Use of the nasal SMAS to reconstruct defects of the tip, alae, columella, or septum.
Reconstruction using traditional methods for small and medium-sized losses of the soft tissues of the lower third of the nose, including the tip, the columella, alae, or the cartilaginous septum, has meant leaving cicatricial stigmata surrounding the region and has required at least two operational stages. A comprehensive study of the local anatomy was completed, and a specific technique (presented herein) was used to transfer and distribute the well-vascularized layer of superficial muscle and aponeurotic tissue (SMAS) from the dorsum of the nose to the needed site, which provided bulk and a well-nourished surface that could be covered by a distant skin graft, using a one-step flap. The surgical approach to the SMAS was carried out through the scar over the site of tissue loss or through the site of regional ablation or the traumatic wound. Several representative cases are presented.


Increase in three alpha,beta-dicarbonyl compound levels in human uremic plasma: specific in vivo determination of intermediates in advanced Maillard reaction.
Methylglyoxal (MGO), glypxal (GO) and 3-deoxyglucosone (3-DG) are reactive alpha,beta-dicarbonyl intermediates in advanced Maillard reaction, which form advanced glycation and oxidation end products (AGEs) by reaction with both lysine and arginine residues in protein. We measured these three dicarbonyl compound levels in human plasma to estimate the relationship between accumulation of alpha, beta-dicarbonyl compounds and AGE formation reactions in uremia and diabetes in human plasma by a highly selective and specific assay, electrospray ionization liquid chromatography mass spectrometry (ESI/LC/MS). We show that 3-DG and MGO levels are significantly higher in uremia and diabetes compared with age-matched healthy controls. Only the GO level in uremic plasma is significantly higher compared to diabetes and healthy controls. In both diabetic and uremic patients, these dicarbonyl compounds promote AGE accumulation in vivo, and especially in uremic patients, increased accumulation of GO could result from accelerating oxidative stress.


Biochemical, Biomedical and Metabolic Aspects of Imidazole-Containing Dipeptides with the Inherent Complexity to Neurodegenerative Diseases and Various States of Mental Well-Being: A Challenging Correction and Neurotherapeutic Pharmaceutical Biotechnology for Treating Cognitive Deficits, Depression and Intellectual Disabilities.
The activities of carnosine (β-alanyl-L-histidine), carnosine imidazole containing dipeptide based derivatives (N-acetylcarnosine, carcinine, homocarnosine) and a carnosine degrading enzyme (serum carnosinase (EC 220.127.116.11); [human tissue carnosinase (EC 126.96.36.199), CN2 (CNDP2)] ) activities have been discrepantly linked to neuropathophysiological processes. Approximately 82% of the U.S. population will experience normal age-related cognitive decline, as compared to the precipitous losses that are associated with dementing disorders. Interventions designed to promote health and function through everyday activity and specific pharmaco-nutritional therapeutic treatments may enhance brain plasticity in key regions that support executive function. Cognitive health is multidimensional cascade of functions. It encompasses an array of functions, including general intellectual ability, memory, language, allowing a person to interact effectively and appropriately with the environment. The risk factors for reduced physical and cognitive functions in elderly people, as identified in longitudinal studies, relate to comorbidities, critical care situations, physical and psychosocial health, environmental conditions, social circumstances, nutrition, and lifestyle. Depression and dementia are both common in older adults; cognitive functioning declines slightly with normal aging; depression itself can be associated with cognitive impairment and dementia. In this study the role of carnosine and related neuron specific naturally-occurring endogenous imidazole-containing dipeptide pharmacoperones (N-acetylcarnosine, carcinine) is revealed presently in a surprisingly large amounts in long-lived human tissues to correct conformational abnormalities leading to distinct neurodegeneration and age-related disease states, treating cognitive deficits, depression and intellectual disabilities. Carnosine serves as a physiological buffering agent and a metal ion (e.g., zinc and copper) chelator, endowed with ferroxidase type activity; possess anti-aging functions, and free-radical scavenging activity, is capable of delaying senescence and extending the life-span of cultured human fibroblasts; is able to kill transformed cells and protect cells against aldehydes and amyloid peptide fragment. Carnosine and carcinine exhibit a well-documented anti-glycating activity against the glycation of proteins, including low-density lipoproteins, glucose degradation products, esterase, histones. A tissue carnosine-degrading enzyme (CN2) colocalized with the activity of histidine decarboxylase to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) plays a key role in the neuro-transmission and neuroregulation roles of imidazole-containing based dipeptides. Carnosine released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. Timing of carnosine present in the chicken broth, the specific patented nutraceutical composition (Can-C Plus™), 1% N-acetylcarnosine lubricant eye drops or 1% carcinine lubricant eye drops formulations are important targeting posology vehicles that are involved in many CNS functions through the central brain histamine system including the vision enhancement functions, physiological regulation of cognitive functions, arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. The roles for the carnosine-stimulated/mediated neuronal histamine system are proposed as a danger and physiological response system active in protection from neurodegenerative diseases and in management of cognitive deficits, depression and intellectual disabilities.


Relationship between upper extremity kinesthetic sense and writing performance by students with low vision.
Kinesthetic sense plays an important role in writing. Children with low vision lack sensory input from the environment given their loss of vision. This study assessed the effect of upper extremity kinesthetic sense on writing function in two groups, one of students with low vision (9 girls and 11 boys, 9.4 +/- 1.9 yr. of age) and one of sighted students (10 girls and 10 boys, 10.1 +/- 1.3 yr. of age). All participants were given the Kinesthesia Test and Jebsen Hand Function Test-Writing subtest. Students with low vision scored lower on kinesthetic perception and writing performance than sighted peers. The correlation between scores for writing performance and upper extremity kinesthetic sense in the two groups was significant (r = -.34). The probability of deficiencies in kinesthetic information in students with low vision must be remembered.


Fc epsilon RI aggregation induces tyrosine phosphorylation of a novel 72 kDa protein downstream of Syk.
Tyrosine phosphorylation of proteins is critical for the Fc epsilon RI-induced signal transduction that leads to the release of inflammatory mediators from mast cells. Here we report the isolation of a monoclonal antibody, mAb BD2, to a 72 kDa protein that becomes rapidly tyrosine phosphorylated after Fc epsilon RI aggregation. By immunoprecipitation, immunoblotting and/or protease digestion this 72 kDa protein was different from the previously identified 68-76 kDa tyrosine phosphorylated proteins Btk, paxillin, SLP-76 or Syk. The phosphorylation of this 72 kDa protein was detectable within 15 sec after receptor aggregation and was independent of Ca2+ influx or the activation of protein kinase C. By in vitro kinase reaction, the 72 kDa protein did not autophosphorylate, which suggests that it is not a kinase, but is associated with a 140 kDa protein that was strongly phosphorylated. Studies in Syk deficient and Syk transfected variants of the RBL-2H3 cells demonstrated that the tyrosine phosphorylation of this 72 kDa protein was downstream of Syk. These data indicate that the 72 kDa protein precipitated by mAb BD2 is a novel phosphoprotein involved in Fc epsilon RI signaling.


Copper accumulation in the cell-wall-deficient slime variant of Neurospora crassa. Comparison with a wild-type strain.
The copper-uptake process in the cell-wall-deficient slime variant of the fungus Neurospora crassa was compared with that in a wild-type strain. In both organisms investigated most of the copper is taken up from the culture medium during the exponential growth period. The wild-type strain, however, accumulates much more copper than does the slime variant. The influence of the copper concentration in the culture medium on the amounts of copper accumulated intracellularly suggests separate ways of copper import used by the two morphologically different N. crassa strains. Copper analyses of three different cytosolic fractions as a function of growth time or exogenous copper concentration indicate both strains to share a very similar copper metabolism. All the data presented are consistent with a detoxification function of the low-Mr copper-binding fraction of N. crassa. Both copper-metallothionein and oxidized glutathione (GSSG) are co-eluted with this fraction. The possible involvement of glutathione in metallothionein biosynthesis is discussed.


Intrinsic optical bistability of thin films of linear molecular aggregates: the one-exciton approximation.
We perform a theoretical study of the nonlinear optical response of an ultrathin film consisting of oriented linear aggregates. A single aggregate is described by a Frenkel exciton Hamiltonian with uncorrelated on-site disorder. The exciton wave functions and energies are found exactly by numerically diagonalizing the Hamiltonian. The principal restriction we impose is that only the optical transitions between the ground state and optically dominant states of the one-exciton manifold are considered, whereas transitions to other states, including those of higher exciton manifolds, are neglected. The optical dynamics of the system is treated within the framework of truncated optical Maxwell-Bloch equations, in which the electric polarization is calculated by using a joint distribution of the transition frequency and the transition dipole moment of the optically dominant states. This function contains all the statistical information about these two quantities that govern the optical response and is obtained numerically by sampling many disorder realizations. We derive a steady-state equation that establishes a relationship between the output and input intensities of the electric field and show that within a certain range of the parameter space this equation exhibits a three-valued solution for the output field. A time-domain analysis is employed to investigate the stability of different branches of the three-valued solutions and to get insight into switching times. We discuss the possibility to experimentally verify the bistable behavior.


