: -6.02 [-10.58 to -1.45]; P = 0.01). Patients whose delirium had resolved by postoperative day 1 showed negative outcomes that were intermediate in severity between those who were never delirious during hospitalization and those whose delirium in the PACU persisted after transfer to hospital wards (adjusted probability [95% confidence interval] of discharge to institution: 3% [0%-10%], 26% [1%-51%], 39% [0%-81%] for the 3 groups, respectively). Delirium in the PACU is common, but not universal. It is associated with subsequent delirium on the ward, and potentially with a decline in cognitive function and increased institutionalization at hospital discharge.


[Comparative studies on the repetitive DNA sequences of diploid and triploid forms of Paragonimus westermani by restriction endonuclease and Southern blotting].
Restriction enzyme digestion of total genomic DNA of two chromosomes forms of Paragonimus westermani showed the presence of homologous highly repeated DNA in both diploid and triploid forms. Southern blotting analysis provided further evidence that the distribution of restriction enzyme sites (with 3 enzymes) on repetitive sequence of DNA of both forms were similar. However, with Pstl, Ddel, HaeIII and HpaII, their polymorphism revealed differences which were also found in each form tested separately with the hybridization technique. The present study, at the molecular level, supports the previously reported biological and biochemical results that they might be considered as different isolates or forms. It is suggested that PstI, DdeI, HaeIII and HpaII digestion pattern might be useful to distinguish the diploid from the triploid forms of Paragonimus westermani.


An automated approach for early detection of diabetic retinopathy using SD-OCT images.
This study was to demonstrate the feasibility of an automatic approach for early detection of diabetic retinopathy (DR) from SD-OCT images. These scans were prospectively collected from 200 subjects through the fovea then were automatically segmented, into 12 layers. Each layer was characterized by its thickness, tortuosity, and normalized reflectivity. 26 diabetic patients, without DR changes visible by funduscopic examination, were matched with 26 controls, according to age and sex, for purposes of statistical analysis using mixed effects ANOVA. The INL was narrower in diabetes (p = 0.14), while the NFL (p = 0.04) and IZ (p = 0.34) were thicker. Tortuosity of layers NFL through the OPL was greater in diabetes (all p < 0.1), while significantly greater normalized reflectivity was observed in the MZ and OPR (both p < 0.01) as well as ELM and IZ (both p < 0.5). A novel automated method enables to provide quantitative analysis of the changes in each layer of the retina that occur with diabetes. In turn, carries the promise to a reliable non-invasive diagnostic tool for early detection of DR.


Dietary Supplement Consumption and Mental Health in Indonesian Adults During Second Wave of COVID-19 Pandemic.
This study aimed to measure supplement consumption behavior and mental health status among Indonesian adults during the second year of COVID-19. Online questionnaire regarding supplement consumption, and Depression, Anxiety, Stress Scale 21 (DASS-21) was distributed from March to June 2021 and obtained 1006 valid and completed questionnaires. Descriptive and inferential analyses were conducted to determine the frequency and predictor factors of the respondents' supplement consumption behavior and mental health status. Respondents were divided into two groups, vulnerable and non-vulnerable individuals. The finding showed that 34.5% respondents were vulnerable individuals, including the elderly and those with comorbid disease(s). The vulnerable and non-vulnerable groups exhibited a high prevalence of supplement consumption, with the vulnerable group demonstrating a greater tendency for regular use. The incidence of mental health problems in both groups did not significantly differ (23-38%), where anxiety was higher than depression and stress. Supplement consumption was associated with mental health status. Several positive predicting factors for supplement consumption behavior included older age, higher economic status, and higher education. While the younger age and unmarried respondents were more likely to develop mental health problems. Taken together, given dietary supplement consumption increased during the pandemic and the potential associations between supplement consumption and mental health, controlling the correct information and regulation regarding supplements, especially their risks and benefits, was important. Additionally, support for mental health issues was necessary, since it might affect self-medication behavior.


Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson's disease.
Patients with Parkinson's disease (PD) are known to experience autonomic nervous system dysfunction: this disruptive symptomatology includes urinary urgency, frequency, and nocturnal polyuria. Anticholinergic and tricyclic medications can be beneficial in controlling these urinary symptoms, but have unpleasant side effects in some patients. Desmopressin has been used to treat nocturnal polyuria successfully in a number of conditions, such as central diabetes insipidus, enuresis, and autonomic failure. The purpose of the present study was to assess the efficacy of desmopressin in patients with PD with significant nocturia. Eight patients were recruited into the study. They were first asked to establish a baseline of number of nocturnal voids; the patients were then prescribed the intranasal form of desmopressin and asked to continue to record the number of nocturnal voids. The five patients who completed the trial demonstrated clinically and statistically significant reductions in the frequency of nocturnal voids. One patient became hyponatremic and confused during desmopressin administration; his symptoms resolved soon after the desmopressin was discontinued. Two patients failed to complete the trial due to compliance problems. Thus, desmopressin appears to be a safe and effective medication for nocturnal polyuria in PD.


