Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.
Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.


HIV coinfection does not compromise liver histological response to interferon therapy in patients with chronic hepatitis C.
Although discrepancies between histological and virological responses to anti-hepatitis C virus (HCV) therapy are well-established in HIV-negative patients, the liver histological outcome has never been assessed in HIV-HCV co-infected patients receiving anti-HCV therapy. We compared histological responses to interferon (IFN) alpha therapy between HIV-positive and HIV-negative injecting drug users (IDU) and determined factors associated with histological response. Retrospective cohort study. Hepatology unit of a tertiary referral hospital. Seventy-nine HCV-infected IDU (32 HIV-positive) receiving a 6-month course of IFN-alpha2b therapy, 3 x 106 U three times a week. Histological response, defined by a > or =2 point decrease in total Knodell score measured on paired liver biopsies over a 2-year follow-up period. The sustained response rate to IFN therapy was lower in HIV-positive patients than in HIV-negative patients (6.2% versus 29.8%;P = 0.012). Conversely, the rates of histological response (40.6% versus 36.2%) were not different between HIV-positive and HIV-negative patients. Independent factors associated with histological response were first total Knodell score (P = 0.0007) and sustained response to IFN therapy (odds ratio, 12.34; P = 0.005). Histological response was observed in 25% of IFN non-responders whatever their HIV status. In HIV-positive patients, the CD4 cell count did not influence the histological response. in HIV-HCV co-infected patients treated with IFN, liver histological improvement is frequently observed, similarly to that observed in HIV-negative patients. Such beneficial effect of interferon therapy supports early treatment of chronic hepatitis C in HIV-infected patients.


Microstructure evolution, mechanical properties, and enhanced bioactivity of Ti-13Nb-13Zr based calcium pyrophosphate composites for biomedical applications.
The present study reports the results of the microstructure, mechanical properties and in vitro bioactivity of the Ti-13Nb-13Zr based composite with 10 wt% CPP (calcium pyrophosphate), densified using spark plasma sintering process (SPS) at different sintering temperatures (900-1200 °C). The results show that the sintered composites mainly consist of β-Ti, α-Ti, and ceramic interphases (Ti2O, CaTiO3, CaZrO3, CaO, TixPy). With the sintering temperature increasing, α-Ti and ceramic interphases gradually increase, and relative density, elastic modulus, compressive strength and yield strength of the composites also reveal an increasing tendency. However, Ti-13Nb-13Zr-10CPP composite sintered at 1000 °C exhibits high matching elastic modulus (46 GPa) and compressive strength (1617 MPa) due to uniform structure and high density. In addition, in vitro mineralization assays demonstrate the apatite-forming ability of the composite (1000 °C) and its higher surface bioactivity as compared to the Ti-13Nb-13Zr alloy. Furthermore, ROS1728 osteoblast culture evidences that the composite (1000 °C) stimulates cell adhesion and growth due to the pore characteristics and ceramic interphases. Therefore, the prepared Ti-13Nb-13Zr-10CPP composite at 1000 °C exhibits immense potential as a biomedical material.


Screening for Cognitive Impairments After Traumatic Brain Injury: A Comparison of a Brief Computerized Battery With the Montreal Cognitive Assessment.
Detecting cognitive dysfunction in a busy traumatic brain injury (TBI) clinic is challenging given the length of conventional assessments and the need for psychometric expertise. The authors report the utility of a 10-minute, easily administered computerized battery that is more sensitive than the Montreal Cognitive Assessment in detecting cognitive impairments in people with a TBI.


Affinity-purified c-Jun amino-terminal protein kinase requires serine/threonine phosphorylation for activity.
The addition of phorbol esters to U937 leukemic cells stimulates the phosphorylation of c-Jun on serines 63 and 73. To isolate the protein kinase which stimulates this phosphorylation, we have used heparin-Sepharose chromatography followed by affinity chromatography over glutathione-Sepharose beads bound with a fusion protein of glutathione S-transferase and amino acids 5-89 of c-Jun (GST-c-Jun). Using this procedure we purify a 67-kDa protein which is capable of phosphorylating GST-c-Jun as well as the complete c-Jun protein. By making mutations in serines 63 and 73 and then creating a fusion protein with GST (GST-c-Jun mut), we demonstrate that this protein kinase specifically phosphorylates these sites in the c-Jun amino terminus. Treatment of purified c-Jun amino-terminal protein kinase (cJAT-PK) with phosphatase 2A inhibits its ability to phosphorylate GST-c-Jun. This inactivated enzyme can be reactivated by phosphorylation with protein kinase C (PKC), although PKC is not capable of phosphorylating the GST-c-Jun substrate. Because v-Jun cannot be phosphorylated in vivo, we compared the ability of cJAT-PK to bind to GST-v-Jun or GST-c-Jun mut. The cJAT-PK bound 50-fold better to GST-c-Jun mut than GST-v-Jun suggesting that the delta domain which is missing in v-Jun plays a role in binding the cJAT-PK. These results suggest that there is a protein kinase cascade mediated by protein phosphatases and PKC which regulates c-Jun phosphorylation.


Doppler echocardiographic methods to estimate severity of aortic stenosis.
The continuity equation should be regarded as the Doppler echocardiographic gold standard for estimation of valve area in patients with aortic stenosis, but a quick, easy, and inexpensive screening test may be desirable in an era of medical cost containment. Aortic valve leaflet separation could be used as such a test. In fact, it could prove especially useful in cases where calculations using the continuity equation or the fractional shortening-velocity ratio are problematic.


The effect of HIF-1alpha siRNA on growth and chemosensitivity of MIA-paca cell line.
Hypoxia-inducible factor-1alpha (HIF-1alpha) primarily mediates the hypoxic response. HIF-1alpha induction by various stimuli contributes to cell proliferation and survival. To investigate the effect of HIF-1alpha, we used small interfering RNA (siRNA), and expected that cell apoptosis and sensitivity to chemotherapeutic drug increase, when we blocked the HIF-1alpha gene. Thus we performed in vitro and in vivo experiment to clarify the effect of hypoxia-inducible factor-1alpha on tumor growth. We made control and HIF-1alpha siRNA using vector plasmid and then transfected Mia-paca cell lines with these RNAs. After selection with geneticin, two new cell lines were made, confirmed via immunoblotting. After treating with gemcitabine, each cell line was assayed to confirm the effect of HIF-1alpha siRNA using the cell proliferation assay and capase-3 assay. And then in vivo study was performed using female athymic nude mice. After subcutaneously injecting each new cell lines, intraperitoneal gemicitabine chemotherapy was performed for 3 weeks. During that period, we analyzed the difference of tumor growth rate. The tumor growth of HIF-1alpha siRNA-transfected group was slower than that of the control group both in vitro and in vivo experiment. The suppression of HIF-1alpha results in decrease of cell proliferation and increase of chemosensitivity of pancreatic cancer cell line. Therefore, targeting the HIF-1alpha may be useful treatment modality for some pancreatic cancers.


The effect of stratification and seasonal variability on the profile of an anaerobic swine waste treatment lagoon.
In this study, the characterization of an anaerobic swine waste treatment lagoon from a farrowing operation (approximately 2000 sows) was carried out to examine the dynamics of the system due to stratification and seasonal variability. Swine waste samples were taken at different depths with a pulley system equipped with a special sampler that allows for sampling exclusively at certain depth. Chemicals and microbial dynamics were monitored throughout a one-year-period. Results showed that nutrient (C, N, P, S) concentrations varied according to stratified lagoon layers and season. Trace minerals (Al, Ca, Fe, and Mg), on the other hand, appeared to be affected more by stratification than seasonal variability. Molecular analysis also showed that microbial community structure appeared to be affected by the stratification and seasonal variability. Based on these data, it is important to consider the effect of stratification and seasonal variability in managing these open lagoons.


Anaerobic and aerobic continuous cultures of Saccharomyces cerevisiae: comparison of plasmid stability and EXG1 gene expression.
Two bioreactor continuous cultures, at anaerobic and aerobic conditions, were carried out using a recombinant Saccharomyces cerevisiae strain that over-expresses the homologous gene EXG1. This recombinant system was used to study the effect of dissolved oxygen concentration on plasmid stability and gene over-expression. Bioreactor cultures were operated at two dilution rates (0.14 and 0.03 h(-1)) to investigate the effect of other process parameters on EXG1 expression. Both cultures suffered severe plasmid instability during the first 16 generations. Segregational plasmid loss rate for the aerobic culture was two-fold that of the anaerobic operation. In spite of this fact, exo-beta-glucanase activity at aerobic conditions was 12-fold that of the anaerobic culture. This maximal activity (30 U ml(-1)) was attained at the lowest dilution rate when biomass reached its greatest value and glucose concentration was zero.


Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: a centre randomised, cross-over, open-label study in the Netherlands.
Compare duration of mechanical ventilation (MV), weaning time, ICU-LOS (ICU-LOS), efficacy and safety of remifentanil-based regimen with conventional sedation and analgesia. Centre randomised, open-label, crossover, 'real-life' study. 15 Dutch hospitals. Adult medical and post-surgical ICU patients with anticipated short-term (2-3 days) MV. Patient cohorts were randomised to remifentanil-based regimen (n = 96) with propofol as required, for a maximum of 10 days, or to conventional regimens (n = 109) of propofol, midazolam or lorazepam combined with fentanyl or morphine. Outcomes were weaning time, duration of MV, ICU-LOS, sedation- and analgesia levels, intensivist/ICU nurse satisfaction, adverse events, mean arterial pressure, heart rate. Median duration of ventilation (MV) was 5.1 days with conventional treatment versus 3.9 days with remifentanil (NS). The remifentanil-based regimen reduced median weaning time by 18.9 h (P = 0.0001). Median ICU-LOS was 7.9 days versus 5.9 days, respectively (NS). However, the treatment effects on duration of MV and ICU stay were time-dependent: patients were almost twice as likely to be extubated (P = 0.018) and discharged from the ICU (P = 0.05) on day 1-3. Propofol doses were reduced by 20% (P = 0.05). Remifentanil also improved sedation-agitation scores (P < 0.0001) and intensivist/ICU nurse satisfaction (P < 0.0001). All other outcomes were comparable. In patients with an expected short-term duration of MV, remifentanil significantly improves sedation and agitation levels and reduces weaning time. This contributes to a shorter duration of MV and ICU-LOS.


