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In the recent paper by Lee et al. 1 reporting reproductive toxicity testing of BVN008, a newly developed tetanus, diphtheria, and acellular pertussis vaccine, the statement is made "BVN008 is a booster vaccine identical to the current Tdap vaccines, Boostrix (GSK) and Adacel (Sanofi)." However, as the authors report, the acellular pertussis portion of BVN008 was provided by BIKEN (Japan). The composition of the BIKEN acellular pertussis product differs in important ways from the compositions of the acellular pertussis components of Boostrix and Adacel.2 Accordingly, the statement cited above is incorrect. A more appropriate statement might have been, "BVN008 is a booster vaccine similar in concept to the current Tdap vaccines, Boostrix (GSK) and Adacel (Sanofi)." • Lee et al. recently stated that BVN008 "is identical to the current Tdap vaccines". • BVN008 incorporates the BIKEN aP vaccine with 2 pertussis components. • The current Tdap vaccines contain 3 and 5 pertussis components respectively. • BVN008 therefore is not identical to the current Tdap vaccines. [ABSTRACT FROM AUTHOR]

Pertussis (whooping cough) is a respiratory infection caused by Bordetella pertussis. All ages are susceptible. In the prevaccine era, almost all children became infected. Pertussis is particularly dangerous in young infants, who account for practically all hospitalizations and deaths, but clinical disease is burdensome at any age. Widespread use of pertussis vaccines dramatically reduced cases, but concern over adverse reactions led to the replacement of standard whole-cell by acellular pertussis vaccines that contain only a few selected pertussis antigens and are far less reactogenic. Routine administration of acellular pertussis vaccines combined with diphtheria and tetanus toxoids is recommended in infancy with toddler and preschool boosters, at age 11, and during pregnancy. Boosting in the second half of every pregancy is critical to protection of the newborn. Waning of vaccine immunity over time has become an increasing concern, and several new pertussis vaccines are being evaluated to address this problem. [ABSTRACT FROM AUTHOR]

• Military medical records were searched electronically for myopericarditis. • The rate of myopericarditis after ACAM2000 smallpox vaccine was 20.06/100,000. • Myopericarditis rates were 21.1/100,000 for those < 40 years vs 6.3/100,000 for 40 +. • Myopericarditis rates were 21.8/100,000 for males vs 8.5/100,000 for females. To evaluate the rates of myopericarditis (primary objective) and rates of cardiovascular and neurological adverse events (secondary objectives) in temporal association with ACAM2000® smallpox vaccine. Observational cohort study conducted through monthly surveillance from 2009 to 2017 of electronic medical records of military service members (SM) for pre-specified cardiac and neurological International Classification of Diseases (ICD) codes reported in the 30 days following smallpox vaccination. ICD codes potentially predictive of myopericarditis and codes for encephalitis, Guillain-Barré syndrome, and sudden death were classified into Group 1. All other cardiovascular and neurological ICD codes were classified into Group 2. Medical records containing Group 1 codes were individually reviewed to confirm coding accuracy and to seek additional data in support of myopericarditis adjudication, which was performed by an independent clinical panel. Chart reviews were not performed for Group 2 codes, which were reported in aggregate only. 897,227 SM who received ACAM2000 smallpox vaccine and 450,000 SM who received Dryvax smallpox vaccine were included in the surveillance population. The rate of adjudicated myopericarditis among ACAM2000 smallpox vaccine recipients was 20.06/100,000 and was significantly higher for males (21.8/100,000) than females (8.5/100,000) and for those < 40 years of age (21.1/100,000) than for those 40 years or older (6.3/100,000). Overall rates for any cardiovascular event (Group 1 plus Group 2) were 113.5/100,000 for ACAM2000 vaccine and 439.3/100,000 for Dryvax vaccine; rate ratio, 0.26 (95% CI, 0.24–0.28). The rates of subjects with one or more defined neurological events were 2.12/100,000 and 1.11/100,000 for ACAM2000 and Dryvax vaccines respectively; rate ratio, 1.91 (95% CI, 0.71–5.10). Electronic records surveillance of the entire vaccinated SM population over a ten-year period found rates of myopericarditis, of defined neurological events, and of overall cardiac events that were consistent with those of prior passive surveillance studies involving Dryvax or ACAM2000 smallpox vaccines. Clinical trials registration: ClinicalTrials.gov NCT00927719. [ABSTRACT FROM AUTHOR]

