Complexities in the pharmacologic management of osteoarthritis pain.
To discuss challenges in the pharmacologic management of osteoarthritis (OA) pain. Literature searches through MEDLINE and Cochrane databases were used to identify relevant journal articles. The search was limited to articles published from January 1982 to January 2013. Additional references were obtained from articles extracted during the database search. Pharmacologic management of OA is aimed at alleviating pain and reducing functional impairment. Limitations of the most commonly prescribed agents (non-steroidal anti-inflammatory drugs [NSAIDs], acetaminophen, and opioids) and conflicting practice guidelines have led to physician and patient dissatisfaction. OA management guidelines advocate the use of acetaminophen, NSAIDs, serotonin-norepinephrine reuptake inhibitors (SNRIs) and opioids; however, these agents are associated with serious adverse events (AEs) and, in some cases, efficacy concerns. Acetaminophen, particularly at higher dosages, may lead to acute liver failure and gastrointestinal (GI) bleeding. NSAIDs present a significant GI bleeding risk and are also associated with a variety of renal complications, myocardial infarction and other serious cardiovascular complications. SNRIs can cause AEs such as hepatotoxicity and drug/drug interactions that can lead to serotonin syndrome. Opioids exhibit abuse potential and tramadol may demonstrate limited efficacy. The safety and efficacy concerns associated with currently available OA treatment options establish a need to develop new treatment strategies. Disease-modifying agents and novel drug formulations are currently under investigation. As these new pharmacologic options evolve, their adoption may lower risk and improve clinical outcomes.


The Effect of Model Misspecification on Semi-Supervised Classification.
Semi-supervised classification--training both on labeled and unlabeled observations--can yield improved performance compared to the classifier based on only the labeled observations. Unlabeled observations are always beneficial to classification if the model we assume is correct. However, they may degrade the classifier performance when the model is misspecified. In the classical classification problem setting, many factors affect the semi-supervised performance, including training data, model specification, estimation method, and the classifier itself. For concreteness, we consider maximum likelihood estimation in finite mixture models and the Bayes plug-in classifier, due to their ubiquitousness and tractability. In this specific setting, we examine the effect of model misspecification on semi-supervised classification performance and shed some light on when and why performance degradation occurs.


The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs.
The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.


Interventions to Reduce Loss to Follow-up During All Stages of the HIV Care Continuum in Sub-Saharan Africa: A Systematic Review.
The continuum of care for successful HIV treatment includes HIV testing, linkage, engagement in care, and retention on antiretroviral therapy (ART). Loss to follow-up (LTFU) is a significant disruption to this pathway and a common outcome in sub-Saharan Africa. This review of literature identified interventions that have reduced LTFU in the HIV care continuum. A search was conducted utilizing terms that combined the disease state, stages of the HIV care continuum, interventions, and LTFU in sub-Saharan Africa and articles published between January 2010 and July 2015. Thirteen articles were included in the final review. Use of point of care CD4 testing and community-supported programs improved linkage, engagement, and retention in care. There are few interventions directed at LTFU and none that span across the entire continuum of HIV care. Further research could focus on devising programs that include a series of interventions that will be effective through the entire continuum.


BASHY Dyes Are Highly Efficient Lipid Droplet-Targeting Photosensitizers that Induce Ferroptosis through Lipid Peroxidation.
Ferroptosis is an iron-dependent lipid-peroxidation-driven mechanism of cell death and a promising therapeutic target to eradicate cancer cells. In this study, we discovered that boronic acid-derived salicylidenehydrazone (BASHY) dyes are highly efficient singlet-oxygen photosensitizers (PSs; ΦΔ up to 0.8) that induce ferroptosis triggered by photodynamic therapy. The best-performing BASHY dye displayed a high phototoxicity against the human glioblastoma multiform U87 cell line, with an IC50 value in the low nanomolar range (4.40 nM) and a remarkable phototoxicity index (PI > 22,700). Importantly, BASHY dyes were shown to accumulate in lipid droplets (LDs) and this intracellular partition was found to be essential for the enhanced phototoxicity and the induction of ferroptosis through lipid peroxidation. The safety and phototoxicity of this platform were validated using an in vivo zebrafish model (Danio rerio).


Is conflict adaptation triggered by feature repetitions? An unexpected finding.
For decades, cognitive adaptation to response conflict has been considered to be the hallmark of cognitive control. Notwithstanding a vast amount of evidence ruling out low-level interpretations of these findings, disbelief still exists with regard to the underlying cause of the observed effects. Especially when considering cognitive adaptation to unconscious conflict, it is still a matter of debate whether repetitions of features between trials might explain this intriguing finding rather than the involvement of unconscious control. To this purpose, we conducted two masked priming experiments in which four different responses to four different stimuli were required. This allowed us to completely eliminate repetitions of prime and target over consecutive trials. Independent of whether conflicting information was presented clearly visible or almost imperceptible, the results showed an unexpected pattern. Contrary to the regular congruency sequence effect (CSE; i.e., classic Gratton effect), in both experiments the congruency effect increased following incongruent trials. Interestingly, this reversed effect completely disappeared when we eliminated all trials with feature repetitions from the analysis. A third experiment, in which feature repetitions were excluded a priori, showed a small but regular CSE in the error rates only. Given that feature repetitions are theoretically thought to create a regular CSE, our results are not in line with an interpretation in terms of feature repetitions nor with an interpretation in terms of cognitive control. We conclude that examining cognitive adaptation with or without feature repetitions might be more difficult to conceive than is often suggested in the literature.


Subcellular localization of Mayven following expression of wild type and mutant EGFP tagged cDNAs.
Process formation by glial cells is crucial to their function. Mayven, an actin binding, multi-domain polypeptide, and member of the BTB-BACK-Kelch family have been shown to be important in oligodendrocyte process extension. To assess the role of Mayven in neural cell process extension we have tracked the subcellular distribution of exogenous Mayven following expression of a rat Mayven -EGFP cDNA in a variety of neural cell backgrounds and specifically in OEC tranfectants following drug treatment to disrupt the integrity of the cytoskeleton. A comparison was made between the subcellular localization following transient transfection of OECs with full-length Mayven cDNA and a series of mutant domain constructs. The subcellular location of Mayven in OEC transfectants showed a characteristic distribution with intense foci of staining towards the process tips corresponding to regions of accumulated Mayven overlapping in part with lammelipodial actin and was absent from the filipodia and the outer membrane. This signature pattern was also observed in Schwann cells, Oli-Neu cells, astrocytes and the neuroblastoma cell line B104 transfectants and resembled the exogenous and endogenous Mayven distribution in oligodendrocytes. This contrasted with the localization pattern in non-neural cells. There was a re-localization of Mayven in OEC transfectants following drug treatment to challenge the integrity of the actin cytoskeleton while breakdown of the microtubular component had no discernible impact on the accumulation of Mayven in the process tips. Deletion of the first three amino acids of the SH3 motif of the putative Fyn Kinase binding domain at the amino terminus significantly compromised this signature pattern as did the removal of the last Kelch repeat unit of six unit Kelch domain comprising the carboxyl terminus. In addition, there was a reduction in process length in mutant transfectants. Co-expression studies with a haemagglutinin (HA) tagged wild type Mayven cDNA and EGFP tagged mutant cDNAs suggested a homomeric interaction mediated by the BTB/POZ domain. Exogenous Mayven is transported to the lamellipodia in neural transfectants associating with the actin cytoskeletal network. In addition to the importance of the internal BTB/POZ domain, this subcellular distribution pattern is dependent on the presence of an intact amino and carboxyl terminus.


Designed Artificial Protein Heterodimers With Coupled Functions Constructed Using Bio-Orthogonal Chemistry.
The formation of protein complexes is central to biology, with oligomeric proteins more prevalent than monomers. The coupling of functionally and even structurally distinct protein units can lead to new functional properties not accessible by monomeric proteins alone. While such complexes are driven by evolutionally needs in biology, the ability to link normally functionally and structurally disparate proteins can lead to new emergent properties for use in synthetic biology and the nanosciences. Here we demonstrate how two disparate proteins, the haem binding helical bundle protein cytochrome b 562 and the β-barrel green fluorescent protein can be combined to form a heterodimer linked together by an unnatural triazole linkage. The complex was designed using computational docking approaches to predict compatible interfaces between the two proteins. Models of the complexes where then used to engineer residue coupling sites in each protein to link them together. Genetic code expansion was used to incorporate azide chemistry in cytochrome b 562 and alkyne chemistry in GFP so that a permanent triazole covalent linkage can be made between the two proteins. Two linkage sites with respect to GFP were sampled. Spectral analysis of the new heterodimer revealed that haem binding and fluorescent protein chromophore properties were retained. Functional coupling was confirmed through changes in GFP absorbance and fluorescence, with linkage site determining the extent of communication between the two proteins. We have thus shown here that is possible to design and build heterodimeric proteins that couple structurally and functionally disparate proteins to form a new complex with new functional properties.


Immunoregulation by T cells. I. Characterization of the IEk-specific Lbd self-reactive T cell clone that helps, suppresses and contrasupresses B cell responses.
This paper describes an L3T4+, Lyt-2- cloned T cell line of CBA/N origin that is specific for IEk-encoded products. Splenic dendritic cells are the predominant stimulatory populations for Lbd cells, being approximately 100 times more effective than large activated B cells. Small B cells and T cells are nonstimulatory. Lbd cells help large B cells to make polyclonal antibody responses, but are unable to activate small B cells and to replace antigen-specific helper T cells in T cell-dependent responses to phosphorylcholine or sheep red blood cells. In the presence of antigen-specific helper T cells, Lbd can amplify, suppress, or contrasuppress T cell function, depending on the type and relative ratios of antigen-reactive cells. We explain our findings as a consequence of the self reactivity among helper T cells.


