Thermodynamics of native protein/foreign surface interactions. IV. Calorimetric and microelectrophoretic study of human fibrinogen sorption onto glass and LTI-carbon.
1. According to a working hypothesis put forward in the previous papers of this series2-4, the initial phases of native blood/foreign surface interactions have been considered within the framework of a physicochemical model of contact activation at the molecular level. The salient features of this hypothesis are: a) the arrival and adsorption of native plasma proteins on a contact surface overwhelmingly precedes that of the cellular blood components; b) the interaction energy that arises between a particular foreign surface and native plasma proteins settling on it, is a characteristic quantity depending upon the effective surface molecular structure as well as the nature of the proteins; c) the "intensity" of native protein/foreign surface interactions can be treated in terms of thermodynamic quantities since these energy terms are independent of the type of forces acting between protein and surface; and d) depending upon the degree to which the adsorption of a native protein is thermodynamically favored by enthalpy and/or entropy factors, the interaction energy can be utilized to induce conformational changes of varying degree in the sorbed protein. 2. Using glass and low temperature isotropic (LTI) carbon adsorbents, i.e., a known procoagulant and a relevant biomaterial, respectively, the adsorption properties and the potential surface-induced conformational changes of high-purity native human fibrinogen (clottability greater than or equal to 92%) were studied, at 25 degrees C, by 3 independent methods. In all of the experiments performed, a) both adsorbents were employed in the form of particles less than or equal to 1.0 mu representing specific surface areas of 9.85 M2/Gm and 27.7 (nominal) M2/Gm for the glass and LTI-carbon powders, respectively, and b) the fibrinogen was absorbed from a standaridized buffer (pH = 7.2, ionic strength 0.05) using the same fixed surface area/protein solution volume ratio with a given adsorbent. 3. The 25 degrees C adsorption isotherms of fibrinogen obtained for both the glass and LTI-carbon powder adsorbents are not amenable to Langmuir type analysis but indicate multilayer sorption with a possible change in binding mechanism after the completion of the first sorbed monolayer. The adsorptivities attained at first monolayer coverage were slightly greater on glass (approximately 0.76 mug/cm2) than on LTI-carbon (approximately 0.52 mug/cm2). 4. Using a custom-built, thermistorized, isothermal-jacketed microcalorimeter routinely capable of resolving temperature changes of 0.00001 degrees C in 100 ml of aqueous sample volume, the "intensity" of interaction between fibrinogen and each of the microparticulate adsorbents was studied by the direct measurement of the net overall enthalpy changes, hI(SLP)25 arising as a result of protein adsorption. From these values, the net heat of protein sorption has been determined...


Tricin Isolated from Enzyme-Treated Zizania latifolia Extract Inhibits IgE-Mediated Allergic Reactions in RBL-2H3 Cells by Targeting the Lyn/Syk Pathway.
Tricin, a flavone present in rice bran, is confirmed as the major efficacious compound present in the enzyme-treated Zizania latifolia extract (ETZL), which protects against UVB-induced skin-aging. However, the suppressive mechanism of tricin on allergic responses remains unknown. The present study, therefore, aimed to determine the mechanisms of tricin and ETZL on mast cell degranulation in IgE-activated rat basophilic leukemia cell line (RBL-2H3) cells. We investigated the regulatory effects of tricin and ETZL on degranulation, production of cytokines and lipid mediators, and signaling proteins involved in the IgE-bound high-affinity IgE receptor activation, mitogen-activated protein kinase, arachidonic acid and Syk. The production of β-hexosaminidase, tumor necrosis factor-α, interleukin-4, leukotrienes (LT) B4, LTC4 and prostaglandin E2 in IgE-stimulated RBL-2H3 cells were significantly inhibited by exposure to tricin or ETZL. Moreover, tricin and ETZL inhibit the phosphorylation of cytosolic phospholipase A2, 5-lipoxygenase and cyclooxygenase-2. Furthermore, the phosphorylation of Akt, ERK, p38, JNK, protein kinase Cδ and phospholipase Cγ1 were effectively suppressed by both samples. Exposure to tricin or ETZL also significantly decreases the phosphorylation of Lyn and Syk, but has minimal effect on Fyn. Taken together, our data indicate that tricin and ETZL are potential anti-allergic materials that could be applied for the prevention of allergy-related diseases.


Pulp condition of successfully formocresol-treated primary molars.
The aim of the study was to assess the state of the pulp of primary teeth successfully treated by formocresol pulpotomy. Nineteen teeth, all of them with clinically and radiographically successful treatments, were extracted 3-24 months after treatment. The pulpal condition had changed in all the teeth. Inflammatory reaction or necrosis was observed in all teeth. Dentinal resorption followed by apposition of hard tissue were common findings. In the teeth with vital tissue only in the apical area, the tissue had minor or no signs of inflammation. Microorganisms could be demonstrated in the necrotic tissue in one tooth. The wide range of pulpal conditions observed indicated that there was no typical tissue reaction to formocresol even though treatment was clinically successful. The present study confirms that the formocresol method should be regarded only as a means to keep primary teeth with pulp exposures functioning for a limited period of time.


Radiographic appearance of cardiogenic pulmonary oedema in 23 cats.
To describe the radiographic appearance of pulmonary oedema in cats with cardiac failure. Thoracic radiographs of 23 cats presented to a first opinion practice with signs of cardiac failure were reviewed. All cats had tachypnoea and/or dyspnoea and enlarged left atrium on echocardiography. Pulmonary oedema was characterised radiographically by an increased opacity associated with a range of patterns and variable distribution. All cats had evidence of a reticular or granular interstitial pattern. This occurred in combination with alveolar pattern in 19 (83 per cent) cats, including six with air bronchograms, with increased diameter of pulmonary vessels in 16 (71 per cent) cats and with bronchial pattern in 14 (61 per cent) cats. The distribution of pulmonary oedema was considered to be diffuse/non-uniform in 14 (61 per cent) cats, diffuse/uniform in four (17 per cent) cats, multi-focal in four (17 per cent) cats and focal in the remaining one (4 per cent). Nine (39 per cent) cats were considered to have a regional distribution of oedema, including five (22 per cent) with a ventral distribution, three (13 per cent) with a caudal distribution and one (4 per cent) cat with a hilar distribution. The distribution of pulmonary opacities was bilaterally symmetrical in five (22 per cent) cats. The variable appearance of feline pulmonary oedema is likely to complicate its radiographic diagnosis.


Development and evaluation of alginate-chitosan gastric floating beads loading with oxymatrine solid dispersion.
Oxymatrine (OM) can be metabolized to matrine in gastrointestinal ileocecal valve after oral administration, which affects pharmacological activity and reduce bioavailability of OM. A type of multiple-unit alginate-chitosan (Alg-Cs) floating beads was prepared by the ionotropic gelation method for gastroretention delivery of OM. A solid dispersion technique was applied and incorporated into beads to enhance the OM encapsulation efficiency (EE) and sustain the drug release. The surface morphology and internal hollow structure of beads were evaluated using optical microscopy and scanning electron microscopy (SEM). The developed Alg-Cs beads were spherical in shape with hollow internal structure and had particle size of 3.49 ± 0.09 mm and 1.33 ± 0.09 mm for wet and dried beads. Over 84% of the optimized OM solid dispersion-loaded Alg-Cs beads were able to continuously float over the simulated gastric fluid for 12 h in vitro. The OM solid dispersion-loaded Alg-Cs beads showed drug EE of 67.07%, which was much higher than that of beads loading with pure OM. Compared with the immediate release of OM capsules and pure OM-loaded beads, the release of OM from solid dispersion-loaded Alg-Cs beads was in a sustained-release manner for 12 h. Prolonged gastric retention time of over 8.5 h was achieved for OM solid dispersion-loaded Alg-Cs floating beads in healthy rabbit in in vivo floating ability evaluated by X-ray imaging. The developed Alg-Cs beads loading with OM solid dispersion displayed excellent performance features characterized by excellent gastric floating ability, high drug EE and sustained-release pattern. The study illustrated the potential use of Alg-Cs floating beads combined with the solid dispersion technique for prolonging gastric retention and sustaining release of OM, which could provide a promising drug delivery system for gastric-specific delivery of OM for bioavailability enhancement.


Subretinal Glial Membranes in Eyes With Geographic Atrophy.
Müller cells create the external limiting membrane (ELM) by forming junctions with photoreceptor cells. This study evaluated the relationship between focal photoreceptors and RPE loss in geographic atrophy (GA) and Müller cell extension into the subretinal space. Human donor eyes with no retinal disease or geographic atrophy (GA) were fixed and the eye cups imaged. The retinal posterior pole was stained for glial fibrillary acidic protein (GFAP; astrocytes and activated Müller cells) and vimentin (Müller cells) while the submacular choroids were labeled with Ulex Europaeus Agglutinin lectin (blood vessels). Choroids and retinas were imaged using a Zeiss 710 confocal microscope. Additional eyes were cryopreserved or processed for transmission electron microscopy (TEM) to better visualize the Müller cells. Vimentin staining of aged control retinas (n = 4) revealed a panretinal cobblestone-like ELM. While this pattern was also observed in the GA retinas (n = 7), each also had a distinct area in which vimentin+ and vimentin+/GFAP+ processes created a subretinal membrane. Subretinal glial membranes closely matched areas of RPE atrophy in the gross photos. Choroidal vascular loss was also evident in these atrophic areas. Smaller glial projections were noted, which correlated with drusen in gross photos. The presence of glia in the subretinal space was confirmed by TEM and cross cross-section immunohistochemistry. In eyes with GA, subretinal Müller cell membranes present in areas of RPE atrophy may be a Müller cell attempt to replace the ELM. These membranes could interfere with treatments such as stem cell therapy.


