Chronic hypercapnia alters lung matrix composition in mouse pups.
permissive hypercapnia, a stretch-limiting ventilation strategy, often results in high Pa(CO(2)). This strategy is associated with reduced morbidity and mortality in premature infants and its benefits have been attributed to diminished barotrauma. However, little is known about the independent effect of high CO(2) levels during the lung development. mice were exposed to 8% CO(2) or room air for 2 wk either from postnatal day 2 through 17 or as adults (approximately 2 mo of age). Lungs were excised and processed for protein, RNA, histology, and total lung volumes. histologic analysis demonstrated that alveolar walls of CO(2)-exposed mouse pups were thinner than those of controls and had twice the total lung volume. Molecular analysis revealed that several matrix proteins in the lung were downregulated in mouse pups exposed to hypercapnia. Interstitial collagen type I alpha1, type III alpha1, elastin and fibronectin protein, and mRNA levels were less than half of controls while collagen IV alpha 5 was unaffected. This decrease in interstitial collagen could thus account for the thinning of the interstitial matrix and the altered lung biomechanics. Matrix metalloproteinase (MMP)-8, a collagenase that has specificity for collagen types I and III, increased in hypercapnic mouse pups, suggesting increased collagen degradation. Moreover, tissue inhibitor of MMP (TIMP)-1, a potent inhibitor of MMP-8, was significantly decreased. However, unlike pups, adult mice exposed to hypercapnia demonstrated only a mild increase in total lung volumes and did not exhibit similar molecular or histologic changes. although permissive hypercapnia may prevent lung injury from barotrauma, our study revealed that exposure to hypercapnia may be an important factor in lung remodeling and function, especially in early life.


The antifungal peptide CGA-N12 inhibits cell wall synthesis of Candida tropicalis by interacting with KRE9.
CGA-N12, an antifungal peptide derived from chromogranin A, has specific antagonistic activity against Candida spp., especially against Candida tropicalis, by inducing cell apoptosis. However, the effect of CGA-N12 on the Candida cell wall is unknown. The Candida protein KRE9, which possesses β-1,6-glucanase activity, was screened by affinity chromatography after binding to CGA-N12. In this study, the effect of CGA-N12 on KRE9 and the interaction between CGA-N12 and KRE9 was studied to clarify the effect of CGA-N12 on C. tropicalis cell wall synthesis. The effect of CGA-N12 on recombinant KRE9 β-1,6-glucanase activity was investigated by analyzing the consumption of glucose. The results showed that CGA-N12 inhibited the activity of KRE9. After C. tropicalis was treated with CGA-N12, the structure of the C. tropicalis cell wall was damaged. The interaction between CGA-N12 and KRE9 was analyzed by isothermal titration calorimetry (ITC). The results showed that their interaction process was involved an endothermic reaction, and the interaction force was mainly hydrophobic with a few electrostatic forces. The results of the fluorescence resonance energy transfer (FRET) assay showed that the distance between CGA-N12 and KRE9 was 7 ∼ 10 nm during their interaction. Therefore, we concluded that the target of CGA-N12 in the C. tropicalis cell membrane is KRE9, and that CGA-N12 weakly binds to KRE9 within a 7 ∼ 10 nm distance and inhibits KRE9 activity.


A possible role for PAF in allergen-induced late responses: modification by a selective antagonist.
We determined whether platelet-activating factor (PAF) plays a role in allergen-induced airway responses by studying the effects of a selective PAF antagonist WEB-2086 on antigen-induced early and late airway responses in allergic sheep. In seven sheep, inhaled Ascaris suum produced significant early (282%) and late (176%) increases in specific lung resistance (sRL). WEB-2086 (1 mg/kg iv) given 20 min before antigen challenge did not affect the early response, but the peak late increase in sRL was only 37% over base line (P less than 0.05 vs. control). To study the mechanism by which PAF contributes to antigen-induced responses, we evaluated the effects of pharmacological probes on PAF-induced bronchoconstriction. Inhaled PAF (dose range 75-700 micrograms) caused reproducible (r = 0.781, P less than 0.05) increases in sRL in eight sheep. The PAF-induced bronchoconstriction was blocked by WEB-2086 (1 mg/kg iv) and by the leukotriene antagonist FPL-55712 (30 mg by aerosol); however, neither the cyclooxygenase blocker indomethacin (2 mg/kg iv) nor the histamine H1-antagonist chlorpheniramine (2 mg/kg iv) blocked the PAF response. WEB-2086, however, did not block bronchoconstriction induced by aerosol leukotriene D4, indicating that PAF acts indirectly through leukotrienes. Finally, we determined whether PAF could induce late airway responses. Inhaled PAF produced an immediate increase in sRL in all seven sheep tested, but late airway responses were observed in only three of the seven sheep.(ABSTRACT TRUNCATED AT 250 WORDS)


Slant from texture and disparity cues: optimal cue combination.
How does the visual system combine information from different depth cues to estimate three-dimensional scene parameters? We tested a maximum-likelihood estimation (MLE) model of cue combination for perspective (texture) and binocular disparity cues to surface slant. By factoring the reliability of each cue into the combination process, MLE provides more reliable estimates of slant than would be available from either cue alone. We measured the reliability of each cue in isolation across a range of slants and distances using a slant-discrimination task. The reliability of the texture cue increases as |slant| increases and does not change with distance. The reliability of the disparity cue decreases as distance increases and varies with slant in a way that also depends on viewing distance. The trends in the single-cue data can be understood in terms of the information available in the retinal images and issues related to solving the binocular correspondence problem. To test the MLE model, we measured perceived slant of two-cue stimuli when disparity and texture were in conflict and the reliability of slant estimation when both cues were available. Results from the two-cue study indicate, consistent with the MLE model, that observers weight each cue according to its relative reliability: Disparity weight decreased as distance and |slant| increased. We also observed the expected improvement in slant estimation when both cues were available. With few discrepancies, our data indicate that observers combine cues in a statistically optimal fashion and thereby reduce the variance of slant estimates below that which could be achieved from either cue alone. These results are consistent with other studies that quantitatively examined the MLE model of cue combination. Thus, there is a growing empirical consensus that MLE provides a good quantitative account of cue combination and that sensory information is used in a manner that maximizes the precision of perceptual estimates.


Efficacy of multiple intraarterial papaverine infusions for improvement in cerebral circulation time in patients with recurrent cerebral vasospasm.
Cerebral vasospasm that is caused by aneurysmal subarachnoid hemorrhage and that is refractory to maximal medical management can be treated with selective intraarterial papaverine infusions. The effects of single papaverine treatments on cerebral circulation time are well known. The purpose of this study was to assess the efficacy of multiple, repeated papaverine infusions on the cerebral circulation time in patients with recurrent vasospasm. A retrospective study was conducted in 17 patients who received multiple intraarterial papaverine infusions in 91 carotid artery (CA) territories for the treatment of cerebral vasospasm. Cerebral circulation times were measured from the first angiographic image, in which peak contrast was seen above the supraclinoid internal CA, to the peak filling of cortical veins. Glasgow Outcome Scale (GOS) scores assessed 12 months after discharge were reviewed. Cerebral circulation times in 16 CA territories were measured in a control group of 11 patients. Seventeen patients received a total of 91 papaverine treatments. Prolonged cerebral circulation times improved after 90 (99%) of 91 papaverine treatments. The prepapaverine mean cerebral circulation time was 6.54 seconds (range 3.35-27 seconds) and the immediate postpapaverine mean cerebral circulation time was 4.19 seconds (range 2.1-12.6 seconds), an overall mean decrease of 2.35 seconds (36%, p < 0.001). Recurrent vasospasm reflected by prolonged cerebral circulation times continued to improve with subsequent papaverine infusions. Repeated infusions were just as successful quantitatively as the primary treatment (mean change 2.06 seconds). The mean cerebral circulation time in the control group was 5.21 seconds (range 4-6.8 seconds). In five patients a dramatic reversal of low-attenuation changes was detected on computerized tomography scans. The mean GOS score at 12 months after discharge was 3.4. The preliminary results indicate that multiple intraarterial papaverine treatments consistently improve cerebral circulation times, even with repeated infusions in cases of recurrent vasospasm.


Basic research in kidney cancer.
Advances in basic research will enhance prognosis, diagnosis, and treatment of renal cancer patients. To discuss advances in our understanding of the molecular basis of renal cancer, targeted therapies, renal cancer and immunity, and genetic factors and renal cell carcinoma (RCC). Data on recently published (2005-2011) basic science papers were reviewed. Advances in basic research have shown that renal cancers can be subdivided based on specific genetic profiles. Now that this molecular basis has been established, it is becoming clear that additional events play a major role in the development of renal cancer. For example, aberrant chromatin remodelling appears to be a main driving force behind tumour progression in clear cell RCC. A large number of potential biomarkers have emerged using various high-throughput platforms, but adequate biomarkers for RCC are still lacking. To bring the potential biomarkers and biomarker profiles to the clinical arena is a major challenge for the field. The introduction of tyrosine kinase inhibitors (TKIs) for therapy has shifted the interest away from immunologic approaches. Nevertheless, a wealth of evidence supports immunotherapy for RCC. Interestingly, studies are now appearing that suggest a combination of TKI and immunotherapy may be beneficial. Thus far, little attention has been paid to patient-specific differences. With high-throughput methods becoming cheaper and with the advances in sequencing possibilities, this situation is expected to change rapidly. Great strides have been made in the understanding of molecular mechanisms of RCC. This has led this field to the enviable position of having a range of molecularly targeted therapies. Large sequencing efforts are now revealing more and more genes responsible for tumour development and progression, offering new targets for therapy. It is foreseen that through integration of high-throughput platforms, personalised cancer treatment for RCC patients will become possible.


