Differential effects of proteinase K on the components of the liver microsomal cytochrome P-450 mixed function oxidase system.
Mild proteolysis of rat liver microsomes with increasing concentrations of proteinase K caused a marked decrease in the levels of microsomal cytochrome P-450 reductase (Fp) without having any significant effect on the cytochrome P-450s. About 20% of the microsomal cytochrome b5 was susceptible to proteolysis at low concentrations of proteinase K, while the remaining 80% was resistant to proteolysis, even at significantly higher proteinase K concentrations. Low concentrations of the proteases released about 30% of Fp from microsomes isolated from both uninduced and phenobarbital-induced rats, but did not affect the rates of benzphetamine bital-induced rats, but did not affect the rates of benzphetamine demethylation significantly. Further depletion of microsomal Fp at higher concentrations of proteinase K resulted in reductions of the rates of benzphetamine demethylation. However, even at higher protease concentrations, the decrease in the rate of the demethylation reaction was significantly less than the loss of Fp. Similar results were observed for the metabolism of two other substrates, 7-ethoxycoumarin and p-nitroanisole, suggesting that the P-450s, not the Fp, were the rate-limiting components in the metabolism of these xenobiotics by microsomes. It is clear that the decreases in the P-450-dependent oxidations were due to depletion of the NADPH-cytochrome P-450 reductase since reconstituting the protease-treated microsomes with native Fp restored the oxidation reactions. The amount of Fp required to completely restore the oxidation of benzphetamine only partially restored the oxidation of 7-ethoxycoumarin and p-nitroanisole.(ABSTRACT TRUNCATED AT 250 WORDS)


Ureteric stent dwelling time: a risk factor for post-ureteroscopy sepsis.
To evaluate the association between stent dwelling time and sepsis after ureteroscopy, and identify risk factors for sepsis in this setting. The prospectively collected database of a single institution was queried for all patients who underwent ureteroscopy for stone extraction between 2010 and 2016. Demographic, clinical, preoperative and operative data were collected. The primary study endpoint was sepsis within 48 h of ureteroscopy. Logistic regressions were performed to identify predictors of post-ureteroscopy sepsis in the ureteroscopy cohort and specifically in patients with prior stent insertion. Between October 2010 and April 2016, 1 256 patients underwent ureteroscopy for stone extraction. Risk factors for sepsis included prior stent placement, female gender and Charlson comorbidity index. A total of 601 patients had a ureteric stent inserted before the operation and were included in the study cohort, in which the median age was 56 years, 90 patients were women (30%), and 97 patients were treated for positive preoperative urine cultures (16.1%). Postoperative sepsis, <48 h after surgery, occurred in eight (1.2%) non-stented patients and in 28 patients (4.7%) with prior stent insertion. Sepsis rates after stent dwelling times of 1, 2, 3 and >3 months were 1, 4.9, 5.5 and 9.2%, respectively. On multivariate analysis, stent dwelling time, stent insertion because of sepsis, and female gender were significantly associated with post-ureteroscopy sepsis in patients with prior stent placement. Patients who undergo ureteroscopy after ureteric stent insertion have a higher risk of postoperative sepsis. Prolonged stent dwelling time, sepsis as an indication for stent insertion, and female gender are independent risk factors. Stent placement should be considered cautiously, and if inserted, ureteroscopy should be performed within 1 month.


Brain Aromatase and the Regulation of Sexual Activity in Male Mice.
The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice. Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear. To determine the role of brain aromatase in regulating male sexual activity, we generated a brain-specific aromatase knockout (bArKO) mouse. A newly generated whole-body total aromatase knockout mouse of the same genetic background served as a positive control. Here we demonstrate that local aromatase expression and estrogen production in the brain is partially required for male sexual behavior and sex hormone homeostasis. Male bArKO mice exhibited decreased sexual activity in the presence of strikingly elevated circulating testosterone. In castrated adult bArKO mice, administration of testosterone only partially restored sexual behavior; full sexual behavior, however, was achieved only when both estradiol and testosterone were administered together. Thus, aromatase in the brain is, in part, necessary for testosterone-dependent male sexual activity. We also found that brain aromatase is required for negative feedback regulation of circulating testosterone of testicular origin. Our findings suggest testosterone activates male sexual behavior in part via conversion to estradiol in the brain. These studies provide foundational evidence that sexual behavior may be modified through inhibition or enhancement of brain aromatase enzyme activity and/or utilization of selective estrogen receptor modulators.


Dutiful daughters: HIV/AIDS, moral pragmatics, female citizenship and structural violence among Devadasis in northern Karnataka, India.
Decades of research have documented how sex workers worldwide, particularly female sex workers (FSWs), shoulder a disproportionate burden of the HIV epidemic. In India, although a substantial progress has been made in controlling the epidemic, its prevalence among FSWs and the Devadasis (also called traditional sex workers) in northern Karnataka is still significantly high. On the other hand, much of the HIV prevention research has focused on their mapping and size estimation, typologies, bio-behavioural surveillance, condom use and other prevention technologies. In this article, drawing on critical theoretical perspectives, secondary historical sources and in-depth interviews, we unravel wider social, cultural and political economic complexities surrounding the lives of Devadasis, and specifically illuminate the moral pragmatics that shed light on their entry into sex trade and vulnerability to HIV. Findings from this research are extremely important since while much is known about Devadasis in social sciences and humanities, relatively little is known about the complexities of their lives within public health discourses related to HIV. Our work has direct implications for ongoing HIV prevention and health promotion efforts in the region and beyond.


Age-Related Left Ventricular Changes and Their Association with Leukocyte Telomere Length in Healthy People.
With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing heart is a cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the structure and function of the LV in people of different ages free of cardiovascular diseases (CVD) and regular drug medication and to assess their relationship with LTL. We hypothesized that age-related changes in LV myocardium are associated with telomere length. The study population consisted of 150 healthy, non-obese volunteers aged 28 to 78 years without history of CVD, significant deviations by 12-lead electrocardiogram and negative exercise test (treadmill stress test). All the participants underwent standardized transthoracic echocardiography using an available system (iE33; Philips). The LTL was measured by real-time quantitative polymerase chain reaction. We determined the relative ratio of telomere repeat copy number (T) to single-copy gene copy number (S). In the older people there was a higher wall thickness than in the younger (1.03 ± 0.09 vs. 0.88 ± 0.10, p<0.01), whereas LV mass index was comparable between them (85.8 ± 15.40 vs. 83.1 ± 11.8, p = 0.20). There was a decrease in LV dimensions with advancing age (p<0.001). Older subjects had impairment in LV relaxation. LTL was associated with decreased E/A, Em/Am ratio (β = -0.323, p = 0.0001) after adjusting for age, sex and risk factors. There is no relation between the LTL and the structure of LV. Our data suggest that the ageing process leads to changes in LV structure and diastolic function and is linked with a phenotype of concentric LV remodeling. Telomere attrition is associated with age-related LV diastolic dysfunction. Telomere length appears to be a biomarker of myocardial ageing.


Tubulin-Dependent Transport of Connexin-36 Potentiates the Size and Strength of Electrical Synapses.
Connexin-36 (Cx36) electrical synapses strengthen transmission in a calcium/calmodulin (CaM)/calmodulin-dependent kinase II (CaMKII)-dependent manner similar to a mechanism whereby the N-methyl-D-aspartate (NMDA) receptor subunit NR2B facilitates chemical transmission. Since NR2B-microtubule interactions recruit receptors to the cell membrane during plasticity, we hypothesized an analogous modality for Cx36. We determined that Cx36 binding to tubulin at the carboxy-terminal domain was distinct from Cx43 and NR2B by binding a motif overlapping with the CaM and CaMKII binding motifs. Dual patch-clamp recordings demonstrated that pharmacological interference of the cytoskeleton and deleting the binding motif at the Cx36 carboxyl-terminal (CT) reversibly abolished Cx36 plasticity. Mechanistic details of trafficking to the gap-junction plaque (GJP) were probed pharmacologically and through mutational analysis, all of which affected GJP size and formation between cell pairs. Lys279, Ile280, and Lys281 positions were particularly critical. This study demonstrates that tubulin-dependent transport of Cx36 potentiates synaptic strength by delivering channels to GJPs, reinforcing the role of protein transport at chemical and electrical synapses to fine-tune communication between neurons.


The tension between data sharing and the protection of privacy in genomics research.
Next-generation sequencing and global data sharing challenge many of the governance mechanisms currently in place to protect the privacy of research participants. These challenges will make it more difficult to guarantee anonymity for participants, provide information to satisfy the requirements of informed consent, and ensure complete withdrawal from research when requested. To move forward, we need to improve the current governance systems for research so that they are responsive to individual privacy concerns but can also be effective at a global level. We need to develop a system of e-governance that can complement existing governance systems but that places greater reliance on the use of technology to ensure compliance with ethical and legal requirements. These new governance structures must be able to address the concerns of research participants while at the same time ensuring effective data sharing that promotes public trust in genomics research.


