Control of choline oxidation in rat kidney mitochondria.
Choline is a quaternary amino cationic organic alcohol that is oxidized to betaine in liver and kidney mitochondria. Betaine acts as an intracellular organic osmolyte in the medulla of the kidney. Evidence is provided that kidney mitochondria have a choline transporter in their inner membrane. The transporter has a Km of 173+/-64 microM and a Vmax of 0.4+/-0.1 nmol/min/mg mitochondrial protein (at 10 degrees C). Uptake of choline is not coupled to betaine efflux. Transporter activity demonstrates a dependence on membrane potential and choline transport is inhibited by hemicholinium-3. Steady-state oxygen consumption due to choline oxidation in kidney mitochondria was measurable at 37 degrees C (125+/-6 pmol O2/min/mg mitochondrial protein), in the absence of other mitochondrial electron transport chain substrates and the choline transporter was shown to be the major site of control (96+/-4%) over choline oxidation flux in isolated kidney mitochondria. We conclude that the choline transporter in rat kidney mitochondria is the major site of control over the production of the organic osmolyte, betaine.


Measuring hunger and satiety in primary school children. Validation of a new picture rating scale.
Measuring hunger and satiety in children is essential to many studies of childhood eating behaviour. Few validated measures currently exist that allow children to make accurate and reliable ratings of hunger/satiety. Three studies aimed to validate the use of a new categorical rating scale in the context of estimated and real eating episodes. Forty-seven 6- to 8-year-olds participated in Study 1, which used a between-participant design. Results indicated that the majority of children were able to make estimated hunger/satiety ratings for a story character using the scale. No significant differences in the ratings of hunger/satiety of children measured before and after lunch were observed and likely causes are discussed. To account for inter-individual differences in hunger/satiety perceptions Study 2 employed a within-participant design. Fifty-four 5- to 7-year-olds participated and made estimated hunger/satiety ratings for a story character and real hunger/satiety ratings before and after lunch. The results indicated that the majority of children were able to use the scale to make estimated and real hunger and satiety ratings. Children were found to be significantly hungrier before compared to after lunch. As it was not possible to establish the types and quantities of food children ate for lunch a third study was carried out in a controlled laboratory environment. Thirty-six 6- to 9-year-olds participated in Study 3 and made hunger/satiety ratings before and after ingesting an ad libitum snack of known composition and quantity. Results indicated that children felt hungrier before than after the snack and that pre-snack hunger/satiety, and changes in hunger/satiety, were associated with snack intake. Overall, the studies indicate that the scale has potential for use with primary school children. Implications of the findings are discussed.


Cerebral Haemodynamics following Acute Ischaemic Stroke: Effects of Stroke Severity and Stroke Subtype.
Acute ischaemic stroke (AIS) patients often show impaired cerebral autoregulation (CA). We tested the hypothesis that CA impairment and other alterations in cerebral haemodynamics are associated with stroke subtype and severity. AIS patients (n = 143) were amalgamated from similar studies. Data from baseline (< 48 h stroke onset) physiological recordings (beat-to-beat blood pressure [BP], cerebral blood flow velocity (CBFV) from bilateral insonation of the middle cerebral arteries) were calculated for mean values and autoregulation index (ARI). Differences were assessed between stroke subtype (Oxfordshire Community Stroke Project [OCSP] classification) and severity (National Institutes of Health Stroke Scale [NIHSS] score < 5 and 5-25). Correlation coefficients assessed associations between NIHSS and physiological measurements. Thirty-two percent of AIS patients had impaired CA (ARI < 4) in affected hemisphere (AH) that was similar between stroke subtypes and severity. CBFV in AH was comparable between stroke subtype and severity. In unaffected hemisphere (UH), differences existed in mean CBFV between lacunar and total anterior circulation OCSP subtypes (42 vs. 56 cm•s-1, p < 0.01), and mild and moderate-to-severe stroke severity (45 vs. 51 cm•s-1, p = 0.04). NIHSS was associated with peripheral (diastolic and mean arterial BP) and cerebral haemodynamic parameters (CBFV and ARI) in the UH. AIS patients with different OCSP subtypes and severity have homogeneity in CA capability. Cerebral haemodynamic measurements in the UH were distinguishable between stroke subtype and severity, including the association between deteriorating ARI in UH with stroke severity. More studies are needed to determine their clinical significance and to understand the determinants of CA impairment in AIS patients.


Biometals as Potential Predictors of the Neurodegenerative Decline in Alzheimer's Disease.
Alzheimer's Disease (AD) is a debilitating neurodegenerative disease that is diagnosed by gradual memory loss and certain cognitive impairments involving attention, reasoning, and language. Most of the research on Alzheimer's disease focuses on the correlation of its neuropathological changes in the neurofibrillary tangles caused by hyper-phosphorylated tau protein and β-amyloid plaques with respect to cognitive impairment. Its pathology, however, remains incompletely understood. Currently, research has demonstrated that environmental factors such as biometals play a crucial role in exacerbating AD progression. The present review examines the role of metals in AD progression and how metal dyshomeostasis attributes to AD pathogenesis. It was found that certain metals possess both beneficial and harmful properties in terms of AD progression. Depending upon the concentration of the metal of interest, copper, zinc, iron, and selenium have general beneficial properties. However, when present in excess, they can lead to oxidative stress and hyperphosphorylation of tau protein, amongst other harmful effects, while calcium and magnesium were seen to have beneficial effects by regulating biometal uptake. In this review, we have provided evidential studies that focus on the involvement of certain metals in antioxidant pathways leading to the formation of reactive species indicative of neurodegeneration.


Comparison of Hand-Held Doppler and Indocyanine Green Angiography in Preoperative Design of Expanded Forehead Flaps for Nasal Reconstruction.
Despite the different approaches for detection of perforators, methods of vascular mapping of the expanded forehead flap for nasal reconstruction are rarely described. This article aimed to present our experience in the preoperative design of the expanded forehead flap for nasal reconstruction and to compare the clinical practice of hand-held Doppler and indocyanine green angiography (ICGA) in vascular mapping for nasal reconstruction with the expanded forehead flap. From October 2019 to April 2022, 26 patients underwent nasal reconstruction using expanded forehead flap. The authors performed preoperative vascular mapping on 16 patients by hand-held Doppler alone, and on 10 patients by hand-held Doppler and ICGA primary outcomes considered were the visualization of the main vascular course of the flap obtained by hand-held Doppler or ICGA, intraoperative observation of the flap, and its postoperative complications. Indocyanine green angiography provides a better detection in distal flap and the branches of the supratrochlear artery. Vein detection by ICGA generally corresponds to the results obtained by the combination of hand-held Doppler and transillumination test. In the group that only used hand-held Doppler, 2 patients presented hemodynamic complications in the margin of the flap and 1 patient presented partial necrosis postoperatively. No complication was found in the group that used ICGA. It is recommended to use the ICGA for preoperative planning, as it yields highly accurate vascular courses. As an alternative to other methods, hand-held Doppler is also an effective tool. IV.


Development of the respiratory compensation to progressive metabolic alkalosis resulting from potassium depletion in conscious rats.
1. 288 arterial blood samples were obtained at successive times, through indwelling catheters, from conscious rats subjected to selective dietary potassium restriction for up to 5 weeks. 2. In control rats with unrestricted access to potassium [HCO-3]a = 25.4 mmol/l, pHa = 7.47, PaCO2 = 34 mmHg, PaO2 = 94 mmHg and [K+]a = 4.3 mmol/l were steady and within the range of values reported in conscious rats. Five weeks of isolated potassium restriction resulted in significant hypokalaemia ([K+]a = 2.15 mmol/l) and metabolic alkalosis ([HCO-3]a = 34.1 mmol/1, pH 7.57). This alkalosis, due mostly to H+ transfer into cells, was accompanied by a significant increase in PaCO2 to 36.4 mmHg and decrease in PaO2 to 88 mmHg, contrary to previous reports in man and dog. The administration of neutral sodium phosphate in addition to potassium restriction enhanced both the alkalosis ([HCO-3]a = 42.3 mmol/l, pH 7.61) and its respiratory compensation (PaCO2 = 40.8, PaO2 = 82 mmHg), without altering the PaCO2: [HCO-3]a relationship. 3. The opposite variations of PaCO2 and PaO2 were significantly correlated to the increase in plasma bicarbonate concentration and described best by crossed sigmoid curves. The equations of both curves were calculated; their point of inflection occurred at the same bicarbonate concentration (36 mmol/l). The maximum intensity of respiratory compensation (0.62 mmHg PaCO2 for each mmol [HCO-3]a/l) observed at this point fell within the range of values yielded by previous estimations.


