Outdoor Light at Night and Breast Cancer Incidence in the Nurses' Health Study II.
Animal and epidemiologic studies suggest that exposure to light at night (LAN) may disrupt circadian patterns and decrease nocturnal secretion of melatonin, which may disturb estrogen regulation, leading to increased breast cancer risk. We examined the association between residential outdoor LAN and breast cancer incidence using data from the nationwide U.S.-based Nurses' Health Study II cohort. We followed 109,672 women from 1989 through 2013. Cumulative LAN exposure was estimated using time-varying satellite data for a composite of persistent nighttime illumination at ∼1 km2 scale for each residence during follow-up. Incident invasive breast cancer cases were confirmed by medical record review. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for anthropometric, reproductive, lifestyle, and socioeconomic risk factors. Over 2,187,425 person-years, we identified 3,549 incident breast cancer cases. Based on a fully adjusted model, the estimated HR for incident breast cancer with an interquartile range (IQR) (31.6 nW/cm2/sr) increase in cumulative average outdoor LAN was 1.05 (95% CI: 1.00, 1.11). An association between LAN and breast cancer appeared to be limited to women who were premenopausal at the time of a case [HR=1.07 (95% CI: 1.01, 1.14) based on 1,973 cases vs. HR=1.00 (95% CI: 0.91, 1.09) based on 1,172 cases in postmenopausal women; p-interaction=0.08]. The LAN-breast cancer association was observed only in past and current smokers at the end of follow-up [HR=1.00 (95% CI: 0.94, 1.07) based on 2,215 cases in never smokers; HR=1.10 (95% CI: 1.01, 1.19) based on 1,034 cases in past smokers vs. HR=1.21 (95% CI: 1.07, 1.37) for 300 cases in current smokers; p-interaction=0.08]. Although further work is required to confirm our results and to clarify potential mechanisms, our findings suggest that exposure to residential outdoor light at night may contribute to invasive breast cancer risk. https://doi.org/10.1289/EHP935.


Fast gas switch for characterizing laser output pulses.
A device is described that allows detailed and sensitive examination of the precursors to both nanosecond and possibly picosecond laser pulses without damaging detectors. A one-to-one telescope, constructed with lenses with focal lengths 5.0 cm and which may be pressurized to 800-Torr argon gas, is used to demonstrate the operation. It is shown that breakdown in the gas, at times before the peak power of the pulses, absorbs the energy allowing only the early portion of the laser pulse to pass unattenuated. Energy loss is observed at argon pressures below the threshold for observation of nonlinear transmission (gas breakdown).


Bilateral pedicle anterolateral thigh (ALT) flap combined with bilateral sartorius muscle flap for reconstruction of extensive perineoscrotal and medial thigh defect because of Fournier's gangrene.
Fournier's gangrene is an acute and potentially lethal necrotizing fasciitis that can lead to extensive defects of the perineoscrotal area and lower abdominal wall as well. Such defect poses challenging tasks for both functional and cosmetic reconstruction. Local perforator pedicle flaps and muscle flaps can be employed and combined for such a reconstruction. In this report we present a case of reconstruction of a massive perineoscrotal and upper medial thigh defect because of Fournier's gangrene using a bilateral pedicle anterolateral thigh (ALT) flap and sartorius muscle flap. A 61 year-old male who suffered from Fournier's gangrene resulted in a perineal, scrotal, and medial thigh defect of 27 × 30 cm2 with exposure of the femoral vessels. A bilateral pedicle ALT flap measuring 30 × 9 cm2 based on two perforators and a bilateral sartorius muscle flap were harvested for soft tissue defect reconstruction and inguinal vessels coverage, respectively. The flaps survived completely, with no recipient or donor site morbidity. The length of follow-up was 6 months and was uneventful. A bilateral pedicle ALT flap combined with bilateral sartorius flap may be considered as a valid and safe option for an extensive inguinal and perineoscrotal reconstruction in selected cases. © 2016 Wiley Periodicals, Inc. Microsurgery 37:669-673, 2017.


Abdominal aortic aneurysm and the association with serum levels of Homocysteine, vitamins B6, B12 and Folate.
Previous investigations have shown hyperhomocysteinemi in patients with abdominal aortic aneurysm (AAA). In the present study we evaluated the circulating level of homocysteine (Hcy) in relation to renal function, vitamins B6, B12 and folate status in AAA patients with special regard to aneurysm size, and rupture. Hcy, Creatinine, B6, B12 and folate were measured in 119 patients with AAA and 36 controls without aneurysm matched by age, gender and smoking habit. As expected there was a weak correlation between Hcy and vitamins B6, B12 or folate. We found similar levels of Hcy, B6 and folic acid in patients with nonruptured AAA compared to the control group matched by age, gender and smoking habit. There was no correlation between maximum diameter of the nonruptured AAA (n=78) and Hcy, B6 or folate. However, the present study shows a significant inverse correlation between maximum diameter of the nonruptured AAA (n=78) and B12 (r = -0.304, p=0.007) with significant higher levels in small AAA compared to large AAA. In conclusion, Hcy does not seem to be a useful biomarker in AAA disease. The unexpected finding of B12 levels correlating to aneurysm diameter warrants urgent further investigation of B12 supplement to prevent progression of small AAA.


Treatment of hypercholesterolemia in NIDDM with policosanol.
To determine whether elevated levels of cholesterol and low-density lipoprotein (LDL) cholesterol in non-insulin-dependent diabetes mellitus (NIDDM) patients could be decreased by policosanol, a new cholesterol-lowering drug. NIDDM predisposes patients to coronary artery disease (CAD) through the direct action of hyperglycemia on the arteries as well as the dyslipidemia induced by NIDDM. This double-blind placebo-controlled trial was performed in 29 patients with NIDDM and hypercholesterolemia. After stable glycemic control was achieved by diet and/or oral hypoglycemic drugs, patients were instructed to follow a cholesterol-lowering diet for 6 weeks. Patients who met entry criteria received, under double-blind conditions, policosanol (5 mg) or placebo tablets twice a day for 12 weeks. Policosanol (10 mg/day) significantly reduced total cholesterol by 17.5% and LDL cholesterol by 21.8% compared with baseline and placebo. Furthermore, high-density lipoprotein (HDL) cholesterol was raised by 11.3% (not significant), and triglycerides showed a statistically nonsignificant decrease of 6.6%. These changes in lipid profile were similar to those induced by policosanol in nondiabetic patients with type II hyperlipoproteinemia. Glycemic control was unaffected by treatment. No clinically or biochemically adverse effects attributable to treatment were observed. Only one patient (placebo) withdrew from the trial because of an adverse experience (erythema). We concluded that policosanol is effective and safe in patients with NIDDM and hypercholesterolemia.


The Computer-Assisted Brief Intervention for Tobacco (CABIT) program: a pilot study.
Health care providers do not routinely carry out brief counseling for tobacco cessation despite the evidence for its effectiveness. For this intervention to be routinely used, it must be brief, be convenient, require little investment of resources, require little specialized training, and be perceived as efficacious by providers. Technological advances hold much potential for addressing the barriers preventing the integration of brief interventions for tobacco cessation into the health care setting. This paper describes the development and initial evaluation of the Computer-Assisted Brief Intervention for Tobacco (CABIT) program, a web-based, multimedia tobacco intervention for use in opportunistic settings. The CABIT uses a self-administered, computerized assessment to produce personalized health care provider and patient reports, and cue a stage-matched video intervention. Respondents interested in changing their tobacco use are offered a faxed referral to a "best matched" tobacco treatment provider (ie, dynamic referral). During 2008, the CABIT program was evaluated in an emergency department, an employee assistance program, and a tobacco dependence program in New Jersey. Participants and health care providers completed semistructured interviews and satisfaction ratings of the assessment, reports, video intervention, and referrals using a 5-point scale. Mean patient satisfaction scores (n = 67) for all domains ranged from 4.00 (Good) to 5.00 (Excellent; Mean = 4.48). Health care providers completed satisfaction forms for 39 patients. Of these 39 patients, 34 (87%) received tobacco resources and referrals they would not have received under standard care. Of the 45 participants offered a dynamic referral, 28 (62%) accepted. The CABIT program provided a user-friendly, desirable service for tobacco users and their health care providers. Further development and clinical trial testing is warranted to establish its effectiveness in promoting treatment engagement and tobacco cessation.


How batrachotoxin modifies the sodium channel permeation pathway: computer modeling and site-directed mutagenesis.
A structural model of the rNav1.4 Na+ channel with batrachotoxin (BTX) bound within the inner cavity suggested that the BTX pyrrole moiety is located between a lysine residue at the DEKA selectivity filter (Lys1237) and an adjacent phenylalanine residue (Phe1236). We tested this pyrrole-binding model by site-directed mutagenesis of Phe1236 at D3/P-loop with 11 amino acids. Mutants F1236D and F1236E expressed poorly, whereas nine other mutants either expressed robust Na+ currents, like the wild-type (F1236Y/Q/K), or somewhat reduced current (F1236G/A/C/N/W/R). Gating properties were altered modestly in most mutant channels, with F1236G displaying the greatest shift in activation and steady-state fast inactivation (-10.1 and -7.5 mV, respectively). Mutants F1236K and F1236R were severely resistant to BTX after 1000 repetitive pulses (+50 mV/20 ms at 2 Hz), whereas seven other mutants were sensitive but with reduced magnitudes compared with the wild type. It is noteworthy that rNav1.4-F1236K mutant Na+ channels remained highly sensitive to block by the local anesthetic bupivacaine, unlike several other BTX-resistant mutant channels. Our data thus support a model in which BTX, when bound within the inner cavity, interacts with the D3/P-loop directly. Such a direct interaction provides clues on how BTX alters the Na+ channel selectivity and conductance.