Dodeca-CLE peptides as suppressors of plant stem cell differentiation.
In plants and animals, small peptide ligands that signal in cell-cell communication have been suggested to be a crucial component of development. A bioassay of single-cell transdifferentation demonstrates that a dodecapeptide with two hydroxyproline residues is the functional product of genes from the CLE family, which includes CLAVATA3 in Arabidopsis. The dodecapeptide suppresses xylem cell development at a concentration of 10(-11) M and promotes cell division. An application, corresponding to all 26 Arabidopsis CLE protein family members, of synthetic dodecapeptides reveals two counteracting signaling pathways involved in stem cell fate.


Malic dehydrogenase isozymes: distribution in developing nucleate and anucleate halves of sea urchin eggs.
Nucleate and anucleate halves of sea urchin eggs have seven and five forms of L-malic dehydrogenase, respectively. Fertilization results in reduction of the number of enzyme forms in both halves. The normal complement of seven isozymes in unfertilized eggs appears to be a synthesis of five soluble and four particulate forms. Reduction in the number of isozymes after fertilization takes place principally in solutble forms and appears to be under cytoplasmic control.


Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances.
The degeneration of light-detecting rod and cone photoreceptors in the human retina leads to severe visual impairment and ultimately legal blindness in millions of people worldwide. Multiple therapeutic options at different stages of degeneration are being explored but the majority of ongoing clinical trials involve adeno-associated viral (AAV) vector-based gene supplementation strategies for select forms of inherited retinal disease. Over 300 genes are associated with inherited retinal degenerations and only a small proportion of these will be suitable for gene replacement therapy. However, while the origins of disease may vary, there are considerable similarities in the physiological changes that occur in the retina. When early therapeutic intervention is not possible and patients suffer loss of photoreceptor cells but maintain remaining layers of cells in the neural retina, there is an opportunity for a universal gene therapy approach that can be applied regardless of the genetic origin of disease. Optogenetic therapy offers such a strategy by aiming to restore vision though the provision of light-sensitive molecules to surviving cell types of the retina that enable light perception through the residual neurons. Here we review the recent progress in attempts to restore visual function to the degenerate retina using optogenetic therapy. We focus on multiple pre-clinical models used in optogenetic strategies, discuss their strengths and limitations, and highlight considerations including vector and transgene designs that have advanced the field into two ongoing clinical trials.


Genomic Epidemiology and Evolution of Escherichia coli in Wild Animals in Mexico.
Escherichia coli is a common bacterial species in the gastrointestinal tracts of warm-blooded animals and humans. Pathogenicity and antimicrobial resistance in E. coli may emerge via host switching from animal reservoirs. Despite its potential clinical importance, knowledge of the population structure of commensal E. coli within wild hosts and the epidemiological links between E. coli in nonhuman hosts and E. coli in humans is still scarce. In this study, we analyzed the whole-genome sequencing data of a collection of 119 commensal E. coli strains recovered from the guts of 55 mammal and bird species in Mexico and Venezuela in the 1990s. We observed low concordance between the population structures of E. coli isolates colonizing wild animals and the phylogeny, taxonomy, and ecological and physiological attributes of the host species, with distantly related E. coli strains often colonizing the same or similar host species and distantly related host species often hosting closely related E. coli strains. We found no evidence for recent transmission of E. coli genomes from wild animals to either domesticated animals or humans. However, multiple livestock- and human-related virulence factor genes were present in E. coli of wild animals, including virulence factors characteristic of Shiga toxin-producing E. coli (STEC) and atypical enteropathogenic E. coli (aEPEC), where several isolates from wild hosts harbored the locus of enterocyte effacement (LEE) pathogenicity island. Moreover, E. coli isolates from wild animal hosts often harbored known antibiotic resistance determinants, including those against ciprofloxacin, aminoglycosides, tetracyclines, and beta-lactams, with some determinants present in multiple, distantly related E. coli lineages colonizing very different host animals. We conclude that genome pools of E. coli colonizing the guts of wild animals and humans share virulence and antibiotic resistance genes, underscoring the idea that wild animals could serve as reservoirs for E. coli pathogenicity in human and livestock infections.IMPORTANCEEscherichia coli is a clinically important bacterial species implicated in human- and livestock-associated infections worldwide. The bacterium is known to reside in the guts of humans, livestock, and wild animals. Although wild animals are recognized as potential reservoirs for pathogenic E. coli strains, the knowledge of the population structure of E. coli in wild hosts is still scarce. In this study, we used fine resolution of whole-genome sequencing to provide novel insights into the evolution of E. coli genomes from a small yet diverse collection of strains recovered within a broad range of wild animal species (including mammals and birds), the coevolution of E. coli strains with their hosts, and the genetics of pathogenicity of E. coli strains in wild hosts in Mexico. Our results provide evidence for the clinical importance of wild animals as reservoirs for pathogenic strains and highlight the need to include nonhuman hosts in the surveillance programs for E. coli infections.


Pluronic F127-based ocular delivery system containing biodegradable polyisobutylcyanoacrylate nanocapsules of pilocarpine.
The objectives of our study were to prepare a biodegradable polyisobutylcyanoacrylate (PIBCA) colloidal particulate system of pilocarpine, to incorporate it into a Pluronic F127(PF127)-based gel delivery system, and to evaluate its ability to prolong the release of pilocarpine. Polyisobutylcyanoacrylate nanocapsules (PIBCA-NC) of pilocarpine were prepared by interfacial polymerization. Physicochemical characterization of the colloidal dispersion of PIBCA-NC of pilocarpine was performed by measuring drug loading, particle size analysis, and scanning electron microscopy. Results indicated that approximately 13.5% of pilocarpine was loaded onto the PIBCA-NC, the nanocapsules ranged from 370 to 460 nm, the distribution was narrow, and there was no significant effect of stirring speed on particle size. The PIBCA-NC dispersion of 1% pilocarpine alone (I) and after incorporation into the Pluronic F127 gel delivery system (II) were compared against 1% pilocarpine incorporated into a PF127 gel containing 5% methylcellulose (PF127MC) alone (III) by measuring the miotic response in the albino rabbit eye. Statistical analysis indicated a rank-order for both the duration and intensity of miosis of II > III >> I, with all differences being significant (p < 0.05). Thus, it appears that II increases the contact time of pilocarpine with the absorbing tissue in the eye, thereby improving ocular bioavailability. The PIBCA-NC of pilocarpine dispersed in the PF127MC gel delivery system has considerable potential for achieving a prolonged delivery for such drugs as pilocarpine and other more hydrophobic drugs.


Energy- and time-resolved detection of prompt gamma-rays for proton range verification.
In this work, we present experimental results of a novel prompt gamma-ray detector for proton beam range verification. The detection system features an actively shielded cerium-doped lanthanum(III) bromide scintillator, coupled to a digital data acquisition system. The acquisition was synchronized to the cyclotron radio frequency to separate the prompt gamma-ray signals from the later-arriving neutron-induced background. We designed the detector to provide a high energy resolution and an effective reduction of background events, enabling discrete proton-induced prompt gamma lines to be resolved. Measuring discrete prompt gamma lines has several benefits for range verification. As the discrete energies correspond to specific nuclear transitions, the magnitudes of the different gamma lines have unique correlations with the proton energy and can be directly related to nuclear reaction cross sections. The quantification of discrete gamma lines also enables elemental analysis of tissue in the beam path, providing a better prediction of prompt gamma-ray yields. We present the results of experiments in which a water phantom was irradiated with proton pencil-beams in a clinical proton therapy gantry. A slit collimator was used to collimate the prompt gamma-rays, and measurements were performed at 27 positions along the path of proton beams with ranges of 9, 16 and 23 g cm(-2) in water. The magnitudes of discrete gamma lines at 4.44, 5.2 and 6.13 MeV were quantified. The prompt gamma lines were found to be clearly resolved in dimensions of energy and time, and had a reproducible correlation with the proton depth-dose curve. We conclude that the measurement of discrete prompt gamma-rays for in vivo range verification of clinical proton beams is feasible, and plan to further study methods and detector designs for clinical use.


Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase.
Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.


Energy-Efficient Distributed Filtering in Sensor Networks: A Unified Switched System Approach.
This paper is concerned with the energy-efficient distributed filtering in sensor networks, and a unified switched system approach is proposed to achieve this goal. For the system under study, the measurement is first sampled under nonuniform sampling periods, then the local measurement elements are selected and quantized for transmission. Then, the transmission rate is further reduced to save constrained power in sensors. Based on the switched system approach, a unified model is presented to capture the nonuniform sampling, the measurement size reduction, the transmission rate reduction, the signal quantization, and the measurement missing phenomena. Sufficient conditions are obtained such that the filtering error system is exponentially stable in the mean-square sense with a prescribed H∞ performance level. Both simulation and experiment studies are given to show the effectiveness of the proposed new design technique.