Characterization of new members of the group 3 outer membrane protein family of Brucella spp.
Impairment of the omp25 gene in Brucella spp. leads to attenuated strains and confers protection to the host. Omp25 and Omp31, whose functions remain unknown, were the first characterized members of group 3 outer membrane proteins (Omps) (25 to 34 kDa). Recently, genomic and proteomic approaches identified five new putative members of this family, some of which are produced in B. melitensis or B. abortus. In the present study, using protein microsequencing, we identified new members of group 3 Omps proteins produced in B. suis. Since several monoclonal antibodies (MAbs) against Omp25 cross-reacted with other members of group 3 Omps, we also performed Western immunoblotting to compare wild-type B. suis with mutants systematically having B. suis omp25-related genes knocked out. We demonstrate the production of three paralogs of Omp31 and/or Omp25 in B. suis, and the existence of a common site of signal peptide cleavage (AXAAD), which is very similar to that present in the five homologous Omps of Bartonella quintana. The seven group 3 Omps were classified in four-subgroups on the basis of percentage amino acid sequence identities: Omp25 alone, the Omp25b-Omp25c-Omp25d cluster, the Omp31/31b subgroup, and the less related Omp22 protein (also called Omp3b). Together with previous data, our results demonstrate that all new members of group 3 Omps are produced in B. suis or in other Brucella species and we propose a nomenclature that integrates all of these proteins to facilitate the understanding of future Brucella interspecies study results.


Muscarinic and antimuscarinic activity of acetamides related to oxotremorine in the guinea pig urinary bladder.
Eight acetamide analogs of oxotremorine, shown previously to be full or nearly full muscarinic agonists on the isolated guinea pig ileum, were investigated for muscarinic activity on muscle strips of guinea pig urinary bladder. Several compounds demonstrated pronounced organ selectivity when compared to carbachol by being partial agonists or antagonists on the bladder. For example, oxotremorine and BM 34, both potent, full agonists on the ileum, were partial agonists, the latter producing less than one-half the maximum response of carbachol. BM 5 elicited no significant response, but instead was a potent antagonist to carbachol. Schild analysis with BM 5 and BM 61 indicated no muscarinic receptor heterogeneity between the bladder and ileum. Also dissociation constants of agonists and partial agonists generally agreed with those determined previously on the ileum. Furthermore, the relative efficacy of each agonist appeared to be similar in the two tissues, confirming the homogeneity of muscarinic receptors in the bladder and ileum with respect to the compounds studied. Compounds having high affinity and low intrinsic efficacy, e.g., BM 5, thus may stimulate contractile responses on the ileum and block responses on the bladder and therefore display tissue selectivity without discriminating between tissue receptors. It is suggested that this selectivity is derived from a smaller effective receptor reserve for muscarinic agonists in the bladder.


Level of contamination with mycobiota and contents of mycotoxins from the group of trichothecenes in grain of wheat , oats, barley, rye and triticale harvested in Poland in 2006- 2008.
The risk of cereal exposure to microbial contamination is high and possible at any time, starting from the period of plant vegetation, through harvest, up to the processing, storage and transport of the final product. Contents of mycotoxins in grain are inseparably connected with the presence of fungal biomass, the presence of which may indicate the occurrence of a fungus, and indirectly also products of its metabolism. Analyses were conducted on 378 grain samples of wheat, triticale, barley, rye and oats collected from grain silos located at grain purchase stations and at mills in Poland in 2006, 2007 and 2008. The concentrations of ERG and mycotoxins from the group of trichothecenes, as well as CFU numbers were analysed. The tested cereals were characterised by similarly low concentrations of both the investigated fungal metabolites and the level of microscopic fungi. However, conducted statistical analyses showed significant variation between tested treatments. Oat and rye grain contained the highest amounts of ERG, total toxins and CFU. In turn, the lowest values of investigated parameters were found in grain of wheat and triticale. Chemometric analyses, based on the results of chemical and microbiological tests, showed slight differences between contents of analysed metabolites between the years of the study, and do not confirm the observations on the significance of the effect of weather conditions on the development of mycobiota and production of mycotoxins; however, it does pertain to treatments showing no significant infestation. Highly significant correlations between contents of trichothecenes and ERG concentration (higher than in the case of the correlation of the total toxin concentrations/log cfu/g), indicate that the level of this metabolite is inseparably connected with mycotoxin contents in grain.


[Research progress on immunohistochemical diagnostic markers for malignant pleural mesothelioma].
Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, characterized by insidious onset, strong local invasiveness, short survival period, and poor prognosis. Clinical diagnosis is of paramount importance for the treatment and prognosis of MPM. Currently, the gold standard for diagnosing MPM is the results of histopathological examinations. Immunohistochemistry (IHC) is an effective auxiliary method in pathological diagnosis. Preliminary examinations can use two positive markers and two negative markers to distinguish pleural metastatic tumors, with additional antibodies selected based on differential diagnosis. The combined use of IHC markers plays a crucial role in the differential diagnosis between MPM and other tumors. This article primarily introduces commonly used IHC markers in MPM and the research progress of novel IHC markers in screening and differential diagnosis, aiming to provide reference for the clinical diagnosis and treatment of MPM.


