Three-dimensional structure of the lantibiotic nisin in the presence of membrane-mimetic micelles of dodecylphosphocholine and of sodium dodecylsulphate.
The lantibiotic nisin is a cationic, polycyclic bacteriocin of 34 residues, including several unusual dehydro residues and thioether-bridged lanthionines. The primary target of its antimicrobial action is the cytoplasmic membrane. Therefore the conformation of nisin when bound to membrane-mimicking micelles of zwitterionic dodecylphosphocholine and of anionic sodium dodecylsulphate was determined with high-resolution NMR spectroscopy. Structures were calculated on the basis of NMR-derived constraints with the distance-geometry program DIANA and were further refined by restrained energy minimization using X-PLOR. The conformation of nisin complexed to both types of micelles is the same, irrespective of the different polar head-groups of the detergents. The structure consists of two structured domains: an N-terminal domain (residues 3-19) containing three lanthionine rings, A, B and C; and a C-terminal domain (residues 22-28) containing two intertwined lanthionine rings numbered D and E. These domains are flanked by regions showing structural variability. Both domains are clearly amphipathic, a property characteristic for membrane-interacting polypeptides. The structures of the ring systems are better defined than those of the linear segments. The four-residue rings B, D and E of nisin all show a beta-turn structure, which is closed by the thioether linkage. The backbones of the rings B and D form type 11 beta-turns. Ring E resembles a type I beta-turn. Preceding the intertwined rings D (residues 23-26) and E (25-28) another type-II beta-turn is found formed by the residues 21-24, so that the C-terminal domain consists of three consecutive beta-turns. The structures of nisin in the micellar systems differ significantly from the previously determined (and now partially recalculated) structure in aqueous solution [van de Ven, F. J. M., van den Hooven, H. W., Konings, R. N. H. & Hilbers, C. W. (1991) Eur J. Biochem. 202, 1181-1188] in the first lanthionine ring around dehydroalanine 5.


Automation failures and patient safety.
The goal of automation is to decrease the anesthesiologist's workload and to decrease the possibility of human error. Automated systems introduce problems of its own, however, including loss of situation awareness, leaving the physician out of the loop, and training physicians how to monitor autonomous systems. This review will discuss the growing role of automated systems in healthcare and describe two types of automation failures. An automation surprise occurs when an automated system takes an action that is unexpected by the user. Mode confusion occurs when the operator does not understand what an automated system is programmed to do and may prevent the clinician from fully understanding what the device is doing during a critical event. Both types of automation failures can decrease a clinician's trust in the system. They may also prevent a clinician from regaining control of a failed system (e.g., a ventilator that is no longer working) during a critical event. Clinicians should receive generalized training on how to manage automation and should also be required to demonstrate competency before using medical equipment that employs automation, including electronic health records, infusion pumps, and ventilators.


Heat-stable proteins and abscisic Acid action in barley aleurone cells.
[(35)S]Methionine labeling experiments showed that abscisic acid (ABA) induced the synthesis of at least 25 polypeptides in mature barley (Hordeum vulgare) aleurone cells. The polypeptides were not secreted. Whereas most of the proteins extracted from aleurone cells were coagulated by heating to 100 degrees C for 10 minutes, most of the ABA-induced polypeptides remained in solution (heat-stable). ABA had little effect on the spectrum of polypeptides that were synthesized and secreted by aleurone cells, and most of these secreted polypeptides were also heatstable. Coomassie blue staining of sodium dodecyl sulfate polyacrylamide gels indicated that ABA-induced polypeptides already occurred in high amounts in mature aleurone layers having accumulated during grain development. About 60% of the total protein extracted from mature aleurone was heat stable. Amino acid analyses of total preparations of heat-stable and heat-labile proteins showed that, compared to heat-labile proteins, heat-stable intracellular proteins were characterized by higher glutamic acid/glutamine (Glx) and glycine levels and lower levels of neutral amino acids. Secreted heat-stable proteins were rich in Glx and proline. The possibilities that the accumulation of the heat-stable polypeptides during grain development is controlled by ABA and that the function of these polypeptides is related to their abundance and extraordinary heat stability are considered.


Research on an in vitro cell system for testing the neurotoxicity of kynurenine pathway metabolites.
Quinolinic acid (QUIN), kynurenine acid (KYNA) and 3-hydroxykynurenine (3-HK) - metabolites of the kynurenine pathway are considered to be associated with many central nervous system diseases. However, in neuroscience research in order to test neurotoxicity or neuroprotection against these compounds only primary cell models are available. In this investigation we aimed to develop a simple, rapid and accurate cellular in vitro model using immortalized human neuroblastoma cell lines, namely SK-N-SH and SH-SY5Y differentiated by treatment with various agents. In order to alter the cell response to the neurotoxins, tumor necrosis factor-alpha and retinoic acid (RA) as differentiating agents and modulation of the cellular metabolism through changing the sugar composition from galactose to glucose in media were used. Our results indicated that although RA-differentiation of both cell lines induced the expression of neuronal features, cell vulnerability after exposure to control neurotoxicants (salsolinol, 6-hydroxydopamine) and 3-HK was decreased in comparison to untreated cells and was not influenced after exposure to QUIN and KYNA. Interestingly, the same observations were done in cells grown in galactose containing media.


21st birthday drinking and associated physical consequences and behavioral risks.
Twenty-first birthday celebrations often involve dangerously high levels of alcohol consumption, yet little is known about risk factors for excessive drinking on this occasion. Participants (N = 150) from a larger prospective study who consumed at least one drink during their celebration completed questionnaires and semistructured interviews about their 21st birthday within four days after the event. Assessments were designed to characterize 21st birthday alcohol use, adjusted for alcohol content, as well as situational/contextual factors (e.g., celebration location, peer influence) that contribute to event-level drinking. Participants reported an average of 10.85 drinks (9.76 adjusted drinks), with experienced drinkers consuming significantly more than relatively naïve drinkers who had no previous binge or drunken episodes. Men consumed more drinks, whereas age of first drunken episode and heavier drinking during the 3-months preceding the 21st birthday predicted higher estimated blood alcohol concentrations (eBACs) on the 21st birthday. Celebrating in bars and engaging in birthday-specific drinking traditions (free drinks at bars) explained additional variance in 21st birthday eBACs. Both physical consequences (e.g., blacking out or having a hangover) and behavioral risks (e.g., sexually provocative behaviors) were prevalent and were predicted by higher eBACs. Together these findings indicate that 21st birthday celebrations are associated with heavy drinking and a variety of physical consequences and behavioral risks.


Thrombus imaging with 99mTc-HMPAO-labeled platelets and 111In-labeled monoclonal antifibrin antibodies.
Eighteen patients with suspicion of deep venous thrombosis (DVT) in the lower extremities were imaged both with autologous 99mTc-HMPAO-labeled platelets (Tc-PLT) and 111In-labeled monoclonal antifibrin antibodies (In-MoAbs) on the same day. Presence or absence of thrombosis was verified by venography. Tc-PLT was given i.v. followed after 30 min by In-MoAbs. Anterior and posterior projections of the lower extremities were obtained with a large field-of-view gamma camera at 5 to 25 min, 2 h, 4 to 6 h, and 20 h after administration of the marker. Both Tc-PLT and In-MoAbs detected DVT well but less frequently than venography. Thrombi were visualized at 2 to 4 h after injection. The quality of images was better with Tc-PLT than with In-MoAbs. In the patients treated during the study, heparin significantly (p < 0.01) inhibited the uptake of Tc-PLT but not of In-MoAbs. We conclude that both Tc-PLT and In-MoAbs are suitable agents for the detection of DVT especially in patients without anticoagulation.


Antagonistic Antibody Targeting TNFR2 Inhibits Regulatory T Cell Function to Promote Anti-Tumor Activity.
Infiltration of regulatory T cells (Tregs) in the tumor microenvironment suppresses anti-tumor immune response, and promotes tumor progression. Tumor necrosis factor receptor-2 (TNFR2), which is highly expressed on Tregs, activates Tregs through nuclear factor kappa B (NF-κB) pathway. Moreover, TNFR2+ Tregs have been shown to be most suppressive among all Tregs populations in tumor. Due to the unique expression pattern and function of TNFR2 on Tregs, a TNFR2 blocking antibody is expected to compromise Tregs function, relieve Tregs-mediated immunosuppression, and hence to enhance anti-tumor immune response. AN3025 is an antagonistic anti-human TNFR2 (hTNFR2) antibody that is currently under preclinical development. This study investigates the immunomodulatory and anti-tumor activity of AN3025. AN3025 was generated through rabbit immunization with extracellular domain of human TNFR2 and subsequent humanization by complementarity-determining regions (CDRs) grafting. AN3025 binds to the extracellular domain of both human and cynomolgus with sub-nanomolar affinity and specificity, but not mouse or rat TNFR2. AN3025 inhibited tumor necrosis factor alpha (TNFα) induced cell death of hTNFR2-overexpressing Jurkat cells by competing with TNFα for binding to hTNFR2. In the Tregs/T effector co-culture assay, AN3025 increased T effector proliferation and enhanced interferon gamma (IFNγ) production. As a monotherapy, AN3025 significantly inhibited MC38 tumor growth in TNFR2 humanized mouse model. Subsequent flow cytometry (FACS) and immunohistochemistry (IHC) analysis revealed that administration of AN3025 led to decreased Tregs population, increased CD4+ and CD8+ T cell numbers in the tumor. The anti-tumor activity of AN3025 was dependent on the existence of CD4+ and CD8+ T cells, as depletion of CD4+ and CD8+ T cells abolished the anti-tumor activity of AN3025. In addition, AN3025 in combination with anti-PD-1 antibody demonstrated stronger in-vivo anti-tumor activity. The potent anti-tumor efficacy of AN3025, either as a monotherapy or in combination with anti-PD-1 antibody, supports its further clinical development for the treatment of various human tumors.


