The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised, placebo controlled trial.
Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis. Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15). Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed. In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted. Australian New Zealand Clinical Trials Registry ACTRN12609000259246.


Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America.
The objective of this guideline is to provide recommendations for treating patients with the more common forms of histoplasmosis. PARTICIPANTS AND CONSENSUS PROCESS: A working group of 8 experts in this field was convened to develop this guideline. The working group developed and refined the guideline through a series of conference calls. The goal of treatment is to eradicate the infection when possible, although chronic suppression may be adequate for patients with AIDS and other serious immunosuppressive disorders. Other important outcomes are resolution of clinical abnormalities and prevention of relapse. The published literature on the management of histoplasmosis was reviewed. Controlled trials have been conducted that address the treatment of chronic pulmonary and disseminated histoplasmosis, but clinical experience and descriptive studies provide the basis for recommendations for other forms of histoplasmosis. VALUE: Value was assigned on the basis of the strength of the evidence supporting treatment recommendations, with the highest value assigned to controlled trials, according to conventions established for developing practice guidelines. BENEFITS AND COSTS: Certain forms of histoplasmosis cause life-threatening illnesses and result in considerable morbidity, whereas other manifestations cause no symptoms or minor self-limited illnesses. The nonprogressive forms of histoplasmosis, however, may reduce functional capacity, affecting work capacity and quality of life for several months. Treatment is clearly beneficial and cost-effective for patients with progressive forms of histoplasmosis, such as chronic pulmonary or disseminated infection. It remains unknown whether treatment improves the outcome for patients with the self-limited manifestations, since this patient population has not been studied. Other chronic progressive forms of histoplasmosis are not responsive to pharmacologic treatment. Options for therapy for histoplasmosis include ketoconazole, itraconazole, fluconazole, amphotericin B (Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomal amphotericin B (AmBisome; Fujisawa, Deerfield, IL), amphotericin B colloidal suspension (ABCD, or Amphotec; Seques, Menlo Park, CA), and amphotericin B lipid complex (ABLC, or Abelcet; Liposome, Princeton, NJ).


Late inception of a resiliently oxygenated upper ocean.
Rising oceanic and atmospheric oxygen levels through time have been crucial to enhanced habitability of surface Earth environments. Few redox proxies can track secular variations in dissolved oxygen concentrations around threshold levels for metazoan survival in the upper ocean. We present an extensive compilation of iodine-to-calcium ratios (I/Ca) in marine carbonates. Our record supports a major rise in the partial pressure of oxygen in the atmosphere at ~400 million years (Ma) ago and reveals a step change in the oxygenation of the upper ocean to relatively sustainable near-modern conditions at ~200 Ma ago. An Earth system model demonstrates that a shift in organic matter remineralization to greater depths, which may have been due to increasing size and biomineralization of eukaryotic plankton, likely drove the I/Ca signals at ~200 Ma ago.


An outbreak of airborne nosocomial varicella.
An outbreak of nosocomial varicella was traced to airborne spread from an immunocompromised child hospitalized from Nov 11-19, 1980. Seventy potentially susceptible children were hospitalized on the ward during that period. Although the index patient remained in strict room isolation throughout his hospital stay, eight of these patients contracted varicella. The afternoon of November 12 was the period of highest risk for acquiring varicella. Eight of 36 patients (22%) present that afternoon, compared to none of 34 patients not present that afternoon, acquired the infection. A patient's risk of contracting varicella was significantly related to how near he/she came to the index patient's room that afternoon. Airflow studies, using the tracer gas, sulfur hexafluoride (SF6), demonstrated that patient rooms on this ward were at positive pressure with respect to the corridor. Despite isolation procedures, SF6 released in the index patient's room achieved concentrations in the corridor as high as 10% of those inside the room. Airborne spread of varicella has rarely been reported, but it may be a common mode of transmission in hospitals. We suggest that patients hospitalized with varicella be placed in strict isolation in negative-pressure rooms to reduce the risk of nosocomial transmission.


Induction of Epstein-Barr virus nuclear antigen and DNA synthesis in a human epithelial cell line after Epstein-Barr virus infection.
The association of Epstein-Barr virus (EBV) with nasopharyngeal carcinoma is supported by the presence of EBV genomes in the epithelial elements of the tumor and by elevated antibody titers to EBV-specific antigens in the patients; the levels of these titers are related to the clinical course of the disease. However, since most laboratory data suggest that EBV is a B-lymphotropic virus, it is unclear how the virus becomes associated with the epithelial elements of the nasopharynx. The purpose of the present work was to find a human model system to study this association. A human epithelial line (U) was found that could be directly infected by EBV, and viral functions, the induction of EBV nuclear antigen and cellular DNA synthesis, were demonstrated. The U line was established in 1957 by the late H. J. Van Kooten (Kok-Doorschodt at the University of Utrecht), and although it is no longer diploid, it exhibits density inhibition. When U cells were infected with EBV, EBV nuclear antigen was expressed in 6 to 16% of the cells, 1 and 2 days after infection with B95-8 virus, but not with the P3HR-1 strain. No evidence for virus replication was obtained; immunofluorescence staining for early antigens and virus capsid antigens gave negative results. Quantitative adsorption experiments for EBV indicated that the adsorption capacity of U cells is significant (60% of Raji cells). The present results also demonstrated that infection with the virus overcomes block(s) in cellular DNA synthesis caused by 5-fluorodeoxyuridine. The induction of DNA synthesis was determined by increased incorporation of [3H]thymidine into the cells. The highest level of isotope incorporation was observed at about 15 h after infection and thereafter decreased. Analysis of the induced DNA indicated that it was of cellular origin.


Nurse-Driven Universal Concussion Screening: A Quality Improvement Initiative.
The purpose of this study was to provide an evaluation of a performance improvement initiative that operationalized universal concussion screening for all pediatric trauma admissions at a Level I pediatric trauma center. Mild traumatic brain injury may be difficult to identify in injured children. We implemented a screening tool to identify the risk for concussion after traumatic injury and to improve access to cognitive evaluation and intervention in children. Prior to implementation of our screening tool, children admitted without obvious head injury or those younger than 12 years were not being screened for concussion risk. We employed a nurse-driven screening tool, derived from the Centers for Disease Control and Prevention Acute Concussion Evaluation, on all pediatric trauma patients ages 0-17 years. The screening tool identifies symptoms of physical, cognitive, sleep, or emotional deficits and prompts a cognitive evaluation with concussion education. The tool was administered by nursing and tracked in the electronic medical record. Key stakeholders were interviewed to identify workflow barriers and education gaps following implementation. Enhancements to the electronic medical record and refocused nursing education improved compliance from 41% in the first 12 months to 91% at 24 months post-implementation (p < .001). The increasing number of evaluations additionally resulted in overall more cognitive evaluations as an initial step in identifying and treating previously unrecognized traumatic brain injury. A pediatric concussion screening tool is simple to administer, applies to all developmental ages, and improves diagnostic capture of traumatic brain injury in pediatric trauma when administered by nurses with support through the electronic medical record.


Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract.
There is substantial epidemiological evidence that infection by Herpes simplex virus type 2 (HSV2) enhances both HIV susceptibility and subsequent sexual transmission. Both infections are extremely common in female sex workers (FSWs) in sub-Saharan Africa, and up to 80% of new HIV infections in urban men in the region are acquired via transactional sex. The present study aimed to elucidate the mucosal immune interactions between HIV and HSV2 in the genital tract. Endocervical immune cell populations, cytokine/chemokine protein levels in cervico-vaginal secretions and cervical immune gene expression profiles were measured in a well-defined cohort of HIV-infected and uninfected Kenyan FSWs. Associations between the genital immune milieu and infection by and/or shedding of common genital co-pathogens were examined. HIV-infected FSWs were much more likely to be infected by HSV2, and to shed HSV2 DNA in the genital tract. There was also a profound negative 'mucosal synergy' between these viruses. In HIV uninfected FSWs, HSV2 infection was associated with a ten-fold increase in cervical immature dendritic cells (iDC) expressing DC-SIGN, and a three-fold increase in cervical CD4+ T cells expressing CCR5. HIV infection was associated with iDC depletion in the cervix, and with increased HSV2 genital reactivation, which in turn was associated with HIV shedding levels. The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.


On the relevance of symbolizing heart rate variability by means of a percentile-based coarse graining approach.
Symbolic transformations of the cardiac interbeat interval series yield a coarse-grained description of the dynamical information of the underlying system and complement standard measures of heart rate variability. The most commonly utilized coarse graining procedures are strongly influenced by the presence of a few extreme values wasting precious symbols to code very unlikely values. Here, we used a transformation procedure that ensured the appearance of each symbol with equal probability using a short alphabet, A 4 = {0, 1, 2, 3}, and a long alphabet, A 6 = {0, 1, 2, 3, 4, 5}. The procedure was applied to the cardiac interbeat interval series of 17 healthy subjects, obtained during graded head-up tilt tests at tilt table inclinations of 0°, 15°, 30°, 45°, 60°, 75°, 90°. The dynamics of the symbolic series was assessed by the rate of symbolic pattern categories. Symbolic patterns of length three were grouped according to the variations of the symbols in each pattern: no variation (0V%), one variation (1V%), two like variations (2LV%) and two unlike variations (2UV%) of the symbols. As for the alphabet A 4, the linear regression analysis on tilt angle showed that 0V% increased with increasing tilt angle whereas 1V%, 2LV% and 2UV% decreased. As for the alphabet A 6, the categories 0V%, and 1V% increased with increasing tilt angle whereas 2LV% and 2UV% decreased. The symbolic transformation ensuring a uniform distribution of the symbols is capable of reflecting changes in the cardiac autonomic nervous system during graded head-up tilt. This approach is more robust against outliers and data with skewed distributions compared to previously used symbolizations.


