Solvent stabilized solution structures of galanin and galanin analogs, studied by circular dichroism spectroscopy.
Circular dichroism spectroscopy has been used to study how different solvents stabilize secondary structure in the neuropeptide galanin (rat), two N-terminal fragments of galanin, galanin(1-12) and galanin(1-16), and six other differently charged analogs. Among these analogs, the peptide M40, galanin(1-13)-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide, is a high affinity, receptor subtype specific galanin receptor antagonist. The different solvents include sodium dodecyl sulfate (SDS) micelle solutions, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) vesicle solutions. 100% 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) and 100% 2,2,2-trifluoroethanol (TFE). DOPC vesicles did not change the structure of the peptides as compared to aqueous solvent. The negatively charged DOPG vesicles and SDS micelles induced similar changes towards alpha-helical structures in all peptides. The HFP and TFE solvents have an even stronger tendency to stabilize alpha-helical conformations in these peptides. Since DOPG vesicles can be considered as a model system for negatively charged biological membranes, the solution structures observed in the presence of DOPG or SDS may be the most relevant for the in vivo situation. Correlations between the binding affinity of the peptides to hippocampal galanin receptors and their observed structures in the DOPG solvent were investigated.


The perfect marriage: solution-focused therapy and motivational interviewing in medical family therapy.
Medical family therapy has many potential uses in behavioral medicine and primary care. Current research was reviewed to determine the most advantageous way to apply solution-focused therapy and motivational interviewing as a perfect marriage in medical family therapy. An extensive literature review was done in the following databases for medical family therapy: Proquest, EBSCO, Medline, and PsychInfo. The search resulted in 86 relevant articles, of which 46 of the most recent were selected for review. Medical family therapy lacks current research that supports solution-focused therapy or motivational interviewing. However, evidence supports the use of solution-focused therapy as a brief format, as well as the closely related intervention, motivational interviewing. While medical family therapy presents many hopeful possibilities in the fields of behavioral medicine, psychology, and marriage and family therapy, little evidence currently exists for the most effective implementation. This review found evidence supporting solution-focused therapy and motivational interviewing as the perfect marriage of the collaborative team approaches for the future implementation and use of specific interventions in medical family therapy.


Towards a climate-dependent paradigm of ammonia emission and deposition.
Existing descriptions of bi-directional ammonia (NH3) land-atmosphere exchange incorporate temperature and moisture controls, and are beginning to be used in regional chemical transport models. However, such models have typically applied simpler emission factors to upscale the main NH3 emission terms. While this approach has successfully simulated the main spatial patterns on local to global scales, it fails to address the environment- and climate-dependence of emissions. To handle these issues, we outline the basis for a new modelling paradigm where both NH3 emissions and deposition are calculated online according to diurnal, seasonal and spatial differences in meteorology. We show how measurements reveal a strong, but complex pattern of climatic dependence, which is increasingly being characterized using ground-based NH3 monitoring and satellite observations, while advances in process-based modelling are illustrated for agricultural and natural sources, including a global application for seabird colonies. A future architecture for NH3 emission-deposition modelling is proposed that integrates the spatio-temporal interactions, and provides the necessary foundation to assess the consequences of climate change. Based on available measurements, a first empirical estimate suggests that 5°C warming would increase emissions by 42 per cent (28-67%). Together with increased anthropogenic activity, global NH3 emissions may increase from 65 (45-85) Tg N in 2008 to reach 132 (89-179) Tg by 2100.


Somatic small RNA pathways promote the mitotic events of megagametogenesis during female reproductive development in Arabidopsis.
Female gamete development in Arabidopsis ovules comprises two phases. During megasporogenesis, a somatic ovule cell differentiates into a megaspore mother cell and undergoes meiosis to produce four haploid megaspores, three of which degrade. The surviving functional megaspore participates in megagametogenesis, undergoing syncytial mitosis and cellular differentiation to produce a multicellular female gametophyte containing the egg and central cell, progenitors of the embryo and endosperm of the seed. The transition between megasporogenesis and megagametogenesis is poorly characterised, partly owing to the inaccessibility of reproductive cells within the ovule. Here, laser capture microdissection was used to identify genes expressed in and/or around developing megaspores during the transition to megagametogenesis. ARGONAUTE5 (AGO5), a putative effector of small RNA (sRNA) silencing pathways, was found to be expressed around reproductive cells during megasporogenesis, and a novel semi-dominant ago5-4 insertion allele showed defects in the initiation of megagametogenesis. Expression of a viral RNAi suppressor, P1/Hc-Pro, driven by the WUSCHEL and AGO5 promoters in somatic cells flanking the megaspores resulted in a similar phenotype. This indicates that sRNA-dependent pathways acting in somatic ovule tissues promote the initiation of megagametogenesis in the functional megaspore. Notably, these pathways are independent of AGO9, which functions in somatic epidermal ovule cells to inhibit the formation of multiple megaspore-like cells. Therefore, one somatic sRNA pathway involving AGO9 restricts reproductive development to the functional megaspore and a second pathway, inhibited by ago5-4 and P1/Hc-Pro, promotes megagametogenesis.


Characterizing occupational risk perception: the case of biological, ergonomic and organizational hazards in Spanish healthcare workers.
Understanding how risk is perceived by workers is necessary for effective risk communication and risk management. This study adapts key elements of the psychometric perspective to characterize occupational risk perception at a worker level. A total of 313 Spanish healthcare workers evaluated relevant hazards in their workplaces related to biological, ergonomic and organizational factors. A questionnaire elicited workers' ratings of 3 occupational hazards on 9 risk attributes along with perceived risk. Factor and regression analyses reveal regularities in how different risks are perceived, while, at the same time, the procedure helps to summarize specificities in the perception of each hazard. The main regularity is the weight of feeling of dread/severity in order to characterize the risk perceived (β ranges from .22 to .41; p < .001). Data also suggest an underestimation of expert knowledge in relation to the personal knowledge of risk. Thus, participants consider their knowledge of the risk related to biological, ergonomic, and organizational hazards to be higher than the knowledge attributed to the occupational experts (mean differences 95% CIs [.10, .30], [.54, .94], and [0.52, 1.05]). We demonstrate the application of a feasible and systematic procedure to capture how workers perceive hazards in their immediate work environment.


A Transparent and Consistent Approach to Assess US Outpatient Drug Costs for Use in Cost-Effectiveness Analyses.
Assessment of drug costs for cost-effectiveness analyses (CEAs) in the United States is not straightforward because the prices paid for drugs are not publicly available and differ between payers. CEAs have relied on list prices that do not reflect the rebates and discounts known to be associated with these purchases. To review available cost measures and propose a novel strategy that is transparent, consistent, and applicable to all CEAs taking a US health care sector perspective or a societal payer's perspective. We propose using the National Average Drug Acquisition Cost (NADAC), the Veterans Affairs Federal Supply Schedule (VAFSS), and their midpoint as the upper bound, lower bound, and base case, respectively, to estimate net drug prices for various payers. We compare this approach with wholesale acquisition cost (WAC), the most common measure observed in our literature review. The minimum WAC is used to provide the most conservative comparison. Our sample consists of 1436 brand drugs and 1599 generic drugs. On average, the upper bound (NADAC) is 1% and 9.8% lower than the WAC for brand and generic drugs respectively, whereas the lower bound (VAFSS) is 48.3% and 54.2% lower than the WAC. The NADAC is less than the WAC in 89.6% of drug groups. The distributions of these relationships do not show a clear mode and have wide variation. Our study suggests that the WAC may be an overestimate for the base case because the minimum WAC is higher than the NADAC for most drugs. Our approach balances uncertainty and lack of data for the cost of pharmaceuticals with the need for a transparent and consistent approach for valid CEAs.


Bisphosphonates: the first 40 years.
The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40years to review the history of their development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from 'bench to bedside'. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural 'water softener' in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved 'block-buster' status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over.


Genetic vulnerability to diabetes and obesity: does education offset the risk?
The prevalence of type 2 diabetes (T2D) and obesity has recently increased dramatically. These common diseases are likely to arise from the interaction of multiple genetic, socio-demographic and environmental risk factors. While previous research has found genetic risk and education to be strong predictors of these diseases, few studies to date have examined their joint effects. This study investigates whether education modifies the association between genetic background and risk for type 2 diabetes (T2D) and obesity. Using data from non-Hispanic Whites in the Health and Retirement Study (HRS, n = 8398), we tested whether education modifies genetic risk for obesity and T2D, offsetting genetic effects; whether this effect is larger for individuals who have high risk for other (unobserved) reasons, i.e., at higher quantiles of HbA1c and BMI; and whether effects differ by gender. We measured T2D risk using Hemoglobin A1c (HbA1c) level, and obesity risk using body-mass index (BMI). We constructed separate genetic risk scores (GRS) for obesity and diabetes respectively based on the most current available information on the single nucleotide polymorphism (SNPs) confirmed as genome-wide significant predictors for BMI (29 SNPs) and diabetes risk (39 SNPs). Linear regression models with years of schooling indicate that the effect of genetic risk on HbA1c is smaller among people with more years of schooling and larger among those with less than a high school (HS) degree compared to HS degree-holders. Quantile regression models show that the GRS × education effect systematically increased along the HbA1c outcome distribution; for example the GRS × years of education interaction coefficient was -0.01 (95% CI = -0.03, 0.00) at the 10th percentile compared to -0.03 (95% CI = -0.07, 0.00) at the 90th percentile. These results suggest that education may be an important socioeconomic source of heterogeneity in responses to genetic vulnerability to T2D.


