B cells compartment in centenarian offspring and old people.
Immunosenescence is considered a major contributory factor to the increased frequency of morbidity and mortality among elderly. On the other hand centenarians are considered the best example of successful ageing. To gain insight into mechanisms of immunosenescence and its clinical relevance, a possible model is represented by centenarians and/or their offspring. Nowadays centenarians are not more a curiosity, but in Europe are 1/8000 inhabitants and it has been demonstrated that the centenarian offspring, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy. Then again, studies on immunosenescence focus mainly on T cell impairment, although B cells are also affected. So, in the present preliminary report, we have studied B cell compartment in two classes of individuals, old people and centenarian offspring. B cell compartment was analysed using IgD and CD27 antibodies which characterize naïve B cells (IgD(+) CD27(-)), memory unswitched B cells (IgD(+)CD27(+)), memory switched B cells(IgD(-)CD27(+)) and double negative B cells (DN) (IgD(-)CD27(-)), i.e. exhausted memory cells. As expected, in both cohorts we observed a decreased B cell count. However, in centenarian offspring, naïve B cells are more abundant whereas exhausted memory cells (DN B cells, IgD(-)CD27(-)) do not show the increase that we have previously demonstrated in healthy elderly donors. These data are similar to that found in previously experiments on young subjects. So, our preliminary results show that centenarian offspring do not have the typical trend of memory/naive B cell subsets observed in elderly people and this is in agreement with the higher levels of IgM in the serum of centenarian offspring in comparison with data obtained in age-matched controls. This reservoir of naive B cell might be one of the causes that make centenarian offspring able to keep fighting off new infections, hence prolonging their life. So, B cell subset changes could represent a hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span, potentially useful for the evaluation of anti-ageing treatment.


High-throughput detection of aberrant imprint methylation in the ovarian cancer by the bisulphite PCR-Luminex method.
Aberrant DNA methylation leads to loss of heterozygosity (LOH) or loss of imprinting (LOI) as the first hit during human carcinogenesis. Recently we developed a new high-throughput, high-resolution DNA methylation analysis method, bisulphite PCR-Luminex (BPL), using sperm DNA and demonstrated the effectiveness of this novel approach in rapidly identifying methylation errors. In the current study, we applied the BPL method to the analysis of DNA methylation for identification of prognostic panels of DNA methylation cancer biomarkers of imprinted genes. We found that the BPL method precisely quantified the methylation status of specific DNA regions in somatic cells. We found a higher frequency of LOI than LOH. LOI at IGF2, PEG1 and H19 were frequent alterations, with a tendency to show a more hypermethylated state. We detected changes in DNA methylation as an early event in ovarian cancer. The degree of LOI (LOH) was associated with altered DNA methylation at IGF2/H19 and PEG1. The relative ease of BPL method provides a practical method for use within a clinical setting. We suggest that DNA methylation of H19 and PEG1 differentially methylated regions (DMRs) may provide novel biomarkers useful for screening, diagnosis and, potentially, for improving the clinical management of women with human ovarian cancer.


Immuno cross-reactivity suggests that catecholamine biosynthesis enzymes and beta-adrenergic receptors may be related.
Turkey red blood cell, beta 1-adrenergic receptors (BARs) were prepared to electrophoretic homogeneity by affinity chromatography, size exclusion high performance liquid chromatography, and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and used to prepare rabbit polyclonal anti-BAR antibodies. Anti-BAR activity was confirmed by immunoadsorption of [125I]cyanopindolol-labeled BAR to a protein A affinity column using the anti-BAR antibodies. BAR was compared to the catecholamine biosynthetic enzyme dopamine B-hydroxylase (DBH) by anti-BAR antibody cross-reactivity. DBH was purified from bovine adrenal medullae chromaffin vesicles by ion exchange, size exclusion, and concanavalin A-Sepharose chromatography. Final DBH specific activities were 42 +/- 4 units/mg of protein. Homogeneity was confirmed by nondenaturing polyacrylamide gel electrophoresis. Both DBH and BAR were recognized by the anti-BAR antibodies on Western transfer and immunoblotting. No interactions were observed with preimmune controls. Similar results were obtained with glycosylated and deglycosylated DBH, suggesting that the anti-BAR antibodies recognize specific portions of DBH amino acid sequence and not associated carbohydrate. DBH-cross-reactive antibodies were also purified by affinity chromatography using immobilized DBH and shown to immunoadsorb [125I]cyanopindolol-labeled BAR by protein A affinity chromatography. These results suggest that the catecholamine biosynthetic enzyme DBH and BAR may be related in structure.


The acute effect of ethanol on albumin, fibrinogen and transferrin synthesis in the rat.
Decrease of absolute synthesis of albumin and fractional synthesis of transferrin was observed within 3h of orally administering ethanol (4ml/kg) to rats maintained on a 40%-protein diet. In contrast, absolute synthesis of fibrinogen was unaffected. With this ethanol intake, the changes in protein synthesis occurred without significant ultrastructural change in the liver. When the ethanol intake was greater (8ml/kg) ultrastructural disruption was observed. However, both the decrease of plasma protein synthesis and the ultrastructural alterations could be prevented by the simultaneous administration of a mixture of amino acids with the ethanol. The latter findings, not reported hitherto, suggest that ethanol may interfere with hepatic plasma protein synthesis and ultrastructure more through a disturbance of amino acid metabolism than through direct physical damage to the hepatocyte. An Appendix outlines the deconvolutional method used to correct for losses of labelled protein in the period during which measurements were made. The principle may also be applied to labelled plasma urea. The details of the calculations are given in a supplementary paper that has been deposited as Supplementary Publication 50007 at the National Lending Library for Science and Technology, Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1972) 126, 5.


An AI-Ready Multiplex Staining Dataset for Reproducible and Accurate Characterization of Tumor Immune Microenvironment.
We introduce a new AI-ready computational pathology dataset containing restained and co-registered digitized images from eight head-and-neck squamous cell carcinoma patients. Specifically, the same tumor sections were stained with the expensive multiplex immunofluorescence (mIF) assay first and then restained with cheaper multiplex immunohistochemistry (mIHC). This is a first public dataset that demonstrates the equivalence of these two staining methods which in turn allows several use cases; due to the equivalence, our cheaper mIHC staining protocol can offset the need for expensive mIF staining/scanning which requires highly-skilled lab technicians. As opposed to subjective and error-prone immune cell annotations from individual pathologists (disagreement > 50%) to drive SOTA deep learning approaches, this dataset provides objective immune and tumor cell annotations via mIF/mIHC restaining for more reproducible and accurate characterization of tumor immune microenvironment (e.g. for immunotherapy). We demonstrate the effectiveness of this dataset in three use cases: (1) IHC quantification of CD3/CD8 tumor-infiltrating lymphocytes via style transfer, (2) virtual translation of cheap mIHC stains to more expensive mIF stains, and (3) virtual tumor/immune cellular phenotyping on standard hematoxylin images. The dataset is available at \url{https://github.com/nadeemlab/DeepLIIF}.


Core-Shell Reactor Partitioning Enzyme and Prodrug by ZIF-8 for NADPH-Sensitive In Situ Prodrug Activation.
Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC50 value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.


Accidental oxygen disconnection in the emergency department.
Accidental oxygen disconnection during rapid sequence intubation (RSI) in the emergency department is a potentially catastrophic yet avoidable event. We report three cases of inadvertent oxygen disconnection during RSI, which resulted in significant oxygen desaturation. This error can potentially be prevented by thorough preparation, focusing on teamwork training, ensuring an ergonomic environment, and by making simple modifications to existing equipment.


Yeast lacking superoxide dismutase(s) show elevated levels of "free iron" as measured by whole cell electron paramagnetic resonance.
A current hypothesis explaining the toxicity of superoxide anion in vivo is that it oxidizes exposed [4Fe-4S] clusters in certain vulnerable enzymes causing release of iron and enzyme inactivation. The resulting increased levels of "free iron" catalyze deleterious oxidative reactions in the cell. In this study, we used low temperature Fe(III) electron paramagnetic resonance (EPR) spectroscopy to monitor iron status in whole cells of the unicellular eukaryote, Saccharomyces cerevisiae. The experimental protocol involved treatment of the cells with desferrioxamine, a cell-permeant, Fe(III)-specific chelator, to promote oxidation of all of the "free iron" to the Fe(III) state wherein it is EPR-detectable. Using this method, a small amount of EPR-detectable iron was detected in the wild-type strain, whereas significantly elevated levels were found in strains lacking CuZn-superoxide dismutase (CuZn-SOD) (sod1 delta), Mn-SOD (sod2 delta), or both SODs, throughout their growth but particularly in stationary phase. The accumulation was suppressed by expression of wild-type human CuZn-SOD (in the sod1 delta mutant), by pmr1, a genetic suppressor of the sod delta mutant phenotype (in the sod1 delta sod2 delta double knockout strain), and by anaerobic growth. In wild-type cells, an increase in the EPR-detectable iron pool could be induced by treatment with paraquat, a redox-cycling drug that generates superoxide. Cells that were not pretreated with desferrioxamine had Fe(III) EPR signals that were equally as strong as those from treated cells, indicating that "free iron" accumulated in the ferric form in our strains in vivo. Our results indicate a relationship between superoxide stress and iron handling and support the above hypothesis for superoxide-related oxidative damage.