Combining genetic markers and clinical risk factors improves the risk assessment of impaired glucose metabolism.
Although several candidate gene polymorphisms (SNPs) have been associated with increased risk of type 2 diabetes mellitus (T2DM), relatively few studies have assessed the ability of T2DM candidate genes to assess the risk of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and T2DM beyond the information provided by clinical risk factors. To test whether the inclusion of genetic markers in a regression model provides a better assessment of the risk of IFG, IGT, and T2DM than a model based only on non-genetic risk factors commonly assessed in clinical settings. Subjects (n = 485; 213 parents, 272 offspring) from the Quebec Family Study, not known to haveT2DM, were measured for several risk factors and underwent an oral glucose tolerance test. Thirty-eight SNPs in 25 susceptibility/ candidate genes previously reported to be associated with T2DM were genotyped. In order to identify risk factors associated with IFG/IGT/T2DM, two logistic regression models were tested: a full model (FM) including age, sex, body mass index (BMI), systolic and diastolic blood pressure, smoking status, and the 38 SNPs; and a reduced model (RM), in which the SNPs were dropped, which allowed us to test the null-hypothesis that the markers are not associated with the risk of IFG/IGT/T2DM. Performances of the models were compared by using a likelihood ratio test and the receiver-operating characteristic curves (ROC).The area under the curve (AUC) was calculated from the ROC curve. The analyses showed that age (P < 0.0001), BMI (P < 0.0001), and six variants (IGF2BP2 rs4402960, P = 0.002; ADIPOQ+276 G>T, P = 0.004; UCP2Ala55Val, P = 0.01; CDKN2AI2B rs3731201, P = 0.02; rs495490, P = 0.02, and rsl 0811661, P = 0.03) were significantly associated with the risk of IFG/IGT/T2DM. Dropping genetic markers from the analysis significantly reduced the fit of the model to the data (chi-square = 38.98, P < 0.00001 contrasting RM to FM), suggesting that the genetic markers are significantly associated with the risk of IFG/IGT/T2DM. Furthermore, the AUC was higher for FM than for RM (0.85 (95% CI 0.81-0.89) versus 0.81 (95% CI 0.76-0.85), P = 0.004). Our results suggest that combining genetic markers with traditional clinical risk factors has the potential to improve our ability to assess the risk of complex diseases such as T2DM.


Homo crystallographicus--quo vadis?
As macromolecular crystal structures are determined and refined in an increasingly automated fashion, careful assessment of the reliability and quality of the resulting models becomes increasingly important. Here, we analyze various issues related to the reliability and quality of macromolecular crystal structures deposited between 1991 and 2000. We find that the average resolution at which these structures are determined is essentially constant. In line with this observation, the average quality as measured by Ramachandran analysis does not improve as a function of time. On the other hand, an observed decrease of the average discrepancy between free and conventional R values suggests that the fit of model and data is improving. Finally, we present a surprising correlation between the tendency of crystallographers to deposit their experimental data and the free R values of their models.


The Experiences of Young Adult Offenders Who Completed a Drug Court Treatment Program.
Although there has been a proliferation of studies on the effectiveness of drug court programs, these studies are largely quantitative in nature. Little is known about the experiences of persons who participate in drug court. In this study, we aimed to fill this knowledge gap by exploring experiences of young adults who completed an adult drug court treatment program. Nine semi-structured interviews were conducted, typed into a word-processing program, and then entered into a data analysis software program. Using grounded theory strategies, analysis revealed several emergent themes, which are presented chronologically to provide a narrative of study participants' experiences before, during, and after the program. Findings provide insights on how participants perceive drug courts and experiences that might facilitate or impede completion of drug court programs. Our findings are particularly important for drug court professionals as they attempt to develop appropriate recommendations for best practices and new policy initiatives.


Evaluation of an electronic health record-supported obesity management protocol implemented in a community health center: a cautionary note.
Primary care clinicians are well-positioned to intervene in the obesity epidemic. We studied whether implementation of an obesity intake protocol and electronic health record (EHR) form to guide behavior modification would facilitate identification and management of adult obesity in a Federally Qualified Health Center serving low-income, Hispanic patients. In three studies, we examined clinician and patient outcomes before and after the addition of the weight management protocol and form. In the Clinician Study, 12 clinicians self-reported obesity management practices. In the Population Study, BMI and order data from 5000 patients and all 40 clinicians in the practice were extracted from the EHR preintervention and postintervention. In the Exposure Study, EHR-documented outcomes for a sub-sample of 46 patients actually exposed to the obesity management form were compared to matched controls. Clinicians reported that the intake protocol and form increased their performance of obesity-related assessments and their confidence in managing obesity. However, no improvement in obesity management practices or patient weight-loss was evident in EHR records for the overall clinic population. Further analysis revealed that only 55 patients were exposed to the form. Exposed patients were twice as likely to receive weight-loss counseling following the intervention, as compared to before, and more likely than matched controls. However, their obesity outcomes did not differ. Results suggest that an obesity intake protocol and EHR-based weight management form may facilitate clinician weight-loss counseling among those exposed to the form. Significant implementation barriers can limit exposure, however, and need to be addressed.


Osteosynthesis of intra-articular fractures in the proximal interphalangeal joint with Kirschner wires.
Twenty-eight consecutive patients, aged 4-68 years, who had had an intra-articular fracture of the proximal interphalangeal (PIP) joint were reviewed retrospectively in 1996. All patients were operated on within a median of three days (range 0-26). Only three patients had open injuries while 11 had fracture-dislocations. A median of half the articular surfaces were involved, and dislocations ranged from 1-4 mm. Twelve patients had their fractures anatomically reduced and 13 had postoperative dislocations of less than 1 mm. Eighteen patients were reviewed after 10-49 months, and four were interviewed by telephone. The median reduction in range of movement in the PIP joint at follow-up was 15 degrees (range 0-90 degrees). Nine patients had subjectively slightly reduced movements, and only three of 17 patients stated that they had limited movement. Ten patients had occasional pain, which eight described as mild and two as moderate. Two patients had ulnar instability less than 5 degrees, and the remainder were stable. Twelve patients had a cold sensation in the affected finger joint in cold weather. No patients had changed occupation as a result of their injury, and only two patients said that they were limited in any way in any activity at work or at home. Open and precise reduction and osteosynthesis with Kirschner (K) wires seems to be an effective treatment for most intra-articular fractures of PIP joints.