A critical site in the core of the CCR5 chemokine receptor required for binding and infectivity of human immunodeficiency virus type 1.
Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (approximately 98-99% identical) CCR5 of African green monkeys (AGMs) avidly binds beta-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely source of the weak R5 gp120 binding and HIV-1 coreceptor properties of AGM CCR5. Accordingly, a G163R mutant of human CCR5 was severely attenuated in its ability to bind R5 gp120s and to mediate infection by R5 HIV-1 isolates. Conversely, the R163G mutant of AGM CCR5 was substantially strengthened as a coreceptor for HIV-1 and had improved R5 gp120 binding affinity relative to the wild-type AGM CCR5. These substitutions at amino acid position 163 had no effect on chemokine binding or signal transduction, suggesting the absence of structural alterations. The 2D7 monoclonal antibody has been reported to bind to ECL2 and to block HIV-1 binding and infection. Whereas 2D7 antibody binding to CCR5 was unaffected by the G163R mutation, it was prevented by a conservative ECL2 substitution (K171R), shared between rhesus and AGM CCR5s. Thus, it appears that the 2D7 antibody binds to an epitope that includes Lys-171 and may block HIV-1 infection mediated by CCR5 by occluding an HIV-1-binding site in the vicinity of Gly-163. In summary, our results identify a site for gp120 interaction that is critical for R5 isolates of HIV-1 in the central core of human CCR5, and we propose that this site collaborates with a previously identified region in the CCR5 amino terminus to enable gp120 binding and HIV-1 infections.


Recovery of horses from general anesthesia after induction with propofol and ketamine versus midazolam and ketamine.
OBJECTIVE To evaluate quality of recovery from general anesthesia in horses after induction with propofol and ketamine versus midazolam and ketamine. DESIGN Prospective randomized crossover study. ANIMALS 6 healthy adult horses. PROCEDURES Horses were premedicated with xylazine (1.0 mg/kg [0.45 mg/lb], IV), and general anesthesia was induced with midazolam (0.1 mg/kg [0.045 mg/lb], IV) or propofol (0.5 mg/kg [0.23 mg/lb], IV), followed by ketamine (3.0 mg/kg [1.36 mg/lb], IV). Horses were endotracheally intubated, and anesthesia was maintained with isoflurane. After 60 minutes, horses were given romifidine (0.02 mg/kg [0.009 mg/lb], IV) and allowed to recover unassisted. Times to first movement, sternal recumbency, and standing and the number of attempts to stand were recorded. Plasma concentrations of propofol or midazolam were measured following induction and immediately before recovery. Recovery quality was scored by 3 graders with a recovery rubric and a visual analog scale. RESULTS Number of attempts to stand was significantly lower when horses received propofol (median, 2; range, 1 to 3) than when they received midazolam (median, 7.5; range, 3 to 16). For both the recovery rubric and visual analog scale, recovery quality was significantly better when horses received propofol than when they received midazolam. Plasma drug concentration at recovery, as a percentage of the concentration at induction, was significantly lower when horses received propofol than when they received midazolam. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that for horses undergoing short (ie, 60 minutes) periods of general anesthesia, recovery quality may be better following induction with propofol and ketamine, compared with midazolam and ketamine.


Sexual dimorphisms in the effect of low-level p25 expression on synaptic plasticity and memory.
p25, a degradation product of p35, has been reported to accumulate in the forebrain of patients with Alzheimer's disease. p25 as well as p35 are activators of cyclin-dependent kinase 5 (Cdk5) although p25/Cdk5 and p35/Cdk5 complexes have distinct properties. Several mouse models with high levels of p25 expression exhibit signs of neurodegeneration. On the contrary, we have shown that low levels of p25 expression do not cause neurodegeneration and are even beneficial for particular types of learning and memory [Angelo et al., (2003) Eur J. Neurosci., 18, 423-431]. Here, we have studied the influence of low-level p25 expression in hippocampal synaptic plasticity and in learning and memory for each sex separately in two different genetic backgrounds (129B6F1 and C57BL/6). Surprisingly, we found that low-level p25 expression had different consequences in male and female mutants. In the two genetic backgrounds LTP induced by a strong stimulation of the Schaffer's collaterals (four trains, 1-s duration, 5-min interval) was severely impaired in male, but not in female, p25 mutants. Furthermore, in the two genetic backgrounds spatial learning in the Morris water maze was faster in female p25 mutants than in male transgenic mice. These results suggest that, in women, the production of p25 in Alzheimer's disease could be a compensation for some early learning and memory deficits.


High-Flow Nasal Cannula Oxygen in Patients with Acute Respiratory Failure and Do-Not-Intubate or Do-Not-Resuscitate Orders: A Systematic Review.
High-flow nasal cannula (HFNC) oxygen may provide tailored benefits in patients with preset treatment limitations. The objective of this study was to assess the effectiveness of HFNC oxygen in patients with do-not-intubate (DNI) and/or do-not-resuscitate (DNR) orders. We conducted a systematic review of interventional and observational studies. A search was performed using MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science, from inception to October 15, 2018. We included six studies evaluating 293 patients. All studies had a high risk of bias. The hospital mortality rates of patients with DNI and/or DNR orders receiving HFNC oxygen were variable and ranged from 40% to 87%. In two before and after studies, the initiation of HFNC oxygen was associated with improved oxygenation and reduced respiratory rates. One comparative study found no difference in dyspnea reduction or morphine doses between patients using HFNC oxygen versus conventional oxygen. No studies evaluated quality of life in survivors or quality of death in nonsurvivors. HFNC was generally well tolerated with few adverse events identified. While HFNC oxygen remains a viable treatment option for hospitalized patients who have acute respiratory failure and a DNI and/or DNR order, there is a paucity of high-quality, comparative, effectiveness data to guide the usage of HFNC oxygen compared with other treatments, such as noninvasive ventilation, conventional oxygen, and palliative opioids.


N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.
N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.


Telomerase in yeast.
The ribonucleoprotein enzyme telomerase synthesizes telomeric DNA by copying an internal RNA template sequence. The telomerase activities of the yeasts Saccharomyces castellii and Saccharomyces cerevisiae--with regular and irregular telomeric sequences, respectively--have now been identified and characterized. The S. cerevisiae activity required the telomerase RNA gene TLC1 but not the EST1 gene, both of which are required for normal telomere maintenance in vivo. This activity exhibited low processivity and produced no regularly repeated products. An inherently high stalling frequency of the S. cerevisiae telomerase may account for its in vitro properties and for the irregular telomeric sequences of this yeast.


Geographical variations in the supply of domiciliary oxygen.
The amounts of oxygen prescribed by general practitioners in each of 90 family practitioner committee areas of England in 1977-9 were compared using data supplied by the Prescription Pricing Authority and were matched with published mortality statistics for these areas. The annual number of 1360-litre cylinders supplied per thousand population ranged among family practitioner committees from 3.3 to 32.5, with a mean for all family practitioner committees of 10.6. Levels of supply were not associated with the degree of urbanisation of the areas and did not correlate with standardised mortality ratios for respiratory diseases. Levels were significantly greater in teaching areas than in non-teaching areas. The rationale for prescribing domiciliary oxygen is ill defined.


Inchworm bipedal nanowalker.
Nanowalkers take either inchworm (IW) or hand-over-hand (HOH) gait. The IW nanowalkers are advantageous over HOH ones in force generation, processivity and high-density integration, though both gaits occur in intracellular nanowalkers from biology. Artificial IW nanowalkers have been realized or proposed, but all rely on different 'head' and 'tail' to gain an adventitious direction. Here we report an inherently unidirectional IW nanowalker that is a biped with two identical legs (i.e., indistinguishable 'head' and 'tail'). This walker is made of DNA, and driven by a light-powered G-quadruplex engine. The directional inchworm motion is confirmed by operating the walker on a DNA duplex track that is designed to show a distinctive fluorescence pattern for IW walkers as compared to HOH ones. Interestingly, this walker exhibits stride-controlled IW-to-HOH gait switch and direction reversal when the track's periodic binding sites have wider and wider separation. The results altogether present an integrated mechanism for implementing nanowalkers of different gaits and directions on molecular tracks, optical potentials or even solid-state surfaces.


