Modeling of sequestration and down regulation in cells containing beta2-adrenergic receptors.
Desensitization of G-protein coupled receptors following agonist occupancy is accompanied by two temporally distinguishable cellular trafficking phenomena of the receptors referred to as sequestration and down regulation. For the beta2-adrenergic receptor, sequestration occurs within minutes of agonist binding and results in a reversible internalization and loss of cell surface receptor binding. With longer occupancy, greater than 1 hour, down regulation results in a variable loss of the complement of cellular receptors. Here we compare the two methods that have been used to monitor these receptor changes, competition of whole cell hydrophobic ligand binding (125I-pindolol) with a hydrophilic ligand (CGP-12177) and flow cytometry quantification of immunologically tagged beta2-adrenergic receptor. While both methods give reliable results, we show that because of a 1:500 partitioning of the hydrophilic ligand into cells, slightly different conditions should be used to assess basally or agonist stimulated sequestered receptor levels. Using a sequestration defective beta2-adrenergic receptor mutant we demonstrate that even though sequestration and down regulation behave as independent processes, sequestration can significantly affect the rate at which receptors are lost by the down regulatory process by removing receptors from the pool of down regulating receptors. A mathematical model expressing these relationships is provided.


Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.
The blood-brain barrier (BBB) prevents the entry of many drugs into the brain and, thus, is a major obstacle in the treatment of CNS diseases. There is some evidence that the LDL receptor (LDLR) is expressed at the BBB and may participate in the transport of endogenous ligands from blood to brain, a process referred to as receptor-mediated transcytosis. We previously described a family of peptide vectors that were developed to target the LDLR. In the present study, in vitro BBB models that were derived from wild-type and LDLR-knockout animals (ldlr-/- ) were used to validate the specific LDLR-dependent transcytosis of LDL via a nondegradative route. We next showed that LDLR-targeting peptide vectors, whether in fusion or chemically conjugated to an Ab Fc fragment, promote binding to apical LDLR and transendothelial transfer of the Fc fragment across BBB monolayers via the same route as LDL. Finally, we demonstrated in vivo that LDLR significantly contributes to the brain uptake of vectorized Fc. We thus provide further evidence that LDLR is a relevant receptor for CNS drug delivery via receptor-mediated transcytosis and that the peptide vectors we developed have the potential to transport drugs, including proteins or Ab based, across the BBB.-Molino, Y., David, M., Varini, K., Jabès, F., Gaudin, N., Fortoul, A., Bakloul, K., Masse, M., Bernard, A., Drobecq, L., Lécorché, P., Temsamani, J., Jacquot, G., Khrestchatisky, M. Use of LDL receptor-targeting peptide vectors for in vitro and in vivo cargo transport across the blood-brain barrier.


The use of specialty training to retain doctors in Malawi: A discrete choice experiment.
Emigration has contributed to a shortage of doctors in many sub-Saharan African countries. Specialty training is highly valued by doctors and a potential tool for retention. Yet not all types of training may be valued equally. In the first study to examine preferences for postgraduate training in depth, we carried out a discrete choice experiment as part of a cross-sectional survey of all Malawian doctors within seven years of graduation and not yet in specialty training. Over August 2012 to March 2013, 148 doctors took part out of 153 eligible in Malawi. Despite evidence that specialty training is highly sought after, Malawian junior doctors would not accept all types of training. Doctors preferred timely training outside of Malawi in core specialties (internal medicine, general surgery, paediatrics, obstetrics & gynaecology). Specialty preferences are particularly strong, with most junior doctors requiring nearly double their monthly salary to accept training all in Malawi and over six-fold to accept training in ophthalmology (representing a bundle of unpopular but priority specialties). In contrast, the location of work before training did not significantly influence most doctors' choices when guaranteed specialty training. Using a latent class model, we identified four subgroups of junior doctors with distinct preferences. Policy simulations showed that these preferences could be leveraged by policymakers to improve retention in exchange for guaranteed specialty training, however incentivising the uptake of training in priority specialties will only be effective in those with more flexible preferences. These results indicate that indiscriminate expansion of postgraduate training to slow emigration of doctors from sub-Saharan African countries may not be effective unless doctors' preferences are taken into account.


Chlorophyll-a in the rivers of eastern England.
Chlorophyll-a concentration variations are described for two major river basins in England, the Humber and the Thames and related to catchment characteristics and nutrient concentrations across a range of rural, agricultural and urban/industrial settings. For all the rivers there are strong seasonal variations, with concentrations peaking in the spring and summer time when biological activity is at its highest. However, there are large variations in the magnitude of the seasonal effects across the rivers. For the spring-summer low-flow periods, average concentrations of chlorophyll-a correlate with soluble reactive phosphorus (SRP). Chlorophyll-a is also correlated with particulate nitrogen (PN), organic carbon (POC) and suspended sediments. However, the strongest relationships are with catchment area and flow, where two straight line relationships are observed. The results indicate the importance of residence times for determining planktonic growth within the rivers. This is also indicated by the lack of chlorophyll-a response to lowering of SRP concentrations in several of the rivers in the area due to phosphorus stripping of effluents at major sewage treatment works. A key control on chlorophyll-a concentration may be the input of canal and reservoir waters during the growing period: this too relates to issues of residence times. However, there may well be a complex series of factors influencing residence time across the catchments due to features such as inhomogeneous flow within the catchments, a fractal distribution of stream channels that leads to a distribution of residence times and differences in planktonic inoculation sources. Industrial pollution on the Aire and Calder seems to have affected the relationship of chlorophyll-a with PN and POC. The results are discussed in relation to the Water Framework Directive.


Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association.
Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.


Pregnancy-associated plasma protein A in human ovarian follicles and its association with intrafollicular hormone levels.
To evaluate follicular fluid (FF) levels of pregnancy-associated plasma protein A (PAPP-A) in relation to levels of intrafollicular hormones. Furthermore, immunostaining of human follicles of varying diameters was studied for PAPP-A, antimüllerian hormone (AMH), and aromatase, and the biological activity of PAPP-A in FF was evaluated. Laboratory investigation. University hospital. A total of 43 women with a total of 80 samples were obtained from three different size-groups of antral follicles collected before and after the LH surge. ELISA measurement of steroids, PAPP-A, and AMH, immunohistochemistry of PAPP-A, AMH, and aromatase on follicles of different diameter, and proteolytic activity of PAPP-A toward insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4). Association between FF levels of PAPP-A and measured ovarian hormones, PAPP-A activity in FF, localization of PAPP-A, AMH, and aromatase in antral follicles. A highly significant association between FF levels of PAPP-A and all measured hormones were obtained with positive associations toward E2 and P, whereas AMH, T, and A showed strong negative associations. PAPP-A proteolytic activity toward IGFBP-4 was detected in human FF. PAPP-A immunostaining shifted from being primarily present in theca cells of small antral follicles to being expressed in granulosa cells (GCs) of preovulatory follicles. In contrast, AMH expression became reduced with increasing follicular diameter. Aromatase expression was highly specifically localized to GCs of preovulatory follicles. The results suggest that PAPP-A is specifically involved in the regulation of steroidogenesis in human antral follicles. Local regulation of IGF-II activity may represent a mechanism by which PAPP-A exerts this function and highlights the importance of IGF signaling during follicular development.


Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
Ubiquitination plays a key role in protein degradation and signal transduction. Ubiquitin is a small protein modifier that is adducted to lysine residues by the combined function of E1, E2, and E3 enzymes and is removed by deubiquitinating enzymes. Characterization of ubiquitination sites is important for understanding the role of this modification in cellular processes and disease. However, until recently, large-scale characterization of endogenous ubiquitination sites has been hampered by the lack of efficient enrichment techniques. The introduction of antibodies that specifically recognize peptides with lysine residues that harbor a di-glycine remnant (K-ε-GG) following tryptic digestion has dramatically improved the ability to enrich and identify ubiquitination sites from cellular lysates. We used this enrichment technique to study the effects of proteasome inhibition by MG-132 and deubiquitinase inhibition by PR-619 on ubiquitination sites in human Jurkat cells by quantitative high performance mass spectrometry. Minimal fractionation of digested lysates prior to immunoaffinity enrichment increased the yield of K-ε-GG peptides three- to fourfold resulting in detection of up to ~3300 distinct K-GG peptides in SILAC triple encoded experiments starting from 5 mg of protein per label state. In total, we identify 5533 distinct K-ε-GG peptides of which 4907 were quantified in this study, demonstrating that the strategy presented is a practical approach to perturbational studies in cell systems. We found that proteasome inhibition by MG-132 and deubiquitinase inhibition by PR-619 induces significant changes to the ubiquitin landscape, but that not all ubiquitination sites regulated by MG-132 and PR-619 are likely substrates for the ubiquitin-proteasome system. Additionally, we find that the proteasome and deubiquitinase inhibitors studied induced only minor changes in protein expression levels regardless of the extent of regulation induced at the ubiquitin site level. We attribute this finding to the low stoichiometry of the majority ubiquitination sites identified in this study.