Resveratrol attenuates inflammation and apoptosis through alleviating endoplasmic reticulum stress via Akt/mTOR pathway in fungus-induced allergic airways inflammation.
Resveratrol has shown pleiotropic effects against inflammation and oxidative response. The present study aimed to investigate the effects and mechanisms of resveratrol on fungus-induced allergic airway inflammation. Female BALB/c mice were injected intraperitoneally with Aspergillus fumigatus (Af) extract emulsified with aluminum on day 0 and 7 and intranasally challenged with Af extracts on day 14 and 15. Resveratrol or dexamethasone or a vehicle was injected intraperitoneally 1 h before each challenge. Mice were sacrificed for serum, bronchoalveolar lavage fluid (BALF), and lungs 24 h after the last challenge. The control group was administered with saline. BEAS-2B was used for the experiments in vitro that Af-exposed airway epithelial cells. Resveratrol and dexamethasone attenuated the airway inflammation and eosinophilia, and reduced not only the production of IL-4, IL-5, and IL-13 in the BALF and lung tissues but also the mRNA levels of lung IL-6, TNF-α, and TGF-β induced by Af challenge (P < 0.05). Furthermore, Af-induced lung endoplasmic reticulum (ER) stress-related proteins PERK, CHOP, and GRP78 and the apoptosis markers including cleaved caspase-3 and cleaved caspase-7 were both suppressed significantly by resveratrol (P < 0.05). In vitro, activation of ER stress and the Akt/mTOR pathway in Af-exposed BEAS-2B cells were effectively ameliorated by resveratrol. Inhibition of the Akt/mTOR pathway using LY294002 suppressed the ER stress while ER stress inhibitor 4-PBA decreased the apoptosis in Af-exposed BEAS-2B cells. Our findings collectively revealed that resveratrol alleviated the Af-exposed allergic inflammation and apoptosis through inhibiting ER stress via Akt/mTOR pathway, exerting therapeutic effects on the fungus-induced allergic lung disorder.


Impact of strabismus and binocular dysfunctions in the developmental eye movement test and test of visual perception skills: A multicentric and retrospective study.
To compare the performance in the Developmental Eye Movement test (DEM) and the Test of Visual Perceptual Skills (TVPS) between three groups: individuals with strabismus and amblyopia, patients with binocular and accommodative dysfunctions, and subjects with normal binocular and accommodative function. A multicentric, retrospective study including 110 children aged 6-14 years old was conducted to investigate the potential impact of strabismus, amblyopia, and different binocular conditions in DEM results (adjusted time in vertical and horizontal parts) and TVPS (percentiles in the seven sub-skills). No significant differences were found in the different subtests of the vertical and horizontal DEM and all the sub-skills in the TVPS between the three groups of the study. We found high variability of performance in the DEM test between participants with strabismus and amblyopia compared with binocular and accommodative problems. DEM and TVPS scores have not been found to be influenced by the presence of strabismus with or without amblyopia, nor by binocular and accommodative dysfunctions. A slightly correlation tendency with horizontal DEM and degree of exotropia deviation was observed.


New trends in the management of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a survey of the Infectious Diseases Working Pary of EBMT.
The management of cytomegalovirus (CMV) infection was assessed with a survey performed in 2020 by the Infectious Diseases Working Party of European Society for Blood and Marrow Transplantation (EBMT). One-hundred-eighty of the 579 EBMT centres (31%) responded. CMV monitoring with quantitative PCR for CMV-DNAemia was used by 97% of centres while the duration of monitoring was variable according to the patient immune recovery and the ongoing immunosuppressive therapy. CMV prophylaxis for high-risk patients was used in 101 (56%) of centres: letermovir in 62 centres (61%), aciclovir/valaciclovir in 19 centres (19%), ganciclovir/valganciclovir in 17 centres (17%), foscarnet in 3 (3%). The most used trigger for pre-emptive therapy was a threshold of >103 copies/ml or >103 IU/ml. Ganciclovir/valganciclovir confirmed the preferred first line treatment both for pre-emptive and CMV disease therapy. CMV-cytotoxic T-cells were used mainly in the setting of relapsing/refractory CMV disease. Forty-eight centres reported CMV refractory/resistant infection due to mutated CMV strain.This survey showed that letermovir prophylaxis is adopted by more than half of centres using a prophylaxis approach for CMV infection. How letermovir prophylaxis will modify other important pillars of daily CMV management, such as frequency of CMV-DNAemia monitoring and preemptive therapy, remain a matter of investigation.


Narrow Complex Tachycardias.
Narrow-complex tachycardias are commonly seen on shift in the emergency department. Although a portion of patients present with hemodynamic instability because of arrhythmia, it is important to know that the tachycardia can be a result of an underlying condition. Rapid identification of the type and etiology of the arrhythmia is vital to directing appropriate management strategies and disposition decisions.


Roles of different humin and heavy-metal resistant bacteria from composting on heavy metal removal.
This study aims to assess the roles of different humin and heavy-metal resistant bacterial community from composting on heavy metal removal. The results showed that the concentration of Cu2+, Zn2+, Ni2+, Pb2+, Cr3+ and Cd2+ decreased with adding the compost-derived humin, but the removal rates were relatively low (<30% on average). The heavy metal resistant bacteria from composting have better metal binding capacities than humin, and the combined addition of humin and bacteria could further stimulate the biosorption of heavy metals with 60-80% removal of metals and improve the diversity and biomass of bacterial community. There was obviously increased synergy between the humin from maturity phase and bacteria for metal biosorption ("1 + 1 > 2"). Structural equation modeling showed that microbial biomass and humin humification are the key factors for the biosorption of heavy metals. Combining humin from maturity phase with heavy-metal resistant bacteria was suggested to control heavy metal pollution in composts.


A compendium of cyclic sugar amino acids and their carbocyclic and heterocyclic nitrogen analogues.
This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their ring size, chemical manipulation of their numerous functional groups and fine-tuning of the stereochemical arrangement of their ring substituents. These building blocks provide access to hydrophilic and hydrophobic peptide isosteres whose physical properties allow entry to a region of chemotherapeutic space which is still under-explored by medicinal chemists. These building blocks are also important in providing amino acids whose inherent conformational bias leads to predisposition to secondary structure upon oligomerisation in relatively short sequences. These foldamers, particularly those containing ω-amino acids, provide an additional opportunity to expand access to the control of structures by artificial peptides. The synthesis and biological evaluation of these building blocks in glycomimetics and peptidomimetics systems keep expanding the reach of the glycosciences to the medical sciences, provide a greater outlook onto the wide range of cellular functions of saccharides and their derivatives involved and greater insight into the nature of oligosaccharide and protein folding.


The cervical spine in rheumatoid arthritis.
Of 53 severely rheumatoid patients, 43% had cervical spine involvement, Six major categories were found: a) C1-C2 subluxation; b) serial subluxation; c) upward translocation of the odontoid; d) odontoid erosion; 3) apophyseal joint fusion; and f) miscellaneous findings of osteoporosis, endplate erosion, and disk space narrowing without osteophytosis. Although disease duration and activity appeared to correlate somewhat with the development of cervical spine disease, this was by no means universal. Rheumatoid cervical spine disease may be dangerous even in the absence of clinical signs and symptoms. It is therefore recommended that the cervical spine be evaluated in patients with severe rheumatoid disease before general anesthesia is scheduled irrespective of cervical spine complaints recorded in the chart.


Canine Caregivers: Paradoxical Challenges and Rewards.
Companion dogs are increasingly popular, 38.4% of households in the United States include at least one dog. There are numerous benefits to sharing one's home with a dog, but because they age more rapidly than people and have shorter lifespans, acquiring a dog often includes caring for it during its senior years. Caring for an elderly dog can be physically and emotionally challenging, yet the impact on guardians' lives when caring for an aging dog has received minimal scientific attention. This study was designed to better understand dog guardians' experiences and perceptions related to caring for their aging dog. Utilizing an exploratory mixed methods design, this study asked dog guardians to complete an online anonymous survey. From a total of 284 participants, we found that the impact on guardians when caring for an aging dog appears to share many similarities with caregivers of human family members. Our quantitative and qualitative results suggest that, for many guardians, caring for an aging dog is a complex dynamic with both positive and negative factors that offers an opportunity to deepen the human-animal bond and create positive, rewarding experiences and memories.


The effect of losartan on the development of post-traumatic joint stiffness in a rat model.
Post-traumatic joint stiffness (PTJS) is accompanied by a multidimensional disturbance of joint architecture. Pharmacological approaches represent promising alternatives as the traumatic nature of current therapeutic standards may lead to PTJS' progression. Losartan is an auspicious candidate, as it has demonstrated an antifibrotic effect in other organs. Forty-eight Sprague Dawley rats were randomized into equally sized losartan or control groups. After a standardized knee trauma, the joint was immobilized for either 2 weeks (n = 16), 4 weeks (n = 16) or 4 weeks with re-mobilization for an additional 4 weeks (n = 16). Pharmacotherapy with losartan or placebo (30 mg/kg/day) was initiated on the day of trauma and continued for the entire course. Joint contracture was measured alongside histological and molecular biological assessments. There were no significant biomechanical changes in joint contracture over time, comparing short-term (2 weeks) with long-term losartan therapy (4 weeks). However, comparing the formation of PTJS with that of the control, there was a trend toward improvement of joint mobility of 10.5° (p 0.09) under the influence of losartan. During the re-mobilization phase, no significant effect of losartan on range of motion (ROM) was demonstrated. At a cellular level, losartan significantly reduced myofibroblast counts by up to 72 % (4 weeks, p ≤ 0.001) without effecting the capsular configuration. Differences in expression levels of profibrotic factors (TGF-β, CTGF, Il-6) were most pronounced at week 4. The antifibrotic properties of losartan are not prominent enough to completely prevent the development of PTJS after severe joint injury.