A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies.
Deforolimus (AP23573), a novel non-prodrug rapamycin analogue, inhibits the mammalian target of rapamycin, a downstream effector of the phosphatidylinositol 3-kinase/Akt and nutrient-sensing pathways. A phase 2 trial was conducted to determine the efficacy and safety of single-agent deforolimus in patients with relapsed or refractory hematologic malignancies. Eligible patients were assigned to one of five disease-specific, parallel cohorts and given 12.5 mg deforolimus as a 30-minute infusion once daily for 5 days every 2 weeks. A Simon two-stage design was used for each cohort. Safety, pharmacokinetics, pharmacodynamics, and antitumor response were assessed. Fifty-five patients received deforolimus as follows: cohort 1 23 acute myelogenous leukemia, two myelodysplastic syndrome and one chronic myelogenous leukemia in nonlymphoid blast phase; cohort 2, one acute lymphocytic leukemia; cohort 3, nine agnogenic myeloid metaplasia; cohort 4, eight chronic lymphocytic leukemia; cohort 5, nine mantle cell lymphoma and two T-cell leukemia/lymphoma. Most patients were heavily pretreated. Of the 52 evaluable patients, partial responses were noted in five (10%), two of seven agnogenic myeloid metaplasia and three of nine mantle cell lymphoma. Hematologic improvement/stable disease was observed in 21 (40%). Common treatment-related adverse events, which were generally mild and reversible, were mouth sores, fatigue, nausea, and thrombocytopenia. Decreased levels of phosphorylated 4E-BP1 in 9 of 11 acute myelogenous leukemia/myelodysplastic syndrome patients after therapy showed mammalian target of rapamycin inhibition by deforolimus. Deforolimus was well-tolerated in patients with heavily pretreated hematologic malignancies, and antitumor activity was observed. Further investigation of deforolimus alone and in combination with other therapeutic agents is warranted in patients with selected hematologic malignancies.


Bilateral metatarsophalangeal valgus and subluxation in two adult llamas treated by medial bone plate arthrodesis.
The clinical signs and diagnostic imaging of two adult llamas with severe metatarsophalangeal valgus angular limb deformity causing metatarsophalangeal instability, severe osteoarthritis and marked bilateral hindlimb lameness are described. The metatarsophalangeal axis was corrected and arthrodesis of the metatarsophalangeal joint was achieved by distal medial metatarsal condylectomy and the medial application of a custom-made angled 4.5 mm dynamic compression plate. A secure construct with normal limb angulation and a good biomechanical outcome was achieved in each of the hindlimbs of both llamas. The development and final dimensions of the implants are described to assist decision making during the evaluation of the surgical management of such cases.


A Novel Single-Site Mutation in the Catalytic Domain of Protoporphyrinogen Oxidase IX (PPO) Confers Resistance to PPO-Inhibiting Herbicides.
Protoporphyrinogen oxidase (PPO)-inhibiting herbicides are used to control weeds in a variety of crops. These herbicides inhibit heme and photosynthesis in plants. PPO-inhibiting herbicides are used to control Amaranthus palmeri (Palmer amaranth) especially those with resistance to glyphosate and acetolactate synthase (ALS) inhibiting herbicides. While investigating the basis of high fomesafen-resistance in A. palmeri, we identified a new amino acid substitution of glycine to alanine in the catalytic domain of PPO2 at position 399 (G399A) (numbered according to the protein sequence of A. palmeri). G399 is highly conserved in the PPO protein family across eukaryotic species. Through combined molecular, computational, and biochemical approaches, we established that PPO2 with G399A mutation has reduced affinity for several PPO-inhibiting herbicides, possibly due to steric hindrance induced by the mutation. This is the first report of a PPO2 amino acid substitution at G399 position in a field-selected weed population of A. palmeri. The mutant A. palmeri PPO2 showed high-level in vitro resistance to different PPO inhibitors relative to the wild type. The G399A mutation is very likely to confer resistance to other weed species under selection imposed by the extensive agricultural use of PPO-inhibiting herbicides.


The impact of buccal corridors on smile attractiveness.
The aim of this study was to assess the impact of various sized buccal corridors (BCs) on smile attractiveness. One female smiling photograph, displaying first molar to first molar (M1-M1), was digitally altered to produce (1) smiles that filled 84, 88, 92, 96, and 100 per cent of the oral aperture; (2) second premolar to second premolar smiles (PM2-PM2) that filled 84, 88, 92, and 96 per cent of the oral aperture; and (3) smiles with asymmetrical BC that filled 88, 90, 94, and 96 per cent of the oral aperture. The 18 smiles produced were evaluated by 82 orthodontists (70 males and 12 females) and 94 laypeople (40 males and 54 females). Paired t-tests were used to evaluate differences within the orthodontist and laypeople groups: independent t-tests were used to compare the two groups. The effect of age and gender on the ratings was evaluated by two-way analysis of variance. Orthodontists and laypeople rated smiles with small BCs as significantly (P < 0.05) more attractive than those with large BCs. Orthodontists rated M1-M1 smiles as more attractive than PM2-PM2 smiles, whereas laypeople preferred PM2-PM2 smiles. Orthodontists rated only two of eight asymmetrical smiles as less attractive than would be expected for symmetrical smiles with similar arch widths; laypeople did not rate any asymmetrical smiles as less attractive than would be expected. Rater age and gender did not significantly influence the impact of BCs on smile attractiveness.


The 54-kD protein of signal recognition particle contains a methionine-rich RNA binding domain.
Signal recognition particle (SRP) plays the key role in targeting secretory proteins to the membrane of the endoplasmic reticulum (Walter, P., and V. R. Lingappa. 1986. Annu. Rev. Cell Biol. 2:499-516). It consists of SRP7S RNA and six proteins. The 54-kD protein of SRP (SRP54) recognizes the signal sequence of nascent polypeptides. The 19-kD protein of SRP (SRP19) binds to SRP7S RNA directly and is required for the binding of SRP54 to the particle. We used deletion mutants of SRP19 and SRP54 and an in vitro assembly assay in the presence of SRP7S RNA to define the regions in both proteins which are required to form a ribonucleoprotein particle. Deletion of the 21 COOH-terminal amino acids of SRP19 does not interfere with its binding to SRP7S RNA. Further deletions abolish SRP19 binding to SRP7S RNA. The COOH-terminal 207 amino acids of SRP54 (M domain) were found to be necessary and sufficient for binding to the SRP19/7S RNA complex in vitro. Limited protease digestion of purified SRP confirmed our results for SRP54 from the in vitro binding assay. The SRP54M domain could also bind to Escherichia coli 4.5S RNA that is homologous to part of SRP7S RNA. We suggest that the methionine-rich COOH terminus of SRP54 is a RNA binding domain and that SRP19 serves to establish a binding site for SRP54 on the SRP7S RNA.


Analysis of the air pollution climate at a background site in the Po valley.
The Po valley in northern Italy is renowned for its high air pollutant concentrations. Measurements of air pollutants from a background site in Modena, a town of 200 thousand inhabitants within the Po valley, are analysed. These comprise hourly data for CO, NO, NO(2), NO(x), and O(3), and daily gravimetric equivalent data for PM(10) from 1998-2010. The data are analysed in terms of long-term trends, annual, weekly and diurnal cycles, and auto-correlation and cross-correlation functions. CO, NO and NO(2) exhibit a strongly traffic-related pattern, with daily peaks at morning and evening rush hour and lower concentrations over the weekend. Ozone shows an annual cycle with a peak in July due to local production; notwithstanding the diurnal cycle dominated by titration by nitrogen oxide, the decreasing long term trend in NO concentration did not affect the long term trend in O(3), whose mean concentration remained steady over the sampling period. PM(10) shows a strong seasonality with higher concentration in winter and lower concentration in summer and spring. Both PM(10) and ozone show a marked weekly cycle in summer and winter respectively. Regressions of PM(10) upon NO(x) show a consistently greater intercept in winter, representing higher secondary PM(10) in the cooler months of the year. There is a seasonal pattern in primary PM(10) to NO(x) ratios, with lower values in winter and higher values in summer, but the reasons are unclear.


Early life bisphenol A exposure and neurobehavior at 8years of age: Identifying windows of heightened vulnerability.
Early life BPA exposure could affect neurobehavior, but few studies have investigated whether there are developmental periods when the fetus or child is more vulnerable to these potential effects. We explored windows of vulnerability to BPA exposure in a multiethnic cohort of 228 mothers and their children from Cincinnati, Ohio. We measured urinary BPA concentrations at up to two prenatal and six postnatal time points from the 2nd trimester of pregnancy until the child was age 8years. At age 8years, we administered the Behavioral Assessment System for Children-2 (BASC-2), Behavior Rating Inventory of Executive Function, and Wechsler Intelligence Scale for Children-IV. We estimated covariate-adjusted differences in composite scores from each instrument using a multiple informant model designed to identify heightened windows of vulnerability. Among all children, there was not strong evidence that the associations between BPA and neurobehavior varied by the timing of exposure (Visit x BPA p-values≥0.16). However, child sex modified the associations of repeated BPA measures with BASC-2 scores (Visit x Sex x BPA p-values=0.02-0.23). For example, each 10-fold increase in prenatal BPA was associated with more externalizing behaviors in girls (β=6.2, 95% CI: 0.8, 11.6), but not boys (β=-0.8, 95% CI: -5.0, 3.4). In contrast, a 10-fold increase in 8-year BPA was associated with more externalizing behaviors in boys (β=3.9, 95% CI: 0.6, 7.2), but not girls (β=0.3, 95% CI: -3.5, 4.1). We found that sex-dependent associations between BPA and child neurobehavior may depend on the timing of BPA exposure.