WHO Global Salm-Surv external quality assurance system for serotyping of Salmonella isolates from 2000 to 2007.
An international external quality assurance system (EQAS) for the serotyping of Salmonella species was initiated in 2000 by WHO Global Salm-Surv to enhance the capacity of national reference laboratories to obtain reliable data for surveillance purposes worldwide. Seven EQAS iterations were conducted between 2000 and 2007. In each iteration, participating laboratories submitted serotyping results for eight Salmonella isolates. A total of 249 laboratories in 96 countries participated in at least one EQAS iteration. A total of 756 reports were received from the participating laboratories during the seven EQAS iterations. Cumulatively, 76% of participating laboratories submitted data for all eight strains, and 82% of strains were correctly serotyped. In each iteration, 84% to 96% of the laboratories correctly serotyped the Salmonella enterica serovar Enteritidis isolate that was included as an internal quality control strain. Regional differences in performance were observed, with laboratories in Central Asia and the Middle East performing less well overall than those in other regions. Errors that resulted in incorrect serovar identification were typically caused by difficulties in the detection of the phase two flagellar antigen or in differentiation within antigen complexes; some of these errors are likely related to the quality of the antisera available. The results from the WHO Global Salm-Surv EQAS, the largest of its kind in the world, show that most laboratories worldwide are capable of correctly serotyping Salmonella species. However, this study also indicates a continuing need for improvement. Future training efforts should be aimed at enhancing the ability to detect the phase two flagellar antigen and at disseminating information on where to purchase high-quality antisera.


Osteoblast-like cell attachment and proliferation on turned, blasted, and anodized titanium surfaces.
The purpose of this study was to investigate the cellular activities of MG63 osteoblast-like cells on modified titanium surfaces. MG63 osteoblast-like cells were cultured on titanium disks (n = 20 in each group) with turned, resorbable blast media (RBM)-treated, or anodized surfaces. The surfaces of commercially available implants of Osstem (Osstem Implant) were reproduced for the titanium disks. The morphology of cells cultured on these disks was examined using scanning electron microscopy. X-ray photoelectron spectroscopy (XPS) was employed for the analysis of surface chemistry. Specimens were also evaluated with an initial cell adhesion assay to compare initial adhesion, with a methyl tetrazol sulfate (MTS) assay to compare the proliferation ability, and with an alkaline phosphatase (ALP) assay to compare the differentiation ability. Statistical significance of the differences was determined using the Kruskal-Wallis test for the cell adhesion assay and analysis of variance for the MTS and ALP assays. Attached cells with more defined lamellopodia and flattened morphology were observed on the anodized and RBM surfaces than on the turned surfaces. The titanium surfaces were all oxidized as titanium oxide and polluted by carbon determinants, as determined by XPS. Anodized titanium surfaces exhibited calcium and phosphorus peaks. Initial cell attachment activity, cell proliferation activity, and ALP activity were higher on the anodized surfaces than on the other surfaces. Cell differentiation on the anodized surfaces at culture day 10 was significantly higher (P < .05) than on the other surfaces. Surface treatment by anodization may improve initial attachment of cells, proliferation ability, and differentiation activity, which play important roles in providing better osseointegration of implants. More rapid and stronger osseointegration of implants may make it possible to offer the best anchorage and shorten the healing time required prior to functional loading.


Subjective sleep impairment in adults with type 1 or type 2 diabetes: Results from Diabetes MILES--The Netherlands.
Despite growing recognition of the impact of sleep on diabetes, a clear profile of people with diabetes regarding subjective sleep impairment has yet to be established. This study examines: (1) subjective sleep characteristics in adults with type 1 and type 2 diabetes; (2) the relationship of poor subjective sleep quality with glycaemic control, self-care and daytime functioning; (3) possible risk markers for poor sleep quality. In a cross-sectional study, Dutch adults with type 1 (n=267) or type 2 diabetes (n=361) completed an online survey, including the Pittsburgh Sleep Quality Index (PSQI), socio-demographic, clinical, self-care and psychological measures. Poor sleep quality (PSQI-score >5) was reported by 31% of adults with type 1 and 42% of adults with type 2 diabetes. Participants with good and poor sleep quality did not differ in self-reported HbA1c or the frequency of meeting lifestyle recommendations. Poor sleep quality was related to a higher self-care burden and higher levels of daytime sleepiness, fatigue, depressive and anxiety symptoms, and diabetes-specific distress. In multivariable logistic regression analyses examining risk markers, poor sleep quality was associated with depressive symptoms in adults with type 1 (OR=1.39, 95% CI 1.25-1.54) and type 2 diabetes (OR=1.31, 1.16-1.47), and with being female in those with type 2 diabetes (OR=2.72, 1.42-5.20). Poor subjective sleep quality is prevalent both in adults with type 1 and type 2 diabetes, and is related to poor daytime functioning and higher self-care burden. The temporal relation with depression and merits of therapy should be explored.


Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat.
We have investigated the co-involvement of endogenous NGF and impulses in the collateral sprouting of cutaneous sensory nerves in adult rats, specifically the A delta-axons involved in mechanonociception and the C-fibers that mediate heat nociception. Their collateral sprouting was measured by the progressive expansion, respectively, of the behaviorally defined "pinch" and "heat" fields into surrounding denervated skin (the light-touch A alpha-fibers do not sprout in adult mammals). The expansions of such "isolated" fields were totally prevented in animals injected daily with anti-NGF serum, but developed normally after treatment was discontinued. Light microscopic and EM examination of the skin confirmed that the effect of the anti-NGF treatment was attributable to its prevention of collateral sprouting. Initiation of treatment would also rapidly halt sprouting already in progress. Finally, intradermal injections of purified NGF protein would not only increase the rate of nociceptive fiber sprouting, but also evoke sprouting de novo within normally innervated skin (again, A alpha-axons were unaffected). We conclude that the collateral sprouting of intact nociceptive nerves following partial denervation of skin is entirely dependent on endogenous NGF. The observed latency of this sprouting was 10-12 d; we estimate, however, that at least 2 d of field expansion is required for its reliable detection. Thus, about 8-10 d are required for NGF levels in the skin to rise to effective levels, and for the neurons to respond and initiate sprouting. From indirect findings, the NGF component of this sprouting latency appears to be about 2 d. In accord with earlier findings, the remaining "initiation time" was reduced by 5-6 d if the neurons were briefly excited, even 2 d prior to the isolation of their fields. Unexpectedly, this phenomenon of "precocious sprouting" requires that endogenous NGF be available; the sprouting latency reverted to normal values when the conditioning impulses were evoked during a 2 d anti-NGF "umbrella." In contrast to the impulse-sensitive neuronal mechanisms involved in the initiation of sprouting, those underlying the sprouting rate were unaffected by nerve activity and were entirely dependent on the level of endogenous NGF. We suggest that interactions like that revealed in these studies between a sprouting agent and impulses that seem to prime the neuron's response to it contribute to plasticity within the nervous system.


Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?
A growing body of evidence supports an important role for the endocannabinoid system as a regulator of appetite, body weight, and systemic metabolism, which is overactive in obesity and type 2 diabetes. While initial attempts to target this system using the cannabinoid receptor inverse agonist rimonabant were successful in producing modest weight loss and improving obesity-related metabolic complications in humans, adverse central nervous system side effects precluded introduction of this drug into clinical practice. However, new data, presented by Tam and colleagues in this issue of the JCI, demonstrate that selective blockade of peripheral cannabinoid receptors may be a novel successful therapeutic approach.


Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump.
Sixty-two patients with metastatic colorectal carcinoma involving the liver were treated by hepatic intra-arterial chemotherapy using an implantable infusion pump. The 53 patients with metastases confined to the liver had a median survival (MS) of 17 months and an objective response rate of 32%. Four patients (8%) demonstrated a complete response (CR), with normal abdominal computed tomography (CT) scan results and plasma carcinoembryonic antigen (CEA) levels, and 13 patients (25%) demonstrated a partial response (PR), with at least a 50% decrease in the liver lesions by CT scan and at least a 50% decrease in CEA levels. Thirty patients (57%) had stable disease (S), and six patients (11%) had no response (NR). Nine patients with extrahepatic tumor plus hepatic metastases had an MS of only 4.9 months. None of these patients had an objective response, and only four patients had S. Quality of response was clearly associated with longevity. Forty patients treated with floxuridine (FUDR) and mitomycin (M) (F + M) showed a 20% objective response rate, while the 13 patients treated with FUDR and dichloromethotrexate (DCMTX) (F + D) attained a 69% objective response rate. Although F + D treatment appears to be superior, there may have been selection biases that make such an observation only preliminary. Twenty-six (49%) of the 53 patients developed hepatitis during infusion chemotherapy, which resolved after temporary cessation of the chemotherapy. Of the 17 patients with CR or PR, 12 patients (71%) had hepatitis, whereas only 14 (39%) of the 36 patients with S or NR had hepatitis. Eleven patients had evidence of peptic ulceration by endoscopic examination during the infusion chemotherapy. All the ulcers healed after chemotherapy was discontinued.