Proton magnetic resonance spectroscopy thermometry: Impact of separately acquired full water or partially suppressed water data on quantification and measurement error.
In proton magnetic resonance spectroscopy (1 H MRS) thermometry, separately acquired full water and partially suppressed water are commonly used for measuring temperature. This paper compares these two approaches. Single-voxel 1 H MRS data were collected on a 3-T GE scanner from 26 human subjects. Every subject underwent five continuous MRS sessions, each separated by a 2-min phase. Each MRS session lasted 13 min and consisted of two free induction decays (FIDs) without water suppression (with full water [FW or w]) and 64 FIDs with partial water suppression (with partially suppressed water [PW or w']). Frequency differences between the two FWs, the first two PWs, the second FW and the first PW (FW2 , PW1 ), or between averaged water ( wav' ) and N-acetylaspartate (NAA), were measured. Intrasubject and intersubject variations of the frequency differences were used as a metric for the error in temperature measurement. The intrasubject variations of frequency differences between FW2 and PW1fw2-fw1' , calculated from the five MRS sessions for each subject, were larger than those between the two FWs or between the first two PWs (p = 1.54 x 10-4 and p = 1.72 x 10-4 , respectively). The mean values of intrasubject variations of fw2-fw1' for all subjects were 4.7 and 4.5 times those of fw2-fw1 and fw2'-fw1' , respectively. The intrasubject variations of the temperatures based on frequency differences, fw2-fNAA or ( fw1'-fNAA ), were about 2.5 times greater than those based on averaged water and NAA frequencies (fwav'-fNAA ). The mean temperature measured from (fwav'-fNAA ) (n = 26) was 0.29°C lower than that measured from fw2-fNAA and was 0.83°C higher than that from ( fw1'-fNAA ). It was concluded that the use of separately acquired unsuppressed or partially suppressed water signals may result in large errors in frequency and, consequently, temperature measurement.


Microsatellite frameshift variants in SGO1 of gastric cancer are not always associated with MSI status.
Although frameshift variants in the microsatellite area of shugoshin 1 (SGO1) have been reported in the context of microsatellite instability-high (MSI-H)/deficient mismatch repair gastrointestinal cancer, most have been evaluated only in early stage I-III patients, and only two of its five microsatellite regions have been evaluated. Therefore, we investigated the frequency and MSI status of microsatellite frameshift variants in gastric cancer cases, including stage IV. In a total of 55 cases, 30 gastric cancer resection and 25 non-resection cases, DNA was extracted from both tumour and normal parts and PCR was performed. The variant was confirmed by TA cloning, and MSI was evaluated using GeneMapper software. A frameshift variant of c.973delA was observed in 16 of the 45 evaluable cases. Its frequency was 35.6%. Of the 25 cases that could be assessed for MSI status, two cases of MSI-H were associated with the c.973delA SGO1 variant. However, c.973delA SGO1 variant was also observed in four cases of microsatellite stable. Our study shows that SGO1 frameshift variants are not always associated with MSI status.


Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy.
We have developed a procedure for labeling lipoproteins with the fluorescent probe 3,3'-dioctadecylindocarbocyanine (Dil) and have used Dil-labeled native and acetoacetylated lipoproteins to differentiate macrophages from fibroblasts in mixed cell culture. Lipoproteins labeled with this probe were suitable for the direct viewing of their binding and internalization by cells in vitro. The labeling technique has been applied to human low density lipoproteins (LDL) and to two canine cholesterol-induced lipoproteins: apo-E HDLc, which contain only the E apoprotein (apo-E), and beta-migrating, very low density lipoproteins (beta-VLDL), which contain apo-B and apo-E. The Dil-labeled lipoproteins showed specific high affinity binding to human fibroblasts via the LDL (apo-B, -E) receptors. The equilibrium dissociation constant for the binding of Dil-labeled apo-E HDLc and LDL were the same as for the respective native lipoproteins. The specific binding of Dil-labeled LDL and apo-E HDLc was further substantiated by fluorescence microscopy. When an excess of native (non-fluorescent) lipoproteins was added to the Dil-labeled lipoproteins, essentially no fluorescently labeled lipoproteins were seen associated with the cells. The Dil-labeled LDL, apo-E HDLc, and beta-VLDL, which were bound to the cells at 4 degrees C, were associated with the cell surface and were often observed in linear arrays. Cells that were either incubated with Dil-labeled lipoproteins at 4 degrees C and subsequently heated to 37 degrees C or incubated with the Dil-labeled lipoproteins at 37 degrees C showed internalized perinuclear fluorescence. When Dil-labeled LDL, apo-E HDLc, or beta-VLDL were treated with diketene to acetoacetylate their lysine residues, and then were incubated at 37 degrees C with mixtures of fibroblasts and mouse peritoneal macrophages in culture, the fibroblasts did not become fluorescently labeled. The macrophages became highly fluorescent, however. The acetoacetylation inhibited the interaction of the lipoproteins with the apo-B, -E receptors of fibroblasts and stimulated their uptake by macrophages. The use of fluorescently labeled native lipoproteins and chemically modified lipoproteins may allow the functional differentiation of macrophages from other cell types (e.g., fibroblasts and smooth muscle cells) in the arterial wall. This differentiation may be useful in determining the origin of the lipid-laden foam cells of atherosclerotic lesions.


Intramuscular fat in gluteus maximus for different levels of physical activity.
We aimed to determine if gluteus maximus (GMAX) fat infiltration is associated with different levels of physical activity. Identifying and quantifying differences in the intramuscular fat content of GMAX in subjects with different levels of physical activity can provide a new tool to evaluate hip muscles health. This was a cross-sectional study involving seventy subjects that underwent Dixon MRI of the pelvis. The individuals were divided into four groups by levels of physical activity, from low to high: inactive patients due to hip pain; and low, medium and high physical activity groups of healthy subjects (HS) based on hours of exercise per week. We estimated the GMAX intramuscular fat content for each subject using automated measurements of fat fraction (FF) from Dixon images. The GMAX volume and lean volume were also measured and normalized by lean body mass. The effects of body mass index (BMI) and age were included in the statistical analysis. The patient group had a significantly higher FF than the three groups of HS (median values of 26.2%, 17.8%, 16.7% and 13.7% respectively, p < 0.001). The normalized lean volume was significantly larger in the high activity group compared to all the other groups (p < 0.001, p = 0.002 and p = 0.02). Employing a hierarchical linear regression analysis, we found that hip pain, low physical activity, female gender and high BMI were statistically significant predictors of increased GMAX fat infiltration.


Non-alcoholic beer in the European Union and UK: Availability and apparent consumption.
Market research indicates an increasing interest in low- and no-alcohol drinks in Europe, but there is no systematic overview of their availability and consumption. In this article, we present data on the availability and apparent consumption of non-alcoholic beer in the European Union and the UK. We use Sold production, exports and imports by PRODCOM list (NACE Rev. 2) dataset, available in Eurostat, to extract the available data on sold production, exports and imports of non-alcoholic beer in the EU-27 (total and country-level) and the UK between 2013 and 2019, and additionally calculate the apparent consumption. Between 2013 and 2019, the sold production volume in the EU increased from 0.59 to 1.38 billion litres, the value from 0.42 to 1.28 billion EUR and value per litre from 0.72 to 0.93 EUR/L. In 2019, the share of non-alcoholic beer represented 3.8% of all beer volume and 4.1% of all beer value produced. Five countries accounted for 80.8% of sold production volume: Germany, the Netherlands, Spain, Poland and Czechia. The Netherlands and Germany were the largest exporters, while importing was distributed more equally. Per capita, average apparent consumption (2017-2019) was highest in Czechia, followed by the Netherlands, Spain, Luxembourg and Germany. Our results show the increasing availability of non-alcoholic beer in the EU-27, although overall changes seem to be driven by a small number of countries. More research is needed at the country-level on no- and low-alcohol consumption trends and drivers, and their impact on alcohol-related harm reduction.


Enhancement of growth, antioxidative status, nonspecific immunity, and disease resistance in gibel carp (Carassius auratus) in response to dietary Flos populi extract.
This study investigated the effects of dietary Flos populi extract (FPE) on the growth, antioxidation capability, innate immune response, and disease resistance in gibel carp. A total of 480 fish were fed with five different diets containing 0, 0.5, 1.0, 1.5, or 2.0 g kg-1 FPE (designated as control, D0.5, D1.0, D1.5, or D2.0 groups) for 45 days. The fish were challenged with A. hydrophila after the feeding trial. Compared with the control, the feed efficiency (FE), weight gain (WG), final body weight (FBW), and specific growth rate (SGR) were significantly improved in groups D1.0 and D1.5. Dietary FPE significantly increased serum superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, as well as glutathione (GSH) content. The contents of protein carbonyl (PCC) and malondialdehyde (MDA) in serum decreased significantly. Additionally, FPE supplementation in diets resulted in significant improvement in serum lysozyme (LZM) and myeloperoxidase (MPO) activities, as well as immunoglobulin M (IgM) and complement 3 (C3) concentrations. The hepatic antioxidant enzymes (CAT and SOD) activities increased, whereas content of MDA decreased in fish treated with dietary FPE than those of control both pre- and post-challenged. After 12 h-challenge, an obvious downregulation of hepatic Kelch-like-ECH-associated protein 1 (Keap1), splenic tumor necrosis factor-α (TNF-α), interleukin (IL)-8, IL-1β, and toll-like receptor 2 (TLR2) mRNA levels was observed in fish treated with dietary FPE, whereas hepatic Nrf2 transcription level was upregulated compared to the control. Furthermore, compared to group D0.5, higher relative percent survival (RPS) was observed in gibel carp fed dietary 1.0-2.0 g/kg FPE. Our results reveal that FPE supplemented diet has a stimulatory effect on antioxidant capacity and nonspecific immune response, along with improved growth performance and enhanced resistance against A. hydrophila infection in juvenile gibel carp.


The trap of genetic tag: The importance of pathogenicity prediction tools in the correct interpretation of variants of uncertain significance in the era of high-throughput genome sequencing.
Although recent advancements in DNA sequencing technologies and their widely used, the interpretation of variants of uncertain significance from these large datasets is not clear-cut. Here, we present the case of a family referred to our metabolic disease department, in which three males' individuals were affected by a suspected a genetic inherited disease, resulting from next-generation sequencing results. A correct assessment of the clinical significance of the genetic variant found in our cases, with a review of the literature, the evaluation of population database and the use of computational predictive program changed the initial suspect. Despite NGS technologies have increased diagnostic sensitivity, most of these variants remains of uncertain clinical significance. An efficient systematic approach is fundamental to determine the pathogenicity of a variant, avoiding incorrect interpretation in a clinical setting.


