Sleep in critically ill patients requiring mechanical ventilation.
To objectively measure sleep in critically ill patients requiring mechanical ventilation and to define selection criteria for future studies of sleep continuity in this population. Prospective cohort analysis. University teaching hospital medical-surgical ICU. Twenty critically ill (APACHE II [acute physiology and chronic health evaluation II] acute physiology score [APS], 10 +/- 5), mechanically ventilated adults (male 12, female 8, age 62 +/- 15 years) with mild to moderate acute lung injury (lung injury score, 1.8 +/- 0.9) 10 +/- 7 days after admission to the ICU. Patients were divided into three groups based on 24-h polysomnography (PSG) findings. No patient demonstrated normal sleep. In the "disrupted sleep" group (n = 8), electrophysiologic sleep was identified and was distributed throughout the day (6:00 AM to 10:00 PM; 4.0 +/- 2.9 h) and night (10:00 PM to 6:00 AM; 3.0 +/- 1.9 h) with equivalent proportions of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Nocturnal sleep efficiency was severely reduced (38 +/- 24%) with an increased proportion of stage 1 NREM sleep (40 +/- 28% total sleep time [TST]) and a reduced proportion of REM sleep (10 +/- 14% TST). Severe sleep fragmentation was reflected by a high frequency of arousals (20 +/- 17/h) and awakenings (22 +/- 25/h). Electrophysiologic sleep was not identifiable in the PSG recordings of the remaining patients. These were classified either as "atypical sleep" (n = 5), characterized by transitions from stage 1 NREM to slow wave sleep with a virtual absence of stage 2 NREM and reduced stage REM sleep, or "coma" (n = 7), characterized by > 50% delta or theta EEG activity with (n = 5) and without (n = 2) evidence of EEG activation either spontaneously or in response to deep painful stimuli. The combined atypical sleep and coma groups had a higher APS (13 +/- 4 vs 6 +/- 4) and higher doses of sedative medications than the disrupted sleep group. Sleep, as it is conventionally measured, was identified only in a subgroup of critically ill patients requiring mechanical ventilation and was severely disrupted. We have proposed specific criteria to select patients for future studies to evaluate potential causes of sleep disruption in this population.


Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres.
This study evaluated the regenerative effects of platelet-rich plasma (PRP) for the degenerated intervertebral disc (IVD) in vivo. After induction of IVD degeneration in rabbits, we prepared PRP by centrifuging blood obtained from these rabbits. These PRP were injected into the nucleus pulposus (NP) of the degenerated IVDs after impregnation into gelatin hydrogel microspheres that can immobilize PRP growth factors physiochemically and release them in a sustained manner with the degradation of the microspheres. As controls, microspheres impregnated with phosphate-buffered saline (PBS) and PRP without microspheres were similarly injected. Histologically, notable progress in IVD degeneration with time courses was observed in the PBS control, PRP-only, and sham groups. In contrast, progress was remarkably suppressed over the 8-week period in the PRP group. Moreover, in immunohistochemistry, intense immunostaining for proteoglycan in the NP and inner layer of the annulus fibrosus was observed 8 weeks after administration of PRP-impregnated microspheres. Almost all microspheres were indistinct 8 weeks after the injection, and there were no apparent side effects in this study. Our results suggest that the combined administration of PRP and gelatin hydrogel microspheres into the IVD may be a promising therapeutic modality for IVD degeneration.


Engineering of plant chromosomes.
Engineered minimal chromosomes with sufficient mitotic and meiotic stability have an enormous potential as vectors for stacking multiple genes required for complex traits in plant biotechnology. Proof of principle for essential steps in chromosome engineering such as truncation of chromosomes by T-DNA-mediated telomere seeding and de novo formation of centromeres by cenH3 fusion protein tethering has been recently obtained. In order to generate robust protocols for application in plant biotechnology, these steps need to be combined and supplemented with additional methods such as site-specific recombination for the directed transfer of multiple genes of interest on the minichromosomes. At the same time, the development of these methods allows new insight into basic aspects of plant chromosome functions such as how centromeres assure proper distribution of chromosomes to daughter cells or how telomeres serve to cap the chromosome ends to prevent shortening of ends over DNA replication cycles and chromosome end fusion.


Effect of the Kinesio tape to muscle activity and vertical jump performance in healthy inactive people.
Elastic taping applied on the triceps surae has been commonly used to improve the performance of lower extremities. However, little objective evidence has been documented. The purpose of this study was to investigate the effect of elastic taping on the triceps surae during a maximal vertical jump. It was hypothesized that elastic taping to the triceps surae would increase muscle activity and cause positive effect to jump height. Thirty-one healthy adults (19 males and 12 females with mean age, body weight and height for 25.3 ± 3.8 years old, 64.1 ± 6.2 kg, and 169.4 ± 7.3 cm, respectively) were recruited. All participants performed vertical jump tests prior to (without taping) and during elastic taping. Two elastic tapes, Kinesio tape and Mplacebo tape from two different manufacturers, were applied to the participants, respectively. The results showed that the vertical ground reaction force increased when Kinesio tape was applied even when the height of jump remained about constant. However, the height of the jump decreased, and there was no difference on the vertical ground reaction force in Mplacebo taping group. Although the EMG activity of medial gastrocnemius tended to increase in Kinesio taping group, we did not see differences in EMG activity for the medial gastrocnemius, tibialis anterior and soleus muscles in either group. Based on the varied effects of Kinesio tape and Mplacebo tape, different intervention technique was suggested for specific purpose during vertical jump movement. Mplacebo tape was demanded for the benefits of stabilization, protection, and the restriction of motion at the ankle joint. On the other hand, the findings may implicate benefits for medial gastrocnemius muscle strength and push-off force when using Kinesio tape.


Oral diagnosis and treatment planning: part 7. Treatment planning for missing teeth.
Although more people are retaining increasing numbers of their natural teeth into older ages, approximately 30-40% of persons over the age of 75 years in Western countries are edentulous. The causes and significance of tooth loss vary widely among individuals and cultures, and missing teeth may be replaced by a variety of means for functional, social and psychological reasons, rather than for significant physical health benefits. Therefore, it is essential to determine what the loss of teeth means to patients and what their expectations are for the outcomes following tooth replacement by various methods.


Timing matters when correcting fake news.
Countering misinformation can reduce belief in the moment, but corrective messages quickly fade from memory. We tested whether the longer-term impact of fact-checks depends on when people receive them. In two experiments (total N = 2,683), participants read true and false headlines taken from social media. In the treatment conditions, "true" and "false" tags appeared before, during, or after participants read each headline. Participants in a control condition received no information about veracity. One week later, participants in all conditions rated the same headlines' accuracy. Providing fact-checks after headlines (debunking) improved subsequent truth discernment more than providing the same information during (labeling) or before (prebunking) exposure. This finding informs the cognitive science of belief revision and has practical implications for social media platform designers.


Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer.
Steroid sulfatase (STS) hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate. In the present study, we have measured STS mRNA levels in 97 breast cancers by reverse transcription-PCR using a fluorescent primer in the presence of an internal standard RNA and evaluated its association with disease-free and overall survival. The median value was 728.0 amol/ng RNA (range, 0-11,778 amol/ng RNA). Levels were significantly higher in tumors demonstrating lymph node metastasis than in those without nodal involvement (P = 0.033) and in patients who experienced a recurrence during the follow-up period (mean, 40.8 months; median, 39 months) compared with those with no evidence of further disease (mean, 49.2 months; median, 48 months; P = 0.029). No significant associations were found between STS mRNA expression and age, menopausal status, tumor size, histological grade, estrogen receptor status, or postoperative adjuvant therapy. High levels of STS mRNA proved to be a significant predictor of reduced relapse-free survival as a continuous variable (log STS mRNA; P = 0.028). As a dichotomous variable with an optimized cutoff point of 1,240 amol/ng RNA, expression was also associated with a significantly shorter relapse-free survival rate (P = 0.002), but no significant correlation was found between the STS mRNA level and overall survival. Expression was found to be an independent factor for predicting relapse-free survival on multivariate analysis. The results thus support a putative role of STS in breast cancer growth and metastasis.


Melanocortin 1 receptor genotype, past environmental sun exposure, and risk of multiple sclerosis.
Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS. Population-based case-control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant. The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15-3.54]) than for men (odds ratio 0.65 [0.27-1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15; difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the sample was restricted to women only. The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.


