Glycoproteins D of equine herpesvirus type 1 (EHV-1) and EHV-4 determine cellular tropism independently of integrins.
Equine herpesvirus type 1 (EHV-1) and EHV-4 are genetically and antigenically very similar, but their pathogenic potentials are strikingly different. The differences in pathogenicity between both viruses seem to be reflected in cellular host range: EHV-1 can readily be propagated in many cell types of multiple species, while EHV-4 entry and replication appear to be restricted mainly to equine cells. The clear difference in cellular tropism may well be associated with differences in the gene products involved in virus entry and/or spread from cell to cell. Here we show that (i) most of the EHV-1 permissive cell lines became resistant to EHV-1 expressing EHV-4 glycoprotein D (gD4) and the opposite was observed for EHV-4 harboring EHV-1 gD (gD1). (ii) The absence of integrins did not inhibit entry into and replication of EHV-1 in CHO-K1 or peripheral blood mononuclear cells (PBMC). Furthermore, integrin-negative K562 cells did not acquire the ability to bind to gD1 when αVβ3 integrin was overexpressed. (iii) PBMC could be infected with similar efficiencies by both EHV-1 and EHV-4 in vitro. (iv) In contrast to results for equine fibroblasts and cells of endothelial or epithelial origin, we were unable to block entry of EHV-1 or EHV-4 into PBMC with antibodies directed against major histocompatibility complex class I (MHC-I), a result that indicates that these viruses utilize a different receptor(s) to infect PBMC. Cumulatively, we provide evidence that efficient EHV-1 and EHV-4 entry is dependent mainly on gD, which can bind to multiple cell surface receptors, and that gD has a defining role with respect to cellular host range of EHV-1 and EHV-4.


Effect of an inhaled glucocorticosteroid on mast cell and smooth muscle beta 2 adrenergic tolerance in mild asthma.
Regular inhaled beta 2 agonist therapy is associated with loss of bronchoprotection to indirect bronchial provocation challenges such as allergen or adenosine monophosphate (AMP), while directly acting challenge is less affected, implying preferential mast cell tolerance. Glucocorticosteroids may reverse such beta 2 adrenoreceptor tolerance and upregulate mast cell beta 2 adrenoceptor function. The effect of single high dose glucocorticosteroids on terbutaline induced loss of bronchoprotection was studied in a placebo controlled, double blind, cross-over study. Fifteen asthmatic subjects who were not taking inhaled glucocorticosteroids underwent two 10-day treatment periods with terbutaline (500 micrograms four times daily via Turbohaler), each followed by a single dose of inhaled budesonide (800 micrograms via Turbohaler) or identical placebo. Regular treatment with terbutaline resulted in significant loss of bronchoprotection to AMP (mean difference (95% CI) -1.7 (-3.0 to 0.4) doubling dilutions) but not to methacholine (mean difference -0.1 (-1.0 to 0.8) doubling dilutions). Single high dose budesonide increased the protective effect of terbutaline more to AMP than to methacholine challenge (+0.76 (0.3) doubling dilutions compared with +0.13 (0.4) doubling dilutions, respectively). The mean (SE) difference between budesonide and placebo for methacholine challenge was 0.08 (0.14) whereas that for AMP was 0.075 (0.15); p = NS. The difference in PC20 was not statistically significant when compared with placebo for either challenge agent. Inhaled glucocorticosteroids in a single dose had no significant effect in restoring terbutaline induced loss of bronchoprotection, implying that mast cell beta 2 adrenoceptor sensitivity is not restored by a single dose of an inhaled glucocorticosteroid in asthma.


Interventional Therapies for Acute Pulmonary Embolism: Current Status and Principles for the Development of Novel Evidence: A Scientific Statement From the American Heart Association.
Pulmonary embolism (PE) represents the third leading cause of cardiovascular mortality. The technological landscape for management of acute intermediate- and high-risk PE is rapidly evolving. Two interventional devices using pharmacomechanical means to recanalize the pulmonary arteries have recently been cleared by the US Food and Drug Administration for marketing, and several others are in various stages of development. The purpose of this document is to clarify the current state of endovascular interventional therapy for acute PE and to provide considerations for evidence development for new devices that will define which patients with PE would derive the greatest net benefit from their use in various clinical settings. First, definitions and limitations of commonly used risk stratification tools for PE are reviewed. An adjudication of risks and benefits of available interventional therapies for PE follows. Next, considerations for optimal future evidence development in this field are presented in the context of the current US regulatory framework. Finally, the document concludes with a discussion of the pros and cons of the rapidly expanding PE response team model of care delivery.


The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics.
Vaginal microbicides, designed to prevent HIV infection in women, are one of the most promising biomedical interventions. Clinical trials of second-generation microbicides have begun; if shown to be effective, they could be licensed within 5-10 years. Because these microbicides contain antiretrovirals (ARVs), they could be highly effective. However, there is concern that, if used by HIV-positive women, ARV resistance may evolve. By analyzing a mathematical model, we find that adherence could have both beneficial and detrimental effects on trial outcomes. Most importantly, we show that planned trial designs could mask resistance risks and therefore enable high-risk microbicides to pass clinical testing. We then parameterize a transmission model using epidemiological, clinical, and behavioral data to predict the consequences of wide-scale usage of high-risk microbicides in a heterosexual population. Surprisingly, we show that reducing a participant's risk of resistance during a trial could lead to unexpectedly high rates of resistance afterward when microbicides are used in public health interventions. We also find that, paradoxically, although microbicides will be used by women to protect themselves against infection, they could provide greater benefit to men. More infections in men than in women will be prevented if there is a high probability that ARVs are systemically absorbed, microbicides are less than approximately 50% effective, and/or adherence is less than approximately 60%. Men will always benefit more than women in terms of infections prevented per resistant case; but this advantage decreases as the relative fitness of drug-resistant strains increases. Interventions that use ARV-based microbicides could have surprising consequences.


Adverse Childhood Experiences among Veterinary Medical Students: A Multi-Site Study.
This research explores Adverse Childhood Experiences (ACEs) among veterinary medical students across six academic institutions of veterinary medicine, and their relationship with depression, stress, and desire to become a veterinarian. Between April 1, 2016, and May 23, 2016, 1,118 veterinary medical students in all 4 years of the curriculum (39% response rate) completed an anonymous web-based questionnaire about ACEs, depression using the Center for Epidemiological Studies Depression scale (CESD), stress using the Perceived Stress Scale (PSS), and the age at which they wanted to become a veterinarian. Sixty-one percent (677) of respondents reported having at least one ACE. The most prevalent ACE reported was living with a household member with a mental illness (31%). Students who had experienced four or more ACEs had an approximately threefold increase in signs of clinical depression and higher than average stress when compared to students who had experienced no ACEs. The number of ACEs showed an overall graded relationship to signs of clinical depression and higher than average stress. There was no statistically significant relationship between age at which a student wanted to become a veterinarian and exposure to ACEs. Veterinary students report being exposed to ACEs before age 18 at a rate similar to that of other population-based studies. These findings do not suggest that veterinary students enter the veterinary medical education system more at risk for poor mental health due to ACEs than the general population.


Functional Hyaluronic Acid-Polylactic Acid/Silver Nanoparticles Core-Sheath Nanofiber Membranes for Prevention of Post-Operative Tendon Adhesion.
In this study, we prepared core-sheath nanofiber membranes (CSNFMs) with silver nanoparticles (Ag NPs) embedding in the polylactic acid (PLA) nanofiber sheath and hyaluronic acid (HA) in the nanofiber core. The PLA/Ag NPs sheath provides mechanical support as well as anti-bacterial and anti-inflammatory properties. The controlled release of HA from the core could exert anti-adhesion effects to promote tendon sliding while reducing fibroblast attachment. From the microfibrous structural nature of CSNFMs, they function as barrier membranes to reduce fibroblast penetration without hampering nutrient transports to prevent post-operative peritendinous adhesion. As the anti-adhesion efficacy will depend on release rate of HA from the core as well as Ag NP from the sheath, we fabricated CSNFMs of comparable fiber diameter, but with thick (Tk) or thin (Tn) sheath. Similar CSNFMs with thick (Tk+) and thin (Tn+) sheath but with embedded Ag NPs in the sheath were also prepared. The physico-chemical properties of the barrier membranes were characterized in details, together with their biological response including cell penetration, cell attachment and proliferation, and cytotoxicity. Peritendinous anti-adhesion models in rabbits were used to test the efficacy of CSNFMs as anti-adhesion barriers, from gross observation, histology, and biomechanical tests. Overall, the CSNFM with thin-sheath and Ag NPs (Tn+) shows antibacterial activity with low cytotoxicity, prevents fibroblast penetration, and exerts the highest efficacy in reducing fibroblast attachment in vitro. From in vivo studies, the Tn+ membrane also shows significant improvement in preventing peritendinous adhesions as well as anti-inflammatory efficacy, compared with Tk and Tn CSNFMs and a commercial adhesion barrier film (SurgiWrap®) made from PLA.


Early detection of pancreatic cancer in patients with chronic pancreatitis: diagnostic utility of a K-ras point mutation in the pancreatic juice.
Point mutations of the K-ras oncogene at codon 12 have been described several months before the onset of pancreatic cancer in isolated cases of chronic pancreatitis (CP). The aim of this study was to evaluate the interest of a prospective follow-up of patients with CP and K-ras mutations at codon 12 in the detection of early pancreatic cancer. From February 1996 to March 1998, 36 patients (mean age 52.6 yr, 31 men, five women) with CP (alcoholic: 61.1%, pancreas divisum: 5.6%, autoimmune: 5.6%, unknown origin: 27.7%) were included and then prospectively monitored (median duration of 22 months) for detection of pancreatic carcinoma. K-ras point mutations were examined by two-step polymerase chain reaction combined with restriction enzyme digestion in pancreatic juice collected during endoscopic retrograde pancreatography. Ten patients (27.8%) were positive for K-ras mutation. Patients with and without the mutation were not different with respect to age and sex ratio. K-ras mutations were homogeneously distributed according to the etiology (alcoholic vs nonalcoholic) and morphological characteristics (ductal stricture or mass vs none) of CP. A pancreatic carcinoma was discovered at an invasive stage in two patients, respectively at 7 and 17 months after disclosure of a K-ras mutation, versus none in patients without the mutation (p < 0.02). Presence of a K-ras gene mutation is not rare in patients with CP and represents an increased risk of developing pancreatic cancer. However, its utility for the detection of early pancreatic cancer remains doubtful in clinical practice.


