Initial outcome after selective intraarterial radionuclide therapy with yttrium-90 microspheres as salvage therapy for unresectable metastatic liver disease.
The aim of the study was to retrospectively evaluate the potential benefit on survival outcomes of selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 microspheres as a salvage therapy in liver metastasis of different tumors. Sixty-one patients who had unresectable liver metastases from colorectal carcinoma (n=23), neuroendocrine tumor (NET; n=12), cholangiocarcinoma (n=9), and others (n=17) received yttrium-90 microspheres. All patients were treated in a salvage setting with an 11-month mean follow-up. Early metabolic treatment response was evaluated by 18F-Fluorodeoxyglucose positron emission tomography (FDG PET-CT) in the sixth week after treatment. Of the 61 patients, 32 were alive at the end of the study; median overall survival (OS) was 17.0 ± 2.5 months (95% confidence interval: 11.9-22.0). A subset analysis of colorectal and noncolorectal groups demonstrated median OS rates of 14.0 ± 5.8 and 17.0 ± 4.8 months, respectively (p=0.543). The mean OS for patients with NET and cholangiocarcinoma was 29.0 ± 3.1 months and 17.7 ± 3.2 months, respectively (p=0.010). According to the early metabolic treatment response, the mean OS of responder and nonresponder groups was 32.0 ± 5.6 months and 11.4 ± 2.1 months, respectively (p=0.054). Eastern Cooperative Oncology Group performance status <1 (p=0.018) and chemotherapy-naive patients (p=0.008) showed significant correlation with survival. SIRT is an effective treatment option for patients with metastatic liver disease in a salvage setting with acceptable toxicity.


Specificity of substrate recognition by Pseudomonas fluorescens N3 dioxygenase. The role of the oxidation potential and molecular geometry.
Pseudomonas fluorescens N3 is able to grow on naphthalene as the sole carbon and energy source. The mutant TTC1, blocked at the dihydrodiol dehydrogenase level, which can transform the hydrocarbon into the corresponding dihydrodiol, has been used to produce bioconversion products. To rationalize the different grades of conversion obtained with different substrates, a study was performed using non-naphthalene derivatives, including benzenes, conjugated benzenes, and polycyclic aromatic hydrocarbons. The corresponding diols obtained by bioconversion have been isolated and characterized. A theoretical model that considers both energy and geometry factors has been proposed to rationalize the experimental data. Good agreement has been found between the calculated values and the experimental results.


Frictional dynamics of fluorine-terminated alkanethiol self-assembled monolayers.
The frictional dynamics of fluorine-terminated alkanethiol (S(CH2)8CF3) self-assembled monolayers (SAMs) on gold are studied using molecular dynamics simulations. The simulations treat the interactions between two SAMs on flat surfaces. The structure and frictional behavior are investigated as a function of applied pressure (200 MPa to 1 GPa) for a shear velocity of 2 m/s and compared to methyl-terminated alkanethiol SAMs. The maximum adhesive pressure between the SAMs is 220 MPa for both end groups. In agreement with experiments on the molecular scale, the shear stress and the coefficient of friction for CF3-terminated alkanethiols are larger than for CH3-terminated alkanethiols. The main source for the difference is primarily the tighter packing of the fluorinated terminal group resulting in a higher degree of order. The molecular scale coefficient of friction is correlated with the degree of order among all the systems.


Molecular Rotors Provide Insights into Microscopic Structural Changes During Protein Aggregation.
Changes in microscopic viscosity represent an important characteristic of structural transitions in soft matter systems. Here we demonstrate the use of molecular rotors to explore the changes in microrheology accompanying the transition of proteins from their soluble states into a gel phase composed of amyloid fibrils. The formation of beta-sheet rich protein aggregates, including amyloid fibrils, is a hallmark of a number of neurodegenerative disorders, and as such, the mechanistic details of this process are actively sought after. In our experiments, molecular rotors report an increase in rigidity of approximately three orders of magnitude during the aggregation reaction. Moreover, phasor analysis of the fluorescence decay signal from the molecular rotors suggests the presence of multiple distinct mechanistic stages during the aggregation process. Our results show that molecular rotors can reveal key microrheological features of protein systems not observable through classical fluorescent probes operating in light switch mode.


A systematic review of substandard, falsified, unlicensed and unregistered medicine sampling studies: a focus on context, prevalence, and quality.
Substandard and falsified (SF) medicines are a global issue contributing to antimicrobial resistance and causing economic and humanitarian harm. To direct law enforcement efficiently, halt the spread of SF medicines and antimicrobial resistance, academics, NGOs and government organisations use medicine quality sampling studies to estimate the prevalence of the problem. A systematic review of medicine quality studies was conducted to estimate how the methodological quality of these studies and SF prevalence has changed between 2013 and 2018. We also aimed to critique medicine sampling study methodologies, and the systematic review process which generates prevalence estimates. Based on 33 studies, the overall estimated median (Q1-Q3) prevalence of SF medicines appears to have remained high at 25% (7.7%-34%) compared with 28.5% in 2013. Furthermore, the methodological quality of prevalence studies has improved over the last 25 years. Definitive conclusions regarding the prevalence of SF medicines cannot be drawn due to the variability in sample sizes, consistency of design methods, and a lack of information concerning contextual factors affecting medicine quality studies. We contend that studies which present cumulative average prevalence figures are useful in a broad sense but could be improved to create more reliable estimates. We propose that medicine quality studies record the context of the study environment to allow systematic reviewers to compare like with like. Although, the academic rigour of medicine quality studies is improving, medicine sampling study limitations still exist. These limitations inhibit the accurate estimation of SF medicine prevalence which is needed to support detailed policy changes.


Arthroscopically assisted anterior cruciate ligament reconstruction: comparison of bone-patellar tendon-bone versus hamstring tendon autograft.
The bone-patellar tendon-bone (BPTB) and the hamstring tendons are commonly used for arthroscopially-assisted anterior cruciate ligament (ACL) reconstruction. To compare the results of arthroscopically-assisted ACL reconstruction using bone-patellar tendon-bone and hamstring tendons grafts in terms of postoperative knee stability, knee functions and clinical rating scale, and patient satisfaction. There was no difference in the outcomes of the two grafts. Retrospective non-randomized clinical trial. Two groups of patients, 45 in the BPTB group and 30 in the hamstring group, were followed for at least one year. The two groups had similar pre-operative data except the hamstring group which had a significantly shorter duration of injury before operation (9.5 versus 18 months, p < 0.05). There was no difference in median pre-operative Lysholm knee score (74 in the BPTB group versus 75 in the hamstring group, p > 0.05) and the post-operative one (95 in the BPTB group versus 99 in the hamstring group, p > 0.05). There was also no difference in the median pre-operative HSS knee score (58 in the BPTB group versus 61 in the hamstring group, p > 0.05). Although there was a statistically significant difference in the median post-operative HSS knee score between the two groups (95 in the BPTB group versus 96 in the hamstring group, p < 0.05), this was not clinically significant since both scores were rated as an excellent result. Both groups had a significantly improved knee stability and knee functions (Lysholm and HSS knee scores). The hamstring group, however, had significantly higher patient satisfaction (88% in the BPTB group versus 93% in the hamstring group, p < 0.05). Both the BPTB and the hamstring tendon grafts resulted in significantly improved knee stability and functions with high patient satisfaction. The hamstring tendon group, however, had a significantly better post-operative patient satisfaction (Visual Analog Scale, VAS).


Immunoglobulin haplotypes: markers of reproductive success?
Immunoglobulin haplotypes are highly polymorphic and are useful for analyses of both macro- and microdifferentiation of populations. The origins of this diversity are not known, but recent reports suggest strong selection at this locus. Increased rates of first-trimester spontaneous abortions have been reported when parents share GM phenotypes. Reduced fertility has been observed in mixed European descent white and Hutterite populations when both parents share immunoglobulin haplotypes. Population samples with completed family information and GM haplotype data are rare; the objective here is to provide this information on another sample. A sample of 242 Mennonite couples with mothers older than 40 years was divided into 3 groups of matings based on how many haplotypes were shared: 0, 1, or 2. The distribution of mean completed family sizes for the three groups were 3.35 +/- 1.85 (n = 23), 3.47 +/- 1.69 (n = 128), and 3.37 +/- 1.60 (n = 91), respectively; these values were not significantly different (F = 0.145, p = 0.865). The log-rank test was used to compare the time-to-next-birth curves. The intervals between first and later births (2-4 births) were not significantly different for the three subgroups either. There is also only limited evidence for segregation distortion in another sample of 923 offspring (in which at least one parent is heterozygous.


Bone Matrix Mineralization in Patients With Gain-of-Function Calcium-Sensing Receptor Mutations Is Distinctly Different From that in Postsurgical Hypoparathyroidism.
The role of the calcium-sensing receptor (CaSR) as a regulator of parathyroid hormone secretion is well established, but its function in bone is less well defined. In an effort to elucidate the CaSR's skeletal role, bone tissue and material characteristics from patients with autosomal dominant hypocalcemia (ADH), a genetic form of primary hypoparathyroidism caused by CASR gain-of-function mutations, were compared to patients with postsurgical hypoparathyroidism (PSH). Bone structure and formation/resorption indices and mineralization density distribution (BMDD), were examined in transiliac biopsy samples from PSH (n = 13) and ADH (n = 6) patients by histomorphometry and quantitative backscatter electron imaging, respectively. Bone mineral density (BMD by DXA) and biochemical characteristics were measured at the time of the biopsy. Because both study groups comprised children and adults, all measured biopsy parameters and BMD outcomes were converted to Z-scores for comparison. Histomorphometric indices were normal and not different between ADH and PSH, with the exception of mineral apposition rate Z-score, which was higher in the ADH group. Similarly, average BMD Z-scores were normal and not different between ADH and PSH. Significant differences were observed for the BMDD: average Z-scores of mean and typical degree of mineralization (CaMean, CaPeak, respectively) were lower (p = 0.02 and p = 0.03, respectively), whereas the heterogeneity of mineralization (CaWidth) and percentage of lower mineralized areas (CaLow) were increased in ADH versus PSH (p = 0.01 and p = 0.002, respectively). The BMDD outcomes point toward a direct, PTH-independent role of the CaSR in the regulation of bone mineralization. © 2018 American Society for Bone and Mineral Research.