Introduction: Numerous thermal free radical stabilization techniques are used in the production of highly cross-linked polyethylene (HXLPE) to improve oxidative stability. Little knowledge exists on the effects of in vivo time on the mechanical properties of HXLPE. The purpose of this study was to determine if free radical stabilization of HXLPE impacts mechanical properties as well as oxidative stability of acetabular liner rims after extended in vivo time. Methods: Retrieved and control remelted, single annealed and sequentially annealed HXLPE liner rims were tested for mechanical properties. Oxidation was measured with FTIR spectroscopy and crystalline phase composition measured with Raman spectroscopy. Results: No correlation was found between in vivo, ex vivo time and hardness for annealed groups. A statistically significant difference in hardness was identified between free radical stabilization groups. No correlation between maximum rim oxidation and in vivo time was found. Detectable levels of rim oxidation were present in 100% of single annealed, 75% of sequentially annealed, and 25% of remelted retrieved liners. Single and sequentially annealed liners demonstrated oxidation and increased crystallinity. Rim mechanical properties change in vivo for implant types. With in vivo time, retrieved remelted HXLPE demonstrated decreased mechanical properties, whereas retrieved single and sequentially annealed HXLPE properties remained stable. All liner cohorts demonstrated evidence of rim oxidation. Subsequent changes in crystallinity were only observed in oxidized annealed liners. Conclusion: HXLPE acetabular liner rims show evidence of in vivo mechanical property degradation, notably in remelted HXLPE, which may be a risk factor in rim fracture and catastrophic implant failure. [ABSTRACT FROM AUTHOR]

Heartland virus is a tickborne phlebovirus first identified in Missouri in 2009; 11 human cases have been reported in the literature. Reported hallmarks of infection have included fever, malaise, anorexia, gastrointestinal complaints, thrombocytopenia, neutropenia, and aminotransferase elevations. We report 1 confirmed and 2 suspected cases and discuss implications for case-finding. [ABSTRACT FROM AUTHOR]

Opioid receptors (ORs) are classified among the oldest and best investigated drug targets due to their fundamental role in the treatment of pain and related disorders. ORs are divided in three conventional subtypes (μ, κ, δ) and the non‐classical nocicepetin receptor. All ORs are family A G protein‐coupled receptors (GPCRs), and are located on the cell surface. Modern biophysical methods use light to investigate physiological processes at organismal, cellular and subcellular level. Many of these methods rely on fluorescent ligands, thus highlighting their importance. This review addresses the advancements in the development of opioid fluorescent ligands and their use in biological, pharmacological and imaging applications. [ABSTRACT FROM AUTHOR]

An efficient and scalable rule‐based syntactic differencing approach is presented. The tool srcDiff is built upon the srcML infrastructure. srcML adds abstract syntactic information into the code via an XML format. A syntactic difference of srcML documents is then taken. During this process, the differences are further refined using a set of rules that model typical editing patterns of source code by developers. Thus, the resulting deltas model edits that are programmer centric versus a purely syntactic tree edit view. Other syntactic differencing approaches focus on obtaining an optimal tree edit distance with the assumption that this will produce an accurate difference. While this may work well for small or simple changes, the differences quickly become unreadable for more complex changes. By contrast, the approach presented here purposely deviates from an optimal tree edit difference in order to create a delta that is both easier to understand and better models changes between the original and modified. To evaluate the approach, a comparison user study against a state‐of‐the‐art syntactic differencing approach and two line‐based differencing tools is conducted as an online within‐participant study with about 70 subjects on 14 sample changes. The results provide support that the rule‐based syntactic differencing produces more accurate and understandable deltas. [ABSTRACT FROM AUTHOR]

• Two globally-distributed Tdap vaccines have differing pertussis formulations. • Each produces robust pertussis antibody responses among young adolescents. • For both, antibody responses were substantially lower for adolescents primed with aP vs wP. It has been reported that persons primed with acellular (DTaP) pertussis vaccines have reduced duration of pertussis protection compared with those primed with whole-cell (DTwP) vaccines. However, due to the rapid transition to acellular vaccines, studies attempting directly to compare protection among DTaP-primed vs DTwP-primed individuals are subject to confounding by age and other limitations of ecological studies. Using validated assay results and stored sera from multiple Tdap studies, we evaluated two licensed Tdap vaccines among DTaP-primed adolescents to allow comparison with results obtained in the same laboratory from earlier studies involving DTwP-primed adolescents. Participants 11–12 years of age who had received exactly 5 doses of DTaP vaccine prior to 7 years of age were randomly assigned in 2012 to receive one of two licensed Tdap vaccines. Serum specimens obtained pre- and post-vaccination were assayed for responses to the vaccines. Current results were then compared to results obtained in the same laboratory from prior randomized Tdap studies conducted among adolescents primed with DTwP or DTaP. Both Tdap vaccines produced strong antibody responses to diphtheria and tetanus; responses to contained pertussis antigens were consistent with the differing levels of those antigens in each Tdap vaccine. However, postvaccination pertussis antibody responses were as much as 71% lower in these DTaP-primed adolescents compared with responses among DTwP-primed adolescents in a prior study of the same two Tdap vaccines. In contrast, results from the present study were similar to those seen in another study of Tdap among DTaP-primed adolescents. Taken together, these results from randomized clinical trials provide direct evidence of reduced antibody responses to both licensed Tdap vaccines among adolescents primed with DTaP vaccine, compared with adolescents primed with DTwP vaccine. Clinical trial registry number: ClinicalTrials.gov, NCT01629589. [ABSTRACT FROM AUTHOR]

