Intraoperative Period and Breast Cancer: Review.
Intraoperative radiation therapy in breast cancer (IORT) delivers a concentrated dose of radiation therapy to a tumor bed during surgery. IORT offers some of the following advantages with typically fewer complications like; maximum effect, sparing healthy tissues and organs, to help the patients finish treatment and get back to their normal activities. The goal of IORT is to improve local tumor control and survival rates for patients with breast cancer. IORT can both be performed with electron beams (ELIOT) and X-rays. Two main randomised trials testing intraoperative partial breast radiotherapy are TARGIT trial and the ELIOT (intraoperative radiotherapy with electrons) trial, but the techniques are fundamentally different. Whereas TARGIT delivers radiation from within the undisturbed tumour bed, for ELIOT, the mammary gland is mobilised, a prepectoral lead shield is inserted, the edges of the tumour bed are apposed, and radiation is delivered from without.


Fear of pain potentiates nocebo hyperalgesia.
Nocebo hyperalgesia has received sparse experimental attention compared to placebo analgesia. The aim of the present study was to investigate if personality traits and fear of pain could predict experimental nocebo hyperalgesia. One hundred and eleven healthy volunteers (76 females) participated in an experimental study in which personality traits and fear of pain were measured prior to induction of thermal heat pain. Personality traits were measured by the Big-Five Inventory-10. Fear of pain was measured by the Fear of Pain Questionnaire III. Heat pain was induced by a PC-controlled thermode. Pain was measured by a computerized visual analog scale. Stress levels during the experiment were measured by numerical rating scales. The participants were randomized to a Nocebo group or to a no-treatment Natural History group. The results revealed that pain and stress levels were significantly higher in the Nocebo group after nocebo treatment. Mediation analysis showed that higher levels of the Fear of Pain Questionnaire III factor "fear of medical pain" significantly increased stress levels after nocebo treatment and that higher stress levels were associated with increased nocebo hyperalgesic responses. There were no significant associations between any of the personality factors and the nocebo hyperalgesic effect. The results from the present study suggest that dispositional fear of pain might be a useful predictor for nocebo hyperalgesia and emotional states concomitant with expectations of increased pain. Furthermore, measurement of traits that are specific to pain experience is probably better suited for prediction of nocebo hyperalgesic responses compared to broad measures of personality.


Multi-level communication of human retinal pigment epithelial cells via tunneling nanotubes.
Tunneling nanotubes (TNTs) may offer a very specific and effective way of intercellular communication. Here we investigated TNTs in the human retinal pigment epithelial (RPE) cell line ARPE-19. Morphology of TNTs was examined by immunostaining and scanning electron microscopy. To determine the function of TNTs between cells, we studied the TNT-dependent intercellular communication at different levels including electrical and calcium signalling, small molecular diffusion as well as mitochondrial re-localization. Further, intercellular organelles transfer was assayed by FACS analysis. Microscopy showed that cultured ARPE-19 cells are frequently connected by TNTs, which are not attached to the substratum. The TNTs were straight connections between cells, had a typical diameter of 50 to 300 nm and a length of up to 120 µm. We observed de novo formation of TNTs by diverging from migrating cells after a short time of interaction. Scanning electron microscopy confirmed characteristic features of TNTs. Fluorescence microscopy revealed that TNTs between ARPE-19 cells contain F-actin but no microtubules. Depolymerisation of F-actin, induced by addition of latrunculin-B, led to disappearance of TNTs. Importantly, these TNTs could function as channels for the diffusion of small molecules such as Lucifer Yellow, but not for large molecules like Dextran Red. Further, organelle exchange between cells via TNTs was observed by microscopy. Using Ca²⁺ imaging we show the intercellular transmission of calcium signals through TNTs. Mechanical stimulation led to membrane depolarisation, which expand through TNT connections between ARPE-19 cells. We further demonstrate that TNTs can mediate electrical coupling between distant cells. Immunolabelling for Cx43 showed that this gap junction protein is interposed at one end of 44% of TNTs between ARPE-19 cells. Our observations indicate that human RPE cell line ARPE-19 cells communicate by tunneling nanotubes and can support different types of intercellular traffic.


Beyond deviancy-training: Deviant adolescent friendships and long-term social development.
Adolescent association with deviant and delinquent friends was examined for its roots in coercive parent-teen interactions and its links to functional difficulties extending beyond delinquent behavior and into adulthood. A community sample of 184 adolescents was followed from age 13 to age 27, with collateral data obtained from close friends, classmates, and parents. Even after accounting for adolescent levels of delinquent and deviant behavior, association with deviant friends was predicted by coercive parent-teen interactions and then linked to declining functioning with peers during adolescence and greater internalizing and externalizing symptoms and poorer overall adjustment in adulthood. Results are interpreted as suggesting that association with deviant friends may disrupt a core developmental task-establishing positive relationships with peers-with implications that extend well beyond deviancy-training effects.


Nurse-led PICC insertion: is it cost effective?
Repeated attempts to cannulate small veins can cause considerable distress for patients and expend substantial staff time.For longer term venous access, a peripherally inserted central catheter(PICC) may be used instead of a peripheral cannula. Previous studies indicate that insertion of a PICC costs three times more than a cannula but the lifespan is substantially longer. This study aimed to compare insertion cost, patient satisfaction, and infection rates of PICCs for the two main staff groups (trained nurses and radiologists) inserting these devices in a district general hospital. The study took place over 4 months in 2012-13.A questionnaire was attached to all identified PICCs in stock at Raigmore Hospital to collect details of the date of insertion, patient involved, time taken, attendant staff grade and experience level,consumables used and insertion success. The lead author's personal observation of PICC insertion by different staff groups allowed estimation of staff time, costs and success rates. Patient experience and satisfaction was assessed before and after insertion using a patient questionnaire. PICC longevity, infection rates and failures were assessed by review of patient notes. The radiologist group had a statistically significant (p< 0.01) increased cost (42%) over the nurse group. Patient satisfaction regarding explanation of treatment before insertion was higher in the nurse group. Insertion success and infection rates were higher in the radiologist group. The authors conclude that the majority of PICCs can be safely performed without x-ray screening in a ward-based environment. This is likely to be the most cost-effective solution for large volume services.


FleaTickRisk: a meteorological model developed to monitor and predict the activity and density of three tick species and the cat flea in Europe.
Mathematical modelling is quite a recent tool in epidemiology. Geographical information system (GIS) combined with remote sensing (data collection and analysis) provide valuable models, but the integration of climatologic models in parasitology and epidemiology is less common. The aim of our model, called "FleaTickRisk", was to use meteorological data and forecasts to monitor the activity and density of some arthropods. Our parasitological model uses the Weather Research and Forecasting (WRF) meteorological model integrating biological parameters. The WRF model provides a temperature and humidity picture four times a day (at 6:00, 12:00, 18:00 and 24:00 hours). Its geographical resolution is 27 x 27 km over Europe (area between longitudes 10.5 degrees W and 30 degrees E and latitudes 37.75 degrees N and 62 degrees N). The model also provides weekly forecasts. Past data were compared and revalidated using current meteorological data generated by ground stations and weather satellites. The WRF model also includes geographical information stemming from United States Geophysical Survey biotope maps with a 30'' spatial resolution (approximately 900 x 900 m). WRF takes into account specific climatic conditions due to valleys, altitudes, lakes and wind specificities. The biological parameters of Ixodes ricinus, Dermacentor reticulatus, Rhipicephalus sanguineus and Ctenocephalides felis felis were transformed into a matrix of activity. This activity matrix is expressed as a percentage, ranging from 0 to 100, for each interval of temperature x humidity. The activity of these arthropods is defined by their ability to infest hosts, take blood meals and reproduce. For each arthropod, the matrix was calculated using existing data collected under optimal temperature and humidity conditions, as well as the timing of the life cycle. The mathematical model integrating both the WRF model (meteorological data + geographical data) and the biological matrix provides two indexes: an activity index (ranging from 0 to 100), calculated for the previous week and predictive for the coming week, and a cumulative index (ranging from 0 to 1000) which takes into account the past 12 weeks. The indexes are calculated twice a day for each geographical point all over Europe and are corrected based on three types of defined biotopes: urban and sub-urban areas, rural areas, and wilderness and forests. To clarify the presentation, indexes are calculated within intervals and are presented as colour maps grouping index isoclines. We hypothesised that the populations of tick and flea hosts are not lacking and therefore do not affect the numbers of arthropods. However, microclimates and biotopes have a major impact, especially on tick populations, and the results provided by the model must therefore be adjusted to local conditions by specialists, such as local veterinarians. Where fleas are concerned, the model takes into account their outdoor activity and ignores their indoor life cycle. The accuracy of the data was verified throughout 2007 and 2008, using sentinel veterinary clinics and tick samples, as well as comparisons with published surveys. The maps constructed with the model are available to veterinary practitioners on www.FleaTickRisk.com.


Cardiac sensitivity in children: sex differences and its relationship to parameters of emotional processing.
In adults, the level of ability to perceive one's own body signals plays an important role for many concepts of emotional experience as demonstrated for emotion processing or emotion regulation. Representative data on perception of body signals and its emotional correlates in children is lacking. Therefore, the present study investigated the cardiac sensitivity of 1,350 children between 6 and 11 years of age in a heartbeat perception task. Our main findings demonstrated the distribution of cardiac sensitivity in children as well as associations with interpersonal emotional intelligence and adaptability. Furthermore, independent of body mass index, boys showed a significantly higher cardiac sensitivity than girls. We conclude that cardiac sensitivity in children appears to show weaker but similar characteristics and relations to emotional parameters as found in adults, so that a dynamic developmental process can be assumed.


