Secular trends in physical fitness and body size in Lithuanian children and adolescents between 1992 and 2012.
There is a paucity of data on contemporary secular trends on the different aspects of physical fitness in school-aged children and adolescents. This study presents the largest ever data set on changes in fitness between 1992, 2002 and 2012 for both genders of schoolchildren aged 11-18 years (n=16 199). Eurofit test battery was used to assess the balance, flexibility, muscular strength and power, agility and cardiorespiratory fitness. Anthropometrics were also measured and body mass index (BMI) was calculated. The study has shown loss of flexibility, leg muscle power, upper body strength and cardiorespiratory fitness between 1992 and 2012, although there was an improvement in abdominal muscle strength in girls, agility in boys and balance in both genders during the same period. At large, negative trends in aspects of fitness seen between 1992 and 2002 have not slowed down between 2002 and 2012. Positive trends in agility and abdominal muscle strength seen before 2002 have regressed or were reversed between 2002 and 2012, while balance continued to improve at increased pace. While the BMI continued to increase in all groups, analysis of covariance has shown that it was not the main cause of changes in fitness. The general decline in physical fitness in Lithuanian schoolchildren observed between 1992 and 2002 continued between 2002 and 2012, although some aspects of fitness showed a positive trend. If this general negative trend continues, it will compromise the well-being of future adults and create a serious economic burden on the society.


Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.
Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant C57BL/6/scid mice. Our results suggest that the NOD genetic background may predispose them to diabetic complications, including insulin resistance in the absence of high circulating glucose levels and without autoimmune destruction of their beta cells. Several of these genes lie within known type 1 and 2 diabetes loci. These data suggest that the NOD mouse may be a good candidate to study an interface between type 1 and type 2 diabetes.


The Irony of Iron - Biogenic Iron Oxides as an Iron Source to the Ocean.
Primary productivity in at least a third of the sunlit open ocean is thought to be iron-limited. Primary sources of dissolved iron (dFe) to the ocean are hydrothermal venting, flux from the sediments along continental margins, and airborne dust. This article provides a general review of sources of hydrothermal and sedimentary iron to the ocean, and speculates upon the role that iron-cycling microbes play in controlling iron dynamics from these sources. Special attention is paid to iron-oxidizing bacteria (FeOB) that live by oxidizing iron and producing biogenic iron oxides as waste products. The presence and ubiquity of FeOB both at hydrothermal systems and in sediments is only beginning to be appreciated. The biogenic oxides they produce have unique properties that could contribute significantly to the dynamics of dFe in the ocean. Changes in the physical and chemical characteristics of the ocean due to climate change and ocean acidification will undoubtedly impact the microbial iron cycle. A better understanding of the contemporary role of microbes in the iron cycle will help in predicting how these changes could ultimately influence marine primary productivity.


Interstitial 6q duplication in an adult male without growth delay or severe mental retardation.
We report on a 28 year-old male with peculiar facies, distal joint contractures and other multiple congenital anomalies. Cytogenetic analysis by G banding revealed a distal tandem interstitial duplication of the long arm of chromosome q6, dup.(6)(6q24.2-->q26). This chromosome abnormality was confirmed by fluorescence in situ hybridization with total chromosome 6 painting. This is probably the second documented case of 6q duplication without growth retardation or severe psychomotor retardation. The clinical findings in our patient are similar to that of whistling face syndrome (WFS) and, in fact, he was diagnosed with WFS as a child. The literature were reviewed and the phenotypic features of this patient were compared with those previously reported for both duplication 6q and whistling face syndromes. There is a significant overlap between the phenotypes of these two syndromes. Careful evaluation of the terminal end of the 6q in cases suggestive of WFS might be warranted.


Manual handling risk controls in hospitals (MARCH): a cross-sectional survey of UK hospitals.
Injury and ill health among healthcare staff associated with handling patients is an important area of risk for UK National Health Service (NHS) employers. Since the introduction of a specific legal duty to control this risk in 1992, many Trusts have developed manual handling risk management strategies. Anecdotally, however, practice varies between Trusts and there is no published description of common practice among NHS employers. The latter would be useful as a benchmark for risk managers. Therefore, we undertook a cross-sectional survey of 158 UK trusts (81% of those invited) using a structured interviewer-administered questionnaire to collect information about manual handling risk controls. Most Trusts had basic systems for risk management, including defined management accountability, written policies, provision of handling equipment, training, expert advice about manual handling and access to occupational health services and physiotherapy for injured employees. However, there was wide variation in important aspects, including the extent of expert manpower and criteria for referral to occupational health. Arrangements for monitoring risk controls were generally poor, and the variation in practice was a cause for concern. These data will help NHS employers by providing a benchmark against which to measure and develop risk management systems for manual handling. Future research should aim to develop standards through consensus opinion and ultimately evidence of effectiveness of risk controls.


Public policy response, aging in place, and big data platforms: Creating an effective collaborative system to cope with aging of the population.
The unprecedented rapid aging of the population is poised to become the next global public health challenge, as is apparent by the fact that 23.1% of the total global burden of disease is attributable to disorders in people aged 60 years and older. Aging of the population is the biggest driver of substantial increases in the prevalence of chronic conditions, and the prevalence of multi-morbidity is much higher in older age groups. This places a large burden on countries' health and long-term care systems. Many behavioral changes and public policy responses to aging of the population have been implemented to cope with these challenges. A system of "aging in place" has been implemented in some high-income countries in order to better provide coordinated and cost-effective health services for the elderly. This approach reduces institutional care while supporting home- or community-based care and other services. Advances in information and communications technology (ICT), assistive devices, medical diagnostics, and interventions offer many ways of more efficiently providing long-term care as part of aging in place. The use of big data on a web services platform in an effective collaborative system should promote systematic data gathering to integrate clinical and public health information systems to provide support across the continuum of care. However, the use of big data in collaborative system is a double-edged sword, as it also bring challenges for information sharing, standardized data gathering, and the security of personal information, that warrant full attention.


Effects of Preferred vs. Nonpreferred Music on Resistance Exercise Performance.
Ballmann, CG, McCullum, MJ, Rogers, RR, Marshall, MR , and Williams, TD. Effects of preferred vs. nonpreferred music on resistance exercise performance. J Strength Cond Res 35(6): 1650-1655, 2021-The purpose of this study was to examine the effects of listening to preferred vs. nonpreferred music on resistance exercise performance. Twelve resistance-trained college-aged males (age = 20.5 ± 1.24 years, height = 183.9 ± 6.8 cm, and body mass = 97.0 ± 18.2 kg) were recruited for this study. In a within-groups counterbalanced study design, subjects either listened to preferred or nonpreferred music during a bench press exercise test. Subjects completed as many repetitions as possible at 75% of their 1 repetition maximum with maximum explosive intent. Power and velocity of the barbell movement was measured for the first 3 repetitions using a linear position transducer. Motivation was measured using a visual analog scale immediately after exercise. Each exercise trial was separated by a 48-hour washout period. Results indicate that listening to preferred music increased overall bench press repetitions completed (p = 0.005; effect size [ES] = 0.84). During the first 3 repetitions, mean velocity (p = 0.001; ES = 1.6), relative mean power (p = 0.012; ES = 0.55), peak velocity (p = 0.011; ES = 0.99), and peak power (p = 0.009; ES = 0.35) were higher while listening to preferred music vs. nonpreferred music. Finally, motivation during the lift (p < 0.001; ES = 5.9) was significantly higher while listening to preferred vs. nonpreferred music. Current findings suggest that listening to preferred music by the individual results in greater performance than nonpreferred during resistance exercise. Athletes may benefit from the option to listen to their preferred music to increase motivation and resistance exercise performance.


