Comparative metabolism of Mesoplasma, Entomoplasma, Mycoplasma, and Acholeplasma.
Cytoplasmic fractions from species of the Mollicutes genera Entomoplasma, Mesoplasma, Mycoplasma, and Acholeplasma were assayed for NADH oxidase (NADH ox), ATP- and PPi-dependent phosphofructokinase (PFK), ATP- and PPi-dependent deoxyguanosine kinase (dGUOK), thymidine kinase (TK), TMP kinase (TMPK), glucose-6-phosphate dehydrogenase (G6Pde), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), phosphoenolpyruvate carboxylase, hypoxanthine-guanine phosphoribosyl transferase, dUTPase, and uracil-DNA glycosylase (UNG) activities. Membrane fractions were also examined for NADH ox activity. These activities were used as indicators of the presence and relative activities of major Mollicutes metabolic and DNA repair pathways. This was the first study to determine the presence of these enzymes in members of the genera Entomoplasma and Mesoplasma. Using the data obtained, we constructed a preliminary scheme for distinguishing genera of the class Mollicutes on the basis of the results of signature functional enzyme assays. This scheme includes phylogenetic relationships deduced from rRNA analyses, but is more informative with respect to metabolic potential. The criteria used include the presence of PPi-dependent PFK, urease, dUTPase, and dGUOK activities. Entomoplasma ellychniae ELCN-1T (T = type strain), Entomoplasma melaleucae M-1T, Mesoplasma seiffertii F7T, Mesoplasma entomophilum TACT, Mesoplasma florum L1T, Mycoplasma fermentans PG18T, and Acholeplasma multilocale PN525T were similar in most respects. NADH ox activity was localized in the cytoplasm of these organisms. These strains had ATP-dependent PFK, MDH, LDH, ATP- and PPi-dependent dGUOK, and UNG activities, but not dUTPase or G6Pde activities. In contrast, Acholeplasma equifetale C112T, Acholeplasma oculi 19LT, Acholeplasma hippikon C1T, Acholeplasma modicum PG49T, and Acholeplasma morum 72-043T had membrane-localized NADH ox activity, PPi-dependent PFK, G6Pde, and dUTPase activities, and significantly lower MDH and LDH activities and exhibited a faster rate with PPi than with ATP in the dGUOK reaction. All of the members of the Mollicutes tested had hypoxanthine-guanine phosphoribosyl transferase, phosphoenolpyruvate carboxylase, and (except for Mesoplasma entomophilum TAC(T)) UNG activities. All of the Acholeplasma strains except Acholeplasma multilocale PN525T had TK, TMPK, and UNG activities. Mesoplasma entomophilum TAC(T) was distinguished by having no detectable dUTPase, UNG, TK, and TMPK activities, indicating that there is a severe restriction in or an absence of a synthetic route to dTTP. Our data also suggest that A. multilocale PN525T is a member of an unrecognized metabolic subgroup of the genus Acholeplasma or is not an Acholeplasma strain.


In situ Immune Signatures and Microbial Load at the Nasopharyngeal Interface in Children With Acute Respiratory Infection.
Acute respiratory infection (ARI) is the most frequent cause for hospitalization in infants and young children. Using multiplexed nCounter technology to digitally quantify 600 human mRNAs in parallel with 14 virus- and 5 bacterium-specific RNAs, we characterized viral and bacterial presence in nasopharyngeal aspirates (NPA) of 58 children with ARI and determined the corresponding in situ immune profiles. NPA contained different groups of organisms and these were classified into bacterial (n = 27), viral (n = 5), codetection [containing both viral and bacterial transcripts (n = 21), or indeterminate intermediate where microbial load is below threshold (n = 5)]. We then identified differentially expressed immune transcripts (DEITs) comparing NPAs from symptomatic children vs. healthy controls, and comparing children presenting NPAs with detectable microbial load vs. indeterminate. We observed a strong innate immune response in NPAs, due to the presence of evolutionarily conserved type I Interferon (IFN)-stimulated genes (ISG), which was correlated with total bacterial and/or viral load. In comparison with indeterminate NPAs, adaptive immunity transcripts discriminated among viral, bacterial, and codetected microbial profiles. In viral NPAs, B cell transcripts were significantly enriched among DEITs, while only type III IFN was correlated with viral load. In bacterial NPAs, myeloid cells and coinhibitory transcripts were enriched and significantly correlated with bacterial load. In conclusion, digital nCounter transcriptomics provide a microbial and immunological in situ "snapshot" of the nasopharyngeal interface in children with ARI. This enabled discrimination among viral, bacterial, codetection, and indeterminate transcripts in the samples using non-invasive sampling.


Implementing a choice of pulmonary rehabilitation models in chronic obstructive pulmonary disease (HomeBase2 trial): protocol for a cluster randomised controlled trial.
There is compelling evidence that either centre-based or home-based pulmonary rehabilitation improves clinical outcomes in chronic obstructive pulmonary disease (COPD). There are known health service and personal barriers which prevent potentially eligible patients from accessing the benefits of pulmonary rehabilitation. The aim of this hybrid effectiveness-implementation trial is to examine the effects of offering patients a choice of pulmonary rehabilitation locations (home or centre) compared with offering only the traditional centre-based model. This is a two-arm cluster randomised, controlled, assessor-blinded trial of 14 centre-based pulmonary rehabilitation services allocated to intervention (offering choice of home-based or centre-based pulmonary rehabilitation) or control (continuing to offer centre-based pulmonary rehabilitation only), stratified by centre-based programme setting (hospital vs non-hospital). 490 participants with COPD will be recruited. Centre-based pulmonary rehabilitation will be delivered according to best practice guidelines including supervised exercise training for 8 weeks. At intervention sites, the home-based pulmonary rehabilitation will be delivered according to an established 8-week model, comprising of one home visit, unsupervised exercise training and telephone calls that build motivation for exercise participation and facilitate self-management. The primary outcome is all-cause, unplanned hospitalisations in the 12 months following rehabilitation. Secondary outcomes include programme completion rates and measurements of 6-minute walk distance, chronic respiratory questionnaire, EQ-5D-5L, dyspnoea-12, physical activity and sedentary time at the end of rehabilitation and 12 months following rehabilitation.Direct healthcare costs, indirect costs and changes in EQ-5D-5L will be used to evaluate cost-effectiveness. A process evaluation will be undertaken to understand how the choice model is implemented and explore sustainability beyond the clinical trial. Alfred Hospital Ethics Committee has approved this protocol. The trial findings will be published in peer-reviewed journals, submitted for presentation at conferences and disseminated to patients across Australia with support from national lung charities and societies. NCT04217330.


Role of evolved host breadth in the initial emergence of an RNA virus.
Understanding how evolution promotes pathogen emergence would aid disease management, and prediction of future host shifts. Increased pathogen infectiousness of different hosts may occur through direct selection, or fortuitously via indirect selection. However, it is unclear which type of selection tends to produce host breadth promoting pathogen emergence. We predicted that direct selection for host breadth should foster emergence by causing higher population growth on new hosts, lower among-population variance in growth on new hosts, and lower population variance in growth across new hosts. We tested the predictions using experimentally evolved vesicular stomatitis virus populations, containing groups of host-use specialists, directly selected generalists, and indirectly selected generalists. In novel-host challenges, viruses directly selected for generalism showed relatively higher or equivalent host growth, lower among-population variance in host growth, and lower population variance in growth across hosts. Thus, two of three outcomes supported our prediction that directly selected host breadth should favor host colonization. Also, we observed that indirectly selected generalists were advantaged over specialist viruses, indicating that fortuitous changes in host breadth may also promote emergence. We discuss evolution of phenotypic plasticity versus environmental robustness in viruses, virus avoidance of extinction, and surveillance of pathogen niche breadth to predict future likelihood of emergence.


Reduction of sodium intake is a prerequisite for preventing and curing high blood pressure in hypertensive patients - first part: therapy.
The studies on the relation between Na intake and blood pressure were started at the Brookhaven National Laboratories in Upton (New York) by Lewis K Dahl in 1961, however the story goes back to our hunter-gatherer predecessors who, between 750,000 and 10,000 years ago, ate diets proving a Na intake of 690 mg/day. The relevance of this finding became evident when the data of the studies on Yanomamo Indians of Brazil and Venezuela (living in the tropical forest) became available. They showed that in these populations sodium intake averages 1.34±2.01 mEq/24 hours,and that their blood pressure increases from the first to the second decade of life and then tapers down. Studies inc himpanzees, a species genetically similar to humans, the DASH Trial, the Intersalt Study, various meta-analyses, the data in persons with stroke, the blood pressure profile of newborns on low Na intake, and various studies in hypertensives with and without Chronic Kidney Disease, have demonstrated the beneficial effects of a restricted low salt intake alone or as an adjunct to drug therapy on blood pressure profiles.


