Measurement equivalence in mixed mode surveys.
Surveys increasingly use mixed mode data collection (e.g., combining face-to-face and web) because this controls costs and helps to maintain good response rates. However, a combination of different survey modes in one study, be it cross-sectional or longitudinal, can lead to different kinds of measurement errors. For example, respondents in a face-to-face survey or a web survey may interpret the same question differently, and might give a different answer, just because of the way the question is presented. This effect of survey mode on the question-answer process is called measurement mode effect. This study develops methodological and statistical tools to identify the existence and size of mode effects in a mixed mode survey. In addition, it assesses the size and importance of mode effects in measurement instruments using a specific mixed mode panel survey (Netherlands Kinship Panel Study). Most measurement instruments in the NKPS are multi-item scales, therefore confirmatory factor analysis (CFA) will be used as the main analysis tool, using propensity score methods to correct for selection effects. The results show that the NKPS scales by and large have measurement equivalence, but in most cases only partial measurement equivalence. Controlling for respondent differences on demographic variables, and on scale scores from the previous uni-mode measurement occasion, tends to improve measurement equivalence, but not for all scales. The discussion ends with a review of the implications of our results for analyses employing these scales.


Global transcriptomic and proteomic responses of Dehalococcoides ethenogenes strain 195 to fixed nitrogen limitation.
Bacteria of the genus Dehalococcoides play an important role in the reductive dechlorination of chlorinated ethenes. A systems-level approach was taken in this study to examine the global transcriptomic and proteomic responses of exponentially growing cells of Dehalococcoides ethenogenes strain 195 to fixed nitrogen limitation (FNL), as dechlorination activity and cell yield both decrease during FNL. As expected, the nitrogen-fixing (nif) genes were differentially upregulated in the transcriptome and proteome of strain 195 during FNL. Aside from the nif operon, a putative methylglyoxal synthase-encoding gene (DET1576), the product of which is predicted to catalyze the formation of the toxic electrophile methylglyoxal and is implicated in the uncoupling of anabolism from catabolism in bacteria, was strongly upregulated in the transcriptome and could potentially play a role in the observed growth inhibition during FNL. Carbon catabolism genes were generally downregulated in response to FNL, and a number of transporters were differentially regulated in response to nitrogen limitation, with some playing apparent roles in nitrogen acquisition, while others were associated with general stress responses. A number of genes related to the functions of nucleotide synthesis, replication, transcription, translation, and posttranslational modifications were also differentially expressed. One gene coding for a putative reductive dehalogenase (DET1545) and a number of genes coding for oxidoreductases, which have implications in energy generation and redox reactions, were also differentially regulated. Interestingly, most of the genes within the multiple integrated elements were not differentially expressed. Overall, this study elucidates the molecular responses of strain 195 to FNL and identifies differentially expressed genes that are potential biomarkers to evaluate environmental cellular nitrogen status.


Retinal ischemia induces α-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion.
Increasing evidence indicates that pericytes are vulnerable cells, playing pathophysiological roles in various neurodegenerative processes. Microvascular pericytes contract during cerebral and coronary ischemia and do not relax after re-opening of the occluded artery, causing incomplete reperfusion. However, the cellular mechanisms underlying ischemia-induced pericyte contraction, its delayed emergence, and whether it is pharmacologically reversible are unclear. Here, we investigate i) whether ischemia-induced pericyte contractions are mediated by alpha-smooth muscle actin (α-SMA), ii) the sources of calcium rise in ischemic pericytes, and iii) if peri-microvascular glycogen can support pericyte metabolism during ischemia. Thus, we examined pericyte contractility in response to retinal ischemia both in vivo, using adaptive optics scanning light ophthalmoscopy and, ex vivo, using an unbiased stereological approach. We found that microvascular constrictions were associated with increased calcium in pericytes as detected by a genetically encoded calcium indicator (NG2-GCaMP6) or a fluoroprobe (Fluo-4). Knocking down α-SMA expression with RNA interference or fixing F-actin with phalloidin or calcium antagonist amlodipine prevented constrictions, suggesting that constrictions resulted from calcium- and α-SMA-mediated pericyte contractions. Carbenoxolone or a Cx43-selective peptide blocker also reduced calcium rise, consistent with involvement of gap junction-mediated mechanisms in addition to voltage-gated calcium channels. Pericyte calcium increase and capillary constrictions became significant after 1 h of ischemia and were coincident with depletion of peri-microvascular glycogen, suggesting that glucose derived from glycogen granules could support pericyte metabolism and delay ischemia-induced microvascular dysfunction. Indeed, capillary constrictions emerged earlier when glycogen breakdown was pharmacologically inhibited. Constrictions persisted despite recanalization but were reversible with pericyte-relaxant adenosine administered during recanalization. Our study demonstrates that retinal ischemia, a common cause of blindness, induces α-SMA- and calcium-mediated persistent pericyte contraction, which can be delayed by glucose driven from peri-microvascular glycogen. These findings clarify the contractile nature of capillary pericytes and identify a novel metabolic collaboration between peri-microvascular end-feet and pericytes.


The N-terminus of Spt16 anchors FACT to MCM2-7 for parental histone recycling.
Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks. Intriguingly, deletion of the Spt16-N domain impairs parental histone recycling, with a more pronounced defect observed on the lagging strand. Mechanistically, the Spt16-N domain interacts with the replicative helicase MCM2-7 and facilitates the formation of a ternary complex involving FACT, histone H3/H4 and Mcm2 histone binding domain, critical for the recycling and transfer of parental histones to lagging strands. Lack of the Spt16-N domain weakens the FACT-MCM interaction and reduces parental histone recycling. We propose that the Spt16-N domain acts as a protein-protein interaction module, enabling FACT to function as a shuttle chaperone in collaboration with Mcm2 and potentially other replisome components for efficient local parental histone recycling and inheritance.


Sorafenib for the treatment of multiple myeloma.
Sorafenib is an orally available compound that acts predominantly by targeting the Ras/Raf/MEK/ERK pathway and by inhibiting the vascular endothelial growth factor (VEGF). Since the Ras/Raf/MEK/ERK pathway is implicated in the proliferation of multiple myeloma (MM) cells and VEGF in bone marrow neovascularization, sorafenib is a drug offering the potential for targeting two important pathogenetic mechanisms involved in MM. Thus, sorafenib is being proposed for use in MM. In this review, the authors discuss the rationale for the use of sorafenib in MM. They then summarize the clinical development of sorafenib in MM, from initial Phase I to Phase II studies. A systematic literature review of the trials was performed using PubMed. Preliminary data from phase I/II trials showed that sorafenib had a good safety profile but minimal anti-myeloma activity as a single agent in relapsed/refractory patients. Results of phase II trials, evaluating sorafenib combined with new drugs, such as bortezomib and lenalidomide are eagerly awaited.


User-friendly, High-throughput, and Fully Automated Data Acquisition Software for Single-particle Cryo-electron Microscopy.
In the past several years, technological and methodological advancements in single-particle cryo-electron microscopy (cryo-EM) have paved a new avenue for the high-resolution structure determination of biological macromolecules. Despite the remarkable advances in cryo-EM, there is still scope for improvement in various aspects of the single-particle analysis workflow. Single-particle analysis demands a suitable software package for high-throughput automatic data acquisition. Several automatic data acquisition software packages were developed for automatic imaging for single-particle cryo-EM in the last eight years. This paper presents an application of a fully automated image acquisition pipeline for vitrified biomolecules under low-dose conditions. It demonstrates a software package, which can collect cryo-EM data fully, automatically, and precisely. Additionally, various microscopic parameters are easily controlled by this software package. This protocol demonstrates the potential of this software package in automated imaging of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) spike protein with a 200 keV cryo-electron microscope equipped with a direct electron detector (DED). Around 3,000 cryo-EM movie images were acquired in a single session (48 h) of data collection, yielding an atomic-resolution structure of the spike protein of SARS-CoV-2. Furthermore, this structural study indicates that the spike protein adopts two major conformations, 1-RBD (receptor-binding domain) up open and all RBD down closed conformations.


Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.
Female protein (FP) is a pentraxin of Syrian hamster which is a homologue of two human pentraxins, C-reaction protein (CRP) and amyloid P component (AP). Functionally, FP has been shown to be similar to CRP, although FP has more homology at the amino terminus with AP. The present work investigated amyloid in the Syrian hamster to determine whether FP was involved in a manner analogous to AP. FP was found to be a constituent of Syrian hamster amyloid. This conclusion was based on the following results: (a) FP was consistently detected in amyloid deposits by fluorescent microscopy with specific antisera; (b) The amount of FP extractable from hamster livers directly correlated with the presence of amyloid; and (c) 125I-FP injected intravenously into amyloidotic hamsters rapidly left the intravascular compartment and was found subsequently in amyloid deposits. This unusual alteration of plasma metabolism and amyloid localization of 125I-FP was a characteristic finding in amyloidotic hamsters and was specific for 125I-FP. Therefore, as an amyloid component, FP appears to be functionally similar to human AP. However, FP synthesis is under sex steroid control and the unique sex-limited expression of this pentraxin was associated with an equally novel propensity for deposition of amyloid in female hamsters under normal or experimental conditions. Thus, a high serum level of FP, as found in normal females or diethylstilbestrol-treated males, was associated with enhanced amyloidosis. Although speculative at present, a primary role for serum FP in hamster amyloid deposition may be experimentally approachable by hormonal manipulation of FP synthesis.


Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Portopulmonary hypertension.
Portopulmonary hypertension (POPH) is defined as pulmonary arterial hypertension (PAH) complicated by portal hypertension, with or without advanced hepatic disease. Significant percentage of patients with cirrhotic liver disease has high cardiac output and subsequently elevated pulmonary arterial pressures (PAP). However, patients with POPH develop a progressive increase in pulmonary vascular resistance (PVR), which is generally lower than that observed in other forms of PAH. The prognosis of untreated patients with POPH is very poor and the outcome of liver transplant (LT) in those patients is determined by the degree of severity of the associated pulmonary hemodynamics. In this narrative review, we describe the clinical presentation of POPH, the pathobiology, and the clinical implication of pulmonary hemodynamics. We also provide evidence-based recommendations for the diagnosic and management approaches of POPH.


Effects of orally administered liposomes with soybean-derived sterols and their glucosides on rat body weight.
The effects on Wistar rat body weight were examined after a single subcutaneous (s.c.) or oral (p.o.) administration of dipalmitoylphosphatidylcholine (DPPC) liposomes composed of soybean-derived sterols (SS) and their glucosides (SG) with or without entrapping recombinant human erythropoietin (Epo) for 1 week. Body weight increased significantly after both types of administration compared with the control groups irrespective of the existence of Epo. The neutral lipid concentration in plasma increased with the increase in body weight whereas the total contents of cholesterol and high density lipoprotein cholesterol in the plasma did not change significantly. The SS and SG suspensions following p.o. administration, however, did not alter the body weight. These findings suggest that liposomal SS and SG may be absorbed through the intestinal membrane and induce a change in the uptake of lipid, in contrast to the suspension state. SS in liposomes significantly increased body weight more than SG after p.o. administration.


Ex-vivo uses and applications of cytokines for adoptive immunotherapy in cancer.
Harnessing the power of the immune system to eliminate infection and cancer is a long-standing goal in clinical immunology. The development of a robust immune response to foreign antigen relies, in part, on communication between cellular components of the immune system. The proteins involved in governing the magnitude and longevity of an immune response are collectively called cytokines. Cytokines act directly on immune cells to induce proliferation, differentiation and tolerance, and signaling errors can lead to autoimmune disease or immune deficiency. Identification of the molecules involved in these signaling processes has allowed investigators to manipulate immune cells for therapeutic effect, both in vivo and ex vivo. While in vivo immune modulation using cytokines has produced some exciting results, the toxicity involved with systemic administration has limited their broad use in the clinic. Therefore, research has been focused on the ex vivo manipulation of immune cells for adoptive transfer to treat cancer and infection. This review will focus on the ex vivo manipulation of immune cells with particular emphasis on stimulating cytotoxic T cell responses. Adoptive transfer of ex vivo generated cell types may then be used to treat malignant and viral disease.


The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status.
Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (P(trend) < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer.


Motion parallax: effects of blur, contrast, and field size in normal and low vision.
Can people with different forms of low vision use motion parallax to improve depth judgments? We used a staircase method to compare depth thresholds using motion parallax and static viewing. We tested eighteen normal-vision subjects with a range of simulated deficits in acuity, contrast sensitivity, and simulated peripheral-field loss, and ten low-vision subjects with a wide range of acuity, contrast sensitivity, and field loss. Subjects viewed three vertical cylinders monocularly and indicated which one was at a different depth from the other two. For motion-parallax trials, observers moved their heads (in a viewing assembly on rollers) from side to side over a range of 6-12 cm. For static trials, the viewing assembly was fixed in place. Normal-vision subjects' depth thresholds with motion parallax were significantly smaller than those with static viewing by an average factor of 1.95 (p < 0.05) across all levels of acuity and contrast. For low-vision observers, the depth thresholds exhibited large individual differences; however, the motion-parallax thresholds were smaller than the static thresholds by an average factor of 2.05 (p < 0.01). These findings indicate that motion parallax can provide useful depth information for people with low vision.


Caffeic Acid Phenethyl Ester (CAPE): Biosynthesis, Derivatives and Formulations with Neuroprotective Activities.
Neurodegenerative disorders are characterized by a progressive process of degeneration and neuronal death, where oxidative stress and neuroinflammation are key factors that contribute to the progression of these diseases. Therefore, two major pathways involved in these pathologies have been proposed as relevant therapeutic targets: The nuclear transcription factor erythroid 2 (Nrf2), which responds to oxidative stress with cytoprotecting activity; and the nuclear factor NF-κB pathway, which is highly related to the neuroinflammatory process by promoting cytokine expression. Caffeic acid phenethyl ester (CAPE) is a phenylpropanoid naturally found in propolis that shows important biological activities, including neuroprotective activity by modulating the Nrf2 and NF-κB pathways, promoting antioxidant enzyme expression and inhibition of proinflammatory cytokine expression. Its simple chemical structure has inspired the synthesis of many derivatives, with aliphatic and/or aromatic moieties, some of which have improved the biological properties. Moreover, new drug delivery systems increase the bioavailability of these compounds in vivo, allowing its transcytosis through the blood-brain barrier, thus protecting brain cells from the increased inflammatory status associated to neurodegenerative and psychiatric disorders. This review summarizes the biosynthesis and chemical synthesis of CAPE derivatives, their miscellaneous activities, and relevant studies (from 2010 to 2023), addressing their neuroprotective activity in vitro and in vivo.


Localization of kinesin in cultured cells.
Kinesin was isolated from bovine brain and used to elicit polyclonal antibodies in rabbits. The specificities of the resulting antibodies were evaluated by immunoblotting. Antibodies purified from these sera by their affinity for brain kinesin react with a polypeptide of approximately 120 kD in extracts from bovine brain, PtK1 cells, and mouse neuroblastoma cells. They bind to a pair of polypeptides of approximately 120 kD present in crude kinesin prepared from Xenopus eggs and with a single polypeptide of approximately 115 kD in extracts from Drosophila embryos. Antibodies raised against kinesin prepared from fruit fly embryos (by W. M. Saxton, Indiana University, Bloomington, IN) and from neural tissues of the squid (by M. P. Sheetz, Washington University, St. Louis, MO) cross react with the mammalian, the fly, and the frog polypeptides. Kinesin antigen was localized in cultured cells by indirect immunofluorescence. PtK1 cells in interphase showed dim background staining of cytoplasmic membranous components and bright staining of a small, fibrous, juxtanuclear structure. Double staining with antibodies to microtubules showed that the fibrous object was usually located near the centrosome. On the basis of shape, size, and location, we identify the kinesin-positive structure as a primary cilium. PtK1 cells in mitosis are stained at their poles during all stages of division. The structure stained is approximately spherical, but wisps of faint fluorescence also extend into the body of the spindle. Antibodies to squid or fruit fly kinesin produce identical patterns in PtK1 cells. Controls with preimmune and preabsorbed sera show that the centrosome staining is not due simply to the common tendency of rabbit antisera to stain this structure. Similar centrosome and spindle pole staining was visible when antibodies to bovine brain or squid kinesin were applied to the A6 cell line (kidney epithelial cells from Xenopus laevis). Some possible functions of kinesin localized at the spindle poles are discussed.


Coherence properties of a broadband femtosecond mid-IR optical parametric oscillator operating at degeneracy.
We study coherence properties of a χ(²) optical parametric oscillator (OPO), which produces 2/3-octave-wide spectrum centered at the subharmonic (3120 nm) of the femtosecond pump laser. Our method consists of interfering the outputs of two identical, but independent OPOs pumped by the same laser. We demonstrate that the two OPOs show stable spatial and temporal interference and are mutually locked in frequency and in phase. By observing a collective heterodyne beat signal between the two OPOs we show that one can deterministically choose, by cavity length adjustment, between the two frequency states corresponding to the two sets of modes shifted with respect to each other by half of the laser pulse repetition rate. Moreover, we observe that the existence of two opposite phase states, a known common feature of a parametrically driven n = 2 subharmonic oscillator, reveals itself in our experiment as a common phase, 0 or π, being established through the whole set of some 300 thousand longitudinal modes.


Phonological processing in human auditory cortical fields.
We used population-based cortical-surface analysis of functional magnetic imaging data to characterize the processing of consonant-vowel-consonant syllables (CVCs) and spectrally matched amplitude-modulated noise bursts (AMNBs) in human auditory cortex as subjects attended to auditory or visual stimuli in an intermodal selective attention paradigm. Average auditory cortical field (ACF) locations were defined using tonotopic mapping in a previous study. Activations in auditory cortex were defined by two stimulus-preference gradients: (1) Medial belt ACFs preferred AMNBs and lateral belt and parabelt fields preferred CVCs. This preference extended into core ACFs with medial regions of primary auditory cortex (A1) and the rostral field preferring AMNBs and lateral regions preferring CVCs. (2) Anterior ACFs showed smaller activations but more clearly defined stimulus preferences than did posterior ACFs. Stimulus preference gradients were unaffected by auditory attention suggesting that ACF preferences reflect the automatic processing of different spectrotemporal sound features.