Since the beginning of robotics, the substitution of human labor has been one of the crucial issues. The focus is on the economic perspective, asking how robotics affects the labor market, and on changes in the work processes of human workers. While there are already some lessons learnt from industrial robotics, the area of service robots has been analyzed to a much lesser extent. First insights into these aspects are of utmost relevance to technology assessment providing policy advice. As conclusions for service robots in general cannot be drawn, we identify criteria for the ex-ante evaluation of service robots in concrete application areas. [ABSTRACT FROM AUTHOR]

This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue. [ABSTRACT FROM AUTHOR]

Background Pelvic ring disruptions in blunt trauma are rarely an isolated finding. Many individuals needing operative pelvic fixation also require laparotomy for other injuries. Pelvic fixation can be performed by open reduction and internal fixation (ORIF) or external fixation (Ex-fix). Often when a laparotomy incision is present, ORIF is performed by extending this incision. We hypothesized ORIF performed by extending the laparotomy incision would result in higher rates of ventral hernia and wound complications versus Ex-fix. Methods All patients admitted from 2004–June 2014 who underwent laparotomy and pelvic fixation either by ORIF through extension of a laparotomy incision (ORIF group) or definitive Ex-fix group were identified. Injury severity score, demographics, associated injuries, and complications were collected. Results A total of 35 patients were identified who underwent laparotomy and pelvic fixation, 21 underwent Ex-fix, whereas 14 underwent ORIF through an extended laparotomy incision. There were no differences in injury severity score, demographics, associated injuries, or rate of ventral hernia. The ORIF group had more laparotomy incision infections (50.0% versus 4.8%, P < 0.01) and pelvic abscesses (42.9% versus 9.5%, P < 0.05). They required more procedures to address their complications (13 versus 5, P < 0.05). Conclusions Individuals who have undergone laparotomy and pelvic fixation are a complex group of patients with multiple injuries. These data suggest that when surgical repair of a pelvic ring disruption is indicated and the patient has undergone laparotomy, careful consideration to the method of fixation should be given. [ABSTRACT FROM AUTHOR]

Serotonin fibers densely innervate the cortical sheath to regulate neuronal excitability, but its role in shaping network dynamics remains undetermined. We show that serotonin provides an excitatory tone to cortical neurons in the form of spontaneous synaptic noise through 5-HT3 receptors, which is persistent and can be augmented using fluoxetine, a selective serotonin re-uptake inhibitor. Augmented serotonin signaling also increases cortical network activity by enhancing synaptic excitation through activation of 5-HT2 receptors. This in turn facilitates the emergence of epileptiform network oscillations (10-16 Hz) known as fast runs. A computational model of cortical dynamics demonstrates that these two combined mechanisms, increased background synaptic noise and enhanced synaptic excitation, are sufficient to replicate the emergence fast runs and their statistics. Consistent with these findings, we show that blocking 5-HT2 receptors in vivo significantly raises the threshold for convulsant-induced seizures. [ABSTRACT FROM AUTHOR]

In the 4th to early 7th centuries Palestinian and Egyptian wines were shipped and consumed widely throughout the Mediterranean and beyond. In part the flourishing commerce was a product of the booming pilgrim trade that the region witnessed, but other factors, such as the rise of Constantinople as an imperial capital, also played a role. This trade, however, suffered dramatically in the mid-seventh century - the period coinciding with the aftermath of the Persian and the Arab conquest of Palestine and Egypt - when the material markers of the commerce vanish. The present evidence indicates that the seventh-century invasions led to the end of the overseas wine trade and with it the loss of a considerable source of revenue and economic vitality. The Egyptian and Levantine wine trade, which persisted into the Umayyad and early 'Abbasid era, was neither comparable in scale nor scope to its late antique predecessor. [ABSTRACT FROM AUTHOR]

Service robotics has increasingly become the focus of reflective research on new technologies over the last decade. The current state of technology is characterized by prototypical robot systems developed for specific application scenarios outside factories. This has enabled context-based Science and Technology Studies and technology assessments of service robotic systems. This contribution describes the status quo of this reflective research as the starting point for interdisciplinary technology assessment (TA), taking account of TA studies and, in particular, of publications from the ethical and empirical social science perspective. Finally, based on this status quo, evaluation criteria for service robots are developed, which are relevant for further reflective research. [ABSTRACT FROM AUTHOR]

In 2010, the German Federal Ministry of Education and Research started a series of citizens' dialogues on future technologies. In the context of the German history of public participation in technology-oriented policy making, these dialogues are unique for at least two reasons: The Federal Ministry retains the responsibility for the entire process and is heavily involved in its planning, organization and communication, and the number of participants and process elements is significantly higher than in most other participative events. The paper presents insights into the political background of the citizens' dialogues, its general concept as well as first observations from the dialogue rounds on energy and high-tech medicine. In addition, it discusses reactions of other political actors and expectations regarding legitimacy and representativeness of the dialogue results. [ABSTRACT FROM AUTHOR]