Mechanistic consequences of chiral radical clock probes: analysis of the mononuclear non-heme iron enzyme HppE with 2-hydroxy-3-methylenecyclopropyl radical clock substrates.
(S)-2-Hydroxypropylphosphonic acid [(S)-HPP] epoxidase (HppE) is a mononuclear iron enzyme that catalyzes the last step in the biosynthesis of the antibiotic fosfomycin. HppE also processes the (R)-enantiomer of HPP but converts it to 2-oxo-propylphosphonic acid. In this study, all four stereoisomers of 3-methylenecyclopropyl-containing substrate analogues, (2R, 3R)-8, (2R, 3S)-8, (2S, 3R)-8, and (2S, 3S)-8, were synthesized and used as radical probes to investigate the mechanism of the HppE-catalyzed reaction. Upon treatment with HppE, (2S, 3R)-8 and (2S, 3S)-8 were converted via a C1 radical intermediate to the corresponding epoxide products, as anticipated. In contrast, incubation of HppE with (2R, 3R)-8 led to enzyme inactivation, and incubation of HppE with (2R, 3S)-8 yielded the 2-keto product. The former finding is consistent with the formation of a C2 radical intermediate, where the inactivation is likely triggered by radical-induced ring cleavage of the methylenecyclopropyl group. Reaction with (2R, 3S)-8 is predicted to also proceed via a C2 radical intermediate, but no enzyme inactivation and no ring-opened product were detected. These results strongly suggest that an internal electron transfer to the iron center subsequent to C-H homolysis competes with ring-opening in the processing of the C2 radical intermediate. The different outcomes of the reactions with (2R, 3R)-8 and (2R, 3S)-8 demonstrate the need to carefully consider the chirality of substituted cyclopropyl groups as radical reporting groups in studies of enzymatic mechanisms.


Suppression of adrenal function by low-dose prednisone: assessment with 24-hour urinary steroid hormone profiles--a review of five cases.
The impact of the synthetic glucocorticoid prednisone on adrenal steroid hormone production was examined using 24-hour urinary steroid hormone profiling. Five women, who were chronically taking low-dose prednisone, were tested, and the relevant literature was reviewed. As expected, adrenal glucocorticoid production, measured by urinary terminal cortisol and cortisone metabolites, was markedly suppressed compared to reference range values (p=0.03). Urinary cortisol and cortisone, reflecting circulating glucocorticoids, were decreased to a lesser extent than their terminal metabolites. Urinary dehydroepiandrosterone (DHEA) excretion was dramatically suppressed (p=0.03), while the downstream androgen metabolites androsterone and etiocholanolone were suppressed to a lesser extent. Aldosterone and tetrahydrocorticosterone production demonstrated modest suppression after prednisone administration, but allo-tetrahydrocorticosterone, which is highly sensitive to adrenocorticotropic hormone (ACTH) secretion, was suppressed to a greater extent. Prednisone administration results in a decrease in ACTH secretion by the anterior pituitary, suppressing synthesis of glucocorticoids, DHEA, and DHEA metabolites. Decreased glucocorticoid synthesis is adaptive, because prednisone is active at the glucocorticoid receptor, but suppression of DHEA synthesis is not mitigated by prednisone. DHEA is an important sex hormone precursor, neurosteroid, and endocrine and immune modulator; therefore, DHEA depletion may have significant adverse consequences in terms of sex hormone production, bone health, endocrine and immune system function, and neuropsychiatric status. Studies of DHEA replacement in patients taking prednisone for lupus demonstrate amelioration of some of these adverse effects.


Sequence-optimized and targeted double-stranded RNA as a therapeutic antiviral treatment against infectious myonecrosis virus in Litopenaeus vannamei.
Infectious myonecrosis virus (IMNV) is a significant and emerging pathogen that has a tremendous impact on the culture of the Pacific white shrimp Litopenaeus vannamei. IMNV first emerged in Brazil in 2002 and subsequently spread to Indonesia, causing large economic losses in both countries. No existing therapeutic treatments or effective interventions currently exist for IMNV. RNA interference (RNAi) is an effective technique for preventing viral disease in shrimp. Here, we describe the efficacy of a double-stranded RNA (dsRNA) applied as an antiviral therapeutic following virus challenge. The antiviral molecule is an optimized dsRNA construct that targets an IMNV sequence at the 5' end of the genome and that showed outstanding antiviral protection previously when administered prior to infection. At least 50% survival is observed with a low dose of dsRNA administered 48 h post-infection with a lethal dose of IMNV; this degree of protection was not observed when dsRNA was administered 72 h post-infection. Additionally, administration of the dsRNA antiviral resulted in a significant reduction of the viral load in the muscle of shrimp that died from disease or survived until termination of the present study, as assessed by quantitative RT-PCR. These data indicate that this optimized RNAi antiviral molecule holds promise for use as an antiviral therapeutic against IMNV.


Lactate: creatinine ratio in babies with thin meconium staining of amniotic fluid.
ACOG states meconium stained amniotic fluid (MSAF) as one of the historical indicators of perinatal asphyxia. Thick meconium along with other indicators is used to identify babies with severe intrapartum asphyxia. Lactate creatinine ratio (L:C ratio) of 0.64 or higher in first passed urine of babies suffering severe intrapartum asphyxia has been shown to predict Hypoxic Ischaemic Encephalopathy (HIE). Literature review shows that meconium is passed in distress and thin meconium results from mixing and dilution over time, which may be hours to days. Thin meconium may thus be used as an indicator of antepartum asphyxia. We tested L:C ratios in a group of babies born through thin and thick meconium, and for comparison, in a group of babies without meconium at birth. 86 consecutive newborns, 36 to 42 weeks of gestation, with meconium staining of liquor, were recruited for the study. 52 voided urine within 6 hours of birth; of these 27 had thick meconium and 25 had thin meconium at birth. 42 others, who did not have meconium or any other signs of asphyxia at birth provided controls. Lactate and creatinine levels in urine were tested by standard enzymatic methods in the three groups. Lactate values are highest in the thin MSAF group followed by the thick MSAF and controls. Creatinine was lowest in the thin MSAF, followed by thick MSAF and controls. Normal babies had an average L:C ratio of 0.13 (+/- 0.09). L:C ratio was more among thin MSAF babies (4.3 +/- 11.94) than thick MSAF babies (0.35 +/- 0.35). Median L:C ratio was also higher in the thin MSAF group. Variation in the values of these parameters is observed to be high in the thin MSAF group as compared to other groups. L:C ratio was above the cutoff of 0.64 of Huang et al in 40% of those with thin meconium. 2 of these developed signs of HIE with convulsions (HIE Sarnat and Sarnat Stage II) during hospital stay. One had L:C Ratio of 93 and the other of 58.6. A smaller proportion (20%) of those with thick meconium had levels above the cutoff and 2 developed HIE and convulsions with L:C ratio of 1.25 and 1.1 respectively. In evolving a cutoff of L:C ratios that would be highly sensitive and specific (0.64), Huang et al studied it in a series of babies with severe intrapartum asphyxia. Our study shows that the specificity may not be as good if babies born through thin meconium are also included. L:C ratios are much higher in babies with thin meconium. It may be that meconium alone is not a good indicator of asphyxia and the risk of HIE. However, if the presence of meconium implies asphyxia then perhaps a higher cut-off than 0.64 is needed. L:C ratios should be tested in a larger sample that includes babies with thin meconium, before L:C ratios can be applied universally.


High-throughput analysis of epistasis in genome-wide association studies with BiForce.
Gene-gene interactions (epistasis) are thought to be important in shaping complex traits, but they have been under-explored in genome-wide association studies (GWAS) due to the computational challenge of enumerating billions of single nucleotide polymorphism (SNP) combinations. Fast screening tools are needed to make epistasis analysis routinely available in GWAS. We present BiForce to support high-throughput analysis of epistasis in GWAS for either quantitative or binary disease (case-control) traits. BiForce achieves great computational efficiency by using memory efficient data structures, Boolean bitwise operations and multithreaded parallelization. It performs a full pair-wise genome scan to detect interactions involving SNPs with or without significant marginal effects using appropriate Bonferroni-corrected significance thresholds. We show that BiForce is more powerful and significantly faster than published tools for both binary and quantitative traits in a series of performance tests on simulated and real datasets. We demonstrate BiForce in analysing eight metabolic traits in a GWAS cohort (323 697 SNPs, >4500 individuals) and two disease traits in another (>340 000 SNPs, >1750 cases and 1500 controls) on a 32-node computing cluster. BiForce completed analyses of the eight metabolic traits within 1 day, identified nine epistatic pairs of SNPs in five metabolic traits and 18 SNP pairs in two disease traits. BiForce can make the analysis of epistasis a routine exercise in GWAS and thus improve our understanding of the role of epistasis in the genetic regulation of complex traits. The software is free and can be downloaded from http://bioinfo.utu.fi/BiForce/. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors.
Few studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information. We investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods. We identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process. This study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer.