Protective mechanisms of 6-gingerol in dextran sulfate sodium-induced chronic ulcerative colitis in mice.
Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease of the colon, with an increasing incidence worldwide. 6-Gingerol (6G) is a bioactive constituent of Zingiber officinale, which has been reported to possess various biological activities. This study was designed to evaluate the role of 6G in chronic UC. Chronic UC was induced in mice by three cycles of 2.5% dextran sulfate sodium (DSS) in drinking water. Each cycle consisted of 7 days of 2.5% DSS followed by 14 days of normal drinking water. 6G (100 mg/kg) and a reference anti-colitis drug sulfasalazine (SZ) (100 mg/kg) were orally administered daily to the mice throughout exposure to three cycles of 2.5% DSS. Administration of 6G and SZ significantly prevented disease activity index and aberrant crypt foci formation in DSS-treated mice. Furthermore, 6G and SZ suppresses immunoexpression of tumor necrosis factor alpha, interleukin-1β, inducible nitric oxide synthase, Regulated on activation, normal T cell expressed and secreted (RANTES), and Monocyte chemoattractant protein-1 (MCP-1) in the DSS-treated mice. 6G effectively protected against colonic oxidative damage by augmenting the antioxidant status with marked decrease in lipid peroxidation levels in DSS-treated mice. Moreover, 6G significantly inhibited nuclear factor kappa B (P65), p38, cyclooxygenase-2, and β-catenin whereas it enhanced IL-10 and adenomatous polyposis coli expression in DSS-treated mice. In conclusion, 6G prevented DSS-induced chronic UC via anti-inflammatory and antioxidative mechanisms and preservation of the Wnt/β-catenin signaling pathway.


Inoculation of Triatoma virus (Dicistroviridae: Cripavirus) elicits a non-infective immune response in mice.
Dicistroviridae is a new family of small, non-enveloped, +ssRNA viruses pathogenic to both beneficial arthropods and insect pests. Little is known about the dicistrovirus replication mechanism or gene function, and any knowledge on these subjects comes mainly from comparisons with mammalian viruses from the Picornaviridae family. Due to its peculiar genome organization and characteristics of the per os viral transmission route, dicistroviruses make good candidates for use as biopesticides. Triatoma virus (TrV) is a pathogen of Triatoma infestans (Hemiptera: Reduviidae), one of the main vectors of the human trypanosomiasis disease called Chagas disease. TrV was postulated as a potential control agent against Chagas' vectors. Although there is no evidence that TrV nor other dicistroviruses replicate in species outside the Insecta class, the innocuousness of these viruses in humans and animals needs to be ascertained. In this study, RT-PCR and ELISA were used to detect the infectivity of this virus in Mus musculus BALB/c mice. In this study we have observed that there is no significant difference in the ratio IgG2a/IgG1 in sera from animals inoculated with TrV when compared with non-inoculated animals or mice inoculated only with non-infective TrV protein capsids. We conclude that, under our experimental conditions, TrV is unable to replicate in mice. This study constitutes the first test to evaluate the infectivity of a dicistrovirus in a vertebrate animal model.


Behavioral and cognitive effects of microwave exposure.
This paper presents an overview of the recent behavioral literature concerning microwave exposure and discusses behavioral effects that have supported past exposure standards. Other effects, which are based on lower levels of exposure, are discussed as well, relative to setting exposure standards. The paper begins with a brief discussion of the ways in which behavioral end points are investigated in the laboratory, together with some of the methodological considerations pertinent to such studies when radio frequency (RF) exposure is involved. It has been pointed out by several sources that exposure to RF radiation can lead to changes in the behavior of humans and laboratory animals that can range from the perceptions of warmth and sound to lethal body temperatures. Behavior of laboratory animals can be perturbed and, under certain other conditions, animals will escape and subsequently avoid RF fields; but they will also work to obtain a burst of RF energy when they are cold. Reports of change of cognitive function (memory and learning) in humans and laboratory animals are in the scientific literature. Mostly, these are thermally mediated effects, but other low level effects are not so easily explained by thermal mechanisms. The phenomenon of behavioral disruption by microwave exposure, an operationally defined rate decrease (or rate increase), has served as the basis for human exposure guidelines since the early 1980s and still appears to be a very sensitive RF bioeffect. Nearly all evidence relates this phenomenon to the generation of heat in the tissues and reinforces the conclusion that behavioral changes observed in RF exposed animals are thermally mediated. Such behavioral alteration has been demonstrated in a variety of animal species and under several different conditions of RF exposure. Thermally based effects can clearly be hazardous to the organism and continue to be the best predictor of hazard for homosapiens. Nevertheless, similar research with man has not been conducted. Although some studies on human perception of RF exist, these should be expanded to include a variety of RF parameters.


Weight-Based Adaptation of TNF-Antagonist Induction versus Maintenance Dose.
Biologics are highly specific and exhibit few problems in regard to overdosages. In clinical practice, induction schemes with an initial loading dose and a subsequent lower maintenance dose have been established and are of higher efficacy for psoriasis than starting directly with the maintenance dose. As obese patients sometimes respond less well to standard dosages, increases of the maintenance dose, but not the loading doses, have been tried with variable success. In our study, we increased the loading (160 mg instead of 80 mg) but not the maintenance dose of adalimumab in an obese patient with severe psoriasis resistant to previous biologics and methotrexate. Within 12 weeks, both PASI (11 to 1.6) and DLQI (22/30 to 5/30) decreased. This strategy might be an effective and less costly alternative to doubling the maintenance doses, and could be further evaluated for psoriasis patients refractory to previous treatments.


Effectiveness of Physio Acoustic Sound (PAS) therapy in demented nursing home residents with nocturnal restlessness: study protocol for a randomized controlled trial.
Many older people with neuropsychiatric disorders such as Alzheimer's disease and frontotemporal dementia suffer from sleeping problems and often show nocturnal restlessness. Professionals and informal carers face considerable problems in solving these problems. Attempts to diminish these problems with medication in a safe and responsible manner have proven hardly effective or not effective at all. Therefore, nowadays the focus lies more on non-pharmacological solutions, for example by influencing environmental factors. There are indications that treatment with low-frequency acoustic vibrations, that is Physio Acoustic Sound (PAS) therapy, has a positive effect on sleeping problems. Therefore we study the effectiveness of PAS therapy in demented patients with nocturnal restlessness. In a randomized clinical trial, 66 nursing home patients will be divided into two groups: an intervention group and a control group. For both groups nocturnal restlessness will be measured with actiwatches during a period of six weeks. In addition, a sleep diary will be filled in.For the intervention group the baseline will be assessed, in the first two weeks, reflecting the existing situation regarding nocturnal restlessness. In the next two weeks, this group will sleep on a bed identical to their own, but with a mattress containing an in-built PAS device. As soon as the patient is lying in bed, the computer programme inducing the vibrations will be switched on for the duration of 30 min. In the last two weeks, the wash-out period, the measurements of the intervention group are continued, without the PAS intervention.During the total study period, other relevant data of all the implied patients will be recorded systematically and continuously, for example patient characteristics (data from patient files), the type and seriousness of the dementia, occurrence of neuropsychiatric symptoms during the research period, and the occurrence of intermittent co-morbidity. If PAS therapy turns out to be effective, it can be of added value to the treatment of nocturnal restlessness in demented patients. Non-pharmacological PAS therapy is not only safe and patient-friendly, but it can also be widely used in a simple and relatively inexpensive way, both in institutions such as nursing homes and residential homes for the elderly, and at home. Ultimately, this may lead to a decrease in the frequent and still common use of psychotropic drugs. In addition, care needs of demented patients also may decrease as well as the number of preventable admissions to care institutions. Netherlands Trial Register (NTR): NTR3242.


Carbohydrate and carbohydrate + protein for cycling time-trial performance.
Carbohydrate intake during endurance exercise delays the onset of fatigue and improves performance. Two recent cycling studies have reported increased time to exhaustion when protein is ingested together with carbohydrate. The purpose of the present study was to test the hypothesis that ingestion of a carbohydrate + protein beverage will lead to significant improvements in cycling time-trial performance relative to placebo and carbohydrate alone. Thirteen cyclists completed 120 min of constant-load ergometer cycling. Thereafter, participants performed a time-trial in which they completed a set amount of work (7 kJ kg(-1)) as quickly as possible. Participants completed four experimental trials, the first for familiarization and then three randomized, double-blind treatments consisting of a placebo, carbohydrate, and carbohydrate + protein. Participants received 250 ml of beverage every 15 min during the constant-load ride. Time-trial performance for carbohydrate (37.1 min, s = 3.8) was significantly (P < 0.05) faster than placebo (39.7 min, s = 4.6). Time-trial performance for carbohydrate + protein (38.8 min, s = 5.5) was not significantly different from either placebo or carbohydrate. Ingestion of a carbohydrate beverage during two hours of constant-load cycling significantly enhanced subsequent time-trial performance compared with placebo. The carbohydrate + protein beverage provided no additional performance benefit.