The economic implications of three biochemical screening algorithms for pheochromocytoma.
Pheochromocytoma is a rare, life-threatening condition. Using a modeling technique, we studied the economic implications of detection strategies for pheochromocytoma (third-party payer perspective). The diagnostic efficacy of biochemical tests was based on Mayo Clinic Rochester data. In all hypothetical algorithms, positive biochemical tests were followed by abdominal computerized tomography and, if negative, metaiodobenzylguanidine scintigraphy. In each hypothetical algorithm, imaging would be indicated after positive biochemical testing as follows: algorithm A, fractionated plasma metanephrine measurements above the laboratory reference range; or algorithm B, abnormal measurements of 24-h urinary total metanephrines or catecholamines. In algorithm C, subjects with fractions of plasma metanephrine at or above 0.5 nmol/liter or normetanephrine at or above 1.80 nmol/liter would undergo imaging, whereas those with values between the reference range and these cutoffs would undergo 24-h urinary measurements (total metanephrines and fractionated catecholamines) and be imaged if positive. We determined that, if 100,000 hypertensive patients (including 500 patients with pheochromocytoma) were tested, algorithm A (measurement of fractionated plasma metanephrines alone) would detect 489 pheochromocytoma patients at a cost of 56.6 million dollars, whereas B (24-h urinary measurements) would detect 457 pheochromocytoma patients for 39.5 million dollars, and C (combination of measurements of fractionated plasma metanephrines and urines) would detect 478 patients for 28.6 million dollars. None of the screening strategies for pheochromocytoma described are affordable if implemented on a routine basis in extremely low-risk patients. However, algorithm C may be the least costly, and at a reasonable level of sensitivity, for subjects in whom the suspicion of disease is moderate.


Swimming dynamics and propulsive efficiency of squids throughout ontogeny.
Squids encounter vastly different flow regimes throughout ontogeny as they undergo critical morphological changes to their two locomotive systems: the fins and jet. Squid hatchlings (paralarvae) operate at low and intermediate Reynolds numbers (Re) and typically have rounded bodies, small fins, and relatively large funnel apertures, whereas juveniles and adults operate at higher Re and generally have more streamlined bodies, larger fins, and relatively small funnel apertures. These morphological changes and varying flow conditions affect swimming performance in squids. To determine how swimming dynamics and propulsive efficiency change throughout ontogeny, digital particle image velocimetry (DPIV) and kinematic data were collected from an ontogenetic range of long-finned squid Doryteuthis pealeii and brief squid Lolliguncula brevis swimming in a holding chamber or water tunnel (Re = 20-20 000). Jet and fin wake bulk properties were quantified, and propulsive efficiency was computed based on measurements of impulse and excess kinetic energy in the wakes. Paralarvae relied predominantly on a vertically directed, high frequency, low velocity jet as they bobbed up and down in the water column. Although some spherical vortex rings were observed, most paralarval jets consisted of an elongated vortical region of variable length with no clear pinch-off of a vortex ring from the trailing tail component. Compared with paralarvae, juvenile and adult squid exhibited a more diverse range of swimming strategies, involving greater overall locomotive fin reliance and multiple fin and jet wake modes with better defined vortex rings. Despite greater locomotive flexibility, jet propulsive efficiency of juveniles/adults was significantly lower than that of paralarvae, even when juvenile/adults employed their highest efficiency jet mode involving the production of periodic isolated vortex rings with each jet pulse. When the fins were considered together with the jet for several juvenile/adult swimming sequences, overall propulsive efficiency increased, suggesting that fin contributions are important and should not be overlooked in analyses of the swimming performance of squids. The fins produced significant thrust and consistently had higher propulsive efficiency than did the jet. One particularly important area of future study is the determination of coordinated jet/fin wake modes that have the greatest impact on propulsive efficiency. Although such research would be technically challenging, requiring new, powerful, 3D approaches, it is necessary for a more comprehensive assessment of propulsive efficiency of the squid dual-mode locomotive system.


Critical water temperature during water immersion at various atmospheric pressures.
The present work was undertaken to determine the effect of atmospheric pressure [ranging from a high altitude of 4,300 m above sea level or 0.6 atmospheres absolute (ATA) to depths of 10 m deep or 2 ATA] on the critical water temperature (Tcw), defined as the lowest water temperature a subject can tolerate at rest for 2 h without shivering, of the unprotected subject during water immersion. Nine healthy males wearing only shorts were subjected to immersion to the neck in water at 0.6, 1, and 2 ATA while resting for 2 h. Continuous measurements included esophageal (Tes) and skin (Tsk) temperatures, direct heat loss from the skin (Htissue), and insulation of the tissue (Itissue). The Tcw was significantly higher at 0.6 ATA than 1 and 2 ATA: however, Tcw at 1 ATA was identical to that at 2 ATA. The metabolic heat production remained unchanged among the pressures. During the 2-h immersion in Tcw, Tes was identical among all atmospheric pressures: however, Tsk was significantly higher (P less than 0.05) at 0.6 ATA and was identical between 1 and 2 ATA. The overall mean Itissue was near maximal during immersion in Tcw in each pressure, and no difference was detected among the pressures. However, Itissue at the acral extremities (arm, hand, and foot) decreased significantly at 0.6 ATA, and subsequently heat loss from these parts was increased, which elevated an extremity-to-trunk heat loss ratio to 1.4 at 0.6 ATA from 1.1 at 1 and 2 ATA.(ABSTRACT TRUNCATED AT 250 WORDS)


Nurses' and pharmacists' learning experiences from participating in interprofessional medication reviews for elderly in primary health care - a qualitative study.
Traditionally, drug prescription and follow up have been the sole responsibility of physicians. However, interprofessional medication reviews (IMRs) have been developed to prevent drug discrepancies and patient harm especially for elderly patients with polypharmacy and multimorbidity. What participating nurses and pharmacists learn from each other during IMR is poorly studied. The aim of this study was to investigate nurses' and pharmacists' perceived learning experience after participating in IMRs in primary health care for up to two years. A qualitative study with semi-structured focus group interviews and telephone interviews with nurses and pharmacists with experience from IMRs in nursing homes and home based services. The data was analysed thematically by using systematic text condensation. Thirteen nurses and four pharmacists were interviewed. They described some challenges concerning how to ensure participation of all three professions and how to get thorough information about the patient. As expected, both professions talked of an increased awareness with time of the benefit of working as a team and the perception of contributing to better and more individual care. The nurses' perception of the pharmacist changed from being a controller of drug management routines towards being a source of pharmacotherapy knowledge and a discussant partner of appropriate drug therapy in the elderly. The pharmacists became more aware of the nurses' crucial role of providing clinical information about the patient to enable individual advice. Increasingly the nurses learned to link the patient's symptoms of effect and side effect to the drugs prescribed. Although experiencing challenges in conducting IMRs, the nurses and pharmacists had learning experiences they said improved both their own practice and the quality of drug management. There are some challenges concerning how to ensure participation of all three professions and how to get thorough information about the patient.


Dominant and recessive suppressors that restore glucose transport in a yeast snf3 mutant.
The SNF3 gene of Saccharomyces cerevisiae encodes a high-affinity glucose transporter that is homologous to mammalian glucose transporters. To identify genes that are functionally related to SNF3, we selected for suppressors that remedy the growth defect of snf3 mutants on low concentrations of glucose or fructose. We recovered 38 recessive mutations that fall into a single complementation group, designated rgt1 (restores glucose transport). The rgt1 mutations suppress a snf3 null mutation and are not linked to snf3. A naturally occurring rgt1 allele was identified in a laboratory strain. We also selected five dominant suppressors. At least two are tightly linked to one another and are designated RGT2. The RGT2 locus was mapped 38 cM from SNF3 on chromosome IV. Kinetic analysis of glucose uptake showed that the rgt1 and RGT2 suppressors restore glucose-repressible high-affinity glucose transport in a snf3 mutant. These mutations identify genes that may regulate or encode additional glucose transport proteins.


Next-generation sequencing to guide cancer therapy.
As a result of multiple technological and practical advances, high-throughput sequencing, known more commonly as "next-generation" sequencing (NGS), can now be incorporated into standard clinical practice. Whereas early protocols relied on samples that were harvested outside of typical clinical pathology workflows, standard formalin-fixed, paraffin-embedded specimens can more regularly be used as starting materials for NGS. Furthermore, protocols for the analysis and interpretation of NGS data, as well as knowledge bases, are being amassed, allowing clinicians to act more easily on genomic information at the point of care for patients. In parallel, new therapies that target somatically mutated genes identified through clinical NGS are gaining US Food and Drug Administration (FDA) approval, and novel clinical trial designs are emerging in which genetic identifiers are given equal weight to histology. For clinical oncology providers, understanding the potential and the limitations of DNA sequencing will be crucial for providing genomically driven care in this era of precision medicine.


