The role of arginine vasopressin in the development of tolerance to ethanol in normal and Brattleboro rats.
Administration of AVP and related peptide fragments following ethanol (EtOH) administration has been shown to enhance retention of tolerance to ethanol. The present studies were designed specifically to: (1) examine the influence of AVP given concurrently with EtOH on the development of tolerance to the ataxic and hypothermic effects of EtOH in Long-Evans rats, and (2) to determine if tolerance to these effects develops in Brattleboro rats which are deficient in AVP. In Experiment 1, EtOH (2.5 g/kg, 15% v/v) was administered IP to 2 groups of rats in combination with a SC injection of either AVP (6 micrograms/kg) or an equal volume of saline. Two additional control groups received IP saline injections in combination with either saline or AVP. After 13 days, EtOH-treated rats were significantly more tolerant than saline-treated animals. AVP significantly increased the hypothermic and ataxic effects of EtOH and failed to enhance tolerance development. AVP delayed the extinction of tolerance to the hypothermic (but not the ataxic) effects of ethanol when administered during the extinction phase to rats previously treated with EtOH. In Experiment 2, Brattleboro rats were injected with EtOH or an equivalent volume of saline and tested for ataxia and hypothermia. Rats receiving EtOH failed to demonstrate significant tolerance to either effect of ethanol after 12 treatment days.


Steady-state fluctuations of a genetic feedback loop: an exact solution.
Genetic feedback loops in cells break detailed balance and involve bimolecular reactions; hence, exact solutions revealing the nature of the stochastic fluctuations in these loops are lacking. We here consider the master equation for a gene regulatory feedback loop: a gene produces protein which then binds to the promoter of the same gene and regulates its expression. The protein degrades in its free and bound forms. This network breaks detailed balance and involves a single bimolecular reaction step. We provide an exact solution of the steady-state master equation for arbitrary values of the parameters, and present simplified solutions for a number of special cases. The full parametric dependence of the analytical non-equilibrium steady-state probability distribution is verified by direct numerical solution of the master equations. For the case where the degradation rate of bound and free protein is the same, our solution is at variance with a previous claim of an exact solution [J. E. M. Hornos, D. Schultz, G. C. P. Innocentini, J. Wang, A. M. Walczak, J. N. Onuchic, and P. G. Wolynes, Phys. Rev. E 72, 051907 (2005), and subsequent studies]. We show explicitly that this is due to an unphysical formulation of the underlying master equation in those studies.


A new method of cranioplasty.
A new method of cranioplasty is described in which the skull defect is exposed and multiple angled holes through the outer cortical bone are made. Methyl methacrylate is molded into the defect continuous with the perforating holes. The major advantage of this technique is the resulting good cosmetic appearance, in addition to the strength and firmness of position it provides.


A novel procedure for protein extraction from formalin-fixed paraffin-embedded tissues.
Most of the archived pathological specimens in hospitals are kept as formalin-fixed paraffin-embedded tissues (FFPE) for long-term preservation. Up to now, these samples are only used for immunohistochemistry in a clinical routine as it is difficult to recover intact protein from these FFPE tissues. Here, we report a novel, short time-consuming and cost-effective method to extract full-length, non-degraded proteins from FFPE tissues. This procedure is combined with an effective and non-toxic deparaffinisation process and an extraction method based on antigen-retrieval, high concentration of SDS and high temperature. We have obtained enough intact protein to be detected by Western blotting analysis. This technique will allow utilising these stored FFPE tissues in several applications for protein analysis helping to advance the translational studies in cancer and other diseases.


Incorporating outpatient perceptions into definitions of quality.
This paper reviews the ways in which quality measures have been defined by reference to objective measures and applied by the producers of health care to patients. Patient satisfaction surveys may be thought to redress this imbalance and will be addressed as a precursor to the discussion of the SERVQUAL methodology, developed to measure the gap between expectations and performance in service industries. An argument will be advanced that quality measurement is still producer-led and should incorporate the views of patients more directly into the quality measurement process. It is suggested that calibration or baseline surveys of patients be conducted which then identify the issues that may be subject to more sustained quantitative analysis. Quality monitoring should be conducted in such a way that particular sub-groups can be subject to routine analysis. Models of quality measurement need to incorporate the perspectives of many 'key players' in which the views of patients are complemented by relevant professional, clinical and managerial groups. The extent to which there is a disjunction between quality as objectively measured (e.g. by waiting times) and as experienced by patients will receive attention. Suggestions will be made that monitoring and clinic operations need to be more mutually reinforcing.


Fabrication and testing of planar chalcogenide waveguide integrated microfluidic sensor.
We have fabricated and tested, to the best of our knowledge, the first microfluidic device monolithically integrated with planar chalcogenide glass waveguides on a silicon substrate. High-quality Ge(23)Sb(7)S(70) glass films have been deposited onto oxide coated silicon wafers using thermal evaporation, and high-index-contrast channel waveguides have been defined using SF(6) plasma etching. Microfluidic channel patterning in photocurable resin (SU8) and channel sealing by a polydimethylsiloxane (PDMS) cover completed the device fabrication. The chalcogenide waveguides yield a transmission loss of 2.3 dB/cm at 1550 nm. We show in this letter that using this device, N-methylaniline can be detected using its well-defined absorption fingerprint of the N-H bond near 1496 nm. Our measurements indicate linear response of the sensor to varying N-methylaniline concentrations. From our experiments, a sensitivity of this sensor down to a N-methylaniline concentration 0.7 vol. % is expected. Given the low-cost fabrication process used, and robust device configuration, our integration scheme provides a promising device platform for chemical sensing applications.


Origins of gene, genetic code, protein and life: comprehensive view of life systems from a GNC-SNS primitive genetic code hypothesis.
We have investigated the origin of genes, the genetic code, proteins and life using six indices (hydropathy, alpha-helix, beta-sheet and beta-turn formabilities, acidic amino acid content and basic amino acid content) necessary for appropriate three-dimensional structure formation of globular proteins. From the analysis of microbial genes, we have concluded that newly-born genes are products of nonstop frames (NSF) on antisense strands of microbial GC-rich genes [GC-NSF(a)] and from SNS repeating sequences [(SNS)n] similar to the GC-NSF(a) (S and N mean G or C and either of four bases, respectively). We have also proposed that the universal genetic code used by most organisms on the earth presently could be derived from a GNC-SNS primitive genetic code. We have further presented the [GADV]-protein world hypothesis of the origin of life as well as a hypothesis of protein production, suggesting that proteins were originally produced by random peptide formation of amino acids restricted in specific amino acid compositions termed as GNC-, SNS- and GC-NSF(a)-0th order structures of proteins. The [GADV]-protein world hypothesis is primarily derived from the GNC-primitive genetic code hypothesis. It is also expected that basic properties of extant genes and proteins could be revealed by considerations based on the scenario with four stages.


Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer.
The purpose of this study aimed to investigate the clinicopathologic characteristics of breast cancer according to its cancer-associated fibroblast (CAF) phenotype. Immunohistochemistry staining of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER-2), Ki-67, podoplanin, prolyl 4-hydroxylase, fibroblast activation protein alpha (FAPα), S100A4, platelet-derived growth factor receptor alpha (PDGFRα), PDGFRβ, and chondroitin sulfate proteoglycan (NG2) was performed on tissue microarray consisting of 642 breast cancer cases. Samples were categorized into luminal A, luminal B, HER-2, or triple-negative breast cancer (TNBC) according to immunohistochemical results, whereas tumor stroma was classified into desmoplastic, sclerotic, normal-like, or inflammatory type based on histological findings. Expression of CAF-related proteins in the stroma differed depending on breast cancer molecular subtypes. All CAF-related protein expression was high (p < 0.05) in HER-2 type, whereas in luminal A, the expression of FAPα, PDGFα, PDGFβ, and NG2 was low, and in TNBC, the expression of podoplanin, prolyl 4-hydroxylase, and S100A4 was low. In the stromal component, CAF-related protein expression differed according to stromal phenotype (p < 0.001). The desmoplastic type showed high expression of podoplanin, prolyl 4-hydroxylase, S100A4, PDGFRα, and PDGFRβ, whereas the sclerotic type exhibited low expression of FAPα, PDGFα, PDGFβ, and NG2. The inflammatory type had high expression of FAPα and NG2 with low podoplanin, while normal-like type showed low expression of prolyl 4-hydroxylase and S100A4. Our results suggested that differential CAF-related protein expression depended on the molecular subtypes and stromal histologic features of breast cancer, indicating that in the future, this system could potentially use these markers for prognosis prediction and targeted therapy of breast cancer.


Physiological function and metabolism of free D-alanine in aquatic animals.
Aquatic crustaceans and some bivalve mollusks contain a large amount of free D-alanine (up to 100 mumol/g wet wt.) in their tissues. Under high salinity stress, crustaceans and bivalve mollusks largely accumulate D- and L-alanine irrespective of species examined, together with L-glutamine, L-proline, and glycine of which increases are species dependent. These data indicate that D-alanine is one of the major compatible osmolytes responsible for the intracellular isosmotic regulation in the tissues of crustaceans and bivalves. Alanine racemase has been proven to catalyze the interconversion of D- and L-alanine in these invertebrates. The enzyme has been isolated to homogeneity from the muscle of black tiger prawn Penaeus monodon and its cDNA has been cloned from the muscle and hepatopancreas of kuruma prawn Penaeus japonicus for the first time in eukaryotes other than yeast. Several fish species fed on crustaceans and mollusks contain D-amino acid and D-aspartate oxidases that catalyze the decomposition of D-amino acids. A cDNA of D-amino acid oxidase has been cloned from the hepatopancreas of omnivorous common carp Cyprinus carpio. During oral administration of free D-alanine to carp, the activity and mRNA of D-amino acid oxidase increased rapidly in hepatopancreas and the increases were highest in intestine followed by hepatopancreas and kidney. These data suggest that D-amino acid oxidase is inducible in carp and an important enzyme responsible for the efficient utilization of carbon skeleton of D-alanine in their feeds.


