The Use of Computer Simulation Modeling to Estimate Complications in Patients with Type 2 Diabetes Mellitus: Comparative Validation of the Cornerstone Diabetes Simulation Model.
The objective of this study was to assess the validity of the Cornerstone Diabetes Simulation (CDS), a Microsoft Excel®-based patient-level simulation for type 2 diabetes mellitus based on risk equations from the revised United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS-OM2, also known as UKPDS 82). Three levels of validation were conducted. Internal validation was assessed through independent review and model stress-testing. External validation was addressed by populating the CDS with baseline characteristics and treatment effects from three major diabetes clinical trials used in the Fifth Mount Hood Diabetes Challenge (MH5) for computer simulation models. Cross-validation of predicted outcomes was tested versus eight models that participated in the MH5. Simulated results were compared with observed clinical outcomes via the coefficient of determination (R2) for both the absolute risk of each clinical outcome and the difference in absolute risk between control and intervention arm in each trial. We ensured transparency of all model inputs and assumptions in reporting. The CDS could be used to predict 18 of 39 single and composite endpoints across the three trials. The model obtained an R2 of 0.637 for predicted versus observed absolute risks, and an R2 of 0.442 for predicted versus observed risk differences between control and intervention. Among the other eight models, only one obtained a higher R2 value under both definitions, albeit based on only four predicted endpoints. The CDS provides good predictions of diabetes-related complications when compared to observed trial outcomes and previously validated models. The model has value as a validated tool in cost-effectiveness evaluations.


Endobronchial metastasis from primary anorectal melanoma.
Male, 64 FINAL DIAGNOSIS: Metastatic anorectal melanoma with endotracheal metastasis Symptoms: Fatigue • weight loss • hematochezia • cough None Clinical Procedure: Biopsy of anal mass • rigid bronchoscopy Specialty: Internal medicine • oncology • pulmonology. Rare disease. Anorectal melanoma is a rare cancer with a poor prognosis. The mean survival after diagnosis is 15-25 months. At the time of diagnosis, 61% of patients have local regional lymph node metastases, and 21% have distant metastases. The lungs are a common site for metastasis for all tumors including melanoma. However endobronchial metastasis is a rare phenomenon. Endotracheal metastases are even rarer, occurring in only 5% of patients with extrapulmonary endobronchial metastases. It is most commonly seen in breast, colorectal, and kidney cancers. It is extremely rare for cutaneous melanoma. The mean survival after diagnosis is only 15 months and treatment options are limited. We report the case of a 64 year-old gentleman with newly diagnosed metastatic anorectal melanoma. A 3 cm by 3 cm bluish-black, oval-shaped, exophytic mass protruding from his anus was found on physical exam. Endobronchial and endotracheal metastasis to the trachea were discovered on computed tomography and he was subsequently taken to the operating room for argon plasma coagulation laser recanalization of his trachea via rigid bronchoscopy, and resection of his anal mass. We have presented the first known case of anorectal melanoma with endobronchial metastasis. Palliative APC laser recanalization was used to prevent asphyxiation from the endotracheal mass. Endobronchial metastasis is uncommon and can be easily mistaken for primary bronchogenic carcinoma. It should always be considered when evaluating patients with new lung masses.


Ahmed glaucoma valve implant: surgical technique and complications.
Implantation of Ahmed glaucoma valve is an effective surgical technique to reduce intraocular pressure in patients affected with glaucoma. While in the past, the use of this device was reserved to glaucoma refractory to multiple filtration surgical procedures, up-to-date mounting experience has encouraged its use also as a primary surgery for selected cases. Implantation of Ahmed glaucoma valve can be challenging for the surgeon, especially in patients who already underwent previous multiple surgeries. Several tips have to be acquired by the surgeon, and a long learning curve is always needed. Although the valve mechanism embedded in the Ahmed glaucoma valve decreases the risk of postoperative hypotony-related complications, it does not avoid the need of a careful follow-up. Complications related to this type of surgery include early and late postoperative hypotony, excessive capsule fibrosis around the plate, erosion of the tube or plate edge, and very rarely infection. The aim of this review is to describe surgical technique for Ahmed glaucoma valve implantation and to report related complications.


The effect of diminished osteogenic signals on reduced osteoporosis recovery in aged mice and the potential therapeutic use of adipose-derived stem cells.
Adipose-derived stem cells (ADSCs) have been shown to be pluoripotent and explored for their usage in tissue engineering. Previously, we have established a cell-based approach comprised of platelet-enriched plasma and osteo-progenitor cells for treating osteoporosis in an ovariectomized-senescence-accelerated mice (OVX-SAMP8) model. In the present study, we intend to explore the feasibility of using ADSCs as a cell-based therapeutic approach for treating osteoporosis, and to examine the effects of aging on the pluoripotency of ADSCs and the efficiency of bone formation both in vitro and in vivo. Flow cytometry was used to characterize ADSCs isolated from young and aged female SAMP8 mice and showed that the highly positive expression of surface markers such as CD44 and CD105 and negative for CD34 and CD45. Therefore, to compare the aging effects on the growth kinetics and differentiation potential of young and aged ADSCs, we found that there was a significant decline in both the proliferation rate (approximately 13.3%) and osteo-differentiation potential in aged ADSC. Subsequently, young and aged ADSCs were transplanted into the bone marrow of osteoporotic mice (OVX-SAMP8) to evaluate their bone formation ability. ADSC transplants were shown effective in restoring bone mineral density in the right/left knees, femurs and spine, 4 months post-transplantation; mice which received young ADSC transplants showed significantly higher bone regeneration (an average of 24.3% of improved BMD) over those received aged ADSCs. In conclusion, these findings showed that aging impedes osteoporosis-ameliorating potential of ADSC by diminishing osteogenic signal, and that ADSC could be used as a potential cell-based therapy for osteoporosis.


Memetic algorithms for ligand expulsion from protein cavities.
Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper, two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics (MD) and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic G-protein-coupled receptor, enzyme nitrile hydratase, and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform simulated annealing and random acceleration molecular dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied.


MAPK inhibitors enhance cell death in pyrogallol-treated human pulmonary fibroblast cells via increasing O2•- levels.
Pyrogallol (PG) induces apoptosis in lung cancer cells via the overproduction of O2•- and affects mitogen-activated protein kinases (MAPKs) in these cells. The aim of the present study was to elucidate the effect of PG and/or MAPK inhibitors on human pulmonary fibroblast (HPF) cell viability in relation to reactive oxygen species (ROS) and glutathione (GSH). Treatment with 50 or 100 µM PG inhibited the viability of HPF cells, and induced cell death and the loss of mitochondrial membrane potential (MMP; ΔΨm). In particular, treatment with 100 µM PG induced cell death via apoptosis as well as necrosis in HPF cells. PG increased mitochondrial O2•- levels and the number of GSH-depleted HPF cells. All the MAPK (mitogen-activated protein kinase kinase, c-Jun N-terminal kinase and p38) inhibitors enhanced the inhibition of cell viability, cell death and MMP (ΔΨm) loss in 100 µM PG-treated HPF cells. All the inhibitors increased the O2•- levels in 100 µM PG-treated HPF cells, but none of the inhibitors significantly altered the PG-induced GSH depletion. In conclusion, PG treatment induced cell death via apoptosis and necrosis in HPF cells. Treatment with MAPK inhibitors slightly enhanced cell death in PG-treated HPF cells. HPF cell death induced by PG and/or MAPK inhibitors was at least partially associated with changes in O2•- levels and GSH content. The present data provided useful information to understand PG-induced normal lung cell death in association with MAPK signaling pathways and ROS levels.


Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer.
To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.


Alpha-smooth muscle actin distribution in the pulmonary vasculature comparing hypoplastic and normal fetal lungs.
We investigated the intra-acinar pulmonary vascular muscularization in the developing human fetal lung between the 17th and 24th gestational weeks, that is, during the canalicular phase of lung development. Fifteen hypoplastic and 25 normal developed lungs were included in this study using monoclonal alpha-smooth muscle (sm) actin antibodies for smooth muscle detection. Computer-aided image analysis was performed for morphometrical measurements and statistical evaluation. Alpha-sm-actin-immunoreactive intra-acinar vessels down to a luminal diameter of less than 10 microns were detected in hypoplastic as well as in normally developed lungs. Crucial differences presented as follows: significantly higher density of intra-acinar vessels, especially due to alpha-sm-actin-negative vessels less than 30 microns in luminal diameter, in the control group; significantly higher alpha-sm-actin immunore-activity per section unit as well as per vessel in the hypoplastic lung group. As suggested by others, alpha-sm-actin-positive cells of the intra-acinar vessel wall in the developing human lung were demonstrated to be smooth muscle cells, their immediate precursors, and pericytes. We conclude that the increased alpha-sm-actin immunoreactivity represents muscularization of the vessel wall in functional terms and may be regarded as one structural cause among others for the establishment of persistent fetal circulation in hypoplastic lungs.


Childhood-Onset Granulomatosis With Polyangiitis as a Palatal Defect: A Case Report.
Granulomatosis with polyangiitis (GPA) is a necrotizing systemic vasculitis of small and medium-sized vessels with renal and sinopulmonary involvement. Its symptoms include chronic sinusitis, recurrent pneumonia, glomerulonephritis, constitutional symptoms, and skin manifestations with a typical onset in the fourth to sixth decade of life. We present a rare case of GPA in a 16-year-old female who presented with facial numbness and nasal regurgitation via a palatal defect. The patient reported a several-month history of recurrent epistaxis and chronic nasal congestion accompanied by several weeks of night sweats, lower right-sided facial numbness and pain, nasal regurgitation of food and liquids, and a 30-pound weight loss. A physical exam found a 3-cm defect on the right side of her palate. CT of the sinuses showed significant sinonasal destruction and petrous apicitis. GPA was confirmed via pathognomonic chest X-ray findings and biopsy results. The patient was treated with maxillary antrostomy and anterior ethmoidectomy and a follow-up was scheduled to address sequelae of the destructive sinopulmonary lesions. This case report highlights a unique presentation of GPA with an insidious development of autoimmune sinonasal destruction in an adolescent female. This presentation is rare and highlights the importance of considering autoimmune disease in cases of tissue destruction where the etiology is not apparent, even in patients at low risk for autoimmune conditions.