Differential Expression of Platelet Activation Markers, CD62P and CD63, after Exposure to Breast Cancer Cells Treated with Kigelia Africana, Ximenia Caffra and Mimusops Zeyheri Seed Oils In Vitro.
Cancer patients, including breast cancer patients, live in a hypercoagulable state. Chemo- and hormone- therapy used in the treatment of breast cancer increases the risk of thrombosis. Due to differences in health care services between developed and developing countries, the survival rate of women with breast cancer in developing countries is low. Consequently, ethnomedicines are used and their efficacy as potential alternatives are being scientifically explored. The seed oils of Kigelia africana, Ximenia caffra and Mimusops zeyheri have anti-proliferative effects on hormone-dependent (MCF-7) and cytotoxic effects on hormone-independent (MDA-MB-231) breast cancer cells. In this study, we determined if these seed oils reduce the thrombogenic ability of breast cancer cells by measuring the platelet surface expression of the activation-specific antigens CD62P and CD63. MDA-MB-231 and MCF-7 cells were pretreated with the seed oils before being exposed to whole blood of human female volunteers. An increase in CD62P and CD63 expression following whole blood exposure to untreated breast cancer cells was observed. Treated MDA-MB-231 cells reduced CD62P and CD63 expression while treated MCF-7 cells increased CD62P and decreased CD63 expression. Kigelia africana, Ximenia caffra and Mimusops zeyheri seed oils are able to reduce the thrombogenic ability of MDA-MB-231 breast cancer cells.


Hypoxia in neonatal calves: effect on intestinal transport of immunoglobulins.
The effect of reduced oxygen tension in arterial blood (hypoxic hypoxia) for 24 h postpartum on the absorption of colostral Ig was studied in 12 neonatal calves. During this period, inspired air for hypoxic calves contained 10.5% O2, whereas that for normoxic calves contained 21% O2. After 24 h, inspired air for all calves contained 21% O2. Three dietary regimens also were imposed during the initial 24-h period: colostrum at 0 and 12 h, whole milk at 0 and 12 h, or fasting. Colostrum was fed to all calves at 24, 36, and 48 h. During the initial 24-h period, means for arterial partial pressure of oxygen were 26 and 73 mm Hg for hypoxic and normoxic calves, respectively. In those fed colostrum at 0 and 12 h, hypoxia extended the period of Ig absorption from 20 to 40.5 h. In calves fed whole milk or those that were fasted, no such effect was noted. These observations suggest that the effect of hypoxia on the cessation of Ig absorption by the small intestine is mediated through a secondary and as yet undetermined mechanism.


Integrating Acupuncture for the Management of Costochondritis in Adolescents.
Background: Costochondritis is a common condition involving inflammation of the costochondral or chondrosternal joints. Conventional management of costochondritis includes pain medications, but these do not provide full recovery in all patients. There is limited information on adjunctive acupuncture for pediatric costochondritis. Cases: This article describes the use of acupuncture in the management of costochondritis in adolescent patients. A retrospective chart review was conducted for 3 patients who received acupuncture treatment for costochondritis at a tertiary pediatric medical center. Patient demographics, Numerical Rating Scale, and the Brief Pain Inventory were recorded. Results: All patients demonstrated satisfactory symptomatic reduction following acupuncture treatment. Conclusions: Integrating acupuncture with conventional medicine appeared to reduce the costochondritis symptoms in the adolescent patients.


AFM Nanoindentation To Quantify Mechanical Properties of Nano- and Micron-Sized Crystals of a Metal-Organic Framework Material.
The mechanical properties of individual nanocrystals and small micron-sized single crystals of metal-organic frameworks (MOFs), hitherto, cannot be measured directly by employing the conventional instrumented nanoindentation approach. Here we propose the application of atomic force microscopy (AFM)-based nanoindentation technique, equipped with a calibrated diamond cube-corner indenter tip to quantify the Young's modulus, hardness, adhesion energy, and interfacial and fracture strengths of a zeolitic imidazolate framework (ZIF-8) porous material. We use ZIF-8 as a model MOF system to develop AFM nanoindentation leveraging the concept of unloading strain rate, enabling us to critically assess the practicality and technical limitations of AFM to achieve quantitative measurements of fine-scale MOF crystals. We demonstrate the advantages of using a high unloading strain rate (ε̇ > 60 s-1) to yield reliable force-displacement data in the few μN load range, corresponding to a shallow indentation depth of ∼10s nm. We found that the Young's moduli (∼3-4 GPa) determined by AFM nanoindentation of the nanocrystals (<500 nm) and micron-sized crystals (∼2 μm) are in agreement with magnitudes derived previously from other techniques, namely instrumented nanoindentation and Brillouin spectroscopy (however, these methods requiring large 100-μm sized crystals) and also in line with density functional theory predictions of an idealized ZIF-8 crystal.


Rheological Analysis of the Synthesis of High-Molecular-Weight Epoxy Resins from Modified Soybean Oil and Bisphenol A or BPA-Based Epoxy Resins.
The research undertaken in this work is one of the examples of the engineering of modern polymer materials. This manuscript presents studies on the gelation process which might occur during the synthesis of epoxy resin using the modified vegetable oil via the epoxy fusion process conducted in bulk. Based on obtained results we determined rheological parameters related to the properties of reacting mixture during the polyaddition process, especially before and after occurring the phenomenon of gelation (via (1) theoretical determination of the gel point using the degree of conversion of reactants before occurring the gelation process of reacting mixture and (2) experimentally-the dynamic mechanical properties such as storage modulus, G'; loss modulus, G″; and loss tangent, tg δ). Theoretical investigations show that for both systems: epoxidized soybean oil and bisphenol A (ESBO_BPA), as well as the hydroxylated soybean oil and low molecular weight epoxy resin (SMEG_EPR), theoretical values of the degree of conversion at the gel point are characterized by similar values (ESBO_BPA: xgel-theoretical = 0.620, xgel-theoretical = 0.620 and SMEG_EPR: xgel-theoretical = 0.614, xgel-experiment = 0.630, respectively), while the one determined based on the initial assumptions are greater than the above-mentioned (ESBO_BPA: xgel-assumed = 0.696 and SMEG_EPR: xgel-assumed = 0.667). Moreover, experimental studies in the viscoelastic fluid stage showed that the SMEG_EPR system is characterized by lower values of G' and G″, which indicates lower elasticity and lower viscosity than the epoxidized derivative. It was found that alike during the conventional polyaddition reaction, both systems initially are homogeneous liquids of increasing viscosity. Wherein gradual increase in viscosity of the reaction mixture is related to the fusion of oligomer molecules and the formation of higher molecular weight products. In the critical stage of the process, known as the gelation point, the reaction mixture converts into the solid form, containing an insoluble cross-linked polymer.


Patients' attitudes towards oral health and experiences of periodontal treatment: a qualitative interview study.
The aim of the present qualitative study was to analyse patients' attitudes towards oral health and experiences of periodontal treatment. Patients who were referred to a specialist clinic in periodontics were subjected to open-ended interviews before (Abrahamsson et al, 2008), as well as after, the phase of cause-related periodontal therapy. An interview guide was used with themes of interest. The time interval between the interviews was about 6 months. Because the study focused on psychosocial interactions, the qualitative method used for the analysis was Grounded Theory (Glaser and Strauss, 1967). Data collection and analysis were simultaneous processes that focus on psychosocial processes, existing problems and how these problems were dealt with. The interviews were tape-recorded and transcribed verbatim, and consequently analysed in a hierarchical coding process until saturation was met (n = 16). In the analysis, a core category was identified: 'Understanding the seriousness of the disease condition'. This core concept was related to four additional categories and dimensions: 'The need to be treated respectfully', 'To gain insight', 'Frustration about the financial cost for treatment' and 'Feelings of control over the situation'. Taken together, the core category and its related subcategories described a psychosocial process that was related to periodontal treatment. The results elucidated the patients' vulnerability and the importance of patient communication in the treatment for chronic periodontitis in order for the patient to feel in control of the situation.


Effects of planting system design on the toxicological sensitivity of Myriophyllum spicatum and Elodea canadensis to atrazine.
The triazine herbicide atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-trazine) was selected as a chemical stressor in an investigation of how toxicological responses of individually grown macrophytes reflect those of plants grown in more natural model populations and two-species communities. Phytotoxicity of the compound to Myriophyllumspicatum L. and Elodeacanadensis Michx. was assessed under semi-natural field conditions using 12000l outdoor microcosms. Exposure concentrations of 25, 50, 100, 250microgl(-1) plus controls (n=3) were evaluated, selected to fall within a range of concentrations known to produce a toxic response in the tested macrophytes, and effective concentrations required to cause a decrease in biomass endpoints by 10%, 25%, and 50% were estimated. The sensitivities of aquatic plants to atrazine did not differ substantially between planting systems, and few interactions between the effects of the planting method and atrazine effects on macrophyte biomass were detected using a two-way ANOVA. A lack of significant differences in biomass and relative growth rate measures between plants grown under the various test systems also indicated that interactions between and among species did not influence growth of plants in the model population and communities. Under these test conditions, the use of the "cone-tainer" method provided estimates of toxicity consistent with those from plants grown in assemblages, and potential interactions between plants were not found to modify the response of macrophytes to atrazine.