FLIPPER, a combinatorial probe for correlated live imaging and electron microscopy, allows identification and quantitative analysis of various cells and organelles.
Ultrastructural examination of cells and tissues by electron microscopy (EM) yields detailed information on subcellular structures. However, EM is typically restricted to small fields of view at high magnification; this makes quantifying events in multiple large-area sample sections extremely difficult. Even when combining light microscopy (LM) with EM (correlated LM and EM: CLEM) to find areas of interest, the labeling of molecules is still a challenge. We present a new genetically encoded probe for CLEM, named "FLIPPER", which facilitates quantitative analysis of ultrastructural features in cells. FLIPPER consists of a fluorescent protein (cyan, green, orange, or red) for LM visualization, fused to a peroxidase allowing visualization of targets at the EM level. The use of FLIPPER is straightforward and because the module is completely genetically encoded, cells can be optimally prepared for EM examination. We use FLIPPER to quantify cellular morphology at the EM level in cells expressing a normal and disease-causing point-mutant cell-surface protein called EpCAM (epithelial cell adhesion molecule). The mutant protein is retained in the endoplasmic reticulum (ER) and could therefore alter ER function and morphology. To reveal possible ER alterations, cells were co-transfected with color-coded full-length or mutant EpCAM and a FLIPPER targeted to the ER. CLEM examination of the mixed cell population allowed color-based cell identification, followed by an unbiased quantitative analysis of the ER ultrastructure by EM. Thus, FLIPPER combines bright fluorescent proteins optimized for live imaging with high sensitivity for EM labeling, thereby representing a promising tool for CLEM.


Osteoblast and monocyte responses to 444 ferritic stainless steel intended for a magneto-mechanically actuated fibrous scaffold.
The rationale behind this work is to design an implant device, based on a ferromagnetic material, with the potential to deform in vivo promoting osseointegration through the growth of a healthy periprosthetic bone structure. One of the primary requirements for such a device is that the material should be non-inflammatory and non-cytotoxic. In the study described here, we assessed the short-term cellular response to 444 ferritic stainless steel; a steel, with a very low interstitial content and a small amount of strong carbide-forming elements to enhance intergranular corrosion resistance. Two different human cell types were used: (i) foetal osteoblasts and (ii) monocytes. Austenitic stainless steel 316L, currently utilised in many commercially available implant designs, and tissue culture plastic were used as the control surfaces. Cell viability, proliferation and alkaline phosphatase activity were measured. In addition, cells were stained with alizarin red and fluorescently-labelled phalloidin and examined using light, fluorescence and scanning electron microscopy. Results showed that the osteoblast cells exhibited a very similar degree of attachment, growth and osteogenic differentiation on all surfaces. Measurement of lactate dehydrogenase activity and tumour necrosis factor alpha protein released from human monocytes indicated that 444 stainless steel did not cause cytotoxic effects or any significant inflammatory response. Collectively, the results suggest that 444 ferritic stainless steel has the potential to be used in advanced bone implant designs.


Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis.
Wnt/beta-catenin signaling inhibits adipogenesis. Genome-wide profiling studies have revealed the enrichment of histone H3K27 methyltransferase Ezh2 on Wnt genes. However, the functional significance of such a direct link between the two types of developmental regulators in mammalian cells, and the role of Ezh2 in adipogenesis, remain unclear. Here we show Ezh2 and its H3K27 methyltransferase activity are required for adipogenesis. Ezh2 directly represses Wnt1, -6, -10a, and -10b genes in preadipocytes and during adipogenesis. Deletion of Ezh2 eliminates H3K27me3 on Wnt promoters and derepresses Wnt expression, which leads to activation of Wnt/beta-catenin signaling and inhibition of adipogenesis. Ectopic expression of the wild-type (WT) Ezh2, but not the enzymatically inactive F667I mutant, prevents the loss of H3K27me3 and the defects in adipogenesis in Ezh2(-/-) preadipocytes. The adipogenesis defects in Ezh2(-/-) cells can be rescued by expression of adipogenic transcription factors PPARgamma, C/EBPalpha, or inhibitors of Wnt/beta-catenin signaling. Interestingly, Ezh2(-/-) cells show marked increase of H3K27 acetylation globally as well as on Wnt promoters. These results indicate that H3K27 methyltransferase Ezh2 directly represses Wnt genes to facilitate adipogenesis and suggest that acetylation and trimethylation on H3K27 play opposing roles in regulating Wnt expression.


Effects of smoking during pregnancy on DNA damage and ROS level consequences in maternal and newborns' blood.
Some of the genotoxic/carcinogenic substances or metabolites in cigarette smoke are capable of passing through the placenta and harming a newborn's health. Smoking is also known as a factor in the formation of oxidative damage and the main mechanism involved in the carcinogenic process. Predetermining this genotoxic risk can be successfully achieved by measuring certain parameters of oxidative stress. The comet assay is considered an important biomarker for the evaluation of genotoxic substances and is effective for detecting DNA damage caused by smoking. This study examined third trimester bloods and the cord blood of 28 actively smoking and 22 non-smoking mothers in terms of DNA damage and oxidative stress parameters. Cu/Zn superoxide dismutase (CuZn-SOD), malondialdehyde (MDA), catalase (CAT), plasma nitrite/nitrates (NO2-/NO3-), selenium-dependent glutathione peroxidase (Se-GPx), Cu, and Zn levels were measured as indicators of oxidative damage. There were no significant increases in DNA damage of the actively smoking pregnant group in comparison with the non-smoking pregnant group, either in the third trimester or cord blood. Oxidative stress parameters of smoker and non-smoker groups were statistically different for MDA (p<0.05), CuZn-SOD (p<0.01), Se-GPx (p<0.05) values while the difference was not significant for NO2-/NO3-, CAT, Zn, and Cu values. The same values were also investigated in cord blood,and only NO2/NO3-(p<0.01), Se-GPx (p<0.01 and CAT (p<0.001) values were found statistically different.Smoking mothers may have been exposed to more oxidative stress than non-smoking mothers


Damage to insula abolishes cognitive distortions during simulated gambling.
Gambling is a naturalistic example of risky decision-making. During gambling, players typically display an array of cognitive biases that create a distorted expectancy of winning. This study investigated brain regions underpinning gambling-related cognitive distortions, contrasting patients with focal brain lesions to the ventromedial prefrontal cortex (vmPFC), insula, or amygdala ("target patients") against healthy comparison participants and lesion comparison patients (i.e., with lesions that spare the target regions). A slot machine task was used to deliver near-miss outcomes (i.e., nonwins that fall spatially close to a jackpot), and a roulette game was used to examine the gambler's fallacy (color decisions following outcome runs). Comparison groups displayed a heightened motivation to play following near misses (compared with full misses), and manifested a classic gambler's fallacy effect. Both effects were also observed in patients with vmPFC and amygdala damage, but were absent in patients with insula damage. Our findings indicate that the distorted cognitive processing of near-miss outcomes and event sequences may be ordinarily supported by the recruitment of the insula. Interventions to reduce insula reactivity could show promise in the treatment of disordered gambling.


Allopurinol pharmacogenetics: assessment of potential clinical usefulness.
Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics.


Clinical patterns and pathophysiology of hypermotor seizures: an ictal SPECT study.
Hypermotor seizures (HMS) can include different forms of hypermotor behaviour due to various mechanisms associated with generation of ictal automatisms. Despite the varied location of seizure onset, similar semiologic features during seizures may exist. Ictal single-photon emission tomography (SPECT) apparently reflects not only the origin of epileptic discharge but also the spread to adjacent cortical areas. Taking this benefit of SPECT studies into account, preoperative SPECT results from 13 patients with HMS who underwent epilepsy surgery were analysed. The radioisotope 99mTc-ECD was injected in all patients within five seconds after seizure onset. Group analysis was performed with statistical parametric mapping (SPM) of paired ictal-interictal SPECTs in order to identify regions of significant ictal hyperperfusion. Hyperperfused regions with a corrected cluster-level significance p-value of < 0.002 were considered significant. Seizure onset at implanted subdural electrodes was defined as the epileptic focus in 12 of 13 patients. Two patterns were recognized: HMS-1 with marked agitation and HMS-2 with mild agitation. Ictal hyperperfusion images revealed significant hyperperfusion in the anterior cingulate cortex, orbito-frontal gyrus, lentiform nucleus, midbrain and pons. These hyperperfused areas represent the symptomatogenic zone which was different from the epileptogenic zone, as confirmed by the favourable outcomes after surgical resection. The present findings suggest that a network, including frontal and possibly extrafrontal brainstem and limbic structures, is involved in the genesis of the complex epileptic manifestations of HMS. Moreover, ictal SPECT analysed by SPM is a useful method for studying the neural networks of different types of seizures.