A plasma concentration of α-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1.
The purpose of the present study was to determine whether a physiologic plasma concentration of α-ketoglutarate (αKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular αKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and β-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular αKG competitively inhibited PAH and cidofovir transport with Ki values (∼5 μM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular αKG (5 μM) significantly increased IC50 values for some inhibitors (up to 4-fold), such as probenecid, but not for others (an inhibitor-dependent effect). For some inhibitors, a significant increase in IC50 value was observed when cidofovir was the substrate, but not PAH (a substrate-dependent effect). A significant increase in IC50 value was also observed for inhibition of PAH transport by probenecid in renal basolateral membrane vesicles (5.2-fold). The substrate- and inhibitor-dependent effect of extracellular αKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular αKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.


Heath Sector Network Governance and State-building in South Kivu, Democratic Republic of Congo.
Longstanding patterns of interaction exist between state and non-state actors seeking to improve public health in Democratic Republic of Congo (DRC). DRC is a weak state, and, in many cases, private actors have stepped in to fill the void created by the lack of state health care provision. However, the role of these interactions in creating a governance network in the health sector has been underexplored. Using data from 18 months of qualitative field research, this study aimed to explore governance networks in DRC's health sector, examining how multiple stakeholders work to manage the health system and how the resulting governance network has been relevant for the state-building process. The findings demonstrate that the health sector in South Kivu is emerging as an arena of networked governance based on active partnerships between state institutions and non-state actors. Interactions between state and non-state actors account for the persistence of the health sector in a setting characterized by state weakness. However, networked governance does not function optimally, because, although non-state interventions fill the void where the state falls short, the DRC state has faced the challenge of interacting with partners with fragmented and horizontally competing agendas. Although weak, the shadow of state authority is present in the arena of stakeholders' interactions, as the state plays a determining role by providing a regulatory framework. Overall, the findings show that the interactive engagement of non-state actors contributes to improving institutional capacity through these actors' engagement with state institutions for health system management and institutional development. However, although networked health sector governance does contribute to state capacity, it is difficult to assess the real influence of these interactions on the state-building process in a context of critical fragility, where coordination and alignment have been problematic.


DBZ regulates cortical cell positioning and neurite development by sustaining the anterograde transport of Lis1 and DISC1 through control of Ndel1 dual-phosphorylation.
Cell positioning and neuronal network formation are crucial for proper brain function. Disrupted-in-Schizophrenia 1 (DISC1) is anterogradely transported to the neurite tips, together with Lis1, and functions in neurite extension via suppression of GSK3β activity. Then, transported Lis1 is retrogradely transported and functions in cell migration. Here, we show that DISC1-binding zinc finger protein (DBZ), together with DISC1, regulates mouse cortical cell positioning and neurite development in vivo. DBZ hindered Ndel1 phosphorylation at threonine 219 and serine 251. DBZ depletion or expression of a double-phosphorylated mimetic form of Ndel1 impaired the transport of Lis1 and DISC1 to the neurite tips and hampered microtubule elongation. Moreover, application of DISC1 or a GSK3β inhibitor rescued the impairments caused by DBZ insufficiency or double-phosphorylated Ndel1 expression. We concluded that DBZ controls cell positioning and neurite development by interfering with Ndel1 from disproportionate phosphorylation, which is critical for appropriate anterograde transport of the DISC1-complex.


Evaluation of ruminally protected methionine and lysine or blood meal and fish meal as protein sources for lactating Holsteins.
Forty lactating Holstein cows averaging 55 days in milk were used in a randomized block designed experiment to evaluate the effectiveness of ruminally protected Met and Lys compared with that of ruminally undegradable protein for supporting lactation. Cows were fed total mixed diets for 15 wk. Diets were formulated to be isonitrogenous with the same base ingredients resulting in base crude protein percentage of 15.5. Supplemental crude protein supplied by urea, soybean meal, or a 50:50 (wt/wt) mixture of fish and blood meal increased total dietary nitrogen to 18.0% of diet DM. Two additional diets consisted of the basal diets soybean meal and urea, which were supplemented with ruminally protected DL-Met and Lys-HCL at 10 and 25 g/d, respectively (soybean meal + amino acids (AA), urea + AA). Mean measures of dry matter intake, milk yield, milk protein percentage, and milk fat percentage were not affected by protein supplement. Milk protein yield, milk fat yield, casein yield, and casein percentage also were not affected by source of supplemental protein. Results indicate that at the level of crude protein intake relative to milk production in this experiment, the source of protein did not affect lactational performance.


P-glycoprotein (PGP) polymorphisms and sexual dysfunction in female patients with depression and SSRI-associated sexual side effects.
Sexual dysfunction is common with selective serotonin reuptake inhibitor use for major depressive disorder. Studies have shown associations between genetic variation in the adenosine triphosphate (ATP)-binding cassette, subfamily B, member 1 gene (ABCB1), which encodes the drug efflux transporter P-glycoprotein (PGP), and selective serotonin reuptake inhibitor response. This study measured functionally implicated ABCB1 variants (rs2235015, rs1128503, rs2032582, and rs1045642) and sexual dysfunction using the Changes in Sexual Functioning Questionnaire. This study included outpatients (18-40 years of age) treated for major depressive disorder with a selective serotonin reuptake inhibitor for 6 weeks. Changes in Sexual Functioning Questionnaire outcomes were stratified by ABCB1 genotype and PGP substrate status. The authors recruited 82 individuals (22 men and 57 women). Women receiving a PGP substrate with a rs1128503 TT genotype had a significantly lower Changes in Sexual Functioning Questionnaire total score (37.2 ± 5.4), indicating greater sexual dysfunction, than did those with the CT (42.9 ± 6.3) or CC genotypes (46.6 ± 5.6), F(2) = 6.00, p = .005, p = .02, with multiple testing correction. The results indicate a relationship between genotypes at rs1128503, total sexual dysfunction, and PGP substrates use for women and may explain some of the sexual dysfunction variability seen with selective serotonin reuptake inhibitor treatment. Results need to be confirmed with a larger sample size that includes men.


Development of platelet contractile force as a research and clinical measure of platelet function.
This article reviews work performed at the Medical College of Virginia of Virginia Commonwealth University during the development of a whole-blood assay of platelet function. The new assay is capable of assessing platelet function during clotting and thus allows measurement of the contribution of platelets to thrombin generation. Because platelets are monitored in the presence of thrombin, the test gages platelets under conditions of maximal activation. Three parameters are simultaneously assessed on one 700 microL sample of citrated whole blood. Platelet contractile force (PCF), the force produced by platelets during clot retraction, is directly measured as a function of time. This parameter is sensitive to platelet number, platelet metabolic status, glycoprotein IIb/IIIa status, and the presence of antithrombin activities. Clot elastic modulus (CEM), also measured as a function of time, is sensitive to fibrinogen concentration, platelet concentration, the rate of thrombin generation, the flexibility of red cells, and the production of force by platelets. The third parameter, the thrombin generation time (TGT) is determined from the PCF kinetics curve. Because PCF is absolutely thrombin dependent (no thrombin-no force), the initial upswing in PCF occurs at the moment of thrombin production. TGT is sensitive to clotting factor deficiencies, clotting factor inhibitors, and the presence of antithrombins, all of which prolong the TGT and are known to be hemophilic states. Treatment of hemophilic states with hemostatic agents shortens the TGT toward normal. TGT has been demonstrated to be shorter and PCF to be increased in coronary artery disease, diabetes mellitus, and several other thrombophilic states. Treatment of thrombophilic states with a variety of heparin and nonheparin anticoagulants prolongs the TGT toward normal. The combination of PCF, CEM, and TGT measured on the same sample may allow rapid assessment of global hemostasis and the response to a variety of procoagulant and anticoagulant medications.


"Genes to society"--the logic and process of the new curriculum for the Johns Hopkins University School of Medicine.
In August 2009, the Johns Hopkins University School of Medicine implemented a new curriculum, "Genes to Society" (GTS), aimed at reframing the context of health and illness more broadly, to encourage students to explore the biologic properties of a patient's health within a larger, integrated system including social, cultural, psychological, and environmental variables. This approach presents the patient's phenotype as the sum of internal (genes, molecules, cells, and organs) and external (environment, family, and society) factors within a defined system. Unique genotypic and societal factors bring individuality and variability to the student's attention. GTS rejects the phenotypic dichotomy of health and illness, preferring to view patients along a phenotypic continuum from "asymptomatic and latent" to "critically ill." GTS grew out of a perceived need to reformulate the student experience to meet the oncoming revolution in medicine that recognizes individuality from the genome to the environment. This article describes the five-year planning process that included the definition of objectives, development of the new curriculum, commission of a new education building, addition of enhancements in student life and faculty development, and creation of a vertical and horizontal structure, all of which culminated in the GTS curriculum. Critical ingredients in meeting the challenges of implementing GTS were leadership support, dialogue with faculty, broad engagement of the institutional community, avoidance of tunnel vision, and the use of pilot courses to test concepts and methods. GTS can be viewed as the foundation for the scientific and clinical career development of future physicians.