Simple system to record jaw movements by a home digital camcorder.
Systems of recording jaw movements that are used in prosthodontics and orthodontics are too expensive and complicated for daily clinical diagnosis. This pilot study presents the development of a simple system using a camcorder and motion-capturing software. Markers to detect jaw movement were attached to the mandibular incisors of a subject. A mirror was assembled beside the subject's face to detect anteroposterior movement. Jaw movements were recorded by a home digital camcorder. Movements of the markers were analyzed by motion-capturing software and transferred to 3-D data. The results were compared with those of a conventional system. To examine the accuracy of the measurements, the markers were placed on a computer-controlled x-y working stage and displaced. The positions of the markers were measured and analyzed, then compared with the true values indicated by the x-y working stage. The trajectories of the mandibular incisors recorded by the new system were very similar to those of the conventional system. On measurement accuracy, the mean differences between the measured and true values of the vertical and transverse movements were 0.07 mm (SD 0.03) and 0.06 mm (SD 0.04), respectively. On anteroposterior movement, the difference was 0.11 mm (SD 0.05). This new system can be useful for simple recording of jaw movements with satisfactory accuracy.


Ferritin Nanocarrier Traverses the Blood Brain Barrier and Kills Glioma.
Over the last decades, considerable efforts have been put into developing active nanocarrier systems that cross the blood brain barrier (BBB) to treat brain-related diseases such as glioma tumors. However, to date none have been approved for clinical usage. Here, we show that a human H-ferritin (HFn) nanocarrier both successfully crosses the BBB and kills glioma tumor cells. Its principle point of entry is the HFn receptor (transferrin receptor 1), which is overexpressed in both BBB endothelial cells (ECs) and glioma cells. Importantly, we found that HFn enters and exits the BBB via the endosome compartment. In contrast, upon specifically targeting and entering glioma cells, nearly all of the HFn accumulated in the lysosomal compartment, resulting in the killing of glioma tumor cells, with no HFn accumulation in the surrounding healthy brain tissue. Thus, HFn is an ideal nanocarrier for glioma therapy and possesses the potential to serve as a therapeutic approach against a broad range of central nervous system diseases.


Enhanced Brief Motivational Intervention for College Student Drinkers With ADHD: Goal-Directed Activation as a Mechanism of Change.
College students with attention-deficit/hyperactivity disorder (ADHD) are at risk for alcohol-related problems and disorders relative to their typically developing peers. Despite risk, the optimal therapeutic approach for reducing problem alcohol use in students with ADHD, and mechanisms of change underlying treatment effects in this population, are largely unknown. The current study evaluated putative mechanisms of change in a randomized controlled trial of two harm reduction interventions for college student drinkers with ADHD (N = 113; 49% male): brief motivational intervention plus supportive counseling (BMI + SC) versus brief motivational intervention plus behavioral activation (BMI + BA). Results showed that participants in the BMI + BA condition engaged in more goal-directed activation and less avoidant behavior over the course of treatment compared to those in the BMI + SC condition, in turn predicting reductions in alcohol-related negative consequences. Effects were more robust 1 month following intervention, and diminished by 3 months. Sensitivity analyses revealed a significant indirect effect of treatment condition on alcohol-related negative consequence via reductions in avoidance over treatment. Post hoc moderated mediations showed that BMI + BA engaged target mechanisms more robustly for students with more severe ADHD and depressive symptoms compared to BMI + SC. These findings support the application of BMI + BA intervention, particularly in targeting goal-directed activation and avoidance/rumination in at-risk student drinkers with ADHD.


Infección de Amor (Infectious Love): Development and Acceptability of a Telenovela/Soap Opera Intervention for HIV Prevention For Latinas.
Latinas continue to be disproportionately affected by HIV in the United States. Effective interventions to address HIV-related disparities among Latinas are available; however, they have not achieved widespread dissemination due to implementation challenges for real-world settings. A culturally tailored intervention that increases access to HIV prevention is urgently needed. The objective of this study was to develop a culturally tailored telenovela (i.e., a soap opera) to promote HIV prevention behaviors (condom use; HIV testing; and pre-exposure prophylaxis awareness, access, and use) among Latinas. The study was conducted in community organizations throughout South Florida. A total of 44 Spanish-speaking Latinas, 18-35 years old, and sexually active with a man in the past 6 months participated in the study. The final product was an HIV prevention telenovela that incorporated Latinas' ideas and feedback and was produced as four 10-minute filmed episodes. This study aimed to develop innovative approaches to reduce HIV-related disparities for Latinas.


Estimating Risk: Stereotype Amplification and the Perceived Risk of Criminal Victimization.
This paper considers the process by which individuals estimate the risk of adverse events, with particular attention to the social context in which risk estimates are formed. We compare subjective probability estimates of crime victimization to actual victimization experiences among respondents from the 1994 to 2002 waves of the Survey of Economic Expectations (Dominitz and Manski 2002). Using zip code identifiers, we then match these survey data to local area characteristics from the census. The results show that: (1) the risk of criminal victimization is significantly overestimated relative to actual rates of victimization or other negative events; (2) neighborhood racial composition is strongly associated with perceived risk of victimization, whereas actual victimization risk is driven by nonracial neighborhood characteristics; and (3) white respondents appear more strongly affected by racial composition than nonwhites in forming their estimates of risk. We argue these results support a model of stereotype amplification in the formation of risk estimates. Implications for persistent racial inequality are considered.


Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer.
The role of PD-L1 as a prognostic and predictive biomarker is an area of great interest. However, there is a lack of consensus on how to deliver PD-L1 as a clinical biomarker. At the heart of this conundrum is the subjective scoring of PD-L1 IHC in most studies to date. Current standard scoring systems involve separation of epithelial and inflammatory cells and find clinical significance in different percentages of expression, e.g., above or below 1%. Clearly, an objective, reproducible and accurate approach to PD-L1 scoring would bring a degree of necessary consistency to this landscape. Using a systematic comparison of technologies and the application of QuPath, a digital pathology platform, we show that high PD-L1 expression is associated with improved clinical outcome in Triple Negative breast cancer in the context of standard of care (SoC) chemotherapy, consistent with previous findings. In addition, we demonstrate for the first time that high PD-L1 expression is also associated with better outcome in ER- disease as a whole including HER2+ breast cancer. We demonstrate the influence of antibody choice on quantification and clinical impact with the Ventana antibody (SP142) providing the most robust assay in our hands. Through sampling different regions of the tumour, we show that tumour rich regions display the greatest range of PD-L1 expression and this has the most clinical significance compared to stroma and lymphoid rich areas. Furthermore, we observe that both inflammatory and epithelial PD-L1 expression are associated with improved survival in the context of chemotherapy. Moreover, as seen with PD-L1 inhibitor studies, a low threshold of PD-L1 expression stratifies patient outcome. This emphasises the importance of using digital pathology and precise biomarker quantitation to achieve accurate and reproducible scores that can discriminate low PD-L1 expression.


Tumor necrosis factor-α inhibitors and chronic hepatitis C: a comprehensive literature review.
Tumor necrosis factor-α (TNF-α) inhibitors are known to increase reactivation of concurrent chronic hepatitis B, but their impact on the hepatitis C virus (HCV) is controversial. Some conditions of immunosuppression, such as liver transplantation, typically cause an increase in the rate of HCV evolution. Inhibition of TNF-α, a cytokine involved in the apoptotic signaling pathway of hepatocytes infected by HCV, could potentially increase viral replication. Currently available clinical data appear to contradict this hypothesis. A review of medical literature revealed that a total of 216 patients with HCV were exposed to one or more treatments with TNF-α inhibitors, with a median observation time of 1.2 years and 260 cumulative patient-years of exposure. Only three cases of drug withdrawal due to suspected HCV liver disease recrudescence were reported. Treatment with TNF-α inhibitors in patients with HCV infection appears to be safe in the short term, but there are insufficient data to assess their long-term safety. Universal screening for HCV before beginning treatment with TNF-α inhibitors is currently controversial. The presence of HCV is not a contraindication to therapy with TNF-α inhibitors, with the exception of cirrhotic patients. In cases of cirrhosis, the benefit/risk ratio should be evaluated at the individual level. Prior to treatment with TNF-α inhibitors, patients with HCV should be referred to a hepatologist to determine the necessity of hepatic disease assessment, using liver biopsy or non-invasive methods, and the potential indication for antiviral therapy. In patients with HCV infection who are treated with TNF-α inhibitors, liver function monitoring every three months is advised.


[Effect of a water-pipe network on the sensory quality of drinking water].
Object of studies was aimed at determining the effect of a water-pipe system on the sensory quality of drinking water originating from various intakes. The aim was to be achieved through analyses of the sensory quality (odor and flavor) of drinking water originating from various reception points within the water-pipe system. Based on the analyses carried out in the research, it may be stated that, transport of water through the water-pipe system in Olsztyn in the winter season does not affect deterioration of odor or flavor of water supplied to consumers. Besides worse sensory quality of drinking water at consumers' reception points may be determined by its worse quality immediately after treatment. As a result of water transport through a water-pipe network, it is possible to reduce the intensity of some odor and flavor attributes to an undetectable level.