Robust Perpendicular Skyrmions and Their Surface Confinement.
Magnetic skyrmions are two-dimensional magnetization swirls that stack in the form of tubes in the third dimension and which are proposed as prospective information carriers for nonvolatile memory devices due to their unique topological properties. From resonant elastic X-ray scattering measurements on Cu2OSeO3 with an in-plane magnetic field, we find that a state of perpendicularly ordered skyrmions forms, in stark contrast to the well-studied bulk state. The surface state is stable over a wide temperature range, unlike the bulk state in out-of-plane fields which is confined to a narrow region of the temperature-field phase diagram. In contrast to ordinary skyrmions found in the bulk, the surface state skyrmions result from the presence of magnetic interactions unique to the surface which stabilize them against external perturbations. The surface guiding makes the robust state particular interesting for racetracklike devices, ultimately allowing for much higher storage densities due to the smaller lateral footprint of the perpendicular skyrmions.


Detection and imaging the expression of the trans-membrane protein CD44 in RT112 cells by use of enzyme-labeled antibodies and SECM.
The deposition of human RT112 cells in a patterned fashion onto glass substrates and subsequent imaging of the expression of the trans-membrane protein CD44 have been studied using scanning electrochemical microscopy (SECM). Patterns of RT112 cells derived from a transitional cell carcinoma of the bladder could be deposited on amino-modified glass substrates by cytospinning. These were then treated with horseradish peroxidase (HRP) labeled secondary antibodies to the trans-membrane protein CD44. Expression of CD44 protein by the cells directly leads to immobilisation of the labeled antibodies. The presence of the enzyme substrate (hydrogen peroxide) along with a hydroquinone mediator then allowed an enzymatic reaction to proceed, generating benzoquinone. Reduction of benzoquinone gave rise to positive feedback between the substrate and the SECM microelectrode tip. Control samples such as blank slides or slides not treated with HRP-labeled antibody showed negative feedback effects. Patterns of RT112 cells could be assembled and their expression of the target protein imaged whereas control samples showed minimal activity.


Minimum skills required by children to complete health-related quality of life instruments for asthma: comparison of measurement properties.
To gain a complete picture of a child's health-status, measurement of health-related quality of life (HRQL) is necessary. Since parents do not accurately perceive children's HRQL, information must be obtained from the children themselves. The aim of this study was to determine the minimum age and reading skills required by children to complete competently the Paediatric Asthma Quality of Life Questionnaire (PAQLQ), the Health Utilities Index (HUI), the Feeling Thermometer and the Standard Gamble, and to evaluate the validity of each for measuring HRQL in children with asthma. Fifty two children (age 7-17 yrs) with symptomatic asthma participated in a 9 week single cohort study with HRQL and clinical asthma control assessed every 4 weeks. All children provided very reliable data for the PAQLQ and the HUI but they needed > or = grade 6 reading skills to complete the Standard Gamble and > or = grade 2 skills for the Feeling Thermometer. In those children who were able to provide reliable data, the PAQLQ had the best discriminative and evaluative measurement properties, followed closely by the Feeling Thermometer. Measurement properties in the Standard Gamble were weaker and although the HUI was very reliable it was not actually measuring asthma-specific HRQL. The Paediatric Asthma Quality of Life Questionnaire may be used with confidence in clinical studies and practice to provide a profile of children's day-to-day experiences. In those children with adequate skills to complete the test reliably, the Feeling Thermometer provides a good estimate of the value that children place on their asthma health status.


Kidney-specific alloantigen system in the rat. Characterization and role in transplantation.
The alloantibody response of LEW rats immunized with DA kidney homogenate or given vascularized DA kidney grafts was studied using an 125I-anti-Ig binding assay with kidney homogenate as the target tissue. A major component of the sera was found to be directed at a kidney-specific alloantigen. Analysis of LEW X (DA X LEW) F1 backcross rats showed that the locus coding for this antigen was not linked to the major histocompatibility complex (MHC). The use of these backcross rats, typed for both MHC and the kidney alloantigen, as kidney donors to LEW rats showed that the kidney alloantigen did not induce detectable graft damage and that only the DA MHC was involved in primary graft rejection of DA kidneys by LEW rats. Immunofluorescence studies localized the antigen to the basement membrane of proximal convoluted tubules, and to some Bowman's capsules. Strain distribution studies showed that only 2 of 11 strains were negative for the allele under study; these were the LEW and AS strains. Species cross-reactivity studies showed that rabbit, dog, and human kidneys could absorb this specificity, although more weakly than DA kidney.


Improving support for heart failure patients: a systematic review to understand patients' perspectives on self-care.
This systematic review aimed to generate patient-focussed recommendations to enhance support of heart failure self-care by examining patients' experiences, perspectives and self-care behaviours. Despite increased recognition of the importance of heart failure self-care, patients' knowledge and practices around this self-care and interventions to improve it are inconsistent. Consequently, current guidelines focus on what the domains of heart failure self-care are, more so than the ways to improve this care. Systematic review and qualitative interpretive synthesis. A systematic, comprehensive and detailed search of 11 databases was conducted until March, 2012 for papers published 1995-2012: 37 studies were included (1343 patients, 75 caregivers, 63 health care professionals) that contained a qualitative research component and data on adult patients' heart failure self-care. This interpretive synthesis used a recognized approach consisting of a multi-stage analytic process; in addition, the included studies underwent quality appraisal. Findings indicate that while patients could often recall health professionals' self-care advice, they were unable to integrate this knowledge into daily life. Attempts to manage HF were based on how patients 'felt' rather than clinical indicators of worsening symptoms. Self-efficacy and learning from past management experiences facilitated favourable outcomes - these enabled patients and caregivers to adeptly apply self-care strategies into daily activities. Addressing common but basic knowledge misconceptions regarding the domains of HF self-care is insufficient to increase effective HF self-care; this should be supplemented with strategies with patients and family members to promote self-efficacy, learning and adaptation/application of recommendations to daily life.


Comparative SEM analysis of nine F22 aligner cleaning strategies.
The orthodontics industry has paid great attention to the aesthetics of orthodontic appliances, seeking to make them as invisible as possible. There are several advantages to clear aligner systems, including aesthetics, comfort, chairside time reduction, and the fact that they can be removed for meals and oral hygiene procedures. Five patients were each given a series of F22 aligners, each to be worn for 14 days and nights, with the exception of meal and brushing times. Patients were instructed to clean each aligner using a prescribed strategy, and sections of the used aligners were observed under SEM. One grey-scale SEM image was saved per aligner in JPEG format with an 8-bit colour depth, and a total of 45 measurements on the grey scale ("Value" variable) were made. This dataset was analysed statistically via repeated measures ANOVA to determine the effect of each of the nine cleaning strategies in each of the five patients. A statistically significant difference in the efficacy of the cleaning strategies was detected. Specifically, rinsing with water alone was significantly less efficacious, and a combination of cationic detergent solution and ultrasonication was significantly more efficacious than the other methods (p < 0.05). Of the nine cleaning strategies examined, only that involving 5 min of ultrasonication at 42 k Hz combined with a 0.3% germicidal cationic detergent was observed to be statistically effective at removing the bacterial biofilm from the surface of F22 aligners.


Uncertainty-aware guided volume segmentation.
Although direct volume rendering is established as a powerful tool for the visualization of volumetric data, efficient and reliable feature detection is still an open topic. Usually, a tradeoff between fast but imprecise classification schemes and accurate but time-consuming segmentation techniques has to be made. Furthermore, the issue of uncertainty introduced with the feature detection process is completely neglected by the majority of existing approaches.In this paper we propose a guided probabilistic volume segmentation approach that focuses on the minimization of uncertainty. In an iterative process, our system continuously assesses uncertainty of a random walker-based segmentation in order to detect regions with high ambiguity, to which the user's attention is directed to support the correction of potential misclassifications. This reduces the risk of critical segmentation errors and ensures that information about the segmentation's reliability is conveyed to the user in a dependable way. In order to improve the efficiency of the segmentation process, our technique does not only take into account the volume data to be segmented, but also enables the user to incorporate classification information. An interactive workflow has been achieved by implementing the presented system on the GPU using the OpenCL API. Our results obtained for several medical data sets of different modalities, including brain MRI and abdominal CT, demonstrate the reliability and efficiency of our approach.


The relationship between childhood poverty, military service, and later life depression among men: Evidence from the Health and Retirement Study.
Childhood poverty has been associated with depression in adulthood, but whether this relationship extends to later life major depression (MD) or is modified by military service is unclear. Data come from the Health and Retirement Study (HRS) 2010 wave, a longitudinal, nationally representative study of older adults. Men with data on military service and childhood poverty were included (N=6330). Childhood poverty was assessed by four indicators (i.e., parental unemployment, residential instability) experienced before age 16. Military service was categorized as veteran versus civilian, and during draft versus all-volunteer (after 1973) eras. Past year MD was defined by the Composite International Diagnostic Inventory. Four in ten men ever served, with 13.7% in the all-volunteer military. Approximately 12% of civilians, 8% draft era and 24% all-volunteer era veterans had MD. Childhood poverty was associated with higher odds of MD (Odds Ratio (OR): 2.38, 95% Confidence Interval (CI): 1.32-4.32) and higher odds of military service (OR: 2.58, 95% CI: 1.58-4.21). Military service was marginally associated with MD (OR: 1.28, 95% CI: 0.98-1.68) and did not moderate the association between childhood poverty and MD. Self-report data is subject to recall bias. The HRS did not assess childhood physical and emotional abuse, or military combat exposure. Men raised in poverty had greater odds of draft and all-volunteer military service. Early-life experiences, independent of military service, appear associated with greater odds of MD. Assessing childhood poverty in service members may identify risk for depression in later life.