Door-to-Needle Delays in Minor Stroke: A Causal Inference Approach.
Thrombolysis rates among minor stroke (MS) patients are increasing because of increased recognition of disability in this group and guideline changes regarding treatment indications. We examined the association of delays in door-to-needle (DTN) time with stroke severity. We performed a retrospective analysis of all stroke patients who received intravenous tissue-type plasminogen activator in our emergency department between July 1, 2011, and February 29, 2016. Baseline characteristics and DTN were compared between MS (National Institutes of Health Stroke Scale score ≤5) and nonminor strokes (National Institutes of Health Stroke Scale score >5). We applied causal inference methodology to estimate the magnitude and mechanisms of the causal effect of stroke severity on DTN. Of 315 patients, 133 patients (42.2%) had National Institutes of Health Stroke Scale score ≤5. Median DTN was longer in MS than nonminor strokes (58 versus 53 minutes; P=0.01); fewer MS patients had DTN ≤45 minutes (19.5% versus 32.4%; P=0.01). MS patients were less likely to use emergency medical services (EMS; 62.6% versus 89.6%, P<0.01) and to receive EMS prenotification (43.9% versus 72.4%; P<0.01). Causal analyses estimated MS increased average DTN by 6 minutes, partly through mode of arrival. EMS prenotification decreased average DTN by 10 minutes in MS patients. MS had longer DTN times, an effect partly explained by patterns of EMS prenotification. Interventions to improve EMS recognition of MS may accelerate care.


Multimodality imaging of the tricuspid valve with implication for percutaneous repair approaches.
Nowadays some percutaneous options for tricuspid valve (TV) repair are available: Tricinch (4Tech Cardio, Galway, Ireland) mimicking the Kay procedure, Trialign (Mitralign, Boston, MA, USA) aiming to bicuspidise TV, MitraClip (Abbott Vascular, Abbott Park, Illinois, USA) mimicking Alfieri's stitch, direct transcatheter annuloplasty with Cardioband (Valtech Cardio, Or Yehuda, Israel) and transcatheter Forma Repair (Edwards Lifesciences, Irvine, California, USA) providing a surface for leaflet coaptation. A multimodality imaging approach is fundamental for defining the pathophysiology of tricuspid regurgitation (TR), preprocedural planning and intraprocedural monitoring. Both 2-dimensional and 3-dimensional (3D) transthoracic echocardiography and transoesophageal echocardiography (TOE) are essential for grading and anatomical characterisation of TR, and evaluation of dimensions and function of right ventricle (RV) and estimation of pulmonary pressure. In particular, 3D echocardiography provides a better anatomical definition of TV apparatus and tricuspid annulus (TA) and additional information about the anatomical relationships of TV and surrounding structures. CT offers complementary information during the preprocedural planning especially for procedures targeting TA such as annular structure and dimensions, quality and amount of annular tissue and its relationship with the right coronary artery, and the sizing of the inferior vena cava. Moreover, appropriate patient selection is crucial. The best candidate seems to be a patient with functional TR due to predominant annular dilatation with modest apical tethering, at least partial preservation of leaflets coaptation, not severe pulmonary hypertension and not advanced RV dilation and dysfunction. An example of intraprocedural multimodality imaging approach with TOE, fluoroscopy, angiography and intracardiac echocardiography is also reported.


Determination of effective capacities of ion-exchangeable materials by measuring the equilibrium conductivity.
The effective ion-exchange capacities of ion-exchange materials were determined by measuring the change in the equilibrium conductivity of a column packed with analyte. The developed instrumental method can provide effective ion-exchange capacities for both cation and anion exchangers with simple operations. The cation-exchange capacity of a weak-acid cation-exchange resin (TSKgel SuperIC-Cation column) depended on the conditioning pH and the molar concentration of the conditioning agent. Plots of effective cation-exchange capacities over the conditioning pH exhibited three inflection points, suggesting the presence of two carboxy groups and one phenolic OH group in the resin, probably due to the inherent base polymer. This method was applied to several commercial analytical columns for ion chromatography, and could provide scientifically useful results for characterizing the resin properties.


Abstract inference of unchosen option values.
Reinforcement learning research has pursued a persistent question: Does reward feedback prompt inferences that transcend simple associations? Reversal learning data suggest an affirmative answer: When the positive stimulus (S+) becomes the negative stimulus (S-), trained humans rapidly switch to choosing the former S-. The operations supporting such inferences remain ambiguous. Do participants identify transitions between stimulus-specific contexts (i.e., A+B- and A-B+), or deduce values by learning the abstract contingency structure? Across two experiments, we probed humans' use of abstract rules to infer the values of unchosen alternatives. In Experiment 1, 37 participants attempted a task that originally demonstrated monkeys' difficulty with this form of inference. We presented modified discrimination problems in which the initially chosen stimulus (abstract inference group) or unchosen stimulus (control group) was replaced with a novel stimulus of identical status on Trial 2. In the abstract inference condition, accurate performance can be achieved by applying the consistent contingency structure (but not memory of stimulus-specific reward associations) to infer to the unchosen stimulus' value. The abstract inference group learned to make accurate choices, but only after committing substantially more errors than were observed among control participants-suggesting that unchosen value inferences are infrequently drawn in standard discrimination scenarios. In Experiment 2, 17 participants completed abstract inference problems that had been modified to be suitable for fMRI investigations. Behavioral results both corroborated the Experiment 1 trends and further revealed marked individual differences in explicit awareness of the novel stimulus values.


Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.
Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of I(Na) generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of I(Na) by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0+/-0.1% versus 18.23+/-0.04% at 10 micromol/L measured at 10 Hz, respectively). A dose of 10 micromol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1+/-0.3 mV and -4.8+/-0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.


Cross-lagged relations among parenting, children's emotion regulation, and psychosocial adjustment in early adolescence.
Numerous studies have reported substantive correlations between indicators of parenting, children's emotion regulation (ER), and children's psychosocial adjustment. However, studies on underlying mechanisms are scarce. Particularly in early adolescence, it is still unclear whether relations between parenting and ER are caused by adolescent behavior, by parent behavior, or by reciprocal processes. Moreover, it is unclear whether ER can be seen as an antecedent or a consequence of psychosocial adjustment. The aim of this study was to examine predictive relations among parenting and adolescents' ER, and adolescents' ER and psychosocial adjustment, respectively. We collected longitudinal, multiple informant data at two measurement occasions (Grade 6, Grade 7). All told, 1,100 adolescents (10-14 years) and their parents filled out questionnaires assessing responsiveness and psychological control, adolescents' anger regulation, and adolescents' problem and prosocial behavior. Cross-lagged analyses revealed reciprocal effects between parenting, ER, and adjustment for the parent and boys', but not for the girls', report. Moreover, relations were different for adolescents with versus without clinically elevated symptoms of psychopathology. Our findings support the assumption that reciprocal relations between parenting, ER, and psychosocial adjustment are likely to persist until early adolescence. Nevertheless, the moderating role of gender and psychopathology should be taken into account. Possible reasons for the different findings, and practical implications, are discussed.


Cation permeation through the voltage-dependent potassium channel in the squid axon. Characteristics and mechanisms.
Characteristics of cation permeation through voltage-dependent delayed rectifier K channels in squid giant axons were examined. Axial wire voltage-clamp measurements and internal perfusion were used to determine conductance and permeability properties. These K channels exhibit conductance saturation and decline with increases in symmetrical K+ concentrations to 3 M. They also produce ion- and concentration-dependent current-voltage shapes. K channel permeability ratios obtained with substitutions of internal Rb+ or NH+4 for K+ are higher than for external substitution of these ions. Furthermore, conductance and permeability ratios of NH+4 or Rb+ to K+ are functions of ion concentration. Conductance measurements also reveal the presence of an anomalous mole fraction effect for NH+4, Rb+, or Tl+ to K+. Finally, internal Cs+ blocks these K channels in a voltage-dependent manner, with relief of block by elevations in external K+ but not external NH+4 or Cs+. Energy profiles for K+, NH+4, Rb+, Tl+, and Cs+ incorporating three barriers and two ion-binding sites are fitted to the data. The profiles are asymmetric with respect to the center of the electric field, have different binding energies and electrical positions for each ion, and (for K+) exhibit concentration-dependent barrier positions.


Endothelial dysfunction associated with obesity and the effect of weight loss interventions.
Endothelial damage is central to the initiation and progression of atherosclerosis, while in addition vascular endothelial cells secrete several anti-atherogenic substances including the potent vasodilator nitric oxide. Increased adhesion molecule expression, in response to pathophysiological stimuli is perhaps the earliest indicator of compromised endothelial integrity. Obesity and adiposity are associated with an increased risk of CVD, influencing disease progression via a number of mechanisms, including enhanced endothelial activation. This review discusses possible mechanisms linking adiposity and more specifically regional fat depots with endothelial function and evaluates studies investigating the effect of weight loss on endothelial function, assessed by biochemical and physiological measurements. Overall, the research to date suggests that visceral adiposity is a stronger predictor of endothelial activation than overall adiposity, possibly mediated via the action of NEFA in circulation. While in general there is a suggestion that weight loss is associated with significant improvements in endothelial function, this is not apparent in all interventions and published literature to date provides less than convincing evidence for the effects of weight loss on endothelial activation.


A biodegradable "one-for-all" nanoparticle for multimodality imaging and enhanced photothermal treatment of breast cancer.
Silver sulfide nanoparticles (Ag 2 S-NP) have been proposed for various optical-based biomedical applications, such as near-infrared fluorescence (NIRF) imaging, photoacoustics (PA) and photothermal therapy (PTT). However, their absorbance is relatively low in the NIR window used in these applications, and previous formulations were synthesized using toxic precursors under harsh conditions and have clearance issues due to their large size. Herein, we synthesized sub-5 nm Ag 2 S-NP and encapsulated them in biodegradable, polymeric nanoparticles (AgPCPP). All syntheses were conducted using biocompatible reagents in the aqueous phase and under ambient conditions. We found that the encapsulation of Ag 2 S-NP in polymeric nanospheres greatly increases their NIR absorbance, resulting in enhanced optical imaging and photothermal heating effects. We therefore found that AgPCPP have potent contrast properties for PA and NIRF imaging, as well as for computed tomography (CT). We demonstrated the applicability of AgPCPP nanoparticles as a multimodal imaging probe that readily improves the conspicuity of breast tumors in vivo . PTT was performed using AgPCPP with NIR laser irradiation, which led to significant reduction in breast tumor growth and prolonged survival compared to free Ag 2 S-NP. Lastly, we observed a gradual decrease in AgPCPP retention in tissues over time with no signs of acute toxicity, thus providing strong evidence of safety and biodegradability. Therefore, AgPCPP may serve as a "one-for-all" theranostic agent that degrades into small components for excretion once the diagnostic and therapeutic tasks are fulfilled, thus providing good prospects for translation to clinical use.