Elucidating the role of the proximal cysteine hydrogen-bonding network in ferric cytochrome P450cam and corresponding mutants using magnetic circular dichroism spectroscopy.
Although extensive research has been performed on various cytochrome P450s, especially Cyt P450cam, there is much to be learned about the mechanism of how its functional unit, a heme b ligated by an axial cysteine, is finely tuned for catalysis by its second coordination sphere. Here we study how the hydrogen-bonding network affects the proximal cysteine and the Fe-S(Cys) bond in ferric Cyt P450cam. This is accomplished using low-temperature magnetic circular dichroism (MCD) spectroscopy on wild-type (wt) Cyt P450cam and on the mutants Q360P (pure ferric high-spin at low temperature) and L358P where the "Cys pocket" has been altered (by removing amino acids involved in the hydrogen-bonding network), and Y96W (pure ferric low-spin). The MCD spectrum of Q360P reveals fourteen electronic transitions between 15200 and 31050 cm(-1). Variable-temperature variable-field (VTVH) saturation curves were used to determine the polarizations of these electronic transitions with respect to in-plane (xy) and out-of-plane (z) polarization relative to the heme. The polarizations, oscillator strengths, and TD-DFT calculations were then used to assign the observed electronic transitions. In the lower energy region, prominent bands at 15909 and 16919 cm(-1) correspond to porphyrin (P) → Fe charge transfer (CT) transitions. The band at 17881 cm(-1) has distinct sulfur S(π) → Fe CT contributions. The Q band is observed as a pseudo A-term (derivative shape) at 18604 and 19539 cm(-1). In the case of the Soret band, the negative component of the expected pseudo A-term is split into two features due to mixing with another π → π* and potentially a P → Fe CT excited state. The resulting three features are observed at 23731, 24859, and 25618 cm(-1). Most importantly, the broad, prominent band at 28570 cm(-1) is assigned to the S(σ) → Fe CT transition, whose intensity is generated through a multitude of CT transitions with strong iron character. For wt, Q360P, and L358P, this band occurs at 28724, 28570, and 28620 cm(-1), respectively. The small shift of this feature upon altering the hydrogen bonds to the proximal cysteine indicates that the role of the Cys pocket is not primarily for electronic fine-tuning of the sulfur donor strength but is more for stabilizing the proximal thiolate against external reactants (NO, O(2), H(3)O(+)), and for properly positioning cysteine to coordinate to the iron center. This aspect is discussed in detail.


Contrasting Topological Effect of PEG-Containing Amphiphiles to Natural Lipids on Stability of Vesicles.
Topology of amphiphiles is important to control physicochemical properties of supramolecular assemblies. Nature demonstrates higher stability of membrane composed of lipids with a macrocyclic aliphatic tail than those with linear tails, which likely results from the restricted molecular structures of the macrocyclic lipids, allowing for closer molecular packing. In contrast, here we report that a PEG-containing macrocyclic amphiphile shows lower stability of vesicles than the corresponding acyclic one. The macrocyclic amphiphile consists of an aromatic hydrophobic part with chirality in which both ends are strapped by octaethylene glycol via phosphoric ester groups, while the acyclic amphiphile bears tetraethylene glycol chains attached to both ends of the hydrophobic part. Because of the thermoresponsive property of PEG to change its conformation, the hydrophobic part of the macrocyclic amphiphile undergoes a larger thermal conformational change than that of the acyclic one. In addition, the cyclic amphiphile has a larger molecular area, which likely reduces the vesicular stability compared with the acyclic one. Such a contrasting topological effect caused by macrocyclization at the aliphatic part seen in the natural system and at the hydrophilic part demonstrated in this study leads to expand the molecular design of amphiphiles for both increasing and decreasing the stability of vesicles by molecular topology.


Urine drug screen findings among ambulatory oncology patients in a supportive care clinic.
Professional organizations provide no guidelines regarding assessment and management of opioid abuse risk in cancer. Universal precautions (UP) developed for non-cancer pain, include assessments for aberrant behavior, screening questionnaires, and urine drug screens (UDS). The role of UDS for identifying opioid abuse risk in cancer is uncertain. Our aim is to characterize inappropriate UDS, and identify a potential role for UDS in therapeutic decision-making. An observational retrospective chart review of 232 consecutive supportive care clinic patients were seen during the study. Twenty-eight of the two hundred thirty-two did not meet inclusion criteria. One hundred fifty of the two hundred four had active cancer, while 54 had no evidence of active disease. Clinicians ordered UDS based on their clinical judgment of patients' substance misuse risk. Edmonton symptom assessment scores, history of substance abuse, alcohol use, tobacco use, aberrant behavior, and morphine equivalent daily dose (MEDD) were obtained. Pain scores and MEDD were higher (p = 0.021; p < 0.001) in the UDS group vs non-UDS. Forty percent of the patients (n = 82/204) had at least one UDS and 70% (60/82) had an inappropriate result. Thirty-nine percent (32) were inappropriately negative, showing no prescribed opioids. Forty-nine of the eighty-two were positive for non-prescribed opioids, benzodiazepine, or illicit substance. Eleven of the forty-nine had only cannabis metabolites in their urine. There were no significant differences between appropriate and inappropriate UDS groups regarding pain scores, MEDD or referral to psychology, psychiatry, or substance abuse specialists. UDS on the 82 oncology patients at high risk for substance misuse were frequently positive (46%) for non-prescribed opioids, benzodiazepines or potent illicit drugs such as heroin or cocaine, and 39% had inappropriately negative UDS, raising concerns for diversion.


Does tobacco industry marketing excessively impact lesbian, gay and bisexual communities?
Tobacco industry documents have revealed marketing plans specifically to reach lesbian, gay and bisexual (LGB) populations. Research supports a causal linkage between receptivity and exposure to tobacco industry marketing and tobacco use uptake among adolescents. Pro-tobacco messages may diminish the effectiveness of tobacco control activities and contribute to the high smoking prevalence among LGB populations. To compare receptivity and exposure to tobacco industry marketing between LGB and heterosexual populations. Nearly 400 gay or bisexual men and more than 600 lesbian or bisexual women were identified in the 2003-2006 Washington State Behavioral Risk Factor Surveillance System (BRFSS), a state-wide, population-based telephone survey of adults. The BRFSS included questions measuring receptivity and exposure to tobacco industry marketing. Multiple logistic regression models stratified by gender were used to assess differences for lesbians, gays and bisexuals separately, in comparison to their heterosexual counterparts. As expected, smoking prevalence was higher among LGB populations than among heterosexuals. After adjustment for demographic differences and smoking status, gay and bisexual men reported more exposure to tobacco industry marketing (free sample distribution) than straight men, but were equally receptive to it. Lesbian and bisexual women were more receptive to and reported more exposure to tobacco industry marketing than straight women. LGB communities, especially lesbian and bisexual women, appear to be effectively targeted by tobacco industry marketing activities. Strategies to limit tobacco industry marketing, and increase individuals' resistance to marketing, may be critical to reducing smoking among LGB populations.


Long Noncoding RNA SNHG7 Accelerates Proliferation, Migration and Invasion of Non-Small Cell Lung Cancer Cells by Suppressing miR-181a-5p Through AKT/mTOR Signaling Pathway.
Non-small cell lung cancer (NSCLC) is a typical epithelial lung cancer with high metastasis, incidence and mortality. In recent years, long noncoding RNA small nucleolar RNA host gene 7 (SNHG7) has been identified as significant regulator in different cancer types, including NSCLC. However, the underlying molecular mechanism of SNHG7 during NSCLC tumorigenesis and progression remains largely unclear. SNHG7 and miR-181a-5p expression in NSCLC tumors and cells were detected by qRT-PCR. Cell viability, migration, invasion and apoptosis were evaluated by CCK-8, transwell and flow cytometry assay, respectively. A549 and NCI-H1299 xenograft mice model was constructed by subcutaneously injecting cells stably transfected with sh-SNHG7 and sh-NC. The interaction between SNHG7 and miR-181a-5p was validated by luciferase reporter system, RIP and RNA pull down assay. Protein expression of cleaved caspase 3, proliferating cell nuclear antigen (PCNA), AKT, p-AKT, mammalian target of rapamycin (mTOR) and p-mTOR was analyzed by Western blot. SNHG7 expression was up-regulated while miR-181a-5p expression was down-regulated in NSCLC tumors, especially those from patients at Phase III+IV, compared with normal tissues. However, SNHG7 depletion attenuated tumor growth in vitro and in vivo. Moreover, miR-181a-5p inhibitor abolished SNHG7 silencing induced inhibition on proliferation, migration and invasion in NSCLC. Subsequently, we found SNHG7 modulated cell progression by targeting miR-181a-5p and activating AKT/mTOR signaling pathway. SNHG7 accelerates proliferation, migration and invasion of NSCLC by suppressing miR-181a-5p through AKT/mTOR signaling pathway, thus presenting desirable biomarkers for NSCLC therapy.


Indications and outcome of surgery for pulmonary aspergilloma.
The indications and the outcome of surgery for pulmonary aspergilloma remain highly controversial. The short term and long term results of lung resection or cavernostomy in 24 patients with pulmonary aspergilloma are reported. The case notes of 27 consecutive patients referred for surgical assessment for pulmonary aspergilloma at the Royal Brompton Hospital over the last 14 years were reviewed. Patients were categorised into four classes according to their fitness for lung resection and the severity of their symptoms. Severe symptoms were defined as life threatening haemoptysis or other symptoms requiring more than one hospital admission. Class I (n = 1), fit individual with mild or no symptoms; class II (n = 17), fit individuals with severe symptoms; class III (n = 1), unfit individual with no symptoms; and class IV (n = 8), unfit individuals with severe symptoms. Two asymptomatic patients and one on an IVOX pump were not accepted for surgery. Lung resection was performed in all 17 patients with class II disease, comprising segmentectomy only in five patients, lobectomy and segmentectomy in seven, and a completion pneumonectomy in five patients. Cavernostomy was performed in seven patients with class IV disease. Surgery was often complicated by prolonged air leakage and infection of residual space. There was no operative mortality in the group treated by resection whereas two of those who underwent cavernostomy died in the early postoperative period. All survivors were followed up for a median of 17 months (range 1-72 months); 19 were alive and had no symptoms attributable to aspergilloma. Late recurrence occurred in two patients in the cavernostomy group. The only late death occurred in the resection group five months postoperatively and was attributed to end stage renal disease. Lung resection in selected patients with complicated aspergilloma can be performed with low operative mortality. Cavernostomy is associated with high mortality and morbidity and should therefore only be performed in patients with life threatening symptoms who are unfit for lung resection.