Application of waves for remediation of contaminated aquifers.
A theory developed suggested that significant displacement of solute in saturated porous media results from the propagation of compression waves. Four independent one-dimensional experimental setups and a variety of laboratory methods were used to confirm the predictions of the theory, specifically aimed at developing a novel method of inducing compression waves for use in remediation of contaminated aquifers. Compaction and shock waves were emitted through granular porous media saturated with saline water. The changes in solute concentration at observation points along the propagating wave were used to verify the validity of theory. The first setup was designed mainly to provide a qualitative assessment (i.e., changes in pressure due to the propagating wave were not recorded). In situ quantitative measurements of the pressure and electrical conductivity profiles along a sand column were done with the second and third experimental setups, respectively, to short and long shock waves. In the fourth setup, solute displacement was visualized by X-ray absorption. The findings were consistent with the theory in all experimental setups.


In situ self-assembly of conjugated polyelectrolytes for cancer targeted imaging and photodynamic therapy.
The construction of intelligent self-assembly systems with cancer targeting photodynamic therapy abilities is highly required for increasing the precise therapeutic efficiency in clinical treatment. Herein, a cationic water soluble conjugated polymer (PFT-SH) functionalized with thiol groups was designed and synthesized via a palladium-catalyzed Suzuki coupling reaction. Firstly, PFT-SH can enter cells and form loose aggregations by hydrophobic and π-π stacking interactions. Secondly, a high level of H2O2 in cancer cells oxidizes sulfhydryl groups to disulfide bonds and then forms more and larger aggregations. Finally, PFT-SH showed remarkable ROS producing ability under white light irradiation with 78% quantum yields (ΦΔ). Due to this unique self-aggregation property, PFT-SH was successfully used to achieve in situ self-assembly specifically inside cancer cells for targeted imaging. Both the specific aggregation of PFT-SH in cancer cells and its ROS producing ability led to its use in the targeted killing of cancer cells through efficient photodynamic therapy.


Contact and fumigant toxicity of hexane flower bud extract of Syzygium aromaticum and its compounds against Pediculus humanus capitis (Phthiraptera: Pediculidae).
The head lice, Pediculus humanus capitis De Geer is an obligate ectoparasite of humans that causes pediculosis capitis, a nuisance for millions of people worldwide, with high prevalence in children. P. humanus capitis has been treated by methods that include the physical remotion of lice, various domestic treatments, and conventional insecticides. None of these methods render complete protection, and there is clear evidence for the evolution of resistance and cross-resistance to conventional insecticides. Non-toxic alternative options are hence needed for head lice treatment and/or prevention, and natural products from plants are good candidates for safer control agents that may provide good anti-lice activity. The plant extracts are good and safe alternatives due to their low toxicity to mammals and easy biodegradability. The present study carried out the pediculocidal activity using the hexane flower bud extract of Syzygium aromaticum (Myrtaceae) against P. humanus capitis examined by direct contact and fumigant toxicity (closed- and open-container methods) bioassay. The chemical composition of S. aromaticum flower bud hexane extract was analyzed by gas chromatography-mass spectrometry. The major chemical constituent (58.79%) of flower bud hexane extract S. aromaticum was identified as chavibetol (5-allyl-2-methoxyphenol) by comparison of mass spectral data and retention times. The hexane extract of S. aromaticum was subjected to gas chromatography analysis, and totally 47 compounds were detected, of which chavibetol was predominantly present. The other major constituents present in the hexane extract were eugenol acetate (phenol,2-methoxy-4-(2-propenyl)-,acetate (15.09%), caryophyllene-(I1) (2,6,10,10-tetramethyl bicyclo [7.2.0] undeca-1,6-diene (13.75%), caryophyllene oxide (3.04%), 2,6,6,9-tetramethyl-1,4,8-cycloundecatriene (1.67%), and copaene (1.33%). The filter paper contact bioassay study showed pronounced pediculicidal activity in the flower bud hexane extract of S. aromaticum. The toxic effect was determined for every five in an 80-min treatment. The result showed percent mortality of 40, 82, and 100 at 5, 10, and 20 min, and the median lethal time (LT(50)) value was 5.83 (0.5 mg/cm(2)); 28, 82, and 100 at 5, 10, and 30 min. (LT(50) = 6.54; 0.25 mg/cm(2)); and 13, 22, 42, 80, and 100 at 5, 10, 20, 40, and 80 min (LT(50) = 18.68; 0.125 mg/cm(2)), respectively. The vapor phase toxicity was tested at 0.25 mg/cm(2). There was a significant difference in pediculicidal activity of S. aromaticum extract against P. humanus capitis between closed- and open-container methods. Adult mortalities were determined for every five in 60 min (closed method) and for every ten in 180 min (open method). The closed method showed the percent mortality was 45, 88, and 100 at 5, 10, and 15 min (LT(50) = 5.39), respectively. In the open-container method, the percent mortality was observed 5, 20, 47, 84, and 100 at 10, 20, 60, 120, and 180 min (LT(50) = 47.91), respectively. The mortality was more effective in the closed containers than in open ones, indicating that the effect of hexane extract was largely a result of action in the vapor phase exhibited fumigant toxicity. Studies of anti-lice activity of extract provide the basis for preliminary conclusions of structure activity relationships; although no clear patterns can yet be drawn. We here attempt to provide a concise compilation of the available information on anti-lice activity of plant extracts and plant-derived compounds.


Comparison of MANTA versus Perclose Prostyle large-bore vascular closure devices during transcatheter aortic valve implantation.
New vascular closure devices (VCD) are being introduced for achieving hemostasis after transcatheter aortic valve implantation (TAVI). However, no safety or efficacy data have been published compared to other contemporary VCD. To compare the safety and efficacy of suture-based Perclose Prostyle as compared to plug-based MANTA device. A total of 408 consecutive TAVI patients from two high volume TAVI centers were included in the present study. Patients were grouped according to VCD: Prostyle versus MANTA. Propensity score matching (PSM) and multivariable analysis were utilized to compare clinical endpoints between the two groups. The primary endpoint was any vascular complication (VC) according to VARC-3 criteria. After PSM, a total of 264 patients were analyzed, of them 132 in each group. Overall baseline characteristics of the two groups were comparable. Primary end-point was similar between MANTA as compared to Prostyle (16.7% vs. 15.3% respectively, p = 0.888). The main driver for VC among MANTA group were minor vascular complications (15.2%). Conversely, minor and major VC contributed equally to the primary endpoint among Prostyle group (7.6%) (p = 0.013). No outcome predictors were identified in multivariate analysis. VCD for transfemoral TAVI using the new-generation Prostyle device or the MANTA device achieved comparable VARC-3 VC rates.


Increasing risk over time of weather-related hazards to the European population: a data-driven prognostic study.
The observed increase in the effects on human beings of weather-related disasters has been largely attributed to the rise in population exposed, with a possible influence of global warming. Yet, future risks of weather-related hazards on human lives in view of climate and demographic changes have not been comprehensively investigated. We assessed the risk of weather-related hazards to the European population in terms of annual numbers of deaths in 30 year intervals relative to the reference period (1981-2010) up to the year 2100 (2011-40, 2041-70, and 2071-100) by combining disaster records with high-resolution hazard and demographic projections in a prognostic modelling framework. We focused on the hazards with the greatest impacts-heatwaves and cold waves, wildfires, droughts, river and coastal floods, and windstorms-and evaluated their spatial and temporal variations in intensity and frequency under a business-as-usual scenario of greenhouse gas emissions. We modelled long-term demographic dynamics through a territorial modelling platform to represent the evolution of human exposure under a corresponding middle-of-the-road socioeconomic scenario. We appraised human vulnerability to weather extremes on the basis of more than 2300 records collected from disaster databases during the reference period and assumed it to be static under a scenario of no adaptation. We found that weather-related disasters could affect about two-thirds of the European population annually by the year 2100 (351 million people exposed per year [uncertainty range 126 million to 523 million] during the period 2071-100) compared with 5% during the reference period (1981-2010; 25 million people exposed per year). About 50 times the number of fatalities occurring annually during the reference period (3000 deaths) could occur by the year 2100 (152 000 deaths [80 500-239 800]). Future effects show a prominent latitudinal gradient, increasing towards southern Europe, where the premature mortality rate due to weather extremes (about 700 annual fatalities per million inhabitants [482-957] during the period 2071-100 vs 11 during the reference period) could become the greatest environmental risk factor. The projected changes are dominated by global warming (accounting for more than 90% of the rise in risk to human beings), mainly through a rise in the frequency of heatwaves (about 2700 heat-related fatalities per year during the reference period vs 151 500 [80 100-239 000] during the period 2071-100). Global warming could result in rapidly rising costs of weather-related hazards to human beings in Europe unless adequate adaptation measures are taken. Our results could aid in prioritisation of regional investments to address the unequal burden of effects on human beings of weather-related hazards and differences in adaptation capacities. European Commission.


Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients.
In a double-blind placebo substitution study, 27 chronic schizophrenic patients successfully treated for more than 2 years with fluphenazine decanoate were withdrawn from the drug. These patients showed a significantly higher relapse rate than the matched control group of 26 patients who continued to receive fluphenazine (56% versus 19%, p less than .001). This high rate of relapse is viewed as indicating the need for continued medication in most chronic schizophrenic patients.