Adaptive Fuzzy Control for a Class of MIMO Underactuated Systems With Plant Uncertainties and Actuator Deadzones: Design and Experiments.
In the field of modern industrial engineering, many mechanical systems are underactuated, exhibiting strong nonlinear characteristics and high flexibility. However, the lack of control inputs brings about many difficulties for controller design and stability/convergence analysis., some unavoidable practical issues, e.g., plant uncertainties and actuator deadzones, make the control of underactuated systems even more challenging. Hence, with the aid of elaborately constructed finite-time convergent surfaces, this article provides the first solution to address the control problem for a class of multi-input-multi-output (MIMO) underactuated systems subject to plant uncertainties and actuator deadzones. Specifically, this article overcomes the main obstacle in sliding-mode surface analysis for MIMO underactuated systems, that is, by the presented analysis method, the asymptotic stability of the system equilibrium point is strictly proven based on the composite surfaces. In addition, the unknown parts of the actuated/unactuated dynamic equations and actuator deadzones can be simultaneously handled, which is important for real applications. Furthermore, we apply the proposed method to two kinds of typical underactuated systems, that is: 1) tower cranes and 2) double-pendulum cranes, and implement a series of hardware experiments to verify its effectiveness and robustness.


[Serum ABO immune antibodies in 1944 pregnant women].
The ABO+ Rh blood groups and serum anti- A and anti -B anti bodies were examined in 1944 pregnant women. The results showed that 475 cases (24.4%) were positive for serum immune antibodies resulting in ABO incompatibility, and in 68 (3.4%) newborns haemolytic disease (HDN) occurred. The incidence of ABO blood group incompatibility increased with the increase of maternal serum immune antibody titer, the difference between different titers was significant (chi 2 = 4.13, P less than 0.05). Pregnant women with a high titer of serum immune antibody greater than 1:64 should be followed up regularly and those greater than 1:128 should be treated immediately. The relationship between positive serum immune antibody and blood group was discussed. We consider it is important to do maternal serum immune antibodies examination for antenatal care.


Brazilian dialysis survey 2019.
National data on chronic dialysis treatment are essential for the development of health policies that aim to improve the treatment of patients. To present data from the Brazilian Dialysis Survey 2019, promoted by the Brazilian Society of Nephrology. Data collection from dialysis units in the country through a completed online questionnaire for 2019. 314 (39%) centers responded the questionnaire. In July 2019, the estimated total number of patients on dialysis was 139,691. Estimates of the prevalence and incidence rates of patients undergoing dialysis treatment per million of the population (pmp) were 665 and 218, respectively, with mean annual increases of 25 pmp and 14 pmp for prevalence and incidence, respectively. The annual gross mortality rate was 18.2%. Of the prevalent patients, 93.2% were on hemodialysis and 6.8% on peritoneal dialysis; and 33,015 (23.6%) on the waiting list for transplantation. 55% of THE centers offered treatment with peritoneal dialysis. Venous catheters were used as access in 24.8% of THE patients on hemodialysis. 17% of the patients had K ≥ 6.0mEq/L; 2.5% required red blood cell transfusion in July 2019 and 10.8% of the patients had serum levels of 25-OH vitamin D < 20 ng/mL. The absolute number of patients, the incidence and prevalence rates in dialysis in the country continue to increase, as well as the percentage of patients using venous catheter as dialysis access. There was an increase in the number of patients on the list for transplantation and a tendency to reduce gross mortality.


Practice revenue and cost distribution for ophthalmology, 1988 to 1993.
As opthalmologists need to better manage their practices, information regarding distribution of practice costs becomes more relevant. In this study, we compare revenues and costs from published sources to determine changes over time and across surveys. We also evaluate the reliability and validity of these statistics. Data were obtained from the Health Care Financing Administration (for 1988), the American Medical Association (for 1988, 1990, 1992, and 1993), and the Medical Group Management Association (for 1988, 1990, 1992, and 1993) and were compared across years and surveys. We found large differences among the surveys in both dollar amounts and percentages of total revenue for some of the reported cost categories. Analysis of the data over time showed less of a decline in physician earnings than expected, although there were large increases in the category "other costs." We found considerable divergence among the statistical results. Opthalmologists, public policymakers, and managed care organizations must exercise great caution in interpreting such data and in applying their findings to individual ophthalmic practices and practitioners.


Cellular blue nevus with nevus cells in a sentinel lymph node.
Regional lymph node involvement by a cellular blue nevus has been reported. However, it has recently been suggested that specific cases with "benign metastasizing" cellular blue nevi are actually rare. This study describes a typical case of a cellular blue nevus with nevus cells in a sentinel lymph node. We demonstrated that a cellular blue nevus clearly involved the regional lymph node and investigated the immunohistochemical profiles of such nodal cellular blue nevus cells. The location of the nevus cells fundamentally indicated a benign type, with limitation to the capsule and the fibrous trabeculae. However, only a few, isolated nevus cells were also seen in the parenchyma of the lymph node. The nevus cells in the capsule and the fibrous trabeculae were positive for c-kit, like the migrating melanocytes from the neural crest. In cellular blue nevi or lesions with similar histopathological features, it may be appropriate to consider the predominant involvement of the capsule as well as the benign cytological features and the immunohistochemical profiles (Ki-67-, PCNA-, and c-kit+) of the nodal cells to be a benign sign.


Increased efficacy for in-house validation of real-time PCR GMO detection methods.
To improve the efficacy of the in-house validation of GMO detection methods (DNA isolation and real-time PCR, polymerase chain reaction), a study was performed to gain insight in the contribution of the different steps of the GMO detection method to the repeatability and in-house reproducibility. In the present study, 19 methods for (GM) soy, maize canola and potato were validated in-house of which 14 on the basis of an 8-day validation scheme using eight different samples and five on the basis of a more concise validation protocol. In this way, data was obtained with respect to the detection limit, accuracy and precision. Also, decision limits were calculated for declaring non-conformance (>0.9%) with 95% reliability. In order to estimate the contribution of the different steps in the GMO analysis to the total variation variance components were estimated using REML (residual maximum likelihood method). From these components, relative standard deviations for repeatability and reproducibility (RSD(r) and RSD(R)) were calculated. The results showed that not only the PCR reaction but also the factors 'DNA isolation' and 'PCR day' are important factors for the total variance and should therefore be included in the in-house validation. It is proposed to use a statistical model to estimate these factors from a large dataset of initial validations so that for similar GMO methods in the future, only the PCR step needs to be validated. The resulting data are discussed in the light of agreed European criteria for qualified GMO detection methods.


Enhanced Water Solubility and Oral Bioavailability of Paclitaxel Crystal Powders through an Innovative Antisolvent Precipitation Process: Antisolvent Crystallization Using Ionic Liquids as Solvent.
Paclitaxel (PTX) is a poor water-soluble antineoplastic drug with significant antitumor activity. However, its low bioavailability is a major obstacle for its biomedical applications. Thus, this experiment is designed to prepare PTX crystal powders through an antisolvent precipitation process using 1-hexyl-3-methylimidazolium bromide (HMImBr) as solvent and water as an antisolvent. The factors influencing saturation solubility of PTX crystal powders in water in water were optimized using a single-factor design. The optimum conditions for the antisolvent precipitation process were as follows: 50 mg/mL concentration of the PTX solution, 25 °C temperature, and 1:7 solvent-to-antisolvent ratio. The PTX crystal powders were characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, high-performance liquid chromatography-mass spectrometry, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Raman spectroscopy, solid-state nuclear magnetic resonance, and dissolution and oral bioavailability studies. Results showed that the chemical structure of PTX crystal powders were unchanged; however, precipitation of the crystalline structure changed. The dissolution test showed that the dissolution rate and solubility of PTX crystal powders were nearly 3.21-folds higher compared to raw PTX in water, and 1.27 times higher in artificial gastric juice. Meanwhile, the bioavailability of PTX crystal increased 10.88 times than raw PTX. These results suggested that PTX crystal powders might have potential value to become a new oral PTX formulation with high bioavailability.


Bullous cellulitis as an extraordinary manifestation of a Vibrio cholerae O1 Ogawa infection.
Vibrio cholerae is a gram-negative bacterium synonymous with its namesake disease, cholera. Thus, gastrointestinal symptoms are the norm and V. cholerae is very rarely associated with skin and soft tissue infections. We describe a case of a 63-year-old Chinese woman with multiple medical comorbidities on corticosteroid therapy who developed fever and a painful swelling on her left leg after being pricked by a branch while gardening. There was no abdominal pain, vomiting or diarrhea. A diagnosis of bullous cellulitis was made clinically, and blood was sent for bacteriological culture. A beta-hemolytic commashaped gram-negative bacillus was isolated from the blood. It was also oxidase-positive and produced an acid/alkaline (A/K) reaction on triple sugar iron agar. It was identified biochemically as Vibrio cholerae. After additional testing, it was found to be of the O1 serogroup and Ogawa serotype. The infection resolved following a 10-day course of high-dose co-trimoxazole therapy.


Prasugrel Dose De-escalation Therapy After Complex Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: A Post Hoc Analysis From the HOST-REDUCE-POLYTECH-ACS Trial.
De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. However, whether such benefits are similarly observed in those receiving complex procedures is unknown. To investigate whether the benefits of prasugrel dose de-escalation therapy are maintained in the complex percutaneous coronary intervention (PCI) subgroup. This was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, a randomized, open-label, adjudicator-blinded, multicenter trial performed at 35 hospitals in South Korea. Study participants included patients with ACS who were receiving PCI. Data were collected from September 30, 2014, to December 18, 2015, and analyzed from September 17, 2020, to June 15, 2021. Patients were randomized to a prasugrel dose de-escalation (5 mg daily) at 1 month post-PCI group or a conventional (10 mg daily) group. Complex PCI was defined as having at least 1 of the following features: 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI, total stent length 60 mm or larger, left main PCI, or heavy calcification. The main analysis end points were MACE (major adverse cardiac event, a composite of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and repeat revascularization) at 1 year for ischemic outcomes, and BARC (Bleeding Academic Research Consortium) class 2 or higher bleeding events at 1 year for bleeding outcomes. Of 2271 patients (mean [SD] age, 58.9 [9.0] years; 2024 [89%] male patients) for whom full procedural data were available, 705 patients received complex PCI, and 1566 patients received noncomplex PCI. Complex PCI was associated with higher rates of ischemic outcomes but not with bleeding outcomes. Prasugrel dose de-escalation did not increase the risk of MACE (hazard ratio [HR], 0.88; 95% CI, 0.47-1.66; P = .70 in complex PCI; HR, 0.81; 95% CI, 0.45-1.46; P = .48 in noncomplex PCI; P for interaction = .84) but decreased BARC class 2 or higher bleeding events (HR, 0.25; 95% CI, 0.10-0.61; P = .002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P = .05 in noncomplex PCI; P for interaction = .08), albeit with wide 95% CIs. In this post hoc analysis of patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity. ClinicalTrials.gov Identifier: NCT02193971.