Characterization of a novel impedance cytometer design and its integration with lateral focusing by dielectrophoresis.
This paper reports a novel impedance cytometer design, easily integrable with dielectrophoretic focusing using a simple fabrication process with a single metal layer. Patterning of electrodes recessed in lateral channels - so-called "liquid electrodes" - allows the use of large electrodes while keeping a good spatial resolution. This larger area allows measurements at low frequencies, down to 1 kHz. It also decreases the current density, leading to electrodes more robust against electrochemical degradation. The relative change in impedance is simulated and compared to values reported in the literature for traditional designs, showing a smaller sensitivity for the proposed design due to the larger measurement volume. The device is evaluated with specific target applications, such as viability measurement and high-speed cell counting. Numerical simulations indicate that the proposed design reduces the dependence of the measurement on the vertical position of the particle compared to conventional designs, with a variation of only 5%, but is still dependent on its lateral position. This dependence is studied using focusing by dielectrophoresis (DEP) at different lateral positions across the microchannel, showing a larger sensitivity when the particles are close to the measurement electrodes, as confirmed by the numerical simulations. The integration of lateral dielectrophoresis to focus particles in the middle of the channel reduces the variation of the measurements to very small values, with a coefficient of variation of 5.6%, and allows precise particle sizing. Such a design can be very powerful to simplify the fabrication process of impedance cytometers and enables the production of cost-effective, possibly disposable devices.


Thoracic myelopathy caused by ossification of ligamentum flavum of which fluorosis as an etiology factor.
To evaluate the clinical feature, operative method and prognosis of thoracic ossification of ligamentum flavum caused by skeletal fluorosis. All the patients with thoracic OLF, who underwent surgical management in the authors' hospital from 1993-2003, were retrospectively studied. The diagnosis of skeletal fluorosis was made by the epidemic history, clinical symptoms, radiographic findings, and urinalysis. En bloc laminectomy decompression of the involved thoracic levels was performed in all cases. Cervical open door decompression or lumbar laminectomy decompression was performed if relevant stenosis existed. The neurological statuses were evaluated with the Japanese Orthopaedic Association (JOA) scoring system preoperatively and at the end point of follow up. Also, the recovery rate was calculated. 23 cases have been enrolled in this study. Imaging study findings showed all the cases have ossification of ligamentum flavum together with ossification of many other ligaments and interosseous membranes, i.e. interosseous membranes of the forearm in 18 of 23 (78.3%), of the leg in 14 of 23 (60.1%) and of the ribs in 11 of 23 (47.8%). Urinalysis showed markedly increased urinary fluoride in 14 of 23 patients (60.9%). All the patients were followed up from 12 months to 9 years and 3 months, with an average of 4 years and 5 months. The JOA score increased significantly at the end of follow up (P = 0.0001). The recovery rate was 51.83 +/- 32.36%. Multiple regression analysis revealed that the preoperative JOA score was an important predictor of surgical outcome (p = 0.0022, r = 0.60628). ANOVA analysis showed that patients with acute onset or too long duration had worse surgical result (P = 0.0003). Fluorosis can cause ossification of thoracic ligamentum flavum, as well as other ligaments. En bloc laminectomy decompression was an effective method. Preoperative JOA score was the most important predictor of surgical outcome. Patients with acute onset or too long duration had worse surgical outcome.


Transformation of mackinawite to greigite by trichloroethylene and tetrachloroethylene.
Trichloroethylene (TCE) and tetrachloroethylene (PCE) are common ground water contaminants susceptible to reductive dechlorination by FeS (mackinawite) in anaerobic environments. The objective of this study was to characterize the mineral-associated products that form when mackinawite reacts with TCE and PCE. The dissolved products of the reaction included Cl- and Fe2+, and trace amounts of cis 1,2-dichloroethylene (for TCE) and TCE (for PCE). Selected area electron diffraction (SAED) analysis identified greigite as a mackinawite oxidation product formed after reaction between TCE or PCE and FeS over seven weeks. Release of Fe2+ is consistent with the solid state transformation of mackinawite to greigite, resulting in depletion of the solid with Fe. X-ray photoelectron spectroscopy of the sulfur 2p peak showed a shift to a higher binding energy after FeS reacted with TCE or PCE, also observed in other studies of mackinawite oxidation to greigite. The results may help efforts to maintain the reactivity of FeS generated to remediate chlorinated aliphatic contaminants in ground water.


The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.
The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine β-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.


Trajectory of Cognitive Decline After Incident Stroke.
Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors' cognitive changes after stroke is uncertain. To measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories. Prospective study of 23,572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23,057 remained stroke free. Time-dependent incident stroke. The primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score <5 [impaired] vs ≥5 [unimpaired]). For all tests, higher scores indicate better performance. Stroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P < .001). For a 70-year-old black woman with average values for all covariates at baseline, stroke at year 3 was associated with greater incident cognitive impairment: absolute difference of 4.0% (95% CI, -1.2% to 9.2%) at year 3 and 12.4% (95% CI, 7.7% to 17.1%) at year 6. Incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.


GABA and glutamate pathways are spatially and developmentally affected in the brain of Mecp2-deficient mice.
Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder.


Towards an anatomically correct repair for anomalous left coronary artery arising from the pulmonary trunk.
Anomalous origin of the left coronary artery from the pulmonary trunk is rare, occurring at an incidence of 1 in 300,000. If not diagnosed and treated early, it is life-threatening. Children with the anomaly usually present in infancy with congestive cardiac failure, and are occasionally referred for cardiac transplant. We investigated the medium term outcome for patients following creation of a two-coronary arterial circulation. Between 1992 and 2007, we diagnosed 15 patients seen at our Institution as having anomalous origin of the left coronary artery from the pulmonary trunk. Over a period of 13 years, aortic reimplantation was undertaken in 12 of these patients, who form the studied cohort. Direct reimplantation was performed in 5 patients. In 3 cases, a tension-free anastomosis was created using a caudally based flap. In another 3 cases, an extended flap was used, while a patch arterioplasty was fashioned in the final patient. There were no deaths. Left ventricular function recovered in all but one of the patients, and all patients had a reduction in the degree of mitral regurgitation. Among the variety of surgical techniques, transfer of the anomalous left coronary artery to the aorta is the ideal method for long-term patency and adequate blood supply. This can be achieved by creating flaps based on the walls of the pulmonary trunk and aorta, producing a dual coronary arterial supply with no mortality and low morbidity.


Diagnostic orphans: comparing self-report lifetime course to groups with DSM-IV alcohol abuse and dependence.
Research has highlighted the significant alcohol symptoms and mental health problems experienced by diagnostic orphans - individuals who experience 1-2 criteria of DSM-IV alcohol dependence but do not meet the criteria for a DSM-IV alcohol use disorder. This study used a sub-sample (n=34827) from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), and formed mutually exclusive groups to compare the self-report retrospective course of diagnostic orphans to individuals with DSM-IV abuse and dependence. Multinomial logistic regressions were conducted to examine the associations between the groups and a range of demographic and clinical variables. Collectively, the findings demonstrate that diagnostic orphans shared similar characteristics to the abuse and dependence groups, but appeared to experience specific comorbid mental health problems. Orphan status has the potential to be a persistent condition and may result in significant dysfunction. In conclusion, diagnostic orphans represent a distinct group that may benefit from cost-effective treatment or intervention, designed to prevent the escalation of alcohol symptoms.


Generation of live rat offspring by intrauterine insemination with epididymal spermatozoa cryopreserved at -196 degrees C.
This study reports the development of a reliable method for cryopreservation of rat epididymal spermatozoa and the production of live young by artificial insemination using these cryopreserved spermatozoa. The motility and membrane integrity of rat spermatozoa were investigated after spermatozoa had been subjected to physical stress and frozen with various concentrations of glycerol (0, 3 and 6%) either in the presence or absence of Equex Stem as cryoprotective agents. The ability of cryopreserved spermatozoa to generate normal offspring by intrauterine insemination was also evaluated. Rat spermatozoa that had been centrifuged at 700 g for 5 min showed a significant decrease in motility compared with non-centrifuged spermatozoa. In addition, after centrifugation three times the percentage of membrane-intact spermatozoa decreased to approximately 0%. The percentage of membrane-intact spermatozoa was significantly higher (P < 0.01) in semen samples that had been frozen in medium without glycerol than in samples frozen in medium with 3% glycerol. Although the addition of 0.7% Equex Stem to medium without glycerol or with 3% glycerol did not influence rates of sperm motility after freezing and thawing, the percentage of membrane-intact spermatozoa was improved by the presence of 0.7% Equex (P < 0.05). Therefore, rat spermatozoa were handled gently to avoid physical stress and were frozen in medium containing 23% egg yolk, 8% lactose monohydrate and 0.7% Equex Stem, at pH 7.4 adjusted with 10% Tris(hydroxymethyl)aminomethane solution. Thirteen female rats were inseminated into the oviductal end of both uterine horns with frozen-thawed spermatozoa. Forty-one normal live offspring were obtained from nine of the inseminated females. These results indicate that frozen-thawed rat spermatozoa can generate normal offspring. To our knowledge, this procedure is the first successful production of offspring using spermatozoa cryopreserved in liquid nitrogen.