Co-existence of different host-adapted forms of the Myzus persicae group (Hemiptera: Aphididae) in southern Italy.
Multivariate morphometric analysis (method of canonical variates) was used to compare 38 parthenogenetic lineages and three field collections of aphids of the Myzus persicae (Sulzer) group sampled on peach and tobacco in the Caserta region of southern Italy. Comparisons were also made with the morphology of lineages collected on peach in Lehonia, in central eastern Greece away from tobacco-growing regions, and on tobacco in Naphplion, in southern Greece. The lineages were measured after parthenogenetic rearing for one to three generations on the same host (potato) under constant conditions. As in previous work, the multivariate morphometric approach separated the aphids from peach from those feeding on tobacco. The life cycle category of the lineages was also examined. Almost all the lineages from peach in Caserta were holocyclic, yet the lineages from tobacco in the same region were unable to produce sexual morphs. The results suggest that tobacco-adapted and non-tobacco-adapted forms co-exist in the same region in southern Italy, not only because they colonize different host plants, but also because they have different life cycles. This is in complete contrast to the situation in peach-growing areas of northern Greece, and shows that the ecology and population structure of M. persicae is different in neighbouring counties of the Mediterranean area, even where climatic conditions and cultivated crops are similar.


Increased intraindividual reaction time variability in persons with neuropsychiatric manifestations of systemic lupus erythematosus.
Systemic Lupus Erythematosus (SLE) can affect multiple organ systems, including the central (CNS) and/or peripheral nervous system. Individuals with nervous system involvement (termed Neuropsychiatric SLE or NPSLE) can present with nonspecific symptoms such as cognitive dysfunction. It is difficult to ascertain whether this is a direct consequence of lupus disease activity on the brain. Intraindividual variability, measured through trial-to-trial reaction time variation, has been proposed as a behavioral marker of CNS integrity. We compared 14 NPSLE, 20 non-NPSLE, and 27 age-matched healthy participants using multiple variability metrics. Variability was increased in NPSLE compared with non-NPSLE participants, and was increased throughout the distribution rather than there being a selective increase in extreme reaction times. Variability metrics were strongly intercorrelated providing convergent evidence that the different metrics are tapping similar processes. The results suggest that there is ongoing disruption to cognitive processing in NPSLE and may indicate small fluctuations in attention.


Evaluating Retinal and Choroidal Perfusion Changes After Ocular Massage of Healthy Eyes Using Optical Coherence Tomography Angiography.
Background and objectives: Ocular massage (OM) is used as a treatment option for acute retinal artery occlusion, under the assumption that it induces vessel dilatation and enhances perfusion. Since evidence of ocular perfusion alteration due to OM is lacking, we investigate the impact of OM on the hemodynamics of the posterior pole in healthy eyes in a noninvasive fashion by using optical coherence tomography angiography (OCTA). Materials and Methods: A prospective study was conducted on healthy volunteers, each of whom underwent measurements of intraocular pressure (IOP), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), radial peripapillary capillary perfusion (RPCP), superficial capillary plexus perfusion (SCPP), deep capillary plexus perfusion (DCPP), choriocapillaris perfusion (CCP), Sattler's layer perfusion (SLP) and Haller's layer perfusion (HLP) before and after OM. OM was performed for 2 min, consisting of 10-s turns of compression and decompression of the globe. Results: A total of 21 eyes from 21 participants (median age 29) were included. After OM, IOP significantly declined (p < 0.001), while SFCT (p < 0.005), SCPP (p < 0.001), DCPP (p = 0.004) and CCP (p = 0.008) significantly increased. CMT, RPCP, SLP and HLP did not show any significant alteration due to OM. Changes in SCPP correlated positively with changes in CCP and vice versa. Conclusions: OCTA-based analysis in healthy adults following OM demonstrated a significant increase of retinal perfusion values, assumed to be due to failure of autoregulatory mechanisms. These findings may indicate a positive effect of OM as a treatment option for patients with acute retinal artery occlusion.


Polylactide-graft-doxorubicin nanoparticles with precisely controlled drug loading for pH-triggered drug delivery.
Nanoparticles (NPs) with high drug loading and pH-responsivity were prepared by nanoprecipitation of a hydrophobic polymer-drug conjugate (PDC). The PDC, polylactide-graft-doxorubicin (PLA-g-DOX), was synthesized by azide-alkyne click reaction to transform acetylene-functionalized PLA into PLA-graft-aldehyde (PLA-g-ALD), followed by DOX conjugation to form acid-sensitive Schiff base linkage between drug moieties and polymer scaffold. The DOX loading amount in PLA-g-DOX PDC was determined to be 32 wt % by (1)H NMR and UV-vis spectroscopies. PLA-g-DOX PDC was further used to prepare NPs with precisely controlled drug loading by nanoprecipitation in the presence of a PEGylated surfactant. The effects of organic solvent, PLA-g-DOX PDC concentration and PLA-g-DOX/surfactant mass ratio on size and size distribution of NPs were systematically examined based on analysis by dynamic light scattering (DLS) and transmission electron microscopy (TEM). NPs prepared under the optimal conditions exhibited well-defined spherical morphology with volume-average hydrodynamic diameter (Dh) around 100 nm. Due to the Schiff base conjugation linkage in PLA-g-DOX PDC, acid-sensitive drug release behavior of the NPs was observed. In vitro studies against MCF-7 breast cancer cells showed that the NPs can be readily taken up and result in enhanced therapeutic efficiency as compared to DOX·HCl, indicating their promising potential applications as anticancer nanomedicines.


Quality of life and outcomes after nonintubated versus intubated video-thoracoscopic pleurodesis for malignant pleural effusion: comparison by a case-matched study.
Malignant pleural effusion can be treated successfully by video-assisted thoracic surgery (VATS) talc pleurodesis. This procedure can also be performed using local anesthesia on nonintubated patients. To evaluate quality of life and major outcomes after VATS talc pleurodesis performed under local anesthesia in nonintubated patients with malignant pleural effusion. Retrospective, nonrandomized case-matched comparison (nonintubated versus intubated) pairing the patients by computer according to their clinical features. Since 2002, 231 consecutive patients underwent uniport VATS talc pleurodesis under local anesthesia (nonintubated group). These patients were case matched with 231 homogeneous subjects, selected from a larger group that preferred general anesthesia (intubated group) in the same period. Quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 core questionnaire) and other major outcomes were considered. Pleurodesis was successful in 198 (85.7%) nonintubated and 193 (83.5%) intubated patients, but the former group showed shorter total operating room time (65.8±7.5 versus 84.9±13.3 minutes, p<0.0001), duration of postoperative pleural fluid leakage (2.5±1.0 versus 4.0±1.5 days, p=0.014), postoperative hospital stay (3.1±2.5 versus 4.9±2.8 days, p=0.011), as well as lower perioperative mortality (0% versus 2.3%, p=0.017), morbidity (5.2% versus 9.0%, p=0.042), and costs (6,090±517 versus 9,660±713€, p=0.015). Quality of life presented a similar evolution between groups, however, the early postoperative improvement in physical function (p<0.05), global health (p<0.05), and dyspnea (p<0.01) was significantly greater in nonintubated patients. Significant improvements in respiratory exchanges, postoperative acute stress markers, and mental confusion were also documented. Effusion-free (p=0.35) and overall (p=0.52) survival was similar between groups. Nonintubated VATS talc pleurodesis can achieve similar results in pleural effusion to the same operation performed under general anesthesia but with earlier improvement of some quality-of-life domains as well as better mortality, morbidity, hospital stay, and costs.


Characterization of Bacterial Community Dynamics during the Decomposition of Pig Carcasses in Simulated Soil Burial and Composting Systems.
Soil burial is the most widely used disposal method for infected pig carcasses, but composting has gained attention as an alternative disposal method because pig carcasses can be decomposed rapidly and safely by composting. To understand the pig carcass decomposition process in soil burial and by composting, pilot-scale test systems that simulated soil burial and composting were designed and constructed in the field. The envelope material samples were collected using special sampling devices without disturbance, and bacterial community dynamics were analyzed by high-throughput pyrosequencing for 340 days. Based on the odor gas intensity profiles, it was estimated that the active and advanced decay stages were reached earlier by composting than by soil burial. The dominant bacterial communities in the soil were aerobic and/or facultatively anaerobic gram-negative bacteria such as Pseudomonas, Gelidibacter, Mucilaginibacter, and Brevundimonas. However, the dominant bacteria in the composting system were anaerobic, thermophilic, endospore-forming, and/or halophilic gram-positive bacteria such as Pelotomaculum, Lentibacillus, Clostridium, and Caldicoprobacter. Different dominant bacteria played important roles in the decomposition of pig carcasses in the soil and compost. This study provides useful comparative date for the degradation of pig carcasses in the soil burial and composting systems.


Crystallizing membrane proteins for structure-function studies using lipidic mesophases.
The lipidic cubic phase method for crystallizing membrane proteins has posted some high-profile successes recently. This is especially true in the area of G-protein-coupled receptors, with six new crystallographic structures emerging in the last 3½ years. Slowly, it is becoming an accepted method with a proven record and convincing generality. However, it is not a method that is used in every membrane structural biology laboratory and that is unfortunate. The reluctance in adopting it is attributable, in part, to the anticipated difficulties associated with handling the sticky viscous cubic mesophase in which crystals grow. Harvesting and collecting diffraction data with the mesophase-grown crystals is also viewed with some trepidation. It is acknowledged that there are challenges associated with the method. However, over the years, we have worked to make the method user-friendly. To this end, tools for handling the mesophase in the pico- to nano-litre volume range have been developed for efficient crystallization screening in manual and robotic modes. Glass crystallization plates have been built that provide unparalleled optical quality and sensitivity to nascent crystals. Lipid and precipitant screens have been implemented for a more rational approach to crystallogenesis, such that the method can now be applied to a wide variety of membrane protein types and sizes. In the present article, these assorted advances are outlined, along with a summary of the membrane proteins that have yielded to the method. The challenges that must be overcome to develop the method further are described.


Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.
Environmental factors including ionizing radiation and chemical agents have been known to be able to induce DNA rearrangements and cause genomic structural variations (SVs); however, the roles of intrinsic characteristics of the human genome, such as regional genome architecture, in SV formation and the potential mechanisms underlying genomic instability remain to be further elucidated. Recently, locus-specific observations showed that 'self-chain' (SC), a group of short low-copy repeats (LCRs) in the human genome, can induce autism-associated SV mutations of the MECP2 and NRXN1 genes. In this study, we conducted a genome-wide analysis to investigate SCs and their potential roles in genomic SV formation. Utilizing a vast amount of human SV data, we observed a significant biased distribution of human germline SV breakpoints to SC regions. Notably, the breakpoint distribution pattern is different between SV types across deletion, duplication, inversion and insertion. Our observations were coincident with a mechanism of SC-induced DNA replicative errors, whereas SC may sporadically be used as substrates of nonallelic homologous recombination (NAHR). This contention was further supported by our consistent findings in somatic SV mutations of cancer genomes, suggesting a general mechanism of SC-induced genome instability in human germ and somatic cells.


Impact of Bariatric Surgery on ABC Subtilisin/Kexin Type 9 (PCSK9) Gene Expression and Inflammation in the Adipose Tissue of Obese Diabetic Rats.
Bariatric surgery improves dyslipidaemia and reduces body weight, but it remains unclear how bariatric surgery modulates gene expression in fat cells to influence the proprotein convertase subtilisin/kexin type 9 (PCSK-9) and low-density lipoprotein receptor (LDLR) gene expression. The expression of the PCSK9/LDLR/tumor necrosis factor-alpha (TNFα) gene in adipose tissue was measured in two groups of Zucker Diabetic Sprague Dawley (ZDSD) rats after Roux-en-Y gastric bypass (RYGB) surgery or 'SHAM' operation. There was lower PCSK9 (p = 0.02) and higher LDLR gene expression (p = 0.02) in adipose tissue in rats after RYGB. Weight change did not correlate with PCSK9 gene expression (r = -0.5, p = 0.08) or TNFα gene expression (r = -0.4, p = 0.1). TNFα gene expression was positively correlated with PCSK9 gene expression (r = 0.7, p = 0.001) but not correlated with LDLR expression (r = -0.3, p = 0.3). Circulating triglyceride levels were lower in RYGB compared to the SHAM group (1.1 (0.8-1.4) vs. 1.5 (1.0-4.2), p = 0.038) mmol/L with no difference in cholesterol levels. LDLR gene expression was increased post-bariatric surgery with the potential to reduce the number of circulating LDL particles. PCSK9 gene expression and TNFα gene expression were positively correlated after RYGB in ZDSD rats, suggesting that the modulation of pro-inflammatory pathways in adipose tissue after RYGB may partly relate to PCSK9 and LDLR gene expression.


Phylogeography of the Rhabditis (Pellioditis) marina species complex: evidence for long-distance dispersal, and for range expansions and restricted gene flow in the northeast Atlantic.
Pinpointing processes that structure the geographical distribution of genetic diversity of marine species and lead to speciation is challenging because of the lack of obvious dispersal barriers and the likelihood of substantial (passive) dispersal in oceans. In addition, cryptic radiations with sympatric distributions abound in marine species, challenging the allopatric speciation mechanism. Here, we present a phylogeographical study of the marine nematode species complex Rhabditis (Pellioditis) marina to investigate processes shaping genetic structure and speciation. Rhabditis (P.) marina lives on decaying macroalgae in the intertidal, and may therefore disperse over considerable distances. Rhabditis (P.) marina consists of several cryptic species sympatrically distributed at a local scale. Genetic variation in the COI gene was screened in 1362 specimens from 45 locations around the world. Two nuclear DNA genes (ITS and D2D3) were sequenced to infer phylogenetic species. We found evidence for ten sympatrically distributed cryptic species, seven of which show a strong genetic structuring. A historical signature showed evidence for restricted gene flow with occasional long-distance dispersal and range expansions pre-dating the last glacial maximum. Our data also point to a genetic break around the British Isles and a contact zone in the Southern Bight of the North Sea. We provide evidence for the transoceanic distribution of at least one cryptic species (PmIII) and discuss the dispersal capacity of marine nematodes. The allopatric distribution of some intraspecific phylogroups and of closely related cryptic species points to the potential for allopatric speciation in R. (P.) marina.


Bovine Leukemia Virus Infection in Dairy Cattle: Effect on Serological Response to Immunization against J5 Escherichia coli Bacterin.
Thirteen bovine leukemia virus- (BLV-) negative and 22 BLV-positive Holstein cows were immunized with J5 Escherichia coli bacterin at dry off, three weeks before calving, during the second week after calving, and three weeks after the third immunization. Serum was collected before the initial immunization, immediately before the third and fourth immunizations, and 21 days after the fourth immunization. Anti-J5 E. coli IgM, IgG1, and IgG2 titers were determined by ELISA. Anti-J5 E. coli IgM titers did not differ significantly (P = .98) between groups. Increases in anti-J5 E. coli IgG1 titers were higher in the BLV-negative cows (P = .057). Geometric mean anti-J5 E. coli IgG2 titers increased fourfold in the BLV-negative cows, which was significantly higher (P = .007) than the twofold increase in the BLV-positive cows. Cattle infected with BLV may have impaired serologic responses following immunization with J5 bacterin, and response may differ according to antibody isotype.


Delivery of oligonucleotides into mammalian cells by anionic peptides: comparison between monomeric and dimeric peptides.
The use of antisense oligonucleotides as putative therapeutic agents is limited by their poor delivery into the cytosol and/or the nucleus because they are not able to efficiently cross lipid bilayers. To circumvent this pitfall, anionic amphipathic peptides derived from the influenza virus fusogenic peptide have been used to destabilize membranes in an acidic environment. In this paper, we compare the ability of a monomeric and a dimeric peptide to introduce oligonucleotides into the cytosol and nuclei of several types of cultured cells. Cells incubated at pH 6.2 or at a slightly lower pH in the presence of the monomeric peptide but not the dimeric peptide were efficiently permeabilized. The location of fluorescent derivatives of peptides and of oligonucleotides was assessed by confocal microscopy. Both the peptides and oligonucleotides remained entrapped in vesicular compartments at neutral pH; at acidic pH, oligonucleotides in the presence of the monomeric peptide were mainly in the nucleus, while in the presence of the dimeric peptide they co-localized with the peptide into vesicles. The data are interpreted on the basis of the spectroscopic behaviour of monomeric and dimeric peptides in relation to the environmental pH.


Differential activity of candidate microbicides against early steps of HIV-1 infection upon complement virus opsonization.
HIV-1 in genital secretions may be opsonized by several molecules including complement components. Opsonized HIV-1 by complement enhances the infection of various mucosal target cells, such as dendritic cells (DC) and epithelial cells. We herein evaluated the effect of HIV-1 complement opsonization on microbicide candidates' activity, by using three in vitro mucosal models: CCR5-tropic HIV-1JR-CSF transcytosis through epithelial cells, HIV-1JR-CSF attachment on immature monocyte-derived dendritic cells (iMDDC), and infectivity of iMDDC by CCR5-tropic HIV-1BaL and CXCR4-tropic HIV-1NDK. A panel of 10 microbicide candidates [T20, CADA, lectines HHA & GNA, PVAS, human lactoferrin, and monoclonal antibodies IgG1B12, 12G5, 2G12 and 2F5], were investigated using cell-free unopsonized or opsonized HIV-1 by complements. Only HHA and PVAS were able to inhibit HIV trancytosis. Upon opsonization, transcytosis was affected only by HHA, HIV-1 adsorption on iMDDC by four molecules (lactoferrin, IgG1B12, IgG2G5, IgG2G12), and replication in iMDDC of HIV-1BaL by five molecules (lactoferrin, CADA, T20, IgG1B12, IgG2F5) and of HIV-1NDK by two molecules (lactoferrin, IgG12G5). These observations demonstrate that HIV-1 opsonization by complements may modulate in vitro the efficiency of candidate microbicides to inhibit HIV-1 infection of mucosal target cells, as well as its crossing through mucosa.


Mild dehydration affects mood in healthy young women.
Limited information is available regarding the effects of mild dehydration on cognitive function. Therefore, mild dehydration was produced by intermittent moderate exercise without hyperthermia and its effects on cognitive function of women were investigated. Twenty-five females (age 23.0 ± 0.6 y) participated in three 8-h, placebo-controlled experiments involving a different hydration state each day: exercise-induced dehydration with no diuretic (DN), exercise-induced dehydration plus diuretic (DD; furosemide, 40 mg), and euhydration (EU). Cognitive performance, mood, and symptoms of dehydration were assessed during each experiment, 3 times at rest and during each of 3 exercise sessions. The DN and DD trials in which a volunteer attained a ≥1% level of dehydration were pooled and compared to that volunteer's equivalent EU trials. Mean dehydration achieved during these DN and DD trials was -1.36 ± 0.16% of body mass. Significant adverse effects of dehydration were present at rest and during exercise for vigor-activity, fatigue-inertia, and total mood disturbance scores of the Profile of Mood States and for task difficulty, concentration, and headache as assessed by questionnaire. Most aspects of cognitive performance were not affected by dehydration. Serum osmolality, a marker of hydration, was greater in the mean of the dehydrated trials in which a ≥1% level of dehydration was achieved (P = 0.006) compared to EU. In conclusion, degraded mood, increased perception of task difficulty, lower concentration, and headache symptoms resulted from 1.36% dehydration in females. Increased emphasis on optimal hydration is warranted, especially during and after moderate exercise.