Learning Energy-Based Spatial-Temporal Generative ConvNets for Dynamic Patterns.
Video sequences contain rich dynamic patterns, such as dynamic texture patterns that exhibit stationarity in the temporal domain, and action patterns that are non-stationary in either spatial or temporal domain. We show that an energy-based spatial-temporal generative ConvNet can be used to model and synthesize dynamic patterns. The model defines a probability distribution on the video sequence, and the log probability is defined by a spatial-temporal ConvNet that consists of multiple layers of spatial-temporal filters to capture spatial-temporal patterns of different scales. The model can be learned from the training video sequences by an "analysis by synthesis" learning algorithm that iterates the following two steps. Step 1 synthesizes video sequences from the currently learned model. Step 2 then updates the model parameters based on the difference between the synthesized video sequences and the observed training sequences. We show that the learning algorithm can synthesize realistic dynamic patterns. We also show that it is possible to learn the model from incomplete training sequences with either occluded pixels or missing frames, so that model learning and pattern completion can be accomplished simultaneously.


The results of transsphenoidal surgery for 44 consecutive acromegalic patients.
A series of 44 patients with acromegaly underwent transsphenoidal surgery between 1987 and 1996. The early postoperative mean basal GH level < 5 ng/ml or < 3 ng/ml was achieved in 43 (97.7%) or 38 (86.4%) out of 44 patients, respectively. Preoperative abnormal GH secretory response to TRH, GnRH and oral glucose administration was restored to normal both after surgery and at the time of the final follow-up in all patients whose early postoperative mean basal GH levels were reduced to < 3 ng/ ml, whereas they remained abnormal in those with mean basal GH levels of > or = 3 ng/ml. In contrast, insulin-like growth factor 1 (IGF-1) levels, when measured by the extraction method, tended to be reduced gradually to normal between 6 months and 2 years after surgery in some patients with a successful operation. Therefore, 34 (87.1%) out of 39 patients who have been followed up longer than 6 months met the following stringent criteria at the time of the final follow-up: mean basal GH level < 3 ng/ml, a normal IGF-1 level, and normal GH response to TRH, GnRH and oral glucose administration. In this series, the most unfavorable preoperative factor influencing operative outcome is tumor invasion of the cavernous sinus. Our results clearly indicate that selective adenomectomy by transsphenoidal surgery is the therapy of first choice in any patient with acromegaly and that the complete biochemical cure of acromegaly can be achieved in 87% of patients by surgery alone with an acceptable low surgical morbidity.


Correlation between healthcare workers' knowledge of influenza vaccine and vaccine receipt.
Influenza vaccine receipt by healthcare workers (HCWs) is important because HCWs are at risk for occupational exposure to influenza and may act as vectors in the nosocomial transmission of influenza. HCWs were surveyed to determine whether belief in commonly held influenza vaccine misconceptions was associated with influenza vaccine acceptance. Cross-sectional study. A large urban teaching hospital. A self-administered survey was used to assess nursing and physician staff influenza vaccine knowledge, current vaccination status, and potential reasons for vaccine declination. Two hundred twelve of 215 surveys were completed. The overall influenza vaccination rate was 73%. Physician staff were significantly more likely to have been vaccinated compared with nursing staff (82% vs 62%, respectively; P = .0009). HCWs answering the 5 influenza vaccine basic knowledge questions correctly were significantly more likely to have been vaccinated than those responding incorrectly to any question (84% vs 64%, respectively; P = .002). This association was present in the nursing group where 80% of those answering the knowledge questions correctly were vaccinated, but only 49% of those answering incorrectly were vaccinated (P = .000005). However, in the physician group, there was no significant difference in the influenza vaccination rates between those answering correctly and those answering incorrectly (P = .459). Belief in commonly held influenza vaccine misconceptions was significantly associated with influenza vaccine declination among nursing staff and may act as a barrier to greater rates of influenza vaccination. Reasons for influenza vaccine nonreceipt may differ between nursing and physician staff.


P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer.
Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination. In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. Pak1 kindles resistance via modulation of epithelial-mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1-a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.


Healthcare policy and urologic practice.
Healthcare policy is currently a topic of national debate, with numerous implications for the practice of urology. Healthcare policy has broad reaching effects, both predicted and unforeseen. The effects of healthcare policy are manifested through clinical practice guidelines, payment reform and the overall structure of the healthcare system. This review describes each of these topics and their impact on clinical practice, with a specific focus on urology and urologic practice. Guidelines are useful for guiding and determining what is considered appropriate clinical practice, but there are drawbacks including poor implementation and overabundance. Payment reform is constantly evolving, with multiple efforts being implemented to move away from a fee-for-service model of reimbursement. The structure of healthcare delivery is moving toward more outpatient procedures, with varying amount of physician ownership of facilities and equipment, which is itself a controversial topic.


Reducing Operating Room Costs Through Real-Time Cost Information Feedback: A Pilot Study.
To create a protocol for providing real-time operating room (OR) cost feedback to surgeons. We hypothesize that this protocol will reduce costs in a responsible way without sacrificing quality of care. All OR costs were obtained and recorded for robot-assisted partial nephrectomy and laparoscopic donor nephrectomy. Before the beginning of this project, costs pertaining to the 20 most recent cases were analyzed. Items were identified from previous cases as modifiable for replacement or omission. Timely feedback of total OR costs and cost of each item used was provided to the surgeon after each case, and costs were analyzed. A cost analysis of the robot-assisted partial nephrectomy before the washout period indicates expenditures of $5243.04 per case. Ten recommended modifiable items were found to have an average per case cost of $1229.33 representing 23.4% of the total cost. A postwashout period cost analysis found the total OR cost decreased by $899.67 (17.2%) because of changes directly related to the modifiable items. Therefore, 73.2% of the possible identified savings was realized. The same stepwise approach was applied to laparoscopic donor nephrectomies. The average total cost per case before the washout period was $3530.05 with $457.54 attributed to modifiable items. After the washout period, modifiable items costs were reduced by $289.73 (8.0%). No complications occurred in the donor nephrectomy cases while one postoperative complication occurred in the partial nephrectomy group. Providing surgeons with feedback related to OR costs may lead to a change in surgeon behavior and decreased overall costs. Further studies are needed to show equivalence in patient outcomes.


Physiological and performance adaptations of elite Greco-Roman wrestlers during a one-day tournament.
The aim of this study was to determine the effects of a simulated one-day Greco-Roman wrestling tournament on selected performance and inflammatory status indices. Twelve competitive wrestlers (22.1 ± 1.3 years) completed five matches according to the official Olympic wrestling tournament regulations following a ~6% weight loss. Performance measurements, muscle damage assessment, and blood sampling were performed before and following each match. Performance and inflammatory markers were not affected by weight loss. Mean wrestling heart rate reached ~85% of maximal and lactate concentration exceeded 17 mM. Fatigue rating demonstrated a progressive rise (P < 0.05) throughout the tournament, peaking in match 4. Performance demonstrated a progressive deterioration (P < 0.05) throughout the tournament, especially in the last two matches (P < 0.05), with upper-body measures exhibiting a greater decline (P < 0.05) and remaining below baseline (P < 0.05) until the end of the tournament. Muscle damage markers increased during the course of the tournament with upper limbs affected more. Creatine kinase activity, CRP levels, IL-6 concentration, and leukocyte counts increased (P < 0.05) progressively throughout the tournament, peaking in the last two matches. Cortisol, epinephrine and norepinephrine increased (P < 0.05) after each match, but testosterone declined (P < 0.05) progressively, reaching a nadir before the last match. This inflammatory response was accompanied by a marked increase (p < 0.05) in lipid peroxidation, protein oxidation, and antioxidant status markers indicating the development of oxidative stress. These results suggest that a one-day wrestling tournament may induce significant physiological demands on wrestlers that may adversely affect their performance and inflammatory status especially during the later stages of the tournament.


Social integration and pulmonary function in the elderly.
This study sought to determine whether social integration, defined as number of social roles, is associated with better pulmonary function in the elderly and which roles are associated with greatest benefit. It also examined pathways that connect social integration to better lung health. High functioning men (n = 518) and women (n = 629) ages 70-79 were recruited as part of the MacArthur Study of Successful Aging, and data were collected on social roles as well as pulmonary function as assessed by peak expiratory flow rate (PEFR). Multiple regressions predicting PEFR from the number of social roles controlled for age, sex, race, education, weight, and height. Physiological, behavioral, social, and psychological factors were tested as mediators of the association between the number of social roles and PEFR. More social roles were associated with better PEFR. Analysis of specific roles indicated that marriage was the strongest positive correlate of PEFR. However, greater numbers of roles were also associated with better PEFR independent of marriage. Being a relative or friend were each also individually associated with better PEFR. Even so, greater numbers of social roles were associated with better PEFR independent of relative and friend. The data were consistent with greater happiness, not smoking, and more physical activity acting as pathways linking the number of roles to PEFR. Number of social roles is an important correlate of healthy lung function in the elderly. This association may be driven by healthier behaviors and greater feelings of well-being.


Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity.
Restructuring of extracellular matrix at actively extending blood vessel tips involves secretion of plasminogen activator (PA). Findings in earlier studies conducted in the authors' laboratory have suggested that angiostatic steroids suppress the PA activity essential for the invasive aspect of angiogenesis by increasing synthesis of plasminogen activator inhibitor (PAI)-1. This experiment was designed to test the effect of administration of exogenous PAI-1 on retinal neovascularization (NV) in an animal model of retinopathy of prematurity (ROP). At birth, Sprague-Dawley rats were placed into incubators and exposed to an atmosphere alternating between 50% and 10% O(2) every 24 hours. After 14 days, the animals were removed to room air, at which time each received a single intravitreal injection of 5 microL of buffer vehicle or one of five doses of PAI-1, ranging from 3.0 microg/mL to 2.0 mg/mL. Animals were killed 6 days later, and retinal NV was assessed using adenosine diphosphatase (ADPase) histochemical staining. Retinal neovascularization decreased with increasing PAI-1 dosage. The most effective dose tested (2.0 mg/mL) caused a 52% reduction in retinal NV relative to vehicle (P < 0.005). Normal vasculogenesis, as determined by measuring retinal vascular area, was unaffected. PAI-1 inhibits pathologic angiogenesis without adversely affecting normal vasculogenesis, an attractive feature for ROP therapies. Moreover, PAI's relationship to matrix metalloproteinases, which are also implicated in angiogenesis, suggests that the proteolytic aspect of the process may provide additional downstream therapeutic targets.


Weekly irinotecan and cisplatin in advanced non-small cell lung cancer: a multicenter phase II study.
The combination of weekly irinotecan (CPT-11) and monthly cisplatin has shown promising activity in advanced non-small cell lung cancer (NSCLC) in previous Phase I and II studies. However, same-day administration of these agents may better exploit their therapeutic synergy and minimize toxicities. This multicenter Phase II study was undertaken to evaluate the efficacy and safety of a combination of weekly CPT-11 and weekly cisplatin in patients with advanced NSCLC. Patients with chemotherapy-naive stage IIIB or IV NSCLC were treated with repeated cycles of therapy comprising weekly treatment with both cisplatin and CPT-11 for 4 weeks, followed by a 2-week rest. The starting doses of CPT-11 and cisplatin were 65 and 30 mg/m2, respectively. Treatment was continued until the occurrence of disease progression, unacceptable toxicity, or a maximum of six cycles. Fifty patients were enrolled. The median age was 59 years (range, 44-79 years). Eastern Cooperative Oncology Group performance status was 0 in 22 patients, 1 in 19 patients, and 2 in 9 patients. Seven and 43 patients had stages IIIB and IV disease, respectively. Five patients had brain metastasis. Patients received a median of three 6-week cycles (range, 1-6). The objective response rate was 36% (18 of 50; 95% confidence interval, 24-54%) and included 18 partial responses. Median time to tumor progression was 6.9 months (range, 0.6-15.2). The median survival was 11.6 months (range, 0.16-21.9 months), and the 1-year survival rate was 46%. Grade 3/4 nonhematological toxicities included vomiting (12%) and diarrhea (26%). Grade 3/4 hematological toxicities included anemia (14%), neutropenia (26%), and thrombocytopenia (14%). Relative dose intensities for CPT-11 and cisplatin were 89 and 62%, respectively. Weekly combined administration of CPT-11 and cisplatin achieved a promising overall response rate, median time to tumor progression, and median survival in patients with stage IIIB/IV NSCLC. The regimen was well tolerated, and the planned dose intensity was well maintained. Further evaluation of this combination in NSCLC is warranted.


Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines.
In animal models of arthritis induced with Ags or infectious agents, disease severity correlates with a dominant Th1-type response characterized by a higher ratio of IFN-gamma to IL-4. Analysis of BALB/c mice revealed a genetic predisposition toward developing CD4+ Th2-type responses. The bias toward an IL-4-dominant response in BALB/c mice protects mice from severe Lyme-induced arthritis and spontaneous autoimmune disease. Since BALB/c mice immunized with proteoglycan develop severe arthritis, we were interested in testing whether arthritis is associated with a Th2-type response and thus is different from other arthritic models. BALB/c mice immunized with proteoglycan generated a higher ratio of IFN-gamma to IL-4 that peaks at the onset of arthritis. We investigated whether when Th1 cells were dominant, disease outcome could be modified with pharmacological amounts of Th2 cytokines. Treatment with IL-4 prevented disease and induced a switch from a Th1-type to a Th2-type response. Proinflammatory cytokine mRNA transcripts were reduced in joints of cytokine-treated mice. Th2 cytokine therapy at the time of maximum joint inflammation also suppressed symptoms of disease. Despite the predisposition of BALB/c mice to a Th2-type response, proteoglycan-induced arthritis is a Th1-type disease. The effectiveness of IL-4 treatment was particularly striking because in other models of arthritis, treatment in a similar manner with IL-4 was not sufficient to inhibit arthritis. The effective control of arthritis and the switch from a Th1 to Th2 response suggest that levels of endogenous IL-4 in BALB/c mice may increase their responsiveness to Th2 cytokine therapy.


Glyphosate-tolerant corn: the composition and feeding value of grain from glyphosate-tolerant corn is equivalent to that of conventional corn (Zea mays L.).
Glyphosate-tolerant (Roundup Ready) corn line GA21 has been developed by genetic modification to tolerate glyphosate, the active ingredient in Roundup herbicide. The purpose of this study was to evaluate the compositional and nutritional safety of corn line GA21 compared to that of conventional corn. Compositional analyses were conducted to measure proximate, fiber, amino acid, fatty acid, and mineral contents of grain and proximate, fiber, and mineral contents of forage collected from 16 field sites over two growing seasons. The nutritional safety of corn line GA21 was evaluated in a poultry feeding study conducted with 2-day old, rapidly growing broiler chickens, at a dietary concentration of 50-60% w/w. Compositional analysis results showed that, except for a few minor differences that are unlikely to be of biological significance, the grain and forage of GA21 corn were comparable in their composition to that of the control corn line and to conventional corn. Results from the poultry feeding study showed that there were no differences in growth, feed efficiency, adjusted feed efficiency, and fat pad weights between chickens fed with GA21 grain or with parental control grain. These data taken together demonstrate that Roundup Ready corn is as safe and nutritious as conventional corn for food and feed use.


Sex-related differences in within-subject biological variation estimates for 22 essential and non-essential amino acids.
Measurement of serum amino acid (AA) concentrations is important in particular for the diagnosis and monitoring of inborn errors of AA metabolism. To ensure optimal clinical interpretation of AAs, reliable biological variation (BV) data are essential. In the present study, we derived BV data for 22 non-essential, conditionally essential, and essential AAs and assessed differences in BV of AAs related to sex. Morning blood samples were drawn from 66 subjects (31 males and 35 females) once a week for 10 consecutive weeks. All samples were analyzed in duplicate using liquid chromatography-tandem mass-spectrometry. The data were assessed for outliers, trends, normality and variance homogeneity analysis prior to estimating within-subject (CVI) and between-subject (CVG) BV. CVI estimates ranged from 9.0 % for histidine (male) to 33.0 % for taurine (male). CVI estimates in males and females were significantly different for all AAs except for aspartic acid, citrulline and phenylalanine, in most cases higher in females than in males. Apart from for arginine, CVG estimates in males and females were similar. In this highly powered BV study, we provide updated BV estimates for 22 AAs and demonstrate that for most AAs, CVI estimates differ between males and females, with implications for interpretation and use of AAs in clinical practice.


Unusually stable abnormal karyotype in a highly aggressive melanoma negative for telomerase activity.
Malignant melanomas are characterized by increased karyotypic complexity, extended aneuploidy and heteroploidy. We report a melanoma metastasis to the peritoneal cavity with an exceptionally stable, abnormal pseudodiploid karyotype as verified by G-Banding, subtelomeric, centromeric and quantitative Fluorescence in Situ Hybridization (FISH). Interestingly this tumor had no detectable telomerase activity as indicated by the Telomere Repeat Amplification Protocol. Telomeric Flow-FISH and quantitative telomeric FISH on mitotic preparations showed that malignant cells had relatively short telomeres. Microsatellite instability was ruled out by the allelic pattern of two major mononucleotide repeats. Our data suggest that a combination of melanoma specific genomic imbalances were sufficient and enough for this fatal tumor progression, that was not accompanied by genomic instability, telomerase activity, or the engagement of the alternative recombinatorial telomere lengthening pathway.


Revisiting the β-Lactams for Tuberculosis Therapy with a Compound-Compound Synthetic Lethality Approach.
The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis.


Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice.
Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.


Enterococcus faecium SF68 enhances the immune response to Giardia intestinalis in mice.
We studied the ability of the probiotic organism Enterococcus faecium SF68 to antagonize Giardia intestinalis infection in mice. Oral feeding of E. faecium strain SF68 starting 7 d before inoculation with Giardia trophozoites significantly increased the production of specific anti-Giardia intestinal IgA and blood IgG. This humoral response was mirrored at the cellular level by an increased percentage of CD4(+) T cells in the Peyer's patches and in the spleens of SF68-fed mice. The improvement of specific immune responses in probiotic-fed mice was associated with a diminution in the number of active trophozoites in the small intestine as well as decreased shedding of fecal Giardia antigens (GSA65 protein). The ability of SF68 to stimulate the immune system at both mucosal and systemic levels highlights mechanisms by which this probiotic might antagonize pathogens in vivo. Taken together, the data demonstrate the strong potential of strain SF68 to prevent protozoa from causing intestinal infections.