Analysis of host-assisted guest protonation exemplified for p-sulfonatocalix[4]arene--towards enzyme-mimetic pKa shifts.
The pD dependence of the complexation of p-sulfonatocalix[4]arene (CX4) with the azoalkanes 2,3-diazabicyclo[2.2.1]hept-2-ene (1), 2,3-diazabicyclo[2.2.2]oct-2-ene (2), 2,3-diazabicyclo[2.2.3]non-2-ene (3), and 1-methyl-4-isopropyl-2,3-diazabicyclo[2.2.2]oct-2-ene (4) in D(2)O has been studied. The pD-dependent binding constants, determined by (1)H NMR spectroscopy, were analyzed according to a seven-state model, which included the CX4 tetra- and penta-anions, the protonated and unprotonated forms of the azoalkanes, the corresponding complexes, as well as the complex formed between CX4 and the deuteriated hydronium ion. The variation of the UV absorption spectra, namely the hypsochromic shift in the near-UV band of the azo chromophore upon protonation, was analyzed according to a four-state model. Measurements by independent methods demonstrated that complexation by CX4 shifts the pK(a) values of the guest molecules by around 2 units, thereby establishing a case of host-assisted guest protonation. The pK(a) shift can be translated into improved binding (factor of 100) of the protonated guest relative to its unprotonated form as a result of the cation-receptor properties of CX4. The results are discussed in the context of supramolecular catalytic activity and the pK(a) shifts induced by different types of macrocyclic hosts are compared.


[Alternatives to steroid therapy in chronic uveitis].
In a search for alternative therapeutic methods other than corticosteroids and cytostatics, the effect of a dialyzable leukocyte extract (DLE), the antimetabolite 5-fluorouracil and the immunosuppressive agent cyclosporin A in corticosteroid-resistant idiopathic uveitis was studied. When DLE was administered to 26 patients who had uveitis forms with exogenous triggering (e.g., infection), as well as forms with an autoimmune background, there was a reduction in the number and duration of recurrences and a statistically proven prolongation of the inflammation-free intervals. This was particularly true in anterior and posterior uveitis and to a lesser extent in the intermediate form. No side effects were observed. 5-Fluorouracil, injected subconjunctivally, is indicated in intermediate uveitis with marked vitreous infiltration and beginning proliferation. Corneal erosion occurs relatively often. During treatment with cyclosporin A (low dose, 5 mg/kg of body weight per day), 14 of 17 patients (9 with intermediate uveitis, 6 with retinal vasculitis, 1 with sympathetic ophthalmia, 1 with panuveitis) showed improved results; in 2 cases the findings remained stationary and only 1 case had low-grade deterioration. If one takes into consideration the fact that in this patient any therapy would have failed, the results are convincing. This is particularly true of retinal vasculitis. There is no effect in cases of central hemorrhagic chorioretinopathy. So far, there have been no serious side effects.


Seasonal variation in high-risk phenotypes of cutaneous malignant melanoma diagnosed in Eastern England: An observational study.
Despite seasonal variation in malignant melanoma diagnosis being well described, data on the annual variation in high-risk melanomas are scarce. We set out to investigate the relationship between seasonality, the incidence of melanoma, and the distribution of melanoma characteristics, including Breslow thickness, ulceration, mitotic rate, lymphovascular and perineural invasion, and the presence of microsatellites. Primary cutaneous malignant melanomas diagnosed between 2011 and 2019 in Eastern England were identified from our prospectively maintained melanoma database (n = 2199). These were analysed by year and season of diagnosis, patient demographics, and melanoma characteristics. There was a variation in rates of melanoma diagnosis across the year, with Summer having the highest incidence (p < 0.0001). There was a significant trend towards more male than female diagnosis in Winter (p = 0.0354). There were no significant seasonal trends in Breslow thickness, ulceration, tumour infiltrating lymphocytes, or mitotic rate. Multivariate analysis showed that microsatellites were more likely to be diagnosed in the Winter (OR=2.00 (1.19-3.43), p = 0.010), lymphovascular invasion significantly more likely to be diagnosed in Autumn (OR=1.78 (1.16-2.76), p = 0.009), and perineural invasion was more likely to be diagnosed in the Summer (OR=0.44 (0.23-0.79), p = 0.007). These data confirm that high-risk phenotypes are associated with increasing Breslow thickness and mitotic rate. However, season variability as an independent risk factor for the phenotypes is a novel finding.


Antissaliva Antibodies of Lutzomyia Longipalpis in area of Visceral Leishmaniasis.
The aim of the present study was to assess the presence of antissaliva antibodies of Lutzomyia longipalpis in human hosts living in area of visceral leishmaniasis, located in the Center-West region of Brazil. The presence of antissaliva antibodies of L. longipalpis exhibited a strong correlation with the protection and development of antibodies against Leishmania sp. Of the 492 children studied, elevated antissaliva antibodies of L. longipalpis were detected in 38.4% of the participants. There was a higher percentage of positivity (64.7%) among children who exhibited anti-Leishmania sp. antibodies and among those who were positive in the delayed hypersensitivity test (34.8%).


Changes in acetylcholinesterase and cholinesterase activities in rat pancreas during postnatal development. Lack of relation with muscarinic receptor maturation.
This study was undertaken to establish if there is a correlation between the ontogenesis of cholinesterase activities and the cholinergic muscarinic receptors in the development of rat pancreas. Two different cholinesterase activities were detected in the pancreas: a true acetylcholinesterase and a pseudocholinesterase. The ratio of acetylcholinesterase to total cholinesterase activities varied as a function of age. Acetylcholinesterase and total cholinesterase specific activities (units per milligram protein) decreased sharply at weaning. When expressed on a DNA basis, both activities decreased constantly until age 30 days to increase slightly thereafter. However, a correlation could not be established between the development of acetylcholinesterase activity and the muscarinic receptors.


Detecting determinism with improved sensitivity in time series: rank-based nonlinear predictability score.
The rank-based nonlinear predictability score was recently introduced as a test for determinism in point processes. We here adapt this measure to time series sampled from time-continuous flows. We use noisy Lorenz signals to compare this approach against a classical amplitude-based nonlinear prediction error. Both measures show an almost identical robustness against Gaussian white noise. In contrast, when the amplitude distribution of the noise has a narrower central peak and heavier tails than the normal distribution, the rank-based nonlinear predictability score outperforms the amplitude-based nonlinear prediction error. For this type of noise, the nonlinear predictability score has a higher sensitivity for deterministic structure in noisy signals. It also yields a higher statistical power in a surrogate test of the null hypothesis of linear stochastic correlated signals. We show the high relevance of this improved performance in an application to electroencephalographic (EEG) recordings from epilepsy patients. Here the nonlinear predictability score again appears of higher sensitivity to nonrandomness. Importantly, it yields an improved contrast between signals recorded from brain areas where the first ictal EEG signal changes were detected (focal EEG signals) versus signals recorded from brain areas that were not involved at seizure onset (nonfocal EEG signals).


Myositis ossificans demonstrated by positive gallium-67 and technetium-99m-HMDP bone imaging but negative technetium-99m-MIBI imaging.
Gallium-67-citrate and 99mTc-diphosphate bone imaging agents are localized in myositis ossificans, a tumor-like benign soft-tissue mass that makes it impossible to differentiate between malignant tumor and the infection/inflammatory process. We present such a myositis ossificans patient whose bone and 67Ga-citrate imagings showed increased uptake in the left thigh and two foci of the right gluteal region leading to inconclusive results. Technetium-99m-MIBI imaging showed the absence of substantial uptake in these regions. ACT scan confirmed myositis ossificans. The lack of 99mTc-MIBI uptake in myositis ossificans means that 99mTc-MIBI imaging may be useful in the differential diagnosis.


Pulse transmission through a dielectric optical waveguide.
Waveguide propagation of a pulse-modulated carrier wave is formulated to include distortion due to dispersion in both attentuation and phase velocity. An optimum input gaussian pulse width exists for maximum information carrying capacity. Results are applied to a numerical study of several singlemode glass optical waveguides in which mode and dielectric dispersion may total zero at some wavelength. For our low-loss (20 dB/km) guides in kilometer lengths, information rates of at least 3 x 10(10) bits/sec should be attainable.


The Medical Outcome Study-HIV Health Survey: A systematic review and reliability generalization meta-analysis.
The Medical Outcome Study-HIV Health Survey (MOS-HIV) is one of the most used questionnaires for the evaluation of the health-related quality of life (HRQoL) in people living with HIV (PLWHIV) in both medical settings and research studies. This study aimed to estimate the average reliability of the MOS-HIV scores and to evaluate the characteristics of the studies that could explain the variability between reliability estimates. Furthermore, the study aimed to estimate the induction rate of the reliability of the MOS-HIV. A systematic review of the previous literature, including studies that reported α and/or test-retest coefficients with the data at hand for the total score of the MOS-HIV and the subscales, was conducted. Fifty studies (52 samples; N = 14,132) were included in the reliability generalization meta-analysis. The average α coefficient for the total score of MOS-HIV was .91 and above .80 for all of the subscales, except for role functioning, which had an average coefficient of .76. Different study dimensions were related to the heterogeneity of reliability between studies. Reliability induction was found to be 76.1%. The results obtained in the present study indicate that the MOS-HIV is a reliable instrument for HRQoL evaluation in PLWHIV, for clinical and research purposes. In the clinical practice of health services, nurses could employ this gold standard for reliable evaluations of HRQoL in PLWHIV.