A fully automated hybrid human sperm detection and classification system based on mobile-net and the performance comparison with conventional methods.
Sperm morphology, as an indicator of fertility, is a critical tool in semen analysis. In this study, a smartphone-based hybrid system that fully automates the sperm morphological analysis is introduced with the aim of eliminating unwanted human factors. Proposed hybrid system consists of two progressive steps: automatic segmentation of possible sperm shapes and classification of normal/ab-normal sperms. In the segmentation step, clustering techniques with/without group sparsity approach were tested to extract region of interests from the images. Subsequently, a novel publicly available morphological sperm image data set, whose labels were identified by experts as non-sperm, normal and abnormal sperm, was created as the ground truths of classification step. In the classification step, conventional and ensemble machine learning methods were applied to domain-specific features that were extracted by using wavelet transform and descriptors. Additionally, as an alternative to conventional features, three deep neural network architectures, which can extract high-level features from raw images after using statistical learning, were employed to increase the proposed method's performance. The results show that, for the conventional features, the highest classification accuracies were achieved as 80.5% and 83.8% by using the wavelet- and descriptor-based features that were fed to the Support Vector Machines respectively. On the other hand, the Mobile-Net, which is a very convenient network for smartphones, achieved 87% accuracy. In the light of obtained results, it is seen that a fully automatic hybrid system, which uses the group sparsity to enhance segmentation performance and the Mobile-Net to obtain high-level robust features, can be an effective mobile solution for the sperm morphology analysis problem. A fully automated hybrid human sperm detection and classification system based on mobile-net.


Osteoarthritis: what to look for, and when to treat it. Interview by Peter Pompei.
In patients with suspected osteoarthritis, start with a thorough history aimed at finding the mechanical component of the condition. Ask about past and current activities that may be loading or stressing a painful joint. Conditions to consider in the differential diagnosis are those affecting soft tissues-muscles, tendons, ligaments, and bursae. Injecting the tender are with lidocaine will help identify a separate or coexisting soft tissue disorder. Before considering drug therapy, attempt to correct any mechanical factors that may be contributing to the problem. Modify the patient's exercise routine, if necessary, and begin patients on a walking aid if a weight-bearing joint is affected.


Development of a xenograft glioma model in mouse brain.
Xenograft intracerebral glioma models have been developed in normal mice by growing the rat C6 glioma in either adult or neonatal mouse brains. Using this tumor line it was possible to grow discrete intracerebral gliomas in either CBA or AKR adult mice or neonatal mice. The size of the tumor mass and length of survival was directly related to the number of tumor cells injected and the time after implantation. To obtain localized intracranial tumor growth cells were suspended in a 1% agarose solution before implantation. Following injection of 10(6) cells into the frontal lobe of adult CBA or AKR mice, discrete tumor masses greater than 4 mm in diameter were obtained in 90% of animals at 14 days, and the largest tumors in adult mice occurred between 21 and 28 days after implantation. The tumor size following implantation of 10(6) cells was significantly greater than with 10(5) cells at 7 days (P less than 0.05) and at 14 and 21 days (P less than 0.01). Less than 60% of mice of BALB/c, RIII, or C57 black strains developed tumors greater than 4 mm diameter at 14 days after intracerebral injection of 10(6) C6 cells. Using neonatal mice it was found that when 10(5) cells were injected intracranially tumors greater than 4 mm in diameter developed in 14 of 15 animals within 2 weeks (CBA mice). Similar results were seen in the RIII, AKR, C57 black, and BALB/c strains. Longer growth periods resulted in larger tumors, up to 8 mm in diameter (6 of 10 animals at 20 days). The tumors in the neonatal animals were not as discrete as in the adult mice, and tumor often spread to the meninges and into the lateral ventricles. The tumor harvested from the brain had a cloning efficiency of 1.2 +/- 0.4% (SD). A panel of monoclonal antibodies was raised to the C6 glioma, and this was used to define clearly the margins of the tumor within the brain. The xenograft mouse models should prove useful for the study of the therapy of gliomas.


Puerperal breast feeding does not stimulate circulating opioids in humans.
ACTH, beta lipotropin (beta LPH), beta endorphin (beta EP), Prolactin (PRL) and Cortisol were measured in the first five days of puerperium at 9:00, before and 30 minutes after suckling, in 7 healthy lactating women. With the exception of PRL plasma levels which decline, although remaining at high concentrations during the observation period, all the other parameters showed a sudden fall from the high levels found at delivery, reaching stable normal levels (beta LPH, beta EP, Cortisol) or concentrations which were 50% lower than normal (ACTH), from the second day of puerperium. Suckling confirms its capacity to release plasma PRL, while all the other indices remain unmodified. Despite the experimental evidence that serotoninergic neurons are involved both in the PRL response to suckling and the circadian rhythmicity and stress response of proopiocortin-related peptides, the present results suggest that breast feeding is not a stressful situation, as no typical proopiocortin-related peptide response is evident, and that the activation of PRL release is related to stimulation of serotoninergic neurons which differ from those involved in the control of proopiocortin-related peptide secretion.


Suppression of cytomegalovirus retinitis in persons with AIDS with high-dose intravenous acyclovir.
To evaluate the efficacy and safety of high-dose intravenous acyclovir combined with oral zidovudine as suppressive therapy for cytomegalovirus retinitis in patients with AIDS, a single-arm, outpatient, open-label, phase II pilot study was performed. Between July 1989 and July 1990, 12 men with AIDS, cytomegalovirus retinitis, and salvageable vision received intravenous acyclovir, 10 mg/kg of body weight every 8 h, and oral zidovudine after successful induction therapy with intravenous ganciclovir, 5 mg/kg every 12 h for 14 days. Patients were evaluated weekly. Ten of 12 patients were followed to the time of retinitis progression; two were withdrawn from the study because of concomitant life-threatening infection. The median duration of acyclovir and zidovudine therapy before retinitis progression occurred was 32 days. None of the eight uninvolved eyes in the 10 evaluatable patients developed cytomegalovirus retinitis during study participation. These data suggest that high-dose intravenous acyclovir with zidovudine provides some benefit in suppressing cytomegalovirus retinitis.


Methanococcus jannaschii coenzyme F420 analogs contain a terminal alpha-linked glutamate.
Analyses of the F(420)s present in Methanococcus jannaschii have shown that these cells contain a series of gamma-glutamyl-linked F(420)s capped with a single, terminal alpha-linked L-glutamate. The predominant form of F(420) was designated as alpha-F(420)-3 and represented 86% of the F(420)s in these cells. Analyses of Methanosarcina thermophila, Methanosarcina barkeri, Methanobacterium thermoautotrophicum, Archaeoglobus fulgidus, and Mycobacterium smegmatis showed that they contained only gamma-glutamyl-linked F(420)s.


Cross-SEAN: A cross-stitch semi-supervised neural attention model for COVID-19 fake news detection.
As the COVID-19 pandemic sweeps across the world, it has been accompanied by a tsunami of fake news and misinformation on social media. At the time when reliable information is vital for public health and safety, COVID-19 related fake news has been spreading even faster than the facts. During times such as the COVID-19 pandemic, fake news can not only cause intellectual confusion but can also place people's lives at risk. This calls for an immediate need to contain the spread of such misinformation on social media. We introduce CTF, a large-scale COVID-19 Twitter dataset with labelled genuine and fake tweets. Additionally, we propose Cross-SEAN, a cross-stitch based semi-supervised end-to-end neural attention model which leverages the large amount of unlabelled data. Cross-SEAN partially generalises to emerging fake news as it learns from relevant external knowledge. We compare Cross-SEAN with seven state-of-the-art fake news detection methods. We observe that it achieves 0.95 F1 Score on CTF, outperforming the best baseline by 9%. We also develop Chrome-SEAN, a Cross-SEAN based chrome extension for real-time detection of fake tweets.


Interleukin-6 (IL-6) as a Predictor of Clinical Outcomes in Patients with COVID-19.
Interleukin-6 (IL-6) has been known to be involved in immune regulation, inflammatory response, and metabolism. It is also recognized as the major cause to underscore the pathology of severe COVID-19 patients. However, it remains to be seen if IL-6 is superior to other inflammatory biomarkers in ascertaining clinical severity and mortality rate for COVID-19. This study aimed to determine the value of IL-6 as a predictor of severity and mortality in COVID-19 patients and compare it with other pro-inflammatory biomarkers in the South Asian region. An observational study was conducted, including all adult SARS-CoV-2 patients who had undergone IL-6 testing from December 2020 to June 2021. The patients' medical records were reviewed to collect demographic, clinical, and biochemical data. Other pro-inflammatory biomarkers apart from IL-6 included Neutrophils to Lymphocyte Ratio (NLR), D-dimer, C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and procal-citonin for analysis. SPSS version 22.0 was utilized. Out of the 393 patients who underwent IL-6 testing, 203 were included in the final analysis with a mean (SD) age of 61.9 years (12.9) and 70.9% (n = 144) were male. Fifty-six percent (n = 115) subjects had critical disease. IL-6 levels were elevated (> 7 pg/mL) in 160 (78.8%) patients. Levels of IL-6 significantly correlated with age, NLR, D-dimer, CRP, ferritin, LDH, length of stay, clinical severity, and mortality. All the inflammatory markers were significantly increased in critically ill and expired patients (p < 0.05). The receiver operator curve showed that IL-6 had the best area under the curve (0.898) compared to other pro-inflammatory biomarkers for mortality with comparable results for clinical severity. Study findings show that though IL-6 is an effective marker of inflammation and can be helpful for clinicians in recognizing patients with severe COVID-19. However, we still need further studies with larger sample size.


Skin conductance activity in post-term pregnancies.
The pain threshold in humans rises during late pregnancy, and the woman becomes less sensitive to stress. The aim of this study was to investigate whether monitoring the sympathetic nervous system response to stimuli by skin conductance activity might be a useful predictor of spontaneous onset of labour in post-term pregnancies. A prospective observational study. Fifty-two healthy pregnant women were consecutively asked for inclusion in the study at their post-term pregnancy examination. Initially, a Ctg (cardiotocography) registration was performed, followed by 5 min of skin conductance measurement including a "cold pressor test". Finally, a vaginal examination with a cervical assessment were performed according to clinical guidelines. A statistically significant lower pain reaction during the period of provocation was seen in deliveries close to spontaneous onset of labour compared with induced deliveries with an non-spontaneous onset of labour before 294 days (p = 0.02). Sixty-three per cent (19/30) of the women with spontaneous onset had a negative value at provocation compared with 30% (6/20) in the induced group. Decreased response to pain stimuli, as an indication of decreased activity in the sympathetic nervous system, has a correlation to spontaneous onset of labour in post-term pregnancies.