Posterior urethral obstruction. Prenatal sonographic findings and clinical outcome in fourteen cases.
Fourteen cases of fetal urethral obstruction were reviewed retrospectively. The purpose of this study was to emphasize the following: 1) prenatal sonographic findings: 2) clinical outcome: and 3) associated congenital anomalies. Decreased amniotic fluid volume complicated 12 pregnancies (86%). A dilated posterior urethra was identified in nine fetuses (64%) and an enlarged bladder in 13 (93%). Evaluation of the fetal kidneys revealed hydronephrosis in 81%, increased parenchymal echogenicity in 73% and macroscopic renal cysts in 15%. There were seven live births, but only two neonates survived beyond 5 weeks. Pulmonary hypoplasia contributed to the five postnatal deaths. Associated congenital anomalies were noted at autopsy in six cases.


Pandemic scientific data sharing recommendations: examining and re-imagining pre-print servers after the end of the world-wide emergency.
Early in the pandemic, pre-print servers sped rapid evidence sharing. A collaborative of major medical journals supported their use to ensure equitable access to scientific advancements. In the intervening three years, we have made major advancements in the prevention and treatment of COVID-19 and learned about the benefits and limitations of pre-prints as a mechanism for sharing and disseminating scientific knowledge. Pre-prints increase attention, citations, and ultimately impact policy, often before findings are verified. Evidence suggests that pre-prints have more spin relative to peer-reviewed publications. Clinical trial findings posted on pre-print servers do not change substantially following peer-review, but other study types (e.g., modeling and observational studies) often undergo substantial revision or are never published. Nuanced policies about sharing results are needed to balance rapid implementation of true and important advancements with accuracy. Policies recommending immediate posting of COVID-19-related research should be re-evaluated, and standards for evaluation and sharing of unverified studies should be developed. These may include specifications about what information is included in pre-prints and requirements for certain data quality standards (e.g., automated review of images and tables); requirements for code release and sharing; and limiting early postings to methods, results, and limitations sections. Academic publishing needs to innovate and improve, but assessments of evidence quality remains a critical part of the scientific discovery and dissemination process.


Recurrent adrenocortical carcinoma in a 4 year old girl.
Adrenocortical tumours are rare in the paediatric age group. This is a report of a 4 year old girl with recurrent adrenocortical carcinoma emphasizing the role of surgery as the definitive form of therapy even in recurrent cases.


[The bacteriological and immunological efficacy of biosporin in nonspecific ulcerative colitis].
The results from examination of intestinal microflora and immune status in 75 patients with nonspecific ulcerative colitis with different degree of disease seriousness are presented. The deviations in the composition of normal microflora were primarily expressed in a decrease of the number of bifidobacteria. In 64.9% of patients the disease proceeded against the background of deficit of T-cellular immunity link. The sufficiently expressed bacteriological and immunological efficiency of complex therapy including preparation from spore-forming bacteria as a normalizer of microflora is shown.


Community nurses' perceptions of a good death: a qualitative exploratory study.
This study sought to gain an insight into perceptions of a 'good death' among community nurses, and to identify its central components. By understanding these factors, it was hoped that common difficulties could be identified, enabling recommendations to be made to enhance patient care and reduce the pressures to which nurses are exposed. This qualitative exploratory study relied on semi-structured interviews, incorporating the critical incident technique to elicit retrospective accounts of experiences of palliative care and a good death. Data was obtained from a purposive sample of 17 community nurses, working in a single primary care trust in south-east England. The participants identified eight key themes in supporting a good death: symptom control, patient choice, honesty, spirituality, interprofessional relationships, effective preparation and organization and provision of seamless care. When these are in place, a good death is possible. Factors such as lack of necessary medication/resources, unsuccessful interprofessional relationships and lack of teamwork were significant determinants of less successful care. The provision of seamless care was an important criterion for success. In identifying the contributory factors, this study has shown that a good death can be provided in the community, although it has also revealed many challenges associated with such care. While it could be argued that due to the unpredictability of death, such challenges may always be a threat to effective care anticipatory planning and a recognition that patients need and are entitled to specialist care many of these difficulties could be overcome.


Vaccine indicator and reminder band to improve demand for vaccination in Northern Nigeria: A qualitative evaluation of implementation outcomes.
Vaccination coverage is low in Nigeria, partly due to poor demand for the vaccines. Till date, there is limited understanding of what works to improve demand for vaccination. A Vaccine Indicator and Reminder (VIR) band was designed to be worn on a child's ankle to serve as a constant reminder to parents/caregivers on when to bring their children for vaccinations. This study assessed the acceptability of the band as a wearable reminder for infant vaccination in Kebbi State, Nigeria. A total of 503 infants who met the eligibility criteria were enrolled between August 2017 and February 2018. The intervention involved 1) sensitisation and mobilisation of community gatekeepers to advocate for immunisation; 2) engaging traditional birth attendants (TBAs) to refer mothers for vaccination and VIR bands; and 3) training facility-based health workers to secure the band on an eligible child. Focus group discussions and in-depth interviews were conducted at baseline (May 2016) and end-line (July 2018) with purposively selected participants. These interviews were analysed thematically. There was general acceptability of the band at all levels, especially among community members who likened it to a "wristwatch" that constantly reminds mothers when next to vaccinate their children. The strong support from community leaders, TBAs and participating health workers increased acceptability of the band. Similarly, the VIR band's aesthetics, ease of use and perceived benefits contributed to its acceptability. Wearing the VIR band was not perceived as an impediment because similar accessories are worn on new-borns. However, there were concerns about wearing accessories on the ankle, the red indicator colour, and the malfunctioning of some bands. This study demonstrates that cultural adaptability of interventions and engagement with community structures are important in facilitating acceptability of new innovations. Further studies will evaluate the effectiveness of VIR band in improving vaccination coverage.


A note on the Philadelphia Regional Medical Library Committee.
No rigid library plan can fullfil the needs of every region. The Philadelphia Regional Medical Library Committee, composed of representatives of the five medical schools, the College of Physicians, and other medical organizations, was formed to determine cooperative activities that best suit its own needs. The committee has reviewed plans for new libraries at several medical schools to avoid duplication of library resources. It envisions, also, cooperative storage of little-used materials, messenger service, an acquisition program to expand regional resources, improved communication by means of mechanical devices, and the establishment of a regional center and distribution of bibliographies from regionally located MEDLARS tapes.


Generation of femtosecond diffraction-compensated beam through an opaque disk.
The generation of a femtosecond diffraction-compensated beam through an opaque disk is presented: 100 fs pulses are focused in the vicinity of an opaque disk. A bright beam surrounded by concentric rings is generated. The beam can be collimated by a lens. A non-diffracting femtosecond beam which conserves a 500microm large central spot over more than 1.7m is then observed, without any nonlinear mechanism. Our theoretical analysis predicts well the results.


The impact of individual variation analysis on myocardial perfusion imaging utilization within a hospitalist group.
Increased recognition of ionizing radiation risks has placed an emphasis on the appropriate use of myocardial perfusion imaging (MPI). Hospitalists frequently order MPI in the evaluation of chest pain and are thus at the forefront of its inpatient utilization. We collected baseline figures for a group MPI rate (March 2010-February 2011) as well as individual MPI rates for hospitalists caring for cardiac floor patients at a community teaching hospital. We performed a 2-part intervention; we presented the individual MPI rate data back to the hospitalist division and carried out longitudinal educational efforts on MPI appropriateness criteria. We then calculated the group MPI utilization rate for 3 postintervention periods (March 2011-February 2012, March 2012-February 2013, and March 2013-February 2014) and the MPI rate for the subgroup of cardiac floor patients. Finally, we calculated the percentage of inappropriately performed stress tests before and after our intervention. Group MPI rate declined from 6.1% to 5.0% in the first year after our intervention (P = 0.009); a decrease was maintained a year later-MPI rate 4.9% (P = 0.004)-and became even more pronounced 2 years later-MPI rate 3.9% (P < 0.0001). The MPI rate for the subgroup of patients on the cardiac floor similarly decreased from 8.0% to 6.7% (P = 0.039). Finally, we report a particularly encouraging and significant trend of a 46% postintervention decrease (from 16.5% to 9%, P = 0.034) in the proportion of inappropriate stress tests ordered. Analyzing individual ordering rates and combining them with educational efforts was an effective strategy for impacting MPI utilization in the hospitalist group studied.


Changes in lower limb muscle function and muscle mass following exercise-based interventions in patients with chronic obstructive pulmonary disease: A review of the English-language literature.
Chronic obstructive pulmonary disease (COPD) patients often experience lower limb muscle dysfunction and wasting. Exercise-based training has potential to improve muscle function and mass, but literature on this topic is extensive and heterogeneous including numerous interventions and outcome measures. This review uses a detailed systematic approach to investigate the effect of this wide range of exercise-based interventions on muscle function and mass. PUBMED and PEDro databases were searched. In all, 70 studies ( n = 2504 COPD patients) that implemented an exercise-based intervention and reported muscle strength, endurance, or mass in clinically stable COPD patients were critically appraised. Aerobic and/or resistance training, high-intensity interval training, electrical or magnetic muscle stimulation, whole-body vibration, and water-based training were investigated. Muscle strength increased in 78%, muscle endurance in 92%, and muscle mass in 88% of the cases where that specific outcome was measured. Despite large heterogeneity in exercise-based interventions and outcome measures used, most exercise-based trials showed improvements in muscle strength, endurance, and mass in COPD patients. Which intervention(s) is (are) best for which subgroup of patients remains currently unknown. Furthermore, this literature review identifies gaps in the current knowledge and generates recommendations for future research to enhance our knowledge on exercise-based interventions in COPD patients.