Telomere-specific reverse transcriptase (hTERT) and cell-free RNA in plasma as predictors of pathologic tumor response in rectal cancer patients receiving neoadjuvant chemoradiotherapy.
To investigate whether the plasma levels of cell-free RNA (cfRNA) and telomere-specific reverse transcriptase mRNA (hTERT) are associated with tumor response in rectal cancer patients who received preoperative chemoradiotherapy (pCRT). Patients who underwent pCRT for rectal cancer and for whom baseline and paired post-pCRT blood samples were available were studied. On the basis of tumor regression score, patients were classified as having response or having no response. Clinical variables and plasma levels of cfRNA and hTERT before and after the pCRT were evaluated. The association between each predictor and tumor response was assessed by univariate and multivariate analyses. Of 98 eligible patients, 45 were determined to respond to therapy, and 53 did not respond to therapy. In univariate analysis, gender (P = 0.040), baseline levels of cfRNA (P = 0.026), post-pCRT levels of both hTERT and cfRNA (P < 0.0001 and P = 0.001, respectively), and the difference between the post- and pre-pCRT levels of both hTERT and cfRNA (P = 0.009 and P = 0.001, respectively) were found to be significant predictors of tumor response. In multivariate analysis, using variables that were available before pCRT, cfRNA levels and gender independently predicted the tumor response, while in multivariate analysis, which used all of the variables available before the surgical procedure, the post-pCRT levels of cfRNA and the difference between the post- and pre-pCRT levels of cfRNA independently predicted tumor response. Plasma levels of cfRNA and hTERT are promising markers of tumor response to pCRT for rectal cancer.


Inclusions of a two dimensional fluid with competing interactions in a disordered, porous matrix.
The behavior of a fluid with competing interaction ranges adsorbed in a controlled pore size disordered matrix is studied by means of grand canonical Monte Carlo simulations in order to analyze the effects of confinement. The disordered matrix model is constructed from a two-dimensional non-additive hard-sphere fluid (which shows close to its demixing critical point large fluctuations in the concentration), after a subsequent quenching of the particle positions and removal of one of the components. The topology of the porous network is analyzed by means of a Delaunay tessellation procedure. The porous cavities are large enough to allow for cluster formation, which is however somewhat hindered as a result of the confinement, as seen from the comparison of cluster size distributions calculated for the fluid under confinement and in the bulk. The occurrence of lamellar phases is impeded by the disordered nature of the porous network. Analysis of two-dimensional density maps of the adsorbed fluid for given matrix configurations shows that clusters tend to build up in specific locations of the porous matrix, so as to minimize inter-cluster repulsion.


Therapist-Guided Tablet-Based Telerehabilitation for Patients With Aphasia: Proof-of-Concept and Usability Study.
Aphasia is the loss or impairment of language functions and affects everyday social life. The disorder leads to the inability to understand and be understood in both written and verbal communication and affects the linguistic modalities of auditory comprehension, verbal expression, reading, and writing. Due to heterogeneity of the impairment, therapy must be adapted individually and dynamically to patient needs. An important factor for successful aphasia therapy is dose and intensity of therapy. Tablet computer-based apps are a promising treatment method that allows patients to train independently at home, is well accepted, and is known to be beneficial for patients. In addition, it has been shown to ease the burden of therapists. The aim of this project was to develop an adaptive multimodal system that enables aphasic patients to train at home using language-related tasks autonomously, allows therapists to remotely assign individualized tasks in an easy and time-efficient manner, and tracks the patient's progress as well as creation of new individual exercises. The system consists of two main parts: (1) the patient's interface, which allows the patient to exercise, and (2) the therapist's interface, which allows the therapist to assign new exercises to the patient and supervise the patient's progress. The pool of exercises is based on a hierarchical language structure. Using questionnaires, therapists and patients evaluated the system in terms of usability (ie, System Usability Scale) and motivation (ie, adapted Intrinsic Motivation Inventory). A total of 11 speech and language therapists (age: mean 28, SD 7 years) and 15 patients (age: mean 53, SD 10 years) diagnosed with aphasia participated in this study. Patients rated the Bern Aphasia App in terms of usability (scale 0-100) as excellent (score >70; Z=-1.90; P=.03) and therapists rated the app as good (score >85; Z=-1.75; P=.04). Furthermore, patients enjoyed (scale 0-6) solving the exercises (score>3; mean 3.5, SD 0.40; Z=-1.66; P=.049). Based on the questionnaire scores, the system is well accepted and simple to use for patients and therapists. Furthermore, the new tablet computer-based app and the hierarchical language exercise structure allow patients with different types of aphasia to train with different doses and intensities independently at home. Thus, the novel system has potential for treatment of patients with aphasia as a supplement to face-to-face therapy.


The absolute neutrophil count: is it the best indicator for occult bacteremia in infants?
Occult bacteremia affects approximately 5% of febrile children ages 2 to 36 months. Many physicians empirically treat children who have a temperature higher than 39 degrees C, a white blood cell (WBC) count of more than 15.0 x 10(9)/L, and no focus of infection with antibiotics. We undertook this investigation to better define predictive indicators for bacteremia. Specifically we were concerned with determining whether the absolute neutrophil count (ANC) is a better diagnostic indicator than the total WBC count and whether the manual differential (which includes a band cell count) is necessary or helpful. Three separate groups of patients aged 2 to 36 months were assessed retrospectively. Group A consisted of febrile children (temperature, > 39 degrees C) who had positive blood cultures (50 patients). Group B included febrile children (temperature, > 39 degrees C) who had negative blood cultures (59 patients). Group C, nonfebrile children admitted to the hospital was the control group (61 patients). The ANC and the total WBC count were significantly higher in group A than in group B. Although they were equally sensitive, the ANC was more specific than the total WBC count. Band cell counts of greater than 10% and the percentage of total neutrophils also were greater in group A than in group B. The values for group C were not significantly different from those for group B. Although a total WBC count of 15.0 x 10(9)/L is currently used to identify children at risk for occult bacteremia, the ANC seems to be as sensitive an indicator and may be more specific. Our study demonstrated that (1) the WBC count is a good indicator of occult bacteremia, (2) the ANC is as sensitive as the WBC count and may be more specific, (3) automated ANCs are comparable to manual ANCs, and (4) the band cell count is insensitive as an indicator and does not add any predictive value.


Fallout deposition in the Marshall Islands from Bikini and Enewetak nuclear weapons tests.
Deposition densities (Bq m(-2)) of all important dose-contributing radionuclides occurring in nuclear weapons testing fallout from tests conducted at Bikini and Enewetak Atolls (1946-1958) have been estimated on a test-specific basis for 32 atolls and separate reef islands of the Marshall Islands. A complete review of various historical and contemporary data, as well as meteorological analysis, was used to make judgments regarding which tests deposited fallout in the Marshall Islands and to estimate fallout deposition density. Our analysis suggested that only 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in substantial fallout deposition on any of the 23 inhabited atolls. This analysis was confirmed by the fact that the sum of our estimates of 137Cs deposition from these 20 tests at each atoll is in good agreement with the total 137Cs deposited as estimated from contemporary soil sample analyses. The monitoring data and meteorological analyses were used to quantitatively estimate the deposition density of 63 activation and fission products for each nuclear test, plus the cumulative deposition of 239+240Pu at each atoll. Estimates of the degree of fractionation of fallout from each test at each atoll, as well as of the fallout transit times from the test sites to the atolls were used in this analysis. The estimates of radionuclide deposition density, fractionation, and transit times reported here are the most complete available anywhere and are suitable for estimations of both external and internal dose to representative persons as described in companion papers.


Human selection of elk behavioural traits in a landscape of fear.
Among agents of selection that shape phenotypic traits in animals, humans can cause more rapid changes than many natural factors. Studies have focused on human selection of morphological traits, but little is known about human selection of behavioural traits. By monitoring elk (Cervus elaphus) with satellite telemetry, we tested whether individuals harvested by hunters adopted less favourable behaviours than elk that survived the hunting season. Among 45 2-year-old males, harvested elk showed bolder behaviour, including higher movement rate and increased use of open areas, compared with surviving elk that showed less conspicuous behaviour. Personality clearly drove this pattern, given that inter-individual differences in movement rate were present before the onset of the hunting season. Elk that were harvested further increased their movement rate when the probability of encountering hunters was high (close to roads, flatter terrain, during the weekend), while elk that survived decreased movements and showed avoidance of open areas. Among 77 females (2-19 y.o.), personality traits were less evident and likely confounded by learning because females decreased their movement rate with increasing age. As with males, hunters typically harvested females with bold behavioural traits. Among less-experienced elk (2-9 y.o.), females that moved faster were harvested, while elk that moved slower and avoided open areas survived. Interestingly, movement rate decreased as age increased in those females that survived, but not in those that were eventually harvested. The latter clearly showed lower plasticity and adaptability to the local environment. All females older than 9 y.o. moved more slowly, avoided open areas and survived. Selection on behavioural traits is an important but often-ignored consequence of human exploitation of wild animals. Human hunting could evoke exploitation-induced evolutionary change, which, in turn, might oppose adaptive responses to natural and sexual selection.


Multimodal fusion of muscle and brain signals for a hybrid-BCI.
Practical Brain-Computer Interfaces (BCIs) for disabled people should allow them to use all their remaining functionalities as control possibilities. Sometimes these people have residual activity of their muscles, most likely in the morning when they are not exhausted. In this work we fuse electromyographic (EMG) with electroencephalographic (EEG) activity in the framework of a so called "Hybrid-BCI" (hBCI) approach. Thereby, subjects could achieve a good control of their hBCI independently of their level of muscular fatigue. Furthermore, although EMG alone yields good performance, it is outperformed by the hybrid fusing of EEG and EMG. Two different fusion techniques are explored showing graceful performance degradation in the case of signal attenuation. Such a system allows a very reliable control and a smooth handover if the subjects get exhausted or fatigued during the day.