Adsorption of CO(2), CH(4), N(2)O, and N(2) on MOF-5, MOF-177, and zeolite 5A.
Adsorption equilibrium and kinetics of CO(2), CH(4), N(2)O, and N(2) on two newly discovered adsorbents, metal-organic frameworks MOF-5 and MOF-177 and one traditional adsorbent, zeolite 5A were determined to assess their efficacy for CO(2), CH(4), and N(2)O removal from air and separation of CO(2) from CH(4) in pressure swing adsorption processes. Adsorption equilibrium and kinetics data for CO(2), CH(4), N(2)O, and N(2) on all three adsorbents were measured volumetrically at 298K and gas pressures up to 800 Torr. Adsorption equilibrium capacities of CO(2) and CH(4) on all three adsorbents were determined gravimetrically at 298 K and elevated pressures (14 bar for CO(2) and 100 bar for CH(4)). The Henry's law and Langmuir adsorption equilibrium models were applied to correlate the adsorption isotherms, and a classical micropore diffusion model was used to analyze the adsorption kinetic data. The adsorption equilibrium selectivity was calculated from the ratio of Henry's constants, and the adsorbent selection parameter for pressure swing adsorption processes were determined by combining the equilibrium selectivity and working capacity ratio. Based on the selectivity and adsorbent selection parameter results, zeolite 5A is a better adsorbent for removing CO(2) and N(2)O from air and separation of CO(2) from CH(4), whereas MOF-177 is the adsorbent of choice for removing CH(4) from air. However, both MOF adsorbents have larger adsorption capacities for CO(2) and CH(4) than zeolite 5A at elevated pressures, suggesting MOF-5 and MOF-177 are better adsorbents for CO(2) and CH(4) storage. The CH(4) adsorption capacity of 22 wt.% on MOF-177 at 298K and 100 bar is probably the largest adsorption uptake of CH(4) on any dry adsorbents. The average diffusivity of CO(2), CH(4) and N(2)O in MOF-5 and MOF-177 is in the order of 10(-9) m(2)/s, as compared to 10(-11) m(2)/s for CO(2), CH(4) and N(2)O in zeolite 5A. The effects of gas pressure on diffusivity for different adsorabte-adsorbent systems were also investigated.


The burden of pediatric status epilepticus: Epidemiology, morbidity, mortality, and costs.
To summarize the epidemiology, morbidity, mortality, and costs of status epilepticus (SE) in the pediatric population. Review of the medical literature. The overall incidence of pediatric SE is roughly 20 per 100,000 children per year, with overall mortality of 3%. Underlying etiology is the biggest risk factor for SE, with symptomatic (acute > remote) etiologies associated with worse outcomes. The most common cause of SE in children is febrile SE, though this entity occurs primarily in early childhood. After a first episode, the risk of recurrence is similar to the risk after a first unprovoked seizure (25-40%). SE is expensive, regularly costing more than $10,000 per episode and often more than $100,000 for refractory cases. SE is not an uncommon neurologic emergency and depending on the associated etiology can carry significant morbidity, mortality, and cost especially if treatment is not performed in a timely manner.


Remission of Gilles de la Tourette Syndrome after Heat-Induced Dehydration.
Heat has been reported to exert variable effects on people with Gilles de la Tourette syndrome (TS). At age 24 years, a 32-year-old right-handed man with TS experienced a marked reduction in tics for two years after undergoing dehydration by entering a hot tub at 103°F (39.4°C) to 104°F (40.0°C) for 3 to 4 hours. On the Yale Global Tic Severity Scale (YGTSS) he scored 55 seven months before dehydration and 13 one month after dehydration. An intense heat exposure and dehydration led to an apparent remission in tics. The remission continued without the use of prescribed or nonprescribed medications or substances for two years until tics returned in the worst ever exacerbation after a tetanus immunization. The heat exposure may have altered at least temporarily his thermostat for normal heat-loss mechanisms through dopaminergic pathways from the anterior hypothalamus to the basal ganglia and the substantia nigra. Whether or not that mechanism or some other mechanism relevant to the heat exposure and/or dehydration is at play, the sudden and marked improvement in his tics needs further attention. Prospective testing of the heat and dehydration effect on tics should be pursued.


Early time-locked gamma response and gender specificity.
The aim was to investigate whether gender is a causative factor in the gamma status according to which some individuals respond with time-locked, early gamma response, G+, while the others do not show this response, G-. The sample consisted of 42 volunteer participants (between 19 and 37 years of age with at least 9 years of education). There were 22 females and 20 males. Data were collected under the oddball paradigm. Auditory stimulation (10 ms r/f time, 50 ms duration, 65 dB SPL) consisted of target (2000 Hz; p = .20) stimuli that occurred randomly within a series of standard stimuli (1000 Hz; p = .80). Gamma responses were studied in the amplitude frequency characteristics, in the digitally filtered event-related potentials (f-ERPs) and in the distributions which were obtained using the recently developed time-frequency component analysis (TFCA) technique. Participants were classified into G+ and G- groups with a criterion of full agreement between the results of an automated gamma detection technique and expert opinion. The 2 x 2 x 2 ANOVA on f-ERPs and 2 x 2 x 2 multivariate ANOVA on TFCA distributions showed the main effect of gamma status and gender as significant, and the interaction between gamma status and gender as nonsignificant. Accordingly, individual difference in gamma status is a reliable phenomenon, but this does not depend on gender. There are conflicting findings in the literature concerning the effect of gender on ERP components (N100, P300). The present study showed that if the gamma status is not included in research designs, it may produce a confounding effect on ERP parameters.


Effects of Kinesio taping on scapular kinematics of overhead athletes following muscle fatigue.
Scapular kinematics alterations have been found following muscle fatigue. Considering the importance of the lower trapezius in coordinated scapular movement, this study aimed to investigate the effects of elastic taping (Kinesio taping, KT) for muscle facilitation on scapular kinematics of healthy overhead athletes following muscle fatigue. Twenty-eight athletes were evaluated in a crossover, single-blind, randomized design, in three sessions: control (no taping), KT (KT with tension) and sham (KT without tension). Scapular tridimensional kinematics and EMG of clavicular and acromial portions of upper trapezius, lower trapezius and serratus anterior were evaluated during arm elevation and lowering, before and after a fatigue protocol involving repetitive throwing. Median power frequency decline of serratus anterior was significantly lower in KT session compared to sham, possibly indicating lower muscle fatigue. However, the effects of muscle fatigue on scapular kinematics were not altered by taping conditions. Although significant changes were found in scapular kinematics following muscle fatigue, they were small and not considered relevant. It was concluded that healthy overhead athletes seem to present an adaptive mechanism that avoids the disruption of scapular movement pattern following muscle fatigue. Therefore, these athletes do not benefit from the use of KT to assist scapular movement under the conditions tested.


Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.
Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).


Mechanisms of inhibition in cat visual cortex.
1. Neurones from layers 2-6 of the cat primary visual cortex were studied using extracellular and intracellular recordings made in vivo. The aim was to identify inhibitory events and determine whether they were associated with small or large (shunting) changes in the input conductance of the neurones. 2. Visual stimulation of subfields of simple receptive fields produced depolarizing or hyperpolarizing potentials that were associated with increased or decreased firing rates respectively. Hyperpolarizing potentials were small, 5 mV or less. In the same neurones, brief electrical stimulation of cortical afferents produced a characteristic sequence of a brief depolarization followed by a long-lasting (200-400 ms) hyperpolarization. 3. During the response to a stationary flashed bar, the synaptic activation increased the input conductance of the neurone by about 5-20%. Conductance changes of similar magnitude were obtained by electrically stimulating the neurone. Neurones stimulated with non-optimal orientations or directions of motion showed little change in input conductance. 4. These data indicate that while visually or electrically induced inhibition can be readily demonstrated in visual cortex, the inhibition is not associated with large sustained conductance changes. Thus a shunting or multiplicative inhibitory mechanism is not the principal mechanism of inhibition.