Automatic Sleep Staging in Patients With Obstructive Sleep Apnea Using Single-Channel Frontal EEG.
Reliable sleep staging is difficult to obtain from home sleep testing for diagnosis of obstructive sleep apnea (OSA), especially when it is self-applied. Hence, the current study aimed to develop a single frontal electroencephalography-based automatic sleep staging system (ASSS). The ASSS system was developed on a clinical dataset, with a high percentage of participants with OSA. The F4-M1 signal extracted from 62 participants (62.9% having OSA) was used to build a four-stage classifier. Performance of the ASSS was tested in a holdout set of 58 patients (60.3% having OSA) with epoch-by-epoch and whole-night agreement for sleep staging compared with expert scoring of polysomnography. Mean all-stage percentage agreement was 75.52% (95% confidence interval, 72.90 to 78.13) (kappa 0.62; 95% confidence interval, 0.58 to 0.65), with mean percentage agreement for wake, light sleep, deep sleep (DS), and rapid eye movement of 78.04%, 70.97%, 83.65%, and 75.00%, respectively. The whole-night agreement was good-excellent (intraclass correlation coefficient, 0.74 to 0.88) for sleep onset latency, wake after sleep onset, total sleep time, and sleep efficiency. Compared to the non-OSA subset, the OSA subset had lower agreement for DS. Our results indicate that a single-channel F4-M1 based ASSS was sufficient for sleep staging in a population with a high percentage of participants with OSA.


Prevalence and significance of narrow anterior chamber angles in optometric practice.
Assessment of anterior chamber width made according to the visibility of the angle structures during gonioscopic examination was carried out on 300 consecutively attending optometric patients. The assessments were made in the superior quadrant of the chamber angle of the left eyes. The sample yielded 6.0% of eyes in which some or all the trabeculae were obscured and 2.0% in which only the anterior half of the trabeculae was visible. The clinical import of these findings is discussed.


Methods to explain the clinical significance of health status measures.
One can classify ways to establish the interpretability of quality-of-life measures as anchor based or distribution based. Anchor-based measures require an independent standard or anchor that is itself interpretable and at least moderately correlated with the instrument being explored. One can further classify anchor-based approaches into population-focused and individual-focused measures. Population-focused approaches are analogous to construct validation and rely on multiple anchors that frame an individual's response in terms of the entire population (eg, a group of patients with a score of 40 has a mortality of 20%). Anchors for population-based approaches include status on a single item, diagnosis, symptoms, disease severity, and response to treatment. Individual-focused approaches are analogous to criterion validation. These methods, which rely on a single anchor and establish a minimum important difference in change in score, require 2 steps. The first step establishes the smallest change in score that patients consider, on average, to be important (the minimum important difference). The second step estimates the proportion of patients who have achieved that minimum important difference. Anchors for the individual-focused approach include global ratings of change within patients and global ratings of differences between patients. Distribution-based methods rely on expressing an effect in terms of the underlying distribution of results. Investigators may express effects in terms of between-person standard deviation units, within-person standard deviation units, and the standard error of measurement. No single approach to interpretability is perfect. Use of multiple strategies is likely to enhance the interpretability of any particular instrument.


The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease.
Gain-of-function variants of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A) cause hypercoagulability and are established risk factors for venous thrombosis. A meta-analysis of 66,155 cases and 91,307 controls found that either polymorphism is associated with a moderately increased risk of coronary artery disease (CAD). Because genetic factors play a particularly important role when acute myocardial infarction (AMI) occurs in the young, we chose to replicate these results by investigating, in the frame of a case-control study, a large cohort of Italian patients who had AMI before the age of 45years. In 1880 patients with AMI (1680 men and 210 women) and an equal number of controls, the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with an increased risk of AMI, the association remaining significant after adjustment for traditional risk factors (OR, 1.66; 95% CI, 1.15-2.38; P=0.006). The positive association with AMI for the minor A allele of F2 G20210A (2.5% frequency in cases and 1.9% in controls) did not reach statistical significance (OR, 1.32; 95% CI, 0.96-1.80; P=0.159). In a large cohort of young AMI patients the gain-of-function variant F5 G1691A was associated with an increased risk of AMI. The findings on the variant F2 G20210A confirmed the previously reported results, but the association was statistically not significant. These data suggest that a number of young patients with AMI carry gene variants associated with a procoagulant phenotype.


Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union.
Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of €157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of €109 billion that differed modestly from base case probability inputs. EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.


Autoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells.
Few data exist regarding mechanisms of mucosal CD8+ T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8+ T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I-restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4+ T cells induced in vivo were tested to control these autoreactive CD8+ T cells. Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8+ T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8+ T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression. Transgenic CD8+ T cells from VILLIN-HA x CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8+ T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4+ and CD8+, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8+ T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8+ T cells secreted vigorous amounts of proinflammatory cytokines like interferon gamma/tumor necrosis factor alpha. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4+ T cells. Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8+ T-cell-mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.


Skeletal defects in paternal uniparental disomy for chromosome 14 are re-capitulated in the mouse model (paternal uniparental disomy 12).
Human paternal uniparental disomy for chromosome 14 (upd(14)pat) presents with skeletal abnormalities, joint contractures, dysmorphic facial features and developmental delay/mental retardation. Distal human chromosome 14 (HSA14) is homologous to distal mouse chromosome 12 (MMU12) and both regions have been shown to contain imprinted genes. In humans, consistent radiographic findings include a narrow, bell-shaped thorax with caudal bowing of the anterior ribs, cranial bowing of the posterior ribs and flaring of the iliac wings without shortening or dysplasia of the long bones. Mice with upd(12)pat have thin ribs with delayed ossification of the sternum, skull and feet. In both mice and humans, the axial skeleton is predominantly affected. We hypothesize that there is an imprinted gene or genes on HSA14/MMU12 that specifically affects rib/thorax development and the maturation of ossification centers in the sternum, feet and skull with little effect on long bone development.


[Behavioral strategies in pediatric dental treatment. A necessity?].
The American Academy of Pediatric DEntistry is regularly publishing updates of protocols and guidelines. The article Dutch summary of and comment on a special issue of the journal Pediatric Dentistry with evaluated protocols and articles on guidelines for dentists. The protocols have been adapted to modern insights, but not very practical described. To use these protocols and guideliness in Dutch pediatric dentistry, it is advocated to take into consideration the individual child's age and behaviour and to base one's strategies on data of randomized clinical trials.


Accuracy in static guided implant surgery: Results from a multicenter retrospective clinical study on 21 patients treated in three private practices.
To evaluate the accuracy of a static computer-assisted implant surgery (s-CAIS) system across different private practices. This retrospective clinical study was based on data retrieved from 21 patients who received 61 implants between 2018 and 2020 in 3 private practices run by surgeons with extensive experience with s-CAIS. All patients were treated using the same s-CAIS system, planning software, template manufacturing process, and surgical guides. The standard tessellation language (STL) file of the intraoral scan of the fixture taken immediately after implant placement was matched with that of the preoperative plan for comparisons of preoperative and planned implant positions with postoperative and actual implant positions. The study outcomes were linear and angular deviations between the planned and actual implant positions. No surgical or postsurgical complications occurred. The overlap of the two STL files resulted in a mean angular deviation of 2.94° The mean linear deviation at the implant shoulder was 0.73 mm, and that at the apex was 1.06 mm. The mean vertical deviations at the implant shoulder and the apex were 0.29 mm and 0.01 mm, respectively. All cases showed satisfactory accuracy within the limits of this study (small number of patients and retrospective design). These results might be related to the use of a standardized digital workflow by experienced operators. The study shows that careful control of each step, from data acquisition to final execution, is key for the accuracy of stent-guided systems.


Participation in cooperative prey capture and the benefits gained from it are associated with individual personality.
In animal societies, behavioral idiosyncrasies of the individuals often guide which tasks they should perform. Such personality-specific task participation can increase individual task efficiency, thereby improving group performance. While several recent studies have documented group-level benefits of within-group behavioral (i.e., personality) diversity, how these benefits are realized at the individual level is unclear. Here we probe the individual-level benefits of personality-driven task participation in the social spider Stegodyphus dumicola. In S. dumicola, the presence of at least one highly bold individual catalyzes foraging behavior in shy colony members, and all group constituents heavily compete for prey. We assessed boldness by examining how quickly spiders resumed normal movement after a simulated predator attack. We test here whether (1) participants in collective foraging gain more mass from prey items and (2) whether bold individuals are less resistant to starvation than shy spiders, which would motivate the bold individuals to forage more. Next, we assembled colonies of shy spiders with and without a bold individual, added one prey item, and then tracked the mass gain of each individual spider after this single feeding event. We found that spiders that participated in prey capture (whether bold or shy) gained more mass than nonparticipators, and colonies containing a single bold spider gained more total mass than purely shy colonies. We also found that bold spiders participated in more collective foraging events and were more susceptible to starvation than shy spiders, suggesting that the aggressive foraging of bold individuals may represent a strategy to offset starvation risk. These findings add to the body of evidence that animal personality can shape social organization, individual performance, and group success.