Interpretation of mandibular condyle fractures using 2D- and 3D-computed tomography.
Computed tomography (CT) has been increasingly used in the examination of patients with craniofacial trauma. This technique is useful in the examination of the temporomandibular joint and allows the diagnosis of fractures of the mandibular condyle. Aiming to verify whether the three-dimensional reconstructed images from CT (3D-CT) produce more effective visual information than the two-dimensional (2D-CT) ones, we evaluated 2D-CT and 3D-CT examinations of 18 patients with mandibular condyle fractures. We observed that 2D-CT and 3D-CT reconstructed images produced similar information for the diagnosis of fractures of the mandibular condyle, although the 3D-CT allowed a better visualization of the position and displacement of bone fragments, as well as the comminution of fractures. These results, together with the possibility of refining and manipulating perspectives in 3D images, reinforce the importance of its use in the surgical planning and evaluation of treatment. We concluded that 3D-CT presented supplementary information for a more effective diagnosis of mandibular condyle fractures.


Photochemical transformations accelerated in continuous-flow reactors: basic concepts and applications.
Continuous-flow photochemistry is used increasingly by researchers in academia and industry to facilitate photochemical processes and their subsequent scale-up. However, without detailed knowledge concerning the engineering aspects of photochemistry, it can be quite challenging to develop a suitable photochemical microreactor for a given reaction. In this review, we provide an up-to-date overview of both technological and chemical aspects associated with photochemical processes in microreactors. Important design considerations, such as light sources, material selection, and solvent constraints are discussed. In addition, a detailed description of photon and mass-transfer phenomena in microreactors is made and fundamental principles are deduced for making a judicious choice for a suitable photomicroreactor. The advantages of microreactor technology for photochemistry are described for UV and visible-light driven photochemical processes and are compared with their batch counterparts. In addition, different scale-up strategies and limitations of continuous-flow microreactors are discussed.


Palladium Nanoparticles Synthesized by Laser Ablation in Liquids for Antimicrobial Applications.
Antibiotic resistance is a leading cause of death worldwide. In this paper, we explore new alternatives in the treatment of infections. Noble metal nanoparticles could help to mitigate this problem. In this work, palladium nanoparticles were synthesized by laser ablation in order to explore their antimicrobial capacity. To obtain palladium nanoparticles, a palladium plate immersed in water, or methanol, was ablated, using two pulsed lasers that emit radiation with wavelengths of 532 nm and 1064 nm, respectively. Pure Pd-NPs with crystalline microstructure and rounded shape were obtained. The nanoparticles' size is more homogeneous if the laser wavelength is 532 nm, and it decreases when methanol is used as solvent, reaching mean diameters smaller than 6 nm. With the objective of studying antimicrobial activity against Staphylococcus aureus, the Pd-NPs were immobilized on the surface of titanium discs. The release of palladium ions was recorded during the first seven days, and the cytotoxicity of the immobilized NPs was also tested with L929 mouse fibroblast cell line. Palladium nanoparticles synthesized by means of the infrared laser in methanol showed a strong inhibitory effect on S. aureus and good cytocompatibility, with no toxic effect on fibroblast cells.


Monoclonal antibodies to human interferon-gamma. II: Antibodies with neutralizing activity.
Two types of hybridomas secreting monoclonal antibodies (MAB) with neutralizing activity against human interferon-r (HuIFN-r) were obtained by somatic cell hybridization between mouse myeloma P3UI cells and spleen cells from BALB/c mice immunized with purified recombinant HuIFN-r and a conjugate of a synthetic amino-terminal peptide (residues 4-21) of HuIFN-r and bovine thyroglobulin. One of these MAB recognized the amino-terminal region (residues 4-21) of HuIFN-r, and the other recognized some region in the internal part (residues 22-130) of the molecule. These results suggest that another region, in addition to the amino-terminal region, contributed to the biological activity of rHuIFN-r. A combination of one of these MAB and a previously described MAB directed to the carboxyl-terminal region (residues 131-146) of HuIFN-r enables a quantitative and sensitive assay method of biologically active rHuIFN-r.


Early embryonic modification of maternal hormones differs systematically among embryos of different laying order: A study in birds.
Vertebrate embryos are exposed to maternal hormones that can profoundly affect their later phenotype. Although it is known that the embryo can metabolize these maternal hormones, the metabolic outcomes, their quantitative dynamics and timing are poorly understood. Moreover, it is unknown whether embryos can adjust their metabolic activity to, for example, hormones or other maternal signals. We studied the dynamics of maternal steroids in fertilized and unfertilized rock pigeon eggs during early incubation. Embryos of this species are naturally exposed to different amounts of maternal steroids in the egg according to their laying position, which provides a natural context to study differential embryonic regulation of the maternal signals. We used mass spectrometric analyses to map changes in the androgen and estrogen pathways of conversion. We show that the active hormones are heavily metabolized only in fertilized eggs, with a corresponding increase in supposedly less potent metabolites already within one-fourth of total incubation period. Interestingly, the rate of androgen metabolism was different between embryos in different laying positions. The results also warrant a re-interpretation of the timing of hormone mediated maternal effects and the role of the supposedly biologically inactive metabolites. Furthermore, the results also provide a potential solution as to how the embryo can prevent maternal steroids in the egg from interfering with its sexual differentiation processes as we show that the embryo can metabolize most of the maternal steroids before sexual differentiation starts.


The novel, major locus Rpi-phu1 for late blight resistance maps to potato chromosome IX and is not correlated with long vegetation period.
Despite the long history of breeding potatoes resistant to Phytophthora infestans, this oomycete is still economically the most important pathogen of potato worldwide. The correlation of high levels of resistance to late blight with a long vegetation period is one of the bottlenecks for progress in breeding resistant cultivars of various maturity types. Solanum phureja was identified as a source of effective late blight resistance, which was transferred to the cultivated gene pool by interspecific crosses with dihaploids of Solanum tuberosum. A novel major resistance locus, Rpi-phu1, derived most likely from S. phureja and conferring broad-spectrum resistance to late blight, was mapped to potato chromosome IX, 6.4 cM proximal to the marker GP94. Rpi-phu1 was highly effective in detached leaflet, tuber slice and whole tuber tests during 5 years of quantitative phenotypic assessment. The resistance did not show significant correlation with vegetation period length. Our findings provide a well-characterized new source of resistance for breeding early and resistant-to-P. infestans potatoes.


The interplay between genetic background and sexual dimorphism of doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors. Nevertheless, DOX is known to have cardiotoxic effects that may lead to cardiac dysfunction and failure. In experimental studies, female animals have been shown to be protected against DOX-induced cardiotoxicity; however, the evidence of this sexual dimorphism is inconclusive in clinical studies. Therefore, we sought to investigate whether genetic background could influence the sexual dimorphism of DOX-induced cardiotoxicity. Male and female Wistar Kyoto (WKY) and Spontaneous Hypertensive Heart Failure (SHHF) rats were used. DOX was administered in eight doses of 2 mg/kg/week and the rats were followed for an additional 12 weeks. Cardiac function was assessed by trans-thoracic echocardiography, systolic blood pressure was measured by the tail cuff method, and heart and kidney tissues were collected for histopathology. Female sex protected against DOX-induced weight loss and increase in blood pressure in the WKY rats, whereas it protected against DOX-induced cardiac dysfunction and the elevation of cardiac troponin in SHHF rats. In both strains, female sex was protective against DOX-induced nephrotoxicity. There was a strong correlation between DOX-induced renal pathology and DOX-induced cardiac dysfunction. This study highlights the importance of studying the interaction between sex and genetic background to determine the risk of DOX-induced cardiotoxicity. In addition, our findings suggest that DOX-induced nephrotoxicity may play a role in DOX-induced cardiac dysfunction in rodent models.


Club drugs: reasons for and consequences of use.
This preliminary descriptive study was designed to assess the reasons, primary contexts, and consequences (physical, psychological, lifestyle) of club drug use in a sample of young adults in a mid-size U.S. city. Fifty young adults (18 to 30 years old) reported on their use of club drugs (Ecstasy, GHB, ketamine, Rohypnol, methamphetamine, LSD) in face-to-face interviews that included quantitative and qualitative measures. Ecstasy was the most frequently used club drug followed by ketamine, LSD and methamphetamine. All of the participants reported using club drugs to "experiment" and most reported using these drugs to feel good and enhance social activities. Club drugs were frequently used at raves, in bars or clubs, and at home with friends. An average of 16 negative physical, psychological, and lifestyle consequences were reported for club drug use. Despite substantial negative consequences, participants perceived several positive consequences of regular recreational club drug use. These findings corroborate descriptions of club drug use in other countries (e.g., Australia, United Kingdom) and provide additional information on perceived positive consequences that users experience with club drug use. Further exploration of the reasons and positive consequences that are associated with use of each of the club drugs may provide important information on the growing trend in use of these drugs.


Benzoporphyrin derivative monacid ring A (Verteporfin) alone has no inhibitory effect on intimal hyperplasia: in vitro and in vivo results.
Benzoporphyrin derivative monoacid ring A (Verteporfin, BPD-MA), a photosensitizing drug, has been suggested as having inhibitory effects on smooth muscle cell (SMC) proliferation in rabbit aortic intimal injuries. The effect of BPD-MA on vascular SMCs in the absence of light stimulation in vitro and in vivo was studied using models of intimal hyperplasia. Human SMCs were incubated with BPD-MA for 4 h in darkness. A small (20%) but significant decrease in viability (n =42,p < .05) was noted for BPD-MA concentrations above 15 microg/mL. This was an all-or-none phenomenon with no further decrease in viability at higher concentrations. Treatment with BPD-MA was also carried out in vivo using a balloon injury model of intimal hyperplasia in rabbit aortas. Thirty-three rabbits were randomized into five groups and given intravenous BPD-MA (2 mg/kg) according to the following schedule: Group 1 (n = 8), BPD-MA 25 min prior to injury; Group 2 (n = 8), BPD-MA 25 min prior to injury plus a second dose 4 weeks later; Group 3 (n = 4), BPD-MA immediately postinjury; Group 4 (n = 7), BPD-MA immediately postinjury plus a second dose 4 weeks later; or Group 5 (n = 6), no drug (control group). No statistically significant difference was seen in the amount of intimal hyperplasia that developed in the five groups.