A rare 300 kilometer dispersal by an adult male white-tailed deer.
Despite the key roles that dispersal plays in individual animal fitness and meta-population gene flow, it remains one of the least understood behaviors in many species. In large mammalian herbivores, dispersals might span long distances and thereby influence landscape-level ecological processes, such as infectious disease spread. Here, we describe and analyze an exceptional long-distance dispersal by an adult white-tailed deer (Odocoileus virginianus) in the central United States. We also conducted a literature survey to compare the dispersal to previous studies. This dispersal was remarkable for its length, duration, and the life history stage of the dispersing individual. Dispersal is typical of juvenile deer seeking to establish postnatal home ranges, but this dispersal was undertaken by an adult male (age = 3.5). This individual dispersed ~300 km over a 22-day period by moving, on average, 13.6 km/day and achieving a straight-line distance of ~215 km, which was ~174 km longer than any other distance recorded for an adult male deer in our literature survey. During the dispersal, which occurred during the hunting season, the individual crossed a major river seven times, an interstate highway, a railroad, and eight state highways. Movements during the dispersal were faster (mean = 568.1 m/h) and more directional than those during stationary home range periods before and after the dispersal (mean = 56.9 m/h). Likewise, movements during the dispersal were faster (mean = 847.8 m/h) and more directional at night than during the day (mean = 166.4 m/h), when the individual frequently sheltered in forest cover. This natural history event highlights the unpredictable nature of dispersal and has important implications for landscape-level processes such as chronic wasting disease transmission in cervids. More broadly, our study underscores how integrating natural history observations with modern technology holds promise for understanding potentially high impact but rarely recorded ecological events.


Effects of land-use changes on landslides in a landslide-prone area (Ardesen, Rize, NE Turkey).
Various natural hazards such as landslides, avalanches, floods and debris flows can result in enormous property damages and human casualties in Eastern Black Sea region of Turkey. Mountainous topographic character and high frequency of heavy rain are the main factors for landslide occurrence in Ardesen, Rize. For this reason, the main target of the present study is to evaluate the landslide hazards using a sequence of historical aerial photographs in Ardesen (Rize), Turkey, by Photogrammetry and Geographical Information System (GIS). Landslide locations in the study area were identified by interpretation of aerial photographs dated in 1973 and 2002, and by field surveys. In the study, the selected factors conditioning landslides are lithology, slope gradient, slope aspect, vegetation cover, land class, climate, rainfall and proximity to roads. These factors were considered as effective on the occurrence of landslides. The areas under landslide threat were analyzed and mapped considering the landslide conditioning factors. Some of the conditioning factors were investigated and estimated by employing visual interpretation of aerial photos and topographic data. The results showed that the slope, lithology, terrain roughness, proximity to roads, and the cover type played important roles on landslide occurrence. The results also showed that degree of landslides was affected by the number of houses constructed in the region. As a consequence, the method employed in the study provides important benefits for landslide hazard mitigation efforts, because a combination of both photogrammetric techniques and GIS is presented.


Disparities in the surgical management of early stage non-small cell lung cancer: how far have we come?
It is currently estimated that nearly one-third of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage I-II disease on clinical evaluation. Curative-intent surgical resection has been a cornerstone of the therapeutic management of such patients, offering the best clinical and oncologic outcomes in the long-term. In 1999, Peter Bach and colleagues brought attention to racial disparities in the receipt of curative-intent surgery in the NSCLC population. In the time since this seminal study, there is accumulating evidence to suggest that disparities in the receipt of definitive surgery continue to persist for patients with early stage NSCLC. In this review, we sought to provide an up-to-date assessment of 20 years of surgical disparities literature in the NSCLC population. We summarized common and unrecognized disparities in the receipt of surgical resection for early stage NSCLC and demonstrated that demographic and socioeconomic factors such as race/ethnicity, special patient groups, income and insurance continue to impact the receipt of definitive resection. Additionally, we found that discrepancies in patient and provider perceptions of and attitudes toward surgery, access to invasive staging, distance to treatment centers and negative stigmas about lung cancer that patients experience may act to perpetuate disparities in surgical treatment of early stage lung cancer.


Electrophysiological characterization of peptidergic neurosecretory terminals.
Electrical activity recorded intracellularly from peptidergic neurosecretory terminal dilatations in the sinus gland of crabs (principally Cardisoma guanhumi and C. carnifex) is described. Recordings were made from the neurohaemal organ in situ on the neural tissue of the isolated eyestalk and from isolated sinus gland-sinus gland nerve preparations. Verification that electrodes penetrated terminals was obtained by dye marking. Resting potentials ranged between -30 and -80mV. Overshooting action potentials of long duration (5-20 ms at 1/2 amplitude) relative to those of non-secretory axons (less than 2ms) were recorded in approximately 70% of stable penetrations. Action potentials occurred spontaneously at slow (less than 0.2s-1) rates in 75% of penetrations. Sequential intra- and extracellular recordings with the same microelectrode, on the same terminal, indicate impulse generation by the terminal itself. Extracellular stimulation of the axon tract evokes an all-or-none action potential at distinct threshold and latency. At rates of stimulation exceeding 5s-1, discrete fluctuations in the form of responses occur. Similar waveforms occur spontaneously and can be evoked by passing current through the electrode. They are interpreted to be electrotonically recorded activity of other parts of a complex axonal terminal arborization. Some, but not all, terminals exhibit impulse broadening (up to three-fold at 1/2 amplitude) during repetitive firing exceeding 1s-1. The same terminals show reduced impulse duration with hyperpolarization and broadened impulses with imposed depolarization. The changes are due to altered repolarization rates. Terminals sustain steady impulse firing at rates (up to 5s-1) linearly related to the imposed depolarizing current. Regenerative potentials, though of reduced rate of rise and amplitude, can be evoked by depolarizing current passed through the electrode during perfusion with salines having 1/2 normal [Na+], or containing tetrodotoxin (10(-6)moll-1). However, these block axonal conduction. Nominally Ca-free saline causes increased spontaneity and depolarization of about 5 mV in half the preparations examined, but reaching 20 mV in the others, with resultant inactivation of regenerative activity. Impulses in low-Ca saline show alterations of the falling phase, it being faster initially and then slower than normal. Thus, while the action potentials of neurosecretory axons are Na dependent, the terminals support regenerative impulses mediated by both Na and Ca.


Accuracy of a Proactive Case Detection Tool for Internalizing and Externalizing Problems Among Children and Adolescents.
Lack of identification and referral of children and adolescents with mental health problems contributes to the treatment gap in low- and middle-income countries, and especially in humanitarian settings. The Community Case Detection Tool (CCDT) is developed to improve community-based detection and increase help-seeking among children and adolescents in need of mental health care. The CCDT uses brief, easily understood pictorial vignettes that represent common symptoms of childhood internalizing and externalizing problems. The tool is developed for gatekeepers to support proactive detection of children in need of mental health care and to subsequently encourage help-seeking. This study evaluates the accuracy of the CCDT in detecting children and adolescents aged 6-18 years with significant mental health care needs in a conflict-affected setting: the occupied Palestinian territory. Teachers and community workers were trained to use the CCDT. Children detected using the tool were invited for a structured clinical interview with a psychologist using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version, as well as the Strengths and Difficulties Questionnaire, to test the accuracy of CCDT-based detection. Our sample consists of 52 children positively detected as matching with one of the vignettes. Approximately three of four detected children were indicated for psychological treatment based on the clinical interview (positive predictive value = .769), and 64.6% returned 'borderline' or 'abnormal' total difficulty scores on the Strengths and Difficulties Questionnaire. The CCDT offers a promising low-cost solution to mitigate underdetection of mental health problems in challenging settings.


Salivary cortisol patterns and cognitive speed in major depression: a comparison with allergic rhinitis and healthy control subjects.
Few studies have investigated the relationship between cortisol and cognitive functions other than memory in depression. This study investigated daily salivary cortisol patterns (basal cortisol levels at 08:00, 16:00, and 21:00 h and flatness of the diurnal curve) in relation to cognitive speed and memory. Twenty-seven unmedicated outpatients with major depressive disorder (MDD) were compared with 36 healthy controls and with 20 allergic rhinitis patients, to determine whether effects should be ascribed to MDD or to more general disease-related processes. MDD patients were characterised by a flatter diurnal cortisol curve and by reduced cognitive speed. Flatter cortisol curves were associated with cognitive slowness. However, this relationship is unlikely to be causal; after control for depressive symptoms and group membership, flatness of the diurnal cortisol curve was no longer a significant predictor of cognitive slowness. Thus, MDD and related depressive symptoms appeared to be independently associated with altered cortisol secretory patterns and with decrements in cognitive speed.


Accessing HIV treatment and care services in fishing communities around Lake Victoria in Uganda: mobility and transport challenges.
Qualitative research exploring the influence of community-level factors on access to and use of HIV treatment and care services among people living in fishing communities is limited, especially with respect to those already in receipt of HIV care and on treatment. To enhance understanding of these issues, semi-structured in-depth interviews were conducted with 42 HIV-positive fisherfolk and 15 health care providers from two HIV clinics located in two fishing communities in Uganda. Fisherfolk's mobility and poor transport systems were significant barriers to access to and use of HIV treatment and care. Mobility, which involved regular movement between communities, sometimes led to fisherfolk's inability to access HIV treatment and care. A poor transport system in fishing communities - characterised by irregular transport services and boats in a poor condition - was reported to force both fisherfolk and health care providers sometimes to cancel journeys to centres providing treatment and support. Community-level factors such as these, which relate to the organisation and provision of transport in local community settings, are significant influences on access to HIV treatment and care. Interventions that address these challenges are needed to improve access to and use of HIV treatment and care in fishing communities.


