Joint effects of child temperament and maternal sensitivity on the development of childhood obesity.
The interplay between child characteristics and parenting is increasingly implicated as crucial to child health outcomes. This study assessed the joint effects of children's temperamental characteristics and maternal sensitivity on children's weight status. Data from the National Institute of Child Health and Human Development's Study of Early Child Care and Youth Development were utilized. Infant temperament, assessed at child's age of 6 months by maternal report, was categorized into three types: easy, average, and difficult. Maternal sensitivity, assessed at child's age of 6 months by observing maternal behaviors during mother-child semi-structured interaction, was categorized into two groups: sensitive and insensitive. Children's height and weight were measured longitudinally from age 2 years to Grade 6, and body mass index (BMI) was calculated. BMI percentile was obtained based on the Centers for Disease Control and Prevention's BMI charts. Children, who had a BMI ≥ the 85th percentile, were defined as overweight-or-obese. Generalized estimating equations were used to analyze the data. The proportions of children overweight-or-obese increased with age, 15.58% at 2 years old to 34.34% by Grade 6. The joint effects of children's temperament and maternal sensitivity on a child's body mass status depended on the child's age. For instance, children with difficult temperament and insensitive mothers had significantly higher risks for being overweight-or-obese during the school age phase but not during early childhood. Specific combinations of child temperament and maternal sensitivity were associated with the development of obesity during childhood. Findings may hold implications for childhood obesity prevention/intervention programs targeting parents.


Myelin vs axon abnormalities in white matter in bipolar disorder.
White matter (WM) abnormalities are among the most commonly reported neuroimaging findings in bipolar disorder. Nonetheless, the specific nature and pathophysiology of these abnormalities remain unclear. Use of a combination of magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) permits examination of myelin and axon abnormalities separately. We aimed to examine myelination and axon geometry in euthymic patients with bipolar disorder with psychosis (BDP) by combining these two complementary noninvasive MRI techniques. We applied a combined MRI approach using MTR to study myelin content and DTS to study metabolite (N-acetylaspartate, NAA) diffusion within axons in patients with BDP (n=21) and healthy controls (n=24). Data were collected from a 1 × 3 × 3-cm voxel within the right prefrontal cortex WM at 4 Tesla. Clinical and cognitive data were examined in association with MTR and DTS data. MTR was significantly reduced in BDP, suggesting reduced myelin content. The apparent diffusion coefficient of NAA did not differ from healthy controls, suggesting no changes in axon geometry in patients with BDP. These findings suggest that patients with BDP exhibit reduced myelin content, but no changes in axon geometry compared with controls. These findings are in contrast with our recent findings, using the same techniques, in patients with schizophrenia (SZ), which suggest both myelination and axon abnormalities in SZ. This difference may indicate that alterations in WM in BDP may have unique causes and may be less extensive than WM abnormalities seen in SZ.


Aggregation and pH responsive disassembly of a new acid-labile surfactant synthesized by thiol-acrylate Michael addition reaction.
Nucleophilic thiol-acrylate Michael reaction between a hydrophobic thiol and hydrophilic acrylate derivative generated a nonionic surfactant with acid-labile β-thiopropionate linker. Micellization of the surfactant, its ability to encapsulate hydrophobic dye, acid-induced disruption of the aggregate and pH-selective dye release profile have been revealed in this report. The micellar aggregates were found to be stable under neutral conditions, but they could be disrupted in acidic pH (5.3), and thus the encapsulated hydrophobic dye molecules could be selectively released. Appropriate control experiments revealed that the sulfur atom in the β-position is essential for acidic hydrolysis of the ester functionality of the surfactant.


Mechanisms of classical crystal growth theory explain quartz and silicate dissolution behavior.
The central control of mineral weathering rates on biogeochemical systems has motivated studies of dissolution for more than 50 years. A complete physical picture that explains widely observed variations in dissolution behavior is lacking, and some data show apparent serious inconsistencies that cannot be explained by the largely empirical kinetic "laws." Here, we show that mineral dissolution can, in fact, be understood through the same mechanistic theory of nucleation developed for mineral growth. In principle, this theory should describe dissolution but has never been tested. By generalizing nucleation rate equations to include dissolution, we arrive at a model that predicts how quartz dissolution processes change with undersaturation from step retreat, to defect-driven and homogeneous etch pit formation. This finding reveals that the "salt effect," recognized almost 100 years ago, arises from a crossover in dominant nucleation mechanism to greatly increase step density. The theory also explains the dissolution kinetics of major weathering aluminosilicates, kaolinite and K-feldspar. In doing so, it provides a sensible origin of discrepancies reported for the dependence of kaolinite dissolution and growth rates on saturation state by invoking a temperature-activated transition in the nucleation process. Although dissolution by nucleation processes was previously unknown for oxides or silicates, our mechanism-based findings are consistent with recent observations of dissolution (i.e., demineralization) in biological minerals. Nucleation theory may be the missing link to unifying mineral growth and dissolution into a mechanistic and quantitative framework across the continuum of driving force.


An initiative to promote value-based stress test selection in primary care and cardiology clinics: A mixed methods evaluation.
Exercise stress echocardiograms (stress echos) are overused, whereas exercise stress electrocardiograms (stress ECGs) can be an appropriate, lower-cost substitute. In this post hoc, mixed methods evaluation, we assessed an initiative promoting value-based, guideline-concordant ordering practices in primary care (PC) and cardiology clinics. Change in percent of stress ECGs ordered of all exercise stress tests (stress ECGs and echos) was calculated between three periods: baseline (January 2019-February 2020); Period 1 with reduced stress ECG report turnaround time + PC-targeted education (began June 2020); and Period 2 with the addition of electronic health record-based alternative alert (AA) providing point-of-care clinical decision support. The AA was deployed in two of five PC clinics in July 2020, two additional PC clinics in January 2021, and one of four cardiology clinics in February 2021. Nineteen primary care providers (PCPs) and five cardiologists were interviewed in Period 2. Clinicians reported reducing ECG report turnaround time was crucial for adoption. PCPs specifically reported that value-based education helped change their practice. In PC, the percent of stress ECGs ordered increased by 38% ± 6% (SE) (p < 0.0001) from baseline to Period 1. Most PCPs identified the AA as the most impactful initiative, yet stress ECG ordering did not change (6% ± 6%; p = 0.34) between Periods 1 and 2. In contrast, cardiologists reportedly relied on their expertise rather than AAs, yet their stress ECGs orders increased from Period 1 to 2 to a larger degree in the cardiology clinic with the AA (12% ± 5%; p = 0.01) than clinics without the AA (6% ± 2%; p = 0.01). The percent of stress ECGs ordered was higher in Period 2 than baseline for both specialties (both p < 0.0001). This initiative influenced ordering behaviour in PC and cardiology clinics. However, clinicians' perceptions of the initiative varied between specialties and did not always align with the observed behaviour change.


Persianorchestia, a new talitrid genus (Crustacea: Amphipoda: Talitridae) from Gulf of Oman, Iran.
A new genus and species, Persianorchestia nirvana gen. et sp. nov., is described from the south coast of Iran along the Gulf of Oman. The new genus is characterized by large eyes, gnathopod 1 posterior margin of carpus and propodus each with lobe covered in palmate setae, smooth posterior margin on dactylus of male gnathopod 2, a slender dactylus on pereopod 5, uropod 1 outer ramus without marginal robust setae and with apical spear-shaped setae on the rami of uropods 1 and 2. Persianorchestia is most similar to Pseudorchestoidea Bousfield, 1982.


Psychometric evaluation of a questionnaire to document side-effects of chemotherapy.
This paper reports the psychometric testing of the Worthing Chemotherapy Questionnaire (WCQ). The WCQ is a patient self-report instrument to document side-effects of chemotherapy. Literature review of relevant studies shows that psychometric testing of similar instruments is rarely rigorous. Content validity for the WCQ was established in five ways: literature review, Delphi review among oncology staff, pre-pilot unstructured interviews, pilot study and amendment of the instrument and items for spontaneous reporting of problems on the questionnaire. A three-stage approach to construct validity was used. The hypothesis adopted was that as certain cytotoxic agents cause stomatitis, incidence and severity of stomatitis will decrease following cessation of treatment. Stage 1: factor analysis confirmed the presence of a sole factor, with an eigenvalue of 5.3, for mouth problems which explained 65.5% of the variance. Stage 2: the hypothesis was confirmed using research findings. Stage 3: the Wilcoxon test showed highly significant results for during and post chemotherapy stomatitis scores. Reliability of the questionnaire was assessed using the test-retest method. Weighted kappa was chosen as the test statistic. A median value of wk = 0.87 was obtained. The results indicate that the WCQ is a reliable and valid instrument.


Significance of absent or faint kidney sign on bone scan.
Seven men, six suffering from widespread bone metastases of prostatic origin and one with urinary bladder carcinoma, demonstrated minimal or no discernible radioactivity in the kidneys and urinary bladder at the time of bone scanning using 99mTc-stannous polyphosphate. The mechanism behind this scan finding is thought to be rapid and enhanced uptake of the radiopharmaceutical by pathologic bone. The significance of the faint or absent kidney sign in bone scanning, particularly in cases where abnormally homogeneous and symmetric radioactivity exists, is discussed.


Copper chloride induces antioxidant gene expression but reduces ability to mediate H2O2 toxicity in Xanthomonas campestris.
Copper (Cu)-based biocides are currently used as control measures for both fungal and bacterial diseases in agricultural fields. In this communication, we show that exposure of the bacterial plant pathogen Xanthomonas campestris to nonlethal concentrations of Cu(2+) ions (75 µM) enhanced expression of genes in OxyR, OhrR and IscR regulons. High levels of catalase, Ohr peroxidase and superoxide dismutase diminished Cu(2+)-induced gene expression, suggesting that the production of hydrogen peroxide (H2O2) and organic hydroperoxides is responsible for Cu(2+)-induced gene expression. Despite high expression of antioxidant genes, the CuCl2-treated cells were more susceptible to H2O2 killing treatment than the uninduced cells. This phenotype arose from lowered catalase activity in the CuCl2-pretreated cells. Thus, exposure to a nonlethal dose of Cu(2+) renders X. campestris vulnerable to H2O2, even when various genes for peroxide-metabolizing enzymes are highly expressed. Moreover, CuCl2-pretreated cells are sensitive to treatment with the redox cycling drug, menadione. No physiological cross-protection response was observed in CuCl2-treated cells in a subsequent challenge with killing concentrations of an organic hydroperoxide. As H2O2 production is an important initial plant immune response, defects in H2O2 protection are likely to reduce bacterial survival in plant hosts and enhance the usefulness of copper biocides in controlling bacterial pathogens.