Risk-based management of invading plant disease.
Effective control of plant disease remains a key challenge. Eradication attempts often involve removal of host plants within a certain radius of detection, targeting asymptomatic infection. Here we develop and test potentially more effective, epidemiologically motivated, control strategies, using a mathematical model previously fitted to the spread of citrus canker in Florida. We test risk-based control, which preferentially removes hosts expected to cause a high number of infections in the remaining host population. Removals then depend on past patterns of pathogen spread and host removal, which might be nontransparent to affected stakeholders. This motivates a variable radius strategy, which approximates risk-based control via removal radii that vary by location, but which are fixed in advance of any epidemic. Risk-based control outperforms variable radius control, which in turn outperforms constant radius removal. This result is robust to changes in disease spread parameters and initial patterns of susceptible host plants. However, efficiency degrades if epidemiological parameters are incorrectly characterised. Risk-based control including additional epidemiology can be used to improve disease management, but it requires good prior knowledge for optimal performance. This focuses attention on gaining maximal information from past epidemics, on understanding model transferability between locations and on adaptive management strategies that change over time.


Biomarker responses of Peromyscus leucopus exposed to lead and cadmium in the Southeast Missouri Lead Mining District.
Biomarker responses and histopathological lesions have been documented in laboratory mammals exposed to elevated concentrations of lead and cadmium. The exposure of white-footed mice (Peromyscus leucopus) to these metals and the potential associated toxic effects were examined at three contaminated sites in the Southeast Missouri Lead Mining District and at a reference site in MO, USA. Mice from the contaminated sites showed evidence of oxidative stress and reduced activity of red blood cell δ-aminolevulinic acid dehydratase (ALAD). Histological examinations of the liver and kidney, cytologic examination of blood smears, and biomarkers of lipid peroxidation and DNA damage failed to show indications of toxic effects from lead. The biomagnification factor of cadmium (hepatic concentration/soil concentration) at a site with a strongly acid soil was 44 times the average of the biomagnification factors at two sites with slightly alkaline soils. The elevated concentrations of cadmium in the mice did not cause observable toxicity, but were associated with about a 50% decrease in expected tissue lead concentrations and greater ALAD activity compared to the activity at the reference site. Lead was associated with a decrease in concentrations of hepatic glutathione and thiols, whereas cadmium was associated with an increase. In addition, to support risk assessment efforts, we developed linear regression models relating both tissue lead dosages (based on a previously published a laboratory study) and tissue lead concentrations in Peromyscus to soil lead concentrations.


Genetic and environmental parameters for mature weight and other growth measures in Polled Hereford cattle.
Variances and covariances were estimated for birth weight (BWT), weaning weight (WW), yearling gain (YG), yearling weight (YW), yearling height (YH), relative growth from birth to weaning (RGW) and weaning to yearling (RGY), and mature weight (MW). Field records on 572,446 Polled Hereford cattle were analyzed. Because multiple dam weights were collected on a cow the MW used in the analysis was calculated using a nonlinear regression correction factor computed by fitting a quadratic with a plateau to the data. If the cow had an observation(s) beyond the inflection point (IP), the closest weight to that point was used. If the cow only had observation(s) before the IP the closest weight to that point was nonlinearly adjusted to the plateau. The IP for this data set was 1,506 d and the plateau was 554.7 kg. Heritabilities and genetic and environmental correlations were calculated from the appropriate (co)variances and phenotypic correlations were computed. Heritability estimates for BWT, WW, YG, YW, YH, RGW, RGY, and MW were .49, .24, .23, .30, .59, .24, .15, and .52, respectively. Genetic correlations between MW with BWT, WW, YG, YW, YH, RGW, and RGY were .64, .80, .76, .89, .73, -.29, and .35, respectively, environmental correlations were .15, .43, .05, .40, 1.03, .32, and -.10, respectively, and phenotypic correlations were .33, .32, .28, .46, .70, .00, and .07, respectively.


Facile fabrication of composite cellulose fibrous materials for efficient and consecutive dyeing wastewater treatment.
Fabricating dye adsorbents with efficient adsorption properties is of great significance in the treatment of printing and dyeing wastewater. Herein, composite materials of polydopamine decorated cellulose fibrous nonwovens (PDA@CF NWs) were fabricated by constructing a PDA functional layer on the surface of cellulose fibers via in situ polymerization. In addition, a three-dimensional adsorbent of 3D PDA@CF NWs with good hydrophilicity, structural stability, and compression resistance could be obtained using a facilely laminating and traditional loop bonding reinforcing technique. Attributed to the efficient and uniform loading of an active PDA functional layer, the resulting PDA@CF NWs exhibited a relatively large adsorption capacity of around 91 mg g-1 towards the template dye of methylene blue within a fast equilibrium time of 2 h, which was superior to most of the fibrous adsorbents. In addition, the treatment column of 3D PDA@CF NWs exhibited a breakthrough capacity of 40.9 mg g-1, reaching nearly 50% of the static saturated dye-binding capacity. More importantly, the 3D PDA@CF NWs column could effectively and continuously separate the mixture of different dyes under gravity, highlighting an excellent practical performance. Thus, the PDA@CF NWs are expected to provide a promising candidate for environment-friendly, large-scale and efficient treatment of industrial printing and dyeing wastewater.


Origin of the "waterfall" effect in phonon dispersion of relaxor perovskites.
We have undertaken an inelastic neutron scattering study of the perovskite relaxor ferroelectric Pb(Zn(1/3)Nb(2/3))O3 with 8% PbTiO3 (PZN-8%PT) in order to elucidate the origin of the previously reported unusual kink on the low frequency transverse phonon dispersion curve (known as the "waterfall effect"). We show that its position (q(wf)) depends on the choice of the Brillouin zone and that the relation of q(wf) to the size of the polar nanoregions is highly improbable. The waterfall phenomenon is explained in the framework of a simple model of coupled damped harmonic oscillators representing the acoustic and optic phonon branches.


Synthesis and properties of castor oil-based waterborne polyurethane/sodium alginate composites with tunable properties.
In this paper, bio-based waterborne polyurethane dispersions were successfully prepared from castor oil using 2, 2-dimethylolbutanoic acid as the chain extender. Then, a series of bio-based composite dispersions and films were prepared by blending different amounts of sodium alginate aqueous solution with these bio-based polyurethane dispersions. The chemical structures, thermo-mechanical properties, thermal stability, and mechanical properties of the resulting composite films were characterized and discussed. The results show that the tensile strength and storage moduli of the composite films increase while the elongation at break of the composite films decrease with increasing the sodium alginate content. In addition, the contact angle and thermal stability of the composite films also increase with increasing sodium alginate content. These improvements are related to the increase of the crosslink density and the formation of interpenetrating networks with introduction of sodium alginate macromolecule.


Between certainty and uncertainty--observations on psychoanalysis in Russia.
'Diversity', the theme of our conference, carries a subversive sub-text in totalitarian societies. This is one of the themes presented as the current revival of psychoanalysis in the more democratic post-Communist Russia is explored. The history of psychoanalysis in Russia is summarized with a focus on its politicization, which led to initial interest in its theory (by way of a misapprehension of its tenets), and then to ultimate suppression of psychoanalytic thinking as an ideology deemed antagonistic to the totalitarian regime. In contrast, features of psychoanalysis and democracy are explored for their mutual affinities. The background of the resourceful new generation of analytic therapists is discussed, especially in regard to their experience of the parallel meanings of the word 'repression' (political, psychological). There is a persistence of some traits in patients and practitioners alike that are referable to past repression, such as the newness of verbal treatments, the inhibition of psychological curiosity, the ambivalent lure of certainty, and the pressure of authoritarian introjects. It is noted that psychoanalysis has its own history of a posture opposed to pluralism and diversity, which deepens the dialogue on the mutual engagement between psychoanalysis and the vicissitudes of its history in Russian culture.


Rapid "step capture" of holes in chloroform during pulse radiolysis.
The fundamental process of hole capture in solution was investigated following pulse radiolysis with polyfluorene and 4-cyano-4″-pentyl-p-terphenyl scavengers. Contrary to expectation, a large fraction of holes were captured in experimental time-resolution limited ∼20 ps steps, by a process much faster than diffusion of the initially formed solvent molecular cation. At the highest concentrations, 1.92 mM for a 52 unit long polyfluorene and 800 mM for 4-cyano-4″-pentyl-p-terphenyl, 66% and 99%, respectively, of the initially formed holes were captured by 20 ps, with radiation chemical yield G = 1.2 × 10(-7) and 1.7 × 10(-7) mol J(-1). The data can be explained by capture of presolvated holes, analogous to presolvated electrons, possibly possessing extended wave functions, high mobilities, or excess kinetic energy for the first few picoseconds after their creation. Such a process is not generally known in solution; however, the observed step capture as a function of solute concentration is shown to be well explained by this model. In addition to understanding the capture process in solution, the very large step yields formed in 20 ps will provide the ability to resolve subsequent hole transfer on the polymers with >2 orders of magnitude better time resolution than expected.


Biochemical basis of the immunogenicity of the common enterobacterial antigen.
Of the numerous members of the family Enterobacteriaceae only a few strains, notably Escherichia coli O14 and R mutants of the E. coli R1-core type, engender antibodies against the common enterobacterial antigen (CA) following immunization of rabbits with heated suspensions or culture supernatants; other members produce nonimmunogenic CA of identical serological specificity. The biochemical basis of the immunogenic properties of CA of the former strains was investigated by determining the relationship between the CA determinant and the lipopolysaccharide molecule. Lipopolysaccharides extracted from R mutants of the E. coli R1-core type or of E. coli O14 by the phenol-chloroform-petrol ether method contain the CA determinant, in contrast to extracts of other CA-producing R mutants. This is evident from the observation that only the former absorb CA antibodies, utilizing erythrocytes coated with alkali-treated lipopolysaccharide preparations. Based on the findings that CA of R mutants of E. coli R1-core type follows lipopolysaccharide during all purification steps and that alkali treatment increases its affinity for erythrocytes parallel to that of the lipopolysaccharide, it is concluded that the CA determinant either is part of the lipopolysaccharide molecule or is strongly complexed with it. It is suggested that this association between CA and the lipopolysaccharide of E. coli R1-core type and E. coli O14 accounts for the heat stability of the immunogenicity of CA of these unusual strains.