Immunological reactivity in patients with carcinoma of colon.
Sixty cases of colonic carcinoma have been investigated for antitumour immunoreactivity. The tests employed were blood lymphocyte reactivity and complement-dependent serum cytotoxicity against cultured tumour cells, and immunofluorescence for membrane staining of viable tumour cells and cytoplasmic staining of dried tumour cells in films. Nineteen cases were positive by one or more tests and the most frequent positive response, lymphocytotoxicity, was detected in 8 of the 24 cases tested in this way. The lymphocytotoxicity persisted in a case tested three times over a year. Immunoreactivity against tumour cell surface, as by lymphocyte or serum cytotoxicity or membrane immunofluorescence, was restricted to colonic carcinomas but there was an additional element of individual specificity; cross-reactivity with other tissues and tumours was not observed. Lymphocytes from regional lymph nodes were non-reactive even in a case with positive blood lymphocyte cytotoxicity against the carcinoma cells.


Potentiometric platform for the quantification of cellular potassium efflux.
Renewed interest in the measurement of cellular K(+) effluxes has been prompted by the observation that potassium plays an active and important role in numerous key cellular events, in particular cell necrosis and apoptosis. Although necrosis and apoptosis follow different pathways, both induce intracellular potassium effluxes. Here, we report the use of potassium-selective microelectrodes located in a microfluidic platform for cell culture to monitor and quantify such effluxes in real time. Using this platform, we observed and measured the early signs of cell lysis induced by a modification of the extracellular osmolarity. Furthermore, we were able to quantify the number of dying cells by evaluating the extracellular potassium concentration. A comparison between the potentiometric measurement with a fluorescent live-dead assay performed under similar conditions revealed the delay between potassium effluxes and cell necrosis. These results suggest that such platforms may be exploited for applications, such as cytotoxicological screening assays or tumor cell proliferation assays, by using extracellular K(+) as cell death marker.


Burn Trauma Acutely Increases the Respiratory Capacity and Function of Liver Mitochondria.
A complete understanding of the role of the liver in burn-induced hypermetabolism is lacking. We investigated the acute effect of severe burn trauma on liver mitochondrial respiratory capacity and coupling control as well as the signaling events underlying these alterations. Male BALB/c mice (8-12 weeks) received full-thickness scald burns on ∼30% of the body surface. Liver tissue was harvested 24 h postinjury. Mitochondrial respiration was determined by high-resolution respirometry. Citrate synthase activity was determined as a proxy of mitochondrial density. Male Sprague-Dawley rats received full-thickness scald burns to ∼60% of the body surface. Serum was collected 24 h postinjury. HepG2 cells were cultured with serum-enriched media from either sham- or burn-treated rats. Protein levels were analyzed via western blot. Mass-specific (P = 0.01) and mitochondrial-specific (P = 0.01) respiration coupled to ATP production significantly increased in the liver after burn. The respiratory control ratio for ADP (P = 0.04) and the mitochondrial flux control ratio (P = 0.03) were elevated in the liver of burned animals. Complex III and Complex IV protein abundance in the liver increased after burn by 17% and 14%, respectively. Exposure of HepG2 cells to serum from burned rats increased the pAMPKα:AMPKα ratio (P < 0.001) and levels of SIRT1 (P = 0.01), Nrf2 (P < 0.001), and PGC1α (P = 0.02). Severe burn trauma augments respiratory capacity and function of liver mitochondria, adaptations that augment ATP production. This response may be mediated by systemic factors that activate signaling proteins responsible for regulating cellular energy metabolism and mitochondrial biogenesis.


Generic lures attract cerambycid beetles in a tropical montane rain forest in southern China.
The attraction of cerambycid beetles to 10 known cerambycid pheromones was tested in a tropical montane rain forest in southern China. From 28 May to 25 June 2010, 1,526 cerambycids representing 71 species were captured in pheromone-baited traps, with 14 species accounting for 92% of the specimens. Test compounds with a 3-hydroxyalkan-2-one or 2,3-alkanediol motif attracted significant numbers of both sexes for eight species in the subfamily Cerambycinae, including species of Demonax, Rhaphuma, and Xylotrechus. Rhaphuma horsfieldi (White) was the only species that was strongly attracted to more than one test compound, with significant attraction to both (2R*,3R*)-2,3-hexanediol and (2R*,3R*)-2,3-octanediol. Within the Lamiinae, males and females of five species were significantly attracted to 2-(undecyloxy) ethanol, including Acalolepta formosana (Breuning), Monochamus bimaculatus Gahan, Pharsalia subgemmata (Thomson), Pseudomacrochenus antennatus (Gahan), and Xenohammus bimaculatus Schwarzer. Only male Megopis costipennis White (Prioninae) were significantly attracted to (2R*,3S*)-2,3-octanediol, suggesting that this compound may be a sex pheromone component for this species. To date, 2,3-octanediols have only been reported as aggregation pheromone components for cerambycids in the subfamily Cerambycinae. Our results support the hypothesis that both closely related (congeners) and more distantly related cerambycid species (different tribes and even subfamilies) may share pheromone components. Our results also demonstrate that traps baited with even a limited number of different classes of pheromones may be useful tools for surveying cerambycid diversity, as well as for detecting and monitoring particular species, especially those that have the potential to be invasive pests in other parts of the world.


Novel approaches to risk stratification to support malaria elimination: an example from Cambodia.
Accurate malaria stratification is essential for effective targeting of interventions but represents a particular challenge in pre-elimination settings. In these settings transmission is typically sufficiently low and spatially heterogeneous to warrant a need for estimates of malaria risk at sub-district or village level but is also likely to be sufficiently high to render the type of decision support systems appropriate to the final stages of malaria elimination impractical. In such a scenario it is arguably more feasible to strengthen existing passive malaria surveillance systems so that routinely generated case data can provide an effective basis for stratifying malaria risk. This paper explores the utility of routine malaria surveillance data for the stratification of malaria risk in Cambodia, where the target is malaria elimination by 2025. A malaria information system (MIS) was developed to generate timely, routine data on temporal and spatial variations in malaria cases reported through public health facilities and village malaria workers (VMWs). The MIS was implemented across all malaria endemic districts in the country during 2010-11. In 2012 MIS data were extracted and assessed on the basis of coverage and completeness. Village-level incidence estimates for 2011 were generated using predefined data inclusion criteria. In 2011, the MIS covered 681 health facilities and 1,489 VMW villages; the overall completeness of monthly reporting was 82& and 97& for health facilities and VMWs respectively. Using these data it was possible to estimate malaria incidence for 89& of villages covered by the MIS. The resulting stratification highlights the highly heterogeneous nature of malaria transmission in Cambodia and underlines the importance of village-level data for effective targeting of interventions, including VMWs. Challenges associated with implementing the MIS and the implications of these for developing viable and sustainable MIS in Cambodia and elsewhere are discussed. This study demonstrates the operational feasibility of introducing a system to routinely generate village level malaria case data in Cambodia. Although resulting incidence estimates are subject to various limitations and biases the data provide an objective, repeatable basis for a dynamic system of stratification which is appropriate for guiding the transition between malaria pre-elimination and elimination phases.


Thermography and sonic anemometry to analyze air heaters in Mediterranean greenhouses.
The present work has developed a methodology based on thermography and sonic anemometry for studying the microclimate in Mediterranean greenhouses equipped with air heaters and polyethylene distribution ducts to distribute the warm air. Sonic anemometry allows us to identify the airflow pattern generated by the heaters and to analyze the temperature distribution inside the greenhouse, while thermography provides accurate crop temperature data. Air distribution by means of perforated polyethylene ducts at ground level, widely used in Mediterranean-type greenhouses, can generate heterogeneous temperature distributions inside the greenhouse when the system is not correctly designed. The system analyzed in this work used a polyethylene duct with a row of hot air outlet holes (all of equal diameter) that expel warm air toward the ground to avoid plant damage. We have observed that this design (the most widely used in Almería's greenhouses) produces stagnation of hot air in the highest part of the structure, reducing the heating of the crop zone. Using 88 kW heating power (146.7 W ∙ m(-2)) the temperature inside the greenhouse is maintained 7.2 to 11.2 °C above the outside temperature. The crop temperature (17.6 to 19.9 °C) was maintained above the minimum recommended value of 10 °C.


Model-based analysis on the extractability of information from data in dynamic fed-batch experiments.
Dynamic changes of physiological bioprocess parameters, e.g. a change in the specific growth rate μ, are frequently observed during industrial manufacturing as well as bioprocess development. A quantitative description of these variations is of great interest, since it can bring elucidation to the physiological state of the culture. The goal of this contribution was to show limitations and issues for the calculation of rates with regard to temporal resolution for dynamic fed-batch experiments. The impact of measurement errors, temporal resolution and the physiological activity on the signal to noise ratio (SNR) of the calculated rates was evaluated using an in-silico approach. To make use of that in practice, a generally applicable rule of thumb equation for the estimation of the SNR of specific rates was presented. The SNR calculated by this rule of thumb equation helps with definition of sampling intervals and making a decision whether an observed change is statistically significant or should be attributed to random error. Furthermore, a generic reconciliation approach to remove random as well as systematic error from data was presented. This reconciliation technique requires only little prior knowledge. The validity of the proposed tools was checked with real data from a fed-batch culture of E. coli with dynamic variations due to feed profile.