Literature mining for the discovery of hidden connections between drugs, genes and diseases.
The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also well-suited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs.


Cortical Bone Mineralization in the Human Femoral Neck in Cases and Controls from Synchrotron Radiation Study.
To compare the degree and distribution of mineralization in femoral neck cortex from 23 women with hip fractures (age 65-96 years) and 17 female controls (age 72-103 years), we obtained 3D data by synchrotron radiation microtomography (SRμCT). Variables were degree of mineralization of bone (DMB) in total cortex (cDMBSRMEAN), osteons (oDMBSRMEAN), and pure interstitial tissue (intDMBSRMEAN). The cortex on SRμCT images was divided into nine to twelve 50-μm zones from the periosteum to the endosteum; cDMBSRMEAN, oDMBSRMEAN, and intDMBSRMEAN were measured in each zone. We used descriptive statistics and t tests, general linear model analyses to compare DMBSR values across zones and individuals, one-way analysis of variance for within-group comparisons of zones. In patients, the variance of mineral content value was not different than in controls, but mean values of degree of mineralization varied across zones. These cross-sectional data suggest that bone fragility may be related to a greater heterogeneity of the distribution of mineralization in femoral neck cortex.


The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review.
Letrozole is a third-generation aromatase inhibitor for use in postmenopausal women with hormonal-sensitive breast cancer. This drug was found to reduce or effectively shrink tumors in a significant number of such patients. It exhibits antitumor activity at a relatively low daily dose, and is highly potent and selective and well tolerated. Results from recent phase III clinical studies have confirmed the efficacy and the key role of this drug in the therapy of advanced breast cancer in postmenopausal women. Moreover, letrozole demonstrated higher activity and lower toxicity compared to tamoxifen in the first-line therapy of postmenopausal women affected with advanced breast cancer. However, it also represents a valid option in second-line therapy after tamoxifen failure. New data on this agent in adjuvant or neoadjuvant treatment also suggest efficacy in the treatment of early breast cancer. This article reviews the clinical data on letrozole in all settings and its future potential in chemoprevention. (c) 2001 Prous Science. All rights reserved.


Genetic characterization of Plasmodium falciparum allelic variants infecting mothers at delivery and their children during their first plasmodial infections.
Infants born to mothers with placental malaria at delivery develop Plasmodium falciparum parasitemia earlier than those born to mothers without placental infection. This phenomenon may be explained by the development of immune tolerance due to exposure to P. falciparum antigens in utero. The hypothesis of this study is that this increased susceptibility might be related to infections by parasites expressing the same blood stage allele's antigens as those to which the infants were exposed in utero. The comparison of P.falciparum msp2 (3D7 and FC27) and glurp gene polymorphisms of infected mothers at delivery to those of their offspring's infections during infancy was realized and the possible associations of the different polymorphisms with clinical outcomes were assessed. A second approach consisted in the use of a Geographic Information System to determine whether the antigen alleles were homogeneously distributed in the area of study. This was necessary to analyze whether the biological observations were due to high exposure to a particular antigen allelic form in the environment or to high infant permissiveness to the same allelic antigen polymorphism as the placental one. Infants born to mothers with placental malaria at delivery were more susceptible to infections by parasites carrying the same glurp allele as encountered in utero compared to distinct alleles, independently of their geographic distribution. The increased permissiveness of infants to plasmodial infections with shared placental-infant glurp alleles sheds light on the role that P. falciparum blood stage antigen polymorphisms may play in the first plasmodial infections in infancy.


EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer.
The EPH and ephrins function as both receptor and ligands and the output on their complex signaling is currently investigated in cancer. Previous work shows that some EPH family members have clinical value in breast cancer, suggesting that this family could be a source of novel clinical targets. Here we quantified the mRNA expression levels of EPH receptors and their ligands, ephrins, in 65 node positive breast cancer samples by RT-PCR with TaqMan® Micro Fluidics Cards Microarray. Upon hierarchical clustering of the mRNA expression levels, we identified a subgroup of patients with high expression, and poor clinical outcome. EPHA2, EPHA4, EFNB1, EFNB2, EPHB2 and EPHB6 were significantly correlated with the cluster groups and particularly EPHB2 was an independent prognostic factor in multivariate analysis and in four public databases. The EPHB2 protein expression was also analyzed by immunohistochemistry in paraffin embedded material (cohort 2). EPHB2 was detected in the membrane and cytoplasmic cell compartments and there was an inverse correlation between membranous and cytoplasmic EPHB2. Membranous EPHB2 predicted longer breast cancer survival in both univariate and multivariate analysis while cytoplasmic EPHB2 indicated shorter breast cancer survival in univariate analysis. Concluding: the EPH/EFN cluster analysis revealed that high EPH/EFN mRNA expression is an independent prognostic factor for poor survival. Especially EPHB2 predicted poor breast cancer survival in several materials and EPHB2 protein expression has also prognostic value depending on cell localization.


The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus.
Tuberculosis (TB) is a contagious, infectious disease, due to Mycobacterium tuberculosis (MT) that has always been a permanent challenge over the course of human history, because of its severe social implications. It has been hypothesized that the genus Mycobacterium originated more than 150 million years ago. In the Middle Ages, scrofula, a disease affecting cervical lymph nodes, was described as a new clinical form of TB. The illness was known in England and France as "king's evil", and it was widely believed that persons affected could heal after a royal touch. In 1720, for the first time, the infectious origin of TB was conjectured by the English physician Benjamin Marten, while the first successful remedy against TB was the introduction of the sanatorium cure. The famous scientist Robert Koch was able to isolate the tubercle bacillus and presented this extraordinary result to the society of Physiology in Berlin on 24 March 1882. In the decades following this discovery, the Pirquet and Mantoux tuberculin skin tests, Albert Calmette and Camille Guérin BCG vaccine, Selman Waksman streptomycin and other anti-tuberculous drugs were developed.


In vitro protein adsorption studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy.
Nevirapine is a poorly water-soluble antiretroviral drug. Intravenous nevirapine nanosuspensions (NS) (457 ± 10 nm) were prepared by high-pressure homogenization. NS were surface modified by stabilizer adsorption, e.g., serum albumin, polysaccharide and polyethylene glycol (PEG) 1000. The NS were characterized for mean particle size, particle size distribution and polydispersity index. The targeting potential of the nonmodified and three surface-modified NS to the mononuclear phagocytic system (MPS) cells that serve as potent viral reservoirs was assessed by in vitro protein adsorption studies using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). The adsorption patterns were qualitatively identical, but showed quantitative differences. The relatively adsorbed high amounts of immunoglobulins indicate uptake by liver and spleen, observed quantitative differences (e.g., the amount of dysopsonin albumin and apolipoproteins) can modulate the organ distribution. Controlled in vitro optimization of the protein adsorption by surface modification of the nanocrystals can reduce the number of animals required for in vivo studies and accelerate development of targeted nanoparticles. In this study, intravenous nevirapine (a poorly water-soluble antiretroviral drug) nanosuspensions were prepared by high-pressure homogenization and characterized.


The Concepts of Risk, Safety, and Security: Applications in Everyday Language.
The concepts of risk, safety, and security have received substantial academic interest. Several assumptions exist about their nature and relation. Besides academic use, the words risk, safety, and security are frequent in ordinary language, for example, in media reporting. In this article, we analyze the concepts of risk, safety, and security, and their relation, based on empirical observation of their actual everyday use. The "behavioral profiles" of the nouns risk, safety, and security and the adjectives risky, safe, and secure are coded and compared regarding lexical and grammatical contexts. The main findings are: (1) the three nouns risk, safety, and security, and the two adjectives safe and secure, have widespread use in different senses, which will make any attempt to define them in a single unified manner extremely difficult; (2) the relationship between the central risk terms is complex and only partially confirms the distinctions commonly made between the terms in specialized terminology; (3) whereas most attempts to define risk in specialized terminology have taken the term to have a quantitative meaning, nonquantitative meanings dominate in everyday language, and numerical meanings are rare; and (4) the three adjectives safe, secure, and risky are frequently used in comparative form. This speaks against interpretations that would take them as absolute, all-or-nothing concepts.


Leaf cuticular lipids on the Shandong and Yukon ecotypes of saltwater cress, Eutrema salsugineum, and their response to water deficiency and impact on cuticle permeability.
The impact of water-deficit stress on leaf cuticular waxes and cutin monomers, and traits associated with cuticle permeability were examined in Shandong and Yukon ecotypes of Eutrema salsugineum (syn. Thellungiella salsuginea). Although Shandong exhibits glaucous leaves, and Yukon is non-glaucous, wax amounts on non-stressed Yukon leaves were 4.6-fold higher than on Shandong, due mainly to Yukon's eightfold higher wax fatty acids, especially the C22 and C24 acid homologues. Water deficit caused a 26.9% increase in total waxes on Shandong leaves, due mainly to increased C22 and C24 acids; and caused 10.2% more wax on Yukon, due mainly to an increase in wax alkanes. Total cutin monomers on non-stressed leaves of Yukon were 58.3% higher than on Shandong. Water deficit caused a 28.2% increase in total cutin monomers on Shandong, whereas total cutin monomers were not induced on Yukon. With or without stress, more abundant cuticle lipids were generally associated with lower water loss rates, lower chlorophyll efflux rates and an extended time before water deficit-induced wilting. In response to water deficit, Shandong showed elevated transcription of genes encoding elongase subunits, consistent with the higher stress induction of acids by Shandong. Yukon's higher induction of CER1 and CER3 transcripts may explain why alkanes increased most on Yukon after water deficit. Eutrema, with its diverse cuticle lipids and responsiveness, provides a valuable genetic resource for identifying new genes and alleles effecting cuticle metabolism, and lays groundwork for studies of the cuticle's role in extreme stress tolerance.