Molecular investigation into outbreak of HIV in a Scottish prison.
To support already established epidemiological links between inmates of Glenochil prison positive for HIV infection by using molecular techniques and thus provide evidence of the extent of acquisition during a recent outbreak of the disease resulting from needle sharing. To identify possible sources of the outbreak, and to demonstrate the ability of the methodology to make further links beyond the original outbreak. Viral sequences obtained from the blood of HIV positive prisoners previously identified by standard epidemiological methods were compared with each other and with sequences from other Scottish patients. Glenochil prison for men, central Scotland. Adult inmates and their possible contacts. Phylogenetic analysis of viral sequences in two different genomic regions showed that 13 of the 14 HIV positive prisoners had been infected from a common source. Previous research had shown that six of these had acquired their infection in Glenochil; molecular evidence suggests that more than double this number were infected while incarcerated. Virus from two long term HIV positive patients who were in the prison at the time of the outbreak but who were not identified in the original or subsequent surveys was sufficiently different to make it unlikely that they were the source. A viral sequence from heterosexual transmission from one inmate showed the ability of these techniques to follow the infection through different routes of infection. The number of prisoners infected with HIV during the 1993 outbreak within Glenochil prison was more than twice that previously shown. This shows the potential for the spread of bloodborne diseases within prisons by injecting drugs.


Prospectives and surgical usefulness of perioperative parathyroid hormone assay in thyroid surgery.
Hypocalcemia is the most frequent complication after thyroid surgery. The incidence varies and has been reported as ranging from 1.2 to 40%. Permanent hypoparathyroidism occurs in less than 3% of patients, whereas transient postoperative hypocalcemia is much more common. Postoperative hypoparathyroidism is traditionally detected by serial measurement of serum calcium concentrations and requires multiple venepunctures and, potentially, several days of hospitalization following the procedure. The parathyroid hormone (PTH) molecule is a polypeptide composed of an 84-amino acid sequence with an active amino terminal on one end and an inactive carboxyl unit on the other. Measurement of the intact PTH (iPTH) is an accurate representation of the true parathyroid state. In recent years, iPTH assay has been under investigation for thyroid surgery in many centers as an early iPTH measurement may be of value for prediction of postoperative symptomatic hypocalcemia, guiding the surgeon for parathyroid autotransplatation, and selection of patients requiring onset of calcium substitution or safe discharge home. This paper reviews the relevant medical literature published regarding the influence of PTH assay technology on the quality of thyroid surgery, as well as on the prevention of postoperative symptomatic hypocalcemia. Searches were last updated in April 2008.


[Rehabilitation of stroke patients].
The present article is devoted to the problems of the organization and carrying out of rehabilitation in post stroke patients. The features of stroke patient's management with the help of multidisciplinary team are discussed. Main principles and rules of physical, psychotherapeutic and medication rehabilitation are reviewed.


Dopaminergic drugs in the management of chronic heart failure.
The importance of the dopaminergic system in heart failure is unknown and the therapeutic potential of orally active compounds stimulating dopaminergic receptors has yet to be established. Despite similar acute haemodynamic changes in heart failure and despite a comparable profile of receptor stimulation, oral levodopa (the prodrug of dopamine) and oral ibopamine (the prodrug of epinine) produce opposite effects on plasma norepinephrine and have different pharmacokinetics. Placebo-controlled studies indicate a beneficial effect of ibopamine on exercise tolerance in patients with heart failure, whereas invasive evaluation of left ventricular function indicate that at the doses used in these trials, ibopamine does not act as a positive inotropic drug but rather as a vasodilator. This suggests that DA1 and DA2 receptor stimulation may be beneficial in heart failure. Further studies are, however, needed to specify the exact role of this therapeutic approach in comparison with other agents, such as ACE inhibitors, also able to modulate neuro-humoral activation in heart failure.


Diverging views on health information exchange organizations.
Health information exchange (HIE) capabilities meet the demands for a more effective, efficient, and safer health care system. However, organizations and individual providers have pursued different strategies to meet their respective needs for HIE capabilities. Because effective information sharing is necessary to a learning health system, this study sought to explore the perceptions of different approaches' effect on key features of an effective health care system. An anonymous web-based survey was sent to a convenience sample of the membership of the Healthcare Information and Management Systems Society and the Strategic Health Information Exchange Collaborative with knowledge of HIE (n=68). A series of 7-point Likert-type items measured perceptions of enterprise health information exchanges (eHIEs) and community health information organizations (cHIOs) in the areas of effect on exchange participation, effect on market dynamics, relationship to DIRECT Secure Messaging and vendor-mediated exchange, and effect on quality. Also, respondents were asked to rate 13 qualities and services as "more about eHIE" or "more about cHIO." Respondents tended to agree on the importance of cHIO and eHIE. Community benefits and support for public health agencies were concepts more often applied to cHIOs. This study affirmed much of the conventional wisdom and anecdotal comments about perceptions of cHIOs and eHIEs. Although the respondents viewed cHIOs and eHIEs differently in terms of broader societal benefit and strategic advantage, nonetheless consistent agreement appeared in areas of importance in relationship to other information sharing strategies and overall effect on the quality of care.


Quantification of the urban water-energy nexus in México City, México, with an assessment of water-system related carbon emissions.
Global urbanisation will put considerable stress on both water and energy resources. While there is much research at the national and regional levels on the energy implications of water supply (the urban water-energy 'nexus'), there is relatively little at the city scale. This literature is further diminished when attempting to account for the climate impact of urban water systems. A study of the urban water-energy-climate nexus is presented for México City. It is shown that 50% of México City water comes from a local aquifer with a further 30% deriving from energy-intensive surface sources which are pumped over considerable topography. The water supply system consumes 90% of the water system energy demand, and is responsible for the majority (90%) of the CO2e emissions. In the wastewater sector, 80-90% is discharged with no or little treatment, with correspondingly low energy demand. The small fraction that is treated accounts for the majority of energy use in the wastewater sector. This study shows the uncertainty in energy demand and CO2e emissions when reliant on secondary data which considerably over/under-estimate energy use compared with primary data. This has implications when assessing energy and carbon budgets. Three water savings options are assessed for their impact on energy and CO2e emissions reductions. Considerable reductions in water supply volumes and concomitant energy consumption and CO2e emissions are possible. However the extent of implementation, and the effectiveness of any implemented solutions depend on financing, institutional backing and public support. An additional measure to reduce the climate impact is to switch from traditional to renewable fuels. This work adds city-level quantification of the urban water-energy-climate nexus, allowing policy makers to discern which water-system elements are responsible for the greatest energy use and climate impact, and are better equipped to make targeted operational decisions.


Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?
Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in good physical condition after withdrawing anti-neurosyphilis regimen. We did not see an exacerbation of neutropenia in patients with the readministration of benzylpenicillin.


No interface energy barrier and increased surface pinning in low temperature baked niobium.
Superconducting Radio-Frequency cavities are currently made out of niobium. Niobium cavities are limited by the magnetic field on the cavity walls due to the entry of vortices at the field of first vortex penetration, H[Formula: see text]. Low temperature baking in vacuum or low pressure gas atmosphere removes the strong decrease of the quality factor with accelerating gradient (high field Q-slope). Some cavities reach surface magnetic field above the lower critical field H[Formula: see text]. One hypothesis for this performance increase is that the outer layer affected by the treatments acts as a barrier for vortex penetration (effective bilayer). Using a vibrating sample magnetometer the field of first flux penetration (H[Formula: see text]) was measured for Nb ellipsoids with various low temperature treatments. All H[Formula: see text] values were found to be consistent with the lower critical field, H[Formula: see text], as predicted for clean niobium. This led to the conclusion that a metastable flux free state above H[Formula: see text] cannot be observed in DC magnetometry for low temperature baked niobium unlike for bilayers consisting of two superconductors as previously published. The effect of flux pinning differed significantly between treatments, suggesting that the high field Q-slope mitigation might be related to vortex pinning in the surface of the cavities.


Decreased glucose tolerance, not decreased insulin sensitivity, is a maturational abnormality in the male offspring of a parent with early coronary artery disease.
We investigated whether the male offspring of a parent with early coronary artery disease (before the age of 60; n = 61) exhibit decreased insulin sensitivity compared with controls matched for age and body mass index (BMI) (n = 39). The insulin sensitivity index (S[I]) was determined by the minimal modeling method of Bergman from a frequently sampled intravenous glucose tolerance test with intravenous tolbutamide. Offspring and controls had a similar S[I], insulin-independent glucose utilization (S[G]), first-phase insulin response (AIR[G]), and area under the glucose curve. When subjects were separated into two age groups, younger subjects aged 15 to 30 years and older subjects aged 31 to 45 years, important differences were seen. S[G] was significantly increased in younger offspring compared with controls (22.8 +/- 2.3 v 16.8 +/- 2.3 x 10(-3) x min(-1), P < .05). Older offspring had a significantly increased area under the glucose curve compared with controls (18,250 +/- 322 v 17,225 +/- 347 mg/dL x min(-1), P < .05). Older offspring also had decreased S[I] compared with younger offspring (5.0 +/- 0.4 v 6.6 +/- 0.9 x 10(-4) x min(-1) x micro U/mL, P < .05), but this difference was eliminated after adjusting for BMI and waist to hip ratio (5.5 +/- 0.4 v5.8 +/- 0.9 x 10(-3) x min(-1), nonsignificant). This study does not support the concept that insulin resistance is an early atherogenic risk factor in offspring at risk for coronary disease because of their family history. However, it does point to the importance of maturational changes in glucose homeostasis in these offspring.