Abstract: This review highlights some of the many contributions of the late Dr. Jerry J. Buccafusco to the neurobiology of nicotinic acetylcholine receptors (nAChRs) and cognition over a 25 year period. The article is written by two of Dr. Buccafusco''s professional colleagues, one from academia and one from the pharmaceutical industry. While Dr. Buccafusco''s expertise in the cholinergic field was extensive, his insights into the practical relevance of his work (with a long-term goal of formulating new drug development strategies) were unique, and a great asset to both the basic science community and pharmaceutical companies. In 1988, Dr. Buccafusco''s laboratory was the first to report the cognitive enhancing action of low doses of nicotine in non-human primates. Since that time he studied a large number of novel pro-cognitive agents from several pharmacological classes in rodents as well as monkeys. Based on years of observing paradoxical effects of nicotinic ligands in vitro and in vivo, Dr. Buccafusco made the provocative argument that it might be possible to develop new chemical entities (with pro-cognitive actions) that have the ability to desensitize nAChRs without producing an antecedent agonist action. Some of his more recent work focused on development of single molecular entities that act on multiple CNS targets (including nAChRs) to enhance cognition, provide neuroprotection, and/or provide additional therapeutic actions (e.g., antipsychotic effects). Dr. Buccafusco''s influence will live on in the work of the numerous graduate students, postdoctoral fellows, and junior faculty that he mentored over the years who now serve in prestigious positions throughout the world. [Copyright &y& Elsevier]

Background: It is common for hip arthroscopy patients to demonstrate significant gluteus medius muscle weakness and concurrent iliopsoas tendinitis. Restoration of gluteus medius muscle function is essential for normal hip function. Hypothesis: A progression of hip rehabilitation exercises to strengthen the gluteus medius muscle could be identified that minimize concurrent iliopsoas muscle activation to reduce the risk of developing or aggravating hip flexor tendinitis Study Design: Descriptive laboratory study. Methods: Electromyography (EMG) signals of the gluteus medius and iliopsoas muscles were recorded from 10 healthy participants during 13 hip rehabilitation exercises. The indwelling fine-wire EMG electrodes were inserted under ultrasound guidance. The average and peak EMG amplitudes, normalized by the peak EMG amplitude elicited during maximum voluntary contractions, were determined and rank-ordered from low to high. The ratio of iliopsoas to gluteus medius muscle activity was calculated for each exercise. Exercises were placed into respective time phases based on average gluteus medius EMG amplitude, except that exercises involving hip rotation were avoided in phase I (phase I, initial 4 or 8 weeks; phase II, subsequent 4 weeks; phase III, final 4 weeks). Results: A continuum of hip rehabilitation exercises was identified. Resisted terminal knee extension, resisted knee flexion, and double-leg bridges were identified as appropriate for phase I and resisted hip extension, stool hip rotations, and side-lying hip abduction with wall-sliding for phase II. Hip clam exercises with neutral hips may be used with caution in patients with hip flexor tendinitis. Prone heel squeezes, side-lying hip abduction with internal hip rotation, and single-leg bridges were identified for phase III. Conclusion/Clinical Relevance: This study identified the most appropriate hip rehabilitation exercises for each phase to strengthen the gluteus medius muscle after hip arthroscopy and those to avoid when iliopsoas pain or tendinitis is a concern. [ABSTRACT FROM AUTHOR]

Service-Robotic-mainly defined as 'non-industrial robotics'-is identified as the next economical success story to be expected after robots have been ubiquitously implemented into industrial production lines. Under the heading of service-robotic, we found a widespread area of applications reaching from robotics in agriculture and in the public transportation system to service robots applied in private homes. We propose for our interdisciplinary perspective of technology assessment to take the human user/worker as common focus. In some cases, the user/worker is the effective subject acting by means of and in cooperation with a service robot; in other cases, the user/worker might become a pure object of the respective robotic system, for example, as a patient in a hospital. In this paper, we present a comprehensive interdisciplinary framework, which allows us to scrutinize some of the most relevant applications of service robotics; we propose to combine technical, economical, legal, philosophical/ethical, and psychological perspectives in order to design a thorough and comprehensive expert-based technology assessment. This allows us to understand the potentials as well as the limits and even the threats connected with the ongoing and the planned implementation of service robots into human lifeworld-particularly of those technical systems displaying increasing grades of autonomy. [ABSTRACT FROM AUTHOR]

Technology assessment (TA) is generally classified as problem-oriented and thus transdisciplinary research. This is due to the fact that the aim of TA is to work out solutions for problems outside science in order to offer advice to its addressees, namely those working in politics and science and members of society in general. In this paper, we propose that the problem-oriented approach also be used as the basis for the decision regarding when a TA should be conducted in a particular situation, and which TA should be used. As a first step to this end, a broad range—almost like a kind of coarse radar—and large number of topics or problem sketches are created, which then serve as a basis for a discursive process of negotiation, during which topics are to be carried over into a detailed problem analysis (“fine radar”). These detailed problem analyses, which are important for transdisciplinary research, represent in themselves small research projects (pre-projects). They provide, in addition, some initial indications for a methodologically promising project design. The methodological approach described here is currently being tested in a procedure in which TA topics are being monitored for the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF). [ABSTRACT FROM AUTHOR]

