Network deconvolution as a general method to distinguish direct dependencies in networks.
Recognizing direct relationships between variables connected in a network is a pervasive problem in biological, social and information sciences as correlation-based networks contain numerous indirect relationships. Here we present a general method for inferring direct effects from an observed correlation matrix containing both direct and indirect effects. We formulate the problem as the inverse of network convolution, and introduce an algorithm that removes the combined effect of all indirect paths of arbitrary length in a closed-form solution by exploiting eigen-decomposition and infinite-series sums. We demonstrate the effectiveness of our approach in several network applications: distinguishing direct targets in gene expression regulatory networks; recognizing directly interacting amino-acid residues for protein structure prediction from sequence alignments; and distinguishing strong collaborations in co-authorship social networks using connectivity information alone. In addition to its theoretical impact as a foundational graph theoretic tool, our results suggest network deconvolution is widely applicable for computing direct dependencies in network science across diverse disciplines.


Spatiotemporal multi-disease transmission dynamic measure for emerging diseases: an application to dengue and zika integrated surveillance in Thailand.
New emerging diseases are public health concerns in which policy makers have to make decisions in the presence of enormous uncertainty. This is an important challenge in terms of emergency preparation requiring the operation of effective surveillance systems. A key concept to investigate the dynamic of infectious diseases is the basic reproduction number. However it is difficult to be applicable in real situations due to the underlying theoretical assumptions. In this paper we propose a robust and flexible methodology for estimating disease strength varying in space and time using an alternative measure of disease transmission within the hierarchical modeling framework. The proposed measure is also extended to allow for incorporating knowledge from related diseases to enhance performance of surveillance system. A simulation was conducted to examine robustness of the proposed methodology and the simulation results demonstrate that the proposed method allows robust estimation of the disease strength across simulation scenarios. A real data example is provided of an integrative application of Dengue and Zika surveillance in Thailand. The real data example also shows that combining both diseases in an integrated analysis essentially decreases variability of model fitting. The proposed methodology is robust in several simulated scenarios of spatiotemporal transmission force with computing flexibility and practical benefits. This development has potential for broad applicability as an alternative tool for integrated surveillance of emerging diseases such as Zika.


Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.
The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.


The use of hydrophobic, alpha-helix-defined peptides in delineating the T cell determinant for pigeon cytochrome c.
The B10.A T cell proliferative response to pigeon cytochrome c is largely directed to a single site in the molecule located at the carboxyl terminus within the amino acid sequence of residues 81 to 104. This study uses the pigeon cytochrome c-specific T cell clone A.E7 and synthetic peptide analogs to clarify the role of certain residues within this sequence in T cell recognition. By using the helically constrained amino acid, alpha-aminoisobutyric acid, alternated with alanine in an amino-terminal leader sequence, we generated a series of molecules of similar length and alpha-helical conformation but which contain increasing lengths of the native sequence. By comparing the stimulatory ability of this series of peptides, we have clearly identified that the isoleucyl residue at position 95 in pigeon cytochrome c is essential for T cell recognition. This series, when compared with a series containing the same native sequences but without the leader sequence, also showed that the presence of the leader sequence has a general effect on enhancement of T cell recognition. An analysis of the conformational preferences of the peptides using circular dichroism indicated that all of the peptides with leader sequences have a strong preference for the alpha-helical conformation in nonpolar solvents. However, the introduction of helix-breaking residues into these peptides, with a concomitant measured reduction in alpha-helix, did not affect their recognition by clone A.E7. This implies that factors other than conformational stabilization are responsible for the full potency of these peptides. Binding studies to phospholipid vesicles indicated that residues in the leader sequence and in the amino terminus of segment 81-104 beyond residue 95 were important in increasing the ability of the antigens to bind to membranes. These results suggest that the capacity to bind to membranes may be a significant factor in the dose response of T cells to exogenously presented peptides.


Factors affecting birth weight of a newborn--a community based study in rural Karnataka, India.
Low birth weight (LBW) is a major public health problem in many developing countries, especially so in India. Although we do not know all the causes of LBW, maternal and environmental factors appear to be significant risk factors in its occurrence. To know the factors affecting the birth weight of a newborn and to estimate the prevalence of LBW. The present study was carried out amongst 1138 pregnant women and their newborns residing in area covered by Kinaye Primary Health Centre in rural Karnataka, India. The study was conducted from 1(st) June 2008 to 31(st) December 2009. The mean birth weight of newborns was 2.6 kg with a range of 1.2 to 3.8 kg. The prevalence of LBW was 22.9%. Among the studied risk factors, 25 of them were significantly associated with the birth weight of a newborn on univariate logistic regression analysis. Maternal education [Odds Ratio (OR) 3.2], exposure to passive smoking [OR 2.3], age at first pregnancy ≥25 years [OR 3.6], birth interval <2 years [OR 2.4], previous history of LBW baby [OR 3.3], weight gain ≤4 kg during pregnancy [OR 7.0], maternal weight at last week of gestation ≤45 kg [OR 2.3], pregnancy induced hypertension [OR 3.3], high risk pregnancy [OR 3.6] and late antenatal registration [OR 3.6] emerged as significant risk factors on multivariate analysis. The problem of LBW is multidimensional, and hence, we need an integrated approach incorporating medical, social, economical and educational measures to address this issue.


[A rare case of hyperandrogenism: bilateral Leydig cell tumor of the ovary].
The androgen-secreting tumors constitute fewer than 1% of ovarian tumors. Leydig cell tumor is one of the most common of this type of lesion and it is usually benign, small and unilateral. A 67 year old woman was referred to the Endocrine clinic due to hirsutism (score 22 Ferriman-Gallwey) and male type alopecia with 3 years of evolution and progressive worsening. Biochemically she had high levels of serum testosterone - 662 ng/dl (N < 62 ng/dl). Transvaginal ultrasonography and abdomen-pelvic CT scan didn't show any signs of adrenal or ovarian tumors. Bilateral oophorectomy was performed and histopathologic exam revealed bilateral Leydig cell tumors, measuring 1cm each. Four months after surgery, the patient had a marked improvement of the signs (score 3 Ferriman-Gallwey) and normalized testosterone levels (35.9 ng/dl). Androgen-secreting tumors are rare, but they should be excluded in cases of rapid onset of virilization and elevated androgen levels. Tumors are frequently undetectable by imaging techniques because of their small dimensions, exploratory surgery by a skilled team is frequently necessary and is often the best treatment for the majority of these cases. In this case report we present a rare case of bilateral Leydig cell tumor. Only five cases have been reported in the literature.The clinical history and the elevated levels of testosterone had suggested the presence of an androgen-producing tumor, despite the difficulty of the diagnosis on imaging techniques. Due to the fact that our patient was in a post-menopausal stage, we decided that the appropriate treatment would be bilateral oophorectomy. The histopathologic disclosed the diagnosis and allowed the patient's cure.


Lipidomics reveals multiple pathway effects of a multi-components preparation on lipid biochemistry in ApoE*3Leiden.CETP mice.
Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p<0.001), CETP levels (-31%, p<0.001), CETP activity (-74%, p<0.001) and increased HDL-C (39%, p<0.05). It influenced lipidomics classes of cholesterol esters and triglycerides the most. Rimonabant induced a weight loss (-9%, p<0.05), but only a moderate improvement of lipid profiles. In vitro, SUB885C extract caused adipolysis stimulation and adipogenesis inhibition in 3T3-L1 cells. SUB885C, a multi-components preparation, is able to produce anti-atherogenic changes in lipids of the ApoE*3Leiden.CETP mice, which are comparable to those obtained with compounds belonging to known drugs (e.g. rimonabant, atorvastatin, niacin). This study successfully illustrated the power of lipidomics in unraveling intervention effects and to help finding new targets or ingredients for lifestyle-related metabolic abnormality.


Theory and methods in comparative drug and alcohol policy research: Response to a review of the literature.
Comparative drug and alcohol policy analysis (CPA) is alive and well, and the emergence of robust alternatives to strict prohibition provides exciting research opportunities. As a multidisciplinary practice, however, CPA faces several methodological challenges. This commentary builds on a recent review of CPA by Ritter et al. (2016) to argue that the practice is hampered by a hazy definition of policy that leads to confusion in the specification and measurement of the phenomena being studied. This problem is aided and abetted by the all-too-common omission of theory from the conceptualization and presentation of research. Drawing on experience from the field of public health law research, this commentary suggests a distinction between empirical and non-empirical CPA, a simple taxonomic model of CPA policy-making, mapping, implementation and evaluation studies, a narrower definition of and rationale for "policy" research, a clear standard for measuring policy, and an expedient approach (and renewed commitment) to using theory explicitly in a multi-disciplinary practice. Strengthening CPA is crucial for the practice to have the impact on policy that good research can.


Targeted mutagenesis of the murine IRP1 and IRP2 genes reveals context-dependent RNA processing differences in vivo.
We report the targeted mutagenesis of the murine iron regulatory protein (IRP)-1 and IRP2 genes, respectively, with a classical gene trap construct. Insertion of the targeting cassette into the second intron of either gene by homologous recombination interrupts their open reading frames near the N termini. Mice that are homozygous for the correctly modified IRP1 or IRP2 alleles, respectively, display a strong reduction (90%, IRP1(-/-)) or nondetectable levels (IRP2(-/-)) of the targeted proteins. Interestingly, the pre-mRNAs transcribed from the identical targeting cassettes are processed differently within the two different contexts. Detailed analysis of the respective products identifies the choice of alternative splice and 3' end processing sites in the same tissues in vivo. We discuss the implications for the understanding of RNA processing and for targeting strategies for functional genomics in the mouse.