Comparison of the efficacy of subgingival irrigation with 2% povidone-iodine and tetracycline HCl in subjects with chronic moderate periodontitis: A clinico microbiological study.
This study was performed to evaluate and compare the clinical and antimicrobial efficacy of subgingival irrigation with tetracycline and povidone-iodine as an adjunct to nonsurgical periodontal therapy. Twenty subjects with chronic moderate periodontitis were recruited in this split-mouth study with probing pocket depth of >3 and ≤5 mm and clinical attachment loss of 3-4 mm in relation to 16, 36, and 46. In each subject, three selected periodontal pockets were assigned to receive one out of three irrigants (1) sterile water (control) in 16; (2) tetracycline at 10 mg/ml in 36; (3) 2% povidone-iodine in 46, and these sites were designated as Group A, Group B, and Group C, respectively. Plaque score, gingival score, pocket probing depth, and clinical attachment level were evaluated before treatment and at 1 and 3 months posttreatment. Multiplex polymerase chain reaction was used to detect Porphyromonas gingivalis and Tannerella forsythensis which have been implicated as the major risk factors for periodontal disease. Subgingival plaque collected before treatment and at 1 and 3 months posttreatment. Data were analysed using ANOVA and repeated measure ANOVA. Results were considered significant if P < 0.05. Clinical and microbiological parameters were reduced posttreatment, the reduction being significantly higher in Group B compared to Group C. It can be concluded that chemical and mechanical therapies were of slight benefit in the treatment of chronic moderate periodontitis, and there was an adjunctive effect of significance when scaling and root planing was combined with a single subgingival irrigation with tetracycline or povidone-iodine in lower concentration.


Generative and predictive neural networks for the design of functional RNA molecules.
RNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, and in vivo information-processing systems. However, the complex relationship between the sequence and structural properties of an RNA molecule and its ability to perform specific functions often necessitates extensive experimental screening of candidate sequences. Here we present a generalized neural network architecture that utilizes the sequence and structure of RNA molecules (SANDSTORM) to inform functional predictions. We demonstrate that this approach achieves state-of-the-art performance across several distinct RNA prediction tasks, while learning interpretable abstractions of RNA secondary structure. We paired these predictive models with generative adversarial RNA design networks (GARDN), allowing the generative modelling of novel mRNA 5' untranslated regions and toehold switch riboregulators exhibiting a predetermined fitness. This approach enabled the design of novel toehold switches with a 43-fold increase in experimentally characterized dynamic range compared to those designed using classic thermodynamic algorithms. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of diagnostic and therapeutic RNA molecules with improved function.


Shot-to-shot flat-field correction at X-ray free-electron lasers.
X-ray free-electron lasers (XFELs) provide high-brilliance pulses, which offer unique opportunities for coherent X-ray imaging techniques, such as in-line holography. One of the fundamental steps to process in-line holographic data is flat-field correction, which mitigates imaging artifacts and, in turn, enables phase reconstructions. However, conventional flat-field correction approaches cannot correct single XFEL pulses due to the stochastic nature of the self-amplified spontaneous emission (SASE), the mechanism responsible for the high brilliance of XFELs. Here, we demonstrate on simulated and megahertz imaging data, measured at the European XFEL, the possibility of overcoming such a limitation by using two different methods based on principal component analysis and deep learning. These methods retrieve flat-field corrected images from individual frames by separating the sample and flat-field signal contributions; thus, enabling advanced phase-retrieval reconstructions. We anticipate that the proposed methods can be implemented in a real-time processing pipeline, which will enable online data analysis and phase reconstructions of coherent full-field imaging techniques such as in-line holography at XFELs.


Potential years of life and productivity loss due to malignant mesothelioma in Turkey.
The study aimed to calculate years of life lost (YLL) and years of potential life lost (YPLL) due to malignant mesothelioma (MM) in Turkey. YLL was computed by estimating the difference between age at death due to MM and the expected death age. To calculate YPLL, all deaths above 65 years (retirement age) were disregarded. Of the 5,617 deaths due to MM in the study period, 3,241 (57.70%) were male and 2,376 (42.30%) were female. The median YLL and YPLL were 16.58 and 25.13 for males and 19.83 and 28.50 years for females. YLL and YPLL were shorter in males than females (p < 0.001). Premature mortality cost per death was $ 45,963.57 (2.23 times higher for males). MM is associated with high YLL, YPLL and economic burden in a country with environmental asbestos exposure in the rural areas.


Understanding Supramolecular Assembly of Supercharged Proteins.
Ordered supramolecular assemblies have recently been created using electrostatic interactions between oppositely charged proteins. Despite recent progress, the fundamental mechanisms governing the assembly of oppositely supercharged proteins are not fully understood. Here, we use a combination of experiments and computational modeling to systematically study the supramolecular assembly process for a series of oppositely supercharged green fluorescent protein variants. We show that net charge is a sufficient molecular descriptor to predict the interaction fate of oppositely charged proteins under a given set of solution conditions (e.g., ionic strength), but the assembled supramolecular structures critically depend on surface charge distributions. Interestingly, our results show that a large excess of charge is necessary to nucleate assembly and that charged residues not directly involved in interprotein interactions contribute to a substantial fraction (∼30%) of the interaction energy between oppositely charged proteins via long-range electrostatic interactions. Dynamic subunit exchange experiments further show that relatively small, 16-subunit assemblies of oppositely charged proteins have kinetic lifetimes on the order of ∼10-40 min, which is governed by protein composition and solution conditions. Broadly, our results inform how protein supercharging can be used to create different ordered supramolecular assemblies from a single parent protein building block.


High-Mobility Group Box 1 Expression in Mandibular Bone Cells of Experimental Periodontitis.
High-mobility group box 1 (HMGB1) was suggested to be associated with the pathogenesis of chronic periodontitis which characterized by alveolar bone loss. HMGB1 was defined as a bone-active cytokine, but the rule of HMGB1 in bone loss of chronic periodontitis is still understood. The aim of this study is to investigate the expression of HMGB1 on osteoblasts and osteoclasts in the mandible of chronic periodontitis. This experimental study was conducted to rats injected by Porphyromonas gingivalis into the buccal and lingual subgingival area at a concentration of 2 × 109 CFU/mL three times a week with 2-day apart for 2, 3, 4, and 6 weeks as chronic periodontitis group and injected by normal saline as control group. Analysis of variance was used to examine the differences between groups followed by least significant difference post hoc test with the level of significance was <0.05. The HMGB1 expression was found in both osteoclasts and osteoblasts of mandibular bone by immunohistochemistry analysis. There was a difference of HMGB1 expression on osteoblasts and osteoclasts of chronic periodontitis. HMGB1 expression was found increased significantly in mandibular osteoblasts of chronic periodontitis, whereas the HMGB1 expression in mandibular osteoclast is higher in 2 and 3 weeks, but it was lower in 4 and 6 weeks. This study indicated a potential role for HMGB1 in bone loss of chronic periodontitis. HMGB1 on mandibular osteoclasts and osteoblasts may play different rules in the onset and progression of chronic periodontitis.


The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is responsible of variable clinical manifestations, ranging from no symptoms to severe pneumonia with acute respiratory distress syndrome, septic shock, and multi-organ failure resulting in death. To date no specific antiviral drug have been approved for COVID-19, so the treatment of the disease is mainly focused on symptomatic treatment and supportive care. Moreover, there are no treatments of proven efficacy to reduce the progression of the disease from mild/moderate to severe/critical. An activation of the coagulation cascade leading to severe hypercoagulability has been detected in these patients, therefore early anticoagulation may reduce coagulopathy, microthrombus formation, and the risk of organ damages. The role of heparin in COVID-19 is supported by a lot of studies describing its pleiotropic activity but it must be proven in clinical trials. Several protocols have been designed to assess the risk-benefit profile of heparin (low-molecular-weight or unfractionated heparin) in hospitalized subjects. Although prophylactic doses may be adequate in most patients, it is important to wait the results of clinical trials in order to define the appropriate effective dose able to improve disease outcome.


Repression of intracellular virulence factors in Salmonella by the Hha and YdgT nucleoid-associated proteins.
The Hha/YmoA family of nucleoid-associated proteins is involved in gene regulation in enterobacteria. In Salmonella enterica serovar Typhimurium, virulence genes required for intracellular growth are induced following host cell invasion but the proteins responsible for repressing these genes prior to host cell entry have not been fully identified. We demonstrate here that Hha is the major repressor responsible for silencing virulence genes carried in Salmonella pathogenicity island 2 prior to bacteria sensing an intracellular environmental cue.