Chemically induced intestinal damage models in zebrafish larvae.
Several intestinal damage models have been developed using zebrafish, with the aim of recapitulating aspects of human inflammatory bowel disease (IBD). These experimentally induced inflammation models have utilized immersion exposure to an array of colitogenic agents (including live bacteria, bacterial products, and chemicals) to induce varying severity of inflammation. This technical report describes methods used to generate two chemically induced intestinal damage models using either dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS). Methods to monitor intestinal damage and inflammatory processes, and chemical-genetic methods to manipulate the host response to injury are also described.


Timing of medical diagnosis and treatment: clino-circadian quantification of suppression by dexamethasone of the adrenal cortical cycle in healthy men.
The inhibitory effect exerted upon the cyclic activity of the adrenal cortex by a synthetic steroid analog (dexamethasone-21-phosphate) administered at different circadian stages, has been studied previously. Reexamination of the same data by microscopic methods herein provides two sets of objective quantitative endpoints for further studies, namely 1. the characteristics of a rhythm isolated from a superimposed trend as well as noise, and 2. the endpoints of the trend itself. These endpoints quantify the effect of dose and, with the appropriate dose, the optimal timing for a given purpose may also be found.


Spontaneous Electric Fields Play a Key Role in Thermochemical Catalysis at Metal-Liquid Interfaces.
Large oriented electric fields spontaneously arise at all solid-liquid interfaces via the exchange of ions and/or electrons with the solution. Although intrinsic electric fields are known to play an important role in molecular and biological catalysis, the role of spontaneous polarization in heterogeneous thermocatalysis remains unclear because the catalysts employed are typically disconnected from an external circuit, which makes it difficult to monitor or control the degree of electrical polarization of the surface. Here, we address this knowledge gap by developing general methods for wirelessly monitoring and controlling spontaneous electrical polarization at conductive catalysts dispersed in liquid media. By combining electrochemical and spectroscopic measurements, we demonstrate that proton and electron transfer from solution controllably, spontaneously, and wirelessly polarize Pt surfaces during thermochemical catalysis. We employ liquid-phase ethylene hydrogenation on a Pt/C catalyst as a thermochemical probe reaction and observe that the rate of this nonpolar hydrogenation reaction is significantly influenced by spontaneous electric fields generated by both interfacial proton transfer in water and interfacial electron transfer from organometallic redox buffers in a polar aprotic ortho-difluorobenzene solvent. Across these vastly disparate reaction media, we observe quantitatively similar scaling of ethylene hydrogenation rates with the Pt open-circuit electrochemical potential (E OCP). These results isolate the role of interfacial electrostatic effects from medium-specific chemical interactions and establish that spontaneous interfacial electric fields play a critical role in liquid-phase heterogeneous catalysis. Consequently, E OCP-a generally overlooked parameter in heterogeneous catalysis-warrants consideration in mechanistic studies of thermochemical reactions at solid-liquid interfaces, alongside chemical factors such as temperature, reactant activities, and catalyst structure. Indeed, this work establishes the experimental and conceptual foundation for harnessing electric fields to both elucidate surface chemistry and manipulate preparative thermochemical catalysis.


Hypertonic saline resuscitation improves intestinal microcirculation in a rat model of hemorrhagic shock.
Conventional resuscitation (CR) from hemorrhagic shock (HS) often restores and maintains hemodynamics but fails to restore intestinal perfusion. Post-CR intestinal ischemia has been implicated in the initiation of a gut-derived exaggerated systemic inflammatory response and in the progressive organ failure following HS. We propose that intestinal ischemia can be prevented with hypertonic saline resuscitation (HTSR). Anesthetized male Sprague-Dawley rats (200 to 215 g) were hemorrhaged to 50% of mean arterial pressure (MAP) for 60 minutes and randomly assigned to 1 of the resuscitation groups (n = 7 each): Group I: sham operation and no HS; Group II: HS + CR with the return of the shed blood + 2 volumes of normal saline (NS); Group III: HS + return of the shed blood + hypertonic saline (HTS); (7.5 % NaCl, 4 ml/kg); Group IV: HS + HTS, then return of the shed blood after 60 minutes; Group V: HS + HTS, then 1 volume of NS after 60 minutes. Microvascular diameters of inflow (A1) and proximal and distal premucosal arterioles (A3) in terminal ileum and flow in A1 were measured using in vivo videomicroscopy and optical Doppler velocimetry. Hematocrit, plasma osmolarity, and electrolytes were measured in Groups II and III. HS caused a selective vasoconstriction in A1 arterioles that was not seen in the premucosal arterioles. CR restored and maintained MAP and caused generalized, progressive vasoconstriction at all intestinal arteriolar levels that is associated with hypoperfusion. HTSR failed to restore or maintain MAP or intestinal A1 arteriolar blood flow until the shed blood was returned. However, HTSR prevented the post-resuscitation, premucosal vasoconstriction and produced an insidious selective vasodilation in the A3 arterioles, which was most significant with early blood return (Group III). This selective arteriolar vasoactivity was associated with a significant improvement of endothelial cell function. Plasma hyperosmolality and hypernatremia persisted during the entire 2 hours post-resuscitation with HTS. Small-volume HTSR can be used as a resuscitation regimen at the trauma scene and for selective clinical conditions where hypotensive resuscitation is indicated. HTSR improves intestinal perfusion by selective vasodilation of the precapillary arterioles even at MAP close to shock levels.


[The effects of early intensive therapy on islet beta cell function and long-term glycemia control in newly diagnosed type 2 diabetic patients with different fasting plasma glucose levels.].
To investigate the effects of early intensive therapy on beta cell function and long-term glycemic control in newly diagnosed type 2 diabetic patients with different recruiting fasting plasma glucose (FPG) levels. A total of 382 newly diagnosed type 2 diabetic patients with FPG 7.0 - 16.7 mmol/L were randomly assigned to therapy with insulin in the form of continuous subcutaneous insulin infusion (CSII) or multiple daily injection (MDI) or oral hypoglycemic agents (OHA, by using gliclazide and/or metformin) for initial rapid correction of hyperglycemia. The treatments were stopped after euglycemia had been maintained for 2 weeks. The patients were followed longitudinally on diet alone for 1 year. Intravenous glucose tolerances tests (IVGTTs) were performed and blood glucose, insulin and proinsulin were measured before and after therapy as well as at 1-year follow-up. Homeostasis model assessment (HOMA) of beta cell function and insulin resistance index (HOMA-beta and HOMA-IR) were calculated. All the patients were stratified on the recruiting FPG: stratum A (7.0 mmol/L </= FPG < 11.1 mmol/L), stratum B (11.1 mmol/L </= FPG </= 16.7 mmol/L). More patients in stratum A achieved target glycemic control (94.4% vs 89.8%) and in shorter time [(5.9 +/- 3.8) d vs (6.9 +/- 3.6) d, P < 0.05] as compared with those in stratum B. beta cell function represented by HOMA-beta and acute insulin response (AIR) improved significantly after intensive interventions in both stratum A and B patients. However, the remission rate at 1 year was significantly higher in stratum A patients (47.8%) than those in stratum B (35.7%, P < 0.05). The patients treated with insulin (especially with CSII) had higher remission rates and better improvement of AIR at 1 year follow-up irrespective of the recruiting FPG (CSII or MDI vs OHA: 57.1%, 51.8% vs 32.8% in stratum A, P < 0.05; 44.4%, 38.7% vs 18.6% in stratum B, P < 0.05). Compared with OHA, early short time intensive insulin treatment had more favorable outcomes on maintaining AIR and prolonged glycemic remission in newly diagnosed type 2 diabetic patients irrespective of the recruiting FPG levels.


PCR-RFLP is used to investigate relations among species in the entomopathogenic genera Eryniopsis and Entomophaga.
The shape and nucleation of primary conidia are important characters in the classification of the Entomophthoraceae (Zygomycetes). The five species in the genus Eryniopsis vary in the shapes of primary conidia, although within most genera in the order Entomophthorales species have the same shapes of primary conidia. Using PCR-RFLP, we investigated two species in Eryniopsis, Ery. caroliniana with oblong-ovoid primary conidia and Ery. ptychopterae with pear-shaped primary conidia, with five species of Entomophaga, all having pear-shaped conidia. Molecular results merged with morphological data indicate that Ery. ptychopterae belongs in the genus Entomophaga while Ery. caroliniana clearly differs from Entomophaga. Ery. ptychopterae and Ery. transitans are transferred to the genus Entomophaga. Our results support the idea that morphology of primary conidia is of major importance in defining entomophthoralean genera. These results also show that such studies can be conducted with species that have not been isolated, if fungal-filled cadavers can be obtained.


Stirring rate regulates the proliferation and metabolism of microencapsulated recombinant CHO cells.
Stirred tank bioreactors are the most widely used method for the large-scale culture of mammalian cells. However, the scale of stirred tank bioreactors is limited by insufficient oxygen/nutrient mixing and the accumulation of waste products in high cell density cultures. The most effective method to solve these problems is to increase the stirring rate; this usually leads to increased cell proliferation, but can decrease the utilization of nutrients for recombinant protein synthesis. To investigate the effects of stirring rate on the proliferation, metabolism, and recombinant protein yield of microencapsulated recombinant Chinese hamster ovary (rCHO) cells, the cells were cultured under different stirring rates, and cell viability, metabolic activity, and protein yield were measured. Microencapsulation promoted Desmodus rotundus salivary plasminogen activator expression, and higher stirring rates promoted increases in microencapsulated cell density and metabolic activity. However, the maximum yield of recombinant protein was obtained at a moderate stirring rate, whereas protein yield was decreased at the highest tested stirring rate. The stirring rate had a significant impact on the growth and protein expression of microencapsulated rCHO cells, and a specific stirring rate was identified to maximize the yield of recombinant protein.