Anatomical variations: How do surgical and radiology training programs teach and assess them in their training curricula?
Sound knowledge of anatomy and Anatomical variations plays an integral role in surgical and radiology specialties. This study investigated the current teaching and assessment trends on Anatomical variations in various surgical and radiology specialty training curricula in Canada and Australia. A survey was sent to 122 Program Directors and Chairs of specialty committees in Canada and Directors of Training/Education in Australia of selected surgical and radiology specialties. A total of 80.7% of respondents report that their training curricula include Anatomical variations. The highest rated classes of variations included in the curriculum are arterial (76%), venous (68%), followed by organs (64%). All trainees learn about Anatomical variations from surgeons and radiologists (100%) and via suggested textbooks of the specialty (87.1%). A total of 54.8% report that specialty training curricula do not suggest specific anatomical variation classifications for the trainees to learn, and 16.1% are uncertain if the colleges provide such kind of instruction. Trainees typically communicated findings of variations in case presentations and clinic's meetings. About 32.3% of respondents report that Anatomical variations are not assessed in their training curriculum. About 39.3% of experienced clinicians in the study report they encounter variations on a monthly basis and 25 and 21.4% on a weekly and daily basis, respectively. Surgical and radiology colleges need to investigate for hidden curriculum in their specialty training programs to ensure there are no gaps in knowledge and training related to Anatomical variations. Most educational leaders surveyed believe more teaching on Anatomical variations in the first 4 years of training would benefit resident doctors.


Effect of indomethacin on urine concentration and dilution in the rat.
The precise role of prostaglandins in modulating urine concentration and dilution is unclear. Evidence in vitro has recently cast doubt on the accepted theory that renal prostaglandins inhibit the hydro-osmotic effect of vasopressin. Urine clearance studies were performed on indomethacin treated (prostaglandin deficient) and control anaesthetized water diuretic rats both before and during the addition of vasopressin in maximal (10 m-units) and supramaximal (100 m-units) concentrations. Before the addition of vasopressin, indomethacin treatment inhibited the excretion of a water load by 48.7%. The mean papillary sodium concentration was also greater in this group of rats. Vasopressin (10 m-units) increased the urine osmolality in control and indomethacin treated rats; however, the mean urine osmolality was greater in the indomethacin group (1521 +/- 103 compared with 1120 +/- 98 mosmol/kg; P less than 0.01), as was the papillary sodium concentration. A ten-fold increase in vasopressin depressed the papillary sodium concentration to a level similar to that in the control group and produced a marked natriuresis. Consequently, the mean urine osmolalities and urine flows were similar in control and indomethacin treated rats. These experiments suggest that a major function of renal prostaglandins is to increase the ability of the kidney to excrete a water load. Renal prostaglandins do not interfere with the vasopressin induced increase in distal nephron water permeability.


3D matrix adhesion feedback controls nuclear force coupling to drive invasive cell migration.
Cell invasion is a multi-step process, initiated by the acquisition of a migratory phenotype and the ability to move through complex 3D extracellular environments. We determine the composition of cell-matrix adhesion complexes of invasive breast cancer cells in 3D matrices and identify an interaction complex required for invasive migration. βPix and myosin18A (Myo18A) drive polarized recruitment of non-muscle myosin 2A (NM2A) to adhesion complexes at the tips of protrusions. Actomyosin force engagement then displaces the Git1-βPix complex from paxillin, establishing a feedback loop for adhesion maturation. We observe active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. The recruitment of NM2A to adhesions creates a non-muscle myosin isoform gradient, which extends from the protrusion to the nucleus. We postulate that this gradient facilitates coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity.


Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating BCR-ABL mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML). It is unclear where in the hemopoietic hierarchy additional mutations are acquired in BP-CML, how the hemopoietic hierarchy is altered as a consequence, and the cellular identity of the resulting leukemia-propagating stem cell (LSC) populations. Here, we show that myeloid BP-CML is associated with expanded populations that have the immunophenotype of normal progenitor populations that vary between patients. Serial transplantation in immunodeficient mice demonstrated functional LSCs reside in multiple populations with the immunophenotype of normal progenitor as well as stem cells. Multicolor fluorescence in situ hybridization detected serial acquisition of cytogenetic abnormalities of chromosome 17, associated with transformation to BP-CML, that is detected with equal frequency in all functional LSC compartments. New effective myeloid BP-CML therapies will likely have to target all these LSC populations.


Tumor cell energy metabolism and its common features with yeast metabolism.
During the last decades a considerable amount of research has been focused on cancer. A number of genetic and signaling defects have been identified. This has allowed the design and screening of a number of anti-tumor drugs for therapeutic use. One of the main challenges of anti-cancer therapy is to specifically target these drugs to malignant cells. Recently, tumor cell metabolism has been considered as a possible target for cancer therapy. It is widely accepted that tumors display an enhanced glycolytic activity and oxidative phosphorylation down-regulation (Warburg effect). Therefore, it seems reasonable that disruption of glycolysis might be a promising candidate for specific anti-cancer therapy. Nonetheless, the concept of aerobic glycolysis as the paradigm of tumor cell metabolism has been challenged, as some tumor cells use oxidative phosphorylation. Mitochondria are of special interest in cancer cell energy metabolism, as their physiology is linked to the Warburg effect. Besides, their central role in apoptosis makes these organelles a promising "dual hit target" for selectively eliminate tumor cells. Thus, it is desirable to have an easy-to-use and reliable model in order to do the screening for energy metabolism-inhibiting drugs to be used in cancer therapy. From a metabolic point of view, the fermenting yeast Saccharomyces cerevisiae and tumor cells share several features. In this paper we will review these common metabolic properties and we will discuss the possibility of using S. cerevisiae as an early screening test in the research for novel anti-tumor compounds used for the inhibition of tumor cell metabolism.


A geometrical model for testing bilateral symmetry of bamboo leaf with a simplified Gielis equation.
The size and shape of plant leaves change with growth, and an accurate description of leaf shape is crucial for describing plant morphogenesis and development. Bilateral symmetry, which has been widely observed but poorly examined, occurs in both dicot and monocot leaves, including all nominated bamboo species (approximately 1,300 species), of which at least 500 are found in China. Although there are apparent differences in leaf size among bamboo species due to genetic and environmental profiles, bamboo leaves have bilateral symmetry with parallel venation and appear similar across species. Here, we investigate whether the shape of bamboo leaves can be accurately described by a simplified Gielis equation, which consists of only two parameters (leaf length and shape) and produces a perfect bilateral shape. To test the applicability of this equation and the occurrence of bilateral symmetry, we first measured the leaf length of 42 bamboo species, examining >500 leaves per species. We then scanned 30 leaves per species that had approximately the same length as the median leaf length for that species. The leaf-shape data from scanned profiles were fitted to the simplified Gielis equation. Results confirmed that the equation fits the leaf-shape data extremely well, with the coefficients of determination being 0.995 on average. We further demonstrated the bilateral symmetry of bamboo leaves, with a clearly defined leaf-shape parameter of all 42 bamboo species investigated ranging from 0.02 to 0.1. This results in a simple and reliable tool for precise determination of bamboo species, with applications in forestry, ecology, and taxonomy.


Effects of guizhi-fuling-wan on male infertility with varicocele.
Thirty-seven infertile patients with varicocele were treated with Guizhi-Fuling-Wan (7.5 g/day) for at least 3 months. Before and after the administration, semen qualities such as sperm concentration and motility were examined, and the varicocele was graded. A varicocele disappearance rate of 80% was obtained with 40 out of 50 varicocele, and improvement of sperm concentration and motility were found in 71.4% and 62.1% of patients, respectively. From these results, Guizhi-Fuling-Wan is considered to be effective for circulation disorders in varicocele as well as semen quality.


Feasibility and Acceptability of Nurse-Led Primary Palliative Care for Older Adults with Chronic Conditions: A Pilot Study.
Many older adults live with serious illness for years before their death. Nurse-led primary palliative care could improve their quality of life and ability to stay in their community. To assess feasibility and acceptability of a nurse-led Transitional Palliative Care (TPC) program for older adults with serious illness. The study was a pilot trial of the TPC program in which registered nurses assisted patients with symptom management, communication with care providers, and advance care planning. Forty-one older adults with chronic conditions were enrolled in TPC or standard care groups. Feasibility was assessed through enrollment and attrition rates and degree of intervention execution. Acceptability was assessed through surveys and exit interviews with participants and intervention nurses. Enrollment rate for those approached was 68%, and completion rate for those enrolled was 71%. The TPC group found the intervention acceptable and helpful and was more satisfied with care received than the control group. However, one-third of participants perceived that TPC was more than they needed, despite the number of symptoms they experienced and the burdensomeness of their symptoms. More than half of the participants had little to no difficulty participating in daily activities. This study demonstrated that the nurse-led TPC program is feasible, acceptable, and perceived as helpful. However, further refinement is needed in selection criteria to identify the population who would most benefit from primary palliative care before future test of the efficacy of this intervention.


Anti-interleukin 6 receptor antibody inhibits murine AA-amyloidosis.
AA-amyloidosis is a severe complication in chronic inflammatory diseases. AA-amyloidosis is caused by the deposition of insoluble fibrils containing AA amyloid protein derived from serum amyloid A (SAA), which is synthesized by inflammatory cytokine stimulation. We examined whether anti-interleukin 6 receptor (IL-6R) antibody prevented the development of AA-amyloidosis in mouse models. A transient model was induced by the injection of amyloid enhancing factor (AEF) and adjuvant treatment in C57BL/6 mice. Monoclonal IgG1 antibody, MR16-1, was injected intraperitoneally just once before the injection of AEF and adjuvant. After 2 and 5 weeks, mice were sacrificed and histologically examined. In contrast, a chronic model was induced by AEF injection into IL-6 transgenic mice. One week later, in order to avoid neutralizing antibody production, MR16-1 (200 mg/kg) was injected intravenously. MR16-1 (5 mg/kg) was injected subcutaneously twice a week from the next week. Three and 6 weeks after AEF injection, mice were sacrificed and histologically examined. In the transient model, amyloid deposition was observed in the spleen, liver, and kidney as early as 2 weeks after treatment. MR16-1 completely prevented amyloid deposition. Although IL-6 production was not suppressed, SAA production was significantly suppressed. In the chronic model, substantial amyloid deposition was seen in multiple organs and tissues as well as the spleen, liver, and kidney. MR16-1 suppressed amyloid deposition in many organs, even when injected one week after AEF injection; it showed a tendency to decrease SAA and IL-6 levels were decreased. IL-6 is a key cytokine for the induction of AA-amyloidosis, and anti-IL-6R therapy appears promising for the treatment of AA-amyloidosis.