Nitric Oxide-Releasing Biomaterials for Biomedical Applications.
Nitric oxide (NO), as an essential signaling molecule, participates in various physiological processes such as cardiovascular homeostasis, neuronal transmission, immunomodulation, and tumor growth. The multiple role of NO in physiology and pathophysiology has triggered a massive interest in the strategies of delivering exogenous NO for biomedical applications. Hence, different kinds of NO prodrugs have been developed up to date, including diazeniumdiolates, S-nitrosothiol, metal-nitrosyl, nitrobenzene, and so on. However, the clinical application of these low molecular weight NO donors has been restricted due to the problems of burst release, low payloads, and untargeted delivery. The delivery of NO by biomaterialbased carrier offers a beneficial strategy to realize the controlled and sustained delivery of NO to the targeted tissues or organs. In detail, NO-donor prodrugs have been attached and loaded to diverse biomaterials to fabricate nanoparticles, hydrogels, and coating platforms by means of physical, chemical, or supramolecular techniques. These NO-releasing biomaterials hold promise for a number of biomedical applications ranging from therapy of the ischemic disease and several types of cancer to cardiovascular devices and wound dressing. First, surface coating with NO-releasing biomaterials could mimic the physiological function of vascular endothelium, therefore promoting vascularization and improving the patency of cardiovascular implants. Next, because NO also mediates many important processes that take place after cutaneous injury, NO-releasing biomaterials could serve as ideal wound dressing to accelerate tissue regeneration. Finally, biomaterials enable localized delivery of high dose of NO to tumors in a sustained manner, thus generating potent tumoricidal effect. In this review, we will summarize the progress of different NO-releasing biomaterials, and highlight their biomedical applications with a hope to inspire new perspectives in the area of biomaterial-based NO-delivery systems.


Asymmetric Hybrid Polymer-Lipid Giant Vesicles as Cell Membrane Mimics.
Lipid membrane asymmetry plays an important role in cell function and activity, being for instance a relevant signal of its integrity. The development of artificial asymmetric membranes thus represents a key challenge. In this context, an emulsion-centrifugation method is developed to prepare giant vesicles with an asymmetric membrane composed of an inner monolayer of poly(butadiene)-b-poly(ethylene oxide) (PBut-b-PEO) and outer monolayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The formation of a complete membrane asymmetry is demonstrated and its stability with time is followed by measuring lipid transverse diffusion. From fluorescence spectroscopy measurements, the lipid half-life is estimated to be 7.5 h. Using fluorescence recovery after photobleaching technique, the diffusion coefficient of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl) (DOPE-rhod, inserted into the POPC leaflet) is determined to be about D = 1.8 ± 0.50 μm2 s-1 at 25 °C and D = 2.3 ± 0.7 μm2 s-1 at 37 °C, between the characteristic values of pure POPC and pure polymer giant vesicles and in good agreement with the diffusion of lipids in a variety of biological membranes. These results demonstrate the ability to prepare a cell-like model system that displays an asymmetric membrane with transverse and translational diffusion properties similar to that of biological cells.


In Vitro Endothelialization of Surface-Integrated Nanofiber Networks for Stretchable Blood Interfaces.
Despite major technological advances within the field of cardiovascular engineering, the risk of thromboembolic events on artificial surfaces in contact with blood remains a major challenge and limits the functionality of ventricular assist devices (VADs) during mid- or long-term therapy. Here, a biomimetic blood-material interface is created via a nanofiber-based approach that promotes the endothelialization capability of elastic silicone surfaces for next-generation VADs under elevated hemodynamic loads. A blend fiber membrane made of elastic polyurethane and low-thrombogenic poly(vinylidene fluoride- co-hexafluoropropylene) was partially embedded into the surface of silicone films. These blend membranes resist fundamental irreversible deformation of the internal structure and are stably attached to the surface, while also exhibiting enhanced antithrombotic properties when compared to bare silicone. The composite material supports the formation of a stable monolayer of endothelial cells within a pulsatile flow bioreactor, resembling the physiological in vivo situation in a VAD. The nanofiber surface modification concept thus presents a promising approach for the future design of advanced elastic composite materials that are particularly interesting for applications in contact with blood.


Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum.
WR319691 has been shown to exhibit reasonable Plasmodium falciparum potency in vitro and exhibits reduced permeability across MDCK cell monolayers, which as part of our screening cascade led to further in vivo analysis. Single-dose pharmacokinetics was evaluated after an IV dose of 5 mg/kg in mice. Maximum bound and unbound brain levels of WR319691 were 97 and 0.05 ng/g versus approximately 1,600 and 3.2 ng/g for mefloquine. The half-life of WR319691 in plasma was approximately 13 h versus 23 h for mefloquine. The pharmacokinetics of several N-dealkylated metabolites was also evaluated. Five of six of these metabolites were detected and maximum total and free brain levels were all lower after an IV dose of 5 mg/kg WR319691 compared to mefloquine at the same dose. These data provide proof of concept that it is feasible to substantially lower the brain levels of a 4-position modified quinoline methanol in vivo without substantially decreasing potency against P. falciparum in vitro.


Evolutionary Biology and Gene Editing of Cat Allergen, Fel d 1.
Allergy to domestic cat affects up to 15% of the population, and sensitization to cat allergen is associated with asthma. Despite the pervasiveness of cat allergic disease, current treatments have limited impact. Here, we present a bioinformatics analysis of the major cat allergen, Fel d 1, and demonstrate proof of principle for CRISPR gene editing of the allergen. Sequence and structural analyses of Fel d 1 from 50 domestic cats identified conserved coding regions in genes CH1 and CH2 suitable for CRISPR editing. Comparative analyses of Fel d 1 and orthologous sequences from eight exotic felid species determined relatively low-sequence identities for CH1 and CH2, and implied that the allergen may be nonessential for cats, given the apparent lack of evolutionary conservation. In vitro knockouts of domestic cat Fel d 1 using CRISPR-Cas9 yielded editing efficiencies of up to 55% and found no evidence of editing at predicted potential off-target sites. Taken together, our data indicate that Fel d 1 is both a rational and viable candidate for gene deletion, which may profoundly benefit cat allergy sufferers by removing the major allergen at the source.


Chemo killed the small-talk gene.
Urvashi Vaid is a community organizer and writer active in the lesbian, gay, bisexual, and transgender (LGBT) and social justice movements for over three decades. She is currently Director of the Engaging Tradition Project at the Center for Gender and Sexuality Law at Columbia University Law School. She is founder of LPAC, the first lesbian political action committee, and sits on the Board of Directors of the Gill Foundation. Vaid's past positions include Executive Director of the Arcus Foundation, Deputy Director of Governance and Civil Society Unit for the Ford Foundation, Executive Director of the National Gay and Lesbian Task Force, and staff attorney for the ACLU National Prison Project. She is author of the books Irresistible Revolution: Confronting Race, Class and The Assumptions of Lesbian, Gay, Bisexual, and Transgender Politics, and Virtual Equality: The Mainstreaming of Gay & Lesbian Liberation, and co-editor of the book Creating Change: Public Policy, Sexuality and Civil Rights. Urvashi has had thyroid cancer and stage III breast cancer.


[Systematic investigation of surgical site infections (SSI) in plastic reconstructive and aesthetic surgery (ERCS): Feedback].
Surgical site infection (SSI) in plastic, reconstructive and aesthetic surgery (ERCP) is quite uncommon compared to other surgical specialities but remains one of the main complications. The aim of our study was to provide feedback on the systematic investigation of SSI in ERCP. This is a monocentric retrospective study, including all paediatric and adult patients who have undergone ERCP surgery between 01/01/2014 and 31/12/2021. During this period, the department systematically investigated all SSI cases. Eight thousand eight hundred and seventy-eight surgical procedures were performed. The SSI rate was 0.34%. Thirty SSIs (19W,11M), with a mean age of 56 years (none paediatric), were investigated. Twenty-seven patients suffered from comorbidities. The surgical indications included 17 cases of skin cancer, 7 cases of weight loss, 4 cases of breast reconstruction, 1 lipoma, 1 pectus excavatum. Eleven surgeries consisted in lymphnode procedures (8 sentinel lymphnodes, 3 curage). The average operating time was 116minutes. Nineteen patients received antibiotic prophylaxis. The average time to onset of SSI after surgery was 10 days. The most prevalent bacteria were commensals of the skin flora and the digestive tract. Apart from surgical management, 100% of patients were treated with antibiotics. High age, multiple comorbidities, long, combined procedures, placement of equipment, lymph node surgery, post-operative punctures on implanted equipment, are all risks factors for SSI. The implementation of a systematic monitoring of SSI within our department has provided us with the opportunity to analyse our data in real time and allow us to adjust our practices if necessary. This process can be used in other plastic reconstructive and aesthetic surgery departments. The collection and analysis of SSIs is both easily done and the procedure is well standardized. The assistance of the operational hygiene team is a key asset for the success of this project. The development of this type of procedure on a national level could be an asset to improve the management of SSI by taking advantage of the experience of a larger number of centres.


Characterization of the CNBr peptides generated from the factor B cleavage fragments, Ba and Bb, by molecular exclusion high performance liquid chromatography.
Highly purified human factor B of the alternative complement pathway was treated with factor D in the presence of cobra venom factor to generate its Ba and Bb cleavage fragments. These cleavage fragments were isolated by preparative polyacrylamide gradient gel electrophoresis followed by electrodialysis elution and treatment with CNBr. The resultant CNBr cleavage peptides were isolated by molecular exclusion high performance liquid chromatography and characterized by SDS polyacrylamide gel electrophoresis. Results of these experiments indicate that the Ba fragment essentially consisted of a 28,000 CNBr peptide, whereas 34,700 (28,000 + 3,500 when characterized under reducing polyacrylamide gel electrophoresis conditions); 14,500 (=20,000); and 8,300 CNBr peptides were derived from the Bb fragment.