Engineering Cu surfaces for the electrocatalytic conversion of CO2: Controlling selectivity toward oxygenates and hydrocarbons.
In this study we control the surface structure of Cu thin-film catalysts to probe the relationship between active sites and catalytic activity for the electroreduction of CO2 to fuels and chemicals. Here, we report physical vapor deposition of Cu thin films on large-format (∼6 cm2) single-crystal substrates, and confirm epitaxial growth in the <100>, <111>, and <751> orientations using X-ray pole figures. To understand the relationship between the bulk and surface structures, in situ electrochemical scanning tunneling microscopy was conducted on Cu(100), (111), and (751) thin films. The studies revealed that Cu(100) and (111) have surface adlattices that are identical to the bulk structure, and that Cu(751) has a heterogeneous kinked surface with (110) terraces that is closely related to the bulk structure. Electrochemical CO2 reduction testing showed that whereas both Cu(100) and (751) thin films are more active and selective for C-C coupling than Cu(111), Cu(751) is the most selective for >2e- oxygenate formation at low overpotentials. Our results demonstrate that epitaxy can be used to grow single-crystal analogous materials as large-format electrodes that provide insights on controlling electrocatalytic activity and selectivity for this reaction.


Species: turning a conundrum into a research program.
The most appropriate ontological basis for understanding the role of species in evolutionary biology is the Evolutionary Species Concept. The ESC is not an operational concept, but one version of the Phylogenetic Species Concept is. Linking the ontology of species with the epistemological basis of actual biological studies requires that we specify both a discovery mode for identifying collections of organisms that we believe are evolutionary species, and a series of evaluation criteria for assessing those entities we have discovered. Simply naming a collection of specimens, no matter how strong one's evolutionary beliefs, is not sufficient for declaring that evolutionary species have been discovered. All operational historical species concepts represent discovery modes with minimal evaluation criteria; all operational non-dimensional species concepts represent evaluation criteria that do not specify discovery modes. Thus, both categories of knowledge are necessary and neither is sufficient for assigning species status. This leads naturally to a hierarchical research program in historical ecology, beginning with phylogenetic analysis of a group of entities postulated to be evolutionary species, which provides a productive arena for our arguments about species concepts.


Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase.
Sulfonamides were amongst the first clinically useful antibacterial agents to be discovered. The identification of sulfanilamide as the active component of the dye Prontosil rubrum led to the synthesis of clinically useful analogues. Today sulfamethoxazole (in combination with trimethoprim), is used to treat urinary tract infections caused by bacteria such as Escherichia coli and is also a first-line treatment for pneumonia caused by the fungus Pneumocystis carinii, a common condition in AIDS patients. The site of action is the de novo folate biosynthesis enzyme dihydropteroate synthase (DHPS) where sulfonamides act as analogues of one of the substrates, para-aminobenzoic acid (pABA). We report here the crystal structure of E.coli DHPS at 2.0 A resolution refined to an R-factor of 0.185. The single domain of 282 residues forms an eight-stranded alpha/beta-barrel. The 7,8-dihydropterin pyrophosphate (DHPPP) substrate binds in a deep cleft in the barrel, whilst sulfanilamide binds closer to the surface. The DHPPP ligand site is highly conserved amongst prokaryotic and eukaryotic DHPSs.


A global survey of arsenic-related genes in soil microbiomes.
Environmental resistomes include transferable microbial genes. One important resistome component is resistance to arsenic, a ubiquitous and toxic metalloid that can have negative and chronic consequences for human and animal health. The distribution of arsenic resistance and metabolism genes in the environment is not well understood. However, microbial communities and their resistomes mediate key transformations of arsenic that are expected to impact both biogeochemistry and local toxicity. We examined the phylogenetic diversity, genomic location (chromosome or plasmid), and biogeography of arsenic resistance and metabolism genes in 922 soil genomes and 38 metagenomes. To do so, we developed a bioinformatic toolkit that includes BLAST databases, hidden Markov models and resources for gene-targeted assembly of nine arsenic resistance and metabolism genes: acr3, aioA, arsB, arsC (grx), arsC (trx), arsD, arsM, arrA, and arxA. Though arsenic-related genes were common, they were not universally detected, contradicting the common conjecture that all organisms have them. From major clades of arsenic-related genes, we inferred their potential for horizontal and vertical transfer. Different types and proportions of genes were detected across soils, suggesting microbial community composition will, in part, determine local arsenic toxicity and biogeochemistry. While arsenic-related genes were globally distributed, particular sequence variants were highly endemic (e.g., acr3), suggesting dispersal limitation. The gene encoding arsenic methylase arsM was unexpectedly abundant in soil metagenomes (median 48%), suggesting that it plays a prominent role in global arsenic biogeochemistry. Our analysis advances understanding of arsenic resistance, metabolism, and biogeochemistry, and our approach provides a roadmap for the ecological investigation of environmental resistomes.


Effects of Peripapillary Scleral Stiffening on the Deformation of the Lamina Cribrosa.
Scleral stiffening has been proposed as a treatment for glaucoma to protect the lamina cribrosa (LC) from excessive intraocular pressure-induced deformation. Here we experimentally evaluated the effects of moderate stiffening of the peripapillary sclera on the deformation of the LC. An annular sponge, saturated with 1.25% glutaraldehyde, was applied to the external surface of the peripapillary sclera for 5 minutes to stiffen the sclera. Tissue deformation was quantified in two groups of porcine eyes, using digital image correlation (DIC) or computed tomography imaging and digital volume correlation (DVC). In group A (n = 14), eyes were subjected to inflation testing before and after scleral stiffening. Digital image correlation was used to measure scleral deformation and quantify the magnitude of scleral stiffening. In group B (n = 5), the optic nerve head region was imaged using synchrotron radiation phase-contrast microcomputed tomography (PC μCT) at an isotropic spatial resolution of 3.2 μm. Digital volume correlation was used to compute the full-field three-dimensional deformation within the LC and evaluate the effects of peripapillary scleral cross-linking on LC biomechanics. On average, scleral treatment with glutaraldehyde caused a 34 ± 14% stiffening of the peripapillary sclera measured at 17 mm Hg and a 47 ± 12% decrease in the maximum tensile strain in the LC measured at 15 mm Hg. The reduction in LC strains was not due to cross-linking of the LC. Peripapillary scleral stiffening is effective at reducing the magnitude of biomechanical strains within the LC. Its potential and future utilization in glaucoma axonal neuroprotection requires further investigation.


Tilt Map: Interactive Transitions Between Choropleth Map, Prism Map and Bar Chart in Immersive Environments.
We introduce Tilt Map, a novel interaction technique for intuitively transitioning between 2D and 3D map visualisations in immersive environments. Our focus is visualising data associated with areal features on maps, for example, population density by state. Tilt Map transitions from 2D choropleth maps to 3D prism maps to 2D bar charts to overcome the limitations of each. Our article includes two user studies. The first study compares subjects' task performance interpreting population density data using 2D choropleth maps and 3D prism maps in virtual reality (VR). We observed greater task accuracy with prism maps, but faster response times with choropleth maps. The complementarity of these views inspired our hybrid Tilt Map design. Our second study compares Tilt Map to: a side-by-side arrangement of the various views; and interactive toggling between views. The results indicate benefits for Tilt Map in user preference; and accuracy (versus side-by-side) and time (versus toggle).


Biodistribution of the multidentate hydroxypyridinonate ligand [(14) C]-3,4,3-LI(1,2-HOPO), a potent actinide decorporation agent.
The pharmacokinetics and biodistribution of the (14) C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of (14) C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [(14) C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.


Monocular occlusions determine the perceived shape and depth of occluding surfaces.
Recent experiments have established that monocular areas arising due to occlusion of one object by another contribute to stereoscopic depth perception. It has been suggested that the primary role of monocular occlusions is to define depth discontinuities and object boundaries in depth. Here we use a carefully designed stimulus to demonstrate empirically that monocular occlusions play an important role in localizing depth edges and defining the shape of the occluding surfaces in depth. We show that the depth perceived via occlusion in our stimuli is not due to the presence of binocular disparity at the boundary and discuss the quantitative nature of depth perception in our stimuli. Our data suggest that the visual system can use monocular information to estimate not only the sign of the depth of the occluding surface but also its magnitude. We also provide preliminary evidence that perceived depth of illusory occluders derived from monocular information can be biased by binocular features.


Mitochondrial Aging and Physical Decline: Insights From Three Generations of Women.
Decline in mitochondrial DNA (mtDNA) copy number, function, and accumulation of mutations and deletions have been proposed to contribute to age-related physical decline, based on cross sectional studies in genetically unrelated individuals. There is wide variability of mtDNA and functional measurements in many population studies and therefore we assessed mitochondrial function and physical function in 18 families of grandmothers, mothers, and daughters who share the same maternally inherited mtDNA sequence. A significant age-related decline in mtDNA copy number, mitochondrial protein expression, citrate synthase activity, cytochrome c oxidase content, and VO2 peak were observed. Also, a lower abundance of SIRT3, accompanied by an increase in acetylated skeletal muscle proteins, was observed in grandmothers. Muscle tissue-based full sequencing of mtDNA showed greater than 5% change in minor allele frequency over a lifetime in two locations, position 189 and 408 in the noncoding D-loop region but no changes were noted in blood cells mtDNA. The decline in oxidative capacity and muscle function with age in three generations of women who share the same mtDNA sequence are associated with a decline in muscle mtDNA copy number and reduced protein deacetylase activity of SIRT3.