Potentiality of the "Gum Metal" titanium-based alloy for biomedical applications.
In this study, the "Gum Metal" titanium-based alloy (Ti-23Nb-0.7Ta-2Zr-1.2O) was synthesized by melting and then characterized in order to evaluate its potential for biomedical applications. Thus, the mechanical properties, the corrosion resistance in simulated body fluid and the in vitro cell response were investigated. It was shown that this alloy presents a very high strength, a low Young's modulus and a high recoverable strain by comparison with the titanium alloys currently used in medicine. On the other hand, all electrochemical and corrosion parameters exhibited more favorable values showing a nobler behavior and negligible toxicity in comparison with the commercially pure Ti taken as reference. Furthermore, the biocompatibility tests showed that this alloy induced an excellent response of MC3T3-E1 pre-osteoblasts in terms of attachment, spreading, viability, proliferation and differentiation. Consequently, the "Gum Metal" titanium-based alloy processes useful characteristics for the manufacturing of highly biocompatible medical devices.


How can we make the pain go away? Public policies to manage pain at the end of life.
The continued undertreatment of pain at the end of life is a substantive public health problem that has not been resolved through increased public awareness, the issuance of clinical guidance for providers, or expanded organizational commitments. In this forum, we illuminate the role of public policies in promoting pain management. We review federal and state policies and consider empirical evaluations that compared the quality of state policies and the factors that contributed to their formation. We resolve that any organized interest in improving end-of-life care should begin by focusing on the development and expansion of those state policies that support the provision of evidence-based medicine for reducing the amount of pain an individual experiences at the end of life. Although empirical research is needed to determine which particular aspects of state pain policy are most critical and how these policies can be implemented most effectively, any organized effort that advances state medical board activity or another state policy would appear to be making an important step toward making the pain at the end of life go away.


Influence of Vanadium 4+ and 5+ Ions on the Differentiation and Activation of Human Osteoclasts.
In the pathophysiology of implant failure, metal ions and inflammation-driven osteoclasts (OC) play a crucial role. The aim of this study was to investigate whether vanadium (V) ions induce differentiation of monocytic OC precursors into osteoresorptive multinucleated cells. In addition, the influence of V ions on the activation and function of in vitro generated OC was observed. Human monocytes and osteoclasts were isolated from peripheral blood monocytic cells (PBMCs). Exposition with increasing concentrations (0-3 μM) of V4+/V5+ ions for 7 days followed. Assessment of OC differentiation, cell viability, and resorptional ability was performed by standard colorimetric cell viability assay 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2H-tetrazolium (MTS), tartrate-resistant acid phosphatase (TRAP) expression, and functional resorption assays on bone slides during a period of 21 days. No significant differences were noted between V4+/V5+ ions (p > 0.05). MTS showed significant reduction in cellular viability by V concentrations above 3 μM (p < 0.05). V concentrations above 0.5 μM showed negative effects on OC activation/differentiation. Higher V concentrations showed negative effects on resorptive function (all p < 0.05) without affecting cell viability. V4+/V5+ concentrations below 3 μM have negative effects on OC differentiation/function without affecting cell survival. Vanadium-containing implants may reduce implant failure rate by influencing osteoclast activity at the bone-implant interface. V-ligand complexes might offer new treatment options by accumulating in the bone.


Fallopian tube malignancies: experience of Social Security Agency Aegean Maternity Hospital.
The aim of the study was to determine the clinical characteristics and management of fallopian tube malignancies together with the results there unto that had been diagnosed and treated in our oncology department retrospectively. Twelve cases of fallopian tube malignancies, of a total of 2155 gynecologic malignancies (0.55%), that had been diagnosed in or referred to our hospital between January 1986 and December 2001 were evaluated retrospectively. Eight of 12 cases were diagnosed after surgical intervention in our department. Staging laparotomies were applied to all of the eight cases. Complementary surgeries of other four cases who were referred to our department were done according to the same principles of cytoreductive surgery. Staging of the cases was done according to Federation of International Gynecologists and Obstetricians (FIGO). Adjuvant chemotherapy was applied to all of the cases except two (10 cases, 83.3%). Second-look laparotomy (SLL) was applied to two of the cases. Mean age of the cases was 54.2 (range 35-72) years. Histopathology of the cases was as follows: serous adenocarcinoma in 10 cases (83.3%), endometrioid adenocarcinoma in one case (8.3%), and undifferentiated carcinoma in one case (8.3%). Adjuvant chemotherapy (PAC regimen to eight of the cases and PP regimen to two cases) was applied to 10 of the cases (83.3%). SLL was applied to two cases. Another case had died because of local recurrence at the 27th month of the follow-up. Mean follow-up period of the cases was 37.8 months (range 1-144 months). Fallopian tube malignancies are very rare malignancies. Diagnosis can be made generally peri- or postoperatively. More extensive clinical research must be performed in order to have definite etiologic, diagnostic, management modalities, and prognostic markers.


Use of Debye's series to determine the optimal edge-effect terms for computing the extinction efficiencies of spheroids.
The extinction efficiencies of atmospheric particles are essential to determining radiation attenuation and thus are fundamentally related to atmospheric radiative transfer. The extinction efficiencies can also be used to retrieve particle sizes or refractive indices through particle characterization techniques. This study first uses the Debye series to improve the accuracy of high-frequency extinction formulae for spheroids in the context of Complex angular momentum theory by determining an optimal number of edge-effect terms. We show that the optimal edge-effect terms can be accurately obtained by comparing the results from the approximate formula with their counterparts computed from the invariant imbedding Debye series and T-matrix methods. An invariant imbedding T-matrix method is employed for particles with strong absorption, in which case the extinction efficiency is equivalent to two plus the edge-effect efficiency. For weakly absorptive or non-absorptive particles, the T-matrix results contain the interference between the diffraction and higher-order transmitted rays. Therefore, the Debye series was used to compute the edge-effect efficiency by separating the interference from the transmission on the extinction efficiency. We found that the optimal number strongly depends on the refractive index and is relatively insensitive to the particle geometry and size parameter. By building a table of optimal numbers of edge-effect terms, we developed an efficient and accurate extinction simulator that has been fully tested for randomly oriented spheroids with various aspect ratios and a wide range of refractive indices.


Studies on the mechanism of action of progesterone in regulation of the synthesis of specific protein.
To study the process of hormone action, we have developed an in vitro system utilizing minced oviduct from estrogen-treated chicks incubated in tissue culture medium. Progesterone added to the medium induced synthesis of a specific protein, avidin, that continued for up to 96 hr. During this period there was no increase in total oviduct protein, ovalbumin, or lysozyme, which suggests the specificity of the progesterone effect. The induction process was dependent on new protein synthesis, since cycloheximide inhibited the induction completely. Actinomycin D in doses that prevented nuclear RNA synthesis, but not general protein synthesis, inhibited avidin production 70-90%. Avidin synthesis was not affected by 5-fluorouracil. The rate of DNA synthesis examined by thymidine-(3)H pulse labeling was not stimulated during avidin induction. Hydroxyurea (an inhibitor of DNA synthesis) and colchicine (a mitotic inhibitor) did not prevent induction. Studies utilizing uridine-(3)H pulses showed an effect on rapdly labeled nuclear RNA coincident with induction. Nuclear RNA polymerase activity increased before avidin induction. Since avidin was the only new protein synthesized in response to progesterone, the early stimulation of nuclear RNA synthesis and RNA polymerase activity would suggest a mechanism of action for this steroid at the transcription level of protein synthesis.


Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease.
Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Ovalbumen exposure caused early- and late-phase bronchoconstrictor responses, measured in conscious animals by whole-body plethysmography. Twenty-four hours after ovalbumen exposure there was airway hyperreactivity (AHR) to inhaled histamine and significantly elevated macrophages, eosinophils, and nitric oxide (NO) metabolites in bronchoalveolar lavage fluid. Sildenafil treatment (1 mg/kg, intraperitoneally) failed to affect the early and late responses but significantly reduced AHR, leukocyte influx, and elevated NO. LPS exposure (30 microg/ml) caused AHR to histamine at 1 hour and macrophage, eosinophil, and neutrophil influx at 24 hours with raised NO. Sildenafil pretreatment inhibited LPS-induced AHR, leukocyte influx, and NO generation. The effectiveness of sildenafil was not dependent on endogenous NO because inhibition of NO synthase with Nomega-nitro-L-arginine methyl ester did not prevent its action. Inhibition of PDE5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicillamine-induced cGMP generation in isolated lungs. These antiinflammatory actions of sildenafil in guinea pig models suggest that PDE5 inhibitors may have potential in treating airways disease.


Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study.
The relative risks and benefits of strategies of rate control vs rhythm control in patients with atrial fibrillation (AF) remain to be fully explored. The How to Treat Chronic Atrial Fibrillation (HOT CAFE) Polish trial was designed to evaluate in a randomized, multicenter, and prospective manner the feasibility and long-term outcomes of rate control vs rhythm control strategies in patients with persistent AF. Our study population comprised 205 patients (134 men and 71 women; mean [+/- SD] age, 60.8 +/- 11.2 years) with a mean AF duration of 273.7 +/- 112.4 days. The mean observation period was 1.7 +/- 0.4 years. One hundred one patients were randomly assigned to the rate control group and received rate-slowing therapy guided by repeated 24-h Holter monitoring. Direct current cardioversion and atrioventricular junctional ablation with pacemaker placement were alternative nonpharmacologic strategies for patients with tachycardia that was resistant to medical therapy. One hundred four patients were randomized to sinus rhythm restoration and maintenance using serial cardioversion supported by a predefined stepwise antiarrhythmic drug regimen (ie, disopyramide, propafenone, sotalol, and amiodarone). In both groups, thromboembolic prophylaxis followed current guidelines. At the end of follow-up, 63.5% of patients in the rhythm control arm remained in sinus rhythm. No significant differences in the composite end point (ie, all-cause mortality, number of thromboembolic events, or major bleeding) were found between the rate control group and the rhythm control group (odds ratio, 1.98; 95% confidence interval, 0.28 to 22.3; p > 0.71). The incidence of hospital admissions was much lower in the rate control arm (12% vs 74%, respectively; p < 0.001). New York Heart Association functional class improved in both study groups, while mean exercise tolerance, as measured by the maximal treadmill workload, improved only in the rhythm control group (5.2 +/- 5.1 vs 7.6 +/- 3.3 metabolic equivalents, respectively; p < 0.001). The rhythm control strategy led to an increased mean left ventricular fractional shortening (29 +/- 7% vs 31 +/- 7%, respectively; p < 0.01). One episode of pulmonary embolism occurred in the rate control group despite oral anticoagulation therapy, while three patients in the rhythm control arm of the study experienced ischemic strokes (not significant). The Polish HOT CAFE study revealed no significant differences in major end points between the rate control group and the rhythm control group.


Juvenile nasopharyngeal angiofibroma: a revised staging system.
To discuss the shortcomings of current staging systems and to suggest modifications according to new surgical methods and data. A retrospective chart review. The medical records of 36 patients, all of whom underwent resection of juvenile nasopharyngeal angiofibroma by external or endonasal approach between 1983 and 2002, were reviewed retrospectively. Follow-up period of patients ranged from 3 to 7 years (mean, 4.5 years). Tumour extent, sites and rate of persistent disease were analyzed and compared with the literature. Persistent or recurrent disease was found in 12 of the 36 patients (33%). The primary tumour of these 12 cases invaded one or more anatomic region beside nasopharynx: the base of the pterygoid process in 9 cases (75%), the infratemporal fossa in 4 (33%), the pterygomaxillar fossa in 4 (33%), and the sphenoid sinus in 2 cases (17%). Involvement of the pterygoid process base was observed in only 3 of the 24 patients without persistent disease, whereas it was found 10 out of 12 patients with persistent disease. Advances in radiographic imaging, embolization, and surgical methods of treating angiofibromas have changed the sites associated with a high risk for persistent disease or morbidity. These changes have made it necessary for the authors to devise more appropriate classifications and, subsequently, several new staging systems were gradually introduced. Recent technological advances, particularly angled endoscopes, have resulted in improved exposure. In the light of all these recent advances, data from our series, and the literature, we suggested a new classification for determining the risk of persistent disease, choosing the appropriate surgical method, and for maintaining uniformity.


Genome-wide transcriptional analysis of the Arabidopsis thaliana interaction with the plant pathogen Pseudomonas syringae pv. tomato DC3000 and the human pathogen Escherichia coli O157:H7.
Pseudomonas syringae pv. tomato DC3000 (Pst) is a virulent pathogen that causes disease on tomato and Arabidopsis. The type III secretion system (TTSS) plays a key role in pathogenesis by translocating virulence effectors from the bacteria into the plant host cell, while the phytotoxin coronatine (COR) contributes to virulence and disease symptom development. Recent studies suggest that both the TTSS and COR are involved in the suppression of host basal defenses. However, little is known about the interplay between the host gene expression changes associated with basal defenses and the virulence activities of the TTSS and COR during infection. In this study, we used the Affymetrix full genome chip to determine the Arabidopsis transcriptome associated with basal defense to Pst DC3000 hrp mutants and the human pathogenic bacterium Escherichia coli O157:H7. We then used Pst DC3000 virulence mutants to characterize Arabidopsis transcriptional responses to the action of hrp-regulated virulence factors (e.g. TTSS and COR) during bacterial infection. Additionally, we used bacterial fliC mutants to assess the role of the pathogen-associated molecular pattern flagellin in induction of basal defense-associated transcriptional responses. In total, our global gene expression analysis identified 2800 Arabidopsis genes that are reproducibly regulated in response to bacterial pathogen inoculation. Regulation of these genes provides a molecular signature for Arabidopsis basal defense to plant and human pathogenic bacteria, and illustrates both common and distinct global virulence effects of the TTSS, COR, and possibly other hrp-regulated virulence factors during Pst DC3000 infection.


Horizontal and vertical movements of Caribbean reef sharks (Carcharhinus perezi): conservation implications of limited migration in a marine sanctuary.
Despite the ecological and economic importance of the Caribbean reef shark (Carcharhinus perezi), little data exist regarding the movements and habitat use of this predator across its range. We deployed 11 pop-up satellite archival tags on Caribbean reef sharks captured in the northeast Exuma Sound, The Bahamas, to assess their horizontal and vertical movements throughout the water column. Sharks showed high site fidelity to The Bahamas suggesting Bahamian subpopulations remain protected within the Bahamian Shark Sanctuary. Depth data indicate that Caribbean reef sharks spent a significant proportion (72-91%) of their time above 50 m in narrow vertical depth bands, which varied considerably on an individual basis. This may be indicative of high site fidelity to specific bathymetric features. Animals exhibited three broadly categorized sporadic off-bank excursions (more than 50 m excursions) down to a depth of 436.1 m, which were more frequent during the night. These deeper excursions during night may be indicative of foraging in relation to prey on mesophotic reefs, as well as diel-vertically migrating prey from the deeper meso- and bathypelagic zones. These vertical movements suggest that Caribbean reef sharks can be significant vectors of ecosystem connectivity further warranting holistic multi-system management and conservation approaches.


A practical gloving and handwashing regimen for dental practice.
The debate concerning the re-use of gloves in dental practice continues, despite the fact that recent guidelines on cross-infection control recommend that a new pair of gloves should be used for each patient. Whichever policy for glove use is adopted, it is important to take the maximum possible precautions in hand care. This paper presents a practical regimen for hand/glove washing which is simple, quick and effective. The importance of establishing a hand-care regimen in dental practice is emphasised.


Beating-heart mitral valve suture annuloplasty under real-time three-dimensional echocardiography guidance: an ex vivo study.
We are developing an alternative mitral valve suture annuloplasty technique on the beating-heart under real-time three-dimensional echocardiography (RT3DE) guidance. The purpose of this initial study was to evaluate a feasibility of this technique using commercially available suturing devices (Sutur Tek Endo 360-degree, Sutur Tek Inc, North Chelmsford, MA, USA). Isolated porcine hearts (n=10) were mounted in a water-filled tank and attached to an ex vivo pulse simulation device, where varying left ventricle pressures with associated valve motion were generated by pulsatile flow through an apical cannula. The suturing device was inserted through the left atrium. Intra-annular (De Vega type) suture annuloplasty was performed under RT3DE guidance. The procedure was successfully performed in all cases. The diameter of the annulus was effectively reduced (85.5+/-4.2% of original antero-posterior dimension, 86.7+/-6.1% of original transverse dimension). The number of tissue bites was 7.4+/-0.8. The maximum distance between the annulus and sutures placed was 1.1 mm. The total procedure time was 9.4+/-2.4 min. There was no collateral tissue injury in any of the cases. This ex vivo study demonstrates the feasibility of beating-heart mitral valve suture annuloplasty under RT3DE guidance.


DOT: Gene-set analysis by combining decorrelated association statistics.
Historically, the majority of statistical association methods have been designed assuming availability of SNP-level information. However, modern genetic and sequencing data present new challenges to access and sharing of genotype-phenotype datasets, including cost of management, difficulties in consolidation of records across research groups, etc. These issues make methods based on SNP-level summary statistics particularly appealing. The most common form of combining statistics is a sum of SNP-level squared scores, possibly weighted, as in burden tests for rare variants. The overall significance of the resulting statistic is evaluated using its distribution under the null hypothesis. Here, we demonstrate that this basic approach can be substantially improved by decorrelating scores prior to their addition, resulting in remarkable power gains in situations that are most commonly encountered in practice; namely, under heterogeneity of effect sizes and diversity between pairwise LD. In these situations, the power of the traditional test, based on the added squared scores, quickly reaches a ceiling, as the number of variants increases. Thus, the traditional approach does not benefit from information potentially contained in any additional SNPs, while our decorrelation by orthogonal transformation (DOT) method yields steady gain in power. We present theoretical and computational analyses of both approaches, and reveal causes behind sometimes dramatic difference in their respective powers. We showcase DOT by analyzing breast cancer and cleft lip data, in which our method strengthened levels of previously reported associations and implied the possibility of multiple new alleles that jointly confer disease risk.