No Impact of Body Mass Index on Outcome in Stroke Patients Treated with IV Thrombolysis BMI and IV Thrombolysis Outcome.
The impact of excess body weight on prognosis after stroke is controversial. Many studies report higher survival rates in obese patients ("obesity paradox"). Recently, obesity has been linked to worse outcomes after intravenous (IV) thrombolysis, but the number and sample size of these studies were small. Here, we aimed to assess the relationship between body weight and stroke outcome after IV thrombolysis in a large cohort study. In a prospective observational multicenter study, we analyzed baseline and outcome data of 896 ischemic stroke patients who underwent IV thrombolysis. Patients were categorized according to body mass index (BMI) as underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-34.9 kg/m2) or severely obese (>35 kg/m2). Using uni- and multivariate modeling, we assessed the relationship of BMI with favorable outcome (defined as modified Rankin Scale 0 or 1) and mortality 3 months after stroke as well as the occurrence of symptomatic intracerebral hemorrhages (sICH). We also measured the incidence of patients that had an early neurological improvement of >40% on the National Institutes of Health Stroke Scale (NIHSS) after 24 hours. Among 896 patients, 321 were normal weight (35.8%), 22 underweight (2.5%), 378 overweight (42.2%), 123 obese (13.7%) and 52 severely obese (5.8%). Three-month mortality was comparable in obese vs. non-obese patients (8.1% vs. 8.3%) and did not differ significantly among different BMI groups. This was also true for favorable clinical outcome, risk of sICH and early neurological improvement on NIHSS at 24 hours. These results remained unchanged after adjusting for potential confounding factors in the multivariate analyses. BMI was not related to clinical outcomes in stroke patients treated with IVT. Our data suggest that the current weight-adapted dosage scheme of IV alteplase is appropriate for different body weight groups, and challenge the existence of the obesity paradox after stroke.


Pan-cancer detection of driver genes at the single-patient resolution.
Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions. We present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways. sysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types ( https://github.com/ciccalab/sysSVM2 ).


Osteolytic changes around biodegradable cement restrictors in hip surgery.
Background and purpose - Biodegradable cement restrictors are widely used in hip arthroplasty. Like others, we observed osteolytic reactions associated with a specific cement restrictor (SynPlug; made of PolyActive) and reviewed our patients. Patients and methods - We identified 703 patients with suitable radiographs from our database (2007 to 2012) who underwent cemented hip arthroplasty and received a SynPlug biodegradable cement restrictor. We reviewed all available radiographs to determine the incidence, severity, and progression of osteolysis. Mean postoperative follow-up was 1.8 (1-7) years Results - 1 year after implantation, the femoral cortex showed thinning by 12% in the anterior-posterior view and by 8% in the axial view. This had increased to 14% and 12%, respectively, at the latest available follow-up postoperatively (at a mean of 4 years). Cortical thinning of less than 10% was found in 37% of patients, but cortical thinning of 10-30% was found in 56% of patients. In the remaining 7%, a reduction of more than 30% of the original cortical thickness was observed. Interpretation - Osteolytic changes associated with the SynPlug biodegradable bone restrictors are inconsistent and highly variable. While some patients showed increased weakening of the femoral cortex with the potential risk of periprosthetic fracture, in others the degree of osteolysis only increased slightly or stabilized after 2 or more years. Any cortical bone loss after total hip replacement should be avoided, so the use of PolyActive biodegradable cement restrictors should be discontinued. Patients with a PolyActive cement restrictor in place should be followed up closely after surgery.


Microwave photonic signal processing.
Photonic signal processing offers the advantages of large time-bandwidth capabilities to overcome inherent electronic limitations. In-fibre signal processors are inherently compatible with fibre optic microwave systems that can integrate with wireless antennas, and can provide connectivity with in-built signal conditioning and electromagnetic interference immunity. Recent methods in wideband and adaptive signal processing, which address the challenge of realising programmable microwave photonic phase shifters and true-time delay elements for phased array beamforming; ultra-wideband Hilbert transformers; single passband, widely tunable, and switchable microwave photonic filters; and ultra-wideband microwave photonic mixers, are described. In addition, a new microwave photonic mixer structure is presented, which is based on using the inherent frequency selectivity of the stimulated Brillouin scattering loss spectrum to suppress the carrier of a dual-phase modulated optical signal. Results for the new microwave photonic mixer demonstrate an extremely wide bandwidth operation of 0.2 to 20 GHz and a large conversion efficiency improvement compared to the conventional microwave photonic mixer.


Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy.
Quantitative NMRI and (31)P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6-18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia ) and an alkaline (Pib) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2 . Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78-100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2 . However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy.


Granulins: the structure and function of an emerging family of growth factors.
The granulin/epithelin motif defines a family of structurally unique proteins, of great evolutionary antiquity, which have been implicated as regulators of cell growth. Recurrent in granulin research are the surprising parallels between the granulin and EGF systems. Both are cysteinerich peptides of approximately 6 kDa that can modify cell growth. They show similar, but not identical, biological activities, although granulin/epithelin peptides do not bind EGF receptors; the three-dimensional folds of granulin and EGF are partially superimposible; and the precursors for mammalian granulin/epithelins and EGF are both organized as multiple repeats of conserved cysteine modules. Given the dissimilarity between amino acid sequences of members of the granulin/epithelin family and EGF-related peptides, the parallelism between the two systems probably represents convergent evolution towards related solutions to common biological problems. The granulin/epithelin precursor gene is expressed throughout the body, but its expression is predominantly in epithelial and haematopoietic cells. There is a great deal of versatility in the means by which cells process and handle the granulin/epithelin precursor. In some instances, the precursor is secreted intact (Zhou et al. 1993), and in others it is stored in a vesicular organelle, such as the sperm acrosome (Baba et al. 1993a). It may be processed into small 6-kDa peptides, which, in the neutrophil, can also be stored in vesicles (Bateman et al. 1990, Couto et al. 1992). The 6-kDa peptide forms, the intact precursor, and related proteins such as TGFe, regulate the growth of epithelial and mesenchymal cells. Epithelial cells express putative receptors for granulin/epithelin peptides and TGFe (Culouscou et al. 1993, Parnell et al. 1995). Thus, although much remains to be clarified, granulin/epithelin polypeptides and related proteins are emerging as widely distributed potential autocrine and paracrine growth modulating factors for epithelial and mesenchymal cells.


New functionality of chalcogenide glasses for radiation sensing of nuclear wastes.
Data about gamma radiation induced effects in Ge40Se60 chalcogenide thin films and radiation induced silver diffusion within these are presented. Blanket films and devices were created to study the structural changes, diffusion products, and device performance. Raman spectroscopy, X-ray diffraction, current vs. voltage (I-V) and impedance measurements expound the behavior of Ge40Se60 glass and silver diffusion within this glass under radiation. Raman study shows that there is a decrease in the area ratio between edge shared and corner shared structural units revealing structural reorganization occurring in the glasses as a result of gamma radiation. X-ray diffraction studies revealed that with sufficiently radiation dose it is also possible to create Ag2Se in selenium-depleted systems. Oxidation of the Ge enriched chalcogenide backbone is confirmed through the electrical performance of the sensing elements based on these films. Combination of these structural and diffusion products influences the device performance. The I-V behavior is characterized by increase in current and then stabilization as a function of radiation dose. Additionally, device modeling is also presented using Silvaco software and analytical methods to shed light on the device behavior. This type of sensor design and material characterizations facilitate in improving the radiation sensing capabilities of silver containing chalcogenide glass thin films.


Status of paratyphoid fever vaccine research and development.
Salmonella enterica serovars Typhi and Paratyphi (S. Paratyphi) A and B cause enteric fever in humans. Of the paratyphoid group, S. Paratyphi A is the most common serovar. In 2000, there were an estimated 5.4 million cases of S. Paratyphi A worldwide. More recently paratyphoid fever has accounted for an increasing fraction of all cases of enteric fever. Although vaccines for typhoid fever have been developed and in use for decades, vaccines for paratyphoid fever have not yet been licensed. Several S. Paratyphi A vaccines, however, are in development and based on either whole cell live-attenuated strains or repeating units of the lipopolysaccharide O-antigen (O:2) conjugated to different protein carriers. An O-specific polysaccharide (O:2) of S. Paratyphi A conjugated to tetanus toxoid (O:2-TT), for example, has been determined to be safe and immunogenic after one dose in Phase I and Phase II trials. Two other conjugated vaccine candidates linked to diphtheria toxin and a live-attenuated oral vaccine candidate are currently in preclinical development. As promising vaccine candidates are advanced along the development pipeline, an adequate supply of vaccines will need to be ensured to meet growing demand, particularly in the most affected countries.