Association Between Receipt of a Medically Tailored Meal Program and Health Care Use.
Whether interventions to improve food access can reduce health care use is unknown. To determine whether participation in a medically tailored meal intervention is associated with fewer subsequent hospitalizations. A retrospective cohort study was conducted using near/far matching instrumental variable analysis. Data from the 2011-2015 Massachusetts All-Payer Claims database and Community Servings, a not-for-profit organization delivering medically tailored meals (MTMs), were linked. The study was conducted from December 15, 2016, to January 16, 2019. Recipients of MTMs who had at least 360 days of preintervention claims data were matched to nonrecipients on the basis of demographic, clinical, and neighborhood characteristics. Weekly delivery of 10 ready-to-consume meals tailored to the specific medical needs of the individual under the supervision of a registered dietitian nutritionist. Inpatient admissions were the primary outcome. Secondary outcomes were admission to a skilled nursing facility and health care costs (from medical and pharmaceutical claims). There were 807 eligible MTM recipients. After matching, there were 499 MTM recipients, matched to 521 nonrecipients for a total of 1020 study participants (mean [SD] age, 52.7 [14.5] years; 568 [55.7%] female). Prior to matching and compared with nonrecipients in the same area, health care use, health care cost, and comorbidity were all significantly higher in recipients. For example, preintervention mean (SD) inpatient admissions were 1.6 (6.5) in MTM recipients vs 0.2 (0.8) in nonrecipients (P < .001), and mean health care costs were $80 617 ($312 337) vs $16 138 ($68 738) (P < .001). Recipients compared with nonrecipients were also significantly more likely to have HIV (21.9% vs 0.7%, P < .001), cancer (37.9% vs 11.3%, P < .001), and diabetes (33.7% vs 7.0%, P < .001). In instrumental variable analyses, MTM receipt was associated with significantly fewer inpatient admissions (incidence rate ratio [IRR], 0.51; 95% CI, 0.22-0.80; risk difference, -519; 95% CI, -360 to -678 per 1000 person-years). Similarly, MTM receipt was associated with fewer skilled nursing facility admissions (IRR, 0.28; 95% CI, 0.01-0.60; risk difference, -913; 95% CI, -689 to -1457 per 1000 person-years). The models estimated that, had everyone in the matched cohort received treatment owing to the instrument (and including the cost of program participation), mean monthly costs would have been $3838 vs $4591 if no one had received treatment owing to the instrument (difference, -$753; 95% CI, -$1225 to -$280). Participation in a medically tailored meals program appears to be associated with fewer hospital and skilled nursing admissions and less overall medical spending.


Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife.
Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.


Normocaloric versus hypocaloric feeding on the outcomes of ICU patients: a systematic review and meta-analysis.
Current clinical practice guidelines recommend providing ICU patients a daily caloric intake estimated to match 80-100 % of energy expenditure (normocaloric goals). However, recent clinical trials of intentional hypocaloric feeding question this approach. We performed a systematic review and meta-analysis to compare the outcomes of ICU patients randomized to intentional hypocaloric or normocaloric goals. We included randomized controlled trials that enrolled ICU patients and compared intentional hypocaloric with normocaloric nutritional goals. We included studies that evaluated both trophic feeding as well as permissive underfeeding. Data sources included MEDLINE, Cochrane Register of Controlled Trials and citation review of relevant primary and review articles. The outcomes of interest included hospital acquired infection, hospital mortality, ICU length of stay (LOS) and ventilator-free days (VFDs). Six studies which enrolled 2517 patients met our inclusion criteria. The mean age and body mass index (BMI) across the studies were 53 ± 5 years and 29.1 ± 1.5 kg/m(2), respectively. Two studies compared normocaloric feeding (77% of goal) with trophic feeding (20% of goal), while four studies compared normocaloric feeding (72% of goal) with permissive underfeeding (49% of goal). Overall, there was no significant difference in the risk of infectious complications (OR 1.03; 95% CI 0.84-1.27, I(2) = 16%), hospital mortality (OR 0.91; 95% CI 0.75-1.11, I(2) = 8%) or ICU LOS (mean difference 0.05 days; 95% CI 1.33-1.44 days; I(2) = 37%) between groups. VFDs were reported in three studies with no significant difference between the normocaloric and intentional hypocaloric groups (data not pooled). This meta-analysis demonstrated no difference in the risk of acquired infections, hospital mortality, ICU length of stay or ventilator-free days between patients receiving intentional hypocaloric as compared to normocaloric nutritional goals.


TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis.
Despite significant progress in improving access to antiretroviral therapy over the past decade, substantial numbers of people living with HIV (PLHIV) in all regions continue to experience severe illness and require hospitalization. We undertook a global review assessing the proportion of hospitalizations and in-hospital deaths because of tuberculosis (TB) in PLHIV. Seven databases were searched to identify studies reporting causes of hospitalizations among PLHIV from 1 January 2007 to 31 January 2015 irrespective of age, geographical region or language. The proportion of hospitalizations and in-hospital mortality attributable to TB was estimated using random effects meta-analysis. From an initial screen of 9049 records, 66 studies were identified, providing data on 35,845 adults and 2792 children across 42 countries. Overall, 17.7% (95% CI 16.0 to 20.2%) of all adult hospitalizations were because of TB, making it the leading cause of hospitalization overall; the proportion of adult hospitalizations because of TB exceeded 10% in all regions except the European region. Of all paediatric hospitalizations, 10.8% (95% CI 7.6 to 13.9%) were because of TB. There was insufficient data among children for analysis by region. In-hospital mortality attributable to TB was 24.9% (95% CI 19.0 to 30.8%) among adults and 30.1% (95% CI 11.2 to 48.9%) among children. TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV worldwide.


Aircraft-Based Estimate of Total Methane Emissions from the Barnett Shale Region.
We present estimates of regional methane (CH4) emissions from oil and natural gas operations in the Barnett Shale, Texas, using airborne atmospheric measurements. Using a mass balance approach on eight different flight days in March and October 2013, the total CH4 emissions for the region are estimated to be 76 ± 13 × 10(3) kg hr(-1) (equivalent to 0.66 ± 0.11 Tg CH4 yr(-1); 95% confidence interval (CI)). We estimate that 60 ± 11 × 10(3) kg CH4 hr(-1) (95% CI) are emitted by natural gas and oil operations, including production, processing, and distribution in the urban areas of Dallas and Fort Worth. This estimate agrees with the U.S. Environmental Protection Agency (EPA) estimate for nationwide CH4 emissions from the natural gas sector when scaled by natural gas production, but it is higher than emissions reported by the EDGAR inventory or by industry to EPA's Greenhouse Gas Reporting Program. This study is the first to show consistency between mass balance results on so many different days and in two different seasons, enabling better quantification of the related uncertainty. The Barnett is one of the largest production basins in the United States, with 8% of total U.S. natural gas production, and thus, our results represent a crucial step toward determining the greenhouse gas footprint of U.S. onshore natural gas production.


Is paper-based documentation in an emergency medical service adequate for retrospective scientific analysis? An evaluation of a physician-run service.
To investigate if paper-based documentation in the authors' emergency medical service (EMS) satisfies scientific requirements. From 1 July 2007 to 28 February 2008, data from all paper-based protocols of a physician-run EMS in Aachen, Germany, were transferred to a SQL database (n=4815). Database queries were conducted after personal data had been anonymised. Documentation ratios of 11 individual parameters were analysed at two points in time (T1, scene; T2, arrival in emergency department). The calculability of the Mainz Emergency Evaluation Score (MEES, embracing seven vital parameters) was investigated. The calculability of the Revised Trauma Score (RTS) was also determined for all trauma patients (n=408). Fisher's exact test was used to compare differences in ratios at T1 versus T2. The documentation ratios of vital parameters ranged from 99.33% (Glasgow Coma Scale, T1) to 40.31% (respiratory rate, T2). The calculability of the MEES was poor (all missions: 28.31%, T1; 22.40%, T2; p<0.001). In missions that required cardiopulmonary resuscitation (n=87), the MEES was calculable in 9.20% of patients at T1 and 29.89% at T2 (p<0.001). In trauma missions, the RTS was calculable in 37.26% at T1 and 27.70% at T2 (p=0.004). Documentation of vital parameters is carried out incompletely, and documentation of respiratory rate is particularly poor, making calculation of accepted emergency scores infeasible for a significant fraction of a given test population. The suitability of paper-based documentation is therefore limited. Electronic documentation that includes real-time plausibility checks might improve data quality. Further research is warranted.