Short telomere length is associated with renal impairment in Japanese subjects with cardiovascular risk.
Short telomere length has been suggested to be associated with atherosclerotic changes in Western populations. We examined the relationships between leukocyte telomere length and cardiovascular and renal function in a Japanese cohort. We enrolled 770 subjects who each had at least one cardiovascular risk factor. The mean age was 59.5 ± 12.2 years; mean BMI was 25.1 ± 4.6 kg/m2. We measured leukocyte telomere length (LTL) by quantitative PCR (T/S ratio), and measured other biomarkers from blood and urine samples. In addition, we assessed surrogate markers of arterial stiffness, cardiovascular organ damage and kidney function, including flow-mediated vasodilation (FMD), pulse wave velocity (PWV), carotid artery augmentation index (CAAI), and urinary albumin creatinine ratio (UACR) and eGFR. Leukocyte telomere length (T/S ratio) was inversely associated with age (r = -0.194, P<0.001), and was lower in men (1.13 ± 0.29%) than in women (1.20 ± 0.31%, P = 0.002). T/S ratio was positively associated with BMI in women (r = 0.11, P = 0.047), but not in men. LTL did not show a significant relationship to cardiovascular surrogate markers, including arterial stiffness, FMD, and PWV, but did show some relationship to CAAI, which was inversely associated with T/S ratio only in men (r = -0.159, P = 0.015). LTL did show a significant positive association with renal function measured by eGFR (r = 0.16, P<0.001) both in men and women. In this Japanese sample of persons with increased cardiovascular risk, telomere length showed a relationship of longer telomere length to better renal function, but did not overall show convincing association with cardiovascular measures of arterial stiffness and target organ damage.


Peroxisome proliferator-activated receptor gamma, the ultimate liaison between fat and transcription.
The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes.


The emergence of consciousness: Science and ethics.
The newborn human infant is conscious at a minimal level. It is aware of its body, itself and to some extent of the outside world. It recognizes faces and vowels to which it has been exposed. It expresses emotions like joy. Functional magnetic resonance imaging of the newborn brain shows highest activity in the somatosensory, auditory, and visual cortex but less activity in association area and the prefrontal cortex as compared with adults. There is an incomplete default mode network which is assumed to be related to consciousness. Although the fetus reacts to pain, maternal speaking, etc., it is probably not aware of this due to the low oxygen level and sedation. Assuming that consciousness is mainly localized in the cortex, consciousness cannot emerge before 24 gestational weeks when the thalamocortical connections from the sense organs are established. Thus the limit of legal abortion at 22-24 weeks in many countries makes sense. It should also be possible to withdraw or withhold life-saving therapy of extremely preterm infants, especially if they are severely brain-damaged. This may also apply to full-term infants with grade III hypoxic-ischemic encephalopathy, who show no signs of consciousness.


Use of predator odors as repellents to reduce feeding damage by herbivores : I. Snowshoe hares (Lepus americanus).
The effectiveness of predator odors (fecal, urine, and anal scent gland) in suppressing feeding damage by snowshoe hares was investigated in pen bioassays at the University of British Columbia Research Forest, Maple Ridge, British Columbia, Canada. A total of 28 bioassay trials tested the effects of these odors on hare consumption of willow browse and coniferous seedlings. Lynx and bobcat feces, weasel anal gland secretion, and lynx, bobcat, wolf, coyote, fox, and wolverine urines resulted in the most effective suppression of hare feeding damage. Novel odors of domestic dog urine and 2-methylbutyric acid did not reduce feeding. A field bioassay with lodgepole pine seedlings and weasel scent provided significant results comparable to the pen bioassays. The short-term (up to seven days) effectiveness of these treatments was more likely due to evaporative loss of the active repellent components of a given odor than habituation of hares to the stimulus. Predator odors as repellents have a biological basis compared with the anthropomorphic origins of commercial repellents. When encapsulated in weather-proof controlled-release devices, these odors could provide long-term protection for forestry plantations and agricultural crops which experience hare/rabbit feeding damage.


Morphology of the nymphoid replacement reproductives in the neotropical termite Armitermes euamignathus (Isoptera, Termitidae, Nasutitermitinae).
Numerous nymphoid reproductives were found in three field nests of Armitermes euamignathus collected in Brazil. We report here a morphological description and a biometric study of these individuals. Nymphoid replacements displayed narrow wing buds when compared with those present in nymphs from the three last instars. Thorax morphology of the nymphoids was similar to the penultimate nymphal instar (N4) or to the ultimate nymphal instar (N5), and their origin from these instars of nymphs is discussed. All the nymphoids had eyes, ocelli, and 15 antennal segments. The nymphoid females from nest 1 had different grades of physogastry and royal fat body. The nymphoid females from nests 2 and 3, the nymphoid males from all nests, and the primary king from nests 2 and 3 had a common fat body, which is similar to that present in alates. The ovaries and the testes of nymphoids were fully mature and the corpora allata larger than those in imagoes. The mandibular glands were also enlarged in nymphoids but the tergal glands were absent. J. Morphol. 239:131-141, 1999. © 1999 Wiley-Liss, Inc.


A Model to Predict the Use of Surgical Resection for Advanced-Stage Non-Small Cell Lung Cancer Patients.
For advanced-stage non-small cell lung cancer, chemotherapy and chemoradiotherapy are the primary treatments. Although surgical intervention in these patients is associated with improved survival, the effect of selection bias is poorly defined. Our objective was to characterize selection bias and identify potential surgical candidates by constructing a Surgical Selection Score (SSS). Patients with clinical stage IIIA, IIIB, or IV non-small cell lung cancer were identified in the National Cancer Data Base from 1998 to 2012. Logistic regression was used to develop the SSS based on clinical characteristics. Estimated area under the receiver operating characteristic curve was used to assess discrimination performance of the SSS. Kaplan-Meier analysis was used to compare patients with similar SSSs. We identified 300,572 patients with stage IIIA, IIIB, or IV non-small cell lung cancer without missing data; 6% (18,701) underwent surgical intervention. The surgical cohort was 57% stage IIIA (n = 10,650), 19% stage IIIB (n = 3,483), and 24% stage IV (n = 4,568). The areas under the receiver operating characteristic curve from the best-fit logistic regression model in the training and validation sets were not significantly different, at 0.83 (95% confidence interval, 0.82 to 0.83) and 0.83 (95% confidence interval, 0.82 to 0.83). The range of SSS is 43 to 1,141. As expected, SSS was a good predictor of survival. Within each quartile of SSS, patients in the surgical group had significantly longer survival than nonsurgical patients (p < 0.001). A prediction model for selection of patients for surgical intervention was created. Once validated and prospectively tested, this model may be used to identify patients who may benefit from surgical intervention.


Atosiban versus betamimetics in the treatment of preterm labour in Germany: an economic evaluation.
The use of tocolytics is central in delaying birth; however, therapeutic options vary in effectiveness and adverse events profiles, which in turn could have consequences for medical resource use and cost of treatment. Betamimetics are commonly used tocolytic agents, but their mechanism of action affects multiple organ systems leading to numerous adverse events. The availability of an oxytocin receptor antagonist, specific for prevention of preterm labour, offers a treatment option that merits further evaluation. We aimed to compare economic implications of tocolysis using atosiban and betamimetics, considering treatment efficacy and safety, as well as cost consequences of treatment of associated adverse events. A systematic literature review identified six randomised clinical trials, three of them double-blinded, comparing atosiban with betamimetics, in which tocolysis was initiated within 48 hours of admission. Cost of drug treatment was calculated based on trial protocols and German hospital drug purchase costs. G-DRG Grouper was used to obtain cost per case. The drug regimen was concordant with the German guidelines for the management of preterm labour, with two alternative modalities of fenoterol analysed: continuous or bolus administrations. According to the results of the meta-analysis of the three double-blinded, placebo-controlled clinical trials, atosiban and betamimetics have similar efficacy (RR = 0.99, 95%CI:0.94-1.04, p = 0.772). Compared to betamimetics, use of atosiban was associated with a significantly lower frequency of adverse events for tachycardia, palpitation, vomiting, headache, hyperglycaemia, tremor, dyspnoea, chest pain, hypocalemia and foetal tachycardia. In our economic analysis, cost savings from using atosiban versus continuous, or bolus, fenoterol was 423euro per patient from the payer's perspective. From the hospital's perspective, savings from using atosiban versus continuous fenoterol ranged from 259euro for 18 hours of tocolysis to 105euro for 48 hours; the respective values for bolus fenoterol were 244euro and 55euro. In the probabilistic sensitivity analysis atosiban was cost saving versus both continuous and bolus fenoterol in 87%-100% of scenarios. In a German setting, atosiban is cost saving versus betamimetics in the treatment of preterm labour from the payer, hospital and combined perspectives. Cost savings stem from the superior safety profile of atosiban.