Since it was first proposed in the 1970s, the concept of an Islamic agricultural revolution, in which new plants and techniques spread rapidly from east to west and transformed agriculture in the Mediterranean basin, has gained widespread acceptance. Based on an investigation of a sample of plants, the present article argues that changes in farming attributed to the era of classical Islam were far more complex and distended than previously acknowledged. This casts doubt on the validity of the theory of a medieval "green revolution" and calls for a reexamination of its fundamental tenets. [ABSTRACT FROM AUTHOR]

The slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the neuromuscular junction caused by gain-of-function mutations to the muscle nicotinic acetylcholine (ACh) receptor (AChR). Although it is clear that the slower deactivation time course of the ACh-elicited currents plays a central role in the etiology of this disease, it has been suggested that other abnormal properties of these mutant receptors may also be critical in this respect. We characterized the kinetics of a panel of five SCCMS AChRs (αS269I, βV266M, ϵL221F, ϵT264P, and ϵL269F) at the ensemble level in rapidly perfused outside-out patches. We found that, for all of these mutants, the peak-current amplitude decreases along trains of nearly saturating ACh pulses delivered at physiologically relevant frequencies in a manner that is consistent with enhanced entry into desensitization during the prolonged deactivation phase. This suggests that the increasingly reduced availability of activatable AChRs upon repetitive stimulation may well contribute to the fatigability and weakness of skeletal muscle that characterize this disease. Also, these results emphasize the importance of explicitly accounting for entry into desensitization as one of the pathways for burst termination, if meaningful mechanistic insight is to be inferred from the study of the effect of these naturally occurring mutations on channel function. Applying a novel single-channel-based approach to estimate the contribution of Ca2+ to the total cation currents, we also found that none of these mutants affects the Ca2+-conduction properties of the AChR to an extent that seems to be of physiological importance. Our estimate of the Ca2+-carried component of the total (inward) conductance of wild-type and SCCMS AChRs in the presence of 150 mM Na+, 1.8 mM Ca2+ and 1.7 mM Mg2+ on the extracellular side of cell-attached patches turned out be in the 5.0-9.4 pS range, representing a fractional Ca2+ current of ~14%, on average. Remarkably, these values are nearly identical to those we estimated for the NR1-NR2A N-methyl-D-aspartate receptor (NMDAR), which has generally been considered to be the main neurotransmitter-gated pathway of Ca2+ entry into the cell. Our estimate of the rat NMDAR Ca2+ conductance (using the same single-channel approach as for the AChR but in the nominal absence of extracellular Mg2+) was 7.9 pS, corresponding to a fractional Ca2+ current of 13%. [ABSTRACT FROM AUTHOR]

The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic β-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic β-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of β-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving β-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed. [ABSTRACT FROM AUTHOR]

Abstract: A set of hybrid molecules were synthesized out of lipoic acid, α,ω-diamines of different lengths serving as spacers, and cholinesterase (ChE) inhibiting [2,1-b]quinazolinimines. Depending on the length of the alkylene spacer the amide hybrids are inhibitors of acetylcholinesterase (AChE) with inhibitory activities of 0.5–4.6μM and inhibitors of butyrylcholinesterase (BChE) with activities down to 5.7nM, therefore greatly exceeding the inhibitory activities of the parent quinazolinimines by factors of up to 1000. Due to increasing activity at BChE with increasing length of the alkylene spacer ∼100-fold selectivity toward BChE is reached with a hepta- and an octamethylene spacer. Kinetic measurements reveal competitive and reversible inhibition of both ChEs by the hybrids. Furthermore, cell viability and antioxidant activity (using the ORAC-fluorescein assay) of several hybrids were evaluated, showing cytotoxicity at concentrations from 3.7 to 10.2μM and antioxidant properties are in the range of 0.4–0.8 Trolox equivalents (lipoic acid=0.6). [Copyright &y& Elsevier]

Autonomous robots that are capable of learning are being developed to make it easier for human actors to achieve their goals. As such, robots are primarily a means to an end and replace human actions (or parts of them). An interdisciplinary technology assessment was carried out to determine the extent to which a replacement of this kind makes ethical sense in terms of technology, economics and legal aspects. Proceeding from an ethical perspective, derived from Kant’s formula of humanity, in this article we analyse the use of robots in the care of the elderly or infirm and then examine robot learning in the context of this kind of cooperation. [ABSTRACT FROM AUTHOR]

Abstract: Autonomic nervous system (ANS) dysfunction has been suggested in patients with chronic fatigue syndrome (CFS). In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR, and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect, and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders. Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] (p <0.0004, each), and reduced low frequency (LF), very low frequency (VLF), and total power (TP) of HRV (p <0.02, all). CFS cases had significantly lower plasma aldosterone (p <0.05), and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine (r =0.23, p =0.05) and moderately with vitality and fatigue scores (r =−0.49 and 0.46, respectively, p <0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p =0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders case-control differences in HR and TP remained significant (p <0.05). Conclusion: the presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed. [Copyright &y& Elsevier]