Comparison of Ultrasound-Guided and Landmark-Based Lumbar Punctures in Inexperienced Resident Physicians.
We sought to determine whether US-guided lumbar puncture reduced the rate of lumbar puncture failures for providers at an academic teaching hospital with variable lumbar puncture and US experience compared to the traditional landmark-based technique. We conducted a prospective randomized controlled trial to compare US-guided lumbar puncture to the traditional landmark technique in an academic emergency department. Thirty-five patients were randomized to either have their lumbar puncture performed either via the landmark or US-guided technique. All procedures were completed by an emergency medicine resident with variable lumbar puncture and US experience. Procedural failures, the number of attempts, the time to completion, and patient pain scores were all recorded. The adjusted odds ratio of successfully obtaining cerebrospinal fluid (CSF) in the US-guided lumbar puncture group was 2.31 compared to the landmark-based lumbar puncture group (P = .377). It took 1.54 times more attempts to obtain CSF in the landmark group as it did in the US group (P = .046). It seemed to have no effect on postprocedural pain or the time to obtain CSF. The use of US guidance to assist in lumbar punctures did not improve the procedural success rate over traditional landmark techniques in an academic setting with novice providers. Although using US for procedural guidance significantly decreased the number of attempts, it seemed to have no effect on postprocedural pain or the time to obtain CSF.


Controversies in the treatment of early stage endometrial carcinoma.
Despite the publication of numerous studies, including some multicentered randomized controlled trials, there continues to be vigorous debate regarding the optimal management of early stage endometrial cancer, including the extent of surgery and the role of adjuvant chemotherapy and radiation. Resolving these questions has become increasingly important in view of the increase of endometrial cancer, related to the aging population and the alarming incidence of obesity. Furthermore, there are more surgical challenges encountered when operating on elderly patients or on patients with increased BMI and the associated comorbidities, such as diabetes, hypertension, heart disease, and pulmonary dysfunction. This paper will focus on the advantages of minimally invasive surgery, the value of lymphadenectomy including sentinel lymph node mapping, and some of the current controversies surrounding adjuvant chemotherapy and radiation.


Percutaneous coronary intervention in chronic stable angina.
Although the therapeutic advantage of percutaneous coronary intervention in acute coronary syndromes have been proved in numerous studies, its position in the treatment of stable angina remains a controversial issue. The results of the recent studies did not lead into definite answers for the proper treatment of chronic coronary artery disease. The identification of the patients that will benefit from the interventional approach is necessary and is probably based on the proper screening for myocardial ischemia with noninvasive diagnostic techniques. In this review article, we mention the most recent studies for the treatment of chronic stable angina with respect to clinical outcome and economical consequences.


Differential thermosensitivity of sensory neurons in the guinea pig trigeminal ganglion.
Intracellular recordings were employed to study the effects of temperature on membrane properties and excitability in sensory neurons of the intact guinea pig trigeminal ganglion (TG) maintained in vitro. Neurons were classified according to the shape and duration of the action potential into F (short-duration, fast spike) and S (long duration, slow spike with a "hump") types. Most type F (33/34) neurons had axons with conduction velocities >1.5 m/s, while only 30% (6/23) of type S neurons reached these conduction speeds suggesting differences in myelination. Cooling reduced axonal conduction velocity and prolonged spike duration in both neuronal types. In F-type neurons with strong inward rectification. cooling also increased the excitability, augmenting the input resistance and reducing the current firing threshold. These effects were not observed in S-type neurons lacking inward rectification. In striking contrast to results obtained in cultured TG neurons, cooling or menthol did not induce firing in recordings from the acutely isolated ganglion. However, after application of submillimolar concentrations (100 microM) of the potassium channel blocker 4-aminopyridine (4-AP), 29% previously unresponsive neurons developed cold sensitivity. An additional 31% developed ongoing activity that was sensitive to temperature. Only neurons with strong inward rectification (mostly F-type) became thermosensitive. Cooling- and 4-AP-evoked firing were insensitive to intracellular application of 4-AP or somatic membrane hyperpolarization, suggesting that their action was most prominent at the level of the axon. The lack of excitatory actions of low temperature in the excised intact ganglion contrasts with the impulse discharges induced by cooling in trigeminal nerve terminals of the same species, suggesting a critical difference between cold-transduction mechanisms at the level of the nerve terminals and the soma.


Center of mass mechanics of chimpanzee bipedal walking.
Center of mass (CoM) oscillations were documented for 81 bipedal walking strides of three chimpanzees. Full-stride ground reaction forces were recorded as well as kinematic data to synchronize force to gait events and to determine speed. Despite being a bent-hip, bent-knee (BHBK) gait, chimpanzee walking uses pendulum-like motion with vertical oscillations of the CoM that are similar in pattern and relative magnitude to those of humans. Maximum height is achieved during single support and minimum height during double support. The mediolateral oscillations of the CoM are more pronounced relative to stature than in human walking when compared at the same Froude speed. Despite the pendular nature of chimpanzee bipedalism, energy recoveries from exchanges of kinetic and potential energies are low on average and highly variable. This variability is probably related to the poor phasic coordination of energy fluctuations in these facultatively bipedal animals. The work on the CoM per unit mass and distance (mechanical cost of transport) is higher than that in humans, but lower than that in bipedally walking monkeys and gibbons. The pronounced side sway is not passive, but constitutes 10% of the total work of lifting and accelerating the CoM. CoM oscillations of bipedally walking chimpanzees are distinctly different from those of BHBK gait of humans with a flat trajectory, but this is often described as "chimpanzee-like" walking. Human BHBK gait is a poor model for chimpanzee bipedal walking and offers limited insights for reconstructing early hominin gait evolution.


A Novel Pattern of Yolk Processing in Developing Snake Eggs (Colubridae: Lampropeltini) and its Functional and Evolutionary Implications.
Early amniotic vertebrates evolved large-yolked eggs that permitted production of well-developed, terrestrial hatchlings. This reproductive pattern required new mechanisms for cellularizing the yolk and mobilizing it for embryonic use. In birds, cells that line the yolk sac cavity phagocytose and digest the yolk material, a pattern that is commonly assumed to be universal among oviparous amniotes. However, recent evidence challenges the assumption that all squamate reptiles conform to the avian developmental pattern. In this paper, scanning electron microscopy and histology were used to study mechanisms of yolk processing in two colubrid snakes, the kingsnake Lampropeltis getula and the milksnake L. triangulum. Endodermal cells from the yolk sac splanchnopleure proliferate massively as they invade the yolk sac cavity, forming elaborate chains of interlinked cells. These cells grow in size as they phagocytose yolk material. Subsequently, vitelline capillaries invade the masses of yolk-laden cells and become coated with the endodermal cells, forming an elaborate meshwork of cell-coated strands. The close association of cells, yolk, and blood vessels allows yolk material to be cellularized, digested, and transported for embryonic use. The overall pattern is like that of the corn snake Pantherophis guttatus, but contrasts markedly with that of birds. Given recent evidence that this developmental pattern may also occur in certain lizards, we postulate that it is ancestral for squamates. Studies of lizards, crocodilians, and turtles are needed to clarify the evolutionary history of this pattern and its implications for the evolution of the amniotic (terrestrial) vertebrate egg.


CpG island hypermethylation profiling of lung cancer using restriction landmark genomic scanning (RLGS) analysis.
Lung cancer remains the leading cause of cancer related mortality, accounting for almost one-third of cancer deaths in men and one-fourth of cancer deaths in women; 160,440 lung cancer deaths are expected in 2004. Survival from lung cancer depends mainly upon the stage at presentation. As localized tumors generally do not cause symptoms, the disease is usually diagnosed in symptomatic patients at advanced stages when the prognosis is poor. As a result, the overall 5-year lung cancer survival rate is only 15%. It is well known that epigenetic alterations such as DNA methylation of CpG dinucleotides located in CpG islands within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could identify potential biomarkers for lung cancer risk. Our goal for this study is to identify novel hypermethylated genes in lung cancer. We have investigated the methylation profiles of DNA samples from 14 paired lung tumor and adjacent normal tissues resected from the same individuals using restriction landmark genomic scanning (RLGS). We could assess the DNA methylation status of an average of 2,012 CpG islands for each tumor. We identified 162 differentially methylated loci where CpG islands were hypermethylated in lung tumors but not in adjacent non-cancer tissues. Among 162 sites of differential DNA methylation, detected from at least one tumor/normal pair, 21 hypermethylated genes were identified that were not reported previously as hypermethylated in lung tumor tissue.


Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase.
The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands. Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid side chains of the target protein.


Baicalein Protects Human Skin Cells against Ultraviolet B-Induced Oxidative Stress.
Baicalein (5,6,7-trihydroxy-2-phenyl-chromen-4-one) is a flavone, a type of flavonoid, originally isolated from the roots of Scutellaria baicalensis. This study evaluated the protective effects of baicalein against oxidative damage-mediated apoptosis induced by ultraviolet B (UVB) radiation in a human keratinocyte cell line (HaCaT). Baicalein absorbed light within the wavelength range of UVB. In addition, baicalein decreased the level of intracellular reactive oxygen species (ROS) in response to UVB radiation. Baicalein protected cells against UVB radiation-induced DNA breaks, 8-isoprostane generation and protein modification in HaCaT cells. Furthermore, baicalein suppressed the apoptotic cell death by UVB radiation. These findings suggest that baicalein protected HaCaT cells against UVB radiation-induced cell damage and apoptosis by absorbing UVB radiation and scavenging ROS.