Treatments of 1242 bulbar urethral strictures: multivariable statistical analysis of results.
We investigated the success rate of different surgical techniques for bulbar stricture repair. Retrospective study of patients with bulbar urethral strictures treated using different techniques. The primary outcome of the study was to evaluate the overall results of treatment (success vs. failure); the secondary outcome was to evaluate the outcome according to any surgical technique. Cysto-urethrography was performed 1 month following surgery. Patients underwent clinical evaluation, uroflowmetry and residual urine measurement every 6 months for 2 years after surgery and later once on year. When patient showed obstructive symptoms, Qmax < 12 ml/s, the urethrography was repeated. Patients who underwent further treatment for recurrent stricture were classified as failures. A bivariable and multivariable statistical analysis was performed. Overall, 1242 patients were included in the study with mean age 40 years (range 12-84). Median stricture length was 4 cm (range 1-8). The median follow-up was 103 months (range 12-362). Over 1242 patients, 916 (73.8%) were success and 326 (26.2%) failures. Fourteen different surgical techniques showed a success rate ranging from 87.5 to 14.3%. The multivariable analysis showed that stricture length was an independent predictor factors for failure: p < 0.0001 CI 1146-1509. End-end anastomosis and oral mucosa graft urethroplasty are independent predictor factor of success after internal urethrotomy failure. Our results showed that treatment of bulbar urethral stricture is satisfactory on 73.8% of patients, but with a wide range of success rate (from 14.3 to 87.5%) using different techniques. Oral mucosa is greatly superior to the skin as substitute material.


Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis.
Gastroparesis can lead to food aversion, poor oral intake, and subsequent malnutrition. We characterized dietary intake and nutritional deficiencies in patients with diabetic and idiopathic gastroparesis. Patients with gastroparesis on oral intake (N = 305) were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry and completed diet questionnaires at 7 centers. Medical history, gastroparesis symptoms, answers to the Block Food Frequency Questionnaire, and gastric emptying scintigraphy results were analyzed. Caloric intake averaged 1168 ± 801 kcal/day, amounting to 58% ± 39% of daily total energy requirements (TER). A total of 194 patients (64%) reported caloric-deficient diets, defined as <60% of estimated TER. Only 5 patients (2%) followed a diet suggested for patients with gastroparesis. Deficiencies were present in several vitamins and minerals; patients with idiopathic disorders were more likely to have diets with estimated deficiencies in vitamins A, B(6), C, K, iron, potassium, and zinc than diabetic patients. Only one-third of patients were taking multivitamin supplements. More severe symptoms (bloating and constipation) were characteristic of patients who reported an energy-deficient diet. Overall, 32% of patients had nutritional consultation after the onset of gastroparesis; consultation was more likely among patients with longer duration of symptoms and more hospitalizations and patients with diabetes. Multivariable logistic regression analysis indicated that nutritional consultation increased the chances that daily TER were met (odds ratio, 1.51; P = .08). Many patients with gastroparesis have diets deficient in calories, vitamins, and minerals. Nutritional consultation is obtained infrequently but is suggested for dietary therapy and to address nutritional deficiencies.


Visualization of regional tau deposits using (3)H-THK5117 in Alzheimer brain tissue.
The accumulation of neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein, starts spreading early in specific regions in the course of Alzheimer's disease (AD), correlating with the progression of memory dysfunction. The non-invasive imaging of tau could therefore facilitate the early diagnosis of AD, differentiate it from other dementing disorders and allow evaluation of tau immunization therapy outcomes. In this study we characterized the in vitro binding properties of THK5117, a tentative radiotracer for positron emission tomography (PET) imaging of tau brain deposits. Saturation and competition binding studies of (3)H-THK5117 in post-mortem AD brain tissue showed the presence of multiple binding sites. THK5117 binding was significantly higher in hippocampal (p < 0.001) and temporal (p < 0.01) tissue homogenates in AD compared to controls. Autoradiography studies with (3)H-THK5117 was performed on large frozen brain sections from three AD cases who had been followed clinically and earlier undergone in vivo (18)F-FDG PET investigations. The three AD cases showed distinct differences in regional THK5117 binding that were also observed in tau immunohistopathology as well as in clinical presentation. A negative correlation between in vivo (18)F-FDG PET and in vitro (3)H-THK5117 autoradiography was observed in two of the three AD cases. This study supports that new tau PET tracers will provide further understanding on the role of tau pathology in the diversity of the clinical presentation in AD.


Infants with late breast milk acquisition of HIV-1 generate interferon-gamma responses more rapidly than infants with early peripartum acquisition.
Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8(+) T lymphocyte secretion of interferon (IFN)-gamma in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-gamma responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-gamma responses was compared using the log-rank test and Kaplan-Meier survival curves. Infants infected late developed HIV-1-specific CD8(+) T cell responses 2.8 months sooner than infants infected peripartum: 2.3 versus 5.1 months after HIV-1 infection (n = 52, P = 0.04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0.03); however, there were no differences in the strength of IFN-gamma responses. In infants infected with HIV-1 after the first month of life, emergence of HIV-1-specific CD8(+) IFN-gamma responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in early-infected infants.


Redox-mediated formation of plutonium oxide nanoparticles.
Precipitates formed by the neutralisation of Pu(iii), Pu(iv), Pu(v), and Pu(vi) solutions were characterised by HRTEM, SAXS, and XRD in the suspensions. PuO2 nanoparticles uniform in size (typical diameter around 2.5 nm) and phase composition were observed in all cases under equilibrium conditions. For Pu(vi), the precipitation reactions proceed via an intermediate product.


Optical spatial solitons at the interface between two dissimilar periodic media: theory and experiment.
Discrete spatial solitons traveling along the interface between two dissimilar one-dimensional arrays of waveguides were observed for the first time. Two interface solitons were found theoretically, each one with a peak in a different boundary channel. One evolves into a soliton from a linear mode at an array separation larger than a critical separation where-as the second soliton always exhibits a power threshold. These solitons exhibited different power thresholds which depended on the characteristics of the two lattices. For excitation of single channels near and at the boundary, the evolution behavior with propagation distance indicates that the solitons peaked near and at the interface experience an attractive potential on one side of the boundary, and a repulsive one on the opposite side. The power dependence of the solitons at variable distance from the boundary was found to be quite different on opposite sides of the interface and showed evidence for soliton switching between channels with increasing input power.


Synthesis of α-hydroxy ketones and vicinal (R,R)-diols by Bacillus clausii DSM 8716T butanediol dehydrogenase.
α-hydroxy ketones (HK) and 1,2-diols are important building blocks for fine chemical synthesis. Here, we describe the R-selective 2,3-butanediol dehydrogenase from B. clausii DSM 8716T (BcBDH) that belongs to the metal-dependent medium chain dehydrogenases/reductases family (MDR) and catalyzes the selective asymmetric reduction of prochiral 1,2-diketones to the corresponding HK and, in some cases, the reduction of the same to the corresponding 1,2-diols. Aliphatic diketones, like 2,3-pentanedione, 2,3-hexanedione, 5-methyl-2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione are well transformed. In addition, surprisingly alkyl phenyl dicarbonyls, like 2-hydroxy-1-phenylpropan-1-one and phenylglyoxal are accepted, whereas their derivatives with two phenyl groups are not substrates. Supplementation of Mn2+ (1 mM) increases BcBDH's activity in biotransformations. Furthermore, the biocatalytic reduction of 5-methyl-2,3-hexanedione to mainly 5-methyl-3-hydroxy-2-hexanone with only small amounts of 5-methyl-2-hydroxy-3-hexanone within an enzyme membrane reactor is demonstrated.


CAMP and Ca2+ interplay: a matter of oscillation patterns.
Ca(2+) and cAMP signalling pathways are tightly interconnected and the cellular effects mediated by the two second messengers depend strictly on reciprocal modulation. The signalling network that derives from such interplay holds the potential for expanding the information content of the signal enormously and, thus, can contribute substantially to the specificity and diversity of the response. Recent work points to interdependent Ca(2+) and cAMP oscillation patterns as a new paradigm for signal transduction.