Dose-adjusted and dose/kg-adjusted concentrations of mycophenolic acid precursors reflect metabolic ratios of their metabolites in contrast with tacrolimus and cyclosporine.
Therapeutic drug monitoring is a valuable tool supporting immunosuppressive therapy. Significant variation of immunosuppressive drug (ISD) concentrations during their use at similar doses is the basis of dose-normalization strategy. The strategy of dose-adjustment is proposed to identify variability in the rate of ISD metabolism. While the parent drug-to-metabolite ratio (metabolic ratio, MR) represents the rate of formation of individual metabolites. The present study was aimed at evaluation of associations between ISDs' metabolism rate expressed as dose-adjusted concentrations (C/D) and dose/kg-adjusted concentrations (C/D/kg) and MRs of individual metabolites of tacrolimus, cyclosporine A and MPA precursors. 506 patients have participated: 284 males (56.13%) and 222 females (43.87%); 318 after kidney (62.85%) and 188 after liver transplantation; median age was 51.34 (39.32-59.95) years and median time after transplantation 78.92 (33.87-138.4) months. Generally, we have not observed significant relationships between dose-adjusted and dose/kg-adjusted concentrations and MRs of cyclosporine and tacrolimus. Significant correlations were found for: AM9/CsA and dMC-CsA/CsA in kidney transplant recipients and MIII/Tac, AM1/CsA and AM4N/CsA in liver transplant recipients. In contrast, MRs of mycophenolic acid (MPA) metabolites correlated significantly with MPA C/D and C/D/kg both in kidney and liver transplant recipients. In conclusion, easily available and easy to use in clinical practice C/D and C/D/kg ratios cannot be considered as parameters directly reflecting the rate of generation of major metabolites of cyclosporine and tacrolimus both in liver and kidney transplant recipients.


Body Mass Index, Overweight, and Obesity in Swedish Women Born Post-term.
There is increasing evidence that post-term birth (≥42 weeks of gestation) is associated with adverse long-term outcomes. We assessed whether women born post-term displayed increased risk of overweight and obesity in adulthood. Data were collected at first antenatal visit (~10-12 weeks of gestation) on singleton Swedish women aged ≥18 years in 1991-2009 (mean age 26.1 years), who were born post-term (n = 27 153) or at term (37-41 weeks of gestation; n = 184 245). Study outcomes were evaluated for continuous associations with gestational age. Stratified analyses were carried out comparing women born post-term or at term. Analyses were also run with a 2-week buffer between groups to account for possible errors in gestational age estimation, comparing women born very post-term (≥43 weeks of gestation; n = 5761) to those born within a narrower term window (38-40 weeks of gestation; n = 130 110). Increasing gestational age was associated with greater adult weight and body mass index (BMI). Stratified analyses showed that women born post-term were 0.5 kg heavier and had BMI 0.2 kg/m(2) greater than those born at term. Differences were more marked between women born very post-term (≥43 weeks) vs. a narrower term group (38-40 weeks): 1.0 kg and 0.3 kg/m(2) . The adjusted relative risks of overweight/obesity and obesity in women born very post-term were 1.13 and 1.12 times higher, respectively, than in those born at term. Post-term birth is associated with greater BMI and increased risk of overweight and obesity in adulthood, particularly among women born ≥43 weeks of gestation.


HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.
Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.


Mycobacterium leprae-specific T cells from a tuberculoid leprosy patient suppress HLA-DR3-restricted T cell responses to an immunodominant epitope on 65-kDa hsp of mycobacteria.
The polar tuberculoid type (TT) of leprosy, characterized by high T cell reactivity to Mycobacterium leprae, is associated with HLA-DR3. Surprisingly, DR3-restricted low T cell responsiveness to M. leprae was found in HLA-DR3-positive TT leprosy patients. This low responsiveness was specifically induced by M. leprae but not by M. tuberculosis and was seen only in patients and not in healthy controls. We studied this patient-specific, M. leprae-induced, DR3-restricted low T cell responsiveness in depth in one representative HLA-DR3-positive TT leprosy patient by using T cell clones. From this patient two types of T cell clones were obtained: one type was cross-reactive with M. tuberculosis and recognized an immunodominant epitope (amino acids 3 to 13) on the 65-kDa heat shock protein (hsp) the other type was M. leprae specific and reacted to a protein other than the 65-kDa one. To examine whether these M. leprae-specific T cell clones were responsible for the DR3-restricted low responsiveness to M. leprae, we tested them for the ability to suppress the proliferation of the DR3-restricted, 65-kDa, hsp-reactive clones. The DR3-restricted, M. leprae-specific T cells completely suppressed the proliferative responses of DR3-restricted, cross-reactive T cell clones to the 65-kDa hsp from the same patient as well as from other individuals. Also, DR3-restricted responses to an irrelevant Ag were suppressed by the M. leprae-specific T cell clones. However, no suppression of non-DR3-restricted T cell responses was seen. Although the mechanism must still be elucidated, this M. leprae-induced, DR3-restricted immunosuppression may at least partly explain the observed DR3-associated low T cell responsiveness in TT leprosy patients.