DNA polymerase alpha-primase complex from the silk glands of the non-mulberry silkworm Philosamia ricini.
The DNA content in the silk glands of the non-mulberry silkworm Philosamia ricini increases continuously during the fourth and fifth instars of larval development indicating high levels of DNA replication in this terminally differentiated tissue. Concomitantly, the DNA polymerase alpha activity also increases in the middle and the posterior silk glands during development, reaching maximal levels in the middle of the fifth larval instar. A comparable level of DNA polymerase delta/epsilon was also observed in this highly replicative tissue. The DNA polymerase alpha-primase complex from the silk glands of P. ricini has been purified to homogeneity by conventional column chromatography as well as by immunoaffinity techniques. The molecular mass of the native enzyme is 560 kDa and the enzyme comprises six non-identical subunits. The identity of the enzyme as DNA polymerase alpha has been established by its sensitivity to inhibitors such as aphidicolin, N-ethylmaleimide, butylphenyl-dGTP, butylanilino-dATP and antibodies to polymerase alpha. The enzyme possesses primase activity capable of initiating DNA synthesis on single-stranded DNA templates. The tight association of polymerase and primase activities at a constant ratio of 6:1 is observed through all the purification steps. The 180 kDa subunit harbours the polymerase activity, while the primase activity is associated with the 45 kDa subunit.


Evidence for deposition of 10 million tonnes of impact spherules across four continents 12,800 y ago.
Airbursts/impacts by a fragmented comet or asteroid have been proposed at the Younger Dryas onset (12.80 ± 0.15 ka) based on identification of an assemblage of impact-related proxies, including microspherules, nanodiamonds, and iridium. Distributed across four continents at the Younger Dryas boundary (YDB), spherule peaks have been independently confirmed in eight studies, but unconfirmed in two others, resulting in continued dispute about their occurrence, distribution, and origin. To further address this dispute and better identify YDB spherules, we present results from one of the largest spherule investigations ever undertaken regarding spherule geochemistry, morphologies, origins, and processes of formation. We investigated 18 sites across North America, Europe, and the Middle East, performing nearly 700 analyses on spherules using energy dispersive X-ray spectroscopy for geochemical analyses and scanning electron microscopy for surface microstructural characterization. Twelve locations rank among the world's premier end-Pleistocene archaeological sites, where the YDB marks a hiatus in human occupation or major changes in site use. Our results are consistent with melting of sediments to temperatures >2,200 °C by the thermal radiation and air shocks produced by passage of an extraterrestrial object through the atmosphere; they are inconsistent with volcanic, cosmic, anthropogenic, lightning, or authigenic sources. We also produced spherules from wood in the laboratory at >1,730 °C, indicating that impact-related incineration of biomass may have contributed to spherule production. At 12.8 ka, an estimated 10 million tonnes of spherules were distributed across ∼50 million square kilometers, similar to well-known impact strewnfields and consistent with a major cosmic impact event.


International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
A multidisciplinary group of 34 experts from 15 countries developed this update and expansion of the recommendations on the management of acute nonvariceal upper gastrointestinal bleeding (UGIB) from 2003. The Appraisal of Guidelines for Research and Evaluation (AGREE) process and independent ethics protocols were used. Sources of data included original and published systematic reviews; randomized, controlled trials; and abstracts up to October 2008. Quality of evidence and strength of recommendations have been rated by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Recommendations emphasize early risk stratification, by using validated prognostic scales, and early endoscopy (within 24 hours). Endoscopic hemostasis remains indicated for high-risk lesions, whereas data support attempts to dislodge clots with hemostatic, pharmacologic, or combination treatment of the underlying stigmata. Clips or thermocoagulation, alone or with epinephrine injection, are effective methods; epinephrine injection alone is not recommended. Second-look endoscopy may be useful in selected high-risk patients but is not routinely recommended. Preendoscopy proton-pump inhibitor (PPI) therapy may downstage the lesion; intravenous high-dose PPI therapy after successful endoscopic hemostasis decreases both rebleeding and mortality in patients with high-risk stigmata. Although selected patients can be discharged promptly after endoscopy, high-risk patients should be hospitalized for at least 72 hours after endoscopic hemostasis. For patients with UGIB who require a nonsteroidal anti-inflammatory drug, a PPI with a cyclooxygenase-2 inhibitor is preferred to reduce rebleeding. Patients with UGIB who require secondary cardiovascular prophylaxis should start receiving acetylsalicylic acid (ASA) again as soon as cardiovascular risks outweigh gastrointestinal risks (usually within 7 days); ASA plus PPI therapy is preferred over clopidogrel alone to reduce rebleeding.


A protocol for geographically randomized snail surveys in schistosomiasis fieldwork using the global positioning system.
A protocol was created for performing geographically randomized snail surveys for schistosomiasis research using the global positioning system (GPS). This protocol differs from traditional surveys in its ability to accurately map and measure the spatial distribution of snail habitat. The protocol was used to map irrigation ditches, the primary habitat for Oncomelania hupensis, in two residence areas in Sichuan Province, China. From the 7,450 meters of mapped ditches, snail surveys were performed at 203 random sites along the ditch network. Of these, 116 (57.1%) sites had snails. The total number of living snails captured was 2,014, resulting in an average snail density of 0.27 snails per linear meter of potential habitat.


Smaller Change in Psychological Readiness to Return to Sport Is Associated With Second Anterior Cruciate Ligament Injury Among Younger Patients.
Lower psychological readiness to return to sport has been reported for younger patients (≤20 years) who go on to a second anterior cruciate ligament (ACL) injury. However, changes in psychological readiness and specific psychological responses associated with second injury have not been identified. To identify changes in psychological readiness over time associated with a second ACL injury. It was hypothesized that younger patients who suffered a second injury would have smaller changes in psychological readiness to return to sport when compared with those who did not have a second injury. Case-control study; Level of evidence, 2. Patients ≤20 years old at the time of surgery who had a primary ACL reconstruction procedure between June 2014 and June 2016 were recruited for this study. The short version of the Anterior Cruciate Ligament Return to Sport After Injury (ACL-RSI) scale was completed by patients before their ACL reconstruction and repeated at 12 months after surgery to assess psychological readiness to return to sport. The primary outcome of interest was the relationship between the change in psychological readiness and second ACL injuries. Among 115 young patients who returned to sport after ACL reconstruction, 21 (18%) experienced a second ACL injury. Injured patients did not show improvement in their ACL-RSI score between the preoperative assessment and 12-month time point (58.5 vs 60.8 points, P = .60) and had a significantly smaller change when compared with noninjured patients (9.2 vs 24.9 points, P = .01). When compared with the noninjured group, the injured group reported they were more nervous about playing sport, less confident in playing sport without concern for the knee, more frustrated with having to consider the knee with respect to sport, and more fearful of reinjuring the knee by playing sport ( P≤ .05). Injured patients exhibited less improvement in psychological readiness at a group level and reported different psychological characteristics with regard to return to sport at 12 months after ACL reconstruction as monitored by the ACL-RSI scale.


Dual-Bayes Localization Filter Extension for Safeguarding in the Case of Uncertain Direction Signals.
In order to run a localization filter for parking systems in real time, the directional information must be directly available when a distance measurement of the wheel speed sensor is detected. When the vehicle is launching, the wheel speed sensors may already detect distance measurement in the form of Delta-Wheel-Pulse-Counts (DWPCs) without having defined a rolling direction. This phenomenon is particularly problematic during parking maneuvers, where many small correction strokes are made. If a localization filter is used for positioning, the restrained DWPCs cannot process in real time. Without directional information in the form of a rolling direction signal, the filter has to ignore the DWPCs or artificially stop until a rolling direction signal is present. For this reason, methods for earlier estimation of the rolling direction based on the pattern of the incoming DWPCs and based on the force equilibrium have been presented. Since the new methods still have their weaknesses and a wrong estimation of the rolling direction can occur, an extension of a so-called Dual-Localization filter approach is presented. The Dual-Localization filter uses two localization filters and an intelligent initialization logic that ensures that both filters move in opposite directions at launching. The primary localization filter uses the estimated and the secondary one the opposite direction. As soon as a valid rolling direction signal is present, an initialization logic is used to decide which localization filter has previously moved in the true direction. The localization filter that has moved in the wrong direction is initialized with the states and covariances of the other localization filter. This extension allows for a fast and real-time capability to be achieved, and the accumulated velocity error can be dramatically reduced.