Lack of efficacy of polysorbate 60 in the treatment of male pattern baldness.
Anecdotal reports have indicated that the nonionic detergent polysorbate 60 may be of some value in male pattern baldness. In this double-blind placebo-controlled trial, a photographic and objective scalp measurement system was developed to assess new hair growth. No significant difference was detected between subjects treated for 16 weeks with polysorbate 60 and control subjects treated with glycerin, indicating that polysorbate 60 is ineffective. Of the 141 subjects who completed the trial, 25% perceived that they grew new hair, 67% said they did not, and 8% were uncertain. Subject-reported new hair growth did not correlate with measurements, indicating that the placebo effect may be a major factor in reports of baldness "cures".


Smart pixels with smart illumination.
Smart pixels with smart illumination is a new concept in sensor array technology based on structured built-in illumination and optoelectronic feedback. It offers many new possibilities and potential advantages over more-traditional sensor arrays. We discuss an edge-detection system as an example of how smart illumination can advantageously be used to achieve a variety of functions. We also present initial experimental results from a fabricated chip based on this concept. The chip includes an integrated array of photodetectors and LED's. The output of each pixel can be controlled based on the feedback received by its dual detectors.


An ACA provision increased treatment for young adults with possible mental illnesses relative to comparison group.
The Affordable Care Act (ACA) required that insurers allow people ages 19-25 to remain as dependents on their parents' health insurance beginning in 2010. Using data from the 2008-12 National Survey of Drug Use and Health, we examined the impact of the ACA dependent coverage provision on people ages 18-25 with possible mental health or substance use disorders. We found that after implementation of the ACA provision, among people ages 18-25 with possible mental health disorders, mental health treatment increased by 5.3 percentage points relative to a comparison group of similar people ages 26-35. Smaller, but consistent, effects were found among all young adults, not only those with possible illnesses. For people using mental health treatment, uninsured visits declined by 12.4 percentage points, and visits paid by private insurance increased by 12.9 percentage points. We observed no changes in mental health treatment setting. Outcomes related to substance abuse treatment did not change during the study period. The dependent coverage provision can contribute to a broader strategy for improving behavioral health treatment for young adults.


Optical spectrum analysis from zero crossings.
A practical method of computing the spectral components directly from measured zero crossings of interferograms is presented. The method requires the sampling of only one zero crossing per Nyquist interval and yields results with a normalized mean-square error that is better than 10(-6) with respect to the fast Fourier transformation when the zero crossing is located within the Nyquist interval with an accuracy of one part in 10(6). The method is also robust against error frequencies that may arise owing to the finite range in the floating-point representation of numbers in a computer. The error frequencies appear whenever a large number of crossings is processed. This type of error is not related to the accuracy of locating the zero crossings and limits the operational bandwidth of a zero-crossing-based optical spectrum analyzer.


A near-full length genotypic assay for HCV1b.
A near-full genome genotypic assay for HCV1b was developed, which may prove useful to investigate antiviral drug resistance, given new combination therapies for HCV1 infection. The assay consists of three partially overlapping PCRs followed by Sanger population or Illumina next-generation sequencing. Seventy-seven therapy-naïve samples, spanning the entire diversity range of currently known HCV1b, were used for optimization of PCRs, of which ten were sequenced using Sanger and of these ten, four using Illumina. The median detection limits for the three regions, 5'UTR-NS2, E2-NS5A and NS4B-NS5B, were 570, 5670 and 56,670 IU/ml respectively. The number of Illumina reads mapped varied according to the software used, Segminator II being the best performing (81%). Consensus Illumina and Sanger sequencing results accord largely (0.013% major discordances). Differences were due almost exclusively to a larger number of ambiguities (presumably minority variants) scored by Illumina (1.50% minor discordances). The assay is easy to perform in an equipped laboratory; nevertheless, it was difficult to reach high sensitivity and reproducibility, due to the high genetic viral variability. This assay proved to be suitable for detecting drug resistance mutations and can also be used for epidemiological research, even though only a limited set of samples was used for validation.


Thyroid hormone levels in children receiving carbamazepine or valproate.
Antiepileptic therapy is associated with alteration of thyroid hormone levels. We evaluated the effect of valproate and carbamazepine therapy on the thyroid hormone profile of epileptic children. Subjects included children aged 2-12 years receiving therapy for at least 6 months. Free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were measured by electrochemiluminescent assay in 30 children receiving carbamazepine, 34 children receiving valproate, and 30 age- and sex-matched control subjects. Groups were similar for age, body mass index, and duration of therapy. Thyroid-stimulating hormone (mean ± S.D.) was 2.67 ± 1.66, 4.53 ± 1.9, and 3.61 ± 1.75 μ IU/mL in the control, valproate, and carbamazepine group, respectively (P < 0.001). Free thyroxine was 1.39 ± 0.19, 1.40 ± 0.63, 1.11 ± 0.19 ng/dL (P = 0.009). Free triiodothyronine was 4.03 ± 0.74, 4.14 ± 0.94, 3.92 ± 0.68 pg/mL (P = 0.54). When groups were compared 2 at a time, there was no difference in free triiodothyronine (P > 0.05). Free thyroxine levels in the carbamazepine group were significantly different from valproate (P = 0.015) and control (P = 0.027). Thyroid-stimulating hormone increased with both valproate and carbamazepine compared to control but was significant with valproate (P < 0.001). We conclude that carbamazepine and valproate therapy alters thyroid functions by decreasing free thyroxine levels. Compensation by increase in thyroid-stimulating hormone is better with valproate. The need for monitoring and supplementation should be assessed further.


Patients with neuromuscular diseases benefit from treatment in a warm climate.
Several studies have shown positive effects of treatment of chronic diseases in a warm climate. The aim of this study was to evaluate the long-term effect of a 4-week rehabilitation programme in a warm climate for patients with neuromuscular diseases. A randomized controlled trial with a cross-over design. One period of intervention and one period of "life as usual". A total of 60 persons with a neuromuscular diagnosis. Long-term effects were defined as changes in physical and psychological functions persisting after 3 months. Several scales were used according to the World Health Organization's classification of functioning. A comparison of the changes in the 2 periods showed significantly better results for all primary outcome scales in favour of the intervention. Mean difference in changes in pain (VAS scale), 6-min walking test and "timed up and go" were 9.0 (SD 28.8) units, 52 (75) m and 1.0 (2.3) sec, p = 0, 03, < 0.01 and 0.01, respectively. Median difference in changes in "Fatigue Severity Scale" and "Life Satisfaction Scale" were 0.4 (-0.5, 1.7) and 0.0 (0.0, 1.0), p = < 0.01 and 0.01, respectively. This study shows positive long-term effects on different dimensions of health after a 4-week rehabilitation programme in a warm climate for patients with neuromuscular diseases. This effect might be due to the programme, the warm climate, or a combination of both.


Identification of actin-, alpha-actinin-, and vinculin-containing plaques at the lateral membrane of epithelial cells.
In this paper, a new type of spot desmosome-like junction (type II plaque) is described that is scattered along the entire lateral plasma membrane of rat and human intestinal epithelium. Ultrastructurally type II plaques differed from the classical type of epithelial spot desmosome ("macula adherens", further denoted as type I desmosome) by weak electron density of the membrane-associated plaque material, association of the plaques with microfilaments rather than intermediate filaments, and poorly visible material across the intercellular space. Thus, type II plaques resemble cross-sections of the zonula adherens. Immunofluorescence-microscopic studies were done using antibodies to a main protein associated with the plaques of type I desmosomes (desmoplakin I) and to the three major proteins located at the plaques of the zonula adherens (actin, alpha-actinin, and vinculin). Two types of plaques were visualized along the lateral surface of intestinal and prostatic epithelium: (a) the type I desmosomes, which were labeled with anti-desmoplakin but did not bind antibodies to actin, alpha-actinin, and vinculin, and (b) a further set of similarly sized plaques, which bound antibodies to actin, alpha-actinin, and vinculin but were not stained with anti-desmoplakin. Three-dimensional computer reconstruction of serial sections double-labeled with anti-desmoplakin and anti-alpha-actinin further confirmed that both types of plaques are spatially completely separated from each other along the lateral plasma membrane. The computer graphs further revealed that the actin-, alpha-actinin-, and vinculin-containing plaques have the tendency to form clusters, a feature also typical of type II plaques. It is suggested that the type II plaques represent spot desmosome-like intercellular junctions, which, like the zonula adherens, appear to be linked to the actin filament system. As the type II plaques cover a considerable part of the lateral cell surface, they might play a particular role in controlling cellular shape and intercellular adhesion.