Abstract: Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach. [Copyright &y& Elsevier]

Abstract: In the course of studies directed toward the discovery of novel acetyl- and butyrylcholinesterase (AChE and BChE) inhibitors for the treatment of Alzheimer‘s disease, we focused on β-carbolines (BCs). 6-Oxygenated β-carboline and β-carbolinium derivatives based on the serotonin template were synthesized and tested in vitro for their ability to inhibit AChE and BChE, respectively. Particularly the carbolinium salts, which can be formed by intracerebral methylation out of the tertiary-BC prodrugs, show inhibitory activity levels reaching those of galantamine, physostigmine, and rivastigmine. [Copyright &y& Elsevier]

Abstract: Tetracyclic nitrogen bridgehead compounds, dibenzodiazecines and tricyclic quinazolinimines, in which the size of the alicyclic ring system and the length of the alkyl chain between the quinazolinimine moiety and a phenyl ring connected to the imine nitrogen atom were changed systematically, were synthesized and their ability to inhibit acetyl- and butyrylcholinesterase (AChE/BChE), respectively, was evaluated. Moderate and strong inhibitors of BChE—compared to galanthamine and rivastigmine—were identified, which show mixed affinities or are moderately or highly selective towards BChE, respectively. [Copyright &y& Elsevier]

Abstract: Derived from the structures of the alkaloids rutaecarpine and dehydroevodiamine (DHED), and the long-known acetylcholinesterase (AChE) inhibitor tacrine, respectively, novel compounds were synthesised, including: 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (12), (8Z)-5,6-dihydro-8H-isoquino[1,2-b]quinazolin-8-imine (13), 5,8-dihydro-6H-isoquino[1,2-b]quinazoline (15a), 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (16), 5,7,8,13-tetrahydroindolo [2′,3′:3,4]pyrido[2,1-b]quinazoline (17), and N-(2-phenylethyl)-N-[(12Z)-7,8,9,10-tetrahydroazepino [2,1-b]quinazolin-12(6H)-ylidene]amine (20), respectively. In a first step to evaluate their possible applicability for antiamnesic therapy, the inhibition of AChE and butyrylcholinesterase (BChE) were determined: compounds 13, 15a, 17, and 20 are moderate or strong inhibitors of ChE, the latter two compounds show a 10-fold higher affinity to BChE. Compound 12 is a moderate inhibitor of AChE showing selectivity towards this enzyme. [Copyright &y& Elsevier]

ABT-702 is a novel and selective non-nucleoside adenosine kinase (AK) inhibitor that produces increases in endogenous extracellular adenosine. Adenosine (ADO) is thought to be an important neuromodulator of sleep, therefore, the effects of ABT-702 and AK inhibition were examined on rat EEG and sleep, and compared to ADO receptor agonists to further evaluate the role of ADO receptor activation on sleep related EEG patterns. ABT-702 (10.0–30.0 μmol/kg, i.p.) increased the amplitude of the 1–4 Hz band (Fast Fourier Transform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 μmol/kg, i.p.), a centrally active, non-selective adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 μmol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 μmol/kg, i.p.), a peripherally active antagonist, did not, indicating that the EEG effects of ABT-702 are mediated by a central ADO receptor mechanism. The selective A1 agonist N6-cyclopentyladenosine (CPA, 30.0 μmol/kg, i.p.) also increased the amplitude of 1–4 Hz band, but was not as efficacious as ABT-702. In contrast, the A2A agonist CGS-21680 (1.0–10.0 μmol/kg, i.p.) and the non-selective agonist, N6-ethylcarboximidoadenosine (NECA, 0.03–0.1 μmol/kg, ip.), lowered 1–4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 μmol/kg, i.p.) was found to significantly increase slow wave sleep and decrease REM sleep in rats implanted with both EEG and EMG electrodes for evaluation of sleep. These studies demonstrate that increased extracellular adenosine through AK inhibition can elicit modulatory effects on EEG slow waves via an interaction with central ADO receptor subtypes. [Copyright &y& Elsevier]

-LE300, a benz[d]indolo[2,3-g]azecine with nanomolar affinities to the hD1 receptor family, has been further pharmacologically characterized and its modelled structure was compared to its X-ray structure in order to explain NMR data, that was not in accordance to the X-ray structure. Moderate affinity at the hD3 receptor was determined, nanomolar affinities were found at the 5-HT2A and 5-HT2C receptors, micromolar affinity at the 5-HT1A receptor using binding assays. Functional studies indicate moderate antagonist activity at the 5-HT2A site . No activity was found at dopamine, serotonin and norepinephrine transporters. These results suggested the use of LE300 for cocaine addiction treatment. High activities were found using in vivo testing: LE300 suppressed spontanous locomotor activity with an ID50 of 1.24 mg/kg and attenuated locomotor activity induced by 20 mg/kg cocaine with an AD50 of 1.50 mg/kg. It failed to substitute for the discriminative stimulus effects produced by cocaine. [Copyright &y& Elsevier]