A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency.
We report the genetic characteristics of a family with familial paraganglioma syndrome. The index patient was diagnosed with carcinoid tumour of the bronchus at the age of 30 years then later diagnosed with bilateral phaeochromocytoma. His sister had bilateral carotid body tumours. Mutational analyses of succinate dehydrogenase B and SDHD on the index patient showed him to be heterozygous for the M1I mutation of the SDHD gene. A genetic analysis revealed that his sister also had succinate dehydrogenase deficiency with the same mutation. Pre-symptomatic testing confirmed the genetic diagnosis, and led to a clinical diagnosis in an otherwise asymptomatic sibling. Comparison with other known cases of M1I mutation suggests that this is a founder mutation in the Chinese population. Genetic analysis of the succinate dehydrogenase genes can provide a specific diagnosis and allow for genetic screening of at-risk individuals.


Simulation With PARTS (Phase-Augmented Research and Training Scenarios): A Structure Facilitating Research and Assessment in Simulation.
Assessment in simulation is gaining importance, as are scenario design methods increasing opportunity for assessment. We present our approach to improving measurement in complex scenarios using PARTS [Phase-Augmented Research and Training Scenarios], essentially separating cases into clearly delineated phases. We created 7 PARTS with real-time rating instruments and tested these in 63 cases during 4 weeks of simulation. Reliability was tested by comparing real-time rating with postsimulation video-based rating using the same instrument. Validity was tested by comparing preintervention and postintervention total results, by examining the difference in improvement when focusing on the phase-specific results addressed by the intervention, and further explored by trying to demonstrate the discrete improvement expected from proficiency in the rare occurrence of leader inclusive behavior. Intraclass correlations [3,1] between real-time and postsimulation ratings were 0.951 (95% confidence interval [CI], 0.794-0.990), 1.00 (95% CI, --to--), 0.948 (95% CI, 0.783-0.989), and 0.995 (95% CI, 0.977-0.999) for 3 phase-specific scores and total scenario score, respectively. Paired t tests of prelecture-postlecture performance showed an improvement of 14.26% (bias-corrected and accelerated bootstrap [BCa] 95% CI, 4.71-23.82; P = 0.009) for total performance but of 28.57% (BCa 95% CI, 13.84-43.30; P = 0.002) for performance in the respective phase. The correlation of total scenario performance with leader inclusiveness was not significant (rs = 0.228; BCa 95% CI. -0.082 to 0.520; P = 0.119) but significant for specific phase performance (rs = 0.392; BCa 95% CI, 0.118-0.632; P = 0.006). The PARTS allowed for improved reliability and validity of measurements in complex scenarios.


Diversity of ageing across the tree of life.
Evolution drives, and is driven by, demography. A genotype moulds its phenotype's age patterns of mortality and fertility in an environment; these two patterns in turn determine the genotype's fitness in that environment. Hence, to understand the evolution of ageing, age patterns of mortality and reproduction need to be compared for species across the tree of life. However, few studies have done so and only for a limited range of taxa. Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga. Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species, including increasing, constant, decreasing, humped and bowed trajectories for both long- and short-lived species. This diversity challenges theoreticians to develop broader perspectives on the evolution of ageing and empiricists to study the demography of more species.


Biological evidence that scrapie agent has an independent genome.
There are many distinct strains of scrapie agent, identified by their relative incubation periods and quantitative and qualitative neuropathological properties in inbred mice of particular genotypes. When serially passaged under specified conditions of mouse strain, route of infection and dose of infectivity these properties are stable. However, they may change in a predictable manner if the passage strategy is altered. The scrapie strain 87A shows what has previously been defined as Class III stability; it is stable when passaged at low dose in C57BL mice, but often suddenly changes its properties in the course of a single passage if high doses are used, always resulting in the same new strain. The latter, designated 7D, has shorter incubation periods and more extensive pathology than 87A, properties which are subsequently stable on serial passage even at high dose. This phenomenon has been seen repeatedly using scrapie isolates from six different natural cases in five different breeds of sheep. These isolates are closely similar in all their properties, showing them to be independent isolations of the 87A strain; there have been no isolations of 87A in which the phenomenon did not occur. On the other hand, none of the many other scrapie strains used in the same laboratory have shown this change. 87A brain samples consistently behave as if they contain 87A together with a smaller amount of 7D. This is so even after 87A has previously been passaged at high dilution, well beyond the limiting dilution for 7D, a procedure which would eliminate any minor agent strain originally present in the isolate. Therefore it is highly likely that the 7D in tissues of mice infected with 87A is generated de novo at each passage by mutational change from 87A during the incubation period. The established fact that many different strains exist and the considerable evidence that mutation can occur lead to the conclusion that scrapie agent has its own independently replicating genome.


Measuring beliefs about taking hypoglycaemic medication among people with Type 2 diabetes.
Identifying patients' beliefs about taking medication can inform interventions to support medication taking, and their evaluation. We set out to establish the range of these beliefs, and measure the frequency of commonly held beliefs and their correlation with intention to take medication and self-reported medication adherence. An exploratory survey among Type 2 diabetic patients aged 40 years or older, registered in general practice, used a questionnaire measuring a range of plausible beliefs about taking and intention to take medication developed from interviews where belief elicitation was guided by the Theory of Planned Behaviour. The Medication Adherence Report Schedule was used as a self-report adherence measure. Questionnaires were returned by 121 (61.7%) people. The majority strongly agreed with statements about the benefits of taking medication. Negative beliefs that taking medication would 'cause unpleasant side effects' and 'lead to weight gain' were held by 32.8 [corrected] and 13.9% of people, respectively. Beliefs about benefit were strongly associated with intention to take medication regularly. Two beliefs were associated with reduced medication adherence: 'changes to my daily routine would make it more difficult to take my diabetes medicines regularly' (P < 0.001), and 'if I were to take my diabetes medicines regularly this would lead to my gaining weight' (P < 0.01) [corrected] Use of a theoretical model to elicit and identify common beliefs about taking medication regularly underscores the importance of exploring weight-gain concerns and how to keep taking tablets when routines change. Beliefs associated with intention and taking medication will inform intervention development, implementation and evaluation in randomized controlled studies.


Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration.
Pesticide exposure has been implicated in the etiopathogenesis of Parkinson's disease (PD); in particular, the organochlorine insecticide dieldrin is believed to be associated with PD. Emerging evidence indicates that histone modifications play a critical role in cell death. In this study, we examined the effects of dieldrin treatment on histone acetylation and its role in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells. In mesencephalic dopaminergic neuronal cells, dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4. Histone acetylation occurred within 10 min of dieldrin exposure indicating that acetylation is an early event in dieldrin neurotoxicity. The hyperacetylation was attributed to dieldrin-induced proteasomal dysfunction, resulting in accumulation of a key histone acetyltransferase (HAT), cAMP response element-binding protein. The novel HAT inhibitor anacardic acid significantly attenuated dieldrin-induced histone acetylation, Protein kinase C delta proteolytic activation and DNA fragmentation in dopaminergic cells protected against dopaminergic neuronal degeneration in primary mesencephalic neuronal cultures. Furthermore, 30-day exposure of dieldrin in mouse models induced histone hyperacetylation in the striatum and substantia nigra. For the first time, our results collectively demonstrate that exposure to the neurotoxic pesticide dieldrin induces acetylation of core histones because of proteasomal dysfunction and that hyperacetylation plays a key role in dopaminergic neuronal degeneration after exposure of dieldrin.


Investigational drugs for anxiety in patients with schizophrenia.
Anxiety is a frequent symptom of schizophrenia, which is highly associated with an increased risk of relapse and suicide. The effect of antipsychotics on this clinical dimension is not specific and the common practice of prescribing benzodiazepines remains unsatisfactory. The authors review recent well-designed clinical trials for anxiety in patients with schizophrenia. The content includes information derived from trial databases, regulatory authorities and scientific literature. Anxiety in schizophrenia has severe consequences and specific clinical features, which require a specific therapy, beyond benzodiazepines. In these past 2 years, two compounds (the anticonvulsant/anxiolytic pregabalin and the atypical antipsychotic quetiapine) were on Phase III/IV clinical trials for schizophrenia, with comorbid anxiety as a primary outcome measure. Potential for success is high, given their strong rationale and the clinical experience with both drugs. Anxiety (as a symptom) was a secondary outcome measure in trials for schizophrenia involving seven other compounds (lurasidone, amisulpride, bitopertin, oxytocin, famotidine, cannabidiol and the L-theanine and pregnenolone combination). Primary completion date is expected in the next 2 years. In spite of ancient positive results and a strong rationale, aripiprazole and related compounds were not in recent clinical trials. The authors believe that these compounds deserve more attention.


Harm to others outweighs harm to self in moral decision making.
Concern for the suffering of others is central to moral decision making. How humans evaluate others' suffering, relative to their own suffering, is unknown. We investigated this question by inviting subjects to trade off profits for themselves against pain experienced either by themselves or an anonymous other person. Subjects made choices between different amounts of money and different numbers of painful electric shocks. We independently varied the recipient of the shocks (self vs. other) and whether the choice involved paying to decrease pain or profiting by increasing pain. We built computational models to quantify the relative values subjects ascribed to pain for themselves and others in this setting. In two studies we show that most people valued others' pain more than their own pain. This was evident in a willingness to pay more to reduce others' pain than their own and a requirement for more compensation to increase others' pain relative to their own. This "hyperaltruistic" valuation of others' pain was linked to slower responding when making decisions that affected others, consistent with an engagement of deliberative processes in moral decision making. Subclinical psychopathic traits correlated negatively with aversion to pain for both self and others, in line with reports of aversive processing deficits in psychopathy. Our results provide evidence for a circumstance in which people care more for others than themselves. Determining the precise boundaries of this surprisingly prosocial disposition has implications for understanding human moral decision making and its disturbance in antisocial behavior.