The amino-terminal domain of G-protein-coupled receptor kinase 2 is a regulatory Gbeta gamma binding site.
G-protein-coupled receptor kinase 2 (GRK2) is activated by free Gbetagamma subunits. A Gbetagamma binding site of GRK2 is localized in the carboxyl-terminal pleckstrin homology domain. This Gbetagamma binding site of GRK2 also regulates Gbetagamma-stimulated signaling by sequestering free Gbetagamma subunits. We report here that truncation of the carboxyl-terminal Gbetagamma binding site of GRK2 did not abolish the Gbetagamma regulatory activity of GRK2 as determined by the inhibition of a Gbetagamma-stimulated increase in inositol phosphates in cells. This finding suggested the presence of a second Gbetagamma binding site in GRK2. And indeed, the amino terminus of GRK2 (GRK2(1-185)) inhibited a Gbetagamma-stimulated inositol phosphate signal in cells, purified GRK2(1-185) suppressed the Gbetagamma-stimulated phosphorylation of rhodopsin, and GRK2(1-185) bound directly to purified Gbetagamma subunits. The amino-terminal Gbetagamma regulatory site does not overlap with the RGS domain of GRK-2 because GRK2(1-53) with truncated RGS domain inhibited Gbetagamma-mediated signaling with similar potency and efficacy as did GRK2(1-185). In addition to the Gbetagamma regulatory activity, the amino-terminal Gbetagamma binding site of GRK2 affects the kinase activity of GRK2 because antibodies specifically cross-reacting with the amino terminus of GRK2 suppressed the GRK2-dependent phosphorylation of rhodopsin. The antibody-mediated inhibition was released by purified Gbetagamma subunits, strongly suggesting that Gbetagamma binding to the amino terminus of GRK2 enhances the kinase activity toward rhodopsin. Thus, the amino-terminal domain of GRK2 is a previously unrecognized Gbetagamma binding site that regulates GRK2-mediated receptor phosphorylation and inhibits Gbetagamma-stimulated signaling.


Plant Desiccation and Protein Synthesis: III. Stability of Cytoplasmic RNA during Dehydration, and Its Synthesis on Rehydration of the Moss Tortula ruralis.
RNA species from the haploid gametophyte generation of the moss Tortula ruralis exhibit typical eukaryotic characteristics. The major ribosomal and soluble RNA species are stable during drying and rehydration. RNA synthesis occurs rapidly on reintroduction of the moss to water and incorporation into high molecular weight RNA fractions was detected after 20 to 30 minutes of rehydration and into low molecular weight fractions after 30-60 minutes. Newly synthesized ribosomal RNA was detected in ribosomes within 2 hours of rehydration, but not in polysomes. It is apparent that the ribosomal and transfer RNA conserved during desiccation is involved in the re-establishment of early protein synthesis during subsequent rehydration and that, initially, there is no requirement for newly synthesized material.


Diversity and Phylogenetic Analyses of Bacterial Symbionts in Three Whitefly Species from Southeast Europe.
Bemisia tabaci (Gennadius), Trialeurodes vaporariorum (Westwood), and Siphoninus phillyreae (Haliday) are whitefly species that harm agricultural crops in many regions of the world. These insects live in close association with bacterial symbionts that affect host fitness and adaptation to the environment. In the current study, we surveyed the infection of whitefly populations in Southeast Europe by various bacterial symbionts and performed phylogenetic analyses on the different symbionts detected. Arsenophonus and Hamiltonella were the most prevalent symbionts in all three whitefly species. Rickettsia was found to infect mainly B. tabaci, while Wolbachia mainly infected both B. tabaci and S. phillyreae. Furthermore, Cardinium was rarely found in the investigated whitefly populations, while Fritschea was never found in any of the whitefly species tested. Phylogenetic analyses revealed a diversity of several symbionts (e.g., Hamiltonella, Arsenophonus, Rickettsia), which appeared in several clades. Reproductively isolated B. tabaci and T. vaporariorum shared the same (or highly similar) Hamiltonella and Arsenophonus, while these symbionts were distinctive in S. phillyreae. Interestingly, Arsenophonus from S. phillyreae did not cluster with any of the reported sequences, which could indicate the presence of Arsenophonus, not previously associated with whiteflies. In this study, symbionts (Wolbachia, Rickettsia, and Cardinium) known to infect a wide range of insects each clustered in the same clades independently of the whitefly species. These results indicate horizontal transmission of bacterial symbionts between reproductively isolated whitefly species, a mechanism that can establish new infections that did not previously exist in whiteflies.


A genetically encoded biosensor reveals spatiotemporal variation in cellular phosphate content in Brachypodium distachyon mycorrhizal roots.
Arbuscular mycorrhizal (AM) symbiosis is accompanied by alterations to root cell metabolism and physiology, and to the pathways of orthophosphate (Pi) entry into the root, which increase with Pi delivery to cortical cells via arbuscules. How AM symbiosis influences the Pi content and Pi response dynamics of cells in the root cortex and epidermis is unknown. Using fluorescence resonance energy transfer (FRET)-based Pi biosensors, we mapped the relative cytosolic and plastidic Pi content of Brachypodium distachyon mycorrhizal root cells, analyzed responses to extracellular Pi and traced extraradical hyphae-mediated Pi transfer to colonized cells. Colonized cortical cells had a higher cytosolic Pi content relative to noncolonized cortical and epidermal cells, while plastidic Pi content was highest in cells at the infection front. Pi application to the entire mycorrhizal root resulted in transient changes in cytosolic Pi that differed in direction and magnitude depending on cell type and arbuscule status; cells with mature arbuscules showed a substantial transient increase in cytosolic Pi while those with collapsed arbuscules showed a decrease. Directed Pi application to extraradical hyphae resulted in measurable changes in cytosolic Pi of colonized cells 18 h after application. Our experiments reveal that cells within a mycorrhizal root vary in Pi content and Pi response dynamics.


HLA-B27 associated cross-reactive marker on the cells of New Zealand patients with ankylosing spondylitis.
We have previously shown that antibodies raised in rabbits to certain enteric bacteria will specifically lyse, in a 51Cr release assay, the peripheral blood lymphocytes (PBL) of 80% of HLA-B27 positive patients with ankylosing spondylitis (B27+ AS+) but not the PBL of HLA-B27 positive normal controls (B27+ AS-). Other laboratories have been unable to reproduce these findings. This study was designed to ascertain whether this lack of reproducibility was due to a peculiarity of our B27+ AS+ patients or to technical difficulties in the complement mediated 51Cr release assay. We have shown in this blind study that the PBL of 16 out of 18 B27+ AS+ patients from a New Zealand population were lysed by our antisera but none of the PBL of 20 B27+ AS- normal controls were lysed. The phenomenon of 'cross reactivity' between certain enteric bacteria and B27+ AS+ PBL is not confined to the Sydney AS population.


Correctional-Facility-Outbreak-Associated COVID-19 Cases Among Asymptomatic Persons Identified Through Universal Testing: Vermont, 2020.
On April 6, 2020, a confirmed COVID-19 case in a correctional facility employee (Staff A) was reported to the Vermont Department of Health (VDH). Staff A worked in the facility while symptomatic, without reporting symptoms, for 10 days. VDH and the facility conducted two facility-wide testing events, implemented symptom monitoring, and initiated contact tracing. All 197 incarcerated persons and 115 (71%) staff were tested for SARS-CoV-2; 45 (23%) incarcerated persons and 17 (10%) staff had positive results (confirmed case), of whom 37 (82%) incarcerated persons and 1 (6%) staff had asymptomatic infections. Case detection enabled isolation of incarcerated persons and staff, work exclusion of staff with COVID-19, and quarantine of staff and incarcerated persons who had close contact with persons with COVID-19. Broad-based SARS-CoV-2 testing identified more cases than symptom monitoring.


Discovery of sterically-hindered phenol compounds with potent cytoprotective activities against ox-LDL-induced retinal pigment epithelial cell death as a potential pharmacotherapy.
Late-stage dry age-related macular degeneration (AMD) or geographic atrophy (GA) is an irreversible blinding condition characterized by degeneration of retinal pigment epithelium (RPE) and the associated photoreceptors. Clinical and genetic evidence supports a role for dysfunctional lipid processing and accumulation of harmful oxidized lipids in the pathogenesis of GA. Using an oxidized low-density lipoprotein (ox-LDL)-induced RPE death assay, we screened and identified sterically-hindered phenol compounds with potent protective activities for RPE. The phenol-containing PPARγ agonist, troglitazone, protected against ox-LDL-induced RPE cell death, whereas other more potent PPARγ agonists did not protect RPE cells. Knockdown of PPARγ did not affect the protective activity of troglitazone in RPE, confirming the protective function is not due to the thiazolidine (TZD) group of troglitazone. Prototypical hindered phenol trolox and its analogs potently protected against ox-LDL-induced RPE cell death whereas potent antioxidants without the phenol group failed to protect RPE. Hindered phenols preserved lysosomal integrity against ox-LDL-induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.


Structure-Guided Design of a "Bump-and-Hole" Bromodomain-Based Degradation Tag.
Chemical biology tools to modulate protein levels in cells are critical to decipher complex biology. Targeted protein degradation offers the potential for rapid and dose-dependent protein depletion through the use of protein fusion tags toward which protein degraders have been established. Here, we present a newly developed protein degradation tag BRD4BD1L94V along with the corresponding cereblon (CRBN)-based heterobifunctional degrader based on a "bump-and-hole" approach. The resulting compound XY-06-007 shows a half-degradation concentration (DC50, 6 h) of 10 nM against BRD4BD1L94V with no degradation of off-targets, as assessed by whole proteome mass spectrometry, and demonstrates suitable pharmacokinetics for in vivo studies. We demonstrate that BRD4BD1L94V can be combined with the dTAG approach to achieve simultaneous degrader-mediated depletion of their respective protein fusions. This orthogonal system complements currently available protein degradation tags and enables investigation into the consequences resulting from rapid degradation of previously undruggable disease codependencies.