Sex-Related Gene Network Revealed by Transcriptome Differentiation of Bisexual and Unisexual Flowers of Orchid Cymbidium tortisepalum.
Despite extensive research on orchid reproductive strategies, the genetic studies of sex differentiation in the orchid family are still lacking. In this study, we compared three sexual phenotypes of Cymbidium tortisepalum bisexual flowers as well as female and male unisexual mutants. Through comparative transcriptomes, we analyzed the sex-biased differentially expressed genes (DEGs) and gene co-expression networks of sex organs (gynostemium and ovary) among them, identified the candidate genes of sex differentiation, and validated their expression by qRT-PCR. The C. tortisepalum unisexual mutants with degenerated phenotypes were compared to the bisexual plants with respect to both the flower organs and plant morphologies. Totally, 12,145, 10,789, and 14,447 genes were uniquely expressed in the female, male, and hermaphrodite sex organs, respectively. A total of 4291 sex-biased DEGs were detected among them, with 871, 2867, and 1937 DEGs in the comparisons of bisexual vs. female, bisexual vs. male, and male vs. female flowers, respectively. Two co-expressed network modules, with 81 and 419 genes were tightly correlated with female sexual traits, while two others with 265 and 135 genes were highly correlated with male sexual traits. Two female-biased hub genes (CtSDR3b and CtSDR3b-like) nested in the female modules, the homologs of maize sex determinant tasselseed2, may control the feminization of C. tortisepalum. At the same time, two male-biased hub genes (CtYAB2 and CtYAB5) nested in the male modules, the homologs of grape sex determinant VviYABBY3, may control the androphany of C. tortisepalum. This study discovered the molecular regulation networks and proposed a model for orchid sex differentiation, therefore providing for the first time the genetic basis for the sex separation in the orchid family.


An improved cryogen for plunge freezing.
The use of an alkane mixture that remains liquid at 77 K to freeze specimens has advantages over the use of a pure alkane that is solid at 77 K. It was found that a mixture of methane and ethane did not give a cooling rate adequate to produce vitreous ice, but a mixture of propane and ethane did result in vitreous ice. Furthermore, the latter mixture produced less damage to specimens mounted on a very thin, fragile holey carbon substrate.


Granulocyte colony-stimulating factor affects the distribution and clonality of TRGV and TRDV repertoire of T cells and graft-versus-host disease.
The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recent data indicated that gamma delta+ T cells might participate in mediating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. However, whether G-CSF could influence the T cell receptors (TCR) of gamma delta+ T cells (TRGV and TRDV repertoire) remains unclear. To further characterize this feature, we compared the distribution and clonality of TRGV and TRDV repertoire of T cells before and after G-CSF mobilization and investigated the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT. The complementarity-determining region 3 (CDR3) sizes of three TRGV and eight TRDV subfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs) from 20 donors before and after G-CSF mobilization, using RT-PCR and genescan technique. To determine the expression levels of TRGV subfamily genes, we performed quantitative analysis of TRGVI~III subfamilies by real-time PCR. The expression levels of three TRGV subfamilies were significantly decreased after G-CSF mobilization (P = 0.015, 0.009 and 0.006, respectively). The pattern of TRGV subfamily expression levels was TRGVII >TRGV I >TRGV III before mobilization, and changed to TRGV I >TRGV II >TRGV III after G-CSF mobilization. The expression frequencies of TRGV and TRDV subfamilies changed at different levels after G-CSF mobilization. Most TRGV and TRDV subfamilies revealed polyclonality from pre-G-CSF-mobilized and G-CSF-mobilized samples. Oligoclonality was detected in TRGV and TRDV subfamilies in 3 donors before mobilization and in another 4 donors after G-CSF mobilization, distributed in TRGVII, TRDV1, TRDV3 and TRDV6, respectively. Significant positive association was observed between the invariable clonality of TRDV1 gene repertoire after G-CSF mobilization and low incidence of GVHD in recipients (P = 0.015, OR = 0.047). G-CSF mobilization not only influences the distribution and expression levels of TRGV and TRDV repertoire, but also changes the clonality of gamma delta+ T cells. This alteration of TRGV and TRDV repertoire might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT.


Surgical removal of infected phalanges from an Asian elephant (Elephas maximus).
A 40-yr-old female Asian elephant (Elephas maximus) developed cellulitis and became lame in her left front leg. A draining tract behind the lateral nail of her left front foot was discovered. This lesion was treated by aggressive irrigation using a variety of disinfectant solutions. Radiographically, there was degeneration and fragmentation of the distal phalanx of the fifth digit and patterns suggestive of osteomyelitis of the second (middle) phalanx. The fragments of the distal phalanx and the affected portion of the second phalanx were removed surgically. Six months after surgery the incision had healed but a fistulous tract remained on the palmar surface of the foot. The tract extended to the second phalanx, and there was radiographic evidence of osteomyelitis in the second phalanx and the distal portion of the proximal phalanx. The remainder of the second phalanx and the distal portion of the proximal phalanx were surgically removed. Aggressive aftercare allowed complete wound closure by second intention.


Effects on Cell Proliferation, Activator Protein-1 and Genotoxicity by Fecal Water from Patients with Colorectal Adenomas.
The free water phase of feces (fecal water) may mediate the effects of diet on colon carcinogenesis. We examined the effects of fecal water from adenoma patients and controls on three parameters in colonocytes believed to be relevant to tumorigenesis, i.e. genotoxicity in intact cells and on isolated DNA, proliferative activity and activator protein-1 (AP-1) activity. Genotoxicity in intact colonic cells was assayed using the single-cell gel electrophoresis assay (`comet' assay) and on isolated DNA using double-stranded DNA from the X-174 RF plasmid. Cell proliferation was assessed using the commercially available `alamar blue' proliferation kit and AP-1 activity using cells transiently transfected with an AP-1-luciferase reporter construct. The data showed that lipid extracts of fecal water samples from the adenoma patients had a significantly higher capacity to induce cell proliferation than those from controls, and that this effect could be explained to a large extent by the concentrations of deoxycholic and chenodeoxycholic acids in the fecal water using regression models. No difference between patients and controls was observed for induction of AP-1 activity or induction of DNA strand breaks in intact cells. However, induction of DNA strand breaks in isolated DNA was significantly higher for the fecal waters from patients than for those from controls, which could be explained in part in a regression model by concentrations of lithocholic acid in fecal water and fecapentaene-12 in feces. Our results support the hypothesis that the biochemistry of fecal waters from adenoma patients and controls differs.


Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.
For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS. Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result. Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%. Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.


Palmitoylation modifies transmembrane adaptor protein PAG for ordered lipid environment: A molecular dynamics simulation study.
We employed all-atom MD simulations to investigate the impact of palmitoylation on the PAG transmembrane peptide within various lipid environments, including the less explored boundary region separating lipid-ordered (Lo) and lipid-disordered (Ld) membrane phases. We found that palmitoylation of the peptide reduces its impact on membrane thickness, particularly within the Lo and boundary environments. Despite their hydrophobic nature, the palmitoyl chains on the peptide did not significantly affect the hydration of the surrounding membrane. Interestingly, the boundary membrane environment was found to be especially compatible with the palmitoylated peptide, suggesting its potential for accumulation in phase boundaries. Our findings highlight the importance of understanding how palmitoylation-modified peptides behave within membranes, with crucial implications for cell signaling and membrane organization. This knowledge may also inform the optimization of lipid membrane-based drug delivery systems, by improving our understanding of how drugs and excipients can be most effectively arranged within these carriers.


Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes.
Induction of cytochrome P450 (P450) activity in the clinic can result in therapeutic failure such as tissue rejection in transplant patients or unwanted pregnancy, among others. CYP3A4 is by far the most abundant isoform and is responsible for the majority of P450-related metabolism of all marketed drugs. However, it is of importance to understand the significance of induction mediated through other P450 enzymes. The objective of this investigation was to evaluate several known inducers in vitro using cryopreserved human hepatocytes, with the aim of assessing the relevant induction of CYP3A4, CYP2B6, CYP2C9, CYP2C19, and CYP3A5, based on mRNA expression. CYP3A4 induction was also assessed based on enzymatic activity in three different lots to investigate whether mRNA expression data have any advantages over enzymatic activity. In general, the mRNA fold-induction data results were more sensitive compared with activity data, and more informative in cases in which the drug is also a P450 inhibitor. The induction of transcription of other drug-metabolizing enzymes including CYP2B6 and CYP2C enzymes occurred every time that CYP3A4 mRNA levels increased, but to a lesser extent, indicating that measurement of CYP3A4 mRNA is a sensitive marker for the induction of these other enzymes. This was the case even for enzymes and inducers that are known to also act via the constitutive androstane receptor pathway. Finally, the utility of in vitro induction measurements in the identification of clinically meaningful inducers was tested by using two simple binary classification approaches: 1) fold-induction versus vehicle control and 2) induction response relative to rifampin. The best classification was observed when the cutoff criteria based on fold induction relative to the vehicle control, using mRNA data are used.