INCIPIENT GERMINATION IN HEAVY SUSPENSIONS OF SPORES OF BACILLUS STEAROTHERMOPHILUS AT SUBMINIMAL GROWTH TEMPERATURES.
Curran, Harold R. (U.S. Department of Agriculture, Washington, D.C.), and Michael J. Pallansch. Incipient germination in heavy suspensions of spores of Bacillus stearothermophilus at subminimal growth temperatures. J. Bacteriol. 86:911-918. 1963.-By use of spore (plate) counts and permeability to stain, labilization was followed periodically in heavy suspensions of washed Bacillus stearothermophilus 1518 spores incubated at different temperatures. Although vegetative proliferation did not occur below 38 C, incipient germination was rapid down to 20 C and much slower and incomplete at 14 C. Dilution of the suspension materially reduced the degree and rate of labilization. The degree of washing and use of deionized water had no appreciable influence upon early development of the spores. The results are discussed from the point of view of the possible origin and nature of the germination stimulant.


Mechanisms of Wheat Allergenicity in Mice: Comparison of Adjuvant-Free vs. Alum-Adjuvant Models.
Wheat protein is considered a major type of food allergen in many countries including the USA. The mechanisms of allergenicity of wheat proteins are not well understood at present. Both adjuvant-based and adjuvant-free mouse models are reported for this food allergy. However, it is unclear whether the mechanisms underlying wheat allergenicity in these two types of models are similar or different. Therefore, we compared the molecular mechanisms in a novel adjuvant-free (AF) model vs. a conventional alum-adjuvant (AA) model of wheat allergy using salt-soluble wheat protein (SSWP). In the AF model, Balb/cJ mice were sensitized with SSWP via skin exposure. In the AA model, mice were sensitized by an intraperitoneal injection of SSWP with alum. In both models, allergic reactions were elicited using an identical protocol. Robust IgE as well as mucosal mast cell protein-1 responses were elicited similarly in both models. However, an analysis of the spleen immune markers identified strikingly different molecular activation patterns in these two models. Furthermore, a number of immune markers associated with intrinsic allergenicity were also identified in both models. Since the AF model uses skin exposure without an adjuvant, the mechanisms in the AF model may more closely simulate the human wheat allergenicity mechanisms from skin exposure in occupational settings such as in the baking industry.


MyD88 is dispensable for resistance to Paracoccidioides brasiliensis in a murine model of blood-borne disseminated infection.
We have studied the role of MyD88, an adaptor protein of Toll-like receptors (TLRs), in murine defenses against Paracoccidioides brasiliensis in a model of blood-borne disseminated infection. Wild-type (WT) and MyD88-deficient mice infected intravenously with P. brasiliensis yeast cells showed an equivalent fungal burden, as well as similar levels of proinflammatory IL-1beta, IL-6, IL-12p70, tumor necrosis factor (TNF)-alpha and MIP-2, T-helper type 1 (Th1) (IFN-gamma) and Th2 cytokines (IL-4) in tissue homogenates. In vitro production of TNF-alpha, IFN-gamma and IL-12p70, by antigen-stimulated splenocytes from infected animals, was also similar in both types of mice; this production of Th1 cytokines correlated with a similar frequency of IFN-gamma-producing CD4 T cells. Recruitment of neutrophils to the peritoneal cavity of intraperitoneally infected mice was not affected in TLR2-/-, TLR4-/- as compared with WT mice, but significantly decreased in MyD88-deficient mice. In vitro production of TNF-alpha by peritoneal macrophages from MyD88-, TLR2- and TLR4-deficient mice in response to P. brasiliensis yeasts was undiminished, as compared with macrophages from WT mice, and, in addition, laminarin failed to inhibit production of TNF-alpha by WT and MyD88-deficient macrophages. Overall, these data suggest that the response to P. brasiliensis yeasts occurs independently of the adaptor molecule MyD88, and indicate that TLR2, TLR4 and dectin-1 do not play a significant role in recognition of P. brasiliensis yeast cells.


Involving citizens in priority setting for public health research: Implementation in infection research.
Public sources fund the majority of UK infection research, but citizens currently have no formal role in resource allocation. To explore the feasibility and willingness of citizens to engage in strategic decision making, we developed and tested a practical tool to capture public priorities for research. A scenario including six infection themes for funding was developed to assess citizen priorities for research funding. This was tested over two days at a university public festival. Votes were cast anonymously along with rationale for selection. The scenario was then implemented during a three-hour focus group exploring views on engagement in strategic decisions and in-depth evaluation of the tool. 188/491(38%) prioritized funding research into drug-resistant infections followed by emerging infections(18%). Results were similar between both days. Focus groups contained a total of 20 citizens with an equal gender split, range of ethnicities and ages ranging from 18 to >70 years. The tool was perceived as clear with participants able to make informed comparisons. Rationale for funding choices provided by voters and focus group participants are grouped into three major themes: (i) Information processing; (ii) Knowledge of the problem; (iii) Responsibility; and a unique theme within the focus groups (iv) The potential role of citizens in decision making. Divergent perceptions of relevance and confidence of "non-experts" as decision makers were expressed. Voting scenarios can be used to collect, en-masse, citizens' choices and rationale for research priorities. Ensuring adequate levels of citizen information and confidence is important to allow deployment in other formats.


Comparative Study of Covalent and van der Waals CdS Quantum Dot Assemblies from Many-Body Perturbation Theory.
Quantum dot (QD) assemblies are nanostructured networks made from aggregates of QDs and feature improved charge and energy transfer efficiencies compared to discrete QDs. Using first-principles many-body perturbation theory, we systematically compare the electronic and optical properties of two types of CdS QD assemblies that have been experimentally investigated: (i) QD gels, where individual QDs are covalently connected via di- or polysulfide bonds, and (ii) QD nanocrystals, where individual QDs are bound via van der Waals interactions. Our work illustrates how the electronic and optical properties evolve when discrete QDs are assembled into 1D, 2D, and 3D gels and nanocrystals, as well as how the one-body and many-body interactions in these systems impact the trends as the dimensionality of the assembly increases. Furthermore, our work reveals the crucial role of the di- or polysulfide covalent bonds in the localization of the excitons, which highlights the difference between QD gels and QD nanocrystals.


Balancing typological and dimensional approaches: Assessment of adult attachment styles with Factor Mixture Analysis.
Many studies show the importance of adult attachment styles and their impact on social and emotional adaptation in adulthood. However, there is no agreement about whether attachment should be regarded as typological or dimensional, and some authors have proposed reconciling both options, so that adult attachment styles can be assessed more accurately and realistically. In this study we have adopted this comprehensive view and used Factor Mixture Analysis, the most appropriate model for assessing this mixture view. More specifically, we attempted to determine the nature and types (if any) of attachment styles that can be assessed with the Adult Attachment Questionnaire (CAA), using this mixture view. A total of 515 adults from Spain took part, with ages between 18 and 56 years old. In addition to the CAA questionnaire, they completed the Parental Bonding Instrument and the emotional stability subscale of the Overall Personality Assessment Scale. On the basis of the CAA scores, the results show that only two profiles-insecure attachment and normal-range-can be univocally differentiated. Furthermore, the results of a full multiple-group structural model show that each of these profiles has a different pattern of validity relations with the external variables maternal care, maternal overprotection and emotional stability. These differential validity results reinforce the general hypothesis that two differentiated clusters of individuals can be distinguished on the basis of the responses to the CAA items.


Maturational trajectories of white matter microstructure underlying the right presupplementary motor area reflect individual improvements in motor response cancellation in children and adolescents.
The ability to effectively suppress motor response tendencies is essential for focused and goal-directed behavior. Here, we tested the hypothesis that developmental improvement in the ability to cancel a motor response is reflected by maturational changes in the white matter underlying the right presupplementary motor area (preSMA) and posterior inferior frontal gyrus (IFG), two cortical key areas of the fronto-basal ganglia "stopping" network. Eighty-eight typically-developing children and adolescents, aged 7-19 years, were longitudinally assessed with the stop-signal task (SST) and diffusion tensor imaging (DTI) of the brain over a period of six years. Participants were examined from two to nine times with an average of 6.6 times, resulting in 576 SST-DTI datasets. We applied tract-based spatial statistics to extract mean fractional anisotropy (FA) from regions-of-interest in the white matter underlying the right IFG (IFGFA) and right preSMA (preSMAFA) at each time point. Motor response cancelation performance, estimated with the stop-signal reaction time (SSRT), improved with age. Initially well performing children plateaued around the age of 11 years, while initially poor performers caught up at the age of 13-14 years. White matter microstructure continued to mature across the investigated age range. Males generally displayed linear maturational trajectories, while females displayed more curvilinear trajectories that leveled off around 12-14 years of age. Maturational increases in right preSMAFA but not right IFGFA were associated with developmental improvements in SSRT. This association differed depending on the mean right preSMAFA across the individual maturational trajectory. Children with lower mean right preSMAFA exhibited poorer SSRT performance at younger ages but steeper developmental trajectories of SSRT improvement. Children with higher mean right preSMAFA exhibited flatter trajectories of SSRT improvement along with faster SSRT already at the first assessments. The results suggest that no further improvement in motor response cancellation is achieved once a certain level of maturity in the white matter underlying the right preSMA is reached. Similar dynamics may apply to other behavioral read-outs and brain structures and, thus, need to be considered in longitudinal MRI studies designed to map brain structural correlates of behavioral changes during development.


Utilizing diversity-oriented synthesis in antimicrobial drug discovery.
The development of resistance to existing antimicrobials has created a threat to human health that is not being addressed through our current drug pipeline. Limitations with the use of commercial vendor libraries and natural products have created a need for new types of small molecules to be screened in antimicrobial assays. Diversity oriented synthesis (DOS) is a strategy for the efficient generation of compound collections with a high degree of structural diversity. Diversity-oriented synthesis molecules occupy the middle ground of both complexity and efficiency of synthesis between natural products and commercial libraries. In this review we focus upon the use of diversity-oriented synthesis compound collections for the discovery of new antimicrobial agents.


Enhanced thermoelectric performance of carbon nanotubes at elevated temperature.
The electronic and transport properties of the (10, 0) single-walled carbon nanotube are studied by performing first-principles calculations and semi-classical Boltzmann theory. It is found that the (10, 0) tube exhibits a considerably large Seebeck coefficient and electrical conductivity which are highly desirable for good thermoelectric materials. Together with the lattice thermal conductivity predicted by non-equilibrium molecular dynamics simulations, the room temperature ZT value of the (10, 0) tube is estimated to be 0.15 for p-type carriers. Moreover, the ZT value exhibits strong temperature dependence and can reach to 0.77 at 1000 K. Such a ZT value can be further enhanced to as high as 1.9 by isotopic substitution and chemisorptions of hydrogen on the tube surface.