Increased induction of osteopetrosis, but unaltered lymphomagenicity, by murine leukemia virus SL3-3 after mutation of a nuclear factor 1 site in the enhancer.
SL3-3 is a murine leukemia virus which is only weakly bone pathogenic but highly T-cell lymphomagenic. A major pathogenic determinant is the transcriptional enhancer comprising several transcription factor binding sites, among which are three identical sites for nuclear factor 1 (NF1). We have investigated the pathogenic properties of NF1 site enhancer mutants of SL3-3. Two different mutants carrying a 3-bp mutation either in all three NF1 sites or in the central site alone were constructed and assayed in inbred NMRI mice. The wild type and both mutants induced lymphomas in all mice, with a mean latency period of 9 weeks. However, there was a considerable difference in osteopetrosis induction. Wild-type SL3-3 induced osteopetrosis in 11% of the mice (2 of 19), and the triple NF1 site mutant induced osteopetrosis in none of the mice (0 of 19), whereas the single NF1 site mutant induced osteopetrosis in 56% (10 of 18) of the mice, as determined by X-ray analysis. A detailed histological examination of the femurs of the mice was carried out and found to support this diagnosis. Thus, the NF1 sites of SL3-3 are major determinants of osteopetrosis induction, without determining lymphomagenesis. This conclusion was further supported by evaluation of the bone pathogenicity of other SL3-3 enhancer variants, the lymphomagenicity of which had been examined previously. This evaluation furthermore strongly indicated that the core sites, a second group of transcription factor binding sites in the viral enhancer, are necessary for the osteopetrosis induction potential of SL3-3.


Theoretical study of N-heterocyclic carbenes-catalyzed cascade annulation of benzodienones and enals.
Growing attention in developing new N-heterocyclic carbene (NHC)-mediated reactions involving homoenolate intermediates has prompted our interest in exploring the mechanistic details of the related reactions. In this work, we carried out a detailed theoretical study for the NHC-catalyzed annulation reaction of cinnamaldehyde (A) and benzodi(enone) (B) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). By performing density functional theory calculations, we show clearly the detailed reaction mechanism and rationalize the experimental observation. The reaction of A and B falls into two stages: the formation of homoenolate intermediate and the annulation of homoenolate with B. In the homoenolate formation stage, three possible paths are characterized. The pathway involving the DBU-assisted 1,2-proton transfer with a stepwise mechanism is kinetically more favorable, and the DBU-assisted C1 proton departure is the rate-determining step of the total reaction. The annulation of homoenolate with B involves four elementary steps. The conformational difference of homoenolate (cis and trans) leads to two slightly different reaction processes. In the total reaction, the process involving cis-conformation of A is kinetically more feasible. This can be clearly understood through the frontier molecular orbital analysis and the electronic inductive effect. The calculated results are expected to offer valuable information for further design and development of NHC-mediated reactions.


Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids.
To use different paradigms of oxidative and metabolic stress in a cellular model of Leber hereditary optic neuropathy (LHON), with the aim of evaluating the efficacy of potentially therapeutic molecules for the treatment of this disease. Cybrids bearing one of the three most common LHON pathogenic mutations (11778/ND4, 3460/ND1, 14484/ND6) were incubated with two compounds known to induce oxidative injury, tert-butyl hydroperoxide (t-BH) and rotenone. To mimic metabolic stress, cells were incubated in a glucose-free medium containing galactose. Cell viability was determined using the MTT assay. To identify the apoptotic type of cell death, nuclear morphology was examined after cell loading with Hoechst. Cellular glutathione (GSH), and oxidized glutathione (GSSG) levels were measured enzymatically. Incubation with t-BH caused apoptotic cell death of control and LHON cybrids, whereas only LHON cybrids were damaged by rotenone concentrations up to 2.5 muM. Both types of stress caused a marked imbalance in the glutathione levels, but an increase in the GSSG/GSH+GSSG ratio was detected only after rotenone treatment. The efficacy of several antioxidant and antiapoptotic compounds was then assessed in cells exposed to these two oxidative paradigms. Only exogenous GSH remarkably protected the t-BH- and rotenone-treated cybrids from cell death. In contrast, GSH was unable to increase the viability of cybrids exposed to metabolic stress. These results suggest that GSH is an effective antioxidant compound to be tested as a potential treatment for LHON.


Writing a successful NIH Mentored Career Development Grant (K award): hints for the junior faculty surgeon.
Surgery is a labor-intensive, time-consuming profession. Young faculty members in surgery are saddled with many clinical time constraints that often allow precious few moments for academic pursuits. Consequently, K award submissions from surgeons trail nonsurgeons. The National Institutes of Health (NIH), however, is actively trying to encourage participation of surgeons in basic science research, translational research, clinical outcomes research, and even in prevention/control research. But, at the same time, the NIH has newly implemented a policy that has made the grant review process more restrictive by only allowing 2 submissions of any grant application. It is imperative, therefore, for junior faculty surgeons to learn "grantsmanship" and have the ability to construct succinct, competitive K award grants. Although most of this information is public knowledge and made available by the NIH itself, many of the practical points presented here are tailored to the special needs of clinically active surgical researchers. Often, these "hints" are buried on expansive websites that require considerable time to read and navigate. The authors have a long combined experience on a study section dedicated to adjudicating K awards. The goal of this review is to present concise, useful information about common errors, research plan dos and don'ts, template examples of superior mentored letters, and many other suggestions that may assist any first-time candidate for these awards.


Single-cell Analysis Reveals Inter- and Intratumour Heterogeneity in Metastatic Breast Cancer.
Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set enrichment analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top differentially expressed genes (DEGs) between these cell states revealed a common set of partial EMT transcription factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.


Sulfate-selective PVC membrane electrode based on a strontium Schiff's base complex.
A strontium Schiff's base complex (SS) can be used as a suitable ionophore to prepare a sulfate-selective PVC-based membrane electrode. The use of oleic acid (OA) and hexadecyltrimethylammonium bromide (HTAB), as additives, and nitrobenzen (NB), dibutyl phthalate (DBP) and benzyl acetate (BA) as solvent mediators, were investigated. The best performance was observed with a membrane composition PVC: NB: SS: HTAB of 30%: 62%: 5%: 3% ratio. The resulting sensor works well over a wide concentration range (1.0 x 10(-2)-1.0 x 10(-6) M) with a Nernstian slope of -29.2 mV per decade of sulfate activity over a pH range 4.0-7.0. The limit of detection of the electrode is 5 x 10(-7) M. The proposed sensor shows excellent discriminating ability toward SO4(2-) ions with regard to many anions. It has a fast response time of about 15 s. The membrane electrode was used to the determination of zinc in zinc sulfate tablets. The sensor was also used as an indicator electrode in the potentiometric titration of SO4(2-) against barium ion.


[Levels of adenosine deaminase and dipeptidyl peptidase IV in patients with panic disorder].
Adenosine deaminase and dipeptidyl peptidase IV are enzymes connected to T cells that play an important role in immune system functioning. In this study, in order to understand the immune processes in panic disorder, we determined the serum levels of adenosine deaminase and dipeptidyl peptidase IV in medication-free panic disorder patients and compared them to those of healthy controls. Enzymes levels were determined in blood samples of 24 healthy controls and 33 panic disorder patients diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV that were medication free during the previous month and medically healthy. Levels of both enzymes were significantly higher in panic disorder patients than in the controls (P<0.001 for adenosine deaminase and P<0.05 for dipeptidyl peptidase IV). The levels of the enzymes did not correlate with sociodemographic variables, duration of the disorder, presence of agoraphobia, presence of stressors, number of panic attack symptoms, and Hamilton depression and anxiety rating scale scores. In addition, the 2 enzymes? levels did not correlate with each other. There was a correlation between Hamilton anxiety rating scale score and the number of panic attack symptoms (P<0.001); however, Hamilton anxiety rating scale scores were not correlated with the other variables. Our results suggest that there may be a primary or secondary impaired immune state in the course of panic disorder, as there is in many other psychiatric disorders, such as major depression. Future studies with larger samples are needed to clarify the relationship between the immune system and panic disorder.


RRR-alpha-tocopheryl succinate inhibits DNA synthesis and enhances the production and secretion of biologically active transforming growth factor-beta by avian retrovirus-transformed lymphoid cells.
The RRR-alpha-tocopheryl succinate form of vitamin E, referred to as vitamin E succinate (VES), inhibits the proliferation of avian reticuloendotheliosis virus-transformed RECC-UTC4-1 (C4-1) lymphoblastoid cells in a dose-dependent manner in vitro. Analyses of conditioned medium (CM) from VES growth-inhibited cells revealed a potent antiproliferative activity. Characterization of the antiproliferative activity as transforming growth factor-beta (TGF-beta) was established by 1) growth inhibition of TGF-beta-responsive Mv1Lu mink lung and murine CTLL-2 cell lines, 2) a combination of physical characteristics including heat stability, acid stability, and Bio-Gel P-60 column chromatography elution profile, 3) neutralization of the antiproliferative activity by antibodies specific for TGF-beta, and 4) immunoprecipitation of metabolically labeled TGF-beta in CM from VES-treated C4-1 cells by use of TGF-beta-specific antibodies. Northern blot analyses of total cellular RNA revealed that VES does not alter the levels of constitutively expressed TGF-beta isoform-specific mRNAs; namely, VES does not alter the levels of the 3.9- and 4.1-kb TGF-beta 2 mRNAs, the 3.0-kb TGF-beta 3 mRNA, or the 2.5-, 2.7-, and 1.7-kb TGF-beta 4 mRNAs. The data show that VES inhibits C4-1 cell proliferation and induces the cells to produce and secrete active forms of TGF-beta, suggesting that one mechanism whereby VES inhibits C4-1 cell proliferation may be via the TGF-beta pathway for cellular growth control.