Aspirin Interacts with Cholesterol-Containing Membranes in a pH-Dependent Manner.
Aspirin has been used for broad therapeutic treatment, including secondary prevention of cardiovascular disease associated with increased cholesterol levels. Aspirin and other nonsteroidal anti-inflammatory drugs have been shown to interact with lipid membranes and change their biophysical properties. In this study, mixed lipid model bilayers made from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) or 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) comprising varying concentrations of cholesterol (10:1, 4:1, and 1:1 mole ratio of lipid:chol), prepared by the droplet interface bilayer method, were used to examine the effects of aspirin at various pH on transbilayer water permeability. The presence of aspirin increases the water permeability of POPC bilayers in a concentration-dependent manner, with a greater magnitude of increase at pH 3 compared to pH 7. In the presence of cholesterol, aspirin is similarly shown to increase water permeability; however, the extent of the increase depends on both the concentration of cholesterol and the pH, with the least pronounced enhancement in water permeability at high cholesterol levels at pH 7. A fusion of data from differential scanning calorimetry, confocal Raman microspectrophotometry, and interfacial tensiometric measurements demonstrates that aspirin can promote significant thermal, structural, and interfacial property perturbations in the mixed-lipid POPC or DOPC membranes containing cholesterol, indicating a disordering effect on the lipid membranes. Our findings suggest that aspirin fluidizes phosphocholine membranes in both cholesterol-free and cholesterol-enriched states and that the overall effect is greater when aspirin is in a neutral state. These results confer a deeper comprehension of the divergent effects of aspirin on biological membranes having heterogeneous compositions, under varying physiological pH and different cholesterol compositions, with implications for a better understanding of the gastrointestinal toxicity induced by the long term use of this important nonsteroidal anti-inflammatory molecule.


Use of Straighteners and Other Hair Products and Incident Uterine Cancer.
Hair products may contain hazardous chemicals with endocrine-disrupting and carcinogenic properties. Previous studies have found hair product use to be associated with a higher risk of hormone-sensitive cancers including breast and ovarian cancer; however, to our knowledge, no previous study has investigated the relationship with uterine cancer. We examined associations between hair product use and incident uterine cancer among 33 947 Sister Study participants aged 35-74 years who had a uterus at enrollment (2003-2009). In baseline questionnaires, participants in this large, racially and ethnically diverse prospective cohort self-reported their use of hair products in the prior 12 months, including hair dyes; straighteners, relaxers, or pressing products; and permanents or body waves. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations between hair product use and uterine cancer using Cox proportional hazard models. All statistical tests were 2-sided. Over an average of 10.9 years of follow-up, 378 uterine cancer cases were identified. Ever vs never use of straightening products in the previous 12 months was associated with higher incident uterine cancer rates (HR = 1.80, 95% CI = 1.12 to 2.88). The association was stronger when comparing frequent use (>4 times in the past 12 months) vs never use (HR = 2.55, 95% CI = 1.46 to 4.45; Ptrend = .002). Use of other hair products, including dyes and permanents or body waves, was not associated with incident uterine cancer. These findings are the first epidemiologic evidence of association between use of straightening products and uterine cancer. More research is warranted to replicate our findings in other settings and to identify specific chemicals driving this observed association.


The Effects of Analgesics and Local Anesthetics on Gene Transcription Mediated by NFATc2 and Sp1 in Pancreatic Carcinoma.
Recent research has identified the transcription factors NFATc2 and Sp1 as key regulators in the carcinogenesis of pancreatic carcinoma. This study aimed to examine the effect of clinically achievable dosages of analgesics including ketamine, s-ketamine, metamizole, and paracetamol as well as that of sufentanil, ropicavaine, and lidocaine on pancreatic carcinoma cells and the expression of NFATc2 and Sp1. The effects of analgesics on the expression of NFATc2 and Sp1 were investigated with immunoblotting. Cell proliferation was measured with the ELISA BrdU assay. In PaTu8988t pancreatic carcinoma cells, 48 h stimulation with ketamine and s-ketamine significantly inhibited proliferation and decreased expression of NFATc2 in the nucleus. The addition of metamizole and lidocaine reduced proliferation of PaTu8988t cells after 48 h. New treatment concepts target specific signaling and transcription pathways. The extent to which drugs influence these mechanisms in pancreatic carcinoma cells needs to be investigated in future studies.


Sociodemographic Factors and the Risk of Pediatric Out-of-Hospital Cardiac Arrest in Ontario, Canada: A Province-Wide Case-Control Study.
Background Pediatric out-of-hospital cardiac arrest (POHCA) is associated with significant mortality and poor neurological outcomes. We aimed to describe the association between sociodemographic factors and POHCA risk in Ontario, Canada. Methods and Results We conducted a province-wide case-control study at ICES, where patient records are linked across administrative databases. The case group included children (1 day to 17 years of age) who experienced an OHCA between 2004 and 2020. Controls were matched up to 1:4 on age, sex, index date, and key comorbidities. We used conditional logistic regression to measure the association between sociodemographic indicators and POHCA risk. The case and control groups included 1,826 and 7,254 children, respectively. Children living in areas with the highest levels of material deprivation (adjusted odds ratio [aOR]: 2.35, 95% CI: 1.94, 2.85) and dependency (aOR: 1.22, 95% CI: 1.01, 1.48) had a higher odds of POHCA, relative to children living in regions with the lowest levels of material deprivation and dependency, respectively. Children living in neighborhoods with the lowest levels of ethnic diversity had a higher odds of POHCA (aOR: 1.62, 95% CI: 1.30, 2.01), relative to children living in neighborhoods with the highest levels of ethnic diversity. The odds of POHCA were lower in immigrants (aOR: 0.67, 95% CI: 0.47, 0.95), relative to the general population. Northern urban residence (aOR: 1.45, 95% CI: 1.13, 1.87) was associated with a higher odds of POHCA, relative to southern urban residence. Conclusions Children living in neighborhoods with high levels of marginalization may have an elevated risk of experiencing POHCA. These findings highlight the importance of addressing disparities through targeted prevention and intervention efforts.


Inherited iron overload disorders.
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.


GPNMB+ Gal-3+ hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis.
Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta ), Epcam+ population with differentiation potential (EP+Diff ) and immunosuppressive malignant transformation subset (MTImmu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu . Importantly, GPNMB+ Gal-3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+ Gal-3+ MTImmu cells. Enrichment of the GPNMB+ Gal-3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB+ Gal-3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.


Differences in knowledge among patients with atrial fibrillation receiving non-vitamin K antagonist oral anticoagulants and vitamin K antagonists.
Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in patients with atrial fibrillation (AF) worldwide. Few articles have compared current understanding of AF patients about the disease and anticoagulant therapy in relation to the medications used. We sought to compare the knowledge of AF and anticoagulation between AF patients treated with NOACs and those on vitamin K antagonists (VKAs). We used the Jessa AF Knowledge Questionnaire (JAKQ), developed and validated in Belgium. Patients were re-cruited at a tertiary centre in Kraków, Poland. A total of 479 AF patients completed the JAKQ. Patients on NOACs (n = 276, 57.6%) compared with those on VKAs (n = 175, 36.5%) did not differ regarding demographic and clinical variables. The mean score of the JAKQ was very similar in the NOAC and VKA group (60.7 ± 17.0% vs. 61.6 ± 17.1%; p = 0.4, respectively). The differences in the proportion of correct responses referred to three questions. Consequences of AF, such as blood clots and cerebral infarction, were more obvious for patients on NOACs compared with those on VKAs (81.5% vs. 70.9%; p = 0.01). The patients on NOACs (78.7% vs. 67.6%; p = 0.009) more frequently considered consulting a physician for advice concerning anticoagulant treatment before surgery, while fewer patients on NOACs were aware of the need to take their medication even if they did not feel AF (76.1% vs. 89.7%; p = 0.0004). Only 25.9% of the VKA patients and 49.3% of the NOAC users knew what to do if they missed a dose of the anticoagulant. The knowledge of arrhythmia and anticoagulation is better regarding the safety issues among subjects on NOACs compared with those on VKAs. Irrespective of the type of oral anticoagulation therapy, education of AF patients should be improved.


Hardware failure in patients with metastatic cancer to the spine.
The spine is the most common site of skeletal metastases, affecting approximately 30% of individuals with cancer. The aim of surgical treatment for metastatic spine disease is generally palliative to address pain and/or neurologic compromise, significantly improving patients' quality of life. Patients with metastatic spine disease, however, represent a vulnerable cohort and may have comorbidities or previous treatments that impair the structural integrity of spinal hardware. As such, identifying factors that may contribute to hardware failure is an essential component in treating individuals with metastatic spine disease. The aim of this study was to identify pre-operative risk factors associated with hardware failure in patients undergoing surgical treatment for metastatic spine disease. A retrospective cohort study was conducted to include patients surgically treated for metastatic spine tumors between 2003 and 2013, at a single institution. A univariate analysis was initially performed to identify associated factors. Any associated factor with a p-value <0.20 was included in the multivariate analysis. 3 patients (1.9%), of the 159 patients included in the study, had failure of the spine instrumentation. 1 patient had metastatic prostate cancer, and 2 had metastatic breast cancer. Patient demographics, co-morbidities, tumor location, and primary tumor etiology were not found to be statistically significant, with respect to hardware failure. Predictive factors included in the multivariate model were other bone metastasis, visceral metastasis, brain metastasis, Modified Rankin scale, previous systemic chemotherapy, previous radiation to the spine, and mean survival. Previous radiation to the spine was the only factor to be significantly associated (p=0.029), present in all three patients with hardware failure. Of note, there was a trend indicating that patients with longer life expectancies were more likely to experience hardware failure (mean survival of 16.7months in non-failure cohort vs. 33months in failure cohort), though this did not achieve statistical significance due to the limited sample size of patients with hardware failure. Hardware failure is a risk for all patients who undergo instrumentation following resection for metastatic spine tumors. This study identified that pre-operative radiation may increase the risk for hardware failure in this population.