Efficient Production of Pyruvate Using Metabolically Engineered Lactococcus lactis.
Microbial production of commodity chemicals has gained increasing attention and most of the focus has been on reducing the production cost. Selecting a suitable microorganism, which can grow rapidly on cheap feedstocks, is of key importance when developing an economically feasible bioprocess. We chose Lactococcus lactis, a well-characterized lactic acid bacterium, as our microbial host to produce pyruvate, which is a commodity chemical with various important applications. Here we report the engineering of Lactococcus lactis into becoming an efficient microbial platform for producing pyruvate. The strain obtained, FS1076 (MG1363 Δ3 ldh Δpta ΔadhE Δals), was able to produce pyruvate as the sole product. Since all the competitive pathways had been knocked out, we achieved growth-coupled production of pyruvate with high yield. More than 80 percent of the carbon flux was directed toward pyruvate, and a final titer of 54.6 g/L was obtained using a fed-batch fermentation setup. By introducing lactose catabolism into FS1076, we obtained the strain FS1080, which was able to generate pyruvate from lactose. We then demonstrated the potential of FS1080 for valorizing lactose contained in dairy side-streams, by achieving a high titer (40.1 g/L) and high yield (78.6%) of pyruvate using residual whey permeate (RWP) as substrate. The results obtained, show that the L. lactis platform is well-suited for transforming lactose in dairy waste into food-grade pyruvate, and the yields obtained are the highest reported in the literature. These results demonstrate that it is possible to achieve sustainable bioconversion of waste products from the dairy industry (RWP) to valuable products.


Computerized, noninvasive tests of lung function. A flexible approach using mass spectrometry.
The design, operation, and some applications of a computerized pulmonary function testing system built around a mass spectrometer are described. The test sequence, performed in 10 to 20 min, includes spirometry, a single-breath N2 washout, and measurement of the diffusing capacity of the lung for CO. Secondary tests, an integral part of the sequence, include rebreathing estimates of lung volume and cardiac output, and a breath-by-breath analysis of over-all gas exchange. These secondary tests lead to computer modeling of a one-compartment lung closely matched to the subject's lungs. Differences between alveolar plateau slopes in the model and real lung provide information about the degree of ventilation-perfusion mismatch in the subject. It is expected that the combination of tests will be useful in the early detection of lung disease.


Green Fluorescent Protein GFP-Chromophore-Based Probe for the Detection of Mitochondrial Viscosity in Living Cells.
Viscosity is a pivotal factor for indicating the dysfunction of the mitochondria. To date, most of the fluorescent probes developed for mitochondrial viscosity have been designed using BODIPY, hemicyanine, or pyridine-based molecular rotors as part of the core structure. Our aim with this research was to extend the range of suitable fluorophores available for the construction of such fluorescent molecular rotors for evaluating the viscosity of mitocondria. Herein, we have developed a green fluorescent protein (GFP)-chromophore-based fluorescent probe (MIT-V) for the detection of mitochondrial viscosity in live cells. MIT-V exhibited a high sensitivity toward viscosity (from 7.9 cP to 438.4 cP). The "off-on" sensing mechanism of MIT-V was ascribed to the restricted rotation of single bonds and excited-state C═C double bonds of MIT-V. Cell studies indicated that MIT-V targets the mitochondria and that it was able to monitor real-time changes in the viscosity of live HeLa cell mitochondria. Therefore, we propose that MIT-V can be used as an effective chemosensor for the real-time imaging of mitochondrial viscosity in live cells. Our results clearly demonstrate the utility of such GFP-chromophore-based derivatives for the development of viscosity-sensitive systems.


Rhizobacterial diversity in India and its influence on soil and plant health.
The rhizosphere or the zone of influence around roots harbors a multitude of microorganisms that are affected by both abiotic and biotic stresses. Among these are the dominant rhizobacteria that prefer living in close vicinity to the root or on its surface and play a crucial role in soil health and plant growth. Both free-living and symbiotic bacteria are involved in such specific ecological niches and help in plant matter degradation, nutrient mobilization and biocontrol of plant disease. While the rhizosphere as a domain of fierce microbial activity has been studied for over a century, the availability of modern tools in microbial ecology has now permitted the study of microbial communities associated with plant growth and development, in situ localization of important forms, as well as the monitoring of introduced bacteria as they spread in the soil and root environment. This interest is linked to environmental concerns for reduced use of chemicals for disease control as well as an appreciation for utilization of biologicals and organics in agriculture. Indian researchers have studied the diversity of rhizobacteria in a variety of plants, cereals, legumes and others along with assessment of their functionality based on the release of enzymes (soil dehydrogenase, phosphatase, nitrogenase, etc.), metabolites (siderophores, antifungals, HCN, etc.), growth promoters (IAA, ethylene) and as inducers of systemic disease resistance (ISR). Based on such primary screening protocols, effective rhizobacteria have been field tested with success stories from various agroecological zones of the country, as reflected in the control of root- and soil-borne diseases, improved soil health and increased crop yields. Several commercial formulations, mostly based on dry powder (charcoal, lignite, farmyard manure, etc.) have been prepared and field tested, however, problems of appropriate shelf-life and cell viability are still to be solved. Also, inherent in such low cost technologies are the problems of variability in field performance and successful establishment of introduced inoculants in the root zone. In addition, most products available in the market are not properly monitored for quality before they reach the farmer. As a consequence, the acceptance of rhizobacterial formulations in the country is limited. However, several laboratories have now developed protocols for the rapid characterization of effective isolates based on molecular fingerprinting and other similar tools. Also, the use of molecular markers (gus, lux, gfp, etc.) makes it easy to monitor introduced inoculants in situ in soil and rhizosphere environments. The government initiative in integrated nutrient management and pest management systems has provided additional incentives to relate rhizobacterial science to other ongoing activities so that the benefit of this research leads to technologies that are environmentally and socially acceptable.


Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3.
Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin.


The microscopes of Antoni van Leeuwenhoek.
The seventeenth-century Dutch microscopist, Antoni van Leeuwenhoek, was the first man to make a protracted study of microscopical objects, and, unlike his contemporary Robert Hooke, he viewed by transmitted light. Leeuwenhoek made over 500 of his own, curious, simple microscopes, but now only nine are known to exist. The exact nature of the lenses Leeuwenhoek made, has for long been a puzzle. The existing microscopes have now been examined in detail, and their optical characteristics measured and tabulated. It is proposed that the lens of highest magnification, x 266, was made using a special blown bubble technique.


Behavioral Interventions Targeting Insufficient Upper Esophageal Sphincter Opening During Swallowing: A Scoping Review.
The upper esophageal sphincter (UES) plays a central role in safe swallowing. Impaired UES opening is commonly observed in individuals presenting with impaired swallowing and various interventions are available aiming to improve bolus passage across the UES during swallowing. This scoping review addressed the following question: Which behavioral interventions are available to improve UES opening for deglutition? We searched MEDLINE, CINAHL, Ovid Emcare, Web of Science, SCOPUS and ProQuest for studies that met the following criteria: i. behavioral interventions targeting UES opening ii. performed over a period of time, which iii. were assessed using UES specific outcome measures. Study quality was assessed using the Joanna Briggs Institute and GRADE frameworks. Data were extracted and synthesized into dominant themes. Of the 357 studies originally identified, 15 met inclusion criteria and reported interventions that were grouped into four intervention types: (1) floor of mouth exercises that were sub-categorized into the Shaker exercise and other strengthening exercises, (2) Mendelsohn maneuver, (3) lingual exercises and (4) mixed exercise paradigms. Across the included studies, varying levels of success in improving various aspects of UES opening metrics were reported. Nine of 15 studies evaluated patients with demonstrated swallowing impairment, whereas six studies evaluated healthy adults. Quality assessment revealed significant variability in study quality, unclear reporting of participant training and treatment fidelity, as well as training dosage. The evidence base for the four behavioral intervention approaches targeting deglutitive UES opening is limited. The translation of existing evidence to clinical practice is hindered by small sample sizes and methodological limitations. Further research in this space is warranted.


[Convenience clinic redefine polycystic ovary syndrome (Stein-Leventhal)].
In 1935 during a medical meeting behalf in New Orleans was presents a study that included seven cases of women that suffered menstrual dysfunctions, hirsutism and sterility, for laparotomy the description of the ovaries had a pearly white color and it was hypertrophic, the cuneiform resection in both ovaries resulted in correction of the menstrual dysfunction and two of them got pregnancy later on, receiving the name of polycystic ovary syndrome (PCOS). The technological advance facilitates the hormonal analyses demonstrating the hyperandrogenism existence and the mechanism of the anovulation, the PCOS showed to be heterogeneous, reason why it was hindered to define it, this advanced the current trend to question the existence of the PCOS and to accept the convenience, either to change the name or to redefine it, leaving it as a simple syndrome with several phenotypes. The endocrine component includes abnormal secretion of insulin and consequently outlying resistance to this hormone, likewise is hyperandrogenism, dislipoproteinemia and obesity. The hormonal exams are unnecessary for the diagnostic and treatment; it is convenient to demonstrate for sonography the ovarian growth. Other dysfunctions like the congenital suprarenal hyperplasia, hyperprolactinemia and hypotiroidism should be discarded. The treatment should be individualized with relationship to the reason of the consultation and the patients age. It has not been demonstrated that the sensibilitizers use to the insulin avoids long term cardiovascular illness and diabetes. Therefore, the phenotype is heterogeneous with a fickle metabolic component and for it has arisen the restlessness of a better definition of the SPO.