Photoaffinity labeling of the antidiuretic hormone receptor.
A study to determine the feasibility of photoaffinity labeling the antidiuretic hormone receptor in the toad urinary bladder has been carried out. Two photoactivated derivatives of oxytocin have been synthesized, purified, and characterized chemically and biologically. Photolysis of the toad bladder in the presence of one of these derivatives, 2-nitro-5-azidobenzoylglycyloxytocin, produces a permanent inhibition of the response to native oxytocin. This inhibition can be relieved by protecting the hormone receptor with excess oxytocin during the photolysis. These results suggest that the photolysis-dependent inhibition of the response to native hormone is due to covalent incorporation of the photoaffinity label into the hormone receptor.


A Pharmacological Review of Bioactive Constituents of Paeonia lactiflora Pallas and Paeonia veitchii Lynch.
The roots of two peony species, Paeonia lactiflora Pallas and Paeonia veitchii Lynch are routinely referred to as either chishao () or baishao (). This paper reviews the botanical origins and traditional medicinal usage of each species, as well as pharmacological like activity of their constituents. A search of herbal pharmacological encyclopaedia, PubChem and PubMed databases identified their known constituents. The biological data for these constituents were evaluated and classified according to pharmacological-like activity, with emphasis on compounds of greatest concentration and bioavailability. It was found that P. lactiflora and P. veitchii have some common compounds; however, their phytochemical bioavailability varies. Furthermore, a larger number of compounds have been identified in P. lactiflora. These have greater potential for antiinflammatory, antiviral, antibacterial and antioxidant therapeutic activity compared with P. veitchii. However, evidence indicates both species are similarly indicated for antiviral and glycaemic activity. Major compounds of each are classified as flavonoids, hydrolysable tannins (polyphenols) and monoterpene glycosides. The evidence suggests both species, when administered in entire botanical form, have an excellent safety profile; however, constituent toxicity risk evidence is limited, requiring further investigation. Although experiments show many compounds have biological activity, further investigation of their therapeutic potential is needed. Copyright © 2016 John Wiley & Sons, Ltd.


Cholestatic hepatitis leading to hepatic failure in a patient with organ-transmitted hepatitis C virus infection.
A 51-year-old heart transplant recipient who developed subfulminant hepatic failure because of organ-transmitted hepatitis C virus (HCV) infection is described. He presented with a predominantly cholestatic liver damage after heart transplantation. An extensive evaluation, including abdominal ultrasound and computed tomography scan and endoscopic retrograde cholangiopancreatography was unrevealing. Liver biopsy, however, was suggestive of a large duct obstruction with prominent portal and pericellular fibrosis, marked cholestasis, pericholangitis with marked ductular proliferation, and diffuse hepatocyte degeneration. Antibody to HCV (anti-HCV) was initially negative. He deteriorated in the ensuing 3 months. A repeat enzyme immunoassay-2 test for anti-HCV 4 months after initial presentation was weakly positive. Quantitation of serum HCV RNA by branched DNA assay revealed high level viremia, 547 x 10(6) genome equivalents per milliliter. Using in situ polymerase chain reaction, HCV RNA was detected in the cytoplasm in > 80% of the hepatocytes. The patient underwent interferon alfa therapy, and serum HCV RNA levels were reduced 20-fold after four doses. Unfortunately, the patient developed pulmonary aspergillosis and died. This case illustrates that in immunosuppressed patients anti-HCV is not a good marker for the diagnosis of HCV infection, and HCV can cause a progressive form of cholestatic liver disease mimicking a large duct obstruction.


The influence of linguistic form and causal explanations on the development of social essentialism.
Generic descriptions of social categories (e.g., boys play baseball; girls have long hair) lead children and adults to think of the referenced categories (i.e., boys and girls) in essentialist terms-as natural ways of dividing up the world. Yet, key questions remain unanswered about how, why, and when generic language shapes the development of essentialist beliefs. The present experiment examined the scope of these effects by testing the extent to which generics elicit essentialist beliefs because of their linguistic form or because of the causal information they convey. Generic language led children (N = 199, Mage = 6.07 years, range = 4.5-7.95) to essentialize a novel social category, regardless of the causal information used to describe category-property relations (either biological or cultural). In contrast, both linguistic form and causal information influenced adults' (N = 234) beliefs. These findings reveal a unique role of linguistic form in the development and communication of essentialist beliefs in young children.


Genomes of the extinct Bachman's warbler show high divergence and no evidence of admixture with other extant Vermivora warblers.
Bachman's warbler1 (Vermivora bachmanii)-last sighted in 1988-is one of the only North American passerines to recently go extinct.2,3,4 Given extensive ongoing hybridization of its two extant congeners-the blue-winged warbler (V. cyanoptera) and golden-winged warbler (V. chrysoptera)5,6,7,8-and shared patterns of plumage variation between Bachman's warbler and hybrids between those extant species, it has been suggested that Bachman's warbler might have also had a component of hybrid ancestry. Here, we use historic DNA (hDNA) and whole genomes of Bachman's warblers collected at the turn of the 20th century to address this. We combine these data with the two extant Vermivora species to examine patterns of population differentiation, inbreeding, and gene flow. In contrast to the admixture hypothesis, the genomic evidence is consistent with V. bachmanii having been a highly divergent, reproductively isolated species, with no evidence of introgression. We show that these three species have similar levels of runs of homozygosity (ROH), consistent with effects of a small long-term effective population size or population bottlenecks, with one V. bachmanii outlier showing numerous long ROH and a FROH greater than 5%. We also found-using population branch statistic estimates-previously undocumented evidence of lineage-specific evolution in V. chrysoptera near a pigmentation gene candidate, CORIN, which is a known modifier of ASIP, which is in turn involved in melanic throat and mask coloration in this family of birds. Together, these genomic results also highlight how natural history collections are such invaluable repositories of information about extant and extinct species.


The immunoarchitecture of the normal human lacrimal gland. Relevancy for understanding pathologic conditions.
To delineate the immunoarchitecture of the normal human lacrimal gland, monoclonal antibodies that detect B- and T-lymphocyte, macrophage, and dendritic cell lineage, subset, and differentiation-associated antigens were used in combination with highly sensitive tissue-section immunoperoxidase techniques. Plasma cells, identified with monoclonal antibody OKT10, represented the predominant mononuclear cell population, accounting for 53.9% of all mononuclear cells present. A qualitative study of plasma cell cytoplasmic immunoglobulin heavy-chain expression in deparaffinized, formalin-fixed tissue sections showed that the vast majority of these plasma cells contained IgA. Rare plasma cells contained IgG, IgM, or IgD. T-cells, identified with monoclonal antibody OKT3, represented the second most common cell type in the normal human lacrimal gland, accounting for 40.3% of all mononuclear cells present. T cells were located predominantly in lymphocytic foci and singly in the interstitium. T8 antigen-positive (suppressor/cytotoxic) T cells predominated over T4 antigen-positive (helper) T cells, averaging 25.2 and 14.7%, respectively. The overall mean T4/T8 ratio was 0.56. T8 antigen-positive T cells were the most numerous cell population outside aggregates and follicles, being distributed almost equally between the acini and the ducts (49%) and the interstitium (51%). Only 16% of T4 antigen-positive cells preferred glands or ducts to the interstitium. B cells, identified with monoclonal antibody BL9, represented only 5.7% of all mononuclear cells present. B cells were exclusively found in the centers of primary and secondary follicles. The majority of the surface immunoglobulin-positive B cells expressed IgM, fewer expressed IgD, and still fewer expressed IgG or IgA. Rare LeuM1+ OKM1+ macrophages were present in the center of B-cell follicles, where rare OKT6+ dendritic cells and activated T cells (IL-2+) were also discovered. These results support the concept that the lacrimal gland belongs to the mucosa-associated lymphoid system.


Correlation of sequential magnetic resonance imaging of experimental brain ischemia with histologic changes in gerbils.
To characterize Gd-DTPA-enhanced T1-weighted images (Gd-T1WI) in the acute phase of cerebral ischemia, sequential magnetic resonance images of 84 Mongolian gerbils with occlusion of the left common carotid artery were evaluated. Twelve gerbils were used for each group, among which the occlusion time (5-180 minutes, permanent) varied. Histopathologic changes developing within the first 2 weeks were compared with patterns on T2-weighted images and Gd-T1WI on a 7.05-Tesla system. Although T2-weighted images and Gd-T1WI both demonstrated abnormal findings as early as 3 hours after occlusion, Gd-T1WI demonstrated more definite abnormalities with shorter occlusion than T2-weighted images (especially when there were only mild histologic changes). The earliest changes were an abnormal enhancement around and within the lateral ventricles in temporary occlusions; this was not demonstrated in permanent occlusions. Magnetic resonance images using Gd-DTPA demonstrated abnormal permeability within 3 hours after occlusion, and the pattern is correlated with intensity of ischemia.


The effects of daylight and daylight saving time on US pedestrian fatalities and motor vehicle occupant fatalities.
This paper analyzes the effects of daylight and daylight saving time (DST) on pedestrian and motor vehicle occupant fatalities in the United States. Multivariate analyses of county level data from the Fatality Analysis Reporting System for 2-week periods in 1998 and 1999 are used. Results show that full year daylight saving time would reduce pedestrian fatalities by 171 per year, or by 13% of all pedestrian fatalities in the 5:00-10.00 a.m. and in the 4:00-9:00 p.m. time periods. Motor vehicle occupant fatalities would be reduced by 195 per year, or 3%, during the same time periods.