Sialidase NEU4 is involved in glioblastoma stem cell survival.
The human sialidase, NEU4, has emerged as a possible regulator of neuronal differentiation and its overexpression has been demonstrated to promote the acquisition of a stem cell-like phenotype in neuroblastoma cells. In this paper, we demonstrated that glioblastoma stem cells (GSCs) isolated from glioblastoma multiforme (GBM) cell lines and patients' specimens as neurospheres are specifically marked by the upregulation of NEU4; in contrast, the expression of NEU4 is very low in non-neurosphere-differentiated GBM cells. We showed that NEU4 silencing by miRNA or a chemical inhibitor of its catalytic activity triggered key events in GSCs, including (a) the activation of the glycogen synthase kinase 3β, with the consequent inhibition of Sonic Hedgehog and Wnt/β-catenin signalling pathways; (b) the decrease of the stem cell-like gene expression and marker signatures, evidenced by the reduction of NANOG, OCT-4, SOX-2, CD133 expression, ganglioside GD3 synthesis, and an altered protein glycosylation profile; and (c) a significant decrease in GSCs survival. Consistent with this finding, increased NEU4 activity and expression induced in the more differentiated GBM cells by the NEU4 agonist thymoquinone increased the expression of OCT-4 and GLI-1. Thus, NEU4 expression and activity appeared to help to determine the molecular signature of GSCs and to be closely connected with their survival properties. Given the pivotal role played by GSCs in GBM lethality, our results strongly suggest that NEU4 inhibition could significantly improve current therapies against this tumour.


Direct C-arylation of beta-enamino esters and ketones with arynes.
An efficient, mild, and general method for the C-arylation of beta-enamino esters and ketones with arynes has been developed. This methodology provides a facile and direct access to a variety of substituted aromatic beta-enamino compounds in moderate to excellent yield. [reaction: see text]


68Ga-PSMA PET/CT Uptake in Intramuscular Myxoma Imitates Prostate Cancer Metastasis.
Ga-PSMA PET/CT is becoming the most promising imaging modality for detecting recurrent prostate cancer. The modality has the advantage of being able to detect recurrent disease, even at very low prostate-specific antigen levels. However, several studies report Ga-PSMA uptake in tissue unrelated to prostate cancer. We present a 74-year-old man who underwent Ga-PSMA PET/CT for recurrent prostate cancer 5 years after radical prostatectomy. The Ga-PSMA PET/CT showed an intramuscular lesion with increased PSMA uptake in the left vastus medialis muscle. The lesion was surgically removed, and histopathology found it to be an intramuscular myxoma that showed immunohistochemical PSMA expression.


Integrated traditional herbal medicine for recurrent urinary tract infection treatment and follow-up: A meta-analysis of randomized controlled trials.
Urinary tract infections (UTIs) with pathogenic strain resistance leading to a high recurrence rate affect health quality and have become a high-priority issue due to the economic burden on the health care system. This study aimed to investigate the supportive benefits of traditional herbal medicines (THMs) for the treatment and prevention of recurrent UTIs through a meta-analysis of randomized controlled trials. Systematic searches of databases, including PubMed/Medline, the Cochrane Library, and China National Knowledge Infrastructure (CNKI), were conducted to collect eligible studies for meta-analysis. The inclusion criteria were randomized controlled trials that investigated UTI recurrence using THM treatment. The results of 22 studies showed that THM treatment led to significantly fewer UTI events in the experimental group than in the control group (OR = 0.348; 95% confidence interval [CI] = 0.257 to 0.473; p < 0.001). Seventeen studies reported UTI events during the follow-up period, and the recurrence rate was lower in the experimental group than in the control group (OR, 0.326; 95% CI, 0.245-0.434; p < 0.01). Subgroup analysis further showed that compared to antibiotics alone, treatment with THM plus antibiotics significantly reduced UTI events in the acute phase (OR = 0.301; 95% CI = 0.201 to 0.431; p < 0.001) as well as in the follow-up period (OR = 0.347; 95% CI = 0.241 to 0.498; p < 0.001). However, THM treatment alone was not superior to antibiotics in the acute treatment phase (OR = 0.540; 95% CI = 0.250 to 1.166; p = 0.117) or in the follow-up period (OR = 0.464; 95% CI = 0.111 to 1.951; p = 0.295). Herbal ingredients for recurrent UTI events also showed benefits compared to placebo treatment in the acute phase (OR = 0.337; 95% CI = 0.158 to 0.717; p = 0.005) and during follow-up (OR = 0.238; 95% CI = 0.139 to 0.409; p < 0.001). THM combined with antibiotics is helpful for people with acute UTIs and for reinfection prevention. THMs alone, although less effective for recurrent UTIs, could be considered a therapeutic alternative to antibiotics.


Circulating HLA-DR+CD4+ effector memory T cells resistant to CCR5 and PD-L1 mediated suppression compromise regulatory T cell function in tuberculosis.
Chronic T cell activation is a hallmark of pulmonary tuberculosis (PTB). The mechanisms underpinning this important phenomenon are however, poorly elucidated, though known to rely on control of T effector cells (Teff) by regulatory T cells (Treg). Our studies show that circulating natural Treg cells in adults with PTB preserve their suppressive potential but Teff cells from such subjects are resistant to Treg-mediated suppression. We found this to be due to expansion of an activated Teff subset identified by Human Leukocyte Antigen (HLA)-DR expression. Sensitivity to suppression was restored to control levels by depletion of this subset. Comparative transcriptome analysis of Teff cells that contain HLA-DR+ cells versus the fraction depleted of this population identified putative resistance mechanisms linked to IFNG, IL17A, IL22, PD-L1 and β-chemokines CCL3L3, CCL4 expression. Antibody blocking experiments confirmed HLA-DR+ Teff cells, but not the fraction depleted of HLA-DR+ effectors, to be resistant to Treg suppression mediated via CCR5 and PD-L1 associated pathways. In the presence of HLA-DR+ Teff cells, activation of NFκB downstream of CCR5 and PD-L1 was perturbed. In addition, HLA-DR+ Teff cells expressed significantly higher levels of Th1/Th17 cytokines that may regulate Treg function through a reciprocal counter-balancing relationship. Taken together, our study provides novel insight on how activated HLA-DR+CD4+ T cells may contribute to disease associated inflammation by compromising Treg-mediated suppression in PTB.


Application of scenario analysis and multiagent technique in land-use planning: a case study on Sanjiang wetlands.
Land-use planning has triggered debates on social and environmental values, in which two key questions will be faced: one is how to see different planning simulation results instantaneously and apply the results back to interactively assist planning work; the other is how to ensure that the planning simulation result is scientific and accurate. To answer these questions, the objective of this paper is to analyze whether and how a bridge can be built between qualitative and quantitative approaches for land-use planning work and to find out a way to overcome the gap that exists between the ability to construct computer simulation models to aid integrated land-use plan making and the demand for them by planning professionals. The study presented a theoretical framework of land-use planning based on scenario analysis (SA) method and multiagent system (MAS) simulation integration and selected freshwater wetlands in the Sanjiang Plain of China as a case study area. Study results showed that MAS simulation technique emphasizing quantitative process effectively compensated for the SA method emphasizing qualitative process, which realized the organic combination of qualitative and quantitative land-use planning work, and then provided a new idea and method for the land-use planning and sustainable managements of land resources.


Adjacent Segment Disease in the Cervical and Lumbar Spine.
Adjacent segment disease (ASD) is disappointing long-term outcome for both the patient and clinician. In contrast to adjacent segment degeneration, which is a common radiographic finding, ASD is less common. The incidence of ASD in both the cervical and lumbar spine is between 2% and 4% per year, and ASD is a significant contributor to reoperation rates after spinal arthrodesis. The etiology of ASD is multifactorial, stemming from existing spondylosis at adjacent levels, predisposed risk to degenerative changes, and altered biomechanical forces near a previous fusion site. Numerous studies have sought to identify both patient and surgical risk factors for ASD, but a consistent, sole predictor has yet to be found. Spinal arthroplasty techniques seek to preserve physiological biomechanics, thereby minimizing the risk of ASD, and long-term clinical outcome studies will help quantify its efficacy. Treatment strategies for ASD are initially nonoperative, provided a progressive neurological deficit is not present. The spine surgeon is afforded many surgical strategies once operative treatment is elected. The goal of this manuscript is to consider the etiologies of ASD, review its manifestations, and offer an approach to treatment.


Precaecal phosphorus digestibility of inorganic phosphate sources in male broilers.
The aim of this study, comprising two experiments, was (1) to determine in Experiment 1 the relationship of incremental dietary P (phosphorus) content on precaecal digestible P in male broilers and (2) to determine in Experiment 2 the precaecal P digestibility of various inorganic P sources at marginal levels of P supply. In Experiment 1, a total of 260 male Ross 308 broilers were divided into groups of 10 birds per pen resulting in 8 replicates for treatment 1 and 6 replicates for treatments 2-4. Experimental diets were formulated to contain 4 incremental concentrations of digestible P by means of increasing concentrations of monocalcium phosphate (MCP). In the second experiment, 480-d-old male Ross 308 broilers were divided in groups of 12 birds per pen resulting in 16 replicates for the basal diet and 6 replicates for each test diet. A total of 4 inorganic P sources, MCP, monodicalcium phosphate (MDCP), dicalcium phosphate (DCP) and defluorinated phosphate (DFP) were added to the basal diet to determine the precaecal P digestibility. Three of the 4 inorganic P sources (MCP, MDCP and DCP) represented a mix of batches from different producers. At the end of both experiments, the chyme of the posterior part of the small intestine was collected. Digestibility of P and Ca was determined using titanium dioxide as indigestible marker. In Experiment 1, a reduction in precaecal digestibility of P was observed above an estimated precaecal digestible dietary P concentration of 4.8 g/kg. The precaecal P digestibility of the tested inorganic P sources in Experiment 2 was 78.3% for MCP, 59.0% for DCP, 70.7% for MDCP and 31.5% for DFP.