Homologous recombination as a mechanism for genome rearrangements: environmental and genetic effects.
Novel findings over the last 2 years have led to an increased emphasis on homologous recombination (HR) as both a pathway for DNA repair and a cause for genomic rearrangements. Indeed, environmental carcinogens increase the frequency of HR, as can be observed when two copies of a duplicated sequence recombine to delete the intervening sequences. Such HR events between dispersed homologous sequences may result in not only deletions, but also gene duplications or translocations. These types of genomic rearrangement have been observed to be the cause of several different genetic diseases, including cancer. In reflection of this, several genes have been identified that, when mutant, predispose an individual to an increased frequency of cancer. These genes have been shown to be either directly or indirectly involved in HR. In addition, HR is induced by a wide variety of carcinogens, preferentially in proliferating cells. This fits the most current models of recombination and its involvement in reinitiating stalled replication forks. Thus, 'correct' HR repair may act with high fidelity, an important issue for proliferating cells, but in the context of alternative homologous partner sequences, 'aberrant' HR can cause genomic rearrangements with dire consequences.


Efficacy and Safety of Upadacitinib in Patients with Psoriatic Arthritis: 2-Year Results from the Phase 3 SELECT-PsA 1 Study.
Efficacy and safety of the Janus kinase (JAK) inhibitor upadacitinib (UPA) was evaluated in patients with psoriatic arthritis (PsA) through week 104 of the ongoing long-term extension of the phase 3 trial SELECT-PsA 1. Exploratory analyses of all primary and secondary endpoints (non-responder imputation and as observed for binary endpoints; mixed-effect model repeated measures and as observed for continuous endpoints), and summary of treatment-emergent adverse events, in patients receiving UPA 15 mg (UPA15) or 30 mg (UPA30) once daily, or adalimumab 40 mg (ADA) every other week, through week 104 are reported. Of 1704 patients, 25.4% discontinued the study drug by week 104. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/50/70), ≥ 75%/90%/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), or minimal disease activity (MDA) were maintained through week 104; greater responses by nominal P value were observed with UPA15 and UPA30 versus ADA for ACR20/50/70 and MDA. Mean change from baseline in modified total Sharp/van der Heijde Score (mTSS) was similar across groups and to week 56 results. The safety profile of UPA was generally comparable to ADA and not altered from week 56 data. Rates of serious infection, herpes zoster, anemia, neutropenia, lymphopenia, and elevated creatine phosphokinase remained numerically higher with UPA15 and/or UPA30 versus ADA. Rates of malignancies excluding non-melanoma skin cancer (NMSC), major adverse cardiovascular events, and venous thromboembolism were similar across groups; rates of NMSC were higher with UPA versus ADA. Two deaths were reported with UPA15, one with UPA30, and one with ADA. In PsA patients, efficacy responses were similar or greater with UPA15 or UPA30 versus ADA through week 104, and inhibition of radiographic progression was maintained. No new safety risks were identified with exposure to UPA through 2 years (week 104). ClinicalTrials.gov, NCT03104400.


Factor Xa or thrombin: is thrombin a better target?
The limitations of the vitamin K antagonists have prompted the development of new oral anticoagulants that target specific clotting enzymes. Most of the novel agents currently under development target either thrombin or factor Xa. As the final effector of blood coagulation and the most potent platelet agonist, thrombin is a logical target for new oral anticoagulants. Clinical trials with parenteral direct thrombin inhibitors revealed that the therapeutic window is wider with reversible inhibitors than with irreversible inhibitors. The results of clinical trials with ximelagatran, an orally active prodrug of melagatran, a reversible direct thrombin inhibitor, validate thrombin as a target. Although ximelagatran was withdrawn from the market because of hepatotoxicity, newer oral thrombin inhibitors, such as dabigatran etexilate, are filling the void. Several oral factor Xa inhibitors also are being tested. Is thrombin a better target for new oral anticoagulants than factor Xa? Only time will tell!


Pulmonary surfactant and drug delivery: Vehiculization, release and targeting of surfactant/tacrolimus formulations.
This work explores the potential for strategizing pulmonary surfactant (PS) for drug delivery over the respiratory air-liquid interface: the interfacial delivery. The efficacy of PS- and interface-assisted drug vehiculization was determined both in vitro and in vivo using a native purified porcine PS combined with the hydrophobic anti-inflammatory drug Tacrolimus (TAC), a calcineurin inhibitor. In vitro assays were conducted in a novel double surface balance setup designed to emulate compression-expansion dynamics applied to interfacially connected drug donor and recipient compartments. In this setup, PS transported TAC efficiently over air-liquid interfaces, with compression/expansion breathing-like dynamics enhancing rapid interface-assisted diffusion and drug release. The efficacy of PS-assisted TAC vehiculization was also evaluated in vivo in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In anesthetized mice, TAC combined with PS was intra-nasally (i.n) instilled prior administering i.n. LPS. PS/TAC pre-treatment caused greater TAC internalization into a higher number of lung cells obtained from bronchoalveolar lavages (BAL) than TAC pre-treatment alone. Additionally, the PS/TAC combination but not TAC or PS alone attenuated the LPS-induced pro-inflammatory effects reducing cells and proteins in BAL fluid. These findings indicated that PS-mediated increase in TAC uptake blunted the pro-injurious effects of LPS, suggesting a synergistic anti-inflammatory effect of PS/drug formulations. These in vitro and in vivo results establish the potential utility of PS to open novel effective delivery strategies for inhaled drugs.


Molecular self-assembly from building blocks synthesized on a surface in ultrahigh vacuum: kinetic control and topo-chemical reactions.
Self-assembly of organic molecules on solid surfaces under ultrahigh vacuum conditions has been the focus of intense study, in particular utilizing the technique of scanning tunneling microscopy. The size and complexity of the organic compounds used in such studies are in general limited by thermal decomposition in the necessary vacuum sublimation step. An interesting alternative approach is to deposit smaller molecular precursors, which react with each other on the surface and form the building blocks for the subsequent self-assembly. This has however hitherto not been explored to any significant extent. Here, we perform a condensation reaction between aldehyde and amine precursors codeposited on a Au(111) surface. The reaction product consists of a three-spoke oligo-phenylene-ethynylene backbone with alkyl chains attached through imine coupling. We characterize the self-assembled structures and molecular conformations of the complex reaction product and find that the combined reaction and self-assembly process exhibits pronounced kinetic effects leading to formation of qualitatively different molecular structures depending on the reaction/assembly conditions. At high amine flux/low substrate temperature, compact triimine structures of high conformational order are formed, which inherit organizational motifs from structures formed from one of the reactants. This suggests a topochemical reaction. At low amine flux/high substrate temperature, open porous networks with a high degree of conformational disorder are formed. Both structures are entirely different from that obtained when the triimine product synthesized ex-situ is deposited onto the surface. This demonstrates that the approach of combined self-assembly and on-surface synthesis may allow formation of unique structures that are not obtainable through self-assembly from conventionally deposited building blocks.


[Intracranial tuberculomas in Nouakchott, Mauritania].
Tuberculosis is a major public health problem in developing countries. Cerebral tuberculomas is a tuberculous granulation tissue mass restrained and limited by immune defenses of the host. This study aims to describe the characteristics and the evolutionary profile of intracranial tuberculomas in Mauritania. Data of 34 patients with intracranial tuberculoma were collected retrospectively in several hospitals in the city of Nouakchott between January 2005 and June 2017. Evolutionary features of patients under treatment were analyzed. Our retrospective study involved 20 men and 14 women (sex ratio 1.4). The average age of our patients was 28.7 years. Twelve patients were less than or equal to 16 years. Symptomatology was dominated by increased intracranial pressure and seizures in 27 cases (79.41%) and 20 cases (58.82%) respectively. Intradermo tuberculin reaction was positive in 14 (41.17%) cases. Supratentorial lesion was found in 24 patients (70.58%). In all patients, therapeutic approach was based on multidrug chemotherapy for a period greater than or equal to 12 months. Surgical procedure was performed in 12 patients (35.29%). Outcome was favorable with complete healing without sequelae in 23 cases, reflecting a rate of 67.64%. Given the non-specific role of imaging exams in the diagnosis of intracranial tuberculoma and the lack of the stereotactic biopsy in our Country where the disease is endemic, we recommend to perform a two-month therapeutic test in patients with suspicious lesions.


Neuromuscular differences between men and prepubescent boys during a peak isometric knee extension intermittent fatigue test.
The aim of this study was to examine the fatigue and recovery in boys and men during a maximal intermittent isometric fatigue test of the knee extensor muscles, by evaluating the electromyogram of vastus lateralis, vastus medialis and biceps femoris. Thirteen boys (10.0 +/- 0.8yrs) and 13 men (26.1 +/- 4.2yrs) were fatigued until torque reached 50% of its initial value. Three and 6 min after, a maximal isometric knee extension test was assessed. Men had faster torque decline during fatigue and slower torque recovery compared with boys. Agonist activity declined in both groups during fatigue but men had greater extent of reduction. After 6 min boys recovered fully in respect to agonist EMG, whereas this was not the case for the men. The lower level of fatigue and faster recovery in boys could be attributed to the limited inhibition that was observed in the boys' agonist muscles, whereas the antagonist activity does not seem to play a role in the fatigue or recovery differences between the groups.