Direct Analysis of Rare Circulating Tumor Cells in Whole Blood Based on Their Controlled Capture and Release on Electrode Surface.
The development of a simple, sensitive, and effective method for the analysis of circulating tumor cells (CTCs) is essential for cancer diagnosis and metastasis prediction. In this work, we have proposed an enzyme-free electrochemical method for specific capture, sensitive quantification, and efficient release of CTCs. To achieve this, the specific interaction between CTCs and the corresponding aptamer designed to be located in the identification probe (IP) will unfold the hairpin structure of IP. Consequently, IP will initiate a hybridization reaction to produce a duplex, which will further trigger the hybridization chain reaction (HCR) process to form a composite product of CTCs and double-stranded DNA polymers. Therefore, a significantly amplified signal readout can be obtained. Moreover, the composite product can be brought to the electrode surface by tetrahedral DNA nanostructures to achieve the purpose of capturing and quantifying CTCs. More significantly, these captured CTCs can be controlled released without compromising cell viability via a simple strand displacement reaction. Taking the breast cancer cell MCF-7 as a representative, the newly developed approach led to an ultralow detection limit of 3 cells mL-1, which is superior to several studies previously reported. The current method has also been demonstrated to analyze CTCs in human whole blood and hence revealed a great potential in the future.


Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.
Preoperative chemotherapy in patients with gastroesophageal cancer is hampered by the lack of reliable predictors of tumor response. This study evaluates whether positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may predict response early in the course of therapy. Forty consecutive patients with locally advanced adenocarcinomas of the esophagogastric junction were studied by FDG-PET at baseline and 14 days after initiation of cisplatin-based polychemotherapy. Clinical response (reduction of tumor length and wall thickness by > 50%) was evaluated after 3 months of therapy using endoscopy and standard imaging techniques. Patients with potentially resectable tumors underwent surgery, and tumor regression was assessed histopathologically. The reduction of tumor FDG uptake (mean +/- 1 SD) after 14 days of therapy was significantly different between responding (-54% +/- 17%) and nonresponding tumors (-15% +/- 21%). Optimal differentiation was achieved by a cutoff value of 35% reduction of initial FDG uptake. Applying this cutoff value as a criterion for a metabolic response predicted clinical response with a sensitivity and specificity of 93% (14 of 15 patients) and 95% (21 of 22), respectively. Histopathologically complete or subtotal tumor regression was achieved in 53% (eight of 15) of the patients with a metabolic response but only in 5% (one of 22) of the patients without a metabolic response. Patients without a metabolic response were also characterized by significantly shorter time to progression/recurrence (P =.01) and shorter overall survival (P =.04). PET imaging may differentiate responding and nonresponding tumors early in the course of therapy. By avoiding ineffective and potentially harmful treatment, this may markedly facilitate the use of preoperative therapy, especially in patients with potentially resectable tumors.


Changes in adipocyte hormones leptin, resistin, and adiponectin in thyroid dysfunction.
Thyroid hormones as well as the recently discovered secretory products of adipose tissue adiponectin and resistin take part in energy metabolism. To study the changes in the adipocyte hormones with changes in the thyroid functional status, we measured adiponectin, resistin, and leptin in 69 subjects with Graves' disease before and 32 patients at follow up after treatment for hyperthyroidism at hypothyroid state. Concentrations of serum adiponectin and resistin were higher in hyperthyroid state than in hypothyroid state (adiponectin: 5.73 +/- 1.1 vs. 3.0 +/- 0.5 ng/ml, P = 0.03) (resistin: 6.378 +/- 0.6 vs. 5.81 +/- 0.57 ng/ml, P < 0.0001). Resistin levels correlate positively with free t4(r = 0.37, P < 0.01), free t3 levels(r = 0.33, P < 0.01) and negatively with TSH(r = -0.22, P < 0.05). Adiponectin levels correlate with free t4(r = 0.33, P < 0.01) and free t3 (r = 0.44, P < 0.01). Though the adiponectin levels did not correlate with leptin or resistin levels, strong positive correlation of both resistin and adiponectin with thyroid hormones is noted. Serum levels of leptin did not change with change in the thyroid functional status (leptin: 53.38 +/- 2.47 vs. 55.10 +/- 2.58 NS). Leptin levels did not correlate with resistin and adiponectin. We conclude that thyroid function has effect on adipocyte hormones adiponectin and resistin but not leptin.


Evaluation of a combinatorial approach to prion inactivation using an oxidizing agent, SDS, and proteinase K.
Prions demonstrate an unusual resistance to methods effective at inactivating conventional microorganisms. This has resulted in a very tangible and difficult infection control challenge to the medical and veterinary communities, as well as animal agriculture and related industries. Currently accepted practices of harsh chemical treatments such as prolonged exposure to sodium hydroxide or sodium hypochlorite, or autoclaving are not suitable in many situations. Less caustic and more readily applicable treatments to contaminated environments are therefore desirable. We recently demonstrated that exposure of the RML scrapie agent to a commercial product containing sodium percarbonate (SPC-P) with or without sodium dodecyl sulfate (SDS) rendered PrP(Sc) sensitive to proteinase K (PK), but did not eliminate infectivity. The current study was designed to evaluate the efficacy of a combinatorial approach to inactivating prions by exposing RML-positive brain homogenate to SPC-P and SDS followed by PK. Treated samples were evaluated for PrP(Sc)-immunoreactivity by western blot, and residual infectivity by mouse bioassay. Treatment of infected brain homogenate with SPC-P and SDS followed by PK exposure resulted in a 4-5 log10 reduction in infectivity when bioassayed in tga20 mice. This study demonstrates that exposure of the RML scrapie agent to SPC-P and SDS followed by PK markedly reduces, but does not eliminate infectivity. The results of this study encourage further investigation into whether consecutive or concomitant exposure to sodium percarbonate, SDS, and a protease may serve as a viable and non-caustic option for prion inactivation.


Assessment of Melatonin and Its Precursors Content by a HPLC-MS/MS Method from Different Romanian Wines.
Because melatonin has strong antioxidant activity and wine is an alcoholic beverage of economic relevance, in the present work, the impact of some variable parameters that may occur in the winemaking process on the concentrations of melatonin and its precursors in Romanian wines was studied. Therefore, a sensitive and selective high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the simultaneous analysis of melatonin, serotonin, and l-tryptophan, and some method performance parameters including selectivity, detection limit, precision (by comparing with an alternative HPLC-FL method), accuracy, and robustness were validated. These determinations are significant and the final amounts of analytes are dependent on the microorganisms involved in the winemaking process, the grape variety, geographic regions of vineyards, and aging of wines. In the future, the method may be useful to increase the melatonin content and the antioxidant activity in wines by improved steps in the winemaking process, especially based on application of selected yeasts and improved fermentation conditions.


Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs.
The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.


Ipecac-induced emesis versus gastric lavage: a controlled study in normal adults.
Ipecac-induced emesis and gastric lavage are the two procedures most widely used to evacuate the stomachs of patients who have ingested poisons. To resolve a long-standing controversy over the relative efficacy of these two methods, the authors carried out a controlled study in which they administered 25 100-micrograms tablets of cyanocobalamin (vitamin B12) to 18 fasting normal adult volunteers on two separate days. On one day, each subject had emesis induced with 30 ml of ipecac syrup followed by 1,000 ml of tap water; on another day, each underwent gastric aspiration and lavage with a 1.1-cm orogastric tube using 3 l of fluid. Both procedures were begun 10 minutes after the ingestion. The recovered vomitus or gastric washings from each procedure were then analyzed for elemental cobalt using atomic absorption spectrophotometry. The mean rate of recovery of the ingested tracer with ipecac-induced emesis was only 28%, whereas gastric lavage resulted in retrieval of 45% (paired t-test, P less than 0.005). In this study, carefully performed gastric lavage was the more effective method of gastric evacuation of tablets in the adult subject.


Two-step hot isostatic pressing densification achieved non-porous fully-densified wood with enhanced physical and mechanical properties.
A new two-step densification method for wooden materials entitled hot isostatic pressing (HIP) is proposed. This method has the advantage over previous densification methods that can achieved almost the full densification of wood, reaching values up to 1.47 kg/m3, which exceeds any value ever reported for a hardwood species. Furthermore, it can preserve about 35% of the original volume, in comparison to other methods which typically can preserve only 20% of the volume. Although not tested in this investigation, in principle, the HIP method should be capable of densifying any shape of wood including circular and tubular cross sections because the main densification mechanism is based on gas pressure that is equally exerted in the entire surface, rather than localized mechanical compression, which can only be effective with rectangular cross sections. In the first stage of the two-step proposed method, the compressive strength of the anatomical wood structure is reduced by delignification, and, in the second, a full densification is achieved by hot isostatic pressing under argon atmosphere. Three tropical hardwood species with distinct anatomical characteristics and properties were used to test the method. The HIP-densified wood's microstructural, chemical, physical, and mechanical properties were assessed. Apart from the high densification values and volume preservation, the results indicate that proposed method was effective for all the tested species, showing homogenous density patterns, stable densification without noticeable shape recovery, and enhanced mechanical properties. Future research should test the HIP method in softwoods and consider the ring orientation in order to enhance the control of the densified geometry.