Fibroblasts are required for Schwann cell basal lamina deposition and ensheathment of unmyelinated sympathetic neurites in culture.
The ability to purify and recombine populations of peripheral neurons, Schwann cells and fibroblasts in tissue culture has enabled us to examine the contribution of fibroblasts to Schwann cell basal lamina assembly and ensheathment of unmyelinated rat superior cervical ganglion neurites in vitro. Purified perinatal superior cervical ganglion neurons were grown in culture either with Schwann cells or with Schwann cells plus fibroblasts derived from either superior cervical ganglion capsule or cranial periosteum. The cultures were maintained for 2-8 weeks on a collagen substratum in a medium known to promote Schwann cell differentiation (myelin, basal lamina formation) in the presence of dorsal root ganglion neurons. The extent of Schwann cell differentiation (ensheathment, basal lamina formation) in the presence of superior cervical ganglion neurons was evaluated in this study using electron microscopy. In superior cervical ganglion neuron plus Schwann cell cultures (without fibroblasts), Schwann cells achieved only a moderate degree of ensheathment; also, Schwann cell basal lamina was discontinuous and extracellular collagen fibrils were sparse. Although only discontinuous basal lamina was demonstrable by electron microscopy in these cultures, surprisingly, Schwann cell/neurite fascicles were uniformly immunostained for laminin, type IV collagen, and heparan sulfate proteoglycan. The addition of fibroblasts to superior cervical ganglion neuron plus Schwann cell cultures increased the deposition of basal lamina around the Schwann cell/neurite units, the number of collagen fibrils, and the extent of neurite ensheathment. We propose that the presence of basal lamina increases the Schwann cell's ability to ensheathe superior cervical ganglion neurites, possibly through an augmentation of specific extracellular matrix components or by increasing in some way the capacity of these components to become organized into basal lamina. We conclude that, unlike dorsal root ganglion neurons, superior cervical ganglion neurons are unable to stimulate full Schwann cell extracellular matrix expression with the result that these Schwann cells require the extraneuronal influence of fibroblasts to deposit basal lamina and attain their mature phenotype in culture.


Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: integrated bioinformatic analysis.
Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.


17 β -Estradiol attenuates poststroke depression and increases neurogenesis in female ovariectomized rats.
Studies have linked neurogenesis to the beneficial actions of specific antidepressants. However, whether 17 β -estradiol (E2), an antidepressant, can ameliorate poststroke depression (PSD) and whether E2-mediated improvement of PSD is associated with neurogenesis are largely unexplored. In the present study, we found that depressive-like behaviors were observed at the first week after focal ischemic stroke in female ovariectomized (OVX) rats, as measured by sucrose preference and open field test, suggesting that focal cerebral ischemia could induce PSD. Three weeks after middle cerebral artery occlusion (MCAO), rats were treated with E2 for consecutive 14 days. We found that E2-treated rats had significantly improving ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test, compared to vehicle-treated group. In addition, we also found that BrdU- and doublecortin (DCX)-positive cells in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) were significantly increased in ischemic rats after E2 treatment, compared to vehicle-treated group. Our data suggest that focal cerebral ischemia can induce PSD, and E2 can ameliorate PSD. In addition, newborn neurons in the hippocampus may play an important role in E2-mediated antidepressant like effect after ischemic stroke.


Insulin acts as a powerful stimulator of axial myopia in chicks.
In animal models, it has been shown that the retina can use the defocus of the projected image to control emmetropization. Glucagon may be involved in the sign of defocus detection, at least in chickens. Since glucagon and insulin often have opposite effects in metabolic pathways, the effect of insulin on eye growth was investigated. Chicks were treated with either positive or negative spectacle lenses and intravitreally injected with saline or different amounts of insulin. Refraction, axial length, and corneal curvature were measured. Effects of insulin on vitreal glucose concentration, on retinal ZENK and glucagon mRNA levels, and on the number of ZENK-immunoreactive glucagon amacrine cells were studied. Insulin injections (0.3 nmol) caused only a small myopic shift in control chicks. When positive lenses were worn, insulin injections (0.3; 0.03 nmol) not only blocked hyperopia but rather induced high amounts of axial myopia. Insulin also enhanced myopia that was induced by negative lenses. Axial elongation was mostly due to an increase in anterior chamber depth and a thickening of the crystalline lens. Insulin temporarily reduced vitreal glucose levels. Insulin increased retinal ZENK mRNA levels, whereas the number of ZENK-immunoreactive glucagon amacrine cells was reduced, a finding that is typically linked to the development of myopia. Given that insulin is used in therapy for human metabolic disorders and has been proposed to treat corneal epithelial disease, its powerful myopiagenic effect, which is mostly due to its effects on the optics of the anterior segment of the eye, merits further investigation.


Clinical epidemiological study of employees exposed to surfactant blend containing perfluorononanoic acid.
An epidemiological study was conducted of a perfluorononanoic acid (PFNA) surfactant blend, to investigate whether clinical differences were apparent between employees who were potentially exposed to the surfactant and those who were not exposed. The surfactant blend, which is related to other previously studied perfluorinated materials, is used in the production of some high-performance polymers. All 630 individuals employed at a polymer production facility using PFNA (CAS No 72968-38-8) at any time between 1 January 1989 and 1 July 2003 were included in the cohort. Plausibly related laboratory test results were abstracted from annual medical examination records, including liver enzyme function and blood lipids. Detailed work histories, available for all employees, provided the basis for determining exposure category. Thirty two clinical parameters were evaluated by exposure level at five points in time, determined to reflect changes in possible exposure intensity, as well as greatest number of records available. Annual cross-sectional analyses and longitudinal analyses that accounted for multiple measurements per person were conducted separately for men and women, by exposure groups. Differences by exposure group for all laboratory measures, adjusted for age and body mass index, were small and not clinically significant. Although some statistically significant pair-wise differences were observed, these observations were not consistent between men and women, or over the five analysis windows. For the seven outcome variables (liver enzymes and blood lipids) examined in separate longitudinal models, no significant increase or decrease was observed by unit increase in cumulative exposure intensity score. This is the first epidemiological study investigating the possible health effects in humans associated with exposure to PFNA blend. Based on laboratory measures assessed over more than a decade, no adverse clinical effects were detected from occupational exposure to PFNA blend.


Models and Methods to Investigate Acute Stress Responses in Cattle.
There is a growing appreciation within the livestock industry and throughout society that animal stress is an important issue that must be addressed. With implications for animal health, well-being, and productivity, minimizing animal stress through improved animal management procedures and/or selective breeding is becoming a priority. Effective management of stress, however, depends on the ability to identify and quantify the effects of various stressors and determine if individual or combined stressors have distinct biological effects. Furthermore, it is critical to determine the duration of stress-induced biological effects if we are to understand how stress alters animal production and disease susceptibility. Common stress models used to evaluate both psychological and physical stressors in cattle are reviewed. We identify some of the major gaps in our knowledge regarding responses to specific stressors and propose more integrated methodologies and approaches to measuring these responses. These approaches are based on an increased knowledge of both the metabolic and immune effects of stress. Finally, we speculate on how these findings may impact animal agriculture, as well as the potential application of large animal models to understanding human stress.


The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells.
Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b+CD33+HLA-DR- MDSCs from peripheral blood of human colon cancer patients are PD-L1+. PD-L1+ MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1+ MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1+in vivo. In contrast, PD-L1+ MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1- in tumor-bearing mice. IFNγ is highly expressed in cells of the tumor tissues and IFNγ neutralization significantly decreased PD-L1+ MDSCs in the tumor microenvironment in vivo. However, IFNγ-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.


Comparison of clinical couse and sequential electrophysiological tests in diabetics with symptomatic polyneuropathy and its implications for clinical trials.
The use of electrophysiological (EP) tests as the primary basis for determining outcome in clinical trials of therapy for symptomatic diabetic polyneuropathy, and the frequently short duration of such trials, is based on assumptions at variance with the pathology and natural history of this disorder and with the evidence that the commonly employed EP tests predominantly reflect the status of the large myelinated nerve fibers. The course of painful, distal symmetrical, primarily sensory polyneuropathy was studied in nine chronic diabetics, aged 21--59 yr, selected for the absence of other forms of diabetic neuropathy, other causes of neuropathy, and other significant illness. All were treated with modifications of diet, insulin, and a daily multivitamin tablet, and, on a randomized basis, also received either placebo or myo-inositol tablets. Initially, and after 2, 4, and 6 mo, a standardized questionnaire was used to assess symptoms, and a standardized neurological examination and battery of EP tests were performed. A minimum of 6 mo was found necessary to assess the clinical course of this syndrome. Clinical improvement occurred in both legs and arms in four patients, as judged by improvement both in symptoms and in the extent of deficits in pinprick and temperature perception; abnormalities in sensory modalities mediated by large myelinated fibers, however, were generally unaltered after 6 mo. A nonuniform distribution of abnormal EP tests of sensory components of the commonly studied nerves of the leg and arm was demonstrated in the study group at the outset, and clinical improvement was not accompanied by evidence of any consistent pattern of improvement in the initially abnormal EP tests. A significant fraction of chronic diabetics with painful, distal symmetrical, primarily sensory polyneuropathy selected by standard criteria appear to have potential for clinical improvement over 6 mo, but primarily in sensory modalities that make it inappropriate to use the common EP tests as the primary basis of judging outcome.