Visual impairment caused by periorbital edema in an infant with acute hemorrhagic edema of infancy.
Acute hemorrhagic edema of infancy (AHEI) is a cutaneous vasculitis seen in children. Many consider it to be a clinical variant of Schönlein-Henoch purpura, but others regard it as a separate entity because of its benign nature, age of onset, lack of visceral involvement, and frequent absence of vascular immunoglobulin A deposition. It is clinically characterized by large "cockade" or rosette-shaped, annular, purpuric lesions involving the face and extremities; erythematous edema; and mild fever. It seems to appear secondary to a history of viral or bacterial infection, course of antibiotics, or vaccination. Because of the unknown etiology and benign character, which leads to spontaneous complete recovery, there is no specific treatment necessary for AHEI, and according to the literature, systemic corticosteroids do not seem to alter the course of the disease. We report the case of an 11-month-old boy who manifested massive periorbital edema along with all of the clinical characteristics of this entity and showed clear improvement of the symptoms after a 24-hour administration of systemic corticosteroid therapy. Given the positive effect of this therapy, we propose that systemic corticosteroids should be used to ameliorate the acute manifestations and avoid the rapid progression of the disease.


An epidermal signal regulates Lmx-1 expression and dorsal-ventral pattern during Xenopus limb regeneration.
The results of recent studies have supported the idea that the ability to organize the formation of axes such as the anteroposterior and proximodistal axes corresponds to limb regeneration ability in Xenopus. In this study, we investigated the mechanism by which the dorsoventral (D-V) axis of regenerating Xenopus limbs is established and the relationships between D-V patterning and regenerative ability. Transplantation experiments were performed to study which epidermis or mesenchyme is responsible for the D-V patterning in regenerating limbs. Naked mesenchyme of a donor limb was rotated and implanted on a host opposite-side limb stump to make a reversed recombination about the D-V axis. The resultant regenerates had a normal-looking D-V pattern, including Lmx-1 expression, muscle pattern, and joints, in stage 52 recombinants and a reversed D-V pattern in stage 55 recombinants. Further experiments in recombination at stage 52 and stage 55 showed that the epidermal signal is responsible for producing the D-V pattern in the regenerating blastema. These results, together with the finding that Lmx-1 expression is absent in the froglet forelimb blastema, suggest that D-V axis formation is a key step in understanding the loss of regenerative ability.


MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition.
Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC. Human MTC-TT cells were treated with MK-2206 (0-20 μM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis. MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked. MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.


Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia.
Because Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) patients have microthrombocytopenia, hemorrhage is a major problem. We asked whether eltrombopag, a thrombopoietic agent, would increase platelet counts, improve platelet activation, and/or reduce bleeding in WAS/XLT patients. In 9 WAS/XLT patients and 8 age-matched healthy controls, platelet activation was assessed by whole blood flow cytometry. Agonist-induced platelet surface activated glycoprotein (GP) IIb-IIIa and P-selectin in WAS/XLT patients were proportional to platelet size and therefore decreased compared with controls. In contrast, annexin V binding showed no differences between WAS/XLT and controls. Eltrombopag treatment resulted in an increased platelet count in 5 out of 8 patients. Among responders to eltrombopag, immature platelet fraction in 3 WAS/XLT patients was significantly less increased compared with 7 pediatric chronic immune thrombocytopenia (ITP) patients. Platelet activation did not improve in 3 WAS/XLT patients whose platelet count improved on eltrombopag. (1) the reduced platelet activation observed in WAS/XLT is primarily due to the microthrombocytopenia; and (2) although the eltrombopag-induced increase in platelet production in WAS/XLT is less than in ITP, eltrombopag has beneficial effects on platelet count but not platelet activation in the majority of WAS/XLT patients. This trial was registered at www.clinicaltrials.gov as #NCT00909363.


Movement Symmetry Assessment by Bilateral Motion Data Fusion.
A new approach, named bilateral motion data fusion, was proposed for the analysis of movement symmetry, which takes advantage of cross-information between both sides of the body and processes the unilateral motion data at the same time. This was accomplished using canonical correlation analysis and joint independent component analysis. It should be noted that human movements include many categories, which cannot be enumerated one by one. Therefore, the gait rhythm fluctuations of the healthy subjects and patients with neurodegenerative diseases were employed as an example for method illustration. In addition, our model explains the movement data by latent parameters in the time and frequency domains, respectively, which were both based on bilateral motion data fusion. They show that our method not only reflects the physiological correlates of movement but also obtains the differential signatures of movement asymmetry in diverse neurodegenerative diseases. Furthermore, the latent variables also exhibit the potentials for sharper disease distinctions. We have provided a new perspective on movement analysis, which may prove to be a promising approach. This method exhibits the potentials for effective movement feature extractions, which might contribute to many research fields such as rehabilitation, neuroscience, biomechanics, and kinesiology.


Is sugar consumption detrimental to health? A review of the evidence 1995-2006.
Many countries set quantitative targets for added sugars, justifying this by expressing concern about the likely impact of sugar on weight control, dental health, diet quality, or metabolic syndrome. This review considers whether current intakes of sugar are harmful to health, and analyses recent literature using a systematic approach to collate, rank, and evaluate published studies from 1995-2006. Results from high quality obesity studies did not suggest a positive association between body mass index and sugar intake. Some studies, specifically on sweetened beverages, highlighted a potential concern in relation to obesity risk, although these were limited by important methodological issues. Diet adequacy appeared to be achieved across sugar intakes of 6 to 20% energy, depending on subject age. Studies on metabolic syndrome reported no adverse effects of sugar in the long-term, even at intakes of 40-50% energy. The evidence for colorectal cancer suggested an association with sugar, but this appeared to have been confounded by energy intake and glycemic load. There was no credible evidence linking sugar with attention-deficit, dementia, or depression. Regarding dental caries, combinations of sugar amount/frequency, fluoride exposure, and food adhesiveness were more reliable predictors of caries risk than the amount of sugar alone. Overall, the available evidence did not support a single quantitative sugar guideline covering all health issues.


Improving mass candidate detection in mammograms via feature maxima propagation and local feature selection.
Mass candidate detection is a crucial component of multistep computer-aided detection (CAD) systems. It is usually performed by combining several local features by means of a classifier. When these features are processed on a per-image-location basis (e.g., for each pixel), mismatching problems may arise while constructing feature vectors for classification, which is especially true when the behavior expected from the evaluated features is a peaked response due to the presence of a mass. In this study, two of these problems, consisting of maxima misalignment and differences of maxima spread, are identified and two solutions are proposed. The first proposed method, feature maxima propagation, reproduces feature maxima through their neighboring locations. The second method, local feature selection, combines different subsets of features for different feature vectors associated with image locations. Both methods are applied independently and together. The proposed methods are included in a mammogram-based CAD system intended for mass detection in screening. Experiments are carried out with a database of 382 digital cases. Sensitivity is assessed at two sets of operating points. The first one is the interval of 3.5-15 false positives per image (FPs/image), which is typical for mass candidate detection. The second one is 1 FP/image, which allows to estimate the quality of the mass candidate detector's output for use in subsequent steps of the CAD system. The best results are obtained when the proposed methods are applied together. In that case, the mean sensitivity in the interval of 3.5-15 FPs/image significantly increases from 0.926 to 0.958 (p < 0.0002). At the lower rate of 1 FP/image, the mean sensitivity improves from 0.628 to 0.734 (p < 0.0002). Given the improved detection performance, the authors believe that the strategies proposed in this paper can render mass candidate detection approaches based on image location classification more robust to feature discrepancies and prove advantageous not only at the candidate detection level, but also at subsequent steps of a CAD system.


Roles of frontal and temporal regions in reinterpreting semantically ambiguous sentences.
Semantic ambiguity resolution is an essential and frequent part of speech comprehension because many words map onto multiple meanings (e.g., "bark," "bank"). Neuroimaging research highlights the importance of the left inferior frontal gyrus (LIFG) and the left posterior temporal cortex in this process but the roles they serve in ambiguity resolution are uncertain. One possibility is that both regions are engaged in the processes of semantic reinterpretation that follows incorrect interpretation of an ambiguous word. Here we used fMRI to investigate this hypothesis. 20 native British English monolinguals were scanned whilst listening to sentences that contained an ambiguous word. To induce semantic reinterpretation, the disambiguating information was presented after the ambiguous word and delayed until the end of the sentence (e.g., "the teacher explained that the BARK was going to be very damp"). These sentences were compared to well-matched unambiguous sentences. Supporting the reinterpretation hypothesis, these ambiguous sentences produced more activation in both the LIFG and the left posterior inferior temporal cortex. Importantly, all but one subject showed ambiguity-related peaks within both regions, demonstrating that the group-level results were driven by high inter-subject consistency. Further support came from the finding that activation in both regions was modulated by meaning dominance. Specifically, sentences containing biased ambiguous words, which have one more dominant meaning, produced greater activation than those with balanced ambiguous words, which have two equally frequent meanings. Because the context always supported the less frequent meaning, the biased words require reinterpretation more often than balanced words. This is the first evidence of dominance effects in the spoken modality and provides strong support that frontal and temporal regions support the updating of semantic representations during speech comprehension.