The mechanism of lactamization of corresponding lactones was investigated by means of gas chromatography and synthesis of possible intermediates as references. Lactones react with amines via the amino acid with subsequent elimination of water to the corresponding lactams. In the first step, also hydroxyamides are in equilibrium with the lactones and amines, respectively, which are not able to form the amide though. This mechanism opens a new approach for the synthesis of Nβ-disubstituted tryptamines. [Copyright &y& Elsevier]

Technology Assessment (TA) is a problem oriented endeavour dealing with political, societal, ecological, etc. problems. Only in rare cases is one individual scientific discipline sufficient to assess these problems. Usually the perspectives of different scientific disciplines have to be combined in order to develop interdisciplinary based recommendations to act. In this paper a quality controlled interdisciplinary discussion process is described which encourages an expert group to generate argumentation chains cross-cutting the disciplinary boundaries. The role of ethical reflection in this procedure depends on the problem situation. Whenever a technical application is on the agenda which cannot be allocated to a so-called “business-as-usual” case, one would ask for ethical reflection. This contribution argues that this ethical reflection has to take place together with the interdisciplinary discussion due to two reasons. Firstly, the technical, economical, legal and social aspects are deeply cross-correlated with the ethical reflection. And secondly, participating in such interdisciplinary discussions enables an ethical reflection which keeps in touch with the real world. Two case studies dealing with robotics applications in health care are mentioned as examples for problem settings, in which interdisciplinary TA succeed in developing discipline-crossing argumentation chains. [ABSTRACT FROM AUTHOR]

Objective. To determine whether gender differences exist in lower extremity joint motions and energy absorption landing strategies between age and skill matched recreational athletes.Design. Mixed factor, repeated measures design.Background. Compared to males, females execute high demand activities in a more erect posture potentially predisposing the anterior cruciate ligament to greater loads and injury. The preferred energy absorption strategy may provide insight for this performance difference.Methods. Inverse dynamic solutions estimated lower extremity joint kinematics, kinetics and energetic profiles for twelve males and nine females performing a 60 cm drop landing.Results. Females demonstrated a more erect landing posture and utilized greater hip and ankle joint range of motions and maximum joint angular velocities compared to males. Females also exhibited greater energy absorption and peak powers from the knee extensors and ankle plantar-flexors compared to the males. Examinations of the energy absorption contributions revealed that the knee was the primary shock absorber for both genders, whereas the ankle plantar-flexors muscles was the second largest contributor to energy absorption for the females and the hip extensors muscles for the males.Conclusions. Females may choose to land in a more erect posture to maximize the energy absorption from the joints most proximal to ground contact.Relevance Females may be at a greater risk to anterior cruciate ligament injury during landing due to their energy absorption strategy. [Copyright &y& Elsevier]

Objective Development of a method using marketing research data to assess food purchase behavior and consequent nutrient availability for purposes of nutrition surveillance, evaluation of intervention effects, and epidemiologic studies of diet-health relationships. Design Data collected on household food purchases accrued over a 13-week period were selected by using Universal Product Code numbers and household characteristics from a marketing research database. Universal Product Code numbers for 39,408 dairy product purchases were linked to a standard reference for food composition to estimate the nutrient content of foods purchased over time. Subjects/setting Two thousand one hundred sixty-one households located in Victoria, Texas, and surrounding communities who were active members of a frequent shopper program. Analyses Demographic characteristics of sample households and the nutrient content of their dairy product purchases were analyzed using frequency distribution, cross tabulation, analysis of variance, and t test procedures. Results A method for using marketing research data was successfully used to estimate household purchases of specific foods and their nutrient content from a marketing database containing hundreds of thousands of records. Distribution of dairy product purchases and their concomitant nutrients between Hispanic and non-Hispanic households were significant (P<.01, P<.001, respectively) and sustained over time. Application/conclusions Purchase records from large, nationally representative panels of shoppers, such as those maintained by major market research companies, might be used to accomplish detailed longitudinal epidemiologic studies or surveillance of national food- and nutrient-purchasing patterns within and between countries and segments of their respective populations. J Am Diet Assoc. 2003;103:445-453. [Copyright &y& Elsevier]

Presents a study which examined the muscle activity of the upper and lower portions of the subscapularies muscle during several resistance exercises that target this muscle. Materials and methods; Results; Discussion.