Subcellular localization of the Hpa RxLR effector repertoire identifies a tonoplast-associated protein HaRxL17 that confers enhanced plant susceptibility.
Filamentous phytopathogens form sophisticated intracellular feeding structures called haustoria in plant cells. Pathogen effectors are likely to play a role in the establishment and maintenance of haustoria in addition to their better-characterized role in suppressing plant defence. However, the specific mechanisms by which these effectors promote virulence remain unclear. To address this question, we examined changes in subcellular architecture using live-cell imaging during the compatible interaction between the oomycete Hyaloperonospora arabidopsidis (Hpa) and its host Arabidopsis. We monitored host-cell restructuring of subcellular compartments within plant mesophyll cells during haustoria ontogenesis. Live-cell imaging highlighted rearrangements in plant cell membranes upon infection, in particular to the tonoplast, which was located close to the extra-haustorial membrane surrounding the haustorium. We also investigated the subcellular localization patterns of Hpa RxLR effector candidates (HaRxLs) in planta. We identified two major classes of HaRxL effector based on localization: nuclear-localized effectors and membrane-localized effectors. Further, we identified a single effector, HaRxL17, that associated with the tonoplast in uninfected cells and with membranes around haustoria, probably the extra-haustorial membrane, in infected cells. Functional analysis of selected effector candidates in planta revealed that HaRxL17 enhances plant susceptibility. The roles of subcellular changes and effector localization, with specific reference to the potential role of HaRxL17 in plant cell membrane trafficking, are discussed with respect to Hpa virulence.


Patterned Anchorage to the Apical Extracellular Matrix Defines Tissue Shape in the Developing Appendages of Drosophila.
How tissues acquire their characteristic shape is a fundamental unresolved question in biology. While genes have been characterized that control local mechanical forces to elongate epithelial tissues, genes controlling global forces in epithelia have yet to be identified. Here, we describe a genetic pathway that shapes appendages in Drosophila by defining the pattern of global tensile forces in the tissue. In the appendages, shape arises from tension generated by cell constriction and localized anchorage of the epithelium to the cuticle via the apical extracellular-matrix protein Dumpy (Dp). Altering Dp expression in the developing wing results in predictable changes in wing shape that can be simulated by a computational model that incorporates only tissue contraction and localized anchorage. Three other wing shape genes, narrow, tapered, and lanceolate, encode components of a pathway that modulates Dp distribution in the wing to refine the global force pattern and thus wing shape.


Quantum dot cytotoxicity and ways to reduce it.
The dramatic increase in the use of nanoparticles (NP) in industry and research has raised questions about the potential toxicity of such materials. Unfortunately, not enough is known about how the novel, technologically-attractive properties of NPs correlate with the interactions that may take place at the nano/bio interface. The academic, industrial, and regulatory communities are actively seeking answers to the growing concerns on the impact of nanotechnology on humans. In this Account we adopt quantum dots (QDs) as an illustrative example of the difficulties associated with the development of a rational science-based approach to nanotoxicology. The optical properties of QDs are far superior to those of organic dyes in terms of emission and absorption bandwidths, quantum yield, and resistance to photobleaching. Moreover, QDs may be decorated with targeting moieties or drugs and, therefore, are candidates for site-specific medical imaging and for drug delivery, for example in cancer treatment. Earlier this year researchers demonstrated that QD-based imaging using monkeys caused no adverse effects although QDs accumulated in lymph nodes, bone marrow, liver, and spleen for up to 3 months after injection. Such persistence of QDs in live animals does, however, raise concerns about the safety of using QDs both in the laboratory and in the clinic. Researchers anticipate that QDs will be increasingly used not only in clinical applications but also in various manufactured products. For example, QD-solar cells have emerged as viable contenders to complement or replace dye-sensitized solar cells; CdTe/CdS thin film cells have already captured approximately 10 percent of the global market, and in addition, QDs can serve as components of sensors and as emitting materials in LEDs. Given the clear indications that QDs will inevitably become components of a wide range of manufactured and consumer products, researchers and policy makers need to understand the possible health risks associated with exposure to QDs. In this Account, we initially review the known mechanisms by which QDs can damage cells, including oxidative stress elicited by reactive oxygen species (ROS). We discuss lesser-known impairments induced in cells by nanomolar to picomolar concentrations of QDs, which imply that cadmium-containing QDs can exert genotoxic, epigenetic, and metalloestrogenic effects. These observations strongly suggest that minute concentrations of QDs could be sufficient to cause long lasting, even transgenerational, effects. We also consider various modes by which humans could be exposed to QDs in their work or through the environment. Although considerable advances have been made in enhancing the stability and overall quality of QDs, over time they can partially degrade in the environment or in biological systems, and eventually cause small, but cumulative undesirable effects. A combination of toxicological, genetic, epigenetic and imaging approaches is required to create comprehensive guidelines for evaluating the nanotoxicity of nanomaterials, including QDs. Prior to biological investigations with these materials, an indispensible step must be the full characterization of NPs by complementary techniques. Specifically, the concentration, size, charge, and ligand stability of NPs in biological media must be known if we are to understand fully how the properties of nanoparticles and of their biological environment contribute to cytotoxicity.


Go for broke: The role of somatic states when asked to lose in the Iowa Gambling Task.
The Somatic Marker Hypothesis (SMH) posits that somatic states develop and guide advantageous decision making by "marking" disadvantageous options (i.e., arousal increases when poor options are considered). This assumption was tested using the standard Iowa Gambling Task (IGT) in which participants win/lose money by selecting among four decks of cards, and an alternative version, identical in both structure and payoffs, but with the aim changed to lose as much money as possible. This "lose" version of the IGT reverses which decks are advantageous/disadvantageous; and so reverses which decks should be marked by somatic responses - which we assessed via skin conductance (SC). Participants learned to pick advantageously in the original (Win) IGT and in the (new) Lose IGT. Using multilevel regression, some variability in anticipatory SC across blocks was found but no consistent effect of anticipatory SC on disadvantageous deck selections. Thus, while we successfully developed a new way to test the central claims of the SMH, we did not find consistent support for the SMH.


Assessment of miR-181b-5p, miR-23a-3p, BCL-2, and IL-6 in Peripheral Blood Mononuclear Cells of Autistic Patients; Likelihood of Reliable Biomarkers.
Autism is a neurodevelopmental disorder that is recognized by stereotypic and repetitive behaviors after 2 years of old. Dysregulation of the immune system, especially inflammation which is mostly regulated by IL-6, imposes a deficit in CNS development. Along with this crucial biomarker, researchers have proposed BCL-2, micro RNA-23a-3p (miR-23a-3p), miR-181b-5p as other probable biomarkers involved in inflammation and apoptosis. The aim of the study was to evaluate the alteration in the expression of these biomarkers in a group of autism spectrum disorder (ASD) children. Peripheral blood mononuclear cells (PBMCs) were obtained from 37 autistic patients. After RNA extraction with precipitation method, the Syber green qReal-time Polymerase Chain Reaction (PCR) was performed in order to evaluate the possible alteration in the expression of IL-6, BCL-2, miR-181b-5p, and miR-23a-3p. The results were compared with healthy controls. IL-6 was significantly upregulated in ASD patients (p=0.003). On the other hand, miR-23a was upregulated and BCL-2 downregulated in ASD patients but the changes were not significant. In initial evaluations, expression changes of miR-181b-5p were not statistically significant. However, when Patients were divided into two groups of upregulated and downregulated, re-evaluation showed that both up- (p=0.005) and down-regulation (p=0.004) (i.e. changes regardless of the direction) of miR-181b were significant in autistic children. IL-6 and miR-181b-5p can have proper diagnostic values and are reliable biomarkers with high sensitivity and specificity. On the other hand, PBMC can be utilized for such studies and also evaluation of patients' condition instead of brain tissue as it is less accessible.


Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma.
Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.


Measures to summarize and compare the predictive capacity of markers.
The predictive capacity of a marker in a population can be described using the population distribution of risk (Huang et al. 2007; Pepe et al. 2008a; Stern 2008). Virtually all standard statistical summaries of predictability and discrimination can be derived from it (Gail and Pfeiffer 2005). The goal of this paper is to develop methods for making inference about risk prediction markers using summary measures derived from the risk distribution. We describe some new clinically motivated summary measures and give new interpretations to some existing statistical measures. Methods for estimating these summary measures are described along with distribution theory that facilitates construction of confidence intervals from data. We show how markers and, more generally, how risk prediction models, can be compared using clinically relevant measures of predictability. The methods are illustrated by application to markers of lung function and nutritional status for predicting subsequent onset of major pulmonary infection in children suffering from cystic fibrosis. Simulation studies show that methods for inference are valid for use in practice.


Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model.
Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.