Dendritic cells injected via different routes induce immunity in cancer patients.
Dendritic cells (DC) represent potent APCs that are capable of generating tumor-specific immunity. We performed a pilot clinical trial using Ag-pulsed DC as a tumor vaccine. Twenty-one patients with metastatic prostate cancer received two monthly injections of DC enriched and activated from their PBMC. DC were cocultured ex vivo with recombinant mouse prostatic acid phosphatase as the target neoantigen. Following enrichment, DC developed an activated phenotype with up-regulation of CD80, CD86, and CD83 expression. During culture, the DC maintained their levels of various adhesion molecules, including CD44, LFA-1, cutaneous lymphocyte-associated Ag, and CD49d, up-regulated CCR7, but lost CD62 ligand and CCR5. In the absence of CD62 ligand, such cells would not be expected to prime T cells efficiently if administered i.v. due to their inability to access lymphoid tissue via high endothelial venules. To assess this possibility, three patient cohorts were immunized with Ag-pulsed DC by i.v., intradermal (i.d.), or intralymphatic (i.l.) injection. All patients developed Ag-specific T cell immune responses following immunization, regardless of route. Induction of IFN-gamma production, however, was seen only with i.d. and i.l. routes of administration, and no IL-4 responses were seen regardless of route, consistent with the induction of Th1-type immunity. Five of nine patients who were immunized by the i.v. route developed Ag-specific Abs compared with one of six for i.d. and two of six for i.l. routes. These results suggest that while activated DC can prime T cell immunity regardless of route, the quality of this response and induction of Ag-specific Abs may be affected by the route of administration.


Linear angioma serpiginosum.
Angioma serpiginosum distributed in a linear fashion along the upper extremity of an adolescent boy is described. Histopathologic examination revealed the characteristic numerous thick-walled capillaries in the dermal papillae.


Novel cephalometric parameters for the assessment of vertical skeletal dysplasia.
The accurate diagnosis of vertical skeletal abnormalities presents several challenges. Specific cephalometric parameters can be effectively used for this purpose; however, their diagnostic utility has not been fully ascertained. This study examined the effectiveness of two novel cephalometric parameters in diagnosing vertical dysplasia. Orthodontic patients were divided into three study groups: average growth group (AGG), horizontal growth group (HGG), and vertical growth group (VGG). The efficacies of the sum of the angles (maxillary, mandibular, and ramal) and the height ratio (lower anterior facial height [LAFH]/upper anterior facial height [UAFH]) in identifying the different growth patterns were examined. Receiver operating characteristic curves were used to quantitatively assess diagnostic precision. A total of 150 patients were included and divided equally among the 3 study groups. The ramal and mandibular angles varied across AGG, HGG, and VGG; however, the maxillary angle and the sum of these three angles did not vary significantly. There was a significant difference in LAFH, UAFH, and their ratios among the three groups. The height ratio had a sensitivity of 88% and 92% for the diagnosis of VGG and HGG, respectively, with cutoff values of 46 and 34, respectively (P < 0.001). The height ratio values varied considerably according to facial growth patterns, suggesting its utility as a diagnostic tool for skeletal dysplasia with greater reliability for positive treatment outcomes.


Radiation Safety Aspects of Iodine-131 metaiodobenzylguanidine (131I mIBG) Therapy Program Startup.
As a medical center without a pre-existing radiopharmaceutical therapy program, it was a daunting endeavor to implement a I metaiodobenzylguanidine (mIBG) high-dose treatment regimen. It took several years of planning with hospital administration, vendors, and Texas Department of Health Radiological Control regulators to establish a viable program. Effective communication between physicians, nursing, nuclear medicine, environmental services, maintenance, and other support staff is essential and paramount for the successful execution and continued sustainability of the mIBG therapy program. Besides providing an effective treatment for patients, an additional goal for the program is to keep radiation exposure As Low As Reasonably Achievable (ALARA) for staff and patient caregivers. As such, start-up presented many training, logistical, and radiation safety challenges. The location of the isolation room and shielding specifications were designed to keep radiation exposure to public access areas to less than 2 microsieverts per hour. Before the first patient was treated the policies and procedures for training, radiation safety, product quality control, and infusion process needed to be developed, tested, and approved by various committees. Furthermore, a similar process was required for developing room set-up, post therapy cleanup, and waste storage procedures. Throughout the maturation process of the program, the departments involved have found that our safety culture has continually improved by the re-enforcement of knowledge and lessons learned, as both the ancillary and treatment staff grew more confident in each other's ability during more patient treatments are performed. This article describes the process and lessons learned during the time leading up to the startup and early years of the mIBG therapy program.


[The effect of carnosine on the healing of a lung wound].
The influence of carnosine (beta-alanine, alpha-histidine) on the process of lung wound reparation was studied in 90 guinea-pigs. Its efficacy was evaluated microscopically, histologically and by means of electronic microscope. It was established that carnosine, as compared to controls nearly twice accelerates reparative processes in the injured lung by activation of fibroblast proliferation, connective tissue generation and intracellular regeneration. In type II epithelial cells more intensive formation of osmiophilic bodies and lamellar bodies contained in them is observed. The alveolus formation in the wound lips by the 7-8th day after lung injury is going on under the carnosine influence, which is due, probably, to massive excretion of osmiophilic contents from type II epithelial cells and surfactant production. This may be connected with rapid decrease of atelectasis and rapid restoration of lung airness within the wound.


Application of a dense genetic map for assessment of genomic responses to selection and inbreeding in Heliothis virescens.
Adaptation of pest species to laboratory conditions and selection for resistance to toxins in the laboratory are expected to cause inbreeding and genetic bottlenecks that reduce genetic variation. Heliothis virescens, a major cotton pest, has been colonized in the laboratory many times, and a few laboratory colonies have been selected for Bacillus thuringiensis (Bt) resistance. We developed 350-bp double-digest restriction-site associated DNA-sequencing (ddRAD-seq) molecular markers to examine and compare changes in genetic variation associated with laboratory adaptation, artificial selection and inbreeding in this nonmodel insect species. We found that allelic and nucleotide diversity declined dramatically in laboratory-reared H. virescens as compared with field-collected populations. The declines were primarily a result of the loss of low frequency alleles present in field-collected H. virescens. A further, albeit modest decline in genetic diversity was observed in a Bt-selected population. The greatest decline was seen in H. virescens that were sib-mated for 10 generations, in which more than 80% of loci were fixed for a single allele. To determine which regions of the genome were resistant to fixation in our sib-mated line, we generated a dense intraspecific linkage map containing three PCR-based and 659 ddRAD-seq markers. Markers that retained polymorphism were observed in small clusters spread over multiple linkage groups, but this clustering was not statistically significant. Overall, we have confirmed and extended the general expectations for reduced genetic diversity in laboratory colonies, provided tools for further genomic analyses and produced highly homozygous genomic DNA for future whole genome sequencing of H. virescens.


