Intercellular adhesion and cancer invasion: a discrete simulation using the extended Potts model.
We develop a discrete model of malignant invasion using a thermodynamic argument. An extension of the Potts model is used to simulate a population of malignant cells experiencing interactions due to both homotypic and heterotypic adhesion while also secreting proteolytic enzymes and experiencing a haptotactic gradient. In this way we investigate the influence of changes in cell-cell adhesion on the invasion process. We demonstrate that the morphology of the invading front is influenced by changes in the adhesiveness parameters, and detail how the invasiveness of the tumour is related to adhesion. We show that cell-cell adhesion has less of an influence on invasion compared with cell-medium adhesion, and that increases in both proteolytic enzyme secretion rate and the coefficient of haptotaxis act in synergy to promote invasion. We extend the simulation by including proliferation, and, following experimental evidence, develop an algorithm for cell division in which the mitotic rate is explicitly related to changes in the relative magnitudes of homotypic and heterotypic adhesiveness. We show that although an increased proliferation rate usually results in an increased depth of invasion into the extracellular matrix, it does not invariably do so, and may, indeed, cause invasiveness to be reduced.


Racial disparities in COVID-19 mortality across Michigan, United States.
Black populations in the United States are being disproportionately affected by the COVID-19 pandemic, but the increased mortality burden after accounting for health and other demographic characteristics is not well understood. We examined characteristics of individuals who died from COVID-19 in Michigan by race stratified by their age, sex and comorbidity prevalence to illustrate and understand this disparity in mortality risk. We evaluate COVID-19 mortality in Michigan by demographic and health characteristics, using individual-level linked death certificate and surveillance data collected by the Michigan Department of Health and Human Services from March 16 to October 26, 2020. We identified differences in demographics and comorbidity prevalence across race among individuals who died from COVID-19 and calculated mortality rates by age, sex, race, and number of comorbidities. Among the 6,065 COVID-19 related deaths in Michigan, Black individuals are experiencing 3·6 times the mortality rate of White individuals (p<0.001), with a mortality rate for Black individuals under 65 years without comorbidities that is 12·6 times that of their White counterparts (p<0.001). After accounting for age, race, sex, and number of comorbidities, we find that Black individuals in all strata are at higher risk of COVID-19 mortality than their White counterparts. Our findings demonstrate that Black populations are disproportionately burdened by COVID-19 mortality, even after accounting for demographic and underlying health characteristics. We highlight how disparities across race, which result from systemic racism, are compounded in crises. ASP, AP and APG were funded by NSF Expeditions grant 1918784, NIH grant 1R01AI151176-01, NSF Rapid Response Research for COVID-19 grant RAPID-2027755, and the Notsew Orm Sands Foundation. MCF was supported by NIH grant K01AI141576.


Evaluation of the acute and chronic safety of the biosense injection catheter system in porcine hearts.
Direct myocardial injection of therapeutic agents has been explored as a new method for myocardial revascularization. The integration of a 3D electromechanical mapping catheter with a retractable injection needle should allow for intramyocardial injection to identified sites, obviating the need for open heart surgery. This study assessed the procedural safety and performance characteristics of a novel guided catheter-based transendocardial injection system. The electromagnetic guidance system was coupled with a retrievable 27G needle for left ventricular endocardial injection. Using this system, we injected, transendocardially, methylene-blue (MB) dye tracer at a volume of 0.1 or 0.2 ml per injection in eight normal pigs. Animals were sacrificed acutely, at 1, 3, and 7 days (two animal in each time). Three animals served as controls. The injections were followed by coronary angiography and echocardiogram to assess possible ventricular or coronary perforation and wall motion abnormalities. CK-MB levels were measured up to 24 hr following the procedure. The animals were sacrificed at the assigned time for gross and histopathology evaluation. A total of 101 injections were made in all regions of the heart except the apex and the mitral valve. No animal died as a result of the mapping or injection procedures. Vital signs did not change relative to baseline after the mapping and injection procedures. CK-MB values did not increase over time and there was no evidence of sustained arrhythmia or hemodynamic compromise. There was no evidence of left ventricular or coronary perforation, global or regional wall motion abnormalities, or hemopericardium. On histologic evaluation, the estimated volume of tissue staining was greater than the volume of the injected MB dye due to dispersion of the injectate in the interstitial and intracellular fluid compartments. It is concluded that using this magnetic guidance catheter-based navigational system, it is feasible and safe to perform the transendocardial injection procedure. Thus, if it is determined that direct intramyocardial injection of drugs is a valid therapeutic strategy, this approach offers a clear advantage over surgically based transepicardial injection procedures. Cathet. Cardiovasc. Intervent. 48:447-453, 1999.


Isolation and characterization of the moxJ, moxG, moxI, and moxR genes of Paracoccus denitrificans: inactivation of moxJ, moxG, and moxR and the resultant effect on methylotrophic growth.
By using the moxF gene encoding the large fragment of methanol dehydrogenase as a probe, a downstream linked chromosomal fragment was isolated from a genomic bank of Paracoccus denitrificans. The nucleotide sequence of the fragment was determined and revealed the 3' part of moxF, four additional open reading frames, and the 5' part of a sixth one. The organization and deduced amino acid sequences of the first three frames downstream from moxF were found to be largely homologous to the moxJ, moxG, and moxI gene products of Methylobacterium extorquens AM1. Directly downstream from these three genes, a new mox gene was identified. The gene is designated moxR. By using the suicide vector pGRPd1, the moxJ, moxG, and moxR genes were inactivated by the insertion of a kanamycin resistance gene. Subsequently, suicide vector pRVS1 was used to replace the marker genes in moxJ and moxG for unmarked deletions made in vitro. As a result, the three insertion strains as well as the two unmarked mutant strains were unable to grow on methanol, even in the presence of pyrroloquinoline quinone. Growth on succinate and on methylamine was not affected. In all five mutant strains, synthesis of the large subunit of methanol dehydrogenase and of inducible cytochrome c553i was observed. The moxJ and moxG insertion mutant strains were unable to synthesize both the cytochrome c551i and the small subunit of methanol dehydrogenase, and this lack of synthesis was attended by the loss of methanol dehydrogenase activity. The moxJ deletion mutant strain partly synthesized the latter two proteins, cytochrome c551i. Partial synthesis of the small subunit of methanol dehydrogenase observed with the latter strain was attended by a corresponding extent of methanol dehydrogenase activity. The moxR insertion mutant strain was shown to synthesize cytochrome c551i as well as the large and small subunits of methanol dehydrogenase, but no methanol dehydrogenase activity was observed. The results show that periplasmic cytochrome c551i is the moxG gene product and the natural electron acceptor of methanol dehydrogenase in P. denitrificans. In contrast to earlier suggestions, this cytochrome was found to be different from membrane-bound cytochrome c552. In addition, it is demonstrated that moxI encodes the small subunit of methanol dehydrogenase. It is suggested that MoxJ is involved in the assemblage of active methanol dehydrogenase in the periplasm and, in addition, that MoxR is involved in the regulation of formation of active methanol dehydrogenase.


Charge-dependent cavity radii for an accurate dielectric continuum model of solvation with emphasis on ions: aqueous solutes with oxo, hydroxo, amino, methyl, chloro, bromo, and fluoro functionalities.
Dielectric continuum solvation models are widely used because they are a computationally efficacious way to simulate equilibrium properties of solutes. With advances that allow for molecular-shaped cavities, they have reached a high level of accuracy, in particular for neutral solutes. However, benchmark tests show that existing schemes for defining cavities are unable to consistently predict accurately the effects of solvation on ions, especially anions. This work involves the further development of a protocol put forth earlier for defining the cavities of aqueous solutes, with resulting advances that are most striking for anions. Molecular cavities are defined as interlocked spheres around atoms or groups of atoms in the solute, but the sphere radii are determined by simple empirically based expressions involving the effective atomic charges of the solute atoms (derived from molecular electrostatic potential) and base radii. Both of these terms are optimized for the different types of atoms or functional groups in a training set of neutral and charged solutes. Parameters in these expressions for radii were fitted by minimizing residuals between calculated and measured standard free energies of solvation (DeltaG(s)*), weighted by the uncertainty in the measured value. The calculations were performed using density functional theory with the B3LYP functional and the 6-311+G** basis set and the COnductor-like Screening MOdel (COSMO). The optimized radii definitions reproduce DeltaG(s)* of neutral solutes and singly charged ions in the training set to within experimental uncertainty and, more importantly, accurately predict DeltaG(s)* of compounds outside the training set, in particular anions (J. Phys. Chem. A 2003, 107, 5778). Inherent to this approach, the cavity definitions reflect the strength of specific solute-water interactions. We surmise that this feature underlies the success of the model, referred to as the CD-COSMO model for Charge-Dependent (also Camaioni-Dupuis) COSMO model. These findings offer encouragement that we can keep extending this scheme to other functional groups and obtain better accuracy in using continuum solvation models to predict equilibrium properties of aqueous ionic solutes. The approach is illustrated for a number of test cases, including the determination of acidities of an amine base, a study of the tautomerization equilibrium of a zwitterionic molecule (glycine), and calculating solvation energies of transition states toward a full characterization of reaction pathways in aqueous phase, here in S(N)2 exchange reactions. The calculated reaction barriers in aqueous solution are in excellent agreement with experimental values.


A quality alert and call for improved curation of public chemistry databases.
In the last ten years, public online databases have rapidly become trusted valuable resources upon which researchers rely for their chemical structures and data for use in cheminformatics, bioinformatics, systems biology, translational medicine and now drug repositioning or repurposing efforts. Their utility depends on the quality of the underlying molecular structures used. Unfortunately, the quality of much of the chemical structure-based data introduced to the public domain is poor. As an example we describe some of the errors found in the recently released NIH Chemical Genomics Center 'NPC browser' database as an example. There is an urgent need for government funded data curation to improve the quality of internet chemistry and to limit the proliferation of errors and wasted efforts.