Platelet-derived growth factor-C promotes human melanoma aggressiveness through activation of neuropilin-1.
Despite recent progress in advanced melanoma therapy, identification of signalling pathways involved in melanoma switch from proliferative to invasive states is still crucial to uncover new therapeutic targets for improving the outcome of metastatic disease. Neuropilin-1 (NRP-1), a co-receptor for vascular endothelial growth factor-A (VEGF-A) tyrosine kinase receptors (VEGFRs), has been suggested to play a relevant role in melanoma progression. NRP-1 can be activated by VEGF-A also in the absence of VEGFRs, triggering specific signal transduction pathways (e.g. p130Cas phosphorylation). Since melanoma cells co-expressing high levels of NRP-1 and platelet derived growth factor-C (PDGF-C) show a highly invasive behaviour and PDGF-C shares homology with VEGF-A, in this study we have investigated whether PDGF-C directly interacts with NRP-1 and promotes melanoma aggressiveness. Results demonstrate that PDGF-C specifically binds in vitro to NRP-1. In melanoma cells expressing NRP-1 but lacking PDGFRα, PDGF-C stimulates extra-cellular matrix (ECM) invasion and induces p130Cas phosphorylation. Blockade of PDGF-C function by neutralizing antibodies or reduction of its secretion by specific siRNA inhibit ECM invasion and vasculogenic mimicry. Moreover, PDGF-C silencing significantly down-modulates the expression of Snail, a transcription factor involved in tumour invasiveness that is highly expressed in NRP-1 positive melanoma cells. In conclusion, our results demonstrate for the first time a direct activation of NRP-1 by PDGF-C and strongly suggest that autocrine and/or paracrine stimulation of NRP-1 by PDGF-C might contribute to the acquisition of a metastatic phenotype by melanoma cells.


[Risk factors related to esophageal cancer in Rio Grande do Sul, Brazil].
Rio Grande do Sul, a State in southern Brazil, shows high mortality rates for esophageal cancer. Important geographical variations suggest external factors in the etiology. The relationship between smoking, alcohol and "mate" to esophageal cancer. 55 patients with esophageal cancer were interviewed, soon after the endoscopy, about risk factors; 110 patients who did not showed esophageal tumor in the endoscopy were the controls. Among the patients with esophageal cancer there were more farmer-workers (OD 3.3; 95% CI 0.9-11.2), father with antecedent cancer (OD 6.9; 95% CI 1.9-25.6), smoking and ex-smoking (OD 2.5; 95% CI 1.1-5.9), drinkers and ex- of alcohol (OD 5.3; 95% CI 2.6-11.0), drinkers and ex- of "mate" (OD 3.6; 95% CI 1.3-9.8). Others variables more frequent in the cases were: smoking for > 20 years; kind of alcohol (spirits), drinking alcohol every day, drinking "mate" every day and adding salt to food. Smoking, alcohol, "mate", farmer-workers and antecedent of father with cancer were significantly more frequent in the cases of esophageal cancer than in the controls.


Mode analysis of binding of fatty acids to mammalian DNA polymerases.
We previously reported that unsaturated long-chain fatty acids were potent DNA polymerase inhibitors (Y. Mizushina et al., J. Biol. Chem. 274 (1999) 25599-25607). In those experiments, the question remained of whether metastable oil droplets (liposomal vesicles) of the unsaturated long-chain fatty acids can non-specifically inhibit the polymerase activity. We report here that only the soluble fatty acid monomers of linoleic acid or nervonic acid could affect the activities of mammalian DNA polymerases, and the metastable oil droplets could not. When we consider the facts that nuclear membranes are a kind of liposomal vesicles, that free fatty acids occur only at the moment the lipids are digested, and that the DNA polymerization possibly occurs on the nuclear membranes, the data shown here are suggestive regarding the mechanism of regulation of DNA polymerization in vivo.


Development of the competitive business in the context of environmental legislation in Croatia.
Environmental protection has a key role in the context of crisis management. It is not just about development of the industry of environmental protection and implementation of new ways of management in innovative solutions in solving problems. Important area of improvement is also revision of environmental legislation aiming at simplification and reduction of costs of procedures for the business. This paper discusses problems of business sector in Croatia related to transposition of demanding environmental EU regulation, it suggests improvements such as simplification of special waste management systems, of environmental impact assessments processes, environmental permitting etc. The paper considers revision of environmental protection not by lowering environmental standards, but by introducing transparent and compromising models between business and environmental protection, based on sustainable development, with control mechanisms which don't impact functioning of business sector (and its competitiveness), therefore allowing successful protection of environment and its renewable and non-renewable resources.


SUMO-1 modification activates the transcriptional response of p53.
The p53 tumour suppressor protein is regulated by ubiquitin-mediated proteasomal degradation. In normal cells p53 is constitutively ubiquitylated by the Mdm2 ubiquitin ligase. When the p53 response is activated by stress signals p53 levels rise due to inhibition of this degradative pathway. Here we show that p53 is modified by the small ubiquitin-like protein SUMO-1 at a single site, K386, in the C-terminus of the protein. Modification in vitro requires only SUMO-1, the SUMO-1 activating enzyme and ubc9. SUMO-1 and ubiquitin modification do not compete for the same lysine acceptor sites in p53. Overexpression of SUMO-1 activates the transcriptional activity of wild-type p53, but not K386R p53 where the SUMO-1 acceptor site has been mutated. The SUMO-1 modification pathway therefore acts as a potential regulator of the p53 response and may represent a novel target for the development of therapeutically useful modulators of the p53 response.


Nanoparticle cages for enzyme catalysis in organic media.
Encapsulation of enzymes in Pickering emulsions results in a large interfacial area of the enzyme-containing aqueous phase for biocatalysis in organic media. This immobilization technique minimizes enzyme inactivation through stabilizing immiscible liquids by particles, facilitates separation processes, and significantly increases catalytic performance of both stable and vulnerable enzymes. Thus, a broad technical applicability can be envisioned.


Higher-order genome organization in platypus and chicken sperm and repositioning of sex chromosomes during mammalian evolution.
In mammals, chromosomes occupy defined positions in sperm, whereas previous work in chicken showed random chromosome distribution. Monotremes (platypus and echidnas) are the most basal group of living mammals. They have elongated sperm like chicken and a complex sex chromosome system with homology to chicken sex chromosomes. We used platypus and chicken genomic clones to investigate genome organization in sperm. In chicken sperm, about half of the chromosomes investigated are organized non-randomly, whereas in platypus chromosome organization in sperm is almost entirely non-random. The use of genomic clones allowed us to determine chromosome orientation and chromatin compaction in sperm. We found that in both species chromosomes maintain orientation of chromosomes in sperm independent of random or non-random positioning along the sperm nucleus. The distance of loci correlated with the total length of sperm nuclei, suggesting that chromatin extension depends on sperm elongation. In platypus, most sex chromosomes cluster in the posterior region of the sperm nucleus, presumably the result of postmeiotic association of sex chromosomes. Chicken and platypus autosomes sharing homology with the human X chromosome located centrally in both species suggesting that this is the ancestral position. This suggests that in some therian mammals a more anterior position of the X chromosome has evolved independently.


Promoting Heart Health Among Rural African Americans.
Cardiovascular disease is a major cause of death for people living in the United States. African Americans bear a disproportionate burden of cardiovascular disease. Interventions designed to target multiple risk factors may facilitate elimination of cardiovascular disease health disparities. The purpose of this study was to evaluate a culturally relevant cardiovascular health promotion intervention that could potentially reduce cardiovascular disease risk among a group of rural African American adults by improving intentions, attitudes, norms, and self-efficacy to increase produce consumption, reduce dietary saturated fat intake, and increase exercise. A cluster randomized controlled trial design was used to evaluate the effect of the "With Every Heartbeat Is Life" cardiovascular health promotion program among rural African Americans. The African American congregants of 12 rural churches located in northern Florida were randomly assigned to either an intervention group that received a culturally relevant cardiovascular health promotion intervention or a control group. Data analysis using linear mixed model was performed to compare group differences from pretest to posttest. The cardiovascular health promotion intervention had a positive influence on the intentions, attitudes, norms, and self-efficacy of rural African Americans to increase produce consumption and reduce dietary saturated fat. The intervention also enhanced participants' attitudes and self-efficacy regarding exercise. The culturally relevant cardiovascular health promotion program presented to cluster groups of rural African American participants had positive influences on psychosocial variables associated with engaging in cardiovascular health recommendations. Nurse-led interventions in community settings can potentially reduce cardiovascular disease risk.


Health-state utility estimates for health technology assessment: a review of the manufacturers' submissions to the French National Authority for Health.
Our aim was to review the selection and methods used for deriving health state utility (HSU) estimates included in the cost-utility analyses (CUA) submitted by manufacturers to the National Authority for Health (HAS) during the first 2 years after the introduction of the economic evaluation for price setting in France. We reviewed all manufacturers' submissions that included a CUA and were assessed by HAS by the end of October 2015 (N = 34). We reviewed the identification, selection, and methods used to estimate HSU and compared them with those recommended by HAS. A literature review to identify HSU was reported in only 13 (38%) submissions. The instruments for describing HSU were a preference-based generic instrument in 20 (59%) submissions; vignettes in five (15%); a condition-specific instrument in three (9%); and a combination of instruments in six (18%). The valuation perspective was the general population in 26 (76%) submissions; in only nine (26%) submissions, the valuation set was derived from the French general population. We identified numerous concerns in the selection, valuation and use of HSU, as well as a frequent lack of clarity in the methods used. Most submissions (79%) included HSU that did not meet HAS recommendations.


Psychoanalysis and empirical research.
At the beginning of the nineteenth century, the idea of reason began to lose its universal and absolute value, undermining the view of science as a form of objective knowledge that reveals a fundamental reality. These changes have also had an impact on psychoanalysis, leading to a proliferation of theories and the end of a positivistic approach, epitomized by a 'neutral' analyst who knows the contents of the patient's mind. Hermeneutic philosophy provides a tool with which to explore both theoretical multiplicity and the contribution of the analyst's subjectivity to the analytic process. Furthermore, a hermeneutic approach does not have to be hostile to empirical science, but can be integrated with it in a 'scientific-hermeneutic model' in which historical and biological principles are given equal value.