Outcomes and complications of open abdomen technique for managing non-trauma patients.
Damage control surgery and the open abdomen technique have been widely used in trauma. These techniques are now being utilized more often in non-trauma patients but the outcomes are not clear. We hypothesized that the use of the open abdomen technique in non-trauma patients 1) is more often due to peritonitis, 2) has a lower incidence of definitive fascial closure during the index hospitalization, and 3) has a higher fistula rate. Retrospective case series of patients treated with the open abdomen technique over a 5-year period at a level-I trauma center. Data was collected from the trauma registry, operating room (OR) case log, and by chart review. The main outcome measures were number of operations, definitive fascial closure, fistula rate, complications, and length of stay. One hundred and three patients were managed with an open abdomen over the 5-year period and we categorized them into three groups: elective (n = 31), urgent (n = 35), and trauma (n = 37). The majority of the patients were male (69%). Trauma patients were younger (39 vs 53 years; P < 0.05). The most common indications for the open abdomen technique were intraabdominal hypertension in the elective group (n = 18), severe intraabdominal infection in the urgent group (n = 19), and damage control surgery in the trauma group (n = 28). The number of abdominal operations was similar (3.1-3.7) in the three groups, as was the duration of intensive care unit (ICU) stay (average: 25-31 days). The definitive fascial closure rates during initial hospitalization were as follows: 63% in the elective group, 60% in the urgent group, and 54% in the trauma group. Intestinal fistula formation occurred in 16%, 17%, and 11%, respectively, in the three groups, with overall mortality rates of 35%, 31%, and 11%. Intra-abdominal infection was a common reason for use of the open abdomen technique in non-trauma patients. However, the definitive fascial closure and fistula rates were similar in the three groups. Despite differences in indications, damage control surgery and the open abdomen technique have been successfully transitioned to elective and urgent non-trauma patients.


Overexpression of eNOS in brain stem reduces enhanced sympathetic drive in mice with myocardial infarction.
Reduced nitric oxide (NO) in the brain might contribute to enhanced sympathetic drive in heart failure (HF). The aim of this study was to determine whether increased NO production induced by local overexpression of endothelial NO synthase (eNOS) in the nucleus tractus solitarius (NTS) of the brain stem reduces the enhanced sympathetic drive in mice with HF. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. MI mice exhibited left ventricular dilatation and a reduced left ventricular ejection fraction. Urinary norepinephrine excretion in MI mice was greater than that in sham-operated mice, indicating that sympathetic drive was enhanced in this model. Thus this model has features that are typical of HF. Western blot analysis and immunohistochemical staining for neuronal NOS (nNOS) indicated that nNOS protein expression was significantly reduced in the brain stem of MI mice. MI mice had a significantly smaller increase in blood pressure evoked by intracisternal injection of N(G)-monomethyl-L-arginine than sham-operated mice. Adenoviral vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbeta gal) were transfected into the NTS to examine the effect of increased NO production in the NTS on the enhanced sympathetic drive in HF. After the gene transfer, urinary norepinephrine excretion was reduced in AdeNOS-transfected MI mice but not in Adbeta gal-transfected MI mice. These results indicate that nNOS expression in the brain stem, especially in the NTS, is reduced in the MI mouse model of HF, and increased NO production induced by overexpression of eNOS in the NTS attenuates the enhanced sympathetic drive in this model.


Adenoviral delivery of recombinant soluble human tumor necrosis factor receptor 1 partially normalized mouse model of asthma.
Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology of asthma and result in resistance to hormone therapy. Tumor necrosis factor α inhibitors have become a major research focus in the treatment of asthma. Recombinant adenovirus (Ad-sTNFR1-IgGFc) expressing a fusion protein (sTNFR1-IgGFc), which was consisted of the soluble extracellular region of TNF receptor 1 and Fc fragment of IgG (sTNFR1-IgGFc), was used to transduce primary human airway smooth muscle cells (HASMCs). Enzyme-linked immunosorbent assay, flow cytometry, and immunocytochemistry confirmed the expression of sTNFR1-IgGFc. MTT was used to test the effect of sTNFR1-IgGFc to antagonism TNF-α-induced proliferates of HASMCs. To investigate the in vivo effectiveness of sTNFR1-IgGFc, mouse model of asthma was established. Ad-sTNFR1-IgGFc was delivered to the lung via nasal spray. Expression of sTNFR1-IgGFc in the tissue was confirmed by in situ hybridization and immunohistochemistry. The 2 major cell types that are involved in the inflamed asthmatic airway, neutrophils and eosinophils, in bronchoalveolar lavage fluid were observed. The sTNFR1-IgGFc isolated from transduced HASMC culture supernatant was able to antagonize HASMC proliferation stimulated by TNF-α. Asthma-induced pathologies and alterations in the cell composition in bronchoalveolar lavage fluid were reduced in mice subjected to Ad-sTNFR1-IgGFc therapy. The soluble extracellular region of TNF receptor 1 and Fc fragment of IgG was able to functionally antagonize TNF-α in vitro and showed promise as a therapeutic agent for the localized treatment of severe refractory asthma.


Magnetic resonance imaging of hepatic neoplasms.
Excellent diagnostic images of the liver can now be obtained with magnetic resonance imaging (MRI) because of new imaging techniques. The flow void phenomenon allows excellent anatomic detail of the liver. Morphologic features, comparison of tumor signal to normal parenchymal signal, and tumor behavior in various pulse sequences help to define liver tumors. The MRI characteristics of primary hepatomas, cavernous hemangiomas, hepatic cysts, liver adenomas, and focal nodular hyperplasia are among the hepatic lesions described. In most instances, MRI helps in differential considerations and in some cases will provide a specific diagnosis.


Imaging in gynecological disease (22): clinical and ultrasound characteristics of ovarian embryonal carcinomas, non-gestational choriocarcinomas and malignant mixed germ cell tumors.
To describe the clinical and ultrasound characteristics of three types of rare malignant ovarian germ cell tumor: embryonal carcinoma, non-gestational choriocarcinoma and malignant mixed germ cell tumor. This was a retrospective multicenter study. From the International Ovarian Tumor Analysis (IOTA) database, we identified patients with a histological diagnosis of ovarian embryonal carcinoma, non-gestational choriocarcinoma or malignant mixed germ cell tumor, who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 2000 and 2020. Additional patients with the same histology were identified from the databases of the departments of gynecological oncology in the participating centers. All tumors were described using IOTA terminology. Three examiners reviewed all available ultrasound images and described them using pattern recognition. One patient with embryonal carcinoma, five patients with non-gestational ovarian choriocarcinoma and seven patients with ovarian malignant mixed germ cell tumor (six primary tumors and one recurrence) were identified. Seven patients were included in the IOTA studies and six patients were examined outside of the IOTA studies. The median age at diagnosis was 26 (range, 14-77) years. Beta-human chorionic gonadotropin levels were highest in non-gestational choriocarcinomas and alpha-fetoprotein levels were highest in malignant mixed germ cell tumors. Most tumors were International Federation of Gynecology and Obstetrics (FIGO) Stage I (9/12 (75.0%)). All tumors were unilateral, and the median largest diameter was 129 (range, 38-216) mm. Of the tumors, 11/13 (84.6%) were solid and 2/13 (15.4%) were multilocular-solid; 9/13 (69.2%) manifested abundant vascularization on color Doppler examination. Using pattern recognition, the typical ultrasound appearance was a large solid tumor with inhomogeneous echogenicity of the solid tissue and often dispersed cysts which, in most cases, were small and irregular. Some tumors had smooth contours while others had irregular contours. A unilateral, large solid tumor with inhomogeneous echogenicity of the solid tissue and with dispersed small cystic areas in a young woman should raise the suspicion of a rare malignant germ cell tumor. This suspicion can guide the clinician to test tumor markers specific for malignant germ cell tumors. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.


ThemeDelta: Dynamic Segmentations over Temporal Topic Models.
We present ThemeDelta, a visual analytics system for extracting and visualizing temporal trends, clustering, and reorganization in time-indexed textual datasets. ThemeDelta is supported by a dynamic temporal segmentation algorithm that integrates with topic modeling algorithms to identify change points where significant shifts in topics occur. This algorithm detects not only the clustering and associations of keywords in a time period, but also their convergence into topics (groups of keywords) that may later diverge into new groups. The visual representation of ThemeDelta uses sinuous, variable-width lines to show this evolution on a timeline, utilizing color for categories, and line width for keyword strength. We demonstrate how interaction with ThemeDelta helps capture the rise and fall of topics by analyzing archives of historical newspapers, of U.S. presidential campaign speeches, and of social messages collected through iNeighbors, a web-based social website. ThemeDelta is evaluated using a qualitative expert user study involving three researchers from rhetoric and history using the historical newspapers corpus.