Effect of Catechins on Upper Respiratory Tract Infections in Winter: A Randomized, Placebo-Controlled, Double-Blinded Trial.
Tea catechins are plant-derived compounds that improve immune functions. Previous randomized control trials have demonstrated the efficacy of primarily epi-type catechins against upper respiratory tract infections (URTIs). Green tea can be consumed in several ways, including popular bottled beverages. These beverages, however, require sterilization during manufacturing, which results in catechin isomerization. We conducted a randomized, double-blinded, placebo-controlled trial involving healthy Japanese participants to evaluate whether catechin consumption via bottled beverages has an alleviating effect on the duration and severity of URTIs in winter. The catechin group (490 mg catechin, 0.14%, containing 59% epi-type catechin, n = 55) showed reduced durations of running nose, nasal congestion, and headache, compared with the placebo group (0 mg catechin, n = 54; p = 0.013, 0.018, and <0.001, respectively). Furthermore, when considering physical symptoms, the duration of nasopharyngeal symptoms improved significantly in the catechin group (p < 0.001) compared with that in the control group. The daily consumption of catechin thus reduced the duration and severity of URTIs in healthy men and women. Humans are regularly exposed to several potential infectious threats, and the oral administration of heat-epimerized tea catechins might help prevent and reduce the severity of URTIs.


Experimental Blind Quantum Computing for a Classical Client.
To date, blind quantum computing demonstrations require clients to have weak quantum devices. Here we implement a proof-of-principle experiment for completely classical clients. Via classically interacting with two quantum servers that share entanglement, the client accomplishes the task of having the number 15 factorized by servers who are denied information about the computation itself. This concealment is accompanied by a verification protocol that tests servers' honesty and correctness. Our demonstration shows the feasibility of completely classical clients and thus is a key milestone towards secure cloud quantum computing.


Casein kinase 1γ acts as a molecular switch for cell polarization through phosphorylation of the polarity factor Tea1 in fission yeast.
Fission yeast undergoes growth polarity transition from monopolar to bipolar during G2 phase, designated NETO (New End Take Off). It is known that NETO onset involves two prerequisites, the completion of DNA replication and attainment of a certain cell size. However, the molecular mechanism remains unexplored. Here, we show that casein kinase 1γ, Cki3 is a critical determinant of NETO onset. Not only did cki3∆ cells undergo NETO during G1- or S-phase, but they also displayed premature NETO under unperturbed conditions with a smaller cell size, leading to cell integrity defects. Cki3 interacted with the polarity factor Tea1, of which phosphorylation was dependent on Cki3 kinase activity. GFP nanotrap of Tea1 by Cki3 led to Tea1 hyperphosphorylation with monopolar growth, whereas the same entrapment by kinase-dead Cki3 resulted in converse bipolar growth. Intriguingly, the Tea1 interactor Tea4 was dissociated from Tea1 by Cki3 entrapment. Mass spectrometry identified four phosphoserine residues within Tea1 that were hypophosphorylated in cki3∆ cells. Phosphomimetic Tea1 mutants showed compromised binding to Tea4 and NETO defects, indicating that these serine residues are critical for protein-protein interaction and NETO onset. Our findings provide significant insight into the mechanism by which cell polarization is regulated in a spatiotemporal manner.


The Effect of Caffeine on the Risk and Progression of Parkinson's Disease: A Meta-Analysis.
Coffee and caffeine are speculated to be associated with the reduced risk of Parkinson's disease (PD). The present study aimed to investigate the disease-modifying potential of caffeine on PD, either for healthy people or patients, through a meta-analysis. The electronic databases were searched using terms related to PD and coffee and caffeinated food products. Articles were included only upon fulfillment of clear diagnostic criteria for PD and details regarding their caffeine content. Reference lists of relevant articles were reviewed to identify eligible studies not shortlisted using these terms. In total, the present study enrolled 13 studies, nine were categorized into a healthy cohort and the rest into a PD cohort. The individuals in the healthy cohort with regular caffeine consumption had a significantly lower risk of PD during follow-up evaluation (hazard ratio (HR) = 0.797, 95% CI = 0.748-0.849, p < 0.001). The outcomes of disease progression in PD cohorts included dyskinesia, motor fluctuation, symptom onset, and levodopa initiation. Individuals consuming caffeine presented a significantly lower rate of PD progression (HR = 0.834, 95% CI = 0.707-0.984, p = 0.03). In conclusion, caffeine modified disease risk and progression in PD, among both healthy individuals or those with PD. Potential biological benefits, such as those obtained from adenosine 2A receptor antagonism, may require further investigation for designing new drugs.


Efficacy of antibiotic prophylaxis in patients undergoing cystoscopy: a randomized clinical trial.
To establish the efficacy of antibiotic prophylaxis prior to cystoscopy in outpatients in decreasing the incidence of post-procedure urinary tract infection. A randomized clinical trial in patients (men and women) older than 18 who underwent cystoscopy for any non-urgent indication. The intervention was Levofloxacin 500 mg single dose, and the control was placebo 500 mg single dose made with similar characteristics. The primary outcome was urinary tract infection (UTI) measured 3-10 days after the procedure. It was performed as per protocol analysis. Hundred and thirty-eight patients in each study arm completed the trial. The incidence of UTI in the intervention group was 0.7% and in the placebo group was 3% (p = 0.17), and no significant differences were found. The incidence of asymptomatic bacteriuria in the intervention group was 5.8% and in the control group was 14.5% (p = 0.01). No significant differences were found in the use of prophylactic antibiotic compared to placebo to reduce the incidence of UTI in patients who undergo cystoscopy as an outpatient procedure with sterile urine demonstrated by urine culture.


Mitochondria-targeted cardioprotection in aldosteronism.
Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signal-transducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized that mitochondria-targeted interventions will prove to be cardioprotective. Accordingly, 8-week-old male Sprague-Dawley rats receiving 4 weeks ALDOST were cotreated with either quercetin, a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared with ALDOST alone or untreated, age/sex-matched controls. We monitored mitochondrial free Ca and biomarkers of oxidative stress, including 8-isoprostane and H2O2 production; mPTP opening; total Ca in cardiac tissue; and collagen volume fraction to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis, and employed terminal deoxynucleotidyl transferase dUTP nick end labeling assay to address apoptosis in coronal sections of ventricular myocardium. Compared with controls, at 4 weeks ALDOST we found a marked increase in mitochondrial H2O2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca]m and total tissue Ca, coupled with a 5-fold rise in collagen volume fraction without any terminal deoxynucleotidyl transferase dUTP nick end labeling-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST was prevented by quercetin or cyclosporine A cotreatment. Thus, mitochondria play a central role in initiating the cellular-subcellular mechanisms that lead to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies.


Drug metabolism by cultured human hepatocytes: how far are we from the in vivo reality?
The investigation of metabolism is an important milestone in the course of drug development. Drug metabolism is a determinant of drug pharmacokinetics variability in human beings. Fundamental to this are phenotypic differences, as well as genotypic differences, in the expression of the enzymes involved in drug metabolism. Genotypic variability is easy to identify by means of polymerase chain reaction-based or DNA chip-based methods, whereas phenotypic variability requires direct measurement of enzyme activities in liver, or, indirectly, measurement of the rate of metabolism of a given compound in vivo. There is a great deal of phenotypic variability in human beings, only a minor part being attributable to gene polymorphisms. Thus, enzyme activity measurements in a series of human livers, as well as in vivo studies with human volunteers, show that phenotypic variability is, by far, much greater than genotypic variability. In vitro models are currently used to investigate the hepatic metabolism of new compounds. Cultured human hepatocytes are considered to be the closest model to the human liver. However, the fact that hepatocytes are placed in a microenvironment that differs from that of the cells in the liver raises the question of to what extent drug metabolism variability observed in vitro actually reflects that in the liver in vivo. This issue has been examined by investigating the metabolism of the model compound, aceclofenac (an approved analgesic/anti-inflammatory drug), both in vitro and in vivo. Hepatocytes isolated from programmed liver biopsies were incubated with aceclofenac, and the metabolites formed were investigated by HPLC. The patients were given the drug during the course of clinical recovery, and the metabolites, largely present in urine, were analysed. In vitro and in vivo data from the same individual were compared. There was a good correlation between the in vitro and in vivo relative abundance of oxidised metabolites (4'-OH-aceclofenac + 4'-OH-diclofenac; Spearman's rho = 0.855), and the hydrolysis of aceclofenac (diclofenac + 4'-OH-aceclofenac + 4'-OH-diclofenac; rho = 0.691), while the conjugation of the drug in vitro was somewhat lower than in vivo. Globally, the metabolism of aceclofenac in vitro correlated with the amount of metabolites excreted in urine after 16 hours (rho = 0.95). Overall, although differing among assays, the in vitro/in vivo metabolism data for each patient were surprisingly similar. Thus, the variability observed in vitro appears to reflect genuine phenotypic variability among the donors.