Immunometabolic Activation of Invariant Natural Killer T Cells.
Invariant natural killer T (iNKT) cells are lipid-reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation to immunometabolic disease, metabolic programming of lipid antigen presentation, and immunometabolic activation of iNKT cells. First, we outline the role of iNKT cells in immunometabolic disease. Second, we discuss the effects of cellular metabolism on lipid antigen processing and presentation to iNKT cells. The synthesis and processing of glycolipids and other potential endogenous lipid antigens depends on metabolic demand and may steer iNKT cells toward adopting a Th1 or Th2 signature. Third, external signals such as toll-like receptor ligands, adipokines, and cytokines modulate antigen presentation and subsequent iNKT cell responses. Finally, we will discuss the relevance of metabolic programming of iNKT cells in human disease, focusing on their role in disorders such as obesity and atherosclerosis. The critical response to metabolic changes places iNKT cells at the helm of immunometabolic disease.


In situ characterization of nanoparticles during growth by means of white light scattering.
A simple method of characterization of suspensions of spherical nanoparticles with monotonically variable size is proposed. It allows for the in situ measurement of the particle size as well as spectral dependence of their refractive indices. The method requires three optical channels: one for the illumination of a suspension by white light and two for the measurements of the spectra of scattered light. Parameters of the particles are determined by fitting the measured temporal spectral surfaces by the calculated Mie scattering functions. The method is applied to the particles being grown in a low-pressure reactive plasma of a discharge in an acetylene-argon mixture.


Gas Vesicle-Blood Interactions Enhance Ultrasound Imaging Contrast.
Gas vesicles (GVs) are genetically encoded, air-filled protein nanostructures of broad interest for biomedical research and clinical applications, acting as imaging and therapeutic agents for ultrasound, magnetic resonance, and optical techniques. However, the biomedical applications of GVs as systemically injectable nanomaterials have been hindered by a lack of understanding of GVs' interactions with blood components, which can significantly impact in vivo behavior. Here, we investigate the dynamics of GVs in the bloodstream using a combination of ultrasound and optical imaging, surface functionalization, flow cytometry, and mass spectrometry. We find that erythrocytes and serum proteins bind to GVs and shape their acoustic response, circulation time, and immunogenicity. We show that by modifying the GV surface we can alter these interactions and thereby modify GVs' in vivo performance. These results provide critical insights for the development of GVs as agents for nanomedicine.


Usefulness of approximate entropy in the diagnosis of schizophrenia.
Diagnosis of the psychiatric diseases is a bit challenging at the first interview due to this fact that qualitative criteria are not as accurate as quantitative ones. Here, the objective is to classify schizophrenic patients from the healthy subject using a quantitative index elicited from their electroencephalogram (EEG) signals. Ten right handed male patients with schizophrenia who had just auditory hallucination and did not have any other psychotic features and ten age-matched right handed normal male control participants participated in this study. The patients used haloperidol to minimize the drug-related affection on their EEG signals. Electrophysiological data were recorded using a Neuroscan 24 Channel Synamps system, with a signal gain equal to 75K (150 xs at the headbox). According to the observable anatomical differences in the brain of schizophrenic patients from controls, several discriminative features including AR coefficients, band power, fractal dimension, and approximation entropy (ApEn) were chosen to extract quantitative values from the EEG signals. The extracted features were applied to support vector machine (SVM) classifier that produced 88.40% accuracy for distinguishing the two groups. Incidentally, ApEn produces more discriminative information compare to the other features. This research presents a reliable quantitative approach to distinguish the control subjects from the schizophrenic patients. Moreover, other representative features are implemented but ApEn produces higher performance due to complex and irregular nature of EEG signals.


Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.
HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.


Dilemmas in the diagnosis of acute community-acquired bacterial meningitis.
Rapid diagnosis and treatment of acute community-acquired bacterial meningitis reduces mortality and neurological sequelae, but can be delayed by atypical presentation, assessment of lumbar puncture safety, and poor sensitivity of standard diagnostic microbiology. Thus, diagnostic dilemmas are common in patients with suspected acute community-acquired bacterial meningitis. History and physical examination alone are sometimes not sufficient to confirm or exclude the diagnosis. Lumbar puncture is an essential investigation, but can be delayed by brain imaging. Results of cerebrospinal fluid (CSF) examination should be interpreted carefully, because CSF abnormalities vary according to the cause, patient's age and immune status, and previous treatment. Diagnostic prediction models that use a combination of clinical findings, with or without test results, can help to distinguish acute bacterial meningitis from other causes, but these models are not infallible. We review the dilemmas in the diagnosis of acute community-acquired bacterial meningitis, and focus on the roles of clinical assessment and CSF examination.


Hemorrhage produces abnormalities in lymphocyte function and lymphokine generation.
Hemorrhage has been shown to produce abnormalities in lymphocyte function, particularly in the proliferative response to mitogens such as PHA and Con A. In order to better examine the hemorrhage-induced alterations in immune function, we determined the effects of blood loss in mice without any surgical manipulation on lymphocyte populations and subpopulations, cellular activation, and lymphokine production. Hemorrhage induced no changes in cell numbers in the spleen, thymus, lymph nodes, and bone marrow. No alterations in the relative percentages of B (B220+, mu+) and T (Lyt-1+, Lyt-2+, T3+, L3T4+) cell subpopulations were found in any organ after blood loss. Significant decreases in splenocyte proliferation in response to Con A, IL-2R expression and blast formation occurred after hemorrhage. IFN-gamma production increased 24 and 48 h post hemorrhage. Decreases in IL-2, IL-3, and IL-5 generation were present 2 h after blood loss. IL-2 production remained significantly decreased for 48 h posthemorrhage, then increased to more than twice normal levels 72 h posthemorrhage, and subsequently returned to prehemorrhage values. These results demonstrate that hemorrhage produces widespread alterations in immune function without affecting lymphocyte population and subpopulation numbers.


High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95.
CD40 and CD27, members of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we prospectively assessed the impact of CD40 and CD27 on outcome in 121 children treated according to the CoALL06-97 protocol. Expression of both CD40 and CD27 was found to be significantly higher in low- than in high-risk patients as defined by standard clinical risk parameters such as age and white blood cell count. In addition, in multivariable analysis, a very high percentage of CD40(+) blasts at diagnosis was identified as an independent favorable prognostic factor for relapse-free survival. Of note, high CD40 expression particularly protected against late relapse. In B cells, CD40 is known to enhance both antigen-presenting capacity and sensitivity to proapoptotic signals. Yet, although CD40 ligation does result in significant up-regulation of CD80/CD86 in our cohort, it is up-regulation of the death receptor CD95 that significantly correlates with the percentage of CD40(+) blasts. Thus very high expression of CD40 on BCP-ALL blasts is an independent prognostic marker indicative of superior relapse-free survival that may in part be due to CD40-dependent death receptor up-regulation.


Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans.
A major challenge in neuroscience is to reliably activate individual neurons, particularly those in deeper brain regions. Current optogenetic approaches require invasive surgical procedures to deliver light of specific wavelengths to target cells to activate or silence them. Here, we demonstrate the use of low-pressure ultrasound as a non-invasive trigger to activate specific ultrasonically sensitized neurons in the nematode, Caenorhabditis elegans. We first show that wild-type animals are insensitive to low-pressure ultrasound and require gas-filled microbubbles to transduce the ultrasound wave. We find that neuron-specific misexpression of TRP-4, the pore-forming subunit of a mechanotransduction channel, sensitizes neurons to ultrasound stimulus, resulting in behavioural outputs. Furthermore, we use this approach to manipulate the function of sensory neurons and interneurons and identify a role for PVD sensory neurons in modifying locomotory behaviours. We suggest that this method can be broadly applied to manipulate cellular functions in vivo.