Case 294: Catastrophic Antiphospholipid Syndrome.
History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 109/L (normal range, [150-400] × 109/L), a C-reactive protein level of 158 mg/L (normal range, <5 mg/L), and a d-dimer level of 2000 mg/L (normal range, <500 mg/L]). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, <0.3 g/ day), and a high serum troponin level of 1066 ng/L (normal range, <14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4).


Sodium-Glucose Cotransporter Inhibitors in Non- Diabetic Heart Failure: A Narrative Review.
Heart failure (HF) is one of the leading public health problems with a substantial burden in the global healthcare system. Although significant efforts are based on prevention, early recognition, and proper management of HF, the worldwide surge of risk factors like hypertension, diabetes, and obesity has further complicated the existing problem. This study aims to define the role of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-diabetic HF. We performed a comprehensive literature review to examine the available evidence in the clinical implications of SGLT2 inhibitors in non-diabetic HF using the online databases (PubMed and Embase). We identified two RCTs-DAPA-HF and DEFINE-HF, which were conducted to analyze the net clinical benefit of dapagliflozin in non-diabetic HF patients. Although we could not study the composite effects of these studies due to the difference in outcome measures, the individual outcomes look promising. The number needed to treat (NNT) to prevent one primary event was 21 (95% CI: 15 to 38) in the DAPA study. In DEFINE HF study, responder analysis showed a significant proportion of patients in the treatment arm experienced improvements in the functional status with clinically meaningful improvement in KCCQ-OS by 3.7 points and KCCQ-CS by 4.6 points with NNT of 10 and 7, respectively, at 12 weeks. Both studies also showed low safety concerns in patients without T2D. The outcomes of the two RCTs, DAPA-HF and DEFINE-HF, that studied the effects of SGLT2 inhibitors in non-diabetic HF showed promising clinical outcomes. Although we are waiting for other prospective RCTs to reflect similar results and safety profiles, it seems the SGLT2 inhibitors can have broader clinical implications in managing non-diabetic HF with improved cardiovascular outcomes.


Mutants of Mycobacterium smegmatis unable to grow at acidic pH in the presence of the protonophore carbonyl cyanide m-chlorophenylhydrazone.
Mycobacterium smegmatis is able to grow and survive at acidic pH, and exhibits intracellular pH homeostasis under these conditions. In this study, the authors have identified low proton permeability of the cytoplasmic membrane, and high cytoplasmic buffering capacity, as determinants of intrinsic acid resistance of M. smegmatis. To identify genes encoding proteins involved in protecting cells from acid stress, a screening method was developed using the electrogenic protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP). CCCP was used to suppress intrinsic acid resistance of M. smegmatis. The screen involved exposing cells to pH 5.0 in the presence of CCCP, and survivors were rescued at various time intervals on solid medium at pH 7.5. Cells capable of responding to intracellular acidification (due to CCCP-induced proton equilibration) will survive longer under these conditions than acid-sensitive cells. From a total pool of 5000 transposon (Tn611) insertion mutants screened, eight acid-sensitive M. smegmatis mutants were isolated. These acid-sensitive mutants were unable to grow at pH 5.0 in the presence of 1-5 microM CCCP, a concentration not lethal to the wild-type strain mc2155. The DNA flanking the site of Tn611 was identified using marker rescue in Escherichia coli, and DNA sequencing to identify the disrupted locus. Acid-sensitive mutants of M. smegmatis were disrupted in genes involved in phosphonate/phosphite assimilation, methionine biosynthesis, the PPE multigene family, xenobiotic-response regulation and lipid biosynthesis. Several of the acid-sensitive mutants were also defective in stationary-phase survival, suggesting that overlapping stress protection systems exist in M. smegmatis.


Application of transthoracic echocardiography in patients receiving intermediate- or high-risk noncardiac surgery.
Cardiovascular events are the leading cause of perioperative complications among patients undergoing noncardiac surgery. However, the role of echocardiography for preoperative cardiac risk stratification prior to major noncardiac surgery is still controversial. This retrospective study included a total of 1453 patients (51% male; age, 67 ± 16) who underwent intermediate- or high-risk major abdominal surgery or orthopedic surgery at two medical centers in South Taiwan between February 2013 and June 2016. All patients underwent preoperative transthoracic echocardiography (TTE). All of the included patients were followed up for 56 days after surgery. The primary endpoints were major adverse events (MAEs), i.e., all-cause mortality and major adverse cardiovascular-cerebral events (MACCEs). A total of 35 patients (2.4%) reached the primary endpoint: 24 patients (1.6%) died, and 17 patients (1.2%) had MACCEs. Patients with postsurgery MAEs had higher average E/e' values, a lower Left ventricular (LV) ejection fraction, and higher prevalence of significant mitral regurgitation (MR) and moderate-advanced chronic kidney disease (CKD). Multivariate analysis showed that the modified Lee index and significant MR were independent prognostic predictors of MAEs. Preoperative identification of significant MR on TTE is associated with increased MAEs at 56 days compared with that predicted by the modified Lee index alone in patients undergoing intermediate- or high-risk noncardiac surgery.


Purine nucleoside phosphorylase deficiency.
Purine nucleoside phosphorylase (PNP) deficiency is a rare inherited disease accounting for approximately 4% of patients with severe combined immunodeficiency. Thirty-three patients have been reported. PNP-deficient patients suffer from recurrent infections, usually beginning in the first year of life. Two thirds of patients have evidence of neurologic disorders. Findings range from spasticity to developmental delay, to mental retardation. One third of patients develop autoimmune disease. The most common manifestation of this is autoimmune hemolytic anemia. Idiopathic thrombocytopenic purpura and systemic lupus erythematosis have also been reported. Patients usually present with infections but approximately one fourth have come to medical care initially for neurological problems. In PNP deficiency, T- and B-cell immunity are affected. T-cell function may be profoundly deficient, may be normal at birth and then decrease with time, or may fluctuate repeatedly between low and normal. B-cell function can be normal but is deficient in approximately one third of patients. PNP protein is a trimer of approximately 90,000 daltons. It is found in most tissues of the body but is at highest levels in lymphoid tissues. This tissue distribution explains why the lymphoid system is predominantly affected in PNP deficiency. Many mechanisms have been proposed to explain the metabolic toxicity in PNP deficiency. The elevated dGTP found in PNP deficiency is thought to inhibit ribonucleotide reductase and, thus, impede cell division. Depressed GTP levels may correlate with neurologic dysfunction. The gene for PNP has been cloned; it is located on the long arm of chromosome 14. Studies of a mutant PNP gene isolated from one patient showed that a point mutation resulting in an amino acid substitution was responsible for PNP deficiency. PNP deficiency has a grave prognosis. No patient has reached the third decade of life. Twenty-nine of the 33 reported patients have died from their disease. Prenatal diagnosis is currently available. Many different therapies have been utilized for PNP deficiency including bone marrow transplantation, red cell transfusions, and supplementation of the diet with purines and pyrimidines. None of these therapies has been consistently successful. In light of the poor prognosis for PNP deficiency, bone marrow transplantation should be considered for all patients. In the future, improved forms of therapy such as gene therapy may become available.


MGP promotes CD8+ T cell exhaustion by activating the NF-κB pathway leading to liver metastasis of colorectal cancer.
Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-κB) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca2+ levels and promoted NF-κB phosphorylation, thereby activated PD-L1 expression to promote CD8+ T cell exhaustion in CRC. The luciferase reporter assay and ChIP-qPCR assay indicated that the transcriptional regulation of NF-κB upregulated PD-L1 expression. In vivo, MGP inhibition significantly decreased the rate of CRC liver metastasis, which was further reduced after combined therapy with αPD1 (anti-PD1). In conclusions, this study revealed that MGP can facilitate CD8+ T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis of CRC. The combination of MGP knockdown and αPD1 can synergistically resist liver metastasis of CRC.


Lorentzian amplitude and phase pulse shaping for nonresonant background suppression and enhanced spectral resolution in coherent anti-Stokes Raman scattering spectroscopy and microscopy.
Femtosecond coherent anti-Stokes Raman scattering (CARS) spectroscopy offers several advantages over spontaneous Raman spectroscopy due to the inherently high sensitivity and low average power deposition in the sample. Femtosecond CARS can be implemented in a collinear pump/probe beam configuration for microspectroscopy applications and has emerged as a powerful technique for chemical imaging of biological specimens. However, one serious limitation of this approach is the presence of a high nonresonant background component that often obscures the resonant signals of interest. We report here an innovative pulse-shaping method based on Lorentzian amplitude and phase spectral modulation of a broadband femtosecond probe pulse that yields spectra with both high spectral resolution and no nonresonant background. No further mathematical analysis is needed to extract Raman spectra. The utility of the proposed method for CARS microscopy is demonstrated using a mixture of polystyrene and latex beads, as well as dry-fixed embryonic stem cells.


Influenza A-induced cystic fibrosis transmembrane conductance regulator dysfunction increases susceptibility to Streptococcus pneumoniae.
Influenza A virus (IAV) infection is commonly complicated by secondary bacterial infections that lead to increased morbidity and mortality. Our recent work demonstrates that IAV disrupts airway homeostasis, leading to airway pathophysiology resembling cystic fibrosis disease through diminished cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we use human airway organotypic cultures to investigate how IAV alters the airway microenvironment to increase susceptibility to secondary infection with Streptococcus pneumoniae (Spn). We observed that IAV-induced CFTR dysfunction and airway surface liquid acidification is central to increasing susceptibility to Spn. Additionally, we observed that IAV induced profound transcriptional changes in the airway epithelium and proteomic changes in the airway surface liquid in both CFTR-dependent and -independent manners. These changes correspond to multiple diminished host defense pathways and altered airway epithelial function. Collectively, these findings highlight both the importance of CFTR function during infectious challenge and demonstrate a central role for the lung epithelium in secondary bacterial infections following IAV.