Biomechanical evaluation of posterior screw fixation in cadaveric cervical spines.
Sixteen fresh-frozen spines from cadavers (C4-T1) were randomized on the basis of dual energy xray absorptiometry analysis of bone mineral density. The specimens were subjected to physiologic loads (<or= 1.5 N-m) in a device that applied pure unconstrained, flexion and extension, lateral bending, and torsional moments. After a major injury, including a wide C6 laminectomy, bilateral capsulectomies, and 65% facetectomy at C6-C7, four constructs were applied to each specimen in a balanced sequence, and the stability tests were repeated. All the constructs were identical posterior cervical rods secured to the spine with lateral mass screws in C5 and pedicle screws in C7. The constructs differed only in the presence or absence of a transverse connector between the rods, presence or absence of lateral mass screws in C6, and unicortical or bicortical lateral mass screws. Insertional screw torque was higher in specimens with greater bone mineral density. Pedicle screws had greater torque than lateral mass screws. Posterior cervical spine rod fixation provided an equivalent stability by use of either unicortical or bicortical lateral mass screws. A transverse stabilizer between the rods reduces the number of lateral mass screws needed in posterior cervical spinal rod systems. Repeated stability tests, even when done with physiologic loads, may compromise the screw-bone interface. This effect is most pronounced in specimens that have low bone mineral density.


Interaction between Bovine leukemia virus (BLV) infection and age on telomerase misregulation.
Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL). BLV can interact with telomerase and inhibits telomere shortening, contributing in leukemogenesis and tumour induction. The role of telomerase in BLV-induced lymphosarcoma and aging has been extensively studied. To date, the interaction of both BLV and aging on telomerase mis-regulation have, however, not been investigated. In the present study, telomerase activity in BLV positive and negative cows was compared over a wide range of ages (11-85 months). Lymphocyte counts were also measured in both BLV positive and negative groups. Telomerase activity was detected in all BLV infected animals with persistent lymphocytosis (PL), especially in older individuals. This study revealed that the cells undergo the natural telomerase shortening even in the presence of an existing viral infection. We also show that viral infection, especially during the PL phase of the disease, increases telomerase activity. A statistically significant interaction between age and viral infection was observed for telomere shortening during BLV infection. Older animals with BLV infection, especially those with persistent lymphocytosis or visible tumors, exhibited a sharp increase in telomerase activity. This study demonstrates that there is a significant interaction between BLV infection and telomerase up-regulation and lymphocytosis.


Psychometric properties of the State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA): comparison to the State-Trait Anxiety Inventory (STAI).
The State-Trait Inventory for Cognitive and Somatic Anxiety (STICSA; M. J. Ree, C. MacLeod, D. French, & V. Locke, 2000) was designed to assess cognitive and somatic symptoms of anxiety as they pertain to one's mood in the moment (state) and in general (trait). This study extended the previous psychometric findings to a clinical sample and validated the STICSA against a well-published measure of anxiety, the State-Trait Anxiety Inventory (STAI; C. D. Spielberger, 1983). Patients (N=567) at an anxiety disorders clinic were administered a battery of questionnaires. The results of confirmatory factor analyses (Bentler-Bonnett nonnormed fit index, comparative fit index, and Bollen fit index>.90; root-mean-square error of approximation<.05); convergent and discriminant validity analyses; and group comparisons supported the reliability and validity of the STICSA as a measure of state and trait cognitive and somatic anxiety. In addition, compared with the STAI (anxiety: rs</=.52; depression: rs>/=.64), the STICSA was more strongly correlated with another measure of anxiety (rs>/=.67) and was less strongly correlated with a measure of depression (rs</=.61). These findings suggest that the STICSA may be a purer measure of anxiety symptomatology than is the STAI.


Life at the mesoscale: the self-organised cytoplasm and nucleoplasm.
The cell contains highly dynamic structures exploiting physical principles of self-organisation at the mesoscale (100 nm to 10 μm). Examples include non-membrane bound cytoplasmic bodies, cytoskeleton-based motor networks and multi-scale chromatin organisation. The challenges of mesoscale self-organisation were discussed at a CECAM workshop in July 2014. Biologists need approaches to observe highly dynamic, low affinity, low specificity associations and to perturb single structures, while biological physicists and biomathematicians need to work closely with biologists to build and validate quantitative models. A table of terminology is included to facilitate multidisciplinary efforts to reveal the richness and diversity of mesoscale cell biology.


Temperature dependence of Raman scattering in bulk 4H-SiC with different carrier concentration.
Raman spectra of three bulk 4H-SiC wafers with different free carrier concentration were measured at temperature from 80 K to 873 K. As temperature increases, Raman peaks of most optical phonon modes show monotonous down shift. An anomalous non-monotonous variation with temperature, was observed in the A(1) longitudinal optical (LO) mode from doped samples. Two methods of theoretical fitting, one-mode (LO-plasma coupled (LOPC) mode) and two-mode (A(1)(LO) + LOPC) fitting, are employed to analyze this anomalous phenomenon. Theoretical simulations for temperature dependent Raman spectra by using two methods are critically examined. It turns out that one-mode method conforms well the experimental results, while two-mode method is untenable in physics. The non-monotonous variation of blue-red shifts with temperature for LOPC mode from doped 4H-SiC could be explained by the influence from ionization process of impurities on the process of Raman scattering. A quantitative description on temperature dependent Raman spectra for doped 4H-SiC is achieved, which matches well to experimental data.


The role of environmental variables on the efficiency of water and sewerage companies: a case study of Chile.
This paper evaluates the efficiency of water and sewerage companies (WaSCs) by introducing the lack of service quality as undesirable outputs. It also investigates whether the production frontier of WaSCs is overall constant returns to scale (CRS) or variable returns to scale (VRS) by using two different data envelopment analysis models. In a second-stage analysis, we study the influence of exogenous and endogenous variables on WaSC performance by applying non-parametric hypothesis tests. In a pioneering approach, the analysis covers 18 WaSCs from Chile, representing about 90% of the Chilean urban population. The results evidence that the technology of the sample studied is characterized overall by CRS. Peak water demand, the percentage of external workers, and the percentage of unbilled water are the factors affecting the efficiency of WaSCs. From a policy perspective, the integration of undesirable outputs into the assessment of WaSC performance is crucial not to penalize companies that provide high service quality to customers.


Role of Oxidative Stress in Male Reproductive Dysfunctions with Reference to Phthalate Compounds.
A wide variety of environmental chemicals/xenobiotics including phthalates have been shown to cause oxidative stress targeting the endocrine system and cause reproductive anomalies. The present review describes various issues by oxidative stress causing male reproductive dysfunctions. Here in this review, the importance and role of phthalate compounds in male reproductive dysfunction has been well documented. One class of environmental endocrine disruptors is phthalates. Phthalate compounds are mostly used as plasticizers, which increase the flexibility, durability, longevity, and etc. of the plastics. Large-scale use of plastic products in our daily life as well as thousands of workers engaged in the manufacture of plastic and plastic products and recycling plastic industry are potentially exposed to these chemicals. Further, general population as well as vulnerable groups i.e. children and pregnant women are also exposed to these chemicals. Phthalates are among wide variety of environmental toxicants capable of compromising male fertility by inducing a state of oxidative stress in the testes. They may also generate reactive oxygen species (ROS) that may affect various physiological and reproductive functions. The available data points out that phthalate compounds may also induce oxidative stress in the male reproductive organs mainly testis and epididymis. They impair spermatogenic process by inducing oxidative stress and apoptosis in germ cells or target sertoli cells and thereby hamper spermatogenesis. They also impair the Leydig cell function by inducing ROS, thereby decreasing the levels of steroidogenic enzymes. Thus in utero and postnatal exposure to phthalate compounds might lead to decreased sperm count and various other reproductive anomalies in the young male.


Hyperpolarization of Frozen Hydrocarbon Gases by Dynamic Nuclear Polarization at 1.2 K.
We report a simple and general method for the hyperpolarization of condensed gases by dynamic nuclear polarization (DNP). The gases are adsorbed in the pores of structured mesoporous silica matrices known as HYPSOs (HYper Polarizing SOlids) that have paramagnetic polarizing agents covalently bound to the surface of the mesopores. DNP is performed at low temperatures and moderate magnetic fields (T = 1.2 K and B0 = 6.7 T). Frequency-modulated microwave irradiation is applied close to the electron spin resonance frequency (f = 188.3 GHz), and the electron spin polarization of the polarizing agents of HYPSO is transferred to the nuclear spins of the frozen gas. A proton polarization as high as P((1)H) = 70% can be obtained, which can be subsequently transferred to (13)C in natural abundance by cross-polarization, yielding up to P((13)C) = 27% for ethylene.