Outlier Loci Detect Intraspecific Biodiversity amongst Spring and Autumn Spawning Herring across Local Scales.
Herring, Clupea harengus, is one of the ecologically and commercially most important species in European northern seas, where two distinct ecotypes have been described based on spawning time; spring and autumn. To date, it is unknown if these spring and autumn spawning herring constitute genetically distinct units. We assessed levels of genetic divergence between spring and autumn spawning herring in the Baltic Sea using two types of DNA markers, microsatellites and Single Nucleotide Polymorphisms, and compared the results with data for autumn spawning North Sea herring. Temporally replicated analyses reveal clear genetic differences between ecotypes and hence support reproductive isolation. Loci showing non-neutral behaviour, so-called outlier loci, show convergence between autumn spawning herring from demographically disjoint populations, potentially reflecting selective processes associated with autumn spawning ecotypes. The abundance and exploitation of the two ecotypes have varied strongly over space and time in the Baltic Sea, where autumn spawners have faced strong depression for decades. The results therefore have practical implications by highlighting the need for specific management of these co-occurring ecotypes to meet requirements for sustainable exploitation and ensure optimal livelihood for coastal communities.


Genetic analysis of default mating behavior in Saccharomyces cerevisiae.
Haploid Saccharomyces cerevisiae cells find each other during conjugation by orienting their growth toward each other along pheromone gradients (chemotropism). However, when their receptors are saturated for pheromone binding, yeast cells must select a mate by executing a default pathway in which they choose a mating partner at random. We previously demonstrated that this default pathway requires the SPA2 gene. In this report we show that the default mating pathway also requires the AXL1, FUS1, FUS2, FUS3, PEA2, RVS161, and BNI1 genes. These genes, including SPA2, are also important for efficient cell fusion during chemotropic mating. Cells containing null mutations in these genes display defects in cell fusion that subtly affect mating efficiency. In addition, we found that the defect in default mating caused by mutations in SPA2 is partially suppressed by multiple copies of two genes, FUS2 and MFA2. These findings uncover a molecular relationship between default mating and cell fusion. Moreover, because axl1 mutants secrete reduced levels of a-factor and are defective at both cell fusion and default mating, these results reveal an important role for a-factor in cell fusion and default mating. We suggest that default mating places a more stringent requirement on some aspects of cell fusion than does chemotropic mating.


Complete reversal by thaliblastine of 490-fold adriamycin resistance in multidrug-resistant (MDR) human breast cancer cells. Evidence that multiple biochemical changes in MDR cells need not correspond to multiple functional determinants for drug resistance.
The emergence of drug resistance is a major obstacle to effective cancer chemotherapy. The identification of novel agents that serve as selective, potent and nontoxic modulators of drug resistance is thus an important goal for improving the success of cancer treatment. Thaliblastine (TBL), a plant alkaloid and P-glycoprotein (P-gp) inhibitor, is presently shown to fully reverse 490-fold resistance to Adriamycin (AdR) in a multidrug-resistant (MDR) human breast cancer cell line (MCF/AdR) that overexpresses P-gp, whereas the same treatment had no effect on AdR cytotoxicity in the drug-sensitive parental MCF-7 cells. Mechanistic studies showed that this striking resistance reversal was achieved without alteration of cellular levels of glutathione and without inhibition of glutathione S-transferase, glutathione peroxidase or P450 reductase by TBL, each of which is significantly altered in MCF/AdR cells, and each of which has been proposed to contribute to AdR resistance in this MDR line. Rather, resistance reversal by TBL can be entirely explained by this drug's capacity to restore the intracellular accumulation of AdR in the resistant cells. These results establish that MDR associated with P-gp overexpression can be fully reversed by the potent P-gp inhibitor TBL. They further indicate that although changes in multiple drug-metabolizing enzymes may accompany the development of MDR, these multiple biochemical alterations need not correspond to multiple functional determinants for drug resistance.


Cochlear Implant Quality of Life (CIQOL): Development of a Profile Instrument (CIQOL-35 Profile) and a Global Measure (CIQOL-10 Global).
Purpose Valid, reliable, and efficient patient-reported outcome measures are needed to quantify quality of life (QOL) outcomes after cochlear implantation to supplement information obtained from performance-based outcomes. We previously developed the Cochlear Implant Quality of Life (CIQOL) item bank to serve as the source of items for subsequent instruments. This study reports the development and psychometric properties for 2 of these new instruments, the CIQOL-35 Profile and the CIQOL-10 Global. Method Cochlear implant (CI) users referred from the CIQOL Development Consortium (n = 371), consisting of 20 CI centers across the United States, provided responses to the 81-item CIQOL item bank, which are grouped into 6 QOL domains (communication, emotional, entertainment, environment, listening effort, and social). Responses to the 81 CIQOL items were analyzed using item response theory to determine individual item difficulty, discrimination, and model fit to select the set of items for the profile instrument and global measure that would optimize their measurement characteristics. Results The 35-item CIQOL-35 Profile instrument assesses outcomes represented in the 6 domains of the CIQOL final item pool. The 10-item CIQOL-10 Global measure produces a single, overall QOL score. After ensuring the upper and lower ends of the item difficulty continuum were represented (item difficulty range: -2.48 to 2.47), the items with the highest discrimination ability for each domain were selected for the CIQOL-35 Profile instrument (discrimination range: 0.67-1.37). Items were selected for the CIQOL-10 Global measure in a similar manner. Conclusion The CIQOL-35 Profile and CIQOL-10 Global instruments provide psychometrically sound and efficient measures that can be used to assess QOL in adult CI users in both clinical and research settings. Supplemental Material https://doi.org/10.23641/asha.9745010.


Clinical, pathologic, and magnetic resonance imaging characteristics of canine disc extrusion accompanied by epidural hemorrhage or inflammation.
Our aim was to characterize the magnetic resonance (MR) imaging features of canine disc extrusion accompanied by epidural hemorrhage or inflammation. We correlated the imaging characteristics of this type of disc extrusion in 46 dogs and compared these features with clinical signs and pathologic findings. Data from 50 control dogs with MR imaging features of a disc extrusion with no associated hemorrhage or inflammation, characterized by a T2-hypointense extradural mass, were used for comparison of the relative location of the two types of lesions and prognosis. Disc extrusion causing epidural hemorrhage or inflammation is more common in the caudal aspect of the lumbar spine than disc extrusions that do not cause signs of hemorrhage or inflammation (P < 0.05) in MR images. In dogs with disc extrusion and associated epidural hemorrhage or inflammation, there was no association between MR imaging features and signalment, the presence or absence of hemorrhage, or pathologic findings. The appearance of the lesion created by disc extrusion with epidural hemorrhage and inflammation encompasses a wide variety of imaging features, likely related to the duration of the hemorrhage and associated inflammatory changes. In 10 of 46 dogs these secondary changes masked identification of the disc extrusion itself in the MR images. An awareness of the variety of MR imaging features of disc extrusion accompanied by extradural hemorrhage or inflammation is important to avoid making an incorrect diagnosis and to facilitate a proper surgical approach. The prognosis of dogs with disc extrusion accompanied by hemorrhage or inflammation does not appear to be different than for dogs with disc extrusion and without imaging signs of epidural hemorrhage or inflammation.


Assessment of luteolin isolated from Eclipta alba leaves in animal models of epilepsy.
Eclipta alba (Linn) Hassk. (Asteraceae) has been reported to be a nerve tonic and has been used to treat epilepsy in folk medicine. The present study isolates and characterizes luteolin from E. alba and evaluates its antiepileptic potential in chemically induced acute and chronic models in mice. The methanol extract (16.85% w/w) of E. alba leaves was subjected to fractionation for isolation of luteolin. In acute pentylenetetrazole (PTZ) model, luteolin (5, 10, 20 mg/kg, i.p.) was administered 30 min prior to PTZ injection (100 mg/kg) in Swiss albino mice. Kindling was induced by chronic administration of PTZ (35 mg/kg) on every alternate day (48 days). Luteolin was investigated on the course of kindling development and oxidative stress markers [reduced glutathione (GSH) and malondialdehyde (MDA)] in kindled mice. Single-dose pretreatment with luteolin (10 and 20 mg/kg, i.p.) was found to be effective in an acute PTZ model (100% protection from mortality) and it did not exhibit any effect on motor coordination at the same doses. PTZ-induced kindling was significantly (p < 0.001) prevented by luteolin (5, 10, 20 mg/kg, i.p.) in a dose-dependent manner. Luteolin restored levels of reduced GSH (p < 0.001) and decreased the level of MDA (p < 0.001), a marker of lipid peroxidation. The results of the present study demonstrated that luteolin had an anticonvulsant effect in an acute PTZ model. Luteolin exhibited and inhibitory effect on the course of kindling and associated oxidative stress and hence could be a potential molecule in the treatment of epilepsy.


Controlling the lectin recognition of glycopolymers via distance arrangement of sugar blocks.
The arrangement of sugars in glycopolymers contributes to their recognition. The molecular recognition of proteins was controlled by the living radical polymerization of glycopolymers. The glycopolymers were prepared by the copolymerization of propargyl methacrylate (Pr-MA) and triethyleneglycol methacrylate (TEG-MA) via living radical polymerization with a reversible addition-fragmentation glycopolymer chain transfer (RAFT) reagent and by subsequent sugar conjugation by click chemistry. The block copolymers were prepared by the polymerization of Pr-MA and TEG-MA. The molecular recognition of glycopolymers was analyzed using the fluorescence quenching of lectin and found to be dependent on the glycopolymer structures. Two-site binding of glycopolymers to concanavalin A (ConA) was attained by both the glycopolymer with a 105-mer and the tri-block glycopolymer with a 103-mer. Glycopolymers with either a 27- or 54-mer showed much weaker interaction because of one-site binding. The molecular recognition of the glycopolymer was controlled by the arrangement and size of the sugar cluster and not by the sugar density.


Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex.
Misfolded proteins in the endoplasmic reticulum (ER) are degraded by ER-associated degradation (ERAD). Although ERAD components involved in degradation of luminal substrates are well characterized, much less is known about quality control of membrane proteins. Here, we analyzed the degradation pathways of two short-lived ER membrane model proteins in mammalian cells. Using a CRISPR-Cas9 genome-wide library screen, we identified an ERAD branch required for quality control of a subset of membrane proteins. Using biochemical and mass spectrometry approaches, we showed that this ERAD branch is defined by an ER membrane complex consisting of the ubiquitin ligase RNF185, the ubiquitin-like domain containing proteins TMUB1/2 and TMEM259/Membralin, a poorly characterized protein. This complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase in degrading their membrane substrates. Our data reveal that ERAD branches have remarkable specificity for their membrane substrates, suggesting that multiple, perhaps combinatorial, determinants are involved in substrate selection.


Efficient Bragg diffraction in thin semiconductor two-dimensional gratings.
Highly improved diffraction properties are demonstrated in a two-dimensional [2D] grating consisting of a transmission grating optically recorded in a semiconductor one-dimensional photonic crystal (1D-PC). Near unity internal diffraction efficiency, high wavelength selectivity, and Bragg diffraction regime operation are demonstrated when the read beam is set at Bragg incidence on the transmission grating while its wavelength corresponds to the band edge of the 3 microm thick 1D-PC. When the 2D grating is grown on a Bragg mirror, a single diffracted beam is obtained, which makes the device promising for optical signal processing.


Clinical Management of the Breast-Feeding Mother-Infant Dyad in Recovery From Opioid Dependence.
Human milk is one of the most health-promoting and cost-effective nutritional substances known to humankind. Breastmilk provides substantial and remarkable physiological and psychological health benefits. Within the last decade, there has been a resurgence of breast-feeding in the United States and worldwide and an increased awareness of the immense health benefits for mothers, infants, and societies that support it. Each mother-baby dyad is a unique pair, with distinct relationships, biases, barriers, and obstacles. This article aims to address clinical management for the opioid-recovering breast-feeding dyad and to translate current evidenced-based practice findings, recommendations, and resources to best support this unique population. The recovering breast-feeding mother and newborn with opioid dependence deserve special consideration and expert care to foster their recovery and breast-feeding efforts. It is our moral and ethical responsibility as healthcare professionals to enable, foster, and promote breast-feeding among all families, especially those who stand to benefit the greatest. Substance recovery cannot be treated in isolation, nor can breast-feeding efforts; an interdisciplinary professional team effort promises the greatest chances for recovery success. With appropriate evidence-based practice support, training, and intervention by knowledgeable professionals, many women can overcome the biases and obstacles associated with opioid recovery to successfully breast-feed their babies.


The major specificity-determining amino acids of the tomato Cf-9 disease resistance protein are at hypervariable solvent-exposed positions in the central leucine-rich repeats.
The interaction between tomato and the leaf mold pathogen Cladosporium fulvum is controlled in a gene-for-gene manner by plant Cf genes that encode membrane-anchored extracytoplasmic leucine-rich repeat (LRR) glycoproteins, which confer recognition of their cognate fungal avirulence (Avr) proteins. Cf-9 and Cf-4 are two such proteins that are 91% identical yet recognize the sequence-unrelated fungal avirulence determinants Avr9 and Avr4, respectively. As shown previously, Cf-4 specificity is determined by three putative solvent-exposed residues in the central LRR and a deletion of two LRR relative to Cf-9. In this study, we focused on identifying the specificity determinants of Cf-9. We generated chimeras between Cf-9 and its close homologue Cf-9B and identified five amino acid residues that constitute major specificity determinants of Cf-9. Introduction of these residues into Cf-9B allowed recognition of Avr9. Consistent with a role in recognition specificity, the identified residues are putatively solvent exposed in the central LRR and occupy hypervariable positions in the global Cf alignment. One of the specificity residues is not found in any other known Cf protein, suggesting the importance of diversifying selection rather than sequence exchange between homologues. Interestingly, there is an overlap between the Cf-4 and Cf-9 specificity-determining residues, precluding a protein with dual specificity.


Fast minimum variance wavefront reconstruction for extremely large telescopes.
We present what we believe to be a new algorithm, FRactal Iterative Method (FRiM), aiming at the reconstruction of the optical wavefront from measurements provided by a wavefront sensor. As our application is adaptive optics on extremely large telescopes, our algorithm was designed with speed and best quality in mind. The latter is achieved thanks to a regularization that enforces prior statistics. To solve the regularized problem, we use the conjugate gradient method, which takes advantage of the sparsity of the wavefront sensor model matrix and avoids the storage and inversion of a huge matrix. The prior covariance matrix is, however, non-sparse, and we derive a fractal approximation to the Karhunen-Loève basis thanks to which the regularization by Kolmogorov statistics can be computed in O(N) operations, with N being the number of phase samples to estimate. Finally, we propose an effective preconditioning that also scales as O(N) and yields the solution in five to ten conjugate gradient iterations for any N. The resulting algorithm is therefore O(N). As an example, for a 128 x 128 Shack-Hartmann wavefront sensor, the FRiM appears to be more than 100 times faster than the classical vector-matrix multiplication method.


Good clinical practice advice for the management of patients with gynaecological cancer during the COVID-19 pandemic in Nigeria and other resource-constrained countries.
The impact of the COVID-19 pandemic on healthcare services in settings with under-resourced health systems such as that of Nigeria is likely to be substantial in the coming months. The gynaecological oncology services still need to be prioritised as an essential core health service. There are increasing concerns from both physicians and patients regarding how to manage patients diagnosed with cancer during this pandemic as evidence suggests a substantial increase in the risk of COVID-19-related deaths amongst patients with cancer. However, we recognise that despite this great challenge, we must continue to provide the highest quality of care to the patients, whereas, at the same time, ensure adequate safety not only for the patients and their families but also for the entire oncology team. We advocate that due to the widespread travel restrictions and inability to refer patients for the highest level of care at this period, centres without radiotherapy facilities as seen in most resource-limited settings should always consider lower level care options such as the use of chemotherapy pending when there is a better access to these facilities. We, therefore, developed this good clinical practice advice to staff of the gynaecological oncology unit in the centre and other resource-constrained settings for the management of patients with gynaecological cancer during the COVID-19 pandemic.


Nht1, a transposable element cloned from a dispensable chromosome in Nectria haematococca.
Certain isolates of the plant-pathogenic fungus Nectria haematococca mating population VI (MPVI) contain dispensable chromosomes that are unstable during sexual reproduction. Several of these chromosomes carry genes for phytoalexin detoxification and thus contribute to the pathogenic potential of this organism. A repeated DNA sequence, Nht1, was cloned from one of these dispensable chromosomes in N. haematococca MPVI. One copy of the repeated element (Nht1A) was completely sequenced. It is 2,198 bp long and it possesses incomplete inverted terminal repeats (ITRs) at each end. Nht1B, a partially sequenced copy of Nht1, has complete ITRs. Nht1A appears to contain 2 introns and encodes a protein of 550 amino acids that is highly similar to the protein encoded by the Fusarium oxysporum transposon, Fot1. Due to the presence of ITRs, its repeated nature, and its similarity to Fot1, we conclude that Nht1 is a transposable element. Within North American N. Haematococca MPVI populations, Nht1 is distributed discontinuously. Its copy number in different field isolates varies from zero to approximately 100 copies per genome. The Nht1A source isolate is estimated to contain nine to 11 copies of Nht1; at least six are on the chromosome from which Nht1A was cloned.


Gene expression profiling of KBH-A42, a novel histone deacetylase inhibitor, in human leukemia and bladder cancer cell lines.
The aim of this study was to investigate the anti-tumor activity of KBH-A42, a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 was shown to significantly suppress the proliferation of all 14 human cancer cell lines tested. Among these cell lines, the human leukemia cell line K562 was the most sensitive, whereas the UM-UC-3 bladder cancer cells were the least sensitive. Additionally, in a human tumor xenograft model using Balb/c nude mice, KBH-A42 was shown to significantly inhibit the growth of K562 tumors, although it only slightly inhibited the growth of UM-UC-3 tumors. The results of flow cytometry analysis and caspase 3/7 activation assays showed that the growth inhibition of K562 cells by KBH-A42 was mediated, at least in part, by the induction of apoptosis, but its growth inhibitory effects on UM-UC-3 cells were not mediated by apoptotic induction. In an effort to gain insight into the mechanism by which KBH-A42 inhibits the growth of cancer cells, a microarray analysis was conducted. Four genes were selected from the genes that were down-regulated or up-regulated by KBH-A42 and confirmed via reverse transcription-polymerase chain reaction as follows: Harakiri (HRK), tumor necrosis factor receptor superfamily, member 10b (TNFRSF10B), PYD and CARD domain containing protein gene (PYCARD) and tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Collectively, the in vitro and in vivo results suggested that KBH-A42 exhibits anti-cancer activity, but various types of cells may be regulated differentially by KBH-A42.


Novel primate miRNAs coevolved with ancient target genes in germinal zone-specific expression patterns.
Major nonprimate-primate differences in cortico-genesis include the dimensions, precursor lineages, and developmental timing of the germinal zones (GZs). microRNAs (miRNAs) of laser-dissected GZ compartments and cortical plate (CP) from embryonic E80 macaque visual cortex were deep sequenced. The CP and the GZ including ventricular zone (VZ) and outer and inner subcompartments of the outer subventricular zone (OSVZ) in area 17 displayed unique miRNA profiles. miRNAs present in primate, but absent in rodent, contributed disproportionately to the differential expression between GZ subregions. Prominent among the validated targets of these miRNAs were cell-cycle and neurogenesis regulators. Coevolution between the emergent miRNAs and their targets suggested that novel miRNAs became integrated into ancient gene circuitry to exert additional control over proliferation. We conclude that multiple cell-cycle regulatory events contribute to the emergence of primate-specific cortical features, including the OSVZ, generated enlarged supragranular layers, largely responsible for the increased primate cortex computational abilities.