Cytotoxicity, bactericidal and hemostatic evaluation of oxidized cellulose microparticles: Structure and oxidation degree approach.
Oxidized cellulose is the most used hemostatic materials in clinical applications. In addition to its perfect hemostatic efficiency, it is degradable under in vivo conditions and supremely prevents bacterial growth. On the other hand, one of the drawbacks of the oxidized cellulose is cytotoxicity due to the strongly acidic nature during degradation. There is a number of commercially available oxidized cellulose products which are derived from regenerated and non-regenerated cellulose. On the other hand, the effect of oxidation degree and structure (regenerated or non-regenerated) on product efficiency is undetermined. Moreover, oxidation degree which is primary factor for both bactericidal and hemostatic efficiency is also crucial for assessment of the product. In this study, oxidized cellulose versus oxidized regenerated cellulose microparticles with various oxidation degree was produced and characterized. Comparative studies were conducted in terms of bactericidal and hemostatic efficiencies in addition to cytotoxicity. The results could be a reference for the optimized oxidized cellulose product for the hemostatic applications.


Suppression of Nonequilibrium Quasiparticle Transport in Flat-Band Superconductors.
We study nonequilibrium transport through a superconducting flat-band lattice in a two-terminal setup with the Schwinger-Keldysh method. We find that quasiparticle transport is suppressed and coherent pair transport dominates. For superconducting leads, the ac supercurrent overcomes the dc current, which relies on multiple Andreev reflections. With normal-normal and normal-superconducting leads, the Andreev reflection and normal currents vanish. Flat-band superconductivity is, thus, promising not only for high critical temperatures, but also for suppressing unwanted quasiparticle processes.


Steric effects in a mean-field model for polar nematic liquid crystals.
The existence of uniaxial liquid crystals comprising polar molecules, with all the dipoles aligned in a parallel pattern, is classically ruled out. Generally, there are two different avenues to a mean-field theory for liquid crystals: one is based on short-range, repulsive, steric forces, and the other is based on long-range, globally attractive, dispersion forces. Purely polar steric interactions have been shown to have the potential of inducing unexpected orientationally ordered states. In real molecules, anisotropies both in shape and in polarizability coexist; it has been shown that dispersion forces interaction can be combined with hard-core repulsion in a formal theory, based on a steric tensor. Starting from this, we build an interaction Hamiltonian featuring the average electric dipolar energy exchanged between molecules with the same excluded region. Under the assumption that the molecular shape is spheroidal, we propose a mean-field model for polar nematic liquid crystals which can exhibit both uniaxial and biaxial polar phases. By means of a numerical bifurcation analysis, we discuss the stability of the equilibrium against the choice of two model parameters, one describing the degree of molecular shape biaxiality and the other describing the relative orientation of the electric dipole within each molecule. We find only uniaxial stable phases, which are effectively characterized by a single scalar order parameter.


Inactivation of MuxABC-OpmB transporter system in Pseudomonas aeruginosa leads to increased ampicillin and carbenicillin resistance and decreased virulence.
Resistance-Nodulation-Cell Division (RND) pumps play important roles in bacterial resistance to antibiotics. Pseudomonas aeruginosa is an important human pathogen which exhibits high level resistance to antibiotics. There are total of 12 RND pumps present in the P. aeruginosa PAOl genome. The recently characterized MuxABC-OpmB system has been shown to play a role in resistance to novobiocin, aztreonam, macrolides, and tetracycline in a multiple knockout mutation. In this study, we examined the expression levels of all the 12 RND pump gene clusters and tested the involvement of MuxABC-OpmB in pathogenicity. The results indicated that in addition to the four known constitutively expressed RND pumps, mexAB-oprM, mexGHI-opmD, mexVW, and mexXY, relatively high levels of expression were observed with mexJK and muxABC-opmB in the conditions tested. Inactivation of muxA in the muxABC-opmB operon resulted in elevated resistance to ampicillin and carbenicillin. The mutant also showed attenuated virulence in both Brassica rapa pekinensis and Drosophila melanogaster infection models. The decreased virulence at least in part was due to decreased twitching motility in the mutant. These results indicate that the RND pump MuxABC-OpmB is associated with ampicillin and carbenicillin susceptibility and also involved in pathogenesis in P. aeruginosa.


Characteristics of intravascular large B-cell lymphoma on cerebral MR imaging.
IVL is characterized by a propensity for intravascular tumor cell proliferation. Premortem diagnosis of IVL is difficult because of its nonspecific clinical, laboratory, and imaging manifestations. This study examined cerebral MR imaging patterns of IVL and their changes with and without chemotherapy. Nine of 11 patients studied presented with abnormal findings. We define 5 patterns of abnormal MR imaging findings: 1) infarctlike lesions, 2) nonspecific white matter lesions, 3) meningeal enhancement, 4) masslike lesions, and 5) hyperintense lesions in the pons on T2WI. Seven patients presented with only 1 pattern, while 2 patients presented with multiple patterns. Lesions in 7 treated patients responded to chemotherapy. Pathologic specimens revealed intravascular tumor cell infiltration with associated infarctions, necrosis, congestion, demyelination, vasculitis, and tumor cell extravasation. We conclude that MR imaging patterns can be possible manifestations of intravascular-dominant infiltration by tumor cells with associated occlusion or inflammation, depending on the level of affected vessels.


Modelling invasive pathogen load from non-destructive sampling data.
Where microbes colonizing skin surface may help maintain organism homeostasis, those that invade living skin layers cause disease. In bats, white-nose syndrome is a fungal skin infection that affects animals during hibernation and may lead to mortality in severe cases. Here, we inferred the amount of fungus that had invaded skin tissue of diseased animals. We used simulations to estimate the unobserved disease severity in a non-lethal wing punch biopsy and to relate the simulated pathology to the measured fungal load in paired biopsies. We found that a single white-nose syndrome skin lesion packed with spores and hyphae of the causative agent, Pseudogymnoascus destructans, contains 48.93 pg of the pathogen DNA, which amounts to about 1560 P destructans genomes in one skin lesion. Relating the information to the known UV fluorescence in Nearctic and Palearctic bats shows that Nearctic bats carry about 1.7 µg of fungal DNA per cm2, whereas Palearctic bats have 0.04 µg cm-2 of P. destructans DNA. With the information on the fungal load that had invaded the host skin, the researchers can now calculate disease severity as a function of invasive fungal growth using non-destructive UV light transillumination of each bat's wing membranes. Our results will enable and promote thorough disease severity assessment in protected bat species without the need for extensive animal and laboratory labor sacrifices.


Sexual health behaviours among Pacific Island youth in Vanuatu, Tonga and the Federated States of Micronesia.
This study was conducted to describe the sexual risk behaviours of youth within the Pacific Island nations of Vanuatu, Tonga and the Federated States of Micronesia. General health behaviour surveys were conducted with youth aged 15-19 years and not attending school in the three countries. A sample of 390 Ni-Vanuatu youth from the Shefa Province, 934 youth from three island provinces of Tonga and 92 youth from Pohnpei, the main island of the four island states of the Federated States of Micronesia, were interviewed in gender-specific groups. Questions were asked about sexual behaviours that may contribute to unintended pregnancy or sexually transmitted infections (STIs). Moderate to high percentages of youth were sexually active (had a least one sexual partner) in the Pacific island nations of Vanuatu (49.7%), Tonga (35.5%) and the Federated States of Micronesia (76.1%). Young men were more likely to engage in sexually risky behaviour than young women. They were more likely to be sexually active, have had multiple sexual partners and have had sex when drunk or high. Of those sexually active, more young men than women in Vanuatu (36.1% compared with 30.6%) and Micronesia (54.2% compared with 50%) never used protection against STIs. However, of the sexually active Tongan youth, the proportion of females (61.1%) who reported never using protection against STIs was nearly double the proportion reported by Tongan males (32.2%). A high percentage of young people not attending school in the Pacific island nations of Vanuatu, Tonga and the Federated States of Micronesia are at risk of unintended pregnancy and STIs, including HIV, because of patterns of sexual risk behaviour.


Lgr5 Does Not Vary Throughout the Menstrual Cycle in Endometriotic Human Eutopic Endometrium.
Endometriosis is characterized by the abnormal presence of endometrium outside of the uterus, resulting in pelvic pain and infertility. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been postulated to be a marker of stem cells in the endometrium. However, LGR5⁺ cells have a macrophage-like phenotype in this tissue, so it is unclear what role LGR5⁺ cells actually play in the endometrium. Macrophages serve an important function in the endometrium to maintain fertility, while LGR5⁺ cells generally have a role in tumor progression and are involved in invasion in some cancers. We sought to determine whether LGR5⁺ cells vary across the menstrual cycle in women with endometriosis and whether there are implications for LGR5 in the aggressiveness of endometriosis and reproductive outcomes. We performed immunofluorescence, flow cytometry, and primary culture in vitro experiments on eutopic and ectopic endometrium from healthy and endometriosis patients and observed that neither LGR5⁺ cells nor LGR5 expression varied throughout the cycle. Interestingly, we observed that LGR5⁺ cell percentage overexpressing CD163 (anti-inflammatory marker) was higher in healthy endometrium, suggesting that in endometriosis, endometrium presents a more pro-inflammatory phenotype that likely leads to poor obstetric outcomes. We also observed higher levels of LGR5⁺ cells in ectopic lesions compared to eutopic endometrium and specifically in deep infiltrating endometriosis, indicating that LGR5 could be involved in progression and aggressiveness of the disease.