Historical versus contemporary medicinal plant uses in the US Virgin Islands.
Hidden in the documents of the dark past of the trans-Atlantic slavery are gems of ethnomedicinal observations, supported by herbarium specimens, which tell of the traditional medicine of a by-gone slave society in the Caribbean. In the context of the former Danish West Indies (now US Virgin Islands), we identify pre-1900 medicinal plants and their historical uses, and trace their status in the traditional medicine of St. Croix today (2014). By a combined historical and ethnobotanical approach we assess the scale of loss and preservation of traditional medicinal knowledge on St. Croix, and explore the drivers involved in the disappearance of knowledge in the oral tradition of medicine. Names, uses and identities of 18th and 19th century medicinal plant uses in the Danish West Indies were derived from manuscripts and publications of Von Rohr (1757/58), Oldendorp (1777), West (1793), Benzon (1822), Riise (1853), Eggers (1876;1879) and Berg and Eggers (1888). The presence of the plant species in the pre-1900 Danish West Indies was confirmed by review of herbarium specimens in the University of Copenhagen Herbarium (C). The same species were collected on St. Croix in 2014 or their ecological status discussed with local specialists. Semi-structured interviews supported by photographs and specimens were conducted with six medicinal plant specialist on St. Croix, to document and compare contemporary names and uses of the historically used medicinal plants. The historic ethnomedicinal sources revealed 102 medicinal uses of 64 plant species. Thirty-eight (37%) of the pre-1900 medicinal uses were traced in interviews, while sixty-four uses (63%) appear to be forgotten, discontinued or otherwise lost. Thirteen species appear to have entirely lost their status as medicinal plants on St. Croix, while 32 species (50%) have lost uses while retaining or gaining others. While 20% of the lost medicinal plant uses can be explained by biodiversity loss, and others likely have become obsolete due to advances in public health and scientific medicine, 33 of the 64 lost medicinal uses of non-rare species uses fall in the same categories as the preserved uses (fever, stomach, wound, laxative, pulmonary, intestinal, pain, anthelmintic, blood purifier, eye-inflammation). We therefore argue that at least half of the known pre-1900 medicinal plant uses have become culturally extinct for other reasons than to biodiversity loss or modern obsoleteness. The present study utilized knowledge from an oral medicinal tradition, documented in the context of a colonial society. Without doubt, basis for further similar studies exists in the more or less accessible archives, herbaria and collections of former colonial powers. Such studies could directly benefit the descendants of the original intellectual property holders culturally and economically, or serve as stepping stones to integrate, or re-integrate, lost medicinal plant uses in both local and wider evidence-based contexts.


Infra-population and -community dynamics of the parasites Nosema apis and Nosema ceranae, and consequences for honey bee (Apis mellifera) hosts.
Nosema spp. fungal gut parasites are among myriad possible explanations for contemporary increased mortality of western honey bees (Apis mellifera, hereafter honey bee) in many regions of the world. Invasive Nosema ceranae is particularly worrisome because some evidence suggests it has greater virulence than its congener N. apis. N. ceranae appears to have recently switched hosts from Asian honey bees (Apis cerana) and now has a nearly global distribution in honey bees, apparently displacing N. apis. We examined parasite reproduction and effects of N. apis, N. ceranae, and mixed Nosema infections on honey bee hosts in laboratory experiments. Both infection intensity and honey bee mortality were significantly greater for N. ceranae than for N. apis or mixed infections; mixed infection resulted in mortality similar to N. apis parasitism and reduced spore intensity, possibly due to inter-specific competition. This is the first long-term laboratory study to demonstrate lethal consequences of N. apis and N. ceranae and mixed Nosema parasitism in honey bees, and suggests that differences in reproduction and intra-host competition may explain apparent heterogeneous exclusion of the historic parasite by the invasive species.


A longitudinal analysis of mental and general health status of informal carers in Australia.
The study investigated the self-assessed mental and general health status of informal carers in Australia. It evaluated the influence of carer's health behaviours, namely physical activity, smoking and drinking status, along with their social connectedness and workforce engagement on their health status. The study used a retrospective longitudinal design using data from the Household Income and Labour Dynamics of Australia survey, waves 5-15 (2005-2015). It included individuals aged 15 years and older from Australian households surveyed over a period of 11 years. The sample consisted of 23,251 individuals. The outcome measures included: mental health, general health and physical functioning domains of the Short Form 36 Questionnaire, a widely used multi-dimensional measure of health-related quality of life. Using fixed effects regression and following individuals over time, the analysis took care of the issue of individuals self-selecting themselves as carers due to some predisposing factors such as age, poor health, socioeconomic status and sedentary behaviour. There were statistically significant carer-noncarer status differences in mental (Beta = - 0.587, p = 0.003) and general health (Beta = - 0.670, p = 0.001) outcomes. Aging had a modifying impact on carers' mental and general health outcomes. Older carers coped better with their caregiving responsibilities than younger ones. Moreover, while physical activities had a positive influence on both mental and general health for non-carers, with more activities generating better health outcomes, it only had a modifying impact on carers' mental health. Furthermore, the study found that moderate levels of social drinking had beneficial modifying impact on carers' mental and general health. This study added value to the literature on informal carers' mental and general health in Australia by identifying some of the protective and risk factors. The study found the modifying effects of carers' age, health behaviours such as physical activity, smoking and drinking status on their health. Finally, the study identified an apparent beneficial link between moderate levels of social drinking and carer health that needs to be further explored with more targeted future research.


Effectiveness of provision of animal-source foods for supporting optimal growth and development in children 6 to 59 months of age.
Adequate nutrients early in life promote cognitive development and are critical for proper growth and functioning. The effect of individual nutrients consumed through food is often not the same as consuming the same nutrients in supplementary form due to 'food synergy', the biological and chemical interrelations that occur between nutrients. Animal-source foods, such as eggs, meat, fish, and dairy, are energy dense and contain multiple micronutrients and essential fatty acids with high bioavailability. The benefits of animal-source foods may include higher food synergy relative to fortified foods as well as decreasing dependence on external suppliers of fortified foods. To assess the effectiveness of animal-source foods compared to any other feeding interventions or no intervention in improving growth and developmental outcomes in children aged 6 to 59 months. We searched CENTRAL, MEDLINE, Embase, CINAHL, 18 other databases, and three trials registers up to August 2018. We also contacted authors and known experts in the field for assistance in identifying ongoing or unpublished data, and searched the reference lists of included studies and reviews, and websites of relevant organizations, for other studies that may not have been captured by our electronic searches. We included randomized controlled trials and quasi-randomized controlled trials of any duration, where children between 5 months and 59 months (6 years) of age were provided with an animal-source food (e.g. consumption of milk, meat, or eggs), prepared with any cooking method, compared with any intervention or no intervention. Two review authors independently assessed trial eligibility using prespecified criteria, extracted data, assessed risk of bias, and graded the quality of the evidence using the GRADE approach. Study characteristicsWe included 6 studies that analyzed data from 3036 children aged 5 to 50 months. The studies were conducted in China, the Democratic Republic of Congo, Ecuador, Guatemala, Pakistan, the USA, and Zambia, and lasted between 5 and 12 months. Three studies were funded, in part, by government entities; one study was supported by a nonprofit organization. Two studies did not report a funding source.Three studies compared the effects of feeding an animal-source food with a fortified (iron or iron and zinc), or unfortified cereal; two used a control group with no intervention; one compared a meat-based diet to a dairy-based diet. The types of animal-source foods tested included yogurt, eggs, cheese, lyophilized (freeze-dried) beef product, ground and frozen pork, puréed and jarred beef with gravy or pork, and powdered whey protein.We judged four studies to be at unclear risk of bias overall; three studies because they were funded by an industry with a plausible interest in the outcome of the intervention; and one study because there was insufficient information to assess five of the seven bias 'Risk of bias' domains. We judged two of the six studies to be at high risk of bias overall; one study because there was significant baseline imbalance in length-for-age z scores (LAZ) between groups and evidence of selective reporting; the other study because there there was both a significant baseline imbalance in LAZ and weight-for-age z scores (WAZ) between groups, and a large-scale social media campaign that may have influenced care received at home in the control group.Key resultsAnimal-source foods versus cereal-based foods or no interventionFive studies (2972 children) measured change in linear growth with either height-for-age z scores (HAZ) or LAZ. Three studies (592 children) reported a significant increase in HAZ and LAZ in the intervention group compared to the control group. Two studies (2380 children) reported a decline in LAZ in both groups. In one study (1062 children) there was no difference between the groups in the rate of decline; in the other (1318 children) the decrease in LAZ was significantly smaller in the intervention group.Five studies (2972 children) measured weight gain using WAZ. Three studies (592 children) reported a significant increase in WAZ in the intervention group compared to the control group. In two studies (2380 children), WAZ decreased in both groups. In one of these studies (1318 children), the decrease in the intervention group was significantly smaller than in the control group. In the other study (1062 children), there was no difference between the groups.Three studies (1612 children) reported impacts on all-cause morbidity, but metrics were inconsistent between studies. One study with yogurt (402 children) reported a significant reduction in duration and incidence of diarrhea and upper respiratory infections in the intervention group. One study with eggs (148 children) reported a significant increase in the incidence of diarrhea in the intervention group, but this may have been due to cultural associations with eggs and gastrointestional problems. There were no other significant differences in fever, respiratory infections, or skin conditions between groups. The third study (1062 children) found no differences between intervention and control groups across morbidity measures.No studies reported data on anemia.Meat-based diet versus dairy-based dietOne study (64 children) measured change in LAZ and WAZ in infants fed either a meat-based diet or dairy-based diet. There was a significant increase in LAZ among infants consuming the meat-based diet and a significant decrease in LAZ among infants consuming a dairy-based diet. WAZ increased in both groups, with no significant difference between groups.The study did not assess all-cause morbidity or anemia.Quality of the evidenceWe rated the quality of the evidence as very low overall due to baseline imbalances between intervention and control groups, high heterogeneity in meta-analysis, and imprecision due to wide confidence intervals and inconsistent direction of effects. We have little confidence in the results; further research is likely to change the estimate of magnitude and direction of treatment effect. Given the limited quality of the evidence, we are uncertain of the effects of the provision of animal-source food versus cereal products or no intervention on the growth or development of children. More adequately powered trials with deliberately selected animal-source foods are needed.