Molecular genetics of Leber congenital amaurosis.
Leber congenital amaurosis (LCA) is the most common inherited cause of blindness in childhood and is characterised by a severe retinal dystrophy before the age of one year. Six genes have been identified that together account for approximately half of all LCA patients. These genes are expressed preferentially in the retina or the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photoreceptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). The molecular data for CRB1 and RPE65 support previous hypotheses that LCA can represent the severe end of a spectrum of retinal dystrophies. Given the diverse mechanisms underlying the disease, future therapies of LCA may need to be tailored to certain genetically defined subgroups. Based on experimental evidence in mice and dogs, patients with disturbed retinal metabolism of vitamin A through a mutation in the RPE65 gene will likely be the first candidates for future therapeutic trials.


[Treatment of renal arteriovenous fistula by means of embolization using a fibrin sponge].
The selective embolization with fibrin sponge has controlled the persistent hematuria subsequent to a great renal arteriovenous post-operative fistula whereby the kidney recovered immediately after the embolization its normal functioning. A control arteriograph realized six weeks later showed the recanalization of the vessels, without any evidence of fistula. In another case, the renal massive hematuria after a percutaneous renal biopsy which produced a state of acute anemia was treated with the same method. The angiographic control showed the disappearance of the fistula, with a small ischemia zone distant from the embolized zone.


The relationship of trauma exposure to sex offending behavior among male juvenile offenders.
The most common type of adult and juvenile sex offender treatment utilizes a Relapse Prevention (RP) model. In RP clients learn about their offense cycle with an emphasis on recognizing high-risk situations and negative emotional states that can be precursors or triggers to offending behavior. This study identifies ways that traumatic experiences and trauma-associated feelings can be offense triggers for juvenile sex offenders. Researchers interviewed the treating clinicians of 40 male juvenile sex offenders who received at least six months of RP sex offender treatment. Results showed that 95% of the youths had experienced a Post Traumatic Stress Disorder (PTSD) Criterion A traumatic event and that 65% met criteria for PTSD based on clinician judgments. Overall, clinicians identified prior trauma exposure as being related to the offense triggers in 85% of offenders. Specifically, the following trauma-related feelings were identified as offense triggers: intense fear in 37.5% of sex offenders, helplessness in 55%, and horror in 20%. Implications for sex offender treatment programs are discussed.


Pattern and source of secretion of relaxin in the reproductive cycle of the spotted hyena (Crocuta crocuta).
Female spotted hyenas are highly masculinized at birth and have no external vagina. Copulation with males and birth of young are accomplished through the central urogenital canal of the clitoris. This unusual adaptation requires remarkable changes in the elasticity of the connective tissues of the clitoris, without which neither copulation nor birth would be possible. We hypothesized that relaxin, a hormone that increases the extensibility of the connective tissues of the uterus and cervix of many other mammalian species, plays a role in the clitoral changes observed in hyenas. Serum relaxin was determined by specific RIA. Relaxin was not detected in serum of males, pubertal or nonpregnant adult females, or ovariectomized females. Immunoactive relaxin was detected in serum of juveniles at the time of initial growth of the urogenital meatus. High concentrations of immunoactive relaxin appeared in the serum of pregnant hyenas in the 2 wk preceding parturition. Immunoassays of extracts of hyena tissues and serum obtained from uterine and ovarian veins indicated that the placenta was the predominant source of relaxin, with possible ovarian contributions. Circulating relaxin decreased promptly following cesarean section near term. We conclude that relaxin secretion coincides with changes in extensibility of clitoral connective tissues 1) during growth of the clitoris in juveniles and 2) near the time of parturition in adults.


Extracellular nucleic acids in cultures of long-term cultivated eukaryotic cells.
Investigation of the kinetics of nucleic acid release by HeLa (human cervical carcinoma cell line) and A431 (human squamous carcinoma cell line) cells is presented. The released DNA and RNA were shown to accumulate in culture medium and at the cell surface. A portion of cell surface bound RNA can be eluted with PBS/EDTA. Mild trypsin treatment is required for complete detachment of cell surface bound RNA and cell surface bound DNA. Electrophoretic analysis reveals characteristic patterns of cell-associated and free RNA and DNA molecules.


Simultaneous over activation of EGFR, telomerase (h TERT), and cyclin D1 correlates with advanced disease in larynx squamous cell carcinoma: a tissue microarray analysis.
Overexpression of Epidermal Growth Factor Receptor (EGFR) and also of cell cycle control proteins, such as cyclin D1 is a frequent event in squamous cell carcinoma of the larynx (LSSC). Our aim was to correlate their protein levels with telomerase catalytic subunit (h-TERT) expression. Using tissue microarray technology, fifty-five paraffin embedded histologically confirmed primary LSSCs and also ten dysplastic lesions were cored at a diameter of 1.5 mm. Immunohistochemistry (IHC) was performed by the use of anti-EGFR, anti-cyclin D1, and anti-h TERT monoclonal antibodies. Chromogenic in situ hybridization (CISH) analysis was also applied using EGFR gene and chromosome 7 probes, respectively. EGFR, cyclin D1 and h-TERT protein overexpression was observed in 48/55 (87.2%), 19/55 (34.5%) and 21/55 (38.1%) carcinoma cases, respectively. EGFR protein expression was statistically associated with grade (P=0.01), and also with stage (P=0.001) of the examined tumors. Borderline statistical significance was assessed correlating overall cyclin D1 expression to h TERT expression (P=0.06). Simultaneous up regulation of the three proteins was established in 7/55 (12.7%) cases, correlated to the stage of the tumors (P=0.05). EGFR gene amplification was observed in 7/65 (10.7%) carcinomas and dysplasias, whereas chromosome 7 aneuploidy was detected in 4/65 (6.1%) of those cases.Simultaneous up regulation of EGFR, cyclin D1 and h TERT proteins correlates with advanced stage in LSCC. EGFR gene amplification and not only protein over expression maybe is the eligible criterion for targeted therapeutic strategies in those patients.


Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells.
Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.


Estimating US Background Ozone Using Data Fusion.
US background (US-B) ozone (O3) is the O3 that would be present in the absence of US anthropogenic (US-A) emissions. US-B O3 varies by location and season and can make up a large, sometimes dominant, portion of total O3. Typically, US-B O3 is quantified using a chemical transport model (CTM) though results are uncertain due to potential errors in model process descriptions and inputs, and there are significant differences in various model estimates of US-B O3. We develop and apply a method to fuse observed O3 with US-B O3 simulated by a regional CTM (CMAQ). We apportion the model bias as a function of space and time to US-B and US-A O3. Trends in O3 bias are explored across different simulation years and varying model scales. We found that the CTM US-B O3 estimate was typically biased low in spring and high in fall across years (2016-2017) and model scales. US-A O3 was biased high on average, with bias increasing for coarser resolution simulations. With the application of our data fusion bias adjustment method, we estimate a 28% improvement in the agreement of adjusted US-B O3. Across the four estimates, we found annual mean CTM-simulated US-B O3 ranging from 30 to 37 ppb with the spring mean ranging from 32 to 39 ppb. After applying the bias adjustment, we found annual mean US-B O3 ranging from 32 to 33 ppb with the spring mean ranging from 37 to 39 ppb.


Perceived Barriers to Rapid Response Team Activation Among Nurses.
The purpose of this literature review was to investigate the major barriers nurses face when it is necessary to seek additional assistance and resources by calling the rapid response team (RRT) in order to manage and stabilize a clinically deteriorating patient. A total of 40 articles were reviewed. Eight barriers were identified as having an impact on RRT activation, either causing a delay in activation time or preventing activation altogether: a lack of consistent RRT education among nurses, the established hierarchy in the hospital, an uncertainty about when to call the RRT if clinical deterioration is subtle or gradual rather than abrupt, a perceived need to justify a decision to call the RRT, the increased workload for both the ICU nurse and the medical-surgical nurse, negative past experiences with RRTs, an unsupportive unit culture, and less nursing experience. Suggestions for overcoming these barriers include RRT education for nurses and physicians in addition to fostering a supportive unit culture.


Histopathologic Features of Chronic Rhinosinusitis in Diabetic Patients.
To explore how diabetes mellitus impacts chronic rhinosinusitis clinically and on structured histopathology to provide insights on new potential chronic rhinosinusitis endotypes. Retrospective cohort study. Tertiary academic center. A retrospective study of chronic rhinosinusitis patients who underwent functional endoscopic sinus surgery from 2015 to 2020 was performed. Structured 13-variable histopathology reports were generated from intraoperative sinonasal specimens. These variables were compared against demographic factors, comorbidities, culture data, and preoperative Lund-Mackay and SNOT-22 scores using logistic regression. There were 411 patients, including 52 diabetics. Diabetes was associated with higher mean body mass index (34.9 vs 29.2; p < .001), age (57.8 vs 48.0; p < .001), and Gram-negative (40.2% vs 22.7%; p < .030) and coagulase-negative Staphylococcus (49.0% vs 28.5%; p = .008) culture rates. Black (23.1% vs 18.7%) and Hispanic (23.1% vs 8.6%) races were more common with diabetes (p = .026). Gender, smoking, polyp status, and Lund-Mackay and SNOT-22 scores did not differ between groups. Diabetics had more fungal elements (13.5% vs 3.3%, p = .018); no other histopathological differences were seen. When controlling for demographic variables and comorbidities, diabetes independently predicted the presence of fungal elements (HR 4.38, p = .018). Diabetic chronic rhinosinusitis patients demonstrated increased fungal elements on structured histopathology. Other histopathological features were unaffected by diabetes. These findings may have important implications on the medical and surgical management of diabetic chronic rhinosinusitis patients in which early fungal disease assessment is paramount.