TTF-2 does not appear to be a key mediator of the effect of cyclic AMP on thyroglobulin gene transcription in primary cultured dog thyrocytes.
TTF-2 is a thyroid-specific winged-helix transcription factor which has been proposed to play a key role in the hormonal control of thyroglobulin and thyroperoxidase genes transcription in FRTL-5 cells. We have analyzed TTF-2 DNA-binding activity in primary cultures of dog thyrocytes maintained in control condition or in the presence of the cAMP agonist forskolin. Binding of 35S-labelled nuclear proteins to the TTF-2 recognition sequence identified the presence of two molecular species of 41.5 and 42.5 kDa. TTF-2 DNA-binding activity was clearly detectable in nuclear extracts from unstimulated cells and appeared increased in forskolin-treated cells. Thus, the presence of TTF-2 DNA-binding activity does not correlate with the cAMP-dependent activity of thyroglobulin and thyroperoxidase genes in this cell system. In addition, the mutation of the TTF-2 binding site in the thyroglobulin promoter resulted in a very reduced but still clearly cAMP-dependent promoter activity when assayed by transient expression in the same cells. These results do not support a dominant role for TTF-2 in the cAMP-dependent control of thyroglobulin gene transcription in primary cultured thyrocytes.


Effects of anxiety on analogical reasoning: a test of three theoretical models.
Three mediational theories of anxiety and performance, namely, cue utilization theory (Easterbrook, 1959), attentional theory (Mandler & Sarason, 1952; Wine, 1971), and working memory capacity theory (M. W. Eysenck, 1979), were compared for their efficacy in explaining anxiety-induced performance decrements on a task of analogical reasoning. One hundred two subjects who varied in their trait and state anxiety levels completed 100 geometric analogies under either relaxed (reassurance, non-time-limited) or stressed (ego-threat, time-limited) conditions. Response time and error rate data for nine levels of task complexity (1-, 2-, and 3-element analogies with zero, one, or two transformations per element) were analyzed by means of multivariate analysis of variance. Results in the relaxed condition supported attentional theory in that the more anxious subjects were both slower and less accurate than were the less anxious subjects. In the stressed condition, none of the three anxiety-performance theories was supported. More anxious subjects were faster but made more errors than did less anxious subjects. Thus in the stressed condition, performance differences suggested differences in speed-accuracy trade-off strategies rather than differences in processing abilities. The limitations of attentional theory and the need to study the effects of anxiety and time stress on information processing are discussed.


Chromosomal characteristics of childhood brain tumors.
In the present cytogenetic analysis of 116 pediatric brain tumors, chromosomal abnormalities were demonstrated in 44 cases, 48 cases revealed only 46,XX or 46,XY cells, and 24 cases were nonproductive. In contrast to studies of adult brain tumors in which isolated loss of one X or the Y chromosome is often encountered, 45,X,-X and 45,X-Y stemlines or sidelines were not observed in this series of childhood tumors. Among the 17 medulloblastomas with cytogenetic abnormalities, chromosome 1 was most frequently affected by structural deviations; the most prevalent specific alteration (7 of 17 tumors) was loss of 17p, through i(17)(q10) or unbalanced translocation. The majority of low grade astrocytomas had normal stemlines, although one pilocytic astrocytoma and one cerebellar astrocytoma had frequent telomeric associations and a second pilocytic astrocytoma had a clone with trisomy 11. Thirteen of 19 high-grade and recurrent astrocytic tumors had abnormal stemlines that were approximately equally divided among cases with chromosomal counts in the near-diploid, hyperdiploid, and near-triploid-tetraploid ranges. Although no consistent abnormalities were observed, subsets of cases had structural abnormalities of chromosome 3, 7q, 9q, or 17p. The cases of childhood brain tumors described here demonstrate that 45,X,-X, and 45,X,-Y stemlines or sidelines are rare in these tumors and confirm frequent loss of 17p in medulloblastomas. High-grade astrocytic tumors in children frequently have abnormal stemlines, often in the hyperdiploid and polyploid ranges, and they differ from high-grade gliomas in the adult by lacking consistent numerical and structural deviations.


UC Davis Train-the-Trainer Primary Care Pain Management Fellowship: Addressing the Pain Management Education Gap.
Primary care providers are responsible for the majority of pain care and opioid prescribing, but they are often inadequately trained. Training current providers to address the crisis of excessive opioid prescribing and inadequate pain management is a substantial workforce problem that requires urgent action. This educational need is vast and requires a staged solution to amplify its effect. The University of California, Davis Train-the-Trainer (T3) Primary Care Pain Management Fellowship targets the most pressing topics related to pain management, including prescription drug abuse, responsible opioid prescribing, and substance abuse, as well as broad coverage of comprehensive pain management. It offers an innovative, scalable solution to address the education gap in pain management that, in part, fuels the opioid epidemic in the United States. The T3 Fellowship incorporates a competency-based curriculum and a hybrid educational model of in-person and distance-based learning and direct faculty-fellow mentoring to comprehensively train primary care providers in pain care and prepare them to train others. Since it was established in 2017, 2 cohorts (of 17 and 26 fellows) have completed the 10-month fellowship and a third cohort of 38 fellows started the program in September 2019. Pre- and postprogram surveys for the first 2 cohorts, and a 6-month postprogram survey for the first cohort, demonstrated fellows' improvement and sustained performance in pain competencies as well as increased recognition and understanding of pain and related topics. If adopted by other institutions and expanded across the country, the T3 Fellowship holds potential for developing an ever-growing legion of trained professionals who will locally fill the need for effective pain management, including appropriate opioid prescribing. Advancing this model will require further economic and feasibility studies to assess costs, resources, and other variables, as well as a robust comprehensive outcomes program.


3D Shape-Based Myocardial Infarction Prediction Using Point Cloud Classification Networks.
Myocardial infarction (MI) is one of the most prevalent cardiovascular diseases with associated clinical decision-making typically based on single-valued imaging biomarkers. However, such metrics only approximate the complex 3D structure and physiology of the heart and hence hinder a better understanding and prediction of MI outcomes. In this work, we investigate the utility of complete 3D cardiac shapes in the form of point clouds for an improved detection of MI events. To this end, we propose a fully automatic multi-step pipeline consisting of a 3D cardiac surface reconstruction step followed by a point cloud classification network. Our method utilizes recent advances in geometric deep learning on point clouds to enable direct and efficient multi-scale learning on high-resolution surface models of the cardiac anatomy. We evaluate our approach on 1068 UK Biobank subjects for the tasks of prevalent MI detection and incident MI prediction and find improvements of ∼13% and ∼5% respectively over clinical benchmarks. Furthermore, we analyze the role of each ventricle and cardiac phase for 3D shape-based MI detection and conduct a visual analysis of the morphological and physiological patterns typically associated with MI outcomes.Clinical relevance- The presented approach enables the fast and fully automatic pathology-specific analysis of full 3D cardiac shapes. It can thus be employed as a real-time diagnostic tool in clinical practice to discover and visualize more intricate biomarkers than currently used single-valued metrics and improve predictive accuracy of myocardial infarction.


Two-dimensional numerical model of Marangoni surfers: From single swimmer to crystallization.
We numerically study the dynamics of an ensemble of Marangoni surfers in a two-dimensional and unconfined space. The swimmers are modeled as Gaussian sources of surfactant generating surface tension gradients and are shown to follow the Marangoni flow filtered at their spatial scale in the lubrication regime, an unstable situation leading to spontaneous motion as soon as the Marangoni effect is intense enough. As the system is fully unconstrained, it is possible to study the various dynamical regimes from single swimmer, two-body interaction, to the many-particles case characterized by an efficient particle dispersion. We show that, although the present model is very simple, it reproduces the experimentally observed transition between a regime of dispersion by random agitation when the number of swimmers is moderate to the regime of crystallization with imperfect hexagonal lattice at high density.


Psychiatric Disorders and Substance Use Among African American Women in HIV Care.
African-American (AA) women are overrepresented among women with HIV (WWH). In the United States, psychiatric disorders are prevalent among WWH and associated with adverse outcomes. However, little research has examined psychiatric disorders among AA WWH. 315 AA women who were hazardous/heavy drinkers (HD) or moderate/non-drinkers (ND) were recruited from an HIV clinic in a study on alcohol use disorders. We compared sample prevalence of Axis-1 psychiatric diagnoses using the Structured Clinical Interview for DSM-IV with those from general population AA women in the National Comorbidity Survey-Replication (NCS-R). While 29.9% of general population AA women had any lifetime disorder, 66.9% of HD and 62.4% of ND WWH met criteria for a lifetime Axis-1 disorder. Specifically, lifetime PTSD and lifetime MDD were over threefold higher; current PTSD and current MDD respectively were 11-fold and threefold higher. PTSD was the most frequent comorbid diagnosis. HD and ND WWH did not differ in prevalence of psychiatric diagnoses despite significantly higher rates of substance use among HD women. Diagnostic evaluation and intervention for psychiatric disorders should be a priority in HIV medical care settings to improve health outcomes. Interventions should be tailored to address the particular stressors, challenges, and resiliencies among AA WWH.