Peripheral basophil reactivity, CD203c expression by Cryj1 stimulation, is useful for diagnosing seasonal allergic rhinitis by Japanese cedar pollen.
Measuring specific IgE can yield direct, accurate, and objective data. Nevertheless, clinical symptoms of allergy are often inconsistent with these data. Recently, the expression of CD203c, a surface marker of basophils, has been reported as capable of distinguishing allergic patients. This study compared specific IgE in serum and skin tests against antigen to assess CD203c as a biomarker correlated with allergic rhinitis (AR). We asked 3,453 subjects whether they experienced any AR related symptom. All subjects were assessed for six specific IgEs for common aeroallergens. Skin tests were also conducted for six aeroallergens. We observed the reactivity of peripheral basophil by measuring the levels of CD203c by Cryj1 stimulation using flow cytometry. Of the 3,453 participants, 1,987 (57.5%) possessed Japanese cedar pollen (JCP) specific IgE in their serum. Among those 1,987 JCP specific IgE positive participants, 552 (27.8%) had not experienced any allergic symptom during the JCP season. The levels of CD203c in the peripheral basophil by Cryj1 stimulation were significantly higher in SAR-JCP subjects than in non-SAR-JCP subjects (Cryj1 0.5 ng/ml: 2.25 ± 0.90% vs. 60.2 ± 27.4%, p < 0.01, Cryj1 50 ng/ml: 1.89 ± 0.90% vs. 68.0 ± 21.2%, p < 0.01). Our results indicate that the levels of CD203c in peripheral basophils by Cryj1 stimulation is a more objective and reliable marker that better reflects the allergic reaction by SAR-JCP in vivo than measuring specific IgE in serum or skin tests.


Electrifying love: electric fish use species-specific discharge for mate recognition.
Mate choice is mediated by a range of sensory cues, and assortative mating based on these cues can drive reproductive isolation among diverging populations. A specific feature of mormyrid fish, the electric organ discharge (EOD), is used for electrolocation and intraspecific communication. We hypothesized that the EOD also facilitates assortative mating and ultimately promotes prezygotic reproductive isolation in African weakly electric fishes. Our behavioural experiments using live males as well as EOD playback demonstrated that female mate recognition is influenced by EOD signals and that females are attracted to EOD characteristics of conspecific males. The dual function of the EOD for both foraging and social communication (including mate recognition leading to assortative mating) underlines the importance of electric signal differentiation for the divergence of African weakly electric fishes. Thus, the EOD provides an intriguing mechanism promoting trophic divergence and reproductive isolation between two closely related Campylomormyrus species occurring in sympatry in the lower Congo rapids.


Identification of mammalian Pit-1w, possibly involved in spermatogenesis in mice.
Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Alternative splicing of Pit-1 gene transcripts has been shown to give rise to several variants with discrete transactivation properties; however, those arising from alternative promoters such as avian Pit-1 w have not yet been identified in mammals. Here, comparative genomics analysis followed by reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of 5' cDNA ends (5'RACE) were used in identifying Pit-1 w mRNA in the mouse pituitary. The mouse Pit-1 w mRNA is generated by using an alternative promoter located in the first intron, as with chicken Pit-1 w, and is expressed in a wide variety of tissues besides the pituitary. In the testis, Pit-1 w is expressed as the predominant variant and a protein of 33 kDa. During the first wave of spermatogenesis, expression of Pit-1 w mRNA at substantial levels was observed from 3 weeks, but not at 1 or 2 weeks after birth. A combination of immunohistochemistry and in situ hybridization detected Pit-1 mRNA and Pit-1 immunoreactivity in the spermatogonia, spermatocytes, and spermatids in the testis of adult mice. Because secondary spermatocytes and haploid spermatids increase in number between 18 and 20 days after birth in mice, it is possible that mouse Pit-1 w plays a role in spermatogenesis. This is the first report demonstrating the expression of Pit-1 variants arising from alternative promoters in mammals.


Barodontalgia at 12,000 feet.
Persons susceptible to barodontalgia include those with peridontal abscesses, carious teeth, maxillary sinus congestion, or those who have had recent extractions or restorations. A 38-year-old man had acute pain while he was in a depressurized chamber. Treatment of a periodontal abscess alleviated the problem.


Predictors of change in patient treatment outcome expectation during cognitive-behavioral psychotherapy for generalized anxiety disorder.
Positive patient-rated psychotherapy outcome expectation at pre- or early treatment is associated with posttreatment improvement. However, there is limited research on patients' change in outcome expectation across therapy and participant factors that predict both pretreatment outcome expectation and expectation change. The present study aimed to examine (a) the overall trajectory of change in patients' outcome expectation from pretreatment through treatment's end; (b) baseline patient characteristics as predictors of their pretreatment outcome expectation; (c) early change in general self-efficacy (controlling for baseline patient characteristics, early change in symptoms, and treatment condition) as predictor of expectation change; and (d) therapist effects on patients' outcome expectation change. For patients with generalized anxiety disorder (N = 80) receiving variants of cognitive-behavioral therapy, outcome expectation was assessed at pretreatment, Session 5, Session 10, and posttreatment. Using multilevel models with repeated assessments, we found outcome expectation to linearly increase from pre- to posttreatment. When controlling for other patient characteristics at intake, higher depression severity was associated with lower pretreatment outcome expectation. When controlling for baseline patient characteristics, early reduction in generalized anxiety disorder-symptoms and global severity, and treatment condition, an increase in early general self-efficacy was associated with a less steep increase in outcome expectation over the therapy. We also found between-therapist differences in their patients' average outcome expectation change. Results shed additional light on various participant characteristics that influence patients' pretreatment outcome expectation and expectation change through therapy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations.
We report in silico identification and characterisation of a novel member of the ras association domain family 1 (RASSF1)/NORE1 family, namely, RASSF2, located at chromosomal region 20p13. It has three isoforms, all contain a ras association domain in the C-terminus. The longest isoform RASSF2A contains a 5' CpG island. RASSF2A was cloned from a brain cDNA library and directly sequenced, confirming the genomic gene structure. In previous reports, we and others have demonstrated that RASSF1A is epigenetically inactivated in a variety of cancers, including sporadic colorectal cancer (CRC). In the present report, we analysed the methylation status of RASSF2A promoter region CpG island in sporadic CRC and compared it to K-ras mutation status. RASSF2A promoter region CpG island was hypermethylated in a majority of colorectal tumour cell lines (89%) and in primary colorectal tumours (70%), while DNA from matched normal mucosa was found to be unmethylated (tumour-specific methylation). RASSF2A expression was reactivated in methylated tumour cell lines after treatment with 5-aza 2-deoxycytidine. RASSF2A methylation is an early event, detectable in 7/8 colon adenomas. Furthermore, 75% of colorectal tumours with RASSF2A methylation had no K-ras mutations (codons, 12 and 13) (P=0.048), Fisher's exact test). Our data demonstrate that RASSF2A is frequently inactivated in CRCs by CpG island promoter hypermethylation, and that epigenetic (RASSF2A) and genetic (K-ras) changes are mutually exclusive and provide alternative pathways for affecting Ras signalling.


Associating bovine herpesvirus 1 envelope glycoprotein gD with activated phospho-PLC-γ1(S1248).
Phospholipase C gamma 1 (PLC-γ1) may locate at distinct subcellular locations, such as cytosol, plasma membrane, and nucleus for varied biological functions. Bovine herpesvirus 1 (BoHV-1) productive infection activates PLC-γ1 signaling, as demonstrated by increased protein levels of phosphorylated-PLC-γ1 at Ser1248 [p-PLC-γ1(S1248)], which benefits virus productive infection. Here, for the first time, we reported that Golgi apparatus also contains activated p-PLC-γ1(S1248). And BoHV-1 productive infection at later stages (24 hpi) increased the accumulation of p-PLC-γ1(S1248) in the Golgi apparatus, where p-PLC-γ1(S1248) forms highlighted puncta observed via a confocal microscope. Coimmunoprecipitation studies demonstrated that the Golgi p-PLC-γ1(S1248) is specifically associated with the viral protein gD but not gC. In addition, we found that p-PLC-γ1(S1248) is consistently associated with both the plasma membrane-associated virions and the released virions. When the virus-infected cells were treated with PLC-γ1-specific inhibitor, U73122, for a short duration of 4 hours prior to the endpoint of virus infection, we found that the viral protein gD was trapped in the Golgi apparatus, suggesting that the PLC-γ1 signaling may facilitate trafficking of progeny virions out of this organelle. These findings provide a novel insight into the interplay between PLC-γ1 signaling and BoHV-1 replication. IMPORTANCE Bovine herpesvirus 1 (BoHV-1) productive infection increases protein levels of phosphorylated-phospholipase C gamma 1 at Ser1248 [p-PLC-γ1(S1248)]. However, whether it causes any variations to p-PLC-γ1(S1248) localization is not well understood. Here, for the first time, we found that partial p-PLC-γ1(S1248) is residing in the Golgi apparatus, where the accumulation is enhanced by virus infection. p-PLC-γ1(S1248) is consistently associated with virions, partially via binding to gD, in both the Golgi apparatus and cytoplasm membranes. Surprisingly, it also associates with the released virions. Of note, this is the first evidenced BoHV-1 virion-bound host protein. It seems that p-PLC-γ1(S1248) works as an escort during trafficking of progeny virions out of Golgi apparatus to the plasma membranes as well as releasing outside of the cell membranes. Furthermore, we showed that the activated p-PLC-γ1(S1248) is potentially implicated in the transport of virions out of Golgi apparatus, which may represent a novel mechanism to regulate virus productive infection.