Systematic review on quality of life outcomes after gastrectomy for gastric carcinoma.
Despite advances in chemotherapy and radiotherapy, gastrectomy is the only curative intervention for gastric carcinoma. This study reviews post-operative health-related quality of life (HRQOL) after gastrectomy. A literature search was conducted on PubMed for all studies published after January 2000 matching strict eligibility criteria. Bibliographies of included studies were also reviewed. Quality appraisal and data tabulation were performed using pre-determined forms. Results were synthesised by narrative review according to PRISMA guidelines with full tabulation of results of all included studies. A total of 21 studies (3,575 patients) were included. Post-operative HRQOL improvements were demonstrated across most or all domains in different HRQOL instruments. Patients experienced declines in HRQOL 1 month after surgery, but reached at least pre-operative levels with recovery by 1 year. The greatest improvements were demonstrated in the emotional health domain with favourable functional benefits. Partial gastrectomy appears to be superior to total gastrectomy in physical, emotional and functional health domains. However, patients remain susceptible to gastrointestinal symptoms following surgery, which negatively impact upon HRQOL. Post-operative complications did not appear to affect HRQOL. Most studies were prospective, but data is heterogeneous. Gastrectomy results in significant HRQOL benefits across a broad range of health domains. This is critical outcome of surgery and an important consideration in pre-operative decision making.


Pharmacokinetic modulation of radiolabeled chelates facilitated by phosphonate ester coordinating groups.
Chelates are an important part of metal based radiopharmaceuticals. This study examines the possible application of phosphonate ester moieties incorporated into chelates, where the ester group can be changed to modulate the pharmacokinetics of the radiopharmaceutical, while the phosphonate stably binds the metal radioisotope. Two phosphonate ester containing chelates, PCTMB and PCTM(F)E, were compared to the carboxylate containing analogue, p-Bn-PCTA, with respect to radiochemistry with several radionuclides (In-111, Ga-68, Ga-67, Cu-64). The phosphonate ester derivatives were similar to p-Bn-PCTA with respect to efficient radiolabeling with each of the radiometals under mild, aqueous conditions. Each of the radiolabeled phosphonate esters was also shown to be stable under physiological conditions in vitro. The phosphonate ester moieties did exhibit a propensity to degrade under more acidic conditions. Biodistribution studies in mice with the In-111 radiolabeled versions of PCTMB, PCTM(F)E and p-Bn-PCTA demonstrated the ability of the phosphonate ester functionalities to change the pharmacokinetics of the BFCs. With increasing lipophilicity, the phosphonate ester derivatives showed increasing hepatic clearance; but no significant increase in background tissue uptake (bone, muscle) was observed, and all the In-111 radiolabeled BFCs were substantially cleared within 24 h. The substitution of phosphonate ester for carboxylate functional groups in chelates may be an effective strategy to assist in optimizing the pharmacokinetics of radiopharmaceuticals through varying of the ester group.


Comparative Evaluation of Silibinin Effects on Cell Cycling and Apoptosis in Human Breast Cancer MCF-7 and T47D Cell Lines.
Silibinin is a natural polyphenol with high antioxidant and anticancer properties. In this study, its influence on two of the most commonly employed human breast cancer cell lines, MCF-7 and T47D, and one non-malignant MCF-10A cell line, were investigated and compared. Cell viability, the cell cycle distribution and apoptosis induction were analyzed by MTT and flow cytometry, respectively. The effect of silibinin on PTEN, Bcl-2, P21, and P27 mRNAs expression was also investigated by real-time RT-PCR. It was found that silibinin caused G1 cell cycle arrest in MCF-7 and MCF-10A cells but had no effect on the T47D cell cycle. Silibinin induced cytotoxic and apoptotic effects in T47D cells more than the MCF-7 cells and had no cytotoxic effect in MCF-10A cells under the same conditions. Silibinin upregulated PTEN in MCF-7 and caused slightly increased P21 mRNA expression in T47D cells and slightly increased PTEN and P21 expression in MCF-10A cells. Bcl-2 expression decreased in all of the examined cells under silibinin treatment. P27 mRNA expression upregulated in T47D and MCF-10A cells under silibinin treatment. PTEN mRNA in T47D and P21 and P27 mRNAsin MCF-7 were not affected by silibinin. These results suggest that silibinin has mostly different inhibitory effects in breast cancer cells and might be an effective anticancer agent for some cells linked to influence on cell cycle progression.


Frequency-resolved noise figure measurements of phase (in)sensitive fiber optical parametric amplifiers.
We measure the frequency-resolved noise figure of fiber optical parametric amplifiers both in phase-insensitive and phase-sensitive modes in the frequency range from 0.03 to 3 GHz. We also measure the variation in noise figure due to the degradation in pump optical signal to noise ratio and also as a function of the input signal powers. Noise figure degradation due to stimulated Brillouin scattering is observed.


Cardiopulmonary effects of fentanyl-droperidol, nitrous oxide, and atropine sulfate in dogs.
The cardiopulmonary effects of droperidol-fentanyl, nitrous oxide, and atropine were evaluated in 12 adult male Beagle dogs. All dogs were surgically instrumented with a cardiac output thermistor and arterial and venous catheters and were prepared with a chronic tracheostomy. Each dog was used as its own control, and data obtained when dogs were nonanesthetized and nonmedicated were compared with data recorded after the test drugs were administered. The dogs were randomly allotted to 3 groups of 4 dogs each. Group I dogs were given droperidol-fentanyl alone intravenously (IV); group II dogs were given droperidol-fentanyl IV with 67% nitrous oxide; and group III dogs were given atropine sulfate intramuscularly followed by droperidol-fentanyl IV with 67% nitrous oxide. Minute volume was decreased in the 3 groups of dogs for 3 to 5 minutes after droperidol-fentanyl was injected. This resulted in respiratory and metabolic acidosis in all dogs, as indicated by increased arterial carbon dioxide tension, decreased pH, and increased base deficit. In addition, droperidol-fentanyl given alone caused a decrease in systolic pressure and a slight decrease in heart rate. Group 1 dogs were sensitive to auditory stimulation. Cardiovascular changes were not seen when nitrous oxide was added; however, analgesia and muscle relaxation were improved. Premedication with atropine sulfate resulted in increased cardiac output, heart rate, and diastolic pressure, and subsequent administration of droperidol-fentanyl with nitrous oxide caused a transient increase in mean arterial and systolic pressure. This last anesthetic regimen, along with assisted or controlled respiration, seems to provide an excellent anesthetic state with minimal cardiopulmonary depression.


Altered serum levels of thyroxine, triiodothyroinine and thyroid stimulating hormone in patients with depression.
To assess serum level of Thyroxine (T4), Triiodothyronine(T3) and thyroid stimulating hormone(TSH) in patient with depression. Thirty one clinically diagnosed depressed patients and equal number of healthy, age and sex matched control subjects were included in this study. Ham-D scale was used to classify the degree of depression into mild, moderate and severe grades. The biochemical parameters (T3, T4 and TSH) were estimated using commercially available kits. The data were analyzed by using (SPSS-10 software), one way ANOVA and chi2 test. Female depressed (n=17) cases outnumber the male depressed cases. The distributions of patients in mild, moderate and severe categories were similar. The T3 and T4 level were found to be significantly raised in the moderate depression as compared to the healthy controls. ANOVA with multiple comparisons testing among the patient group showed a significant high TSH level (F>3.17) at 5% level of significance. A total of six depressive patients were found to have thyroid abnormalities. This study therefore points towards presence of thyroid dysfunction among the depressive which most often characterized as a "Lower Thyroid Syndrome". Thus inclusion of thyroid screening test among depressive patients may be helpful in proper management of cases.


The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity.
Melanocortin 4 receptor (MC4R) is an important regulator of food intake and number of studies report genetic variations influencing the risk of obesity. Here we explored the role of common genetic variation from MC4R locus comparing with SNPs from gene FTO locus, as well as the frequency and functionality of rare MC4R mutations in cohort of 380 severely obese individuals (BMI > 39 kg/m(2)) and 380 lean subjects from the Genome Database of Latvian Population (LGDB). We found correlation for two SNPs--rs11642015 and rs62048402 in the fat mass and obesity-associated protein (FTO) with obesity but no association was detected for rs17782313 located in the MC4R locus in these severely obese individuals. We sequenced the whole gene MC4R coding region in all study subjects and found five previously known heterozygous non-synonymous substitutions V103I, I121T, S127L, V166I and I251L. Expression in mammalian cells showed that the S127L, V166I and double V103I/S127L mutant receptors had significantly decreased quantity at the cell surface compared to the wild type MC4R. We carried out detailed functional analysis of V166I that demonstrated that, despite low abundance in plasma membrane, the V166I variant has lower EC50 value upon αMSH activation than the wild type receptor, while the level of AGRP inhibition was decreased, implying that V166I cause hyperactive satiety signalling. Overall, this study suggest that S127L may be the most frequent functional MC4R mutation leading to the severe obesity in general population and provides new insight into the functionality of population based variants of the MC4R.


Combination of adjuvant radiotherapy and androgen deprivation therapy after radical prostatectomy in high risk prostate cancer patients - results from retrospective analysis.
We retrospectively evaluated the outcome in prostate cancer (PCa) patients receiving combination of adjuvant radiotherapy (ART) and androgen deprivation therapy (ADT) after radical prostatectomy (RP). Between 2004 and 2012, 132 patients were referred for ART to the Department of Oncology, University Hospital, Split. Fifty-six consecutive patients with at least one proven or possible adverse prognostic factor such as pelvic lymph nodes invasion (LNI), lymphovascular invasion (LVI), high tumor grade and high preoperative prostatic specific antigen (PSA) level received combination of ART and ADT, while 76 patients received ART alone. The ADT consisted of a luteinizing hormone releasing hormone (LHRH) agonist or bicalutamide at a dose of 150 mg per day. The duration of ADT was left at the discretion of the treating physician and it lasted 6 to 36 months (median 24).The effect of combination of ART and ADT on biochemical relapse-free survival (bRFS), metastases-free survival (mFS), disease-specific survival (DSS) and overall survival (OS) was estimated using the Kaplan-Meier method. After a median follow-up time of 61 months (range 13.6-113), the 5- and 7-year bRFS were 90.5 and 77.2%, respectively. Distant relapse occurred in 5 patients, resulting in 5- and 7-year mFS of 95.9 and 81.7%, respectively. During follow-up, 7 patients died (2 PCa deaths), resulting in 5- and 7-year DSS and OS of 100% and 94.7% and 90.6 and 81.5%, respectively. This retrospective study shows high bRFS, mFS, DSS and OS rates with the combination of ART and ADT in high-risk PCa patients.