Genomics Reveals the Origins of Historical Specimens.
Centuries of zoological studies have amassed billions of specimens in collections worldwide. Genomics of these specimens promises to reinvigorate biodiversity research. However, because DNA degrades with age in historical specimens, it is a challenge to obtain genomic data for them and analyze degraded genomes. We developed experimental and computational protocols to overcome these challenges and applied our methods to resolve a series of long-standing controversies involving a group of butterflies. We deduced the geographical origins of several historical specimens of uncertain provenance that are at the heart of these debates. Here, genomics tackles one of the greatest problems in zoology: countless old specimens that serve as irreplaceable embodiments of species concepts cannot be confidently assigned to extant species or population due to the lack of diagnostic morphological features and clear documentation of the collection locality. The ability to determine where they were collected will resolve many on-going disputes. More broadly, we show the utility of applying genomics to historical museum specimens to delineate the boundaries of species and populations, and to hypothesize about genotypic determinants of phenotypic traits.


Controlled and reversible binding of positively charged quantum dots to lambda DNA.
Biomacromolecules/Nanomaterials bioconjugate complexes have many applications in the interdisciplinary research fields. Accessible and easy synthesis methods of these complexes are the key roles for these applications. High quality water-soluble surface-charged quantum dots (QDs) were successfully prepared via surface modification by amphiphilic surfactants. The positively charged QDs can interact with deoxyribonucleic acid (DNA) molecules to form QDs/DNA bioconjugates via self-targeting electrostatic force. The stability of these QDs/DNA bioconjugates is influenced by ionic strength and concentration of negative or neutral surfactants in the solution. High ionic concentration or ca. 10(-3) mol/L surfactants can break the interaction between the QDs and DNA molecules (Lambda DNA/Hind III Marker segments) and controllably release DNA molecules from these bioconjugates. The conformation of DNA molecules has little change during the binding and releasing process. The condensation of lambda DNA molecules can be induced by positively charged QDs. High resolution transmission electron microscopy experiments have revealed the different stages of DNA condensation process, showing the fine structures of QDs/DNA bioconjugates at biomolecular scale. A long chain DNA molecule starts to self-enwind and condense to a porous globule when it is exposing to positively charged QDs but there is no direct interaction between QDs and DNA at early stages of condensation. After the DNA molecule becomes a compact globule, QDs stick onto its surface via electrostatic force. The coil conformation of the DNA molecules can be recovered from globule structure after DNA molecules are controllably released from bioconjugate complexes. These QDs/DNA bioconjugates have great potential applications for gene delivery and at the same time the fluorescence of QDs can be utilized to monitor the DNA releasing process.


Design and Implementation of Advanced Machine Learning Management and Its Impact on Better Healthcare Services: A Multiple Regression Analysis Approach (MRAA).
In the current information and technology era, business enterprises are focusing in performing the process effectively by reducing the waiting time in completing the work, reduce latency and deploy the resources effectively so as to service the patient, medical practitioners, societies, and other stakeholders in an efficient manner. Hence, several organisations are using the emerging technologies so as to obtain high performance and enhance competitive edge. The advancement in machine learning, deep learning, business analytics, etc. enables the health care industry to identify the patterns based on the data collected and create a pivotal position and enhance revenues and profits in a sustainable manner. Machine learning models are considered as computational algorithms which will enable in collected the data, analyze them, and provide the necessary reports to the experts and management in order to make informed decision making. The application of advanced machine learning enables the organisation to process the image effectively, recognize the voice and enable in servicing the customers, process the available data, and identify the patterns so as to make informed decision making. The basic purpose of the study is to analyze the overall implementation of advanced machine learning approaches towards health care services for providing enhanced services, better patient engagement, and support in creating better life for them, the researchers intend to collect the closed-ended questionnaire from employees in different medical centers covering: apprehend the nature of designing and implementation of machine learning approaches in the organisation and understand the effectiveness of these tools in enhancing the sustainable growth and development of the organisation.


The effect of printed educational material from the coroner in Victoria, Australia, on changing aged care health professional practice: a subscriber survey.
There are substantial knowledge and research gaps about the effects of printed educational material on professional practice. This study has examined whether the Residential Aged Care Coronial (RACC) Communiqué, an electronic newsletter of narrative case reports about lessons learned from deaths in residential aged care settings reported to the coroner in Victoria, Australia, prompted subscribers to initiate change in professional practice to improve care. An anonymous electronic survey was distributed to all registered subscribers of the RACC Communiqué to collect information about self-reported changes in professional practice, respondent characteristics, reading behavior, and an assessment of effect and content of the publication. Researchers from the Victoria Institute of Forensic Medicine, Victoria, Australia, conducted the study in 2008. Of 778 subscribers invited to participate in the study, 426 (54.8%) provided valid responses. The majority of respondents were aged 45 and older, female, and working at a residential aged care facility in a management role. Half of the survey respondents reported making a change to their professional practice as a result of reading the RACC Communiqué, with one-fifth of these respondents agreeing that they would not have made the self-reported change if they had not read this publication. These findings are greater than the previously reported small effects of education through printed education material and make an important contribution to understanding the use of printed education material for initiating professional practice change.


The positions of 12 simple sequence repeat markers relative to reference loci on mouse chromosome 16.
The genetic map positions of 12 simple sequence repeat (SSR) markers spanning mouse Chromosome (Chr) 16 were determined relative to reference markers on that chromosome. Interval mapping data were obtained with a panel of DNAs from two intersubspecific backcrosses. All but one of the markers were typed by us of nonradioactive polymerase chain reaction (PCR) products analyzed on agarose gels. The marker order was determined to be Prm-1, D16Mit9, Igl-1, D16Mit29, D16Mit1/D16Mit2, Smst, D16Mit4, D16Mit11, Gap43, D16Mit14, D16Mit30, D16Mit5, Pit-1, D16Mit27, D16H21S16 (formerly D21S16h), D16Mit19, App, D16Mit7, Sod-1. Two of these markers mapped to the known human Chr 21 (HSA21)/Chr 16 conserved linkage group. Nine additional SSR markers could not be typed because they were not polymorphic (four markers), did not amplify MOLD/Rk DNA (three markers), or failed to give PCR products under a range of conditions (two markers). A subset of the most robust SSRs provide a useful marker set for the analysis of previously unmapped crosses.


Parasite remains in archaeological sites.
Organic remains can be found in many different environments. They are the most significant source for paleoparasitological studies as well as for other paleoecological reconstruction. Preserved paleoparasitological remains are found from the driest to the moistest conditions. They help us to understand past and present diseases and therefore contribute to understanding the evolution of present human sociality, biology, and behavior. In this paper, the scope of the surviving evidence will be briefy surveyed, and the great variety of ways it has been preserved in different environments will be discussed. This is done to develop to the most appropriated techniques to recover remaining parasites. Different techniques applied to the study of paleoparasitological remains, preserved in different environments, are presented. The most common materials used to analyze prehistoric human groups are reviewed, and their potential for reconstructing ancient environment and disease are emphasized. This paper also urges increased cooperation among archaeologists, paleontologists, and paleoparasitologists.


Ovarian adrenergic nerves directly participate in the control of luteinizing hormone-releasing hormone and beta-adrenergic receptors during puberty: a biochemical and autoradiographic study.
The rat ovary receives sympathetic innervation from the superior ovarian nerve (SON) and the plexus nerve (OP). To examine the possibility of a direct adrenergic mechanism controlling ovarian receptor distribution during the onset of puberty, we have studied the acute (48-h) effect of unilateral nervotomy (combined section of SON and OP nerves) on ovarian LHRH and beta-adrenergic receptor concentrations and distribution using both radioreceptor assays and in vitro autoradiography. Ovarian LHRH receptor concentration increased sharply between 12 and 20 days of age. At this time receptors were mostly associated with follicles and interstitial cells, whereas at 37 days of age, when a measurable loss in the receptor concentration was observed, light and diffuse autoradiographic labeling of receptors was also found in the corpora lutea. Complete removal of adrenergic input to the gland produced a sharp decrease in LHRH-binding activity within the denervated ovary at each time interval studied, with no effect in the innervated contralateral gland. Autoradiographic data also revealed a decrease in both the number of labeled follicles and the intensity of the labeling. beta-Adrenergic receptor concentration increased progressively between days 12 and 27, reaching a peak value at 37 days of age. Labeling was very weak at 12 days of age and increased progressively at 20 and 27 days of age. At this time, receptors were mostly localized by autoradiography in the interstitial cells, while at 37 days of age corpora lutea were strongly labeled. Ovarian beta-adrenergic receptors showed a marked drop when acutely deprived of their neural tone, as illustrated by the 2- to 3-fold decrease in receptor-binding capacity within the denervated gland. The autoradiographic data also showed marked changes in beta-adrenergic receptor distribution, specially at 37 days of age. At this time, the labeling of corpora lutea was markedly decreased in denervated ovaries. The present results clearly demonstrate that complete removal of ovarian adrenergic tone produces a profound decrease in the concentrations of LHRH and beta-adrenergic receptors within the ovary, although it cannot be excluded that peptidergic factors also arriving via the SON and OP could have some influence on the regulation of these receptors. The results support the concept of a direct involvement of the central nervous system in ovarian function. They also suggest that during ovarian development a neural efferent system might be involved in the adjustment of ovarian responsiveness to stimulation by the gonadotropins via changes in receptor content and/or distribution in the different ovarian compartments.