Loukoumasomes Are Distinct Subcellular Structures from Rods and Rings and Are Structurally Associated with MAP2 and the Nuclear Envelope in Retinal Cells.
"Rods and rings" (RR) and loukoumasomes are similarly shaped, subcellular macromolecular structures with as yet unknown function. RR, so named because of their shape, are formed in response to inhibition in the GTP or CTP synthetic pathways and are highly enriched in the two key enzymes of the nucleotide synthetic pathway. Loukoumasomes also occur as linear and toroidal bodies and were initially inferred to be the same as RR, largely due to their shared shape and size and the fact that it was unclear if they shared the same subcomponents. In human retinoblastoma tissue and cells we have observed toroidal, perinuclear, macromolecular structures of similar size and antigenicity to those previously reported in neurons (neuronal-loukoumasomes). To further characterize the subcomponents of the retinal-loukoumasomes, confocal analysis following immunocytochemical staining for alpha-tubulin, beta-III tubulin and detyrosinated tubulin was performed. These studies indicate that retinal-loukoumasomes are enriched for beta-III tubulin and other tubulins associated with microtubules. Immunofluorescence together with the in situ proximity ligation assay (PLA), confirmed that beta-III tubulin colocalized with detyrosinated tubulin within loukoumasomes. Our results indicate that these tissues contain only loukoumasomes because these macromolecular structures are immunoreactive with an anti-tubulin antibody but are not recognized by the prototype anti-RR/inosine monophosphate dehydrogenase (IMPDH) antibody (It2006). To further compare the RR and retinal-loukoumasomes, retinoblastoma cells were exposed to the IMPDH-inhibitor ribavirin, a drug known to induce the formation of RR. In contrast to RR, the production of retinal-loukoumasomes was unaffected. Coimmunostaining of Y79 cells for beta-III tubulin and IMPDH indicate that these cells, when treated with ribavirin, can contain both retinal-loukoumasomes and RR and that these structures are antigenically distinct. Subcellular fractionation studies indicate that ribavirin increased the RR subcomponent, IMPDH, in the nuclear fraction of Y79 cells from 21.3 ± 5.8% (0 mM ribavirin) to 122.8 ± 7.9% (1 mM ribavirin) while the subcellular localization of the retinal-loukoumasome subcomponent tubulin went unaltered. Further characterization of retinal-loukoumasomes in retinoblastoma cells reveals that they are intimately associated with lamin folds within the nuclear envelope. Using immunofluorescence and the in situ PLA in this cell type, we have observed colocalization of beta-III tubulin with MAP2. As MAP2 is a microtubule-associated protein implicated in microtubule crosslinking, this supports a role for microtubule crosslinkers in the formation of retinal-loukoumasomes. Together, these results suggest that loukoumasomes and RR are distinct subcellular macromolecular structures, formed by different cellular processes and that there are other loukoumasome-like structures within retinal tissues and cells.


Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.
Amino acids are required for cell growth and proliferation, but it remains unclear when and how amino acid availability impinges on the proliferation-quiescence decision. Here, we used time-lapse microscopy and single-cell tracking of cyclin-dependent kinase 2 (CDK2) activity to assess the response of individual cells to withdrawal of single amino acids and found strikingly different cell-cycle effects depending on the amino acid. For example, upon leucine withdrawal, MCF10A cells complete two cell cycles and then enter a CDK2-low quiescence, whereas lysine withdrawal causes immediate cell-cycle stalling. Methionine withdrawal triggers a restriction point phenotype similar to serum starvation or Mek inhibition: upon methionine withdrawal, cells complete their current cell cycle and enter a CDK2-low quiescence after mitosis. Modulation of restriction point regulators p21/p27 or cyclin D1 enables short-term rescue of proliferation under methionine and leucine withdrawal, and to a lesser extent lysine withdrawal, revealing a checkpoint connecting nutrient signaling to cell-cycle entry.


The role of ethnicity and socioeconomic status in Southeast Asian mothers' parenting sensitivity.
Past research indicates that socioeconomic status (SES) accounts for differences in sensitivity across ethnic groups. However, comparatively little work has been conducted in Asia, with none examining whether ethnicity moderates the relation between SES and sensitivity. We assessed parenting behavior in 293 Singaporean citizen mothers of 6-month olds (153 Chinese, 108 Malay, 32 Indian) via the Maternal Behavioral Q-Sort for video interactions. When entered into the same model, SES (F(1,288) = 17.777, p < .001), but not ethnicity, predicted maternal sensitivity (F(2,288) = .542, p = .582). However, this positive relation between SES and sensitivity was marginally moderated by ethnicity. SES significantly positively predicted sensitivity in Chinese, but not Malay dyads. Within Indian dyads, SES marginally positively predicted sensitivity only when permanent residents were included in analyses. We discuss the importance of culture on perceived SES-associated stress. However, because few university-educated Malays participated, we also consider whether university education, specifically, positively influences sensitivity.


Hot and Cold Smells: Odor-Temperature Associations across Cultures.
It is often assumed odors are associated with hot and cold temperature, since odor processing may trigger thermal sensations, such as coolness in the case of mint. It is unknown, however, whether people make consistent temperature associations for a variety of everyday odors, and, if so, what determines them. Previous work investigating the bases of cross-modal associations suggests a number of possibilities, including universal forces (e.g., perception), as well as culture-specific forces (e.g., language and cultural beliefs). In this study, we examined odor-temperature associations in three cultures-Maniq (N = 11), Thai (N = 24), and Dutch (N = 24)-who differ with respect to their cultural preoccupation with odors, their odor lexicons, and their beliefs about the relationship of odors (and odor objects) to temperature. Participants matched 15 odors to temperature by touching cups filled with hot or cold water, and described the odors in their native language. The results showed no consistent associations among the Maniq, and only a handful of consistent associations between odor and temperature among the Thai and Dutch. The consistent associations differed across the two groups, arguing against their universality. Further analysis revealed cross-modal associations could not be explained by language, but could be the result of cultural beliefs.


DHA mediates the protective effect of fish consumption on new episodes of depression among women.
In a longitudinal cohort study of young Australian adults, we reported that for women higher baseline levels of fish consumption were associated with reduced incidence of new depressive episodes during the 5-year follow-up. Fish are high in both n-3 fatty acids and tyrosine. In this study, we seek to determine whether n-3 fatty acids or tyrosine explain the observed association. During 2004-2006, a FFQ (nine fish items) was used to estimate weekly fish consumption among 546 women aged 26-36 years. A fasting blood sample was taken and high-throughput NMR spectroscopy was used to measure 233 metabolites, including serum n-3 fatty acids and tyrosine. During 2009-2011, new episodes of depression since baseline were identified using the lifetime version of the Composite International Diagnostic Interview. Relative risks were calculated using log-binomial regression and indirect effects estimated using the STATA binary_mediation command. Potential mediators were added to separate models, and mediation was quantified as the proportion of the total effect due to the mediator. The n-3 DHA mediated 25·3 % of the association between fish consumption and depression when fish consumption was analysed as a continuous variable and 16·6 % when dichotomised (reference group: <2 serves/week). Tyrosine did not mediate the association (<0·1 %). Components in fish other than n-3 fatty acids and tyrosine might be beneficial for women's mental health.


Host-gut microbiota metabolic interactions.
The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life-style. The gut microbiota is involved in the regulation of multiple host metabolic pathways, giving rise to interactive host-microbiota metabolic, signaling, and immune-inflammatory axes that physiologically connect the gut, liver, muscle, and brain. A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to manipulate the gut microbiota to combat disease and improve health.


Extracellular domains of alpha-neurexins participate in regulating synaptic transmission by selectively affecting N- and P/Q-type Ca2+ channels.
Neurexins constitute a large family of highly variable cell-surface molecules that may function in synaptic transmission and/or synapse formation. Each of the three known neurexin genes encodes two major neurexin variants, alpha- and beta-neurexins, that are composed of distinct extracellular domains linked to identical intracellular sequences. Deletions of one, two, or all three alpha-neurexins in mice recently demonstrated their essential role at synapses. In multiple alpha-neurexin knock-outs, neurotransmitter release from excitatory and inhibitory synapses was severely reduced, primarily probably because voltage-dependent Ca2+ channels were impaired. It remained unclear, however, which neurexin variants actually influence exocytosis and Ca2+ channels, which domain of neurexins is required for this function, and which Ca2+-channel subtypes are regulated. Here, we show by electrophysiological recordings that transgenic neurexin 1alpha rescues the release and Ca2+-current phenotypes, whereas transgenic neurexin 1beta has no effect, indicating the importance of the extracellular sequences for the function of neurexins. Because neurexin 1alpha rescued the knock-out phenotype independent of the alpha-neurexin gene deleted, these data are consistent with a redundant function among different alpha-neurexins. In both knock-out and transgenically rescued mice, alpha-neurexins selectively affected the component of neurotransmitter release that depended on activation of N- and P/Q-type Ca2+ channels, but left L-type Ca2+ channels unscathed. Our findings indicate that alpha-neurexins represent organizer molecules in neurotransmission that regulate N- and P/Q-type Ca2+ channels, constituting an essential role at synapses that critically involves the extracellular domains of neurexins.