Origin and evolution of prebiotic organic matter as inferred from the Tagish Lake meteorite.
The complex suite of organic materials in carbonaceous chondrite meteorites probably originally formed in the interstellar medium and/or the solar protoplanetary disk, but was subsequently modified in the meteorites' asteroidal parent bodies. The mechanisms of formation and modification are still very poorly understood. We carried out a systematic study of variations in the mineralogy, petrology, and soluble and insoluble organic matter in distinct fragments of the Tagish Lake meteorite. The variations correlate with indicators of parent body aqueous alteration. At least some molecules of prebiotic importance formed during the alteration.


Transcriptional responses of PBMC in psychosocially stressed animals indicate an alerting of the immune system in female but not in castrated male pigs.
Brain and immune system are linked in a bi-directional manner. To date, it remained largely unknown why immune components become suppressed, enhanced, or remain unaffected in relation to psychosocial stress. Therefore, we mixed unfamiliar pigs with different levels of aggressiveness. We separated castrated male and female pigs into psychosocially high- and low- stressed animals by skin lesions, plasma cortisol level, and creatine kinase activity obtained from agonistic behaviour associated with regrouping. Peripheral blood mononuclear cells (PBMC) were collected post-mortem and differential gene expression was assessed using the Affymetrix platform (n = 16). Relevant stress-dependent alterations were found only between female samples, but not between castrated male samples. Molecular routes related to TREM 1 signalling, dendritic cell maturation, IL-6 signalling, Toll-like receptor signalling, and IL-8 signalling were increased in high stressed females compared to low stressed females. This indicates a launch of immune effector molecules as a direct response. According to the shifts of transcripts encoding cell surface receptors (e.g. CD14, TLR2, TLR4, TREM1) the study highlights processes acting on pattern recognition, inflammation, and cell-cell communication. The transcriptional response partly affected the degree of 'stress responsiveness', indicating that the high stressed females altered their signal transduction due to potential infections and injuries while fighting.


Integrating genetic data and population viability analyses for the identification of harbour seal (Phoca vitulina) populations and management units.
Identification of populations and management units is an essential step in the study of natural systems. Still, there is limited consensus regarding how to define populations and management units, and whether genetic methods allow for inference at the relevant spatial and temporal scale. Here, we present a novel approach, integrating genetic, life history and demographic data to identify populations and management units in southern Scandinavian harbour seals. First, 15 microsatellite markers and model- and distance-based genetic clustering methods were used to determine the population genetic structure in harbour seals. Second, we used harbour seal demographic and life history data to conduct population viability analyses (PVAs) in the vortex simulation model in order to determine whether the inferred genetic units could be classified as management units according to Lowe and Allendorf's (Molecular Ecology, 19, 2010, 3038) 'population viability criterion' for demographic independence. The genetic analyses revealed fine-scale population structuring in southern Scandinavian harbour seals and pointed to the existence of several genetic units. The PVAs indicated that the census population size of each of these genetic units was sufficiently large for long-term population viability, and hence that the units could be classified as demographically independent management units. Our study suggests that population genetic inference can offer the same degree of temporal and spatial resolution as 'nongenetic' methods and that the combined use of genetic data and PVAs constitutes a promising approach for delineating populations and management units.


Molecularly imprinted sol-gel nanofibers based solid phase microextraction coupled on-line with high performance liquid chromatography for selective determination of acesulfame.
Sol-gel based molecularly imprinted polymer (MIP) nanofiber was successfully fabricated by electrospinning technique on the surface of a stainless steel bar. The manufactured tool was applied for on-line selective solid phase microextraction (SPME) and determination of acesulfame (ACF) as an artificial sweetener with high performance liquid chromatography (HPLC). The selective ability of method for the extraction of ACF was investigated in the presence of some selected sweeteners such as saccharine (SCH), aspartame (ASP) and caffeine (CAF). Electrospinning of MIP sol-gel solution on the stainless steel bar provided an unbreakable sorbent with high thermal, mechanical, and chemical stability. Moreover, application of the MIP-SPME tool revealed a unique approach for the selective microextraction of the analyte in beverage samples. In this work, 3-(triethoxysilyl)-propylamine (TMSPA) was chosen as a precursor due to its ability to imprint the analyte by hydrogen bonding, Van der Walls, and dipole-dipole interactions. Nylon 6 was also added as a backbone and support for the precursor in which sol could greatly growth during the sol-gel process and makes the solution electrospinable. Various effective parameters in the extraction efficiency of the MIP-SPME tool such as loading time, flow rate, desorption time, selectivity, and the sample volume were evaluated. The linearity for the ACF in beverage sample was in the range of 0.78-100.5 ng mL(-1). Limit of detection (LOD) and quantification (LOQ) were 0.23 and 0.78 ng mL(-1) respectively. The RSD values (n=5) were all below 3.5%at the 20 ng mL(-1) level.


Farmers' market use is associated with fruit and vegetable consumption in diverse southern rural communities.
While farmers' markets are a potential strategy to increase access to fruits and vegetables in rural areas, more information is needed regarding use of farmers' markets among rural residents. Thus, this study's purpose was to examine (1) socio-demographic characteristics of participants; (2) barriers and facilitators to farmers' market shopping in southern rural communities; and (3) associations between farmers' market use with fruit and vegetable consumption and body mass index (BMI). Cross-sectional surveys were conducted with a purposive sample of farmers' market customers and a representative sample of primary household food shoppers in eastern North Carolina (NC) and the Appalachian region of Kentucky (KY). Customers were interviewed using an intercept survey instrument at farmers' markets. Representative samples of primary food shoppers were identified via random digit dial (RDD) cellular phone and landline methods in counties that had at least one farmers' market. All questionnaires assessed socio-demographic characteristics, food shopping patterns, barriers to and facilitators of farmers' market shopping, fruit and vegetable consumption and self-reported height and weight. The main outcome measures were fruit and vegetable consumption and BMI. Descriptive statistics were used to examine socio-demographic characteristics, food shopping patterns, and barriers and facilitators to farmers' market shopping. Linear regression analyses were used to examine associations between farmers' market use with fruit and vegetable consumption and BMI, controlling for age, race, education, and gender. Among farmers' market customers, 44% and 55% (NC and KY customers, respectively) reported shopping at a farmers' market at least weekly, compared to 16% and 18% of NC and KY RDD respondents. Frequently reported barriers to farmers' market shopping were market days and hours, "only come when I need something", extreme weather, and market location. Among the KY farmers' market customers and NC and KY RDD respondents, fruit and vegetable consumption was positively associated with use of farmers' markets. There were no associations between use of farmers' markets and BMI. Fruit and vegetable consumption was associated with farmers' market shopping. Thus, farmers' markets may be a viable method to increase population-level produce consumption.


Telomere elongation during early development is independent of environmental temperatures in Atlantic salmon.
There is increasing evidence from endothermic vertebrates that telomeres, which cap the ends of chromosomes and play an important role in chromosome protection, decline in length during postnatal life and are a useful indicator of physiological state and expected lifespan. However, much less is currently known about telomere dynamics in ectothermic vertebrates, which are likely to differ from that of endotherms, at least in part due to the sensitivity of ectotherm physiology to environmental temperature. We report here on an experiment in which Atlantic salmon (Salmo salar) were reared through the embryonic and larval stages of development, and under differing temperatures, in order to examine the effects of environmental temperature during early life on telomere dynamics, oxidative DNA damage and cellular proliferation. Telomere length significantly increased between the embryonic and larval stages of development. Contrary to our expectations, variation in telomere length at the end of the larval stage was unrelated to either cell proliferation rate or the relative level of oxidative DNA damage, and did not vary between the temperature treatments. This study suggests that salmon are able to restore the length of their telomeres during early development, which may possibly help to buffer potentially harmful environmental effects experienced in early life.


Qualification of New Methods for Measuring In Situ Rheology of Non-Newtonian Fluids in Porous Media.
Pressure drop (P) versus volumetric injection rate (Q) data from linear core floods have typically been used to measure in situ rheology of non-Newtonian fluids in porous media. However, linear flow is characterized by steady-state conditions, in contrast to radial flow where both pressure and shear-forces have non-linear gradients. In this paper, we qualify recently developed methods for measuring in situ rheology in radial flow experiments, and then quantitatively investigate the robustness of these methods against pressure measurement error. Application of the new methods to experimental data also enabled accurate investigation of memory and rate effects during polymer flow through porous media. A radial polymer flow experiment using partially hydrolyzed polyacrylamide (HPAM) was performed on a Bentheimer sandstone disc where pressure ports distributed between a central injector and the perimeter production line enabled a detailed analysis of pressure variation with radial distance. It has been suggested that the observed shear-thinning behavior of HPAM solutions at low flux in porous media could be an experimental artifact due to the use of insufficiently accurate pressure transducers. Consequently, a generic simulation study was conducted where the level of pressure measurement error on in situ polymer rheology was quantitatively investigated. Results clearly demonstrate the robustness of the history match methods to pressure measurement error typical for radial flow experiments, where negligible deviations from the reference rheology was observed. It was not until the error level was increased to five-fold of typical conditions that significant deviation from the reference rheology emerged. Based on results from pore network modelling, Chauveteau (1981) demonstrated that polymer flow in porous media may at some rate be influenced by the prior history. In this paper, polymer memory effects could be evaluated at the Darcy scale by history matching the pressure drop between individual pressure ports and the producer as a function of injection rate (conventional method). Since the number of successive contraction events increases with radial distance, the polymer has a different pre-history at the various pressure ports. Rheology curves obtained from history matching the radial flow experiment were overlapping, which shows that there is no influence of geometry on in-situ rheology for the particular HPAM polymer investigated. In addition, the onset of shear-thickening was independent of volumetric injection rate in radial flow.


Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.
Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies.


Direct evidence that initial oxidative stress triggered by preconditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes.
We tested the hypothesis that late preconditioning is associated with increased antioxidant enzyme activity induced by initial oxidative stress. Isolated rat myocytes were preconditioned either with two cycles of 5 minutes of anoxia and 5 minutes of reoxygenation or with exogenous superoxide anion (O2-) generated by reaction of xanthine oxidase with xanthine. Myocytes were allowed to recover for 60 minutes or 24 hours, after which they were subjected to 60 minutes of anoxia and 60 minutes of reoxygenation. After 60 minutes or 24 hours, the protection was evidenced by decreased O2- production, increased Mn superoxide dismutase (Mn-SOD) activity, increased call viability, decreased LDH release, reduced malondialdehyde formation, high-energy phosphate preservation, and improved call morphology in preconditioned and O2(-)-treated myocytes. Immediately after treatment with O2- or repetitive, brief anoxia, O2- production was increased in myocytes. Longer anoxia resulted in loss of Mn-SOD activity in anoxic controls 24 hours later, whereas it was significantly increased in preconditioned and O2- -treated myocytes. O2- production was inhibited in preconditioned and O2(-)-myocytes. Myocytes treated with Mn-SOD during short, intermittent anoxia exhibited decreased activity of Mn-SOD and increased O2- production 24 hours later. Mn-SOD activity in late preconditioning was considerably higher than that in classic preconditioning. These results suggest that a burst of oxygen free radicals generated during the initial periods of brief, repetitive anoxia increases myocardial antioxidant activity 24 hours later and that it contributes to the late cardioprotective effect of preconditioning.


Evaluation of ultrasound-guided diagnostic local anaesthetic hip joint injection for osteoarthritis.
The diagnosis of hip osteoarthritis is often complicated by co-existing pathology in the knee and spine, and mismatch between clinical and radiological signs. Temporary pain relief from a local anaesthetic injection into the hip joint has been reported to help localise symptoms, reducing the risk of unnecessary surgery being performed. We hypothesize that good surgical outcome is predicted by good analgesia following diagnostic injection, and that alternative pathology is present when there is no response to injection. Data were analysed from a prospective database of 163 consecutive patients who underwent diagnostic hip injection for possible osteoarthritis. We recorded result of injection and whether hip arthroplasty was performed. A good outcome to surgery was defined as subsequent pain relief without significant residual symptoms. A total of 138 patients were suitable for inclusion in the study. Fifty-eight patients had hip arthroplasty following a good response to diagnostic injection. Of these 54 had a good outcome following surgery (93%). There was also a quantitative improvement in pain and function in these patients as measured by 1 year post-operative and pre-operative Harris hip scores (P < 0.0001). A total of 44/49 patients had no surgery following no response to injection. A clear alternative diagnosis to hip osteoarthritis was made in 40 of these patients (91%). Diagnostic ultrasound-guided local anaesthetic injection of the hip joint is a useful test in confirming hip pathology. Complete relief of hip pain following intracapsular injection of local anaesthetic is associated with good surgical outcome following joint replacement.


Segmental versican expression in the trabecular meshwork and involvement in outflow facility.
Versican is a large proteoglycan with numerous chondroitin sulfate (CS) glycosaminoglycan (GAG) side chains attached. To assess versican's potential contributions to aqueous humor outflow resistance, its segmental distribution in the trabecular meshwork (TM) and the effect on outflow facility of silencing the versican gene were evaluated. Fluorescent quantum dots (Qdots) were perfused to label outflow pathways of anterior segments. Immunofluorescence with confocal microscopy and quantitative RT-PCR were used to determine versican protein and mRNA distribution relative to Qdot-labeled regions. Lentiviral delivery of shRNA-silencing cassettes to TM cells in perfused anterior segment cultures was used to evaluate the involvement of versican and CS GAG chains in outflow facility. Qdot uptake by TM cells showed considerable segmental variability in both human and porcine outflow pathways. Regional levels of Qdot labeling were inversely related to versican protein and mRNA levels; versican levels were relatively high in sparsely Qdot-labeled regions and low in densely labeled regions. Versican silencing decreased outflow facility in human and increased facility in porcine anterior segments. However, RNAi silencing of ChGn, an enzyme unique to CS GAG biosynthesis, increased outflow facility in both species. The fibrillar pattern of versican immunostaining in the TM juxtacanalicular region was disrupted after versican silencing in perfusion culture. Versican appears to be a central component of the outflow resistance, where it may organize GAGs and other ECM components to facilitate and control open flow channels in the TM. However, the exact molecular organization of this resistance appears to differ between human and porcine eyes.


Hormone responsive human breast cancer in long-term tissue culture: effect of insulin.
The mechanisms of steroid and peptide hormone action in human breast cancer are poorly understood. We have previously characterized a cell line of human breast cancer in long-term tissue culture that possesses various steroid hormone receptors and responses, providing a model for the study of steroid hormone action. The present studies describe a human breast cancer in vitro that responds to physiologie concentrations of insulin with an increased rate of macromolecular synthesis and growth. Thymidine and uridine incorporation in cells in serum-free medium are stimulated by 10(-11) M insulin and are maximal with 10(-8) M. Leucine incorporation is stimulated by 5 X 10(-11) M insulin and is maximal with 10(-9) M. Significant stimulation of uridine and leucine incorporation is evident by 3 hr and maximal by 10 hr. A 10-hr lag period exists for insulin stimulation of thymidine incorporation, which is maximal form 14 to 24 hr. The effect of 10(-8) M insulin on macromolecular synthesis is accompanied by a 69% increase above controls in the number of cells after 24 hr. The effect on macromolecular synthesis is observed in glucose-free medium. Insulin's effect on protein synthesis is not blocked by inhibition of RNA synthesis with actinomycin D. Glucocorticoids partially inhibit the action of insulin in these cells. This system provides a model for studying insulin action, and suggests that some human breast cancer may show growth regulation by insulin.


SU-E-T-548: Case Study of HDR Vs IMRT in Pediatric Sarcomas.
To compare the dose to critical structures using HDR brachytherapy versus IMRT in pediatric tumors. Two sarcoma cases, for which both HDR and IMRT could be options, were selected for this case study. Case 1 targeted a volume on the posterior neck/upper back with an HDR prescription of 600cGy × 5 fractions, 3000cGy total. The IMRT prescription used was 180cGy × 25 fractions, 4500cGy total with a boost of 180cGy × 6 fractions, 1080cGy. The IMRT PTV used was a 0.5cmexpansion of the HDR PTV; the boost PTV was identical to the HDR treatment plan. Case 2 targeted a volume on the palette of the mouth with an HDR prescription of 300cGy × 12 fractions, 3600cGy total. The IMRT prescription used was 180cGy × 28 fractions, 5040cGy total. A 0.5cm expansion of the HDR PTV was used for the IMRT PTV. In both cases, for both HDR and IMRT, at least 95% of the PTV received 100% prescription dose, following Children's Oncology Group protocols. Case 1 : the mean doses to the body, brachial plexus, esophagus, spinal cord and thyroid were higher using IMRT than HDR. Integral dose was 6.6 times higher using IMRT than HDR. Case 2: the mean doses to the body, mandible, and parotids were higher using IMRT than HDR. Integral dose was 2.9 times higher using IMRT than HDR. This study shows the potential benefit of treating with HDR compared to IMRT in select pediatric cases. These results suggest that HDR can be superior to IMRT in the sparing of critical structures and in delivering less integral dose to the patient while still achieving adequate target coverage. However, lower mean doses to critical structures must also be weighed against the possibility of complications from HDR's very high hotspots.


To what extent is the work environment of staff related to person-centred care? A cross-sectional study of residential aged care.
To explore the relationship between staff characteristics, perceived work environment and person-centred care in residential aged care units. Person-centred care is often described as the model of choice in residential aged care and in the care of persons with dementia. Few empirical studies have reported on the relationship between how staff experience different aspects of their work and person-centred care. The study had a cross-sectional quantitative design. Staff in 151 residential aged care units in Sweden (n = 1169) completed surveys which included questions about staff characteristics, valid and reliable measures of person-centred care, satisfaction with work and care, job strain, stress of conscience and psychosocial unit climate. Statistical analyses of correlations, group differences and multiple linear regression analysis estimated with generalised estimating equation were conducted. Higher levels of staff satisfaction, lower levels of job strain, lower levels of stress of conscience, higher levels of a supportive psychosocial unit climate and a higher proportion of staff with continuing education in dementia care were associated with higher levels of person-centred care. Job strain and a supportive psychosocial climate, explained most of the variation in person-centred care. This study shows that the work environment as perceived by staff is associated with the extent to which staff perceive the care as being person-centred in residential aged care. These empirical findings support the theoretical postulation that the work environment is an important aspect of person-centred care. Promoting a positive and supportive psychosocial climate and a work environment where staff experience balance between demands and control in their work, to enable person-centred care practice, seems to be important implications for managers and leaders in residential aged care.