Evolutionary Dynamics Do Not Motivate a Single-Mutant Theory of Human Language.
One of the most controversial hypotheses in cognitive science is the Chomskyan evolutionary conjecture that language arose instantaneously in humans through a single mutation. Here we analyze the evolutionary dynamics implied by this hypothesis, which has never been formalized before. The hypothesis supposes the emergence and fixation of a single mutant (capable of the syntactic operation Merge) during a narrow historical window as a result of frequency-independent selection under a huge fitness advantage in a population of an effective size no larger than ~15 000 individuals. We examine this proposal by combining diffusion analysis and extreme value theory to derive a probabilistic formulation of its dynamics. We find that although a macro-mutation is much more likely to go to fixation if it occurs, it is much more unlikely a priori than multiple mutations with smaller fitness effects. The most likely scenario is therefore one where a medium number of mutations with medium fitness effects accumulate. This precise analysis of the probability of mutations occurring and going to fixation has not been done previously in the context of the evolution of language. Our results cast doubt on any suggestion that evolutionary reasoning provides an independent rationale for a single-mutant theory of language.


Bypassing the selection rule in choosing controls for a case-control study.
It has been argued that in case-control studies, controls should be drawn from the base population that gives rise to the cases. In designing a study of occupational injury and risks arising from long-term illness and prescribed medication, we lacked data on subjects' occupation, without which employed cases (typically in manual occupations) would be compared with controls from the general population, including the unemployed and a higher proportion of white-collar professions. Collecting the missing data on occupation would be costly. We estimated the potential for bias if the selection rule were ignored. We obtained published estimates of the frequencies of several exposures of interest (diabetes, mental health problems, asthma, coronary heart disease) in the general population, and of the relative risks of these diseases in unemployed versus employed individuals and in manual versus non-manual occupations. From these we computed the degree of over- or underestimation of exposure frequencies and exposure ORs if controls were selected from the general population. The potential bias in the OR was estimated as likely to fall between an underestimation of 14% and an overestimation of 36.7% (95th centiles). In fewer than 6% of simulations did the error exceed 30%, and in none did it reach 50%. For the purposes of this study, in which we were interested only in substantial increases in risk, the potential for selection bias was judged acceptable. The rule that controls should come from the same base population as cases can justifiably be broken, at least in some circumstances.


Activated VEGFR2/KDR pathway in tumour cells and tumour associated vessels of colorectal cancer.
Vascular endothelial cell growth factor (VEGF) acts by phosphorylating specific tyrosine kinase receptors on endothelial cell membrane promoting angiogenesis. The study of the activation status of VEGF receptors in human malignancies has recently become feasible by means of specific monoclonal antibodies recognising the phosphorylated form of these receptors. In the current study, we investigate the expression of the phosphorylated VEGFR2/KDR receptor in normal colon and colorectal adenocarcinomas in parallel with histopathological parameters, prognosis and the expression of the 'hypoxia inducible factor' HIF1alpha. pVEGFR2/KDR was weakly expressed in the normal colon, but it was expressed strongly in the cytoplasm and nuclei of cancer cells and in the tumour associated vasculature, mainly at the invading tumour edge. pVEGFR2/KDR expression in cancer cells was significantly associated with a tumour diameter > 6 cm (P = 0.04), poor histological differentiation (P = 0.004) and with high CEF1alpha expression (P = 0.05). High pVEGFR2/KDR expressing vascular density was significantly related with a high VEGF and HIF1alpha expression in cancer cells (P = 0.02 and 0.03, respectively). This was also related significantly to high pVEGFR2/KDR expression in cancer cells. In multivariate analysis, the most significant predictors for death were lympho-vascular invasion (P < 0.001) followed by VEGF (P = 0.014), node status (P = 0.015), standard vascular density (P = 0.022) and necrosis (P = 0.032). pVEGFR2 receptors are largely expressed in colon cancer cells and intratumoural vasculature. As VEGF targeting agents enter the clinical practice, the role of monoclonal antibodies recognising the phosphorylated form of VEGF receptors as predictors of response to targeted therapies should be sought in clinicopathological trials.


Factors associated with location of death (home or hospital) of patients referred to a palliative care team.
To identify factors associated with the location of death (home or hospital) of patients referred to a palliative care home support team. Retrospective case-control chart review. Palliative care inpatient unit with a home support team in a large chronic care hospital. All 75 patients receiving services from the home support team who died at home between June 1988 and January 1990 and 75 randomly selected patients receiving the same services who died in hospital. Place of death (home or hospital). Of the 267 patients referred to the palliative care home support team during the study period 75 (28.1%) died at home. Factors significantly associated with dying at home were the patient's preference for dying at home recorded at the time of the initial assessment (p < 0.001), a family member other than the spouse involved in the patient's care (p = 0.021) and the use of private shift nursing (p < 0.001). The patients who died in hospital were more likely than the other patients to have had no home visits from the palliative care team after the initial assessment (p = 0.04). The patient's preference for dying at home was not met if the caregiver could not cope or if symptoms were uncontrolled. The patient's preference for dying in hospital was not met if his or her condition deteriorated rapidly or if the patient died suddenly. Patients' preference as to place of death, level of caregiver support and entitlement to private shift nursing were significantly associated with patients' dying at home. The determination of these factors should be part of every palliative care assessment. Patients and their families should be informed about available home support services.


Psychometric Properties of Parent Outcome Measures Used in RCTs of Antenatal and Early Years Parent Programs: A Systematic Review.
Parenting programs are effective in the early intervention and treatment of children's social, emotional and behavioural difficulties. However, inconsistency in the use of outcome measures limits the comparability of programs and creates challenges for practitioners seeking to monitor progress of families in their care. A systematic review was conducted to identify measures, appraise their psychometric properties and ease of implementation, with the overall objective of recommending a small battery of measures for use by researchers and practitioners. This article provides an overview of the most commonly used measures in experimental evaluations of parenting programs delivered to parents of children up to, and including, the age of 5 years (including antenatal programs). An in-depth appraisal of the psychometric properties and ease of implementation of parent outcome measures is also presented (findings in relation to child and dyadic outcome measures are presented elsewhere). Following a systematic search, 64 measures were identified as being used in three or more of 279 included evaluation studies. Data on the psychometric properties of 18 parent outcome measures were synthesised from 87 development and validation studies. Whilst it was not possible to identify a definitive battery of recommended measures, we are able to recommend specific measures that could be prioritised in further research and development and hold promise for those seeking to monitor the outcomes of parents and children in receipt of parenting programs.


Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial.
Presence of thyroid autoantibodies in women with normal thyroid function is associated with increased risk of miscarriage. Whether levothyroxine treatment improves pregnancy outcomes among women undergoing in vitro fertilization and embryo transfer (IVF-ET) is unknown. To determine the effect of levothyroxine on miscarriage among women undergoing IVF-ET who had normal thyroid function and tested positive for thyroid autoantibodies. An open-label, randomized clinical trial involving 600 women who tested positive for the antithyroperoxidase antibody and were being treated for infertility at Peking University Third Hospital from September 2012 to March 2017. The intervention group (n = 300) received either a 25-μg/d or 50-μg/d dose of levothyroxine at study initiation that was titrated according to the level of thyroid-stimulating hormone during pregnancy. The women in the control group (n = 300) did not receive levothyroxine. All participants received the same IVF-ET and follow-up protocols. The primary outcome was the miscarriage rate (pregnancy loss before 28 weeks of gestation, which was calculated among women who became pregnant). The secondary outcomes were clinical intrauterine pregnancy rate (fetal cardiac activity seen at sonography observation on the 30th day after the embryo transfer), and live-birth rate (at least 1 live birth after 28 weeks of gestation). Among the 600 women (mean [SD] age, 31.6 [3.8] years) randomized in this trial, 567 women (94.5%) underwent IVF-ET and 565 (94.2%) completed the study. Miscarriage rates were 10.3% (11 of 107) in the intervention group and 10.6% (12 of 113) in the control group, with the absolute rate difference (RD) of -0.34% (95% CI, -8.65% to 8.12%) over the 4.5-year study period. Clinical intrauterine pregnancy rates were 35.7% (107 of 300) in the intervention group and 37.7% (113 of 300) in the control group, with an absolute RD of -2.00% (95% CI, -9.65% to 5.69%). Live-birth rates were 31.7% (95 of 300) in the intervention group and 32.3% (97 of 300) in the control group, with an absolute RD of -0.67% (95% CI, -8.09% to 6.77%). Among women in China who had intact thyroid function and tested positive for antithyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates. Chinese Clinical Trial Registry: ChiCTR-TRC-13004097.