Modulation of Liver P-Glycoprotien Expression May Contribute to Gossypin Protection against Methotrexate-Induced Hepatotoxicity.
Methotrexate (MTX) is a broadly used anticancer. Its major side effect is hepatotoxicity. Gossypin is a flavonoid has a hepatoprotective effect as well as antitumor property. The study aimed at inspecting the protective effect of gossypin against MTX hepatotoxicity. Twenty-four adult male rats arranged into four groups (six rats each): control, gossypin control, MTX, and MTX+ gossypin. Animals were orally administered gossypin at 10 mg kg-1 day-1 for 7 days. MTX was injected i.p. (20 mg/kg-1 once) on 5th day. Liver enzyme and oxidative stress markers were assessed. BAX, transforming growth factor-beta (TGF-β) gene expressions, and P-glycoprotein (P-gp) were assessed. The histopathological study as well as the immunohistochemical study for hepatic caspase 3 and nuclear factor kappa-B (NFκ-B) was done. MTX produced a significant increase of liver enzymes and distortion of hepatic architecture alongside with increased the hepatic collagen content. MTX administration significantly increased the oxidative stress markers and upregulated the pro-apoptotic BAX and the pro-fibrogenic TGF-β. MTX increased caspase 3 and NFκ-B expression, while diminished the expression of P-gp. Gossypin pretreatment improved the previous parameters, restored the normal hepatic architecture, reduced the hepatic fibrosis, and regained nearly normal expressions for BAX, TGF-β, caspase 3, and NFκ-B. Gossypin caused more reduction in P-gp hepatic expression. Gossypin may be a valuable adjuvant therapy that protects the liver against MTX toxicity through antioxidant, anti-inflammatory, antiapoptotic mechanisms, and mediated P-gp expression reduction.


Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity.
Innate immune activation, including a role for cluster of differentiation 14/toll-like receptor 4 co-receptors (CD14/TLR-4) co-receptors, has been implicated in paracrine damage to neurons in several neurodegenerative diseases that also display stratification of risk or clinical outcome with the common alleles of the apolipoprotein E gene (APOE): APOE2, APOE3, and APOE4. Previously, we have shown that specific stimulation of CD14/TLR-4 with lipopolysaccharide (LPS) leads to greatest innate immune response by primary microglial cultures from targeted replacement (TR) APOE4 mice and greatest p38MAPK-dependent paracrine damage to neurons in mixed primary cultures and hippocampal slice cultures derived from TR APOE4 mice. In contrast, TR APOE2 astrocytes had the highest NF-kappaB activity and no neurotoxicity. Here we tested the hypothesis that direct activation of CD14/TLR-4 in vivo would yield different amounts of paracrine damage to hippocampal sector CA1 pyramidal neurons in TR APOE mice. We measured in vivo changes in dendrite length in hippocampal CA1 neurons using Golgi staining and determined hippocampal apoE levels by Western blot. Neurite outgrowth of cultured primary neurons in response to astrocyte conditioned medium was assessed by measuring neuron length and branch number. Our results showed that TR APOE4 mice had slightly but significantly shorter dendrites at 6 weeks of age. Following exposure to intracerebroventricular LPS, there was comparable loss of dendrite length at 24 hr among the three TR APOE mice. Recovery of dendrite length over the next 48 hr was greater in TR APOE2 than TR APOE3 mice, while TR APOE4 mice had failure of dendrite regeneration. Cell culture experiments indicated that the enhanced neurotrophic effect of TR APOE2 was LDL related protein-dependent. The data indicate that the environment within TR APOE2 mouse hippocampus was most supportive of dendrite regeneration while that within TR APOE4 hippocampus failed to support dendrite regeneration in this model of reversible paracrine damage to neurons from innate immune activation, and suggest an explanation for the stratification of clinical outcome with APOE seen in several degenerative diseases or brain that are associated with activated innate immune response.


Bone formation in peri-implant defects grafted with microparticles: a pilot animal experimental study.
This study aimed to evaluate the healing of peri-implant defects grafted with microparticles (MPs). Six domestic pigs received nine standardized defects at the calvaria, and an implant was inserted in the middle of each defect. The space between the implant and lateral bone portion was filled with MP pellets (n = 18) or MP supernatant (n = 18) or left unfilled (n = 18). After 14 and 28 days, three animals were sacrificed and specimens removed for further processing. Samples were microradiographically and histologically analysed. In addition, we immunohistochemically stained for anti-vWF as a marker of angiogenesis. In the case of bone regeneration and vessel formation, the null hypothesis can be partially rejected. After 14 and 28 days, no significant difference was observed within groups regarding de novo bone formation, bone density and osseointegration. However, superior vessel formation was found at both time points. Microparticles represent a promising treatment option to accelerate peri-implant vessel formation. Further studies are needed to investigate the regenerative properties of MPs more precisely.


Supergenes and their role in evolution.
Adaptation is commonly a multidimensional problem, with changes in multiple traits required to match a complex environment. This is epitomized by balanced polymorphisms in which multiple phenotypes co-exist and are maintained in a population by a balance of selective forces. Consideration of such polymorphisms led to the concept of the supergene, where alternative phenotypes in a balanced polymorphism segregate as if controlled by a single genetic locus, resulting from tight genetic linkage between multiple functional loci. Recently, the molecular basis for several supergenes has been resolved. Thus, major chromosomal inversions have been shown to be associated with polymorphisms in butterflies, ants and birds, offering a mechanism for localised reduction in recombination. In several examples of plant self-incompatibility, the functional role of multiple elements within the supergene architecture has been demonstrated, conclusively showing that balanced polymorphism can be maintained at multiple coadapted and tightly linked elements. Despite recent criticism, we argue that the supergene concept remains relevant and is more testable than ever with modern molecular methods.


Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals.
The phytochemical curcumin, from the Indian spice turmeric, has many biological properties, including anti-inflammatory and anti-carcinogenic activities. We have examined the effects of curcumin on the rat C6 glioma cell line. Treated and control cells were analyzed by Hoechst 33342 dye and flow cytometry. We observed a decrease in the side population (SP) of C6 cells after daily curcumin treatment of the C6 cells. Direct incubation of curcumin to C6 cells during the Hoechst assay also decreased SP. Since SP has been associated with stem cell populations, curcumin may be a dietary phytochemical with potential to target cancer stem cells.


N-(methylamino)isobutyric acid inhibits proliferation of CFSC-2C hepatic stellate cells.
Activation of hepatic stellate cells (HSCs) involves the induction of ECM protein synthesis and rapid cell proliferation. Thus, agents that interfere with either process could potentially mitigate the development of liver disease by reducing the synthesis of proteins associated with fibrosis or by reducing the number of activated HSC. Previously, we described that the non-metabolizable amino acid analog N-(methylamino)isobutyric acid (MeAIB) reduced hepatic collagen content of rats in a model of CCl(4)-induced liver injury, and in vitro studies using CFSC-2G cells indicated that MeAIB directly reduced collagen synthesis. However, the MeAIB-mediated reduction of hepatic collagen, in vivo, following liver injury was associated with a decrease in hepatic alpha-smooth muscle actin (alpha-SMA) which suggested that MeAIB also inhibited the activation of HSCs. Because HSC activation is inseparable from proliferation, the purpose of this study was to examine the effect of MeAIB treatment on the proliferation of HSCs in an in vitro model utilizing CFSC-2G cell cultures. In these studies, MeAIB effectively inhibited the proliferation of CFSC-2G cells by interfering with the progression of the cells through the G(1)-phase of the cell cycle which delayed entry into S-phase. MeAIB prevented the phosphorylation of p70S6 kinase (p70S6K) at Thr389 and reduced the phosphorylation at Thr421/Ser424. Because p70S6K is required for G(1)-cell cycle progression and is known to be regulated by nutrient availability, this correlates well with MeAIB interfering with the proliferation of CFSC-2G HSCs. In addition, the rate of protein synthesis was reduced by MeAIB treatment following mitogenic stimulation, which agrees with a p70S6K-mediated reduction in translation. These data are consistent with MeAIB inhibiting the proliferation of CFSC-2G cells by altering the mitogen activated pathway(s) leading to phosphorylation of p70S6K by a yet to be described mechanism.


Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma.
Gene therapy has emerged as a new form of treatment for unresectable hepatocellular carcinoma (HCC). We evaluate here the effect of IL-12 and the suicide gene thymidine kinase as single agents and in combination to treat experimental liver cancer. Recombinant adenoviruses expressing mouse interleukin-12 (AdCMVIL-12) or thymidine kinase of herpes simplex virus (AdCMVtk) or lacZ reporter gene (AdCMVlacZ) were constructed. The efficacy of the treatment was evaluated in a murine HCC model based on subcutaneous implantation of liver tumor cells (BNL). Transduction of BNL cells after in vitro infection with AdCMVlacZ was very low at multiplicity of infection (moi) of 100, whereas 10-15% of cells were transduced when using moi 1,000. Similarly, production of IL-12 was detectable only in BNL cells infected with AdCMVIL-12 at moi 1,000. In vitro infection of BNL cells with AdCMVIL-12 at moi 100 did not abrogate tumorigenicity, whereas moi 1,000 resulted in inhibition of tumor growth in all mice as well as in abrogation of tumor formation in 3 out of 8 animals. In vivo studies showed that intratumor injection of AdCMVIL-12 induced a dose-dependent effect on tumor regression. However, none of the animals exhibited complete tumor elimination with this treatment. We observed that suppression of tumor growth was more intense in animals treated with the combination of AdCMVIL-12 plus AdCMVtk than in animals which received AdCMVtk or AdCMVIL-12 alone. The combined treatment resulted in a significant increase in animal survival, and 25% of treated animals were free of tumor for over 100 days without recurrence of the disease. Combination of AdCMVIL-12 and AdCMVtk is more efficient than either of the two vectors alone for the treatment of the murine model of HCC used in this study.