EEG Amplitude Modulation Analysis across Mental Tasks: Towards Improved Active BCIs.
Brain-computer interface (BCI) technology has emerged as an influential communication tool with extensive applications across numerous fields, including entertainment, marketing, mental state monitoring, and particularly medical neurorehabilitation. Despite its immense potential, the reliability of BCI systems is challenged by the intricacies of data collection, environmental factors, and noisy interferences, making the interpretation of high-dimensional electroencephalogram (EEG) data a pressing issue. While the current trends in research have leant towards improving classification using deep learning-based models, our study proposes the use of new features based on EEG amplitude modulation (AM) dynamics. Experiments on an active BCI dataset comprised seven mental tasks to show the importance of the proposed features, as well as their complementarity to conventional power spectral features. Through combining the seven mental tasks, 21 binary classification tests were explored. In 17 of these 21 tests, the addition of the proposed features significantly improved classifier performance relative to using power spectral density (PSD) features only. Specifically, the average kappa score for these classifications increased from 0.57 to 0.62 using the combined feature set. An examination of the top-selected features showed the predominance of the AM-based measures, comprising over 77% of the top-ranked features. We conclude this paper with an in-depth analysis of these top-ranked features and discuss their potential for use in neurophysiology.


[Experience with the restorative treatment of locomotor injuries at an outpatient rehabilitation center].
The article analyzes the experience with the treatment of 960 trauma patients in the restoration department of the out-patient clinic and makes an assessment of some organizational and clinical aspects of its activities. High percentage of favorable results (95,9%) was shown by late follow-up of the patients after injuries. Bad results were found in 4,1% of cases, 5,4% of the patients had temporary invalidism. A conclusion is made that the efficiency of the treatment in the restoration department may be improved by eliminating some problems of organizational character.


Intraoperative Ultrasound Staging for Colorectal Liver Metastases in the Era of Liver-Specific Magnetic Resonance Imaging: Is It Still Worthwhile?
To assess the efficacy of intraoperative ultrasound (IOUS) compared with liver-specific magnetic resonance imaging (MRI) in patients with colorectal liver metastases (CRLMs). From January 2010 to December 2017, 721 patients underwent MRI as a part of preoperative workup within 1 month before hepatectomy and were considered for the study. Early intrahepatic recurrence (relapse at cut surface excluded) was assessed 6 months after the resection and was considered as residual disease undetected by IOUS and/or MRI. IOUS and MRI performance was compared on a patient-by-patient basis. Long-term results were also studied. A total of 2845 CRLMs were detected by MRI, and the median number of CRLMs per patient was 2 (1-31). Preoperative chemotherapy was administered in 489 patients (67.8%). In 177 patients, 379 new nodules were intraoperatively found and resected. Among 379 newly identified nodules, 317 were histologically proven CRLMs (11.1% of entire series). The median size of new CRLMs was 6 ± 2.5 mm. Relationships between intrahepatic vessels and tumors differed between IOUS and MRI in 128 patients (17.7%). The preoperative surgical plan was intraoperatively changed for 171 patients (23.7%). Overall, early intrahepatic recurrence occurred in 8.7% of cases. To assess the diagnostic performance, 24 (3.3%) recurrences at the cut surface were excluded; thus, 5.4% of early relapses were considered for analysis. The sensitivity of IOUS was superior to MRI (94.5% vs 75.1%), while the specificity was similar (95.7% vs 95.9%). Multivariate analysis at the hepatic dome or subglissonian and mucinous histology revealed predictive factors of metastases missing at MRI. The 5-year OS (52.1% vs 37.8%, p=0.006) and DF survival (45.1% vs 33%, p=0.002) were significantly worse among patients with new CRLMs than without. IOUS improves staging in patients undergoing resection for CRLMs even in the era of liver-specific MRI. Intraoperative detection of new CRLMs negatively affects oncologic outcomes.


Cinnamon users with prediabetes have a better fasting working memory: a cross-sectional function study.
Working memory (WM) is impaired in prediabetes. We hypothesized that culinary herbs and spices may decrease insulin resistance (IR) and improve WM in prediabetes. Healthy people aged ≥60 years with prediabetes (fasting blood glucose 100-125 mg/dL) (47 men and 46 women) whose food and culinary herb intakes were established with a food frequency questionnaire had body composition assessed and fasting glucose and insulin measured. Working memory and Mini-Mental State Examination (MMSE) were assessed on the same occasion. The contributions to associations between WM and diet, body fat, and IR were estimated by linear regression. Compared with nonusers, cinnamon users had significantly less frequent physical activity (2.9 vs. 4.4 times per week) and more often used fresh ginger (93.3% vs. 64.1%) and ginger in cooking (60.0% vs. 32.1%). Cinnamon users also had a better WM (2.9 vs. 2.5, P < .001). Cinnamon had a significant effect (users were 0.446 higher), but not ginger or curry usage, in predicting WM. For sociodemographic variables, only education (years) was significant in predicting WM (β = 0.065). Other significant determinants of WM were total fat mass (kilograms) (β = -0.024) and MMSE (β = 0.075). After adjustment for age and sex, cinnamon use, education, and MMSE remained significant individual predictors. In the final model, in which all variables listed were adjusted simultaneously, cinnamon users still had a significantly higher WM than nonusers. Cinnamon usage is associated with a better WM, not accounted for by dietary quality or IR, in untreated prediabetes.


[Prevalence of anxious and depressive symptoms in Colombian migrants in Chile].
Migratory processes may affect mental health. Data on the health status of migrants are necessary for an adequate public health approach. To describe the prevalence of anxious and depressive symptoms in Colombian migrants living in Chile and to compare it with the Chilean population. Beck and BDI scales for depression and BAI anxiety scale were applied to 1,932 participants living in Arica, Antofagasta and Santiago. Of these, 976 participants (51% women) aged 35 ± 10 years were first generation Colombian migrants and 956 participants aged 34 ± 14 years were Chilean. The scores for depressive and anxious symptoms were higher in Chileans than in Colombians. Women reported worse mental health in both groups. Chilean and Colombian respondents residing in Arica and Antofagasta had a higher degree of anxiety and depression than their counterparts residing in Santiago. Chileans have worse mental health indicators than Colombian migrants. There are differences by sex and city of residence.


The relationship between perceived stress, acupuncture, and pregnancy rates among IVF patients: a pilot study.
The aim of this paper was to determine the effect of acupuncture on perceived stress levels in women on the day of embryo transfer (ET), and to determine if perceived stress levels at embryo transfer correlated with pregnancy rates. The study was an observational, prospective, cohort study based at the University IVF center. 57 infertile patients undergoing IVF or IVF/ICSI. Patients were undergoing Embryo Transfer with or without acupuncture as part of their standard clinical care. Perceive Stress Scale scores, pregnancy rates. women who received this acupuncture regimen achieved pregnancy 64.7%, whereas those without acupuncture achieved pregnancy 42.5%. When stratified by donor recipient status, only non-donor recipients potentially had an improvement with acupuncture (35.5% without acupuncture vs. 55.6% with acupuncture). Those who received this acupuncture regimen had lower stress scores both pre-ET and post-ET compared to those who did not. Those with decreased their perceived stress scores compared to baseline had higher pregnancy rates than those who did not demonstrate this decrease, regardless of acupuncture status. The acupuncture regimen was associated with less stress both before and after embryo transfer, and it possibly improved pregnancy rates. Lower perceived stress at the time of embryo transfer may play a role in an improved pregnancy rate.


The Water@Birth Study: an exploratory study on the requirements of water for hand hygiene during labour and delivery in low-income countries.
Infections acquired during childbirth are one of the leading causes of maternal death; the majority of these deaths occur in low-income settings. Hand hygiene is one of the most effective ways of preventing infection but requires basic resources, such as running water, to be performed. Limited literature on water volume requirements for hand hygiene in healthcare facilities exists despite the importance of this information, particularly in resource-poor settings. To establish the volume of water required for hand hygiene during childbirth in low-income countries. Data was collected in Aberdeen Maternity Hospital (AMH) and Felege Hiwot Referral Hospital, Ethiopia (FHRH), with an average of 14 and 16 deliveries per day respectively. Primary data on hand hygiene opportunities (HHOs) during childbirth were gathered using observational methods, and secondary data gathered from register and case-note reviews. The volume of water required for each HHO (H2O/HHO) was calculated by multiplying flow rate by hand washing time. Estimates of water requirements were derived by calculating the number of HHOs during childbirth and the H2O/HHO. Water requirement estimates from each facility were compared to each other as well as to WHO recommendations. Due to skewed data, Spearman's rho was utilised to explore the relationship between variables. Eleven deliveries were observed in AMH and 20 in FHRH. The number of HHOs was largely determined by the length of labour. Stringently following WHO recommendations lead to a significantly higher number of HHOs than was performed in clinical practice at both sites. Hand washing also occurred for a much shorter time than the WHO recommendation of 40-60 seconds, with an average of 24 seconds in AMH and 25 seconds in FHRH observed. The estimated number of HHOs at sites ranged from 5 to 16 per hour per delivery and water consumption from 21 to 159.6 litres per hour per delivery. Hand hygiene was estimated to require 8937.6 litres and 4838.4 litres per day or 638.4 litres and 302.4 litres per delivery for AMH and FHRH, respectively. Water requirements are variable due to the nature of childbirth but are not currently met in low-income countries. In terms of performance of hand hygiene, there is a large gap between clinical and recommended practice and thus room for improvement. The volume of water required for hand hygiene has significant implications for water requirements within maternity units, particularly in resource-poor settings. Further research on water requirements is merited to improve the targeting of limited resources.