Osteogenic Capacity of the Prefabricated Periosteofascial Flap using Vascular Induction with Skeletonized Pedicle Transfer in Rabbit Calvarium.
The study investigated the osteogenic capacity of a prefabricated periosteal flap created using only skeletonized pedicle transfer without fascia or muscle for vascular induction in rabbit calvarium. A critical-sized bone defect was made in the parietal bone centered on the sagittal suture, and the demineralized bone matrix was implanted. The periosteofascia over the defect was used as a form of prefabricated periosteofascial flap (PPF group, N=10), conventional periosteofascial flap (CPF group, N=10), and nonvascularized free periosteofascial graft (FPG group, N=6). The prefabricated flap was designed via vascular induction by transferring the central artery and vein of the right auricle onto the periosteofascia for 4 weeks prior to flap elevation. A quantitative comparison of volume restoration and radiodensity in the bone defect and a histological study were performed after 6 weeks of covering the bone defect with periosteofascia. The volume restoration of the bone defect covered with the PPF (43.4%) was not different from that of the CPF (46.2%), but significantly increased compared with that of the FPG (24.6%). The radiodensity of the bone defect covered with the PPF (-186.3 HU) was not different from that of the CPF (-153.6 HU), but significantly increased compared with that of the FPG (-329.8 HU). The results were based on adequate vascular development of the periosteum and were closely related to the osteogenic changes in the implanted demineralized bone matrix (DBM). In conclusion, even in the PPF created by transferring only skeletonized vascular pedicles, the osteogenic capacity of the periosteofascial flap is well maintained.


A new atrial lead with improved stability and P-wave detection.
A new segmented polyether polyurethane atrial pacemaker lead has been developed and tested acutely and chronically in dogs. This lead was constructed so that its tip could quickly and accurately be positioned in close proximity to the S-A node and provide long-term stability without the use of active fixation devices such as tines or screws. The acute intrinsic P-wave potentials seen at the S-A node area (9.7 +/- 4.7 mV) were superior to those detected in the appendage (4.7 +/- 2.8 mV) and coronary sinus (6.8 +/- 4.1 mV). There were no significant differences in pacing thresholds between sites. In long-term studies, transvenous (jugular) leads maintained their position for over three months without dislodgment in active unrestrained dogs with only a 25% decrease in intrinsic P-wave potentials. The chronic pacing thresholds for this lead were similar, or superior, to those reported for other pacemaker lead placement sites. The polyurethane coating material produces no adverse tissue reaction or thrombosis.


Hepatic Arterial Infusion Chemotherapy Is a Feasible Treatment Option for Hepatocellular Carcinoma: A New Update.
Hepatic arterial infusion chemotherapy (HAIC) is one option for treating massive tumors and unresectable hepatocellular carcinoma (HCC). However, there is a lack of remedial treatment after these treatments are ineffective or failed. Some studies have discovered that HAIC has greater survival in patients with advanced HCC. A previous study has shown that HAIC is effective in the treatment of advanced HCC, and the data on randomized clinical trials are limited and unclear. More clinical trials and research are needed in order to make HAIC a standard and recommended therapy for advanced HCC. Our review focuses on the clinical applications of hepatic artery infusion treatment.


Junction between the great cerebral vein and the straight sinus: an anatomical, immunohistochemical, and ultrastructural study on 25 human brain cadaveric dissections.
The cerebral venous system is poorly understood, and best appreciated under macroscopic anatomical considerations. We present an anatomical and immunohistochemical studies to better define the morphological characteristics of the junction between the great cerebral vein and the straight sinus. Twenty-five cadaveric specimens from the anatomy laboratory of the University Victor Segalen of Bordeaux were studied. The observation of the venous junctions with the straight sinus was performed under an operating microscope. The smooth muscular actin immunohistochemical staining was performed for 18 veno-sinosal junctions. Five venous junctions were observed using an electron microscope. We observed 3 different anatomic aspects: type 1 was a junction with a small elevation in its floor and a posterior thickening (14 cases); type 2 was a junction with an outgrowth on the floor like a cornice (7 cases); and type 3 was a junction presenting a nodule. Microscopic study of type 1 and 2 junctions showed a positive coloration to orceine attesting the presence of elastic fibers. Immunohistochemistry revealed the presence of smooth muscular actin and S 100 protein attesting the presence of smooth muscular fibers and nervous fibers. We observed in the ultrastructural study, a morphological progression of the endothelium. The venous orifice of the great cerebral vein into the straight sinus could be anatomically assimilated as a true "sphincter." Its function in the regulation of the cerebral blood flow needs further exploration.


DBMF: Dual Branch Multiscale Feature Fusion Network for polyp segmentation.
Accurate and reliable segmentation of colorectal polyps is important for the diagnosis and treatment of colorectal cancer. Most of the existing polyp segmentation methods innovatively combine CNN with Transformer. Due to the single combination approach, there are limitations in establishing connections between local feature information and utilizing global contextual information captured by Transformer. Still not a better solution to the problems in polyp segmentation. In this paper, we propose a Dual Branch Multiscale Feature Fusion Network for Polyp Segmentation, abbreviated as DBMF, for polyp segmentation to achieve accurate segmentation of polyps. DBMF uses CNN and Transformer in parallel to extract multi-scale local information and global contextual information respectively, with different regions and levels of information to make the network more accurate in identifying polyps and their surrounding tissues. Feature Super Decoder (FSD) fuses multi-level local features and global contextual information in dual branches to fully exploit the potential of combining CNN and Transformer to improve the network's ability to parse complex scenes and the detection rate of tiny polyps. The FSD generates an initial segmentation map to guide the second parallel decoder (SPD) to refine the segmentation boundary layer by layer. SPD consists of a multi-scale feature aggregation module (MFA) and parallel polarized self-attention (PSA) and reverse attention fusion modules (RAF). MFA aggregates multi-level local feature information extracted by CNN Brach to find consensus regions between multiple scales and improve the network's ability to identify polyp regions. PSA uses dual attention to enhance the fine-grained nature of segmented regions and reduce the redundancy introduced by MFA and interference information. RAF mines boundary cues and establishes relationships between regions and boundary cues. The three RAFs guide the network to explore lost targets and boundaries in a bottom-up manner. We used the CVC-ClinicDB, Kvasir, CVC-300, CVC-ColonDB, and ETIS datasets to conduct comparison experiments and ablation experiments between DBMF and mainstream polyp segmentation networks. The results showed that DBMF outperformed the current mainstream networks on five benchmark datasets.


Quantitative risk approaches for formaldehyde.
Formaldehyde presents unique data that highlight significant issues in the extrapolation of animal studies to human risk assessments. Formaldehyde causes rare nasal cancer in rats at 15 ppm, but not at lower levels of 2 ppm and 0.5 ppm in the range of human exposures. Mice and hamster studies even at high levels have results similar to low dose rats. Higginson et al. reviewed the human epidemiology studies and concluded that no excess cancer risk was observed; and if a risk exists, it is very low. Formaldehyde is a natural metabolite--the human body turns over 51 g/day. Cells, therefore, have detoxification and other defence mechanisms to formaldehyde. Recent CIIT biomechanism results elucidate these factors. These data raise two issues: First, the appropriateness of linear quantitative risk methodology given the non-linear nature of the biological data. Either a non-linear (threshold) statistical model or NOEL approach are appropriate risk assessment techniques for formaldehyde. Second, the rare nasal cancer observed in rats also occurs in control animals. A comparison of relative risk between background and low formaldehyde exposures has been calculated for both groups. Non-linear (MLE) 5 stage multistage models estimate 0 per million risk from both background and 1 ppm of formaldehyde exposure. Linear or upperbound (95%) estimates are 7,200/million from background and 5,000/million from 1 ppm formaldehyde. These estimates have a significant impact on formaldehyde regulatory programs for warning labels and "safe" exposure levels.


On Silylated Oxonium and Sulfonium Ions and Their Interaction with Weakly Coordinating Borate Anions.
Attempts have been made to prepare salts with the labile tris(trimethylsilyl)chalconium ions, [(Me3 Si)3 E]+ (E=O, S), by reacting [Me3 Si-H-SiMe3 ][B(C6 F5 )4 ] and Me3 Si[CB] (CB- =carborate=[CHB11 H5 Cl6 ]- , [CHB11 Cl11 ]- ) with Me3 Si-E-SiMe3 . In the reaction of Me3 Si-O-SiMe3 with [Me3 Si-H-SiMe3 ][B(C6 F5 )4 ], a ligand exchange was observed in the [Me3 Si-H-SiMe3 ]+ cation leading to the surprising formation of the persilylated [(Me3 Si)2 (Me2 (H)Si)O]+ oxonium ion in a formal [Me2 (H)Si]+ instead of the desired [Me3 Si]+ transfer reaction. In contrast, the expected homoleptic persilylated [(Me3 Si)3 S]+ ion was formed and isolated as [B(C6 F5 )4 ]- and [CB]- salt, when Me3 Si-S-SiMe3 was treated with either [Me3 Si-H-SiMe3 ][B(C6 F5 )4 ] or Me3 Si[CB]. However, the addition of Me3 Si[CB] to Me3 Si-O-SiMe3 unexpectedly led to the release of Me4 Si with simultaneous formation of a cyclic dioxonium dication of the type [Me3 Si-μO-SiMe2 ]2 [CB]2 in an anion-mediated reaction. DFT studies on structure, bonding and thermodynamics of the [(Me3 Si)3 E]+ and [(Me3 Si)2 (Me2 (H)Si)E]+ ion formation are presented as well as mechanistic investigations on the template-driven transformation of the [(Me3 Si)3 E]+ ion into a cyclic dichalconium dication [Me3 Si-μE-SiMe2 ]2 2+ .


Distinct functions for the two importin subunits in nuclear protein import.
The import of nuclear proteins proceeds through the nuclear pore complex and requires nuclear localization signals (NLSs), energy and soluble factors, namely importin-alpha (M(r) 60K), importin-beta (90K) and Ran. Importin-alpha is primarily responsible for NLS recognition and is a member of a protein family that includes the essential yeast nuclear pore protein SRP1p (ref. 16). As the first event, the complex of importin-alpha and importin-beta binds the import substrate in the cytosol. Here we show that this nuclear pore targeting complex initially docks as a single entity to the nuclear pore via importin-beta. Then the energy-dependent, Ran-mediated translocation through the pore results in the accumulation of import substrate and importin-alpha in the nucleus. In contrast, importin-beta accumulates at the nuclear envelope, but not in the nucleoplasm. Immunoelectron microscopy detects importin-beta on both sides of the nuclear pore. This suggests that the nuclear pore targeting complex might move as a single entity from its initial docking site through the central part of the nuclear pore before it disassembles on the nucleoplasmic side.