Noradrenergic and serotonergic receptor system function in panic disorder and depression.
Recent studies which have utilized the administration of neurotransmitter agonists and antagonists to study presynaptic and postsynaptic receptor system function in panic disorder and major depression are reviewed. In panic disorder, patients have been found to be overly sensitive to the alpha-2 adrenergic agonist clonidine, and the alpha-2-adrenergic antagonist yohimbine, but they have relatively normal responses to tryptophan, the precursor of serotonin, and MCPP, a directly acting serotonin agonist. In depression, patients appear to have relatively normal responses to clonidine and yohimbine except for some supersensitivity to yohimbine effects on blood pressure and subjective symptoms. In contrast to the panic disorder patients, depressed patients demonstrate a neuroendocrine subsensitivity to tryptophan. Taken together, these studies suggest a relative abnormality in the alpha-2-adrenergic regulation of the noradrenergic system in panic disorder and a subsensitivity of the serotonergic system in depression. The pharmacologic treatment response in panic disorder and depression is similar in that both conditions respond to tricyclic antidepressants and monoamine oxidase inhibitors, but different in that panic disorder does not respond to atypical antidepressants such as trazodone and bupropion, but does respond to benzodiazepines, in contrast to depression. The possible mechanisms involved in producing these findings and the methods to more fully study possible receptor system abnormalities in these illnesses are discussed.


[History of professionalization of modern clinical pharmacist (2): reformation of medical systems before and after the French Revolution].
Paradoxically the medical reformation at the French Revolution is based on two concepts; one was the free medical and pharmaceutical practices without professional licence and another was the nationalistic centralization. The newborn nationalistically centralized institution was applied simultaneously in the field of politics and modern medicine. The physicians of "Société Royale de Médecine" started to investigate the epidemic diseases all over France in 1778. After the French Revolution, it soon developed into a larger public organization that represented the knowledge of medicine and the collegiate mind of the Société shared among the practicioners.


Bioimaging of fluorescence-labeled mitochondria in subcutaneously grafted murine melanoma cells by the "in vivo cryotechnique".
The microenvironments of organs with blood flow affect the metabolic profiles of cancer cells, which are influenced by mitochondrial functions. However, histopathological analyses of these aspects have been hampered by technical artifacts of conventional fixation and dehydration, including ischemia/anoxia. The purpose of this study was to combine the in vivo cryotechnique (IVCT) with fluorescent protein expression, and examine fluorescently labeled mitochondria in grafted melanoma tumors. The intensity of fluorescent proteins was maintained well in cultured B16-BL6 cells after cryotechniques followed by freeze-substitution (FS). In the subcutaneous tumors of mitochondria-targeted DsRed2 (mitoDsRed)-expressing cells, a higher number of cancer cells were found surrounding the widely opened blood vessels that contained numerous erythrocytes. Such blood vessels were immunostained positively for immunoglobulin M and ensheathed by basement membranes. MitoDsRed fluorescence was detected in scattering melanoma cells using the IVCT-FS method, and the total mitoDsRed volume in individual cancer cells was significantly decreased with the expression of markers of hypoxia. MitoDsRed was frequently distributed throughout the cytoplasm and in processes extending along basement membranes. IVCT combined with fluorescent protein expression is a useful tool to examine the behavior of fluorescently labeled cells and organelles. We propose that the mitochondrial volume is dynamically regulated in the hypoxic microenvironment and that mitochondrial distribution is modulated by cancer cell interactions with basement membranes.


Development of rapid bioconversion with integrated recycle technology for ethanol production from extractive ammonia pretreated corn stover.
High enzyme loading and low productivity are two major issues impeding low cost ethanol production from lignocellulosic biomass. This work applied rapid bioconversion with integrated recycle technology (RaBIT) and extractive ammonia (EA) pretreatment for conversion of corn stover (CS) to ethanol at high solids loading. Enzymes were recycled via recycling unhydrolyzed solids. Enzymatic hydrolysis with recycled enzymes and fermentation with recycled yeast cells were studied. Both enzymatic hydrolysis time and fermentation time were shortened to 24 h. Ethanol productivity was enhanced by two times and enzyme loading was reduced by 30%. Glucan and xylan conversions reached as high as 98% with an enzyme loading of as low as 8.4 mg protein per g glucan. The overall ethanol yield was 227 g ethanol/kg EA-CS (191 g ethanol/kg untreated CS). Biotechnol. Bioeng. 2017;114: 1713-1720. © 2017 Wiley Periodicals, Inc.


Superior oblique overaction from local anesthesia for cataract surgery.
Traumatic superior oblique dysfunction from cataract surgery appears to be rare, with only 3 reported cases of postoperative Brown syndrome and 1 reported case of postoperative superior oblique weakness. We are not aware of any prior reports of superior oblique overaction occurring after cataract surgery. We describe a patient with acquired superior oblique overaction as a cause of vertical strabismus after cataract surgery. Ocular torsion analysis was essential in localizing the malfunction to the superior oblique muscle. The most likely etiology is myotoxicity from inadvertent intramuscular injection of local anesthetic before cataract surgery.


[Effect of neuroleptic treatment on positive and negative symptoms of schizophrenia and the results of the dexamethasone test].
20 schizophrenic patients (14 men and 6 women), aged 18-50, were studied using the BPRS, Hamilton scale and dexamethasone test before and after treatment with neuroleptic drugs. In the BPRS global rating and positive and negative symptoms rating were analyzed separately. The neuroleptic treatment improved mostly positive symptoms and slightly less depressive symptoms. The smallest effect was exerted on the negative symptoms. The neuroleptic treatment significantly reduced all cortisol levels measured during the dexamethasone test (most the cortisol level measured 17 hours after dexamethasone). The dexamethasone test result normalization depends probably on the neuroleptic treatment -- it did not correlate closely with the clinical improvement.


Autologous bone marrow transplantation with alkyl-lysophospholipid-purged marrow.
Autologous bone marrow transplantation (ABMT) appears to offer clinical benefit to leukemia patients, but the major reason for failure is relapse. This may be related to the presence of residual leukemic cells in the harvested marrow. To circumvent this problem, various procedures have been developed to purge ex vivo residual leukemic cells from the marrow. The alkyl-lysophospholipids are a new group of anticancer drugs that target membranes as their major site of action. They are unique in that they are relatively selectively toxic to neoplastic cells and spare normal marrow stem cells and progenitor cells. The most active compound is edelfosine. Twenty-nine patients with acute leukemia in second or subsequent remission or early relapse or in first remission, either with a history of treated extramedullary relapse, or requiring more than one induction program to achieve remission, underwent ablative therapy followed by infusion of autologous marrow which had been purged by a 4-hour exposure to edelfosine prior to cryopreservation. Thirty-one percent of the patients are alive and free of leukemia for a median of 630 days (range 185-1,613). These results in this high-risk group of patients warrant further investigation.


Effect of S-adenosylmethionine on liver regeneration induced by partial hepatectomy.
S-adenosylmethionine (SAMe) is a key metabolite regulating growth, differentiation and death of hepatocytes. Experimentally, exogenous SAMe has been documented to attenuate hepatocarcinogenesis. The aim of our study was to evaluate the effect of SAMe on proliferation of hepatocytes that are not cancerously transformed. Partial 2/3 hepatectomy (PH) was performed in rats, control animals underwent laparotomy. SAMe was injected immediately after the surgery and then at 24 h intervals for two days at 10 or 40 mg/kg. The animals were sacrificed 24, 48 and 72 h after operation and the intensity of liver regeneration was evaluated. SAMe treatment at 10 mg/kg was associated with decrease in the synthesis of liver DNA 48 h after PH, however, it was not reflected in DNA content. SAMe treatment at 40 mg/kg led to the reduction of DNA synthesis 72 h after PH followed by the diminution of DNA content. The results have documented the inhibition of the liver regeneration by SAMe that may be mediated by the suppression of liver fat accumulation. Cell GSH level correlating with the growth rate was not affected by SAMe. Prevention from the decrease in the intracellular content of SAMe, as a factor attenuating regeneration remains to be verified.


Sol-gel synthesis and behaviour of nickel containing ZnO nanoparticles.
An attempt has been made to synthesize nickel (up to 5 at%) containing ZnO diluted magnetic semiconductors by sol-gel process using zinc acetate dihydrate, nickel acetate tetrahydrate and oxalic acid as precursors and ethanol as solvent. The process comprises of gel formation, digestion at 80 degrees C for 24 h to obtain oxalate and calcination at 400 degrees C or above for 2 h for decomposition to oxide. The resulting powders correspond to wurtzite hexagonal structure similar to that of pure ZnO and contain nanoparticles of average diameter decreasing with (i) decrease of calcination temperature and (ii) rise in nickel content (range being 13-29 nm). Evidence has been advanced to suggest occupancy of Ni2+ ions in Zn2+ sites (i.e., in the centre of O2- tetrahedra) without any secondary phase. Further, the first nearest neighbor average distance of Ni2+ ions vary inversely as cube root of nickel content ('x'). Optical absorption peaks are attributed to transitions from 3T1 (F) to 3A2(F), 3T1(P) and 3T2(F) states of Ni2+ ion (3d8 configuration). The bifurcation in magnetization versus temperature curves under zero field cooled (ZFC) and field cooled (FC) conditions indicates the presence of magnetic nanoparticles with the blocking temperature (TB) decreasing with increase in nickel content; typical values being 70 and 30 K for 1 and 5 at% of Ni2+ containing ZnO, respectively. The observations of (i) hysteresis loops both at 10 and 298 K and (ii) shift in electron spin resonance (ESR) spectra from the free electron position enunciate ferromagnetic nature of Zn(1-x)Ni(x)O nanoparticles at room temperature.