Grappling with groups: protecting collective interests in biomedical research.
Strategies for protecting historically disadvantaged groups have been extensively debated in the context of genetic variation research, making this a useful starting point in examining the protection of social groups from harm resulting from biomedical research. We analyze research practices developed in response to concerns about the involvement of indigenous communities in studies of genetic variation and consider their potential application in other contexts. We highlight several conceptual ambiguities and practical challenges associated with the protection of group interests and argue that protectionist strategies developed in the context of genetic research will not be easily adapted to other types of research in which social groups are placed at risk. We suggest that it is this set of conceptual and practical issues that philosophers, ethicists, and others should focus on in their efforts to protect identifiable social groups from harm resulting from biomedical research.


Coupling characteristics of LiNbO3 directional couplers.
An analytic model of a Ti:LiNbO3 channel waveguide has been developed to predict conveniently the coupling coefficient of directional couplers based on near-field intensity measurements. This model is compared to experimental results at wavelengths of 0.63 and 0.81 microm and indicates an accuracy of predicting coupling coefficients within a factor of 2 without prior knowledge of the fabrication parameters.


Terra and Aqua satellites track tiger mosquito invasion: modelling the potential distribution of Aedes albopictus in north-eastern Italy.
The continuing spread of the Asian tiger mosquito Aedes albopictus in Europe is of increasing public health concern due to the potential risk of new outbreaks of exotic vector-borne diseases that this species can transmit as competent vector. We predicted the most favorable areas for a short term invasion of Ae. albopictus in north-eastern Italy using reconstructed daily satellite data time series (MODIS Land Surface Temperature maps, LST). We reconstructed more than 11,000 daily MODIS LST maps for the period 2001-09 (i.e. performed spatial and temporal gap-filling) in an Open Source GIS framework. We aggregated these LST maps over time and identified the potential distribution areas of Ae. albopictus by adapting published temperature threshold values using three variables as predictors (0°C for mean January temperatures, 11°C for annual mean temperatures and 1350 growing degree days filtered for areas with autumnal mean temperatures > 11°C). The resulting maps were integrated into the final potential distribution map and this was compared with the known current distribution of Ae. albopictus in north-eastern Italy. LST maps show the microclimatic characteristics peculiar to complex terrains, which would not be visible in maps commonly derived from interpolated meteorological station data. The patterns of the three indicator variables partially differ from each other, while winter temperature is the determining limiting factor for the distribution of Ae. albopictus. All three variables show a similar spatial pattern with some local differences, in particular in the northern part of the study area (upper Adige valley). Reconstructed daily land surface temperature data from satellites can be used to predict areas of short term invasion of the tiger mosquito with sufficient accuracy (200 m pixel resolution size). Furthermore, they may be applied to other species of arthropod of medical interest for which temperature is a relevant limiting factor. The results indicate that, during the next few years, the tiger mosquito will probably spread toward northern latitudes and higher altitudes in north-eastern Italy, which will considerably expand the range of the current distribution of this species.


Memory-blocking agents: effects on olfactory discrimination in homing salmon.
Homing salmon were injected intracranially with puromycin, actinomycin D, or cycloheximide. From 4 to 7 hours after such treatment these agents markedly inhibited olfactory bulbar discrimination between home water and other natural waters, including spawning sites for other groups of salmon. At longer intervals after treatment there was a partial restoration of olfactory memory-based discrimination. The dosages of the inhibitors used could be shown to have depressed incorporation of H(3)-leucine into protein by 78 percent or of H(3)-uridine into RNA by 41 percent in the salmon brains 4 hours after intracranial injection. These findings suggest that acute blockage of RNA synthesis or protein synthesis can interfere with long-term olfactory memory in anadromous salmon, at least as this function can be analyzed by electrophysiological methods. This implies that long-term olfactory memory depends upon continued metabolism of RNA and continued protein synthesis.


Methylation regulates the intracellular protein-protein and protein-RNA interactions of FMRP.
FMRP, the fragile X mental retardation protein, is an RNA-binding protein that interacts with approximately 4% of fetal brain mRNA. We have recently shown that a methyltransferase (MT) co-translationally methylates FMRP in vitro and that methylation modulates the ability of FMRP to bind mRNA. Here, we recapitulate these in vitro data in vivo, demonstrating that methylation of FMRP affects its ability to bind to FXR1P and regulate the translation of FMRP target mRNAs. Additionally, using double-label fluorescence confocal microscopy, we identified a subpopulation of FMRP-containing small cytoplasmic granules that are distinguishable from larger stress granules. Using the oxidative-stress induced accumulation of abortive pre-initiation complexes as a measure of the association of FMRP with translational components, we have demonstrated that FMRP associates with ribosomes during initiation and, more importantly, that methylation regulates this process by influencing the ratio of FMRP-homodimer-containing mRNPs to FMRP-FXR1P-heterodimer-containing mRNPs. These data suggest a vital role for methylation in normal FMRP functioning.


Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model.
Adoptive immunotherapy using chimeric antigen receptor-modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1-based lentiviral vectors that encode CARs targeting multiple highly conserved sites on the HIV-1 envelope glycoprotein using a two-molecule CAR architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and >97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4+ T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.


General self-efficacy and health-related quality of life after myocardial infarction.
Fatigue after myocardial infarction (MI) has been found to be distressing. A person's self-efficacy will influence his/her health behavior and plays an active role in tackling illness consequences. This study investigated associations between fatigue, disturbed sleep, general self-efficacy, and health-related quality of life (HRQoL) in a sample of 145 respondents admitted to hospital for MI two years earlier. The aim was to identify the predictive value of general self-efficacy and to elucidate mediating factors between self-efficacy and HRQoL. General self-efficacy measured four months after MI was positively related to HRQoL after two years. In tests of indirect effects, fatigue meditated the effects between self-efficacy and the physical and the mental dimension of HRQoL, respectively. The indirect effect of disturbed sleep went through that of fatigue. To conclude, patients who suffer from post-MI fatigue may need support aimed at helping them increase their self-efficacy as well as helping them adapt to sleep hygiene principles and cope with fatigue, both of which will have positive influences on HRQoL.


Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities.
Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-γ and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function.


Acupuncture for the treatment of tinnitus: a systematic review of randomized clinical trials.
Complementary and alternative medicine (CAM) has frequently been used to treat tinnitus, and acupuncture is a particularly popular option. The objective of this review was to assess the evidence concerning the effectiveness of acupuncture as a treatment for tinnitus. Fourteen databases were searched from the dates of their creation to July 4th, 2012. Randomized clinical trials (RCTs) were included if acupuncture was used as the sole treatment. The Cochrane risk of bias tool was used to assess the risk of bias. A total of 9 RCTs met all the inclusion criteria. Their methodological quality was mostly poor. Five RCTs compared the effectiveness of acupuncture or electroacupuncture with sham acupuncture for treating tinnitus. The results failed to show statistically significant improvements. Two RCTs compared a short one-time scalp acupuncture treatment with the use of penetrating sham acupuncture at non-acupoints in achieving subjective symptom relief on a visual analog scale; these RCTs demonstrated significant positive effects with scalp acupuncture. Two RCTs compared acupuncture with conventional drug treatments. One of these RCTs demonstrated that acupuncture had statistically significant effects on the response rate in patients with nervous tinnitus, but the other RCT did not demonstrate significant effects in patients with senile tinnitus. The number, size and quality of the RCTs on the effectiveness of acupuncture for the treatment of tinnitus are not sufficient for drawing definitive conclusions. Further rigorous RCTs that overcome the many limitations of the current evidence are warranted.


Coupling between respiratory and stepping rhythms during locomotion in decerebrate cats.
To determine whether and how the strength of coupling between respiratory and stepping rhythms varies depending on locomotor patterns, correlation analysis was done of diaphragmatic and gastrocnemius muscle activities. In spontaneously breathing cats decerebrated at the precollicular-post-mammillary level, tonic electrical stimulation was delivered to the mesencephalic locomotor region to induce locomotion on a treadmill. Electromyograms were recorded from the left hemidiaphragm and the bilateral gastrocnemius muscles. Various locomotor patterns were elicited by changes in the belt speed of the treadmill and in the intensity of stimulation of the mesencephalic locomotor region. Cross-correlograms between diaphragmatic and gastrocnemius activities showed that coupling was absent or weak when the cats walked slowly. The strength of locomotor-respiratory coupling tended to increase as the mean stepping interval shortened. When the animals were galloping, the respiratory rhythm was entrained 1:1 with the stepping rhythm. This study showed that the strength of coupling between respiratory and stepping rhythms varied depending on the locomotor patterns elicited, especially on whether the animals were running.


Local extinction and the evolution of dispersal rates: causes and correlations.
We present the results of individual-based simulation experiments on the evolution of dispersal rates of organisms living in metapopulations. We find conflicting results regarding the relationship between local extinction rate and evolutionarily stable (ES) dispersal rate depending on which principal mechanism causes extinction: if extinction is caused by environmental catastrophes eradicating local populations, we observe a positive correlation between extinction and ES dispersal rate; if extinction is a consequence of stochastic local dynamics and environmental fluctuations, the correlation becomes ambiguous; and in cases where extinction is caused by dispersal mortality, a negative correlation between local extinction rate and ES dispersal rate emerges. We conclude that extinction rate, which both affects and is affected by dispersal rates, is not an ideal predictor for optimal dispersal rates.