Polarized Neutron Diffraction as a Tool for Mapping Molecular Magnetic Anisotropy: Local Susceptibility Tensors in Co(II) Complexes.
Polarized neutron diffraction (PND) experiments were carried out at low temperature to characterize with high precision the local magnetic anisotropy in two paramagnetic high-spin cobalt(II) complexes, namely [Co(II) (dmf)6 ](BPh4 )2 (1) and [Co(II) 2 (sym-hmp)2 ](BPh4 )2 (2), in which dmf=N,N-dimethylformamide; sym-hmp=2,6-bis[(2-hydroxyethyl)methylaminomethyl]-4-methylphenolate, and BPh4 (-) =tetraphenylborate. This allowed a unique and direct determination of the local magnetic susceptibility tensor on each individual Co(II) site. In compound 1, this approach reveals the correlation between the single-ion easy magnetization direction and a trigonal elongation axis of the Co(II) coordination octahedron. In exchange-coupled dimer 2, the determination of the individual Co(II) magnetic susceptibility tensors provides a clear outlook of how the local magnetic properties on both Co(II) sites deviate from the single-ion behavior because of antiferromagnetic exchange coupling.


Eating 'attentively' reduces later energy consumption in overweight and obese females.
Attentional and memory processes underpin appetite control, but whether encouraging overweight individuals to eat more 'attentively' can promote reductions in energy consumption is unclear. In the present study with a between-subjects design, a total of forty-eight overweight and obese females consumed a fixed lunchtime meal. Their ad libitum energy intake of high-energy snack food was observed during a second laboratory session that occurred later that day. In the focused-attention condition, participants ate their lunch while listening to audio instructions that encouraged them to pay attention to the food being eaten. In a control condition, participants ate while listening to an audio book with a neutral (non-food-related) content. To test whether focused attention influenced food intake via enhancing the memory of the earlier consumed meal, we measured the participants' memory of their lunchtime meal. Ad libitum snack intake was approximately 30 % lower for participants in the focused-attention condition than for those in the control condition, and this difference was statistically significant. There was limited evidence that attention decreased later food intake by enhancing memory representation of the earlier consumed meal. Eating attentively can lead to a substantial decrease in later energy intake in overweight and obese individuals. Behavioural strategies that encourage a more 'attentive' way of eating could promote sustained reductions in energy intake and weight loss.


Common aspects of the development of a kindling epileptogenic focus in the prepyriform cortex of the dog and in the hippocampus of the rat: spontaneous interictal transients with changing polarities.
Long-term records of field potentials during kindling were analysed in 2 preparations: the prepyriform cortex (PPC) in dog and the CA1 subarea of the hippocampus in rat. Besides the occurrence of after-discharges directly following the kindling stimulus, short transients were found to occur spontaneously between seizures: spontaneous inter-ictal transients or SITs. In both the PPC and the hippocampus 2 different types of SITs were encountered. Both types corresponded to a dipole layer centred around the main local pyramidal neurones (PPC or hippocampus). One type occurred early in the course of kindling and had the same polarity as the local evoked potential (EP) produced by stimulation of the lateral olfactory tract in PPC or of the Schaffer collaterals in the hippocampus. The other type occurred at later stages and had a reversed polarity to the EP. These findings were interpreted as indicating that at the onset of kindling spontaneously occurring depolarizations corresponding to the early type of SITs are restricted to the level of the synapses to which the kindling stimulus is applied; at a later stage, when convulsions are likely to occur, large spontaneous depolarizations corresponding to the late type of SITs are generated at the level of the cell bodies.


[Seasonal variations in 25-hydroxyvitamin D in young and elderly and populations in Buenos Aires City].
The purpose of this study was to evaluate the level of hypovitaminosis D in elderly and young outpatients populations of the City of Buenos Aires, and to establish its impact on bone remodeling. A total of 83 elderly and 76 young patients aged 71.9 +/- 8.1 and 29.8 +/- 6.6 years respectively, were evaluated by measuring 25-hydroxyvitamin D, 25 (OH)D, middle-molecular parathyroid hormone, and biochemical measurements of bone and mineral metabolism markers. In winter, insufficient values of 25(OH)D were observed both in elderly and young populations: 14.2% of the elderly and 15.9% of young people showed deficient values of 25(OH)D. In summer, an increase in the two groups was observed. Parathyroid hormone levels were higher in the elderly group. Secondary hyperparathyroidism was reported only in the aged group (28.1% in winter, and 20.5% in summer). The increased levels of parathyroid hormone and the presence of secondary hyperparathyroidism in the elderly would be conditioned by this deficiency and other additional factors such as age, renal insufficiency and nutrition degree. In winter, there was an increase in the bone remodeling markers, with higher values in the elderly group. In the City of Buenos Aires decreased levels of 25(OH)D were seen both in young and elderly individuals, with seasonal variations. Sanitary policies are necessary to prevent hypovitaminosis D, because this condition predisposes for osteoporosis.


Building the Bridge to Quality: An Urgent Call to Integrate Quality Improvement and Patient Safety Education With Clinical Care.
Current models of quality improvement and patient safety (QIPS) education are not fully integrated with clinical care delivery, representing a major impediment toward achieving widespread QIPS competency among health professions learners and practitioners. The Royal College of Physicians and Surgeons of Canada organized a 2-day consensus conference in Niagara Falls, Ontario, Canada, called Building the Bridge to Quality, in September 2016. Its goal was to convene an international group of educational and health system leaders, educators, frontline clinicians, learners, and patients to engage in a consensus-building process and generate a list of actionable strategies that individuals and organizations can use to better integrate QIPS education with clinical care.Four strategic directions emerged: prioritize the integration of QIPS education and clinical care, build structures and implement processes to integrate QIPS education and clinical care, build capacity for QIPS education at multiple levels, and align educational and patient outcomes to improve quality and patient safety. Individuals and organizations can refer to the specific tactics associated with the 4 strategic directions to create a road map of targeted actions most relevant to their organizational starting point.To achieve widespread change, collaborative efforts and alignment of intrinsic and extrinsic motivators are needed on an international scale to shift the culture of educational and clinical environments and build bridges that connect training programs and clinical environments, align educational and health system priorities, and improve both learning and care, with the ultimate goal of achieving improved outcomes and experiences for patients, their families, and communities.


Expression of three cell proliferation-associated antigens, DNA polymerase alpha, Ki-67 antigen and transferrin receptor in nodal and cutaneous T-cell lymphomas.
We studied the expression of three cell proliferation-associated antigens: DNA polymerase alpha, Ki-67 antigen, and transferrin receptor, in 35 T-cell lymphomas of nodal origin (T-NL) and 40 cutaneous T-cell lymphomas (CTCL). Immunohistochemical staining was carried out on frozen tissue sections of these specimens using three monoclonal antibodies, DAKO-PC, CL22-2-42B (DNA polymerase alpha), and OKT9. The proportion of cells positive for CL22-2-42B, DAKO-PC, or OKT9 among all tumor cells was correlated with four histologic subtypes: malignant lymphoma (ML), diffuse, small; mixed; large; and large cell immunoblastic in both T-NL and CTCL. A strong correlation was noted between positivity for CL22-2-42B and that for DAKO-PC or OKT9. On the other hand, no difference in the expression of these three antigens was noted between T-NL and CTCL in the high, intermediate or low grade-malignancy group. In CTCL as well as in T-NL, cells positive for CL22-2-42B, DAKO-PC or OKT9 were significantly more numerous in the high-grade group than the intermediate-grade group, and in the intermediate-grade group than the low-grade group. Furthermore, a significant correlation between survival period and the number of CL22-2-42B-positive cells was noted when the T cell malignancies, CTCL and T-NL were considered (t value = 2.015, p less than 0.05). Thus, the expression of DNA-polymerase alpha, Ki-67 antigen or OKT9 seems to well reflect the biological behavior and/or clinical prognosis of T-cell lymphoma.


One-step production of immobilized alpha-amylase in recombinant Escherichia coli.
Industrial enzymes are often immobilized via chemical cross-linking onto solid supports to enhance stability and facilitate repeated use in bioreactors. For starch-degrading enzymes, immobilization usually places constraints on enzymatic conversion due to the limited diffusion of the macromolecular substrate through available supports. This study describes the one-step immobilization of a highly thermostable alpha-amylase (BLA) from Bacillus licheniformis and its functional display on the surface of polyester beads inside engineered Escherichia coli. An optimized BLA variant (Termamyl) was N-terminally fused to the polyester granule-forming enzyme PhaC of Cupriavidus necator. The fusion protein lacking the signal sequence mediated formation of stable polyester beads exhibiting alpha-amylase activity. The alpha-amylase beads were assessed with respect to alpha-amylase activity, which was demonstrated qualitatively and quantitatively. The immobilized alpha-amylase showed Michaelis-Menten enzyme kinetics exerting a V(max) of about 506 mU/mg of bead protein with a K(m) of about 5 microM, consistent with that of free alpha-amylase. The stability of the enzyme at 85 degrees C and the capacity for repeated usage in a starch liquefaction process were also demonstrated. In addition, structural integrity and functionality of the beads at extremes of pH and temperature, demonstrating their suitability for industrial use, were confirmed by electron microscopy and protein/enzyme analysis. This study proposes a novel, cost-effective method for the production of immobilized alpha-amylase in a single step by using the polyester granules forming protein PhaC as a fusion partner in engineered E. coli.