Genetic variation in response to an indirect ecological effect.
Indirect ecological effects (IEEs) are widespread and often as strong as the phenotypic effects arising from direct interactions in natural communities. Indirect effects can influence competitive interactions, and are thought to be important selective forces. However, the extent that selection arising from IEEs results in long-term evolutionary change depends on genetic variation underlying the phenotypic response-that is, a genotype-by-IEE interaction. We provide the first data on genetic variation in the response of traits to an IEE, and illustrate how such genetic variation might be detected and analysed. We used a model tri-trophic system to investigate the effect of host plants on two populations of predatory ladybirds through a clonal aphid herbivore. A split-family experimental design allowed us to estimate the effects of aphid host plant on ladybird traits (IEE) and the extent of genetic variation in ladybird predators for response to these effects (genotype-by-indirect environmental effect interaction). We found significant genetic variation in the response of ladybird phenotypes to the indirect effect of host plant of their aphid prey, demonstrating the potential for evolutionary responses to selection arising from the prey host.


Broccoli-liked silver phosphate nanoparticles supported on green nanofiber membrane for visible-light driven photodegradation towards water pollutants.
In view of the practical application, it is imperative to develop efficient, exercisable, and visible light driven water pollution treatment materials. Herein, a high-efficiency green photocatalytic membrane for water pollution treatment is proposed and fabricated conveniently. Firstly, silver phosphate (Ag3PO4) nanoparticles with controlled morphology were prepared by simple liquid-phase precipitation method, and then a hierarchical structured Ag3PO4@polylactic acid (PLA) composite nanofiber membrane was prepared by electrospinning. Using electrospun PLA nanofiber membrane as a carrier of photocatalysts can significantly improve the dispersion of Ag3PO4nanoparticles, and increase the contact probability with pollutants and photocatalytic activity. The prepared PLA@Ag3PO4composite membrane was used to degrade methylene blue (MB) and tetracycline hydrochloride (TC) under visible light irradiation. The results showed that the removal ratio of pollutants on Ag3PO4@PLA composite nanofiber membrane was 94.0% for MB and 82.0% for TC, demonstrating an outstanding photocatalytic activity of composite membrane. Moreover, the PLA nanofiber membrane is a self-supported and biodegradable matrix. After five cycles, it can still achieve 88.0% of the initial photocatalytic degradation rate towards MB, showing excellent recyclability. Thus, this composite nanofiber membrane is a high-efficiency and environmental-friendly visible light driven water pollution treatment material that could be used in real applications.


The role of complement in AMD.
Age related macular degeneration (AMD) is a common form of blindness in the western world and genetic variations of several complement genes, including the complement regulator Factor H, the central complement component C3, Factor B, C2, and also Factor I confer a risk for the disease. However deletion of a chromosomal segment in the Factor H gene cluster on human chromosome 1, which results in the deficiency of the terminal pathway regulator CFHR1, and of the putative complement regulator CFHR3 has a protective effect for development of AMD. The Factor H gene encodes two proteins Factor H and FHL1 which are derived from alternatively processed transcripts. In particular a sequence variation at position 402 of both Factor H and FHL1 is associated with a risk for AMD. A tyrosine residue at position 402 represents the protective and a histidine residue the risk variant. AMD is considered a chronic inflammatory disease, which can be caused by defective and inappropriate regulation of the continuously activated alternative complement pathway. This activation generates complement effector products and inflammatory mediators that stimulate further inflammatory reactions. Defective regulation can lead to formation of immune deposits, drusen and ultimately translate into damage of retinal pigment epithelial cells, rupture of the interface between these epithelial cells and the Bruch's membrane and vision loss. Here we describe the role of complement in the retina and summarize the current concept how defective or inappropriate local complement control contributes to inflammation and the pathophysiology of AMD.


Identification of tomato introgression lines with enhanced susceptibility or resistance to infection by parasitic giant dodder (Cuscuta reflexa).
The parasitic flowering plant genus Cuscuta (dodder) is a parasitic weed that infects many important crops. Once it winds around the shoots of potential host plants and initiates the development of penetration organs, called haustoria, only a few plant species have been shown to deploy effective defense mechanisms to ward off Cuscuta parasitization. However, a notable exception is Solanum lycopersicum (tomato), which exhibits a local hypersensitive reaction when attacked by giant dodder (Cuscuta reflexa). Interestingly, the closely related wild desert tomato, Solanum pennellii, is unable to stop the penetration of its tissue by the C. reflexa haustoria. In this study, we observed that grafting a S. pennellii scion onto the rootstock of the resistant S. lycopersicum did not change the susceptibility phenotype of S. pennellii. This suggests that hormones, or other mobile substances, produced by S. lycopersicum do not induce a defense reaction in the susceptible tissue. Screening of a population of introgression lines harboring chromosome fragments from S. pennellii in the genome of the recurrent parent S. lycopersicum, revealed that most lines exhibit the same defense reaction as shown by the S. lycopersicum parental line. However, several lines showed different responses and exhibited either susceptibility, or cell death that extended considerably beyond the infection site. These lines will be valuable for the future identification of key loci involved in the perception of, and resistance to, C. reflexa and for developing strategies to enhance resistance to infection in crop species.


A graphic display for the presentation of site-wise odds ratios for score transitions to augment the traditional findings from clinical studies employing dental indexes.
Many of the parameters used in clinical dental research involve the assessment of a condition at each of a number of sites within the mouth. Traditionally, such measurements are averaged over all sites within the mouth (or over all sites of a specified type) for each study participant before statistical analysis. However, a consideration of the original, site-wise scores may provide some additional insights into the performance of therapeutic modalities that might not be made evident through an application of the traditional, means-based approach. A method based on the calculation of site-wise odds ratios of certain types of baseline-to-final examination score transitions was applied to the modified gingival index data from two clinical studies performed to investigate the effect of the daily chewing of a commercially available chewing gum relative to a mint control. A graphical display of these site-specific findings was prepared, which indicated that the chewing gum regimen tended to be associated with a higher frequency of occurrence of favorable score transitions than was the mint control at several measurement sites throughout the mouth.


Entrepreneurial Resilience: A Case Study on University Students.
Entrepreneurial resilience refers to the capacity to face, overcome and project oneself after suffering life events with a negative impact. Emerging adulthood and the characteristics of university life facilitate the occurrence of stressful situations that can affect well-being. The aim of this phenomenological research is to explore the strategic components of entrepreneurial resilience and how young university students have shaped their entrepreneurial resilience after experiencing negative life events. The present research is a multiple case study that was developed through a mixed methodology. The methodological sequence was quantitative and qualitative, with priority given to the qualitative phase of the research. Ten university students with high levels of resilience were interviewed. The data were analysed using thematic analysis. The results indicate that resilience is built through intrapersonal and exopersonal processes. These processes make up a set of strategic dimensions related to entrepreneurial behaviour that are used for the construction of personal projects.


Clinical Implications of Second and Third Trimester Surveillance Ultrasounds of Growth-Restricted Fetuses.
Objective We sought to investigate the positive predictive value of ultrasound-diagnosed fetal growth restriction (FGR) for estimating small for gestational age (SGA) at birth. Secondary objectives were to describe clinical interventions performed as a result of FGR diagnosis. Study Design This was a retrospective cohort of pregnancies diagnosed with FGR over 3 years at a single institution. Maternal demographics, antenatal and delivery data, and neonatal data were collected. Descriptive statistics and linear regression were conducted. Results We included 406 pregnancies with diagnosis of FGR in second or third trimester. Median birth weight percentile was 17 (interquartile range: 5-50) and only 35.0% of these fetuses were SGA at birth. The positive predictive value of a final growth ultrasound below the 10th percentile for SGA at birth was 56.9%. Patients averaged eight additional growth ultrasounds following FGR diagnosis. One hundred and fourteen (28.1%) received antenatal steroids prior to delivery, and 100% of those delivered after more than 7 days following administration. There were 6 fetal deaths and 14 neonatal deaths. Conclusion In the majority of cases, pregnancies diagnosed with FGR during screening ultrasounds resulted in normally grown neonates and term deliveries. These patients may be receiving unnecessary ultrasounds and premature courses of corticosteroids.


[New aspects in ANCA-associated vasculitides].
Wegener's granulomatosis (WG), microscopic polyangiitis, and Churg-Strauss syndrome belong to the group of ANCA-associated vasculitides. Numerous in vitro studies underscored the role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of vasculitis. More recently, a mouse model provided in vivo evidence of the pathogenic role of ANCA by inducing a vasculitis after the transfer of splenocytes or MPO-ANCA. The target antigens of ANCA, myeloperoxidase (MPO) and proteinase 3 (PR3), are translocated onto the cell surface after priming of neutrophil granulocytes with cytokines. ANCA bind to target antigens and activate neutrophil granulocytes resulting in premature degranulation and endothelial cell damage (ANCA-cytokine sequence theory). Both the F(ab')2 end and the FcgammaR(eceptor) end of the ANCA are involved in activating neutrophil granulocytes. This mode of activation might account for differences to normal neutrophil activation via the FcgammaR. In addition, an expansion of T-cells lacking the co-stimulatory molecule CD28 is seen in WG suggesting an altered cellular immune response. Data from European multicenter studies demonstrated, among other things, that azathioprine can be used for the maintenance of remission after successful induction of remission with cyclophosphamide in ANCA-associated vasculitides.