Review of HPV-related diseases and cancers.
Human papillomavirus (HPV) is a double-stranded circular DNA virus belonging to the papillomavirus family. It is transmitted by skin-to-skin or mucosa-to-mucosa contact and enters the body via cutaneous or mucosal trauma. HPV infection is the most common sexually transmitted disease, although it is usually cured by the immune system. Worldwide, the risk of being infected at least once in a lifetime among both men and women is 50%. HPV infection causes common and anogenital warts, as well as other non-dermatological diseases. The role of HPV in cancer development has been extensively studied, primarily in cervical cancer, but also in other types of neoplasms.


A study of handling cytotoxic drugs and risk of birth defects in offspring of female veterinarians.
We examined the association of occupational exposure to handling cytotoxic drugs at work with risk of birth defects among a cohort of female veterinarians. This study is a follow up survey of 321 female participants (633 pregnancies) who participated in the Health Risks of Australian Veterinarian project. Data on pregnancies and exposure during each pregnancy was obtained by self-administered mailed questionnaire. Female veterinarians handling cytotoxic drugs during their pregnancy had a two-fold increased risk of birth defects in their offspring (RR = 2.08, 95% CI (1.05-4.15)). Results were consistent in subgroup analysis of those who graduated during the period of 1961 to 1980 (RR = 5.04, 95% CI (1.81, 14.03) and in those working specifically in small and large animal practice. There was no increased risk in the subgroup that graduated after 1980. Women with unplanned pregnancies were more likely to handle cytotoxic drugs on a daily basis (RR = 1.86, 95% CI, 1.00-3.48) and had a higher increased risk of birth defects than those who planned their pregnancies in recent graduates and in those who worked specifically in small animal practice (RR = 2.53, 95% CI, 1.18-5.42). This study suggests that the adverse effects of handling cytotoxic drugs in pregnant women may include an increased risk of birth defects. Pregnancy intention status is an important health behavior and should be considered in prenatal programs.


Anal stenosis and megarectum in the elderly.
Anal stenosis, an often unrecognized condition causing acute colonic obstruction in the elderly, is described with reference to three cases. Initial management should include: 1) digital dilatation and rectal examination; 2) sigmoidoscopy; 3) insertion of a rectal tube; 4) correction of fluid and electrolyte imbalance. Sufficient experience is not available to predict the results of sphincterotomy or anoplasty, both of which may result in incontinence, and conservative measures may suffice in most cases. Prevention of this condition may be achieved by adequate intake of dietary fiber or regular bulk laxatives in these debilitated patients.


Advances in Purification of SARS-CoV-2 Spike Ectodomain Protein Using High-Throughput Screening and Non-Affinity Methods.
The spike (S) glycoprotein of the pandemic virus, SARS-CoV-2, is a critically important target of vaccine design and therapeutic development. A high-yield, scalable, cGMP-compliant downstream process for the stabilized, soluble, native-like S protein ectodomain is necessary to meet the extensive material requirements for ongoing research and development. As of June 2021, S proteins have exclusively been purified using difficult-to-scale, low-yield methodologies such as affinity and size-exclusion chromatography. Herein we present the first known non-affinity purification method for two S constructs, S_dF_2P and HexaPro, expressed in the mammalian cell line, CHO-DG44. A high-throughput resin screen on the Tecan Freedom EVO200 automated bioprocess workstation led to identification of ion exchange resins as viable purification steps. The chromatographic unit operations along with industry-standard methodologies for viral clearances, low pH treatment and 20 nm filtration, were assessed for feasibility. The developed process was applied to purify HexaPro from a CHO-DG44 stable pool harvest and yielded the highest yet reported amount of pure S protein. Our results demonstrate that commercially available chromatography resins are suitable for cGMP manufacturing of SARS-CoV-2 Spike protein constructs. We anticipate our results will provide a blueprint for worldwide biopharmaceutical production laboratories, as well as a starting point for process intensification.


Fano q-reversal in topological insulator Bi2Se3.
We studied the magneto-optical response of a canonical topological insulator Bi2Se3 with the goal of addressing a controversial issue of electron-phonon coupling. Magnetic-field induced modifications of reflectance are very pronounced in the infrared part of the spectrum, indicating strong electron-phonon coupling. This coupling causes an asymmetric line-shape of the 60 cm(-1) phonon mode, and is analyzed within the Fano formalism. The analysis reveals that the Fano asymmetry parameter (q) changes sign when the cyclotron resonance is degenerate with the phonon mode. To the best of our knowledge this is the first example of magnetic field driven q-reversal.


Gastrointestinal peptides in children before and after hematopoietic stem cell transplantation.
Gastrointestinal tract function and it's integrity are controlled by a number of peptides whose secretion is influenced by severe inflammation. In stomach the main regulatory peptide is ghrelin. For upper small intestine cholecystokinin and lower small intestine glucagon-like peptide- 1 are secreted, while fibroblast growth factor-21 is secreted by several organs, including the liver, pancreas, and adipose tissue [12]. Hematopoietic stem cell transplantation causes serious mucosal damage, which can reflect on this peptides. The aim of the study was to determine fasting plasma concentrations of ghrelin, cholecystokinin, glucagon- like peptide-1, and fibroblast growth factor-21, and their gene expressions, before and 6 months after hematopoietic stem cell transplantation.27 children were studied, control group included 26 healthy children. Acute graft versus host disease was diagnosed in 11 patients (41%, n = 27). Median pre-transplantation concentrations of gastrointestinal peptides, as well as their gene expressions, were significantly lower in studied group compared with the control group. Only median of fibroblast growth factor-21 concentration was near-significantly higher before stem cell transplantation than in the control group. The post-hematopoietic transplant results revealed significantly higher concentrations of the studied peptides (except fibroblast growth factor-21) and respective gene expressions as compare to pre transplant results. Median glucagone like peptide-1 concentrations were significantly decreased in patients with features of acute graft versus host disease. Moreover, negative correlation between glucagone like peptide-1 concentrations and acute graft versus host disease severity was found. Increased concentrations and gene expressions of gastrointestinal tract regulation peptides can be caused by stimulation of regeneration in the severe injured organ. Measurement of these parameters may be a useful method of assessment of severity of gastrointestinal tract complications of hematopoietic stem cell transplantation.


Particles and Prejudice: Nanomedicine Approaches to Reducing Health Disparities in Endometrial Cancer.
Endometrial cancer is the most common gynecological malignancy worldwide and unfortunately has a much higher mortality rate in Black women compared with White women. Many potential factors contribute to these mortality rates, including the underlying effects of systemic and interpersonal racism. Furthermore, other trends in medicine have potential links to these rates including participation in clinical trials, hormone therapy, and pre-existing health conditions. Addressing the high incidence and disparate mortality rates in endometrial cancer requires novel methods, such as nanoparticle-based therapeutics. These therapeutics have been growing in increasing prevalence in pre-clinical development and have far-reaching implications in cancer therapy. The rigor of pre-clinical studies is enhanced by the likeness of the model to the human body. In systems for 3D cell culture, for example, the extracellular matrix mimics the tumor more closely. The increasing emphasis on precision medicine can be applied to cancer using nanoparticle-based methods and applied to pre-clinical models by using patient-derived model data. This review highlights the intersections of nanomedicine, precision medicine, and racial disparities within endometrial cancer and provides insights into reducing health disparities using recent scientific advances on the nanoscale.


Mortality after hip fracture: regional variations in New Zealand.
To determine the 35-day and one-year mortality rates following a hospital admission for hip fracture, among individuals aged 60 years or older in New Zealand. New Zealand Health Information Service mortality data for the years 1988 to 1992 were examined to determine the case fatality rate among individuals aged 60 years or older admitted to hospital for fractures of the neck of femur (ICD-9 N-code 820). Case fatality rates assessed at 35 days and one year after admission to hospital were examined by age, gender, year of admission, place of residence, area health board region and cause of death. Between 1988 and 1992, the case fatality rate was 8% within 35 days of admission to hospital and 24% within one year of admission. Case fatality rates were found to be twice as high in men compared to women and four to five times higher in individuals aged 85 years and older, compared to people aged between 60 and 64 years. The only regional difference in hip fracture mortality was found in the Canterbury area health board region, which had a 30% higher rate of hip fracture mortality compared to all regions combined. The two main cited underlying causes of death after hip fracture were accidental falls (ICD E880-E888) and ischaemic heart disease (ICD 410-414). Over three-quarters of individuals aged 60 years or older who are hospitalised with a hip fracture in New Zealand survive for at least one year after admission. However, significant variations in mortality exist with age and gender. These data highlight the importance of preventive strategies for hip fracture in older people and the need to identify ways of improving post-admission care.


A quantitative and qualitative review of the effects of testosterone on the function and structure of the human social-emotional brain.
Social and affective research in humans is increasingly using functional and structural neuroimaging techniques to aid the understanding of how hormones, such as testosterone, modulate a wide range of psychological processes. We conducted a meta-analysis of functional magnetic resonance imaging (fMRI) studies of testosterone administration, and of fMRI studies that measured endogenous levels of the hormone, in relation to social and affective stimuli. Furthermore, we conducted a review of structural MRI i.e. voxel based morphometry (VBM) studies which considered brain volume in relation to testosterone levels in adults and in children. In the included testosterone administration fMRI studies, which consisted of female samples only, bilateral amygdala/parahippocampal regions as well as the right caudate were significantly activated by social-affective stimuli in the testosterone condition. In the studies considering endogenous levels of testosterone, stimuli-invoked activations relating to testosterone levels were noted in the bilateral amygdala/parahippocampal regions and the brainstem. When the endogenous testosterone studies were split by sex, the significant activation of the brain stem was seen in the female samples only. Significant stimuli-invoked deactivations relating to endogenous testosterone levels were also seen in the right and left amygdala/parahippocampal regions studies. The findings of the VBM studies were less consistent. In adults larger volumes in the limbic and temporal regions were associated with higher endogenous testosterone. In children, boys showed a positive correlation between testosterone and brain volume in many regions, including the amygdala, as well as global grey matter volume, while girls showed a neutral or negative association between testosterone levels and many brain volumes. In conclusion, amygdalar and parahippocampal regions appear to be key target regions for the acute actions of testosterone in response to social and affective stimuli, while neurodevelopmentally the volumes of a broader network of brain structures are associated with testosterone levels in a sexually dimorphic manner.