Impact of preterm birth on brain development and long-term outcome: protocol for a cohort study in Scotland.
Preterm birth is closely associated with altered brain development and is a leading cause of neurodevelopmental, cognitive and behavioural impairments across the life course. We aimed to investigate neuroanatomic variation and adverse outcomes associated with preterm birth by studying a cohort of preterm infants and controls born at term using brain MRI linked to biosamples and clinical, environmental and neuropsychological data. Theirworld Edinburgh Birth Cohort is a prospective longitudinal cohort study at the University of Edinburgh. We plan to recruit 300 infants born at <33 weeks of gestational age (GA) and 100 healthy control infants born after 37 weeks of GA. Multiple domains are assessed: maternal and infant clinical and demographic information; placental histology; immunoregulatory and trophic proteins in umbilical cord and neonatal blood; brain macrostructure and microstructure from structural and diffusion MRI (dMRI); DNA methylation; hypothalamic-pituitary-adrenal axis activity; social cognition, attention and processing speed from eye tracking during infancy and childhood; neurodevelopment; gut and respiratory microbiota; susceptibility to viral infections; and participant experience. Main analyses include creation of novel methods for extracting information from neonatal structural and dMRI, regression analyses of predictors of brain maldevelopment and neurocognitive outcome associated with preterm birth, and determination of the quantitative predictive performance of MRI and other early life factors for childhood outcome. Ethical approval has been obtained from the National Research Ethics Service (NRES), South East Scotland Research Ethics Committee (NRES numbers 11/55/0061 and 13/SS/0143 (phase I) and 16/SS/0154 (phase II)), and NHS Lothian Research and Development (2016/0255). Results are disseminated through open access journals, scientific meetings, social media, newsletters anda study website (www.tebc.ed.ac.uk), and we engage with the University of Edinburgh public relations and media office to ensure maximum publicity and benefit.


Globin synthesis in mouse erythroleukemia cells in vitro: a switch in beta chains due to inducing agent.
Friend erythroleukemia cells, originally derived from DBA/2 mice, differentiate when cultured with inducing agents. Studies of the different effects of inducing agents on clone 745 have revealed that both dimethyl sulfoxide (DMSO) and hemin produce benzidine-positive cells. Butyric acid produced mature but benzidine-negative cells in this clone. All agents induced globin synthesis above the 0.1% of protein synthesis found in uninduced cells. DMSO induction stimulated globin synthesis 9%, hemin 2%, and butyric acid 3%. Total beta/alpha ratios were approximately unity with all agents. Although the inducing agents all stimulated total globin synthesis in Friend cells, the relative rates of synthesis of the two mouse beta chains were affected differently by the various agents. Hemin markedly increased the proportion of beta minor. For example, DBA/2 mouse reticulocytes synthesized 20% beta minor and 80% beta major. DMSO induction of clone 745 caused 20%-33% synthesis of beta minor. In contrast, hemin increased the proportion of beta minor to 64%-69%. Thus the Friend erythroleukemia cell system provides an in vitro approach to the study of the regulation of globin-chain switching.


Different contribution of the lateral bed nucleus of the stria terminalis in intrahippocampal neostigmine-induced elevation of plasma glucose and adrenocorticotropic hormone in free moving rats.
In our previous study, a lesion in the lateral bed nucleus of the stria terminalis (BNSTL) was found to significantly attenuate the elevation of adrenocorticotropic hormone (ACTH) in plasma during microinjectin of neostigmine, an inhibitor of acetylcholine esterase, into the rat hippocampus. The current study was designed to examine the role of the BNSTL in regulation of blood glucose elevation induced by hippocampal neostigmine injection. Ibotenic acid (15 microg/microl) was stereotaxically bilaterally injected into the BNSTL of rats. Two weeks after the injections, neostigmine methylsulfate (sigma, 5 x 10-8 mol) was microinjected into the rat hippocampus in a volume of 1 microl for 1 min using a CMA/100 microinjection pump. Plasma ACTH and glucose concentrations were examined using radioimmunoassay and immobilized enzyme casing/H2O2 method techniques, respectively. Compared with sham-operated control rats, rats with BNSTL lesions produced by ibotenic acid showed significantly attenuated the elevations of plasma ACTH evoked by the microinjection of neostigmine into the hippocampus. However, no significant difference of blood glucose in response to the injection was observed between the BNSTL-lesioned rats and controls. The results of the present study indicate that the BNSTL plays a role in ACTH regulation and not in blood glucose regulation when the hippocampal cholinergic system is activated.


[Indication of gastrojejunostomy in unresectable pancreatic cancer].
Up to 20% of patients with pancreatic carcinoma subjected to a bilio digestive diversion, develop a delayed gastric emptying due to duodenal infiltration. However the role of prophylactic gastrojejunoanastomosis is not well defined. To compare the effects of gastrojejunoanastomosis performed as prophylaxis or as treatment for duodenal infiltration, in patients with unresectable pancreatic carcinoma. Between 1983 and 1994, 44 gastrojejunoanastomosis were performed in patients with pancreatic carcinoma. In 24 patients the procedure was done as prophylaxis and in 20 as treatment of duodenal infiltration. Of these, three had been subjected previously to a bilio digestive diversion. Postoperative outcome and mortality of both groups of patients were compared. Both groups of patients had similar sex and age. Operative morbidity and mortality were 33% and 0% in the group with the prophylactic procedure and 35 and 10% in the group with duodenal infiltration. Oral feeding was started 6.5 and 6.9 days after operation, and hospital stay was 10.7 and 11.4 days in either group. At the moment of the analysis, 95.5% of patients had died. Survival was significantly longer in the group with the prophylactic procedure (337.2 and 116.9 days respectively, p < 0.01). Thirty eight percent of patients required a further admission to the hospital, but only 4.8% due to gastric retention. Gastrojejunoanastomosis is a good palliative procedure in patients with unresectable pancreatic carcinoma. It should be performed in every such patient who is subjected to a bilio digestive diversion and in whom a survival of some months can be predicted.


Quantification of parapapillary atrophy and optic disc.
A computer-aided measuring tool was devised to automatically detect and quantify both the parapapillary atrophy (PPA) and the optic disc (OD) regions in two-dimensional color fundus images of the retina. The OD region was segmented using the Chan-Vese model with a shape restraint. This region was then removed from the image (OD+PPA), which was cropped in a modified Chan-Vese approach, producing a first-order estimation of the PPA region. Its boundary is subsequently refined by using thresholding, a scanning filter, and multiseed region-growing methods. Dual channels (blue and red) in the red-green-blue space are used to minimize the interference effects of blood vessels and artifacts. The software was tested on 94 randomly selected images of eyes with PPA from 66 subjects of a well-characterized cohort database. Our proposed algorithm achieved a mean accuracy level of 93.8% (SD 5.26) and 94.0% (SD 5.88) in estimating the size of the PPA and OD respectively, compared with the ground estimate defined by an ophthalmologist. In terms of correlation between the data of the ground estimate and our estimation, we obtained a correlation coefficient of 0.98 for both the PPA and the OD. This software offers a means of quantifying the size of PPA on two-dimensional fundus images for the first time. The proposed algorithm is capable of detecting and quantifying PPA and OD regions repeatedly, with a mean accuracy of >93%, and could also provide additional information, such as the transverse and conjugate diameter of OD, which may be useful in eye-screening.


Spatial patterns in ant colonies.
The origins of large-scale spatial patterns in biology have been an important source of theoretical speculation since the pioneering work by Turing (1952) on the chemical basis of morphogenesis. Knowing how these patterns emerge and their functional role is important to our understanding of the evolution of biocomplexity and the role played by self organization. However, so far, conclusive evidence for local activation-long-range inhibition mechanisms in real biological systems has been elusive. Here a well-defined experimental and theoretical analysis of the pattern formation dynamics exhibited by clustering behavior in ant colonies is presented. These experiments and a simple mathematical model show that these colonies do indeed use this type of mechanism. All microscopic variables have been measured and provide the first evidence, to our knowledge, for this type of self-organized behavior in complex biological systems, supporting early conjectures about its role in the organization of insect societies.


Biodegradable stimuli-responsive polypeptide materials prepared by ring opening polymerization.
The stimuli-responsive polypeptides have drawn extensive attention because of their promising applications in biotechnology considering their biocompatibility, biodegradability, and bioactivity. In this tutorial review, we summarize the most recent progress in this area, including thermo-, redox-, photo-, and biomolecule responsive polypeptides over the past decade. The design and synthesis of stimuli-responsive polypeptides will be briefly introduced. The correlation between the structure and properties, particularly the effects of polypeptide conformation, will be emphasized here. In addition, the applications of stimuli-responsive polypeptides in controlled drug release and tissue engineering are briefly discussed.