Skeletal muscle contractile activity in vitro stimulates mitogen-activated protein kinase signaling.
Physical exercise is a potent stimulator of mitogen-activated protein (MAP) kinase signaling. To determine if this activation is secondary to systemic responses to exercise or due to muscle contractile activity per se, an isolated muscle preparation was developed. Contractile activity in vitro significantly increased p44(MAPK) and p42(MAPK) phosphorylation by 2.9- and 2.4-fold, respectively. Contraction-stimulated MAP kinase phosphorylation was not decreased in the presence of D-tubocurarine or calphostin C, suggesting that neither neurotransmitter release nor diacylglycerol-sensitive protein kinase C mediates the contraction-induced activation of this signaling cascade. However, PD-98059, an inhibitor of MAP kinase kinase (MEK), inhibited the contraction-induced increases in MAP kinase phosphorylation. PD-98059 did not alter contraction-induced increases in glucose uptake or glycogen synthase activity, demonstrating that MAP kinase signaling is not necessary for these important metabolic effects of contractile activity in skeletal muscle. These data suggest that contractile activity of the skeletal muscle fibers per se, and not responses to neurotransmitter release, hormones, or other systemic factors, is responsible for the stimulation of MAP kinase signaling with physical exercise.


Melatonin modulates the differentiation of neural stem cells exposed to manganese via SIRT1/β-catenin signaling.
Excessive exposure of children to manganese (Mn) in the environment has a bearing on developmental neurotoxicity. Although melatonin (Mel) can play a neuroprotective role by modulating the differentiation of neural stem cells (NSCs) in the developing brain, its specific mechanism under Mn overexposure remains to be explored. Here, we cultured primary NSCs as an available model to investigate the relevant molecular mechanism of Mel mitigation on Mn-induced disorder of NSCs differentiation through sirtuin 1 (SIRT1)/β-catenin pathway. It was found that Mel could facilitate the differentiation of Mn-treated NSCs into neurons. Further, our results uncovered that the pro-differentiation mechanism of Mel depended upon ascending the activity of SIRT1, thereby weakening β-catenin acetylation and increasing phosphorylation of β-catenin ser675 in the cytoplasm, which facilitates the nuclear translocation of β-catenin. Furthermore, the role of SIRT1 in Mel-mediated signal transduction was investigated through the pretreatment of NSCs using a highly specific SIRT1 inhibitor, EX527. After EX527 pretreatment, Mel could not maintain its protective effect. Overall, our results revealed that Mel could alleviate Mn-induced disorder of NSCs differentiation through the activation of the SIRT1/β-catenin pathway.


Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
Fatal reactions associated with skin testing and injection immunotherapy have not been surveyed in North America since 1989. A survey of fatal reactions related to skin testing and immunotherapy and of near-fatal immunotherapy reactions that transpired from 1990 through 2001 was conducted among member practices of the American Academy of Allergy, Asthma and Immunology. A short survey of fatal reactions was sent to all American Academy of Allergy, Asthma and Immunology physicians, and an 87-item follow-up detailed questionnaire was sent to those reporting fatal reactions. Of 2404 members, 646 (25%) responded to the short survey. There were 20 fatal immunotherapy reactions that were directly reported and 21 indirectly reported cases by local physicians. There were 273 (42% of the responding sample) reports of near-fatal reactions. It was estimated that fatal reactions occurred every 1 per 2.5 million injections, with an average of 3.4 deaths per year. One fatality was confirmed after skin prick testing with multiple food allergens. Of 17 fatal deaths described in long questionnaires, 15 were in asthmatic patients, the majority of whose symptoms were not optimally controlled. Three reactions occurred in a medically unsupervised setting. None were receiving beta-blockers, and one was taking an angiotensin-converting enzyme inhibitor. Most fatal reactions (59%) occurred with maintenance allergen doses. The onset of 3 reactions began more than 30 minutes after injections, with a significant delay in starting epinephrine. Epinephrine was not administered in 3 other fatal reactors. Fatal reactions to immunotherapy injections occurred at similar rates reported in previous surveys. Certain clinical practices have improved (ie, exclusion of beta-blockers), and dosing errors were infrequent. Fatal reactions to immunotherapy often occur in settings inappropriate for optimal treatment of anaphylaxis. Strict adherence to practice guidelines might prevent or minimize future fatal reactions.


Subunit interaction in mammalian aldolases.
Enzyme inactivation was utilized to study subunit interaction in the homotetrameric glycolytic enzyme, aldolase. Isoenzymes from rabbit liver and skeletal muscle were inactivated in the presence of Pi and d-glyceraldehyde-P to a maximum stoichiometry of one modification per aldolase subunit. Subunit modification increased net negative charge on each subunit surface and was used to resolve modified aldolase isoenzymes into various chromatographic species. A combination of anion-(Mono Q) and cation- (Mono S) exchange chromatography separated the modified aldolase homotetramers into three distinct enzyme populations: unchanged enzyme, fully modified enzyme corresponding to one ligand molecule incorporated per subunit and partially modified enzyme in which only one subunit out of four is modified. Both fully and partially modified species were devoid of catalytic activity. Activity loss through modification of a single subunit in both aldolase isoenzymes indicates tightly coupled communication between subunit active sites and suggests simple functional regulation of aldolases.