Micro-Electro-Mechanical System Fourier Transform Infrared (MEMS FT-IR) Spectrometer Under Modulated-Pulsed Light Source Excitation.
Miniaturized Fourier transform infrared (FT-IR) spectrometers suffer from limited optical throughput due to their tiny aperture size. Therefore, coherent wideband sources with high brightness can provide an advantage over the wideband thermal radiation sources. However, the former ones are available based on pulsed operation. In this work, we present and study a miniaturized FT-IR spectrometer with pulsed light sources including chopped thermal source, semiconductor optical amplifier, Q-switched and femtosecond mode-locked laser sources. A system model for the FT-IR spectrometer system under a modulated input light source is presented. The model accounts for the relatively high scanning speed of the micro-electro-mechanical system (MEMS) interferometer. The signal-to-noise ratio of the spectrometer, due to the light source modulation, is calculated at different values of modulation repetition rate ranging from 20 Hz to 2 MHz, and duty cycle values ranging from 1% to 50%. An analytical expression for the worst-case repetition rate for the spectrometer system is derived. The model results are verified by experimental measurements showing good agreement with the theoretical expectations. Spectroscopic measurements for CO2 gas with pressure ranging from 300 mbar to 700 mbar are also performed using a high-repetition rate source, and the measured spectra agree with the simulation results demonstrating the utility of the spectrometer.


Threshold sodium excretory and renal blood flow effects of angiotensin converting enzyme inhibition.
To probe the potential influence of a high renal tubular level of angiotensin II on sodium reabsorption using angiotensin converting enzyme inhibitors and a non-peptide angiotensin antagonist. Systemic arterial blood pressure, renal blood flow (RBF) and electrolyte and urinary excretion were measured in anesthetized uninephrectomized Wistar rats. Captopril (n = 12), ramiprilat (n = 10) or EXP 3174 (n = 9) was infused into the renal artery in graded doses to examine whether the threshold dose that increased RBF was lower than that which increased sodium excretion rate (Na+ excretion rate). Whereas ramiprilat (0.5-4 micrograms/kg/min intra-arterially) and EXP 3174 (0.5-4 micrograms/kg/min intra-arterially) decreased blood pressure in all but the lowest dose of 0.5 micrograms/kg/min, captopril (1-8 micrograms/kg/min intra-arterially) did not change blood pressure except for a slight effect with the two higher doses. These three agents increased RBF to about the same degree, between 6% and 18%, which was relatively large compared with the maximal vasodilator response achievable in the kidney with acetylcholine (30-37%). Captopril given intra-arterially had a more consistent effect on Na+ excretion rate than either ramiprilat or EXP 3174. An increase in Na+ excretion rate occurred with captopril ranging from 44% to 78%, whereas no significant change was obtained with the other drugs. The dose of captopril that increased RBF was the same as that which increased Na+ excretion rate. In those experiments in which ramiprilat resulted in an increase in Na+ excretion rate (five of 10 experiments), the effective dose was the same as that which increased RBF. When administered by the intra-arterial route, captopril was more effective in increasing Na+ excretion rate than either ramiprilat or EXP 3174. Although the threshold dose of captopril and ramiprilat required to increase Na+ excretion rate and RBF was similar, suggesting blockade of a common angiotensin II pool, there was not a good correlation between these two effects.


Overexpression of the transcription factor Sp1 activates the OAS-RNAse L-RIG-I pathway.
Deregulated expression of oncogenes or transcription factors such as specificity protein 1 (Sp1) is observed in many human cancers and plays a role in tumor maintenance. Paradoxically in untransformed cells, Sp1 overexpression induces late apoptosis but the early intrinsic response is poorly characterized. In the present work, we studied increased Sp1 level consequences in untransformed cells and showed that it turns on an early innate immune transcriptome. Sp1 overexpression does not activate known cellular stress pathways such as DNA damage response or endoplasmic reticulum stress, but induces the activation of the OAS-RNase L pathway and the generation of small self-RNAs, leading to the upregulation of genes of the antiviral RIG-I pathway at the transcriptional and translational levels. Finally, Sp1-induced intrinsic innate immune response leads to the production of the chemokine CXCL4 and to the recruitment of inflammatory cells in vitro and in vivo. Altogether our results showed that increased Sp1 level in untransformed cells constitutes a novel danger signal sensed by the OAS-RNase L axis leading to the activation of the RIG-I pathway. These results suggested that the OAS-RNase L-RIG-I pathway may be activated in sterile condition in absence of pathogen.


The strategic role of the nurse in the selection of IV devices.
Use of vascular devices represents one of the most common procedures used as a complementary measure in the treatment of patients. An indication algorithm was established to serve as a guideline for nurses in choosing the best intravenous device, considering the main variables of drug therapy. A protocol approved by the Institute of Orthopedics and Traumatology of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (IOT-HCFMUSP), where the authors work, was subsequently established and the nurse carried out the evaluation for the indication of both the peripheral device and the central device, whether a peripherally inserted central catheter (PICC) or other device inserted by the physician. As a result, there was a decrease in the incidence of phlebitis from 0.77% in 2010 to 0.17% in 2011, with an annual curve of negative tendency. The nursing team also appeared more satisfied, diminishing stress related to puncture failure.


Midterm surgical outcomes of a short fusion strategy for adolescent idiopathic scoliosis with Lenke 5C curve.
A previous study examined the short-term (2 years) outcomes of a short fusion strategy for Lenke type 5C curves. This strategy had a little less correction rate with no difference in coronal and sagittal balance and SRS-22 scores to those of a conventional strategy and was superior in operative time and intraoperative bleeding. However, its effectiveness in longer follow-up periods was unknown. To assess midterm surgical outcomes of a short fusion strategy for adolescent idiopathic scoliosis (AIS) with Lenke type 5C curve, involving posterior correction and fusion surgery (PSF) using pedicle-screw constructs. Retrospective case series. Twenty-nine patients who underwent PSF for AIS with Lenke type 5C curve with a minimum 5-year follow-up. Radiographic parameters and SRS-22. We compared radiographic parameters and clinical outcomes between patients with an upper instrumented vertebra (UIV) at the end vertebra (EV) (n=12) and those treated by short fusion (S), with a UIV one level caudal to the EV (n=17). A preoperative mean Cobb angle of 51.9±13.8° was corrected to 11.7±7.7° in the EV group, and an angle of 46.0±6.6° was corrected to 9.3±5.2° in the S group. The correction was maintained in both groups at the final follow-up, and the mean correction loss was 2.8±6.8° in the EV and 6.5±6.5° in the S group (p=.143). The mean correction rate at the final follow-up was not significantly different between the EV (71.4±11.8%) and S (64.9±13.7%) groups (p=.199). A Cobb angle of a thoracic curve was significantly improved immediately after surgery and maintained during the follow-up period in the both groups. Coronal and sagittal balance, thoracic kyphosis, lumbar lordosis, L4 tilt, UIV/LIV tilt, shoulder balance, and SRS-22 had no difference between the two groups. There was no difference in radiographic parameters and SRS-22 between patients treated with a UIV at the UEV and patients treated using a short fusion strategy, in which the UIV was one level caudal to the UEV. The short fusion strategy can be one of the alternatives in PSF for Lenke type 5C curves, at least in 5-year time frame.


Patterns of pre-operative opioid use affect the risk for complications after total joint replacement.
Preoperative opioid use has been shown to increase the risk for complications following total joint arthroplasty (TJA); however, these studies have not always accounted for differences in co-morbidities and socio-demographics between patients that use opioids and those that do not. They have also not accounted for the variation in degree of pre-operative use. The objective of this study was to determine if preoperative opioid use is associated with risk for surgical complications after TJA, and if this association varied by degree of use. Population-based retrospective cohort study. Older adult patients undergoing primary TJA of the hip, knee and shoulder for osteoarthritis between 2002 and 2015 in Ontario, Canada were identified. Using accepted definitions, patients were stratified into three groups according to their preoperative opioid use: no use, intermittent use and chronic use. The primary outcome was the occurrence of a composite surgical complication (surgical site infection, dislocation, revision arthroplasty) or death within a year of surgery. Intermittent and chronic users were matched separately to non-users in a 1:1 ratio, matching on TJA type plus a propensity score incorporating patient and provider factors. Overall, 108,067 patients were included in the study; 10% (N = 10,441) used opioids on a chronic basis before surgery and 35% (N = 37,668) used them intermittently. After matching, chronic pre-operative opioid use was associated with an increased risk for complications after TJA (HR 1.44, p = 0.001) relative to non-users. Overall, less than half of patients undergoing TJA used opioids in the year preceding surgery; the majority used them only intermittently. While chronic pre-operative opioid use is associated with an increased risk for complications after TJA, intermitted pre-operative use is not.


Carotenoid responses to environmental stimuli: integrating redox and carbon controls into a fruit model.
Carotenoids play an important role in plant adaptation to fluctuating environments as well as in the human diet by contributing to the prevention of chronic diseases. Insights have been gained recently into the way individual factors, genetic, environmental or developmental, control the carotenoid biosynthetic pathway at the molecular level. The identification of the rate-limiting steps of carotenogenesis has paved the way for programmes of breeding, and metabolic engineering, aimed at increasing the concentration of carotenoids in different crop species. However, the complexity that arises from the interactions between the different factors as well as from the coordination between organs remains poorly understood. This review focuses on recent advances in carotenoid responses to environmental stimuli and discusses how the interactions between the modulation factors and between organs affect carotenoid build-up. We develop the idea that reactive oxygen species/redox status and sugars/carbon status can be considered as integrated factors that account for most effects of the major environmental factors influencing carotenoid biosynthesis. The discussion highlights the concept of carotenoids or carotenoid-derivatives as stress signals that may be involved in feedback controls. We propose a conceptual model of the effects of environmental and developmental factors on carotenoid build-up in fruits.