Pectin-chitosan multilayer formation.
The deposition of alternating layers of pectin and chitosan at a solid surface was studied using surface plasmon resonance. The binding of biopolymer to the surface was irreversible over the time scales examined. The deposition was dependent on the flow rate through the measurement cell with mass transport limitation at lower flow rates. The thickness of the deposited layer was dependent on the biopolymer concentration and was particularly marked for pectin. This was consistent with a process of initial attachment, followed by a slower structural rearrangement, which was inhibited at high initial surface concentrations of adsorbed biopolymer. Sequential deposition resulted in the formation of multilayers with an essentially linear growth rate.


Three-dimensional assessment of the normal Japanese glenoid and comparison with the normal French glenoid.
In 2014, reverse total shoulder arthroplasty was approved in Japan. We were concerned that the base plate might be incompatible with Japanese who were generally smaller than Westerners. Therefore, we investigated the dimensions and morphology of the normal Japanese glenoid and compared with the normal French glenoid. One hundred Japanese shoulders without glenoid lesions (50 men and 50 women) were investigated and compared with 100 French shoulders (50 men and 50 women). Computed tomography was performed with 3-dimensional image reconstruction and images were analyzed using Glenosys software. Glenoid parameters (width, height, retroversion and inclination) were compared between Japanese and French subjects. In Japanese subjects, the mean glenoid width was 25.5mm, height was 33.3mm, retroversion was 2.3° and inclination was 11.6° superiorly. In French subjects, the mean glenoid width was 26.7mm, height was 35.4mm, retroversion was 6.0° and inclination was 10.4° superiorly. Glenoid width and height were significantly smaller in Japanese subjects than French subjects (P=0.001 and P<0.001), while retroversion was significantly greater in French subjects (P<0.001). There was no significant difference of inclination. These findings will help surgeons to identify suitable patients for RSA and perform the procedure with appropriate preoperative planning. IV: retrospective or historical series.


A Transcriptomic Classifier Model Identifies High-Risk Endotypes in a Prospective Study of Sepsis in Uganda.
In high-income countries (HICs), sepsis endotypes defined by distinct pathobiological mechanisms, mortality risks, and responses to corticosteroid treatment have been identified using blood transcriptomics. The generalizability of these endotypes to low-income and middle-income countries (LMICs), where the global sepsis burden is concentrated, is unknown. We sought to determine the prevalence, prognostic relevance, and immunopathological features of HIC-derived transcriptomic sepsis endotypes in sub-Saharan Africa. Prospective cohort study. Public referral hospital in Uganda. Adults (n = 128) hospitalized with suspected sepsis. None. Using whole-blood RNA sequencing data, we applied 19-gene and 7-gene classifiers derived and validated in HICs (SepstratifieR) to assign patients to one of three sepsis response signatures (SRS). The 19-gene classifier assigned 30 (23.4%), 92 (71.9%), and 6 (4.7%) patients to SRS-1, SRS-2, and SRS-3, respectively, the latter of which is designed to capture individuals transcriptionally closest to health. SRS-1 was defined biologically by proinflammatory innate immune activation and suppressed natural killer-cell, T-cell, and B-cell immunity, whereas SRS-2 was characterized by dampened innate immune activation, preserved lymphocyte immunity, and suppressed transcriptional responses to corticosteroids. Patients assigned to SRS-1 were predominantly (80.0% [24/30]) persons living with HIV with advanced immunosuppression and frequent tuberculosis. Mortality at 30-days differed significantly by endotype and was highest (48.1%) in SRS-1. Agreement between 19-gene and 7-gene SRS assignments was poor (Cohen's kappa 0.11). Patient stratification was suboptimal using the 7-gene classifier with 15.1% (8/53) of individuals assigned to SRS-3 deceased at 30-days. Sepsis endotypes derived in HICs share biological and clinical features with those identified in sub-Saharan Africa, with major differences in host-pathogen profiles. Our findings highlight the importance of context-specific sepsis endotyping, the generalizability of conserved biological signatures of critical illness across disparate settings, and opportunities to develop more pathobiologically informed sepsis treatment strategies in LMICs.


The Effects of Replacing Soybean Meal with Rapeseed Meal, Cottonseed Cake, and Fava Beans on the Milk Yield and Quality Traits in Milking Ewes.
The replacement of soybean meal (SBM) from intensively reared dairy sheep diets has emerged as a significant challenge for sustainable production. However, the effects of this replacement on milk production have not been sufficiently elucidated. The objective of this study was to prospectively assess the effects of replacing SBM with a mixture of alternative protein sources on the milk yield (MY) and the milk quality traits (MQT) in intensively reared dairy sheep. A total of 112 multiparous, purebred milking ewes of the Chios and Frizarta breeds, from two intensive dairy sheep farms, were involved in the study, postweaning, and were assigned to either the control (CR) or the experimental ration (ER) group. In the ER, 3/4 of the SBM was replaced by a mixture of rapeseed meal, cottonseed cake, and fava beans, producing a ration of a similar nutritional value. MY, MQT, and body condition scores were recorded for each individual ewe monthly for a period of 4 months during lactation. The experimental ration was associated with beneficial effects on daily and 100-day fat yields and on the electrical conductivity of milk as an improved udder health status indicator, with no adverse effects on any of the rest of the studied milk production traits.


Patient discomfort and intensity of intraseptal anesthesia of computer-controlled articaine/epinephrine delivery for scaling and root planing.
The primary aim was to assess the pain during intraseptal anesthesia (ISA) administration, as well as during and after scaling and root planing (SRP). The secondary aims pertained to comparing the pain in different jaw regions and evaluating the factors affecting pain during ISA administration, during and after SRP. ISA was obtained with three different doses of 4% articaine with 1:100,000 epinephrine (4%Ar + Ep) in 360 patients. The pain levels were measured using the visual analogue scales (VAS) for pain intensity during ISA administration (VASa), during SRP (VASi), and after SRP (VASp). These findings were then correlated with periodontal parameters. Regression analysis was performed for pain during ISA, during and after SRP. Anesthesia administration was painful in 80.8% of cases. VASa negatively correlated with pocket depth (PPD). VASi showed no dose-dependency, except in mandibular premolars. VASi negatively correlated with the clinical attachment level (CAL). VASp positively correlated with PPD and CAL. Positive bleeding on probing reduced the chance of pain during ISA administration. Longer anesthesia duration and wider anesthetic field (orally) increased the prospects of painless SRP. No dose-dependent differences were found regarding patient discomfort and pain intensity of ISA delivery of 4%Ar + Ep for SRP. The pain during ISA administration was mild and well tolerated regardless of the anesthetic dose. A lower intensity of pain during SRP can be expected in patients with greater CAL. Post-treatment pain can be anticipated after SRP in the regions with greater PPD and CAL. NCT04392804 (May 9th, 2020).


Land use regulates the spectroscopic properties and sources of dissolved organic matter in the inflowing rivers of a large plateau lake in southwestern China: implication for organic pollution control.
Dissolved organic matter (DOM) transported by inflowing rivers can considerably contribute to the organic loadings of lakes. The current study characterized the DOM properties and source apportionment in the inflowing rivers of Dianchi Lake, the sixth largest freshwater lake in China suffering from organic pollution, during the rainy season by using spectroscopic and carbon stable isotope techniques, and the regulation role of land use was assessed. The results showed that land use (urbanized, agricultural, or mixed) largely affected DOM properties. Greater concentrations and fluorescence intensities of DOM with low aromaticity and dominant autochthonous sources were observed in the urban rivers than in the agricultural rivers. The proportion of humic-like substances increased, while that of tryptophan-like matter decreased from upstream to downstream of two main urban rivers. DOM in the agricultural rivers was characterized by more amounts of aromatic humic-like substances with dominant allochthonous sources compared to that in the urban rivers. Stable isotope analysis showed that the decomposition of macrophytes and input of terrestrial sources from C3 plant-dominated soil and sewage were the major DOM origins in the rivers. The positive linear relationship between the chemical oxygen demand (COD) concentration and fluorescence intensities of terrigenous DOM components implied the necessity of controlling exogenous inputs to alleviate organic pollution in the Dianchi Lake.


Choosing a career: online resources for every scientist.
Looking for a job? Not even sure what kind of job you are looking for? Don't wait until all your experiments are wrapped up and your manuscript is in press. While slaving away doing research, it is easy to lose sight of what comes next. But graduate students and postdoctoral researchers should start planning the next chapter of their careers before the end is in sight. This article highlights different online resources for choosing a career and finding a job.


The challenge of individualised risk assessment and therapy planning in elderly high-risk myelodysplastic syndromes (MDS) patients.
Myelodysplastic syndromes (MDS) represent one of the most frequent and serious haematologic diseases of the elderly. Effective therapies exist ranging from best supportive care to haematologic stem cell transplantation (HSCT). Decision making, however, is rather complex in this group of patients because ageing is a multidimensional process involving not only physiological changes but also changes in functional, social, emotional and cognitive capacities. All these factors can have a significant impact on the efficacy and tolerability of a potential therapy and therefore have to be thoroughly assessed before deciding on individual treatment regimens. Risk assessment tools are available both to classify the stage and prognosis of MDS and to meet the needs of elderly patients. A tool explicitly focussing on elderly MDS patients, however, is still missing. The current report approached this issue by combining the well established MDS-risk score 'International Prognostic Scoring System' (IPSS) with the 'Multidimensional Geriatric Assessment' (MGA). As decision making is most complex in high-risk MDS patients, the new algorithm is presented exemplarily for this group of patients. In a first step, MDS-related risk is identified using IPSS, in a second step, patients are assigned to one of three risk categories of the MGA (go-go/fit, slow-go/vulnerable, no-go/frail). While go-go patients might be subjected to therapies comparable to those given to younger patients, in no-go patients, a palliative therapy combined with best supportive care will probably be most appropriate. In slow-go patients, age-related life expectancy taken from public age statistics should be compared to the MDS-related life expectancy. Based on this combined assessment procedure and also on treatment tolerance in terms of the expectations/wishes of the patient and his/her family, an individualised therapeutic approach should be developed. Specific treatment recommendations for these three groups of patients are given, including HSCT, azanucleosides and best supportive care. To illustrate its practicability, i.e. the implementation of the novel algorithm in clinical practice, the case of an elderly high-risk MDS patient is presented and discussed in detail. This new algorithm will facilitate the identification of the very particular needs and conditions of elderly MDS patients in clinical practice. Based on this, individually tailored therapeutic approaches can be developed--the prerequisite for the best possible clinical outcome.