Rational engineering of recombinant picornavirus capsids to produce safe, protective vaccine antigen.
Foot-and-mouth disease remains a major plague of livestock and outbreaks are often economically catastrophic. Current inactivated virus vaccines require expensive high containment facilities for their production and maintenance of a cold-chain for their activity. We have addressed both of these major drawbacks. Firstly we have developed methods to efficiently express recombinant empty capsids. Expression constructs aimed at lowering the levels and activity of the viral protease required for the cleavage of the capsid protein precursor were used; this enabled the synthesis of empty A-serotype capsids in eukaryotic cells at levels potentially attractive to industry using both vaccinia virus and baculovirus driven expression. Secondly we have enhanced capsid stability by incorporating a rationally designed mutation, and shown by X-ray crystallography that stabilised and wild-type empty capsids have essentially the same structure as intact virus. Cattle vaccinated with recombinant capsids showed sustained virus neutralisation titres and protection from challenge 34 weeks after immunization. This approach to vaccine antigen production has several potential advantages over current technologies by reducing production costs, eliminating the risk of infectivity and enhancing the temperature stability of the product. Similar strategies that will optimize host cell viability during expression of a foreign toxic gene and/or improve capsid stability could allow the production of safe vaccines for other pathogenic picornaviruses of humans and animals.


Improving tuberculosis care in low income countries - a qualitative study of patients' understanding of "patient support" in Nepal.
In the new Stop TB Strategy for Tuberculosis (TB) Care, direct observation of treatment has been replaced by "supervision and patient support". However, it is still unclear what patient support means and how it is to be best implemented. The objective of this study was to accurately document patients' support needs during TB treatment from their own perspectives, to inform development of appropriate support and supervision strategies that meet patients' needs. In-depth individual interviews and focus group discussions were conducted in three districts in Nepal. Analysis took place concurrently with data collection to allow emerging issues to guide selection of subsequent interviewees. In total 23 patients, 15 male and 8 female, were interviewed and six focus group discussions were held. Issues from these interviews were grouped into emergent themes. Respondents reported that the burden of treatment for TB was high, particularly in terms of difficulties with social and psychological aspects of undergoing treatment. They saw three main areas for support during their treatment: relevant information for them and their families about their disease, its treatment, potential side-effects and what they should do if side-effects arise; approachable and supportive healthcare staff with whom patients feel comfortable discussing (often non-medical) problems that arise during treatment; and some flexibility in treatment to allow essential elements of patients' lives (such as income generation, food-growing and childcare) to continue. They were anxious to ensure that family support did not absolve healthcare workers from their own support responsibilities. In order to support people with TB more during their treatment, health policy and practice must appreciate that TB affects all aspects of TB patients' lives. A focus on caring for each patient as an individual should underlie all aspects of treatment. Improved communication between healthcare providers and patients and increased patient knowledge and understanding of the treatment programme would give those receiving treatment a sense of individual empowerment and raise their confidence in treatment.


De novo computational design of retro-aldol enzymes.
The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model.


SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor growth in vivo by inducing G2/M cell cycle arrest.
Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment.


An OSL chronology for the sedimentary deposits from Pinnacle Point Cave 13B--a punctuated presence.
Optically stimulated luminescence (OSL) measurements are reported for single aliquots and single grains of quartz from sedimentary deposits within Cave 13B at Pinnacle Point, South Africa (PP13B). Ages have been obtained for 30 samples from the Middle Stone Age and from sterile geological deposits at the base and top of the sediment sequence. The ages for all the archaeological units have been obtained from single-grain measurements that enable unrepresentative grains to be rejected after they have been scrutinized for their OSL behavior. The shape of the equivalent dose distribution and the degree of spread in equivalent dose for each sample have also been scrutinized for evidence of depositional and post-depositional effects that can influence the accuracy of the age estimates. This study also used the same systematic approach as that used for the dating of the Howieson's Poort and Still Bay in South Africa. This single-grain approach results in more accurate and precise age estimates that place all ages measured and analyzed in this way on a common timescale. Four periods of human occupation have been dated to ~162ka, ~125ka, ~110ka, and ~99-91ka during Marine Isotope Stage (MIS) 6, 5e, 5d, and 5c, respectively. Occupation of the site appears to have occurred at periods of higher sea level and increased aeolian activity, and the cave was ultimately sealed by the accumulation of a large dune ~90ka ago that infilled the cave, but also blanketed the cliff face above the cave, thus preventing further habitation of the site until ~39ka.


CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis.
The role of CD4(+) T cells as effector cells in corneal allograft rejection is poorly understood. We investigated the role of CD4(+) T cells as helper cells in the generation of allospecific effector macrophages in corneal graft rejection and the role of CD4(+) T cells as apoptosis-inducing effector cells. Corneal allografts were transplanted to CD4 knockout, FasL-deficient, and macrophage-depleted hosts. An Annexin-V binding assay was used to evaluate the susceptibility of corneal cells to both Fas-dependent and CD4 T-cell-mediated apoptosis in vitro. Macrophages were essential for graft rejection, but not as effector cells. Anti-BALB/c CD4(+) T cells from immunized C57BL/6 mice induced apoptosis of BALB/c corneal epithelial and endothelial cells. However, anti-BALB/c CD4(+) T cells from FasL-deficient gld/gld mice did not induce apoptosis of BALB/c corneal endothelial cells. Moreover, gld/gld mice had a reduced capacity to reject BALB/c corneal allografts. Although the initial results suggested a role for Fas-induced apoptosis in corneal graft rejection, additional experiments indicated otherwise. The incidence and tempo of immune rejection of Fas-deficient lpr/lpr corneal allografts were no different than those for corneal grafts from Fas-bearing C57BL/6 donors. Moreover, CD4(+) T-cell-mediated apoptosis of corneal cells could not be blocked with either Fas-Fc fusion protein or anti-FasL blocking antibody. The results suggest that CD4(+) T cells function directly as effector cells and not as helper cells in the rejection of corneal allografts. Although the corneal endothelium is highly susceptible to Fas-induced apoptosis, this is apparently not the primary mechanism of CD4(+) T-cell-dependent rejection.


Evidence of shallow fault zone strengthening after the 1992 M7.5 landers, california, earthquake
Repeated seismic surveys of the Landers, California, fault zone that ruptured in the magnitude (M) 7.5 earthquake of 1992 reveal an increase in seismic velocity with time. P, S, and fault zone trapped waves were excited by near-surface explosions in two locations in 1994 and 1996, and were recorded on two linear, three-component seismic arrays deployed across the Johnson Valley fault trace. The travel times of P and S waves for identical shot-receiver pairs decreased by 0.5 to 1.5 percent from 1994 to 1996, with the larger changes at stations located within the fault zone. These observations indicate that the shallow Johnson Valley fault is strengthening after the main shock, most likely because of closure of cracks that were opened by the 1992 earthquake. The increase in velocity is consistent with the prevalence of dry over wet cracks and with a reduction in the apparent crack density near the fault zone by approximately 1.0 percent from 1994 to 1996.


Effect of engineering Hsp70 copy number on Hsp70 expression and tolerance of ecologically relevant heat shock in larvae and pupae of Drosophila melanogaster.
To determine how the accumulation of the major Drosophila melanogaster heat-shock protein, Hsp70, affects inducible thermotolerance in larvae and pupae, we have compared two sister strains generated by site-specific homologus recombination. One strain carried 12 extra copies of the Hsp70 gene at a single insertion site (extra-copy strain) and the other carried remnants of the transgene construct but lacked the extra copies of Hsp70 (excision strain). Hsp70 levels in whole-body lysates of larvae and pupae were measured by ELISA with an Hsp70-specific antibody. In both extra-copy and excision strains, Hsp70 was undetectable prior to heat shock. Hsp70 concentrations were higher in the extra-copy strain than in the excision strain at most time points during and after heat shock. Pretreatment (i.e. exposure to 36 degrees C before heat shock) significantly improved thermotolerance, and this improvement was greater and more rapid in larvae and pupae of the extra-copy strain than in those of the excision strain. The experimental conditions resemble thermal regimes actually experienced by Drosophila in the field. Thus, these findings represent the best evidence to date that the amount of a heat-shock protein affects the fitness of a complex animal in the wild.


The bHLH repressor Deadpan regulates the self-renewal and specification of Drosophila larval neural stem cells independently of Notch.
Neural stem cells (NSCs) are able to self-renew while giving rise to neurons and glia that comprise a functional nervous system. However, how NSC self-renewal is maintained is not well understood. Using the Drosophila larval NSCs called neuroblasts (NBs) as a model, we demonstrate that the Hairy and Enhancer-of-Split (Hes) family protein Deadpan (Dpn) plays important roles in NB self-renewal and specification. The loss of Dpn leads to the premature loss of NBs and truncated NB lineages, a process likely mediated by the homeobox protein Prospero (Pros). Conversely, ectopic/over-expression of Dpn promotes ectopic self-renewing divisions and maintains NB self-renewal into adulthood. In type II NBs, which generate transit amplifying intermediate neural progenitors (INPs) like mammalian NSCs, the loss of Dpn results in ectopic expression of type I NB markers Asense (Ase) and Pros before these type II NBs are lost at early larval stages. Our results also show that knockdown of Notch leads to ectopic Ase expression in type II NBs and the premature loss of type II NBs. Significantly, dpn expression is unchanged in these transformed NBs. Furthermore, the loss of Dpn does not inhibit the over-proliferation of type II NBs and immature INPs caused by over-expression of activated Notch. Our data suggest that Dpn plays important roles in maintaining NB self-renewal and specification of type II NBs in larval brains and that Dpn and Notch function independently in regulating type II NB proliferation and specification.