Trajectories of higher- and lower-order dimensions of negative and positive affect relative to restrictive eating in anorexia nervosa.
Despite robust support for the role of affect in the maintenance of binge eating and purging, the relationship between affect and restrictive eating remains poorly understood. To investigate the relationship between restrictive eating and affect, ecological momentary assessment data from 118 women with anorexia nervosa (AN) were used to examine trajectories of higher-order dimensions of negative affect (NA) and positive affect (PA), as well as lower-order dimensions of NA (Fear, Guilt) and PA (Joviality, Self-Assurance) relative to restrictive eating. Affect trajectories were modeled before and after restrictive eating episodes and AN subtype was examined as a moderator of these trajectories. Across the sample, Guilt significantly increased before and decreased after restrictive eating episodes. Global NA, Global PA, Fear, Joviality, and Self-Assurance did not vary relative to restrictive eating episodes across the sample. However, significant subtype by trajectory interactions were detected for PA indices. Among individuals with AN restricting subtype, Global PA, Joviality, and Self-Assurance decreased prior to and Self-Assurance increased following restrictive eating episodes. In contrast, Global PA and Self-Assurance increased prior to, but did not change following, restrictive eating episodes among individuals with AN binge eating/purging subtype. Results suggest that dietary restriction may function to mitigate guilt across AN subtypes and to enhance self-assurance among individuals with AN restricting subtype. (PsycINFO Database Record


Enzymes or redox couples? The kinetics of thioredoxin and glutaredoxin reactions in a systems biology context.
Systems biology approaches, such as kinetic modelling, could provide valuable insights into how thioredoxins, glutaredoxins and peroxiredoxins (here collectively called redoxins), and the systems that reduce these molecules are regulated. However, it is not clear whether redoxins should be described as redox couples (with redox potentials) or as enzymes (with Michaelis-Menten parameters) in such approaches. We show that in complete redoxin systems, redoxin substrate saturation and other purported enzymatic behaviours result from limitations in the redoxin redox cycles in these systems. Michaelis-Menten parameters are therefore inappropriate descriptors of redoxin activity; data from redoxin kinetic experiments should rather be interpreted in terms of the complete system of reactions under study. These findings were confirmed by fitting kinetic models of the thioredoxin and glutaredoxin systems to in vitro datasets. This systems approach clarifies the inconsistencies with the descriptions of redoxins and emphasizes the roles of redoxin systems in redox regulation.


PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor-Treated Melanoma Patients.
To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors. Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n = 28) or combination of BRAF and MEK inhibitors (Combi; n = 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome. Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P = 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P = 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4(+), CD8(+), and PD-1(+) lymphocytes from PRE to EDT (P = 0.001, P = 0.001, P = 0.017, respectively), and Combi-treated patients showed similar increases in CD4(+) and CD8(+) lymphocytes from PRE to EDT (P = 0.017, P = 0.021). The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.


Comparative Genomic Analysis of the Class Epsilonproteobacteria and Proposed Reclassification to Epsilonbacteraeota (phyl. nov.).
The Epsilonproteobacteria is the fifth validly described class of the phylum Proteobacteria, known primarily for clinical relevance and for chemolithotrophy in various terrestrial and marine environments, including deep-sea hydrothermal vents. As 16S rRNA gene repositories have expanded and protein marker analysis become more common, the phylogenetic placement of this class has become less certain. A number of recent analyses of the bacterial tree of life using both 16S rRNA and concatenated marker gene analyses have failed to recover the Epsilonproteobacteria as monophyletic with all other classes of Proteobacteria. In order to address this issue, we investigated the phylogenetic placement of this class in the bacterial domain using 16S and 23S rRNA genes, as well as 120 single-copy marker proteins. Single- and concatenated-marker trees were created using a data set of 4,170 bacterial representatives, including 98 Epsilonproteobacteria. Phylogenies were inferred under a variety of tree building methods, with sequential jackknifing of outgroup phyla to ensure robustness of phylogenetic affiliations under differing combinations of bacterial genomes. Based on the assessment of nearly 300 phylogenetic tree topologies, we conclude that the continued inclusion of Epsilonproteobacteria within the Proteobacteria is not warranted, and that this group should be reassigned to a novel phylum for which we propose the name Epsilonbacteraeota (phyl. nov.). We further recommend the reclassification of the order Desulfurellales (Deltaproteobacteria) to a novel class within this phylum and a number of subordinate changes to ensure consistency with the genome-based phylogeny. Phylogenomic analysis of 658 genomes belonging to the newly proposed Epsilonbacteraeota suggests that the ancestor of this phylum was an autotrophic, motile, thermophilic chemolithotroph that likely assimilated nitrogen from ammonium taken up from the environment or generated from environmental nitrate and nitrite by employing a variety of functional redox modules. The emergence of chemoorganoheterotrophic lifestyles in several Epsilonbacteraeota families is the result of multiple independent losses of various ancestral chemolithoautotrophic pathways. Our proposed reclassification of this group resolves an important anomaly in bacterial systematics and ensures that the taxonomy of Proteobacteria remains robust, specifically as genome-based taxonomies become more common.


Orchard factors associated with resistance and cross resistance to sterol demethylation inhibitor fungicides in populations of Venturia inaequalis from Pennsylvania.
Orchard management practices, such as destroying of overwintered inoculum and limiting the number of fungicide applications, are often recommended as tactics for slowing the development of resistance to sterol demethylation-inhibitor (DMI) fungicides in populations of Venturia inaequalis. However, there is little quantitative evidence relating the use of such practices to levels of resistance in orchards. The aim of this study was to evaluate the sensitivity of V. inaequalis isolates from Pennsylvania to DMI fungicides, and to identify orchard management factors related to the incidence of resistant isolates. In total, 644 single-spore V. inaequalis cultures obtained from 20 apple orchards in 2008 or 2009 were tested for sensitivity to myclobutanil, fenbuconazole, or difenoconazole. Growers provided management history of the sampled plots. Widespread shifts toward resistance to the three fungicides were noted, with mean effective concentration for 50% inhibition (EC(50)) values of 2.136, 0.786, and 0.187 μg/ml for myclobutanil, fenbuconazole, and difenoconazole, respectively. Cross resistance to the three fungicides was documented in high correlation (Spearman's r > 0.6) between mean EC(50) values for 14 orchards. Based on a 0.5-μg/ml threshold, 66 and 26% of isolates were resistant to myclobutanil and fenbuconazole, respectively, and 22% were cross resistant to the two fungicides. A significant between-year shift toward increased resistance was noted in two of three orchards surveyed in both years. Failure to use dormant copper sprays, older trees, larger orchards, orchards with ≤10 cultivars, and application of >4 DMI sprays were positively correlated (0.0001 < P < 0.05) with the incidence of resistant isolates. Isolates from orchards with >4 DMI sprays were four times as likely to be resistant to fenbuconazole (odds ratio = 4.57; P = 0.015). Isolates from orchards without dormant copper sprays were twice as likely to be cross-shifted toward resistance to all three fungicides (odds ratio = 1.76; P = 0.048). Results identify management practices that can reduce the risk of V. inaequalis developing resistance to DMI fungicides.


Information and support from dietary consultation for mothers of children with food allergies.
Professional dietetic input is essential to ensure that children with diagnosed food allergies have an individualized avoidance plan and nutritionally adequate diet. However, it is not clear what dietary information and support parents require. To explore what information and support parents of children with food allergies require from a dietary consultation. Focus groups were conducted with 17 mothers who attend an allergy center for dietary advice for their food allergic child. A number of issues around food allergy dietary advice needs were explored and analyzed using thematic analysis. Six themes were identified. The mothers described how they sought to protect their child from harm, to maintain normality for their child, and to promote child independence. They described needing to become an expert in their child's food allergy and fight their corner when needed. The dietitian supported their needs by ensuring their child's diet was safe and nutritionally adequate and giving information and support to help them provide a normal life for their child. Dietitians also taught mothers about food allergy and provided advocacy and emotional support. Mothers of children with food allergies want to understand how to provide a nutritionally adequate, allergen-safe diet while maintaining a normal life. Hence, mothers value a range of support from dietitians, including monitoring their child's health and providing information, practical advice and support, and emotional support.


Haematological changes in human immunodeficiency virus infection. Part I: Review article.
This review attempts to put together the changes in the blood and bone marrow observed in those who are infected with human immunodeficiency virus (HIV). These are contribution of many published and unpublished data and experience on; blood counts, blood film and bone marrow films prepared and stained by MayGrunwald-Giemsa or Leishman stain. Some changes in haemostasis are also included. The salient changes are cytopaenias; leucopaenia, anaemia, thrombocytopaenia, and bone marrow hypoplasia, although the latter occurs, it is found in a minority of cases. Other changes include myelodysplasia, functionally defective cells, and enhanced bleeding tendency particularly in those with bleeding defects. There are also malignancies associated with HIV infection such as Kaposi's Sarcoma and malignant lymphomas. The pathogenesis of these events are multi-factorial, varied and involve; killing of cells by the virus, syncytial formation by the cells, destruction of the stem cells, immune and drugs effects. These mechanisms are modified by factors of viral, host environment and their interactions. Changes are commonly found in patients with acquired immunodeficiency syndrome (AIDS) but can be seen in some cases anytime during the course of the disease. Once developed the changes are progressive. The management of these complications remain individualised and symptomatic. Treatment trials with the haematopoesis growth factors, particularly colony stimulating factors are producing some encouraging results. However other cytokines, for example, interleukin-6 may be having untoward effect such as association with the causation of Kaposi's sarcoma and the malignant non-Hodgkin's lymphomas. While standard approaches to the management of the malignancies tend to be the practice, adjustments are usually necessary in most patients.