The formulation, characterization and in vivo evaluation of a magnetic carrier for brain delivery of NIR dye.
This work reports the targeting of the near infrared (NIR) dye indocyanine green (ICG) to the brain using composite nanoparticles. Thermal decomposition of iron pentacarbonyl was used to synthesize monodisperse oleic acid coated magnetic nanoparticles (OAMNP). Synthesized OAMNP and ICG were encapsulated in a poly (lactide-co-glycolide) matrix using an emulsion evaporation method. Different batches containing OAMNP:PLGA ratios (1:4, 1:2 and 3:4) were prepared with ICG (group B-1, 2, 3) and without ICG (group A-1, 2, 3) loading. All the formulations were characterized in terms of morphology, particle size, zeta potential, magnetic content, ICG encapsulation efficiency and the spectral properties of ICG. The optimized formulation showed an encapsulation efficiency of 56 +/- 4.6% for ICG and 57 +/- 1.37% for OAMNP. The biodistribution and brain targeting study involved three groups of six animals, each with 0.4 mg kg(-1) equivalent of ICG, given as neat ICG solution, composite nanoparticles without the aid of a magnetic field, and composite nanoparticles under the influence of a magnetic field (8000 G) to groups 1, 2 and 3 respectively. The tissue analysis and microscopy images revealed a significantly higher brain concentration of ICG (p < 0.05) for group 3 than the two control groups. These results are encouraging for the brain delivery of hydrophilic dyes/drugs using this method for biomedical applications.


Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse.
Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics-assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease.


A Cough-Based Algorithm for Automatic Diagnosis of Pertussis.
Pertussis is a contagious respiratory disease which mainly affects young children and can be fatal if left untreated. The World Health Organization estimates 16 million pertussis cases annually worldwide resulting in over 200,000 deaths. It is prevalent mainly in developing countries where it is difficult to diagnose due to the lack of healthcare facilities and medical professionals. Hence, a low-cost, quick and easily accessible solution is needed to provide pertussis diagnosis in such areas to contain an outbreak. In this paper we present an algorithm for automated diagnosis of pertussis using audio signals by analyzing cough and whoop sounds. The algorithm consists of three main blocks to perform automatic cough detection, cough classification and whooping sound detection. Each of these extract relevant features from the audio signal and subsequently classify them using a logistic regression model. The output from these blocks is collated to provide a pertussis likelihood diagnosis. The performance of the proposed algorithm is evaluated using audio recordings from 38 patients. The algorithm is able to diagnose all pertussis successfully from all audio recordings without any false diagnosis. It can also automatically detect individual cough sounds with 92% accuracy and PPV of 97%. The low complexity of the proposed algorithm coupled with its high accuracy demonstrates that it can be readily deployed using smartphones and can be extremely useful for quick identification or early screening of pertussis and for infection outbreaks control.


Enhanced Fluorescent Protein Activity in Polymer Scaffold-Stabilized Phospholipid Nanoshells Using Neutral Redox Initiator Polymerization Conditions.
Phospholipid nanoshells, for example, liposomes, provide a versatile enabling platform for the development of nanometer-sized biosensors and molecular delivery systems. Utilization of phospholipid nanoshells is limited by the inherent instability in complex biological environments, where the phospholipid nanoshell may disassemble and degrade, thus releasing the contents and destroying sensor function. Polymer scaffold stabilization (PSS), wherein the phospholipid nanoshells are prepared by partitioning reactive monomers into the lipid bilayer lamella followed by radical polymerization, has emerged to increase phospholipid nanoshell stability. In this work, we investigated the effects of three different radical initiator conditions to fabricate stable PSS-phospholipid nanoshells yet retain the activity of encapsulated model fluorescent sensor proteins. To identify nondestructive initiation conditions, UV photoinitiation, neutral redox initiation, and thermal initiation were investigated as a function of PSS-phospholipid nanoshell stabilization and fluorescence emission intensity of enhanced green fluorescent protein (eGFP) and tandem dimer Tomato (td-Tomato). All three initiator approaches yielded comparably stable PSS-phospholipid nanoshells, although slight variations in PSS-phospholipid nanoshell size were observed, ranging from ca. 140 nm for unstabilized phospholipid nanoshells to 300-500 nm for PSS-phospholipid nanoshells. Fluorescence emission intensity of encapsulated eGFP was completely attenuated under thermal initiation (0% vs control), moderately attenuated under UV photoinitiation (40 ± 4% vs control), and unaffected by neutral redox initiation (97 ± 3% vs control). Fluorescence emission intensity of encapsulated td-Tomato was significantly attenuated under thermal initiation (13 ± 3% vs control), moderately attenuated UV photoinitiation (64 ± 5% vs control), and unaffected by neutral redox initiation (98% ± 4% vs control). Therefore, the neutral redox initiation method provides a significant advancement toward the preparation of protein-functionalized PSS-phospholipid nanoshells. These results should help to guide future applications and designs of biosensor platforms using PSS-phospholipid nanoshells and other polymer systems employing protein transducers.


[Morbidity after stapled haemorrhoidectomy: long-term results about 140 patients and review of the literature].
The aim of this study was to determine the results and the complications of the treatment of hemorrhoids with circular stapler with a follow-up of 18 months, and to review the complications in the literature. From April 1998 to August 1999, 140 patients (83 males and 57 females) with an average age of 43.8 years (range: 19-83 years) underwent haemorrhoidectomy using a circular stapler in three university hospital centers. The degree of hemorrhoids has been classified: three cases of degree II, 97 cases of degree III, and 40 cases of degree IV. All the patients were prospectively evaluated at two weeks, two and 18 months after surgery. The average length of the operation was 18 minutes (range: 8-60 minutes). Mean hospital stay was 36 hours (range: 8-72 hours). There was no intraoperative complication. There was no mortality. The postoperative complication rate was 7.8% (N = 11): there were five cases of bleeding that two complicated by a submucosal hematoma (one was infected and needed a rectotomy on day 21), two cases of urinary retention, and two cases of external hemorrhoid thrombosis. The bleeding occurred in the 12 hours after surgery except for one patient with antivitamin K whith presented a secondary bleeding on day 16. At 18 months, five patients presented a moderate asymptomatic stricture dilated on digital examination. Two patients complained of persistent skin tags. Neither functional trouble nor incontinence to gas, liquids, or solids was presented. With a mean follow-up of 40 months, 90% (N = 112) of the patients were fully satisfied. Treatment of hemorrhoids with circular stapler appears to be effective with 96% of patients fully satisfied at 18 months. The morbidity rate was low, and no higher than the diathermy excision hemorrhoidectomy. The results are directly dependent on the practice that required a learning, and not on the technique itself.


The effect of platelet-rich plasma in vitro on primary cells: rat osteoblast-like cells and human endothelial cells.
The aim of this study was to evaluate the effects of standardized platelet-rich plasma (PRP) concentrates from 10 human donors on cellular behavior. The standardized PRPs used were fivefold average and fivefold maximum baseline values in whole blood. Both these standardized PRPs were characterized by determining platelet numbers and subsequently growth factor concentrations in activated PRPs, called PRP derivatives. Platelet numbers in both types of standardized PRPs were significantly increased compared with whole blood. Further, both PRP derivatives contained significantly higher concentrations of platelet-derived growth factor-AA, platelet-derived growth factor-AB, and transforming growth factor-beta 1. Vascular endothelial growth factor concentrations were significantly elevated in only the most concentrated PRP derivative. Cell culture experiments with osteoblast-like cells showed that both PRP derivatives stimulated cell proliferation without inducing cell differentiation, whereas tube formation in endothelial cell cultures was significantly increased by adding low volume percentages of PRP derivative (2%–8%). Consequently, it can be concluded that there is no direct relationship between the number of platelets and the level of growth factors released from these platelets. PRP derivatives have the potency to stimulate angiogenesis dose dependently, while lacking the capacity to induce osteogenic differentiation. Yet, the proliferation of osteoblast-like cells can significantly be enhanced by supplementation of PRP derivatives.


Solution crystallisation via a submerged liquid-liquid phase boundary: oiling out.
In many situations the process of crystallisation from solution is known to occur via metastable crystalline states (polymorphs or solvates). Here we present what we believe to be a novel example of small molecule crystallisation in which the initial separation of a solute rich liquid phase precedes the crystallisation event. We believe this occurs because a submerged liquid-liquid phase boundary is accessible within the metastable zone of the crystal nucleation process.


Coronary artery involvement in type A aortic dissection: Fate of the coronaries.
Type A aortic dissection (TAAD) involves a tear in the intimal layer of the thoracic aorta proximal to the left subclavian artery, and hence, carries a high risk of mortality and morbidity and requires urgent intervention. This dissection can extend into the main coronary arteries. Coronary artery involvement in TAAD can either be due to retrograde extension of the dissection flap into the coronaries or compression and/or blockage of these vessels by the dissection flap, possibly causing myocardial ischemia. Due to the emergent nature of TAAD, coronary involvement is often missed during diagnosis, thereby delaying the required intervention. The main scope of this review is to summarize the literature on the incidence, mechanism, diagnosis, and treatment of coronary artery involvement in TAAD. A comprehensive literature search was performed using multiple electronic databases, including PubMed, Ovid, Scopus and Embase, to identify and extract relevant studies. Incidence of coronary artery involvement in TAAD was seldom reported in the literature, however, some studies have described patients diagnosed either preoperatively, intraoperatively following aortic clamping, or even during autopsy. Among the few studies that reported on this matter, the treatment choice for coronary involvement in TAAD was varied, with the majority revascularizing the coronary arteries using coronary artery bypass grafting or direct local repair of the vessels. It is well-established that coronary artery involvement in TAAD adds to the already high mortality and morbidity associated with this disease. Lastly, the right main coronary artery was often more implicated than the left. This review reiterates the significance of an accurate diagnosis and timely and effective interventions to improve prognosis. Finally, further large cohort studies and longer trials are needed to reach a definitive consensus on the best approach for coronary involvement in TAAD.