Honeycomb-lattice plasmonic absorbers at NIR: anomalous high-order resonance.
We design, fabricate and characterize a plasmonic honeycomb lattice absorber with almost perfect absorption at 1140 nm over a wide incident angle range. This absorber also possesses a narrow-band, angle- and polarization-dependent high-order resonance in the short-wavelength range, with a bandwidth of 19 nm and angle sensitivity of 3 nm per degree. The nature of this high-order absorption band is analyzed through finite-element simulations. We believe it is due to Bragg coupling of the incident light to the backward-propagating surface plasmon polariton through the periodic modulation of the structure.Such fine absorption bands can find applications in plasmonic sensors and spectrally selective thermal emitters.


Impact of Hepatitis C Treatment as Prevention for People Who Inject Drugs is sensitive to contact network structure.
Treatment as Prevention (TasP) using directly-acting antivirals has been advocated for Hepatitis C Virus (HCV) in people who inject drugs (PWID), but treatment is expensive and TasP's effectiveness is uncertain. Previous modelling has assumed a homogeneously-mixed population or a static network lacking turnover in the population and injecting partnerships. We developed a transmission-dynamic model on a dynamic network of injecting partnerships using data from survey of injecting behaviour carried out in London, UK. We studied transmission on a novel exponential-clustered network, as well as on two simpler networks for comparison, an exponential unclustered and a random network, and found that TasP's effectiveness differs markedly. With respect to an exponential-clustered network, the random network (and homogeneously-mixed population) overestimate TasP's effectiveness, whereas the exponential-unclustered network underestimates it. For all network types TasP's effectiveness depends on whether treated patients change risk behaviour, and on treatment coverage: higher coverage requires fewer total treatments for the same health gain. Whilst TasP can greatly reduce HCV prevalence, incidence of infection, and incidence of reinfection in PWID, assessment of TasP's effectiveness needs to take account of the injecting-partnership network structure and post-treatment behaviour change, and further empirical study is required.


Imaging skins: an imaging modality with ultra-thin form factor.
Reduction of the volume and mass of an imaging system would be advantageous in a variety of applications. However, the far-field resolution of any such system is fundamentally limited by aperture size. We present a new imaging modality based on waveguide coupling that is completely confined to a two-dimensional surface. One such imaging skin was shown to have the same resolution as a 0.5 cm diameter lens while maintaining an imaging system depth of a few micrometers.


In vitro antimicrobial activity and the mode of action of indole-3-carbinol against human pathogenic microorganisms.
Indole-3-carbinol (I3C) is a naturally occurring constituent of cruciferous vegetables. The aim of this study was to assess the in vitro antimicrobial activity of I3C and its mode of action. By using an NCCLS broth microdilution assay, the activity of I3C was evaluated against human pathogenic microorganisms including clinically isolated antibiotic-resistant bacterial strains. The results indicated that I3C exhibited broad spectrum antimicrobial activities. To elucidate the physiological changes of the fungal cells induced by I3C, we performed a flow cytometric analysis for a cell cycle. The results showed that I3C arrested the cell cycle at the G(2)/M phase in Candida albicans. To understand the antifungal mode of action of I3C, the change in the membrane dynamics was monitored by using fluorescence changing experiments against C. albicans. The results suggest that I3C may exert antifungal activity by disrupting the structure of the cell membrane. The present study indicates that I3C has considerable antimicrobial activity, deserving further investigation for clinical applications.


Methodological issues in emergent evaluations of health programs: lessons from Iberoamerica.
There has been growing interest in nonmainstream approaches to assessing health programs, but methodological strategies have not been a concern. In this article, we review methodological strategies used in emergent evaluations of health policies and programs in Iberoamerica, focusing on participatory, qualitative, critical, hermeneutical, bottom-up, collaborative, and transdisciplinary approaches. A literature search was performed combining strategies: database review, consultation of bibliography, expert interviews, and search engines. The review took place from 2003 to 2006. Research published in the past two decades was included. Nearly 70 articles were found on emergent research and evaluation of health programs in the region. Participatory and qualitative approaches were the most used. Theoretical issues are more emphasized than are methodological ones. Data gathering also was more explored than were design, participant selection, or analysis. The frequently used methodological strategies contradict some basic assumptions of the emergent evaluative research, such as its participatory and collaborative nature.


Combination of honey with metformin enhances glucose metabolism and ameliorates hepatic and nephritic dysfunction in STZ-induced diabetic mice.
Honey is a natural sweetener that contains a large amount of monosaccharides such as glucose and fructose, as well as small amounts of disaccharides and trisaccharides such as sucrose and pine trisaccharides. In addition to carbohydrates, honey also contains vitamins, minerals, enzymes, amino acids, and polyphenols including phenolic acids and flavonoids. The polyphenols in honey have been proved to have great antioxidant activity, besides inhibiting α-glycosidase activity and improving blood-lipid metabolism. However, whether it is safe for diabetic patients to consume honey remains controversial. This study investigated the effects of honey, metformin and their combination on the characteristic pathological changes and glucose metabolism in STZ-induced diabetic mice over five weeks. Our results showed that honey and its combination with metformin could prevent hyperglycemia, stimulate insulin secretion, reduce liver fat accumulation, attenuate liver injury and kidney damage in STZ-induced diabetic mice. Moreover, treatment with honey or combination of honey and metformin significantly enhanced glucokinase (GK) activity (p < 0.05), and meanwhile suppressed the activities of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase (PC) and pyruvate dehydrogenase kinases (PDK) (p < 0.05) in diabetic mice.


On the definition of complementary, alternative, and integrative medicine: societal mega-stereotypes vs. the patients' perspectives.
Much confusion exists regarding the definitions of complementary, alternative, and integrative medicine. Whereas 'complementary and alternative medicine' (CAM) is used to describe a variable set of diagnostic and therapeutic modalities considered as non-conventional, 'integrative medicine' is commonly used to describe the combination of allopathy and CAM. CAM, however, is nothing more than a categorical label that subsumes numerous therapeutic modalities generally sharing few commonalities. Creating a unique category out of such diversity has lead to misunderstanding and skepticism. From the physician's stand-point, this can generate numerous stereotypes, prejudices, and misconceptions that may compromise the therapeutic relationship, impede compliance, and lead to treatment failure. To help avoid this dangerous pitfall, we propose a distinctly new operational definition for CAM; one that shifts the focus from the traditional, population-based approach to a definition that focuses on the individual. This paper outlines various definitions of CAM and discusses their relative strengths and weaknesses for the 21st century practice of medicine. It is our conclusion that individual patients, rather than society, should be the frame of reference and defining source for what constitutes integrative medicine and CAM.


The determinants and consequences of information seeking among cancer patients.
This research was designed to examine information seeking behavior among cancer patients. We present a model which identifies the determinants and consequences of information seeking and, in turn, examines the effects of prior variables on four outcome variables: whether patients discussed with their physicians information that they received from other sources, whether the information they obtained helped them make decisions about treatment or care, whether the patient sought a second opinion about his/her diagnosis or treatment, and changes in self-reported stress levels from diagnosis to the time of interview. The model is estimated separately for three groups: patients who sought information from multiple sources including the National Cancer Institute's Cancer Information Service, patients who sought information from multiple sources but did not call the Cancer Information Service, and patients who did not seek information other than from their physician(s). We discuss variables that have similar impacts on outcome variables in all three groups as well as variables that operate differently within the groups. The results indicate that the desire for information and the desire for involvement in medical care decisions are independent factors. Some patients have a strong desire for both information and involvement in making health care decisions. These patients actively seek involvement in their treatment plans. Other patients, however, want to be informed about their disease and treatment but prefer to delegate most decision-making to their physicians. Still other patients choose to delegate information gathering and decision making exclusively to their physicians. We discuss the implications of these results for both patients and providers.


Hepatitis C virus in sickle cell disease.
To determine the prevalence of hepatitis C virus antibodies (anti-HCV) in patients with sickle cell disease. Between 1983 and 2001, 150 patients from the Howard University Hospital Center for Sickle Cell Disease were screened for HCV antibody (52% women, 48% men, mean age 34 years). Frozen serum samples from 56 adult sickle cell patients who had participated in previous surveys (1983-92) of HIV and HTLV-1 serology and who were tested in 1992 for anti-HCV antibody--when commercial ELISA test (Ortho) became available--were included in this paper. Of the 150 patients in the study, 132 had sickle cell anemia genotype (SS), 15 had sickle cell hemoglobin-C disease (SC) and three had sickle beta thalassemia. Clinical charts were reviewed for history of blood transfusion, IV drug abuse, homosexuality, tattooing, iron overload, and alcohol abuse. Antibodies to HCV were detected in 53 patients (35.3%). Of the 55 patients who had frozen serum samples tested in 1992, 32 (58%) were reactive for anti-HCV, while only 21 of the 95 patients (22%) tested after 1992 were positive for HCV antibodies (P<0.001). Thirty-nine of 77 patients (51%) who received more than 10 units of packed red blood cells were positive for HCV antibody, and only 14 of 61 patients (23%) who received less than 10 units of packed red blood cells transfusion were positive for HCV antibodies (P<0.001). None of the 12 patients who never received transfusion were positive for HCV antibody. In the 53 anti-HCV positive patients, the mean alanine amino-transferase (ALT) value was 98- and 81 U/L, respectively, for males and females. These values were normal for the HCV-antibody negative patients. The aspartate amino-transferase (AST) and the total bilirubin were also higher in the anti-HCV positive patients compared to patients in the anti-HCV negative group. Forty-four patients (57.1%) who were transfused more than 10 units developed iron overload defined by a serum ferritin level higher than 1,000 ng/ml. A total of 20 of the patients with iron overload underwent liver biopsies. Seven of these 20 patients (35%) were HCV positive. These patients often had more severe liver disease and higher degree of iron deposition. The prevalence of HCV antibody and iron overload is directly related to the number of blood transfusions in patients with sickle cell disease. The prevalence of HCV infection has decreased significantly, since blood donor screening for HCV became available. Chronic HCV infection and iron overload place sickle cell patients at risk for significant liver disease.