Strategies for monitoring and managing mass populations of toxic cyanobacteria in recreational waters: a multi-interdisciplinary approach.
Mass populations of toxin-producing cyanobacteria commonly develop in fresh-, brackish- and marine waters and effective strategies for monitoring and managing cyanobacterial health risks are required to safeguard animal and human health. A multi-interdisciplinary study, including two UK freshwaters with a history of toxic cyanobacterial blooms, was undertaken to explore different approaches for the identification, monitoring and management of potentially-toxic cyanobacteria and their associated risks. The results demonstrate that (i) cyanobacterial bloom occurrence can be predicted at a local- and national-scale using process-based and statistical models; (ii) cyanobacterial concentration and distribution in waterbodies can be monitored using remote sensing, but minimum detection limits need to be evaluated; (iii) cyanotoxins may be transferred to spray-irrigated root crops; and (iv) attitudes and perceptions towards risks influence the public's preferences and willingness-to-pay for cyanobacterial health risk reductions in recreational waters.


Migration and transformation behavior of volatile phenol in the vadose zone.
Research on the migration and transformation of phenol with space and temporal variability in the vadose zone is hindered by monitoring technology in field experiments. Four column experiments were conducted to investigate the effect of porous media size, volatilization, biological effects, and oxidation on the transport of phenol in the vadose zone. The initial inflow phenol concentration of each column was 500 mg/L, and the final outflow concentrations were 0, 348, 240, and 365 mg/L, More than 90% of reduction of phenol concentration occurred at the top of the simulation column. Results show that volatilization and oxidation are the main factors that could lead to the decrease of phenol concentration in an open system. However, these two processes cannot be accurately separated. The migration rate of phenol was larger in coarse sands (6.06 cm/d) than in fine sands (4.55 cm/d). Phenol biodegradation did not occur under experimental conditions. However, mercury (as biological inhibitor) could react with phenol to generate a mercury-phenol complex, which could lead to the reduction of phenol concentration to 21.6% in the simulation experiment.


The netrin protein family.
The name netrin is derived from the Sanskrit Netr, meaning 'guide'. Netrins are a family of extracellular proteins that direct cell and axon migration during embryogenesis. Three secreted netrins (netrins 1, 3 and 4), and two glycosylphosphatidylinositol (GPI)-anchored membrane proteins, netrins G1 and G2, have been identified in mammals. The secreted netrins are bifunctional, acting as attractants for some cell types and repellents for others. Receptors for the secreted netrins include the Deleted in Colorectal Cancer (DCC) family, the Down's syndrome cell adhesion molecule (DSCAM), and the UNC-5 homolog family: Unc5A, B, C and D in mammals. Netrin Gs do not appear to interact with these receptors, but regulate synaptic interactions between neurons by binding to the transmembrane netrin G ligands NGL1 and 2. The chemotropic function of secreted netrins has been best characterized with regard to axon guidance during the development of the nervous system. Extending axons are tipped by a flattened, membranous structure called the growth cone. Multiple extracellular guidance cues direct axonal growth cones to their ultimate targets where synapses form. Such cues can be locally derived (short-range), or can be secreted diffusible cues that allow target cells to signal axons from a distance (long-range). The secreted netrins function as short-range and long-range guidance cues in different circumstances. In addition to directing cell migration, functional roles for netrins have been identified in the regulation of cell adhesion, the maturation of cell morphology, cell survival and tumorigenesis.


Human-relevant exposure to di-n-butyl phthalate tampers with the ovarian insulin-like growth factor 1 system and disrupts folliculogenesis in young adult mice.
Phthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human-relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF1) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 µg/kg/day, 100 µg/kg/day, or 1000 mg/kg/day) for 20-32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 (Igf1 and Igf2), IGF1 receptor (Igf1r), and IGF-binding proteins 1-6 (Ifgbp1-6) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 µg/kg/day for 20-32 days), reduced ovarian Igf1 and Igf1r mRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females.


Morphology, epidemiology, and phylogeny of Babesia: An overview.
Babesiosis is a tick-borne hemoprotozoan disease of domestic and wild animals. The disease is caused by various species of Babesia and some species of Babesia have also zoonotic significance. The parasite in vertebrate hosts' remains in erythrocytes and the morphology of Babesia spp. is not uniform in all vertebrate hosts. With the advancement of science, particularly the use of molecular techniques made it easy to study the evolution of parasites and thereby reclassifying Babesia spp. as per their phylogeny and to establish the relation of one isolate of Babesia spp. with isolates throughout the world. An attempt also made in this communication to enlighten the readers regarding relationship of one isolate of Babesia spp. of a particular area to another isolate of Babesia spp. of that area or other parts of the world and phylogenetic classification of Babesia spp. was also discussed. It has been concluded that as the study on Babesia is complex in nature so monitoring of the infection with the use of modern techniques is very much needed to control the infection. Second, more research work on phylogenetic relationship of Babesia spp. isolated from different hosts is needed, particularly in India to know the evolution of Babesia spp. of a particular area, as it has great importance to study the trans boundary diseases of animals.


Systematic discovery of TLR signaling components delineates viral-sensing circuits.
Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.


Smallpox vaccine, ACAM2000: Sites and duration of viral shedding and effect of povidone iodine on scarification site shedding and immune response.
The U.S. Department of Defense vaccinates personnel deployed to high-risk areas with the vaccinia virus (VACV)-based smallpox vaccine. Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections. The objectives of this study were to investigate, in naïve smallpox vaccinees, (a) whether the vaccination site can remain contagious after the scab separates and (b) whether the application of povidone iodine ointment (PIO) to the vaccination site inactivates VACV without affecting the immune response. These objectives were tested in 60 individuals scheduled to receive smallpox vaccine. Thirty individuals (control) did not receive PIO; 30 subjects (treatment) received PIO starting on post-vaccination day 7. Counter to current dogma, this study showed that VACV continues to shed from the vaccination site after the scab separates. Overall viral shedding levels in the PIO group were significantly lower than those in the control group (p=0.0045), and PIO significantly reduced the duration of viral shedding (median duration 14.5 days and 21 days in the PIO and control groups, respectively; p=0.0444). At least 10% of control subjects continued to shed VACV at day 28, and 3.4% continued to shed the virus at day 42. PIO reduced the proportion of subjects shedding virus from the vaccination site from day 8 until days 21-23 compared with control subjects. Groups did not differ significantly in the proportion of subjects mounting an immune response, as measured by neutralizing antibodies, IgM, IgG, and interferon-gamma enzyme-linked immunospot assay. When applied to the vaccination site starting on day 7, PIO reduced viral shedding without altering the immune response. The use of PIO in addition to a semipermeable dressing may reduce the rates of autoinoculation and contact transmission originating from the vaccination site in smallpox-vaccinated individuals.


Using dynamic low-coherence interferometry to image Brownian motion within highly scattering media.
Dynamic low-coherence interferometry was used to measure Brownian motion of submicrometer particles within highly scattering media. Strong rejection of multiply scattered light was obtained by combination of a coherence gate with a confocal microscope, thus allowing particle characterization methods generally reserved for optically dilute materials to be applied to optically concentrated suspensions. The Brownian diffusion coefficient of highly scattering media was determined with an accuracy better than 5%. Furthermore, we show that spatial variations in the Brownian diffusion coefficient can be imaged with an axial resolution determined by the coherence length of the light source (~30 mum) . The experiments also show broadening of the power spectrum as a function of depth into the sample, most likely as a result of detecting multiply scattered light.


A mixed-methods study of health worker migration from Jamaica.
This study sought to better understand the drivers of migration, its consequences, and the various strategies countries have employed to mitigate its negative impacts. The study was conducted in four countries-Jamaica, India, the Philippines, and South Africa-that have historically been 'sources' of health workers migrating to other countries. The aim of this paper is to present the findings from the Jamaica portion of the study. Data were collected using surveys of Jamaica's generalist and specialist physicians, nurses, midwives, and dental auxiliaries, as well as structured interviews with key informants representing government ministries, professional associations, regional health authorities, healthcare facilities, and educational institutions. Quantitative data were analyzed using descriptive statistics and regression models. Qualitative data were analyzed thematically. Multiple stakeholder engagement workshops were held across Jamaica to share and validate the study findings and discuss implications for the country. Migration of health workers from Jamaica continues to be prevalent. Its causes are numerous, long-standing, and systemic, and are largely based around differences in living and working conditions between Jamaica and 'destination' countries. There is minimal formal tracking of health worker migration from Jamaica, making scientific analysis of its consequences difficult. Although there is evidence of numerous national and international efforts to manage and mitigate the negative impacts of migration, there is little evidence of the implementation or effectiveness of such efforts. Potential additional strategies for better managing the migration of Jamaica's health workers include the use of information systems to formally monitor migration, updating the national cadre system for employment of health personnel, ensuring existing personnel management policies, such as bonding, are both clearly understood and equitably enforced, and providing greater formal and informal recognition of health personnel. Although historically common, migration of Jamaica's health workers is poorly monitored and understood. Improved management of the migration of Jamaica's health workers requires collaboration from stakeholders across multiple sectors. Indeed, participating stakeholders identified a wide range of potential strategies to better manage migration of Jamaica's health workers, the implementation and testing of which will have potential benefits to Jamaica as well as other 'source' countries.