Retrograde intraciliary trafficking of opsin during the maintenance of cone-shaped photoreceptor outer segments of Xenopus laevis.
Photoreceptor outer segments (OSs) are essential for our visual perception, and take either rod or cone forms. The cell biological basis for the formation of rods is well established; however, the mechanism of cone formation is ill characterized. While Xenopus rods are called rods, they exhibit cone-shaped OSs during the early process of development. To visualize the dynamic reorganization of disk membranes, opsin and peripherin/rds were fused to a fluorescent protein, Dendra2, and expressed in early developing rod photoreceptors, in which OSs are still cone-shaped. Dendra2 is a fluorescent protein which can be converted from green to red irreversibly, and thus allows spatiotemporal labeling of proteins. Using a photoconversion technique, we found that disk membranes are assembled at the base of cone-shaped OSs. After incorporation into disks, however, Opsin-Dendra2 was also trafficked from old to new disk membranes, consistent with the hypothesis that retrograde trafficking of membrane components contributes to the larger disk membrane observed toward the base of the cone-shaped OS. Such retrograde trafficking is cargo-specific and was not observed for peripherin/rds-Dendra2. The trafficking is unlikely mediated by diffusion, since the disk membranes have a closed configuration, as evidenced by CNGA1 labeling of the plasma membrane. Consistent with retrograde trafficking, the axoneme, which potentially mediates retrograde intraflagellar trafficking, runs through the entire axis of OSs. This study provides an insight into the role of membrane reorganization in developing photoreceptor OSs, and proves that retrograde trafficking of membrane cargoes can occur there.


Protective effect of lactulose on dextran sulfate sodium-induced colonic inflammation in rats.
Promising results have recently been obtained with pre- and probiotic therapy in ulcerative colitis (UC). The prebiotic potential of lactulose is well established, but it has not yet been investigated in experimental colitis models. The purpose of the study was to examine the effect of lactulose on an UC model induced by 3% dextran sulfate sodium (DSS) solution added to drinking water for 7 days in male Wistar rats. Lactulose (300-1000 mg/kg) or 5-aminosalicylic acid (5-ASA; 150 mg/kg) was administered orally twice daily for 6 days. Colonic ulceration area, colon length, body weight changes, diarrhea/bloody feces, colonic mucosal myeloperoxidase activity (MPO), thiobarbituric acid reactive substances (TBARS), and histology were examined. Treatment of animals with DSS for 7 days resulted in severe colonic lesions accompanied by diarrhea, bloody feces, a decrese in body weight, shortening of the colon length, and an increase in MPO activity as well as TBARS, compared to normal rats. Lactulose treatment ameliorated DSS-induced colitis in a dose-dependent manner, and at 1000 mg/kg all of the parameters examined, except TBARS, were shown to improve significantly as compared to controls. Daily administration of 5-ASA also significantly reduced the severity of colonic lesions following DSS treatment. These results demonstrated the protective effect of lactulose in this rat colitis model and suggested that the background of this lactulose effect may be due to alterations of colonic microflora.


Sexually transmitted diseases and carcinogenesis.
Issues related to the development of cancer of the urogenital system in men and women and the possible role played by agents of sexually transmitted diseases are discussed. Research evidence supporting the role of specific viral agents in the etiology of cancer of the uterine cervix, penis, testis, prostate, and urinary bladder is presented. Also included is a discussion of the current speculations about the role played by agents of sexually transmitted diseases in acquired immune deficiency syndrome (AIDS).


Simple surface coating of electrospun poly-L-lactic acid scaffolds to induce angiogenesis.
Tissue-engineered constructs often fail due to poor integration with the patient's tissues. Specifically, they fail to be neovascularised, leading to the death and loss of the implanted tissues. Thus, there is a need to produce angiogenic materials to improve tissue integration. We describe the development of a layer-by-layer approach to coat electrospun scaffolds to help promote angiogenesis into these biomaterials once implanted. Electrospun poly-L-lactic acid was coated comparing two different techniques - one using alternative layers of polyethyleneImine (PEI) and polyacrylic Acid (PAC) and one with alternative layers of PEI and heparin for a total of seven layers in both cases. Both scaffolds were then coated with heparin as the final layer. The scaffold coated with alternate PEI and PAC showed a clear ability to bind the most heparin. This scaffold was then studied further for its ability to bind vascular endothelial growth factor, which was confirmed using an ELISA. The scaffold coated with seven alternate layers of PEI and PAC and heparin was then implanted in a chick chorionic allantoic membrane (CAM) assay. After a period of 7 days in the CAM, the coated scaffold showed strong angiogenic activity. In contrast, the uncoated scaffolds did not promote angiogenesis. We conclude that this approach to functionalising scaffolds is effective within a clinically relevant time period (7 days in an in-vivo angiogenic model) and suggest this will be useful for improving integration of scaffolds once implanted.


VIP interview: Alain C. Enthoven, Ph.D.
Alain C. Enthoven, Ph.D., is the Mariner S. Eccles Professor of Public and Private Management in the Graduate School of Business at Stanford University. He hold degrees in Economics from Stanford University, Oxford University (where he was a Rhodes scholar), and the Massachusetts Institute of Technology. Professor Enthoven has been an articulate advocate for restructuring the health care system. His far-reaching proposals on "consumer choice health plans" and "managed competition" in the 1930s established an intellectual framework for much of the current debate on national health policy. As a leader of the Jackson Hole Group, he favors internal market reform and employer tax incentives as the most effective means to control unnecessary medical costs.


Synthesis and photophysical properties of multichromophoric carbonyl-bridged triarylamines.
The synthesis and photophysical properties of two novel multichromophoric compounds is presented. Their molecular design comprises a carbonyl-bridged triarylamine core and either naphthalimides or 4-(5-hexyl-2,2'-bithiophene)naphthalimides as second chromophore in the periphery. The lateral chromophores are attached to the core via an amide linkage and a short alkyl spacer. The synthetic approach demonstrates a straightforward functionalization strategy for carbonyl-bridged triarylamines. Steady-state and time-resolved spectroscopic investigations of these compounds, in combination with three reference compounds, provide clear evidence for energy transfer in both multichromophoric compounds. The direction of the energy transfer depends on the lateral chromophore used. Furthermore, the compound bearing the lateral 4-(bithiophene)naphthaimides is capable of forming fluorescent gels at very low concentrations in the sub-millimolar regime whilst retaining its energy transfer properties.


Field-level validation of a CLIMEX model for Cactoblastis cactorum (Lepidoptera: Pyralidae) using estimated larval growth rates.
Invasive pests, such as the cactus moth, Cactoblastis cactorum (Berg) (Lepidoptera: Pyralidae), have not reached equilibrium distributions and present unique opportunities to validate models by comparing predicted distributions with eventual realized geographic ranges. A CLIMEX model was developed for C. cactorum. Model validation was attempted at the global scale by comparing worldwide distribution against known occurrence records and at the field scale by comparing CLIMEX "growth indices" against field measurements of larval growth. Globally, CLIMEX predicted limited potential distribution in North America (from the Caribbean Islands to Florida, Texas, and Mexico), Africa (South Africa and parts of the eastern coast), southern India, parts of Southeast Asia, and the northeastern coast of Australia. Actual records indicate the moth has been found in the Caribbean (Antigua, Barbuda, Montserrat Saint Kitts and Nevis, Cayman Islands, and U.S. Virgin Islands), Cuba, Bahamas, Puerto Rico, southern Africa, Kenya, Mexico, and Australia. However, the model did not predict that distribution would extend from India to the west into Pakistan. In the United States, comparison of the predicted and actual distribution patterns suggests that the moth may be close to its predicted northern range along the Atlantic coast. Parts of Texas and most of Mexico may be vulnerable to geographic range expansion of C. cactorum. Larval growth rates in the field were estimated by measuring differences in head capsules and body lengths of larval cohorts at weekly intervals. Growth indices plotted against measures of larval growth rates compared poorly when CLIMEX was run using the default historical weather data. CLIMEX predicted a single period conducive to insect development, in contrast to the three generations observed in the field. Only time and more complete records will tell whether C. cactorum will extend its geographical distribution to regions predicted by the CLIMEX model. In terms of small scale temporal predictions, this study suggests that CLIMEX indices may agree with field-specific population dynamics, provided an adequate metric for insect growth rate is used and weather data are location and time specific.


Reversible respiratory failure due to rhabdomyolysis associated with cytomegalovirus infection.
A 58-year-old woman presented with muscle weakness, whole body myalgia, and dyspnea. On admission, neurological examination showed proximal muscle weakness in the extremities. The weakness gradually extended to the bulbar and respiratory muscles, necessitating an artificial ventilator. Serum CK level was markedly increased (33,774 IU/L; normal <150 IU/L) and myoglobinuria was noted in urinalysis. There was no sign of renal failure. Nerve conduction study was normal, but needle EMG showed myopathic changes in the weak muscles. Serological studies for virus titers showed more than a four-fold increase of cytomegalovirus (CMV) antibody titer during the disease course. The IgM anti-GM2 antibody was also elevated in the acute phase and decreased in the recovery phase. The muscle weakness and respiratory failure gradually improved after intravenous methylprednisolone administration, and the serum CK level was normalized in several days. CMV infection was thought to have played a central role in the rhabdomyolysis, leading to critical but reversible respiratory muscle paralysis.


Rapid automated molecular replacement by evolutionary search.
A new procedure for molecular replacement is presented in which an efficient six-dimensional search is carried out using an evolutionary optimization algorithm. In this procedure, a population of initially random molecular-replacement solutions is iteratively optimized with respect to the correlation coefficient between observed and calculated structure factors. The sensitivity and reliability of the method is enhanced by uniform sampling of the rotational-search space and the use of continuously variable rotational and translational parameters. The process is several orders of magnitude faster than a systematic six-dimensional search, and comparisons show that it can identify solutions using significantly less accurate or less complete search models than is possible with two existing molecular-replacement methods. A program incorporating the method, EPMR, allows the rapid and highly automated solution of molecular-replacement problems involving single or multiple molecules in the asymmetric unit. EPMR has been used to solve a number of difficult molecular-replacement problems.