We describe, in Ethiopia, a third successful pattern of human adaptation to high-altitude hypoxia that contrasts with both the Andean "classic" (erythrocytosis with arterial hypoxemia) and the more recently identified Tibetan (normal venous hemoglobin concentration with arterial hypoxemia) patterns. A field survey of 236 Ethiopian native residents at 3,530 m (11,650 feet), 14-86 years of age, without evidence of iron deficiency, hemoglobinopathy, or chronic inflammation, found an average hemoglobin concentration of 15.9 and 15.0 g/dl for males and females, respectively, and an average oxygen saturation of hemoglobin of 95.3%. Thus, Ethiopian highlanders maintain venous hemoglobin concentrations and arterial oxygen saturation within the ranges of sea level populations, despite the unavoidable, universal decrease in the ambient oxygen tension at high altitude. [ABSTRACT FROM AUTHOR]

Plasma endothelin elevations have been associated with cerebrovascular pathology. Mechanisms of stimulation, however, are unknown. Therefore, in healthy subjects a marked physiological cerebrovascular response was experimentally provoked by hypercapnia, hypocapnia, and alternating capneic conditions. During these challenges plasma immunoreactive-endothelin-1 (ir-ET-1) concentrations were determined using a radioimmunassay. Physiological effects were continuously recorded for pCO2, cerebral blood flow velocity, pulse frequency, and arterial blood pressure. No alterations in plasma ET-1 levels were found upon any of the cerebrovascular stimuli. We conclude that massive cerebrovascular challenges in healthy individuals do not lead to high circulating ET-1 levels. [Copyright &y& Elsevier]

Das Forschungsgebiet der G‐Protein‐gekoppelten Rezeptoren (GPCRs) hat stark vom Gewinn an räumlich‐zeitlicher Auflösung profitiert, der mit der Entwicklung licht‐kontrollierbarer und ‐schaltbarer Verbindungen einhergeht. Die meisten der synthetisierten molekularen Werkzeuge adressieren die Klasse A GPCRs (Rhodopsin‐ähnlich), die größte Subfamilie dieser Rezeptorklasse. All diese molekularen Werkzeuge wurden entworfen, um die orthosterische Bindungsstelle der GPCRs zu adressieren. In dieser Arbeit berichten wir über die ersten photoschaltbaren allosterischen Modulatoren an Klasse A GPCRs, die entwickelt wurden, um den muscarinischen Acetylcholinrezeptor Subtyp 1 (M1) zu aktivieren. Die dargestellten Derivate der Benzylchinoloncarbonsäure (BQCA), nämlich Photo‐BQCisA and Photo‐BQCtrAns, zeigen komplementäres photopharmakologisches Verhalten und erlauben die reversible Kontrolle über den M1R mittels Licht als externem Stimulus. Dieses Verhalten lässt diese Substanzen wertvoll erscheinen, etwa um das M1R‐Signalling zu untersuchen und zudem dient diese Arbeit als Machbarkeitsstudie für die Darstellung anderer photoschaltbarer Modulatoren für Klasse A‐Rezeptoren [ABSTRACT FROM AUTHOR]

The field of G protein‐coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, i.e., photoswitchable ligands. Most of the developed tools have targeted the Rhodopsin‐like family (Class A), the largest family of GPCRs. However, to date, all such Class A photoswitchable ligands were designed to act at the orthosteric binding site of these receptors. Herein, we report the development of the first photoswitchable allosteric modulators of Class A GPCRs, designed to target the M1 muscarinic acetylcholine receptor. The presented benzyl quinolone carboxylic acid (BQCA) derivatives, Photo‐BQCisA and Photo‐BQCtrAns, exhibit complementary photopharmacological behavior and allow reversible control of the receptor using light as an external stimulus. This makes them valuable tools to further investigate M1 receptor signaling and a proof of concept for photoswitchable allosteric modulators at Class A receptors. [ABSTRACT FROM AUTHOR]

Through close analysis of first-hand narratives of modern wildfire from residents in underrepresented rural communities in the American West, framed with cutting edge research in affect studies and narrative theory, we argue for an expansion of a theory of narrative empathy to make legible an alternate emotional response to texts: narrative compassion, in which narrative interpreters feel "toward" instead of "with" characters and/or narrators. We assess the capacity for narrative compassion to function as both a feeling toward and a standing with others, which maintains agency and lines of difference while still fostering prosocial relationships. We argue for the urgency of this expansion, given that many personal experience narratives about the environmental crisis in which we write, like narratives of modern wildfire, feature a high degree of evaluation as narrators attempt to make sense of confusing and unsettling experiences of a rapidly changing world. As such, these narratives tend to resist the emotional "twinning" upon which empathy relies and demand alternative modes of emotional engagement between narrators and interpreters. [ABSTRACT FROM AUTHOR]

Provides information on a study which documented the electromyographic activity and applied resistance associated with eight scapulohumeral exercises performed below shoulder height. Materials and methods; Results and discussion.

Reveals the interchangeability of conjugated Haemophilus influenzae type b (Hib) vaccines in infants. Safety and immunogenicity of Hib; Increase in antibody following immunization; Adverse reactions.

Evaluates the safety and immunogenicity in adults of several different concentrations of an acellular pertussis vaccine. Conclusion that routine immunization of adults with a vaccine containing acellular pertussis antigens in addition to diphtheria and tetanus toxoids can substantially enhance pertussis antibody levels without an increase in adverse reactions. More.