Single-cell proteomic analysis of glucosinolate-rich S-cells in Arabidopsis thaliana.
Single-cell analysis is essential for understanding the processes of cell differentiation and metabolic specialisation in rare cell types. The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis. The development of modern mass spectrometers possessing increased sensitivity and mass accuracy in combination with nano-LC-MS/MS now enables the analysis of single-cell contents. In Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis. Dehydrin (ERD14_ARATH), two myrosinases (BGL37_ARATH and BGL38_ARATH), annexin (ANXD1_ARATH), vegetative storage proteins (VSP1_ARATH and VSP2_ARATH) and four proteins belonging to the S-adenosyl-l-methionine cycle (METE_ARATH, SAHH1_ARATH, METK4_ARATH and METK1/3_ARATH) with associated adenosine kinase (ADK1_ARATH), were amongst the proteins identified in these single-S-cell samples. Comparison of the functional groups of proteins identified in S-cells with epidermal/cortical cells and whole tissue provided a unique insight into the metabolism of S-cells. We conclude that S-cells are metabolically active and contain the machinery for de novo biosynthesis of methionine, a precursor for the most abundant glucosinolate glucoraphanine in these cells. Moreover, since abundant TGG2 and TGG1 peptides were consistently found in single-S-cell samples, previously shown to have high amounts of glucosinolates, we suggest that both myrosinases and glucosinolates can be localised in the same cells, but in separate subcellular compartments. The complex membrane structure of S-cells was reflected by the presence of a number of proteins involved in membrane maintenance and cellular organisation.


Intravenous administration of the food-derived opioid peptide gluten exorphin B5 stimulates prolactin secretion in rats.
Gluten Exorphin B5 (GE-B5) is a food-derived opioid peptide, identified in vitro in enzymatic digests of wheat gluten. It has been suggested that this peptide may play a regulatory role on pituitary secretion, since it stimulates prolactin (PRL) secretion when administered in the cerebral ventricles in rats. It is not known, however, if GE-B5 can exert this stimulatory action after peripheral administration. In order to clarify this aspect, we gave the following treatments to four groups of male rats: intravenous (i.v.) vehicle, GE-B5 3 mg/kg body weight i.v., naloxone intraperitoneally (i.p.) followed by vehicle i.v., naloxone i.p. followed by GE-B5 i.v. Blood samples for PRL were taken at intervals for 60 min after vehicle or GE-B5 administration. At the dose of 3 mg/kg body weight, GE-B5 induced a significant increase in PRL levels; naloxone completely abolished any effect of GE-B5 on PRL secretion. The present study indicates that GE-B5 stimulates PRL secretion after peripheral administration and that its action is mediated via classical opioid receptors; moreover, it identifies the minimum peptide dose which must reach the blood in order to exert its action on PRL secretion.


Mortality in systemic sclerosis: an international meta-analysis of individual patient data.
Studies on mortality associated with systemic sclerosis have been limited by small sample sizes. We aimed to obtain large-scale evidence on survival outcomes and predictors for this disease. We performed a meta-analysis of individual patient data from cohorts recruited from seven medical centers in the United States, Europe, and Japan, using standardized definitions for disease subtype and organ system involvement. The primary outcome was all-cause mortality. Standardized mortality ratios and predictors of mortality were estimated. The main analysis was based only on patients enrolled at each center within 6 months of diagnosis (incident cases). Among 1645 incident cases, 578 deaths occurred over 11,521 person-years of follow-up. Standardized mortality ratios varied by cohort (1.5 to 7.2). In multivariate analyses that adjusted for age and sex, renal (hazard ratio [HR] = 1.9; 95% confidence interval [CI]: 1.4 to 2.5), cardiac (HR = 2.8; 95% CI: 2.1 to 3.8), and pulmonary (HR = 1.6; 95% CI: 1.3 to 2.2) involvement, and anti-topoisomerase I antibodies (HR = 1.3; 95% CI: 1.0 to 1.6), increased mortality risk. Renal, cardiac, and pulmonary involvement tended to occur together (P <0.001). For patients without adverse predictors for 3 years after enrollment, the subsequent risk of death was not significantly different from that for the general population in three cohorts, but was significantly increased in three cohorts that comprised mostly referred patients. Analyses that included all cases in each center (n = 3311; total follow-up: 19,990 person-years) yielded largely similar results. Systemic sclerosis confers a high mortality risk, but there is considerable heterogeneity across settings. Internal organ involvement and anti-topoisomerase I antibodies are important determinants of mortality.


Family of origin environments in two clinical samples of survivors of intra-familial, extra-familial, and both types of sexual abuse.
It has been suggested that survivors of ongoing childhood sexual abuse (CSA) tend to have been reared in ineffective family environments that render them particularly vulnerable to maltreatment and which foster psychological difficulties beyond those accounted for solely by their abuse. If this conjecture is valid, one would expect that the family of origin environments of CSA survivors would be disturbed whether their abuser was intra-familial or extra-familial. To assess this hypothesis, two studies compared the childhood family of origin environments and supportive parenting characteristics of a clinical sample of women sexually abused by family members only (the intra-familial group), by non-family members only (the extra-familial group), and by both family and non-family members (the "both" group). Study 1 compared the three groups (total N = 213) using the Family Environment Scale (FES). Study 2 compared groups (total N = 86) on the positive parenting scales of the Exposure to Abusive and Supportive Environments Parenting Inventory (EASE-PI). In Study 1, multivariate analyses indicated significant differences on the independence, cohesion, and conflict subscales of the FES. Pairwise comparisons revealed that the extra-familial group reported significantly higher levels of family independence and lower levels of conflict than the other two groups. In addition, the extra-familial group reported higher levels of cohesion than the intra-familial group. However, the effect sizes of these comparisons were extremely small. In Study 2, multivariate analyses revealed no group differences on the EASE-PI scales. Low effect sizes on the three significant FES scales, non-significance on the remaining seven FES scales, and non-significance on the EASE-PI scales suggest that there is considerable similarity in the family of origin environments of adult female CSA survivors seeking therapy regardless of whether their perpetrators were family members, non-family members, or both family and non-family members.


Retro-cue benefits in working memory without sustained focal attention.
In working memory (WM) tasks, performance can be boosted by directing attention to one memory object: When a retro-cue in the retention interval indicates which object will be tested, responding is faster and more accurate (the retro-cue benefit). We tested whether the retro-cue benefit in WM depends on sustained attention to the cued object by inserting an attention-demanding interruption task between the retro-cue and the memory test. In the first experiment, the interruption task required participants to shift their visual attention away from the cued representation and to a visual classification task on colors. In the second and third experiments, the interruption task required participants to shift their focal attention within WM: Attention was directed away from the cued representation by probing another representation from the memory array prior to probing the cued object. The retro-cue benefit was not attenuated by shifts of perceptual attention or by shifts of attention within WM. We concluded that sustained attention is not needed to maintain the cued representation in a state of heightened accessibility.


Fabrication of ultrathin CoMoO₄ nanosheets modified with chitosan and their improved performance in energy storage device.
Ultrathin nanosheet-assembled cobalt molybdate (CoMoO4) with a mesoporous morphology was synthesized by a urea-assisted solution combustion route at a temperature of 400 °C. The as-prepared CoMoO4 was modified using chitosan cross-linked with glutaraldehyde (glu) and employed as a cathode material in an aqueous hybrid capacitor. The physical and electrochemical behaviour of CoMoO4 modified with chitosan and the as-prepared (chitosan free) CoMoO4 has been compared and discussed. The modified CoMoO4 exhibited excellent electrochemical performance with a specific capacitance of 135 F g(-1) at 0.6 A g(-1) and an energy density of 31 W h kg(-1). It also exhibited good cycling stability with high coulombic efficiency over 2000 cycles retaining a specific capacitance of 81 F g(-1) at 3 A g(-1), comparatively much better than that of nanostructured chitosan free CoMoO4 which yielded 17 F g(-1). The results indicated that chitosan gel strongly adheres to the molybdate moiety of CoMoO4 and increases the capacitance four-fold compared to a chitosan free material. The modified CoMoO4 electrode shows potential for high performance, and is an environmentally friendly and low-cost energy storage device.