Genetic risk factors and markers for Alzheimer's disease and/or depression in the VITA study.
In ageing population, both Alzheimer's disease (AD) and depression are common. Significant depressive symptoms are often co-morbid with cognitive impairment and dementia. In this study, we attempted to find various factors and markers for both AD and depression in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. The VITA-Study consisted of 305 healthy subjects, 174 subjects with depression only, 55 subjects diagnosed with AD only and 72 subjects with depression as well as AD. Associations between AD and/or depression to gene polymorphisms APO E (epsilon4), choline acetyltransferase (ChAT) 4G to A, serotonin-transporter gene promoter-length, dopamine-D4-receptor, ciliary-neurotrophic-factor-null mutation and brain-derived neurotrophic factor (C270T) and to various known factors were analyzed. AD and depression were significant associated. Significant risk factors found for AD were low education, low folic acid and depressive-symptoms, while for depression were low education and higher nonsteroidal anti-inflammatory drugs (NSAID) consume. Moreover, the ChAT polymorphism associated significant to depression. Gender, education, and ChAT significantly associated with the combination AD and/or depression. Such studies must be conducted cautiously, as co-morbidities and gene-environmental-social influences may sway the results dramatically. We found in the VITA-study significant association between depression and AD and between ChAT polymorphism and depression.


Meniscal allografts: cryopreservation vs deep-frozen technique. An experimental study in goats.
Meniscal transplantation was performed in two groups of 15 adult goats each, using cryopreserved (group I) and deep-frozen (group II) allografts. Animals were killed at 2 weeks, 1, 3, 6 and 12 months, and a gross, histological and biochemical (water and glycosaminoglycan) evaluation of the menisci was performed. The allografts of both groups showed a normal gross appearance and had in most cases healed at the horn attachments and at the peripheral capsular tissue with a dense scar tissue and no signs of rejection. Histological analysis showed that at 2 weeks in group I the cell number was decreased compared with the controls, and the cells were mainly distributed in the superficial layers. In group II at 2 weeks, only a few cells were present at the peripheral attachment of the menisci. At 1 month in both groups, the cell repopulation can be seen extending from the peripheral area to the superficial layers. Cell proliferation and vascularization are particularly evident in both groups in the 3-month samples. At 6 months and 1 year the grafts can be seen to be completely remodelled and morphologically similar to normal menisci in both groups. Biochemical analysis showed in both groups an increase in water content and a progressive decrease in the concentration of glycosaminoglycans. At 1 year in both groups, there were moderate degenerative changes in the articular cartilage of the tibial plateau, which were more evident in the area of exposed cartilage than in that covered by the meniscus. These results suggest that there are no significant differences between the cryopreserved and deep-frozen grafts, and that even if cryopreservation makes it possible to maintain a partial cell viability in the tissue, this does not seem to improve the morphological and biochemical characteristics of the graft.


Validity of diabetes self-reports in the Women's Health Initiative: comparison with medication inventories and fasting glucose measurements.
Although diabetes is conveniently assessed by self-report, few validation studies have been performed. Therefore, we studied whether self-report of prevalent and incident diabetes in Women's Health Initiative (WHI) participants was concordant with other diagnostic evidence of diabetes. A total of 161 808 postmenopausal women aged 50-79 were enrolled at 40 clinical centers in the U.S. in 1993-1998 and followed prospectively. At baseline, prevalent medication treated diabetes was defined as a self-report of physician diagnosis and treatment with insulin or oral antidiabetic drugs. During followup, incident treated diabetes was defined as a self-report of a new physician diagnosis of diabetes treated with insulin or oral drugs. Diabetes self-reports were compared with medication inventories and fasting glucose levels at baseline and during follow-up. At baseline, self-reported treated diabetes was concordant with the medication inventory in 79% of clinical trial, and 77% of observational study participants. Self-reported incident treated diabetes was concordant with the medication inventory in 78% between baseline and Year 1 in the clinical trials, in 62% between Year 1 and Year 3 in the clinical trials, and in 72% between baseline and Year 3 in the observational study. Over similar periods, 99.9% of those who did not report treated diabetes had no oral antidiabetic drugs or insulin in the medication inventory. At baseline, about 3% not reporting diabetes had fasting glucose >126 mg/dl, and 88% of these subjects subsequently reported treated diabetes during 6.9 years of follow-up. Incident self-reported diabetes treated by lifestyle alone was not determined in WHI. Medication inventories may have been incomplete and fasting glucose may have been lowered by treatment; therefore, concordance with self-reported treatment or fasting glucose > or = 126 may have been underestimated. In the WHI, self-reported prevalent and incident diabetes was consistent with medication inventories, and a high proportion of those with undiagnosed diabetes subsequently reported diabetes treatment. Self-reports of ;treated diabetes' are sufficiently accurate to allow use in epidemiologic studies.


Reflux esophagitis and the risk of stroke in young adults: a 1-year population-based follow-up study.
Reflux esophagitis (RE) is the most common manifestation of gastro-esophageal reflux disease with esophageal injury. To the best of our knowledge, there has been no specific study to evaluate the risk of stroke after diagnosis of RE in young adults. This study aims to evaluate the risk of stroke among RE patients aged 18 to 50 years during a 1-year period after diagnosis of RE compared to a cohort of non-RE patients during the same period. This study used the Taiwan Longitudinal Health Insurance Database 2005. A total of 2340 RE patients were included as the study cohort and 11 700 non-RE patients were included as the comparison cohort. Each patient was individually tracked for 1 year from the index ambulatory visit to identify those in whom stroke developed. Out of the sample of 14 040 patients, 78 patients (0.56%) had strokes develop during the 1-year follow-up period: 22 from the study cohort (0.94% of the RE patients) and 56 from the comparison cohort (0.48% of patients without RE). Patients with RE were 1.68-times more likely to have strokes develop (95% confidence interval, 1.03-2.76) than patients in the comparison cohort during the follow-up period after adjusting for patients' medical comorbidities, such as hypertension, diabetes, coronary heart disease, renal disease, heart failure, and hyperlipidemia, as well as their demographic differences, such as the level of urbanization of their communities, monthly income, and geographical location. We conclude that RE is associated with an increased risk of subsequent stroke in young adults.


Updated genetic score based on 34 confirmed type 2 diabetes Loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program.
Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes-associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP). We genotyped 34 type 2 diabetes-associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment. In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00-1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93-0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001). A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.


Loss of KDM6A confers drug resistance in acute myeloid leukemia.
Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.


TCR Repertoire as a Novel Indicator for Immune Monitoring and Prognosis Assessment of Patients With Cervical Cancer.
There is increasing evidence that deep sequencing-based T cell repertoire can sever as a biomarker of immune response in cancer patients; however, the characteristics of T cell repertoire including diversity and similarity, as well as its prognostic significance in patients with cervical cancer (CC) remain unknown. In this study, we applied a high throughput T cell receptor (TCR) sequencing method to characterize the T cell repertoires of peripheral blood samples from 25 CC patients, 30 cervical intraepithelial neoplasia (CIN) patients and 20 healthy women for understanding the immune alterations during the cervix carcinogenesis. In addition, we also explored the signatures of TCR repertoires in the cervical tumor tissues and paired sentinel lymph nodes from 16 CC patients and their potential value in predicting the prognosis of patients. Our results revealed that the diversity of circulating TCR repertoire gradually decreased during the cervix carcinogenesis and progression, but the circulating TCR repertoires in CC patients were more similar to CIN patients than healthy women. Interestingly, several clonotypes uniquely detected in CC patients tended to share similar CDR3 motifs, which differed from those observed in CIN patients. In addition, the TCR repertoire diversity in sentinel lymphatic nodes from CC patients was higher than in tumor tissues. More importantly, less clonotypes in TCR repertoire of sentinel lymphatic node was associated with the poor prognosis of the patients. Overall, our findings suggested that TCR repertoire might be a potential indicator of immune monitoring and a biomarker for predicting the prognosis of CC patients. Although functional studies of T cell populations are clearly required, this study have expanded our understanding of T cell immunity during the development of CC and provided an experimental basis for further studies on its pathogenesis and immunotherapy.


The association of uremic toxins and inflammation in hemodialysis patients.
Cardiovascular disease is the leading cause of mortality in hemodialysis patients and is associated with chronic inflammation. Elevation of uremic toxins, particular protein-bound uremic toxins, is a possible cause of hyper-inflammation in hemodialysis patients. But the association between uremic toxins and inflammatory markers in hemodialysis is still unclear. We conducted a cross-sectional study to evaluate the association of the serum uremic toxins and inflammatory markers in hemodialysis patients. The uremic toxins were not associated with inflammatory markers--including high sensitivity C-reactive protein, IL(Interleukin) -1β, IL-6, tumor necrosis factor-α. In multiple linear regression, serum levels of total p-cresol sulfate (PCS) were independently significantly associated with serum total indoxyl sulfate (IS) (standardized coefficient: 0.274, p<0.001), and co-morbidity of diabetes mellitus (DM) (standardized coefficient: 0.342, p<0.001) and coronary artery disease (CAD) (standardized coefficient: 0.128, p = 0.043). The serum total PCS levels in hemodialysis with co-morbidity of DM and CAD were significantly higher than those without co-morbidity of DM and CAD (34.10±23.44 vs. 16.36±13.06 mg/L, p<0.001). Serum levels of total IS was independently significantly associated with serum creatinine (standardized coefficient: 0.285, p<0.001), total PCS (standardized coefficient: 0.239, p = 0.001), and synthetic membrane dialysis (standardized coefficient: 0.139, p = 0.046). The study showed that serum levels of total PCS and IS were not associated with pro-inflammatory markers in hemodialysis patients. Besides, serum levels of total PCS were independently positively significantly associated with co-morbidity of CAD and DM.