Smartphone-Enhanced Low-Threshold Intervention for adolescents with Anorexia Nervosa (SELTIAN) waiting for outpatient psychotherapy: study protocol of a randomised controlled trial.
As smartphones are widely distributed nowadays, mental health apps seem to be a promising treatment tool. First self-help apps for eating disorders have been developed recently. However, studies assessing the efficacy of such apps are scarce. A smartphone app could prevent further weight reduction and increase commitment during waiting time for outpatient treatment, especially for adolescents with anorexia nervosa (AN). In this study protocol, a randomised controlled trial to assess the efficacy of a smartphone-enhanced low-threshold intervention for AN during waiting time is described. 30 adolescents with AN aged 12-19 years will be recruited at three child and adolescent psychiatry centres in Germany. All participants will be randomised to consultations only or consultations and the use of the Jourvie Research app. The app will be installed either on their own smartphone or on a research device. The participants will receive biweekly to monthly consultations for 3 months to review meal plans and weight management with a clinician. In addition, the Jourvie Research app for meal, behaviour and emotion protocolling will be provided to the intervention group. The protocols will be discussed with a clinician during the consultations. Dialectical behaviour therapy-informed skills for tension regulation to increase compliance with the meal plan will be taught in the intervention group and the app will remind the participant of a skill in a moment of need. The primary outcome is the age-adjusted and height-adjusted weight gain in standard deviation score after 3 months. Results will be disseminated at conferences and through peer-reviewed publications. The trial was approved by the ethics review board of the local medical association, Mainz, Germany, under the reference number 837.338.15. German clinical trials register, reference number DRKS00008946.


Cancer cell cannibalism and the SASP: Ripples in the murky waters of tumor dormancy.
Relapse in cancer patients following an apparent cure and a prolonged latency period, known as tumor dormancy, remains an unrelenting clinical crisis. Here, I expand on our recent findings that potentially link cancer cell cannibalism of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to the senescence-associated secretory phenotype (SASP) and tumor dormancy.


PLS1, a gene encoding a tetraspanin-like protein, is required for penetration of rice leaf by the fungal pathogen Magnaporthe grisea.
We describe in this study punchless, a nonpathogenic mutant from the rice blast fungus M. grisea, obtained by plasmid-mediated insertional mutagenesis. As do most fungal plant pathogens, M. grisea differentiates an infection structure specialized for host penetration called the appressorium. We show that punchless differentiates appressoria that fail to breach either the leaf epidermis or artificial membranes such as cellophane. Cytological analysis of punchless appressoria shows that they have a cellular structure, turgor, and glycogen content similar to those of wild type before penetration, but that they are unable to differentiate penetration pegs. The inactivated gene, PLS1, encodes a putative integral membrane protein of 225 aa (Pls1p). A functional Pls1p-green fluorescent protein fusion protein was detected only in appressoria and was localized in plasma membranes and vacuoles. Pls1p is structurally related to the tetraspanin family. In animals, these proteins are components of membrane signaling complexes controlling cell differentiation, motility, and adhesion. We conclude that PLS1 controls an appressorial function essential for the penetration of the fungus into host leaves.


Interaction mechanism of in-situ nano-TiN-AlN particles and solid/liquid interface during solidification.
This paper deals with the interaction mechanism between in situ nanometer-grade TiN-AlN particles and the solid/liquid (S/L) interface during the solidification of an in situ TiN-AlN/Al composite. According to the setting of a force balance for the particles in front of the S/L interface during solidification, F = F(buoyant) + F(repulsive) + F(viscous). We obtained the relationship between the critical cooling velocity of the liquid composite, Vr, and the size of the ceramic particle, rp. By this relationship formula, we can know that the S/L interface engulfs particles or pushes them to the crystal grain boundary during the solidification of a TiN-AlN/Al composite. It is found that Vr is proportional to the radius of ceramic particles by transmission electron microscope (TEM) observation. The TEM test indicates that the smaller the particle is, the more easily the S/L interface engulfs particles.


Aspirin and urologic cancer risk: an update.
Aspirin has been associated with a reduced risk of colorectal cancer. With specific reference to urological cancers, a protective role for aspirin has been suggested for prostate cancer, but data for cancers of the bladder and kidney have been limited and inconsistent. Epidemiological evidence suggests that prostate cancer risk is reduced by 10% in regular aspirin users, with similar risk reductions reported in both case-control and cohort studies, and for both slow-growing and aggressive cancers. However, risk estimates were significantly heterogeneous and there was no relationship between risk reduction and frequency, dose or duration of use. Thus, inference for causality and public health implications remain far from conclusive. Although a few case-control studies have reported a favorable effect of aspirin on bladder cancer, most investigations did not find any meaningful association. A modest nonsignificant increased risk was reported for kidney cancer. Such excess risk, however, might be due to exposure to phenacetin-containing analgesics, which have been reported to increase renal cell cancer risk.


Residual Gas Adsorption and Desorption in the Field Emission of Titanium-Coated Carbon Nanotubes.
Titanium (Ti)-coated multiwall carbon nanotubes (CNTs) emitters based on the magnetron sputtering process are demonstrated, and the influences of modification to CNTs on the residual gas adsorption, gas desorption, and their field emission characteristic are discussed. Experimental results show that Ti nanoparticles are easily adsorbed on the surface of CNTs due to the "defects" produced by Ar+ irradiation pretreatment. X-ray photoelectron spectroscopy (XPS) characterization showed that Ti nanoparticles contribute to the adsorption of ambient molecules by changing the chemical bonding between C, Ti, and O. Field emission of CNTs coated with Ti nanoparticles agree well with the Fowler-Nordheim theory. The deviation of emission current under constant voltage is 6.3% and 8.6% for Ti-CNTs and pristine CNTs, respectively. The mass spectrometry analysis illustrated that Ti-coated CNTs have a better adsorption capacity at room temperature, as well as a lower outgassing effect than pristine CNTs after degassing in the process of field emission.


Differential regulation of thyroid hormone receptor messenger ribonucleic acid levels by thyrotropin-releasing hormone.
In addition to its well known actions in stimulating TSH and PRL synthesis and secretion, TRH has been shown to decrease the concentration of thyroid hormone receptors (TRs) in GH4C1 cells as measured by nuclear thyroid hormone (T3) binding. In the present study we have investigated the effects of TRH on the levels of mRNA encoding the different forms of TR, TR beta-1, TR beta-2, and TR alpha-1 as well as that of the non-T3-binding variant, c-erbA alpha-2. GH3 cells were incubated with 100 nM TRH in the presence or absence of 1 nM T3 for 48 h, and mRNA levels were determined by Northern blot analysis. Results revealed that there is differential regulation of the individual TRs by TRH at the pretranslational level. The mRNA for the pituitary-specific form of TR, TR beta-2, was down-regulated by 60% by TRH in GH3 cells, while that of its alternative splice product, TR beta-1, was unchanged. A modest change was observed in TR alpha-1 mRNA levels, which were down-regulated by 20%; there was no change in c-erbA alpha-2 mRNA levels. Levels of nuclear T3 binding were assessed under the same conditions, and 100 nM TRH was found to decrease binding by 40% from 0.78 to 0.46 fmol/micrograms DNA. A similar change in nuclear T3 binding was seen after incubation with 1 nM T3. The effect of TRH on the GH mRNA response to T3 was investigated. In the absence of TRH there was a 4-fold induction of GH mRNA after incubation with 1 nM T3. In the presence of 100 nM TRH, no significant induction in GH mRNA by T3 was seen, indicating that T3 responsiveness as well as receptor concentration are diminished by TRH under these conditions.


Geographic Variation of Hospice Use Patterns at the End of Life.
Little is known about state-level variation in patterns of hospice use, an important indicator of quality of care at the end of life. Findings may identify states where targeted efforts for improving end-of-life care may be warranted. Our aim was to characterize the state-level variation in patterns of hospice use among decedents and to examine state, county, and individual factors associated with these patterns. We conducted a retrospective analysis of Medicare fee-for-service decedents. The primary outcome measures were state-level hospice use during the last 6 months of life and the state's proportion of hospice users with very short hospice enrollment (≤7 days), very long hospice enrollment (≥180 days), and hospice disenrollment prior to death. In 2011, the percentage of decedents who used hospice in the last 6 months of life nationally was 47.1%, and varied across states from 20.3% in Alaska to 60.8% in Utah. Hospice utilization patterns also varied by state, with the percentage of hospice users with very short hospice enrollment ranging from 23.0% in the District of Columbia to 39.9% in Connecticut. The percentage of very long hospice use varied from 5.7% in Connecticut to 15.9% in Delaware. The percentage of hospice disenrollment ranged from 6.2% in Hawaii to 19.0% in the District of Columbia. Nationally, state-level hospice use among decedents was positively correlated with the percentage of potentially concerning patterns (including very short hospice enrollment, very long hospice enrollment, and hospice disenrollment) among hospice users (the Pearson correlation coefficient=0.52, p value<0.001). Oregon was the only state in the highest quartile of hospice use and the lowest quartiles of both very short and very long hospice enrollment. The percentage of decedents who use hospice may mask important state-level variation in these patterns, including the timing of hospice enrollment, a potentially important component of the quality of end-of-life care.


[The biological characteristics of dermal fibroblasts of the diabetic rats with deep-partial thickness scald].
To investigate the biological characteristics of dermal fibroblasts of the diabetic rats with deep partial thickness scald, and to explore its relationship with delayed wound healing due to diabetes. Sprague-Dawley rats weighing 250 g were randomly divided into control (NM, n=40) and STZ-induced diabetic (DM, n=50) groups, and then deep partial thickness scald involving 10% TBSA were reproduced in the two groups. Skin samples were harvested from the wounds on 0, 3, 7, 14 and 21 post scald day (PSD) for the determination of certain histological characteristics. The thickness of dermis layer in DM group before injury was obviously thinner than that in NM group (P < 0.01). There was an infiltration of a large amount of chronic inflammatory cells and increased content of cutaneous glucose in the dermal tissue in DM group (2.77 mg/g) compared with 0.85 mg/g in NM group, (P < 0.01). An accumulation of advanced glycation end products (AGEs) was found in the dermal tissue in DM group. After the scalding, the percentage of fibroblasts in S phase and hydroxyproline synthesis in DM group was evidently lower than those in NM group. But the apoptosis rate of fibroblasts was much higher in DM group than that in NM group (P < 0.05 or 0.01). It is found that the high contents of glucose and AGEs in diabetic skin exert untoward effects on biological characteristics of dermal fibroblast, probably constituting one of the underlying mechanisms of delay wound healing of scald in diabetic rats.