2-year clinical follow-up from the randomized comparison of biolimus-eluting stents with biodegradable polymer and sirolimus-eluting stents with durable polymer in routine clinical practice.
This study sought to investigate safety and efficacy of biolimus-eluting stents (BES) with biodegradable polymer as compared with sirolimus-eluting stents (SES) with durable polymer through 2 years of follow-up. BES with a biodegradable polymer provide similar efficacy and safety as SES with a durable polymer at 9 months. Clinical outcomes beyond the period of biodegradation of the polymer used for drug release and after discontinuation of dual antiplatelet therapy are of particular interest. A total of 1,707 patients were randomized to unrestricted use of BES (n = 857) or SES (n = 850) in an all-comers patient population. At 2 years, BES remained noninferior compared with SES for the primary endpoint, which was a composite of cardiac death, myocardial infarction, or clinically indicated target vessel revascularization (BES 12.8% vs. SES 15.2%, hazard ratio [HR]: 0.84, 95% confidence interval [CI]: 0.65 to 1.08, p(noninferiority) < 0.0001, p(superiority) = 0.18). Rates of cardiac death (3.2% vs. 3.9%, HR: 0.81, 95% CI: 0.49 to 1.35, p = 0.42), myocardial infarction (6.3% vs. 5.6%, HR: 1.12, 95% CI: 0.76 to 1.65, p = 0.56), and clinically indicated target vessel revascularization (7.5% vs. 8.6%, HR: 0.86, 95% CI: 0.62 to 1.20, p = 0.38) were similar for BES and SES. The rate of definite stent thrombosis through 2 years was 2.2% for BES and 2.5% for SES (p = 0.73). For the period between 1 and 2 years, event rates for definite stent thrombosis were 0.2% for BES and 0.5% for SES (p = 0.42). After discontinuation of dual antiplatelet therapy, no very late definite stent thrombosis occurred in the BES group. At 2 years of follow-up, the unrestricted use of BES with a biodegradable polymer maintained a similar safety and efficacy profile as SES with a durable polymer. (Limus Eluted From a Durable Versus Erodable Stent Coating [LEADERS]; NCT00389220).


Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with a 382-nucleotide deletion (∆382) in the open reading frame 8 (ORF8) region of the genome have been detected in Singapore and other countries. We investigated the effect of this deletion on the clinical features of infection. We retrospectively identified patients who had been screened for the ∆382 variant and recruited to the PROTECT study-a prospective observational cohort study conducted at seven public hospitals in Singapore. We collected clinical, laboratory, and radiological data from patients' electronic medical records and serial blood and respiratory samples taken during hospitalisation and after discharge. Individuals infected with the ∆382 variant were compared with those infected with wild-type SARS-CoV-2. Exact logistic regression was used to examine the association between the infection groups and the development of hypoxia requiring supplemental oxygen (an indicator of severe COVID-19, the primary endpoint). Follow-up for the study's primary endpoint is completed. Between Jan 22 and March 21, 2020, 278 patients with PCR-confirmed SARS-CoV-2 infection were screened for the ∆382 deletion and 131 were enrolled onto the study, of whom 92 (70%) were infected with the wild-type virus, ten (8%) had a mix of wild-type and ∆382-variant viruses, and 29 (22%) had only the ∆382 variant. Development of hypoxia requiring supplemental oxygen was less frequent in the ∆382 variant group (0 [0%] of 29 patients) than in the wild-type only group (26 [28%] of 92; absolute difference 28% [95% CI 14-28]). After adjusting for age and presence of comorbidities, infection with the ∆382 variant only was associated with lower odds of developing hypoxia requiring supplemental oxygen (adjusted odds ratio 0·07 [95% CI 0·00-0·48]) compared with infection with wild-type virus only. The ∆382 variant of SARS-CoV-2 seems to be associated with a milder infection. The observed clinical effects of deletions in ORF8 could have implications for the development of treatments and vaccines. National Medical Research Council Singapore.


Autoradiographic studies of the utilization of Ca45 by the chick embryo.
Calcium-45 was injected into the dense albumen of fertile hen's eggs, to the extent of 25 microc. per egg. The eggs were incubated under standard conditions and three or more embryos removed daily and fixed in 10 per cent neutral formalin. Stripping-film autoradiograms were prepared from paraffin sections of the tibiofibulae. Exposure varied with the isotope concentration. The tissue sections with their autoradiograms in place were stained with dilute Giemsa, while other sections were stained with hematoxylin-azure-eosin and by von Kossa to demonstrate bone salt. At about 9 days, Ca(45) is found in the cartilage template both intra- and extracellularly. Between 9 and 11 days, a primary diaphyseal lamella is deposited which is largely acellular. The lamella is eroded by capillaries from the periosteum and a resorption center is established in the cartilage. New lamellae of bone are deposited centrifugally in an imbricated pattern. Bone matrix formation precedes calcification by about 1 to (1/2) days, and calcification in a particular lamella is not uniform. Endochondral bone formation is described, as well as calcification of the epiphyseal/diaphyseal cartilage. Calcium-45 occurs intracellularly in the osteocyte during bone formation.


Effect of insulin resistance, apoE2 allele, and smoking on combined hyperlipidemia.
Combined hyperlipidemia may result from the interaction of several metabolic and environmental factors. We explored to what extent fasting insulin concentration, apolipoprotein (apo) E2 frequency, and cigarette smoking explained the serum levels of triglyceride and high-density lipoprotein cholesterol (HDL-C) in patients with combined hyperlipidemia. Forty-nine untreated patients with combined hyperlipidemia were compared with 49 hypercholesterolemic patients who were matched for gender, age, and body mass index. All laboratory values were obtained after 9 weeks of standardized dietary intake and after an overnight fast. The patients with combined hyperlipidemia had a significantly higher (33 pmol/L, 50%) mean insulin concentration than matched hypercholesterolemic control subjects, indicating that the combined hyperlipidemic patients were more insulin resistant. However, the differences in the fasting insulin and triglyceride concentrations within the pairs were only slightly correlated (adjusted r = .29). The combined hyperlipidemic patients were also characterized by a higher frequency of apoE2 alleles (25% versus 6%) and smokers (41% versus 16%). In a matched multiple linear regression model, the differences in insulin concentration, apoE2 allele frequency, and smoking explained 12%, 8%, and 9%, respectively, of the mean paired difference in triglyceride concentration. The differences in insulin concentration or apoE2 allele frequency did not significantly explain the mean paired difference in HDL-C concentration, whereas smoking explained 17% of the difference. In conclusion, fasting insulin concentration, the presence of the apoE2 allele, and smoking may explain 30% of the hypertriglyceridemia and the low levels of HDL-C in nonobese patients with combined hyperlipidemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts.
Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m2)], but factors modifying these variance components are poorly understood.Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity.Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs).Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI.Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population.


A training program for defendants with intellectual disabilities who are found incompetent to stand trial.
In this study, we examined whether a specialized training program, the Slater Method, affects rates at which persons with intellectual disabilities attain competence to stand trial. We reviewed records of all 30 persons with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) clinical diagnoses of mental retardation (in this article, intellectual disability) or borderline intellectual functioning whom courts sent to Eleanor Slater Hospital for competency restoration from 2001 through 2006. Significantly more persons exposed to the Slater Method attained clinical trial competence (61.1%) than did persons who received traditional treatment alone (16.7%). Discussion focuses on potential limitations of the study, ethics-related concerns regarding use of the Slater Method, and directions for future research.


Caffeine and blood pressure: a critical review perspective.
The WHO reported that high blood pressure (BP) is one of the primary causes of death worldwide. Hypertension (HPT) is a major risk factor for CVD and related diseases as well as for diseases, leading to a considerable increase in cardiovascular risk. Since BP response could also be influenced by caffeine, which is widely consumed with coffee and other items, it is important to define the possible effects associated with caffeine intake. The most recent findings aimed at clarifying the role of caffeine consumption on BP and HPT risk/incidence are conflicting and difficult to interpret. Therefore, in the present narrative review, we aimed to examine various methodological inaccuracies/aspects and factors that make studies difficult to be compared, in order to obtain a single consensus on the effects of caffeine intake on the risk of BP and HPT. We observed that this heterogeneity in results could be due to the presence of: (i) several variables affecting BP (such as age, sex, genetic and lifestyle aspects); (ii) different caffeine content of food and beverages; and (iii) caffeine metabolism. Moreover, different methodological aspects in the evaluation of daily dietary caffeine intake and in the BP measurement could add some other bias in the interpretation of results. Therefore, it is mandatory to consider all methodological aspects and confounding factors to generate a standardised methodology in order to increase cross-study consistency and minimise confounding effects of different variables on the relationship between BP response and HPT risk/incidence after caffeine intake.


Breath alcohol concentrations of designated drivers.
This study established breath alcohol concentrations (BrACs) and alcohol-related behaviors of designated drivers (DDs) to determine (a) whether DDs are abstaining from drinking, (b) whether alcohol-related behaviors of non-DDs and DDs were different, and (c) whether the alcohol consumption of DDs resulted in BrAC levels that affected driving performance or caused psychomotor impairment. We conducted six anonymous field studies during a 3-month period in a southeastern college community restaurant and bar district. Intercept interviews were conducted with 1,071 bar patrons. Alcohol-related behaviors, BrAC, and whether one was serving as a DD were measured. The sample was primarily White (72.7%), male (62.4%) college students (64.7%). Descriptive statistics and an independent sample t test compared the BrACs of DDs versus non-DDs. A one-way analysis of variance examined the differences in the alcohol-related behaviors (Alcohol Use Disorders Identification Test-consumption [AUDIT-C] score) across DDs abstaining from drinking (BrAC = .00 g/210 L), drinking DDs (BrACs ≥ .02 and < .05 g/210 L), and impaired DDs (BrACs ≥ .05 g/210 L). A logistic regression assessed the impact of alcohol-related behaviors (AUDIT-C) on whether one was serving as a DD. Of the 165 DDs, approximately 40% did not abstain from drinking. Approximately 17% of DDs had BrACs between .02 g/210 L and .049 g/210 L, whereas 18% recorded BrACs at .05 g/210 L or greater. The mean AUDIT-C score for impaired DDs significantly differed from both abstaining DDs and drinking DDs. Participants with greater AUDIT-C scores were more likely to serve as a DD and have a BrAC that significantly inhibited driving ability and psychomotor function. These findings identify the need for consensus across researcher, layperson, and communication campaigns that a DD must be someone who has abstained from drinking entirely.