One-dimensional harmonic chain model of vibration-mode matching in solid-liquid interfacial thermal transport.
Understanding the atomistic mechanism of interfacial thermal transport at solid-liquid interfaces is a key challenge in thermal management at the nanoscale. A recent molecular-dynamics study demonstrated that interfacial thermal resistance (ITR) at the interface between a solid and a surfactant solution can be minimized by adjusting the molecular mass of the surfactant. In the present study, we explain the mechanism of this ITR minimization in view of vibration-mode matching using a one-dimensional (1D) harmonic chain model of a solid-liquid interface having an interfacial adsorption layer of surfactant molecules. The equation of motion for the 1D chain is described by a classical Langevin equation and is analytically solved by the nonequilibrium Green's function (NEGF) method. The resultant ITR is expressed in a form of vibrational matching, and its relationship to the overlap of the vibrational density of states is also discussed. The analysis leads to a conclusion that the damping coefficient η in the Langevin equation should be a finite and sufficiently large value to represent the rapid damping of vibration modes at solid-liquid interfaces. This conclusion provides a clue to seamlessly extend the conventional NEGF-phonon transmission picture of solid-solid interfacial thermal transport, which assumes η to be infinitesimal, to solid-liquid interfaces.


Senior driving under the influence: A five-year retrospective study of alcoholized road-users aged 70 and over.
The demographic development in Germany shows a steady increase to senior citizens. The driving suitability of older road-users is of large social and political concern, because awareness and reactivity can be influenced by age-related diseases and potential medication, particularly in combination with the consumption of alcohol. This study provides an overview of senior road-users under the influence of alcohol. Therefore, 404 cases of drunken-driving by road-users aged 70 and over within the purview of the Institute of Legal Medicine at Justus-Liebig-University, Giessen, from the years 2009-2013 were evaluated in retrospect. The vast majority of the drivers were male (88.4% of the cases). Distribution of the blood alcohol concentrations were almost equally in male and female drivers with 62.8% of all cases showing a blood alcohol concentration (BAC) of more than 1.1‰ and 10.9% a BAC of more than 2.0‰. In 48.5% of the cases, drunk driving was associated with an accident. 54.5% of the drivers stated suffering from at least one disease and 60% admitted a regular medication or an intake prior to the incident. Moreover, the collected data includes aspects such as the kind of traffic participation as well as neurological and physiological deficits of the road-users. If accidents were caused by drunk driving, the external circumstances and consequences of these accidents were analyzed, too. The evaluation revealed, that the standard medical examination protocol proved to be improbable to cover polypharmacy and multimorbidity of older alcoholized drivers. So, an evaluation and adaptation of the common medical examination protocol must be considered.


Caring for tomorrow's workforce: Moral resilience and healthcare ethics education.
Preparing tomorrow's healthcare workforce for managing the growing complexity of care places high demands on students, educators, and faculties. In the light of worrying data about study-related stress and burnout, understanding how students manage stressors and develop resilience has been identified as a priority topic of research. In addition to study-related stressors, also moral stressors are known to characterize the students' first clinical experiences. However, current debates show that it remains unclear how healthcare ethics education should address them. In order to clarify this issue, this study first develops the notion of moral resilience as a response to moral stressors involving both situations of moral complexity and moral wrongness. Second, it explores the potential of healthcare ethics education in fostering moral resilience. For this purpose, it defines moral resilience operationally as a reduction of moral distress in a given axis of time measured by a validated tool. The educational transferability was assessed within an explorative, quantitative pre-post interventional study with a purposive sample of 166 nursing students. The educational intervention comprised a lecture introducing the typology of moral stressors. Before and after the lecture, students were presented vignettes depicting morally stressful situations. The competent research ethics committee confirmed that no ethical approval was needed. Informed consent was obtained from participants. Three of four vignettes showed a modest but statistically significant reduction in measured levels of distress after the lecture (p < 0.05, α = 5%). The study shows the potential of healthcare ethics education in providing students with transformative knowledge that fosters moral resilience. In times of global scarcity of educational resources, healthcare ethics education has an important contribution to offer in the promotion of students' mental and physical health by strengthening the knowledge base of moral resilience. This legitimates its costs for societies, faculties, and professional bodies.


Reovirus receptors, cell entry, and proapoptotic signaling.
Mammalian orthoreoviruses (reoviruses) are members of the Reoviridae. Reoviruses contain 10 double-stranded (ds) RNA gene segments enclosed in two concentric protein shells, called outer capsid and core. These viruses serve as a versatile experimental system for studies of viral replication events at the virus-cell interface, including engagement of cell-surface receptors, internalization and disassembly, and activation of the innate immune response, including NF-κB-dependent cellular signaling pathways. Reoviruses also provide a model system for studies of virus-induced apoptosis and organ-specific disease in vivo.Reoviruses attach to host cells via the filamentous attachment protein, σ1. The σ1 protein of all reovirus serotypes engages junctional adhesion molecule-A (JAM-A), an integral component of intercellular tight junctions. The σ1 protein also binds to cell-surface carbohydrate, with the type of carbohydrate bound varying by serotype. Following attachment to JAM-A and carbohydrate, reovirus internalization is mediated by β1 integrins, most likely via clathrin-dependent endocytosis. In the endocytic compartment, reovirus outer-capsid protein σ3 is removed by acid-dependent cysteine proteases in most cell types. Removal of σ3 results in the exposure of a hydrophobic conformer of the viral membrane-penetration protein, μ1, which pierces the endosomal membrane and delivers transcriptionally active reovirus core particles into the cytoplasm.Reoviruses induce apoptosis in both cultured cells and infected mice. Perturbation of reovirus disassembly using inhibitors of endosomal acidification or protease activity abrogates apoptosis. The μ1-encoding M2 gene is genetically linked to strain-specific differences in apoptosis-inducing capacity, suggesting a function for μ1 in induction of death signaling. Reovirus disassembly leads to activation of transcription factor NF-κB, which modulates apoptotic signaling in numerous types of cells. Inhibition of NF-κB nuclear translocation using either pharmacologic agents or expression of transdominant forms of IκB blocks reovirus-induced apoptosis, suggesting an essential role for NF-κB activation in the death response. Multiple effector pathway s downstream of NF-κB-directed gene expression execute reovirus-induced cell death. This chapter will focus on the mechanisms by which reovirus attachment and disassembly activate NF-κB and stimulate the cellular proapoptotic machinery.


Nanoengineering room temperature ferroelectricity into orthorhombic SmMnO3 films.
Orthorhombic RMnO3 (R = rare-earth cation) compounds are type-II multiferroics induced by inversion-symmetry-breaking of spin order. They hold promise for magneto-electric devices. However, no spontaneous room-temperature ferroic property has been observed to date in orthorhombic RMnO3. Here, using 3D straining in nanocomposite films of (SmMnO3)0.5((Bi,Sm)2O3)0.5, we demonstrate room temperature ferroelectricity and ferromagnetism with TC,FM ~ 90 K, matching exactly with theoretical predictions for the induced strain levels. Large in-plane compressive and out-of-plane tensile strains (-3.6% and +4.9%, respectively) were induced by the stiff (Bi,Sm)2O3 nanopillars embedded. The room temperature electric polarization is comparable to other spin-driven ferroelectric RMnO3 films. Also, while bulk SmMnO3 is antiferromagnetic, ferromagnetism was induced in the composite films. The Mn-O bond angles and lengths determined from density functional theory explain the origin of the ferroelectricity, i.e. modification of the exchange coupling. Our structural tuning method gives a route to designing multiferroics.


Failure of adjunctive minocycline-HCl to eliminate oral Actinobacillus actinomycetemcomitans.
Considerable problems have been reported in the eradication of Actinobacillus actinomycetemcomitans from periodontal sites. The present communication describes the 2-year results of a comprehensive combined mechanical/surgical and adjunctive minocycline (200 mg/day for 3 and another 2 weeks) treatment regimen in 28 patients with A. actinomycetemcomitans-associated periodontitis. Elimination of A. actinomycetemcomitans at periodontal sites was a prerequisite for gain of clinical attachment of > or = 2 mm or decrease of probing depth to < or = 4 mm after subgingival scaling plus minocycline (p < 0.01). Whereas 2 years after active treatment A. actinomycetemcomitans could not be detected at monitored sites in 23 patients, the organism was found on buccal mucosa and in saliva in 17 and 12 cases, respectively. One or 2 years after periodontal surgery, there was a significant association between log10-numbers of A. actinomycetemcomitans in buccal samples and numbers of residual pockets of > or = 7 mm as well as gingival sites with overt gingivitis (R2 = 0.687, p < 0.001). Present results indicate failure of an even prolonged administration of adjunctive minocycline to eliminate oral A. actinomycetemcomitans in most cases of A. actinomycetemcomitans-associated periodontitis.


Characteristics of 3H-tifluadom binding in guinea-pig brain membranes.
3H-Tifluadom labels specifically recognition sites of opioid kappa receptors. Membranes of guinea-pig whole brain bind 3H-tifluadom with two affinities, in contrast to the cerebellum where almost all opioid sites are kappa.


Systolic time intervals in patients with progressive muscular dystrophy of the Duchenne type.
Systolic time intervals (STIs) were measured in 57 patients with progressive muscular dystrophy (PMD) of the Duchenne type, and were correlated with the stages of physical disability. The total electromechanical systole (Q-A2), pre-ejection period (PEP), and left ventricular ejection time (LVET) were corrected for heart rate using the linear regression equations calculated from 91 normal subjects. Each systolic time interval index (STII), i.e. corrected STI, was analyzed. In 15 ambulatory patients (Group P-1), the STIIs did not differ significantly from those in normal controls. In 37 patients who were unable to walk (Group P-2) and 5 patients who were confined to bed (Group P-3), there was a significant increase (p less than 0.001) in the PEP index (PEPI), a decrease (p less than 0.001) in the LVET index (LVETI), and an increase (p less than 0.001) in the PEP/LVET compared with those in controls. The PEPI (p less than 0.001), LVETI (p less than 0.025), and PEP/LVET (p less than 0.001) in Group P-2 differed significantly from those in Group P-1. In Group P-3, the PEPI (p less than 0.005), LVET (p less than 0.001), and PEP/LVET (p less than 0.001) were significantly changed in comparison with those in Group P-2. Remarkable myocardial histopathologic changes suggestive of dystrophy were revealed in autopsies of 3 patients who had been in the severely disabled stage and had shown impaired STIs. It is suggested that cardiac function in patients with moderate to advanced PMD of the Duchenne type is deteriorated in proportion to the disability stages, i.e. the severity of changes in the skeletal muscles.