Image DNA-index (ploidy) analysis in cancer diagnosis.
DNA measurements performed with image cytometry in nuclei isolated from paraffin-embedded tissue of (pre)malignant lesions are described. DNA histograms are obtained in which one or more peaks are present, the latter representing one or more (pre)malignant cell populations. The DNA index [modal DNA peak value of the (pre)malignant cells divided by that of normal cells] can be computed and is comparable with that obtained with flow cytometry, a widely accepted technique to perform DNA cytometry. Quality of the histograms can be improved by eliminating the nonrelevant tissue in advance, and examples are shown of histograms of morphologically different regions in the same tissue. The use of DNA index in the clinical application on dysgeminomas of the ovary and small-cell lung cancer is discussed and its use for the characterization of cervical intraepithelial neoplasms grade III and metastases of small-cell carcinomas of the lung.


Murine Models of Central Nervous System Disease following Congenital Human Cytomegalovirus Infections.
Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections.


Evaluation of cytotoxicity, genotoxicity and hematotoxicity of the recombinant spore-crystal complexes Cry1Ia, Cry10Aa and Cry1Ba6 from Bacillus thuringiensis in Swiss mice.
The insecticidal properties of Cry-endotoxins from Bacillus thuringiensis (Bt) have long been used as spore-crystals in commercial spray formulations for insect control. Recently, some Bt-endotoxin genes have been cloned in many different plants. Toxicological evaluations of three spore-crystal endotoxins, BtCry1Ia, BtCry10Aa and BtCry1Ba6 from B. thuringiensis, were carried out on mice to understand their adverse effects on hematological systems and on genetic material. These three spore-crystals have shown toxic activity to the boll weevil, which is one of the most aggressive pests of the cotton crop. Cry1Ia, Cry10Aa and Cry1Ba6 did not increase the micronucleus frequency in the peripheral erythrocytes of mice and did not cause changes in the frequency of polychromatic erythrocytes. However, some hematologic disburbances were observed, specifically related to Cry1Ia and Cry1Ba6, respectively, for the erythroid and lymphoid lineage. Thus, although the profile of such adverse side effects can be related to their high level of exposure, which is not commonly found in the environment, results showed that these Bt spore-crystals were not harmless to mice, indicating that each spore-crystal endotoxin presents a characteristic profile of toxicity and might be investigated individually.


Molecular analysis of foot-and-mouth disease type O viruses isolated in Saudi Arabia between 1983 and 1995.
Partial nucleotide sequence of the capsid polypeptide coding gene 1D (VP1) was determined for 68 serotype O foot-and-mouth disease viruses isolated between 1983 and 1995 from outbreaks occurring in Saudi Arabia. The sequences were compared with previously published sequences: 14 viruses of Middle Eastern origin (isolated between 1987 and 1991); and with four vaccine virus strain sequences, three originating from the Middle East (O1/Turkey/Manisa/69, O1/Sharquia/Egypt/72 and O1/Israel/2/85) and one from Europe (O1/BFS 1860/UK/67). The virus isolates from Saudi Arabia and the Middle East vaccine virus strains formed a related genetic group distinct from the European O1 virus. Within this large group 12 distinct genetic sublineages were observed.


Meeting report of the 2016 bone marrow adiposity meeting.
There is considerable interest in the physiology and pathology, as well as the cellular and molecular biology, of bone marrow adipose tissue (BMAT). Because bone marrow adiposity is linked not only to systemic energy metabolism, but also to both bone marrow and musculoskeletal disorders, this biologic compartment has become of major interest to investigators from diverse disciplines. Bone marrow adiposity represents a virtual multi-tissue endocrine organ, which encompasses cells from multiple developmental lineages (e.g., mesenchymal, myeloid, lymphoid) and occupies all the non-osseous and non-cartilaginous space within long bones. A number of research groups are now focusing on bone marrow adiposity to understand a range of clinical afflictions associated with bone marrow disorders and to consider mechanisms-based strategies for future therapies.


A PCR-Induced Mutagenesis-Restriction Fragment Length Polymorphism Method for the Detection of CRISPR-Induced Indels.
As CRISPR-based technologies are widely used for knocking out genes in cell lines and organisms, there is a need for the development of reliable, cost-effective, and fast methods that identify fully mutated clones. In this context, we present a novel strategy named PCR-induced mutagenesis-restriction fragment length polymorphism (PIM-RFLP), which is based on the well-documented robustness and simplicity of the classical PCR-RFLP approach. PIM-RFLP allows the assessment of the editing efficiency in pools of edited cells and the effective identification of fully mutated single-cell clones. It is based on the creation by mutagenic PCR of a restriction enzyme degenerate cleavage site in the PCR product of the wild-type allele, which can then be distinguished from the indel-containing alleles following the standard RFLP procedure. PIM-RFLP is highly accessible, can be executed in a single day, and appears to outperform Sanger sequencing deconvolution algorithms in the detection of fully mutated clones.


Ursolic acid isolated from Isodon excisoides induces apoptosis and inhibits invasion of GBC-SD gallbladder carcinoma cells.
Gallbladder carcinoma (GBC) is a relatively rare but terminal malignancy, and drug/chemical development is an important aspect of prevention and treatment of GBC. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported to exhibit various pharmaceutical effects. In the present study, the antiproliferative and anti-invasive effects of UA and the associated mechanisms in GBC were examined. UA was isolated from Isodon excisoides. The GBC cells (GBC-SD and NOZ) were treated with UA and subjected to a Cell Counting Kit-8 assay. The GBC-SD cells were subsequently selected for an Annexin V-FITC/propidium iodide assay, Transwell chamber assay, RT2 profiler polymerase chain reaction (PCR) array and western blot analysis. The results indicated that UA inhibited the proliferation and invasion and induced the apoptosis of GBC-SD cells in a dose-dependent manner. Furthermore, the PCR arrays demonstrated that there were 24 differentially expressed genes between the UA-treated and untreated groups. These differentially expressed genes suggested that UA induced the apoptosis of GBC-SD cells through activation of the cell extrinsic pathway. According to Kyoto Encyclopedia of Genes and Genomes pathway analysis of these differentially expressed genes, the suppression of nuclear factor (NF)-κB and protein kinase B (Akt) signaling pathways was further validated. In summary, UA induces the apoptosis and inhibits the invasion of GBC-SD cells, which may be associated with the suppression of NF-κB and Akt signaling pathways. These results may offer a potential therapeutic strategy for the chemoprevention or chemotherapy of GBC in humans.


Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers.
Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases.


Tricyclic antidepressants in the treatment of peptic ulcer disease.
Doxepin hydrochloride was given to 12 patients with duodenal ulcer and one patient with an anastomotic ulcer. The dose of doxepin hydrochloride was 100 mg at bedtime, except in patients receiving hemodialysis, where only 50 mg at bedtime was given. Eight patients, including the four receiving hemodialysis, has not responded to treatment after eight weeks of cimetidine and/or antacid therapy. All patients (except one where a minor erosion was left in the duodenum) responded, and healing of the ulcer was demonstrated by endoscopy after four to six weeks of treatment. In two patients the ulcer recurred in four to eight weeks after discontinuation of doxepin therapy; however, ulcers healed after four weeks when therapy was reintroduced. Five previously untreated patients with duodenal ulcer were also given the same treatment. Four healed six weeks after starting doxepin therapy. In one patient the dose of doxepin hydrochloride had to be raised to 150 mg for complete healing.


Epidemiology and etiology of denture stomatitis.
Denture stomatitis, a common disorder affecting denture wearers, is characterized as inflammation and erythema of the oral mucosal areas covered by the denture. Despite its commonality, the etiology of denture stomatitis is not completely understood. A search of the literature was conducted in the PubMed electronic database (through November 2009) to identify relevant articles for inclusion in a review updating information on the epidemiology and etiology of denture stomatitis and the potential role of denture materials in this disorder. Epidemiological studies report prevalence of denture stomatitis among denture wearers to range from 15% to over 70%. Studies have been conducted among various population samples, and this appears to influence prevalence rates. In general, where reported, incidence of denture stomatitis is higher among elderly denture users and among women. Etiological factors include poor denture hygiene, continual and nighttime wearing of removable dentures, accumulation of denture plaque, and bacterial and yeast contamination of denture surface. In addition, poor-fitting dentures can increase mucosal trauma. All of these factors appear to increase the ability of Candida albicans to colonize both the denture and oral mucosal surfaces, where it acts as an opportunistic pathogen. Antifungal treatment can eradicate C. albicans contamination and relieve stomatitis symptoms, but unless dentures are decontaminated and their cleanliness maintained, stomatitis will recur when antifungal therapy is discontinued. New developments related to denture materials are focusing on means to reduce development of adherent biofilms. These may have value in reducing bacterial and yeast colonization, and could lead to reductions in denture stomatitis with appropriate denture hygiene.