Characterisation of the Porphyromonas gingivalis Manganese Transport Regulator Orthologue.
PgMntR is a predicted member of the DtxR family of transcriptional repressors responsive to manganese in the anaerobic periodontal pathogen Porphyromonas gingivalis. Our bioinformatic analyses predicted that PgMntR had divalent metal binding site(s) with elements of both manganous and ferrous ion specificity and that PgMntR has unusual twin C-terminal FeoA domains. We produced recombinant PgMntR and four variants to probe the specificity of metal binding and its impact on protein structure and DNA binding. PgMntR dimerised in the absence of a divalent transition metal cation. PgMntR bound three Mn(II) per monomer with an overall dissociation constant Kd 2.0 x 10(-11) M at pH 7.5. PgMntR also bound two Fe(II) with distinct binding affinities, Kd1 2.5 x 10(-10) M and Kd2 ≤ 6.0 x 10(-8) M at pH 6.8. Two of the metal binding sites may form a binuclear centre with two bound Mn2+ being bridged by Cys108 but this centre provided only one site for Fe2+. Binding of Fe2+ or Mn2+ did not have a marked effect on the PgMntR secondary structure. Apo-PgMntR had a distinct affinity for the promoter region of the gene encoding the only known P. gingivalis manganese transporter, FB2. Mn2+ increased the DNA binding affinity of PgMntR whilst Fe2+ destabilised the protein-DNA complex in vitro. PgMntR did not bind the promoter DNA of the gene encoding the characterised iron transporter FB1. The C-terminal FeoA domain was shown to be essential for PgMntR structure/function, as its removal caused the introduction of an intramolecular disulfide bond and abolished the binding of Mn2+ and DNA. These data indicate that PgMntR is a novel member of the DtxR family that may function as a transcriptional repressor switch to specifically regulate manganese transport and homeostasis in an iron-dependent manner.


Treatment of venous thromboembolism in cancer patients.
The occurrence of venous thromboembolism complicates the management of the patient with malignant disease because of the need for anticoagulant therapy. Cancer patients have an ongoing thrombotic stimulus due to the underlying cancer and its associated treatments, but are also considered to be at increased risk for anticoagulant-related bleeding. In recent years, the results of clinical trials have demonstrated the safety and efficacy of bodyweight-adjusted subcutaneous low-molecular-weight heparin administered at home for patients with acute deep vein thrombosis. This approach is particularly attractive in patients with cancer, in whom quality of life is an important consideration. There are no trials to date which specifically address the question of the duration of oral anticoagulant therapy in cancer patients. However, data can be extrapolated from trials evaluating the duration of oral anticoagulant therapy in other high-risk patients. Hence, cancer patients should continue oral anticoagulant therapy for as long the cancer remains active (usually at least 6 months). There remain a number of unanswered questions regarding the clinical management of thromboembolism in the cancer patient.


Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.
Quantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease. Prospective cross-sectional study at an academic referral center. Thirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy. Autofluorescence (AF) images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7° to 9° in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both. Quantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants. ABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9±8.3 years) than patients without ABCA4 mutations (mean age, 42.1±14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range. The qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.


Regional variation in pig farmer awareness and actions regarding Japanese encephalitis in Nepal: implications for public health education.
Japanese encephalitis (JE) is a mosquito-borne zoonotic disease that has pigs as the major amplifying hosts. It is the most important cause of viral encephalitis in people in Nepal and is spreading in its geographic distribution in that country. Pig farming is increasing in Nepal due to reducing cultural biases against pigs and government programs to support pig farming for poverty alleviation. Major strategies for JE prevention and control include education, vector control, and immunization of people and pigs. This study used a survey of 400 pig farmers in 4 areas of Nepal with different JE and pig farming histories to explore regional variations in farmer awareness and actions towards JE, the association of awareness and actions with farm and farmer variables, and the implications of these associations for public health education. Exposure to JE risk factors was common across pig farms and pig farming districts but there were significant district level differences in knowledge and practices related to on-farm JE risk reduction. Social factors such as literacy, gender, and cultural practices were associated with farmer attitudes, knowledge and practices for JE control. JE vaccine uptake was almost non-existent and mosquito control steps were inconsistently applied across all 4 districts. Income was not a determining factor of the differences, but all farmers were very poor. The low uptake of vaccine and lack of infrastructure or financial capacity to house pigs indoors or away from people suggest that farmer personal protection should be a priority target for education in Nepal. This study re-enforces the need to attack root causes of people's personal disease prevention behaviours and take into account local variation in needs and capacities when designing health or agriculture education programs.


[Reiterative poly(A) synthesis on oligonucleotide templates in an Escherichia coli RNA-polymerase system].
The poly(A) synthesis in the E. coli RNA-polymerase system on the oligothymidilates, oligouridilates and oligonucleotides d(5'-OH-CCATCTTTT-3'-OH) and d(5'-HO-TCTTTT-3'-OH) as templates was studied. The reaction was shown to proceed more intensively on the oligothymidilates compared to oligouridilates. The insertion of phosphate residues into 3' end of oligouridilates deteriorates properties of their templates though the length of the synthesized poly(A) is not changed in this case. The synthesis of poly(A) on the nonanucleotide d(CCATCTTTT) proceeds intensively, but there is no AMP incorporation on the hexanucleotide of similar structure. The author's data combined with certain literature results suppose that the template activity of the oligonucleotides containing homopolymer sequences is determined in the RNA-polymerase system in reiterative regime by two factors: by the total amount of oligonucleotide links and by the homopolymer block size. The total amount of links seems to be important for the oligonucleotide enzyme bind stability and must comprise not less than 6 charges of the phosphate groups. The homopolymer block size must be no less than of 4 links.


Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart.
The origin and developmental mechanisms underlying coronary vessels are not fully elucidated. Here we show that myocardium-derived angiopoietin-1 (Ang1) is essential for coronary vein formation in the developing heart. Cardiomyocyte-specific Ang1 deletion results in defective formation of the subepicardial coronary veins, but had no significant effect on the formation of intramyocardial coronary arteries. The endothelial cells (ECs) of the sinus venosus (SV) are heterogeneous population, composed of APJ-positive and APJ-negative ECs. Among these, the APJ-negative ECs migrate from the SV into the atrial and ventricular myocardium in Ang1-dependent manner. In addition, Ang1 may positively regulate venous differentiation of the subepicardial APJ-negative ECs in the heart. Consistently, in vitro experiments show that Ang1 indeed promotes venous differentiation of the immature ECs. Collectively, our results indicate that myocardial Ang1 positively regulates coronary vein formation presumably by promoting the proliferation, migration and differentiation of immature ECs derived from the SV.


Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine.
Bupivacaine is currently the most widely used long-acting local anaesthetic. Its uses include surgery and obstetrics; however, it has been associated with potentially fatal cardiotoxicity, particularly when given intravascularly by accident. Levobupivacaine, a single enantiomer of bupivacaine, has recently been introduced as a new long-acting local anaesthetic with a potentially reduced toxicity compared with bupivacaine. Numerous preclinical and clinical studies have compared levobupivacaine with bupivacaine and in most but not all studies there is evidence that levobupivacaine is less toxic. Advantages for levobupivacaine are seen on cardiac sodium and potassium channels, on isolated animal hearts and in whole animals, anaesthetised or awake. In particular the intravascular dose of levobupivacaine required to cause lethality in animals is consistently higher compared with bupivacaine. In awake sheep, for example, almost 78% more levobupivacaine was required to cause death. In contrast, in anaesthetised dogs no differences were seen in the incidence of spontaneous or electrical stimulation- induced ventricular tachycardia and fibrillations among animals exposed to levobupivacaine or bupivacaine. The reversibility of levobupivacaine-induced cardiotoxicity has also been assessed. Some data point to an advantage of levobupivacaine over bupivacaine but this potential advantage was not confirmed in a recent study in anaesthetised dogs. Three clinical studies have been conducted using surrogate markers of both cardiac and CNS toxicity. In these studies levobupivacaine or bupivacaine were given by intravascular injection to healthy volunteers. Levobupivacaine was found to cause smaller changes in indices of cardiac contractility and the QTc interval of the electrocardiogram and also to have less depressant effect on the electroencephalogram. Assuming that levobupivacaine has the same local anaesthetic potency as bupivacaine, then, all things being equal, it is difficult to argue that levobupivacaine should not displace bupivacaine as the long-acting local anaesthetic of choice. It would appear, however, that levobupivacaine has not yet significantly displaced bupivacaine from the markets in which it is sold. This may be due to a lack of perceived safety benefit and/or consideration of the additional costs that are associated with switching to levobupivacaine, which is approximately 57% more expensive than bupivacaine. If the price of levobupivacaine were closer to bupivacaine then the argument to switch to levobupivacaine would undoubtedly be much stronger. With the continued clinical use of levobupivacaine the database available to make comparisons will increase and this may allow cost-benefit arguments to be made more forcefully for levobupivacaine in the future.