Differential responses to immune checkpoint inhibitor dictated by pre-existing differential immune profiles in squamous cell carcinomas caused by same initial oncogenic drivers.
While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood. To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs). We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80+ TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CAAmp/TP53Mutated HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors. We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy.


Differences in malaria vector biting behavior and changing vulnerability to malaria transmission in contrasting ecosystems of western Kenya.
Designing, implementing, and upscaling of effective malaria vector control strategies necessitates an understanding of when and where transmission occurs. This study assessed the biting patterns of potentially infectious malaria vectors at various hours, locations, and associated human behaviors in different ecological settings in western Kenya. Hourly indoor and outdoor catches of human-biting mosquitoes were sampled from 19:00 to 07:00 for four consecutive nights in four houses per village. The human behavior study was conducted via questionnaire surveys and observations. Species within the Anopheles gambiae complex and Anopheles funestus group were distinguished by polymerase chain reaction (PCR) and the presence of Plasmodium falciparum circumsporozoite proteins (CSP) determined by enzyme-linked immunosorbent assay (ELISA). Altogether, 2037 adult female anophelines were collected comprising the An. funestus group (76.7%), An. gambiae sensu lato (22.8%), and Anopheles coustani (0.5%). PCR results revealed that Anopheles arabiensis constituted 80.5% and 79% of the An. gambiae s.l. samples analyzed from the lowland sites (Ahero and Kisian, respectively). Anopheles gambiae sensu stricto (hereafter An. gambiae) (98.1%) was the dominant species in the highland site (Kimaeti). All the An. funestus s.l. analyzed belonged to An. funestus s.s. (hereafter An. funestus). Indoor biting densities of An. gambiae s.l. and An. funestus exceeded the outdoor biting densities in all sites. The peak biting occurred in early morning between 04:30 and 06:30 in the lowlands for An. funestus both indoors and outdoors. In the highlands, the peak biting of An. gambiae occurred between 01:00 and 02:00 indoors. Over 50% of the study population stayed outdoors from 18:00 to 22:00 and woke up at 05:00, coinciding with the times when the highest numbers of vectors were collected. The sporozoite rate was higher in vectors collected outdoors, with An. funestus being the main malaria vector in the lowlands and An. gambiae in the highlands. This study shows heterogeneity of anopheline distribution, high outdoor malaria transmission, and early morning peak biting activity of An. funestus when humans are not protected by bednets in the lowland sites. Additional vector control efforts targeting the behaviors of these vectors, such as the use of non-pyrethroids for indoor residual spraying and spatial repellents outdoors, are needed.


Mean pulmonary arterial pressures in Angus steers increase from cow-calf to feedlot-finishing phases.
Pulmonary arterial hypertension due to hypoxia-induced pulmonary vascular remodeling is the predominant cause of right-sided congestive heart failure (CHF) in cattle. Historically, heart failure was problematic only at altitudes over 2,134 m. However, anecdotal reports suggest that the incidence of heart failure is increasing in feedlot cattle at moderate altitude (800 to 1,600 m), with late-fed, or fat, cattle at greatest risk. The goal of this study was to evaluate pulmonary arterial pressures (PAP) in a cohort of male Angus calves from suckling to finishing to better understand why heart failure is particularly problematic in fat cattle. It was hypothesized that mean PAP would increase through the feeding period and that the calves with the greatest pressures at high altitude would have the greatest pressures as fat cattle. A total of 362 PAP measurements were obtained from 153 calves. Calves were tested at altitudes of 2,170 (4 and 6 mo old), 1,560 (13 mo old), and 1,300 m (13 and 18 mo old). Mean PAP were greater in 18-mo-old steers than any other age group (mean = 50.3 mm Hg; 95% confidence interval 48.2 to 52.4; < 0.05). Calves that had the greatest mean pressure at 6 mo of age tended to have the greatest mean pressures at 18 mo of age ( = 0.45, < 0.001). The increase in mean PAP with increasing age and adiposity likely predisposed the steers to an increased risk of CHF during the finishing phase.


Arabidopsis ROOT HAIR DEFECTIVE3 is involved in nitrogen starvation-induced anthocyanin accumulation.
Anthocyanin accumulation is a common phenomenon seen in plants under environmental stress. In this study, we identified a new allele of ROOT HAIR DEFECTIVE3 (RHD3) showing an anthocyanin overaccumulation phenotype under nitrogen starvation conditions. It is known that ethylene negatively regulates light- and sucrose-induced anthocyanin biosynthesis. We hypothesized that RHD3 achieves its negative effect on anthocyanin biosynthesis via an ethylene-regulating pathway. In support of this, similar to rhd3 mutants, the Arabidopsis ethylene signaling mutants etr1, ein2, and ein3/eil1 showed an anthocyanin overaccumulation phenotype under nitrogen starvation conditions. The ethylene precursor ACC strongly suppressed anthocyanin accumulation, dependent on ETR1, EIN2, EIN3/EIL1, and, partially, RHD3. In addition, inactivating RHD3 partially reversed the suppressive effect of ETO1 inactivation-evoked endogenous ethylene production on anthocyanin accumulation. The expression of nitrogen starvation-induced anthocyanin biosynthesis genes was negatively regulated by RHD3, but ethylene response genes were positively regulated by RHD3. Wild-type seedlings overexpressing RHD3 showed similar phenotypes to rhd3 mutants, indicating the existence of a fine-tuned relationship between gene expression and function. RHD3 was initially identified as a gene involved in root hair development. This study uncovered a new physiological function of RHD3 in nitrogen starvation-induced anthocyanin accumulation and ethylene homeostasis. [Correction added on 6 August 2015, after first online publication: "RND3" corrected to "RHD3".].


HaCaT cell proliferation influenced by melatonin.
The hormone melatonin is characterized by numerous pharmacological effects. The influence of melatonin on the growth of the human hair follicle was shown in previous investigations. In the present study, the effects of melatonin were investigated by means of proliferation tests of HaCaT keratinocytes using the [3H]thymidine incorporation, a fluorescence assay with Hoechst dye 33342 and the ATP bioluminescence assay. The aim of the study was to find melatonin concentrations suitable for treatments of the skin and whether there is a cytotoxic effect on HaCaT cells. The different proliferative activity of melatonin depending on its concentration and the time of incubation could be shown in all investigations.


Association Between Psoriasis and Sexual and Erectile Dysfunction in Epidemiologic Studies: A Systematic Review.
Sexual health is a major aspect of life. Increasing scientific evidence shows a potential association between psoriasis and sexual dysfunction (SD) and erectile dysfunction (ED). To evaluate the available scientific evidence regarding epidemiologic associations and treatment outcomes between psoriasis and SD and ED. Information sources were MEDLINE and Embase databases, using the Scopus search engine. The search was performed on August 25, 2017. Search terms were psoriasis and sexual or sexual dysfunction, and the search was limited to epidemiologic studies published in English answering any of the 4 research questions. Quality was assessed according to the Centre for Evidence-Based Medicine. Twenty-eight studies representing 52 520 cases of psoriasis and 1 806 022 controls were included for review. Of the 28 studies, 19 were cross-sectional, 3 were clinical trials, 3 were quasi-experimental, 2 were population-based cohort, and 1 was population-based case-control. Prevalence of SD and ED ranged from 40.0% to 55.6% and 34.2% to 81.1%, respectively. Two of 2 studies observed an association between psoriasis and SD after adjusting for physical and psychological comorbidities. Five of 8 studies observed an independent association between ED and psoriasis. Among patients with psoriasis, the features that showed the strongest association with SD were anxiety and depression (5 of 5 studies), psoriatic arthritis (3 of 4 studies), and genital psoriasis (5 of 7 studies). Regarding ED, anxiety and depression (2 of 2 studies) and increasing age (3 of 3 studies) showed the strongest association. All 3 clinical trials using biologic drugs showed an improvement in SD compared with placebo. Patients with psoriasis have physical and psychological comorbidities that have been associated with a higher risk of SD. In addition, psoriasis may play a role in its development. The presence of anxiety, depression, psoriatic arthritis, genital lesions, and increasing age should raise the awareness of SD. Biologic drugs have demonstrated the improvement of SD in patients with psoriasis.


One week of levofloxacin plus dexamethasone eye drops for cataract surgery: an innovative and rational therapeutic strategy.
Cataract surgery is the most common operation performed worldwide. A fixed topical corticosteroid-antibiotic combination is usually prescribed in clinical practice for 2 or more weeks to treat post surgical inflammation and prevent infection. However, this protracted schedule may increase the incidence of corticosteroid-related adverse events and notably promote antibiotic resistance. This International, multicentre, randomized, blinded-assessor, parallel-group clinical study evaluated the non-inferiority of 1-week levofloxacin/dexamethasone eye drops, followed by 1-week dexamethasone alone, vs. 2-week gold-standard tobramycin/dexamethasone (one drop QID for all schedules) to prevent and treat ocular inflammation and prevent infection after uncomplicated cataract surgery. Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) around a treatment difference >-10%. The study randomized 808 patients enrolled in 53 centres (Italy, Germany, Spain and Russia). The primary endpoint was the proportion of patients without anterior chamber inflammation on day 15 defined as the end of treatment. Endophthalmitis was the key secondary endpoint. This study is registered with EudraCT code: 2018-000286-36. After the end of treatment, 95.2% of the patients in the test arm vs. 94.9% of the control arm had no signs of inflammation in the anterior chamber (difference between proportions of patients = 0.028; 95% CI: -0.0275/0.0331). No case of endophthalmitis was reported. No statistically significant difference was evident in any of the other secondary endpoints. Both treatments were well tolerated. Non-inferiority of the new short pharmacological strategy was proven. One week of levofloxacin/dexamethasone prevents infection, ensures complete control of inflammation in almost all patients and may contain antibiotic resistance.