Occurrence and transformation of unknown organochlorines in the wastewater treatment plant using specific Fragment-Based method with LC Q-TOF MS.
Wastewater treatment plants (WWTPs) are important point sources of organochlorines in surface waters. However, comprehensive molecular-level understanding of the occurrence and transformation of organochlorines in WWTPs remains elusive. In this study, a specific fragment-based screening method with SWATH of LC Q-TOF MS was established to better understand the molecular composition of organochlorines. This method effectively excludes the non-chlorinated signals and provides multi-dimensional information (e.g., retention time, precursor ion mass, product ions, and molecular formula) with one injection to identify the possible structures of organochlorines. Eighty-seven organochlorines were successfully screened in practical wastewater samples, where 8 chlorinated sulfonic acids, 4 chlorophenols, 4 chlorinated benzenediols, and 6 chlorinated benzoic acids were further (tentatively) identified. Relative abundance of organochlorines showed that their occurrence was associated with the treatment units. In particular, anaerobic biological and NaClO treatment units contributed to the formation of chlorinated by-products. Most chlorinated by-products were substituted with more chlorine atoms than organochlorines from the influent. Furthermore, the relative abundance indicated that the fate of organochlorines were related to their structures. Chlorinated benzene sulfonic acids would be removed by adsorption on activated sludge. Most chlorinated benzoic acids were refractory, but some were likely to be chlorinated during the anaerobic process. Chlorophenols and chlorinated benzenediols might undergo chlorination, dealkylation/C-O bond breakage, and bromination. Our study offers a new tool to gain molecular information on organochlorines in complex environmental samples and highlights the importance of molecular structures when evaluating the fate of organochlorines and managing effluent discharge to surrounding waters.


Improved continuous wave frequency modulated sonars with aural displays.
This paper discusses methods for reducing the effects of the reset hiatus and wavelength related variations in received signal strength on the aural displays produced by simple continuous wave frequency modulated sonars. Two techniques that have been developed for reducing the effects of signal phase and amplitude discontinuities are described. As a practical example of the improved performance afforded by one of these techniques, a novel short range sonar for examining cardiovascular structures is discussed in detail.


Fluorescent In Situ Detection of RNA-Protein Interactions in Intact Cells by RNA-PLA.
RNA-protein proximity ligation assay (RNA-PLA) enables the detection of specific RNA-protein interactions in fixed cells. In RNA-PLA, bridging and ligation of a circular DNA template occurs if the target RNA and protein are within 40 nanometers of each other. The resulting circular template is amplified by rolling circle amplification and abundantly recognized by fluorescent antisense DNA oligonucleotides. This strategy therefore enables localization of RNA-protein interactions in situ with high specificity and sensitivity. Here, we describe the use of RNA-PLA to detect interactions between a nuclear viral RNA and a host RNA-binding protein in Epstein-Barr virus (EBV)-infected B cells.


Time-saving effect of real-time ultrasound-guided cannulation for extracorporeal cardiopulmonary resuscitation: A multicenter retrospective cohort study.
Extracorporeal cardiopulmonary resuscitation (ECPR), a bridge to treatments for cardiac arrest patients, can be technically challenging and requires expertise. While ultrasound guidance is frequently used for vascular access, its effects on cannulation time in patients treated with ECPR are poorly defined. We hypothesized that real-time ultrasound guidance would contribute to faster and safer cannulation for ECPR. This nationwide, multicenter, retrospective study analyzed data from 36 Japanese institutions. Patients who were over age 18 years and underwent ECPR between January 1, 2013, and December 31, 2018, were included. Patients who underwent open surgical vascular access were excluded. Cannulation time and outcomes of patients who underwent real-time ultrasound-guided cannulation (i.e., ultrasound-guided group) were compared to those cannulated without the use of real-time ultrasound guidance (control group) using propensity score matching analysis. The ultrasound-guided group comprised 510 cases, whereas the control group comprised 941 cases. Of those, 443 propensity score-matched pairs were evaluated. Cannulation time in the ultrasound-guided group was 2.5 minutes shorter than in the control group [difference, -2.5 minutes; 95% Confidence interval (CI), -3.7 to -1.3, p < 0.001]. The incidence of catheter-related complications and the incidence of the poor neurological outcomes (Cerebral Performance Category ≥3) did not differ between groups [Odds ratio (OR), 1.51; 95% CI, 0.64-3.74; OR, 1.08; 95% CI, 0.83-1.59]. Real-time ultrasound-guided cannulation was associated with shorter cannulation time of ECPR.


Position and spatial frequency in large-scale localization judgments.
The frequency-channel model and the position, or "local-signs," model that have been proposed to account for hyperacuity (i.e. small-scale relative spatial localization) are examined in the context of large-scale relative spatial localization. As a basis for subsequent experiments, localization accuracy is measured over a large range of object separations, and previous findings that the "Weber fraction for localization" is constant are replicated. The effects on localization accuracy of both high- and low-spatial frequency components in the objects being localized are examined in some detail. Localization accuracy is found not to rely exclusively on either the high- or the low-frequency components. Neither the frequency-channel nor the position hypothesis as defined here is consistent with all of the observed results. However, with a slight modification, the position hypothesis can account qualitatively for all of the observed results, whereas no reasonable modification of the frequency-channel hypothesis appears able to do as well.


Key factors in psychotherapy training: an analysis of trainers', trainees' and psychotherapists' points of view.
The literature on clinical training lacks identifications of the factors that are most relevant in training programs; accordingly, the main aim of this work is to fill this research gap by assessing which factors that trainers, trainees and psychotherapists consider most relevant in psychotherapy training programs. A secondary aim is to identify whether these factors differ among trainers, trainees and psychotherapists. An ad hoc questionnaire was created and administered at 24 psychotherapy schools from 14 institutions; the sample included 641 trainees, 172 trainers and 218 psychotherapists of various theoretical orientations. The questionnaire included 63 items and used a 5-point Likert scale. An exploratory factor analysis was completed to identify the latent structure. The reliability of the dimensions was then checked. Finally, an analysis of variance and a multivariate analysis of variance were completed to achieve the study's aims. Four factors emerged from the study's results: trainers' relational characteristics, supervision, transmission of clinical know-how, and theoretical background and technical support. All these factors displayed acceptable reliability and internal consistency. Moreover, their relative rankings varied based on the participants' roles and theoretical backgrounds. This study's results indicate that the new instrument's psychometric qualities are acceptable. It thus could be used to develop a new approach to psychotherapy training, as this study's results regarding trainees' needs underline the differences between trainees' perceptions of those needs, as compared to trainers' and psychotherapists' perceptions.


[The role of metabolic activation of promutagens in the genome destabilization under pheromonal stress in the house mouse (Mus musculus)].
The hypothesis on a relationship between the high frequency of mitotic disturbances in bone marrow cells and the change in the activity of the S9 liver fraction containing promutagen-activating enzymes under olfactory stress in the house mouse Mus musculus has been tested. For this purpose, the effect of the pheromone 2,5-dimethylpyrazine on the frequency of mitotic disturbances in mouse bone marrow cells has been measured by the anaphase-telophase assay. The Ames test using Salmonella typhimurium has been employed to compare the capacities of the S9 liver fractions from stressed and intact mice for activating the promutagen 2-aminofluorene. It has been demonstrated that the increased frequency of mitotic disturbances in bone marrow cells induced by the pheromonal stressor in male house mice is accompanied by an increased promutagen-activating capacity of the S9 liver fraction. The model system used in the study allowed the genetic consequences of the exposure to the olfactory stressor to be estimated and the possible mechanisms of genome destabilization to be assumed.


Study on the spatial interaction between carbon emission intensity and shadow economy in China.
Both high carbon emission intensity (CEI) and large scale of shadow economy in China are the undesirable products of economic development with too fast growth rate. For the rapid and healthy development of the economy in China, the research on the relationship between the two should attract more attention, while the relevant literatures are very few at present. According to the panel data of 30 provinces in China from 2004 to 2016, this paper firstly examines the spatial correlation between CEI and the scale of shadow economic. Then verifies the interaction relationship between them with SPDM (spatial panel Dubin Model). Moreover, the robustness test is conducted with three different spatial weight matrices. As the interaction between CEI and shadow economy has been proved, providing new ideas for carbon emission reduction, environmental protection, and healthy economic development with rapid rate in the future. The specific conclusions are as follows: first, CEI and shadow economy both have significant positive spatial autocorrelation. Second, there is a spatial interaction between CEI and shadow economy, indicating provincial cooperation plays a very important role in both economic growth and environment protection. Third, the impacts from economic development on both CEI and shadow economy satisfy the EKC hypothesis. Also, the development of the tertiary industry plays a positive role in promoting the growth of CEI, while promotes and inhibits the expansion of shadow economic scale at the same time.


Freely dissolved PBDEs in water and porewater of an urban estuary.
Polyethylene passive samplers (PE) were deployed in Narragansett Bay, RI, to examine freely dissolved concentrations of polybrominated diphenyl ethers (PBDEs) in surface, bottom, and sediment porewater. PBDE congeners in the water column and porewater were below 3 pg L(-1). In the surface water, only PBDE congeners containing up to 5 bromines were detected, while in the deeper water congeners 153 and 154 (6 bromines) were also detected. Activity ratios of surface-bottom water and porewater-bottom water suggested that lower brominated (di-tetra) congeners reached Narragansett Bay from surface waters and sediments. PBDEs in the surface water probably originated from a combination of air-water exchange, freshwater runoff, rivers, and wastewater treatment plants. It is suggested that deep water was the source of higher brominated PBDEs to the Bay implying that the more hydrophobic PBDEs reached depth on particles and/or that these congeners were degraded in sediments. On-going sources supply PBDEs to Narragansett Bay.