Novel thiophene oligomers containing a redox active hexaarylethane unit.
[structure: see text] Novel thiophene oligomers containing a redox active hexaarylethane unit have been prepared as a new class of molecular wires having a large electrochemical bistability and definitely characterized by using single-crystal X-ray structure analysis and redox potential measurements. They constitute reversible redox pairs with the corresponding bis(thioxanthyl) dications by undergoing C-C bond making/breaking. They show unique electrochromism and a fluorescence change during interconversion.


The accuracy of combined physical examination and ultrasonography for the detection of abdominal aorta aneurysm.
Atherosclerosis is the most frequent cause in the appearance of an abdominal aorta aneurysm (AAA) and plays an important role in his development. Most AAA does not cause any symptoms, especially when talking about elderly patients, however, many of those aneurysms can be detected during physical examination. Their detection is very important because the natural evolution and the major reason in treating AAA is their tendency to rupture. We present the case of an adult man with a complex clinical pathology, but not related to the AAA. The diagnosis of the AAA has been suspicion through palpation, and the abdominal ultrasound exam confirmed it. This case is particular interesting, as the AAA requires surgical intervention, while patient's health status was poor. An essential issue is establishing the importance of the AAA screening, when there are no symptoms present. For now, there are not satisfactory studies to be used as a guide.


Validation of EQ-5D and 15D in the assessment of health-related quality of life in chronic pain.
Chronic pain has a significant impact on quality of life. Measurement of health-related quality of life (HRQoL) is essential in the assessment of pain management outcomes, but different instruments have produced varying results. We assessed the validity of 2 HRQoL instruments, EuroQol 5 dimensions questionnaire (EQ-5D) and 15-dimensional health-related quality of life measure (15D), in patients with challenging chronic pain. Three hundred ninety-one chronic noncancer pain patients referred to tertiary pain clinics completed EQ-5D, 15D, and a broad set of questionnaires mapping socioeconomic factors, self-rated health, pain intensity and interference, depression, pain acceptance, pain-related anxiety, and sleep. The 2 HRQoL instruments were compared with each other, and head-to-head comparisons were made with self-rated health and the symptom-specific questionnaires. 15D and EQ-5D showed moderate agreement (ρ = 0.66), but there were also considerable differences between the instruments. 15D correlated better with self-rated health than EQ-5D (ρ = -0.62 vs -0.45, P < 0.001). The EQ-5D appeared less sensitive than 15D especially in those patients with chronic pain who had a better health status. The principal component constructed from measures of pain intensity and interference, anxiety, pain acceptance, depression, and sleep had higher standardized beta coefficients with 15D than with EQ-5D (P = 0.038). The principal component explained more variance in the 15D (R = 0.65) than in the EQ-5D (R = 0.43). The study identified differences in the pain-related variables between the EQ-5D and the 15D. In patients with chronic pain, both instruments are valid, but 15D appears somewhat more sensitive than EQ-5D.


[Tic suppression is a new evidence-based non-farmacological treatment of chronic tic disorder].
Chronic tic disorder and Tourette syndrome are both chronic and impairing neurobiological disorders starting in childhood with a prevalence between 0.4 and 1.6%. Traditionally, pharmacological therapies have been first-line treatment but are often associated with adverse effects. Recently behavioural therapy has shown to be effective in treating tics and today both habit reversal (HR) and exposure and response prevention (ERP) are recommended as first-line treatments. HR and ERP are now available for Danish patients. This article describes the evidence and recommendations for both therapies.


Abdominal Aortocaval Vascular Injury following Routine Lumbar Discectomy.
Vascular complications following spinal surgery are potentially fatal; however, fortunately they are rare. This risk is often focused on the close proximity of the surgical field to retroperitoneal structures. Prompt diagnosis is essential; however, bleeding is often occult, and this may therefore delay management of this condition. Despite previous reports many clinicians may not be aware of this potentially fatal complication. The overall morbidity and mortality may be reduced by prompt diagnosis and treatment. Clinicians must, therefore, have a high degree of suspicion in all patients who undergo spinal surgery. We therefore present a case of a 51-year-old man who sustained an aortocaval injury during a revisional lumbar discectomy. The patient developed refractory hypotension, which deteriorated into PEA arrest. Emergency laparotomy was performed which revealed an aortocaval injury. Immediate primary vascular repair was successfully performed. The patient was resuscitated and made a full recovery.


Projections of the medial cerebellar nucleus to oculomotor-related midbrain areas in the rat: an anterograde and retrograde HRP study.
The mesencephalic projections of the medial cerebellar nucleus (MCN) were studied in the rat by using the method of anterograde transport of wheat germ agglutinin/horseradish peroxidase to establish connections of the nucleus with oculomotor-related nuclei as a basis for its proposed role in eye movement. The principal targets of projections were the supraoculomotor ventral periaqueductal gray (PAG) and lateral PAG, and paraoculomotor cell groups (nucleus of Darkschewitsch and medial accessory nucleus of Bechterew). Lesser projections were observed to the intermediate layer of the superior colliculus, nucleus of the posterior commissure, and prerubral field. Following transcannular HRP gel implants into the oculomotor complex that included adjacent paraoculomotor nuclei, the largest number of retrogradely labeled cells was found in the caudal MCN. The findings suggest that the caudal MCN in the rat, like the primate fastigial nucleus, is involved in the control of eye movement.


Squamous Cell Carcinoma In Situ of the Breast: Report of a Case.
We present the case of a 73-year-old woman with pure squamous cell carcinoma in situ of the left breast. This non-invasive malignancy exhibited pure squamous type of architectural and cytologic features without any evidence of glandular differentiation either in the initial needle core biopsy or in the subsequently performed excisional biopsy and simple mastectomy. The tumor spanned 1.6 cm, involved numerous ducts and terminal ducts and extended into lobules, and was characterized by keratinizing squamous cells with intermediate-grade nuclei. Intercellular bridges extended between the malignant squamous cells. Keratinous debris with "pearl" formation was evident in most involved glands. No invasive carcinoma was identified. There was no evidence of metastatic disease in the ipsilateral sentinel lymph nodes. Thus far, only three cases of squamous cell carcinoma in situ of the breast have been reported in one series-none of which showed any evidence of recurrent or metastatic disease at last follow-up. In our case, treated exclusively by surgery, there was no evidence of disease 11 years after diagnosis.


Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization.
STRADalpha is a pseudokinase that forms a heterotrimeric complex with the scaffolding protein MO25 and the tumor suppressor serine threonine protein kinase LKB1. Mutations in the LKB1 gene are responsible for the Peutz-Jeghers Syndrome (PJS) characterized by a predisposition to hamartomatous polyps and hyperpigmentation of the buccal mucosa. Mutations in LKB1 have also been observed in some sporadic tumours unrelated to PJS. The LKB1/STRAD/MO25 complex is involved in the regulation of numerous signaling pathways including metabolism, proliferation and cellular polarity of human intestinal epithelial cells. Cell polarization, together with tissue-restricted transcription, represents the main feature of enterocyte differentiation. Since a full-length STRADalpha transcript has not been identified thus far in these cells, we evaluated the expression of endogenous STRADalpha in five colorectal cancer cell lines characterized by their diverse ability to differentiate in vitro. We report herein the discovery of several novel splice isoforms of STRADalpha that differentially affect the kinase activity, complex assembly, subcellular localization of LKB1 and the activation of the LKB1-dependent AMPK pathway.


Internal carotid occlusion in a patient with previous history of periodontitis: case report.
Although inflammatory periodontal disease has been proven to be related to carotid intima media thickness, it has been recently suggested that even an alteration of carotid hemodynamics might contribute to atherosclerosis in patients with periodontal disease. A 52-year-old female patient was referred to periodontology department due to painful alveolar mucosa. On the basis of dental history, we concluded that the patient had a severe form of generalized aggressive periodontitis that led to complete edentulism. The patient was advised to undergo ultrasonography of carotid arteries with arterial stiffness measurements at neurology department. A diagnosis of the right internal carotid artery occlusion was established. Inflammatory periodontal disease may affect arterial hemodynamics and even lead to artery occlusion. It is advisable that patients with a severe form of periodontitis should be referred for carotid artery ultrasonography.


Embracing Paradigmatic Diversity in Nursing: The Stadium Model in Nursing.
Arguably, the quest for a central, unifying paradigm in nursing has distracted from moving disciplinary knowledge forward in an accessible, meaningful manner. In this discursive philosophical article, we uphold that multiparadigmatic research teams and diverse approaches inform effective nursing praxis. We provide an overview of our worldviews (dialectical pluralism, critical realism, humanism, and pragmatism) and their philosophical assumptions and describe how they are commensurate with nursing. We present the Stadium Model in Nursing as a metaphor to illustrate how various worldviews function like different sections of a stadium to offer diverse, yet important vantages of our nursing phenomena of interest.


Excellent outcome of tubulointerstitial nephritis and uveitis: case report and five-year follow-up.
Acute tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease usually having a good prognosis. But the recurrence of uveitis and the chronic progression of kidney injury are still main problems. We report a 15-year-old girl with TINU who showed proteinuria, pathological renal change, multiple organ dysfunction, and immune disorders. After 2 months of 1 mg/kg/day corticosteroid therapy, 24-h urine protein, liver function tests, and creatine kinase returned to normal level. In spite of this, steroid was tapered off slowly and small dose of steroid maintenance therapy lasted for 1 year. Her kidney and ocular symptoms did not recur during 5 years of follow-up. We suggest low-dose steroid maintenance therapy to decrease the recurrence of the TINU syndrome.