Interactive effects of 9-cis-retinoic acid and androgen on proliferation, differentiation, and apoptosis of LNCaP prostate cancer cells.
9-cis-Retinoic acid (9cRA), which binds to both retinoic acid receptors and retinoic X receptors, inhibits prostate cancer induction in rats and reduces growth of prostate cancer cells. However, the nature of this growth inhibition and the interactive influence of androgens are not well defined and are the subject of this report. LNCaP and PC-3 cells were cultured and treated with a range of 9cRA concentrations for 3-6 days in the absence or presence of 5α-dehydrotestosterone. 9cRA inhibited cell proliferation in a dose-dependent manner, plateauing at 10 mol/l. Treatment of cells with 10 mol/l 9cRA inhibited 5α-dihydroxytestosterone (DHT)-stimulated proliferation, the effect of which was maximal at 10 mol/l DHT. Treatment of DHT (10 mol/l)-exposed cells with 9cRA caused a dose-dependent increase in prostate-specific antigen in the medium after 6 days, but not 3 days. 9cRA caused a dose-dependent increase in apoptotic cells stained with H33258 after 3 days, but not 6 days; however, on using flow cytometry, apoptosis was apparent at both 3 and 6 days. Flow cytometry also revealed interference of G0/G1 to S phase transition by 9cRA. Inhibition by 9cRA of anchorage-independent growth of PC-3 cells was also found; LNCaP cells did not grow colonies in soft agar. 9cRA inhibited growth and induced differentiation of human LNCaP prostate cancer cells in vitro and inhibited anchorage-independent growth of PC-3 cells. Because 9cRA and 13-cis-retinoic acid, which is retinoic acid receptor-selective, prevent prostate carcinogenesis in rats, and 13-cis-retinoic acid also inhibits growth of human prostate cancer cells, the RAR is a potential molecular target for prostate cancer prevention and therapy.


Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease.
Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.


Disseminated, persistent, and fatal infection due to the vaccine strain of varicella-zoster virus in an adult following stem cell transplantation.
Live attenuated varicella vaccine is recommended for healthy individuals who are susceptible to varicella. Although the vaccine is safe, effective, and used worldwide, serious adverse events have been reported, mainly in immunocompromised patients who subsequently recovered. Here, we describe the fatality of an immunocompromised patient who received the varicella vaccine. His medical history provides a cautionary lens through which to view the decision of when vaccination is appropriate. A middle-aged man with non-Hodgkin lymphoma received chemotherapy and a stem cell transplant. He was vaccinated 4 years post-transplantation, despite diagnosis of a new low-grade lymphoma confined to the lymph nodes. Within 3 months of vaccination, he developed recurrent rashes with fever, malaise, weakness, hepatitis, weight loss, and renal failure. The syndrome was eventually determined to be associated with persistent disseminated zoster caused by the vaccine virus. This case illustrates a circumstance when a live viral vaccine should not be used.


Controllable Transformation of Aligned ZnO Nanorods to ZIF-8 as Solid-Phase Microextraction Coatings with Tunable Porosity, Polarity, and Conductivity.
While a growing number of solid-phase microextraction (SPME) coatings have been developed, a generalized protocol is still needed to tailor-make SPME coatings with desirable properties for efficient extraction of diverse analytes from sample matrixes. In this work, we developed a versatile approach to prepare SPME coatings with tunable properties by controllable in situ transformation of well-aligned ZNRs into zeolitic imidazolate frameworks-8 (ZIF-8) via reaction with 2-methylimidazole (2-MI). During this process, ZNRs supplied Zn2+ and served as a "hard template" for the in situ growth of well-aligned ZIF-8 with enhanced surface area for adsorption. Because ZNRs and ZIF-8 exhibit markedly different properties, we obtained a series of ZNRs/ZIF-8 hybrid composites, whose morphology, porosity, polarity, and charge transfer resistance can be fine-tuned by simply controlling the concentration of 2-MI. Preparing ZNRs/ZIF-8 SPME coatings with desired properties enabled effective extraction of a wide range of polar and nonpolar compounds including aliphatic hydrocarbons, polycyclic aromatic hydrocarbons, alcohols, phenols, anilines, and ionic drugs.


Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program.
Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro-B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell-programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation.


Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives.
Hallucinogen Persisting Perception Disorder (HPPD) is a rare, and therefore, poorly understood condition linked to hallucinogenic drugs consumption. The prevalence of this disorder is low; the condition is more often diagnosed in individuals with a history of previous psychological issues or substance misuse, but it can arise in anyone, even after a single exposure to triggering drugs. The aims of the present study are to review all the original studies about HPPD in order to evaluate the following: (1) the possible suggested etiologies; (2) the possible hallucinogens involved in HPPD induction; (3) the clinical features of both HPPD I and II; (4) the possible psychiatric comorbidities; and (5) the available and potential therapeutic strategies. We searched PubMed to identify original studies about psychedelics and Hallucinogen Persisting Perception Disorder (HPPD). Our research yielded a total of 45 papers, which have been analyzed and tabled to provide readers with the most updated and comprehensive literature review about the clinical features and treatment options for HPPD.


The experiences and preparedness of family carers for best interest decision-making of a relative living with advanced dementia: A qualitative study.
To explore the experience and the preparedness of family carers in their caregiving role as best interest decision-makers of a relative living with advanced dementia. The prevalence of dementia is a global issue. The role of being a carer of a relative living with dementia does not necessarily lessen once they are admitted to a nursing home. Best interest decision-making including end-of-life care decisions need to be made and reaching these choices can be challenging. The preparedness of family carers in this role needs greater understanding. Descriptive qualitative study. During 2015 twenty semi-structured interviews were conducted of family carers of nursing home residents living with advanced dementia, then analysed using Braun and Clarke's thematic analysis. Three themes were identified: (1) Caring for someone living with dementia. The impact on the carer's holistic well-being and their experience of being a best interest decision-maker; (2) Accessing support. The influential nature of formal and informal networks; (3) Perceived knowledge and understanding of the dementia trajectory of carers and nursing staff. The experiences and preparedness of informal carers is a reflection of their personal response, but the distress experienced highlights the significant need of adequate support availability and of enhancing nursing staffs' dementia expertise to maximize their role in facilitating best interest decision-making. This has significant implications for nursing practice and for service user and nursing staff education. Considering the global impact of dementia, our findings have international relevance to similar nursing homes across the world.


Synthetic cytotoxicity: digenic interactions with TEL1/ATM mutations reveal sensitivity to low doses of camptothecin.
Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics.


Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway.
Calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (NFAT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective β blocker/α-1 blocker carvedilol or the selective β-1 blocker metoprolol, but not the selective α-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.


Anal intraepithelial neoplasia: diagnosis, screening, and treatment.
Anal intraepithelial neoplasia (AIN) is a premalignant lesion for anal cancer. It is more commonly found in high-risk patients (e.g., human papilloma virus (HPV)/human immunodeficiency virus infections, post-organ transplantation patients, and men who have sex with men) and development is driven by HPV infection. The incidence of AIN is difficult to estimate, but is heavily skewed by preexisting conditions, particularly in high-risk populations. The diagnosis is made from cytology or biopsy during routine examinations, and can be performed at a primary care provider's office. A pathologist can then review and classify cells, based on nucleus-to-cytoplasm ratios. The classification of low or high grade can better predict progression from AIN to anal cancer. There is little debate that AIN can develop into anal cancer, and the main rationale for treatment is to delay the progression. Significant controversy remains regarding screening, surveillance, and treatment for AIN. Management options are separated into surveillance (watchful waiting) and interventional strategies. Emerging data suggest that close patient follow up with a combination of ablative and topical treatments may offer the greatest benefit. HPV vaccination offers a unique treatment prior to HPV infection and the subsequent development of AIN, but its use after the development of AIN is limited. Ablative treatment includes excision, fulguration, and laser therapy.


Development of a molecularly imprinted polymer for selective extraction followed by liquid chromatographic determination of sitagliptin in rat plasma and urine.
A novel water-compatible molecularly imprinted solid-phase extraction (MISPE) combined with zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) method for selective extraction and determination of sitagliptin in rat serum and urine was developed and validated. The effects of progenic solvents, pH, cross linker and amount of monomer were studied to optimize the efficiency and selectivity. The adsorption kinetics and isotherms were measured. The molecularly imprinted polymer (MIP) showed good specific adsorption capacity with an optimum of 180 mg/g at pH 7.5 and selective extraction of sitagliptin from rat plasma and urine. The recovery of sitagliptin from rat urine and plasma was >98%. The limits of detection (LOD) and quantification (LOQ) were 0.03 and 0.10 μg/L respectively. The proposed method overcomes the matrix effects of phospholipids generally encountered while preparation of plasma samples by precipitation of proteins.