Nature-Derived Hollow Micron-Tubular Signal Tracers Conquering the Size Limitations for Multimodal Immunochromatographic Detection of Antibiotics.
Developing signal tracers (STAs) with large size, multifunctionality, and high retention bioaffinity is believed to be a potential solution for achieving high-performance immunochromatographic assays (ICAs). However, the size limitations of STAs on strips are always a challenge because of the serious steric hindrance. Here, based on metal-quinone coordination and further metal etching, hollow micron-tubular STAs formed by natural alizarin and Fe3+ ions (named ALIFe) are produced to break through size limitations, provide more active sites, and achieve three-mode ICAs (ALIFe STAs-ICAs). Thanks to the special tubular morphology, ALIFe can successfully pass through the strip and provide an ideal signal intensity within 7 min at low mAb and probe dosages to achieve stable ICA analysis. Importantly, ALIFe shows excellent antibody enrichment and bioaffinity retention capability. With a proof-of-concept for streptomycin, the ALIFe STAs-ICAs showed the limit of detection (LOD) at 0.39 ng mL-1 for colorimetric mode, 0.32 ng mL-1 for catalytic mode, and 0.016 ng mL-1 for photothermal mode with total recoveries ranging from 80.46 to 121.59% in mike and honey samples. We anticipate that our study will help expand the ideas for the design of high-performance STAs with large size and broaden the practical application of ICA.


Affirming the Abuse Liability and Addiction Potential of Menthol: Differences in Subjective Appeal to Smoking Menthol Versus Non-Menthol Cigarettes Across African American and White Young Adult Smokers.
Menthol cigarettes are popular among young adults and are disproportionately used by African American smokers. Menthol's minty and cooling sensations have been hypothesized to enhance the appeal and reinforcement of smoking; however, differences in menthol's subjective appeal across races have been inconsistent. This secondary data analysis examined differences in subjective appeal for smoking menthol versus non-menthol cigarettes between African American and White young adult smokers. Young adults (ages 18-24) recruited from Amazon Mechanical Turk (December 2018-January 2019) completed an online survey of tobacco use behavior. Past year smokers (n = 1726) answered questions about subjective responses to smoking (reward, satisfaction, throat hit, craving reduction, and aversion). Significantly more African American (73.2%) compared to White (52.4%) smokers preferred menthol cigarettes (p < .001). Menthol smokers reported greater positive and negative subjective responses to smoking than non-menthol smokers. Positive and negative subjective response were both associated with greater smoking intensity and lower cigarette harm perceptions. Interactions of menthol preference and race on indices of subjective appeal also emerged. African American non-menthol smokers reported lower levels of satisfaction, reward, and craving reduction compared to White non-menthol smokers. The relationship between menthol preference and subjective response to smoking differs by race. Menthol is rated as more appealing than non-menthol smoking, and appeal indices were linked to smoking intensity and lower harm perceptions, indicating greater abuse liability of menthol cigarettes. Policies that ban menthol cigarettes may have a particularly positive impact on the cigarette smoking of African American young adult smokers. The FDA issued an Advanced Notice of Proposed Rule Making to examine the role menthol in tobacco products to inform regulations to restrict or ban flavors. This study showed that menthol smokers reported greater appeal to smoking than non-menthol smokers; and an interaction of race x menthol preference showed African American non-menthol smokers reported the lowest levels of appeal to smoking. Multiple indices of cigarette appeal were positively correlated with smoking intensity and lower cigarette harm perceptions, highlighting the addiction potential of menthol cigarettes. Findings suggest a menthol cigarette ban could help reduce tobacco use among young adults.


Pain distress: the negative emotion associated with procedures in ICU patients.
The intensity of procedural pain in intensive care unit (ICU) patients is well documented. However, little is known about procedural pain distress, the psychological response to pain. Post hoc analysis of a multicenter, multinational study of procedural pain. Pain distress was measured before and during procedures (0-10 numeric rating scale). Factors that influenced procedural pain distress were identified by multivariable analyses using a hierarchical model with ICU and country as random effects. A total of 4812 procedures were recorded (3851 patients, 192 ICUs, 28 countries). Pain distress scores were highest for endotracheal suctioning (ETS) and tracheal suctioning, chest tube removal (CTR), and wound drain removal (median [IQRs] = 4 [1.6, 1.7]). Significant relative risks (RR) for a higher degree of pain distress included certain procedures: turning (RR = 1.18), ETS (RR = 1.45), tracheal suctioning (RR = 1.38), CTR (RR = 1.39), wound drain removal (RR = 1.56), and arterial line insertion (RR = 1.41); certain pain behaviors (RR = 1.19-1.28); pre-procedural pain intensity (RR = 1.15); and use of opioids (RR = 1.15-1.22). Patient-related variables that significantly increased the odds of patients having higher procedural pain distress than pain intensity were pre-procedural pain intensity (odds ratio [OR] = 1.05); pre-hospital anxiety (OR = 1.76); receiving pethidine/meperidine (OR = 4.11); or receiving haloperidol (OR = 1.77) prior to the procedure. Procedural pain has both sensory and emotional dimensions. We found that, although procedural pain intensity (the sensory dimension) and distress (the emotional dimension) may closely covary, there are certain factors than can preferentially influence each of the dimensions. Clinicians are encouraged to appreciate the multidimensionality of pain when they perform procedures and use this knowledge to minimize the patient's pain experience.


Examining the characteristics of workplace violence in one non-tertiary hospital.
This study sought to determine the prevalence and characteristics of workplace violence directed at a volunteer sample of nurses at one non-tertiary hospital. Respondents' reasons for not reporting these incidents were also investigated. Incidents of workplace violence are increasing worldwide. However, no studies have investigated this phenomenon from the perspective of nurses in Western Australian non-tertiary hospitals. Survey. A survey was distributed to all 332 nurses working in several areas of one non-tertiary hospital in Western Australia to determine their experiences of workplace violence over a 12 month period. Of the 113 nurses who agreed to participate in this study, 75% reported experiencing workplace violence in the previous twelve months. When asked about their most recent incident, 50% of the nurses said they had reported it verbally, mostly to more senior staff. Only 16% of the nurses completed an official incident report. Reasons for not reporting included the view that WPV is just part of the job and the perception that management would not be responsive. This study showed that for this sample of nurses violent events are occurring at a rate that is similar to those reported in other studies. This finding should be of great concern to the organisation and the community in general. Organisations are obliged to improve the safety of the workplace environment for both staff and patients. The findings of our study may be of help to healthcare institutions in developing education programmes for nurses, patients and their friends and relatives to reduce the impact and frequency of workplace violence.


Disruption of CD154:CD40 blocks generation of allograft immunity without affecting APC activation.
CD154 (CD40 ligand, gp39) interaction with its receptor CD40 has been shown to be critically important for the generation of cell-mediated as well as humoral immunity. It has been proposed that ligation of CD40 on APCs, presumably by activated Th cells, leads to increased APC function as defined by up-regulation of costimulatory molecules and enhancement of IL-12 production. In this report, we directly examined the contribution of the CD154:CD40 pathway in a murine model of allograft rejection. Generation of both the CTL and alloantibody responses following injection with allogeneic P815 tumor cells was severely compromised in CD154 knockout mice and wild-type C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic production of IL-2, IFN-gamma, and TNF was significantly suppressed from CD154-deficient mice, indicating a lack of T cell priming. However, splenic cells from CD154 knockout mice induced comparable levels of CD86 expression and IL-12 production when compared with their wild-type littermates. The treatment of CD154-/- mice with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed to restore either the CTL or alloantibody responses to P815. Likewise, immunization with B7-transfected P815 tumor cells failed to generate expansion of the CTL effector population in CD154-/- mice. These results suggest that the generation of allograft immunity is dependent on the interaction of CD154 with CD40 but not primarily for the activation of APCs.


Bacteriophages reduce experimental contamination of hard surfaces, tomato, spinach, broccoli, and ground beef by Escherichia coli O157:H7.
A bacteriophage cocktail (designated ECP-100) containing three Myoviridae phages lytic for Escherichia coli O157:H7 was examined for its ability to reduce experimental contamination of hard surfaces (glass coverslips and gypsum boards), tomato, spinach, broccoli, and ground beef by three virulent strains of the bacterium. The hard surfaces and foods contaminated by a mixture of three E. coli O157:H7 strains were treated with ECP-100 (test samples) or sterile phosphate-buffered saline buffer (control samples), and the efficacy of phage treatment was evaluated by comparing the number of viable E. coli organisms recovered from the test and control samples. Treatments (5 min) with the ECP-100 preparation containing three different concentrations of phages (10(10), 10(9), and 10(8) PFU/ml) resulted in statistically significant reductions (P = <0.05) of 99.99%, 98%, and 94%, respectively, in the number of E. coli O157:H7 organisms recovered from the glass coverslips. Similar treatments resulted in reductions of 100%, 95%, and 85%, respectively, in the number of E. coli O157:H7 organisms recovered from the gypsum board surfaces; the reductions caused by the two most concentrated phage preparations were statistically significant. Treatment with the least concentrated preparation that elicited significantly less contamination of the hard surfaces (i.e., 10(9) PFU/ml) also significantly reduced the number of viable E. coli O157:H7 organisms on the four food samples. The observed reductions ranged from 94% (at 120 +/- 4 h posttreatment of tomato samples) to 100% (at 24 +/- 4 h posttreatment of spinach samples). The data suggest that naturally occurring bacteriophages may be useful for reducing contamination of various hard surfaces, fruits, vegetables, and ground beef by E. coli O157:H7.