Adaptive genetic variation and heart disease risk.
Obesity, dyslipidemia and cardiovascular disease are complex and determined by both genetic and environmental factors and their inter-relationships. Many associations from genome-wide association studies and candidate gene approaches have described a multitude of polymorphisms associating with lipid and obesity phenotypes but identified genetic variants account for only a small fraction of phenotypic variation. That many genotype-phenotype associations involve variants under positive selection and that those variants respond to environmental cues together suggest prominent roles for both genetic adaptation and their interactions with the environment. Adaptive genetic variations interacting with environment modulate disease susceptibility but the level to which those variants contribute to dyslipidemia and obesity and how environmental factors, especially diet, alter the genetic association is not yet completely known. It is evident that genetic variants under positive selection make important contributions to obesity and heart disease risk. Advances in resequencing the entire human genome will enable accurate identification of adaptive variants. Considering interactions between environmental factors and genotypes will empower both genome-wide association studies and characterization of the relationship between positive selection and the obese and dyslipidemic conditions.


Forensic medicine part II.
The role of the doctor is to: (see also: Child abuse: management of physical abuse) 1. Take a full medical history without detail about the CSA (role of social worker/police). 2. do a complete physical examination of the child. 3. collect medico-legal evidence using a crime kit if abuse is recent (<72 hours). 4. Do further investigations, e.g. special investigations for physical abuse, pregnancy test if pubertal, and syphilis and HIV serology. 5. Explain the findings to parent(s) and the child if the latter is old enough. 6. Mobilise the child abuse management team. 7. Write detailed notes, necessary reports and complete J88 form if requested. 8. Ensure the safety of the child. 9. Give treatment and prophylaxis as clinically indicated. 10. Arrange referral(s) and follow-up appointments.


The impact of on-site hospital wastewater treatment on the downstream communal wastewater system in terms of antibiotics and antibiotic resistance genes.
This study quantified antibiotic and antibiotic resistance gene (ARG) concentrations in hospital and communal wastewaters as well as the influents and effluents of the receiving urban wastewater treatment plants (UWWTP) in two Dutch cities. In only one city, hospital wastewater was treated on-site using advanced technologies, including membrane bioreactor treatment (MBR), ozonation, granulated activated carbon (GAC) and UV-treatment. On-site hospital wastewater (HWW) treatment reduced gene presence of hospital-related antibiotic resistance genes and antibiotic concentrations in the receiving urban wastewater treatment plant. These findings support the need for on-site treatment of high-risk point sources of antibiotic resistance genes. 13 antibiotic resistance genes, Integrase Class 1 and 16S rRNA concentrations were quantified using multiplex quantitative real-time PCR (qPCR) assays and the presence and/or concentration of 711 antibiotics were analyzed. Hospital wastewater contained approximately 25% more antibiotics and gene concentrations between 0.4 log to 1.8-fold higher than communal wastewater (CWW). blaKPC and vanA could be identified as hospital-related genes and were reduced to under the limit of detection (LOD) during on-site treatment. Advanced on-site treatment removed between 0.5 and 3.6-fold more genes than conventional biological urban wastewater treatment (activated sludge). Advanced on-site treatment was able to eliminate 12 out of 19 detected antibiotics, while urban waste water treatment eliminated up to 1 (out of 21 detected). Different advanced treatment technologies were able to target different pollutants to varying extents, making sequential alignment more effective. MBR treatment was most efficient in antibiotic resistance gene reduction and ozonation in antibiotic reduction. blaKPC could only be detected in the influent of the urban wastewater treatment plant receiving untreated hospital wastewater. Similarly, vanA was only consistently detected in this treatment plant. These results indicate a positive effect of on-site treatment of hospital wastewater on the communal sewage system.


Deletion by in vivo recombination shows that the 28-kilodalton cytolytic polypeptide from Bacillus thuringiensis subsp. israelensis is not essential for mosquitocidal activity.
The cytA gene encoding the 28-kDa polypeptide of Bacillus thuringiensis subsp. israelensis crystals was disrupted in the 72-MDa resident plasmid by in vivo recombination, thus indicating that homologous recombination occurs in B. thuringiensis. The absence of the 28-kDa protein in B. thuringiensis did not affect the crystallization of the other toxic components of the parasporal body (68-, 125-, and 135-kDa polypeptides). The absence of the 28-kDa protein abolished the hemolytic activity of B. thuringiensis subsp. israelensis crystals. However, the mosquitocidal activity of the 28-kDa protein-free crystals did not differ significantly from that of the wild-type crystals when tested on Aedes aegypti and Culex pipiens larvae. The 28-kDa protein contributed slightly to the toxicity to Anopheles stephensi larvae. This indicates that the 28-kDa protein is not essential for mosquitocidal activity, at least against the three species tested.


Circular RNA expression profiles in hippocampus from mice with perinatal glyphosate exposure.
Glyphosate is the active ingredient in numerous herbicide formulations. The roles of glyphosate in embryo-toxicity and neurotoxicity have been reported in human and animal models. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. However, the role of glyphosate in neuronal development is still not fully understood. Our previous study found that perinatal glyphosate exposure resulted in differential microRNA expression in the prefrontal cortex of mouse offspring. However, the mechanism of glyphosate-induced neurotoxicity in the developing brain is still not fully understood. Considering the pivotal role of Circular RNAs (circRNAs) in the regulation of gene expression, a circRNA microarray method was used in this study to investigate circRNA expression changes in the hippocampus of mice with perinatal glyphosate exposure. The circRNA microarrays revealed that 663 circRNAs were significantly altered in the perinatal glyphosate exposure group compared with the control group. Among them, 330 were significantly upregulated, and the other 333 were downregulated. Furthermore, the relative expression levels of mmu-circRNA-014015, mmu-circRNA-28128 and mmu-circRNA-29837 were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that stress-associated steroid metabolism pathways, such as aldosterone synthesis and secretion pathways, may be involved in the neurotoxicity of glyphosate. These results showed that circRNAs are aberrantly expressed in the hippocampus of mice with perinatal glyphosate exposure and play potential roles in glyphosate-induced neurotoxicity.


Everyday episodic memory in amnestic mild cognitive impairment: a preliminary investigation.
Decline in episodic memory is one of the hallmark features of Alzheimer's disease (AD) and is also a defining feature of amnestic Mild Cognitive Impairment (MCI), which is posited as a potential prodrome of AD. While deficits in episodic memory are well documented in MCI, the nature of this impairment remains relatively under-researched, particularly for those domains with direct relevance and meaning for the patient's daily life. In order to fully explore the impact of disruption to the episodic memory system on everyday memory in MCI, we examined participants' episodic memory capacity using a battery of experimental tasks with real-world relevance. We investigated episodic acquisition and delayed recall (story-memory), associative memory (face-name pairings), spatial memory (route learning and recall), and memory for everyday mundane events in 16 amnestic MCI and 18 control participants. Furthermore, we followed MCI participants longitudinally to gain preliminary evidence regarding the possible predictive efficacy of these real-world episodic memory tasks for subsequent conversion to AD. The most discriminating tests at baseline were measures of acquisition, delayed recall, and associative memory, followed by everyday memory, and spatial memory tasks, with MCI patients scoring significantly lower than controls. At follow-up (mean time elapsed: 22.4 months), 6 MCI cases had progressed to clinically probable AD. Exploratory logistic regression analyses revealed that delayed associative memory performance at baseline was a potential predictor of subsequent conversion to AD. As a preliminary study, our findings suggest that simple associative memory paradigms with real-world relevance represent an important line of enquiry in future longitudinal studies charting MCI progression over time.


Functional analysis of the effect of monoclonal antibodies on monkey liver phenylalanine hydroxylase.
An analysis of the effect of eleven monoclonal antibodies on the functional characteristics of monkey liver phenylalanine hydroxylase is presented. These eleven antibodies have been found to react with eight distinct regions on the phenylalanine hydroxylase protein. PH1 antibody inhibits enzyme activity, is dependent on phenylalanine for its binding, and appears to be related to structural changes occurring during phenylalanine activation of the enzyme activity. PH2 and PH3 antibodies stimulate enzyme activity, their binding is inhibited by lysolecithin and this group apparently is recognizing structures involved in lysolecithin activation of the enzyme activity. PH5, PH10, PH12 and PH6 recognise sites on phenylalanine hydroxylase affected by lysolecithin activation.


Vitamin D-VDR Signaling Inhibits Wnt/β-Catenin-Mediated Melanoma Progression and Promotes Antitumor Immunity.
1α,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As patients with melanoma commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signaling and replicated the findings in The Cancer Genome Atlas metastases. VDR expression was independently protective for melanoma-related death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and corresponding with higher imputed immune cell scores and histologically detected tumor-infiltrating lymphocytes. High VDR-expressing tumors had downregulation of proliferative pathways, notably Wnt/β-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (<25 nmol/L ∼ 10 ng/mL) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/β-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail-vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppressive Wnt/β-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of a causal relationship between vitamin D-VDR signaling and melanoma survival, which should be explored as a therapeutic target in primary resistance to checkpoint blockade. SIGNIFICANCE: VDR expression could potentially be used as a biomarker to stratify patients with melanoma that may respond better to immunotherapy.