Intracranial hemorrhage alters scalp potential distribution in bioimpedance cerebral monitoring: Preliminary results from FEM simulation on a realistic head model and human subjects.
Current diagnostic neuroimaging for detection of intracranial hemorrhage (ICH) is limited to fixed scanners requiring patient transport and extensive infrastructure support. ICH diagnosis would therefore benefit from a portable diagnostic technology, such as electrical bioimpedance (EBI). Through simulations and patient observation, the authors assessed the influence of unilateral ICH hematomas on quasisymmetric scalp potential distributions in order to establish the feasibility of EBI technology as a potential tool for early diagnosis. Finite element method (FEM) simulations and experimental left-right hemispheric scalp potential differences of healthy and damaged brains were compared with respect to the asymmetry caused by ICH lesions on quasisymmetric scalp potential distributions. In numerical simulations, this asymmetry was measured at 25 kHz and visualized on the scalp as the normalized potential difference between the healthy and ICH damaged models. Proof-of-concept simulations were extended in a pilot study of experimental scalp potential measurements recorded between 0 and 50 kHz with the authors' custom-made bioimpedance spectrometer. Mean left-right scalp potential differences recorded from the frontal, central, and parietal brain regions of ten healthy control and six patients suffering from acute/subacute ICH were compared. The observed differences were measured at the 5% level of significance using the two-sample Welch t-test. The 3D-anatomically accurate FEM simulations showed that the normalized scalp potential difference between the damaged and healthy brain models is zero everywhere on the head surface, except in the vicinity of the lesion, where it can vary up to 5%. The authors' preliminary experimental results also confirmed that the left-right scalp potential difference in patients with ICH (e.g., 64 mV) is significantly larger than in healthy subjects (e.g., 20.8 mV; P < 0.05). Realistic, proof-of-concept simulations confirmed that ICH affects quasisymmetric scalp potential distributions. Pilot clinical observations with the authors' custom-made bioimpedance spectrometer also showed higher left-right potential differences in the presence of ICH, similar to those of their simulations, that may help to distinguish healthy subjects from ICH patients. Although these pilot clinical observations are in agreement with the computer simulations, the small sample size of this study lacks statistical power to exclude the influence of other possible confounders such as age, sex, and electrode positioning. The agreement with previously published simulation-based and clinical results, however, suggests that EBI technology may be potentially useful for ICH detection.


The immunogenicity of the tumor-associated antigen α-fetoprotein is enhanced by a fusion with a transmembrane domain.
To investigate the ability of recombinant modified vaccinia virus Ankara (rMVA) vector to induce an immune response against a well-tolerated self-antigen. rMVA vectors expressing different form of α-fetoprotein (AFP) were produced and characterized. Naïve mice were vaccinated with MVA vectors expressing the AFP antigen in either a secreted, or a membrane-bound, or an intracellular form. The immune response was monitored by an IFNΓ ELISpot assay and antibody detection. Vaccination with the membrane-associated form of AFP induced a stronger CD8(+) T-cell response compared to the ones obtained with the MVA encoding the secreted or the intracellular forms of AFP. Moreover, the vaccination with the membrane-bound AFP elicited the production of AFP-specific antibodies. The AFP transmembrane form is more immunogenic. Expressing a membrane-bound form in the context of an MVA vaccination could enhance the immunogenicity of a self-antigen.


Antioxidant intake and cognitive function of elderly men and women: the Cache County Study.
We prospectively examined associations between intakes of antioxidants (vitamins C, vitamin E, and carotene) and cognitive function and decline among elderly men and women of the Cache County Study on Memory and Aging in Utah. In 1995, 3831 residents 65 years of age or older completed a baseline survey that included a food frequency questionnaire and cognitive assessment. Cognitive function was assessed using an adapted version of the Modified Mini-Mental State examination (3MS) at baseline and at three subsequent follow-up interviews spanning approximately 7 years. Multivariable-mixed models were used to estimate antioxidant nutrient effects on average 3MS score over time. Increasing quartiles of vitamin C intake alone and combined with vitamin E were associated with higher baseline average 3MS scores (p-trend = 0.013 and 0.02 respectively); this association appeared stronger for food sources compared to supplement or food and supplement sources combined. Study participants with lower levels of intake of vitamin C, vitamin E and carotene had a greater acceleration of the rate of 3MS decline over time compared to those with higher levels of intake. High antioxidant intake from food and supplement sources of vitamin C, vitamin E, and carotene may delay cognitive decline in the elderly.


Structures of Escherichia coli DNA adenine methyltransferase (Dam) in complex with a non-GATC sequence: potential implications for methylation-independent transcriptional repression.
DNA adenine methyltransferase (Dam) is widespread and conserved among the γ-proteobacteria. Methylation of the Ade in GATC sequences regulates diverse bacterial cell functions, including gene expression, mismatch repair and chromosome replication. Dam also controls virulence in many pathogenic Gram-negative bacteria. An unexplained and perplexing observation about Escherichia coli Dam (EcoDam) is that there is no obvious relationship between the genes that are transcriptionally responsive to Dam and the promoter-proximal presence of GATC sequences. Here, we demonstrate that EcoDam interacts with a 5-base pair non-cognate sequence distinct from GATC. The crystal structure of a non-cognate complex allowed us to identify a DNA binding element, GTYTA/TARAC (where Y = C/T and R = A/G). This element immediately flanks GATC sites in some Dam-regulated promoters, including the Pap operon which specifies pyelonephritis-associated pili. In addition, Dam interacts with near-cognate GATC sequences (i.e. 3/4-site ATC and GAT). Taken together, these results imply that Dam, in addition to being responsible for GATC methylation, could also function as a methylation-independent transcriptional repressor.


Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases.
For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl- and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G2-M cell cycle arrest.


Roles of the lipid-binding motifs of Atg18 and Atg21 in the cytoplasm to vacuole targeting pathway and autophagy.
Atg18 and Atg21 are homologous WD-40 repeat proteins that bind phosphoinositides via a novel conserved Phe-Arg-Arg-Gly motif and function in autophagy-related pathways. Atg18 is required for the cytoplasm to vacuole targeting (Cvt) pathway and autophagy, whereas Atg21 is only required for the Cvt pathway. Currently, the functions of both proteins are poorly understood. Here, we examined the relationship between the phosphatidylinositol 3-phosphate (PtdIns(3)P)-binding abilities of Atg18 and Atg21 and autophagy by expressing variants of these proteins that have mutations in their phosphoinositide-binding motifs. Cells expressing PtdIns(3)P-binding mutants of both these proteins showed highly reduced autophagy. Furthermore, the localization of components of two related ubiquitin-like protein conjugation systems, Atg8 and Atg16, to the phagophore assembly site is affected. Consistent with the aberrant localization of the above Atg proteins, precursor Ape1, a cargo of the Cvt pathway and autophagy, is partially protease-sensitive in starvation conditions. This finding suggests a requirement for the PtdIns(3)P binding capability of Atg18 and Atg21 in efficient completion of the sequestering autophagic vesicles. Finally, using a multiple knock-out strain, we found that Atg18 and Atg21 facilitate the recruitment of Atg8-PE to the site of autophagosome formation and protect it from premature cleavage by Atg4, which represents a key aspect of post-translational autophagy regulation. Taken together, our results suggest that PtdIns(3)P binding by at least Atg18 or Atg21 is required for robust autophagic activity and that the PtdIns(3)P-binding motifs of Atg18 and Atg21 can compensate for one another in the recruitment of Atg components that are dependent on PtdIns(3)P for their phagophore assembly site association.


Hypothermia therapy after traumatic brain injury in children.
Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown. In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5 degrees C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0 degrees C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months. A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1+/-1.2 degrees C and 36.9+/-0.5 degrees C, respectively. At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14). There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P=0.06). There was more hypotension (P=0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups. In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality. (Current Controlled Trials number, ISRCTN77393684 [controlled-trials.com].).


Bright nanoscale source of deterministic entangled photon pairs violating Bell's inequality.
Global, secure quantum channels will require efficient distribution of entangled photons. Long distance, low-loss interconnects can only be realized using photons as quantum information carriers. However, a quantum light source combining both high qubit fidelity and on-demand bright emission has proven elusive. Here, we show a bright photonic nanostructure generating polarization-entangled photon pairs that strongly violates Bell's inequality. A highly symmetric InAsP quantum dot generating entangled photons is encapsulated in a tapered nanowire waveguide to ensure directional emission and efficient light extraction. We collect ~200 kHz entangled photon pairs at the first lens under 80 MHz pulsed excitation, which is a 20 times enhancement as compared to a bare quantum dot without a photonic nanostructure. The performed Bell test using the Clauser-Horne-Shimony-Holt inequality reveals a clear violation (S CHSH > 2) by up to 9.3 standard deviations. By using a novel quasi-resonant excitation scheme at the wurtzite InP nanowire resonance to reduce multi-photon emission, the entanglement fidelity (F = 0.817 ± 0.002) is further enhanced without temporal post-selection, allowing for the violation of Bell's inequality in the rectilinear-circular basis by 25 standard deviations. Our results on nanowire-based quantum light sources highlight their potential application in secure data communication utilizing measurement-device-independent quantum key distribution and quantum repeater protocols.