Simultaneous subcortical and cortical electrophysiological recordings of spectro-temporal processing in humans.
Objective assessment of auditory discrimination has often been measured using the Auditory Change Complex (ACC), which is a cortically generated potential elicited by a change occurring within an ongoing, long-duration auditory stimulus. In cochlear implant users, the electrically-evoked ACC has been used to measure electrode discrimination by changing the stimulating electrode during stimulus presentation. In addition to this cortical component, subcortical measures provide further information about early auditory processing in both normal hearing listeners and cochlear implant users. In particular, the frequency-following response (FFR) is thought to reflect the auditory encoding at the level of the brainstem. Interestingly, recent research suggests that it is possible to simultaneously measure both subcortical and cortical physiological activity. The aim of this research was twofold: first, to understand the scope for simultaneously recording both the FFR (subcortical) and ACC (cortical) responses in normal hearing adults. Second, to determine the best recording parameters for optimizing the simultaneous capture of both responses with clinical applications in mind. Electrophysiological responses were recorded in 10 normally-hearing adults while they listened to 16-second-long pure tone sequences. The carrier frequency of these sequences was either steady or alternating periodically throughout the sequence, generating an ACC response to each alternation-the alternating ACC paradigm. In the "alternating" sequences, both the alternating rate and the carrier frequency varied parametrically. We investigated three alternating rates (1, 2.5, and 6.5 Hz) and seven frequency pairs covering the low-, mid-, and high-frequency range, including narrow and wide frequency separations. Our results indicate that both the slowest (1 Hz) and medium (2.5 Hz) alternation rates led to significant FFR and ACC responses in most frequency ranges tested. Low carrier frequencies led to larger FFR amplitudes, larger P1 amplitudes, and N1-P2 amplitude difference at slow alternation rates. No significant relationship was found between subcortical and cortical response amplitudes, in line with different generators and processing levels across the auditory pathway. Overall, the alternating ACC paradigm can be used to measure sub-cortical and cortical responses as indicators of auditory early neural encoding (FFR) and sound discrimination (ACC) in the pathway, and these are best obtained at slow alternation rates (1 Hz) in the low-frequency range (300-1200 Hz).


In vitro drug release from acetylated high amylose starch-zein films for oral colon-specific drug delivery.
This study describes the preparation of free films of zein with and without acetylated high amylose maize starch (HAS) and their corresponding coated tablets as a novel approach to colonic drug delivery. We hypothesise that the embedding of a digestible starch component within the inert zein would allow the film to remain intact until the large intestine is reached. Free films of zein alone and starch/zein were prepared and characterized. SEM and AFM images of film surface showed that films were morphologically inhomogeneous, particularly at lower HAS/Zein ratios; however, nanothermal analysis data suggested that these differences in appearance within the same film are not compositional differences. Moreover, FT-IR could detect no molecular interaction between the two polymers. Paracetamol tablets were coated with HAS/Zein aqueous based coatings of different compositions to a TWG of 20%. Drug release from zein alone and 1:5 HAS/Zein coated tablets under upper gastrointestinal conditions (pH 1.2, pH 6.8 with pepsin and pancreatin included) was very similar (for example approximately 12% and 14% of the drug was released, respectively, after 6 h in a sequential in vitro test), suggesting that release in this region is limited and is not influenced by the presence of HAS in the ratio to zein under study. Studies using an in vitro colon model showed that under simulated colonic conditions, the drug release was significantly (p < 0.05) more rapid from 1:5 HAS/Zein, compared to the zein alone coating formulation. These data therefore support the potential use of zein-starch mixed films for colonic targeting purposes.


The influence of fractional surface coverage on the core-core separation in ordered monolayers of thiol-ligated Au nanoparticles.
We report the results of grazing incidence X-ray diffraction (GIXD) measurements from water supported Langmuir monolayers of gold nanoparticles ligated with dodecanethiol (12 carbons), tetradecanethiol (14 carbons), hexadecanethiol (16 carbons), and octadecanethiol (18 carbons). These monolayers are formed from solutions with varying concentrations of the respective thiols. We show that equilibrium between adsorbed thiol molecules and the thiols in the bulk solution implies fractional coverage of the Au nanoparticle core. We also show that the nanoparticle-nanoparticle separation and the correlation length of particles in these ordered films increases with thiol concentration in the parent solution, and that excess thiol can be found in the space between particles as well as in islands away from the particles. Using the equilibrium constant relating ligand solution concentration and nanoparticle surface coverage of the gold core by the ligand molecules, we interpret the way in which varying thiol concentration affects the nanoparticle-nanoparticle separation as a function of surface coverage of the gold core by the ligand molecules.


An immunological study of the uncoupling protein of brown adipose tissue mitochondria.
1. Ewes were injected with purified 32,000-Mr uncoupling protein from mitochondria of brown adipose tissue of cold-adapted rats in order to raise antibodies. 2. The existence of antibodies in the plasma of ewes and the cross-reactivity of plasmas were demonstrated and studied by 125I-labelled antigen-antibody reaction, double immunodiffusion, the inhibition of GDP binding to the 32,000 Mr protein and by immunohistochemistry. 3. The antibodies raised against the homogeneous protein yielded a single immunoprecipitation band with detergent-solubilized mitochondrial membranes of brown adipose tissue from rat, hamster, guinea-pig, rabbit and with the purified uncoupling protein of these animals. No immunoprecipitation was obtained with the protein purified from brown adipose tissue of term lamb foetus. 4. The GDP-binding activity of the uncoupling protein (isolated or in solubilized membranes) was largely inhibited by the antiserum. 5. The anti-(rat uncoupling protein) could not cross-react with solubilized membranes from liver or muscle, nor with the purified beef heart or rat liver ADP/ATP translocator.


The quest for knowledge transfer efficacy: blended teaching, online and in-class, with consideration of learning typologies for non-traditional and traditional students.
The pedagogical paradigm shift in higher education to 24-h learning environments composed of teaching delivery methods of online courses, blended/hybrid formats, and face-to-face (f2f) classes is increasing access to global, lifelong learning. Online degrees have been offered at 62.4% of 2800 colleges and universities. Students can now design flexible, life-balanced course schedules. Higher knowledge transfer rates may exist with blended course formats with online quizzes and valuable class time set for Socratic, quality discussions and creative team presentations. Research indicates that younger, traditional students exhibit heightened performance goal orientations and prefer entertaining professors who are funny, whereas non-traditional students exhibit mastery profiles and prefer courses taught by flexible, yet organized, professors. A 5-year study found that amongst 51,000 students taking both f2f and online courses, higher online failure rates occurred. Competing life roles for non-traditional students and reading and writing needs for at-risk students suggest that performance may be better if programs are started in f2f courses. Models on effective knowledge transfer consider the planning process, delivery methods, and workplace application, but a gap exists for identifying the diversity of learner needs. Higher education enrollments are being compromised with lower online retention rates. Therefore, the main purpose of this review is to delineate disparate learning styles and present a typology for the learning needs of traditional and non-traditional students. Secondly, psychology as a science may need more rigorous curriculum markers like mapping APA guidelines to knowledge objectives, critical assignments, and student learning outcomes (SLOs) (e.g., online rubric assessments for scoring APA style critical thinking essays on selected New York Times books). Efficacious knowledge transfer to diverse, 21st century students should be the Academy's focus.


[Effectiveness of prodigiozan in the therapy of chronic nonspecific diseases of the lungs].
The efficiency of the Soviet prodigiozan in therapy of chronic non-specific diseases of the lungs (18 cases with bronchial asthma and 26 cases with chronic pneumonia of the 1st and 2nd stages) in the phase of exacerbation was studied. The results of the treatment were estimated by the clinico-roentgenological pictures. The effect of prodigiozan on breathing and the functional state of the adrenal gland was studied in particular. Satisfactory results were obtained in the patients suffering from chronic pneumonia of the 1st and 2nd stages without clinical signs of the bronchial tree affection and in the patients with infection-allergic forms of bronchial asthma. Modest results were observed in the patients suffering from chronic pneumonia of the 1st and 2nd stages with the bronchial tree affection, especially when exacerbated by the asthma syndrome. In some patients the results of the treatment with prodigiozan were not stable. Prodigiozan improved the bronchial permeability, stimulated the sympatho-adrenal system and had no effect on the adrenal cortex.


Waste biorefineries using filamentous ascomycetes fungi: Present status and future prospects.
Filamentous ascomycetes fungi have had important roles in natural cycles, and are already used industrially for e.g. supplying of citric, gluconic and itaconic acids as well as many enzymes. Faster human activities result in higher consumption of our resources and producing more wastes. Therefore, these fungi can be explored to use their capabilities to convert back wastes to resources. The present paper reviews the capabilities of these fungi in growing on various residuals, producing lignocellulose-degrading enzymes and production of organic acids, ethanol, pigments, etc. Particular attention has been on Aspergillus, Fusarium, Neurospora and Monascus genera. Since various species are used for production of human food, their biomass can be considered for feed applications and so biomass compositional characteristics as well as aspects related to culture in bioreactor are also provided. The review has been further complemented with future research avenues.


The effects of behaviourally relevant temperatures on mechanosensory neurones of the grasshopper, Schistocerca americana.
Grasshopper mechanosensory hair neurones respond to displacement of their associated hairs in a temperature sensitive manner: comparable increases in the number of spikes per stimulus result from increases in temperature with constant stimulus strengths and from increasing stimulus strengths at constant temperature. It is therefore not obvious that neurones in the CNS which receive inputs from mechanosensory hairs would be able to distinguish between these two parameters. The temperatures which populations of mechanosensory hairs on the thorax, head and tarsus experienced were measured in freely moving animals. Animals in thermally heterogeneous environments spent 90% of the accounted time in locations where thoracic temperatures of 32-44 degrees C were maintained (the behaviourally 'preferred' range). Head temperatures covered a wider range, and tarsal temperatures the widest. Different populations of mechanosensory hair neurones exhibited different sensitivities to temperature. Thoracic hair neurones were significantly more temperature sensitive than one of the two populations of head hairs studied, and tarsal hairs exhibited a pronounced temperature compensation in the behaviourally 'preferred' range. Wind sensitive head hairs, however, showed exceptionally high temperature sensitivities. There is a negative correlation between the temperature sensitivity of a population of mechanosensory hair neurones and the temperature variability to which those neurones are normally exposed. Implications of this correlation for the central interpretation of mechanosensory input are considered.