Ethical questions identified in a study of local and expatriate responders' perspectives of vulnerability in the 2010 Haiti earthquake.
Situations of disaster that prompt international humanitarian responses are rife with ethical tensions. The 2010 Haiti earthquake caused great destruction and prompted a massive humanitarian response. The widespread needs experienced by the population and the scale of the response inevitably rendered priority-setting difficult, and gave rise to ethical challenges. This paper presents four ethical questions identified in the analysis of a study on vulnerability and equity in the humanitarian response to the 2010 Haiti earthquake. Using interpretive description methodology, the interdisciplinary research team analysed 24 semi-structured in-depth interviews conducted with expatriate and Haitian health workers and decision-makers involved in the response. Ethical questions identified through the analysis were: (1) How should limited resources be allocated in situations of widespread vulnerability and elevated needs? (2) At what point does it become ethically problematic to expend (considerable) resources to sustain expatriate disaster responders? (3) How ought rapid and reactive interventions be balanced with more deliberated and coordinated approaches? (4) What trade-offs are justified when interventions to address acute needs could contribute to long-term vulnerabilities? The questions arise in light of an immense gap between available resources and widespread and elevated needs. This gap is likely unavoidable in large-scale crises and may be a source of ethical distress for both local and international responders. The analysis of ethical questions associated with crisis response can advance discussions about how relief efforts can best be designed and implemented to minimise ethical distress and improve assistance to local populations.


Chikungunya virus transmission potential by local Aedes mosquitoes in the Americas and Europe.
Chikungunya virus (CHIKV), mainly transmitted in urban areas by the mosquitoes Aedes aegypti and Aedes albopictus, constitutes a major public health problem. In late 2013, CHIKV emerged on Saint-Martin Island in the Caribbean and spread throughout the region reaching more than 40 countries. Thus far, Ae. aegypti mosquitoes have been implicated as the sole vector in the outbreaks, leading to the hypothesis that CHIKV spread could be limited only to regions where this mosquito species is dominant. We determined the ability of local populations of Ae. aegypti and Ae. albopictus from the Americas and Europe to transmit the CHIKV strain of the Asian genotype isolated from Saint-Martin Island (CHIKV_SM) during the recent epidemic, and an East-Central-South African (ECSA) genotype CHIKV strain isolated from La Réunion Island (CHIKV_LR) as a well-characterized control virus. We also evaluated the effect of temperature on transmission of CHIKV_SM by European Ae. albopictus. We found that (i) Aedes aegypti from Saint-Martin Island transmit CHIKV_SM and CHIKV_LR with similar efficiency, (ii) Ae. aegypti from the Americas display similar transmission efficiency for CHIKV_SM, (iii) American and European populations of the alternative vector species Ae. albopictus were as competent as Ae. aegypti populations with respect to transmission of CHIKV_SM and (iv) exposure of European Ae. albopictus to low temperatures (20°C) significantly reduced the transmission potential for CHIKV_SM. CHIKV strains belonging to the ECSA genotype could also have initiated local transmission in the new world. Additionally, the ongoing CHIKV outbreak in the Americas could potentially spread throughout Ae. aegypti- and Ae. albopictus-infested regions of the Americas with possible imported cases of CHIKV to Ae. albopictus-infested regions in Europe. Colder temperatures may decrease the local transmission of CHIKV_SM by European Ae. albopictus, potentially explaining the lack of autochthonous transmission of CHIKV_SM in Europe despite the hundreds of imported CHIKV cases returning from the Caribbean.


Intrinsic neural activity predisposes susceptibility to a body illusion.
Susceptibility to the rubber hand illusion (RHI) varies. To date, however, there is no consensus explanation of this variability. Previous studies, focused on the role of multisensory integration, have searched for neural correlates of the illusion. But those studies have failed to identify a sufficient set of functionally specific neural correlates. Because some evidence suggests that frontal α power is one means of tracking neural instantiations of self, we hypothesized that the higher the frontal α power during the eyes-closed resting state, the more stable the self. As a corollary, we infer that the more stable the self, the less susceptible are participants to a blurring of boundaries-to feeling that the rubber hand belongs to them. Indeed, we found that frontal α amplitude oscillations negatively correlate with susceptibility. Moreover, since lower frequencies often modulate higher frequencies, we explored the possibility that this might be the case for the RHI. Indeed, some evidence suggests that high frontal α power observed in low-RHI participants is modulated by δ frequency oscillations. We conclude that while neural correlates of multisensory integration might be necessary for the RHI, sufficient explanation involves variable intrinsic neural activity that modulates how the brain responds to incompatible sensory stimuli.


Cutting Edge: Allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B.
Although it is clear that KIR3DL1 recognizes Bw4(+) HLA-B, the role of Bw4(+) HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4(+) HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4(+) tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLA-A*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4(+) ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.


Description of a new actinosporean type from South African freshwaters.
Actinospore infection of oligochaetes collected from the mud of 2 freshwater biotopes in South Africa was studied. Using the 'cell-well plate method', a new aurantiactinomyxon type was found in 1.1% of the examined Branchiura sowerbyi oligochaete specimens from the Rietvlei River, north of Johannesburg, Gauteng, South Africa. In 1.5% of B. sowerbyi collected in a pond (Padda Dam), near the Rand Afrikaans University, Johannesburg, the same aurantiactinomyxon type was found. Infected oligochaetes were found only after collection and no actinosporean release was recorded in Branchiura specimens kept alive for several weeks. Actinospore infection showed a high intensity in oligochaetes in both positive cases. Until now, no actinosporean stages of myxosporeans have been described from South Africa. The aurantiactinospore type presented in this communication differs from the known types already described in the literature.


Pattern of central nervous system anomalies in a population with a high rate of consanguineous marriages.
Nine thousand six hundred and ten births were prospectively studied in the three major hospitals in Al-Ain, United Arab Emirates (UAE) between October 1995 and January 1997. Babies suspected of, or diagnosed, as having central nervous system (CNS) abnormalities were evaluated by a neonatologist, a clinical geneticist and a pediatric neurologist. Brain computerized tomography/magnetic resonance imaging (CT/MRI) was performed on all babies suspected of having CNS abnormalities. In addition, metabolic screening and chromosome analysis were also performed when indicated. Of the 225 babies with congenital anomalies identified, 31 had CNS abnormalities (3.2/1000). Syndromic abnormalities of the CNS were present in 13 cases (42%), chromosomal abnormalities in one case (3.2%) and the rest included: neural tube defect (NTD) in 11 cases (36%), holoprosencephaly in two cases (6.4%) and hydrocephalus in four cases (12.9%). Detailed analysis of the syndromic types revealed that out of the 13 cases, 12 were inherited as autosomal recessive (AR) and in one case the inheritance was undetermined. Consanguinity with high level of inbreeding was present in 12 cases and the majority of the syndromes identified were extremely rare. The study indicates that CNS anomalies are fairly common in the UAE, particularly, the recessive syndromic types. Careful and detailed analysis of such anomalies is required so that accurate genetic advice can be given.


How do I get out of this jam? Overcoming common intraoperative problems in primary total hip arthroplasty.
Prompt attention is typically required in managing intraoperative problems associated with total hip arthroplasty. There is often limited time for consultation or a review of the literature. The treating surgeon should be familiar with treatment options, favored treatment methods, and should be able to implement the most appropriate and optimal treatment for his or her patient. Common intraoperative complications associated with primary total hip arthroplasty include difficulty gaining sufficient exposure, problems with cup fixation, challenges with implant anteversion, intraoperative fracture of the femur, and difficulties with intraoperative limb length and hip instability.


Parsing the life-shortening effects of dietary protein: effects of individual amino acids.
High-protein diets shorten lifespan in many organisms. Is it because protein digestion is energetically costly or because the final products (the amino acids) are harmful? To answer this question while circumventing the life-history trade-off between reproduction and longevity, we fed sterile ant workers on diets based on whole proteins or free amino acids. We found that (i) free amino acids shortened lifespan even more than proteins; (ii) the higher the amino acid-to-carbohydrate ratio, the shorter ants lived and the lower their lipid reserves; (iii) for the same amino acid-to-carbohydrate ratio, ants eating free amino acids had more lipid reserves than those eating whole proteins; and (iv) on whole protein diets, ants seem to regulate food intake by prioritizing sugar, while on free amino acid diets, they seem to prioritize amino acids. To test the effect of the amino acid profile, we tested diets containing proportions of each amino acid that matched the ant's exome; surprisingly, longevity was unaffected by this change. We further tested diets with all amino acids under-represented except one, finding that methionine, serine, threonine and phenylalanine are especially harmful. All together, our results show certain amino acids are key elements behind the high-protein diet reduction in lifespan.