Childhood Trauma Linked to Adult Waterpipe Smoking: A Survey of Health Science Students in Iran.
Explaining the risk and protective factors of waterpipe tobacco smoking (WTS) is the most important principle in designing preventive interventions. This study examined the relationship between self-reported childhood abuse and WTS among health science students in Iran. This cross-sectional study was conducted among 776 health science students in Kerman City, located in southeast of Iran, who were selected by quota sampling approach. The study was performed using two valid short instruments for measuring WTS and child abuse including physical, emotional, and sexual abuse using a self-report method. The prevalence of ever use and current use (last 30 days) of WTS among participants was 49.6% and 33.4%, respectively. The initiation age of WTS in 60% of students was < 18 years. Child sexual abuse (CSA) was [odds ratio (OR) = 3.05, 95% confidence interval (CI): 2.06-4.52, P < 0.001] the main predictor for WTS among students. Protecting children during childhood to prevent them from becoming victims may be an essential primordial preventive strategy for WTS.


cAMP-guanine exchange factor protection from bile acid-induced hepatocyte apoptosis involves glycogen synthase kinase regulation of c-Jun NH2-terminal kinase.
Cholestatic liver disorders are accompanied by the hepatic accumulation of cytotoxic bile acids that induce cell death. Increases in cAMP protect hepatocytes from bile acid-induced apoptosis by a cAMP-guanine exchange factor (cAMP-GEF)/phosphoinositide-3-kinase (PI3K)/Akt pathway. The aim of these studies was to identify the downstream substrate in this pathway and to determine at what level in the apoptotic cascade cytoprotection occurs. Since inhibitory phosphorylation of glycogen synthase kinase-3 (GSK) occurs downstream of PI3K/Akt and this phosphorylation has been implicated in cell survival, we conducted studies to determine whether GSK was downstream in cAMP-GEF/PI3K/Akt-mediated cytoprotection. Our results show that treatment of hepatocytes with the cAMP-GEF-specific analog, 4-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cAMP, results in PI3K-dependent phosphorylation of GSK. Direct chemical inhibition of GSK in rat hepatocytes or human HUH7-NTCP cells with several structurally and functionally distinct inhibitors including bromoindirubin-3'-oxime (BIO), maleimides (SB216763, SB415286), thiadiazolidine derivatives, and LiCl attenuates apoptosis induced by glycochenodeoxycholate (GCDC). In addition, genetic silencing of the GSK β isoform with small interfering RNA attenuates GCDC apoptosis in HUH7-NTCP cells. Adenoviral inhibition of the Rap1 blocks both cAMP-GEF-mediated cytoprotection against GCDC-induced apoptosis and Akt/GSK3β phosphorylation. GCDC-induced phosphorylation of the proapoptotic kinase, c-Jun NH(2)-terminal kinase (JNK) is inhibited by GSK inhibition or cAMP-GEF activation. GCDC-induced apoptosis is accompanied by phosphorylation of the endoplasmic reticulum stress markers pIEF2α and IRE-1, and pretreatment with the cAMP-GEF analog or GSK inhibitors prevents this phosphorylation. Collectively, our results support the presence of a cAMP/cAMP-GEF/Rap1/PI3K/Akt/GSKβ survival pathway in hepatocytes that inhibits bile acid-induced JNK phosphorylation.


The SseC translocon component in Salmonella enterica serovar Typhimurium is chaperoned by SscA.
Salmonella enterica is a causative agent of foodborne gastroenteritis and the systemic disease known as typhoid fever. This bacterium uses two type three secretion systems (T3SSs) to translocate protein effectors into host cells to manipulate cellular function. Salmonella pathogenicity island (SPI)-2 encodes a T3SS required for intracellular survival of the pathogen. Genes in SPI-2 include apparatus components, secreted effectors and chaperones that bind to secreted cargo to coordinate their release from the bacterial cell. Although the effector repertoire secreted by the SPI-2 T3SS is large, only three virulence-associated chaperones have been characterized. Here we report that SscA is the chaperone for the SseC translocon component. We show that SscA and SseC interact in bacterial cells and that deletion of sscA results in a loss of SseC secretion, which compromises intracellular replication and leads to a loss of competitive fitness in mice. This work completes the characterization of the chaperone complement within SPI-2 and identifies SscA as the chaperone for the SseC translocon.


[Characteristics of the development of tolerance to nitrazepam and phenobarbital under experimental conditions].
Despite the similarity of the nitrazepam and phenobarbital spectra it was found that with their single usage the nature of tolerance for these substances differs quite substantially. With long-term introduction of nitrazepam to mice and rats in invariable and increasing doses there is seen a development of tolerance in the sense of the muscle relaxant and anticonvulsive action and in lethality without any marked attenuation of the tranquillizing effect. In contradistinction to this a long-term administration of phenobarbital is followed by a diminution of its tranquillizing action and by a slowly proceeding reduction of muscle relaxing manifestations. Crosswise tolerance among nitrazepam, diazepam and phenobarbital is marked but feebly. It is presumed that one of the possible mechanisms responsible for the nitrazepam tolerance in mice and rats may be a change in metabolic transformations and redistribution of metabolites.


Protective effects of ginseng stem-leaf saponins on D-galactose-induced reproductive injury in male mice.
Panax ginseng is a perennial plant in the Araliaceae family. In this study, we investigated the protective effects of ginseng stem-leaf saponins (GSLS) isolated from P. ginseng against D-galactose-induced reproductive function decline, oxidative stress, and inflammatory response. Reproductive injuries were induced in mice via the subcutaneous injection of D-galactose (300 mg/kg) for six weeks. The mice were then treated with GSLS by intragastric administration. GSLS inhibited markers of oxidative stress and inflammatory cytokines induced by D-galactose in serum, liver and kidney, whereas GSLS increased the activities of antioxidant enzymes. Compared to the mice treated only with D-galactose, GSLS treatment significantly increased the average path velocity, straight line velocity, curvilinear velocity, and amplitude of the lateral head displacement of mouse sperm. Meanwhile, GSLS significantly increased the testosterone level and reduced the cortisol, FSH, and LH levels. Histopathological examination revealed alterations in the number and the arrangement of spermatogenic cells in the seminiferous tubules of the mice in the GSLS group. GSLS treatment suppressed MAPKs pathway activation in testes. These results suggest that GSLS can attenuate D-galactose-induced oxidative stress and inflammatory response in serum, liver and kidney, and ameliorate reproductive damage by inhibiting MAPKs signaling pathway.


Paving the path toward multi-omics approaches in the diagnostic challenges faced in thyroid pathology.
Despite advancements in diagnostic methods, the classification of indeterminate thyroid nodules still poses diagnostic challenges not only in pre-surgical evaluation but even after histological evaluation of surgical specimens. Proteomics, aided by mass spectrometry and integrated with artificial intelligence and machine learning algorithms, shows great promise in identifying diagnostic markers for thyroid lesions. This review provides in-depth exploration of how proteomics has contributed to the understanding of thyroid pathology. It discusses the technical advancements related to immunohistochemistry, genetic and proteomic techniques, such as mass spectrometry, which have greatly improved sensitivity and spatial resolution up to single-cell level. These improvements allowed the identification of specific protein signatures associated with different types of thyroid lesions. Among all the proteomics approaches, spatial proteomics stands out due to its unique ability to capture the spatial context of proteins in both cytological and tissue thyroid samples. The integration of multi-layers of molecular information combining spatial proteomics, genomics, immunohistochemistry or metabolomics and the implementation of artificial intelligence and machine learning approaches, represent hugely promising steps forward toward the possibility to uncover intricate relationships and interactions among various molecular components, providing a complete picture of the biological landscape whilst fostering thyroid nodule diagnosis.


Growth and metal accumulation in vetiver and two Sesbania species on lead/zinc mine tailings.
The lead (Pb)/zinc (Zn) tailings contained high concentrations of heavy metals (total Pb, Zn, Cu and Cd concentrations 4164, 4377, 35 and 32 mg kg(-1), respectively), and low contents of major nutrient elements (N, P, and K) and organic matter. A field trial was conducted to compare growth performance, metal accumulation of Vetiver (Vetiveria zizanioides) and two legume species (Sesbania rostrata and Sesbania sesban) grown on the tailings amended with domestic refuse and/or fertilizer. It was revealed that domestic refuse alone and the combination of domestic refuse and artificial fertilizer significantly improved the survival rates and growth of V. zizanioides and two Sesbania species, especially the combination. However, artificial fertilizer alone did not improve both the survival rate and growth performance of the plants grown on tailings. Roots of these species accumulated similar levels of heavy metals, but the shoots of two Sesbania species accumulated higher (3-4 folds) concentrations of Pb, Zn, Cu and Cd than shoots of V. zizanioides. Most of the heavy metals in V. zizanioides were accumulated in roots, and the translocation of metals from roots to shoots was restricted. Intercropping of V. zizanioides and S. rostrata did not show any beneficial effect on individual plant species, in terms of height, biomass, survival rate, and metal accumulation, possibly due to the rather short experimental period of 5 months.