British-English norms and naming times for a set of 539 pictures: the role of age of acquisition.
In the present study, we presented picture-naming latencies along with ratings for a set of important characteristics of pictures and picture names: age of acquisition, frequency, picture-name agreement, name agreement, visual complexity, familiarity, and word length. The validity of these data was established by calculating correlations with previous studies. Regression analyses show that our ratings account for a larger amount of variance in RTs than do previous data. RTs were predicted by all variables except complexity and length. A complete database presenting details about all of these variables is available in the supplemental materials, downloadable from http://brm.psychonomic-journals.org/content/supplemental.


Intraoperative MET-receptor targeted fluorescent imaging and spectroscopy for lymph node detection in papillary thyroid cancer: novel diagnostic tools for more selective central lymph node compartment dissection.
Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n = 741) and NTT (n = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (p < 0.0001) and spectroscopy (p < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. NCT03470259.


Bipyridine complexes of E3+ (E = P, As, Sb, Bi): strong Lewis acids, sources of E(OTf)3 and synthons for EI and EV cations.
Triflate salts of trications [(bipy)2E]3+ ([6E][OTf]3) and [(tbbipy)2E]3+ ([6'E][OTf]3) (bipy = 2,2'-bipyridine, tbbipy = 4,4'-di- t butyl-2,2'-bipyridine; E = P, As, Sb, Bi) have been synthesized and comprehensively characterized. The unique molecular and electronic structures of this new class of complexes involving pnictogen Lewis acids has been assessed in the solid, solution and gas phases to reveal systematic variations in metric parameters, ligand lability and charge concentration. While the Lewis acidity of E3+ has the trend E = Bi < Sb < As < P as determined by gas-phase calculations and 1H NMR spectroscopy, the Lewis acidity of [6E]3+ has the trend E = P < As < Sb < Bi according to gas-phase calculations. Derivatives of [6'E][OTf]3 (E = P, As) are latent sources of E(OTf)3 as demonstrated by their reactions with dmap, which give the corresponding derivatives of [(dmap)3E][OTf]3. The highly oxidizing nature of P(OTf)3 and As(OTf)3 is evidenced in reactions of [6'E][OTf]3 (E = P, As) with phosphines, which give EI-containing monocations [(R3P)2E]1+ and oxidatively coupled dications [R3PPR3]2+, illustrating new P-P and P-As bond forming strategies. Cations [6'E]3+ (E = P, As) are C-H bond activating agents that dehydrogenate 1,4-cyclohexadiene, with higher activity observed for E = P. Combinations of [6'E]3+ and t Bu3P activate H2 and D2 under mild conditions, evidencing frustrated Lewis pair activity. Oxidation of [6'P][OTf]3 with SO2Cl2 gives [(tbbipy)2PCl2][OTf]3, containing a PV-trication, but there is no evidence of the analogous reaction with [6'As][OTf]3. The observations highlight new directions in the chemistry of highly charged cations and reveal a rich reactivity for p-block triflates E(OTf)3, which can be accessed through derivatives of [6E][OTf]3 and [6'E][OTf]3.


Diffusion Of Innovations Theory, Principles, And Practice.
Aspects of the research and practice paradigm known as the diffusion of innovations are applicable to the complex context of health care, for both explanatory and interventionist purposes. This article answers the question, "What is diffusion?" by identifying the parameters of diffusion processes: what they are, how they operate, and why worthy innovations in health care do not spread more rapidly. We clarify how the diffusion of innovations is related to processes of dissemination and implementation, sustainability, improvement activity, and scale-up, and we suggest the diffusion principles that can be readily used in the design of interventions.


Endothelial dysfunction as a potential contributor in diabetic nephropathy.
The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.


Affective disorder and hyperandrogenism.
A 40-year-old female patient with bipolar disorder and premenstrual dysphoric disorder did not present any physical evidence of virilization, treated with quetiapine and lithium carbonate. Laboratory testing showed evidence of hyperandrogenism (Testosterone levels 88.5ng/dL). After control, testosterone levels were normal (free testosterone 0.20 pg/ml, total testosterone 27.90ng/dl), as free thyroxine levels decreased (T4 0.83ng/dl) and increased progesterone levels (progesterone 3.80ng/ml). We consider an association between increased androgenic hormone levels in women, quetiapine and lithium carbonate treatment as well as the presence of an affective disorder and premenstrual dysphoric disorder. Some relevant patents are also outlined in this review.


Momordica charantia: a popular health-promoting vegetable with multifunctionality.
Products derived from edible medicinal plants have been used for centuries to prevent, treat, and even cure multiple diseases. Momordica charantia L., widely cultivated around the world, is a typical one bred for vegetables and medicinal usage. All parts of M. charantia possess important medicinal properties, including antidiabetic, anticancer, hypotensive, anti-obesity, antimicrobial, antihyperlipidemic, antioxidant, anti-inflammatory, immuno-modulatory, anthelmintic, neuro-protective, as well as hepato-protective properties both in vitro and in vivo. This review summarizes the active components and medicinal properties of M. charantia, especially the activities and mechanisms of its anti-diabetic and anti-cancer properties. The anti-diabetic properties involve inhibiting intestinal α-glucosidase and glucose transport, protecting islet β-cells, enhancing insulin secretion, increasing hepatic glucose disposal, decreasing gluconeogenesis, and even ameliorating insulin resistance. Moreover, the expressions of PPARs could also be activated and up-regulated. Meanwhile, its anticancer properties are mostly due to apoptosis, cell cycle arrest, and expression of serum factors associated with immunity. In this review, we aim to provide an overview of M. charantia and its benefits for development as a functional food.


Semen quality in relation to antioxidant intake in a healthy male population.
To assess the relationship between dietary antioxidant intake and semen quality in young healthy males. Cross-sectional study. University and college campuses in the Rochester, New York, area. One hundred eighty-nine university-aged men. None. Semen volume, total sperm count, concentration, motility, total motile count, and morphology. Progressive motility was 6.5 (95% confidence interval [CI], 0.6, 12.3) percentage units higher among men in the highest quartile of β-carotene intake compared with men in the lowest quartile. Similar results were observed for lutein intake. Lycopene intake was positively related to sperm morphology. The adjusted percentages (95% CI) of morphologically normal sperm in increasing quartiles of lycopene intake were 8.0 (6.7, 9.3), 7.7 (6.4, 9.0), 9.2 (7.9, 10.5), and 9.7 (8.4, 11.0). There was a nonlinear relationship between vitamin C intake and sperm concentration, with men in the second quartile of intake having, on average, the highest sperm concentrations and men in the top quartile of intake having the lowest concentrations. In a population of healthy young men, carotenoid intake was associated with higher sperm motility and, in the case of lycopene, better sperm morphology. Our data suggest that dietary carotenoids may have a positive impact on semen quality.


Hand to mouth: automatic imitation across effector systems.
The effector dependence of automatic imitation was investigated using a stimulus-response compatibility (SRC) procedure during which participants were required to make an open or closed response with their hand or their mouth. The correct response for each trial was indicated by a pair of letters in Experiments 1 and 2 and by a colored square in Experiment 3. Each of these imperative stimuli was accompanied by task-irrelevant action images depicting a hand or mouth opening or closing. In relation to the response, the irrelevant stimulus was movement compatible or movement incompatible, and effector compatible or effector incompatible. A movement compatibility effect was observed for both hand and mouth responses. These movement compatibility effects were present when the irrelevant stimulus was effector compatible and when it was effector incompatible, but were smaller when the irrelevant stimulus and response effectors were incompatible. Consistent with the associative sequence learning (ASL) model of imitation, these findings indicate that automatic imitation is partially effector dependent and therefore that the effector dependence of intentional imitation reflects, at least in part, the nature of the mechanisms that mediate visuomotor translation for imitation.


Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.