Endogenous blood maximal interferon-gamma production may predict response to interferon-gamma 1beta treatment in patients with idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disorder with a mean survival of 3 years after diagnosis. Treatment with interferon-gamma (IFN-gamma) 1beta has been reported to significantly improve lung function and arterial oxygen saturation in a first randomized controlled trial; unexpectedly, these findings have not been confirmed in a subsequent large placebo-controlled randomized study. Another larger placebo-controlled randomized trial has been stopped because data analyzed at interim analysis excluded the possibility that treatment with IFN-gamma 1beta would cause a significant reduction in the risk of death. Seven Italian male patients diagnosed with IPF were treated with IFN-gamma 1beta (200 microg/die subcutaneously three times a week), accordingly to the indications of the Italian Drug Agency. Based on available studies the response to treatment was pre-defined as changes in either lung function (FVC and DLCO) or oxygen arterial saturation. All patients consented to provide a peripheral blood sample for endogenous IFN-gamma production measurement with the ELISpot assay before treatment and 6 months thereafter. Four of 7 patients improved or stabilized their lung function after 6 months treatment. Using the ELISpot assay to quantify the maximal production of endogenous IFN-gamma on peripheral blood samples, these 4 patients had a significantly higher endogenous IFN-gamma production before therapy, as compared to the 3 patients who deteriorated (91.3 +/- 49.6 vs. 277.8 +/- 34.2 spot forming cells, p = 0.023). No significant differences were observed after 6 months of treatment. These preliminary results suggest that some IPF patients might benefit from treatment with IFN-gamma 1beta and may help to interpret the results of large randomized trials, suggesting that individual susceptibility could determine clinical response to treatment.


Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6.receptor complex.
The high affinity interleukin-6 (IL-6) signaling complex consists of IL-6 and two membrane-associated receptor components: a low affinity but specific IL-6 receptor and the affinity converter/signal transducing protein gp130. Monomeric (IL-6M) and dimeric (IL-6D) forms of Escherichia coli-derived human IL-6 and the extracellular ("soluble") portions of the IL-6 receptor (sIL-6R) and gp130 have been purified in order to investigate the effect of IL-6 dimerization on binding to the receptor complex. Although IL-6D has a higher binding affinity for immobilized sIL-6R, as determined by biosensor analysis employing surface plasmon resonance detection, IL-6M is more potent than IL-6D in a STAT3 phosphorylation assay. The difference in potency is significantly less pronounced when measured in the murine 7TD1 hybridoma growth factor assay and the human hepatoma HepG2 bioassay due to time-dependent dissociation at 37 degrees C of IL-6 dimers into active monomers. The increased binding affinity of IL-6D appears to be due to its ability to cross-link two sIL-6R molecules on the biosensor surface. Studies of the IL-6 ternary complex formation demonstrated that the reduced biological potency of IL-6D resulted from a decreased ability of the IL-6D (sIL-6R)2 complex to couple with the soluble portion of gp130. These data imply that IL-6-induced dimerization of sIL-6R is not the driving force in promoting formation of the hexameric (IL-6 IL-6R gp130)2 complex. A model is presented whereby the trimeric complex of IL-6R, gp130, and IL-6M forms before the functional hexamer. Due to its increased affinity for the IL-6R but its decreased ability to couple with gp130, we suggest that a stable IL-6 dimer may be an efficient IL-6 antagonist.


Selection kinetics during serial cell culture passage of mixtures of wild-type Autographa californica nuclear polyhedrosis virus and its recombinant Ac360-beta-gal.
Detailed analysis of the selection process in serial co-infections of cell cultures by wild-type Autographa californica nuclear polyhedrosis virus (AcNPV) strain E2 (AcNPV/E2) and Ac360-beta-gal, a genetically engineered strain, shows that the unaltered strain was clearly dominant even when it initially constituted the minority component in the inoculum. A method of calculating a selection coefficient that quantifies the relative advantage of one strain of virus over the other under specific culture conditions is described. Calculated selection coefficients were relatively homogeneous and almost exclusively favoured the progenitor. Selection pressure was not influenced by the relative proportions of the two strains in the population. Selection coefficients, as determined in the present study, may be useful for evaluating the effect of a genetic alteration on viral fitness under specified conditions. Unexpected high frequencies of mixed phenotype plaques were observed during infectivity titrations of media from early serial passages of co-infected cultures. Statistical evaluation implicates some non-heritable combinational phenomenon. Virus plated from mixed phenotype plaques show high segregation of phenotypes implying that genetic recombination does not contribute in a major way to the high mixed phenotype frequencies. Electron microscopic examination of virion pellets from infected 72 h cell culture media similarly argue against co-envelopment as a major contributory factor to the high frequency of mixed phenotype plaques. The cause remains undetermined.


How safe is triage by an after-hours telephone call center?
Our goals were to assess (1) compliance with nurse disposition recommendations, (2) frequency of death or potential underreferral associated with hospitalization within 24 hours after a call, and (3) factors associated with potential underreferral, for children receiving care within an integrated health care delivery organization who were triaged by a pediatric after-hours call center. The study population included all pediatric patients enrolled in Kaiser Permanente Colorado whose families called the Children's Hospital after-hours call center in Denver, Colorado, during the period between October 1, 1999, and March 31, 2003. Postcall disposition recommendations were categorized as urgent (visit within 4 hours), next day (visit in > 4 hours but within 24 hours), later visit (visit in > 24 hours), or home care (care at home without a visit). Compliance with the nurses' triage disposition recommendations was calculated as the proportion of cases for which utilization data matched the disposition recommendations. Of the 32,968 eligible calls during the study period, 21% received urgent, 27% next day, 4% later visit, and 48% home care disposition recommendations. Rates of compliance with both urgent and home care disposition recommendations were 74%, and the rate of compliance with next day recommendations was 44%. No deaths occurred within < 1 week after the after-hours calls. The rate of potential underreferral with subsequent hospitalization was 0.2%, or 1 case per 599 triaged calls. In multivariate modeling, age of < 6 weeks or > 12 years and being triaged after 11 pm were associated with higher rates of potential under-referral. Approximately three fourths of families complied with recommendations for their child to be evaluated urgently or to be treated at home, with much lower rates of compliance with intermediate dispositions. The rate of potential underreferral with hospitalization was low, and age and time of call triage were associated with this outcome.


Laterally assembled nanowires for ultrathin broadband solar absorbers.
We studied optical resonances in laterally oriented Si nanowire arrays by conducting finite-difference time-domain simulations. Localized Fabry-Perot and whispering-gallery modes are supported within the cross section of each nanowire in the array and result in broadband light absorption. Comparison of a nanowire array with a single nanowire shows that the current density (J(SC)) is preserved for a range of nanowire morphologies. The J(SC) of a nanowire array depends on the spacing of its constituent nanowires, which indicates that both diffraction and optical antenna effects contribute to light absorption. Furthermore, a vertically stacked nanowire array exhibits significantly enhanced light absorption because of the emergence of coupled cavity-waveguide modes and the mitigation of a screening effect. With the assumption of unity internal quantum efficiency, the J(SC) of an 800-nm-thick cross-stacked nanowire array is 14.0 mA/cm², which yields a ~60% enhancement compared with an equivalent bulk film absorber. These numerical results underpin a rational design strategy for ultrathin solar absorbers based on assembled nanowire cavities.


CC14 administration to strain A/J mice or rats and the arachidonic acid content of their liver microsomal prospholipids.
CC14 administration of Sprague-Dawley male rats causes a significant decrease in the arachidonic acid content of their liver microsomal phospholipids. On the contrary, its administration to strain A/J male mice does not modify the concentration during periods of intoxication up to 24 hr. Since this strain of mice is more susceptible to CC14-induced injury than the rat, results indicate that lipid peroxidation can not be the key event in damage induced by this haloalkane.


Aqueous humour lactic dehydrogenase isoenzymes in retinoblastoma.
LDH activity was determined in aqueous humour samples from 11 eyes (of 10 children), four of which contained retinoblastoma. Simultaneous serum LDH levels were also determined in eight of the children. There was no correlation between serum and aqueous humour LDH activity. Total aqueous humour LDH activity ranged from 0 to 99 i.u/l. in the seven eyes with non-neoplastic conditions. It was 56, 124, 158, and 1832 i.u./l. respectively, in the four eyes with retinoblastoma. In all four eyes the ratio of isoenzymes LDH5:LDH1 was greater than 5. The total aqueous humour LDH levels in retinoblastoma was neither consistently elevated, nor related to the total serum LDH. There was a characteristic LDH isoenzyme fractionation pattern which, it is suggested, may be present before the total aqueous humour LDH becomes elevated.


CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcgamma receptor-mediated but not scavenger receptor-mediated recognition by macrophages.
CD47 functions as a marker of self on red blood cells (RBCs) by binding to signal regulatory protein alpha on macrophages, preventing phagocytosis of autologous RBCs by splenic red pulp macrophages, and Fcgamma receptor (FcgammaR)- or complement receptor-mediated phagocytosis by macrophages in general. RBC senescence involves a series of biochemical changes to plasma membrane proteins or lipids, which may regulate phagocytosis by macrophages. Here, we investigated whether CD47 on experimentally senescent murine RBCs affects their phagocytosis by macrophages in vitro. Clustering of CD47 with antibodies was more pronounced in the plasma membrane of untreated RBCs, compared with that in in vitro oxidized RBCs (Ox-RBCs). Phagocytosis of Ox-RBCs was mediated by scavenger receptors (SRs) distinct from SR-A or CD36 and required serum factors. We found that wild-type (WT) and CD47(-/-) Ox-RBCs were phagocytosed equally well by macrophages in the presence of serum, suggesting that phagocytosis via SRs is not inhibited by CD47. Despite this, FcgammaR-mediated phagocytosis of IgG-opsonized Ox-RBCs was strongly inhibited by CD47. These data suggest that based on the specific prophagocytic receptors mediating uptake of senescent RBCs, the phagocytosis-inhibitory role of CD47 may be more or less involved.


Economics and Energy Consumption of Brackish Water Reverse Osmosis Desalination: Innovations and Impacts of Feedwater Quality.
Brackish water desalination, using the reverse osmosis (BWRO) process, has become common in global regions, where vast reserves of brackish groundwater are found (e.g., the United States, North Africa). A literature survey and detailed analyses of several BWRO facilities in Florida have revealed some interesting and valuable information on the costs and energy use. Depending on the capacity, water quality, and additional scope items, the capital cost (CAPEX) ranges from USD 500 to USD 2947/m3 of the capacity (USD 690-USD 4067/m3 corrected for inflation to 2020). The highest number was associated with the City of Cape Coral North Plant, Florida, which had an expanded project scope. The general range of the operating cost (OPEX) is USD 0.39 to USD 0.66/m3 (cannot be corrected for inflation), for a range of capacities from 10,000 to 70,000 m3/d. The feed-water quality, in the range of 2000 to 6000 mg/L of the total dissolved solids, does not significantly impact the OPEX. There is a significant scaling trend, with OPEX cost reducing as plant capacity increases, but there is considerable scatter based on the pre- and post-treatment complexity. Many BWRO facilities operate with long-term increases in the salinity of the feedwater (groundwater), caused by pumping-induced vertical and horizontal migration of the higher salinity water. Any cost and energy increase that is caused by the higher feed water salinity, can be significantly mitigated by using energy recovery, which is not commonly used in BWRO operations. OPEX in BWRO systems is likely to remain relatively constant, based on the limitation on the plant capacity, caused by the brackish water availability at a given site. Seawater reverse osmosis facilities, with a very large capacity, have a lower OPEX compared to the upper range of BWRO, because of capacity scaling, special electrical energy deals, and process design certainty.


[Methods of experimental validation of potential target proteins for creation of new drugs].
Review is devoted to the description of the main existing and developing technologies for experimental validation of potential targets predicted in silico by comparative genomics and bioinformatics methods. Since this problem has not been solved yet, the description of a wide set of methods, suitable for the validation of potential targets, is given. The following questions have been considered: (1) applications of proteomic technologies (control of potential targets expression and their variability, analysis of protein-protein interactions); (2) use of genomics technologies in experimental validation of targets (inactivation of the target genes, suppression of transcription, inactivation of the target mRNA, suppression of translation); (3) methods of direct inactivation of target proteins (monoclonal antibodies, light-inactivation, one-chain antibodies, intrabodies, aptamers); (4) high-throughput technologies; (5) targets validations in vivo.


Magnetic Resonance Imaging of Cerebral Aspergillosis: Imaging and Pathological Correlations.
Cerebral aspergillosis is associated with a significant morbidity and mortality rate. The imaging data present different patterns and no full consensus exists on typical imaging characteristics of the cerebral lesions. We reviewed MRI findings in 21 patients with cerebral aspergillosis and correlated them to the immune status of the patients and to neuropathological findings when tissue was available. The lesions were characterized by their number, topography, and MRI signal. Dissemination to the brain resulted from direct spread from paranasal sinuses in 8 patients, 6 of them being immunocompetent. Hematogenous dissemination was observed in 13 patients, all were immunosuppressed. In this later group we identified a total of 329 parenchymal abscesses involving the whole brain with a predilection for the corticomedullary junction. More than half the patients had a corpus callosum lesion. Hemorrhagic lesions accounted for 13% and contrast enhancement was observed in 61% of the lesions. Patients with hematogenous dissemination were younger (p = 0.003), had more intracranial lesions (p = 0.0004) and had a higher 12-week mortality rate (p = 0.046) than patients with direct spread from paranasal sinuses. Analysis of 12 aneurysms allowed us to highlight two distinct situations. In case of direct spread from the paranasal sinuses, aneurysms are saccular and located on the proximal artery portions, while the hematogenous dissemination in immunocompromised patients is more frequently associated with distal and fusiform aneurysms. MRI is the exam of choice for cerebral aspergillosis. Number and type of lesions are different according to the mode of dissemination of the infection.


Inhibition of NO synthesis or endothelium removal reveals a vasoconstrictor effect of insulin on isolated arterioles.
In this study we tested the hypothesis that insulin may differentially affect isolated arterioles from red (RGM) and white gastrocnemius muscles (WGM) because of their differences in function and metabolic profile. We also determined whether the responses of these arterioles are endothelium dependent and mediated by either prostaglandins or nitric oxide (NO). Arterioles were isolated, pressurized to 85 mmHg, equilibrated in Krebs bicarbonate-buffered solution (pH 7.4) gassed with 10% O2 (5% CO2-85% N2), and studied in a no-flow state. Control diameters for first-order arterioles from RGM averaged 77 +/- 8 micrometers and from WGM averaged 77 +/- 5 micrometers. Cumulative dose-response curves to insulin (10 microU/ml, 100 microU/ml, 1 mU/ml, and 10 mU/ml) were obtained in arterioles before and after endothelium removal or administration of either indomethacin (Indo, 10(-5) M) or NG-nitro-L-arginine (L-NNA, 10(-4) M). Insulin evoked concentration-dependent increases in control diameter of intact RGM and WGM arterioles of 6-26% and 9-28%, respectively. Indo was without any effect on insulin-induced dilation in RGM and WGM arterioles. Insulin-evoked dilation in both RGM and WGM arterioles was completely inhibited and converted to vasoconstriction by endothelium removal and administration of L-NNA. These results indicate that in endothelium-intact arterioles from RGM and WGM, insulin evokes an endothelium-dependent dilation that is equivalent and mediated by NO. In contrast, in the absence of a functional endothelium, insulin evokes arteriolar constriction. The finding that insulin can constrict arterioles, at physiological concentrations, suggests that insulin may play a more significant role in the regulation of vascular tone and total peripheral resistance than previously appreciated.


Involvement of birds in the epidemiology of the Lyme disease agent Borrelia burgdorferi.
Borrelia burgdorferi, the causative agent of Lyme disease, was isolated from the liver of a passerine bird, Catharus fuscescens (veery), and from larval Ixodes dammini (tick) feeding on Pheucticus ludovicianus (rose-breasted grosbeak) and Geothlypis trichas (common yellowthroat). In indirect immunofluorescence antibody tests, isolates reacted with polyclonal and monoclonal (H5332) antibodies. Studies on the DNA composition of the veery liver isolate and the strain cultured from an I. dammini larva indicated that both were B. burgdorferi and not Borrelia anserina or Borrelia hermsii. The veery liver isolate infected hamsters and a chick. In contrast, B. anserina infected chicks but not hamsters. B. burgdorferi is unique among Borrelia spp. in being infectious to both mammals and birds. We suggest that the cosmopolitan distribution of B. burgdorferi may be caused by long-distance dispersal of infected birds that serve as hosts for ticks.


The collagen substrate specificity of rat uterus collagenase.
The collagen substrate specificity of rat uterus collagenase was studied as a function of both collagen type and species of substrate origin. For each collagen examined, values for the basic kinetic parameters, Km and Vmax (kcat), were determined on collagen in solution at 25 degrees C. In all cases, Lineweaver-Burk plots were linear and rat uterus collagenase behaved as a normal Michaelis-Menten enzyme. Collagen types I, II, and III of all species tested were degraded by rat uterus collagenase. Collagen types IV and V were resistant to enzymatic attack. Both enzyme-substrate affinity and catalytic rates were very similar for all susceptible collagens (types I-III). Values for Km ranged from 0.9 to 2.5 X 10(-6) M. Values for kcat varied from 10.7 to 28.1 h-1. The homologous rat type I collagen was no better a substrate than the other animal species type I collagens. The ability of rat uterus collagenase to degrade collagen types I, II, and III with essentially the same catalytic efficiency is unlike the action of human skin fibroblast collagenase or any other interstitial collagenase reported to date. The action of rat uterus collagenase on type I collagen was compared to that of human skin fibroblast collagenase, with regard to their capacity to cleave collagen as solution monomers versus insoluble fibrils. Both enzymes had essentially equal values for kcat on monomeric collagen, yet the specific activity of the rat uterus collagenase was 3- to 6-fold greater on collagen fibrils than the skin fibroblast enzyme. Thus, in spite of their similar activity on collagen monomers in solution, the rat uterus collagenase can degrade collagen aggregated into fibrils considerably more readily than can human skin fibroblast collagenase.