Self-Management Interventions to Improve Activities of Daily Living and Rest and Sleep for Adults With Chronic Conditions: A Systematic Review.
Chronic conditions often cause functional impairments in activities of daily living (ADLs) and rest and sleep, leading to decreased independence and self-efficacy. To aid occupational therapy practitioners in making informed decisions regarding self-management interventions to improve ADLs and rest and sleep for community-dwelling adults with chronic conditions. We identified literature published from 1995 to 2019 through searches of the Cochrane Database of Systematic Reviews, MEDLINE, PsycINFO, CINAHL, and OTseeker. Study Selection and Data Collection: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to abstract and assess data quality and validity. The review followed American Occupational Therapy Association Evidence-Based Practice Project methodology. Studies addressing self-management interventions for community-dwelling adults ages 18 and older with chronic cardiovascular disease, Type 2 diabetes, heart disease, hypertension, chronic respiratory problems, or kidney disease were included. Fifteen articles met inclusion criteria and were categorized into ADLs and sleep. Strong evidence supports education to improve diabetic foot self-care. Low evidence addresses exercise and education to improve ADLs for people with heart disease and chronic obstructive pulmonary disease. Moderate evidence supports mind-body self-care education to enhance sleep. Occupational therapy practitioners working with adults with diabetes are encouraged to routinely offer education that includes discussion of risk factors and daily foot inspections and hygiene. When addressing sleep, education that addresses sleep hygiene, nutrition, relaxation techniques, and physical activity should routinely be provided to adults with chronic conditions. Further research is needed to understand the dosage needed. What This Article Adds: This systematic review supports the role of occupational therapy in providing self-management interventions to address ADLs and sleep for adults with diabetes and other chronic conditions.


Single-cell RNA sequencing reveals immune microenvironment of small cell lung cancer-associated malignant pleural effusion.
We used 10 × genomics single-cell transcriptome sequencing technology to reveal the tumor immune microenvironment characteristics of small cell lung cancer (SCLC) in a patient with malignant pleural effusion (MPE). A total of 8008 high-quality cells were finally obtained for subsequent bioinformatic analysis, which were divided into 10 cell clusters further identified as B cells, T cells, myeloid cells, NK cells, and cancer cells. Such SCLC related genes as NOTCH1, MYC, TSC22D1, SOX4, BLNK, YBX3, VIM, CD8A, CD8B, and KLF6 were expressed in different degrees during differentiation of T and B cells. Different ligands and receptors between T, B and tumor cells almost interact through MHC II, IL-16, galectin, and APP signaling pathway.


The prevalence of osteoporosis, osteopenia, and fractures among adults with cystic fibrosis: a systematic literature review with meta-analysis.
Observational studies have indicated a high but heterogeneous prevalence of low bone mineral density for adult patients with cystic fibrosis. Fracture complications were also described. The objective of this study was to determine the prevalence of osteoporosis, osteopenia, and fractures among adult patients with cystic fibrosis. A systematic literature review was conducted using electronic databases. The keywords used were "cystic fibrosis [MeSH] AND bone density." Original studies were eligible if they reported the prevalence of osteoporosis and/or osteopenia and/or fractures in adult patients with cystic fibrosis. A meta-analysis of pooled proportions was performed. Heterogeneity was tested with the Cochran Q statistic, and in the case of heterogeneity a random effect model was used. Of 117 studies, 12 were selected, i.e., that represented a total of 1055 patients. Mean age ranged from 18.5 to 32 years (median: 28.2 years). Mean body mass index ranged from 19.9 to 22.4 (median: 20.7); 53.8% were men. The pooled prevalence of osteoporosis in adults with cystic fibrosis was 23.5% (95% CI, 16.6-31.0). The pooled prevalence of osteopenia was 38% (95% CI, 28.2-48.3). The pooled prevalences of radiological vertebral fractures and nonvertebral fractures were 14% (95% CI, 7.8-21.7) and 19.7% (95% CI, 6.0-38.8), respectively. In conclusion, this systematic literature review with meta-analysis emphasized the high prevalence of osteopenia and osteoporosis in young adults with cystic fibrosis. The prevalence of fracture was also high.


Low colostrum yield in Jersey cattle and potential risk factors.
Consumption of an adequate volume of high-quality colostrum is vital to a dairy calf's ability to survive and become a productive herd member. However, some dairy herds have reported a deficiency of colostrum production, which ranges from a low volume to no colostrum produced, by cows during fall and winter. Little information regarding this phenomenon exists. The purpose of this study was to characterize the syndrome and identify potential risk factors for low colostrum yield. A 2,500-cow Jersey dairy farm was enrolled in a prospective cohort study in May 2016, to evaluate possible effects of photoperiod, temperature, and cow factors on colostrum production. Dairy personnel were trained to collect, weigh, and evaluate colostrum quality. Information on parity, previous lactation length, previous 305-d mature-equivalent milk production, and dry period length were collected through the farm's dairy management software. Weather and photoperiod data were also collected. Over the year of enrollment, 2,988 eligible cows calved and had colostrum weights recorded and 38% were primiparous (n = 1,143), 25% were in their second lactation (n = 752), and 37% were in their third or greater lactation (n = 1,093). The overall average colostrum yield was 6.6 kg/cow in June 2016, 2.5 kg/cow in December 2016, and 4.8 kg/cow in May 2017. Multiparous cows had a larger decline in colostrum production between June and December (6.6 to 1.3 kg/cow) compared with primiparous animals (6.5 to 4.2 kg/cow). Overall, average colostrum production decreased by 0.17 kg/cow per week during this time, 0.22 kg for multiparous cows and 0.08 kg for primiparous cows. A logistic regression model was constructed for all cows to evaluate effects of cow factors on low colostrum production (<2.7 kg at first milking). Dry period length, calf sex, singleton or twin, age at freshening, month of calving and previous lactation length were significantly associated with the probability of low colostrum yield (<2.7 kg at first milking). A cross-correlation function analysis between the time series for colostrum yield and photoperiod revealed a high correlation at the time of calving and 1 mo prior, particularly for multiparous cows. A pedigree analysis showed that extreme colostrum yield (low vs. high) followed some sire lines. Low colostrum production in this herd could have an economic effect on the dairy and calf health and appears to have a strong seasonal and, potentially, a genetic component.


Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes.
Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6C(hi)CX(3)CR1(low) monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally "re-educating" the TAM compartment.


A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.


Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.
Ventilator-associated pneumonia (VAP) is an important patient safety issue in critically ill patients. To develop an evidence-based guideline for the prevention of VAP. MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. The authors systematically searched for relevant randomized, controlled trials and systematic reviews that involved mechanically ventilated adults and were published before 1 April 2003. Physical, positional, and pharmacologic interventions that may influence the development of VAP were considered. Independently and in duplicate, the authors scored the validity of trials; the effect size and confidence intervals; the homogeneity of results; and safety, feasibility, and economic issues. Recommended: The orotracheal route of intubation, changes of ventilator circuits only for each new patient and if the circuits are soiled, use of closed endotracheal suction systems that are changed for each new patient and as clinically indicated, heat and moisture exchangers in the absence of contraindications, weekly changes of heat and moisture exchangers, and semi-recumbent positioning in the absence of contraindications. Consider subglottic secretion drainage and kinetic beds. Not recommended: Sucralfate to prevent VAP in patients at high risk for gastrointestinal bleeding and topical antibiotics to prevent VAP. Because of insufficient or conflicting evidence, no recommendations were made about systematically searching for maxillary sinusitis, chest physiotherapy, the timing of tracheostomy, prone positioning, prophylactic intravenous antibiotics, or intravenous plus topical antibiotics. No formal economic analysis was performed, and patient perspectives were not considered. If effectively implemented, this guideline may decrease the morbidity, mortality, and costs of VAP in mechanically ventilated patients.