Comparative expression of two abscisic acid-inducible genes and proteins in seeds of aromatic indica rice cultivar with that of non-aromatic indica rice cultivars.
As an integral part of stress signal transduction, the phytohormone abscisic acid (ABA) regulates important cellular reactions, including up-regulation of stress-associated genes, the products of which are involved directly or indirectly in plant protection. Being accompanied by an increased endogenous ABA level, the matured seeds, embryo and aleurone tissues of cereals accumulate several genes and proteins, associated with desiccation. The present study was aimed at investigating how the contrasting rice genotypes, varying in their salt-stress sensitivity, differ with respect to the expression pattern of two abiotic stress-inducible genes, Rab16A and SamDC, and corresponding proteins, in the seeds, at the background level (dry or water-imbibed state) and ABA-imbibed conditions, which could be related to the varietal differences in tolerance. The rice genotypes selected were M-1-48 (salt-sensitive), Nonabokra (salt-tolerant) and Gobindobhog (aromatic). An extremely low abundance of Rab16A or practically undetectable SamDC transcripts were observed in M-1-48 and Gobindobhog seeds under control conditions, induced only after exogenous ABA treatment, whereas they were expressed at a much higher level even in dry and water-imbibed seeds of Nonabokra, and lesser induced by ABA. The RAB16A (=dehydrin) and SAMDC protein expression in the three varieties were also identical to the gene expression patterns. Thus, the expression was stress-inducible in M-1-48 and Gobindobhog, while constitutive in Nonabokra. Our study reflected the similarity of the molecular responses to exogenous ABA of the seeds of the aromatic rice Gobindobhog to that of the salt-sensitive M-1-48, in exhibiting lower expression of stress-tolerant proteins only after stress. This work also proved that variation in gene/protein expression in seeds could be highly correlated with the variation in the tolerance mechanism of rice varieties.


[Prevalence of colorectal adenoma is increased in patients with gastric adenoma].
It has been reported that patients with gastric cancer may be at increased risk of synchronous or metachronous colorectal cancer. However, the incidence of colorectal adenoma in patients with gastric adenoma has not been discussed earlier. The aims of this study were to investigate the incidence of colorectal adenoma and to evaluate the necessity of colonoscopic surveillance in patients with gastric adenoma. We performed colonoscopy in 221 patients with gastric adenoma between January 2002 and June 2008. As a control group, 387 consecutive patients without gastric adenoma on gastroscopy who underwent colonoscopy were included. We retrospectively examined the endoscopic and colonoscopic findings as well as the clinicopathologic features. Colorectal adenoma were diagnosed in 57.5% (127/221) of the gastric adenoma group and 38.0% (147/387) of the control group (p<0.001). Univariate analysis demonstrated that gender, age, past history of diabetes, and past history of gastric adenoma were associated with the risk of colorectal adenoma. Multivariate analysis demonstrated that gender (male, aOR 2.31, 95% CI 1.61-3.31), age (> or =50 years, aOR 2.47, 95% CI 1.53-4.01), past history of diabetes (aOR 2.35, 95% CI 1.32-4.20), and presence of gastric adenoma (aOR 1.63, 95% CI 1.13-2.36) appeared to be independent risk factors for colorectal adenoma. The risk of colorectal adenoma increases significantly in patients with gastric adenoma. We suggest that colonoscopic surveillance may be necessary in patients with gastric adenoma.


Spaceflight influences both mucosal and peripheral cytokine production in PTN-Tg and wild type mice.
Spaceflight is associated with several health issues including diminished immune efficiency. Effects of long-term spaceflight on selected immune parameters of wild type (Wt) and transgenic mice over-expressing pleiotrophin under the human bone-specific osteocalcin promoter (PTN-Tg) were examined using the novel Mouse Drawer System (MDS) aboard the International Space Station (ISS) over a 91 day period. Effects of this long duration flight on PTN-Tg and Wt mice were determined in comparison to ground controls and vivarium-housed PTN-Tg and Wt mice. Levels of interleukin-2 (IL-2) and transforming growth factor-beta1 (TGF-β1) were measured in mucosal and systemic tissues of Wt and PTN-Tg mice. Colonic contents were also analyzed to assess potential effects on the gut microbiota, although no firm conclusions could be made due to constraints imposed by the MDS payload and the time of sampling. Spaceflight-associated differences were observed in colonic tissue and systemic lymph node levels of IL-2 and TGF-β1 relative to ground controls. Total colonic TGF-β1 levels were lower in Wt and PTN-Tg flight mice in comparison to ground controls. The Wt flight mouse had lower levels of IL-2 and TGF-β1 compared to the Wt ground control in both the inguinal and brachial lymph nodes, however this pattern was not consistently observed in PTN-Tg mice. Vivarium-housed Wt controls had higher levels of active TGF-β1 and IL-2 in inguinal lymph nodes relative to PTN-Tg mice. The results of this study suggest compartmentalized effects of spaceflight and on immune parameters in mice.


Phylogenetic host specificity and understanding parasite sharing in primates.
Understanding how parasites are transmitted to new species is of great importance for human health, agriculture and conservation. However, it is still unclear why some parasites are shared by many species, while others have only one host. Using a new measure of 'phylogenetic host specificity', we find that most primate parasites with more than one host are phylogenetic generalists, infecting less closely related primates than expected. Evolutionary models suggest that phylogenetic host generalism is driven by a mixture of host-parasite cospeciation and lower rates of parasite extinction. We also show that phylogenetic relatedness is important in most analyses, but fails to fully explain patterns of parasite sharing among primates. Host ecology and geographical distribution emerged as key additional factors that influence contacts among hosts to facilitate sharing. Greater understanding of these factors is therefore crucial to improve our ability to predict future infectious disease risks.


The effect of clockwise and counterclockwise twisting moments on abutment screw loosening.
Abutment screw loosening is one of the most common complications of dental implants. When occlusal loading is applied, bending and twisting moments are counteracted by the implant-abutment connection held with the abutment screw. Restorations in different quarters of the oral cavity might bear clockwise or counterclockwise twisting moments that result from a regular chewing pattern. The aim of this study was to investigate the effect of different directional twisting moments on abutment screws. Twenty 3i implants were divided into four groups of C, R, L, and O. Each assembly consisted of an implant, abutment, and superstructure. For group C, a cyclic load of 10-100 N for 10(6) cycles was applied centrally and perpendicular to the long axis of the implant, whereas for groups R and L, the same load conditions were applied eccentrically in clockwise and counterclockwise directions, respectively. Group O was left unloaded. The difference between the initial torque and post-load reverse torque was defined as the total torque loss. The data were analyzed by Kruskal-Wallis test. The surface of the abutment hexagon corners were examined with SEM after loading. No abutment screw loosening was found after loading. Total torque loss of groups C, R, L, and O were 10.50 ± 0.58, 9.56 ± 1.01, 9.98 ± 1.81, and 9.58 ± 0.94 Ncm, respectively. There were no statistical differences among the four groups. SEM observations showed marked burnishing at the hexagonal corners on the compression sides of the R and L groups. Within the limitations of this study, there was little effect of twisting moment direction on the total torque loss of an internal hexagon connection implant system. This could be attributed to the anti-twisting mechanism of the internal hexagon connection.


IgG antibodies against deamidated gliadin peptides for diagnosis of celiac disease in patients with IgA deficiency.
Assays for IgG antibodies against deamidated gliadin (IgG-anti-dGli) are comparable in performance with tests detecting IgA antibodies against tissue transglutaminase (IgA-anti-tTG) in diagnosing celiac disease (CD). IgA-anti-tTG are absent in IgA deficiency, a condition often associated with CD. In IgA deficiency, IgG-anti-tTG, which have a lower overall diagnostic accuracy, are routinely measured. We examined whether IgG-anti-dGli would be useful for diagnosing CD in patients with IgA deficiency. We studied 34 IgA-deficient CD patients, 185 IgA-competent newly diagnosed children with CD, 316 children without CD, 400 adult blood donors, and 6 control IgA-deficient individuals without CD. Anti-dGli and anti-tTG were measured by ELISA, and endomysium antibodies (EmA) were measured by immunofluorescence on monkey esophagus (IgA as well as IgG class for all antibodies). We calculated diagnostic sensitivity (percentage of patients above cutoff with 95% CIs) according to age-specific cutoffs for 95% diagnostic specificity and according to cutoffs proposed by the manufacturer of the assays. No IgA-deficient CD patients were positive for any IgA-based antibody assay. Diagnostic sensitivity of IgG-anti-tTG was 91.2% (95% CI 76.3%-97.7%) according to age-specific cutoffs and 82.4% (66.1%-92.0%) according to manufacturer cutoffs. The diagnostic sensitivity of IgG-EmA was 75.8% (58.8%-87.4%) and the sensitivity of IgG-anti-dGli was 88.2% (72.8%-95.9%) according to both cutoffs. IgG-anti-dGli and IgG-anti-tTG have comparable diagnostic sensitivities for IgA-deficient celiac patients. IgG-anti-dGli may be useful for diagnosing CD in IgA-deficient patients.