Generation and regulation of developing immortalized neural cell lines.
The genetic and environmental signals that regulate progressive lineage elaboration in the mammalian brain are poorly understood. In addition, characterization of the developmental profiles of early central nervous system (CNS) stem/ progenitor cells and analysis of the mechanisms involved in their clonal expansion, lineage restriction, and cellular maturation have been fragmentary and elusive. These seminal neurodevelopmental issues have been examined using a series of clonally derived neural stem/progenitor cell lines established by retroviral transduction of embryonic (E16.5-E17.5) murine hippocampal and cerebellar cells using temperature-sensitive alleles (A58/U19) of the simian virus (SV) 40 large tumor (T) antigen. Under conditions permissive for T-antigen expression (33 degrees C), single neural stem cells exhibited self-renewal, clonal expansion, and both symmetric and asymmetric modes of cell division. By contrast, at the nonpermissive temperature for T-antigen expression (39 degrees C), specific sets of cytokines potentiated the progressive elaboration of neuronal, oligodendroglial, and astroglial lineage species. These observations demonstrate that a spectrum of genetic and epigenetic signals and distinct cellular processes are involved in orchestrating the evolution of individual neural lineages from regional CNS stem/progenitor species. Further, the availability of conditionally immortalized neural cell lines that can be transplanted back into the mammalian brain may represent an important experimental resource for the detailed characterization of cellular and molecular mechanisms involved in the developmental sculpting, plasticity, and regeneration of the mammalian CNS.


Echocardiographic Features of Cardiac Injury Related to COVID-19 and Their Prognostic Value: A Systematic Review.
The available information on the echocardiographic features of cardiac injury related to the novel coronavirus disease 2019 (COVID-19) and their prognostic value are scattered in the different literature. Therefore, the aim of this study was to investigate the echocardiographic features of cardiac injury related to COVID-19 and their prognostic value. Published studies were identified through searching PubMed, Embase (Elsevier), and Google scholar databases. The search was performed using the different combinations of the keywords "echocard*," "cardiac ultrasound," "TTE," "TEE," "transtho*," or "transeso*" with "COVID-19," "sars-COV-2," "novel corona, or "2019-nCOV." Two researchers independently screened the titles and abstracts and full texts of articles to identify studies that evaluated the echocardiographic features of cardiac injury related to COVID-19 and/or their prognostic values. Of 783 articles retrieved from the initial search, 11 (8 cohort and 3 cross-sectional studies) met our eligibility criteria. Rates of echocardiographic abnormalities in COVID-19 patients varied across different studies as follow: RV dilatation from 15.0% to 48.9%; RV dysfunction from 3.6% to 40%; and LV dysfunction 5.4% to 40.0%. Overall, the RV abnormalities were more common than LV abnormalities. The majority of the studies showed that there was a significant association between RV abnormalities and the severe forms and death of COVID-19. The available evidence suggests that RV dilatation and dysfunction may be the most prominent echocardiographic abnormality in symptomatic patients with COVID-19, especially in those with more severe or deteriorating forms of the disease. Also, RV dysfunction should be considered as a poor prognostic factor in COVID-19 patients.


Equitable Design and Use of Digital Surveillance Technologies During COVID-19: Norms and Concerns.
Given the unprecedented scale of digital surveillance in the COVID-19 pandemic, designing and implementing digital technologies in ways that are equitable is critical now and in future epidemics and pandemics. Yet to date there has been very limited consideration about what is necessary to promote their equitable design and implementation. In this study, literature relating to the use of digital surveillance technologies during epidemics and pandemics was collected and thematically analyzed for ethical norms and concerns related to equity and social justice. Eleven norms are reported, including procedural fairness and inclusive approaches to design and implementation, designing to rectify or avoid exacerbating inequities, and fair access. Identified concerns relate to digital divides, stigma and discrimination, disparate risk of harm, and unfair design processes. We conclude by considering what dimensions of social justice the norms promote and whether identified concerns can be addressed by building the identified norms into technology design and implementation practice.


Chemical signals from eggs facilitate cryptic female choice in humans.
Mate choice can continue after mating via chemical communication between the female reproductive system and sperm. While there is a growing appreciation that females can bias sperm use and paternity by exerting cryptic female choice for preferred males, we know surprisingly little about the mechanisms underlying these post-mating choices. In particular, whether chemical signals released from eggs (chemoattractants) allow females to exert cryptic female choice to favour sperm from specific males remains an open question, particularly in species (including humans) where adults exercise pre-mating mate choice. Here, we adapt a classic dichotomous mate choice assay to the microscopic scale to assess gamete-mediated mate choice in humans. We examined how sperm respond to follicular fluid, a source of human sperm chemoattractants, from either their partner or a non-partner female when experiencing a simultaneous or non-simultaneous choice between follicular fluids. We report robust evidence under these two distinct experimental conditions that follicular fluid from different females consistently and differentially attracts sperm from specific males. This chemoattractant-moderated choice of sperm offers eggs an avenue to exercise independent mate preference. Indeed, gamete-mediated mate choice did not reinforce pre-mating human mate choice decisions. Our results demonstrate that chemoattractants facilitate gamete-mediated mate choice in humans, which offers females the opportunity to exert cryptic female choice for sperm from specific males.


Evaluation of some biochemical changes in diabetic patients.
Hyperglycemia is considered a primary cause of diabetic vascular complications and is associated with oxidative stress, impaired trace element and lipid metabolism as well as pancreatic enzyme abnormalities. The role of trace elements in some of the metabolic dysfunctions and their contributions in the development of vascular complications is not clear. Therefore, the present study investigates the relationship among diabetes mellitus, trace elements status, advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), lipid profiles, antioxidant status, nitric oxide and pancreatic amylase activity in the sera of 55 non-insulin-dependent diabetes mellitus (NIDDM; 35 with microvascular complications and 20 without vascular complications), 40 insulin-dependent diabetes mellitus (IDDM; 25 with microvascular and 15 without microvascular complications), and 20 nondiabetic healthy control subjects. The mean age of the diabetic patients was similar to that of control. The mean duration of the disease was 11.8 +/- 6.8 years (3-27 years) in IDDM and 7.1 +/- 4.7 years (1-15 years) in NIDDM. Plasma Cu, Zn, Mg, Ca, thiobarbituric acid-reactive substance (i.e. malondialdehyde; MDA), nitric oxide (NO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), ceruloplasmin (Cp) and amylase activities as well as AOPP were assessed spectrophotometrically whereas AGEs were estimated spectrofluorometrically in two types of diabetes mellitus (DM) as well as control subjects of matched sex and ages. SOD, CAT and Cp activities were decreased whereas serum alpha-amylase activity was increased in two types of DM in comparison to the corresponding activities of the control subjects. The plasma levels of MDA, NO and Cu were increased but GSH, Zn, Mg and Ca levels were significantly diminished in diabetic patients as compared to the controls. The averages of total cholesterol (CHOL), triglyceride (TG) and low-density lipoprotein-cholesterol (LDLc) were higher in both types of diabetes mellitus in comparison to the control subjects. The mean value of high-density lipoprotein-cholesterol (HDLc) was lower in both types of diabetes mellitus. Further, the mean values of AGEs and AOPP were elevated in diabetic patients vs. control. These parameters are significantly higher in NIDDM patients when compared to the IDDM subjects. Slight but not significant differences in these parameters were observed in patients with diabetic complications when compared to that of without diabetic complications. These findings may explain the role of impaired trace element status, defect of antioxidants and increased of AGE and AOPP in the pathogenesis of pancreas and the vascular complications of diabetes mellitus. Oxidative stress is increased in both types of DM, but it is more in NIDDM patients than in IDDM subjects. In addition, oxidative stress also plays an important role in the formation of AGEs and AOPP in DM.


Frontoparietal activity and its structural connectivity in binocular rivalry.
To understand the brain areas associated with visual awareness and their anatomical interconnections, we studied binocular rivalry with functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). Binocular rivalry occurs when one image is viewed by one eye and a different image by the other; it is experienced as perceptual alternations between the two images. Our first experiment addressed problems with a popular comparison condition, namely permanent suppression, by comparing rivalry with binocular fusion instead. We found an increased fMRI signal in right frontal, parietal, and occipital regions during rivalry viewing. The pattern of neural activity differed from findings of permanent suppression comparisons, except for adjacent activity in the right superior parietal lobule. This location was near fMRI signal changes related to reported rivalry alternations in our second experiment, indicating that neighbouring areas in the right parietal cortex may be involved in different components of rivalry. In our second experiment, we used probabilistic tractography to detect white matter fibres between right-hemispheric areas that showed event-related fMRI signal changes time-locked to reported perceptual alternations during rivalry viewing. Most of these functionally defined areas were linked by probabilistic fibre tracts, some of which followed long-distance connections such as the inferior occipitofrontal fasciculus. Corresponding anatomical pathways might mediate communication within the functional network associated with changes in conscious perception during binocular rivalry.