Tributyltin-resistant bacteria from estuarine and freshwater sediments.
Resistance to tributyltin (TBT) was examined in populations from TBT-polluted sediments and nonpolluted sediments from an estuary and from fresh water as well as in pure cultures isolated from those sediments. The 50% effective concentrations (EC50s) for populations were higher at a TBT-polluted freshwater site than at a site without TBT, suggesting that TBT selected for a TBT-resistant population. In contrast, EC50s were significantly lower for populations from a TBT-contaminated estuarine site than for those from a site without TBT, suggesting that other factors in addition to TBT determine whether populations become resistant. EC50s for populations from TBT-contaminated freshwater sediments were nearly 30 times higher than those for populations from TBT-contaminated estuarine sediments. We defined a TBT-resistant bacterium as one which grows on trypticase soy agar containing 8.4 microM TBT, a concentration which prevented the growth of 90% of the culturable bacteria from these sediments. The toxicity of TBT in laboratory media was influenced markedly by the composition of the medium and whether it was liquid or solid. Ten TBT-resistant isolates from estuarine sediments and 19 from freshwater sediments were identified to the genus level. Two isolates, each a Bacillus sp., may be the first gram-positive bacteria isolated from fresh water in the presence of a high concentration of TBT. There was a high incidence of resistance to heavy metals: metal resistance indices were 0.76 for estuarine isolates and 0.68 for freshwater isolates.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional Domains of the Herpes Simplex Virus Type 1 Tegument Protein pUL37: The Amino Terminus is Dispensable for Virus Replication in Tissue Culture.
The herpes simplex virus type 1 (HSV-1) UL37 gene encodes for a multifunctional component of the virion tegument, which is necessary for secondary envelopment in the cytoplasm of infected cells, for motility of the viral particle, and for the first steps in the initiation of virus infection. This 120 kDa protein has several known viral interacting partners, including pUL36, gK/pUL20, pUS10, and VP26, and cellular interacting proteins which include TRAF6, RIG-I, and dystonin. These interactions are likely important for the functions of pUL37 at both early and late stages of infection. We employed a genetic approach to determine essential domains and amino acid residues of pUL37 and their associated functions in cellular localization and virion morphogenesis. Using marker-rescue/marker-transfer methods, we generated a library of GFP-tagged pUL37 mutations in the HSV-1 strain KOS genome. Through viral growth and ultra-structural analysis, we discovered that the C-terminus is essential for replication. The N-terminal 480 amino acids are dispensable for replication in cell culture, although serve some non-essential function as viral titers are reduced in the presence of this truncation. Furthermore, the C-terminal 133 amino acids are important in so much that their absence leads to a lethal phenotype. We further probed the carboxy terminal half of pUL37 by alanine scanning mutagenesis of conserved residues among alphaherpesviruses. Mutant viruses were screened for the inability to form plaques-or greatly reduced plaque size-on Vero cells, of which 22 mutations were chosen for additional analysis. Viruses discovered to have the greatest reduction in viral titers on Vero cells were examined by electron microscopy (EM) and by confocal light microscopy for pUL37-EGFP cellular localization. This genetic approach identified both essential and non-essential domains and residues of the HSV-1 UL37 gene product. The mutations identified in this study are recognized as significant candidates for further analysis of the pUL37 function and may unveil previously undiscovered roles and interactions of this essential tegument gene.


Specific binding of non-steroidal anti-inflammatory drugs (NSAIDs) to phospholipase A2: structure of the complex formed between phospholipase A2 and diclofenac at 2.7 A resolution.
Type IIA secretory phospholipase A2 (PLA2) enzymes catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids to release fatty acids and lysophospholipids. In order to elucidate the role of PLA2 in inflammatory disorders and to determine the mode of binding of non-steroidal anti-inflammatory drugs (NSAIDs) to PLA2, the detailed three-dimensional structure of a complex formed between a group IIA PLA2 from Daboia russelli pulchella and 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid (diclofenac) has been determined. The preformed complex was crystallized by equilibrating the protein solution against a mixture of 0.20 M ammonium sulfate and 30% PEG 4000. The crystals belong to space group P4(3), with unit-cell parameters a = b = 53.0, c = 48.4 A. The structure was solved by the molecular-replacement method and refined to R(cryst) and R(free) factors of 0.192 and 0.211, respectively, using reflections to 2.7 A resolution. The structure showed that diclofenac occupies a very favourable position in the centre of the substrate-binding hydrophobic channel that allows a number of intermolecular interactions. The binding mode of diclofenac involved crucial interactions with important residues for substrate recognition such as Asp49, His48 and Gly30. In addition, it included three new interactions involving its Cl atoms with Phe5, Ala18 and Tyr22. It also showed an extensive network of hydrophobic interactions involving almost all of the residues of the substrate-binding hydrophobic channel. The binding affinity of diclofenac was determined using surface plasmon resonance, which gave an equilibrium constant of 4.8 +/- 0.2 x 10(-8) M.


ASTRONOMY: The Distance to the Large Magellanic Cloud.
The Large Magellanic Cloud (LMC), a satellite of the Milky Way, is an important yardstick by which most intergalactic distances are measured. But as Cole explains in this Perspective, how far away the LMC is remains a matter of dispute, with far reaching implications in cosmology. But observations of Cepheids and of eclipsing binaries, two types of stars that allow absolute luminosity and thus absolute distances to be determined, are promising to resolve this important issue in the not too distant future.


Patients With Type 2 Diabetes: Anesthetic Management in the Ambulatory Setting: Part 2: Pharmacology and Guidelines for Perioperative Management.
Type 2 diabetes is a disease of metabolism in which the afflicted patient cannot properly utilize carbohydrates, fats, and proteins. Because the prevalence of type 2 diabetes is rapidly increasing throughout the general population, anesthesia providers must realize that a significant percentage of their patients will present with the disease. Anesthesia providers should have an intimate knowledge of the comorbidities and complications that are associated with type 2 diabetes and know the specific pharmacokinetics and pharmacodynamics of the drugs used to treat the disease. Part 1 of this series on the anesthetic management of type 2 diabetes in the ambulatory theater addressed the pathology of diabetes and its comorbid disease states. Part 2 of the series now focuses on the pharmacology associated with the many medications used to treat the disorder and the most recent guidelines for blood glucose management recommended for patients in an ambulatory surgery setting.


Leveraging Viscous Peeling to Create and Activate Soft Actuators and Microfluidic Devices.
The research fields of microfluidics and soft robotics both involve complex small-scale internal channel networks, embedded within a solid structure. This study examines leveraging viscous peeling as a mechanism to create and activate soft actuators and microchannel networks, including complex elements such as valves, without the need for fabrication of structures with micron-scale internal cavities. We consider configurations composed of an internal slender structure embedded within another elastic solid. Pressurized viscous fluid is introduced into the interface between the two solids, thus peeling the two elastic structures and creating internal cavities. Since the gap between the solids is determined by the externally applied pressure, the characteristic size of the fluid network may vary with time and be much smaller than the resolution of the fabrication method. This study presents a model for the highly nonlinear elastic-viscous dynamics governing the flow and deformation of such configurations. Fabrication and experimental demonstrations of micron-scale valves and channel networks created from millimeter scale structures are presented, as well as the transient dynamics of viscous peeling-based soft actuators. The experimental data are compared with the suggested model, showing very good agreement.


Role of DOR in neuronal plasticity changes promoted by food-seeking behaviour.
Several lines of evidence support that food overconsumption may be related to the role of the endogenous opioid system in the control of food palatability. The opioid system, and particularly the delta opioid receptor (DOR), plays a crucial role in the regulation of food rewarding properties. In our study, we used operant conditioning maintained by chocolate-flavoured pellets to investigate the role of DOR in the motivation for palatable food and the structural plasticity changes promoted by this behaviour. For this purpose, we evaluated the specific role of this receptor in the behavioural and neuroplastic changes induced by palatable food in the prefrontal cortex (PFC), hippocampus (HCP) and nucleus accumbens (NAc) in constitutive knockout (KO) mice deficient in DOR. Mutant mice and their wild-type littermates were trained to obtain chocolate-flavoured pellets on fixed ratio 1 (FR1), FR5 and progressive ratio (PR) schedule of reinforcement. No significant differences between genotypes were revealed on operant behaviour acquisition in FR1. DOR knockout mice displayed lower number of active lever-presses than wild-type mice on FR5, and a similar decrease was revealed in DOR KO mice in the breaking point during the PR. This operant training to obtain palatable food increased dendritic spine density in the PFC, HCP and NAc shell of wild-type, but these plasticity changes were abolished in DOR KO mice. Our results support the hypothesis that DOR regulates the reinforcing effects and motivation for palatable food through neuroplastic changes in specific brain reward areas.


Diagnostic Testing of Vaginitis: Improving the Value of Care.
Vaginitis is one of the most common reasons women access health care in the United States. Despite its prevalence and disruptive impact, it is frequently misdiagnosed and untreated, resulting in unnecessary patient discomfort, follow-up visits, and health care costs. This study presents a costs analysis of diagnostic testing technologies to demonstrate the potential of molecular tests to improve the value of care for women with vaginitis. This study tracks health care spending among women diagnosed with vaginitis and finds that nucleic acid amplification tests (NAATs) are cost-effective for the diagnosis of vaginal symptoms. Women who receive a NAAT on the day of their diagnosis have significantly lower 12-month follow-up costs compared to women who receive a direct probe test or those women who are clinically evaluated without the use of a molecular test. However, despite Food and Drug Administration approval, widely available molecular diagnostics have not been incorporated into clinical guidelines, and many payer policies fail to cover these tests. Greater utilization of NAAT for the diagnosis of vaginitis has the potential to improve the care of women seeking treatment for this prevalent condition and facilitate sexually transmitted infection testing without additional visits.