Childhood origins of adult resistance to science.
Resistance to certain scientific ideas derives in large part from assumptions and biases that can be demonstrated experimentally in young children and that may persist into adulthood. In particular, both adults and children resist acquiring scientific information that clashes with common-sense intuitions about the physical and psychological domains. Additionally, when learning information from other people, both adults and children are sensitive to the trustworthiness of the source of that information. Resistance to science, then, is particularly exaggerated in societies where nonscientific ideologies have the advantages of being both grounded in common sense and transmitted by trustworthy sources.


Comparison of T Tube Ileostomy and Bishop Koop Ileostomy for the Management of Uncomplicated Meconium Ileus.
Meconium ileus is a common cause of neonatal intestinal obstruction. Various surgical procedures are in practice for uncomplicated meconium ileus. Bishop Koop ileostomy allows distal passage of gut content and uses the distal absorptive area. T tube ileostomy avoids the need for gut resection and formal closure of stoma. The aim of this prospective interventional study was to compare the outcome of T-tube ileostomy and Bishop Koop ileostomy for the treatment of uncomplicated meconium ileus. It was a prospective interventional study from January 2015 to December 2016. Patients were randomly assigned to the T-tube ileostomy group (group A) and Bishop Koop ileostomy group (group B). The patients were followed up for 6 weeks post-operatively. Surgical outcomes between the two groups were compared. The age range of the patients was 1 to 7 days; majority of the patients were males. Mean operation time of group A (60.76±5.81 minutes) and group B (87.05±6.49 minutes) showed significant difference (p =0.0001). After operation, mean time to start bowel movements in group A (4.90±1.41days) and group B (6.53±2.58 days) showed significant difference (p= 0.020). Times to establish oral feeding, irrigation tube removal and postoperative complications showed no significant difference. All patients that survived in the group B required formal stoma closure, while in the group A stomas closed spontaneously. One patient in the group A had intraperitoneal leakage leading to mortality after second operation. Four patients had leakage in the group B; 2 of them died. T-tube ileostomy was found as an effective and safe procedure for the management of uncomplicated meconium ileus.


Preliminary Studies on Immune Response and Viral Pathogenesis of Zika Virus in Rhesus Macaques.
Zika Virus (ZIKV) is primarily transmitted through mosquito bites. It can also be transmitted during sexual intercourse and in utero from mother to fetus. To gain preliminary insight into ZIKV pathology and immune responses on route of transmission, rhesus macaques (RMs) were inoculated with ZIKV (PRVABC59) via intravaginal (IVAG) (n = 3) or subcutaneous (sub Q) (n = 2) routes. Systemic ZIKV infection was observed in all RMs, regardless of the route of inoculation. After 9 days postinfection (dpi), ZIKV was not detected in the plasma of IVAG- and sub-Q-inoculated RMs. Importantly, RMs harbored ZIKV up to 60 dpi in various anatomical locations. Of note, ZIKV was also present in several regions of the brain, including the caudate nucleus, parietal lobe, cortex, and amygdala. These observations appear to indicate that ZIKV infection may be systemic and persistent regardless of route of inoculation. In addition, we observed changes in key immune cell populations in response to ZIKV infection. Importantly, IVAG ZIKV infection of RMs is associated with increased depletion of CD11C hi myeloid cells, reduced PD-1 expression in NK cells, and elevated frequencies of Ki67⁺ CD8⁺ central memory cells as compared to sub Q ZIKV-infected RMs. These results need to interpreted with caution due to the small number of animals utilized in this study. Future studies involving large groups of animals that have been inoculated through both routes of transmission are needed to confirm our findings.


What Represents Treatment Efficacy in Long-term Studies of Gout Flare Prevention? An Interview Study of People With Gout.
The patient experience of gout flares is multidimensional, with several contributing factors including pain intensity, duration, and frequency. There is currently no consistent method for reporting gout flare burden in long-term studies. This study aimed to determine which factors contribute to patient perceptions of treatment efficacy in long-term studies of gout flare prevention. This study involved face-to-face interviews with people with gout using visual representations of gout flare patterns. Participants were shown different flare scenarios over a hypothetical 6-month treatment period that portrayed varying flare frequency, pain intensity, and flare duration. The participants were asked to indicate and discuss which scenario they believed was most indicative of successful treatment over time. Quantitative data relating to the proportion of participants selecting each scenario were reported using descriptive statistics. A qualitative descriptive approach was used to code and categorize the data from the interview transcripts. Twenty-two people with gout participated in the semistructured interviews. All 3 factors of pain intensity, flare duration, and flare frequency influenced participants' perception of treatment efficacy. However, a shorter flare duration was the most common indicator of successful treatment, with half of participants (n = 11, 50%) selecting the scenario with a shorter flare duration over those with less painful flares. Flare duration, flare frequency, and pain severity are all taken into account by patients with gout when considering treatment efficacy over time. Long-term studies of gout should ideally capture all these factors to better represent patients' experience of treatment success.


Quantification of Molecular Interactions in Living Cells in Real Time using a Membrane Protein Nanopattern.
Molecular processes within cells have traditionally been studied with biochemical methods due to their high degree of specificity and ease of use. In recent years, cell-based assays have gained more and more popularity since they facilitate the extraction of mode of action, phenotypic, and toxicity information. However, to provide specificity, cellular assays rely heavily on biomolecular labels and tags while label-free cell-based assays only offer holistic information about a bulk property of the investigated cells. Here, we introduce a cell-based assay for protein-protein interaction analysis. We achieve specificity by spatially ordering a membrane protein of interest into a coherent pattern of fully functional membrane proteins on the surface of an optical sensor. Thereby, molecular interactions with the coherently ordered membrane proteins become visible in real time, while nonspecific interactions and holistic changes within the living cell remain invisible. Due to its unbiased nature, this new cell-based detection method presents itself as an invaluable tool for cell signaling research and drug discovery.


Factors contributing to urban malaria transmission in sub-saharan Africa: a systematic review.
Sub-Saharan Africa suffers by far the greatest malaria burden worldwide and is currently undergoing a profound demographic change, with a growing proportion of its population moving to urban areas. Urbanisation is generally expected to reduce malaria transmission; however the disease still persists in African cities, in some cases at higher levels than in nearby rural areas. Objective. This paper aims to collate and analyse risk factors for urban malaria transmission throughout sub-Saharan Africa and to discuss their implications for control. Methods. A systematic search on malaria and urbanisation was carried out focusing on sub-Saharan Africa. Particular interest was taken in vector breeding sites in urban and periurban areas. Results. A variety of urban vector breeding sites were catalogued, the majority of which were artificial, including urban agriculture, tyre tracks, and ditches. Natural breeding sites varied according to location. Low socioeconomic status was a significant risk factor for malaria, often present in peri-urban areas. A worrying trend was seen in the adaptation of malaria vector species to the urban environment. Urban malaria is highly focused and control programs should reflect this. Conclusion. As urbanisation continues and vector species adapt, continued monitoring and control of urban malaria in sub-Saharan Africa is essential.


Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I).
Worldwide research efforts have driven recent pharmaceutical successes, and consequently, the emerging role of Protein-Protein Interactions (PPIs) as drug targets has finally been widely embraced by the scientific community. Inhibitors of these Protein-Protein Interactions (2P2Is or i-PPIs) are likely to represent the next generation of highly innovative drugs that will reach the market over the next decade. This review describes up-to-date knowledge on this particular chemical space, with a specific emphasis on a subset of this ensemble. We also address current structural knowledge regarding both protein-protein and protein-inhibitor complexes, that is, the 2P2I database. Finally, ligand efficiency analyses permit us to relate potency to size and polarity and to discuss the need to co-develop nanoparticle drug delivery systems.


Updates on ophthalmic imaging features of optic disc drusen, papilledema, and optic disc edema.
Optic nerve head elevation can be associated with vision loss. This review provides an update regarding key features of optic disc drusen (ODD) compared with papilledema from increased intracranial pressure and optic disc edema from other causes. Clinical history and funduscopic examination are not sufficient to correctly diagnose different causes of optic nerve head elevation. Multimodal ophthalmic imaging is noninvasive and should be used as first-line diagnostic testing to distinguish optic disc edema or papilledema from pseudoedema. Advanced ophthalmic imaging, including enhanced depth imaging optical coherence tomography (EDI-OCT) and autofluorescence imaging, can visualize ODD at high resolution and determine whether there is optic disc edema. OCT angiography does not require contrast and can rapidly visualize papillary, peripapillary, and macular microvasculature and identify important vascular biomarker of ischemia and, potentially, visual prognosis. Multimodal ophthalmic imaging can help in the diagnosis of ODD and optic disc edema and identify patients at high risk of vision loss and neurological issues in order to ensure appropriate diagnosis and treatment.