The Relationship of Steroid Hormones, Genes Related to Testosterone Metabolism and Behavior in Boys With Autism in Slovakia.
Purpose of the study was to identify the relationship among actual plasmatic levels of steroid hormones and behavioral manifestations in boys with autism and to assess the genetic contribution to these manifestations. 172 boys with autism under 10 years of age and 135 neurotypical boys attended the study. ADI-R and ADOS-2 were used to evaluate the core symptom severities. Problem behavior was assessed using BPI-01 questionnaire. Levels of testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) were measured in plasma of autistic boys. Three SNPs (in ESR1, SHBG, SRD5A2 genes) and one STR in AR gene (number of CAG repeats in first exon) were assessed. Hormonal levels and number of CAG repeats in AR gene were used for correlation analysis with behavioral measures. Genotype and allelic frequencies were compared among autistic and neurotypical boys. We found negative relationship among SHBG levels and restricted, repetitive behaviors (measured by ADOS-2) and positive relationship among actual testosterone levels and frequency of stereotyped behavior (measured by BPI-01). Actual levels of SHBG and testosterone are related to severities of restricted and repetitive behaviors in boys with autism. Mechanisms of action of these hormones in brain require further investigation.


Endurance exercise training programs intestinal lipid metabolism in a rat model of obesity and type 2 diabetes.
Endurance exercise has been shown to improve metabolic outcomes in obesity and type 2 diabetes; however, the physiological and molecular mechanisms for these benefits are not completely understood. Although endurance exercise has been shown to decrease lipogenesis, promote fatty acid oxidation (FAO), and increase mitochondrial biosynthesis in adipose tissue, muscle, and liver, its effects on intestinal lipid metabolism remain unknown. The absorptive cells of the small intestine, enterocytes, mediate the highly efficient absorption and processing of nutrients, including dietary fat for delivery throughout the body. We investigated how endurance exercise altered intestinal lipid metabolism in obesity and type 2 diabetes using Otsuka Long-Evans Tokushima Fatty (OLETF) rats. We assessed mRNA levels of genes associated with intestinal lipid metabolism in nonhyperphagic, sedentary Long-Evans Tokushima Otsuka (LETO) rats (L-Sed), hyperphagic, sedentary OLETF rats (O-Sed), and endurance exercised OLETF rats (O-EndEx). O-Sed rats developed hyperphagia-induced obesity (HIO) and type 2 diabetes compared with L-Sed rats. O-EndEx rats gained significantly less weight and fat pad mass, and had improved serum metabolic parameters without change in food consumption compared to O-Sed rats. Endurance exercise resulted in dramatic up-regulation of a number of genes in intestinal lipid metabolism and mitochondrial content compared with sedentary rats. Overall, this study provides evidence that endurance exercise programs intestinal lipid metabolism, likely contributing to its role in improving metabolic outcomes in obesity and type 2 diabetes.


Reactive Ion Plasma Modification of Poly(Vinyl-Alcohol) Increases Primary Endothelial Cell Affinity and Reduces Thrombogenicity.
Bulk material properties and luminal surface interaction with blood determine the clinical viability of vascular grafts, and reducing intimal hyperplasia is necessary to improve their long-term patency. Here, the authors report that the surface of a biocompatible hydrogel material, poly(vinyl alcohol) (PVA) can be altered by exposing it to reactive ion plasma (RIP) in order to increase primary endothelial cell attachment. The power and the carrier gas of the RIP treatment are varied and the resultant surface nitrogen, water contact angle, as well as the ability of the RIP-treated surfaces to support primary endothelial colony forming cells is characterized. Additionally, in a clinically relevant shunt model, the amounts of platelet and fibrin attachment to the surface were quantified during exposure to non-anticoagulated blood. Treatments with all carrier gases resulted in an increase in the surface nitrogen. Treating PVA with O2 , N2 , and Ar RIP increased affinity to primary endothelial colony forming cells. The RIP treatments did not increase the thrombogenicity compared to untreated PVA and had significantly less platelet and fibrin attachment compared to the current clinical standard of expanded polytetrafluoroethylene (ePTFE). These findings indicate that RIP-treatment of PVA could lead to increased patency in synthetic vascular grafts.


Recycling and resensitization of the neurokinin 1 receptor. Influence of agonist concentration and Rab GTPases.
Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration. High SP (10 nM) induced translocation of the NK1R and beta-arrestin 1 to perinuclear sorting endosomes containing Rab5a, where NK1R remained for >60 min. Low SP (1 nM) induced translocation of the NK1R to early endosomes located immediately beneath the plasma membrane that also contained Rab5a and beta-arrestin 1, followed by rapid recycling of the NK1R. Overexpression of Rab5a promoted NK1R translocation to perinuclear sorting endosomes, whereas the GTP binding-deficient mutant Rab5aS34N caused retention of the NK1R in superficial early endosomes. NK1R translocated from superficial early endosomes to recycling endosomes containing Rab4a and Rab11a, and Rab11aS25N inhibited NK1R recycling. Rapid NK1R recycling coincided with resensitization of SP-induced Ca2+ mobilization and with the return of surface SP binding sites. Resensitization was minimally affected by inhibition of vacuolar H(+)-ATPase and phosphatases but was markedly suppressed by disruption of Rab4a and Rab11a. Thus, whereas beta-arrestins mediate NK1R endocytosis, Rab5a regulates translocation between early and sorting endosomes, and Rab4a and Rab11a regulate trafficking through recycling endosomes. We have thus identified a new function of Rab5a as a control protein for directing concentration-dependent trafficking of the NK1R into different intracellular compartments and obtained evidence that Rab4a and Rab11a contribute to G-protein-coupled receptor recycling from early endosomes.


Integrins modulate cellular fibrogenesis at multiple levels; Regulation of TGF-β signaling.
Fibrosis could occur in virtually any organ or tissue. The fibrotic lesion indolently disrupts the structure of the healthy organ, thereby hampering its proper function, consequence of which is devastating. Among the myriad factors that modulate fibrogenesis, transforming growth factor β (TGF-β) is one of the most studied and its central role for fibrotic disorders has been strongly suggested. Due to the pleiotropic nature of this cytokine, TGF-β modulates multiple cellular responses throughout fibrogenesis. The complexity is supported by the TGF-β receptor-specific phosphorylation of both the canonical, Smad-, and non-canonical, "non-Smad," pathways. The latter modulates Smad activity either independent of Smad or by phosphorylating the Smad linker region, distinct from those receptor-regulated. Despite the commodity of this mediator, the mechanism by which TGF-β signaling causes specific pathogenesis and disease varies depending on the nature of the organ and the cells that compose that organ. Cells express a specific series of integrins that act as cellular sensors for the extracellular environment, determining subsequent cellular signals in a cell-type specific manner. Integrins may change their expression pattern under pathological conditions and contribute to the regulation of fibrogenesis via modulating ambient TGF-β activity. This regulation includes release of active TGF-β from its latent form and modulation of various signals downstream of integrin-engagement, which participate in the non-canonical regulation of TGF-β signaling. TGF-β also induces expression of integrins, as well as their ligand extracellular matrix, generating an amplification loop. Furthermore, myriads of intracellular signaling molecules that associate with integrin engagement could non-canonically modulate TGF-β signals. The entire picture of this mutual regulation between integrin and the TGF-β pathways might be difficult to draw. Instead, this review intends to depict several critical aspects of this regulation, with examples from various types of fibrosis in different tissues to help understanding the integrin-modulation of fibrogenesis, a critical clue for therapeutic approaches to fibrosis.


Global quantitative SILAC phosphoproteomics reveals differential phosphorylation is widespread between the procyclic and bloodstream form lifecycle stages of Trypanosoma brucei.
We report a global quantitative phosphoproteomic study of bloodstream and procyclic form Trypanosoma brucei using SILAC labeling of each lifecycle stage. Phosphopeptide enrichment by SCX and TiO2 led to the identification of a total of 10096 phosphorylation sites on 2551 protein groups and quantified the ratios of 8275 phosphorylation sites between the two lifecycle stages. More than 9300 of these sites (92%) have not previously been reported. Model-based gene enrichment analysis identified over representation of Gene Ontology terms relating to the flagella, protein kinase activity, and the regulation of gene expression. The quantitative data reveal that differential protein phosphorylation is widespread between bloodstream and procyclic form trypanosomes, with significant intraprotein differential phosphorylation. Despite a lack of dedicated tyrosine kinases, 234 phosphotyrosine residues were identified, and these were 3-4 fold over-represented among site changing >10-fold between the two lifecycle stages. A significant proportion of the T. brucei kinome was phosphorylated, with evidence that MAPK pathways are functional in both lifecycle stages. Regulation of gene expression in T. brucei is exclusively post-transcriptional, and the extensive phosphorylation of RNA binding proteins observed may be relevant to the control of mRNA stability in this organism.