Influence of Short Term Inhibitor Treatment on the Flowering of Lemna perpusilla 6746.
Short term inhibitor treatment can be used to examine the processes that occur during an inductive dark period in the short day plant Lemna perpusilla Torr., strain 6746. Several inhibitors of protein biosynthesis are most effective in reducing per cent flowering when treatment occurs over the 2-hour intervals beginning at the 12th hour or the 14th hour of a 8 (16) photoperiodic cycle. The antimetabolite, 5-fluorouracil, is most effective when treatment occurs early in the dark period. Evidence is cited suggesting that distilled water incubation inhibits flowering by interfering with protein biosynthesis.


NMR screening for lead compounds using tryptophan-mutated proteins.
NMR-based drug screening methods provide the most reliable characterization of binding propensities of ligands to their target proteins. They are, however, one of the least effective methods in terms of the amount of protein required and the time needed for acquiring an NMR experiment. We show here that the introduction of tryptophan to proteins permits rapid screening by monitoring a simple 1D proton NMR signal of the NH side chain ((N)H(epsilon)) of the tryptophan. The method could also provide quantitative characterization of the antagonist-protein and antagonist-protein-protein interactions in the form of KDs and fractions of the released proteins from their mutual binding. We illustrate the method with the lead compounds that block the Mdm2-p53 interaction and by studying inhibitors that bind to cyclin-dependent kinase 2 (CDK2).


[Dysthyroid orbitopathy: imaging].
Computed tomography and magnetic resonance imaging are useful tools for assessing orbital content. Using these imaging modalities, one can quantify orbital involvement in Graves disease. This analysis is based upon five items: proptosis, fat, muscles, optic nerve and ethmoid.


Effect of lameness on the calving-to-conception interval in dairy cows.
To examine the relationship between lameness and the duration of the interval from calving to subsequent conception in lactating dairy cows. Cohort study. 837 dairy cows. Cows affected with lameness were classified into 1 of 4 groups on the basis of types of disease or lesions observed, including foot rot, papillomatous digital dermatitis, claw lesions, or multiple lesions. Cows not affected with lameness were classified as healthy. Time from calving to conception was compared between lame cows and healthy cows. 254 (30%) cows were affected with lameness during lactation. Most lame cows (59%) had claw lesions. Lame cows with claw lesions were 0.52 times as likely to conceive as healthy cows. Median time to conception was 40 days longer in lame cows with claw lesions, compared with healthy cows. Number of breedings per conception for lame cows with claw lesions was significantly higher than that for healthy cows. Claw lesions were the most important cause of lameness, impairing reproductive performance in dairy cows, as indicated by a higher incidence of affected cows and a greater time from calving to conception and a higher number of breedings required per conception, compared with healthy cows.


Oxidative metabolism in sepsis and sepsis syndrome.
The high mortality associated with sepsis syndrome and multiple organ dysfunction syndrome has persisted despite extraordinary research efforts in the laboratory and the intensive care unit. These syndromes produce systemic tissue damage that is likely to result from widespread inflammation and subsequent endothelial injury. This article reviews the oxidative metabolic effects and responses to sepsis syndrome at several levels: the oxygen transport system, the cell, and the mitochondrion. Specifically, aerobic metabolism of carbon substrates and oxygen is altered in sepsis. As a result of systemic inflammation and nonmetabolic oxygen use, oxidative stress may occur both outside and inside the cell. The consequences of these oxidative processes during sepsis may be ongoing cell damage mediated by reactive oxygen and nitrogen oxide species that culminates in multisystem organ failure.


Robotic Ureteral Reconstruction in the Pediatric Population.
Robot-assisted laparoscopic (RAL) surgery is a safe, minimally invasive technique that has become more widely used in pediatric urology over recent decades. With several advantages over standard laparoscopy, robotic surgery is particularly well-suited to reconstructive surgery involving delicate structures like the ureter. A robotic approach provides excellent access to and visualization of the ureter at all levels. Common applications include upper ureteral reconstruction (e.g., pyeloplasty, ureteropelvic junction polypectomy, ureterocalicostomy, and high uretero-ureterostomy in duplex systems), mid-ureteral reconstruction (e.g., mid uretero-ureterostomy for stricture or polyp), and lower ureteral reconstruction (e.g., ureteral reimplantation and lower ureter-ureterostomy in duplex systems). Herein, we describe each of these robotic procedures in detail.


[Therapy of extracranial carotid artery aneurysms--literature review].
Extracranial carotid artery aneurysms are unusually rare. Their aetiology and clinical picture have significant meaning for their recognition, with the majority involving the common carotid artery--ACC. Approximately one third of these lesions are confined to the ICA, with an equal distribution between the proximal, middle, and distal segments. Nonoperated treatment is associated with a high risk of stroke compare to surgical, wich is think as necessary from most authors, because of the high level of neurologic symptomatic in the studies. Surgical treatment is used for prevention from cerebrovascular deficit.


An evaluation of alprazolam in the treatment of reactive or neurotic (secondary) depression.
To investigate the effectiveness of a new benzodiazepine, alprazolam, and to compare this with amitriptyline (AMT) and with placebo, a trial was undertaken in 65 patients in whom depression was considered to be the dominating feature but not considered to be the primary cause of their condition; it was designed to exclude endogenous depressions. A consistent pattern was found favouring alprazolam over AMT both in rate of response and in total response, as well as significant differences in favour of both alprazolam and AMT over placebo. A comparison of side effects showed a definite trend in favour of alprazolam and placebo over AMT.


The Right to Say No: Why Adult Sexual Assault Patients Decline Medical Forensic Exams and Sexual Assault Kit Evidence Collection.
The International Association of Forensic Nurses (2018) affirms the importance of evidence-based, trauma-informed, patient-centered forensic nursing services that engage patients as autonomous decision makers. Past research indicates that forensic nurses consistently respect patients' choices and control as they navigate the decisions of medical forensic examinations (MFEs) and sexual assault kit (SAK) collection. Building on that work, this study examined which options patients decline and what factors are associated with those declination decisions. We collected prospective data from seven state-funded sexual assault nurse examiner programs. Forensic nurses recorded information about all adult sexual assault patients (N = 783) regarding four primary decisions: whether to have a MFE, whether to consent to all parts of the MFE or to decline specific services, whether to have a SAK collected, and whether to release the SAK to law enforcement for forensic DNA testing. Most patients consented to a MFE (95%), to all parts of the MFE (81%), to SAK collection (99%), and to release the SAK for forensic DNA testing (80%). Younger patients and those with disabilities were more likely to decline some options. Patients who had not disclosed the assault to others before seeking sexual assault nurse examiner care were also more likely to decline a MFE. Whether patients sought post assault care for more health-focused reasons or legally focused reasons was associated with declination decisions. Healthcare providers should communicate clearly about each step in post assault care and allow patients to decline services as they choose.


Propagating fronts in thin tubes: concentration, electric, and pH effects in a two-dimensional precipitation pulse system.
In this paper, we studied the dynamics of a CaCO3 precipitate deposition pulse in a thin, long tube connecting two reservoir sinks of coprecipitates. The pulse profile, as well as the time t(c) and distance x(c) of the first appearance of precipitate, is studied as a function of the initial concentration of CO(3)(2-) in the right reservoir, [CO(3)(2-)](0), and later as a function of an applied external electric field at different voltages. The time variations of the pulse location and the pH at the center of the tube are determined. The distance from the calcium chloride sink (x) at any fixed time decreases as [CO(3)(2-)](0) increases. The time evolution of the front location exhibits a crossover between an early time regime and a late time regime. The pH-time curve shows a marked resemblance with a sigmoid shape. At any time, the pH consistently increases with [CO(3)(2-)](0). In the presence of a constant electric field applied across the tube (fixed voltage), t(c) decreased with the field strength, whereas x(c) exhibited a correlated increase. Irregularities in the variation of distance with the applied voltage (at a fixed time) were noted. The pH experiences a slight increase with the applied voltage. The pulse width exhibits a nonlinear time dependence, of the form w = a + bt(1/6). The shape of the deposition pulse deviates from a Gaussian distribution. This study is of special interest in the experimental simulation and modeling of precipitate deposition and potential clogging in microcapillary channels.


[Subcutaneous implantable cardioverter-defibrillator in prevention of sudden cardiac death in Poland - opinion paper endorsed by the Polish Cardiac Society Working Group on Heart Rhythm].
In the past years, cardiovascular mortality has decreased but despite these cardiovascular diseases are responsible for millions of deaths every year in the world and approximately 25% of which are sudden cardiac death (SCD). Implantable defibrillators (ICD) is proven therapy used in primary and secondary SCD prevention. Currently majority of devices use transvenous leads inserted predominantly into the right heart for both pacing and defibrillation. On the other hand, ICD may cause complica-tions, including inappropriate shocks, device-related infection and lead failure. Problems with transvenous leads prompted the development of a subcutaneous defibrillator (S-ICD) with an electrode system that is placed entirely subcutaneously, outside the thoracic cavity. The device may be useful when venous access is difficult, in young patients and in patients at particular risk of infection. S-ICD is not suitable for patients with indications for bradycardia pacing, cardiac resynchronisation therapy and in cases with tachyarrhythmia easily terminated by antitachycardia pacing.


Colitis and colonic mucosal barrier dysfunction.
Trauma, infection, neoplasia, and inflammation can all disrupt the intact intestinal mucosal barrier to intraluminal bacteria and bacterial antigens. This study investigated the relation between colonic inflammation and colonic mucosal barrier function in three experimental models of colitis. There were significantly increased systemic endotoxin concentrations in rats with acetic acid (7.5 (1.7-119.5) pg/ml), ethanol (13.7 (0-111.2) pg/ml), and hapten induced (14.4 (5-31.1) pg/ml) colitis compared with saline controls (3.3 (0-13.7) pg/ml). Data expressed as median (range). There were significant correlations between the systemic endotoxin concentration and both the severity of colitis and of illness in acetic acid induced colitis. A significant increase in colonic permeability to 14C-polyethylene glycol was shown in rats with acetic acid (3.42 (1.36-5.63)%) and hapten induced colitis (2.86 (1.03-8.10)%) compared with saline controls (1.20 (0.67-1.36)%). Data expressed as median (range) of percentage of the intracolonic bolus excreted in urine. There was a significant positive correlation between the severity of colitis and % colonic permeability to 14C-polyethylene glycol. This and other studies provide evidence that mucosal barrier dysfunction is a feature of colitis irrespective of aetiology or species. Such barrier dysfunction may be responsible for the systemic inflammatory response and complications seen in patients with inflammatory bowel disease.