Involvement in caregiving and adjustment to death of a spouse: findings from the caregiver health effects study.
Most deaths in the United States occur among older persons who have 1 or more disabling conditions. As a result, many deaths are preceded by an extended period during which family members provide care to their disabled relative. To better understand the effect of bereavement on family caregivers by examining predeath vs postdeath changes in self-reported and objective health outcomes among elderly persons providing varying levels of care prior to their spouse's death. Prospective, population-based cohort study conducted in 4 US communities between 1993 and 1998. One hundred twenty-nine individuals aged 66 to 96 years whose spouse died during an average 4-year follow-up. Individuals were classified as noncaregivers (n = 40), caregivers who reported no strain (n = 37), or strained caregivers (n = 52). Changes in depression symptoms (assessed by the 10-item Center for Epidemiological Studies-Depression [CES-D] scale), antidepressant medication use, 6 health risk behaviors, and weight among the 3 groups of participants. Controlling for age, sex, race, education, prevalent cardiovascular disease at baseline, and interval between predeath and postdeath assessments, CES-D scores remained high but did not change among strained caregivers (9.44 vs 9.19; P =.76), while these scores increased for both noncaregivers (4.74 vs 8.25; F(1,116) = 14.33; P<.001) and nonstrained caregivers (4.94 vs 7.13; F(1,116) = 4.35; P =.04). Noncaregivers were significantly more likely to be using nontricyclic antidepressant medications following the death than the nonstrained caregiver group (odds ratio [OR], 12.85; 95% confidence interval [CI], 1.02-162.13; P =.05). The strained caregiver group experienced significant improvement in health risk behaviors following the death of their spouse (1.47 vs 0.66 behaviors; F(1,118) = 20.23; P<.001), while the noncaregiver and nonstrained caregiver groups showed little change (0.27 vs 0.27 [P =.99] and 0.46 vs 0.27 [P =.39] behaviors, respectively). Noncaregivers experienced significant weight loss following the death (149.1 vs 145.3 lb [67.1 vs 65.4 kg]; F(1,101) = 8.12; P =.005), while the strained and nonstrained caregiving groups did not show significant weight change (156.2 vs 155.2 lb [70.3 vs 69.8 kg] [P =.41] and 156.2 vs 154.0 lb [70.3 vs 69.3 kg] [P =.12], respectively). These data indicate that the impact of losing one's spouse among older persons varies as a function of the caregiving experiences that precede the death. Among individuals who are already strained prior to the death of their spouse, the death itself does not increase their level of distress. Instead, they show reductions in health risk behaviors. Among noncaregivers, losing one's spouse results in increased depression and weight loss.


Meta-analysis of open versus endovascular repair for ruptured descending thoracic aortic aneurysm.
Ruptured descending thoracic aortic aneurysm (rDTAA) is associated with high mortality rates. Data supporting endovascular thoracic aortic aneurysm repair (TEVAR) to reduce mortality compared with open repair are limited to small series. We investigated published reports for contemporary outcomes of open and endovascular repair of rDTAA. We systematically reviewed all studies describing the outcomes of rDTAA treated with open repair or TEVAR since 1995 using MEDLINE, Cochrane Library CENTRAL, and Excerpta Medica Database (EMBASE) databases. Case reports or studies published before 1995 were excluded. All articles were critically appraised for relevance, validity, and availability of data regarding treatment outcomes. All data were systematically pooled, and meta-analyses were performed to investigate 30-day mortality, myocardial infarction, stroke, and paraplegia rates after both types of repair. Original data of 224 patients (70% male) with rDTAA were identified: 143 (64%) were treated with TEVAR and 81 (36%) with open repair. Mean age was 70 +/- 5.6 years. The 30-day mortality was 19% for patients treated with TEVAR for rDTAA compared 33% for patients treated with open repair, which was significant (odds ratio [OR], 2.15, P = .016). The 30-day occurrence rates of myocardial infarction (11.1% vs 3.5%; OR, 3.70, P < .05), stroke (10.2% vs 4.1%; OR, 2.67; P = .117), and paraplegia (5.5% vs 3.1%; OR, 1.83; P = .405) were increased after open repair vs TEVAR, but this failed to reach statistical significance for stroke and paraplegia. Five additional patients in the TEVAR group died of aneurysm-related causes after 30 days, during a median follow-up of 17 +/- 10 months. Follow-up data after open repair were insufficient. The estimated aneurysm-related survival at 3 years after TEVAR was 70.6%. Endovascular repair of rDTAA is associated with a significantly lower 30-day mortality rate compared with open surgical repair. TEVAR was associated with a considerable number of aneurysm-related deaths during follow-up.


Acute effects of breaking up prolonged sedentary time on cardiovascular disease risk markers in adults with paraplegia.
Elevated levels of cardiovascular disease (CVD) risk markers are highly prevalent in people with a spinal cord injury (SCI). Breaking up prolonged sedentary time with short, regular bouts of physical activity can reduce postprandial glucose and lipid levels in able-bodied individuals. The effects in people with paraplegia are unknown. The study aims were to examine the acute postprandial glucose (primary aim), lipid, blood pressure, and psychological responses (secondary aims) to breaking up prolonged sedentary time in individuals with paraplegia. This was a randomized crossover design trial. Fourteen participants with paraplegia (age 51 ± 9 years, trunk fat mass 44.3 ± 7.7%) took part in the following two, 5.5-hour conditions: (1) uninterrupted sedentary time (SED), and (2) sedentary time interrupted with 2 minutes of moderate-intensity arm crank ergometer physical activity every 20 minutes (SED-ACT). Standardized breakfast and lunch test meals were consumed during each condition. The outcomes were compared between conditions using linear mixed models. Glucose area under the curve (AUC) was significantly lower during the lunch postprandial period in SED-ACT vs SED (incremental AUC 1.9 [95% CI 1.0, 2.7) and 3.0 [2.1, 3.9] mmol/L∙2.5 hour, respectively, P = .015, f = 0.34). There were no differences between conditions for the breakfast or total 5.5 hours postprandial periods (P > .05). Positive affect was higher in SED-ACT than SED (P = .001). Breaking up prolonged sedentary time acutely attenuates lunch postprandial glucose and improves positive affect in people with paraplegia. This may have clinical relevance for reducing CVD risk and improving psychological well-being in this population.


Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers.
We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.


Are automatic postural responses in patients with Parkinson's disease abnormal due to their stooped posture?
Abnormal automatic postural responses are thought to contribute to balance impairment in Parkinson's disease. However, because postural responses are modifiable by stance, we have speculated that some postural abnormalities in patients with Parkinson's disease are secondary to their stooped stance. We have studied this assumption by assessing automatic postural responses in 30 healthy subjects who were instructed either to stand upright or to assume a typical parkinsonian posture. During both conditions, subjects received 20 serial 4 degrees 'toe-up' rotational perturbations from a supporting forceplate. We recorded short-latency (SL) and medium-latency (ML) responses from stretched gastrocnemius muscles and long-latency (LL) responses from shortened tibialis anterior muscles. We also assessed changes in the center of foot pressure (CFP) and the center of gravity (COG). The results were qualitatively compared to a previously described group of patients with Parkinson's disease who, under these circumstances, typically have large ML responses, small LL responses and insufficient voluntary postural corrections, accompanied by a slow rate of backward CFP displacement and an increased posterior COG displacement. The stooped posture resulted in unloading of medial gastrocnemius muscles and loading of tibialis anterior muscles. Onset latencies of stretch responses in gastrocnemius muscles were delayed in stooped subjects, but the onset of LL responses was markedly reduced. Amplitudes of both ML and LL responses were reduced in stooped subjects. Prestimulus COG and, to a lesser extent, CFP were shifted forwards in stooped subjects. Posterior COG displacement and the rate of backward CFP displacement were diminished in stooped subjects. Voluntary postural corrections were unchanged while standing stooped. These results indicate that some postural abnormalities of patients with Parkinson's disease (most notably the reduced LL responses) can be reproduced in healthy subjects mimicking a stooped parkinsonian posture. Other postural abnormalities (most notably the increased ML responses and insufficient voluntary responses) did not appear in stooped controls and may contribute to balance impairment in Parkinson's disease.


Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses.
The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.


Distribution of aged 14C-PCB and 14C-PAH residues in particle-size and humic fractions of an agricultural soil.
Organic matter is considered to be the single most importantfactor limiting availability and mobility of persistent organic pollutants (POPs) in soil. This study aimed to characterize the distribution of 14C-PCB (congeners 28 and 52) and 14C-PAH (fluoranthene and benzo[a]pyrene) residues in an Orthic Luvisol soil obtained from two lysimeter studies initiated in 1990 at the Agrosphere Institute (Forschungszentrum Jülich GmbH, Germany). The lysimeter soils contained a low-density OM fraction, isolated during soil washing, which contained a significant fraction (3-12%) of the total 14C-activity. Soils were also fractionated according to three particle sizes: >20, 20-2, and <2 microm. Relative affinity values of 14C-activity for the different particle sizes varied in the order 20-2 microm > (<2 microm) approximately (>20 microm) for the PCBs. Relative affinity values of 14C-activity for the different particle sizes varied in the order 20-2 microm > (<2 microm) > (>20 microm) for the PAHs. The distribution of 14C-PCB or 14C-PAH residues in the organic and inorganic matrixes of the particle-size fractions was determined using methyl isobutyl ketone (MIBK). 14C-PCB and 14C-PAH-associated activities were primarily located in the humin fraction of the 20-2 and <2 microm particle-size fractions of the soil. A small fraction was associated with the fulvic and humic acid fractions; these were quantitatively more important for the PAHs than the PCBs. There appeared to be a high degree of association of 14C-activity with the mineral fraction following MIBK separation of the humic fractions, ranging between 8 and 52% for 14C-PCBs and 57-80% for 14C-PAHs. The mineral (inorganic) component of the soils apparently played a significant (previously unreported) role in the sequestration of both PCBs 28 and 52 and the PAHs fluoranthene and benzo[a]pyrene.