Effective elastic modulus of isolated gecko setal arrays.
Conventional pressure sensitive adhesives (PSAs) are fabricated from soft viscoelastic materials that satisfy Dahlquist's criterion for tack with a Young's modulus (E) of 100 kPa or less at room temperature and 1 Hz. In contrast, the adhesive on the toes of geckos is made of beta-keratin, a stiff material with E at least four orders of magnitude greater than the upper limit of Dahlquist's criterion. Therefore, one would not expect a beta-keratin structure to function as a PSA by deforming readily to make intimate molecular contact with a variety of surface profiles. However, since the gecko adhesive is a microstructure in the form of an array of millions of high aspect ratio shafts (setae), the effective elastic modulus (E(eff)) is much lower than E of bulk beta-keratin. In the first test of the E(eff) of a gecko setal adhesive, we measured the forces resulting from deformation of isolated arrays of tokay gecko (Gekko gecko) setae during vertical compression, and during tangential compression at angles of +45 degrees and -45 degrees . We tested the hypothesis that E(eff) of gecko setae falls within Dahlquist's criterion for tack, and evaluated the validity of a model of setae as cantilever beams. Highly linear forces of deformation under all compression conditions support the cantilever model. E(eff) of setal arrays during vertical and +45 degrees compression (along the natural path of drag of the setae) were 83+/-4.0 kPa and 86+/-4.4 kPa (means +/- s.e.m.), respectively. Consistent with the predictions of the cantilever model, setae became significantly stiffer when compressed against the natural path of drag: E(eff) during -45 degrees compression was 110+/-4.7 kPa. Unlike synthetic PSAs, setal arrays act as Hookean elastic solids; setal arrays function as a bed of springs with a directional stiffness, assisting alignment of the adhesive spatular tips with the contact surface during shear loading.


Determination of dopamine and its metabolites in small volumes of rat brain dialysates using small-bore liquid chromatography with electrochemical detection.
A miniaturized liquid chromatographic system with electrochemical detection (LC-ED) was developed and applied to the analysis of dopamine and its metabolites in dialysate samples collected from the rat brain in vivo. An existing LC-ED system was down-scaled using a 1 mm I.D. small-bore column operated at a reduced flow-rate and with an injection volume of 1 microliter. With the small-bore system the limit of detection for dopamine of ca. 0.06 pg was almost 50 times less than with the conventional system, which represents a two-fold improvement in concentration sensitivity. Miniaturization was accomplished with negligible loss in resolution by using a conventional commercial amperometric detector with minor modifications. The results indicate that a number of useful advantages could be realized by the combination of this small-bore LC-ED system and the in vivo brain dialysis method.


Limb distribution, motor impairment, and functional classification of cerebral palsy.
This study explored the relationships between the Gross Motor Function Classification System (GMFCS), limb distribution, and type of motor impairment. Data used were collected in the Ontario Motor Growth study, a longitudinal cohort study with a population-based sample of children with cerebral palsy (CP) in Canada (n=657; age 1 to 13 years at study onset). The majority (87.8%) of children with hemiplegia were classified as level I. Children with a bilateral syndrome were represented in all GMFCS levels, with most in levels III, IV, and V. Classifications by GMFCS and 'limb distribution' or by GMFCS and 'type of motor impairment' were statistically significantly associated (Pearson's chi2 p<0.001), though the correlation for limb distribution (two categories) by GMFCS was low (tau-b=0.43). An analysis of function (GMFCS) by impairment (limb distribution) indicates that the latter clinical characteristic does not add prognostic value over GMFCS. Although classification of CP by impairment level is useful for clinical and epidemiological purposes, the value of these subgroups as an indicator of mobility is limited in comparison with the classification of severity with the GMFCS.


A kinetic analysis of the endplate ion channel blocking action of disopyramide and its optical isomers.
The effects of the antiarrhythmic agent disopyramide was studied on responses from voltage-clamped endplates at the neuromuscular junction of the garter snake. Disopyramide reduced endplate current amplitude and decay time constant in a concentration- and voltage-dependent manner. Endplate current decays remained monophasic in the presence of the drug. These results were interpreted in terms of the drug blocking the open form of the acetylcholine receptor-ion channel complex. Disopyramide produced a greater reduction of the amplitude of endplate currents than of miniature endplate currents. The reduction in miniature endplate current amplitude was not voltage-dependent. Analysis of endplate current driving functions showed that this was due to the rapid occurrence of channel block during the rising phase of the endplate current. The residual reduction, apart from that produced by channel block, is most probably due to receptor block. Disopyramide had a voltage-dependent blocking rate constant of about 10(7) M-1 S-1 at -90 mV. The unblocking rate constant was estimated from the results of experiments using paired ionophoretically applied pulses of acetylcholine. This value was again voltage-dependent and approximately 1 s-1. The actions of the (+)- and (-)-stereoisomers of disopyramide on endplate current decay were identical, indicating that the channel binding site at the neuromuscular junction is not stereoselective.


A Review of Epigenetics of PTSD in Comorbid Psychiatric Conditions.
Post-traumatic stress disorder (PTSD) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. Genetic, epigenetic, and environmental factors act together to determine both an individual's susceptibility to PTSD and its clinical phenotype. In this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the PTSD phenotype. We discuss the importance of the epigenetic regulation of these candidate genes. We review the general epigenetic mechanisms that are currently understood, with examples of each in the PTSD phenotype. Our focus then turns to studies that have examined PTSD in the context of comorbid psychiatric disorders or associated social and behavioral stressors. We examine the epigenetic variation in cases or models of PTSD with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. We reviewed the literature that has explored epigenetic regulation in PTSD in adverse childhood experiences and suicide phenotypes. Finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of PTSD. We discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.


Continuation and maintenance treatments for depression in older people.
Depressive illness in older people causes significant suffering and health service utilisation. Relapse and recurrence rates are high. To examine the efficacy of antidepressants and psychological therapies in preventing the relapse and recurrence of depression in older people. Search of the Cochrane Depression, Anxiety and Neurosis Review Group's specialized register (the CCDANCTR) up to 22 June 2012. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE, (1974 to date) MEDLINE (1950 to date) and PsycINFO (1967 to date). We handsearched relevant journals, contacted experts in the field and examined reference lists, conference proceedings and bibliographies. Both review authors independently selected studies. We included randomised controlled trials (RCTs) involving people aged 60 and over successfully treated for an episode of depression and randomised to receive continuation and maintenance treatment with antidepressants, psychological therapies, or combination. Data were extracted independently by the two authors.The primary outcome was relapse/recurrence rate of depression (reaching a cut-off on any depression rating scale) at six-monthly intervals. Secondary outcomes included global impression of change, social functioning, and deaths. Meta-analysis was performed using risk ratio for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals. Seven studies met the inclusion criteria (803 participants). Six compared antidepressant medication with placebo; two involved psychological therapies. There was marked heterogeneity between the studies.Comparing antidepressants with placebo, at six months follow-up there was no significant difference. At 12 months follow-up there was a statistically significant difference favouring antidepressants in reducing recurrence compared with placebo (three RCTs, N = 247, RR = 0.67, 95% CI 0.55 to 0.82; NNTB = five). At 24 months there was no significant difference for antidepressants overall, however, for the subgroup of tricyclic antidepressants there was significant benefit (three RCTs, N = 169, RR = 0.70, 95% CI 0.50 to 0.99; NNTB = five). At 36 months there was no significant difference for antidepressants overall. There was no difference in treatment acceptability or death rates between antidepressant and placebo.There was no significant difference between psychological treatment and antidepressant in recurrence rates at 12, 24, and 36 months (one RCT, N = 53) or between combination and antidepressant alone.Overall, the included studies were at low risk of bias. The long-term benefits of continuing antidepressant medication in the prevention of recurrence of depression in older people are not clear and no firm treatment recommendations can be made on the basis of this review. Continuing antidepressant medication for 12 months appears to be helpful but this is based on only three small studies with relatively few participants using differing classes of antidepressants in clinically heterogeneous populations. Comparisons at other time points did not reach statistical significance. Data on psychological therapies and combined treatments are too limited to draw any conclusions.


Adolescents' externalizing behaviors and antisocial text messaging across the broader peer network: Implications for socialization and selection effects.
Adolescents' peer networks provide an important context that can contribute to increases in antisocial behavior. By a process called deviancy training, peers can both model and reinforce these behaviors, thereby conveying group norms about the acceptability of such behaviors. This research examined the relationship between the proportion of adolescents' peers who exchanged antisocial text messages and externalizing behaviors during high school. In Study 1, parent-, teacher-, and self-reports of rule-breaking and aggression were collected for a sample of adolescents (n = 167, 80 girls; 22.2% Black, 51.5% Caucasian, 18.7% Hispanic) during the summers before and after 9th grade. Total text frequency, frequency of antisocial texts, and the proportion of the peer network who exchanged antisocial messages were examined as predictors of antisocial behavior. The proportion of peers who exchanged antisocial texts significantly predicted rule-breaking, but not aggression. Study 2 examined the direction of the relationship documented in Study 1 more thoroughly. Externalizing behaviors at 9th, 10th, and 11th grade were evaluated as predictors of the proportion of the peer network that exchanged texts about antisocial topics (n = 205, 98 girls; 22.4% Black, 53.7% Caucasian, 16.9% Hispanic). Externalizing behaviors predicted the proportion of adolescents' peer network that exchanged antisocial texts in each of the subsequent years, but this proportion of the peer network exchanging antisocial communication did not predict subsequent externalizing behaviors. The findings suggest that the extent to which antisocial communication permeates the peer group is a selection effect.