2% Ganciclovir Eye Drops Control Posner-Schlossman Syndrome Relapses With/Without Cytomegalovirus Intraocular Reactivation.
To observe and compare the efficacy of 2% ganciclovir eye drops in the treatment of Posner-Schlossman Syndrome relapses with/without cytomegalovirus intraocular reactivation. A prospective cohort study enrolling 101 patients diagnosed unilateral Posner-Schlossman Syndrome in Eye & ENT hospital, Fudan University, Shanghai, China. Thorough ophthalmic examinations were given. Aqueous humor sample was collected from the attacked eye of each patient and all pathogen immunoglobulins tests were performed. All patients were treated with appropriate corticosteroids and intraocular pressure-lowering drugs. 2% ganciclovir eye drops were given to patients whose cytomegalovirus antibody aqueous humor/serum correction ratio >0. Patients were followed up for 2 months. Ocular manifestations and cumulative drug dose were recorded. A cytomegalovirus ratio >0.40 was considered cytomegalovirus reactivation. The reactivation group (N = 46) had significantly higher percent of iris depigmentation (78.26%, P < 0.05) and endothelial cell loss rate (19.46%, P < 0.001) than the latent group (N = 55, 58.18% and 10.86%, respectively). The cumulative treatment time and 2% ganciclovir doses were 6.50 ± 4.67 weeks and 181.70 ± 130.95 drops for the reactivation group; 5.95 ± 4.11 weeks and 161.89 ± 110.66 drops for the latent group (P > 0.05). The median cumulative 2% ganciclovir estimated for inflammation control were 252.00 ± 50.71 and 224.00 ± 32.45 drops for the reactivation and latent group. The residual rate of uncontrolled cases was 0.19 ± 0.15 and 0.00, respectively (P < 0.05). A treatment course of 8-9 weeks' 2% ganciclovir is recommended to relapses both with and without cytomegalovirus intraocular reactivation. Preventive ganciclovir application may benefit patients with historical cytomegalovirus infections. www.chictr.org.cn, identifier: ChiCTR1900022340, Date: 2019/04/06.


Quantification of cell culture factors affecting recombinant protein yields in baculovirus-infected insect cells.
An experimental study was undertaken to quantify the effects of infection cell density, medium condition, and surface aeration on recombinant protein yields in insect cells. In the absence of surface aeration and fresh medium, insect cells generated higher product yields (on a per cell basis) when infected with recombinant baculovirus at low cell densities, LCD (3 x 10(5)-4 x 10(5) cells/mL), than at high cell densities, HCD (>0.9 x 10(6) cells/mL), for two distinct baculovirus types. Surface aeration of a HCD culture infected in spent medium improved beta-galactosidase yields 5-fold over the nonaerated case. Surface aeration and medium replenishment improved beta-galactosidase yields of a HCD culture by 20-fold (compared to a 1.6-fold improvement for a LCD culture), resulting in cultures with productivties that were independent of the cell density at infection.


[Significance of glaucoma and the mediation of meanings of aging from the Vygotsky's perspective: contribution to health education].
The objective was to obtain support to the health education of elderly with glaucoma. We interviewed three glaucoma patients, with ages above 60 years, individually, prior to a group session. We identified and analyzed the senses and meanings of glaucoma and of life itself as well the relationship between them, from the Vygotsky's perspective. The significance of glaucoma takes form during the patient's emotional constitution and experiences, remodelling of their subjective condition and their lives. The central motivation in this significance is the hope of a cure for glaucoma and the desire to preserve the autonomy and independence.


Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells.
The homomeric α7 nicotinic receptor (nAChR) is one of the most abundant nAChRs in the central nervous system where it contributes to cognition, attention, and working memory. α7 nAChR is also present in lymphocytes, dendritic cells (DCs), and macrophages and it is emerging as an important drug target for intervention in inflammation and sepsis. Natural killer (NK) cells display cytotoxic activity against susceptible target cells and modulate innate and adaptive immune responses through their interaction with DCs. We here show that human NK cells also express α7 nAChR. α7 nAChR mRNA is detected by RT-PCR and cell surface expression of α7 nAChR is detected by confocal microscopy and flow cytometry using α-bungarotoxin, a specific antagonist. Both mRNA and protein levels increase during NK stimulation with cytokines (IL-12, IL-18, and IL-15). Exposure of cytokine-stimulated NK cells to PNU-282987, a specific α7 nAChR agonist, increases intracellular calcium concentration ([Ca(2+)]i) mainly released from intracellular stores, indicating that α7 nAChR is functional. Moreover, its activation by PNU-282987 plus a specific positive allosteric modulator greatly enhances the Ca(2+) responses in NK cells. Stimulation of NK cells with cytokines and PNU-282987 decreases NF-κB levels and nuclear mobilization, down-regulates NKG2D receptors, and decreases NKG2D-dependent cell-mediated cytotoxicity and IFN-γ production. Also, such NK cells are less efficient to trigger DC maturation. Thus, our results demonstrate the anti-inflammatory role of α7 nAChR in NK cells and suggest that modulation of its activity in these cells may constitute a novel target for regulation of the immune response.


Hemodynamic responses to surgical stimuli in brain-death organ donors.
Though spinal reflexes have been described in experimental brain-death animals, no documentation has been previously provided for human. The hemodynamic responses to surgical stimuli have been investigated here in eight brain-death organ donors. Baseline systolic blood pressure, diastolic blood pressure, and heart rate in observed patients were 99 +/- 15 mmHg, 61 +/- 13 mmHg, and 105 +/- 22 beats/min respectively. After skin incision, these parameters elevated maximally to 130 +/- 23 mmHg, 74 +/- 17 mmHg, and 119 +/- 18 beats/min (p < 0.05). Either spinal reflex arcs or adrenal medullary stimulation, or both, have been speculated to possibly play the role in these hemodynamic responses. However, the existence of such responses should not invalidate the diagnosis of brain death.


Serine-γPNA, Invader probes, and chimeras thereof: three probe chemistries that enable sequence-unrestricted recognition of double-stranded DNA.
Three probe chemistries are evaluated with respect to thermal denaturation temperatures, UV-Vis and fluorescence characteristics, recognition of complementary and mismatched DNA hairpin targets, and recognition of chromosomal DNA targets in the context of non-denaturing fluorescence in situ hybridization (nd-FISH) experiments: (i) serine-γPNAs (SγPNAs), i.e., single-stranded peptide nucleic acid (PNA) probes that are modified at the γ-position with (R)-hydroxymethyl moieties, (ii) Invader probes, i.e., DNA duplexes modified with +1 interstrand zippers of 2'-O-(pyren-1-yl)methyl-RNA monomers, a molecular arrangement that results in a violation of the neighbor exclusion principle, and (iii) double-stranded chimeric SγPNAs:Invader probes, i.e., duplexes between complementary SγPNA and Invader strands, which are destabilized due to the poor compatibility between intercalators and PNA:DNA duplexes. Invader probes resulted in efficient, highly specific, albeit comparatively slow recognition of the model DNA hairpin targets. Recognition was equally efficient and faster with the single-stranded SγPNA probes but far less specific, whilst the double-stranded chimeric SγPNAs:Invader probes displayed recognition characteristics that were intermediate of the parent probes. All three probe chemistries demonstrated the capacity to target chromosomal DNA in nd-FISH experiments, with Invader probes resulting in the most favorable and consistent characteristics (signals in >90% of interphase nuclei against a low background and no signal in negative control experiments). These probe chemistries constitute valuable additions to the molecular toolbox needed for DNA-targeting applications.


Effects of lithium on oxidative stress and behavioral alterations induced by lisdexamfetamine dimesylate: relevance as an animal model of mania.
Lisdexamfetamine dimesylate (LDX) is a prodrug that requires conversion to d-amphetamine (d-AMPH) for bioactivity. Treatment with d-AMPH induces hyperlocomotion and is regarded as a putative animal model of bipolar mania. Therefore, we sought to determine the behavioral and oxidative stress alterations induced by sub-chronic LDX administration as well as their reversal and prevention by lithium in rats. A significant increment in locomotor behavior was induced by LDX (10 and 30 mg/kg). To determine Li effects against LDX-induced alterations, in the reversal protocol rats received LDX (10 or 30 mg/kg) or saline for 14 days. Between days 8 and 14 animals received Li (47.5 mg/kg, i.p.) or saline. In the prevention paradigm, rats were pretreated with Li or saline prior to LDX administration. Glutathione (GSH) levels and lipid peroxidation was determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) of rats. Lithium prevented LDX-induced hyperlocomotion at the doses of 10 and 30 mg/kg, but only reversed LDX-induced hyperlocomotion at dose of 10mg/kg. In addition, both doses of LDX decreased GSH content (in ST and PFC), while Li was able to reverse and prevent these alterations mainly in the PFC. LDX (10 and 30 mg/kg) increased lipid peroxidation which was reversed and prevented by Li. In conclusion, LDX-induced hyperlocomotion along with associated increments in oxidative stress show promise as an alternative animal model of mania.


Real-time 3-dimensional echocardiography in the operating room.
Real-time 3-dimensional transesophageal echocardiography (RT-3D-TEE) represents a novel clinical and intuitively educational perioperative cardiovascular imaging modality. The development of RT-3D-TEE allows for live 3D imaging as it circumvents most of the disadvantages of reconstructive 3D methods. RT-3D-TEE will likely revolutionize perioperative assessment of complex 3D structures, such as the mitral valve (MV), as it provides important mechanistic insights into functional and ischemic mitral regurgitation. The MV is particularly suited to live RT-3D-TEE assessment because of the complex interrelationships among the valve, chordae, papillary muscles, and myocardial walls. The 3D en face view of the MV is in accordance with the surgical view and allows to illustrate the unique saddle shape of the MV annulus and to define and localize mitral leaflet lesions in MV prolapse, endocarditis, or congenital MV abnormalities, all potentially important in guiding surgical repair. RT-3D-TEE will soon be integrated into routine perioperative practice. Its unique ability of real-time acquisition, online rendering and cropping capabilities, accurate identification of the precise pathology and location of cardiac disease, together with its ability to promptly quantify 3D data sets using built-in software, will likely help in transitioning this modality into standard of care.