Sinistral, Dextral, and Mixed Coiling Patterns Observed in Heligmonellid Nematodes (Trichostrongyloidea).
Coiling patterns of heligmonellid nematodes were examined for 520, 208, and 33 individuals of Nippostrongylus brasiliensis, Orientostrongylus tenorai, and Sabanema sp., respectively, collected from murine rodents of Indonesia. Besides typical sinistral coiling, complete dextral coiling was found in 3.3% of N. brasiliensis and 12.1% of Sabanema sp. Mixed coiling with partial sinistral and dextral patterns was also observed in 38.8% of N. brasiliensis, 60.7% of Sabanema sp., and 3.4% of O. tenorai. In dextral coils, the left ventral area with large ridges was located inside as in sinistral coils, keeping the ability to cling to intestinal villi. The cuticular dilatation at left to left dorsal area was located caudally in sinistral coils but rostrally in dextral coils. Presence of mixed coiling indicates that the coiling patterns can change. As the transition of coiling pattern accompanies a change in direction of coil axis, it is surmised that the dextral coiling may be chosen when a worm leaves a villus to move to another villus.


An Ecological Conceptualization of Extreme Sports.
Currently, there are various definitions for extreme sports and researchers in the field have been unable to advance a consensus on what exactly constitutes an 'extreme' sport. Traditional theory-led explanations, such as edgeworks, sensation seeking and psychoanalysis, have led to inadequate conceptions. These frameworks have failed to capture the depth and nuances of experiences of individuals who refute the notions of risk-taking, adrenaline- and thrill-seeking or death-defiance. Instead, participants are reported to describe experiences as positive, deeply meaningful and life-enhancing. The constant evolution of emerging participation styles and philosophies, expressed within and across distinguishable extreme sport niches, or forms of life, and confusingly dissimilar definitions and explanations, indicate that, to better understand cognitions, perceptions and actions of extreme sport participants, a different level of analysis to traditional approaches needs to be emphasized. This paper develops the claim that a more effective definition, reflecting the phenomenology, and framework of an ecological dynamics rationale, can significantly advance the development of a more comprehensive and nuanced future direction for research and practice. Practical implications of such a rationale include study designs, representative experimental analyses and developments in coaching practices and pedagogical approaches in extreme sports. Our position statement suggests that extreme sports are more effectively defined as emergent forms of action and adventure sports, consisting of an inimitable person-environment relationship with exquisite affordances for ultimate perception and movement experiences, leading to existential reflection and self-actualization as framed by the human form of life.


Borderline personality disorder diagnosis in a new key.
Conceptualizations of personality disorders (PD) are increasingly moving towards dimensional approaches. The definition and assessment of borderline personality disorder (BPD) in regard to changes in nosology are of great importance to theory and practice as well as consumers. We studied empirical connections between the traditional DSM-5 diagnostic criteria for BPD and Criteria A and B of the Alternative Model for Personality Disorders (AMPD). Raters of varied professional backgrounds possessing substantial knowledge of PDs (N = 20) characterized BPD criteria with the four domains of the Level of Personality Functioning Scale (LPFS) and 25 pathological personality trait facets. Mean AMPD values of each BPD criterion were used to support a nosological cross-walk of the individual BPD criteria and study various combinations of BPD criteria in their AMPD translation. The grand mean AMPD profile generated from the experts was compared to published BPD prototypes that used AMPD trait ratings and the DSM-5-III hybrid categorical-dimensional algorithm for BPD. Divergent comparisons with DSM-5-III algorithms for other PDs and other published PD prototypes were also examined. Inter-rater reliability analyses showed generally robust agreement. The AMPD profile for BPD criteria rated by individual BPD criteria was not isomorphic with whole-person ratings of BPD, although they were highly correlated. Various AMPD profiles for BPD were generated from theoretically relevant but differing configurations of BPD criteria. These AMPD profiles were highly correlated and showed meaningful divergence from non-BPD DSM-5-III algorithms and other PD prototypes. Results show that traditional DSM BPD diagnosis reflects a common core of PD severity, largely composed of LPFS and the pathological traits of anxiousness, depressively, emotional lability, and impulsivity. Results confirm the traditional DSM criterion-based BPD diagnosis can be reliably cross-walked with the full AMPD scheme, and both approaches share substantial construct overlap. This relative equivalence suggests the vast clinical and research literatures associated with BPD may be brought forward with DSM-5-III diagnosis of BPD.


Do HMOs make a difference? Consumer assessments of health care.
This study examines the effects of health maintenance organizations (HMOs) on consumer assessments of health care among the privately insured, nonelderly population. After controlling for population and location differences, the study finds that HMO enrollees are less likely than those in non-HMOs to be satisfied with their care, to rate their last medical visit highly, and to express trust in their physicians. One exception is a finding of little or no statistically significant difference between HMO and non-HMO enrollees in the likelihood of distrust that a physician may provide unnecessary services.


High-resolution synchrotron-based X-ray microtomography as a tool to unveil the three-dimensional neuronal architecture of the brain.
The assessment of neuronal number, spatial organization and connectivity is fundamental for a complete understanding of brain function. However, the evaluation of the three-dimensional (3D) brain cytoarchitecture at cellular resolution persists as a great challenge in the field of neuroscience. In this context, X-ray microtomography has shown to be a valuable non-destructive tool for imaging a broad range of samples, from dense materials to soft biological specimens, arisen as a new method for deciphering the cytoarchitecture and connectivity of the brain. In this work we present a method for imaging whole neurons in the brain, combining synchrotron-based X-ray microtomography with the Golgi-Cox mercury-based impregnation protocol. In contrast to optical 3D techniques, the approach shown here does neither require tissue slicing or clearing, and allows the investigation of several cells within a 3D region of the brain.


Quality of life and contact dermatitis: a disease-specific questionnaire.
Contact dermatitis (CD) is a chronic disease with a significant impact on quality of life (QoL). There have been relatively few reports in the literature on specific QoL outcomes for patients suffering from CD. To develop a new instrument specifically designed to measure QoL in CD and to investigate which disease features could strongly influence QoL. Three hundred seventy-two patients affected by CD were administered a 20-item questionnaire, which comprised some questions taken and modified from the Dermatology Life Quality Index and the Skindex 16. Six more items were added. Univariate analysis and a chi-square test were performed. Females reported lower QoL scores than males. Three aspects (itching, discomfort, and difficulty in daily activities) were strongly associated with a poor QoL; even if patients who experienced difficulty in using their hands at work had a poor QoL, the statistical significance was very low. A CD-specific questionnaire can be used to understand a priori the impact on psychological behaviour of the patient and can lead to specific choices, such as the appropriate therapy to be used, the evaluation of treatment efficacy, the choice of preventive devices, and the comparison with QoL of other dermatoses.


Revisiting Reverse Cholesterol Transport in the Context of High-Density Lipoprotein Free Cholesterol Bioavailability.
Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance. In mice, most macrophage-derived FC is rapidly cleared from plasma (t1/2 < 5 min) without esterification by hepatic uptake; the remainder is taken up by multiple tissue and cell types, especially erythrocytes. Further, some FC is cleared by the nonhepatic transintestinal pathway. Lastly, FC movement among lipid surfaces is reversible, so that a higher-than-normal level of HDL-FC bioavailability-defined by high plasma HDL levels concurrent with a high mol% HDL-FC-leads to the transfer of excess FC to cells in vivo. SR-B1-/- mice provide an animal model to study the mechanistic consequences of high HDL-FC bioavailability that provokes atherosclerosis and other metabolic abnormalities. Future efforts should aim to reduce HDL-FC bioavailability, thereby reducing FC accretion by tissues and the attendant atherosclerosis.


Direct presentation of a melanocyte-associated antigen in peripheral lymph nodes induces cytotoxic CD8+ T cells.
Encounter of self-antigens in the periphery by mature T cells induces tolerance in the steady-state. Hence, it is not understood why the same peripheral antigens are also promiscuously expressed in the thymus to mediate central tolerance. Here, we analyzed CD8(+) T-cell tolerance to such an antigen constituted by ovalbumin under the control of the tyrosinase promoter. As expected, endogenous CD8(+) T-cell responses were altered in the periphery of transgenic mice, resulting from promiscuous expression of the self-antigen in mature medullary epithelial cells and deletion of high-affinity T cells in the thymus. In adoptive T-cell transfer experiments, we observed constitutive presentation of the self-antigen in peripheral lymph nodes. Notably, this self-antigen presentation induced persisting cytotoxic cells from high-affinity CD8(+) T-cell precursors. Lymph node resident melanoblasts expressing tyrosinase directly presented the self-antigen to CD8(+) T cells, independently of bone marrow-derived antigen-presenting cells. This peripheral priming was independent of the subcellular localization of the self-antigen, indicating that this mechanism may apply to other melanocyte-associated antigens. Hence, central tolerance by promiscuous expression of peripheral antigens is a mandatory, rather than a superfluous, mechanism to counteract the peripheral priming, at least for self-antigens that can be directly presented in lymph nodes. The peripheral priming by lymph node melanoblasts identified here may constitute an advantage for immunotherapies based on adoptive T-cell transfer.


Structure-function analysis of the RNA polymerase cleft loops elucidates initial transcription, DNA unwinding and RNA displacement.
The active center clefts of RNA polymerase (RNAP) from the archaeon Pyrococcus furiosus (Pfu) and of yeast RNAP II are nearly identical, including four protruding loops, the lid, rudder, fork 1 and fork 2. Here we present a structure-function analysis of recombinant Pfu RNAP variants lacking these cleft loops, and analyze the function of each loop at different stages of the transcription cycle. All cleft loops except fork 1 were required for promoter-directed transcription and efficient elongation. Unprimed de novo transcription required fork 2, the lid was necessary for primed initial transcription. Analysis of templates containing a pre-melted bubble showed that rewinding of upstream DNA drives RNA separation from the template. During elongation, downstream DNA strand separation required template strand binding to an invariant arginine in switch 2, and apparently interaction of an invariant arginine in fork 2 with the non-template strand.