Common femoral artery ligation and local debridement: a safe treatment for infected femoral artery pseudoaneurysms.
The management of infected femoral artery pseudoaneurysms (IFAPs) is difficult and controversial. Use of synthetic or autologous conduit during arterial revascularization in these cases is complicated by the presence of sepsis and unavailability of autologous venous conduit. We present the results of common femoral artery (CFA) ligation and local drainage with debridement for the treatment of IFAP. A retrospective chart review of six consecutive patients from 1995 to 1999 who presented with IFAP from intravenous drug abuse was performed. Inpatient records, anesthesia records, and outpatient clinic charts were reviewed. All patients were men with right-sided lesions. All six patients abused heroin, and five (83%) abused heroin and cocaine. All six patients had a duplex ultrasound scan, and five (83%) patients had a digital subtraction angiogram to confirm the clinical diagnosis. Proximal vascular control was achieved retroperitoneally through an oblique suprainguinal incision. After vascular isolation and test clamping of the distal external iliac artery (EIA), the pedal pulses were examined with continuous wave Doppler scan. If a Doppler signal was present, this was followed with CFA ligation and local drainage and debridement of the IFAP. Pain at injection site and fever with chills were present in five (83%) and three (50%) patients, respectively. A pulsatile groin mass and thigh or leg edema were present in five (83%) patients. Three patients (50%) had a palpable pedal pulse, and all six had a Doppler signal over a pedal artery at presentation. The mean white cell count was 15.6 thousand per cubic millimeter (range, 9.2-19.3). All patients had a Doppler signal over a pedal artery after distal EIA/CFA test occlusion and ligation. None of the patients required an amputation, and all six patients regained their preoperative ambulatory status. The mean follow-up period was 25 months. Two patients had mild claudication (5-6 blocks) at 18 months and 2 years after surgery. All six patients received drug rehabilitation, but they admitted to drug abuse after surgery and rehabilitation. CFA ligation and local debridement are safe treatment modalities for IFAP, if there is an intraoperative Doppler signal over a pedal artery during test occlusion of the distal EIA/CFA. CFA ligation avoids the use and therefore the risk of synthetic conduit infection, because there is a high incidence of postoperative drug injection despite aggressive drug rehabilitation.


Pitfalls in the response evaluation after peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate.
Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) is a treatment with good results in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEPNETs). However, there are some pitfalls that should be taken into consideration when evaluating the treatment response after PRRT. 354 Dutch patients with GEPNETs who were treated with 177Lu-DOTATATE between March 2000 and December 2011 were retrospectively selected. Liver function parameters and chromogranin A were measured before each therapy and in follow-up. Anatomical imaging was performed before therapy and in follow-up. An increase in aminotransferases by ≥20% compared to baseline was observed in 83 of 351 patients (24%). In patients with an objective response (OR) and stable disease (SD) this increase was observed in 71/297 (24%) and in patients with progressive disease (PD) it was observed in 12/54 patients (22%). An increase in chromogranin A by ≥20% compared to baseline was observed in 76 patients (29%). This was present in 34% of patients who eventually had PD and 27% of patients who had OR/SD. In 70% of patients this tumour marker returned to baseline levels after therapy. An increase in liver enzymes and chromogranin A is not uncommon after PRRT. In the vast majority of patients this will resolve in follow-up. Clinicians should be aware that these changes may occur due to radiation-induced inflammation or disease progression and that repeated measurements over time are necessary to differentiate between the two.


Effect of wealth inequality on chronic under-nutrition in Cambodian children.
The problems of food insecurity and under-nutrition remain particularly severe in countries recovering from recent wars or civil unrest, where improvements in economic conditions have tended to benefit the advantaged groups and resulted in widespread inequalities in health. Using information on 3235 children aged 0-59 month(s) included in the 2000 Cambodia Demographic and Health Survey, this study examined how economic inequality was associated with inequalities in chronic childhood under-nutrition. An under-nourished (stunted) child was defined as having his/her height-for-age more than two standard deviations below the reference median. Household wealth status was measured by an index based on household ownership of durable assets. Binary and multinomial logistic regressions were used for estimating the effects of household wealth status on moderate and severe stunting. The results indicated that children in the poorest 20% households were more than twice as likely to suffer from stunting as children in the richest 20% households (odds ratio [OR]=2.54; 95% confidence interval [CI] 1.91-3.39). Adjusting for child's age, sex, birth order, and duration of breastfeeding; age of mother at childbirth, body mass index, and education; and household access to safe drinking-water, hygienic toilet facility, residence, and geographic region made little difference to this effect (OR=2.05; 95% CI 1.28-3.28). The adjusted effect of wealth status was somewhat stronger on severe stunting (relative risk ratio [RRR]=2.26; 95% CI 1.22-4.18) than on moderate stunting (RRR=1.89; 95% CI 1.12-3.20). The study concludes that wealth inequality is strongly associated with chronic childhood under-nutrition and emphasizes that reducing poverty and making services more accessible to the poor will be key to improving the health and nutritional status of children in Cambodia.


Substrate-specific clades of active marine methylotrophs associated with a phytoplankton bloom in a temperate coastal environment.
Marine microorganisms that consume one-carbon (C(1)) compounds are poorly described, despite their impact on global climate via an influence on aquatic and atmospheric chemistry. This study investigated marine bacterial communities involved in the metabolism of C(1) compounds. These communities were of relevance to surface seawater and atmospheric chemistry in the context of a bloom that was dominated by phytoplankton known to produce dimethylsulfoniopropionate. In addition to using 16S rRNA gene fingerprinting and clone libraries to characterize samples taken from a bloom transect in July 2006, seawater samples from the phytoplankton bloom were incubated with (13)C-labeled methanol, monomethylamine, dimethylamine, methyl bromide, and dimethyl sulfide to identify microbial populations involved in the turnover of C(1) compounds, using DNA stable isotope probing. The [(13)C]DNA samples from a single time point were characterized and compared using denaturing gradient gel electrophoresis (DGGE), fingerprint cluster analysis, and 16S rRNA gene clone library analysis. Bacterial community DGGE fingerprints from (13)C-labeled DNA were distinct from those obtained with the DNA of the nonlabeled community DNA and suggested some overlap in substrate utilization between active methylotroph populations growing on different C(1) substrates. Active methylotrophs were affiliated with Methylophaga spp. and several clades of undescribed Gammaproteobacteria that utilized methanol, methylamines (both monomethylamine and dimethylamine), and dimethyl sulfide. rRNA gene sequences corresponding to populations assimilating (13)C-labeled methyl bromide and other substrates were associated with members of the Alphaproteobacteria (e.g., the family Rhodobacteraceae), the Cytophaga-Flexibacter-Bacteroides group, and unknown taxa. This study expands the known diversity of marine methylotrophs in surface seawater and provides a comprehensive data set for focused cultivation and metagenomic analyses in the future.


Influence on motility of Escherichia coli and Salmonella typhimurium by a naturally occurring conjugative plasmid.
In a collection of 45 R-plasmids, one was found to be associated with loss of motility of its Escherichia coli K-12 and Salmonella typhimurium host bacteria when tested in conventional motility agar. Genetic experiments, as well as analyses of deoxyribonucleic acid, showed that inhibition of motility was caused by a conjugative plasmid that was separate from the R-plasmid. This second plasmid, named pUM5, was fi- and mediated the same type of sex pilus (F-like) as the accompanying R-plasmid but lacked resistance determinants. Preliminary studies indicated that bacterial cells carrying the motility inhibition plasmid pUM5 were still equipped with flagella. The mechanism by which flagellar action is disturbed by the plasmid is presently not known.


Eutrophication in the Yunnan Plateau lakes: the influence of lake morphology, watershed land use, and socioeconomic factors.
Lakes play an important role in socioeconomic development and ecological balance in China, but their water quality has deteriorated considerably in recent decades. In this study, we investigated the spatial-temporal variations of eutrophication parameters (secchi depth, total nitrogen, total phosphorus, chemical oxygen demand, chlorophyll-a, trophic level index, and trophic state index) and their relationships with lake morphology, watershed land use, and socioeconomic factors in the Yunnan Plateau lakes. Results indicated that about 77.8% of lakes were eutrophic according to trophic state index. The plateau lakes showed spatial variations in water quality and could be classified into high-nutrient and low-nutrient groups. However, because watersheds were dominated by vegetation, all eutrophication parameters except chlorophyll-a showed no significant differences between the wet and dry seasons. Lake depth, water residence time, volume, and percentage of built-up land were significantly related to several eutrophication parameters. Agricultural land use and social-economic factors had no significant correlation with all eutrophication parameters. Stepwise regression analyses demonstrated that lake depth and water residence time accounted for 73.8% to 87.6% of the spatial variation of single water quality variables, respectively. Redundancy analyses indicated that lake morphology, watershed land use, and socioeconomic factors together explained 74.3% of the spatial variation in overall water quality. The results imply that water quality degradation in the plateau lakes may be mainly due to the domestic and industrial wastewaters. This study will improve our understanding of the determinants of lake water quality and help to design efficient strategies for controlling eutrophication in the plateau region.


A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.
Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.


In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment.
The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells.


Immunophenotyping leukemias: the new force in hematology.
To review basic concepts of immunophenotyping leukemias and introduce clinical laboratory scientists (CLSs) to the technological changes utilized in this laboratory methodology. Literature review. Immunophenotyping in the clinical laboratory is emerging as an advantageous way to separate and classify leukemic malignancies. Immunophenotyping involves the use of flow cytometers and immunofluorescence in order to achieve great sensitivity and specificity for malignant cells. A basic understanding of components of the flow cytometer and how it works is necessary to understand immunophenotyping. Monoclonal antibodies specific to the malignant cells of question play an essential part in this technique. Various fluorescent dyes and cell panels also must be incorporated into the system. Analysis is done and statistics are plotted on dot plots that can be read by the CLS to give helpful insight into the etiology of disease process. Immunophenotyping is a very powerful tool that has the ability to revolutionize the clinical laboratory setting. The CLS working in hematology must become aware of and comfortable with this methodology.