Acute and chronic responses of activated sludge viability and performance to silica nanoparticles.
Recently, the potential health and environmental risks of silica nanoparticles (SiO(2) NPs) are attracting great interest. However, little is known about their possible impacts on wastewater biological nitrogen and phosphorus removal. In this study, the acute and chronic effects of SiO(2) NPs on activated sludge viability and biological nutrient removal performance were investigated. It was found that the presence of environmentally relevant concentration (1 mg/L) of SiO(2) NPs caused no adverse acute and chronic effects on sludge viability and wastewater nitrogen and phosphorus removal. However, chronic exposure to 50 mg/L SiO(2) NPs induced the increase of effluent nitrate concentration, and thus depressed the total nitrogen (TN) removal efficiency from 79.6% to 51.6% after 70 days of exposure, which was due to the declined activities of denitrifying enzymes, nitrate reductase and nitrite reductase. Wastewater phosphorus removal was insensitive to 1 and 50 mg/L SiO(2) NPs after either the acute or chronic exposure, because the critical factors closely related to biological phosphorus removal were not significantly changed, such as the activities of exopolyphosphatase and polyphosphate kinase and the intracellular transformations of polyhydroxyalkanoates and glycogen. Denaturing gradient gel electrophoresis (DGGE) analysis revealed that the bacterial community structure was changed after long-term exposure to 50 mg/L SiO(2) NPs, and the quantitative PCR assays indicated that the abundance of denitrifying bacteria was decreased, which was consistent with the declined wastewater nitrogen removal.


Independent and interchangeable multimerization domains of the AbrB, Abh, and SpoVT global regulatory proteins.
The global regulators AbrB, Abh, and SpoVT are paralogous proteins showing their most extensive sequence homologies in the DNA-binding amino-terminal regions (about 50 residues). The carboxyl-terminal portion of AbrB has been hypothesized to be a multimerization domain with little if any role in DNA-binding recognition or specificity. To investigate the multimerization potentials of the carboxyl-terminal portions of AbrB, Abh, and SpoVT we utilized an in vivo multimerization assay system based upon fusion of the domains to the DNA binding domain of the lambda cI repressor protein. The results indicate that the N and C domains of all three paralogues are independent dimerization modules and that the intact Abh and SpoVT proteins are most probably tetramers. Chimeric proteins consisting of the AbrB N-terminal DNA-binding domain fused to the C domain of either Abh or SpoVT are indistinguishable from wild-type AbrB in their ability to regulate an AbrB target promoter in vivo.


Genetic Variants of the MGAT5 Gene Are Functionally Implicated in the Modulation of T Cells Glycosylation and Plasma IgG Glycome Composition in Ulcerative Colitis.
The impact of genetic variants (single nucleotide polymorphisms [SNPs]) in the clinical heterogeneity of ulcerative colitis (UC) remains unclear. We showed that patients with UC exhibit a deficiency in MGAT5 glycogene transcription in intestinal T cells associated with a hyperimmune response. Herein, we evaluated whether MGAT5 SNPs might functionally impact on T cells glycosylation and plasma IgG glycome in patients with UC, as well as in UC clinical outcomes. Three selected MGAT5 SNPs (rs3814022, rs4953911, and rs1257220), previously associated with severity of autoimmune disease or with plasma glycome composition in healthy individuals, were functionally evaluated in patients with UC through analysis of MGAT5 mRNA levels in colonic (n = 14) and circulating (n = 24) T cells and through profiling the plasma IgG Fc glycosylation (n = 152). MGAT5 SNPs were genotyped in 931 patients with UC from 2 European cohorts and further associated with patients' prognosis. Targeted next-generation sequencing for MGAT5 coding and regulatory regions was also performed. MGAT5 SNPs were shown to be functionally associated with low transcription levels of MGAT5 in colonic and circulating T cells from patients with UC and with agalactosylation of IgGs, often associated with a proinflammatory phenotype. The SNPs rs3814022 and rs4953911 were further associated with the need of biologics. Next-generation sequencing data further revealed a combination of MGAT5 SNPs that stratify patients with UC according to their severity. Our results revealed that MGAT5 SNPs have a phenotypic impact on T cells glycosylation and in plasma IgG glycome composition associated with UC pathogenesis. MGAT5 SNPs display a tendency in the association with a worse disease course in patients with UC.


Understanding the Effect of Functional Groups on the Seeded Growth of Copper on Carbon Nanotubes for Optimizing Electrical Transmission.
We present a study of the seeded growth of copper on the surface of two classes of single-walled carbon nanotubes (SWNTs) in order to compare the effects of surface functional groups. Pyridine-functionalized HiPco SWNTs and ultrashort SWNTs (US-SWNTs) were synthesized (py-SWNTs and py-US-SWNTs, respectively), and the functionality was used as seed sites for copper, via an aqueous electroless deposition reaction, as a comparison to the carboxylic acid functionality present on piranha-etched SWNTs and the native US-SWNTs. UV-vis spectroscopy demonstrated the take-up of Cu(II) ions by the functionalized SWNTs. TEM showed that the SWNTs with pyridine functionality more rapidly produced a more even distribution of copper seeds with a narrower size distribution (3-12 nm for py-US-SWNTs) than those SWNTs with oxygen functional groups (ca. 30 nm), showing the adventitious role of the pyridine functional group in the seeding process. Seed composition was confirmed as Cu(0) by XPS and SAED. Copper growth rate and morphology were shown to be affected by degree of pyridine functionality, the length of the SWNT, and the electroless reaction solvent used.


Transcriptional and Histone Acetylation Changes Associated with CRE Elements Expose Key Factors Governing the Regulatory Circuit in the Early Stage of Huntington's Disease Models.
Huntington's disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.


Immunosuppression by the disease modifying antirheumatic drug bucillamine: inhibition of human T lymphocyte function by bucillamine and its metabolites.
Bucillamine: N-(2-mercapto-2-methyl-propanoyl)-L-cysteine has recently been suggested to be effective in the treatment of rheumatoid arthritis (RA). The molecular structure of this compound is similar to that of D-penicillamine, except that bucillamine has 2 free sulfhydryl groups in its structure whereas D-penicillamine has only one. The goal of our studies was to determine whether bucillamine exerted immunosuppressive effects in vitro. The effect of bucillamine and its metabolites on mitogen induced proliferation and IL-2 production by human T cells was examined. Bucillamine, and its metabolites SA 679, and SA 981 inhibited mitogen induced T cell responses. The inhibitory effect of bucillamine and SA 679, in which one sulfhydryl group is S-methylated, was markedly augmented in the presence of CuSO4, and the effect was completely prevented by the addition of catalase. The capacity of SA 981, the internal disulfide of bucillamine, to inhibit T lymphocyte responses was not dependent on the presence of CuSO4. SA 672, in which both sulfhydryl groups are S-methylated, did not inhibit T cell proliferation. Our results suggest that bucillamine has 2 distinct inhibitory effects on T cell function. One is the ability to generate H2O2 in the presence of CuSO4 and is attributable to its free thiol groups. The other is related to a separate inhibitory mechanism, that is not dependent on CuSO4 or the reduced thiol groups. These 2 immunosuppressive effects may account for the potency of bucillamine in suppressing rheumatoid inflammation.


Idiopathic erythrocytosis--additional new study techniques suggest a heterogenous group.
25 patients with idiopathic erythrocytosis (absolute increase in red cell mass without conventional criteria of primary polycythaemia or known underlying cause) have been further studied for evidence of primary or secondary polycythaemia. Additional non-conventional criteria used were: platelet distribution width, platelet nucleotide ratio, serum erythropoietin, clinical evidence of ischaemic vascular disease and erythroid culture variables in serum-free system. All had been used in an earlier study in score form to assist in the diagnosis of primary polycythaemia. These patients were also newly assessed for the presence of hypoxia (supine oximeter values, history suggestive of sleep apnoea), for renal lesions and for splenic enlargement (impalpable) by ultrasound or computerized tomography. 7 patients had erythroid culture scores suggesting primary polycythaemia but the addition of non-culture criteria did not result in any scores more strongly predictive of primary polycythaemia. Supine oximeter values < 92% suggested hypoxaemia as the mechanism of polycythaemia in 3 patients in whom it had not previously been suspected. Some splenic enlargement (impalpable) was demonstrated in 6 patients, only 1 of whom had erythroid culture scores suggesting primary polycythaemia. 12 patients had confirmed, raised erythropoietin levels. We conclude that idiopathic erythrocytosis refers to a heterogenous group of patients. Features of primary or secondary polycythaemia may be demonstrated in some of them by additional new study techniques. The raised erythropoietin values found in half the patients were unexpected.


Changes in contractile properties by androgen hormones in sexually dimorphic muscles of male frogs (Xenopus laevis).
1. Male frogs (Xenopus laevis) were castrated then given either empty or testosterone-filled implants to produce animals with low or high levels of circulating testosterone. Eight weeks later the contractile properties of an androgen-sensitive forelimb flexor, the flexor carpi radialis muscle (FCR), were measured in vitro. Another forelimb flexor muscle, the coracoradialis, and a hindlimb muscle, the iliofibularis, were analysed similarly. 2. Plasma testosterone levels were 0.9 +/- 0.3 ng/ml (+/- S.E.M.) in castrated frogs with blank implants (C) and 61.3 +/- 4.7 ng/ml in castrates with testosterone implants (CT). Unoperated males, sampled at various times of the year, ranged between 10.8 and 51.0 ng/ml. 3. With direct electrical stimulation of the FCR, contraction time of the isometric twitch was not affected by testosterone levels. Relaxation times were affected, however. Half- and 90% relaxation times were 27 and 42% longer, respectively, for CT compared to C muscles. 4. Testosterone also had no effect on the contraction time of twitches elicited by stimulation of the FCR nerve. Half- and 90% relaxation times were 51 and 76% longer, respectively, for CT compared to C muscles. 5. Tetanus tension, elicited by direct stimulation of the FCR at 50 Hz, was 86% greater in CT compared to C muscles. The average cross-sectional area of FCR muscle fibres was 84% greater in CT muscles. These results implied that testosterone treatment had no effect on specific muscle tension. 6. Stimulation of the FCR nerve at 50 Hz resulted in 53% less tension than the same stimulus applied directly to CT muscles. In C muscles the difference was only 14%. This suggested that testosterone treatment reduced synaptic efficacy. 7. In CT muscles, direct or nerve stimulation of fibres in the shoulder region of the FCR elicited twitches that contracted and relaxed more slowly than fibres in the elbow region. In C muscles there was no difference in contraction or relaxation time between fibres in the shoulder and elbow regions. 8. Testosterone treatment had little effect on contraction and relaxation times or tension levels of coracoradialis or iliofibularis muscles.