Genetic Diversity in the Italian Holstein Dairy Cattle Based on Pedigree and SNP Data Prior and After Genomic Selection.
Genetic diversity has become an urgent matter not only in small local breeds but also in more specialized ones. While the use of genomic data in livestock breeding programs increased genetic gain, there is increasing evidence that this benefit may be counterbalanced by the potential loss of genetic variability. Thus, in this study, we aimed to investigate the genetic diversity in the Italian Holstein dairy cattle using pedigree and genomic data from cows born between 2002 and 2020. We estimated variation in inbreeding, effective population size, and generation interval and compared those aspects prior to and after the introduction of genomic selection in the breed. The dataset contained 84,443 single-nucleotide polymorphisms (SNPs), and 74,485 cows were analyzed. Pedigree depth based on complete generation equivalent was equal to 10.67. A run of homozygosity (ROH) analysis was adopted to estimate SNP-based inbreeding (FROH). The average pedigree inbreeding was 0.07, while the average FROH was more than double, being equal to 0.17. The pattern of the effective population size based on pedigree and SNP data was similar although different in scale, with a constant decrease within the last five generations. The overall inbreeding rate (ΔF) per year was equal to +0.27% and +0.44% for Fped and FROH throughout the studied period, which corresponded to about +1.35% and +2.2% per generation, respectively. A significant increase in the ΔF was found since the introduction of genomic selection in the breed. This study in the Italian Holstein dairy cattle showed the importance of controlling the loss of genetic diversity to ensure the long-term sustainability of this breed, as well as to guarantee future market demands.


Giants on Clay Feet-COVID-19, infection control and public health laboratory networks in England, the USA and (West-)Germany (1945-2020).
In early 2020, COVID-19 exposed differences in public health laboratory systems' testing abilities. Focusing on Germany, the USA and the UK between 1900 and 2020, this article argues that studying the distinct evolution of laboratory infrastructures is critical to understanding the history of infection control and the limits of template-based reforms in global health. While each analysed laboratory infrastructure was shaped by a unique national context, neoliberal visions of lean public services and declining resources led to significant reform pressure from the 1970s. The US Center of Disease Control's model of epidemic intelligence provided an attractive template to integrate resources and focus planning on preparedness scenarios. It also helped justify cuts to local laboratory infrastructures. Effects were uneven: in the USA and the UK, improved integration failed to compensate for local laboratory cuts and loss of autonomy. By contrast, Germany's subsidiary principle allowed for limited federal integration while leaving local services mostly intact.


Luminescent copper(I) halide adducts of [Au(im(CH2py)2)2]PF6 exhibiting short Au(I)···Cu(I) separations and unusual semibridging NHC ligands.
The picolyl-substituted NHC complex [Au(im(CH(2)py)(2))(2)]PF(6) (1) reacts with two equivalents of copper(I) halides, affording compounds [Au(im(CH(2)py)(2))(2)(CuX)(2)]PF(6) (X = Cl, 2; Br, 3; I, 4). Each complex contains a nearly linearly coordinated [Au(NHC)(2)](+) center where the two picolyl groups on each im(CH(2)py)(2) ligand chelate a single copper atom. The Cu(I) center resides in a distorted tetrahedral environment and is coordinated to two pyridyl groups, a halide ion, and a gold metalloligand. The Au(I)-Cu(I) separations measure 2.7030(5), 2.6688(9), and 2.6786(10) Å for 2-4, respectively. Additionally, each Cu(I) center is further coordinated by a semibridging NHC ligand with short Cu-C separations of ~2.3 Å. In solution, these complexes dissociate the Cu(I) ion. In the solid state, 2-4 are photoluminescent with respective emission maxima of 512, 502, and 507 nm. The reaction of [Au(im(CH(2)py)(2))(2)]PF(6) with four equivalents of CuBr afforded the coordination polymer {[AuCu(2)Br(2)(im(CH(2)py)(2))(2)]Br·3CH(3)CN}(n) (5). This polymeric complex contains [Au(NHC)(2)](+) units interconnected by Cu(2)Br(2) dimers. In 5, the Au-Cu separations are long at 4.23 and 4.79 Å, while the Cu-Cu distance is considerably shorter at 2.9248(14) Å. In the solid state, 5 is photoluminescent with a broad band appearing at 533 nm.


Factors influencing performance of Global Fund-supported tuberculosis grants.
To explore grant and country characteristics associated with the performance of tuberculosis (TB) grants supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund), which uses performance-based funding of grants. We used Global Fund grant data to compute the average programmatic performance of 108 TB grants in 88 countries. Using stepwise regression models, we examined the correlation of grant performance with a range of grant and country characteristics. Funding duration and funding per estimated smear-positive TB case were positively correlated with grant performance (partial correlations of 0.386-0.416 for the former, 0.200 for the latter). Successful completion of an evaluation of a grant during the second year of funding was linked to higher performance (0.357). Performance was further influenced by the independent organisation hired by the Global Fund to provide ongoing monitoring of the grants (0.197-0.243). Two country-specific factors were significantly correlated with performance: political stability (0.197-0.234) and disease burden (-0.211). Successful evaluation that leads to continued funding predicts higher performance of TB grants, even in challenging settings such as weak health services. However, other contextual factors affect grant performance and should be considered when assessing grants to ensure that countries that have a high disease burden and are politically unstable are not penalized.


Leptin is associated with craving in females with alcoholism.
The appetite and weight regulating peptide leptin was associated recently with alcohol craving during withdrawal. Nevertheless, correlations were only significant with craving displayed on the visual analogue scale for maximum craving during the previous week (VAS), and not if assessed with the highly validated Obsessive Compulsive Drinking Scale (OCDS). The objective of the following study, therefore, is to elucidate further the associations between the leptin system and craving concepts during alcohol withdrawal. A sufficiently large sample size should allow multiple statistical subgroup and confounder analyses. We prospectively investigated 102 chronic alcoholic inpatients (23 females, 79 males) during withdrawal on days 0 (admission), 1, 2 and days 7-10. In addition to the statistical analysis of the total sample, females and males were to be analysed separately. For detecting associations between leptin levels and craving scores multiple regression analysis was performed. Plasma leptin levels were determined, and craving for ethanol was assessed by both the OCDS and the VAS. Leptin plasma levels significantly increased during alcohol withdrawal compared to day 0, while all craving scores decreased. Body mass corrected leptin plasma levels predicted craving on day 0 in the OCDS total score (R=0.55, F=7.91, df=1.19, p<0.05) and in the OCDS obsessive subscore (R=0.57, F>=8.48, df=1.19, p<0.05) in females. Neither in males nor in the total population did multiple regression analysis reveal any significant results. Leptin levels seem to change during inpatient alcohol withdrawal. In a multivariate model, correlations between leptin levels and the highly validated craving scores of the OCDS can only be assumed in females. Hence, gender differences have to be taken into account when searching for neurobiological models of alcohol craving.


The economy and absenteeism: a macro-level study.
Despite much speculation, little is known about the net effects of the economy on the employed workforce. To fill this gap, we used state-level data collected by the Bureau of Labor Statistics to examine the effects of the condition of the economy, as indicated by the unemployment rate, on incidence rates of absence reportedly due to symptoms of illness and violent acts in the workplace for 43 states from 1992 to 2009. Our results suggest that the unemployment rate is positively associated with these indicators of absenteeism, and that these effects are delayed in time.


Evolutionary origin of the tumor suppressor hyperplastic discs protein.
Previous evolutionary study of the tumor suppressor Merlin revealed that this protein family was produced by very early metazoans with the exception of some or all flatworm lineages [Golovnina et al., 2005]. We ask whether other tumor-suppressor proteins had also been in existence in these times and focus our attention on hyperplastic discs (Hyd) protein, a classic tumor suppressor in Drosophila melanogaster which, when mutated, may cause over-proliferation and malignancy. Phylogenetic analysis of the Hyd protein indicates that it was present among metazoa by the time Trichoplax adhaerens had emerged from the common unicellular ancestor of the Animalia.


Sesame oil in injectable gold: two drugs in one?
To investigate the potential anti-inflammatory effects of sesame oil, which is present in the injectable gold preparation Auromyose, the synthesis of tumour necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) by in vitro stimulated blood cells was measured before, during and after 12 weeks of dietary supplementation with 18 g of sesame oil daily in 11 healthy male volunteers. Neither TNF-alpha, PGE2 nor LTB4 production levels showed statistically significant changes during the 12 weeks of dietary supplementation with sesame oil. These results do not suggest an anti-inflammatory effect of sesame oil as present in injectable gold preparations which are used in the treatment of rheumatoid arthritis.


Brønsted-acid and Brønsted-base catalyzed Diels-Alder reactions.
The enantioselective Diels-Alder reaction is one of the most important reactions for the synthesis of complex molecules. It provides access to chiral six-membered carbocyclic compounds containing up to four stereogenic centers in a single step. Asymmetric catalysis in the Diels-Alder reaction has mainly been realized using chiral Lewis acids. In this perspective, we describe several cases of chiral Brønsted-acid and Brønsted-base catalyzed Diels-Alder reactions, providing an overview of this rapidly growing field.