NLS-dependent nuclear localization of p120ctn is necessary to relieve Kaiso-mediated transcriptional repression.
The Armadillo catenin p120(ctn) regulates cadherin adhesive strength at the plasma membrane and interacts with the novel BTB/POZ transcriptional repressor Kaiso in the nucleus. The dual localization of p120(ctn) at cell-cell junctions and in the nucleus suggests that its nucleocytoplasmic trafficking is tightly regulated. Here we report on the identification of a specific and highly basic nuclear localization signal (NLS) in p120(ctn). The functionality of the NLS was validated by its ability to direct the nuclear localization of a heterologous beta-galactosidase-GFP fusion protein. Mutating two key positively charged lysines to neutral alanines in the NLS of full-length p120(ctn) inhibited both p120(ctn) nuclear localization as well as the characteristic p120(ctn)-induced branching phenotype that correlates with increased cell migration. However, while these findings and others suggested that nuclear localization of p120(ctn) was crucial for the p120(ctn)-induced branching phenotype, we found that forced nuclear localization of both wild-type and NLS-mutated p120(ctn) did not induce branching. Recently, we also found that one role of p120(ctn) was to regulate Kaiso-mediated transcriptional repression. However, it remained unclear whether p120(ctn) sequestered Kaiso in the cytosol or directly inhibited Kaiso transcriptional activity in the nucleus. Using minimal promoter assays, we show here that the regulatory effect of p120(ctn) on Kaiso transcriptional activity requires the nuclear translocation of p120(ctn). Therefore, an intact NLS in p120(ctn) is requisite for its first identified regulatory role of the transcriptional repressor Kaiso.


Economic Cost of Severe Acute Respiratory Infection Associated to Influenza in Colombian Children: A Single Setting Analysis.
Influenza is considered a leading public health problem because its large economic burden of disease worldwide, especially in low-and middle-income countries, such as Colombia. We aimed to estimate the economic costs of influenza-confirmed patients in a pediatric hospital in Cartagena, Colombia. We conducted a retrospective costing analysis. We estimated the direct (direct medical and out-of-pocket expenditures) and indirect costs for influenza-confirmed severe acute respiratory infection cases from a societal perspective. Total economic costs were calculated adding direct medical costs, out-of-pocket expenditures, and indirect costs owing to loss of productivity of caregivers. Mean, median, 95% confidence interval (95% CI) and interquartile range (IQR) of costs were measured. All costs are reported in USD ($1.00 = COP$2000.7) RESULTS: Forty-four cases were included in the analysis: 30 had influenza B, 10 influenza A and B, and 4 influenza AH1N1. Thirty patients were hospitalized in the general ward, 14 went to the intensive care unit. The average duration of stay was ∼9 days (95% CI, 6.3-11.5). The median direct medical cost for hospitalized case in general ward was $743.50 (IQR $590.20-$1404.60) and in intensive care unit $4669.80 (IQR $1614.60-$7801.50). The economic cost per hospitalized case was $1826.10 (IQR $1343.30-$2376.50); direct medical costs represented 93.8% of this cost. The median indirect cost was $82.10 (IQR $41.10-$133.40) and the median out-of-pocket expenditure per case was $45.70 (IQR $29.50-$64.90). Severe acute respiratory infection is an important source of economic burden for the health system, families, and society in Colombia. Seasonal influenza vaccination should be strengthened to prevent more cases and save economic resources.


Ecological risk assessment of boreal sediments affected by metal mining: Metal geochemistry, seasonality, and comparison of several risk assessment methods.
The mining industry is a common source of environmental metal emissions, which cause long-lasting effects in aquatic ecosystems. Metal risk assessment is challenging due to variations in metal distribution, speciation, and bioavailability. Therefore, seasonal effects must be better understood, especially in boreal regions in which seasonal changes are large. We sampled 4 Finnish lakes and sediments affected by mining for metals and geochemical characteristics in autumn and late winter, to evaluate seasonal changes in metal behavior, the importance of seasonality in risk assessment, and the sensitivity and suitability of different risk assessment methods. We compared metal concentrations in sediment, overlying water, and porewater against environmental quality guidelines (EQGs). We also evaluated the toxicity of metal mixtures using simultaneously extracted metals and an acid volatile sulfides (SEM-AVS) approach together with water quality criteria (US Environmental Protection Agency equilibrium partitioning benchmarks). Finally, site-specific risks for 3 metals (Cu, Ni, Zn) were assessed using 2 biotic ligand models (BLMs). The metal concentrations in the impacted lakes were elevated. During winter stratification, the hypolimnetic O2 saturation levels were low (<6%) and the pH was acidic (3.5-6.5); however, abundant O2 (>89%) and neutral pH (6.1-7.5) were found after the autumnal water overturn. Guidelines were the most conservative benchmark for showing an increased risk of toxicity in the all of the lakes. The situation remained stable between seasons. On the other hand, SEM-AVS, equilibrium partition sediment benchmarks (ESBs), and BLMs provided a clearer distinction between lakes and revealed a seasonal variation in risk among some of the lakes, which evidenced a higher risk during late winter. If a sediment risk assessment is based on the situation in the autumn, the overall risk may be underestimated. It is advisable to carry out sampling and risk assessment during periods in which metals are assumed to be the most environmentally harmful. Integr Environ Assess Manag 2016;12:759-771. © 2015 SETAC.


Osmotic pressure in polyelectrolyte solutions: cell-model and bulk simulations.
The osmotic pressure of polyelectrolyte solutions as a function of concentration has been calculated by Monte Carlo simulations of a spherical cell model and by molecular dynamics simulations with periodic boundary conditions. The results for the coarse-grained polyelectrolyte model are in good agreement with experimental results for sodium polyacrylate and the cell model is validated by the bulk simulations. The cell model offers an alternative perspective on osmotic pressure and also forms a direct link to even simpler models in the form of the Poisson-Boltzmann approximation applied to cylindrical and spherical geometries. As a result, the non-monotonic behaviour of the osmotic coefficient seen in simulated salt-free solutions is shown not to rely on a transition between a dilute and semi-dilute regime, as is often suggested when the polyion is modelled as a linear flexible chain. The non-monotonic behaviour is better described as the combination of a finite-size effect and a double-layer effect. Parameters that represent the linear nature of the polyion, including an alternative to monomer concentration, make it possible to display a generalised behaviour of equivalent chains, at least at low concentrations. At high concentrations, local interactions become significant and the exact details of the model become important. The effects of added salt are also discussed and one conclusion is that the empirical additivity rule, treating the contributions from the polyelectrolyte and any salt separately, is a reasonable approximation, which justifies the study of salt-free solutions.


High-dynamic range image projection using an auxiliary MEMS mirror array.
We introduce a new concept to improve the contrast and peak brightness of conventional data projectors. Our method provides a non-homogenous light source by dynamically directing fractions of the light from the projector lamp before it reaches the display mechanism. This will supply more light to the areas that need it most, at the expense of the darker parts of the image. In effect, this method will produce a low resolution version of the image onto the image-forming element. To manipulate the light in this manner, we propose using an intermediate array of microelectromechanical system (MEMS) mirrors. By directing the light away from the dark parts earlier in the display chain, the amount of light that needs to be blocked will be reduced, thus decreasing the black level of the final image. Moreover, the ability to dynamically allocate more light to the bright parts of the image will allow for peak brightness higher than the average maximum brightness of display.


Depression, chronic diseases, and decrements in health: results from the World Health Surveys.
Depression is an important public-health problem, and one of the leading causes of disease burden worldwide. Depression is often comorbid with other chronic diseases and can worsen their associated health outcomes. Few studies have explored the effect of depression, alone or as a comorbidity, on overall health status. The WHO World Health Survey (WHS) studied adults aged 18 years and older to obtain data for health, health-related outcomes, and their determinants. Prevalence of depression in respondents based on ICD-10 criteria was estimated. Prevalence values for four chronic physical diseases--angina, arthritis, asthma, and diabetes--were also estimated using algorithms derived via a Diagnostic Item Probability Study. Mean health scores were constructed using factor analysis and compared across different disease states and demographic variables. The relation of these disease states to mean health scores was determined through regression modelling. Observations were available for 245 404 participants from 60 countries in all regions of the world. Overall, 1-year prevalence for ICD-10 depressive episode alone was 3.2% (95% CI 3.0-3.5); for angina 4.5% (4.3-4.8); for arthritis 4.1% (3.8-4.3); for asthma 3.3% (2.9-3.6); and for diabetes 2.0% (1.8-2.2). An average of between 9.3% and 23.0% of participants with one or more chronic physical disease had comorbid depression. This result was significantly higher than the likelihood of having depression in the absence of a chronic physical disease (p<0.0001). After adjustment for socioeconomic factors and health conditions, depression had the largest effect on worsening mean health scores compared with the other chronic conditions. Consistently across countries and different demographic characteristics, respondents with depression comorbid with one or more chronic diseases had the worst health scores of all the disease states. Depression produces the greatest decrement in health compared with the chronic diseases angina, arthritis, asthma, and diabetes. The comorbid state of depression incrementally worsens health compared with depression alone, with any of the chronic diseases alone, and with any combination of chronic diseases without depression. These results indicate the urgency of addressing depression as a public-health priority to reduce disease burden and disability, and to improve the overall health of populations.