Genetic dissection of growth traits in a Chinese indigenous × commercial broiler chicken cross.
In China, consumers often prefer indigenous broiler chickens over commercial breeds, as they have characteristic meat qualities requested within traditional culinary customs. However, the growth-rate of these indigenous breeds is slower than that of the commercial broilers, which means they have not yet reached their full economic value. Therefore, combining the valuable meat quality of the native chickens with the efficiency of the commercial broilers is of interest. In this study, we generated an F2 intercross between the slow growing native broiler breed, Huiyang Beard chicken, and the fast growing commercial broiler breed, High Quality chicken Line A, and used it to map loci explaining the difference in growth rate between these breeds. A genome scan to identify main-effect loci affecting 24 growth-related traits revealed nine distinct QTL on six chromosomes. Many QTL were pleiotropic and conformed to the correlation patterns observed between phenotypes. Most of the mapped QTL were found in locations where growth QTL have been reported in other populations, although the effects were greater in this population. A genome scan for pairs of interacting loci identified a number of additional QTL in 10 other genomic regions. The epistatic pairs explained 6-8% of the residual phenotypic variance. Seven of the 10 epistatic QTL mapped in regions containing candidate genes in the ubiquitin mediated proteolysis pathway, suggesting the importance of this pathway in the regulation of growth in this chicken population. The main-effect QTL detected using a standard one-dimensional genome scan accounted for a significant fraction of the observed phenotypic variance in this population. Furthermore, genes in known pathways present interesting candidates for further exploration. This study has thus located several QTL regions as promising candidates for further study, which will increase our understanding of the genetic mechanisms underlying growth-related traits in chickens.


Does functional system segregation mediate the effects of lifestyle on cognition in older adults?
Healthy aging is typically accompanied by cognitive decline. Previous work has shown that engaging in multiple, non-work activities during midlife can have a protective effect on cognition several decades later, rendering it less dependent on brain structural health; the definition of "cognitive reserve". Other work has shown that increasing age is associated with reduced segregation of large-scale brain functional networks. Here we tested the hypothesis that functional segregation (SyS) mediates this effect of middle-aged lifestyle on late-life cognition. We used fMRI data from three tasks in the CamCAN dataset, together with cognitive data on fluid intelligence, episodic memory, and retrospective lifestyle data from the Lifetime of Experiences Questionnaire (LEQ). In all three tasks, we showed that SyS related to fluid intelligence even after adjusting for the (nonlinear) age effects. However, we found no evidence that SyS in late-life mediated the relationship between non-specific (non-occupation) midlife activities and either measure of cognition in late-life. Thus, the brain correlates of cognitive reserve arising from mid-life activities remain to be discovered.


The retroperitoneal, left flank approach to the supraceliac aorta for difficult and repeat aortic reconstructions.
Between 1986 and 1990, 11 patients with relative or absolute contraindications to standard infrarenal reconstructions underwent supraceliac aortofemoral bypass. The operation was performed through a left-flank incision extended into the eleventh intercostal space with retroperitoneal and extrapleural dissection. Indications included multiple failed infrarenal reconstructions in four patients, previous removal of infected aortofemoral bypass graft with failure of extra-anatomic bypass in five patients, prior para-aortic lymph node dissection and radiotherapy in one patient, and aortic aneurysmal disease proximal to the renal arteries in one patient. Bypass conduits included either a bifurcated Dacron graft or a tube graft to the left femoral artery with a femorofemoral cross-over graft; concomitant left renal artery reconstruction was performed in three patients. The mean supraceliac cross-clamp time was 24 minutes, and only one patient experienced transient postoperative acute tubular necrosis. There was no operative mortality. The graft limb patency was 95% after mean follow-up extending to 17 months (range: 5 months to 5 years). We conclude that the supraceliac aorta is a useful inflow source for aortofemoral reconstruction in difficult repeat cases. It can be approached easily without thoracotomy and avoids difficult infrarenal aortic dissection in a scarred field. The tunneling is easier than with descending thoracic aorta or ascending aorta inflow sources. In addition, this bypass is likely to be more durable than inflow reconstructions based on the axillary artery.


Recurrent secondary displacement of long-term indwelling silastic atrial catheters.
In the case I have presented, the recurrence of displacement of the catheter tip after its initial correction sheds important light on the mechanism of this problem and suggests a method for preventing displacement.


Orientation and conformation of a lipase at an interface studied by molecular dynamics simulations.
Electron density profiles calculated from molecular dynamics trajectories are used to deduce the orientation and conformation of Thermomyces lanuginosa lipase and a mutant adsorbed at an air-water interface. It is demonstrated that the profiles display distinct fine structures, which uniquely characterize enzyme orientation and conformation. The density profiles are, on the nanosecond timescale, determined by the average enzyme conformation. We outline a computational scheme that from a single molecular dynamics trajectory allows for extraction of electron density profiles referring to different orientations of the lipase relative to an implicit interface. Profiles calculated for the inactive and active conformations of the lipase are compared with experimental electron density profiles measured by x-ray reflectivity for the lipase adsorbed at an air-water interface. The experimental profiles contain less fine structural information than the calculated profiles because the resolution of the experiment is limited by the intrinsic surface roughness of water. Least squares fits of the calculated profiles to the experimental profiles provide areas per adsorbed enzyme and suggest that Thermomyces lanuginosa lipase adsorbs to the air-water interface in a semiopen conformation with the lid oriented away from the interface.


ADP modulates the dynamic behavior of the glycolytic pathway of Escherichia coli.
A mathematical model that includes biochemical interactions among the PTS system, phosphofructokinase (PFK), and pyruvate kinase (PK) is used to evaluate the dynamic behavior of the glycolytic pathway of Escherichia coli under steady-state conditions. The influence of ADP, phosphoenolpyruvate (PEP), and fructose-6-phosphate (F6P) on the dynamic regulation of this pathway is also analyzed. The model shows that the dynamic behavior of the system is affected significantly depending on whether ADP, PEP, or F6P is considered constant a steady state. Sustained oscillations are observed only when dADP/dt not equal 0 and completely suppressed if dADP/dt = 0 at any steady-state value. However, when PEP or F6P is constant, the system evolves toward the formation of stable limit cycles with periods ranging from 0.2 min to hours.


A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults.
The use of all-trans-retinoic acid (atra) and anthracyclines (with or without cytarabine) in the treatment of acute promyelocytic leukemia (apl) has dramatically changed the management and outcome of the disease over the past few decades. The addition of arsenic trioxide (ato) in the relapsed setting-and, more recently, in reduced-chemotherapy or chemotherapy-free approaches in the first-line setting-continues to improve treatment outcomes by reducing some of the toxicities associated with anthracycline-based approaches. Despite those successes, a high rate of early death from complications of coagulopathy remains the primary cause of treatment failure before treatment begins. In addition to that pressing issue, clarity is needed about the use of ato in the first-line setting and the role of hematopoietic stem-cell transplantation (hsct) in the relapsed setting. The aim for the present consensus was to provide guidance to health care professionals about strategies to reduce the early death rate, information on the indications for hsct and on the use of ato in induction and consolidation in low-to-intermediate-risk and high-risk apl patients.


The Impact of Atrial Fibrillation on One-Year Mortality in Patients with Severe Lower Extremity Arterial Disease.
Atrial fibrillation (Afib) is associated with the presence of lower extremity arterial disease (LEAD), but its effect on a severe LEAD prognosis remains unclear. We investigated the association between Afib and clinical outcomes. We retrospectively enrolled consecutive severe LEAD patients undergoing percutaneous transluminal angioplasty between 1 January 2013 and 31 December 2018. Patients were divided according to the history of any type of Afib and followed for at least one year. The primary outcome was all-cause mortality. Secondary outcomes were cardiac-related mortality and major adverse cardiovascular events (MACEs). The study included 222 patients aged 74 ± 11 years (54% male), and 12.6% had acute limb ischemia. The Afib group had significantly higher rates of all-cause mortality (42.9% vs. 20.1%, p = 0.014) and MACEs (32.1% vs. 14.4%, p = 0.028) than the non-Afib group. Afib was independently associated with all-cause mortality (adjusted HR: 2.153, 95% CI: 1.084-4.276, p = 0.029) and MACEs (adjusted HR: 2.338, 95% CI: 1.054-2.188, p = 0.037). The other factors associated with all-cause mortality included acute limb ischemia (adjusted HR: 2.898, 95% CI: 1.504-5.586, p = 0.001), Rutherford classification, and heart rate. Afib was significantly associated with increased risks of one-year all-cause mortality and MACEs in patients with severe LEAD. Future studies should investigate whether oral anticoagulants benefit these patients.


Quick-FLIC--a short questionnaire for assessing quality of life of cancer patients.
Health-related quality of life instruments tend to include a great many items. This imposes a burden on the respondents as well as undermining response rate and data quality. In this study we developed a shortened version of the Functional Living Index-Cancer (FLIC), now called Quick-FLIC, and examined its measurement properties. A questionnaire package, self-administered by 140 patients, included the FLIC and the Functional Assessment of Cancer Therapy-General. A factor analysis and clinical judgement were used to shorten the FLIC, which included 22 items. Each subscale of FLIC was shortened to include two or three items only. The Quick-FLIC included a total of only 11 items. Nevertheless, the measurement properties of the Quick-FLIC and its subscales were comparable to those of the original FLIC. It is concluded that the shortening of established health-related quality of life instruments is viable in oncology research.


A Multi-level Model to Understand Cervical Cancer Disparities in Appalachia.
The Appalachian region experiences higher incidence and mortality due to cervical cancer compared with other regions of the United States. The goal of the Ohio State University Center for Population Health and Health Disparities (CPHHD), called the Community Awareness Resources and Education (CARE) project, was to understand reasons for this disparity. The first wave (2003-2008) of funding included three projects focusing on the known risk factors for cervical cancer, lack of screening, smoking, and infection with human papillomavirus (HPV). On the basis of the results of these projects, the second wave (2011-2017) included four projects, designed to address a multi-level model of factors contributing to cervical disparities in Appalachia. The results of these projects were then used to refine a multi-level model that explains cervical cancer disparities in Appalachia. Future funded projects will take these multi-level explanations for cervical disparities and focus on implementation science strategies to reduce the burden of cervical cancer morbidity and mortality in Appalachia.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.


Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.
Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C(max)) ranged between 4.3 and 16.3 micro M for total genistein and 0.066 and 0.17 micro M for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.