Conversion in laparoscopic cholecystectomy after gastric resection: a 15-year review.
Gastrectomy or truncal vagotomy is known to increase the incidence of cholelithiasis. Many of these patients will become symptomatic, and the adhesions from their gastric resection may make laparoscopic cholecystectomy much more difficult. We prospectively assessed the data for the 15-year cumulative laparoscopic cholecystectomy experience of 1 surgeon at a university teaching hospital with respect to conversion and postoperative outcomes, with particular attention to patients having had previous gastric resections. Patients with previous gastrectomies had similar operative times (mean 81.1, range 45-120 min), a higher conversion rate (64.2%) and a higher complication rate (35.7%) than those who had had other previous upper abdominal surgeries (mean 73.2, range 35-130 min, conversion 25% and complication 11.3%) and those without previous abdominal surgeries (mean 66.5, range 25-250 min, conversion 2.7% and complication 4.5%). Preoperative knowledge of the increased conversion rate and increased morbidity will inform surgical planning for both the surgeon and the patient.


Influence of reaming versus nonreaming in intramedullary nailing on local infection rate: experimental investigation in rabbits.
The question of whether the impairment of the endosteal blood supply, which is induced by nailing with reaming of the medullary cavity, increases the risk of a postoperative infection cannot be conclusively answered by studying existing literature. The aim of this study was to investigate the effect of medullary reaming on the occurrence of local infection based on an infection model in the rabbit tibia (n = 44). An infection rate of 50% was found after unreamed nailing, as opposed to an infection rate of 64% after medullary reaming. The number of bacteria observed after reaming was significantly higher than after nail insertion without previous reaming. The differing susceptibilities to infection as observed in this model are statistically significant (p < or = 0.05).


Neamine is preferential as an anti-prostate cancer reagent by inhibiting cell proliferation and angiogenesis, with lower toxicity than cis-platinum.
Hormone therapy is the most commonly used treatment for prostate cancer, but for androgen-independent cancer, few effective treatment methods are available. Therefore, the requirement to develop novel and effective anti-prostate cancer drugs is extremely urgent. Angiogenin has been suggested as a molecular target for prostate cancer treatment; its overexpression contributes to androgen-dependent prostate cancer growth and castration-resistant growth of androgen-independent prostate cancer. The aim of the present study was to investigate whether neamine, a low toxicity angiogenin nuclear translocation inhibitor, has preferential anti-prostate cancer activity compared with cis-platinum (DDP) and the mechanisms involved. Immunofluorescence and MTT assays were used to observe the effect of neamine on the nuclear translocation of angiogenin and cell proliferation, and a PC-3 cell transplanted tumor model was used to investigate the in vivo activity of neamine and DDP. Immunohistochemistry was performed to observe the expression of angiogenin, cluster of differentiation (CD)31 and Ki-67. It was found that neamine blocked nuclear translocation of angiogenin effectively and inhibited angiogenin-induced human umbilical vein endothelial cell and PC-3 cell proliferation in a dose-dependent manner. Neamine exerted a comparative antitumor effect, but lower toxicity (weight loss), in the PC-3 xenograft models treated with DDP. Neamine consistently reduced the expression of angiogenin and CD31 significantly, but no difference was found in Ki-67 expression compared with DDP. These data suggested that neamine may be a promising agent for prostate cancer treatment.


The trade in medicinal animals in northeastern Brazil.
Over the centuries, a significant part of the Brazilian fauna is widely sold, more specifically in retail stores or street markets. The objective was to characterize the sale of medicinal animals in five large northeast cities. Information about the sale of zootherapeutic items was obtained in the cities of Aracaju-SE, Fortaleza-CE, Maceio-AL, Recife-PE, and Salvador-BA. A total of 68 animal species were sold for medicinal purposes in the cities studied; these are the first results on the use and sale of zootherapeutics in the markets of Aracaju, Fortaleza, and Salvador and first recorded on the medicinal use of the Achatina fulica, Trachycardium muricatum, Philodryas olfersii, Desmodus rotundus, and Leptodactylus vastus. Knowledge of the fauna utilized popular medicine is indispensable for conservation, demonstrating that research on this subject is necessary to determine appropriate practices for the management of the fauna.


[Gas embolism].
Gas embolism is an iatrogenic injury that has high morbidity and mortality. It's a complication of clinical-surgical procedures, and it's necessary that the health professionals know this entity. The aim of this study was to realize a review of the gas embolism, considering its pathophysiology, diagnosis and therapeutics aspects. This article revises conceptually the gas embolism, dividing it in arterial and venous. Relate the mains physiopathology, diagnosis and therapeutics characteristics of the arterial and venous embolism. In addition, it's also approach the paradoxical embolism, event that occurs by conversion of a venous embolism to an arterial embolism. Gas embolism is an important complication, and it's present in many medical specialties. Knowledge about its physiopathology, and its diagnosis and therapeutic methods is essential to guarantee higher safety to the patients.


Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era.
Hematopoietic stem cell transplantation (HSCT) is an effective treatment option for several malignant and non-malignant hematological diseases. The clinical outcome of this procedure relies to a large extent on optimal recovery of adaptive immunity. In this regard, the thymus plays a central role as the primary site for de novo generation of functional, diverse, and immunocompetent T-lymphocytes. The thymus is exquisitely sensitive to several insults during HSCT, including conditioning drugs, corticosteroids, infections, and graft-vs.-host disease. Impaired thymic recovery has been clearly associated with increased risk of opportunistic infections and poor clinical outcomes in HSCT recipients. Therefore, better understanding of thymic function can provide valuable information for improving HSCT outcomes. Recent data have shown that, besides gender and age, a specific single-nucleotide polymorphism affects thymopoiesis and may also influence thymic output post-HSCT, suggesting that the time of precision medicine of thymic function has arrived. Here, we review the current knowledge about thymic role in HSCT and the recent work of genetic control of human thymopoiesis. We also discuss different transplant-related factors that have been associated with impaired thymic recovery and the use of T-cell receptor excision circles (TREC) to assess thymic output, including its clinical significance. Finally, we present therapeutic strategies that could boost thymic recovery post-HSCT.


Evaluation of Dietary Curcumin Nanospheres in a Weaned Piglet Model.
Curcumin is a polyphenolic compound present in turmeric with extensive uses in cooking foods and biomedical applications. However, due to its hydrophobic nature, it is poorly soluble in water and its bioavailability is very low on oral administration in organisms. In this study, we investigated the dietary curcumin nanospheres in a weaned piglet model based on the growth, serum biochemistry, proteomics, fecal coliform bacteria, and malodors in the feces of piglets. A total of 135 weaned piglets (Duroc × [Yorkshire × Landrace]) with an average initial body weight of 7.0 ± 1.0 kg (28 ± 1 days of age) were randomly distributed in 9 pens (15 pigs in each pen) fed the dietary curcumin nanospheres (CN) at 0 (control), 0.5 (T1), and 1.0 mL (T2) CN/kg of diet in triplicates for 21 days. At the end of the feeding trial, the results showed piglets fed 1.0 mL CN/kg diet had significantly higher growth performance and feed utilization than control diet (without CN). However, there were no significant differences in growth and feed utilization between piglets fed T1 and T2 diets. Serum glucose, gamma-glutamyl transferase, total bilirubin, amylase, and lipase contents were unaffected in piglets fed the experimental diets. Interestingly, piglets fed T1 and T2 diets showed significantly lower total cholesterol levels than control diet. In serum proteomics, a total of 103 differentially expressed proteins (DEPs) were identified in the piglets fed control, T1, and T2 diets, of which 14 DEPs were upregulated and 4 DEPs were downregulated. Fecal coliform bacteria and ammonia gas were significantly reduced in piglets fed T1 and T2 diets. Overall, the results indicated dietary supplementation of CN could enhance the growth, feed utilization, and immunity-and reduce fecal pathogenic bacteria as well as ammonia gas emissions-in weaned piglets.


Trachythyoneflaccida, a new sea cucumber species from southern Angola (Echinodermata:Holothuroidea:Dendrochirotida:Cucumariidae) with key to the genus.
A new species of a cucumariid holothuroid, Trachythyone flaccida, is described from shallow water off the southern coast of Angola. This increases to 20 the number of species in the genus Trachythyone. The new species is characterized by a soft, barrel-shaped body, scattered non-retractile tube feet, and body wall ossicles comprising a superficial layer of cup-like baskets and a deeper layer of simple, smooth, multilocular plates; cross-shaped deposits may also occur. The new species appears most closely related to the subantarctic T. bouvatensis (Ludwig & Heding, 1935) and to the Brazilian T. crassipeda Cherbonnier, 1965. A key is provided to all species currently classified in this genus.


Comparison of retinal nerve fiber layer measurements using time domain and spectral domain optical coherent tomography.
To determine the agreement between peripapillary retinal nerve fiber layer (RNFL) thickness measurements from Stratus time domain optical coherence tomography (OCT) and Cirrus spectral domain OCT (Carl Zeiss Meditec, Dublin, CA) in normal subjects and subjects with glaucoma. Evaluation of diagnostic test or technology. A total of 130 eyes from 130 normal subjects and subjects with glaucoma were analyzed. The subjects were divided into groups by visual field criteria: normal (n = 29), glaucoma suspect (n = 12), mild glaucoma (n = 41), moderate glaucoma (n = 18), and severe glaucoma (n = 30). Peripapillary RNFL thickness was measured with Stratus Fast RNFL and Cirrus 200 x 200 Optic Disc Scan on the same day in 1 eye of each subject to determine agreement. Two operators used the same instruments for all scans. Student paired t testing, Pearson's correlation coefficient, and Bland-Altman analysis of RNFL thickness measurements. The average age of the glaucoma group was significantly more than that of the normal group: 68.3+/-12.3 years versus 55.7+/-12.1 years, respectively. For Stratus OCT, the average RNFL thickness (mean +/- standard deviation) was 99.4+/-13.2 microm, 94.5+/-15.0 microm, 79.0+/-14.5 microm, 62.7+/-10.2 microm, and 51.0+/-8.9 microm for the normal, suspect, mild, moderate, and severe groups, respectively. For Cirrus OCT, the corresponding measurements were 92.0+/-10.8 microm, 88.1+/-13.5 microm, 73.3+/-11.8 microm, 60.9+/-8.3 microm, and 55.3+/-6.6 microm. All Stratus-Cirrus differences were statistically significant by paired t testing (P<0.001) except for the moderate group (P = 0.11). For average RNFL, there was also a highly significant linear relationship between Stratus minus Cirrus difference and RNFL thickness (P<0.001). Bland-Altman plots showed that the systematic difference of Stratus measurements are smaller than Cirrus at thinner RNFL values but larger at thicker RNFL values. RNFL thickness measurements between Stratus OCT and Cirrus OCT cannot be directly compared. Clinicians should be aware that measurements are generally higher with Stratus than with Cirrus except when the RNFL is very thin, as in severe glaucoma. This difference must be taken into account if comparing Stratus measurements with Cirrus measurements.