Symptoms of ill health ascribed to electromagnetic field exposure--a questionnaire survey.
From June 2001, health questionnaires were distributed to people who complained about symptoms of ill health which they ascribed to exposure to electromagnetic fields (EMF). The objective of the survey was to gain a better knowledge of the anxieties of complainants, to obtain hints of possible problems and of actions that should be taken to solve the problems. The survey was not designed to establish a causal association between exposure to EMF and symptoms of ill health. Within one year, 429 questionnaires were returned of which 394 persons reported symptoms. The average age of the complainants was 51.0 years and 57 percent were female. The complainants were older, had a higher educational level and were more likely to be married compared to the general Swiss population. A mean of 2.7 different symptoms were reported. Sleep disorders (58%), headaches (41%), nervousness or distress (19%), fatigue (18%), and concentration difficulties (16%) were most common complaints. Complainants related their symptoms most frequently to exposure to mobile phone base stations (74%), followed by mobile phones (36%), cordless phones (29%) and power lines (27%). No distinct symptoms related to a specific field source could be identified. Eighty-five percent of the people who consulted a public authority because of their symptoms were unsatisfied with the response, whereas consultation of self-help groups or building ecologists usually fulfilled expectations. Two thirds of complainants had taken some action to reduce their symptoms. The most common measure was to avoid exposure if possible. Removing or disconnecting indoor sources was judged to be the most effective action.


Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity.
MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.


Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.
Previously, hepatic iron overload resembling that in hereditary hemachromatosis (HH) has been found in beta 2-microglobulin knockout (beta 2m-/-) mice. We have now characterized iron metabolism in beta 2m-/- mice. The mutant mice fail to limit the transfer of iron from mucosal cells into the plasma. Transferrin saturation is abnormally high. Pathologic iron depositions occur predominantly in liver parenchymal cells. Reconstitution with normal hematopoietic cells redistributes the iron from parenchymal to Kupffer cells, but does not correct the mucosal defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m-/- mice; and (b) a beta 2m-dependent gene product is involved in iron homeostasis. Recently, a novel gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Our data provide functional support for the proposed causative role of HLA-H mutations in HH.


Effects of a memory-enhancing drug on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents and synaptic transmission in hippocampus.
The benzoylpiperidine drug BDP-12 (1-(quinoxalin-6-ylcarbonyl)piperidine) enhances the encoding of transient and stable forms of memory by rats. Results reported here show that the drug increases fast, excitatory (glutamatergic) synaptic responses in hippocampal slices by about 50% with an EC50 of 170 microM. Analyses with polysynaptic responses indicated that the drug has a facilitatory action at concentrations as low as 12.5 microM. BDP-12 at 1 mM did not change the resting membrane potential, input resistance or spiking threshold and it did not alter monosynaptic potentials mediated by gamma-aminobutyric acid (GABA) receptors; it did, however, enhance disynaptic inhibitory responses. In membrane patches excised from hippocampal neurons, BDP-12 at moderate concentrations (50 microM) increased the steady-state currents mediated by DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and slowed the rate at which the receptors desensitize, with a much larger effect on the former; the drug delayed the closing of the AMPA receptor channel after 1-msec agonist pulses. BDP-12 had no detectable effect on [3H]AMPA binding affinity. A related and more potent analog produced a different pattern of results in that it had about equal effects on steady-state currents and desensitization rates and significantly increased binding to AMPA receptors. These results indicate that the benzoylpiperidine family of modulators has functionally distinct subclasses. The findings also establish that BDP-12: 1) enhances synaptic responses in the same concentration range at which it alters AMPA receptor kinetics, 2) has a lower apparent threshold for effects on complex network operations than on monosynaptic transmission, 3) does not directly influence inhibitory responses and 4) is likely to modulate AMPA receptors on interneurons as well as on pyramidal neurons.


Primary biliary cirrhosis has high wait-list mortality among patients listed for liver transplantation.
Patients with primary sclerosing cholangitis (PSC) have frequent episodes of cholangitis with potential for high mortality while waiting for liver transplantation. However, data on wait-list mortality specific to liver disease etiology are limited. Using United Network for Organ Sharing (UNOS) database (2002-2013), of 81 592 listed patients, 11 284 (13.8%) died while waiting for transplant. Primary biliary cirrhosis (PBC) patients (N = 3491) compared to PSC (N = 4905) differed with age (56 vs. 47 years), female gender (88% vs. 33%), black race (6% vs. 13%), and BMI (25 vs. 27), P < 0.0001 for all. A total of 993 (11.8%) patients died while waiting for the transplant list. Using competing risk analysis controlling for baseline recipient factors and accounting for receipt of liver transplantation (LT), PBC compared to patients with PSC had higher overall and 3-month wait-list mortality (21.6% vs. 12.7% and 5.0% vs. 2.9%, respectively, Gray's test P < 0.001), [1.25 (1.07-1.47)]. Repeat analysis including all etiologies showed higher wait-list mortality for PBC compared to most etiologies, except for patients listed for diagnosis of alcoholic liver disease (ALD) + hepatitis C virus (HCV). Patients with PBC have high mortality while waiting for liver transplantation. These novel findings suggest that patients with PBC listed for LT may be considered for model for end-stage disease (MELD) exception points.


Sampling populations of humans across the world: ELSI issues.
There are an increasing number of population studies collecting data and samples to illuminate gene-environment contributions to disease risk and health. The rising affordability of innovative technologies capable of generating large amounts of data helps achieve statistical power and has paved the way for new international research collaborations. Most data and sample collections can be grouped into longitudinal, disease-specific, or residual tissue biobanks, with accompanying ethical, legal, and social issues (ELSI). Issues pertaining to consent, confidentiality, and oversight cannot be examined using a one-size-fits-all approach-the particularities of each biobank must be taken into account. It remains to be seen whether current governance approaches will be adequate to handle the impact of next-generation sequencing technologies on communication with participants in population biobanking studies.


Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function.
Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell-based therapies against chronic infectious diseases and cancer.


Design of a Continuous Blood Pressure Measurement System Based on Pulse Wave and ECG Signals.
With increasingly fierce competition for jobs, the pressures on people have risen in recent years, leading to lifestyle and diet disorders that result in significantly higher risks of cardiovascular disease. Hypertension is one of the common chronic cardiovascular diseases; however, mainstream blood pressure measurement devices are relatively heavy. When multiple measurements are required, the user experience and the measurement results may be unsatisfactory. In this paper, we describe the design of a signal collection module that collects pulse waves and electrocardiograph (ECG) signals. The collected signals are input into a signal processing module to filter the noise and amplify the useful physiological signals. Then, we use a wavelet transform to eliminate baseline drift noise and detect the feature points of the pulse waves and ECG signals. We propose the concept of detecting the wave shape associated with an instance, an approach that minimizes the impact of atypical pulse waves on blood pressure measurements. Finally, we propose an improved method for measuring blood pressure based on pulse wave velocity that improves the accuracy of blood pressure measurements by 58%. Moreover, the results meet the american medical instrument promotion association standards, which demonstrate the feasibility of our measurement system.


Learning from dispersed manual annotations with an optimized data weighting policy.
Purpose: Deep learning methods have become essential tools for quantitative interpretation of medical imaging data, but training these approaches is highly sensitive to biases and class imbalance in the available data. There is an opportunity to increase the available training data by combining across different data sources (e.g., distinct public projects); however, data collected under different scopes tend to have differences in class balance, label availability, and subject demographics. Recent work has shown that importance sampling can be used to guide training selection. To date, these approaches have not considered imbalanced data sources with distinct labeling protocols. Approach: We propose a sampling policy, known as adaptive stochastic policy (ASP), inspired by reinforcement learning to adapt training based on subject, data source, and dynamic use criteria. We apply ASP in the context of multiorgan abdominal computed tomography segmentation. Training was performed with cross validation on 840 subjects from 10 data sources. External validation was performed with 20 subjects from 1 data source. Results: Four alternative strategies were evaluated with the state-of-the-art baseline as upper confident bound (UCB). ASP achieves average Dice of 0.8261 compared to 0.8135 UCB ( p < 0.01 , paired t -test) across fivefold cross validation. On withheld testing datasets, the proposed ASP achieved 0.8265 mean Dice versus 0.8077 UCB ( p < 0.01 , paired t -test). Conclusions: ASP provides a flexible reweighting technique for training deep learning models. We conclude that the proposed method adapts the sample importance, which leverages the performance on a challenging multisite, multiorgan, and multisize segmentation task.