Influence of licensed characters on children's taste and snack preferences.
The goal was to study how popular licensed cartoon characters appearing on food packaging affect young children's taste and snack preferences. Forty 4- to 6-year-old children tasted 3 pairs of identical foods (graham crackers, gummy fruit snacks, and carrots) presented in packages either with or without a popular cartoon character. Children tasted both food items in each pair and indicated whether the 2 foods tasted the same or one tasted better. Children then selected which of the food items they would prefer to eat for a snack. Children significantly preferred the taste of foods that had popular cartoon characters on the packaging, compared with the same foods without characters. The majority of children selected the food sample with a licensed character on it for their snack, but the effects were weaker for carrots than for gummy fruit snacks and graham crackers. Branding food packages with licensed characters substantially influences young children's taste preferences and snack selection and does so most strongly for energy-dense, nutrient-poor foods. These findings suggest that the use of licensed characters to advertise junk food to children should be restricted.


Participation bias in a sexuality survey: psychological and behavioural characteristics of responders and non-responders.
Few studies of sexual attitudes and behaviour have quantified the direction and magnitude of participation bias, primarily because information on non-responders is difficult to obtain in cross-sectional surveys. Australian adult twins (n = 9112) aged 17-52 years enrolled in a national, longitudinal research register were asked to participate in a postal survey concerning their sexual behaviour and attitudes. Individual consent was determined by separate return of a consent form; 27% explicitly refused, 19% initially agreed to receive a questionnaire, but subsequently did not return consent forms and 52% explicitly consented. Participation data were matched to social, psychological and behavioural information in a longitudinal data set. People who explicitly consented had higher levels of education, attended church less often, had less conservative sexual attitudes and voting preferences, were more likely to smoke cigarettes and drank alcohol more often than people who explicitly refused. On standard personality scales, responders were more novelty-seeking and reward-dependent and less harm-avoidant than refusers. Structured psychiatric telephone interview data from 3674 individuals showed that, compared to refusers, responders had higher lifetime prevalence of major depression, alcohol dependence and childhood conduct disorder and also reported an earlier age at first sexual intercourse and higher rates of sexual abuse. In general, those who had initially agreed to receive the sex questionnaire but were subsequently lost were more similar to consenters than to refusers. Effect sizes on most measures were small. The broad profile suggests that postal surveys of sexual attitudes and behaviour may overestimate sexual liberalism, activity and adversity, although this bias should not seriously compromise population estimates.


Molecular evidence for historical presence of knock-down resistance in Anopheles albimanus, a key malaria vector in Latin America.
Anopheles albimanus is a key malaria vector in the northern neotropics. Current vector control measures in the region are based on mass distributions of long-lasting insecticidal nets (LLINs) and focal indoor residual spraying (IRS) with pyrethroids. Resistance to pyrethroid insecticides can be mediated by increased esterase and/or multi-function oxidase activity and/or mutations in the voltage-gated sodium channel gene. The aim of this work was to characterize the homologous kdr region of the voltage-gated sodium channel gene in An. albimanus and to conduct a preliminary retrospective analysis of field samples collected in the 1990's, coinciding with a time of intense pyrethroid application related to agricultural and public health insect control in the region. Degenerate primers were designed to amplify the homologous kdr region in a pyrethroid-susceptible laboratory strain (Sanarate) of An. albimanus. Subsequently, a more specific primer pair was used to amplify and sequence the region that contains the 1014 codon associated with pyrethroid resistance in other Anopheles spp. (L1014F, L1014S or L1014C). Direct sequencing of the PCR products confirmed the presence of the susceptible kdr allele in the Sanarate strain (L1014) and the presence of homozygous-resistant kdr alleles in field-collected individuals from Mexico (L1014F), Nicaragua (L1014C) and Costa Rica (L1014C). For the first time, the kdr region in An. albimanus is described. Furthermore, molecular evidence suggests the presence of kdr-type resistance in field-collected An. albimanus in Mesoamerica in the 1990s. Further research is needed to conclusively determine an association between the genotypes and resistant phenotypes, and to what extent they may compromise current vector control efforts.


Mechanical, degradation and cytocompatibility properties of magnesium coated phosphate glass fibre reinforced polycaprolactone composites.
Retention of mechanical properties of phosphate glass fibre reinforced degradable polyesters such as polycaprolactone and polylactic acid in aqueous media has been shown to be strongly influenced by the integrity of the fibre/polymer interface. A previous study utilising 'single fibre' fragmentation tests found that coating with magnesium improved the fibre and matrix interfacial shear strength. Therefore, the aim of this study was to investigate the effects of a magnesium coating on the manufacture and characterisation of a random chopped fibre reinforced polycaprolactone composite. Short chopped strand non-woven phosphate glass fibre mats were sputter coated with degradable magnesium to manufacture phosphate glass fibre/polycaprolactone composites. The degradation behaviour (water uptake, mass loss and pH change of the media) of these polycaprolactone composites as well as of pure polycaprolactone was investigated in phosphate buffered saline. The Mg coated fibre reinforced composites revealed less water uptake and mass loss during degradation compared to the non-coated composites. The cations released were also explored and a lower ion release profile for all three cations investigated (namely Na(+), Mg(2+) and Ca(2+)) was seen for the Mg coated composite samples. An increase of 17% in tensile strength and 47% in tensile modulus was obtained for the Mg coated composite samples. Both flexural and tensile properties were investigated and a higher retention of mechanical properties was obtained for the Mg coated fibre reinforced composite samples up to 10 days immersion in PBS. Cytocompatibility study showed both composite samples (coated and non-coated) had good cytocompatibility with human osteosarcoma cell line.


Investigation of the H(+)-myo-inositol transporter (HMIT) as a neuronal regulator of phosphoinositide signalling.
Phosphoinositide signalling regulates a series of important neuronal processes that are thought to be altered in mood disorders. Furthermore, mood-stabilizing drugs inhibit key enzymes that regulate phosphoinositide production and alter neuronal growth cone morphology in an inositol-reversible manner. Inositol is taken up by neurons from the extracellular fluid, presumably via membrane transporters; it can also be synthesized by the enzyme MIP-synthase (myo-inositol-1-phosphate synthase) and, in addition, it is generated by inositol phospholipid hydrolysis. The neuronal-specific HMIT (H(+)-myo-inositol transporter) represents a potential regulator of inositol signalling in neurons that warrants further investigation.


Understanding the Bioinformatics Challenges of Integrating Genomics into Healthcare.
Genomic data is paving the way towards personalized healthcare. By unveiling genetic disease-contributing factors, genomic data can aid in the detection, diagnosis, and treatment of a wide range of complex diseases. Integrating genomic data into healthcare is riddled with a wide range of challenges spanning social, ethical, legal, educational, economic, and technical aspects. Bioinformatics is a core integration aspect presenting an overwhelming number of unaddressed challenges. In this paper we tackle the fundamental bioinformatics integration concerns including: genomic data generation, storage, representation, and utilization in conjunction with clinical data. We divide the bioinformatics challenges into a series of seven intertwined integration aspects spanning the areas of informatics, knowledge management, and communication. For each aspect, we provide a detailed discussion of the current research directions, outstanding challenges, and possible resolutions. This paper seeks to help narrow the gap between the genomic applications, which are being predominantly utilized in research settings, and the clinical adoption of these applications.


Siglecs induce tolerance to cell surface antigens by BIM-dependent deletion of the antigen-reactive B cells.
Infusion of blood cells from a donor can induce humoral tolerance in a recipient and increase the probability of successful organ transplant, a clinical method defined as donor-specific transfusion (DST). Despite the clinical success of DST, the immunological mechanisms by which blood cells displaying a foreign Ag induce tolerance remain poorly understood. Based on recent findings showing that the B cell siglecs, CD22 and Siglec-G, can promote tolerance to Ags presented on the same surface as their ligands, we speculated that the B cell siglecs are key players in tolerance induced by DST. Using a variety of chemical and genetic approaches, we show that the B cell siglecs mediate tolerance to cell surface Ags by initiating an inhibitory signal that culminates in elimination of the Ag-reactive B cell. CD22 and Siglec-G are recruited to the immunological synapse by sialic acid ligands on the Ag-bearing cells, producing a tolerogenic signal involving Lyn and the proapoptotic factor BIM that promotes deletion of the B cell and failure of mice to develop Abs to the Ag upon subsequent challenge. We speculate that this tolerogenic mechanism is a contributing factor in DST and a mechanism of peripheral B cell tolerance to cell surface autoantigens.


Morphological characteristics of tendon cells cultured on synthetic fibers.
Filamentous carbon is currently being used as an implant material for tendon and ligament repair in humans. This material acts as a scaffold for the organization of new fibrous tissue growth. Primary cultures of rat tendon fibroblast cells (1 degrees RTF cells) were grown on carbon, Dacron, polyethylene and Nylon fibers in vitro. The morphological characteristics of these cells were examined. The process of cell migration from tendon explant to fiber substrate was similar for all four materials. Three morphological categories of cells were observed on these materials. (1) spherical dividing cells, (2) spindle-shaped migrating cells, (3) sheath-like migrating or stationary cells. The morphological characteristics and orientational behavior of cultured fibroblasts on these fiber materials were strongly influenced by the diameters of the fibers and by fiber surface characteristics such as longitudinal striations. The possible mechanisms of cell response to substrate geometric configuration are discussed along with the clinical significance of these experiments.