Dual-Energy Contrast-Enhanced Spectral Mammography: Enhancement Analysis on BI-RADS 4 Non-Mass Microcalcifications in Screened Women.
Mammography screening is a cost-efficient modality with high sensitivity for detecting impalpable cancer with microcalcifications, and results in reduced mortality rates. However, the probability of finding microcalcifications without associated cancerous masses varies. We retrospectively evaluated the diagnosis and cancer probability of the non-mass screened microcalcifications by dual-energy contrast-enhanced spectral mammography (DE-CESM). With ethical approval from our hospital, we enrolled the cases of DE-CESM for analysis under the following inclusion criteria: (1) referrals due to screened BI-RADS 4 microcalcifications; (2) having DE-CESM prior to stereotactic biopsy; (3) no associated mass found by sonography and physical examination; and (4) pathology-based diagnosis using stereotactic vacuum-assisted breast biopsy. We analyzed the added value of post-contrast enhancement on DE-CESM. A total of 94 biopsed lesions were available for analysis in our 87 women, yielding 27 cancers [19 ductal carcinoma in situ (DCIS), and 8 invasive ductal carcinoma (IDC)], 32 pre-malignant and 35 benign lesions. Of these 94 lesions, 33 showed associated enhancement in DE-CESM while the other 61 did not. All 8 IDC (100%) and 16 of 19 DCIS (84.21%) showed enhancement, but the other 3 DCIS (15.79%) did not. Overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 88.89%, 86.56%, 72.72%, 95.08% and 87.24%, respectively. The performances of DE-CESM on both amorphous and pleomorphic microcalcifications were satisfactory (AUC 0.8 and 0.92, respectively). The pleomorphous microcalcifications with enhancement showed higher positive predictive value (90.00% vs 46.15%, p = 0.013) and higher cancer probability than the amorphous microcalcifications (46.3% VS 15.1%). The Odds Ratio was 4.85 (95% CI: 1.84-12.82). DE-CESM might provide added value in assessing the non-mass screened breast microcalcification, with enhancement favorable to the diagnosis of cancers or lack of enhancement virtually diagnostic for non-malignant lesions or noninvasive subgroup cancers.


Capillary Hemangioma as an Unexpected Pathology in the External Auditory Canal.
Hemangiomas are benign vascular lesions frequently observed in infancy and childhood. A 14-year-old boy was referred to the hospital with a left-sided ear canal mass and hearing impairment. Otoscopic examination revealed a mass that occluded the canal. The transcanal surgical excision was performed. The mass was dissected from the skin, no bony erosion was noted intraoperatively, and the skin was returned back properly. The histopathological report demonstrated a capillary hemangioma of the external auditory canal. Hemangiomas are relatively common in the head and neck, but rarely detected in the external ear canal and tympanic membrane. Hemangioma of the ear canal may be asymptomatic and accidentally observed. Despite the rarity of the mass, it is important to consider them in the differential diagnosis of external auditory canal masses. The computed tomography and magnetic resonance imaging with gadolinium help to reveal the vascular nature of the mass. Complete surgical excision is the treatment of choice.


Taxanes: an overview of the pharmacokinetics and pharmacodynamics.
Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisynthetic taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits nonlinear kinetics, which results in a disproportionate change in plasma concentration and area under the curve (AUC) with dose alterations. In contrast, docetaxel has a linear disposition over the dose ranges used clinically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H1 and H2 receptor antagonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxanes are metabolized in the liver by the cytochrome P-450 enzymes and are eliminated in the bile. The known metabolites are either inactive or less potent than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiotoxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulative dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependent interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a preliminary study. The future holds increasing indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens.


An overview of drug screening using primary and embryonic stem cells.
Cellular technologies are widely used in drug discovery to treat human diseases. Most studies involve the expression of recombinant targets in immortalized cells and measure drug interactions using simple, quantifiable responses. Such cells are also amenable to high throughput screening (HTS) methods. However, the cell phenotype employed in HTS is often determined by the assay technology available, rather than the physiological relevance of the cell background. They are, therefore, suboptimal surrogates for cells that accurately reflect human diseases. Consequently, there is growing interest in adopting primary and embryonic stem cells in drug discovery. Primary cells are already used in secondary screening assays in conjunction with confocal imaging techniques, as well as in target validation studies employing, for example, gene silencing approaches. Stem cells can be grown in unlimited quantities and can be derived from transgenic animals engineered to express disease causing proteins better coupling the molecular target with function in vivo. Human stem cells also offer unique opportunities for drug discovery in that they can be directed to specific phenotypes thus providing a framework to identify tissue-selective agents. Organizing stem cells into networks resembling those in native tissues, potentially returns drug discovery back to the highly successful pharmacological methods of the past, in which organ and tissue based systems were used, but with the advantage that they can be utilized using modern HTS technologies. This emerging area will lead to discovery of compounds whose effect in vivo is more predictable thereby increasing the efficiency of drugs that ameliorate human disease.


Effects of valsartan/hydrochlorothiazide and amlodipine on ambulatory blood pressure and plasma norepinephrine levels in high-risk hypertensive patients.
The efficacy and tolerability of the combination of valsartan and hydrochlorothiazide (HCTZ) were compared with that of amlodipine in reducing ambulatory blood pressure and plasma norepinephrine levels in patients with mild to moderate hypertension and at least 1 cardiovascular risk factor. At the end of a 2-week washout period, 92 outpatients with a sitting diastolic blood pressure > or =95 and <110 mm Hg, associated with at least 1 additional risk factor, were randomly assigned to receive either valsartan 160 mg and HCTZ 12.5 mg once daily (n=46) or amlodipine 10 mg alone once daily (n=46) for 12 weeks, according to a prospective, randomized, open-label, blinded end point, parallel-group design. At the end of the washout period and after 6 and 12 weeks of active treatment, 24-hour ambulatory blood pressure monitoring was performed, and clinical blood pressure and heart rate and plasma norepinephrine levels were assessed (by high-performance liquid chromatography). Both the valsartan/HCTZ combination and amlodipine had a demonstrable antihypertensive effect, but the combination showed an antihypertensive effect significantly greater than that of amlodipine, as demonstrated by the 24-hour (P<.001), daytime (P<.001), and nighttime ambulatory blood pressure values (P<.01) and by the clinical blood pressure values at trough, which were all significantly lower. Although the trough-to-peak ratios were similar in both groups, the smoothness indexes pertaining to both systolic and diastolic pressures were significantly higher (P<.05 and P<.001, respectively) in patients receiving valsartan/HCTZ, suggesting the combination produces a more homogeneous anti-hypertensive effect. A significant increase in plasma norepinephrine levels was associated with amlodipine (+9% at 6 weeks, +15% at 12 weeks) but not with the valsartan/HCTZ combination. The valsartan/HCTZ combination was better tolerated than amlodipine, which was associated with a higher frequency of ankle edema. These results indicate that the combination of valsartan 160 mg and HCTZ 12.5 mg provides more sustained and homogeneous control of blood pressure than does amlodipine 10 mg in high-risk hypertensive patients, without producing reflex sympathetic activation.


Divergent Access to Seven/Five-Membered Rings Based on [1,6]-Hydride Shift/Cyclization Process.
We have achieved a divergent access to seven/five-membered rings based on a [1,6]-hydride shift/cyclization process from benzylidenemalonate with an o-alkoxymethyl group. Whereas Yb(OTf)3 afforded benzoxepines (with a seven-membered ring) selectively, indanes (with a five-membered ring) were the main products when Sc(OTf)3 was employed.


Fluoride Toxicity.
Fluoridation of the drinking water is one of the most impactful public health interventions ever done. Dental caries experience importantly decreased in all parts of the world that adopted the intervention. Implementation of fluoridation of the drinking water to populations has always been the focus of criticism, and these discussions often focus on the safety of the intervention. When asked about safety, many people will tend to assume a more cautious position, and the question regarding safety of fluoridation of the drinking water never goes away. Fluoridation of toothpastes also provides the same impact on dental caries experience in populations. It is reasonable to propose that water fluoridation may not be implemented anymore since there is a feasible and effective replacement for it. Finally, this chapter revisits the discussed effects of fluorides on overall health, with particular emphasis on cognition and intelligence.


Characterization of fear memory reconsolidation.
Reactivation of consolidated memories returns them to a protein synthesis-dependent state. One interpretation of these findings is that the memory reconsolidates after use. Two alternative interpretations are that protein synthesis inhibition facilitates extinction and that postreactivation protein synthesis inhibition leads to an inability to retrieve the consolidated memory. First, using two different approaches, we report that reconsolidation cannot be reduced down to facilitated extinction. We show that the reconsolidation deficit does not show renewal after a contextual shift, whereas an extinguished auditory fear memory does under the same conditions and the deficit occurs regardless of whether the memory is reactivated with an extinction [conditioned stimulus (CS) alone] or a reinforced trial (CS-unconditioned stimulus). To address the issue of whether postreactivation anisomycin leads to an inability to retrieve the consolidated memory, we used two traditional assays for retrieval deficits. First, we demonstrate that the amnesia induced by blockade of reconsolidation does not show any spontaneous recovery. Second, we show that application of reminder shock does not result in the reinstatement of the memory. These findings support the idea that reactivation of consolidated memories initiates a second time-dependent memory formation process.