How raising the age of eligibility for Social Security and Medicare might affect the disability insurance and Medicare programs.
The normal age of retirement is scheduled to increase to 67 by 2022, and several proposals to increase it to age 70 are being considered. The Medicare eligibility age is not scheduled to increase under current law, but proposals to raise it in step with the retirement age were recently considered by the National Bipartisan Commission on the Future of Medicare (1999). This article examines how raising both the normal retirement age and the Medicare eligibility age would affect Social Security Disability Insurance (DI) eligibility, Medicare eligibility, and Medicare expenditures under two hypothetical policy scenarios. The first (the 2022 age-67 scenario) assumes that the eligibility age is raised to 67 by 2022, in step with the scheduled increase in the normal retirement age. The second (the 2040 age-70 scenario) assumes that the eligibility ages are increased to 70 by 2040. The findings are based on a summary of two reports. The earlier one (Wittenburg and others 1999) describes a series of microsimulation models developed from data in the Survey of Income and Program Participation (SIPP) and the Medicare Current Beneficiary Survey (MCBS). The base simulations in that report assume that the normal retirement and Medicare eligibility ages had already been increased in 1993, when the SIPP and MCBS respondents were observed. In the later report (Wittenburg, Stapleton, and Scrivner 2000), adjustment factors were developed to reflect future increases in Medicare expenditures, population growth, and increased participation in DI. The base simulations were then adjusted by those factors, yielding a final set of annual projections under the two policy scenarios. The hypothetical policy scenarios illustrate that the major cost reductions from jointly raising the Medicare eligibility age and the normal age of retirement would not be realized until after 2020, when the increases are fully phased in and a large portion of baby boomers have reached age 65. Although the projections provide important cost estimates, the equity and efficiency of those policies must be studied before the desirability of any specific proposal can be evaluated fully.


Toddler socioemotional behavior in a northern plains Indian tribe: associations with maternal psychosocial well-being.
M.C. Sarche, C.D. Croy, C. Big Crow, C. Mitchell, and P. Spicer (2009) provided first-ever information relating the socioemotional development of American Indian toddlers to the immediate context of their mothers' lives. The current study sought to replicate and build on their earlier work by examining the impact of additional maternal risk factors, identified in previous research with non-American Indian populations, on the development of American Indian toddlers: maternal depression, negative social influences, and mother's feelings of isolation. At 27 months, American Indian mothers (N = 110) completed the Parent Demographic Questionnaire, which measured maternal psychosocial characteristics (e.g., depressed affect, social support, drug and alcohol use, isolation) and demographics. Mothers also completed the Infant-Toddler Social Emotional Assessment (A.S. Carter & M.J. Briggs-Gowan, 2006) and the Parent-Child Dysfunctional Interaction subscale of the Parenting Stress Index (R.R. Abidin, 1995, 1997). Some results replicated the original study, but others did not. Reports of a dysfunctional mother-child relationship related to externalizing and internalizing problems, replicating the earlier study. This study also found associations between a dysfunctional mother-child relationship and socioemotional competence as well as dysregulation. The previous finding of a relationship between American Indian identity and socioemotional competence was supported. Adding the effects of maternal depressed affect and isolation significantly increased prediction of toddler behavior problems.


Contribution of targeted conditional somatic mutagenesis to deciphering retinoid X receptor functions and to generating mouse models of human diseases.
The last decade has witnessed an enormous rise in the interest for retinoid signalling and its cognate receptors, because of their central role in the coordination of development and homeostasis, through their ability to orchestrate the expression of numerous target genes. These receptors include six nuclear receptor (NR) family members, the retinoic acid receptor (RAR) alpha, beta and gamma, and the retinoid X receptor (RXR) alpha, beta and gamma, which are expressed in many cell types in mammals. Analysis of the development of mouse embryos bearing retinoid receptor null mutations demonstrated that these receptors transduce the effects of retinoic acid (RA, the active derivative of vitamin A) in vivo, and revealed impressive complexity. However, frequent redundancy in receptor functions and lethality of compound RAR-null mutants, as well as of RXRalpha-null mutants, precluded the characterisation of the functions of these receptors during late development and postnatally. We illustrate here how recent developments of conditional targeted somatic mutagenesis have opened new avenues in analysing the physiological functions of retinoid X receptor signalling in a variety of tissues and cell types, as well as in exploring the pathophysiological consequences of their alteration that led to novel mouse models of human diseases.


The role of mass media campaigns in reducing high-risk drinking among college students.
This article categorizes and describes current media campaigns to reduce college student drinking, reviews key principles of campaign design and outlines recommendations for future campaigns. The article describes three types of media campaigns on student drinking: information, social norms marketing, and advocacy. Key principles of campaign design are derived from work in commercial marketing, advertising, and public relations and from evaluations of past public health campaigns. Information campaigns on the dangers of high-risk drinking are common, but none has been rigorously evaluated. Quasi-experimental studies suggest that social norms marketing campaigns, which correct misperceptions of campus drinking norms, may be effective, but more rigorous research is needed. As of this writing, only one major media campaign has focused on policy advocacy to reduce college student drinking, but it is still being evaluated. Lessons for campaign design are organized as a series of steps for campaign development, implementation and assessment: launch a strategic planning process, select a strategic objective, select the target audience, develop a staged approach, define the key promise, avoid fear appeals, select the right message source, select a mix of media channels, maximize media exposure, conduct formative research, and conduct process and outcome evaluations. Future campaigns should integrate information, social norms marketing, and advocacy approaches to create a climate of support for institutional, community and policy changes that will alter the environment in which students make decisions about their alcohol consumption.


An analysis of the re-test artefact in longitudinal studies of psychiatric symptoms and personality.
When general population samples are assessed on two occasions with psychiatric symptom or personality measures, a mean change in scores towards less psychopathology is often observed. This re-test artefact is a potential threat to the validity of longitudinal studies. Data from a longitudinal general population study were analysed to discover under what circumstances the re-test artefact occurs. It was found that the artefact is unrelated to the time lag between occasions, being equally strong at intervals ranging from 4 to 34 weeks. However, the artefact did not occur for all measures, but was confined to those assessing negative self-characteristics and administered orally by an interviewer. These findings are consistent with both the 'mechanical responding' and 'social desirability' hypotheses of the re-test artefact.


Effects of green tea catechins in a rat multi-organ carcinogenesis model.
The effects of dietary administration of green tea catechins (GTC) were examined using a multi-organ carcinogenesis model. Groups of 15 F344 male rats were initially treated with a single i.p. administration of 100 mg/kg body wt N-diethyl-nitrosamine, 4 i.p. administrations of 20 mg/kg body wt N-methylnitrosourea, 4 s.c. doses of 40 mg/kg body wt 1,2-dimethylhydrazine, together with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine for 2 weeks and then 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine for 2 weeks, both in the drinking water, for a total initiation period of 4 weeks. GTC in the diet, at doses of 1.0 or 0.1%, was administered from 1 day before and during carcinogen exposure, after carcinogen exposure or both during and after carcinogen exposure. Further groups of animals were treated with carcinogen, 1% GTC or basal diet alone as controls. All animals were killed at the end of week 36, and all major organs examined histopathologically. The numbers of small intestinal tumors (adenomas and carcinomas) per rat were significantly reduced in the groups treated with 1% GTC during (0.13 +/- 0.35) and after carcinogen exposure (0.31 +/- 0.48) and in those receiving 1% and 0.1% GTC both during and after carcinogen exposure (0.14 +/- 0.36, 0.46 +/- 0.97 respectively) as compared with the carcinogen alone group (1.07 +/- 1.21). On the other hand, numbers of glutathione S-transferase placental form positive liver foci per cm2 were slightly but significantly increased in the groups treated with 1 and 0.1% GTC during carcinogen exposure, 1% GTC after carcinogen exposure and 1% GTC both during and after carcinogen exposure. The results indicated that while GTC inhibits small intestinal carcinogenesis it slightly enhances hepatocarcinogenesis in a dose dependent manner when applied both during and after carcinogen exposure.


alpha-Adrenergic effects on Na+-K+ pump current in guinea-pig ventricular myocytes.
1. The whole-cell patch clamp was employed to study Na+-K+ pump current (Ip) in acutely isolated myocytes. alpha-Adrenergic receptors were activated with noradrenaline (NA) after blocking beta-adrenergic receptors with propranolol. Ip was measured as the current blocked by strophanthidin (Str). 2. Activation of alpha-receptors by NA increased Ip in a concentration-dependent manner. The K0.5 depended on intracellular calcium ([Ca2+]i), however maximal stimulation did not. At 15 nM [Ca2+]i the K0.5 was 219 nM NA whereas at 1.4 microM [Ca2+]i it was 3 nM. 3. The voltage dependence of Ip was not shifted by NA at either high or low [Ca2+]i. At each voltage, maximal stimulation of Ip was 14-15 %. 4. Staurosporine (St), an inhibitor of protein kinase C (PKC), eliminated the alpha-receptor-mediated stimulation of Ip at either high or low[Ca2+]i. 5. The stimulation of Ip was independent of changes in intracellular sodium or external potassium concentrations, and did not reflect a change in affinity for Str. 6. Phenylephrine, methoxamine and metaraminol, three selective alpha1-adrenergic agonists, stimulate Ip in a similar manner to NA. Stimulation of Ip by NA was eliminated by prazosin, an alpha1-antagonist, but was unaffected by yohimbine, an alpha2-antagonist. 7. We conclude noradrenaline activates ventricular alpha1-receptors, which are specifically coupled via PKC to increase Na+-K+ pump current. The sensitivity of the coupling is [Ca2+]i dependent, however the maximal increase in pump current is [Ca2+]i and voltage independent.


[Neuroarthropathy, kyphoscoliosis and progressive tetraparesis in cervical syringomyelia].
The clinical picture of syringomyelia with special emphasis of its effects of the locomotor system is described on the basis of an individual case history. A 64 year old female patient experienced recurring subluxations of the right shoulder due to a neuroarthropathy. A marked throraco-lumbar kyphoscoliosis was present since childhood. The neurological picture was dominated by symmetrical muscular atrophy of both hands and an incomplete spastic paraparesis. Myelography of high cervical region shows an enlarged epidural space and atrophy of the myelon. MRI reveals a syrinx within the atrophied cervical spinal cord. Most likely the spinal cord has been enlarged and compressed from within by the syrinx which subsequently collapsed leaving the atrophied cervical spinal cord.