Human quadrupeds, primate quadrupedalism, and Uner Tan Syndrome.
Since 2005, an extensive literature documents individuals from several families afflicted with "Uner Tan Syndrome (UTS)," a condition that in its most extreme form is characterized by cerebellar hypoplasia, loss of balance and coordination, impaired cognitive abilities, and habitual quadrupedal gait on hands and feet. Some researchers have interpreted habitual use of quadrupedalism by these individuals from an evolutionary perspective, suggesting that it represents an atavistic expression of our quadrupedal primate ancestry or "devolution." In support of this idea, individuals with "UTS" are said to use diagonal sequence quadrupedalism, a type of quadrupedal gait that distinguishes primates from most other mammals. Although the use of primate-like quadrupedal gait in humans would not be sufficient to support the conclusion of evolutionary "reversal," no quantitative gait analyses were presented to support this claim. Using standard gait analysis of 518 quadrupedal strides from video sequences of individuals with "UTS", we found that these humans almost exclusively used lateral sequence-not diagonal sequence-quadrupedal gaits. The quadrupedal gait of these individuals has therefore been erroneously described as primate-like, further weakening the "devolution" hypothesis. In fact, the quadrupedalism exhibited by individuals with UTS resembles that of healthy adult humans asked to walk quadrupedally in an experimental setting. We conclude that quadrupedalism in healthy adults or those with a physical disability can be explained using biomechanical principles rather than evolutionary assumptions.


Tribal vs. Public Schools: Perceived Discrimination and School Adjustment among Indigenous Children from Early to Mid-Adolescence.
The purpose of this study is to assess the differential effects of perceived discrimination by type of school on positive school adjustment among Indigenous children during late elementary and early middle school years. The analysis utilizes a sample of 654 Indigenous children from four reservations in the Northern Midwest and four Canadian First Nation reserves. Multiple group linear growth modeling within a structural equation framework is employed to investigate the moderating effects of school type on the relationship between discrimination and positive school adjustment. Results show that students in all school types score relatively high on positive school adjustment at time one (ages 10-12). However, in contrast to students in tribal schools for whom positive school adjustment remains stable, those attending public schools and those moving between school types show a decline in school adjustment over time. Furthermore, the negative effects of discrimination on positive school adjustment are greater for those attending public schools and those moving between schools. Possible reasons for this finding and potential explanations for why tribal schools may provide protection from the negative effects of discrimination are discussed.


Poly(ethylene glycol)-graft-poly(vinyl acetate) single-chain nanoparticles for the encapsulation of small molecules.
Amphiphilic poly(ethylene glycol)-graft-poly(vinyl acetate) copolymers with a low degree of grafting undergo self-folding in water driven by hydrophobic interactions, resulting in single-chain nanoparticles (SCNPs) possessing a hydrodynamic radius of about 10 nm. A temperature scan revealed a lower critical solution temperature (LCST)-type phase behavior. In addition, SAXS data collected close to the LCST showed that these SCNPs aggregate into one-dimensional elongated objects, preferentially. With respect to the typical linear complex-structured polymer chains, this material is ideally suited for industrial and/or biomedical applications because of its simple molecular architecture and persistence of SCNPs up to 100 mg mL-1. The so-obtained single-chain globular particles are able to swell upon loading with small hydrophobic molecules therefore promoting solubilization of flavors or drugs, which could be of interest in the food and pharmaceutical industry.


Effect of nucleants in photothermally assisted crystallization.
Laser-induced crystallization is emerging as a promising technique to crystallize biomolecules like amino acids and proteins. The use of external materials as nucleants and novel seeding methods open new paths for protein crystallization. We report here the results of experiments that explore the effect of nucleants on laser-based crystallization of microlitre droplets of small molecules, amino acids, and proteins. The role of parameters like solute concentration, droplet volume, type and size of the nucleant, and laser power, are systematically investigated. In addition to crystallization of standard molecules like NaCl, KCl, and glycine, we demonstrate the crystallization of negatively (l-histidine), and positively (l-aspartic acid) charged amino acids and lysozyme protein. Single crystal X-ray diffraction and Raman spectroscopy studies unequivocally indicate that the nucleants do not alter the molecular structure of glycine, hydrogen bonding patterns, and packing. Localized vaporization of the solvent near the nucleant due to photothermal heating has enabled us to achieve rapid crystallization - within 3 s - at laser intensities of 0.1 MW cm-2, significantly lower than those reported earlier, with both saturated and unsaturated solutions. The outcome of the current experiments may be of utility in tackling various crystallization problems during the formation of crystals large enough to perform X-ray crystallography.


Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors.
Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences. The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression. The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time. Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.


Immuno-regenerative biomaterials for in situ cardiovascular tissue engineering - Do patient characteristics warrant precision engineering?
In situ tissue engineering using bioresorbable material implants - or scaffolds - that harness the patient's immune response while guiding neotissue formation at the site of implantation is emerging as a novel therapy to regenerate human tissues. For the cardiovascular system, the use of such implants, like blood vessels and heart valves, is gradually entering the stage of clinical translation. This opens up the question if and to what extent patient characteristics influence tissue outcomes, necessitating the precision engineering of scaffolds to guide patient-specific neo-tissue formation. Because of the current scarcity of human in vivo data, herein we review and evaluate in vitro and preclinical investigations to predict the potential role of patient-specific parameters like sex, age, ethnicity, hemodynamics, and a multifactorial disease profile, with special emphasis on their contribution to the inflammation-driven processes of in situ tissue engineering. We conclude that patient-specific conditions have a strong impact on key aspects of in situ cardiovascular tissue engineering, including inflammation, hemodynamic conditions, scaffold resorption, and tissue remodeling capacity, suggesting that a tailored approach may be required to engineer immuno-regenerative biomaterials for safe and predictive clinical applicability.


Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab.
Human epidermal growth factor receptor type 3 (HER3) is recognized to be involved in resistance to HER-targeting therapies. A number of HER3-targeting monoclonal antibodies are under clinical investigation as potential cancer therapeutics. Smaller high-affinity scaffold proteins are attractive non-Fc containing alternatives to antibodies. A previous study indicated that anti-HER3 affibody molecules could delay the growth of xenografted HER3-positive tumors. Here, we designed a second-generation HER3-targeting construct (TAM-HER3), containing two HER3-specific affibody molecules bridged by an albumin-binding domain (ABD) for extension of blood circulation. Receptor blocking activity was demonstrated in vitro. In mice bearing BxPC-3 xenografts, the therapeutic efficacy of TAM-HER3 was compared to the HER3-specific monoclonal antibody seribantumab (MM-121). TAM-HER3 inhibited heregulin-induced phosphorylation in a panel of HER3-expressing cancer cells and was found to be equally as potent as seribantumab in terms of therapeutic efficacy in vivo and with a similar safety profile. Median survival times were 60 days for TAM-HER3, 54 days for seribantumab, and 41 days for the control group. No pathological changes were observed in cytopathological examination. The multimeric HER3-binding affibody molecule in fusion to ABD seems promising for further evaluation as candidate therapeutics for treatment of HER3-overexpressing tumors.


Early-Life Circumstances, Health Behavior Profiles, and Later-Life Health in Great Britain.
Objectives: Drawing on UK Household Longitudinal Study data, this study assessed a pathway from early-life disadvantage to suboptimal later-life health via health behavior. Methods: Latent class analysis was used to identify distinct smoking, nutrition, alcohol, and physical activity health behavior profiles. Mediation analyses were performed to assess indirect effects of early-life disadvantage via health behavior on allostatic load, an objective measure of physiological wear and tear. Results: Four health behavior profiles were identified: (1) broadly healthy and high alcohol consumption, (2) low smoking and alcohol consumption, healthy nutrition, and physically inactive, (3) broadly unhealthy and low alcohol consumption, and (4) broadly moderately unhealthy and high alcohol consumption. Having grown up in a higher socioeconomic position family was associated with lower later-life allostatic load. This was partly attributable to health behavioral differences. Discussion: Growing up under disadvantageous socioeconomic circumstances may initiate a chain of risk by predisposing people to health behavior profiles associated with poorer later-life health.


Integrated oncogeriatric approach: a systematic review of the literature using concept analysis.
The purpose of this study was to provide a more precise definition of an integrated oncogeriatric approach (IOGA) through concept analysis. The literature was reviewed from January 2005 to April 2011 integrating three broad terms: geriatric oncology, multidisciplinarity and integrated care delivery models. Citation selection was based on: (1) elderly cancer patients as the study population; (2) disease management and (3) case studies, intervention studies, assessments, evaluations and studies. Inclusion and exclusion criteria were refined in the course of the literature search. Initiatives in geriatric oncology that relate to oncology services, social support services and primary care services for elderly cancer patients. Elderly cancer patients aged 70 years old or more. Rodgers' concept analysis method was used for this study. The analysis was carried out according to thematic analysis based on the elements of the Chronic Care Model. The search identified 618 citations. After in-depth appraisal of 327 potential citations, 62 articles that met our inclusion criteria were included in the analysis. Three IOGA main attributes were identified, which constitute IOGA's core aspects: geriatric assessment (GA), comorbidity burden and treatment outcomes. The IOGA concept comprises two broad antecedents: coordinated healthcare delivery and primary supportive care services. Regarding the consequents of an integrated approach in geriatric oncology, the studies reviewed remain inconclusive. Our study highlights the pioneering character of the multidimensional IOGA concept, for which the relationship between clinical and organisational attributes, on the one hand, and contextual antecedents, on the other, is not well understood. We have yet to ascertain IOGA's consequents. IMPLICATIONS OF KEY FINDINGS: There is clearly a need for a whole-system approach to change that will provide direction for multilevel (clinical, organisational, strategic) interventions to support interdisciplinary practice, education and research.