Post-translational regulation of signaling mucins.
Signaling mucins are large transmembrane glycoproteins that regulate signal transduction pathways. Recent advances have shown that two major types of post-translational modifications, protein glycosylation and proteolytic processing, play important and unexpected roles in regulating signaling mucin function. New O-glycosyltransferases and proteases have been identified, and the structure of the domain that undergoes auto-proteolysis has been solved. A picture is beginning to emerge where specific glycosyl modifications and regulated processing control the signaling and adherence properties of signaling glycoproteins and contribute to the routing of signals to specific pathways.


Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice.
Administration of recombinant factor VIII (FVIII), an important co-factor in blood clotting cascade, elicits unwanted anti-FVIII antibodies in hemophilia A (HA) patients. Previously, FVIII associated with phosphatidylserine (PS) showed significant reduction in the anti-FVIII antibody response in HA mice. The reduction in the immune response to FVIII-PS could be due either to a failure of the immune system to recognize the antigen (i.e. immunological ignorance) or to an active induction of an antigen-specific nonresponsiveness (i.e. immunological tolerance). If it were a result of tolerance, one would predict that pre-exposure to FVIII-PS would render the mice hypo-responsive to a subsequent FVIII challenge. Here, we have demonstrated that naive HA mice that were pretreated with FVIII-PS showed a significantly reduced FVIII immune response to further challenge with native FVIII and that this decreased responsiveness could be adoptively transferred to other mice. An increase in number of FoxP3-expressing CD4(+) regulatory T-cells (Treg) was observed for the FVIII-PS-immunized group as compared with animals that received FVIII alone, suggesting the involvement of Treg in PS-mediated hypo-responsiveness. The PS-mediated reduction in antibody response was reversed by the co-administration of function-blocking anti-TGF-β antibody with FVIII-PS. The decreased response to FVIII induced by FVIII-PS was determined to be antigen-specific because the immune response to another non-cross-reactive antigen (ovalbumin) was not altered. These results are consistent with the notion that FVIII-PS is tolerogenic and suggest that immunization with this tolerogenic form of the protein could be a useful treatment option to minimize immunogenicity of FVIII and other protein-based therapeutics.


Reaching international GMP standards for vaccine production: challenges for developing countries.
Standards for vaccine production have been increasing at a rapid rate. Current standards of good manufacturing practice (GMP) had been thought to be out of the reach of developing country vaccine producers, many of whom are in the public sector, overseen by unvalidated national regulatory authorities (NRAs). With the advent of the GMP regulations in 1963 and their application to vaccine production, even many industrialized country manufacturers with stringent NRA oversight had difficulties. This article assesses the ability of developing country manufacturers to meet GMP by the only currently available global indicator: WHO prequalification. As recently as 1996, no developing country NRA was considered able to enforce GMP compliance. That number increased to four in 2002 and six in 2006, with a concomitant increase in the number of manufacturers considered to be operating to GMP standards. Examples of the difficulties faced by manufacturers in achieving this are given, as well as implications for the future vaccine market.


Risk Factors and Predictors of Survival Among Patients with Amelanotic Melanoma Compared to Melanotic Melanoma in the National Cancer Database.
Amelanotic melanoma (AM) is a rare form of melanoma lacking pigment. Data on AM risk factors and factors predicting survival are limited. We sought to identify predictors of AM, survival differences in AM and melanotic melanoma, and AM-specific survival rates. Using 2004 through 2015 National Cancer Database data, we compared 358,543 melanoma cases to 1,384 AM cases. Multivariable logistic regression identified AM risk factors, and AM survival was explored using Kaplan-Meier and multivariable Cox regression. Increased age; tumor location on the face, scalp, and neck; increased Breslow thickness; metastatic disease; ulceration; and higher mitotic rate were associated with AM. Five- and ten-year survival rates were higher for patients with MM (melanotic melanoma) than AM tumors (75.4% vs. 58.8% and 62.4% vs 45.1%; log-rank P<0.0001). No survival difference was seen after adjusting for staging factors. Among patients with AM, more recent diagnosis was associated with improved survival. Increased age, T4 tumor size, higher N-stage, metastasis, and ulceration predicted poorer survival. No survival advantage was seen for chemotherapy, immunotherapy, or radiation therapy, likely due to confounding. AM is more common in older patients on sun-exposed skin and is diagnosed at later stages. Advanced staging at diagnosis explains the survival differences. In patients with AM, regional and metastatic disease were the primary contributors of poorer outcomes. In at-risk patients, the threshold to biopsy should be lower for suspicious nonpigmented lesions.


Effects of irradiation on red cells stored in CPDA-1 and CPD-ADSOL (AS-1).
Red blood cells (pRBC) collected in citrate, phosphate, dextrose, adenine-formula 1 (CPDA-1) and citrate, phosphate, dextrose-adenine, manitol saline solution (CPD-ADSOL [AS-1]) anticoagulants are increasingly being stored for variable periods in transfusion service inventories following irradiation. While anecdotal reports of increased K+ following irradiation and storage have recently appeared in the literature, concomitant in vitro biochemical changes resulting from differences in anticoagulants have not been reported. Utilizing two venipunctures, two units each of 225 mL of blood from five volunteers were collected in anticoagulant-adjusted CPDA-1 and AS-1 bags. Within two hours of collection, each unit was equally divided. One of each pair was irradiated (2000 rads). Samples were analyzed on Days 0, 1, 3, 7, and every seven days to expiration. Irradiation resulted in a 2.3 fold increase in K+ during the first seven days of storage for both anticoagulants, although significantly greater K+ levels were observed in the CPDA-1 pairs compared to the AS-1 pairs. Comparison of glucose utilization, plasma free hemoglobin, 2,3-diphosphoglycerate (2,3-DPG) and lactate dehydrogenase between control and irradiated CPDA-1 and AS-1 pairs and between anticoagulants were documented.


Systematic surveillance and meta-analysis on the prevalence of metallo-β-lactamase producers among carbapenem resistant clinical isolates in Pakistan.
Emergence of carbapenem resistance (CR) is a health concern of pertinent importance. Epidemiological surveillance of CR at global and indigenous level (Pakistan) can help to improve infection control and establish pharmacovigilance programs. This study evaluates the prevalence of clinically significant CR isolates, and its genetic variant distribution among geographical regions of Pakistan. A meta-analysis was conducted to present the current rate of CR infections and prevalence of Metallo-β-lactamases (MBLs). The proposed subject was researched using electronic databases to identify the available literature. Thereafter, relevant data was extracted and statistical analysis was performed using STATA version 14. A total of 110 relevant studies were identified with 19 meeting the inclusion criteria for the meta-analysis of CR, while 22 for MBLs. Pooled rate for carbapenem resistance was determined to be 0.28 (95% CI: 0.26-0.31) with overall significant heterogeneity (I2=99.61%, P<0.001) and significant estimated score ES=0 (Z=22.65, P<0.001). In Pakistan, the pooled proportion of MBL producers was 0.34 (95% CI: 0.29-0.39) with overall heterogeneity significance (I2=99.62%, P<0.001) and significant ES=0 (Z=13.17, P<0.001). Conclusively, diverse variants of carbapenemases (VIM, IMP, NDM, KPC, GIM) along with other β-lactamase variants (OXA, TEM, SHV, CTX-M) have been reported across the country. However, New Delhi Metallo-β-lactamase (NDM)-variants were reported in predominant literature. The prevalence of CR isolates in Pakistan is alarming, associated with MBL production primarily evident from the studies. The study emphasizes the need for regular surveillance, pharmacovigilance and antibiotic stewardship programs to ensure the availability of data to the authorities for preemptive measures of infection control.


[Regulative mechanism of budesonide on endogenous hydrogen sulfide, cystathionine-gamma-lyase and cystathionine-beta-synthase system in asthmatic rats].
To investigate plasma hydrogen sulfide (H₂S) levels and cystathionine-gamma- lyase (CSE) and cystathionine-beta-synthase (CBS) mRNA expression in the lung tissues in asthmatic rats and to explore the roles of endogenous H₂S, CSE and CBS system in the pathogenesis of asthma. Thirty male Sprague-Dawley rats (age 5 to 7 weeks) were randomly divided into three groups: control, asthma and budesonide treatment (n = 10 each). The asthma model was established by ovalbumin (OVA) sensitization and challenge. The budesonide treatment group received inhaled budesonide before challenge. The contents of plasma H₂S were measured by spectrophotometry. The levels of CSE and CBS mRNA in the lung tissues were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The contents of plasma H₂S in the asthma group (61 ± 16 μmol/L) were significantly lower than those in the control group (84 ± 15 μmol/L) (P<0.01). The contents of plasma H₂S in the budesonide treatment group (71 ± 14 μmol/L) were not statistically different from those in the control and asthma groups. CSE mRNA and CBE mRNA expression in the asthma group were significantly lower than those in the control group (P < 0.01). The budesonide treatment group had a decreased CSE mRNA expression and CBE mRNA expression compared with the control group, but had significantly increased CSE and CBE mRNA expression compared with the asthma group (P < 0.01). There was a significantly negative correlation between H₂S contents in plasma and total inflammatory cells in bronchoalveolar lavage fluid (n = 30, r = -0.549, P < 0.01). Plasma H₂S levels and CSE and CBS expression in the lung decrease in asthmatic rats, which possibly promotes inflammatory cell aggregation to the airway. Budesonide may alleviate airway inflammation in asthmatic rats possibly through the system of endogenous H₂S, CSE and CBS.


Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice.
To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7 versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24 +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury.