Structural MRI-Based Predictions in Patients with Treatment-Refractory Depression (TRD).
The application of machine learning techniques to psychiatric neuroimaging offers the possibility to identify robust, reliable and objective disease biomarkers both within and between contemporary syndromal diagnoses that could guide routine clinical practice. The use of quantitative methods to identify psychiatric biomarkers is consequently important, particularly with a view to making predictions relevant to individual patients, rather than at a group-level. Here, we describe predictions of treatment-refractory depression (TRD) diagnosis using structural T1-weighted brain scans obtained from twenty adult participants with TRD and 21 never depressed controls. We report 85% accuracy of individual subject diagnostic prediction. Using an automated feature selection method, the major brain regions supporting this significant classification were in the caudate, insula, habenula and periventricular grey matter. It was not, however, possible to predict the degree of 'treatment resistance' in individual patients, at least as quantified by the Massachusetts General Hospital (MGH-S) clinical staging method; but the insula was again identified as a region of interest. Structural brain imaging data alone can be used to predict diagnostic status, but not MGH-S staging, with a high degree of accuracy in patients with TRD.


The quest to decipher HLA immunogenicity: Telling friend from foe.
Molecular mismatch load analysis was recently introduced as a means for performing risk stratification following organ transplantation. However, although good correlation was demonstrated between molecular mismatch load and generation of de novo donor-specific HLA antibody (DSA), quite a few exceptions exist, and the underlying factors that define HLA immunogenicity remain unclear. Herein, we present a new paradigm to interrogate differences between molecular mismatches that lead to the generation of de novo DSA and those that do not (the 2MM1DSA cohort). Specifically, patients transplanted across 2 HLA-DQ mismatches, who formed de novo DSA only to one mismatch (foe) but not the other (friend), provide a unique environment in which patient-specific factors that affect the immune response other than immunogenicity, such as infection and immunosuppression, can be controlled for. It further permits focusing on mismatches uniquely exhibited by the de novo DSA allele, rather than mismatches shared by both DSA and non-DSA alleles. This concept paper illustrates several examples, highlights the need for center-specific or population-specific cutoff values for posttransplant risk stratification, and mostly argues that if there is no direct correlation between molecular mismatch load and immunogenicity, then molecular mismatch load must not be adopted as an approach for equitable organ allocation.


The Remarkable Journey of a Weed: Biology and Management of Annual Ryegrass (Lolium rigidum) in Conservation Cropping Systems of Australia.
Annual ryegrass (Lolium rigidum Gaud.), traditionally utilised as a pasture species, has become the most problematic and difficult-to-control weed across grain production regions in Australia. Annual ryegrass has been favoured by the adoption of conservation tillage systems due to its genetic diversity, prolific seed production, widespread dispersal, flexible germination requirements and competitive growth habit. The widespread evolution of herbicide resistance in annual ryegrass has made its management within these systems extremely difficult. The negative impacts of this weed on grain production systems result in annual revenue losses exceeding $93 million (AUD) for Australian grain growers. No single method of management provides effective and enduring control hence the need of integrated weed management programs is widely accepted and practiced in Australian cropping. Although annual ryegrass is an extensively researched weed, a comprehensive review of the biology and management of this weed in conservation cropping systems has not been conducted. This review presents an up-to-date account of knowledge on the biology, ecology and management of annual ryegrass in an Australian context. This comprehensive account provides pragmatic information for further research and suitable management of annual ryegrass.


Continuity of information in cancer care: evaluation of a logbook.
A logbook, or patient-dossier, was developed, to improve continuity of information in the treatment and care of head-and-neck cancer patients. It contained information modules on different aspects of care, as well as forms to facilitate communication both between patient and care-professional and between the various care-professionals. The logbook's effectiveness was evaluated in two hospitals in Rotterdam, by comparing outcomes for trial and comparison groups of, respectively, 71 and 54 patients and 59 and 35 care-professionals. Trial patients proved to be better informed, to receive more support and to experience fewer psychosocial problems. Professionals who used the logbook were better informed about their patients, and about the care-activities of fellow-professionals than those who did not. They recognised an improvement in their contact with colleagues and in the harmonisation of their respective care-activities.


Transmission of bovine spongiform encephalopathy and scrapie to mice.
Transmission from four cases of bovine spongiform encephalopathy (BSE) to mice resulted in neurological disease in 100% of recipient animals, after incubation periods of between 265 and 700 days post-injection. The results from the four cases were very similar to one another. There were major differences in the incubation period between the four inbred strains of mice tested, and even between strains of the same Sinc genotype, and the incubation periods of Sinc heterozygote mice were much longer than those for any of the inbred strains. Transmission from a case of natural scrapie differed in two important respects: there were no differences in the incubation period between mouse strains of the same Sinc genotype, and that of the heterozygotes was between those of the Sinc homozygotic parental strains. The distribution of vacuolar degeneration in the brains of mice infected with scrapie also differed from those infected with the BSE isolates. Transmission was also achieved from formol-fixed BSE brain. These results show that the same strain of agent caused disease in the BSE cases, and that the relationship of BSE to scrapie in sheep is unclear.


[Trans- and early postoperative complications in gastric surgery for gastric carcinoma. Experience from the General Hospital of Mexico].
We undertook this study to determine the morbimortality in gastric surgery for gastric carcinoma. We carried out a retrospective, observational study performed at the Gastroenterology Service of the General Hospital of Mexico City between January 2004 and October 2005. Variables included sex, age, diagnosis, surgery performed and trans- and postoperative complications. Clinical files of 2208 patients were reviewed: 36 (1.63%) cases with gastric carcinoma were found. Twenty patients fulfilled inclusion criteria; there were nine (45%) females and 11 (55%) males with a median age of 60.3 years. Radiological studies performed were upper gastrointestinal series, esophagogastroduodenoscopy, chest x-ray, and computed tomography (CT). Localization of the tumors was as follows: 15 in the antrum, three in the fundus and body and two in the body portion of the stomach. Clinical staging was T3 N0 M0. Surgical procedures were as follows: 11 partial gastrectomies and 4 gastrojejunostomies. In three cases, total gastrectomy was done and in two cases lymphatic biopsy was done. No mortality was reported. Morbidity was reported in one case (5%) with enterocutaneous fistula. Surgery is the treatment for gastric carcinoma. Preoperative staging is done with CT and laparoscopy. There was no mortality in our study. Morbidity is similar to that reported by other hospitals.


Binding of autologous IgG to human red blood cells before and after ATP-depletion. Selective exposure of binding sites (autoantigens) on spectrin-free vesicles.
Binding of autologous IgG to fresh, ATP-depleted red blood cells as well as to spectrin-free vesicles was studied by a non-equilibrium binding assay using 125I-iodinated protein A from Staphylococcus aureus. IgG binding was 14-times higher to spectrin-free vesicles than to ATP-maintaining red blood cells and 4-times higher than to ATP-depleted erythrocytes from which these vesicles were released. Protein A binding to vesicles that were released from washed and nutrient-deprived erythrocytes, was dependent on added autologous IgG. However, spectrin-free vesicles that were spontaneously released from erythrocytes conserved in whole blood, bound similar amounts of protein A with or without added autologous IgG (0.45-0.55 ng/micrograms band 3 protein). These findings demonstrate that opsonization of spectrin-free vesicles by autologous IgG occurs not only in the test tube, but also under blood blank conditions. The binding characteristics of IgG to spectrin-free vesicles are indicative of a natural autoantibody rather than an unspecific binding of autologous IgG. The preferential binding of IgG to spectrin-free vesicles implies a selective exposure of corresponding autoantigens in membrane regions that have lost cytoskeletal anchorage and bud off.


Association of transcatheter edge-to-edge repair with improved survival in older patients with severe, symptomatic degenerative mitral regurgitation.
Randomized clinical trials demonstrated transcatheter edge-to-edge repair (TEER) efficacy in improving outcome vs. medical management for functional mitral regurgitation, but limited randomized data are available for the treatment of degenerative mitral regurgitation (DMR). We aimed to compare the outcome of older patients treated with TEER vs. unoperated DMR. Registries including consecutive patients ≥65 years with symptomatic severe DMR treated with TEER (MitraSwiss and Minneapolis Heart Institute registries) or unoperated (MIDA registry) were analysed. Survival was compared overall and after matching for age, sex, EuroSCORE II, and ejection fraction. The study included 1187 patients (872 treated with TEER and 315 unoperated). During 24 ± 17 months of follow-up, 430 patients died, 18 ± 1% at 1 year and 50 ± 2% at 4 years. Patients undergoing TEER had similar age (82 ± 6 vs. 82 ± 7 years) and sex to unoperated patients, but higher surgical risk/comorbidity (EuroSCORE II 3.98 ± 4.28% vs. 2.77 ± 2.46%), more symptoms, and atrial fibrillation (P < 0.0001). Transcatheter edge-to-edge repair was associated with lower mortality accounting for age, sex, EuroSCORE II, New York Heart Association class, atrial fibrillation, and ejection fraction [hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.37-0.58; P < 0.0001]. After propensity matching (247 pairs of patients), TEER consistently showed better survival compared with unoperated patients (49 ± 6% vs. 37 ± 3% at 4 years, P < 0.0001) even in comprehensive multivariable analysis (HR: 0.60, 95% CI: 0.40-0.91; P = 0.03). Procedural failure was infrequent but post-procedural mitral regurgitation, remaining moderate-to-severe in 66 (7.6%) patients, was associated with excess mortality vs. trivial residual regurgitation (30 ± 6% vs. 11 ± 1% at 1 year, P < 0.0001). Amongst older patients with severe symptomatic DMR at high surgical risk, mitral TEER was associated with higher survival vs. unoperated patients. Successful control of mitral regurgitation was key to survival improvement with mitral TEER, which should be actively considered in patients deemed inoperable.