Rapid biomonitoring of heterocyclic aromatic amines in human urine by tandem solvent solid phase extraction liquid chromatography electrospray ionization mass spectrometry.
A rapid and facile tandem solvent solid phase extraction method was established to isolate the heterocyclic aromatic amines (HAAs) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and 2-amino-9H-pyrido[2,3-b]indole from urine. The HAAs were separated by reversed phase liquid chromatography and quantified by electrospray ionization tandem mass spectrometry (ESI/MS/MS) using selected reaction monitoring. The limits of detection and quantitation of these HAAs approached 1-3 and 2-8 pg/mL, respectively, using only 0.3 mL of urine for analysis. Full product ion spectra were acquired to corroborate analyte identities. The pretreatment of urine from human volunteers that had consumed a grilled beef meal with acid or base at 70 degrees C increased the concentration of HAAs by as much as 6-fold, indicating the presence of phase II conjugates of the parent compounds. HAAs containing an N-methylimidazole moiety undergo facile cleavage of the N-methyl group under collision-induced dissociation conditions, and MS/MS analysis in the constant neutral loss scan mode monitoring the transition [M + H](+) --> [M + H - CH(3)(*)](+) revealed the presence of two other HAAs. 2-Amino-3-methylimidazo[4,5-f]quinoxaline (IQx) was identified by coelution of the analyte with synthetic IQx and by acquisition of the product ion spectrum. The second HAA was present in a relatively high abundance in urine. The molecule had the same nominal mass as 8-MeIQx (MH(+) at m/z 214), and the product ion spectrum was similar to that of 8-MeIQx. This novel HAA was also found in the grilled meat consumed by the volunteers at a concentration of 8 parts per billion. The accurate mass measurement and product ion spectrum of this molecule by ESI quadrupole time-of-flight mass spectrometry revealed that it was an isomer of 8-MeIQx. This tandem solvent solid phase extraction LC/ESI/MS/MS procedure may be used to rapidly assess the daily exposure to a variety of HAAs in urine.


Penalized Least Squares for Structural Equation Modeling with Ordinal Responses.
Statistical modeling with sparsity has become an active research topic in the fields of statistics and machine learning. Because the true sparsity pattern of a model is generally unknown aforehand, it is often explored by a sparse estimation procedure, like least absolute shrinkage and selection operator (lasso). In this study, a penalized least squares (PLS) method for structural equation modeling (SEM) with ordinal data is developed. PLS describes data generation by an underlying response approach, and uses a least squares (LS) fitting function to construct a penalized estimation criterion. A numerical simulation was used to compare PLS with existing penalized likelihood (PL) in terms of averaged mean square error, absolute bias, and the correctness of the model. Based on these empirical findings, a hybrid PLS was also proposed to improve both PL and PLS. The hybrid PLS first chooses an optimal sparsity pattern by PL, then estimates model parameters by an unpenalized LS under the model selected by PL. We also extended PLS to cases of mixed type data and multi-group analysis. All proposed methods could be realized in the R package lslx.


The Development of Young Peoples' Internalising and Externalising Difficulties Over the First Three-Years in the Public Care System.
Although we know there are high rates of mental health difficulties amongst young people in out-of-home care (i.e. social welfare-involved children), there is limited evidence on the longitudinal development of these problems, particularly from when they enter the care system. Using the routinely collected carer-reported strengths and difficulties questionnaire, we explored internalising (emotional and peer) and externalising (conduct and hyperactivity) difficulties for 672 young people across their first 3 years in the UK care system (2-16 yrs, 51% boys, 76% Caucasian). In all cases stable profiles (resilient or chronic) were most common, while changing profiles (recovery or delayed) were less common. Findings showed that entry into the care system is not enough of an intervention to expect natural recovery from mental health difficulties. Number of placements and being separated from siblings were associated with greater difficulties. Implications for child welfare and mental health systems are discussed.


Photoluminescence and photocurrent from InP nanowires with InAsP quantum dots grown on Si by molecular beam epitaxy.
InP nanowires with InAsP quantum dots (QDs) were grown by molecular beam epitaxy on a Si (111) substrates. The structure of the InAsP QDs were studied using transmission electron microscopy, allowing the development of a model where QD growth occurs by group V desorption from the surrounding substrate surface. Micro-photoluminescence was performed at 10 K showing emission at 1.47-1.49 eV from the InP wurtzite structure, and various emission peaks between 0.93 and 1.33 eV attributed to the QDs. The emission was tuned by the QD composition. The effectiveness of an AlInP passivation shell was demonstrated via an improvement in the photoluminescence intensity. Spectrally-resolved photocurrent measurements at room temperature demonstrated infrared response due to absorption within the QDs. The absorption red-shifted with increasing As composition of the QD.


Human suppressor T cells: induction, differentiation, and regulatory functions.
T-cell-mediated suppression of human immune responses involves a complex interaction between distinct lymphocyte subsets with suppressor-inducer and suppressor-effector functions. Recent studies with subset-specific monoclonal antibodies have defined a characteristic phenotype of suppressor-inducer cells (CD4+ Leu8+ 2H4+ 4B4-) that can be distinguished from that of helper cells for antibody synthesis (CD4+ Leu8- 2H4- 4B4+). Similarly, suppressor-effector cells (CD8+CD11+Tp44-) can typically be defined as a subset separable from cytotoxic T cells (CD8+CD11-Tp44+). Both antigen-specific and nonspecific interactions are important in suppressor T-cell activation and function. Soluble signals required for differentiation of CD8+ suppressor cells include an indomethacin-sensitive monocyte product and interferon gamma. In contrast, proliferation of the CD8+ suppressor cell subset depends on stimulation first by a product of CD4+Leu8+ cells, T suppressor cell growth factor, and second by interleukin 2. Although the molecular basis of antigen-specific interactions between CD4+ and CD8+ cells in suppressor cell generation has not been defined, it may involve both conventional, presumably MHC-restricted, interactions between antigen and antigen receptors, as well as anti-idiotypic interactions of suppressor-effectors with determinants on suppressor-inducer receptors. Progress in elucidating requirements for activation, growth, and differentiation of suppressor cells should facilitate long-term culture of such cells and lead to clearer understanding of mechanisms of suppressor-cell mediated immunoregulation.


The relationship of self-reported sleep disturbance, mood, and menopause in a community study.
The aim of this study was to assess the relationship between sleep disturbance, mood, menopausal status, and vasomotor symptoms in middle-aged women in Kinmen. A community-based sample of 1,113 Taiwanese women aged 43 to 57 years who were living on the island of Kinmen were recruited in this cross-sectional study. Menopausal status was determined by menstrual history. Sleep quality was measured by self-reported sleep problems. Anxiety and depression were assessed by the Hospital Anxiety Depression Scale. Forty-six percent of middle-aged women reported feeling dissatisfied with their sleep. Total sleep hours were not significantly different as a function of menopausal status. Generally, the occurrence of sleep problems or poor sleep quality was most prevalent in the postmenopausal group and least prevalent in premenopausal women. After analysis by multiple logistic regression, menopausal status was the independent factor of difficulty initiating sleep and sleep fragmentation. The Hospital Anxiety Depression Scale anxiety score was related to all sleep problems except for "excessive daytime sleepiness" and "awakening without further sleep." Almost half of the Taiwanese middle-aged women felt dissatisfied with their sleep. Both menopausal status and higher anxiety score were associated with poor sleep quality of midlife women.


Innate immune response of human pluripotent stem cell-derived airway epithelium.
The acquisition of innate immune response is requisite to having bona fide differentiation of airway epithelium. Procedures developed to differentiate lung airway from human pluripotent stem cells (hPSCs) have demonstrated anecdotal evidence for innate immune response, but an in-depth exploration of response levels is lacking. Herein, using an established method of airway epithelial generation from hPSCs, we show that hPSC-derived epithelial cells are able to up-regulate expression of TNFα, IL8 and IL1β in response to challenge with bacterial endotoxin LPS, but lack response from genes associated with innate immune response in other cell types. Further, stimulation of cells with TNF-α resulted in auto-induction of TNFα transcript, as well as cytokine responses of IL8 and IL1β. The demonstration of innate immune induction in hPSC-derived airway epithelia gives further strength to the functionality of in vitro protocols aimed at generating differentiated airway cells that can potentially be used in a translational setting. Finally, we propose that innate immune challenge of airway epithelium from human pluripotent stem cell sources be used as a robust validation of functional in vitro differentiation.


HDL interfere with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production.
Direct cellular contact with stimulated T cells is a potent mechanism that induces cytokine production in human monocytes in the absence of an infectious agent. This mechanism is likely to be relevant to T cell-mediated inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. Microparticles (MP) generated by stimulated T cells (MPT) display similar monocyte activating ability to whole T cells, isolated T cell membranes, or solubilized T cell membranes. We previously demonstrated that high-density lipoproteins (HDL) inhibited T cell contact- and MPT-induced production of IL-1beta but not of its natural inhibitor, the secreted form of IL-1 receptor antagonist (sIL-1Ra). Labeled MPT were used to assess their interaction with monocytes and T lymphocytes by flow cytometry. Similarly, interactions of labeled HDL with monocytes and MPT were assessed by flow cytometry. In parallel, the MPT-induction of IL-1beta and sIL-1Ra production in human monocytes and the effect of HDL were assessed in cell cultures. The results show that MPT, but not MP generated by activated endothelial cells, bond monocytes to trigger cytokine production. MPT did not bind T cells. The inhibition of IL-1beta production by HDL correlated with the inhibition of MPT binding to monocytes. HDL interacted with MPT rather than with monocytes suggesting that they bound the activating factor(s) of T cell surface. Furthermore, prototypical pro-inflammatory cytokines and chemokines such as TNF, IL-6, IL-8, CCL3 and CCL4 displayed a pattern of production induced by MPT and inhibition by HDL similar to IL-1beta, whereas the production of CCL2, like that of sIL-1Ra, was not inhibited by HDL. HDL inhibit both MPT binding to monocytes and the MPT-induced production of some but not all cytokines, shedding new light on the mechanism by which HDL display their anti-inflammatory functions.


Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1.
Metabolic factors have been associated with liver damage in patients with genotype 1 chronic hepatitis C (G1 CHC). We tested visceral adiposity index (VAI), a new marker of adipose dysfunction in G1 CHC, patients to assess its association with host and viral factors and its link to both histological findings and sustained virological response (SVR). Two hundred thirty-six consecutive G1 CHC patients were evaluated by way of liver biopsy and anthropometric and metabolic measurements, including insulin resistance (IR), homeostasis model assessment (HOMA), and VAI using waist circumference, body mass index, triglycerides, and high-density lipoprotein cholesterol. All biopsies were scored by one pathologist for staging and grading and graded for steatosis, which was considered moderate to severe if ≥ 30%. Multiple linear regression analysis revealed that VAI score was independently associated with higher HOMA score (P = 0.009), log10 hepatitis C virus RNA levels (P = 0.01), necroinflammatory activity (P = 0.04), and steatosis (P = 0.04). Multiple logistic regression analysis revealed that IR (OR 3.879, 95% CI 1.727-8.713, P = 0.001), higher VAI score (OR 1.472, 95% CI 1.051-2.062, P = 0.02), and fibrosis (OR 2.255, 95% CI 1.349-3.768, P = 0.002) were linked to steatosis ≥ 30%. Logistic regression analysis revealed that older age (OR 1.030, 95% CI 1.002-1.059, P = 0.03), higher VAI score (OR 1.618, 95% CI 1.001-2.617, P = 0.04), and fibrosis (OR 2.608, 95% CI 1.565-4.345, P < 0.001) were independently associated with moderate to severe necroinflammatory activity. No independent associations were found between VAI score and both fibrosis and SVR. In G1 CHC patients, higher VAI score is independently associated with both steatosis and necroinflammatory activity and has a direct correlation with viral load.


Localization and dynamics of amylose-lipophilic molecules inclusion complex formation in starch granules.
Inclusion complex formation between lipophilic dye molecules and amylose polymers in starch granules is investigated using laser spectroscopy and microscopy. By combining confocal laser scanning microscopy (CLSM) with spatial resolved photoluminescence (PL) spectroscopy, we are able to discriminate the presence of amylose in the peripheral region of regular and waxy granules from potato and corn starch, associating a clear optical fingerprint with the interaction between starch granules and lipophilic dye molecules. We show in particular that in the case of regular starch the polar head of the lipophilic dye molecules remains outside the amylose helix experiencing a water-based environment. The measurements performed on samples that have been extensively washed provide a strong proof of the specific interaction between lipid dye molecules and amylose chains in regular starch. These measurements also confirm the tendency of longer amylopectin chains, located in the hilum of waxy starch granules, to form inclusion complexes with ligands. Through real-time recording of CLSM micrographs, within a time frame of tens of seconds, we measured the dynamics of occurrence of the inclusion process between lipids and amylose located at the periphery of starch granules.


Indoor residual spraying for preventing malaria.
Primary malaria prevention on a large scale depends on two vector control interventions: indoor residual spraying (IRS) and insecticide-treated mosquito nets (ITNs). Historically, IRS has reduced malaria transmission in many settings in the world, but the health effects of IRS have never been properly quantified. This is important, and will help compare IRS with other vector control interventions. To quantify the impact of IRS alone, and to compare the relative impacts of IRS and ITNs, on key malariological parameters. We searched the Cochrane Infectious Diseases Group Specialized Register (September 2009), CENTRAL (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to September 2009), EMBASE (1974 to September 2009), LILACS (1982 to September 2009), mRCT (September 2009), reference lists, and conference abstracts. We also contacted researchers in the field, organizations, and manufacturers of insecticides (June 2007). Cluster randomized controlled trials (RCTs), controlled before-and-after studies (CBA) and interrupted time series (ITS) of IRS compared to no IRS or ITNs. Studies examining the impact of IRS on special groups not representative of the general population, or using insecticides and dosages not recommended by the World Health Organization (WHO) were excluded. Two authors independently reviewed trials for inclusion. Two authors extracted data, assessed risk of bias and analysed the data. Where possible, we adjusted confidence intervals (CIs) for clustering. Studies were grouped into those comparing IRS with no IRS, and IRS compared with ITNs, and then stratified by malaria endemicity. IRS versus no IRSStable malaria (entomological inoculation rate (EIR) > 1): In one RCT in Tanzania IRS reduced re-infection with malaria parasites detected by active surveillance in children following treatment; protective efficacy (PE) 54%. In the same setting, malaria case incidence assessed by passive surveillance was marginally reduced in children aged one to five years; PE 14%, but not in children older than five years (PE -2%). In the IRS group, malaria prevalence was slightly lower but this was not significant (PE 6%), but mean haemoglobin was higher (mean difference 0.85 g/dL).In one CBA trial in Nigeria, IRS showed protection against malaria prevalence during the wet season (PE 26%; 95% CI 20 to 32%) but not in the dry season (PE 6%; 95% CI -4 to 15%). In one ITS in Mozambique, the prevalence was reduced substantially over a period of 7 years (from 60 to 65% prevalence to 4 to 8% prevalence; the weighted PE before-after was 74% (95% CI 72 to 76%).Unstable malaria (EIR < 1): In two RCTs, IRS reduced the incidence rate of all malaria infections;PE 31% in India, and 88% (95% CI 69 to 96%) in Pakistan. By malaria species, IRS also reduced the incidence of P. falciparum (PE 93%, 95% CI 61 to 98% in Pakistan) and P. vivax (PE 79%, 95% CI 45 to 90% in Pakistan); There were similar impacts on malaria prevalence for any infection: PE 76% in Pakistan; PE 28% in India. When looking separately by parasite species, for P. falciparum there was a PE of 92% in Pakistan and 34% in India; for P. vivax there was a PE of 68% in Pakistan and no impact demonstrated in India (PE of -2%).IRS versus Insecticide Treated Nets (ITNs)Stable malaria (EIR > 1): Only one RCT was done in an area of stable transmission (in Tanzania). When comparing parasitological re-infection by active surveillance after treatment in short-term cohorts, ITNs appeared better, but it was likely not to be significant as the unadjusted CIs approached 1 (risk ratio IRS:ITN = 1.22). When the incidence of malaria episodes was measured by passive case detection, no difference was found in children aged one to five years (risk ratio = 0.88, direction in favour of IRS). No difference was found for malaria prevalence or haemoglobin.Unstable malaria (EIR < 1): Two studies; for incidence and prevalence, the malaria rates were higher in the IRS group compared to the ITN group in one study. Malaria incidence was higher in the IRS arm in India (risk ratio IRS:ITN = 1.48) and in South Africa (risk ratio 1.34 but the cluster unadjusted CIs included 1). For malaria prevalence, ITNs appeared to give better protection against any infection compared to IRS in India (risk ratio IRS:ITN = 1.70) and also for both P. falciparum (risk ratio IRS:ITN = 1.78) and P. vivax (risk ratio IRS:ITN = 1.37). Historical and programme documentation has clearly established the impact of IRS. However, the number of high-quality trials are too few to quantify the size of effect in different transmission settings. The evidence from randomized comparisons of IRS versus no IRS confirms that IRS reduces malaria incidence in unstable malaria settings, but randomized trial data from stable malaria settings is very limited. Some limited data suggest that ITN give better protection than IRS in unstable areas, but more trials are needed to compare the effects of ITNs with IRS, as well as to quantify their combined effects.


A detailed analysis of rats' spatial memory in a probe trial of a Morris task.
In the present study, we evaluated the search behavior of rats during a probe trial of a Morris water escape task. More specifically, the spatial memory during different stages of a 2 min probe trial in different zones was examined. After rats were trained for 4 days with four trials per day, their spatial memory was tested in a first probe trial. The rats showed a preference for the target quadrant during each of four 30-s intervals. The time in the annulus decreased across the four 30-s intervals. The preference for the previous target quadrant was also observed in a second probe trial, when the rats had received additional training for 4 days with four trials per day. However, the time spent in the annulus was highest during the first 30-s of the probe trial, and was lower and similar during the next three 30-s intervals. Therefore, probe trials of 60s seem to underestimate the spatial ability of rats. It appears that using a quadrant for assessing the performance may overestimate the spatial ability of a rat. Our findings suggest that the evaluation of the spatial memory of rats in a probe trial in the Morris water escape task requires a more detailed analysis.


Efficacy and safety of secukinumab treatment in adults with extensive alopecia areata.
Alopecia areata (AA) is a common form of non-scarring hair loss. The pathogenesis of AA is believed to involve multiple inflammatory cytokines, including possibly IL-17A. To assess the efficacy and safety of the IL-17A antagonist secukinumab in AA, we conducted a double-blinded, randomized prospective pilot study in which 11 subjects were treated with either secukinumab (n = 7) or placebo (n = 4) subcutaneously at weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter until (inclusive of) week 20. The primary endpoint for the study was the percentage of patients achieving SALT50 at 24 weeks. A total of three subjects out of 11 completed the study through the primary endpoint, and therefore, we used the last observation carried forward method to analyze the missing data. At the primary endpoint or last completed observation, 0% (0/7) of the secukinumab-treated subjects achieved a 50% reduction in SALT score (SALT50), and likewise, 0% (0/4) of the placebo-treated subjects achieved SALT50. In the secukinumab group, one (14.3%) subject had some hair regrowth, one (14.3%) subject had worsening hair loss, and five (71.4%) subjects had no change in response to treatment. No adverse events attributable to the study drug were observed. The lack of a treatment response to most of our treated patients suggests that the TH17/IL-17 axis likely has no pathogenic role in AA and an alternative therapeutic approach should be considered for this disease. However, due to the low statistical power of this study, future studies may be required to corroborate these findings.