Overexpression of apolipoprotein A-IV enhances lipid transport in newborn swine intestinal epithelial cells.
Apolipoprotein A-IV (apoA-IV) has myriad functions, including roles as a post-prandial satiety factor and lipid antioxidant. ApoA-IV is expressed in mammalian small intestine and is up-regulated in response to lipid absorption. In newborn swine jejunum, a high fat diet acutely induces a 7-fold increase in apoA-IV expression. To determine whether apoA-IV plays a role in the transport of absorbed lipid, swine apoA-IV was overexpressed in a newborn swine enterocyte cell line, IPEC-1, followed by analysis of the expression of genes related to lipoprotein assembly and lipid transport, as well as quantitation of lipid synthesis and secretion. A full-length swine apoA-IV cDNA was cloned, sequenced, and inserted into a Vp and Rep gene-deficient adeno-associated viral vector, containing the cytomegalovirus immediate early promoter/enhancer and neomycin resistance gene, and was used to transfect IPEC-1 cells. Control cells were transfected with the same vector minus the apoA-IV insert. Using neomycin selection, apoA-IV-overexpressing (+AIV) and control (-AIV) clones were isolated for further study. Both undifferentiated (-D) and differentiated (+D) +AIV cells expressed 40- to 50-fold higher levels of apoA-IV mRNA and both intracellular and secreted apoA-IV protein compared with -AIV cells. Expression of other genes was not affected by apoA-IV overexpression in a manner that would contribute to enhanced lipid secretion. +D +AIV cells secreted 4.9-fold more labeled triacylglycerol (TG), 4.6-fold more labeled cholesteryl ester (CE), and 2-fold more labeled phospholipid (PL) as lipoproteins, mostly in the chylomicron/very low density lipoprotein (VLDL) density range. ApoA-IV overexpression in IPEC-1 cells enhances basolateral TG, CE, and PL secretion in chylomicron/VLDL particles. This enhancement is not associated with up-regulation of other genes involved in lipid transport. ApoA-IV may play a role in facilitating enterocyte lipid transport, particularly in the neonate receiving a diet of high fat breast milk.


Mode of action of a herbicide : johnsongrass and methanearsonic Acid.
Johnsongrass (Sorghum halepense (L.) Pers.) is sensitive to methanearsonate, foliar application resulting in a topkill. Investigation of the pattern of photosynthesis by radioautography revealed an accumulation of malate in methanearsonate-treated leaves. Accumulation of malate was attributed to an inhibition of NADP(+)-malic enzyme which was found to be sensitive to sulfhydryl group reagents including arsenosomethane, CH(3)AsO. Methanearsonate was found to act as an oxidant in the Hill reaction using spinach chloroplasts, the photoproduct being a sulfhydryl group reagent.These results suggest that methanearsonate inhibits CO(2) release from malate in bundle sheath cells, depriving the plant of its source of carbon for sucrose production. The mechanism of inhibition of enzymes sensitive to sulfhydryl group reagents by arsenosomethane is addressed.


Bi-Stable Perception: Self-Coordinating Brain Regions to Make-Up the Mind.
Bi-stable perception is a strong instance of cognitive self-organization, providing a research model for how 'the brain makes up its mind.' The complexity of perceptual bistability prevents a simple attribution of functions to areas, because many cognitive processes, recruiting multiple brain regions, are simultaneously involved. The functional magnetic resonance imaging (fMRI) evidence suggests the activation of a large network of distant brain areas. Concurrently, electroencephalographic and magnetoencephalographic (MEEG) literature shows sub second oscillatory activity and phase synchrony on several frequency bands. Strongly represented are beta and gamma bands, often associated with neural/cognitive integration processes. The spatial extension and short duration of brain activities suggests the need for a fast, large-scale neural coordination mechanism. To address the range of temporo-spatial scales involved, we systematize the current knowledge from mathematical models, cognitive sciences and neuroscience at large, from single-cell- to system-level research, including evidence from human and non-human primates. Surprisingly, despite evidence spanning through different organization levels, models, and experimental approaches, the scarcity of integrative studies is evident. In a final section of the review we dwell on the reasons behind such scarcity and on the need of integration in order to achieve a real understanding of the complexities underlying bi-stable perception processes.


[Signalling mechanisms of cardioprotective effect of hypothermic preconditioning].
The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, and exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning depends upon 3-adrenergic receptor stimulation, an increase in cAMP levels, activation of protein kinase A and protein kinase C, AMP-activated protein kinase (AMPK) and mitochondrial permeability transition pore blocking. The hypothermic preconditioning had no effect on the phosphorylation of GSK-3J3 (glycogen synthase kinase-3beta) and Akt-kinase. The reactive oxygen species end endogenous catecholamines are triggers or mediators of hypothermic preconditioning of heart.


The relationship of emotion regulation and negative lability with socioemotional adjustment in institutionalized and non-institutionalized children.
With this study, we aimed to investigate the contribution of emotion regulation and negative lability to socioemotional adjustment in institutionalized and non-institutionalized children. Ninety-two children aged 6 to 10 years (45 placed in residential care after abuse and 47 non-abused, living with their biological families) participated in this study. Emotion Regulation Questionnaire and Strengths and Difficulties Questionnaire were completed by the main caregivers of the institutions and by the elementary teacher, respectively, for the institutionalized and non-institutionalized groups. No differences were observed between institutionalized and non-institutionalized children in emotion regulation, negative lability, and socioemotional adjustment outcomes. Also, no sex and age effects were observed for both groups. Considering the institutionalized children, the length of institutionalization had a significant effect on negative lability, while no effects of the type of maltreatment on emotion regulation and negative lability were observed. Additionally, in institutionalized children, negative lability was negatively associated with peer relationship problems in socioemotional adjustment, whereas in the non-institutionalized children, no significant associations were verified between emotion regulation and negative lability with socioemotional adjustment outcomes. For institutionalized children, emotional lability seems to have a differential impact on specific maladaptive socioemotional outcomes, which emphasizes the importance of analysing these specific risk developmental pathways.


[A case of asymptomatic adrenal hematoma which progressively enlarged during follow-up].
We report a case of asymptomatic adrenal hematoma that enlarged during a 3-year follow-up. A 66-year-old woman exhibited a 4 cm right adrenal mass, incidentally discovered by computed tomography of abdomen, which progressively enlarged to 6 cm in diameter during the 3 years. The patient underwent right adrenalectomy with a diagnosis of a suspected non-functional adrenal tumor. Histopathological examination indicated adrenal hematoma without tumor cells. The patient had received aspirin medication for 4 years, and it is possible that the enlargement of the mass might have been due to aspirin medication.


Heightened pain facilitation rather than impaired pain inhibition distinguishes those with moderate/severe disability in work-related neck pain.
To better understand the mechanisms underpinning work-related neck pain, this cross-sectional and single-blinded study compared somatosensory profiles among sonographers with varied neck disability levels. Based on K-mean cluster analysis of scores on the neck disability index (NDI), participants were classified into no (NDI ≤ 8%, n = 31, reference group), mild (NDI = 10%-20%, n = 43), or moderate/severe (NDI ≥ 22%, n = 18) disability groups. Data were collected on bodily pain distribution and severity and psychological measures including depression, anxiety, pain-catastrophizing, and fear-avoidance beliefs using validated scales. Participants attended 1 session of quantitative sensory testing performed according to a standardized protocol, including local and remote thermal and mechanical pain thresholds, temporal summation of pain (TSP), conditioned pain modulation, and an exercise-induced analgesia paradigm. Compared with participants with no and mild disability, those with moderate/severe disability showed more widespread pain, cold and mechanical hyperalgesia at a remote nonpainful site, and significantly higher TSP. Participants with mild disability demonstrated significantly higher TSP than those with no disability. These group differences were attenuated after adjusting for depression or anxiety, indicating these psychological factors may mediate the somatosensory changes associated with neck disability. Group differences were not found for conditioned pain modulation or exercise-induced analgesia. These findings suggest that heightened pain facilitation, rather than impaired pain inhibition may underpin nociplastic pain in participants with moderate/severe disability, and it may be associated with depression and anxiety. Clinicians should be aware that individuals with work-related neck pain presenting with moderate/severe disability display distinct somatosensory features and tailor management strategies accordingly.


Musculoskeletal syndromes associated with malignancy.
Evidence has been presented supporting a causal relationship between malignancies and musculoskeletal syndromes. This discussion has dealt primarily with lesser known relationships, more common associations such as hypertrophic osteoarthropathy and dermatomyositis being reviewed elsewhere. The ones discussed herein closely mimic primary connective tissue diseases and offer an insight into the study of the pathogenesis of these primary diseases. In view of the natural history of malignant disease, the hope for such patients arises from the physicians early diagnosis and treatment of the underlying malignancy. Early diagnosis and treatment may in turn be entirely dependent on the physician's awareness of a musculoskeletal syndrome being the presenting feature of an otherwise occult neoplasm. Several connective tissue syndromes appear to predispose to the development of malignancy, and increasing evidence suggests that this development of malignancy may be further enhanced by immunosuppressive therapy.


Disaggregation in population forecasting: do we need it? And how to do it simply.
"We have described a method for reducing the dimensionality of the forecasting problem by parsimoniously modeling the evolution over time of the age schedules of vital rates. This method steers a middle course between forecasting aggregates and forecasting individual age specific rates: we reduce the problem to forecasting a single parameter for fertility and another one for mortality. We have described a number of refinements and extensions of those basic methods, which preserve their underlying structure and simplicity. In particular, we show how one can fit the model more simply, incorporate lower bounds to the forecasts of rates, disaggregate by sex or race, and prepare integrated forecasts of rates for a collection of regions. We also discuss alternate approaches to forecasting the estimated indices of fertility and mortality, including state-space methods. These many versions of the basic method have yielded remarkably similar results." (SUMMARY IN FRE)


Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.
The conformation of HIV-1 envelope (Env) glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs) for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD) was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.