Identification of QTLs Associated with Virulence Related Traits and Drug Resistance in Cryptococcus neoformans.
Cryptococcus neoformans is a basidiomycete fungus capable of causing deadly meningoenchephilitis, primarily in immunocompromised individuals. Formerly, C. neoformans was composed of two divergent lineages, but these have recently been elevated to species status, now C. neoformans (formerly C. neoformans var. grubii) and C. deneoformans (formerly C. neoformans var. neoformans). While both species can cause deadly infections in humans, C. neoformans is much more prevalent in clinical settings than C. deneoformans However, the genetic factors contributing to their significant differences in virulence remain largely unknown. Quantitative trait locus (QTL) mapping is a powerful tool that can be used to identify genomic regions associated with phenotypic differences between strains. Here, we analyzed a hybrid cross between these two species and identified a total of 23 QTL, including five for melanin production, six for cell size, one for cell wall thickness, five for the frequency of capsule production, three for minimal inhibitory concentration (MIC) of fluconazole in broth, and three for MIC on solid medium. For the fluconazole resistance-associated QTL, three showed environment and/or concentration-specific effects. Our results provide a large number of candidate gene regions from which to explore the molecular bases for phenotypic differences between C. neoformans and C. deneoformans.


Highly conserved gene order and numerous novel repetitive elements in genomic regions linked to wing pattern variation in Heliconius butterflies.
With over 20 parapatric races differing in their warningly colored wing patterns, the butterfly Heliconius erato provides a fascinating example of an adaptive radiation. Together with matching races of its co-mimic Heliconius melpomene, H. erato also represents a textbook case of Müllerian mimicry, a phenomenon where common warning signals are shared amongst noxious organisms. It is of great interest to identify the specific genes that control the mimetic wing patterns of H. erato and H. melpomene. To this end we have undertaken comparative mapping and targeted genomic sequencing in both species. This paper reports on a comparative analysis of genomic sequences linked to color pattern mimicry genes in Heliconius. Scoring AFLP polymorphisms in H. erato broods allowed us to survey loci at approximately 362 kb intervals across the genome. With this strategy we were able to identify markers tightly linked to two color pattern genes: D and Cr, which were then used to screen H. erato BAC libraries in order to identify clones for sequencing. Gene density across 600 kb of BAC sequences appeared relatively low, although the number of predicted open reading frames was typical for an insect. We focused analyses on the D- and Cr-linked H. erato BAC sequences and on the Yb-linked H. melpomene BAC sequence. A comparative analysis between homologous regions of H. erato (Cr-linked BAC) and H. melpomene (Yb-linked BAC) revealed high levels of sequence conservation and microsynteny between the two species. We found that repeated elements constitute 26% and 20% of BAC sequences from H. erato and H. melpomene respectively. The majority of these repetitive sequences appear to be novel, as they showed no significant similarity to any other available insect sequences. We also observed signs of fine scale conservation of gene order between Heliconius and the moth Bombyx mori, suggesting that lepidopteran genome architecture may be conserved over very long evolutionary time scales. Here we have demonstrated the tractability of progressing from a genetic linkage map to genomic sequence data in Heliconius butterflies. We have also shown that fine-scale gene order is highly conserved between distantly related Heliconius species, and also between Heliconius and B. mori. Together, these findings suggest that genome structure in macrolepidoptera might be very conserved, and show that mapping and positional cloning efforts in different lepidopteran species can be reciprocally informative.


Mutations within a conserved region of the hepatitis C virus E2 glycoprotein that influence virus-receptor interactions and sensitivity to neutralizing antibodies.
Cell culture-adaptive mutations within the hepatitis C virus (HCV) E2 glycoprotein have been widely reported. We identify here a single mutation (N415D) in E2 that arose during long-term passaging of HCV strain JFH1-infected cells. This mutation was located within E2 residues 412 to 423, a highly conserved region that is recognized by several broadly neutralizing antibodies, including the mouse monoclonal antibody (MAb) AP33. Introduction of N415D into the wild-type (WT) JFH1 genome increased the affinity of E2 to the CD81 receptor and made the virus less sensitive to neutralization by an antiserum to another essential entry factor, SR-BI. Unlike JFH1(WT), the JFH1(N415D) was not neutralized by AP33. In contrast, it was highly sensitive to neutralization by patient-derived antibodies, suggesting an increased availability of other neutralizing epitopes on the virus particle. We included in this analysis viruses carrying four other single mutations located within this conserved E2 region: T416A, N417S, and I422L were cell culture-adaptive mutations reported previously, while G418D was generated here by growing JFH1(WT) under MAb AP33 selective pressure. MAb AP33 neutralized JFH1(T416A) and JFH1(I422L) more efficiently than the WT virus, while neutralization of JFH1(N417S) and JFH1(G418D) was abrogated. The properties of all of these viruses in terms of receptor reactivity and neutralization by human antibodies were similar to JFH1(N415D), highlighting the importance of the E2 412-423 region in virus entry.


Chip-interleaved optical code division multiple access relying on a photon-counting iterative successive interference canceller for free-space optical channels.
In this paper, we design a novel Poisson photon-counting based iterative successive interference cancellation (SIC) scheme for transmission over free-space optical (FSO) channels in the presence of both multiple access interference (MAI) as well as Gamma-Gamma atmospheric turbulence fading, shot-noise and background light. Our simulation results demonstrate that the proposed scheme exhibits a strong MAI suppression capability. Importantly, an order of magnitude of BER improvements may be achieved compared to the conventional chip-level optical code-division multiple-access (OCDMA) photon-counting detector.


Pharmacological modulation of cell death in organ transplantation.
New options to pharmacologically modulate fundamental mechanisms of regulated cell death are rapidly evolving and found first clinical applications in cancer therapy. Here, we present an overview on how the recent advances in the understanding of the biology and pharmacology of cell death might influence research and clinical practice in solid organ transplantation. Of particular interest are the novel opportunities related to organ preservation and immunomodulation, which might contribute to promote organ repair and to develop more selective ways to modulate allogeneic immune responses to prevent rejection and induce immunological tolerance.


Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat.
Although ketamine has many beneficial effects in a rat model of noninfectious inflammation with lipopolysaccharide (LPS), its effects on gut ileus are unknown. We hypothesized that ketamine would improve LPS-induced ileus and therefore examined its effects on gastric emptying and intestinal transit as well as duodenogastric bile reflux and associated gastric bleeding. Male rats received saline or ketamine (7 mg/kg ip) 1 hour before saline or LPS (20 mg/kg ip) for 5 hours. Thirty minutes before killing, rats received orogastric rhodamine B isothiocyanate-labeled dextran and 5 minutes later fluorescein isothiocyanate-labeled dextran via a duodenal catheter. GI contents were collected for dye, bile acid, and hemoglobin (index of bleeding) determinations. LPS significantly impaired intestinal transit and increased duodenogastric bile reflux and gastric luminal hemoglobin content. Ketamine improved intestinal transit, prevented LPS-induced bile reflux, and diminished gastric bleeding. In mechanistic studies, ketamine also attenuated LPS-induced upregulation of the proinflammatory genes inducible nitric oxide synthase and cyclo-oxygenase-2 in the stomach but preserved expression of the anti-inflammatory gene heme-oxygenase-1 (Western blot). These data suggest that ketamine may prevent LPS-induced gastric bleeding by decreasing bile reflux through improved intestinal transit or by local changes in nitric oxide, prostaglandin, and carbon monoxide metabolism.


Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis.
During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.


Vaccination Patterns in Children After Autism Spectrum Disorder Diagnosis and in Their Younger Siblings.
In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Recommended childhood vaccines between ages 1 month and 12 years. The proportion of children who received all of their vaccine doses according to ACIP recommendations. The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child's younger sibling and to limit the number of vaccines administered during the younger sibling's first year of life. Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.