Conformational dynamics of a G-protein α subunit is tightly regulated by nucleotide binding.
Heterotrimeric G proteins play a pivotal role in the signal-transduction pathways initiated by G-protein-coupled receptor (GPCR) activation. Agonist-receptor binding causes GDP-to-GTP exchange and dissociation of the Gα subunit from the heterotrimeric G protein, leading to downstream signaling. Here, we studied the internal mobility of a G-protein α subunit in its apo and nucleotide-bound forms and characterized their dynamical features at multiple time scales using solution NMR, small-angle X-ray scattering, and molecular dynamics simulations. We find that binding of GTP analogs leads to a rigid and closed arrangement of the Gα subdomain, whereas the apo and GDP-bound forms are considerably more open and dynamic. Furthermore, we were able to detect two conformational states of the Gα Ras domain in slow exchange whose populations are regulated by binding to nucleotides and a GPCR. One of these conformational states, the open state, binds to the GPCR; the second conformation, the closed state, shows no interaction with the receptor. Binding to the GPCR stabilizes the open state. This study provides an in-depth analysis of the conformational landscape and the switching function of a G-protein α subunit and the influence of a GPCR in that landscape.


CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and alters serum cytokine/chemokine patterns in the bovine collagen type II induced arthritis in the DBA mouse model.
The mouse model of collagen induced arthritis (CIA) effectively mimics human disease and thus is useful for testing and development of rheumatoid arthritis (RA) therapies. We developed a Ligand Epitope Antigen Presentation System (LEAPS) peptide hetero-conjugate vaccine containing an epitope of human collagen type II (CEL-2000) that acted as a therapeutic vaccine in the collagen induced arthritis (CIA) mouse model. LEAPS technology converts a small peptide containing a disease specific epitope into an immunogen by attaching it to an immune or T cell binding peptide (I/TCBL). For CEL-2000, a peptide from human collagen type II (254-273) is attached to the I/TCBL peptide from human beta2 microglobulin (J). Treatment with CEL-2000 limited disease (CIA) progression, as demonstrated by reduced Arthritic Index (AI) score, and footpad swelling. Efficacy was confirmed by histopathological microscopic examination of tissues at the end of the study. CEL-2000 limited disease progression as well or better than the etanercept (Enbrel) therapeutic control with significantly better histopathological results than the etanercept treated mice. Most interestingly, CEL-2000 therapy modulated serum cytokine levels with an increase in IL-12p70 and IL-10, which are not seen with etanercept therapy, and reduced IL-17 and TNF-alpha, also seen with etanercept, among other cytokines studied. CEL-2000 was safe and well tolerated for the mice that received 5 injections given every 2weeks in a 90day study supporting its potential usage for long term therapy. These studies demonstrate that fewer treatments with CEL-2000 provide therapy at least as effective as etanercept by specifically modulating the disease producing autoimmune response.


Transcriptional regulation of xyr1, encoding the main regulator of the xylanolytic and cellulolytic enzyme system in Hypocrea jecorina.
In Hypocrea jecorina, Xyr1 (xylanase regulator 1) is the main transcription activator of hydrolase-encoding genes, such as xyn1, xyn2, bxl1, cbh1, cbh2, egl1, and bgl1. Even though Xyr1 mediates the induction signal for all these genes derived from various inducing carbon sources and compounds, xyr1 transcription itself is not inducible by any of these substances. However, cultivation on glucose as the carbon source provokes carbon catabolite repression of xyr1 transcription mediated by Cre1. In addition, xyr1 transcription is repressed by the specific transcription factor Ace1. Moreover, Xyr1 is permanently available in the cell, and no de novo synthesis of this factor is needed for a first induction of xyn1 transcription. The constitutive expression of xyr1 leads to a significant elevation/deregulation of the xyn1, xyn2, and bxl1 transcription compared to what is seen for the parental strain. Overall, the corresponding xylanolytic enzyme activities are clearly elevated in a constitutively xyr1-expressing strain, emphasizing this factor as an auspicious target for genetically engineered strain improvement.


Slow waves, synaptic plasticity and information processing: insights from transcranial magnetic stimulation and high-density EEG experiments.
Sleep slow waves are the main phenomenon underlying NREM sleep. They are homeostatically regulated, they are thought to be linked to learning and plasticity processes and, at the same time, they are associated with marked changes in cortical information processing. Using transcranial magnetic stimulation (TMS) and high-density (hd) EEG we can measure slow waves, induce and measure plastic changes in the cerebral cortex and directly assess corticocortical information transmission. In this manuscript we review the results of recent experiments in which TMS with hd-EEG is used to demonstrate (i) a causal link between cortical plastic changes and sleep slow waves and (ii) a causal link between slow waves and the decreased ability of thalamocortical circuits to integrate information and to generate conscious experience during NREM sleep. The data presented here suggest a unifying mechanism linking slow waves, plasticity and cortical information integration; moreover, they suggest that TMS can be used as a nonpharmacological means to controllably induce slow waves in the human cerebral cortex.


Development and pilot testing of a decision aid for drivers with dementia.
An increasing number of older adults drive automobiles. Given that the prevalence of dementia is rising, it is necessary to address the issue of driving retirement. The purpose of this study is to evaluate how a self-administered decision aid contributed to decision making about driving retirement by individuals living with dementia. The primary outcome measure in this study was decisional conflict. Knowledge, decision, satisfaction with decision, booklet use and booklet acceptability were the secondary outcome measures. A mixed methods approach was adopted. Drivers with dementia were recruited from an Aged Care clinic and a Primary Care center in NSW, Australia. Telephone surveys were conducted before and after participants read the decision aid. Twelve participants were recruited (mean age 75, SD 6.7). The primary outcome measure, decisional conflict, improved following use of the decision aid. Most participants felt that the decision aid: (i) was balanced; (ii) presented information well; and (iii) helped them decide about driving. In addition, mean knowledge scores improved after booklet use. This decision aid shows promise as an acceptable, useful and low-cost tool for drivers with dementia. A self-administered decision aid can be used to assist individuals with dementia decide about driving retirement. A randomized controlled trial is underway to evaluate the effectiveness of the tool.


Maternal, neonatal, and child health in southeast Asia: towards greater regional collaboration.
Although maternal and child mortality are on the decline in southeast Asia, there are still major disparities, and greater equity is key to achieve the Millennium Development Goals. We used comparable cross-national data sources to document mortality trends from 1990 to 2008 and to assess major causes of maternal and child deaths. We present inequalities in intervention coverage by two common measures of wealth quintiles and rural or urban status. Case studies of reduction in mortality in Thailand and Indonesia indicate the varying extents of success and point to some factors that accelerate progress. We developed a Lives Saved Tool analysis for the region and for country subgroups to estimate deaths averted by cause and intervention. We identified three major patterns of maternal and child mortality reduction: early, rapid downward trends (Brunei, Singapore, Malaysia, and Thailand); initially high declines (sustained by Vietnam but faltering in the Philippines and Indonesia); and high initial rates with a downward trend (Laos, Cambodia, and Myanmar). Economic development seems to provide an important context that should be coupled with broader health-system interventions. Increasing coverage and consideration of the health-system context is needed, and regional support from the Association of Southeast Asian Nations can provide increased policy support to achieve maternal, neonatal, and child health goals.


Balance control: sex and age differences in 9- to 16-year-olds.
This study investigated sex and age differences in standing balance. Movement of the centre of pressure (COP) was calculated from ground reaction force data collected from a force platform during bipedal stance with eyes open and eyes closed. Three groups of 60 children, with 30 girls and 30 boys in each, were assessed. Mean ages of each group were as follows: 9 years 11 months (standard deviation [SD] 3mo); 12 years 11 months (SD 2mo); and 15 years 11 months (SD 3mo) respectively. Summary sway parameters and frequency domain variables were calculated in the anteroposterior and mediolateral directions. Boys exhibited greater COP movement than girls at 9 to 10 years of age. Age-related 'improvements' in sway occurred in boys, thus some aspects of postural control are still developing after 9 to 10 years of age. As very little age-related difference was seen in girls, boys may lag behind somewhat in terms of developing postural control. Thus there is a need to study the sexes separately when investigating balance in children.


Genetic analysis of HIV-1 strains in rural eastern Cameroon indicates the evolution of second-generation recombinants to circulating recombinant forms.
The HIV-1 genetic diversity in most parts of Cameroon is well described and shown to be very broad. However, little is known about the composition of the HIV-1 epidemic in the rural parts of eastern Cameroon. Therefore, we investigated 25 specimens from this region for their subtypes in gag, pol, and env gene fragments. Along with genetic material of subtypes A1, C, G, CRF01_AE, CRF02_AG, and CRF11_cpx, we also identified a large number (24%, 6/25) of distinct env sequences within the subtype A radiation. CRF02_AG was the predominant genetic form in all genes studied. Half of the specimens studied were considered "pure" based on concordant subtypes in the genes studied, whereas the other half were unique recombinant forms (URFs). Except for 1 URF, all were second-generation recombinants (SGRs), 90% of which contained genetic material of CRF02_AG in at least 1 gene. Notably, we identified individuals from 3 different villages infected with CRF01_AE(gag)CRF02_AG(pol)A(env) strains, which is indicative of the evolution of this URF to a circulating recombinant form (CRF). In addition, we identified a CRF02_AG(pol)C(env) recombinant infecting a man and a woman living in the same village, suggesting horizontal transmission of this recombinant. The current study emphasizes the power of HIV-1 recombination through the generation of SGRs and the evolution of URFs into CRFs. These findings suggest that, in a region where a predominant HIV-1 strain cocirculates among several subtypes, recombination could eventually decrease the proportion of this strain over time, such as CRF02_AG in Cameroon.