New scanning technique for the optical vortex microscope.
In the optical vortex microscopy the focused Gaussian beam with optical vortex scans a sample. An optical vortex can be introduced into a laser beam with the use of a special optical element--a vortex lens. When moving the vortex lens, the optical vortex changes its position inside the spot formed by a focused laser beam. This effect can be used as a new precise scanning technique. In this paper, we study the optical vortex behavior at the sample plane. We also estimate if the new scanning technique results in observable effects that could be used for a phase object detection.


CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer.
The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease.


Who are the European youths willing to engage in radicalisation? A multidisciplinary review of their psychological and social profiles.
A new model of radicalisation has appeared in Western countries since the 2010s. Radical groups are smaller, less hierarchical and are mainly composed of young, homegrown individuals. The aim of this review is to decipher the profiles of the European adolescents and young adults who have embraced the cause of radical Islamism and to define the role of psychiatry in dealing with this issue. We performed a systematic search in several databases from January 2010 to July 2017 and reviewed the relevant studies that included European adolescents and/or young adults and presented empirical data. In total, 22 qualitative and quantitative studies were reviewed from various fields and using different methodologies. Psychotic disorders are rare among radicalised youths. However, they show numerous risk factors common with adolescent psychopathologies. We develop a comprehensive three-level model to explain the phenomenon of radicalisation among young Europeans: (1) individual risk factors include psychological vulnerabilities such as early experiences of abandonment, perceived injustice and personal uncertainty; (2) micro-environmental risk factors include family dysfunction and friendships with radicalised individuals; (3) societal risk factors include geopolitical events and societal changes such as Durkheim's concept of anomie. Some systemic factors are also implicated as there is a specific encounter between recruiters and the individual. The former use sectarian techniques to isolate and dehumanise the latter and to offer him a new societal model. There are many similarities between psychopathological manifestations of adolescence and mechanisms at stake during the radicalisation process. As a consequence, and despite the rarity of psychotic disorders, mental health professionals have a role to play in the treatment and understanding of radical engagement among European youth. Studies with empirical data are limited, and more research should be promoted (in particular in females and in non-Muslim communities) to better understand the phenomenon and to propose recommendations for prevention and treatment.


Effects of pallidotomy and bilateral subthalamic stimulation on cognitive function in Parkinson disease. A controlled comparative study.
Unilateral pallidotomy and bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease (PD) have demonstrated a positive effect on motor functions. However, further studies are needed of the unintended cognitive effects accompanying these new surgical procedures. We studied the consequences of unilateral pallidotomy and STN-DBS on cognitive function in a controlled comparative design. Sixteen consecutive PD patients were assessed before and 6 months after unilateral pallidotomy (n = 8) and bilateral STN-DBS (n = 8). The same assessments were performed in a control group of eight non-operated matched PD patients recruited from surgery candidates who refused operation. The neuropsychological battery consisted of test measuring memory, attention, arithmetic, problem solving and language, as well as visuospatial, executive and premotor functions. An analysis of variance (factors time and treatment) was applied. No statistically significant differences were found in the presurgical evaluation of clinical and demographic data for the three treatment groups. The controlled comparison between presurgical and postsurgical performance revealed no significant changes in the cognitive domains tested in the pallidotomy group. The STN-DBS group showed a selective significant worsening of semantic verbal fluency (p = 0.005). This controlled comparative study suggests that neither unilateral pallidotomy nor bilateral STN-DBS have global adverse cognitive consequences, but bilateral STN-DBS may cause a selective decrease in verbal fluency.


Innate immune response to Streptococcus pyogenes depends on the combined activation of TLR13 and TLR2.
Innate immune recognition of the major human-specific Gram-positive pathogen Streptococcus pyogenes is not understood. Here we show that mice employ Toll-like receptor (TLR) 2- and TLR13-mediated recognition of S. pyogenes. These TLR pathways are non-redundant in the in vivo context of animal infection, but are largely redundant in vitro, as only inactivation of both of them abolishes inflammatory cytokine production by macrophages and dendritic cells infected with S. pyogenes. Mechanistically, S. pyogenes is initially recognized in a phagocytosis-independent manner by TLR2 and subsequently by TLR13 upon internalization. We show that the TLR13 response is specifically triggered by S. pyogenes rRNA and that Tlr13-/- cells respond to S. pyogenes infection solely by engagement of TLR2. TLR13 is absent from humans and, remarkably, we find no equivalent route for S. pyogenes RNA recognition in human macrophages. Phylogenetic analysis reveals that TLR13 occurs in all kingdoms but only in few mammals, including mice and rats, which are naturally resistant against S. pyogenes. Our study establishes that the dissimilar expression of TLR13 in mice and humans has functional consequences for recognition of S. pyogenes in these organisms.


High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention.
High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously. The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity (DAPR) and its impact on clinical outcome. On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry (LTA) (n=921) and the point-of-care VerifyNow system (P2Y12 and aspirin) (n=422) in patients on dual antiplatelet therapy undergoing elective stent implantation. HCPR and HAPR were established by receiver-operator characteristic curve analysis. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and ischaemic stroke at 1-year follow-up. The incidence of DAPR varied between 14.7% and 26.9% depending on the platelet function test used. DAPR, assessed by LTA and the VerifyNow system, was highly associated with an adverse clinical outcome. At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR (11.7%), isolated HAPR (9.6%) or DAPR (10.7%) compared with patients without high on-treatment platelet reactivity (4.2%, all p<0.01) when platelet function was evaluated with LTA. Using the VerifyNow system, patients exhibiting DAPR had the highest risk for the primary endpoint (17.7% vs 4.1% in patients without high on-treatment platelet reactivity, p=0.001). In patients undergoing elective percutaneous coronary intervention, DAPR to aspirin and clopidogrel is present in one in five patients and is associated with a high risk for atherothrombotic events. DAPR measured by the point-of-care VerifyNow system has a higher predictability for atherothrombotic events than LTA. www.clinicaltrials.gov: NCT00352014.


Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.
Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.


Gas sensing at the nanoscale: engineering SWCNT-ITO nano-heterojunctions for the selective detection of NH3 and NO2 target molecules.
The gas response of single-wall carbon nanotubes (SWCNT) functionalized with indium tin oxide (ITO) nanoparticles (NP) has been studied at room temperature and an enhanced sensitivity to ammonia and nitrogen dioxide is demonstrated. The higher sensitivity in the functionalized sample is related to the creation of nano-heterojunctions at the interface between SWCNT bundles and ITO NP. Furthermore, the different response of the two devices upon NO2 exposure provides a way to enhance also the selectivity. This behavior is rationalized by considering a gas sensing mechanism based on the build-up of space-charge layers at the junctions. Finally, full recovery of the signal after exposure to NO2 is achieved by UV irradiation for the functionalized sample, where the ITO NP can play a role to hinder the poisoning effects on SWCNT due to NO2 chemisorption.


Adverse events, healthcare interventions and healthcare utilization during home infusion therapy with daptomycin and vancomycin: a propensity score-matched cohort study.
Vancomycin and daptomycin are the two most frequently prescribed parenteral antimicrobials for resistant Gram-positive bacterial infections. The purpose of this study was to compare antimicrobial adverse event rates and associated healthcare interventions and healthcare utilization in patients treated with the two antimicrobials. All patients aged ≥18 years, discharged home from Cleveland Clinic on outpatient parenteral antimicrobial therapy (OPAT) with daptomycin or vancomycin between 1 July 2007 and 30 June 2010 were screened. Logistic regression models were built to calculate propensity to be treated with daptomycin for each patient. Propensity score-matched vancomycin-treated controls were identified for each daptomycin-treated patient. Adverse event, healthcare intervention and healthcare utilization rates during OPAT were compared in the matched cohort using negative binomial regression models. One thousand, two hundred and eighty-eight patients were identified. Three-to-one matching provided the best matching characteristics and identified 119 daptomycin-treated subjects (2518 OPAT days) and 357 vancomycin-treated controls (6649 OPAT days). The mean patient age was 56 years and the mean OPAT duration was 19 days. Antimicrobial adverse event rates for the daptomycin and vancomycin groups were 3.2 and 7.7 per 1000 OPAT days, respectively [relative risk (RR) 0.38; 95% CI 0.15-0.86; P = 0.02]. Antimicrobial intervention rates were 5.6 and 27.1 per 1000 OPAT days, respectively (RR 0.21; 95% CI 0.11-0.36; P < 0.001). Readmissions for worsening infection or treatment complication were not significantly different between daptomycin (5%) and vancomycin (7%). Patients receiving daptomycin at home have 60% fewer antimicrobial adverse events and require 80% fewer antimicrobial interventions than similar patients receiving vancomycin.