Initial severity-dependent longitudinal model with application to a randomized controlled trial of women with depression.
The assessment of initial severity of a disease is arguably one of the most important factors in identifying appropriate therapies. In this paper, we propose an initial severity-dependent longitudinal model to account for the influence of the initial severity of a disease on the posttreatment severity and the efficacy of medical treatments. The proposed model has the flexibility of nonparametric modeling, as it allows coefficients to vary with the initial severity of the disease. It also provides attractive and practical patient-specific interpretation of initial severity-dependent coefficients. As a result, the proposed model enables patient-specific modeling and treatment recommendations consistent with the assessment of the patient's initial severity, and thus, it can be used as a decision support tool for clinicians. A new empirical likelihood approach is employed for efficient estimation and statistical inference about the initial severity-dependent coefficients. In contrast to the literature on marginal regression models, the proposed estimation procedure allows nuisance parameters associated with the working correlation matrix and the error variances to vary smoothly with the initial severity. The effectiveness of the proposed procedure is demonstrated via simulation studies. We further apply the proposed method by analyzing a data set arising from a randomized controlled trial of women with depression and discover an interesting phenomenon; antidepressant medication intervention is effective for patients with moderate or severe depression, whereas psychotherapy intervention using manual-guided cognitive behavior therapy is effective for patients with a severe case of depression.


[Phosphatase activity in the forearm bones of rats after a flight aboard the biosatellite "Cosmos-936"].
Activities of alkaline and acid phosphatases in ulnar and radial bones of rats flown for 18.5 days aboard Cosmos-936 and kept in a ground-based mock-up were investigated. In both bones activity of acid phosphatase increased significantly and that of alkaline phosphatase decreased 6--10 hours postflight; in the synchronous experiment the only change was a decrease in the activity of alkaline phosphatase in the radius. An exposure of rats to artificial gravity did not normalize changes in phosphatase activities observed postflight. At R + 25 phosphatase activity in bones of flight rats returned to normal and even tended to exceed the control level in synchronous animals.


Between the Baltic and Danubian Worlds: the genetic affinities of a Middle Neolithic population from central Poland.
For a long time, anthropological and genetic research on the Neolithic revolution in Europe was mainly concentrated on the mechanism of agricultural dispersal over different parts of the continent. Recently, attention has shifted towards population processes that occurred after the arrival of the first farmers, transforming the genetically very distinctive early Neolithic Linear Pottery Culture (LBK) and Mesolithic forager populations into present-day Central Europeans. The latest studies indicate that significant changes in this respect took place within the post-Linear Pottery cultures of the Early and Middle Neolithic which were a bridge between the allochthonous LBK and the first indigenous Neolithic culture of north-central Europe--the Funnel Beaker culture (TRB). The paper presents data on mtDNA haplotypes of a Middle Neolithic population dated to 4700/4600-4100/4000 BC belonging to the Brześć Kujawski Group of the Lengyel culture (BKG) from the Kuyavia region in north-central Poland. BKG communities constituted the border of the "Danubian World" in this part of Europe for approx. seven centuries, neighboring foragers of the North European Plain and the southern Baltic basin. MtDNA haplogroups were determined in 11 individuals, and four mtDNA macrohaplogroups were found (H, U5, T, and HV0). The overall haplogroup pattern did not deviate from other post-Linear Pottery populations from central Europe, although a complete lack of N1a and the presence of U5a are noteworthy. Of greatest importance is the observed link between the BKG and the TRB horizon, confirmed by an independent analysis of the craniometric variation of Mesolithic and Neolithic populations inhabiting central Europe. Estimated phylogenetic pattern suggests significant contribution of the post-Linear BKG communities to the origin of the subsequent Middle Neolithic cultures, such as the TRB.


The observed image velocity of a stationary target reflected by a rotating plane mirror.
An equation is presented describing the angular velocity of an image, viewed by an observer when a plane mirror is undergoing angular velocity. The image velocity is determined at the observer's entrance pupil. An expression to determine the size of the mirror aperture for a given exposure time is also presented. The results indicate that, in general, the image velocity is not constant nor twice the mirror velocity, as is usually assumed. Also, if the mirror extends to an equal length on each side of its axis of rotation, then the time in which the image appears to travel from the mirror's edge to the axis of rotation does not equal the time in which it appears to travel from the axis to the other edge.


An observational study on intracutaneous sodium storage in intensive care patients and controls.
The development of ICU-acquired sodium disturbances is not fully understood. Alterations in non-osmotic skin sodium storage, hypothetically inflammation-driven, could play a role. To investigate this in critically ill patients we conducted a patient-control study with skin punch biopsies in patients with sepsis (n = 15), after coronary artery bypass grafting (CABG, n = 15) and undergoing total hip arthroplasty (THA-controls, n = 15) respectively, together representing a range in severity of systemic inflammation. Biopsies were taken within 24 hours (sepsis) and within 2 hours (CABG) after ICU-admission, and prior to arthroplasty. Biopsies were analysed for sodium content. In addition immunostainings and quantitative real time PCR were performed. The primary aim of this study was to detect possible differences in amounts of cutaneous sodium. The secondary aims were to quantify inflammation and lymphangiogenesis with concomitant markers. The highest amounts of both water and sodium were found in patients with sepsis, with slightly lower values after CABG and the lowest amounts in THA-controls. Correlation between water and sodium was 0.5 (p<0.01). In skin biopsies in all groups comparable amounts of macrophages, T-cells and lymph vessels were found. In all groups comparable expression of inflammation markers were found. However, higher mRNA transcript expression levels of markers of lymphangiogenesis were found in patients with sepsis and after CABG. The conjoint accumulation of water and sodium points towards oedema formation. However, the correlation coefficient of 0.5 leaves room for alternative explanations, including non-osmotic sodium storage. No signs of dermal inflammation were found, but upregulation of markers of lymphangiogenesis could indicate future lymphangiogenesis.


Density reduction and diffusion in driven two-dimensional colloidal systems through microchannels.
The behavior of particles driven through a narrow constriction is investigated in experiment and simulation. The system of particles adapts to the confining potentials and the interaction energies by a self-consistent arrangement of the particles. It results in the formation of layers throughout the channel and of a density gradient along the channel. The particles accommodate to the density gradient by reducing the number of layers one by one when it is energetically favorable. The position of the layer reduction zone fluctuates with time while the particles continuously pass this zone. The flow behavior of the particles is studied in detail. The velocities of the particles and their diffusion behavior reflect the influence of the self-organized order of the system.


The reference genome assembly of the bright cobblestone lichen, Acarospora socialis.
Acarospora socialis, the bright cobblestone lichen, is commonly found in southwestern North America. This charismatic yellow lichen is a species of key ecological significance as it is often a pioneer species in new environments. Despite their ecological importance virtually no research has been conducted on the genomics of A. socialis. To address this, we used long-read sequencing to generate the first high-quality draft genome of A. socialis. Lichen thallus tissue was collected from Pinkham Canyon in Joshua Tree National Park, California and deposited in the UC Riverside herbarium under accession #295874. The de novo assembly of the mycobiont partner of the lichen was generated from Pacific Biosciences HiFi long reads and Dovetail Omni-C chromatin capture data. After removing algal and bacterial contigs, the fungal genome was approximately 31.2 Mb consisting of 38 scaffolds with contig and scaffold N50 of 2.4 Mb. The BUSCO completeness score of the assembled genome was 97.5% using the Ascomycota gene set. Information on the genome of A. socialis is important for California conservation purposes given that this lichen is threatened in some places locally by wildfires due to climate change. This reference genome will be used for understanding the genetic diversity, population genomics, and comparative genomics of A. socialis species. Genomic resources for this species will support population and landscape genomics investigations, exploring the use of A. socialis as a bioindicator species for climate change, and in studies of adaptation by comparing populations that occur across aridity gradients in California.


Regulatory factor X transcription factors control Musashi1 transcription in mouse neural stem/progenitor cells.
The transcriptional regulation of neural stem/progenitor cells (NS/PCs) is of great interest in neural development and stem cell biology. The RNA-binding protein Musashi1 (Msi1), which is often employed as a marker for NS/PCs, regulates Notch signaling to maintain NS/PCs in undifferentiated states by the translational repression of Numb expression. Considering these critical roles of Msi1 in the maintenance of NS/PCs, it is extremely important to elucidate the regulatory mechanisms by which Msi1 is selectively expressed in these cells. However, the mechanism regulating Msi1 transcription is unclear. We previously reported that the transcriptional regulatory region of Msi1 is located in the sixth intron of the Msi1 locus in NS/PCs, based on in vitro experiments. In the present study, we generated reporter transgenic mice for the sixth intronic Msi1 enhancer (Msi1-6IE), which show the reporter expression corresponding with endogenous Msi1-positive cells in developing and adult NS/PCs. We found that the core element responsible for this reporter gene activity includes palindromic Regulatory factor X (Rfx) binding sites and that Msi1-6IE was activated by Rfx. Rfx4, which was highly expressed in NS/PCs positive for the Msi1-6IE reporter, bound to this region, and both of the palindromic Rfx binding sites were required for the transactivation of Msi1-6IE. Furthermore, ectopic Rfx4 expression in the developing mouse cerebral cortex transactivates Msi1 expression in the intermediate zone. This study suggests that ciliogenic Rfx transcription factors regulate Msi1 expression through Msi1-6IE in NS/PCs.


Elk1 and SRF transcription factors convey basal transcription and mediate glucose response via their binding sites in the human LXRB gene promoter.
The nuclear receptors LXRalpha (NR1H3) and LXRbeta (NR1H2) are attractive drug targets for the treatment of diabetes and cardiovascular disease due to their established role as regulators of cholesterol and lipid metabolism. A large body of literature has recently indicated their important roles in glucose metabolism and particularly LXRbeta is important for proper insulin production in pancreas. In this study, we report that glucose induces transcription via the LXRB gene promoter. The transcription start site of the human LXRB gene was determined and we identified two highly conserved, and functional, ETS and Elk1 binding sites, respectively, in the LXRB gene promoter. The Elk1 binding site also bound the serum responsive factor (SRF). Mutation of these sites abolished binding. Furthermore, mutation of the binding sites or siRNA knockdown of SRF and Elk1 significantly reduced the promoter activity and impaired the glucose response. Our results indicate that the human LXRB gene is controlled by glucose, thereby providing a novel mechanism by which glucose regulates cellular functions via LXRbeta.