Routine cervical screening by primary HPV testing: early findings in the renewed National Cervical Screening Program.
To report human papillomavirus (HPV) testing patterns and rates of oncogenic HPV-positivity for specimens submitted during the first 6 months after the National Cervical Screening Program switched from cytology- to primary HPV-based screening. Retrospective cross-sectional review of 195 606 specimens submitted for HPV testing, 1 December 2017 - 31 May 2018. Large community-based general pathology laboratory in metropolitan Sydney. Prevalence of oncogenic HPV types (all, HPV16/18, non-HPV16/18) by reason for HPV test (primary screening, non-screening); for oncogenic HPV-positive women in the age band recommended for primary HPV screening (25-74 years), prevalence of cytologic abnormality and rates of 12-month follow-up and colposcopy recommendations. 195 606 samples were received: 157 700 (80.6%) for primary screening, 37 906 (19.4%) for non-screening tests. Oncogenic HPV was detected in 8.1% of screening tests (95% CI, 7.9-8.2%) and 20.9% of non-screening tests (95% CI, 20.5-21.3%); 35.5% (95% CI, 34.7-36.4%) of women of recommended screening age with positive oncogenic HPV screening test results also had a cytologic abnormality. The proportion of HPV16/18-positive samples with high grade abnormality was 15.3% (95% CI, 14.2-16.6%); for samples positive for other oncogenic HPV types, the proportion was 6.3% (95% CI, 5.8-6.8%). Repeat HPV testing after 12 months was recommended for 5.4% (95% CI, 5.3-5.5%) and direct colposcopy for 2.6% (95% CI, 2.5-2.7%) of screened women aged 25-74 years. High grade cytologic abnormalities were more common in women positive for HPV16/18, supporting their higher risk classification. Colposcopy referral rates were higher than during primary cytology-based testing, as predicted by clinical trial and modelling data. The prevalence of HPV was much higher in non-screening than in primary screening samples. Our findings indicate the renewed program is performing as expected during the initial HPV screening round.


The relatively good prognosis of bipolar disorders in a Turkish bipolar clinic.
Bipolar affective disorder is considered to be a disabling illness with a relapsing and remitting course resulting in enduring psychosocial consequences. In this study, we aimed to determine the demographic and clinical characteristics of patients with bipolar illness, types of treatment at inpatient and outpatient settings and their outcome. Life charts of 61 bipolar outpatients and hospital charts of 47 manic inpatients were retrospectively evaluated regarding the demographics, course of illness and the treatment at both settings. 82.5% of the outpatients were euthymic and 42.5% were on lithium monotherapy at the time of investigation. Psychosocial adjustment was good. High level of education and marital status affected compliance positively. In the outpatient group, 24.2% were bipolar 2 (BP-II): they differed from bipolar 1 (BP-I) patients in having a higher number of lifetime episodes. Females outnumbered males in both settings, 11 had suffered higher numbers of previous episodes, as well as longer stays in hospital. Lithium was the most commonly used agent in acute mania (78.7%); 89.4% of the inpatients received combination treatment, mainly a mood stabilizer with a neuroleptic. Adjunctive neuroleptics decreased from 82.4 to 56.7% after 1995: This resulted in longer lengths of stay in hospital. Data were collected naturalistically in a non-blind fashion. Lithium is still the leading mood stabilizer of choice for the acute and maintenance phases of bipolar disorder in our patient population. We submit that family support, high levels of education as well as an in-depth follow-up represented the contributory factors in the good overall outcome.


The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.
The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.


A cuticular protein, BgCPLCP1, contributes to insecticide resistance by thickening the cockroach endocuticle.
Overuse of insecticides has led to severe environmental problems. Insect cuticle, which consists mainly of chitin, proteins and a thin outer lipid layer, serves multiple functions. Its prominent role is as a physical barrier that impedes the penetration of xenobiotics, including insecticides. Blattella germanica (L.) is a major worldwide indoor pest that causes allergic disease and asthma. Extensive use of pyrethroid insecticides, including β-cypermethrin, has selected for the rapid and independent evolution of resistance in cockroach populations on a global scale. We demonstrated that BgCPLCP1, the first CPLCP (cuticular proteins of low complexity with a highly repetitive proline-rich region) family cuticular protein in order Blattodea, contributes to insecticide penetration resistance. Silencing BgCPLCP1 resulted in 85.0 %-85.7 % and 81.0 %-82.0 % thinner cuticle (and especially thinner endocuticle) in the insecticide-susceptible (S) and β-cypermethrin-resistant (R) strains, respectively. The thinner and more permeable cuticles resulted in 14.4 % and 20.0 % lower survival of β-cypermethrin-treated S- and R-strain cockroaches, respectively. This study advances our understanding of cuticular penetration resistance in insects and opens opportunities for the development of new efficiently and environmentally friendly insecticides targeting the CPLCP family of cuticular proteins.