Attention and non-retinotopic feature integration.
Features of moving objects are non-retinotopically integrated along their motion trajectories as demonstrated by a variety of recent studies. The mechanisms of non-retinotopic feature integration are largely unknown. Here, we investigated the role of attention in non-retinotopic feature integration by using the sequential metacontrast paradigm. A central line was offset either to the left or right. A sequence of flanking lines followed eliciting the percept of two diverging motion streams. Although the central line was invisible, its offset was perceived within the streams. Observers attended to one stream. If an offset was introduced to one of the flanking lines in the attended stream, this offset integrated with the central line offset. No integration occurred when the offset was in the non-attended stream. Here, we manipulated the allocation of attention by using an auditory cueing paradigm. First, we show that mandatory non-retinotopic integration occurred even when the cue came long after the motion sequence. Second, we used more than two streams of which two could merge. Offsets in different streams were integrated when the streams merged. However, offsets of one stream were not integrated when this stream had to be ignored. We propose a hierarchical two stage model, in which motion grouping determines mandatory feature integration while attention selects motion streams for optional feature integration.


Managing disease on the goldmines: 'work-related' and 'non-work-related' diseases.
The mining industry in South Africa makes a distinction between work-related and non-work-related diseases because of the legal obligation to provide compensation for work-related diseases such as the various pneumoconioses. In this paper we consider the ways in which this distinction helps or hinders the delivery of health care services in the mining industry in South Africa. In particular we examine the inter-relationship between silicosis, which is compensatable, tuberculosis, for which limited compensation is made, and HIV, which is not compensatable, in order to suggest ways to manage these diseases. Goldmines in South Africa. While the South African mining industry has excellent hospital facilities offering a high standard of care, the incidence of tuberculosis is increasing rapidly, silicosis is common, and although no data have been published on the prevalence of HIV it is probably in the region of 20-30%. The impact of HIV is likely to be particularly severe among this group of workers, especially given the interactions between HIV and tuberculosis and tuberculosis and silicosis, and the likely impact of silicosis on the progression of HIV. Historically the distinction between work-related and non-work-related diseases has been of importance in the mining industry because of the need to provide compensation for the former class of diseases. In order to promote the overall health of workers this distinction is problematical because of the way in which the various diseases interact and because successful health promotion plans should locate diseases within the broader social context in which mineworkers live and work. In order to address the health of workers there is a need to set up appropriate health surveillance systems for the most important diseases, to shift the emphasis from hospital- and clinic-based biomedical interventions to preventive approaches based on sound epidemiological and social studies, and to ensure that health is dealt with jointly by mine management, medical services and the trade unions with the active involvement of the workers.


Low-temperature-flux syntheses of ultraviolet-transparent borophosphates Na4MB2P3O13 (M = Rb, Cs) exhibiting a second-harmonic generation response.
The first non-centrosymmetric mixed-alkali-metal borophosphates, Na4MB2P3O13 (M = Rb 1, Cs 2), were obtained using a low-temperature flux method. Single-crystal X-ray diffraction studies of 1 and 2 reveal that the two compounds are isostructural, both crystallizing in the orthorhombic space group Pna21; their structures consist of novel 1D borophosphate chains constructed from B2P3O14 fundamental building units, assembled into a 3D framework by alkali metal cations. Second-harmonic generation (SHG) measurements show that 1 and 2 are type-I phase-matchable, with SHG responses ca. 0.35 and 0.42 times that of KH2PO4, respectively. The cut-off edges of 1 and 2 are ca. 276 and 267 nm, respectively, which suggests that they are potential ultraviolet nonlinear optical materials. Density functional theory calculations were employed to shed light on the band structure and density of states as well as the electron density distribution.


Artesunate affords protection against aspirin-induced gastric injury by targeting oxidative stress and proinflammatory signaling.
Prolonged use of aspirin, a commonly prescribed non steroidal anti-inflammatory drug, is well known to produce gastrointestinal toxicity which could be minimized by various anti-secretory agents. The present study was carried out to evaluate the protective effect of artesunate against aspirin induced gastric injury in rats. Gastric injury was induced in fasted Wistar rats by oral administration of aspirin. The effect of 50 and 150mg/kg of artesunate was studied on macroscopic changes, gastric secretions, histology, oxidative stress and inflammatory markers in the stomach tissue after 5h of induction of gastric injury. Immunohistochemical analysis for the expression of IL-1β, IL-6, NF-κB(p65) and COX-2 was also carried out. The effect of artesunate was compared with that of standard anti-ulcer drug famotidine (20mg/kg). Artesunate pretreatment produced a dose-dependent reduction in aspirin induced gastric injury and restored the gastric juice parameters. It normalized the tissue levels of oxidative stress markers (glutathione, malondialdehyde and superoxide dismutase activity) and mediators of inflammation (myeloperoxidase and TNF-α). The protection afforded by artesunate was evident from the histoarchitecture of stomach tissue and marked reduction in tissue expression of IL-1β, IL-6, NF-κB(p65) and COX-2. The effect of artesunate was found to be comparable to that of standard drug famotidine. Artesunate markedly ameliorated aspirin induced gastric injury in rats by targeting oxidative stress and COX-2 dependent as well as COX-2 independent proinflammatory signaling pathways and could have a therapeutic potential in gastric ulcer disease.


Marinobufagenin levels in preeclamptic patients: a preliminary report.
Preeclampsia is a disorder resulting in significant fetomaternal complications with no definitive pharmacological intervention. A bufadienolide, marinobufagenin, has been implicated in the etiology of preeclampsia. We investigated both the blood and urine levels of marinobufagenin in preeclamptic and control subjects. Preeclamptic and normotensive pregnant women were recruited at various gestational age periods. Blood and urine specimens were obtained and analyzed for marinobufagenin levels and creatinine. The former determination was performed utilizing a new, novel chemifluorescent enzyme-linked immunosorbent assay. The marinobufagenin levels were higher in preeclamptics than in the controls in both serum and urine at various gestational age periods. Additionally, the mean level of marinobufagenin in the preeclamptic group was significantly greater than in controls in both blood and urine specimens ( P < 0.05). These data are consistent with a role for marinobufagenin in the etiology of preeclampsia. This study demonstrated comparable results in blood and urine samples. This suggests that subsequent studies on levels of marinobufagenin as a screening test for preeclampsia could be done utilizing urine samples, which are easier to obtain, less invasive, more cost-effective, and as accurate as the serological tests.


Immune responses to adenovirus vectors in the nervous system.
Non-replicating adenovirus vectors are being developed as vehicles for gene transfer into cells of the nervous system. An important requirement for successful gene transfer is the absence of deleterious cytotoxic or inflammatory side effects of the delivery system. Despite offering relatively stable reporter gene expression, currently available adenovirus vectors also elicit immune responses in the brain, both at the site of vector delivery and at synaptically linked distant sites. However, although an anti-viral T-lymphocyte response eliminates the vector and damages local tissue in many peripheral organs, the immune response to adenovirus in the brain is less effective and enables the vector to persist. Nevertheless, in this persistent state the adenovirus vector remains a potential target for a destructive immune response that can also cause local demyelination. The development of strategies to minimize this damaging immune response, through either vector modification or immunomodulation, will be crucial for the future success of genetic therapies in the brain.


Neo-vascularization of the stroke cavity by implantation of human neural stem cells on VEGF-releasing PLGA microparticles.
Replacing the tissue lost after a stroke potentially provides a new neural substrate to promote recovery. However, significant neurobiological and biotechnological challenges need to be overcome to make this possibility into a reality. Human neural stem cells (hNSCs) can differentiate into mature brain cells, but require a structural support that retains them within the cavity and affords the formation of a de novo tissue. Nevertheless, in our previous work, even after a week, this primitive tissue is void of a vasculature that could sustain its long-term viability. Therefore, tissue engineering strategies are required to develop a vasculature. Vascular endothelial growth factor (VEGF) is known to promote the proliferation and migration of endothelial cells during angio- and arteriogenesis. VEGF by itself here did not affect viability or differentiation of hNSCs, whereas growing cells on poly(D,L-lactic acid-co-glycolic acid) (PLGA) microparticles, with or without VEGF, doubled astrocytic and neuronal differentiation. Secretion of a burst and a sustained delivery of VEGF from the microparticles in vivo attracted endothelial cells from the host into this primitive tissue and in parts established a neovasculature, whereas in other parts endothelial cells were merely interspersed with hNSCs. There was also evidence of a hypervascularization indicating that further work will be required to establish an adequate level of vascularization. It is therefore possible to develop a putative neovasculature within de novo tissue that is forming inside a tissue cavity caused by a stroke.


Effects of short-term fasting on cancer treatment.
Growing preclinical evidence shows that short-term fasting (STF) protects from toxicity while enhancing the efficacy of a variety of chemotherapeutic agents in the treatment of various tumour types. STF reinforces stress resistance of healthy cells, while tumor cells become even more sensitive to toxins, perhaps through shortage of nutrients to satisfy their needs in the context of high proliferation rates and/or loss of flexibility to respond to extreme circumstances. In humans, STF may be a feasible approach to enhance the efficacy and tolerability of chemotherapy. Clinical research evaluating the potential of STF is in its infancy. This review focuses on the molecular background, current knowledge and clinical trials evaluating the effects of STF in cancer treatment. Preliminary data show that STF is safe, but challenging in cancer patients receiving chemotherapy. Ongoing clinical trials need to unravel if STF can also diminish toxicity and increase efficacy of chemotherapeutic regimes in daily practice.


Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides.
In this report, we investigate the activation of Th1 clones using altered TCR ligand. By changing the immunogenic peptide, cytolytic function can be separated from proliferative and lymphokine responses. These three responses were examined and dissected in two Th1 clones using analogs of the murine hemoglobin [Hb(64-76)] peptide. This analysis was focused on amino acids in the immunogenic peptide that were possible T cell contact residues. Typically, several amino acids were identified as critical contact residues for a Th1 proliferative response. An examination of lymphokine production (IFN-gamma or IL-3) revealed the same pattern of response to the analog peptides indicating that the proliferative and lymphokine responses were directly related. However, for cytolysis, fewer amino acid residues were identified as critical contact residues for effector function. Thus, some altered peptide ligands allowed the disassociation of the cytolytic function from the proliferative and lymphokine responses in Th1 clones. To extend these findings, the activation of T cell hybridomas created from the Th1 clones were similarly examined using the altered TCR ligands. The lymphokine response (IL-2) of the T cell hybridomas identified the same critical amino acids as did the cytolytic response of the Th1 clones. Thus, analog peptides partially activated the Th1 clones such that cytolysis occurred independent from proliferative and lymphokine responses.


The Multilevel Relationships of HIV-Related Stigma to Child and Caregiver Mental Health among HIV-Affected Households in South Africa.
HIV/AIDS-related (HAR) stigma is still a prevalent problem in Sub-Saharan Africa, and has been found to be related to mental health of HIV-positive individuals. However, no studies in the Sub-Saharan African context have yet examined the relationship between HAR stigma and mental health among HIV-negative, HIV-affected adults and families; nor have any studies in this context yet examined stigma as an ecological construct predicting mental health outcomes through supra-individual (setting level) and individual levels of influence. Multilevel modeling was used to examine multilevel, ecological relationships between HAR stigma and mental health among child and caregiver pairs from a systematic, community-representative sample of 508 HIV-affected households nested within 24 communities in KwaZulu-Natal, South Africa. Two distinct dimensions of HAR stigma were measured: individual stigmatizing attitudes, and perceptions of community normative stigma. Findings suggest that individual-level HAR stigma significantly predicts individual mental health (depression and anxiety) among HIV-affected adults; and that community-level HAR stigma significantly predicts both individual-level mental health outcomes (anxiety) among HIV-affected adults, and mental health outcomes (PTSD and externalizing behavior scores) among HIV-affected children. Differentiated patterns of relationships were found using the two different stigma measures. These findings of unique relationships identified when utilizing two conceptually distinct stigma measures, at two levels of analysis (individual and community) suggest that HAR stigma in this context should be conceptualized as a multilevel, multidimensional construct. These findings have important implications both for mental health interventions and for interventions to reduce HAR stigma in this context.


Cohort study from 11 European countries highlighted differences in the use and efficacy of hypothermia prevention strategies after very preterm birth.
This study investigated the different strategies used in 11 European countries to prevent hypothermia, which continues to affect a large proportion of preterm births in the region. We examined the association between the reported use of hypothermia prevention strategies in delivery rooms and body temperatures on admission to neonatal intensive care units (NICUs) in 5861 infants born at 22 + 0 to 31 +6 weeks of gestation. The use of plastic bags, wraps, caps, exothermic heat and mattresses was investigated. The proportion of infants born in units that systematically used one or more hypothermia prevention strategies was 88.2% and 50.9% of those infants were hypothermic on admission to NICUs. Of the 9.6% born in units without systematic hypothermia prevention, 73.2% were hypothermic. Only 2.2% of infants were born in units with no reported prevention strategies. Lower gestational age increased the probability of hypothermia. No significant differences were found between the various hypothermia prevention strategies. Hyperthermia was seen in 4.8% of all admitted infants. Very preterm infants had lower risks of hypothermia on NICU admission if the unit used systematic prevention strategies. All the strategies had similar effects, possibly due to implementation rather than a strategy's specific efficacy.


Hydraulic Lift Increases Herbivory by Diaprepes abbreviatus Larvae and Persistence of Steinernema riobrave in Dry Soil.
Citrus seedlings were grown in double pots that separated the root systems into discrete lower and upper zones to test the hypothesis that hydraulic lift affects persistence and efficacy of entomopathogenic nematodes. Three treatments were established: (i) both pots were irrigated at water potential </= -15 kPa (no drought); (ii) only the bottom pot was irrigated (partial drought); (iii) neither pot was irrigated (complete drought). Steinernema riobrave infective juveniles (IJ) were added to the soil in the top pots of all treatments. During 27 days, the water potential in soil in the top pots of both the partial and complete drought treatments declined to ca. -160 kPa. A greater number of nematodes (P </= 0.01) persisted in soil as motile IJ under conditions of partial drought (143/pot) than under no drought (6.1/pot) or complete drought (4.4/pot). A second experiment was initiated with the same treatments as the first, except that only half of the 20 replicates in each moisture regime were inoculated with nematodes. After 15 days, all top pots were irrigated and two larvae of the insect Diaprepes abbreviatus were added to all of the top pots in each treatment. Irrigation regimes were reinstituted until water potential in the top pots under partial and complete drought had again declined to ca. -150 kPa and the experiment was terminated. In the absence of nematodes, the damage to tap roots caused by D. abbreviatus feeding under partial drought and complete drought was 80% and 32%, respectively, of that under no drought. Numbers of motile IJ in soil were greater under conditions of partial drought (736/pot) than under complete drought (2.0/pot) or no drought (7.2/pot). Survival of D. abbreviatus and insect damage to roots were reduced by the presence of S. riobrave to a greater extent under partial drought as compared to other treatments. Hydraulic lift from the lower to the upper rhizosphere appears to have modulated the effect of dry soil conditions on feeding behavior of D. abbreviatus and created favorable conditions for persistence and efficacy of the entomopathogenic nematode.


Personality change following unemployment.
Unemployment has a strongly negative influence on well-being, but it is unclear whether it also alters basic personality traits. Whether personality changes arise through natural maturation processes or contextual/environmental factors is still a matter of debate. Unemployment, a relatively unexpected and commonly occurring life event, may shed light on the relevance of context for personality change. We examined, using a latent change model, the influence of unemployment on the five-factor model of personality in a sample of 6,769 German adults, who completed personality measures at 2 time points 4 years apart. All participants were employed at the first time point, and a subset became unemployed over the course of the study. By the second time point, participants had either remained in employment, been unemployed from 1 to 4 years, or had experienced some unemployment but become reemployed. Compared with those who had remained in employment, unemployed men and women experienced significant patterns of change in their mean levels of agreeableness, conscientiousness, and openness, whereas reemployed individuals experienced limited change. The results indicate that unemployment has wider psychological implications than previously thought. In addition, the results are consistent with the view that personality changes as a function of contextual and environmental factors.


Optimizing multicompression approaches to elasticity imaging.
Breast lesion visibility in static strain imaging ultimately is noise limited. When correlation and related techniques are applied to estimate local displacements between two echo frames recorded before and after a small deformation, target contrast increases linearly with the amount of deformation applied. However, above some deformation threshold, decorrelation noise increases more than contrast such that lesion visibility is severely reduced. Multicompression methods avoid this problem by accumulating displacements from many small deformations to provide the same net increase in lesion contrast as one large deformation but with minimal decorrelation noise. Unfortunately, multicompression approaches accumulate echo noise (electronic and sampling) with each deformation step as contrast builds so that lesion visibility can be reduced again if the applied deformation increment is too small. This paper uses signal models and analysis techniques to develop multicompression strategies that minimize strain image noise. The analysis predicts that displacement variance is minimal in elastically homogeneous media when the applied strain increment is 0.0035. Predictions are verified experimentally with gelatin phantoms. For in vivo breast imaging, a strain increment as low as 0.0015 is recommended for minimum noise because of the greater elastic heterogeneity of breast tissue.


Electroconvulsive therapy in the treatment of neuropsychiatric conditions and transcranial magnetic stimulation as a pathophysiological probe in neuropsychiatry.
It is a challenging task to review transcranial magnetic stimulation (TMS) studies in neuropsychiatric disorders alongside assessments of longstanding clinical applications of ECT as an empirical treatment. The task is challenging because TMS was developed as a probe of neural mechanisms, whereas, in marked contrast, ECT has been a clinical technique from its inception. Since the onset of modern psychopharmacology, the understanding of the potential applications of ECT to neuropsychiatric disorders is generally restricted to case reports of patients with intractable disease that have had at least a partial response to ECT. Studies of the possible efficacy of TMS in neuropsychiatric conditions have a significant advantage over ECT as the treatments are associated with less morbidity. The only serious known complication in TMS is a risk of seizures that may increase in patients with neuropsychiatric conditions such as course brain disease. Only cortical structures are themselves accessible to TMS using current technology. Present TMS techniques, however, seem capable of affecting activity in deeper brain structures that are functionally linked to cortical brain regions. TMS permits novel explorations of relationships between regional brain activity and symptoms of a number of neuropsychiatric disorders, as well as in research relating activity in functionally related brain regions to modulation of cognition and affective states in healthy individuals. This is particularly true at present because TMS and powerful neuroimaging and neuropsychological tools are all making rapid advances simultaneously.