Relative Computed Tomography (CT) Enhancement Value for the Assessment of Microvascular Architecture in Renal Cell Carcinoma.
BACKGROUND To investigate the correlation between the relative computed tomography (CT) enhancement value and the microvascular architecture in different pathologic subtypes of renal cell carcinoma (RCC). MATERIAL AND METHODS This retrospective study included 55 patients with pathologically confirmed RCC. Immunohistochemistry for CD34 was performed for all surgical specimens. Microvascular architecture parameters (density, area, diameter, and perimeter) for the microvessels and the microvessels with lumen were determined. The CT scan was performed during arterial phase or venous phase. The correlation of parameters on CT and tumor angiogenesis was investigated. RESULTS Density of microvessels showed a positive correlation with CT values of tumors, ratios of tumor to cortex, and differences of tumor and medulla, but no correlation with CT value ratio of tumor to aorta or tumor to medulla. CT parameters were positively correlated with microvascular parameters. However, no CT parameter differences between hypo-vascular clear cell RCC and papillary RCC was observed. Strikingly, the density and area of the microvessels were significantly higher in hypo-vascular clear cell RCC than that in papillary RCC, while the density of the microvessels with lumen in the cyst-present RCC was significantly higher than that in the cyst-absent RCC. The values (especially those of microvessels with lumen) of area density, diameter, and perimeter were higher in the capsule-absent RCC than in the capsule-present RCC. CONCLUSIONS The relative CT enhancement value of RCC was associated with vascular architecture parameters including density, area, and perimeter. Quantitative and semi-quantitative parameters on enhanced CT may shed some light on tumor vasculature and function as indicators of the biological behavior of RCC.


The relation between electrophysiologic channel interaction and electrode pitch ranking in cochlear implant recipients.
The primary goal of this study was to examine the relation between electrophysiologic measures of channel interaction and the ability to discriminate pitch between electrodes in a psychophysical pitch-ranking task. It was hypothesized that cochlear implant recipients should perform better on an electrode pitch-ranking task when using electrodes with less channel interaction as measured with the electrically evoked compound action potential (ECAP). The width of the ECAP channel interaction function was compared with the slope of the pitch-ranking function for 10 adult Nucleus 24 recipients. Results showed no significant correlation between electrode pitch-ranking ability and width of the ECAP channel interaction function for individual subjects or for group data. Additionally, there was no significant correlation between speech perception performance and either pitch-ranking ability or width of the ECAP channel interaction function. These results suggest that the width of the ECAP interaction function may not be an accurate predictor of the ability to discriminate between electrodes on the basis of pitch.


Possible mechanisms of stimulus-induced vacuolation in serous cells of tracheal secretory glands.
Several factors affecting the stimulus-induced vacuolation in cat tracheal submucosal glands described in a companion paper [Am. J. Physiol. 241 (Cell Physiol. 10): C18-C24, 1981] were examined. Stimulation with predominantly alpha-adrenergic, beta-adrenergic, and cholinergic agonists at various concentrations and in the presence of appropriate blockers showed that alpha-adrenergic or cholinergic stimulation is more effective in inducing vacuolation than beta-adrenergic stimulation. In addition, Ca- or HCO3- deficient incubation medium or low incubation temperature either blocked or significantly decreased the vacuolation response. Stimulation in the presence of the Na-K-ATPase inhibitor ouabain prevented vacuolation. The known roles of these factors in fluid transport are consistent with the possibility that stimulus-induced vacuolation possibly arises in response to disturbances in cytoplasmic fluid, which are induced in the secretory cell when the fluid component of secretion is intensely stimulated. A model is presented that possibly relates the observed responses to intracellular event and suggests the possibility of ion pumps in the apical membrane.


Methodological approach to minimal residual disease detection by flow cytometry in adult B-lineage acute lymphoblastic leukemia.
A flow cytometric approach to minimal residual disease (MRD) monitoring useful in childhood B-lineage acute lymphoblastic leukemia (ALL) is discussed here in the context of ALL in adults. Of 64 leukemia samples analyzed, 95.3% had at least one abnormal phenotype (57.3% had two or more) as compared to physiologic B-cell precursors in adult bone marrow. The method was sensitive enough to detect one leukemic cell among 10,000 normal cells in 16/19 experiments (84.2%). Blast phenotypes were stable in culture and at relapse, and were useful for MRD monitoring in patients. Marker combinations for childhood ALL are also applicable to adult cases.


Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder.
Generalized anxiety disorder (GAD) is a chronic psychiatric disorder with significant morbidity and mortality. Antidepressant drugs are the preferred choice for treatment; however, treatment response is often variable. Several studies in major depression have implicated a role of the serotonin receptor gene (HTR2A) in treatment response to antidepressants. We tested the hypothesis that the genetic polymorphism rs7997012 in the HTR2A gene predicts treatment outcome in GAD patients treated with venlafaxine XR. Treatment response was assessed in 156 patients that participated in a 6-month open-label clinical trial of venlafaxine XR for GAD. Primary analysis included Hamilton Anxiety Scale (HAM-A) reduction at 6 months. Secondary outcome measure was the Clinical Global Impression of Improvement (CGI-I) score at 6 months. Genotype and allele frequencies were compared between groups using χ(2) contingency analysis. The frequency of the G-allele differed significantly between responders (70%) and nonresponders (56%) at 6 months (P=0.05) using the HAM-A scale as outcome measure. Similarly, using the CGI-I as outcome, the G-allele was significantly associated with improvement (P=0.01). Assuming a dominant effect of the G-allele, improvement differed significantly between groups (P=0.001, odds ratio=4.72). Similar trends were observed for remission although not statistically significant. We show for the first time a pharmacogenetic effect of the HTR2A rs7997012 variant in anxiety disorders, suggesting that pharmacogenetic effects cross diagnostic categories. Our data document that individuals with the HTR2A rs7997012 single nucleotide polymorphism G-allele have better treatment outcome over time. Future studies with larger sample sizes are necessary to further characterize this effect in treatment response to antidepressants in GAD.


Non-destructive prediction of pigment content in lettuce based on visible-NIR spectroscopy.
Lettuce (Lactuca sativa L.) is one of the most important salad vegetables in the world, with a number of head shapes, leaf types and colors. The lettuce pigments play important physiological functions, such as photosynthetic processes and light stress defense, but they also benefit human health because of their antioxidant action and anticarcinogenic properties. In this study three lettuce cultivars were grown under different farming systems, and partial least squares models were built to predict the leaf chlorophyll, carotenoid and anthocyanin content. The three proposed models resulted in high coefficients of determination and variable importance for the projection values, as well as low estimative errors for calibration and external validation datasets. These results confirmed that it is possible to accurately predict chlorophyll, carotenoid and anthocyanin content of green and red lettuces, grown in different farming systems, based on the spectral reflectance from 500 to 1000 nm. The proposed models were adequate for estimating lettuce pigments in a quick and non-destructive way, representing an alternative to conventional measurement methods. Prediction accuracies were improved by using the detrending, smoothing and first derivative pretreatments to the original spectral signatures prior to estimating lettuce chlorophyll, carotenoid and anthocyanin content, respectively. © 2016 Society of Chemical Industry.


VoxAR: Adaptive Visualization of Volume Rendered Objects in Optical See-Through Augmented Reality.
We present VoxAR, a method to facilitate an effective visualization of volume-rendered objects in optical see-through head-mounted displays (OST-HMDs). The potential of augmented reality (AR) to integrate digital information into the physical world provides new opportunities for visualizing and interpreting scientific data. However, a limitation of OST-HMD technology is that rendered pixels of a virtual object can interfere with the colors of the real-world, making it challenging to perceive the augmented virtual information accurately. We address this challenge in a two-step approach. First, VoxAR determines an appropriate placement of the volume-rendered object in the real-world scene by evaluating a set of spatial and environmental objectives, managed as user-selected preferences and pre-defined constraints. We achieve a real-time solution by implementing the objectives using a GPU shader language. Next, VoxAR adjusts the colors of the input transfer function (TF) based on the real-world placement region. Specifically, we introduce a novel optimization method that adjusts the TF colors such that the resulting volume-rendered pixels are discernible against the background and the TF maintains the perceptual mapping between the colors and data intensity values. Finally, we present an assessment of our approach through objective evaluations and subjective user studies.


Is there any relationship between quality of life and polysomnographically detected sleep parameters/disorders in stable myasthenia gravis?
It is known that quality of life in myasthenia gravis is positively correlated with subjective sleep quality, still no data is available regarding the relationship between QOL and polysomnographically detected sleep parameters and disorders. In this study, we tried to highlighten this relationship, by performing polysomnography. Sleep-related complaints were evaluated in face-to-face interviews with 19 clinically stable MG patients and 26 healthy controls. During the interviews questionnaires assessing sleep quality, excessive daytime sleepiness, fatigue, depression, anxiety, and Turkish version of the MG-QOL 15-item scale [(MG-QOL15(T)] were administered and then an overnight polysomnography was performed. Sleep disorders, especially obstructive sleep apnea and fatigue were higher, whereas subjective sleep duration was significantly lower, in patients than controls. Excessive daytime sleepiness and poor sleep quality were not different between patients and controls. Other than percentage of sleep stage III, which was negatively correlated with MG-QOL15(T) scores, neither other sleep parameters nor sleep disorders were correlated with MG-QOL15(T) scores. MG composite, subjective sleep duration, fatigue severity and Hamilton depression rating scale scores were found to be positively correlated with MG-QOL15(T) scores. It was shown that decreasing disease severity and enhancing psychological well-being will improve patients' quality of life. We recommend that our findings should be repeated in a large prospective cohort of MG patients.