Conformation and template activity of human reovirus genome RNA.
In vitro activation of human reovirus transcriptase by alpha-chymotrypsin digestion of viral outer shell proteins was completely dependent on the ionic size of the monovalent cation in the medium. Cations with nonhydrated ionic radii larger than 1.3 A showed full potency of activation of chymotrypsin digestion, and produced transcriptionally active virus cores. Smaller cations having ionic radii of 0.6 A or 0.95 A, on the other hand, promoted the chymotrypsin digestion to lesser extents, and yielded subviral particles showing latent or very low transcriptase activities. Differential conformational changes would be induced in viral outer shell proteins by these monovalent cations, resulting in the varied accessibility to chymotrypsin. Electron microscopic analyses under denaturing conditions of the cross-linked reovirus core genome RNAs with the AMT photoreaction revealed that they were almost evenly cross-linked by the psoralen adducts forming no reproducible size of "bubbles." This result suggests that the double helical reovirus genome may not be bound tightly by the inner viral proteins forming such nucleoprotein structures as nucleosomes in eukaryotic chromatin.


Age-associated changes in regenerative capabilities of mesenchymal stem cell: impact on chronic wounds repair.
Mesenchymal stem cells (MSCs) represent an ideal source of autologous cell-based therapy for chronic wounds. Functional characteristics of MSCs may benefit wound healing by exerting their multi-regenerative potential. However, cell ageing resulting from chronic degenerative diseases or donor age could cause inevitable effects on the regenerative abilities of MSCs. A variety of studies have shown the relationship between MSC ageing and age-related dysfunction, but few associate these age-related impacts on MSCs with their ability of repairing chronic wounds, which are common in the elderly population. Here, we discuss the age-associated changes of MSCs and describe the potential impacts on MSC-based therapy for chronic wounds. Furthermore, critical evaluation of the current literatures is necessary for understanding the underlying mechanisms of MSC ageing and raising the corresponding concerns on considering their possible use for chronic wound repair.


The influence of trait anxiety and illusory kinesthesia on pain threshold.
[Purpose] It has also been reported that decreased activity in the reward pathway causes a decrease in brain activity in the descending pain control system in people with high trait anxiety. Activation of this system is dependent on both the reward pathway and motor areas. Recently, studies have also shown that motor areas are activated by illusory kinesthesia. It was aimed to explore whether anxiety trait modulates the influence of illusory kinesthesia on pain threshold. [Subjects and Methods] The pain threshold and trait anxiety at rest before vibratory tendon stimulation (the task) were measured. After the task, the pain threshold, the illusory kinesthesia angle, and the intensity of illusory kinesthesia for patients with and without illusory kinesthesia were measured. A total of 35 healthy right-handed students participated, among whom 22 and 13 were included in the illusion and no-illusion groups, respectively. [Results] There was a significant increase in the pain threshold after task completion in both groups; however, there was no statistically significant difference between the two groups. Correlational analysis revealed that State-Trait Anxiety Inventory-trait score correlated negatively with the pain threshold in the no-illusion group, but there was no correlation in the illusion group. [Conclusion] The pain threshold improved regardless of the size of trait anxiety in the illusion group, but did not improve merely through sensory input by vibratory stimulation in the no-illusion group. Thus, illusory kinesthesia has effect of increasing the pain threshold.


Suicide attempt by intravenous potassium self-poisoning: a case report.
Introduction. Overdose of potassium is not as frequently encountered in clinical practice as hyperkalaemia due to acute or chronic renal disease. However, potassium overdoses leading to serious consequences do occur. Case Presentation. A 20-year-old nurse student presented with a cardiac arrest with asystole rhythm. Beside the patient were found four 50-mL syringes and empty vials of potassium chloride (20 mL, 10%). After initial resuscitation with epinephrine, 125 mL of a 4.2% intravenous solution of sodium bicarbonate were injected which resulted in the recovery of an effective cardiac activity. The patient recovered without sequelae. Conclusion. The difficulty in this case was to recognize the potassium poisoning. The advanced resuscitation with the use of a specific treatment helped to resuscitate the patient.


Clinical evaluation of Asaley.
Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.


Counter-regulatory response to a fall in circulating fatty acid levels in rainbow trout. Possible involvement of the hypothalamus-pituitary-interrenal axis.
We hypothesize that a decrease in circulating levels of fatty acid (FA) in rainbow trout Oncorhynchus mykiss would result in the inhibition of putative hypothalamic FA sensing systems with concomitant changes in the expression of orexigenic and anorexigenic factors ultimately leading to a stimulation of food intake. To assess this hypothesis, we lowered circulating FA levels treating fish with SDZ WAG 994 (SDZ), a selective A1 adenosine receptor agonist that inhibits lipolysis. In additional groups, we also evaluated if the presence of intralipid was able to counteract changes induced by SDZ treatment, and the possible involvement of the hypothalamus-pituitary-interrenal (HPI) axis by treating fish with SDZ in the presence of metyrapone, which decreases cortisol synthesis in fish. The decrease in circulating levels of FA in rainbow trout induced a clear increase in food intake that was associated with the decrease of the anorexigenic potential in hypothalamus (decreased POMC-A1 and CART mRNA abundance), and with changes in several parameters related to putative FA-sensing mechanisms in hypothalamus. Intralipid treatment counteracted these changes. SDZ treatment also induced increased cortisol levels and the activation of different components of the HPI axis whereas these changes disappeared in the presence of intralipid or metyrapone. These results suggest that the HPI axis is involved in a counter-regulatory response in rainbow trout to restore FA levels in plasma.


Comparison of Urea-Based Compounding Moisturizers and Similar Commercial Products on Skin Barrier Function: A Randomized Biometric Study.
Although several commercial moisturizers are available in the market, the continued role of pharmaceutical compounding has been still felt in dry skin management. This study aimed to evaluate the effect of a ureabased compounded moisturizer on barrier function, compared with a similar commercial product. Thirty volunteers with a mean age of 36.15 ± 9.55 years (range 21-56 years) and dry skin were recruited in two groups, one group to apply 5% urea containing hydrophilic petrolatum and the other 10% urea containing hydrophilic petrolatum. In each cohort, the upper parts of right and left forearms were randomly assigned for twice a day application of commercial or compounded products. Whereas the right lower forearm was assigned for application of a cream-based formulation, the left lower one served as the control site and with application of no topical product. Biophysical assessments [transepidermal water loss (TEWL), skin hydration, friction coeffi cient, pH, and surface lipids], were performed before intervention, at 1 and 4 h after single application, and at 24 h and 1 week twice daily application. In both groups, commercial and compounded moisturizers showed an appropriate and comparable effect on skin barrier function compared with creambased formulation and no treatment area. However, commercial products led to better improvement in TEWL, 4 h after single application in both groups (p-value = 0.04). In case of 10% urea base formulation, the rate of increase in skin hydration was also signifi cantly higher for a commercial emollient than a compounding product (57.48 ± 11.23 vs. 50.59 ± 11.42, p-value = 0.02). Commercial formulation led to higher acceptability and better improvement in the skin barrier function after single application, probably because of the influence of excipients. The present study did not find sufficient added value for cream-based pharmacy product relative to commercial one and suggests to be replaced in a similar condition.


AIDS and the future of reproductive freedom.
The specter of pediatric AIDS fundamentally challenges elements of the liberal ideological basis of women's reproductive freedom. Many public health officials hold that preventing transmission of HIV from mother to fetus requires efforts to discourage pregnancy by infected women. For over two decades, however, genetic counselors, feminists, and medical ethicists have stressed the importance of nondirective counseling in the context of reproductive choice. The question now confronted by American society is whether it will be possible to frame an ideology of reproductive choice that recognizes the limits of liberal individualism, while preserving the basic features of reproductive freedom.


Improving Adherence to Long-term Opioid Therapy Guidelines to Reduce Opioid Misuse in Primary Care: A Cluster-Randomized Clinical Trial.
Prescription opioid misuse is a national crisis. Few interventions have improved adherence to opioid-prescribing guidelines. To determine whether a multicomponent intervention, Transforming Opioid Prescribing in Primary Care (TOPCARE; http://mytopcare.org/), improves guideline adherence while decreasing opioid misuse risk. Cluster-randomized clinical trial among 53 primary care clinicians (PCCs) and their 985 patients receiving long-term opioid therapy for pain. The study was conducted from January 2014 to March 2016 in 4 safety-net primary care practices. Intervention PCCs received nurse care management, an electronic registry, 1-on-1 academic detailing, and electronic decision tools for safe opioid prescribing. Control PCCs received electronic decision tools only. Primary outcomes included documentation of guideline-concordant care (both a patient-PCC agreement in the electronic health record and at least 1 urine drug test [UDT]) over 12 months and 2 or more early opioid refills. Secondary outcomes included opioid dose reduction (ie, 10% decrease in morphine-equivalent daily dose [MEDD] at trial end) and opioid treatment discontinuation. Adjusted outcomes controlled for differing baseline patient characteristics: substance use diagnosis, mental health diagnoses, and language. Of the 985 participating patients, 519 were men, and 466 were women (mean [SD] patient age, 54.7 [11.5] years). Patients received a mean (SD) MEDD of 57.8 (78.5) mg. At 1 year, intervention patients were more likely than controls to receive guideline-concordant care (65.9% vs 37.8%; P < .001; adjusted odds ratio [AOR], 6.0; 95% CI, 3.6-10.2), to have a patient-PCC agreement (of the 376 without an agreement at baseline, 53.8% vs 6.0%; P < .001; AOR, 11.9; 95% CI, 4.4-32.2), and to undergo at least 1 UDT (74.6% vs 57.9%; P < .001; AOR, 3.0; 95% CI, 1.8-5.0). There was no difference in odds of early refill receipt between groups (20.7% vs 20.1%; AOR, 1.1; 95% CI, 0.7-1.8). Intervention patients were more likely than controls to have either a 10% dose reduction or opioid treatment discontinuation (AOR, 1.6; 95% CI, 1.3-2.1; P < .001). In adjusted analyses, intervention patients had a mean (SE) MEDD 6.8 (1.6) mg lower than controls (P < .001). A multicomponent intervention improved guideline-concordant care but did not decrease early opioid refills. clinicaltrials.gov Identifier: NCT01909076.