β-CD-dextran polymer for efficient sequestration of cholesterol from phospholipid bilayers: Mechanistic and safe-toxicity investigations.
The aim of this work was to investigate the suitability of β-cyclodextrin-dextran (BCD-dextran) polymer as cholesterol sequestering agent in vitro. For this purpose, BCD-dextran-cholesterol complexation was studied by phase solubility studies as well as with a specifically designed in vitro model based on giant unilamellar vesicles (GUVs) to evaluate the ability of this polymer to sequestrate cholesterol from phospholipid bilayers. Cholesterol-sequestering ability of BCD-dextran was also investigated on different cell lines relevant for the hematopoietic system and results were correlated to cells toxicity. BCD-dextran polymer was capable of extracting significant amount of cholesterol from phospholipid bilayers and to a higher extent in comparison to available β-cyclodextrins (BCDs). The ability of BCD-dextran in sequestering cholesterol resulted also very high on cell lines relevant for the hematopoietic system. Moreover, BCD-dextran resulted less toxic on cell cultures due to higher selectivity in sequestering cholesterol in comparison to MBCD (that sequestrated also significant amounts of cholesteryl esters). In conclusion, BCD-dextran resulted an extremely efficient cholesterol-sequestering agent and BCD-dextran resulted more selective to cholesterol extraction in comparison to other BCDs (therefore of lower cytotoxicity). This phenomenon might play a key role to develop an efficient treatment for hypercholesterolemia based on cholesterol segregation.


Out-of-Hospital Cardiac Arrest at Home in Japan.
Although majority of out-of-hospital cardiac arrests (OHCAs) occur in private residential locations, that is, at home, the details of emergency patients with OHCAs occurring at home have not been sufficiently investigated at the national level. We obtained data of OHCA cases from the All-Japan Utstein Registry, including detailed information of the location of cardiac arrest. Cases of OHCA occurring at home from 2013 to 2015 were included. Patient characteristics and outcomes after OHCA were described based on the location of cardiac arrest. During the 3-year study period, a total of 212,722 cases of OHCA were documented at home (186,219 in detached houses and 26,503 in multiple dwelling houses), and it accounted for 65.0% of all OHCA cases in Japan. The majority of OHCAs occurred in the living room/bedroom (67.7%), followed by the bathroom (12.9%), entrance/corridor (5.3%), and toilet (4.8%). The characteristics of OHCA at home, widely varied by location of cardiac arrest and residence type. The proportion of bystander-initiated cardiopulmonary resuscitations was less than half at all locations and ranged from 27.9% to 47.1%. The proportion of public-access defibrillation was also low regardless of the location of arrest and ranged from 0.0% to 0.2%. Consequently, the proportion of 1-month survival with favorable neurological outcome was low regardless of the location of arrest and ranged from 0.3% to 2.3%. In conclusion, OHCA occurrence at home accounted for approximately 2/3 of all OHCA cases in Japan, but their outcomes were extremely poor regardless of the location of cardiac arrest.


A three-step framework for capacity planning in a nursing home context.
This paper presents a three-step conceptual framework that can be used to structure the care-related capacity planning process in a nursing home context. The proposed framework provides a sound practical vehicle to organise client-centred care without overstretching available capacity. Within this framework, an MILP for shift scheduling and a Genetic Algorithm (GA) for task-scheduling are proposed. To investigate the performance of the proposed framework, it is benchmarked against the current situation. The results show that considerable improvements can be achieved in terms of efficiency and waiting time. More specifically, it is shown that very modest waiting times can be achieved without exceeding available capacity, despite the fluctuations in care demand across the day.


Can biomarkers help us understand the nutritional and lifestyle factors important in cancer prognosis?
In attempting to discover the causes of cancer, investigators have recognized that biomarkers can confirm biological plausibility, enhance relative risks, and serve as surrogate endpoints in observational and intervention studies. In the arena of cancer survival, the potential value of biomarkers is increasingly appreciated. A broad range of histological, cellular, and molecular markers have been identified among persons diagnosed with cancer. Molecular and cellular markers are being used to stage disease, predict prognosis, and target therapeutic interventions. Biomarkers in survivors can also help us to understand factors that influence prognosis by both elucidating pertinent biological pathways and sharpening risk estimates. However, as in the case of incident cancer, the use of biomarkers as surrogate endpoints postdiagnosis is problematic because of the potential existence of alternative pathways to recurrence and death that bypass the surrogate endpoint. In evaluating potential surrogates, an understanding of the causal structure underlying the interrelations of exposures, surrogate, and recurrence or death is essential. Three questions can help to shed light on this structure: 1) What is the relation of the surrogate endpoint to recurrence or death? 2) What is the relation of the intervention (or exposure) to the surrogate? 3) To what extent does the surrogate endpoint mediate the relation between intervention (exposure) and recurrence or death? To address these questions, it is imperative to integrate biomarker studies into ongoing pharmacotherapeutic and lifestyle intervention studies with recurrence or mortality as explicit endpoints.


pH dependence of the fluorescence lifetime of FAD in solution and in cells.
We have studied physiological parameters in a living cell using fluorescence lifetime imaging of endogenous chromophores. In this study, pH dependence of the fluorescence lifetime of flavin adenine dinucleotide (FAD), that is a significant cofactor exhibiting autofluorescence, has been investigated in buffer solution and in cells. The fluorescence lifetime of FAD remained unchanged with pH 5 to 9 in solution. However, the fluorescence lifetime in HeLa cells was found to decrease with increasing intracellular pH, suggesting that pH in a single cell can be estimated from the fluorescence lifetime imaging of FAD without adding exogenous fluorescent probes.


Spatial and temporal activation of brain regions in hibernation: c-fos expression during the hibernation bout in thirteen-lined ground squirrel.
Hibernation results in dramatic changes in body temperature and metabolism; however, the central nervous system remains active during deep torpor. By cloning c-fos cDNA from the 13-lined ground squirrel (Spermophilus tridecemlineatus) and using squirrel c-fos mRNA probe for in situ hybridization histochemistry, we systematically analyzed and identified specific brain regions that were activated during six different phases of the hibernation bout. During entrance into torpor, we detected activation of the ventrolateral subdivision of the medial preoptic area ('thermoregulatory center'), and the reticular thalamic nucleus, which is known to inhibit the somatomotor cortex. During torpor, c-fos expression in the cortex was suppressed while the reticular thalamic nucleus remained uniformly active. Throughout torpor the suprachiasmatic nucleus ('biological clock') showed increasing activity, likely participating in phase-change regulation of the hibernation bout. Interestingly, during torpor very strong c-fos activation was seen in the epithelial cells of the choroid plexus and in tanycytes at the third ventricle, both peaking near the beginning of arousal. In arousal, activity of the suprachiasmatic and reticular thalamic nuclei and choroid epithelial cells diminished, while ependymal cells in the lateral and fourth ventricles showed stronger activity. Increasing body temperature during arousal was driven by the activation of neurons in the medial part of the preoptic area. In interbout awake animals, we demonstrated the activation of hypothalamic neurons located in the arcuate nucleus and the dorsolateral hypothalamus, areas involved in food intake. Our observations indicate that the hibernation bout is closely regulated and orchestrated by specific regions of the central nervous system. J. Comp. Neurol. 505:443-458, 2007. (c) 2007 Wiley-Liss, Inc.


Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions.
In the search for improved selective antagonist ligands of the A2B adenosine receptor, which have the potential as antiasthmatic or antidiabetic drugs, we have synthesized and screened a variety of alkylxanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. Competition for 125I-ABOPX (125I-3-(4-amino-3-iodobenzyl)-8-(phenyl-4-oxyacetate)-1-propylxanthine) binding in membranes of stably transfected HEK-293 cells revealed uniformly higher affinity (<10-fold) of these xanthines for human than for rat A2B adenosine receptors. Binding to rat brain membranes expressing A1 and A2A adenosine receptors revealed greater A2B selectivity over A2A than A1 receptors. Substitution at the 1-position with 2-phenylethyl (or alkyl/olefinic groups) and at N-3 with hydrogen or methyl favored A2B selectivity. Relative to enprofylline 2b, pentoxifylline 35 was equipotent and 1-propylxanthine 3 was >13-fold more potent at human A2B receptors. Most N-7 substituents did not enhance affinity over hydrogen, except for 7-(2-chloroethyl), which enhanced the affinity of theophylline by 6.5-fold to 800 nM. The A2B receptor affinity-enhancing effects of 7-(2-chloroethyl) vs 7-methyl were comparable to the known enhancement produced by an 8-aryl substitution. Among 8-phenyl analogues, a larger alkyl group at the 1-position than at the 3-position favored affinity at the human A2B receptor, as indicated by 1-allyl-3-methyl-8-phenylxanthine, with a K(i) value of 37 nM. Substitution on the 8-phenyl ring indicated that an electron-rich ring was preferred for A2B receptor binding. In conclusion, new leads for the design of xanthines substituted in the 1-, 3-, 7-, and 8-positions as A2B receptor-selective antagonists have been identified.


Covalent bonding of PMMA, PBMA, and poly(HEMA)to hydroxyapatite particles.
In our earlier study, we showed that the surface hydroxyl groups of hydroxyapatite have the ability to react with organic isocyanate groups. In this study, the feasibility of grafting poly(methyl methacrylate) (PMMA), poly(n-butyl methacrylate) (PBMA), and Poly(hydroxyethyl methacrylate) [poly(HEMA)] by using the reaction of isocyanate groups with the hydroxyl groups on the surface of HA was investigated. Double bonds were introduced to the surface of HA via the coupling reaction of isocyanateoethyl methacrylate (ICEM) with HA, or through hexamethylene diisocyanate (HMDI) with hydroxyethyl methacrylate (HEMA) and HA, followed by radical polymerization in MMA, BMA, or HEMA. Infrared spectra indicated the existence of polymers on the surfaces of HA. Thermogravimetric analysis also confirmed the presence of grafted polymers on the surface of HA powder particles (20-26 wt%). The polymers gave typical PMMA, PBMA, or poly(HEMA) infrared spectra, with the exception of amide bands, a result of the coupling reaction of ICEM or HMDI with hydroxy groups of HA or HEMA. Therefore it is concluded that the polymers were chemically bonded to the surface of HA through the isocyanate groups of ICEM or HMDI.