Long-term physiologically regulated expression of the low-density lipoprotein receptor in vivo using genomic DNA mini-gene constructs.
Familial hypercholesterolemia (FH) is a condition caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Expression of LDLR is highly regulated and excess receptor expression is cytotoxic. To incorporate essential gene regulation into a gene therapy vector for FH, we generated vectors in which the expression of therapeutic human LDLR gene, or luciferase reporter gene, is driven by 10 kb of human LDLR genomic DNA encompassing the promoter region including elements essential for physiologically regulated expression. Using luciferase expression and specific LDL binding and internalization assays, we have shown in vitro that the genomic promoter element confers long-term, physiologically regulated gene expression and complementation of receptor deficiency in culture for 240 cell-generations. This was demonstrated in the presence of sterols or statins, modifiers of LDLR promoter activity. In vivo, we demonstrate efficient liver-specific delivery and expression of luciferase following hydrodynamic tail-vein injection and confirm that expression from the LDLR promoter element is sensitive to statin administration. We also demonstrate long-term LDLR expression from the 10-kb promoter element up to 9 months following delivery. The vector system that we describe provides the efficient delivery, long-term expression, and physiological regulation required for a successful gene therapy intervention for FH.


Expression of bone morphogenetic proteins and Msx genes during root formation.
Like crown development, root formation is also regulated by interactions between epithelial and mesenchymml tissues. Bone morphogenetic proteins (BMPs), together with the transcription factors Msx1 and Msx2, play important roles in these interactions during early tooth morphogenesis. To investigate the involvement of this signaling pathway in root development, we analyzed the expression patterns of Bmp2, Bmp3, Bmp4, and Bmp7 as well as Msx1 and Msx2 in the roots of mouse molars. Bmp4 was expressed in the apical mesenchyme and Msx2 in the root sheath. However, Bmps were not detected in the root sheath epithelium, and Msx transcripts were absent from the underlying mesenchyme. These findings indicate that this Bmp signaling pathway, required for tooth initiation, does not regulate root development, but we suggest that root shape may be regulated by a mechanism similar to that regulating crown shape in cap-stage tooth germs. Msx2 expression continued in the epithelial cell rests of Malassez, and the nearby cementoblasts intensely expressed Bmp3, which may regulate some functions of the fragmented epithelium.


Context-aware genomic surveillance reveals hidden transmission of a carbapenemase-producing Klebsiella pneumoniae.
Genomic surveillance can inform effective public health responses to pathogen outbreaks. However, integration of non-local data is rarely done. We investigate two large hospital outbreaks of a carbapenemase-carrying Klebsiella pneumoniae strain in Germany and show the value of contextual data. By screening about 10 000 genomes, over 400 000 metagenomes and two culture collections using in silico and in vitro methods, we identify a total of 415 closely related genomes reported in 28 studies. We identify the relationship between the two outbreaks through time-dated phylogeny, including their respective origin. One of the outbreaks presents extensive hidden transmission, with descendant isolates only identified in other studies. We then leverage the genome collection from this meta-analysis to identify genes under positive selection. We thereby identify an inner membrane transporter (ynjC) with a putative role in colistin resistance. Contextual data from other sources can thus enhance local genomic surveillance at multiple levels and should be integrated by default when available.


Spirituality in geriatric psychiatry.
Academic recognition of the implications of religion/spirituality (R/S) for mental health is increasing, with a growing number of studies involving older adults. The present review provides an overview of these studies, highlighting the influence of R/S on older adults' mental health and the clinical implications of addressing R/S in the geriatrics and gerontology context. The available evidence suggests that R/S involvement is usually associated with lower levels of depression, substance use/abuse, and cognitive declining and better quality of life, well being, and functional status in older persons. Despite the number of studies showing this relationship, few have yet investigated the effects of addressing spiritual needs or carrying out R/S interventions in this age group. Evidence is mounting that R/S is most important in geriatric psychiatry. In general, studies have shown a positive relationship between R/S and mental health in the older population. Health professionals should be attentive to these spiritual needs. Nevertheless, more studies are needed to investigate the mechanisms of the R/S-mental health association and how to integrate R/S in clinical practice.


Evolution of increased larval competitive ability in Drosophila melanogaster without increased larval feeding rate.
Multiple experimental evolution studies on Drosophila melanogaster in the 1980s and 1990s indicated that enhanced competitive ability evolved primarily through increased larval tolerance to nitrogenous wastes and increased larval feeding and foraging rate, at the cost of efficiency of food conversion to biomass, and this became the widely accepted view of how adaptation to larval crowding evolves in fruitflies.We recently showed that populations of D. ananassae and D. n. nasuta subjected to extreme larval crowding evolved greater competitive ability without evolving higher feeding rates, primarily through a combination of reduced larval duration, faster attainment of minimum critical size for pupation, greater efficiency of food conversion to biomass, increased pupation height and, perhaps, greater urea/ammonia tolerance. This was a very different suite of traits than that seen to evolve under similar selection in D. melanogaster and was closer to the expectations from the theory of K-selection. At that time, we suggested two possible reasons for the differences in the phenotypic correlates of greater competitive ability seen in the studies with D. melanogaster and the other two species. First, that D. ananassae and D. n. nasuta had a very different genetic architecture of traits affecting competitive ability compared to the long-term laboratory populations of D. melanogaster used in the earlier studies, either because the populations of the former two species were relatively recently wild-caught, or by virtue of being different species. Second, that the different evolutionary trajectories in D. ananassae and D. n. nasuta versus D. melanogaster were a reflection of differences in the manner in which larval crowding was imposed in the two sets of selection experiments. The D. melanogaster studies used a higher absolute density of eggs per unit volume of food, and a substantially larger total volume of food, than the studies on D. ananassae and D. n. nasuta. Here, we show that long-term laboratory populations of D. melanogaster, descended from some of the populations used in the earlier studies, evolve essentially the same set of traits as the D. ananassae and D. n. nasuta crowding-adapted populations when subjected to a similar larval density at low absolute volumes of food. As in the case of D. ananassae and D. n. nasuta, and in stark contrast to earlier studies with D. melanogaster, these crowding-adapted populations of D. melanogaster did not evolve greater larval feeding rates as a correlate of increased competitive ability. The present results clearly suggest that the suite of phenotypes through which the evolution of greater competitive ability is achieved in fruitflies depends critically not just on larval density per unit volume of food, but also on the total amount of food available in the culture vials. We discuss these results in the context of an hypothesis about how larval density and the height of the food column in culture vials might interact to alter the fitness costs and benefits of increased larval feeding rates, thus resulting in different routes to the evolution of greater competitive ability, depending on the details of exactly how the larval crowding was implemented.


Developmental alterations in noxious-evoked EEG activity recorded from rat primary somatosensory cortex.
Primary somatosensory cortex (S1) contains a nociceptive map that localizes potential tissue damage on the body and encodes stimulus intensity. An objective and specific biomarker of pain however is currently lacking and is urgently required for use in non-verbal clinical populations as well as in the validation of pre-clinical pain models. Here we describe studies to see if the responses of the S1 in juvenile rats are different to those in the adult. We recorded electroencephalogram (EEG) responses from S1 of lightly-anesthetized Sprague-Dawley rats at either postnatal day 21 or postnatal day 40 during the presentation of noxious (55 °C) or innocuous (30 °C) thermal stimuli applied to the plantar surface of the left hindpaw. The total EEG power across the recording period was the same in both ages after stimulation but the frequency distribution was significantly affected by age. Noxious heat evoked a significant increase in theta band (4-8 Hz) activity in adults only (P<0.0001 compared to baseline; P<0.0001 compared to juveniles). There were no significant differences in EEG responses to innocuous thermal stimuli. These data show that there are significant alterations in the processing of nociceptive inputs within the maturing cortex and that cortical theta activity is involved only in the adult cortical response to noxious stimulation.


Codeine misuse and dependence in South Africa: Perspectives of addiction treatment providers.
General practitioners are referring patients with codeine-related problems to specialist treatment facilities, but little is known about the addiction treatment providers, the kinds of treatment they provide, and whether training or other interventions are needed to strengthen this sector. To investigate the perspectives of addiction treatment providers regarding treatment for codeine misuse or dependence. Twenty addiction treatment providers linked to the South African Community Epidemiology Network on Drug Use and the South African Addiction Medicine Society were contacted telephonically and asked 20 questions. While many participants had received training in pharmacological management of individuals with opioid dependence, only two had received specific training on codeine management. Between half and two-thirds of the treatment settings they worked in provided detoxification, pharmacotherapy, psychosocial treatment and aftercare. Very few treatment settings offered long-term treatment for codeine misuse and dependence. Participants indicated that over half of their codeine patients entered treatment for intentional misuse for intoxication, and dependence resulting from excessive or long-term use. The main barriers to patients entering treatment were seen as denial of having a problem, not being ready for change, mental health problems, stigma, and affordability of treatment. Participants identified a need for further training in how to manage withdrawal and detoxification, treatment modalities including motivational interviewing, and relapse prevention. Gaps in training among treatment providers need to centre on how to manage withdrawal from codeine use and detoxification, motivational interviewing and relapse prevention. Interventions are needed to address barriers to entering treatment, including user denial.