Normal and abnormal development of the human intrahepatic biliary system: a review.
Morphology and immunohistochemical features of the developmental process of the human intrahepatic biliary system (IBS) are reviewed. Human IBS arises from the ductal plate, a double-layered cylindrical structure located at the interface between portal mesenchyme and primitive hepatocytes. The ductal plate first appears from primitive hepatocytes (hepatoblasts) around 8 gestational weeks (GW), and its formation proceeds from the hepatic hilum to the periphery. The ductal plate gradually undergoes remodeling from 12 GW; some parts of the ductal plate disappear and other parts migrate into the portal mesenchyme. Around 20 GW, the migrated duct cells transform into immature bile ducts and peribiliary glands. Some immature peribiliary glands transform into pancreatic acinar cells around postnatal 3 months. The immature biliary elements express cytokeratins no. 7, 8, 18 and 19. Several growth factors (TGF-alpha, HGF) and their receptors (EGFR, MET, ERBB2) were expressed in the primitive IBS cells. Some extracellular matrix proteins including type IV collagen, laminin and tenascin are expressed in the mesenchyme around the primitive IBS. During IBS remodeling, apoptosis and cell proliferation occur with appropriate expression of apoptosis-related proteins (bcl-2, Fas, c-myc, Lewis(y)). Some pancreatic digestive enzymes (alpha-amylase, trypsinogen, lipase), cathepsin B, and matrix metalloproteinases (MMP-1, 2, 3, 9) and their inhibitors (TIMP-1, 2) are expressed in the remodeling IBS cells. Glycoconjugate residues of glycoproteins gradually appear during IBS development. The appropriate expression of these immunophenotypes may play an important role in the normal development of IBS.


Naturally occurring scaffolds for soft tissue repair and regeneration.
Cell growth supports (i.e., scaffolds) that provide a conducive environment for normal cellular growth, differentiation, and angiogenesis are important components of tissue engineered grafts because rapid integration with the host is essential for long-term graft viability. While many of these scaffold materials are synthetic biodegradable polymers, others are naturally derived from mammalian tissue sources. Naturally occurring scaffold materials include small intestinal submucosa, acellular dermis, amniotic membrane tissue, cadaveric fascia, and the bladder acellular matrix graft. Upon implantation, these materials elicit a host-tissue response that initiates angiogenesis, encourages tissue deposition and culminates in restoration of structure and function specific to the grafted site. The sources, the methods of procurement and processing, and the effects of these naturally occurring materials on angiogenesis and tissue deposition are reviewed.


Bortezomib as a treatment option in patients with Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and immunoglobulin M (IgM) monoclonal gammopathy. It remains incurable, with a median survival of 5-10 years in symptomatic WM. Current first-line treatment options include alkylating agents, nucleoside analogues, and rituximab-based therapies. However, primary or secondary resistance invariably develops. Thus, new treatment options are needed. Preclinical studies have shown that the proteasome inhibitor bortezomib targets signaling pathways of relevance in WM. Bortezomib, alone and in combination with rituximab, has demonstrated notable activity in clinical studies in patients with WM, predominantly in phase II trials in the relapsed or refractory setting. In newly diagnosed patients, bortezomib plus rituximab and dexamethasone is highly active (complete response/near-complete response = 22%). Bortezomib-based therapies result in rapid responses, potentially making them suitable treatment options for patients with hyperviscosity-related symptoms who require a rapid reduction in IgM level. In addition, bortezomib appears unique in reducing rituximab-associated IgM flares. Bortezomib is generally well tolerated in WM. However, neurotoxicity is common and might be the cause of dose reduction or treatment discontinuation. Bortezomib has no adverse effect on stem cell harvesting and engraftment, making it a feasible treatment option in transplantation-eligible patients. These encouraging data have led to the inclusion of bortezomib as a salvage treatment option in the recently updated Fourth International Workshop on Waldenström's Macroglobulinemia treatment recommendations.


RNA-Seq reveals 10 novel promising candidate genes affecting milk protein concentration in the Chinese Holstein population.
Paired-end RNA sequencing (RNA-Seq) was used to explore the bovine transcriptome from the mammary tissue of 12 Chinese Holstein cows with 6 extremely high and 6 low phenotypic values for milk protein percentage. We defined the differentially expressed transcripts between the two comparison groups, extremely high and low milk protein percentage during the peak lactation (HP vs LP) and during the non-lactating period (HD vs LD), respectively. Within the differentially expressed genes (DEGs), we detected 157 at peak lactation and 497 in the non-lactating period with a highly significant correlation with milk protein concentration. Integrated interpretation of differential gene expression indicated that SERPINA1, CLU, CNTFR, ERBB2, NEDD4L, ANG, GALE, HSPA8, LPAR6 and CD14 are the most promising candidate genes affecting milk protein concentration. Similarly, LTF, FCGR3A, MEGF10, RRM2 and UBE2C are the most promising candidates that in the non-lactating period could help the mammary tissue prevent issues with inflammation and udder disorders. Putative genes will be valuable resources for designing better breeding strategies to optimize the content of milk protein and also to provide new insights into regulation of lactogenesis.


Family and physicians' views of surrogate decision-making: the roles and how to choose.
Physicians and family members were compared on the roles played in surrogate decision-making and their views as to how choices should be made by surrogate decision-makers. Thirty-six family members of patients with Alzheimer's disease, 35 family members of patients with schizophrenia, and 34 physicians from a diversity of specialties were the respondents. There was general agreement that shared decision-making was preferred. Physicians seem to make surrogate decisions in accordance with contemporary views about their roles. Families believed they had a strong subjective appreciation of the patient's overall good. The burden of decision-making was greater for families, but that depended to some degree on the diagnosis of the patient.


[Diagnosis of tuberculosis in patients of pulmonological hospital].
Analysis of clinical forms of tuberculosis in patients of a pulmonological showed that 65.5% of them had infiltrative tuberculosis, 13.8% fibrocavernous tuberculosis, 10.4% disseminated tuberculosis, 6.9% focal tuberculosis, and 1.7% tuberculoma. It was ascertained that in these patients destructive tuberculous changes were common and occurred in 67.2% and tuberculosis was concurrent with other lung diseases in 70.7%. This follows that special attention should be given to the patients of pulmonological hospitals and sputum tests for mycobacteria are to be performed 3 times.


Chondromyxoid Fibroma of the Skull Base: Our Experience with an Elusive Disease.
Chondromyxoid fibroma (CMF) is an extremely rare lesion of the skull base. This histologic type typically predilects metaphysis of the long bones. It is locally invasive/infiltrative, and this tendency is more concerning in the skull base, where a radical resection is often technically impossible because of the presence of vital neurovascular structures. We present a case of a 19-year-old woman who presented with a sudden onset of right facial weakness, progressively worsening to a severe disfiguring motor weakness. Gadolinium-enhanced brain magnetic resonance imaging showed an osteolytic lesion located in the right mastoid involving the stylomastoid foramen and the right seventh cranial nerve. A partial mastoidectomy was performed, with an excellent rate of tumor resection and complete local control of the disease at follow-up. The analysis of current literature indicates that a radiologic diagnosis is rarely strictly convincing of CMF. Histologic diagnosis is often difficult due to the lack of a specific immunohistochemical pattern of chondrosarcoma. Surgery is currently recognized as the mainstay to manage this lesion, although a trend toward adjuvant radiation therapy (RT) currently is seen. Although a tendency of local recurrence is well recognized in the literature, the very slow and indolent behavior of this lesion plus the trend to enhance local control of the disease with high-dose RT pushed us to a reappraise the role of radical skull base surgeries burdened by the risks of major complications, cosmetic deformities, and additional neurologic deficits.


Social identification among political party voters and members: an empirical test of optimal distinctiveness theory.
According to optimal distinctiveness theory, minority political parties and parties of intermediate size provide more central and important bases of social identity. The authors tested that prediction in a sample of voters and a sample of political party members. In both samples, adherents of minority and intermediate parties did not perceive their parties to be more representative of them. The authors found no significant differences between political parties on the collective self-esteem questionnaire administered to the sample of political party members.


[Atorvastatin-meloxicam association inhibits neuroinflammation and attenuates the cellular damage in cerebral ischemia by arterial embolism].
Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue .


Prevalence and clustering patterns of human papillomavirus genotypes in multiple infections.
Prevalence of multiple human papillomavirus (HPV) infections, involvement of specific HPV phylogenetic clades in multiple infections, and clustering patterns of multiple infections at the clade level were assessed in 854 HIV (-) and 275 HIV (+) women cross-sectionally. Reverse line blot assay was used to detect 27 HPV genotypes. Involvement of specific clades in coinfections and clustering patterns were assessed using HPV clade/genotype as the unit of analyses. Expected frequencies assuming independence for all possible clade combinations in two-genotype infections were derived using a multinomial expansion and comparisons of observed and expected frequencies were done using a composite goodness-of-fit test. In all, 100 two-genotype infections were detected; 61 in HIV (-) and 39 in HIV (+) women. Clade A9 (HPV types 16, 31, 33, 35, 52, and 58) was significantly less likely to be involved in multiple infections compared with all other clades (55.2% versus 64.6%; adjusted odds ratios, 0.68; 95% confidence interval, 0.48-0.95). Observed patterns for all possible clade combinations (among HPV clades A3, A5, A6, A7, A9, and A10) in two-genotype infections did not significantly differ from those expected in the entire sample, across HIV, Pap smear, and age strata (all goodness-of-fit exact P > 0.20). These results indicate that clade A9 is less likely to be involved in multiple infections and that HPV genotypes predominantly establish multiple infections at random, with little positive/negative clustering for either phylogenetically related or unrelated types. The current method of analysis affords the opportunity to test clustering of a large number of HPV genotype/clade combinations at nominal alpha levels.