Body temperature and its effect on leukocyte mobilization, cytokines and markers of neutrophil activation during and after exercise.
We investigated the influence of rectal temperature on the immune system during and after exercise. Ten well-trained male cyclists completed exercise trials (90 min cycling at 60% VO(2max) + 16.1 - km time trial) on three separate occasions: once in 18 degrees C and twice in 32 degrees C. Twenty minutes after the trials in 32 degrees C, the cyclists sat for approximately 20 min in cold water (14 degrees C) on one occasion, whereas on another occasion they sat at room temperature. Rectal temperature increased significantly during cycling in both conditions, and was significantly higher after cycling in 32 degrees C than in 18 degrees C (P < 0.05). Leukocyte counts increased significantly during cycling but did not differ between the conditions. The concentrations of serum interleukin (IL)-6, IL-8 and IL-10, plasma catecholamines, granulocyte-colony stimulating factor, myeloperoxidase and calprotectin increased significantly following cycling in both conditions. The concentrations of serum IL-8 (25%), IL-10 (120%), IL-1 receptor antagonist (70%), tumour necrosis factor-alpha (17%), plasma myeloperoxidase (26%) and norepinephrine (130%) were significantly higher after cycling in 32 degrees C than in 18 degrees C. During recovery from exercise in 32 degrees C, rectal temperature was significantly lower in response to sitting in cold water than at room temperature. However, immune changes during 90 min of recovery did not differ significantly between sitting in cold water and at room temperature. The greater rise in rectal temperature during exercise in 32 degrees C increased the concentrations of serum IL-8, IL-10, IL-1ra, TNF-alpha and plasma myeloperoxidase, whereas the greater decline in rectal temperature during cold water immersion after exercise did not affect immune responses.


The role of patients and their relatives in 'speaking up' about their own safety - a qualitative study of acute illness.
Poor recognition of and response to acute illness in hospitalized patients continues to cause significant harm despite the implementation of safety strategies such as early warning scores. Patients and their relatives may be able to contribute to their own safety by speaking up about changes in condition, but little is known about the factors that influence this. This study examined the experiences and views of patients and their relatives to determine the potential for involvement in promoting their own safety. This data set is drawn from a wider ethnographic study of the management of the acutely ill patient in hospital. Thirteen patients and seven relatives from two medical settings in two UK NHS Trusts were interviewed. Thematic analysis identified factors likely to influence patients' and their relatives' ability to contribute to the management of deterioration. All patients interviewed had experienced their acute illness within the context of a long-term health problem. Speaking up was influenced by the ability to recognize changes in clinical condition, self-monitoring, confidence and trust, and culture and system of health care. When patients or relatives did raise concerns, health-care staff had a mediating effect on their comfort with and the effectiveness of speaking up. Safety strategies based on patient involvement must take account of the complexities of acute illness. Those that promote partnership may be more acceptable to patients, their families and staff than those that promote challenging behaviour and may ultimately prove to be most safe and effective.


The recognition of infective endocarditis.
Patients with infective endocarditis are frequently first evaluated in an emergency department at a time when clinical data are insufficient for a conclusive diagnosis. The records of 22 patients with proven bacterial endocarditis first seen in our emergency department were reviewed. The most common feature of the initial history was the presence of fever in 11 (50%). The most common physical finding was a heart murmur in 18 (82%). All patients had positive blood cultures. The most frequently isolated organism was Staphylococcus aureus. Pertinent clinical and laboratory data available on admission that enabled the emergency physician to suspect infective endocarditis were systemic manifestations of fever, malaise and arthralgias together with anemia, leukocytosis and hematuria.


Differential role of microtubules in the control of prostaglandin E2 and beta-adrenergic stimulation of cyclic AMP accumulation in the rat myometrium.
A possible modulatory role of microtubules was investigated for the beta-adrenergic and prostaglandin E2 (PGE2)-induced cyclic AMP accumulation in the estrogen-treated rat myometrium. Colchicine, vinblastine and nocodazole, three different antitubulin drugs, enhanced cyclic AMP accumulation caused by PGE2. The effect of inhibitors was dose-(0.1-5 microM) and time-dependent, increased maximal responses without changing EC50 for PGE2, did not occur with trimethyl-colchicinic acid, which does not bind to tubulin, and was totally prevented in tissues pretreated with taxol, an agent that enhances polymerization and stabilization of microtubules. Concomitantly, colchicine reduced the rate and extent of PGE2-induced refractoriness in terms of cyclic AMP. In contrast, the antitubulin drugs failed to affect the rise in cyclic AMP evoked by isoproterenol and cholera toxin but enhanced the response to prostacyclin (PGI2), which is assumed to share common receptors with PGE2. Colchicine and vinblastine also failed to alter the ability of the beta-adrenergic agonist to provoke a cyclic AMP refractory state. Stimulations induced by all effectors were totally insensitive to cytochalasin B. The data suggest a relation between the constraints associated with the microtubules and/or membrane tubulin of the myometrium and the efficacy of PGE2 and PGI2 (but not the beta-adrenergic agonist or cholera toxin) to interact with the cyclic AMP forming system.


Fluctuations in carotid arterial distensibility during the menstrual cycle do not influence cardiovagal baroreflex sensitivity.
Fluctuations in autonomic nervous functions throughout the menstrual cycle and the underlying mechanism concerning them are not well known. This study was designed to test the hypothesis that fluctuations in cardiovagal baroreflex sensitivity (BRS) throughout the menstrual cycles of young women are due to fluctuations in carotid arterial distensibility. In eight eumenorrhoeic healthy young women (18-24 years), we determined the variations in the carotid arterial distensibility coefficient (DC; via simultaneous ultrasonography and applanation tonometry), cardiovagal BRS (phase IV of the Valsalva manoeuvre and the sequence method; up- or down-sequence spontaneous BRS), and serum oestradiol and progesterone concentrations at five points in the menstrual cycle (menstrual = M, follicular = F, ovulatory = O, early luteal = EL, and late luteal = LL). Serum oestradiol and progesterone levels were consistent with the predicted cycle phases. Carotid arterial DC fluctuated cyclically, increasing significantly from the M (52.4 +/- 4.9 x 10(-3) kPa(-1), mean +/- SE) and F (52.7 +/- 4.4) phases to the O (57.6 +/- 4.4) phase and declining sharply in the EL (46.0 +/- 4.0) and LL (45.1 +/- 3.0) phases (F = 6.37, P < 0.05). Contrary to our prediction, however, cardiovagal BRS by the Valsalva manoeuvre (P = 0.73) or sequence method (up-sequence spontaneous BRS; P = 0.84: down-sequence spontaneous BRS; P = 0.67) did not change significantly during the menstrual cycle. The results suggest that, although carotid arterial distensibility fluctuates with the changes in ovarian hormone levels that occur during the menstrual cycle, the fluctuations in carotid arterial distensibility do not influence cardiovagal BRS.


Sociodemographic factors associated with incidence of dementia among senior citizens of a small town in Japan.
Dementia is one of the common causes that lead to dependence of senior citizens in daily living. Clarifying the features of the elderly with dementia is instrumental in planning for their effective care and support in a community, and for attempts at prevention. Our purpose was to investigate the impact of sociodemographic factors among the elderly with the presumptive diagnosis of dementia. We carried out a survey annually from 1998 to 2002 in a dynamic cohort of community-dwelling individuals aged 65 years or older. Of the 945 subjects, 782 were eligible for study because at the first interview they were asymptomatic for dementia and not institutionalized. We found no significant difference in a 5-year average incidence rate between genders. However, the risk of developing dementia increased with age. The study population was categorized into three groups of living arrangement: those living with spouse and others, those living alone, and those living with persons other than the spouse. The incidence rate of dementia among the elderly who lived with spouse and others was significantly lower than for those among the other groups. This was also notable in the subjects without a history of stroke, even after adjustment for age and gender. This result indicates that living with spouse might have an important benefit in reducing the risk of developing dementia, although this effect would vary with the type of dementing disease. We suggest that preventive measures in clinical and community care of the elderly should focus on interactive social conditions such as living environments.


Position statement of the SEMI, SED, redGDPS, SEC, SEEDO, SEEN, SEMERGEN y SEMFYC.
Obesity and excess weight are the main preventable causes of type 2 diabetes (DM2). When diagnosing type 2 diabetes, clinicians should establish the degree of obesity according to the body mass index (BMI) and, for patients with excess weight, measure the waist circumference. The proper treatment of DM2 requires a simultaneous approach to excess weight/obesity and the other cardiovascular risk factors, such as hypertension, dyslipidaemia and smoking. Nondrug interventions (e.g., diet and exercise) have proven benefits in preventing and treating patients with DM2 and excess weight/obesity and should follow an individual and multidisciplinary approach, with structured programs equipped with specific resources. Weight gain associated with antidiabetic treatment can hinder glycaemic control, compromise treatment adherence, worsen the vascular risk profile and limit the cardiovascular benefits of treatment. Therefore, it is significant to avoid weight gain, a measure that can be cost-effective. Antidiabetic drugs with benefits in body weight have also demonstrated their benefit in patients with BMIs <30. In general, the treatment of patients with DM2 and obesity will depend both on the degree of obesity and the associated comorbidity. Clinical trials on DM2 intervention should consider combined objectives that include not only glycaemic control but also other variables such as the risk of hypoglycaemia and the effect of treatment on body weight.


Interleukin 1 and tumour necrosis factor alpha may be responsible for the lytic mechanism during anti-tumour antibody-dependent cell-mediated cytotoxicity.
Antibodies are thought to bring about tumour cell lysis by antibody-dependent cell-mediated cytotoxicity (ADCC), but the exact mechanism is not well elucidated. Monocytes are known to be important mediators of anti-tumour ADCC and are also known to secrete the cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta), both of which have been shown to bring about tumour cell lysis. We examined the release of these cytokines during ADCC and attempted to elucidate which components of the ADCC reaction were necessary for cytokine production. We measured TNF-alpha and IL-1 beta in supernatants collected from a standard ADCC assay using each of the anti-colorectal antibodies m17-1A, c17-1A and cSF25. We found that there was significant TNF-alpha and IL-1 beta release during ADCC mediated by each of these three antibodies and that the magnitude of cytokine release seemed to reflect the degree of tumour cell lysis produced by each antibody. Furthermore, we found that effector cells, target cells and a specific anti-tumour antibody were necessary for this to occur. The presence of only some of the components of the reaction or of an irrelevant antibody produced little or no TNF-alpha or IL-1 beta. We conclude that TNF-alpha and IL-1 beta are released when an effector and tumour target cell are united by a specific tumour antibody and that these cytokines may be important in bringing about tumour cell lysis during the ADCC reaction.