Surface ocean pH variations since 1689 CE and recent ocean acidification in the tropical South Pacific.
Increasing atmospheric CO2 from man-made climate change is reducing surface ocean pH. Due to limited instrumental measurements and historical pH records in the world's oceans, seawater pH variability at the decadal and centennial scale remains largely unknown and requires documentation. Here we present evidence of striking secular trends of decreasing pH since the late nineteenth century with pronounced interannual to decadal-interdecadal pH variability in the South Pacific Ocean from 1689 to 2011 CE. High-amplitude oceanic pH changes, likely related to atmospheric CO2 uptake and seawater dissolved inorganic carbon fluctuations, reveal a coupled relationship to sea surface temperature variations and highlight the marked influence of El Niño/Southern Oscillation and Interdecadal Pacific Oscillation. We suggest changing surface winds strength and zonal advection processes as the main drivers responsible for regional pH variability up to 1881 CE, followed by the prominent role of anthropogenic CO2 in accelerating the process of ocean acidification.


A crosstalk between β1 and β3 integrins controls glycine receptor and gephyrin trafficking at synapses.
The regulation of glycine receptor (GlyR) number at synapses is necessary for the efficacy of inhibition and the control of neuronal excitability in the spinal cord. GlyR accumulation at synapses depends on the scaffolding molecule gephyrin and is linked to GlyR synaptic dwell time. However, the mechanisms that tune GlyR synaptic exchanges in response to different neuronal environments are unknown. Integrins are cell adhesion molecules and signaling receptors. Using single quantum dot imaging and fluorescence recovery after photobleaching, we found in rats that β1 and β3 integrins adjust synaptic strength by regulating the synaptic dwell time of both GlyRs and gephyrin. β1 and β3 integrins crosstalked via calcium/calmodulin-dependent protein kinase II and adapted GlyR lateral diffusion and gephyrin-dependent trapping at synapses. This provides a mechanism for maintaining or adjusting the steady state of postsynaptic molecule exchanges and the level of glycinergic inhibition in response to neuron- and glia-derived signals or extracellular matrix remodeling.


A low-cost, non-invasive phase velocity and length meter and controller for multiphase lab-in-a-tube devices.
Opportunities for accessible microfluidic device integration have sharply grown with the rise of readily available lab-in-a-tube strategies. Herein, we present a facile, non-invasive, plug-and-play phase velocity and length measuring strategy for rapid deployment onto tube-based microfluidic systems, enabling quick and accurate residence (reaction) time measurement and tuning. Our approach utilizes inexpensive off-the-shelf optical phase sensors and requires no prior knowledge of the fluid composition or physical properties. Compared to camera-based measurements in fluoropolymer tubing, the optical phase sensor-based technique shows mean absolute percentage errors of 1.3% for velocity and 3.3% for length. Utilizing the developed multiphase flow monitoring technique, we screen the accessible parameter space of gas-liquid segmented flows. To further demonstrate the functionality of this process monitoring strategy, we implement two feedback controllers to establish simultaneous setpoint control for phase velocity and length. Next, to showcase the effectiveness and versatility of the developed multiphase flow process controller, we apply it to systematic studies of the effect of liquid slug velocity (controlling precursor mixing timescale) on the colloidal synthesis of cesium lead tribromide nanocrystals. By varying the liquid slug velocity and maintaining constant precursor composition, liquid slug length, and residence time, we observe a bandgap tunability from 2.43 eV (510 nm) to 2.52 eV (494 nm).


Sex differences in the physiology of eating.
Hypothalamic-pituitary-gonadal (HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-α (ERα) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.


Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products.
With emerging trends in the incidence of cancer of various organ sites, additional approaches are needed to control human malignancies. Intervention or prevention of cancer by dietary constituents, a strategy defined as chemoprevention, holds great promise in our conquest to control cancer, because it can be implemented on a broader population base with less economic burden. Consistent with this, several epidemiological studies have shown that populations that consume diets rich in fruits and vegetables have an overall lower cancer incidence. Based on these encouraging observations, research efforts from across the globe have focused on identifying, characterizing, and providing scientific basis to the efficacy of various phytonutrients in an effort to develop effective strategy to control various human malignancies. Cancer induction, growth, and progression are multi-step events and numerous studies have demonstrated that various dietary agents interfere with these stages of cancer, thus blocking malignancy. Fruits and vegetables represent untapped reservoir of various nutritive and nonnutritive phytochemicals with potential cancer chemopreventive activity. Grapes and grape-based products are one such class of dietary products that have shown cancer chemopreventive potential and are also known to improve overall human health. This review focuses on recent advancements in cancer chemopreventive and anticancer efficacy of grape seed extract and other grape-based products. Overall, completed studies from various scientific groups conclude that both grapes and grape-based products are excellent sources of various anticancer agents and their regular consumption should thus be beneficial to the general population.


Invariance of polarized reflectance measured at the top of atmosphere by PARASOL satellite instrument in the visible range with marine constituents in open ocean waters.
The influence of oceanic constituents on the polarized reflectance measured at the top of atmosphere (TOA) over open ocean waters in one visible band is investigated. First, radiative transfer modelling is used to quantify the effects of biomass concentration on the TOA polarized signal for a wide range of observation geometries. The results showed that the TOA polarized reflectance remains insensitive to variations in the chlorophyll a concentration whatever the geometrical conditions in oligotrophic and mesotrophic waters, which represent about 90% of the global ocean. The invariance of the polarized signal with water content is explained by the prevailing influence of both atmospheric effects and skylight reflections at the sea surface on the polarization state of the radiation reaching the top of atmosphere level. The simulations also revealed that multidirectional and polarized TOA reflectances obtained in the visible spectrum are powerful tools for the discrimination between the aerosol optical properties. In the second part of the paper, the theoretical results are rigorously validated using original multiangle and polarized measurements acquired by PARASOL satellite sensor, which is used for the first time for ocean color purposes. First, a statistical analysis of the geometrical features of PARASOL instrument showed that the property of invariance of the TOA polarized reflectance is technically verified for more than 85% of viewed targets, and thus, indicating the feasibility of separating between the atmospheric and oceanic parameters from space remotely sensed polarized data. Second, PARASOL measurements acquired at regional and global scales nicely corroborated the simulations. This study also highlighted that the radiometric performance of the polarized visible wavelength of PARASOL satellite sensor can be used either for the aerosol detection or for atmospheric correction algorithms over open ocean waters regardless of the biomass concentration.


The prevention, diagnosis and management of central venous line infections in children.
With advancing paediatric healthcare, the use of central venous lines has become a fundamental part of management of neonates and children. Uses include haemodynamic monitoring and the delivery of lifesaving treatments such as intravenous fluids, blood products, antibiotics, chemotherapy, haemodialysis and total parenteral nutrition (TPN). Despite preventative measures, central venous catheter-related infections are common, with rates of 0.5-2.8/1000 catheter days in children and 0.6-2.5/1000 catheter days in neonates. Central line infections in children are associated with increased mortality, increased length of hospital and intensive care unit stay, treatment interruptions, and increased complications. Prevention is paramount, using a variety of measures including tunnelling of long-term devices, chlorhexidine antisepsis, maximum sterile barriers, aseptic non-touch technique, minimal line accessing, and evidence-based care bundles. Diagnosis of central line infections in children is challenging. Available samples are often limited to a single central line blood culture, as clinicians are reluctant to perform painful venepuncture on children with a central, pain-free, access device. With the advancing evidence basis for antibiotic lock therapy for treatment, paediatricians are pushing the boundaries of line retention if safe to do so, due to among other reasons, often limited venous access sites. This review evaluates the available paediatric studies on management of central venous line infections and refers to consensus guidelines such as those of the Infectious Diseases Society of America (IDSA).


Viscum Album Var Hot Water Extract Mediates Anti-cancer Effects through G1 Phase Cell Cycle Arrest in SK-Hep1 Human Hepatocarcinoma cells.
Viscum album var (VAV) also known as mistletoe, has long been categorized as a traditional herbal medicine in Asia. In addition to its immunomodulating activities, mistletoe has also been used in the treatment of chronic hepatic disorders in China and Korea. There are numerous reports showing that VAV possesses anti-cancer effects, however influence on human hepatocarcinoma has never been elucidated. In the present study, hot water extracts of VAV was evaluated for its potential anti-cancer effect in vitro. SK-Hep1 cells were treated with VAV (50-400 ug/ml) for both 24 and 48 hours then cell viability was measured by cell counting kit-8 (CCK-8). Flow cytometry analysis was used to measure the proportion of SK-Hep1 in the different stages of cell cycle. RT-PCR and Western blot analysis were conducted to measure expression of cell cycle arrest related genes and proteins respectively. VAV dose dependently inhibited the proliferation of SK-Hep1 cells without any cytotoxicity with normal Chang liver cell (CCL-13). Flow cytometry analysis showed that VAV extract inhibited the cell cycle of SK-Hep1 cells via G1 phase arrest. RT-PCR and Western blot analysis both revealed that cyclin dependent kinase 2 (Cdk2) and cyclin D1 gene expression were significantly down regulated while p21 was upregulated dose dependently by VAV treatment. Combined down regulation of Cdk2, Cyclin D1 and up regulation of p21 can result in cell death. These results indicate that VAV showed evidence of anti-cancer activity through G1 phase cell cycle arrest in SK-Hep1 cells.