[Review of our home parenteral nutrition (HPN) and home enteral nutrition (HEN) cases].
We reviewed our cases of HPN and HEN after percutaneous gastrostomy. We had 38 patients (26 men, 12 women) on HPN. Of them, 23 (17 men, 6 women) had an implantable subcutaneous infusion port. The average age of HPN cases was 69 (range 40-92) years, and 34 patients (89%) suffered from a malignant disease. The mean duration of HPN was 104 (range 2-543) days. Home anti-cancer chemotherapy was provided for 2 patients. Percutaneous gastrostomy was performed for 7 patients (4 men, 3 women) by endoscopy (PEG, 6 cases) and 1 patient needed an open laparotomy. Their average age was 60 (range 40-83) years. 5 patients with a malignant disease who were in HPN underwent gastrostomy for decompression drainage of a digestive tract obstruction. 2 patients had a benign disease and were on HEN for a long time. We experienced 2 cases of skin complications, one under HPN and the other under HEN, but no severe complication experienced. HPN and HEN contribute to improve the patients' QOL.


The effects of prehospital plasma on patients with injury: a prehospital plasma resuscitation.
The prehospital resuscitation of the exsanguinating patient with trauma is time and resource dependent. Rural trauma care magnifies these factors because transportation time to definitive care is increased. To address the early resuscitation needs and trauma-induced coagulopathy in the exsanguinating patient with trauma an aeromedical prehospital thawed plasma-first transfusion protocol was used. Retrospective review of trauma and flight registries between February 1, 2009, and May 31, 2011, was performed. The study population included all patients with traumatic injury transported by rotary wing aircraft who met criteria for massive transfusion protocol A total of 59 patients identified over 28 months met criteria for initiation of aeromedical initiation of prehospital blood product resuscitation. Nine patients received thawed plasma-first protocol compared with 50 controls. The prehospital plasma group was more commonly on warfarin (22 vs. 2%, p = 0.036) and had a greater degree of coagulopathy measured by international normalized ratio at baseline (2.6 vs. 1.5, p = 0.004) and trauma center arrival (1.6 vs. 1.3, p < 0.001). The prehospital plasma group had a predicted mortality nearly three times greater than controls based on Trauma and Injury Severity Score (0.24 vs. 0.66, p = 0.005). The use of prehospital plasma resuscitation led to a plasma-red blood cell ratio that more closely approximated a 1:1 resuscitation en route (1.3:1.0 vs. not applicable, p < 0.001), at 30 minutes (1.3:1.0 vs. 0.14:1.0, p < 0.001), at 6 hours (0.95:1.0 vs. 0.42:1.0, p < 0.001), and at 24 hours (1.0:1.0 vs. 0.45:1.0, p < 0.001). An equivalent amount of packed red blood cells were transfused between the groups. Despite more significant hypotension, less crystalloid was used in the prehospital thawed plasma group, through 24 hours after injury (6.3 vs. 16.4 L, p = 0.001). Use of plasma-first resuscitation in the helicopter system creates a field ready, mobile blood bank, allowing early resuscitation of the patient demonstrating need for massive transfusion. There was early treatment of trauma-induced coagulopathy. Although there was not a survival benefit demonstrated, there was resultant damage control resuscitation extending to 24 hours in the plasma-first cohort.


Bone structure: from angstroms to microns.
Bone has a complex hierarchical structure, which despite much investigation, is still not well understood. Here we bring together pieces of this complicated puzzle, albeit from different sources, to present a tentative overview of bone structure. The basic building blocks are the extremely small plate-shaped crystals of carbonate apatite, just hundreds of angstroms long and wide and some 20-30 A thick. They are arranged in parallel layers within the collagenous framework. At the next hierarchical level these mineral-filled collagen fibrils are ordered into arrays in which the fibril axes and the crystal layers are all organized into a 3-dimensional structure that makes up a single layer or lamella of bone a few microns thick. The orientations of the collagen fibrils and the crystal layers in alternating lamellae of rat bone differ such that in the thinner lamellae, the fibrils and the crystal layers are parallel to the lamellar boundaries. In the thicker lamellae the fibrils are parallel to the boundary, but the crystal layers are rotated out of the plane of the boundary. In many bones these alternating lamellae are organized into even larger ordered structures to produce what is truly a remarkably ordered material, all the way from the molecular scale to the macroscopic product.


Gene-environment interaction and the intergenerational transmission of parenting: testing the differential-susceptibility hypothesis.
The current study evaluated the differential-susceptibility hypothesis in explaining the intergenerational transmission of parenting, using data from the National Longitudinal Study of Adolescent Health (Add Health). Exposure to maternal parenting was measured prospectively when respondents were adolescents and parental stress was measured when they were parents themselves, some 14 years later, on average. Cumulative-genetic plasticity was measured by dominantly coding the presence of putative plasticity alleles from four genes: the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, and the short allele of 5HTTLPR. Results showed that the more plasticity alleles individuals carried (range 0-4), the more that parenting experienced in adolescence predicted future parenting experience. Those respondents with the most plasticity alleles not only experienced the highest levels of parental stress when exposed to negative maternal parenting in adolescence but the lowest levels when exposed to positive maternal parenting in adolescence. These results indicate that differential susceptibility is operative in the case of the intergenerational transmission of parenting, which could explain why estimates of such transmission have proven so modest in studies which fail to consider GXE interactions.


Taking the tension out of hypertension: a prospective study of psychological well being and hypertension.
Previous studies have shown that psychological well being is associated with reduced risk of cardiovascular disease. However, whether well being might be specifically associated with reduced risk of hypertension has not been rigorously investigated in prospective studies. This study examined the prospective association between two measures of psychological well being and incident hypertension. Participants were 6384 healthy British civil servants aged 39-63 from the Whitehall II cohort. Psychological well being (emotional vitality and optimism) and cardiovascular risk factors (demographic characteristics, health status, health behaviors, psychological ill being) were assessed during the 1991-1994 baseline. Incident hypertension was defined by clinical measures of SBP or DBP at least 140/90 mmHg, self-reported physician-diagnosed hypertension, or treatment for hypertension. Follow-up assessments of hypertension took place approximately every 3 years through 2002-2004. Cox proportional hazards regression models estimated hazard ratios. There were 2304 cases of incident hypertension during the follow-up period. High versus low emotional vitality was associated with a significantly reduced risk of hypertension in an age-adjusted model (hazard ratio = 0.89; 95% confidence interval 0.80-0.98). This association was maintained after controlling for demographic characteristics and health status, but was slightly attenuated after adjusting for health behaviors and ill being. Optimism was not significantly associated with hypertension. High emotional vitality was associated with reduced hypertension risk; favorable health behaviors explained only part of the relationship. Associations did not differ by age, were similar for men and women, and were maintained after accounting for ill being.


Retrospective assessment of seasonal allergic symptoms: over-rating but useful.
The history of the severity of seasonal allergic symptoms is often obtained post-seasonally as a retrospective assessment. Correct rating is essential when determining the efficacy of pharmaceutical treatment, indications for allergen-specific immunotherapy (SIT), or inclusion into controlled clinical studies. To investigate the agreement between in- and post-seasonal ratings of seasonal symptoms, and to investigate whether the effect of SIT could be detected retrospectively. Thirty-five birch pollen-allergic patients were allocated to SIT or placebo in a double-blind study. Assessment of severity of symptoms from the nose, eyes and lungs were performed daily during the season 2000, and post-seasonally 6 months after the season in 1999 and 2000. A four-point verbal descriptor scale (VDS-4) was used at all occasions. A mean in-seasonal symptom rating was calculated for four periods: the day, the week and the 2 weeks with the highest symptoms score, and the arithmetic season (the period covering the mid-90% of the accumulated pollen count). In- and post-seasonal ratings were compared with Cohen's weighted kappa (kappaw). Agreement between in-seasonal and retrospective ratings was fair to moderate (kappaw: 0.30-0.60). Post-seasonal ratings were most related to symptoms experienced in the week with the highest symptom scores, and least related to the arithmetic season. The post-seasonal ratings were significantly skewed towards higher symptom scores than the mean of in-seasonal ratings in periods >or= 2 weeks. Despite being comparable before intervention, only in the SIT-treated group was a significant decrease in post-season ratings of severity of rhinoconjunctivitis apparent (P < 0.05). Asthma scores were not reduced but fewer patients in the SIT group reported lung symptoms (P < 0.001). Post-seasonal assessment of seasonal allergic symptoms generally describes a shorter period than the arithmetic season. Post-season assessment tends to over-rate average symptom severity, but appears sufficiently sensitive to detect treatment efficacy.


Identifying the Later-Generation Descendants of U.S. Immigrants: Issues Arising from Selective Ethnic Attrition.
Evaluating the long-term socioeconomic integration of immigrants in the United States requires analyses of differences between foreign-born and U.S.-born residents, as well as analyses across generations of the U.S.-born. Regrettably, though, standard data sources used to study these populations provide very limited information pertaining to generation. As a result, research on the U.S.-born descendants of immigrants often relies on the use of subjective measures of racial/ethnic identification. Because ethnic attachments tend to fade across generations, these subjective measures might miss a significant portion of the later-generation descendants of immigrants. Moreover, if such "ethnic attrition" is selective on socioeconomic attainment, it can distort assessments of integration and generational progress. We discuss evidence that suggests that ethnic attrition is sizable and selective for the second- and third-generation populations of key Hispanic and Asian national-origin groups, and that correcting for the resulting biases is likely to raise the socioeconomic standing of the U.S.-born descendants of most Hispanic immigrants relative to their Asian counterparts.