Secular reduction of excess mortality in hip fracture patients >85 years.
More than 20% of the hip fracture patients die within the first year after the incident. Few data are available on the trends in mortality following a hip fracture. The present aim was to study changes in excess mortality after hip fracture from 1978/79 up to 1996/97. Data on 5180 hip fracture patients aged ≥ 50 years, identified in three earlier, well validated, incidence studies from Oslo were used. The studies took place in the two years periods 1978-79 and 1989-89 and in a one year period from 1st of May 1996 to 30th of April 1997. The study was designed as a historic cohort study. Exposure was sustaining a hip fracture in the registration periods. Outcome was death of all causes. Age- and sex-specific one year-mortality rates were provided by Statistics Norway. Standardized mortality ratios (SMR) were calculated for the three cohorts for each sex and age-group, for the 0-6 months, 6-12 months, 0-1 year, 1-5 years and 5-10 years intervals after fracture. To assess the duration of the excess mortality in hip fracture patients, time-framed Kaplan-Meier curves for consecutive 5-years intervals were conducted for the hip fracture patients and the corresponding background population. Only patients still alive at the start of the time interval were included. One sample log rank tests were used to test for statistical significance. The one-year SMR ranged from 3.64 (2.82 - 4.61) to 4.53 (3.67 - 5.54) in men and from 2.78 (2.39 - 3.19) to 3.60 (3.19 - 4.05) in women. In the 0-6 months interval a reduction in SMR from 1978/79 to 1996/97 was observed in women aged ≥85 years. The duration of excess mortality ranged from two years in men ≥85 years to more than ten years in men and women aged 65-84 years. Excess mortality among hip fracture patients remains high. Over the decades, a reduced excess mortality was mainly seen in the oldest patients, suggesting that specific efforts intending to improve prevention and treatment of osteoporosis and osteoporotic fractures in the youngest elderly are required.


Comparative assessment of the composition and charge state of nitrogenase FeMo-cofactor.
A significant limitation in our understanding of the molecular mechanism of biological nitrogen fixation is the uncertain composition of the FeMo-cofactor (FeMo-co) of nitrogenase. In this study we present a systematic, density functional theory-based evaluation of spin-coupling schemes, iron oxidation states, ligand protonation states, and interstitial ligand composition using a wide range of experimental criteria. The employed functionals and basis sets were validated with molecular orbital information from X-ray absorption spectroscopic data of relevant iron-sulfur clusters. Independently from the employed level of theory, the electronic structure with the greatest number of antiferromagnetic interactions corresponds to the lowest energy state for a given charge and oxidation state distribution of the iron ions. The relative spin state energies of resting and oxidized FeMo-co already allowed exclusion of certain iron oxidation state distributions and interstitial ligand compositions. Geometry-optimized FeMo-co structures of several models further eliminated additional states and compositions, while reduction potentials indicated a strong preference for the most likely charge state of FeMo-co. Mössbauer and ENDOR parameter calculations were found to be remarkably dependent on the employed training set, density functional, and basis set. Overall, we found that a more oxidized [Mo(IV)-2Fe(II)-5Fe(III)-9S(2-)-C(4-)] composition with a hydroxyl-protonated homocitrate ligand satisfies all of the available experimental criteria and is thus favored over the currently preferred composition of [Mo(IV)-4Fe(II)-3Fe(III)-9S(2-)-N(3-)] from the literature.


Update on Vaccine-Derived Polioviruses - Worldwide, January 2014-March 2015.
Since the World Health Assembly's 1988 resolution to eradicate poliomyelitis, one of the main tools of the World Health Organization (WHO) Global Polio Eradication Initiative (GPEI) has been the live, attenuated oral poliovirus vaccine (OPV). OPV might require several doses to induce immunity but provides long-term protection against paralytic disease. Through effective use of OPV, GPEI has brought polio to the threshold of eradication. Wild poliovirus type 2 (WPV2) was eliminated in 1999, WPV3 has not been detected since November 2012, and WPV1 circulation appears to be restricted to parts of Pakistan and Afghanistan. However, continued use of OPV carries two key risks. The first, vaccine-associated paralytic poliomyelitis (VAPP) has been recognized since the early 1960s. VAPP is a very rare event that occurs sporadically when an administered dose of OPV reverts to neurovirulence and causes paralysis in the vaccine recipient or a nonimmune contact. VAPP can occur among immunologically normal vaccine recipients and their contacts as well as among persons who have primary immunodeficiencies (PIDs) manifested by defects in antibody production; it is not associated with outbreaks. The second, the emergence of genetically divergent, neurovirulent vaccine-derived polioviruses (VDPVs) was recognized more recently. Circulating VDPVs (cVDPVs) resemble WPVs and, in areas with low OPV coverage, can cause polio outbreaks. Immunodeficiency-associated VDPVs (iVDPVs) can replicate and be excreted for years in some persons with PIDs; GPEI maintains a registry of iVDPV cases. Ambiguous VDPVs (aVDPVs) are isolates that cannot be classified definitively. This report updates previous surveillance summaries and describes VDPVs detected worldwide during January 2014-March 2015. Those include new cVDPV outbreaks in Madagascar and South Sudan, and sharply reduced type 2 cVDPV (cVDPV2) circulation in Nigeria and Pakistan during the latter half of 2014. Eight newly identified persons in six countries were found to excrete iVDPVs, and a patient in the United Kingdom was still excreting iVDPV2 in 2014 after more than 28 years. Ambiguous VDPVs were found among immunocompetent persons and environmental samples in 16 countries. Because the large majority of VDPV case-isolates are type 2, WHO has developed a plan for coordinated worldwide withdrawal of trivalent (types 1, 2, and 3) OPV (tOPV) and replacement with bivalent (types 1 and 3) OPV (bOPV) in April 2016, preceded by introduction of at least 1 dose of injectable inactivated poliovirus vaccine (IPV) into routine immunization schedules worldwide to maintain immunity to type 2 viruses.