Fusiform correlates of facial memory in autism.
Prior studies have shown that performance on standardized measures of memory in children with autism spectrum disorder (ASD) is substantially reduced in comparison to matched typically developing controls (TDC). Given reported deficits in face processing in autism, the current study compared performance on an immediate and delayed facial memory task for individuals with ASD and TDC. In addition, we examined volumetric differences in classic facial memory regions of interest (ROI) between the two groups, including the fusiform, amygdala, and hippocampus. We then explored the relationship between ROI volume and facial memory performance. We found larger volumes in the autism group in the left amygdala and left hippocampus compared to TDC. In contrast, TDC had larger left fusiform gyrus volumes when compared with ASD. Interestingly, we also found significant negative correlations between delayed facial memory performance and volume of the left and right fusiform and the left hippocampus for the ASD group but not for TDC. The possibility of larger fusiform volume as a marker of abnormal connectivity and decreased facial memory is discussed.


Auricular Clyster, Otenchytes, and Pyoulcos: Precursors of the Ear Syringe.
In Western medicine, the long history of the ear syringe dates back at least to the end of the 1st millennium BCE; but the corresponding Ancient Greek word surinx designates another tool. Other Greek and Latin words and phrases, in particular auricular clyster, otenchytes, and pyoulcos, were known as names of the ear syringe until modern times. The aim of this article is to study the Greek and Latin words and phrases referred to as names of the ear syringe up until modern times before syringe became the standard word. Historical and philological review of ancient Greek and Latin medical literature dealing with the subject. Careful reading of ancient medical texts mentioning these tools shows a variety of shapes and uses: beside the piston-driven syringe, the system of a bladder attached to a catheter remained in use throughout Antiquity; the otenchytes, being a piston-driven syringe, obviously was not used to squirt the liquid when the remedy put inside was warmed by a flame; the piston-driven pyoulcos is most likely of greater size, and never linked with ear care in Antiquity. Latin auricular clyster and Greek otenchytes and pyoulcos, in the few ancient texts in which they occur, designate tools of a large variety of shapes and uses, significantly different from Heron's description of piston-driven pyoulcos.


Deep Brain Stimulation, Stereotactic Radiosurgery and High-Intensity Focused Ultrasound Targeting the Limbic Pain Matrix: A Comprehensive Review.
Chronic pain (CP) represents a socio-economic burden for affected patients along with therapeutic challenges for currently available therapies. When conventional therapies fail, modulation of the affective pain matrix using reversible deep brain stimulation (DBS) or targeted irreversible thalamotomy by stereotactic radiosurgery (SRS) and magnetic resonance (MR)-guided focused ultrasound (MRgFUS) appear to be considerable treatment options. We performed a literature search for clinical trials targeting the affective pain circuits (thalamus, anterior cingulate cortex [ACC], ventral striatum [VS]/internal capsule [IC]). PubMed, Ovid, MEDLINE and Scopus were searched (1990-2021) using the terms "chronic pain", "deep brain stimulation", "stereotactic radiosurgery", "radioneuromodulation", "MR-guided focused ultrasound", "affective pain modulation", "pain attention". In patients with CP treated with DBS, SRS or MRgFUS the somatosensory thalamus and periventricular/periaquaeductal grey was the target of choice in most treated subjects, while affective pain transmission was targeted in a considerably lower number (DBS, SRS) consisting of the following nodi of the limbic pain matrix: the anterior cingulate cortex; centromedian-parafascicularis of the thalamus, pars posterior of the central lateral nucleus and internal capsule/ventral striatum. Although DBS, SRS and MRgFUS promoted a meaningful and sustained pain relief, an effective, evidence-based comparative analysis is biased by heterogeneity of the observation period varying between 3 months and 5 years with different stimulation patterns (monopolar/bipolar contact configuration; frequency 10-130 Hz; intensity 0.8-5 V; amplitude 90-330 μs), source and occurrence of lesioning (radiation versus ultrasound) and chronic pain ethology (poststroke pain, plexus injury, facial pain, phantom limb pain, back pain). The advancement of neurotherapeutics (MRgFUS) and novel DBS targets (ACC, IC/VS), along with established and effective stereotactic therapies (DBS-SRS), increases therapeutic options to impact CP by modulating affective, pain-attentional neural transmission. Differences in trial concept, outcome measures, targets and applied technique promote conflicting findings and limited evidence. Hence, we advocate to raise awareness of the potential therapeutic usefulness of each approach covering their advantages and disadvantages, including such parameters as invasiveness, risk-benefit ratio, reversibility and responsiveness.


STAT3 in Breast Cancer Onset and Progression: A Matter of Time and Context.
Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.


Contribution of polyadenylate sequences to the translational efficiency of globin messenger RNAs.
mRNAs from reticulocyte polysomes were fractionated by chromatography on poly(U)-Sepharose and thermal elution. The molar ratio of alpha- to beta-globin mRNA was found to be 2:1 and 1:1 respectively in short- and long-poly(A) size classes. Translational analyses indicated that the globin mRNAs containing long poly(A) tracts (with a mean length of about 70 nucleotides) directed protein synthesis with higher rates than did mRNA containing short poly(A) tracts (15-35 nucleotides). Experiments performed with sub-saturating mRNA concentrations showed that the digestion with RNAase H induced a decrease in the translational capacity of both globin mRNAs and an increase in the alpha- to beta-globin synthesis ratio. No correlation was observed between the size of the poly(A) tail in mRNA and the optimal K+ requirement for translation.


Escherichia coli challenge in newborn pigs.
Escherichia coli F18 is a common porcine enteric pathogen causing diarrhea and edema in weaned pigs. An essential step in the pathogenesis of this enteric colibacillosis is a fimbria-receptor interaction in the small intestine, involving the α(1,2)-fucosyltransferase gene (FUT1) enzyme for bacterial receptor binding to the epithelium. Enzyme expression is genetically determined and increases after weaning at 3 to5 wk, probably due to age- and/or diet-related intestinal maturation. We hypothesized that artificially reared piglets, deprived of sow's milk from birth, show susceptibility to F18 already in the neonatal period. First we verified the intestinal expression of FUT1 in preterm, term, and weaned pigs by quantitative real-time polymerase chain reaction. Then age-related F18 susceptibility (degree of diarrhea) was evaluated in 3-, 10-, and 20-d-old pigs after inoculation of 10(10) cfu E. coli F18 per day for 12 d. Finally, F18 susceptibility was evaluated in caesarean-delivered 0- to 7-d-old piglets inoculated daily with F18 as above. For all pigs, their sows were genotyped to ensure expression of the FUT1 enzyme. FUT1 expression was detected in the proximal and distal small intestine with no apparent differences in levels among preterm, term, and weaned pigs. No consistent F18-induced diarrhea was detected in any of the 3 groups of 3- to 20-d-old pigs. In contrast, 0- to 7-d-old caesarean-delivered pigs showed a higher score of diarrhea in pigs inoculated with F18 compared with controls (2.4 ± 0.1 vs. 1.8 ± 0.1 respectively; P < 0.001). Caesarean-delivered piglets deprived of sow milk are highly susceptible to diarrhea induced by E. coli F18. Lack of the protective effects of birth colonization and sow milk may contribute to high intestinal F18 sensitivity. The newborn pig may be a useful model to investigate factors in maternal milk that protect against F18 diarrhea.


Aging Strikes the Self-Face Advantage in Featural Processing.
Background/Study Context: The face is the most distinctive physical feature of a person. Previous work has shown that one's own face (self-face) is advantageous in perception. Here the authors investigate how aging influences the configural and featural processing of self-face. Older and young adults searched for their own faces and faces of strangers (Experiment 1) or acquaintances (Experiment 2) among distractor faces. The configural and featural processing of faces was assessed with face inversion in Experiment 1 and with changes in point of view in Experiment 2. Experiment 1 revealed a robust self-face advantage for upright faces in both young and older adults. A similar advantage was observed for inverted faces in young but not in older adults. Experiment 2 revealed a self-face advantage in older adults regardless of the point of view; in young adults, however, the self-face advantage only emerged for frontal view faces. The present study shows that older adults have a self-face advantage in configural but not in featural processing. The authors suggest that the impairment in featural processing in older adults is likely the result of age-related changes in perceptual experience.