[Clinical research of chloasma treated with the meridian cosmetology and the impacts on estrogen and progestin].
To observe the efficacy difference between meridian cosmetology and western medicine in the treatment of chloasma and explore the impacts of meridian cosmetology on E2 and PRGE. Three hundreds cases of chloasma were randomized into a meridian cosmetology group and a western medication group according to the visit sequence, 150 cases in each one. In the meridian cosmetology group, the meridian regulation, acupuncture based on pattern/syndrome differentiation [at the body acupoints such as Qihai (CV 6), Xuehai (SP 10), Zusanli (ST 36), Sanyinjiao (SP 6), Ganshu (BL 18), Pishu (BL 20) and Shenshu (BL 23), etc.] and the local surrounding needling therapy on the chloasma skin lesion were adopted. In the western medication group, the oral administration of Vitamin C and E was prescribed for 3 months. The clinical efficacy was observed for the patients in the two groups. Additionally, 30 cases were collected from the meridian cosmetology group randomly for the detection of estrogen (E2) and progestin (PRGE) before and after treatment. The effective rate in the meridian cosmetology group was 92.6% (126/136), which was superior to 67.0% (75/112) in the western medication group (P < 0.05). For the patients collected from the meridian cosmetology group, as compared with that before treatment, E2 level was decreased (P < 0.01) and PRGE level was increased (P < 0.05). The meridian cosmetology achieves the superior efficacy as compared with the western medication group for the chloasma and it can regulate the levels of E2 and PRGE.


The Dysphagia in Stroke Protocol Reduces Aspiration Pneumonia in Patients with Dysphagia Following Acute Stroke: a Clinical Audit.
Cough reflex testing has been evaluated as a component of the clinical swallowing assessment as a means of identifying patients at risk of aspiration during swallowing. A previous study by our research group found good sensitivity and specificity of the cough reflex test for identifying patients at risk of aspiration post-stroke, yet its use did not decrease pneumonia rates, contrary to previous reports. The aim of this study was to expand on our earlier work by implementing a clinical management protocol incorporating cough reflex testing within the same healthcare setting and compare patient outcomes to those from the original study and to evaluate clinical outcomes in patients with acute stroke who were managed using the Dysphagia in Stroke Protocol (DiSP). Secondarily, to compare those outcomes to historical data prior to implementation of the DiSP. This clinical audit measured outcomes from 284 patients with acute stroke managed per the DiSP, which guides use of videofluoroscopic swallowing study and patient management based on clinical exam with cough reflex testing. Data from our previous trial were included for comparison of pre- and post-DiSP patient outcomes. Data collection took place between November 2012 and April 2016 at four urban hospitals within New Zealand. Following implementation of the DiSP, the rate of aspiration pneumonia (10%) was substantially lower than the pre-DiSP rate (28%), with no pneumonia readmissions within 3 months. Pneumonia-related mortality was unchanged. By 3 months, 81% of the patients were on a normal diet and 67% had returned home, compared to pre-DiSP outcomes of 55% and 55% respectively. Previous work has suggested that simply implementing cough reflex testing in dysphagia management may not be sufficient to improve patient outcomes. The present study adds to this picture by suggesting that the true variable of influence may be the way in which the results of the test are applied to patient care. There is a strong case to support the use of a structured protocol if cough reflex testing is to be implemented in clinical practice.


Identification of 2 Novel Mutations in ATP2C1 Gene in Hailey-Hailey Disease and a Literature Review of Variations in a Chinese Han Population.
BACKGROUND Hailey-Hailey disease (HHD) is a rare autosomal dominant skin condition. The ATP2C1 gene was identified as the defective gene in HHD. To date, 166 pathogenic mutations in ATP2C1 have been observed worldwide. The aim of this study was to identify variations in HHD and summarize the features of the mutations identified in China. MATERIAL AND METHODS We examined 2 familial and 2 sporadic cases of HHD. Genomic DNA polymerase chain reaction and direct sequencing of the ATP2C1 were performed from HHD patients, unaffected family members, and 200 healthy individuals. We also searched the published literature for data about the ATP2C1 gene using PubMed and the Chinese Biological Medicine Database. RESULTS We detected 3 heterozygous mutations, including 2 novel frameshift mutations (c.819insA (273LfsX) and c.1264insTAGATGG (421LfsX)) and 1 recurrent nonsense mutation (c.115C>T (R39X)). To the best of our knowledge, 90 different mutations (including our current results) have been reported in China, all of which occurred in the Chinese Han population. CONCLUSIONS Our data may add to the existing list of ATP2C1 mutations and provide new insight into genetic variants of HHD in China.


L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27 914 patients.
The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of L-thyroxine (LT(4)) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with L-T(4) (n=7859). L-T(4)-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 muU/ml, 0.08-0.62 microU/ml versus 0.70 muU/ml, 0.38-1.14 muU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 muU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L-T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.


Evaluation of an AIF correction algorithm for dynamic susceptibility contrast-enhanced perfusion MRI.
For longitudinal studies in patients suffering from cerebrovascular diseases the poor reproducibility of perfusion measurements via dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) is a relevant concern. We evaluate a novel algorithm capable of overcoming limitations in DSC-MRI caused by partial volume and saturation issues in the arterial input function (AIF) by a blood flow stimulation-study. In 21 subjects, perfusion parameters before and after administration of blood flow stimulating L-arginine were calculated utilizing a block-circulant singular value decomposition (cSVD). A total of two different raters and three different rater conditions were employed to select AIFs: Besides 1) an AIF selection by an experienced rater, a beginner rater applied a steady state-oriented strategy, returning; 2) raw; and 3) corrected AIFs. Highly significant changes in regional cerebral blood flow (rCBF) by 9.0% (P < 0.01) could only be found when the AIF correction was performed. To further test for improved reproducibility, in a subgroup of seven subjects the baseline measurement was repeated 6 weeks after the first examination. In this group as well, using the correction algorithm decreased the SD of the difference between the two baseline measurements by 42%.


Explaining savings for visuomotor adaptation: linear time-invariant state-space models are not sufficient.
Adaptation of the motor system to sensorimotor perturbations is a type of learning relevant for tool use and coping with an ever-changing body. Memory for motor adaptation can take the form of savings: an increase in the apparent rate constant of readaptation compared with that of initial adaptation. The assessment of savings is simplified if the sensory errors a subject experiences at the beginning of initial adaptation and the beginning of readaptation are the same. This can be accomplished by introducing either 1) a sufficiently small number of counterperturbation trials (counterperturbation paradigm [CP]) or 2) a sufficiently large number of zero-perturbation trials (washout paradigm [WO]) between initial adaptation and readaptation. A two-rate, linear time-invariant state-space model (SSM(LTI,2)) was recently shown to theoretically produce savings for CP. However, we reasoned from superposition that this model would be unable to explain savings for WO. Using the same task (planar reaching) and type of perturbation (visuomotor rotation), we found comparable savings for both CP and WO paradigms. Although SSM(LTI,2) explained some degree of savings for CP it failed completely for WO. We conclude that for visuomotor rotation, savings in general is not simply a consequence of LTI dynamics. Instead savings for visuomotor rotation involves metalearning, which we show can be modeled as changes in system parameters across the phases of an adaptation experiment.


Microsurgery for intracranial aneurysms: A qualitative survey on technical challenges and technological solutions.
Microsurgery for the clipping of intracranial aneurysms remains a technically challenging and high-risk area of neurosurgery. We aimed to describe the technical challenges of aneurysm surgery, and the scope for technological innovations to overcome these barriers from the perspective of practising neurovascular surgeons. Consultant neurovascular surgeons and members of the British Neurovascular Group (BNVG) were electronically invited to participate in an online survey regarding surgery for both ruptured and unruptured aneurysms. The free text survey asked three questions: what do they consider to be the principal technical barriers to aneurysm clipping? What technological advances have previously contributed to improving the safety and efficacy of aneurysm clipping? What technological advances do they anticipate improving the safety and efficacy of aneurysm clipping in the future? A qualitative synthesis of responses was performed using multi-rater emergent thematic analysis. The most significant reported historical advances in aneurysm surgery fell into five themes: (1) optimising clip placement, (2) minimising brain retraction, (3) tissue handling, (4) visualisation and orientation, and (5) management of intraoperative rupture. The most frequently reported innovation by far was indocyanine green angiography (84% of respondents). The three most commonly cited future advances were hybrid surgical and endovascular techniques, advances in intraoperative imaging, and patient-specific simulation and planning. While some surgeons perceive that the rate of innovation in aneurysm clipping has been dwarfed in recent years by endovascular techniques, surgeons surveyed highlighted a broad range of future technologies that have the potential to continue to improve the safety of aneurysm surgery in the future.


Normal iron absorption and decreased red cell iron uptake in the aged.
Absorption of iron was studied with a double-isotope technique that allowed differentiation between "mucosal uptake," "mucosal transfer," and ultimate "retention" of iron. A physiologic dose of ferrous sulfate was administered to 25 healthy young adults, 40 active aged persons, and 20 patients with uncomplicated iron deficiency. Radioactivity was measured with a whole-body scanner. Iron absorption values were not decreased in aged subjects compared to young adults. Mucosal uptake, mucosal transfer, and retention of iron were equally increased in both young and old patients with iron deficiency. In 12 young adults and 33 aged persons red cell iron uptake was studied in addition to iron absorption. Young adults utilized 91% of the retained, orally administered iron and the aged only 66%. An increase in ineffective erythropoiesis in old age is suggested.