Structure of lipid multilayers via drop casting of aqueous liposome dispersions.
Understanding the structure of solid supported lipid multilayers is crucial to their application as a platform for novel materials. Conventionally, they are prepared from drop casting or spin coating of lipids dissolved in organic solvents, and lipid multilayers prepared from aqueous media and their structural characterisation have not been reported previously, due to their extremely low lipid solubility (i.e.∼10(-9) M) in water. Herein, using X-ray reflectivity (XRR) facilitated by a "bending mica" method, we have studied the structural characteristics of dioleoylphosphatidylcholine (DOPC) multilayers prepared via drop casting aqueous small unilamellar and multilamellar vesicle or liposome (i.e. SUV and MLV) dispersions on different surfaces, including mica, positively charged polyethylenimine (PEI) coated mica, and stearic trimethylammonium iodide (STAI) coated mica which exposes a monolayer of hydrocarbon tails. We suggest that DOPC liposomes served both as a delivery matrix where an appreciable lipid concentration in water (∼25 mg mL(-1) or 14 mM) was feasible, and as a structural precursor where the lamellar structure was readily retained on the rupture of the vesicles at the solid surface upon solvent evaporation to facilitate rapid multilayer formation. We find that multilayers on mica from MLVs exhibited polymorphism, whereas the SUV multilayers were well ordered and showed stronger stability against water. The influence of substrate chemistry (i.e. polymer coating, charge and hydrophobicity) on the multilayer structure is discussed in terms of lipid-substrate molecular interactions determining the bilayer packing proximal to the solid-liquid interface, which then had a templating effect on the structure of the bilayers distal from the interface, resulting in the overall different multilayer structural characteristics on different substrates. Such a fundamental understanding of the correlation between the physical parameters that characterise liposomes and substrate chemistry, and the structure of lipid multilayers underpins the potential development of a simple method via an aqueous liposome dispersion route for the inclusion of hydrophilic functional additives (e.g. drugs or nanoparticles) into lipid multilayer based hybrid materials, where tailored structural characteristics are an important consideration.


[Clinical and psychophysiological characteristics of headache in childhood].
Complex clinical psychophysiological as well as neurophysiological examinations of 210 children with migraine, chronic tension headache (CTH) and chronic posttraumatic headache (CPH) were carried out. Detailed comparative description of cephalalgia types is presented. In a CPH structure, predominates CTH (77.5%), combined type (14.1%); migraine (5.7%) and cervicogenic cephalalgia (2.7%) occur less often. CPH development mechanisms do not principally differ from non-traumatic cephalalgia pathogenesis. Trauma plays a role of a non-specific trigger in realization of these mechanisms. Chronic cephalalgia is caused mainly by poor social and psychological factors and patient's personality peculiarities. Psychovegetative syndrome in children with CTH, migraine or CPH reflects non-specifically diencephal structure disintegration; its clinical signs depending more on child's age than on cephalalgia type.


An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors.
Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.


Impact of COVID-19 pandemic on Moroccan sectoral stocks indices.
In this paper, we make an original contribution by identifying the impact of COVID-19 on Moroccan sectoral stocks indices. For this purpose, we collected data of 22 sectors from the Casablanca stock exchange from January 2017 to December 2021 and investigated two regres- sion models that included a dummy variable representing the onset of COVID-19. In addition, we examined performance measures (Sharp ratio and Treynor ratio) and risk measures (CVaR and Beta) of each individual sector before and during COVID-19. Furthermore, a GARCH model is applied to show conditional variance, aiming to emphasize the volatility of the selected stocks indices overall the chosen period. The results allowed us to divide sectors into two samples: the first one, referred to as sample 1, that was negatively impacted, and the second one, referred to as sample 2, that benefited from the pandemic of COVID-19. Further, conditional variance revealed that COVID-19 boosted, significantly but for a short period, the volatility of all sectors, even though the magnitude of the effect on volatility varies by sample and also by sector. Overall, we see COVID-19 as a crisis for some sectors and an opportunity for a new business transformation, as it is a period that results in significant improvement for some specific sectors. Furthermore, our results reflect the behavior of the sectors of an African emerging market during the COVID-19 outbreak, which is relevant for the formulation of strategies to ensure financial sustainability during future sanitary crises of this magnitude, for this type of economy.


Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis.
Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery. The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals. CRD42023431063. NCT05915806.


Robotic-assisted lung resection for malignant disease.
: There have been few reports of the use of robotic surgery to resect lung malignancies. Feasibility and safety of robotic lung resection for malignant lung lesions will be assessed by performing a retrospective analysis. : Between September 2004 and November 2006, 21 patients (11 male and 10 female patients) underwent robotic lung resection. Twenty resections were performed for primary nonsmall cell lung cancer and two for metastatic lesions. One patient had bilateral resections for two primary tumors. Fourteen lobectomies, five segementectomies, one wedge resection, and two bilobectomies were performed. Seventy-two percent of operative procedures included mediastinoscopy and/or bronchoscopy at the time of resection. : Thirty-day mortality and conversion rate was 0%. The median operating room time and estimated blood loss was 3.6 hours and 100 mL, respectively. The median intensive care unit and total length of hospital stays were 2 and 4 days, respectively. Chest tubes were removed after a median of 2.0 days. The complication rate was 27%, which included atrial fibrillation, need for postoperative bronchoscopy, and pneumonia. The median tumor size and number of lymph nodes harvested was 2.3 cm and 16, respectively. All resection margins were negative. Median follow-up time was 9.8 months, with no local recurrences at this time. : Robotic lung resection appears safe and feasible and allows for significant lymph node retrieval, offers short hospital stays and low morbidity for patients undergoing surgical resection of lung malignancies. Future studies are needed to define the role of robotic surgery in lung cancer treatment.


Thermal exposure of adult Chinook salmon and steelhead: Diverse behavioral strategies in a large and warming river system.
Rising river temperatures in western North America have increased the energetic costs of migration and the risk of premature mortality in many Pacific salmon (Oncorhynchus spp.) populations. Predicting and managing risks for these populations requires data on acute and cumulative thermal exposure, the spatio-temporal distribution of adverse conditions, and the potentially mitigating effects of cool-water refuges. In this study, we paired radiotelemetry with archival temperature loggers to construct continuous, spatially-explicit thermal histories for 212 adult Chinook salmon (O. tshawytscha) and 200 adult steelhead (O. mykiss). The fish amassed ~500,000 temperature records (30-min intervals) while migrating through 470 kilometers of the Columbia and Snake rivers en route to spawning sites in Idaho, Oregon, and Washington. Spring- and most summer-run Chinook salmon migrated before river temperatures reached annual highs; their body temperatures closely matched ambient temperatures and most had thermal maxima in the lower Snake River. In contrast, many individual fall-run Chinook salmon and most steelhead had maxima near thermal tolerance limits (20-22 °C) in the lower Columbia River. High temperatures elicited extensive use of thermal refuges near tributary confluences, where body temperatures were ~2-10 °C cooler than the adjacent migration corridor. Many steelhead used refuges for weeks or more whereas salmon use was typically hours to days, reflecting differences in spawn timing. Almost no refuge use was detected in a ~260-km reach where a thermal migration barrier may more frequently develop in future warmer years. Within population, cumulative thermal exposure was strongly positively correlated (0.88 ≤ r ≤ 0.98) with migration duration and inconsistently associated (-0.28 ≤ r ≤ 0.09) with migration date. All four populations have likely experienced historically high mean and maximum temperatures in recent years. Expected responses include population-specific shifts in migration phenology, increased reliance on patchily-distributed thermal refuges, and natural selection favoring temperature-tolerant phenotypes.


The Ugly Truth About Ourselves and Our Robot Creations: The Problem of Bias and Social Inequity.
Recently, there has been an upsurge of attention focused on bias and its impact on specialized artificial intelligence (AI) applications. Allegations of racism and sexism have permeated the conversation as stories surface about search engines delivering job postings for well-paying technical jobs to men and not women, or providing arrest mugshots when keywords such as "black teenagers" are entered. Learning algorithms are evolving; they are often created from parsing through large datasets of online information while having truth labels bestowed on them by crowd-sourced masses. These specialized AI algorithms have been liberated from the minds of researchers and startups, and released onto the public. Yet intelligent though they may be, these algorithms maintain some of the same biases that permeate society. They find patterns within datasets that reflect implicit biases and, in so doing, emphasize and reinforce these biases as global truth. This paper describes specific examples of how bias has infused itself into current AI and robotic systems, and how it may affect the future design of such systems. More specifically, we draw attention to how bias may affect the functioning of (1) a robot peacekeeper, (2) a self-driving car, and (3) a medical robot. We conclude with an overview of measures that could be taken to mitigate or halt bias from permeating robotic technology.


[Could phimosis have been the cause of sexual difficulties and delayed fertility of Louis XVI (1754-1793)?].
The great majority of historians agree that the marriage of Louis XVI and Marie-Antoinette was only consumated seven years after the official ceremony. This delay could have been due to a genital malformation (phimosis) of Louis XVI, a strict religious education, a traumatic childhood and the young age of the two spouses, factors that may have inhibited their sexuality. In this article, the authors try to determine whether Louis XVI was able to overcome his sexual difficulties following an operation (circumcision) or as a result of spontaneous cure.


CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation.
Immune cells are activated during cellular responses to antigen by two described mechanisms: (i) direct uptake of antigen and (ii) extraction and internalization of membrane components from antigen-presenting cells. Although endocytosis of microbial antigens by pattern recognition molecules (PRM) also activates innate immunity, it is not known whether this involves extraction and internalization of microbial surface components. Epithelial cells on mucosal surfaces use a variety of receptors that are distinct from the classical endocytic PRM to bind and internalize intact microorganisms. Nonclassical receptor molecules theoretically could act as a type of endocytic PRM if these molecules could recognize, bind, extract, and internalize a pathogen-associated molecule and initiate cell signaling. We report here that the interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) and the outer core oligosaccharide of the lipopolysaccharide (LPS) in the outer membrane of Pseudomonas aeruginosa satisfies all of these conditions. P. aeruginosa LPS was specifically recognized and bound by CFTR, extracted from the organism's surface, and endocytosed by epithelial cells, leading to a rapid (5- to 15-min) and dynamic translocation of nuclear transcription factor NF-kappa B. Inhibition of epithelial cell internalization of P. aeruginosa LPS prevented NF-kappa B activation. Cellular activation depended on expression of wild-type CFTR, because both cultured Delta F508 CFTR human airway epithelial cells and lung epithelial cells of transgenic-CF mice failed to endocytose LPS and translocate NF-kappa B. CFTR serves as a critical endocytic PRM in the lung epithelium, coordinating the effective innate immune response to P. aeruginosa infection.