Fasting induces denervation natriuresis in the conscious rat.
The participation of renal nerves in the regulation of sodium excretion was studied in fed and overnight-fasted rats subjected to acute or chronic left kidney denervation or sham operation. Clearance experiments were performed on conscious restrained animals. Urine flow, glomerular filtration rate (GFR), and urinary sodium excretion were not different in left and right kidneys of sham-operated rats. In fed conscious rats, urine flow, GFR, and urinary sodium excretion of innervated (I) and denervated (D) kidneys were similar. In fasted conscious rats, significant denervation natriuresis was observed after both acute (I, 1.06 +/- 0.27; D, 1.56 +/- 0.40 mumol . min-1 . g-1, P less than 0.05) and chronic (I, 1.55 +/- 0.19; D, 2.20 +/- 0.18 mumol . min-1 . g-1, P less than 0.01) renal sympathectomy, whereas urine flow and GFR in I and D kidneys were not different. Additional experiments revealed that extracellular fluid and plasma volumes of fasted rats were decreased by approximately 10% compared with those of fed animals due to a significant overnight natriuresis and negative water balance. In fed conscious rats, the renal nerves do not seem to participate in the regulation of sodium excretion. The presence of denervation natriuresis in conscious fasted rats suggests that renal nerves are involved in sodium conservation during fasting to maintain extracellular fluid and plasma volume.


Establishing a nursing strategic agenda: the whys and wherefores.
The health system nursing leader is responsible for providing high-quality, service-oriented nursing care to deliver such care with disciplined cost management; to lead and develop a group of nursing executives and managers at the facility level; to establish nursing professional development programs; to build and maintain an effective supply of nurses; and to advocate for nurses and patients. Balancing these imperatives requires thoughtful strategic planning and disciplined execution. In their absence, organizations flounder to address a single problem in isolation and struggle to perform against outcomes. One organization approached the challenge by engaging in a comprehensive, accelerated strategic planning process. The experience brought together 11 hospital nursing executives in consensus around a prioritized strategic agenda. This article is a case study of the approach used to define a nursing agenda.


The current state of cognitive therapy: a 40-year retrospective.
The basic framework of the cognitive theory of psychopathology and cognitive therapy of specific psychiatric disorders was developed more than 40 years ago. Since that time, there has been continuing progress in the development of cognitive theory and therapy and in the empirical testing of both. A substantial body of research supports the cognitive model of depression and, to a somewhat lesser extent, the various anxiety disorders. Cognitive therapy (CT), often labeled as the generic term cognitive behavior therapy, has been shown to be effective in reducing symptoms and relapse rates, with or without medication, in a wide variety of psychiatric disorders. Suggestions for future research and applications are presented.


Rising prevalence of antidepressants among US youths.
To examine changes in antidepressant (ATD) prevalence and the sociodemographic and clinical correlates of ATD use among youths who are treated in community practice settings. A retrospective study was undertaken using large data sets from 3 US sites. Outpatient prescription and clinical service records of youths who were aged 2 to 19 and enrolled in Midwestern Medicaid (MWM) and mid-Atlantic Medicaid (MAM) state programs and a group-model health maintenance organization (HMO) were organized into seven 1-year cross-sectional data sets from 1988 through 1994 to evaluate ATD utilization patterns. In 1994, ATD prevalence per 1000 youths was 19.10 (MWM), 17.78 (MAM), and 12.85 (HMO), which represented a consistent increase in prevalence from 1988-1994: 2.9-fold (MWM), 4.6-fold (MAM), and 3.6-fold (HMO). Despite the rapidly expanding use of selective serotonin reuptake inhibitors prescribed mainly for depression, more than half of ATD use in 1994 was still attributable to tricyclic antidepressants prescribed mainly for attention-deficit/hyperactivity disorder. ATD prevalence was generally predominant among 10- to 14-year-old boys and among 15- to 19-year-old girls. In the Medicaid populations, 42% (MAM) and 72% (MWM) of ATD-treated youths had primary care services, whereas the bulk of the remainder had psychiatric services. Attention-deficit/hyperactivity disorder followed by depression led the physician-reported primary care diagnoses associated with ATD use, whereas that diagnostic rank order was reversed for youths who received psychiatric services. ATD treatments among youths substantially increased in the 1990s. This was generated primarily by primary care providers, and thus evaluations of the outcome of ATD treatment need to target primary care in addition to psychiatric providers. Longitudinal study designs are needed to evaluate the use of ATDs in youths in regard to the duration of treatment, combination medications, and the reasons for treatment.


Dihydropyridine receptor alpha subunits in normal and dysgenic muscle in vitro: expression of alpha 1 is required for proper targeting and distribution of alpha 2.
We have studied the subcellular distribution of the alpha 1 and alpha 2 subunits of the skeletal muscle dihydropyridine (DHP) receptor with immunofluorescence labeling of normal and dysgenic (mdg) muscle in culture. In normal myotubes both alpha subunits were localized in clusters associated with the T-tubule membranes of longitudinally as well as transversely oriented T-tubules. The DHP receptor-rich domains may represent the sites where triad junctions with the sarcoplasmic reticulum are being formed. In cultures from dysgenic muscle the alpha 1 subunit was undetectable and the distribution patterns of the alpha 2 subunit were abnormal. The alpha subunit did not form clusters nor was it discretely localized in the T-tubule system. Instead, alpha 2 was found diffusely distributed in parts of the T-system, in structures in the perinuclear region and in the plasma membrane. These results suggest that an interaction between the two alpha subunits is required for the normal distribution of the alpha 2 subunit in the T-tubule membranes. Spontaneous fusion of normal non-muscle cells with dysgenic myotubes resulted in a regional expression of the alpha 1 polypeptide near the foreign nuclei, thus defining the nuclear domain of a T-tubule membrane protein in multi-nucleated muscle cells. Furthermore, the normal intracellular distribution of the alpha 2 polypeptide was restored in domains containing a foreign "rescue" nucleus; this supports the idea that direct interactions between the DHP receptor alpha 1 and alpha 2 subunits are involved in the organization of the junctional T-tubule membranes.


Identification of granulocyte colony-stimulating factor and interleukin-6 as candidate biomarkers of CBLB502 efficacy as a medical radiation countermeasure.
Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure.


Treating Hypertrophic Burn Scar With 2940-nm Er:YAG Laser Fractional Ablation Improves Scar Characteristics as Measured by Noninvasive Technology.
Their group previously demonstrated high-patient satisfaction for the treatment of hypertrophic burn scar (HBS) with the erbium: yttrium aluminum garnet (Er:YAG) laser, but this and other literature supporting the practice suffer from a common weakness of a reliance on subjective assessments by patients or providers. Herein, they sought to prospectively study the effects of Er:YAG fractional ablation on HBS using noninvasive, objective technologies to measure outcomes. Patients with HBS had identical regions of scar designated for treatment by the Er:YAG laser (TREAT) or to be left untreated (CONTROL). They prospectively collected scar measurements of TREAT and CONTROL regions preoperatively, 3 weeks, and 3 months after Er:YAG treatment. Scar measurements included viscoelastometry, transepidermal water loss, optical coherent tomography, and high-frequency ultrasound. Outcomes were measured for the aggregate difference between the TREAT group vs the CONTROL group, as well as within each group in isolation. Seventeen patients were seen preoperatively, followed by n = 15 at 3 weeks and n = 11 at 3 months. A mixed-model repeated measures analysis showed no significant effect of fractional ablation when comparing the overall TREAT group measurements with those of the CONTROL group. However, when considered as within-group measurements, TREAT scars showed significant improvement in viscoelastic deformity (P = .03), elastic deformity (P = .004), skin roughness (P = .05), and wrinkle depth (P = .04) after fractional ablation, whereas CONTROL scars showed no such within-group changes. HBS treated by the Er:YAG laser showed objective improvements, whereas no such changes were seen within the untreated scars over the same time frame.


Prenatal ultrasonographic detection of the tracheal atresia sequence.
We report a rare case of tracheal atresia, without fistula, in a 19 weeks' female fetus. The abnormality was detected by prenatal ultrasonography, which demonstrated a bilateral and uniform hyperechogenicity and enlargement of the lungs, associated with ascites and moderate oligohydramnios. We suggest that oligohydramnios may be helpful in distinguishing the upper respiratory tract obstruction from congenital cystic adenomatoid malformation of the lungs, type III. A morphometric study revealed a three-fold more dense pulmonary vasculature in comparison with two control cases of the same gestational age. The pathological finding of pulmonary and vascular hyperplasia as well as the pathophysiology of the syndrome are discussed.


Stimulated Raman and Brillouin backscattering of collimated beams carrying orbital angular momentum.
We study theoretically the exchange of angular momentum between electromagnetic and electrostatic waves in a plasma, due to the stimulated Raman and Brillouin backscattering processes. Angular momentum states for plasmon and phonon fields are introduced for the first time. We demonstrate that these states can be excited by nonlinear wave mixing, associated with the scattering processes. This could be relevant for plasma diagnostics, both in laboratory and in space. Nonlinearly coupled paraxial equations and instability growth rates are derived.


Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans.
Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.


Dynamic and Label-Free Sensing of Cardiomyocyte Responses to Nanosized Vesicles for Cardiac Oxidative Stress Injury Therapy.
Cardiac oxidative stress is a significant phenotype of myocardial infarction disease, a leading cause of global health threat. There is an urgent need to develop innovative therapies. Nanosized extracellular vesicle (nEV)-based therapy shows promise, yet real-time monitoring of cardiomyocyte responses to nEVs remains a challenge. In this study, a dynamic and label-free cardiomyocyte biosensing system using microelectrode arrays (MEAs) was constructed. Cardiomyocytes were cultured on MEA devices for electrophysiological signal detection and treated with nEVs from E. coli, gardenia, HEK293 cells, and mesenchymal stem cells (MSC), respectively. E. coli-nEVs and gardenia-nEVs induced severe paroxysmal fibrillation, revealing distinct biochemical communication compared to MSC-nEVs. Principal component analysis identified variations and correlations between nEV types. MSC-nEVs enhanced recovery without inducing arrhythmias in a H2O2-induced oxidative stress injury model. This study establishes a fundamental platform for assessing biochemical communication between nEVs and cardiomyocytes, offering new avenues for understanding nEVs' functions in the cardiovascular system.


Leg muscle vibration modulates bodily self-consciousness: integration of proprioceptive, visual, and tactile signals.
Behavioral studies have used visuo-tactile conflicts between a participant's body and a visually presented fake or virtual body to investigate the importance of bodily perception for self-consciousness (bodily self-consciousness). Illusory self-identification with a fake body and changes in tactile processing--modulation of visuo-tactile cross-modal congruency effects (CCEs)--were reported in previous findings. Although proprioceptive signals are deemed important for bodily self-consciousness, their contribution to the representation of the full body has not been studied. Here we investigated whether and how self-identification and tactile processing (CCE magnitude) could be modified by altering proprioceptive signals with 80-Hz vibrations at the legs. Participants made elevation judgments of tactile cues (while ignoring nearby lights) during synchronous and asynchronous stroking of a seen fake body. We found that proprioceptive signals during vibrations altered the magnitude of self-identification and mislocalization of touch (CCE) in a synchrony-dependent fashion: we observed an increase of self-identification and CCE magnitude during asynchronous stroking. In a second control experiment we studied whether proprioceptive signals per se, or those from the lower limbs in particular, were essential for these changes. We applied vibrations at the upper limbs (which provide no information about the position of the participant's body in space) and in this case observed no modulation of bodily self-consciousness or tactile perception. These data link proprioceptive signals from the legs that are conveyed through the dorsal column-medial lemniscal pathway to bodily self-consciousness. We discuss their integration with bodily signals from vision and touch for full-body representations.


Mapping global cropland and field size.
A new 1 km global IIASA-IFPRI cropland percentage map for the baseline year 2005 has been developed which integrates a number of individual cropland maps at global to regional to national scales. The individual map products include existing global land cover maps such as GlobCover 2005 and MODIS v.5, regional maps such as AFRICOVER and national maps from mapping agencies and other organizations. The different products are ranked at the national level using crowdsourced data from Geo-Wiki to create a map that reflects the likelihood of cropland. Calibration with national and subnational crop statistics was then undertaken to distribute the cropland within each country and subnational unit. The new IIASA-IFPRI cropland product has been validated using very high-resolution satellite imagery via Geo-Wiki and has an overall accuracy of 82.4%. It has also been compared with the EarthStat cropland product and shows a lower root mean square error on an independent data set collected from Geo-Wiki. The first ever global field size map was produced at the same resolution as the IIASA-IFPRI cropland map based on interpolation of field size data collected via a Geo-Wiki crowdsourcing campaign. A validation exercise of the global field size map revealed satisfactory agreement with control data, particularly given the relatively modest size of the field size data set used to create the map. Both are critical inputs to global agricultural monitoring in the frame of GEOGLAM and will serve the global land modelling and integrated assessment community, in particular for improving land use models that require baseline cropland information. These products are freely available for downloading from the http://cropland.geo-wiki.org website.


Comparison of hyperpolarized 13 C and non-hyperpolarized deuterium MRI approaches for imaging cerebral glucose metabolism at 4.7 T.
The purpose of this study was to directly compare two isotopic metabolic imaging approaches, hyperpolarized (HP) 13 C MRI and deuterium metabolic imaging (DMI), for imaging specific closely related segments of cerebral glucose metabolism at 4.7 T. Comparative HP-13 C and DMI neuroimaging experiments were conducted consecutively in normal rats during the same scanning session. Localized conversions of [1-13 C]pyruvate and [6,6-2 H2 ]glucose to their respective downstream metabolic products were measured by spectroscopic imaging, using an identical 2D-CSI sequence with parameters optimized for the respective experiments. To facilitate direct comparison, a pair of substantially equivalent 2.5-cm double-tuned X/1 H RF surface coils was developed. For improved results, multidimensional low-rank reconstruction was applied to denoise the raw DMI data. Localized conversion of HP [1-13 C]pyruvate to [1-13 C]lactate, and [6,6-2 H2 ]glucose to [3,3-2 H2 ]lactate and Glx-d (glutamate and glutamine), was detected in rat brain by spectroscopic imaging at 4.7 T. The SNR and spatial resolution of HP-13 C MRI was superior to DMI but limited to a short time window, whereas the lengthy DMI acquisition yielded maps of not only lactate, but also Glx production, albeit with relatively poor spectral discrimination between metabolites at this field strength. Across the individual rats, there was an apparent inverse correlation between cerebral production of HP [1-13 C]lactate and Glx-d, along with a trend toward increased [3,3-2 H2 ]lactate. The HP-13 C MRI and DMI methods are both feasible at 4.7 T and have significant potential for metabolic imaging of specific segments of glucose metabolism.


Soy protein extract (SPE) exhibits differential in vitro cell proliferation effects in oral cancer and normal cell lines.
Prior research has demonstrated that specific isoflavones derived from soy may exhibit antitumor effects against many cancers, including oral cancer. Most of this prior research involved isolation and testing of individual soy components, such as genistein, daidzein, and glycitein, which exhibit cytotoxicity against cancerous cells but may also have residual cytotoxic effects on normal cells. Few studies have evaluated whole soy extract, containing a combination of these isoflavones, and other bioreactive compounds, which may function synergistically and more effectively against oral cancers. This study compared the antiproliferative effects of whole soy protein extract (SPE) on CAL 27 and SCC25 oral cancer cell lines in vitro. Administration of SPE significantly inhibited oral cancer growth and exerted these effects at lower concentrations compared with another class of flavonoids (proanthocyanidins) that were previously tested on these cell lines. This SPE-induced growth inhibition correlated with down-regulated mRNA expression in the oral cancer cell-cycle promoter ornithine decarboxylase (ODC), as well as upregulation of caspase-2 and caspase-8, initiators and effectors of apoptosis. These results suggest that SPE may represent a potential chemopreventive or chemotherapeutic option for oral cancer. Moreover, SPE may be more effective than other flavonoids currently used and may be effective at lower concentrations that approximate physiologic serum levels (0-2 μmol/l). This study may help to explain why diets rich in fruits, vegetables, and soy protein are associated with protection against development and progression of oral cancers, although further study is needed to develop specific public health recommendations for oral cancer treatment and prevention.


In vitro antiviral activity of favipiravir and its 6- and 3-O-substituted derivatives against coronavirus: Acetylation leads to improvement of antiviral activity.
Favipiravir is currently approved for the treatment of the influenza virus and has shown encouraging results in terms of antiviral capacity in clinical studies against severe acute respiratory syndrome coronavirus 2. Favipiravir is a prodrug, where its favipiravir-ribofuranosyl-5B-triphosphate metabolite is capable of blocking RNA replication of the virus. However, the antiviral efficiency of favipiravir is limited by two factors: (i) low accumulation in plasma and rapid excretion/elimination post-administration and (ii) low conversion rate into the active metabolite. To tackle these problems, herein, we have designed new favipiravir analogues focusing on the replacement of the fluorine atom at the 6-position by halogen or hydrogen atoms and 3-O-functionalization with labile groups. The first type of functionalization seeks to increase the antiviral activity because of the better ability of the keto-tautomer as a function of the halogen, and it is hypothesized that the keto-tautomer tends to promote the formation of the ribofuranosyl-5B-triphosphate (RTP) metabolite. Meanwhile, the second type of functionalization seeks to promote lipophilicity and increase accumulation in cells. From the in vitro antiviral activity against two coronavirus models (bovine and human 229E), it was identified that the replacement did not improve the antiviral activity against both the models, which seems to be attributable to the low water solubility of these new 6-functionalized analogues. Meanwhile, with 3-O-functionalization, acetylation provided the most active compounds with higher half-maximal inhibitory concentration and selectivity than favipiravir, whereas benzylation/methanosulfonation yielded the least active compounds. In summary, acetylation is found to be a convenient functionalization to enhance the antiviral profile of favipiravir.


Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry.
Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.