Sequence-tagged high-density genetic maps of Zoysia japonica provide insights into genome evolution in Chloridoideae.
Zoysiagrass (Zoysia spp.), belonging to the genus Zoysia in the subfamily Chloridoideae, is widely used in domestic lawns, sports fields and as forage. We constructed high-density genetic maps of Zoysia japonica using a restriction site-associated DNA sequencing (RAD-Seq) approach and an F1 mapping population derived from a cross between 'Carrizo' and 'El Toro'. Two linkage maps were constructed, one for each of the parents. A map consisting of 2408 RAD markers distributed on 21 linkage groups was constructed for 'Carrizo'. Another map with 1230 RAD markers mapped on 20 linkage groups was constructed for 'El Toro'. The average distance between adjacent markers of the two maps was at 0.56 and 1.4 cM, respectively. Comparative genomics analysis was carried out among zoysiagrass, rice and sorghum genomes and a highly conserved collinearity in the gene order was observed among the three genomes. Chromosome collinearity was disrupted at centromeric regions for each chromosome pair between zoysiagrass and sorghum genomes. However, no obvious synteny gaps were observed across the centromeric regions between zoysiagrass and rice genomes. Two homologous chromosomes for each of the 10 sorghum chromosomes were found in the zoysiagrass genome, indicating an allotetraploid origin for zoysiagrass. The reduction of the basic chromosome number from 12 to 10 in chloridoids and panicoids took place via independent single-step nested chromosome fusion events after the two subfamilies diverged from a common ancestor. The genetic maps will assist in genome sequence assembly, targeted gene isolation and comparative genomic analyses among grasses.


Crocetin Potentiates Neurite Growth in Hippocampal Neurons and Facilitates Functional Recovery in Rats with Spinal Cord Injury.
Crocetin is an ingredient of traditional Chinese medicine and has therapeutic potential in various diseases due to its pharmacological properties, such as neuroprotection, anti-oxidative stress, and anti-inflammation. These properties might benefit the treatment of spinal cord injury. In the present study, we tested the effect of crocetin on neurite growth and sensorimotor dysfunction in a rat model of spinal cord injury. We evaluated the viability of cultured hippocampal neurons with tetrazolium dye and lactate dehydrogenase assays, visualized neurites and axons with antibody staining, and monitored motor and sensorimotor functions in rats with spinal cord injury using the Basso, Beattie, and Bresnahan assay and the contact plantar placement test, respectively, and measured cytokine expression using enzyme-linked immuno-absorbent assays. We found that crocetin (1) did not alter the viability of cultured hippocampal neurons; (2) accelerated neurite growth with preference for the longest process in individual hippocampal neurons; (3) reversed the inhibition of neurite growth by chondroitin sulfate proteoglycan and NogoA; (4) facilitated the recovery of motor and sensorimotor functions after spinal cord injury; and (5) did not inhibit pro-inflammatory responses, but restored the innervation of the descending 5-HT system in injured spinal cord. Crocetin promotes neurite growth and facilitates the recovery of motor and sensorimotor functions after spinal cord injury, likely through repairing neuronal connections.


Successful ingredients of effective Collaborative Care programs in low- and middle-income countries: A rapid review.
Integrating mental health care in primary healthcare settings is a compelling strategy to address the mental health treatment gap in low- and middle-income countries (LMICs). Collaborative Care is the integrated care model with the most evidence supporting its effectiveness, but most research has been conducted in high-income countries. Efforts to implement this complex multi-component model at scale in LMICs will be enhanced by understanding the model components that have been effective in LMIC settings. Following Cochrane Rapid Reviews Methods Group recommendations, we conducted a rapid review to identify studies of the effectiveness of Collaborative Care for priority adult mental disorders of mhGAP (mood and anxiety disorders, psychosis, substance use disorders and epilepsy) in outpatient medical settings in LMICs. Article screening and data extraction were performed using Covidence software. Data extraction by two authors utilized a checklist of key components of effective interventions. Information was aggregated to examine how frequently the components were applied. Our search yielded 25 articles describing 20 Collaborative Care models that treated depression, anxiety, schizophrenia, alcohol use disorder or epilepsy in nine different LMICs. Fourteen of these models demonstrated statistically significantly improved clinical outcomes compared to comparison groups. Successful models shared key structural and process-of-care elements: a multi-disciplinary care team with structured communication; standardized protocols for evidence-based treatments; systematic identification of mental disorders, and a stepped-care approach to treatment intensification. There was substantial heterogeneity across studies with respect to the specifics of model components, and clear evidence of the importance of tailoring the model to the local context. This review provides evidence that Collaborative Care is effective across a range of mental disorders in LMICs. More work is needed to demonstrate population-level and longer-term outcomes, and to identify strategies that will support successful and sustained implementation in routine clinical settings.


MicroRNA dysregulation in the myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are heterogeneous clonal disorders of ineffective hematopoiesis characterized by limited treatment options and a poor prognosis. These poor clinical characteristics stem from a poor understanding of the molecular abnormalities that drive disease pathogenesis. MicroRNAs (miRNAs) have recently been described to play wide-ranging roles in normal and malignant hematopoiesis, but very few miRNAs have been shown to be consistently dysregulated in MDS. Even fewer candidate disease miRNAs have undergone functional validation, and the clinical relevance of these miRNAs remains to be determined. Despite the fact that MDS has been shown to be a disease initiated in hematopoietic stem cells (HSC), most existing studies examining miRNA expression in MDS have used unfractionated or only partially purified bone marrow (BM) cell populations, likely explaining in part the limited insight that provided by these studies. A more robust characterization of purified disease -initiating cell populations followed by rigorous functional validation using in vivo disease models will be vital to identifying dysregulated miRNAs of functional significance in MDS. Such studies promise to provide key insights into disease pathogenesis and potentially open new avenues towards the development of therapies targeting miRNAs themselves or the pathways that they regulate.


Tuning the Structural Rigidity of Two-Dimensional Ruddlesden-Popper Perovskites through the Organic Cation.
Two-dimensional (2D) hybrid organic-inorganic perovskites are an interesting class of semi-conducting materials. One of their main advantages is the large freedom in the nature of the organic spacer molecules that separates the individual inorganic layers. The nature of the organic layer can significantly affect the structure and dynamics of the 2D material; however, there is currently no clear understanding of the effect of the organic component on the structural parameters. In this work, we have used molecular dynamics simulations to investigate the structure and dynamics of a 2D Ruddlesden-Popper perovskite with a single inorganic layer (n = 1) and varying organic cations. We discuss the dynamic behavior of both the inorganic and the organic part of the materials as well as the interplay between the two and compare the different materials. We show that both aromaticity and the length of the flexible linker between the aromatic unit and the amide have a clear effect on the dynamics of both the organic and the inorganic part of the structures, highlighting the importance of the organic cation in the design of 2D perovskites.


Improving multiple-choice questions to better assess dental student knowledge: distractor utilization in oral and maxillofacial pathology course examinations.
How many incorrect response options (known as distractors) to use in multiple-choice questions has been the source of considerable debate in the assessment literature, especially relative to influence on the likelihood of students' guessing the correct answer. This study compared distractor use by second-year dental students in three successive oral and maxillofacial pathology classes that had three different examination question formats and scoring resulting in different levels of academic performance. One class was given all multiple-choice questions; the two other were given half multiple-choice questions, with and without formula scoring, and half un-cued short-answer questions. Use by at least 1 percent of the students was found to better identify functioning distractors than higher cutoffs. The average number of functioning distractors differed among the three classes and did not always correspond to differences in class scores. Increased numbers of functioning distractors were associated with higher question discrimination and greater question difficulty. Fewer functioning distractors fostered more effective student guessing and overestimation of academic achievement. Appropriate identification of functioning distractors is essential for improving examination quality and better estimating actual student knowledge through retrospective use of formula scoring, where the amount subtracted for incorrect answers is based on the harmonic mean number of functioning distractors.


Managing Cardiovascular Disease Risk in Rheumatoid Arthritis: Clinical Updates and Three Strategic Approaches.
: The increase in cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) is well known; however, appropriate management of this elevated risk in rheumatology clinics is less clear. By critically reviewing literature published within the past 5 years, we aim to clarify current knowledge and gaps regarding CVD risk management in RA. We examine recent guidelines, recommendations, and evidence and discuss three approaches: (1) RA-specific management including treat-to-target and medication management, (2) assessment of comprehensive individual risk, and (3) targeting traditional CVD risk factors (hypertension, smoking, hyperlipidemia, diabetes, obesity, and physical inactivity) at a population level. Considering that 75% of US RA visits occur in specialty clinics, further research is needed regarding evidence-based strategies to manage and reduce CVD risk in RA. This review highlights clinical updates including US cardiology and international professional society guidelines, successful evidence-based population approaches from primary care, and novel opportunities in rheumatology care to reduce CVD risk in RA.


Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults.
Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100- fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (≥ 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.


More Than a First Flush: Urban Creek Storm Hydrographs Demonstrate Broad Contaminant Pollutographs.
Stormwater runoff clearly impacts water quality and ecological health of urban receiving waters. Subsequent management efforts are often guided by conceptual models of contaminant "first flushes", defined by disproportionate concentrations or mass loads early in the storm hydrograph. However, studies examining the dynamics of contaminant transport and receiving water hydrology have primarily focused on "traditional" stormwater contaminants and point sources, with less evaluation of chemically complex nonpoint pollution sources. Accordingly, we conducted baseflow and storm sampling in Miller Creek, a representative small, urban watershed in the Puget Sound region (WA, USA). We comprehensively characterized organic contaminant profiles and dynamics via targeted quantification of 35 stormwater-derived chemicals, complementary nontarget HRMS analyses, and surrogate chemical metrics of ecological health. For quantified analytes, total daily baseflow loads were 0.8-3.4 g/day and storm event loads were ∼80-320 g/storm (∼48 h interval), with nine contaminants detected during storms at >500 ng/L. Notably, urban creek "pollutographs" were much broader than relatively sharp storm hydrographs and exhibited transport-limited (rather than mass-limited) source dynamics, with immediate water quality degradation during low-intensity precipitation and continued mobilization of contaminant mass across the entire hydrograph. Study outcomes support prioritization of source identification and focused stormwater management efforts to improve water quality and promote ecosystem function in small urban receiving waters.