A communication and information strategy in health and preparation for childbirth: a randomized cluster trial (PRENACEL).
PRENACEL is a study that incorporates two innovative approaches to maternal and perinatal health: the need to improve women's level of satisfaction with the birthing experience and an assessment of the impacts of information and communication technologies in health. The approaches involve a communication program via short cellphone text messages, developed for Brazilian pregnant women in prenatal care in the Brazilian Unified National Health System. The analysis aims to determine whether the program contributes positively to women's perceived preparedness for childbirth. A randomized cluster trial was performed in 20 primary care units in Ribeirão Preto, São Paulo State, in 2015 and 2016. Data were collected for 1,210 women from interviews and patient charts. The data were submitted to two analytical models, per protocol and intention-to-treat. Women that had received information from the PRENACEL program during pregnancy were more likely to feel prepared for labor and delivery and to feel that prenatal care had helped them feel more prepared. There were also positive impacts on bonding with the newborn and breastfeeding in the delivery room and on knowledge of obstetric interventions. No differences were seen in the other maternal and perinatal outcomes, including women's satisfaction with the birthing care. PRENACEL can help expand women's access to strategic information for them to feel better prepared for the birthing experience.


Craniofacial growth in growth hormone-deficient rats after growth hormone supplementation.
Growth hormone (GH) supplementation is an established therapy to increase stature in GH-deficient or short-for-age children, but comparatively little is known of its effects on the craniofacial skeleton. Using a mutant strain of Lewis rats (dw/dw) in which GH levels were 6% to 10% of normal, but other trophic hormones were unaffected, we investigated the differential susceptibility of craniofacial measures to GH supplementation, characterized their potential for partial or complete catch-up growth, and compared their growth changes with those in long bones. At 24 days of age and for 3 subsequent weeks, radiographs of the lateral head, upper limb, and lower limb were obtained from 3 groups of growing rats (n = 8-9 in each group): dwarf (experimental) with GH injection, dwarf (sham) with vehicle injection, and wild type (control) with vehicle injection. The x-ray images were scanned, standardized points digitized, and linear distances measured. Absolute growth curves were generated for each group by using multilevel modeling procedures and iterative generalized least-squares curve fitting. For every measure, growth differences were evident between the experimental and the sham groups, but the treatment effect varied inversely with relative maturity of the measure. Although all craniofacial measures showed some catch-up growth, only 31% of craniofacial measures had complete catch-up compared with all limb measures. The percentage of catch-up varied inversely with relative maturity of the measure. Our results suggest that the effects of GH supplementation vary considerably, so that measures with the lowest relative maturity (greatest baseline potential) show the greatest treatment effect and catch-up, whereas more mature measures show less growth response to GH replacement. These results suggest that, depending on the timing of GH supplementation, there is potential for change in proportions or shape of the craniofacial complex.


Prognostic importance of advanced age in aggressive non-Hodgkin's malignant lymphoma.
The importance of age as a prognostic factor in aggressive non-Hodgkin's malignant lymphoma (NHL) remains controversial. It is not clear whether age is an independent factor, reflecting the limited physiologic reserves of the patient, and leading in any treatment conditions to the poorer treatment outcome. This study was aimed at assessing the influence of age on treatment results in NHL patients. Therefore, the records of 40 patients with histologically confirmed NHL of intermediate and high-grade malignancy, according to the Working Formulation, who were treated by Adriamycin-containing chemotherapy, were retrospectively reviewed. There were 25 patients above 60 years of age and 15 patients below this age. Myelotoxicity was observed in 60% of the patients in the younger and in 48% patients in the older age group. The median time to dose-limiting toxicity, average percentage of projected dose intensity for all drugs, and percentage of projected dose intensity did not differ significantly in the two groups. Complete remissions (CR) were obtained in 67 and 64% of the younger and older groups, respectively. Progressive disease was observed during the treatment in 20% of the patients in each age group. Median survival was 36.5 and 32 months in the younger and older group, respectively. In conclusion, age alone is not an absolute predictor of survival of treated elderly patients with aggressive NHL. Dose rate, tolerance of treatment and achievement of CR are additional important prognostic factors. Dose intensity should not be automatically reduced at the beginning of the treatment, especially now that growth factors are available.


Update on Targets of Biologic Therapies for Rheumatoid Arthritis.
With the advent of biological therapies, considerable progress has been made in the treatment of rheumatoid arthritis (RA). These revolutionary therapies owe their origin to the role that cytokines play in the pathophysiology of the disease and are best exemplified by the wide use of tumor necrosis factor (TNF) blockade. The identification of additional pro-inflammatory factors and an understanding of their effector function now offer major possibilities for the generation of additional novel biological therapeutics to address unmet clinical needs. Such interventions will ideally fulfill several of the following criteria: control of inflammation, modulation of underlying immune dysfunction by promoting the reestablishment of immune tolerance, protection of targeted tissues such as bone and cartilage, and preservation of host immune capability to avoid profound immune suppression and amelioration of co-morbidity associated with underlying RA. The identification and characterization of the intracellular signaling pathways, in particular, the mitogen-activated protein kinase pathway, the nuclear factor-κB pathway and the cross-talk between these pathways offer several potential therapeutic opportunities. This review will provide an update on cytokine activities and signal transduction pathways that represent, in our opinion, optimal utility as future therapeutic targets.


Unsalaried health workers in Sierra Leone: a scoping review of the literature to establish their impact on healthcare delivery.
The World Health Organisation (WHO) estimates a 10 million health worker shortage by 2030. Despite this shortage, some low-income African countries paradoxically struggle with health worker surpluses. Technically, these health workers are needed to meet the minimum health worker-population ratio, but insufficient job opportunities in the public and private sector leaves available health workers unemployed. This results in emigration and un- or underemployment, as few countries have policies or plans in place to absorb this excess capacity. Sierra Leone, Liberia and Guinea have taken a different approach; health authorities and/or public hospitals 'recruit' medical and nursing graduates on an unsalaried basis, promising eventual paid public employment. 50% Sierra Leone's health workforce is currently unsalaried. This scoping review examines the existing evidence on Sierra Leone's unsalaried health workers (UHWs) to establish what impact they have on the equitable delivery of care. A scoping review was conducted using Joanna Briggs Institute guidance. Medline, PubMed, Scopus, Web of Science were searched to identify relevant literature. Grey literature (reports) and Ministry of Health and Sanitation policy documents were also included. 36 texts, containing UHW related data, met the inclusion criteria. The findings divide into two categories and nine sub-categories: Charging for care and medicines that should be free; Trust and mistrust; Accountability; Informal provision of care, Private practice and lack of regulation. Over-production of health workers; UHW issues within policy and strategy; Lack of personnel data undermines MoHS planning; Health sector finance. Sierra Leone's example demonstrates that UHWs undermine equitable access to healthcare, if they resort to employing a range of coping strategies to survive financially, which some do. Their impact is wide ranging and will undermine Sierra Leone's efforts to achieve Universal Health Coverage if unaddressed. These findings are relevant to other LICs with similar health worker surpluses.


Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.
Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture.


Quantitatively evaluating the effect of social barriers: a case-control study of family members' opposition and women's intention to use contraception in Pakistan.
Uptake of family planning services in Pakistan has remained slow over the past decade despite a rapid increase in availability and awareness, indicating that social barriers may be preventing uptake. Social barriers such as opposition by family members have largely been studied qualitatively; there is a lack of quantitative evidence about the effect of different family members' opposition on women's intention to use contraceptives. The objective of this study was to quantitatively evaluate the effect of family members' opposition to family planning on intention to use contraception amongst poor women in Pakistan who have physical access to family planning services. An unmatched case control study (nested within a larger cohort study) was conducted in two public hospitals in Karachi, Pakistan. Univariable and multivariable logistic regression analyses were conducted to compare risk factors between women that were not intending to use any contraceptive methods in the future (cases) and women that were planning to use contraceptive methods (controls). 248 cases and 496 controls were included in the study. Negative contraceptive intent was associated with no knowledge of contraception (AOR = 3.79 [2.43-5.90]; p < 0.001), husband's opposition (AOR = 21.87 [13.21-36.21]; p < 0.001) and mother-in-law's opposition (AOR = 4.06 [1.77-9.30]; p < 0.001). This study is the first to quantitatively assess the effect of opposition by different family members on women's contraceptive intent in Pakistan. Our results indicate that of all family members, husband's opposition has the strongest effect on women's intention to use contraception, even when the women have knowledge of and physical access to family planning services.


Fiber type traps: revisiting common misconceptions about skeletal muscle fiber types with application to motor control, biomechanics, physiology, and biology.
Skeletal muscle is a highly complex tissue that is studied by scientists from a wide spectrum of disciplines, including motor control, biomechanics, exercise science, physiology, cell biology, genetics, regenerative medicine, orthopedics, and engineering. While this diversity in perspectives has led to many important discoveries, historically there has been limited overlap in discussions across fields. This has led to misconceptions and oversimplifications about muscle biology which can create confusion and potentially slow scientific progress across fields. The purpose of this synthesis paper is to bring together research perspectives across multiple muscle fields to identify common assumptions related to muscle fiber type that are points of concern to clarify. These assumptions include: 1) classification by myosin isoform and fiber oxidative capacity is equivalent, 2) fiber cross-sectional area is a surrogate marker for myosin isoform or oxidative capacity, and 3) muscle force-generating capacity can be inferred from myosin isoform. We address these 3 fiber type traps and provide some context for how these misunderstandings can and do impact experimental design, computational modeling, and interpretations of findings, from the perspective of a range of fields. We stress the dangers of generalizing findings about "muscle fiber types" among muscles or across species or sex, and we note the importance for precise use of common terminology across the muscle fields.