Identifying specific cues and contexts related to bingeing behavior for the development of effective virtual environments.
Binge eating behavior constitutes a central feature of both bulimia nervosa (BN) and binge eating disorder (BED). Cue exposure therapy (CET) has been proposed as an effective intervention. To determine which situations and specific cues trigger higher levels of binge craving and to use the results in the development of virtual reality scenarios in which CET could be applied with BN and BED patients. Participants were 101 outpatients, 50 with BED and 51 with BN, according to DSM-5 criteria, and 63 healthy undergraduate students who completed a self-administered questionnaire to assess binge craving. The likelihood of binge craving in the clinical group was greater when alone at home, during the afternoon/early evening and in the late evening/at night, at weekends, and at dinner time or between meals. Higher levels of craving were produced in the kitchen, bedroom, dining room, and bakery situations. With regard to the specific cues reported, the presence of and access to high calorie food and snacks was the most commonly reported cue. Although some gender differences regarding triggering factors were obtained, no statistical differences were observed between ED subtypes. BN and BED patients showed significantly higher levels of binge craving than controls in all the contexts except when feeling positive affect; in this situation, levels of craving were low in both groups. This information regarding trigger contexts and specific cues can be used to create valid and reliable virtual environments for CET. Indeed, the data from this study may serve to develop a wide range of situations with different levels of binge craving, in which the therapeutic aim is to extinguish conditioned responses and facilitate the generalization of craving extinction.


Oxygen free radicals are not the main factor in experimental gentamicin nephrotoxicity.
As a role for oxygen free radicals has been suggested in gentamicin (G) nephrotoxicity, we tested the hypothesis that exogenously administered glutathione (GSH), able to restore intracellular antioxidant potential, could be useful in reducing damage. Adult Sprague-Dawley rats were injected with saline (n = 30), subcutaneous (s.c.) G 100 (n = 23) and 150 mg/kg/day (n = 14), or s.c. G at the same dosages plus intraperitoneal (i.p.) GSH 1200 mg/kg/day (n = 24 and 14, respectively) for 7 days. In the G-100-day protocol, GSH-treated rats showed significantly lower renal G content (2.79 +/- 0.8 vs. 3.61 +/- 1.4 micrograms/mg prot) coupled with lower plasma urea (153 +/- 79 vs. 188 +/- 61 mg/dL) and creatinine levels (1.63 +/- 1 vs. 2.45 +/- 1 mg/dL). As to renal oxidant/antioxidant balance, local GSH was increased (0.32 +/- 0.01 vs. 0.19 +/- 0.01 microgram/mg prot) while lipid peroxidation, determined by production of thiobarbituric acid reactive substances (TBARS), was decreased (0.35 +/- 0.02 vs. 0.52 +/- 0.02 nmol/mg prot). In the G-150-mg protocol, GSH-treated rats showed no differences in renal gentamicin content or in blood urea and creatinine levels, in spite of a significantly lower renal TBARS production and a significantly higher GSH content. Urine enzyme excretion did not significantly change in GSH-treated vs. not-GSH-treated rats in both protocols. We conclude that: (a) GSH interferes with G nephrotoxicity mainly via a reduction in G uptake; (b) the oxidative renal stress is not crucial in inducing renal damage. In fact, when increased G dosages blunt the ability of GSH in reducing G uptake, no substantial protection is demonstrated.


Diacetyldiamidoximeester of pentamidine, a prodrug for treatment of protozoal diseases: synthesis, in vitro and in vivo biotransformation.
Pentamidine is an effective antimicrobial agent. To increase its poor oral bioavailability due to the strong basic amidine functionality, the less basic O-acetylamidoxime prodrug, the diacetyldiamidoximeester, was used, which has greatly improved lipophilicity. The objectives of this investigation were the synthesis of all potential metabolites of the double prodrug, the conformational analysis of its structure, and to study the in vitro and in vivo biotransformation by ester cleavage and N-reduction to pentamidine via four intermediate metabolites. The biotransformation of diacetyldiamidoximeester to pentamidine involving the reduction of the amidoxime function and the ester cleavage could be demonstrated. The kinetic parameters were determined. Amidoximes were efficiently metabolized by several enzyme systems located in microsomes and mitochondria of different organs including the final formation of the active metabolite pentamidine. The formation of pentamidine after oral administration of the diacetyldiamidoximeester to rats could be demonstrated as well.


Characterization of in-use light-duty gasoline vehicle emissions by remote sensing in Beijing: impact of recent control measures.
China's national government and Beijing city authorities have adopted additional control measures to reduce the negative impact of vehicle emissions on Beijing's air quality. An evaluation of the effectiveness of these measures may provide guidance for future vehicle emission control strategy development. In-use emissions from light-duty gasoline vehicles (LDGVs) were investigated at five sites in Beijing with remote sensing instrumentation. Distance-based mass emission factors were derived with fuel consumption modeled on real world data. The results show that the recently implemented aggressive control strategies are significantly reducing the emissions of on-road vehicles. Older vehicles are contributing substantially to the total fleet emissions. An earlier program to retrofit pre-Euro cars with three-way catalysts produced little emission reduction. The impact of model year and driving conditions on the average mass emission factors indicates that the durability of vehicles emission controls may be inadequate in Beijing.


The Use of Economic Evaluation Tools in Essential Health Benefits Package Selection for Universal Health Coverage.
The sustainable development goals launched in 2015 are a follow-up commitment to the successful Millennium Development Goals. Goal number 3 of ensuring "good health and well-being" is a target to ensure universal health coverage. Universal health coverage means the provision of quality services that meet the needs of populations without risking financial impoverishment in the process. The guaranteed minimum health services in every health system constitute the health benefits package (HBP), which should be explicit and be composed of services that represent the best value for money and guarantee the best return on investment. The objective of this study was to review the application of cost-effectiveness analysis (CEA) and budget impact analysis in the development of HBP in low-to-middle income countries across the world. A literature review using a systematic approach was used. A search of PubMed, Google Scholar, World Health Organization, and World Bank databases was made for articles outlining the development of HBP in low- and middle-income countries, and a narrative synthesis was used for analysis. Results from processes in Armenia, Ethiopia, Kyrgyz Republic, Lebanon, and Malawi showed CEA and budget impact analysis as 2 criteria used in HBP development in a limited number of countries with either no reference to the two or no reporting from the others. Local CEA estimates and cost data limitations were the biggest challenges to efforts to use robust methods. Sustained efforts are needed to understand and address the challenges to the use of economic evaluation in the development of HBPs.


Early life investment in antlers and body growth reflects adult performance in roe deer population under supplementary feeding conditions.
Recent research has challenged the idea that cervid antlers are such costly traits, supporting the assertion early-life antler investment is an honest signal of adult phenotypic quality. However, inferences were made based on antler measurements while growing (velvet) and thus, studies on fully-formed clean antlers are needed to avoid possible bias caused by the inter-individual variation in antler growth phenology. We studied a semi-captive population of European roe deer inhabiting a sub-Mediterranean area (Valsemana research station) and living under optimal conditions (ad libitum food supply and veterinary care). Based on repeated measurements taken from 146 individuals, we assessed whether allocation to secondary sexual traits during early life affected body mass or antler development during adulthood. Furthermore, we evaluated which body measurements better predicted future male quality. Additionally, using 488 individuals, we described age-class-specific variation in male body measurements and assessed the decline in antler size between adult and senescent stages (i.e. magnitude of senescence). Results agree with the assertion that there is no negative effect of a high investment in antler during early life on adult antler size or body mass, but we suggest the use of clean antlers as a more robust and reliable measure. The variables that better predicted body mass during adulthood were yearling body mass and body size at 6 months. Antler score between 10 and 18 months resulted in the best indicator of adult antler size. Finally, we support the idea that the magnitude of senescence in antler size is smaller in environments with higher resource availability during winter.


[Postmenopausal hormone replacement therapy and cancer of the female genitalia and breast].
Oestrogen replacement therapy (ORT) significantly increases the relative risk (RR) of endometrial cancer, especially long-term oestrogen use (RR: 9.5; 95% confidence interval (CI): 7.4-12.3). Addition of a progestin to ORT reduces this increased risk completely or largely. The risk of breast cancer is increased after ORT of 5 years or longer (RR: 1.23; 95% CI: 1.08-1.40). Addition of a progestin does not reduce this increased risk. The possibility cannot be excluded that long-term ORT increases the risk of epithelial ovarian cancer. No significant association between ORT and cervical cancer has been demonstrated. It is safe to prescribe ORT for a period shorter than 5 years for women with menopausal symptoms. Addition of a progestin is indicated when the uterus is in situ. Hormonal supplementation therapy is to be discouraged in women treated for breast cancer, may be considered in young women previously treated for endometrial or ovarian cancer with a good prognosis and severe menopausal symptoms and is justified in women previously treated for cervical cancer.


[The nosological structure of mortality of low-weight fetuses in Novosibirsk].
The nosological structure of mortality was studied among low-weight fetuses, by analyzing 667 autopsy protocols over 2006-2008. There were 255 cases of spontaneous miscarriage and 412 cases of medically indicated abortion. Spontaneous and artificial abortions most frequently occur in repeated pregnant women at 26-27 weeks gestational age. In the nosological structure of fetal mortality, intrauterine fetal asphyxia was most commonly in spontaneous miscarriage; intrauterine pneumonias and generalized infection ranked second; in artificial abortion, the number of congenital malformations doubled and that of intrauterine fetal asphyxia reduced. In spontaneous and artificial abortions, the incidence of decompensated chronic placental insufficiency increased by twice.