Stoma-related complications and stoma size - a 2-year follow up.
The purpose of the study was to prospectively describe stoma configuration and evaluate stoma-related complications and their association with possible risk factors. All elective patients (n = 180) operated on with a formation of colostomy, ileostomy or loop-ileostomy between 2003 and 2005 were included in the study. Follow up took place on the ward postoperatively and five times during 2 years after discharge. On these occasions the diameter and height of the stoma were recorded. Complications such as peristomal skin problems, necrosis, leakage caused by a low stoma, stenosis, granuloma formation, prolapse and peristomal hernia formation were evaluated. Most complications occurred 2 weeks after discharge; 53% of patients with colostomies, 79% with loop-ileostomies and 70% of patients with end-ileostomy had one or more complications. The most common complication was skin problems and it was most common in patients with end-ileostomies (60%) and loop-ileostomies (73%). Postoperatively at ward review, the most common complication was necrosis, which occurred in 20% of patients with a colostomy. Granuloma formation was most frequent in colostomies. Almost all patients with an end-ileostomy and loop-ileostomy with a height lower than 20 mm had leakage and skin problems as had half of the patients with a colostomy height lower than 5 mm. To prevent stoma-related complications, it is important to produce an adequate height of the stoma, with early and regular follow ups and adjustment of the appliance. To work closely in collaboration with the colorectal surgeons is of utmost important to provide feedback and in turn, to improve stoma outcome.


Relative efficacy of spinal alpha-2 agonists, dexmedetomidine, clonidine and ST-91, determined in vivo by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible antagonist.
To examine the relative efficacy of spinally administered alpha-2 adrenergic agonists [dexmedetomidine, clonidine and ST-91 (2-[2,6- diethylphenylamino]-2-imidazole)] on the 52.5 degrees C hot plate in rats, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), an irreversible alpha-2 antagonist, was administered intrathecally (in doses of 0, 8.1, 81 and 810 nmol) 24 hr before the administration of these agonists. EEDQ alone results in an acute mild hyperalgesic effect. Intrathecal dexmedetomidine, clonidine and ST-91 result in a dose-dependent increase in the hot plate response latency: ED50 (95% confidence interval) = 13 (2.1-73), 120 (52-310) and 21 (1.3-240) nmol, respectively. Pretreatment with intrathecal EEDQ (8.1-810 nmol) caused a rightward shift of dose-response curve and reduction of maximal effect of alpha-2 agonists used. For example, 24 hr after 81 nmol of EEDQ, the degree of the rightward shift and the depression of slope was ST-91 greater than clonidine greater than dexmedetomidine. Analysis of the double reciprocal plot indicated that at the ED50, intrathecal dexmedetomidine, clonidine and ST-91 required an apparent occupancy of 10, 36 and 30%, respectively. These results suggest that dexmedetomidine has a higher intrinsic efficacy than clonidine or ST-91.


Allele-specific and peptide-dependent recognition of swine leukocyte antigen class I by human cytotoxic T-cell clones.
The T-cell mediated immune responses play a major role in xenograft rejection. However, the mechanisms behind human T-cell recognition of porcine xenoantigens remain to be elucidated. Human CD8+ T-cell lines were generated against porcine aortic endothelial cells (PAECs) from y/y and z/z haplotypes of Yucatan inbred swine. T-cell clones were obtained by limiting dilution. The human T-cell receptor (TCR)-swine leukocyte antigen (SLA) class I interaction was characterized. The human CD8+ T-cell mediated direct recognition of PAECs was SLA haplotype-specific. The haplotype specificity was restricted by the SLA class I allelic polymorphism. To characterize the role of SLA-bound peptides in the human TCR-SLA class I interaction, we stripped peptides from SLA molecules by a brief acid treatment. Using z/z-specific CD8+ T cells as effectors, we demonstrated that the acid-treatment, which stripped SLA molecules of bound peptides, decreased the lysis of PAECs by 72%. Addition of peptides eluted from affinity purified z/z SLA class I molecules, but not from the irrelevant y/y SLA class I, restored the lysis of acid-treated z/z PAECs. In addition, the lysis of a human HLA class I negative cell line, 721.221, transfected with a relevant SLA class I allele derived from the z/z haplotype, was significantly increased with the addition of relevant z/z peptides. These experiments indicated that both SLA class I and bound peptides were required for recognition by human CD8+ T cells. Cloning studies identified two groups of xenoreactive T-cell clones. Group I clones recognized distinct porcine peptides in the context of SLA class I molecules, whereas group II clones recognized human endogenous cross-reactive peptides presented by SLA class I. Our results demonstrated that, despite the differences in MHC molecules between species, human T-cell recognition of porcine MHC is similar to direct allo-recognition, that is, human TCR recognizes xenogeneic SLA-peptide complexes.


Functional obstruction: the renal pelvis rules.
Failure in the peristaltic mechanism that conducts urine from the kidney to the bladder can lead to hydronephrosis, a common birth defect associated with obstructive nephropathy. New animal models reveal molecular pathways important for peristalsis and point to the central role of the renal pelvis in urine transport.


Cloning and sequencing of Escherichia coli ubiC and purification of chorismate lyase.
In Escherichia coli, chorismate lyase catalyzes the first step in ubiquinone biosynthesis, the conversion of chorismate to 4-hydroxybenzoate. 4-Hydroxybenzoate is converted to 3-octaprenyl-4-hydroxybenzoate by 4-hydroxybenzoate octaprenyltransferase. These two enzymes are encoded by ubiC and ubiA, respectively, and have been reported to map near one another at 92 min on the E. coli chromosome. We have cloned the ubiCA gene cluster and determined the nucleotide sequence of ubiC and a portion of ubiA. The nucleotide sequence abuts with a previously determined sequence that encodes a large portion of ubiA. ubiC was localized by subcloning, and overproducing plasmids were constructed. Overexpression of ubiC allowed the purification of chorismate lyase to homogeneity, and N-terminal sequence analysis of chorismate lyase unambiguously defined the beginning of the ubiC coding region. Although chorismate lyase showed no significant amino acid sequence similarity to 4-amino-4-deoxychorismate lyase (4-amino-4-deoxychroismate----4-aminobenzoate), the product of E. coli pabC, chorismate lyase overproduction could complement the growth requirement for 4-aminobenzoate of a pabC mutant strain. Of the several enzymes that convert chorismate to intermediates of E. coli biosynthetic pathways, chorismate lyase is the last to be isolated and characterized.


Intra-operative vs pre-operative endoscopic sphincterotomy in patients with gallbladder and common bile duct stones: cost-utility and value-of-information analysis.
Patients with gallbladder and common bile duct stones are generally treated by pre-operative endoscopic sphincterotomy (ES) followed by laparoscopic cholecystectomy (POES). Recently, a meta-analysis has shown that intra-operative ES during laparoscopic cholecystectomy (IOES) results in fewer complications than POES, with similar efficacy. The cost effectiveness of IOES versus POES is unknown. The objective of this study was to compare the cost effectiveness of IOES versus POES from the UK NHS perspective. A decision-tree model estimating and comparing costs to the UK NHS and QALYs gained following a policy of either IOES or POES was developed with a time horizon of 3 years. Uncertainty was investigated with probabilistic sensitivity analysis, and the expected value of perfect information (EVPI) and partial information (EVPPI) were also calculated. IOES was less costly than POES (approximately -£623 per patient [year 2008 values]) and resulted in similar quality of life (+0.008 QALYs per patient) as POES. Given a willingness-to-pay threshold of £20 000 per QALY gained, there was a 92.9% probability that IOES is cost effective compared with POES. Full implementation of IOES could save the NHS £2.8 million per annum. At a willingness to pay of £20 000 per QALY gained, the 10-year population EVPI was estimated at £0.6 million. IOES appears to be cost effective compared with POES.


Cold and stable antimatter for fundamental physics.
The field of cold antimatter physics has rapidly developed in the last 20 years, overlapping with the period of the Antiproton Decelerator (AD) at CERN. The central subjects are CPT symmetry tests and Weak Equivalence Principle (WEP) tests. Various groundbreaking techniques have been developed and are still in progress such as to cool antiprotons and positrons down to extremely low temperature, to manipulate antihydrogen atoms, to construct extremely high-precision Penning traps, etc. The precisions of the antiproton and proton magnetic moments have improved by six orders of magnitude, and also laser spectroscopy of antihydrogen has been realized and reached a relative precision of 2 × 10-12 during the AD time. Antiprotonic helium laser spectroscopy, which started during the Low Energy Antiproton Ring (LEAR) time, has reached a relative precision of 8 × 10-10. Three collaborations joined the WEP tests inventing various unique approaches. An additional new post-decelerator, Extra Low ENergy Antiproton ring (ELENA), has been constructed and will be ready in 2021, which will provide 10-100 times more cold antiprotons to each experiment. A new era of the cold antimatter physics will emerge soon including the transport of antiprotons to other facilities.


Infectious Granuloma With Mycobacterium abscessus After Facial Injection of Botulinum Toxin: A Case Report.
Botulinum toxin injections have garnered increasing employment in facial rhytidectomy due to their demonstrable efficacy and safety profile. In this study, the authors present the case of a 39-year-old woman who manifested painful crimson nodules and multiple abscesses on her face, which manifested 1 week postinjection. Subsequent histopathological scrutiny unveiled the development of histiocytic granulomas accompanied by infiltrates of inflammatory cells, and microbiological investigation and polymerase chain reaction assays identified the causative agent as Mycobacterium abscessus .