Characterization of didactic and pedagogical training in Brazilian stricto sensu Postgraduate Programs in Nursing.
To characterize the didactic and pedagogical training offered in Brazilian stricto sensu Postgraduate Programs in Nursing. Descriptive, documentary research, based on data from 30 postgraduate programs that offer an academic master's degree and a PhD degree. We collected the course projects and teaching plans of the disciplines related to didactic and pedagogical training, accessed through the Sucupira Platform or the institutional website. The variables were analyzed by descriptive statistics, through calculations of relative and absolute frequency. Regarding the lines of research of the programs, it was evidenced that 17.4% (n=20) were related to didactic and pedagogical training, 9.4% (n=3) followed this approach and, regarding compulsory didactic and pedagogical disciplines, it was observed that they were expressed differently in the curricula of masters and PhD courses, since part of the masters courses (56.6%, n=17) and of the PhD courses (76.6%, n=23) did not have this requirement. There should be a Brazilian guideline to promote the didactic and pedagogical training of university professors.


Intraosseous infusion devices: a comparison for potential use in special operations.
To determine which intraosseous (IO) devices were easy to learn to use, easy to use once the skill was obtained, and appropriate for the Special Operations environment. Thirty-one Navy SEAL corpsmen, Air Force pararescuemen, Army Special Forces, and Ranger medics, in a prospective, randomly assigned, cross-over study, tested four commercially available, Food and Drug Administration-cleared IO devices. The systems included the injection models First Access for Shock and Trauma (FAST, Pyng Medical) and Bone Injection Gun (Wais Medical, Kress USA Corporation) and the hand-driven threaded-needle SurFast (Cook Critical Care) and straight-needle Jamshidi needle (Baxter) models. The Special Operations medical care providers received a lecture regarding IO use, viewed videotapes of the injection models, and practiced with demonstration units in the classroom. Each participant then entered the cadaver lab where all four of the IO devices were placed in randomly assigned order. A poststudy questionnaire was then completed. The FAST was placed in the sternum, whereas the other units were placed in either medial proximal or distal medial tibia. Each participant was assessed for time, number of attempts, and success. The presence of marrow, extravasation, quality of flow, and security of needle were evaluated in combination to help determine success. All four devices were believed to be easy to learn as well as easy to place. FAST was successful in 29 of 30 insertions (94%) with a placement time of 114 +/- 36 (mean +/- SD) seconds. The Bone Injection Gun was similarly successful (29 of 31 insertions, 94%) with a mean placement time of 70 +/- 33 seconds. This time was statistically significantly faster (p < 0.05) than that with FAST, but not with the other devices. Thirty of 31 SurFast placements (97%) were successful, on average taking 88 +/- 33 seconds to place. The Jamshidi needle also had 30 of 31 successful placements (97%) at an average 90 +/- 59 seconds. No one device was rated by the participants as significantly better than the others; however, the Bone Injection Gun did have 65% of participants rate it as first or second (closest was Jamshidi needle at 52%). These IO devices were easy to teach and learn as well as easy to use. Insertion times compared favorably with peripheral intravenous catheter placement in the face of hemorrhage. All four devices can be appropriately used in the Special Operations environment and are reasonable alternatives when intravenous access cannot be gained. Although no device was rated higher than the others, particular features are desirable (low weight/size, simplicity, reusability, secure, clean, well protected).


The association of inhaled corticosteroid use with serum glucose concentration in a large cohort.
Inhaled corticosteroids (ICSs) are widely used in the treatment of obstructive lung disease. ICSs have been shown to be systemically absorbed. The association between ICS and serum glucose concentration is unknown. To explore the association of ICS dosing with serum glucose concentration, we used a prospective cohort study of US veterans enrolled in 7 primary care clinics between December 1996 and May 2001 with 1 or more glucose measurements while at least 80% adherent to ICS dosing. The association between ICS dose from pharmacy records standardized to daily triamcinolone equivalents and serum glucose concentration was examined with generalized estimating equations controlling for confounders, including systemic corticosteroid use. Of the 1698 subjects who met inclusion criteria, 19% had self-reported diabetes. The mean daily dose of ICS in triamcinolone equivalents was 621 microg (standard deviation 555) and 610 microg (standard deviation 553) for subjects with and without diabetes, respectively. After controlling for systemic corticosteroid use and other potential confounders, no association between ICS and serum glucose was found for subjects without diabetes. However, among subjects with self-reported diabetes, every additional 100 microg of ICS dose was associated with an increased glucose concentration of 1.82 mg/dL (P value .007; 95% confidence interval [CI], 0.49-3.15). Subjects prescribed antiglycemic medications had an increase in serum glucose of 2.65 mg/dL (P value .003; 95% CI, 0.88-4.43) for every additional 100 microg ICS dose. Among diabetic patients, ICS use is associated with an increased serum glucose concentration in a dose-response manner.


Social context as a risk factor for psychopathology in children with epilepsy.
Epilepsy is the number one neurological disorder in children in western society. Childhood epilepsy is highly comorbid with psychopathology. Although neurological and biological factors may partially explain the increased risk of psychopathology in children with epilepsy, social contextual factors are also important to understanding development of psychopathology in children with epilepsy. The current paper examines the development of children with epilepsy utilizing Bronfenbrenner's micro-, meso-, exo-, and macrosystem social contexts. Negative interpersonal interactions within the microsystems and the ripple effect of social context at the other levels may contribute to increased risk for psychopathology.


The pathogenesis of pre-eclampsia.
Syncytiotrophoblast normally sheds redundant placental debris into the maternal circulation, a process, which depends on apoptosis. It is renewed from the underlying mononuclear cytotrophoblast. We propose that the continual clearance of this debris from the maternal circulation causes a systemic inflammatory response that is present in all pregnant women in the third trimester. Pre-eclampsia occurs when the systemic inflammatory response decompensates. This may occur if the burden of the debris is abnormally high, or if the woman's response to the process is excessive. There is evidence that oxidative stress in the placenta could lead to an overload of debris by stimulating apoptosis or necrosis or both. Such stress would be most likely with spiral artery disease either from deficient placentation or acute atherosis, In this model, deficient placentation is not the cause of pre-eclampsia but a powerfully predisposing condition.


Effects of inhaled nitric oxide following lung transplantation.
Lung transplantation offers an established therapeutic option for end-stage lung disease. It is associated with several complications, and early allograft failure is one of the most devastating among all. Different studies are focused on an attempt to minimize these complications, especially transplant failure. We aimed to evaluate the effects of inhaled nitric oxide (iNO) treatment in patients receiving lung transplantation. Nine patients (six female, three male; mean age 42.9 +/- 15.8) requiring lung transplantation for end-stage pulmonary disease--chronic obstructive pulmonary disease (three patients), cystic fibrosis (three patients), scleroderma and systemic sclerosis (two patients), Eisenmenger's syndrome (one patient), and treated with iNO were included in this retrospective study. Hemodynamic data (mean arterial pressure, mean pulmonary arterial pressure, heart rate) and respiratory parameters were analyzed. Pretreatment data were compared with the post-iNO treatment data at 6-8 hours and 12-14 hours. The inhalation of nitric oxide was started with an initial dose of 40 parts per million (ppm) and the dose was gradually decreased until hemodynamic and pulmonary stability was achieved. Six patients underwent double-lung transplantation and three single-lung transplantations were performed. Cardiopulmonary bypass was used in seven patients. The iNO therapy was started before transplantation in five patients, after the procedure in four patients. Mean iNO therapy duration was 83.2 +/- 74.4 hours. The administration of iNO resulted in a significant reduction in mean pulmonary arterial pressure (36.8 +/- 15.8 mm Hg to 22 +/- 6.8 mm Hg at 6-8 hours and 22.8 +/- 7.96 mm Hg at 12-14 hours). Mean systemic arterial pressure slightly increased at 6-8 hours and significantly increased at 12-14 hours (70.2 +/- 6.3 mm Hg to 90.1 +/- 11.96 mm Hg). Heart rate was not significantly affected with the treatment. Arterial oxygenation improved with the treatment. All patients except one showed improvement of overall respiratory functions. The mean duration of mechanical ventilation was 12.8 +/- 10.9 days. Mortality occurred in one patient due to neurologic injury. NO(2) and methemoglobin levels were closely monitored during the treatment. Methemoglobinemia did not occur and NO(2) levels remained between 0.1 and 0.4 ppm. Nitric oxide inhalation for the prevention and treatment of early allograft failure in lung transplant recipients is encouraging. It is superior to other vasodilators with its selectivity to the pulmonary vasculature, while having no significant side effects on systemic circulation. It appears to improve gas exchange and oxygenation properties. Further prospective randomized studies will aid to standardize inhalation nitric oxide therapy.


Structural Modification in Carbon Nanotubes by Boron Incorporation.
We have synthesized boron-incorporated carbon nanotubes (CNTs) by decomposition of ferrocene and xylene in a thermal chemical vapor deposition set up using boric acid as the boron source. Scanning and transmission electron microscopy studies of the synthesized CNT samples showed that there was deterioration in crystallinity and improvement in alignment of the CNTs as the boron content in precursor solution increased from 0% to 15%. Raman analysis of these samples showed a shift of ~7 cm(-1) in wave number to higher side and broadening of the G band with increasing boron concentration along with an increase in intensity of the G band. Furthermore, there was an increase in the intensity of the D band along with a decrease in its wave number position with increase in boron content. We speculate that these structural modifications in the morphology and microstructure of CNTs might be due to the charge transfer from boron to the graphite matrix, resulting in shortening of the carbon-carbon bonds.