Crystal structure of the high-pressure phase of the oxonitridosilicate chloride Ce4[Si4O(3 + x)N(7 - x)]Cl(1 - x)O(x), x approximately = 0.2.
The structural compression mechanism of Ce4[Si4O(3 + x)N(7 - x)]Cl(1 - x)O(x), x approximately = 0.2, was investigated by in situ single-crystal synchrotron X-ray diffraction at pressures of 3.0, 8.5 and 8.6 GPa using the diamond-anvil cell technique. On increasing pressure the low-pressure cubic structure first undergoes only minor structural changes. Between 8.5 and 8.6 GPa a first-order phase transition occurs, accompanied by a change of the single-crystal colour from light orange to dark red. The main structural mechanisms, leading to a volume reduction of about 5% at the phase transition, are an increase in and a rearrangement of the Ce coordination, the loss of the Ce2, Ce3 split position, and a bending of some of the inter-polyhedral Si-N-Si angles in the arrangement of the corner-sharing Si tetrahedra. The latter is responsible for the short c axis of the orthorhombic high-pressure structure compared with the cell parameter of the cubic low-pressure structure.


Fluted Projectile Points: Their Age and Dispersion: Stratigraphically controlled radiocarbon dating provides new evidence on peopling of the New World.
The stratigraphic record shows Clovis projectile points to be restricted to sediments between 11,000 and 11,500 years old. Underlying deposits dating back 11,600 to 13,000 years are without evidence of human occupation. In the High Plains, overlying deposits dating back 10,000 to 11,000 years contain Folsom and Hell Gap artifacts and are without mammoth remains. The glacial history of Alaska, Canada, and the Great Lakes region indicates that, for the first time in at least 15,000 years, an ice-free, trans-Canadian corridor opened up approximately 12,000 years ago. Since Clovis points are distributed from coast to coast south of the Valders ice border, the abrupt appearance of Clovis artifacts in the stratigraphic record of the High Plains some 700 years later suggests that Clovis progenitors passed through Canada during Two Creeks time. If eastern fluted points (for example, Enterline) are older than Clovis points, the difference may be on the order of only a hundred or so years, not thousands. The change from Clovis points to Folsom points in the High Plains may be related to a marked decline in the mammoth population after 11,000 years ago, but whether or not man was a prime factor in the extinction of Pleistocene megafauna is a moot question. On the basis of new data and critical geological evaluation of dates obtained by the radiocarbon method a hypothesis has been offered to explain (i) the abrupt appearance of Clovis points in the stratigraphic record of the United States around 11,500 years ago, and (ii) the lack of a cultural continuum in the United States leading to fluted projectile points. Llano hunters, like the game they pursued, may have persisted longer in some areas of the continent (for example, Bull Brook) than in others, but if a Clovis site can be found for which good stratigraphic evidence supports a date earlier than the Two Creeks interstade, then correlation of this event to the opening of the trans-Canadian ice-free corridor is incorrect (see 41a). Such a misinterpretation of timing would not affect the explanation for the lack of Clovis progenitors in the United States. We must continue to look for an indigenous cultural continuum leading to Clovis points, but if such cannot be demonstrated in the conterminous United States, then it would appear that fluted projectile points were developed elsewhere. Clovis progenitors might best be sought in northern Alaska or the Mackenzie Valley. The interpretations offered here are based on new data and critical geological evaluation of dates previously obtained by the radiocarbon method. How valid these interpretations are can be ascertained only through careful scrutiny of all man-mammoth associations found in the future, to assure precise relating of dates, fossils, and artifacts to the stratigraphic framework. We must pay closer attention to stratigraphic detail if we are to make the fullest use of radiocarbon dating.


Glycosaminoglycan-based biomaterials for growth factor and cytokine delivery: Making the right choices.
Controlled, localized drug delivery is a long-standing goal of medical research, realization of which could reduce the harmful side-effects of drugs and allow more effective treatment of wounds, cancers, organ damage and other diseases. This is particularly the case for protein "drugs" and other therapeutic biological cargoes, which can be challenging to deliver effectively by conventional systemic administration. However, developing biocompatible materials that can sequester large quantities of protein and release them in a sustained and controlled manner has proven challenging. Glycosaminoglycans (GAGs) represent a promising class of bio-derived materials that possess these key properties and can additionally potentially enhance the biological effects of the delivered protein. They are a diverse group of linear polysaccharides with varied functionalities and suitabilities for different cargoes. However, most investigations so far have focused on a relatively small subset of GAGs - particularly heparin, a readily available, promiscuously-binding GAG. There is emerging evidence that for many applications other GAGs are in fact more suitable for regulated and sustained delivery. In this review, we aim to illuminate the beneficial properties of various GAGs with reference to specific protein cargoes, and to provide guidelines for informed choice of GAGs for therapeutic applications.


Neurological monitoring during carotid artery stenting: the Duck Squeezing Test.
To examine the usefulness of a novel method for neurological monitoring during carotid artery stenting (CAS). The records of patients who underwent elective CAS between June 1996 and October 1998 were reviewed to identify those who had neurological changes during the procedure. We examined whether the neurological change had been detected by a change in the ability of the patient to respond to predetermined commands involving a small rubber duck placed in the contralateral hand. hundred seventy patients (320 vessels) underwent monitoring using the Duck Squeezing Test; 10 suffered neurological events during the procedure. Four of these were transient and temporally related to balloon inflation. Another 6 were tentatively ascribed to distal embolism. All instances were accompanied by a change in the patient's ability to perform the Duck Squeezing Test, which allowed the identification of the abnormal clinical situation. In addition, there were 4 false-positive tests secondary to the patient accidentally dropping the rubber duck. The Duck Squeezing Test is a sensitive and specific method for monitoring patients during elective CAS. Its practical applicability is based on sound neurophysiological concepts, which underscore the clinical importance of the test.


Dye bonding to TiO2: in situ attenuated total reflection infrared spectroscopy study, simulations, and correlation with dye-sensitized solar cell characteristics.
Processing dye-sensitized solar cells gains more and more importance as interest in industrial applications grows daily. For large-scale processing and optimizing manufacturing in terms of environmental acceptability as well as time and material saving, a detailed knowledge of certain process steps is crucial. In this paper we concentrate on the sensitizing step of production, i.e., the anchoring of the dye molecules onto the TiO(2) semiconductor. A vacuum-tight attentuated total reflection infrared (ATR-IR) flow-through cell was developed, thus allowing measurements using a vacuum spectrometer to monitor infiltration of dye molecules into the porous TiO(2) film in situ at high sensitivity. In particular, the influence of the anchor and backbone of perylene dye molecules as well as the influence of solvents on the adsorption process was investigated. The experiments clearly show that an anhydride group reacts much slower than an acid group. A significantly lower amount of anhydride dye can be adsorbed on the films. Ex situ transmission experiments furthermore indicate that the availability of OH groups on the TiO(2) surface may limit dye adsorption. Also the backbone and base frame of the dye can influence the adsorption time drastically. Electrical cell characteristics correlate with the amount of adsorbed dye molecules determined by in situ ATR-IR measurements. The latter is also sensitive toward the diffusion of the dye through the porous layer. To gain a deeper understanding of the interplay between diffusion and adsorption, simulations were performed that allowed us to extract diffusion and adsorption constants. Again it was demonstrated that the anchoring group has a strong effect on the adsorption rate. The influence of the solvent was also studied, and it was found that both adsorption and desorption are affected by the solvent. Protic polar solvents are able to remove bound dye molecules, which is a possible pathway of cell degradation. Most importantly, the analysis shows the potential of this approach for the evaluation of molecules or additives concerning their characteristics important for cell processing.


Naphthalene metabolism and growth inhibition by naphthalene in Polaromonas naphthalenivorans strain CJ2.
This study was designed to characterize naphthalene metabolism in Polaromonas naphthalenivorans CJ2. Comparisons were completed using two archetypal naphthalene-degrading bacteria: Pseudomonas putida NCIB 9816-4 and Ralstonia sp. strain U2, representative of the catechol and gentisate pathways, respectively. Strain CJ2 carries naphthalene catabolic genes that are homologous to those in Ralstonia sp. strain U2. Here we show that strain CJ2 metabolizes naphthalene via gentisate using respirometry, metabolite detection by GC-MS and cell-free enzyme assays. Unlike P. putida NCIB 9816-4 or Ralstonia sp. strain U2, strain CJ2 did not grow in minimal medium saturated with naphthalene. Growth assays revealed that strain CJ2 is inhibited by naphthalene concentrations of 78 microM (10 p.p.m.) and higher, and the inhibition of growth is accompanied by the accumulation of orange-coloured, putative naphthalene metabolites in the culture medium. Loss of cell viability coincided with the appearance of the coloured metabolites, and analysis by HPLC suggested that the accumulated metabolites were 1,2-naphthoquinone and its unstable auto-oxidation products. The naphthoquinone breakdown products accumulated in inhibited, but not uninhibited, cultures of strain CJ2. Furthermore, naphthalene itself was shown to directly inhibit growth of a regulatory mutant of strain CJ2 that is unable to metabolize naphthalene. These results suggest that, despite being able to use naphthalene as a carbon and energy source, strain CJ2 must balance naphthalene utilization against two types of toxicity.