Reversible giant photocontraction in chalcogenide glass.
It is shown that chalcogenide glasses with suitably underconstrained network can undergo reversible giant photocontractions up to a micron depth. These effects result from the combination of two attributes particular to these glasses, (i) the high photosensitivity characteristic of low coordination floppy networks and (ii) the wide window of structural configuration characteristic of fragile glass former. Interestingly these effects are reversible and subsequent irradiation with high intensity results in giant photoexpansion in the same glass. The combination of subsequent photocontraction and photoexpansion on the same glass surface has good potential for the design of complex optical elements.


A conceptual review of mate choice: stochastic demography, within-sex phenotypic plasticity, and individual flexibility.
Mate choice hypotheses usually focus on trait variation of chosen individuals. Recently, mate choice studies have increasingly attended to the environmental circumstances affecting variation in choosers' behavior and choosers' traits. We reviewed the literature on phenotypic plasticity in mate choice with the goal of exploring whether phenotypic plasticity can be interpreted as individual flexibility in the context of the switch point theorem, SPT (Gowaty and Hubbell 2009). We found >3000 studies; 198 were empirical studies of within-sex phenotypic plasticity, and sixteen showed no evidence of mate choice plasticity. Most studies reported changes from choosy to indiscriminate behavior of subjects. Investigators attributed changes to one or more causes including operational sex ratio, adult sex ratio, potential reproductive rate, predation risk, disease risk, chooser's mating experience, chooser's age, chooser's condition, or chooser's resources. The studies together indicate that "choosiness" of potential mates is environmentally and socially labile, that is, induced - not fixed - in "the choosy sex" with results consistent with choosers' intrinsic characteristics or their ecological circumstances mattering more to mate choice than the traits of potential mates. We show that plasticity-associated variables factor into the simpler SPT variables. We propose that it is time to complete the move from questions about within-sex plasticity in the choosy sex to between- and within-individual flexibility in reproductive decision-making of both sexes simultaneously. Currently, unanswered empirical questions are about the force of alternative constraints and opportunities as inducers of individual flexibility in reproductive decision-making, and the ecological, social, and developmental sources of similarities and differences between individuals. To make progress, we need studies (1) of simultaneous and symmetric attention to individual mate preferences and subsequent behavior in both sexes, (2) controlled for within-individual variation in choice behavior as demography changes, and which (3) report effects on fitness from movement of individual's switch points.


Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis.
Mycobacterium tuberculosis is an intracellular pathogen of macrophages and escapes the macrophages' bactericidal effectors by interfering with phagosome-lysosome fusion. IFN-γ activation renders the macrophages capable of killing intracellular mycobacteria by overcoming the phagosome maturation block, nutrient deprivation and exposure to microbicidal effectors including nitric oxide (NO). While the importance about NO for the control of mycobacterial infection in murine macrophages is well documented, the underlying mechanism has not been revealed yet. In this study we show that IFN-γ induced apoptosis in mycobacteria-infected macrophages, which was strictly dependent on NO. Subsequently, NO-mediated apoptosis resulted in the killing of intracellular mycobacteria independent of autophagy. In fact, killing of mycobacteria was susceptible to the autophagy inhibitor 3-methyladenine (3-MA). However, 3-MA also suppressed NO production, which is an important off-target effect to be considered in autophagy studies using 3-MA. Inhibition of caspase 3/7 activation, as well as NO production, abolished apoptosis and elimination of mycobacteria by IFN-γ activated macrophages. In line with the finding that drug-induced apoptosis kills intracellular mycobacteria in the absence of NO, we identified NO-mediated apoptosis as a new defense mechanism of activated macrophages against M. tuberculosis.


Chemically crosslinked hyaluronic acid-chitosan hydrogel for application on cartilage regeneration.
Articular cartilage is an avascular tissue that lines the ends of bones in diarthrodial joints, serves as support, acts as a shock absorber, and facilitates joint's motion. It is formed by chondrocytes immersed in a dense extracellular matrix (principally composed of aggrecan linked to hyaluronic acid long chains). Damage to this tissue is usually associated with traumatic injuries or age-associated processes that often lead to discomfort, pain and disability in our aging society. Currently, there are few surgical alternatives to treat cartilage damage: the most commonly used is the microfracture procedure, but others include limited grafting or alternative chondrocyte implantation techniques, however, none of them completely restore a fully functional cartilage. Here we present the development of hydrogels based on hyaluronic acid and chitosan loaded with chondroitin sulfate by a new strategy of synthesis using biodegradable di-isocyanates to obtain an interpenetrated network of chitosan and hyaluronic acid for cartilage repair. These scaffolds act as delivery systems for the chondroitin sulfate and present mucoadhesive properties, which stabilizes the clot of microfracture procedures and promotes superficial chondrocyte differentiation favoring a true articular cellular colonization of the cartilage. This double feature potentially improves the microfracture technique and it will allow the development of next-generation therapies against articular cartilage damage.


One's own country and familiar places in the mind's eye: different topological representations for navigational and non-navigational contents.
Visual mental imagery is a process that draws on different cognitive abilities and is affected by the contents of mental images. Several studies have demonstrated that different brain areas subtend the mental imagery of navigational and non-navigational contents. Here, we set out to determine whether there are distinct representations for navigational and geographical images. Specifically, we used a Spatial Compatibility Task (SCT) to assess the mental representation of a familiar navigational space (the campus), a familiar geographical space (the map of Italy) and familiar objects (the clock). Twenty-one participants judged whether the vertical or the horizontal arrangement of items was correct. We found that distinct representational strategies were preferred to solve different categories on the SCT, namely, the horizontal perspective for the campus and the vertical perspective for the clock and the map of Italy. Furthermore, we found significant effects due to individual differences in the vividness of mental images and in preferences for verbal versus visual strategies, which selectively affect the contents of mental images. Our results suggest that imagining a familiar navigational space is somewhat different from imagining a familiar geographical space.


Do directed cough maneuvers improve cough effectiveness in the early period after open heart surgery? Effect of thoracic support and maximal inspiration on cough peak expiratory flow, cough expiratory volume, and thoracic pain.
Directed cough maneuvers are often included in physiotherapy management aimed at preventing postoperative pulmonary complications after open heart surgery, but there is little scientific evidence of the effectiveness of directed cough maneuvers. We conducted a randomized intra-subject crossover trial to evaluate the effect of thoracic support (patient holds his or her hands over the incision) and maximal inspiration on cough peak expiratory flow (CPEF), cough expiratory volume (CEV), and incision pain during cough in the early period after open heart surgery. Cough evaluation was undertaken on the first and second morning after surgery. On both measurement days the subject did a baseline cough (baseline cough 1) then, in a random sequence, performed 3 cough conditions: an additional baseline cough (baseline cough 2), supported cough, and supported cough preceded by maximal inspiration. In these test conditions a P < .008 was deemed to indicate a statistically significant difference. Twenty-one subjects participated. Thoracic support alone did not significantly affect CPEF or CEV (Bonferroni adjusted P > .008). With a maximal inspiration and thoracic support, CPEF and CPEV were significantly higher than in all other cough conditions (Bonferroni adjusted P < .008). Pain during cough was not influenced by the different cough conditions (P > .05). There was no significant difference in the cough variables or pain during the different cough conditions on the first day versus the second measurement day. Maximal inspiration increased CPEF and CEV, but the method of thoracic support we used did not reduce pain during cough or influence the cough values we measured.


New tick-borne encephalitis virus hot spot in Northern Zealand, Denmark, October 2019.
During summer 2019, three patients residing by Tisvilde Hegn, Denmark were hospitalised with tick-borne encephalitis (TBE) after tick bites. A new TBE virus (TBEV) micro-focus was identified in tick nymphs collected around a playground in Tisvilde Hegn forest. Estimated TBEV prevalence was 8%, higher than in endemic areas around Europe. Whole genome sequencing showed clustering to a TBEV strain from Norway. This is the second time TBEV is found in Ixodes ricinus outside Bornholm, Denmark.


Hypophosphatasia.
Hypophosphatasia (HPP) is a group of inherited disorders characterised by the impaired mineralisation of bones and/or teeth and low serum alkaline phosphatase (ALP) activity. It is caused by a mutation in the ALPL gene encoding the tissue-non-specific isoenzyme of ALP (TNSALP) resulting in a loss of function. The disease is highly heterogenous in its clinical expression ranging from stillbirth without mineralised bone to the mild form of late adult onset with symptoms and signs such as musculoskeletal pain, arthropathy, lower-extremity fractures, premature loss of teeth or an incidental finding of reduced serum ALP activity. A classification based on the age at diagnosis and the presence or absence of bone symptoms was historically used: perinatal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia. These subtypes are known to have overlapping signs and complications. Three forms of HPP distinguishable by their genetic characteristics have been described: severe, moderate and mild. Severe forms of HPP (perinatal and infantile severe) are recessively inherited, whereas moderate HPP may be dominantly or recessively inherited. The biochemical hallmark of HPP is persistently low serum ALP for age and increase in natural substrates of TNSALP, pyridoxal 5'-phosphate and phosphoethanolamine supported by radiological findings. The diagnosis is confirmed by ALPL sequencing. A multidisciplinary team of experts is essential for the effective management. Calcium restriction is recommended in infants/children to manage hypercalcaemia. A targeted enzyme replacement therapy for HPP has become available and correct diagnosis is crucial to allow early treatment.