LRP1 and RAGE Genes Transporting Amyloid and Tau Protein in the Hippocampal CA3 Area in an Ischemic Model of Alzheimer's Disease with 2-Year Survival.
Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer's disease was used to evaluate changes in the expression of genes related to amyloid transport in the CA3 region of the hippocampus after 10 min of brain ischemia with survival of 2, 7 and 30 days and 12, 18 and 24 months. The quantitative reverse transcriptase PCR assay revealed that the expression of the LRP1 and RAGE genes involved in amyloid transport was dysregulated from 2 days to 24 months post-ischemia in the CA3 area of the hippocampus. LRP1 gene expression 2 and 7 days after ischemia was below control values. However, its expression from day 30 to 24 months, survival after an ischemic episode was above control values. RAGE gene expression 2 days after ischemia was below control values, reaching a maximum increase 7 and 30 days post-ischemia. Then, after 12, 18 and 24 months, it was again below the control values. The data indicate that in the CA3 area of the hippocampus, an episode of brain ischemia causes the increased expression of the RAGE gene for 7-30 days during the acute phase and that of LRP1 from 1 to 24 months after ischemia during the chronic stage. In other words, in the early post-ischemic stage, the expression of the gene that transport amyloid to the brain increases (7-30 days). Conversely, in the late post-ischemic stage, amyloid scavenging/cleaning gene activity increases, reducing and/or preventing further neuronal damage or facilitating the healing of damaged sites. This is how the new phenomenon of pyramidal neuronal damage in the CA3 area after ischemia is defined. In summary, post-ischemic modification of the LRP1 and RAGE genes is useful in the study of the ischemic pathways and molecular factors involved in the development of Alzheimer's disease.


Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.
A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by "piggy-backing" on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure-activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC(50) value of 25 nM and a whole cell H-Ras processing IC(50) value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π-π stacking interaction with the Y361β residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.


Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients.
Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era. A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis. The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count < 102 K/μL, no history of stem cell transplantation, transition to BP from chronic phase/accelerated phase, and the presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first-line treatment was found to be predictive of better survival. The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome. Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes, and require newer treatment approaches. Cancer 2017;123:4391-402. © 2017 American Cancer Society.


Vascular, electrophysiological, and metabolic consequences of cortical spreading depression in a mouse model of simulated neurosurgical conditions.
Cortical spreading depression (CSD) is a metabolically taxing wave of cellular depolarization that propagates slowly across the brain. Though CSD is known to occur after brain injury in humans, it is unknown if CSD occurs during neurosurgical procedures. This study evaluates CSD in a mouse model of simulated neurosurgical conditions. Mice were intubated and ventilated, maintained at ~37°C, an arterial line placed to monitor mean arterial pressure and maintain pCO(2) ~30 mmHg. Mice were given simulated neuroanesthesia (fentanyl, propofol, and isofluorane). Burrholes and craniotomies were made to record the response to cortical bipolar cauterization. Separate sets of experiments (three animals each) examined electrocorticographic (ECoG) activity, optical measures of blood volume and vascular diameters (540 nm absorbance), and autofluorescence attributed to NADH (750 nm, two-photon excitation). Ipsilateral cauterization invariably resulted in a propagating CSD wave identified by slow DC potential shifts (2·8±0·2 mm/minute, n = 6) and suppression of ECoG activity (range 0·5-7·3 minutes, n = 10). Each CSD was associated with an initial arteriolar constriction and decreased blood volume, followed by a longer-lasting vasodilation and increased blood volume. Tissue oxygenation, assessed indirectly by NADH imaging, was consistent with demand on oxidative metabolism following each CSD. Repetitive SDs resulted in loss of tissue autofluorescence, suggestive of tissue compromise. CSD is consistently elicited by simulated neurosurgical stimuli under simulated intraoperative conditions in mice. These events caused ECoG depression, transient vasoconstriction, and metabolic demand that propagated from the manipulation site. It is likely that CSD occurs during neurosurgery and may contribute to surgical brain injuries otherwise poorly explained.


Threshold effects of acetylcholine on primary pacemaker cells of the rabbit sino-atrial node.
Leading or primary pacemaker cells located within the rabbit sino-atrial node have been identified by using electrophysiological and pharmacological techniques. Stable intracellular recordings lasting 20-30 min from cells within the s.a. node reveal three distinct patterns of spontaneous intracellular responses: (i) leading or primary pacing; (ii) follower or subsidiary pacing; and (iii) 'anomalous' pacemaker discharge. Our main objective was to measure the first detectable effect, or effects, of acetylcholine on the spontaneous intracellular electrical activity in mammalian primary pacemaker cells. Trains of brief 'field' stimuli were applied to evoke transmitter release from endogenous nerve varicosities. Systematic variations in the amplitude and duration of each stimulus, and in the train length; in conjunction with application of beta blockers (l-pindolol (10(-6) M); l-propranolol, (2 X 10(-7) M)) yielded small and transient, but very consistent negative chronotropic effects. These electrophysiological changes were blocked by atropine (1 X 10(-7) M) and were mimicked by bath application of low doses of acetylcholine (10(-7)-10(-6) M) or muscarine chloride (10(-8)-10(-7) M). In primary cells the first, or threshold effect of vagal excitation is a decrease in the slope of the pacemaker potential, without a detectable (less than 2 m V) hyperpolarization or change in action potential duration. A reduction in the dV/dtmax of the initial depolarization is also quite consistently observed. Application of longer stimulus trains yield the classical hyperpolarizing response, which is often assumed to be the major electrophysiological correlate of the negative chronotropic effect. These data provide a detailed electrophysiological description of the 'physiological' effects of the vagus nerve excitation on primary or leading pacemaker cells of the mammalian s.-a. node. A plausible explanation for the absence of hyperpolarization is suggested; and a working hypothesis is presented for the changes in ionic current or currents, that underlie this negative chronotropic effect.


[Cell motility in a system of mononuclear phagocytes from different strains of mice in the presence of bacteria and their components].
The motility of organospecific macrophages of the abdominal cavity, spleen, lungs and liver, observed in the presence of serogroup A Neisseria meningitidis polysaccharide, formalin-killed Bordetella pertussis and acetone-treated Salmonella typhimurium, has been studied. In these experiments CBA, C57BL/6 and (CBA X C57BL/6)F1 mice have been used. The in vitro study of the motility of cells in the system of mononuclear phagocytes in the presence of bacterial antigens has revealed that these cells are functionally heterogeneous, which is manifested differently in mice of varying strains.


Effects of dietary composition on glucose metabolism in rat adipose cells.
The effect of altered dietary carbohydrate and fat content on equilibrium insulin binding to, and glucose transport activity and metabolism in, isolated rat epididymal adipose cells has been studied. Alterations in basal and insulin-stimulated total glucose utilization induced by changes in the ratio of dietary carbohydrate to fat are accounted for by specific effects of dietary composition at two levels of cellular function: 1) glucose transport across the cell's plasma membrane, specifically, the number of functional glucose transport systems, and 2) the cell's maximal capacity for glucose metabolism. These effects occur without alterations in insulin binding or the cell's sensitivity to insulin. Furthermore, diet-induced changes in the pattern of 14CO2, and 14C-triglyceride glycerol and fatty acid production appear to be accounted for primarily by the influence of dietary composition on the total amount of glucose entering the cell. Thus, under the conditions of this study, changes in dietary composition alter the adipose cell's capacities for glucose transport and metabolism without altering the mechanisms of insulin action or regulating the metabolic flow of glucose carbons.


Sertraline Versus Placebo in Patients with Major Depressive Disorder Undergoing Hemodialysis: A Randomized, Controlled Feasibility Trial.
Depression is common in patients on hemodialysis, but data on the benefits and risks of antidepressants in this setting are limited. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness. Patients on hemodialysis at five United Kingdom renal centers completed the Beck Depression Inventory II. Those scoring ≥16 and not already on treatment for depression were invited to undergo diagnostic interview to confirm major depressive disorder. Eligible patients with major depressive disorder were randomized to receive the study medication-either sertraline or placebo. Outcomes included recruitment and dropout rates, change in the Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory II, and qualitative information to guide design of a large-scale trial. In total, 709 patients were screened and enrolled between April of 2013 and October of 2014; 231 (32.6%) had Beck Depression Inventory II scores ≥16, and 68 (29%) of these were already receiving treatment for depression. Sixty-three underwent diagnostic interview, 37 were diagnosed with major depressive disorder, and 30 were randomized; 21 completed the trial: eight of 15 on sertraline and 13 of 15 on placebo (P=0.05). Dropouts due to adverse and serious adverse events were greater in the sertraline group. All occurred in the first 3 months. Over 6 months, depression scores improved in both groups. Beck Depression Inventory II score fell from 29.1±8.4 to 17.3±12.4 (P<0.001), and Montgomery-Asberg Depression Rating Scale score fell from 24.5±4.1 to 10.3±5.8 (P<0.001). There were no differences between sertraline and placebo groups. Although small, this is the largest randomized trial to date of antidepressant medication in patients on hemodialysis. Our results highlight recruitment issues. No benefit was observed, but trial size and the substantial dropout render consideration of benefit inconclusive. A definitive trial could use shorter follow-up and include depressed patients already taking antidepressants.