Responsiveness and minimal important change of the NeckPix© in subjects with chronic neck pain undergoing rehabilitation.
The NeckPix© is a simple and rapid means of measuring the beliefs of subjects with chronic neck pain concerning pain-related fears of a specific set of activities of daily living. The original version showed satisfactory psychometric properties. This observational study is aimed at evaluating its responsiveness and minimal important changes (MICs) in subjects with chronic neck pain. At the beginning, at the end of an 8-week rehabilitation programme as well as at the one-year follow-up, 153 subjects completed the NeckPix©. After the programme and at follow-up, subjects and physiotherapists also completed the global perceived effect (GPE) scale, which was divided to produce a dichotomous outcome. Responsiveness was calculated by distribution [effect size (ES); standardised response mean (SRM)] and anchor-based methods [receiver-operating characteristics (ROC) curves; correlations between change scores of the NeckPix© and GPEs]. ROC curves were also used to compute MICs. The ES ranged from 0.95 to 1.26 and the SRM from 0.84 to 0.98 at post-treatment and follow-up based on subjects' and physiotherapists' perspective. The ROC analyses revealed AUCs of 0.89 and 0.97 at post-treatment and follow-up, respectively; MICs (sensitivity; specificity) were of 6 (0.82; 0.88) and 8 (0.80; 0.92) at post-treatment and of 8 (0.95; 0.90 based on subjects and 0.95; 0.92 based on physiotherapists perspective) at follow-up. The correlations between change scores of the NeckPix© and GPEs ranged from -0.69 to -0.82. The NeckPix© was sensitive in detecting clinical changes in subjects with chronic neck pain undergoing rehabilitation. We recommend taking the MICs provided into account when assessing subjects' improvement or planning studies in this clinical context.


Transient Weakening of Earth's Magnetic Shield Probed by a Cosmic Ray Burst.
The GRAPES-3 tracking muon telescope in Ooty, India measures muon intensity at high cutoff rigidities (15-24 GV) along nine independent directions covering 2.3 sr. The arrival of a coronal mass ejection on 22 June 2015 18:40 UT had triggered a severe G4-class geomagnetic storm (storm). Starting 19:00 UT, the GRAPES-3 muon telescope recorded a 2 h high-energy (∼20 GeV) burst of galactic cosmic rays (GCRs) that was strongly correlated with a 40 nT surge in the interplanetary magnetic field (IMF). Simulations have shown that a large (17×) compression of the IMF to 680 nT, followed by reconnection with the geomagnetic field (GMF) leading to lower cutoff rigidities could generate this burst. Here, 680 nT represents a short-term change in GMF around Earth, averaged over 7 times its volume. The GCRs, due to lowering of cutoff rigidities, were deflected from Earth's day side by ∼210° in longitude, offering a natural explanation of its night-time detection by the GRAPES-3. The simultaneous occurrence of the burst in all nine directions suggests its origin close to Earth. It also indicates a transient weakening of Earth's magnetic shield, and may hold clues for a better understanding of future superstorms that could cripple modern technological infrastructure on Earth, and endanger the lives of the astronauts in space.


Rifampicin/imipenem combination in the treatment of carbapenem-resistant Acinetobacter baumannii infections.
In the setting of a large endemic of Acinetobacter baumannii infections, treatment of those due to carbapenem-resistant strains, susceptible only to colistin, has become a major problem in our hospital during the past years. Successful results have been reported using colistin, but clinical experience with this antibiotic is limited. In our experimental studies using these strains in a mouse pneumonia model, the best results were observed with a combination of rifampicin and imipenem. From July 2000 to September 2001, we performed a pilot study with patients suffering from serious infections due to carbapenem-resistant A. baumannii. Patients were treated with a rifampicin/imipenem combination and followed up prospectively. Cultures were repeated during and after treatment, and in vitro activity of rifampicin was monitored. Genotyping of these strains was performed by means of PFGE. Ten patients were selected: four with ventilator-associated pneumonia, and six with other infections (one catheter-related bacteraemia, five surgical infections). Three patients died, two of whom were considered therapeutic failures. In five of the seven patients who were cured, other procedures were also performed such as surgical drainage or catheter removal. In vitro development of high resistance to rifampicin was shown in seven (70%). PFGE demonstrated that initial isolates and high-resistant strains belonged to the same clones. The results of our study argue against the use of a rifampicin/imipenem combination for the treatment of carbapenem-resistant A. baumannii infections. However, combinations of rifampicin with other antibiotics merit further studies.


Modulation of the tumour microenvironment in hepatocellular carcinoma by tyrosine kinase inhibitors: from modulation to combination therapy targeting the microenvironment.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs) remain the backbone of systematic therapy for advanced hepatocellular carcinoma. Sorafenib and lenvatinib are currently approved as first-line therapeutic drugs, and regorafenib and cabozantinib are applied as second-line treatments. With inhibition of angiogenesis as the main target, TKIs exert a profound effect on the tumour microenvironment (TME). The TME is a complex mixture of cellular and noncellular components surrounding the tumour mass, and is associated with tumour progression partially through the epithelial-mesenchymal transition. Specifically, the TME of HCC is characterized by profound extracellular matrix remodelling and an immunosuppressive microenvironment. The purpose of this review is to provide a summary of TME remodelling mediated by four Food and Drug Administration approved TKIs in HCC and thus summarize the rationale and potential targets for combination therapy. The modulatory effect of TKIs on the TME of HCC was reported to enhance the antitumour effect of TKIs through pyroptosis of macrophages and subsequent natural killer cell activation, T cell activation, regulatory T cell reduction in HCC. Meanwhile, TKIs also induce drug resistance via M2 polarization and accumulation, recruitment of tumour-associated neutrophils, and induction of the epithelial-mesenchymal transition. In conclusion, the effect of TKIs on TME can enhance its antitumour effect, but might also partially contribute to the drug resistance that hinders the progression of TKIs as treatment for HCC. Additionally, the effect of TKIs also provides the rationale for combination therapy, including combining TKIs with immune checkpoint inhibitors, to facilitate increased drug efficacy of TKIs.


The Correlation between Intraoperative Microelectrode Recording and 3-Tesla MRI in Patients Undergoing ANT-DBS for Refractory Epilepsy.
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus) (ANT) has been suggested as a treatment option in refractory epilepsy. The targeting of ANT is especially challenging due to its poor visualization in commonly used MRI sequences, lack of easily observable symptom relief during surgery and high degree of anatomical variation between individuals. To study whether intraoperative microelectrode recording (MER), a method widely used in movement disorder surgery, provides clinically relevant information during the ANT-DBS implantation procedure. A total of 186 MER samples from 5 patients and 10 thalami obtained from ANT-DBS surgery for refractory epilepsy were analyzed with respect to the signal characteristics and location in 3-tesla (3T) MRI STIR (short T1 inversion recovery) images. The location of each MER sample was calculated relative to visible borders of the ANT after correction of the sample locations according to the position of the final DBS electrode in postoperative CT-MRI fusion images. We found that the lateral aspect of the ANT lacked spiking activity consistent with the presence of white matter. The spike frequency in samples correlating with location at the ANT showed significantly lower spike frequency compared to samples correlating with location at the ventral anterior nucleus (median 3.0 and 7.0 spikes/2 s; p < 0.05), but spike bursts were morphologically similar in appearance. Trajectories entering the dorsomedial nucleus according to 3T MRI STIR images showed a yet different firing pattern with more low-amplitude regular activity. Our data suggest that MER provides clinically relevant information during implantation surgery by demonstrating both nucleus-specific neuronal firing patterns and white matter laminae between different nuclear groups.


Short-term effects of dietary bovine milk on fatty acid composition of human milk: A preliminary multi-analytical study.
The fatty acid (FA) composition of human milk (HM) from N = 9 Italian healthy donors following a free diet exhibited FA-dependent ranges of variability, as assessed by GC-FID. The possible short-term changes in the FA profile were monitored in the milk of lactating mothers (three) collected at five time points over a 6 h period, following an oral load (200 mL) of bovine milk. An array of techniques was exploited, including UHPLC-ESI-MS/MS of intact lipids and MALDI-TOF MS before and after chemical hydrogenation or bromination, in addition to MALDI-TOF MS analysis of FA after saponification, to monitor short-chain and odd-chain FA in HM as markers of bovine milk fat. A single administration of bovine milk did not appreciably modify the lipid pattern, suggesting that the maternal diet could induce not detectable short-term changes on the lipid composition of HM. Diet-induced increase of butyric acid was also excluded by 13C NMR. The functions that HM FA exert in infant physiology appear finely regulated through maternal metabolism.


Polymerizable Ionic Liquid Crystals Comprising Polyoxometalate Clusters toward Inorganic-Organic Hybrid Solid Electrolytes.
Solid electrolytes are crucial materials for lithium-ion or fuel-cell battery technology due to their structural stability and easiness for handling. Emergence of high conductivity in solid electrolytes requires precise control of the composition and structure. A promising strategy toward highly-conductive solid electrolytes is employing a thermally-stable inorganic component and a structurally-flexible organic moiety to construct inorganic-organic hybrid materials. Ionic liquids as the organic component will be advantageous for the emergence of high conductivity, and polyoxometalate, such as heteropolyacids, are well-known as inorganic proton conductors. Here, newly-designed ionic liquid imidazolium cations, having a polymerizable methacryl group (denoted as MAImC₁), were successfully hybridized with heteropolyanions of [PW12O40]3- (PW12) to form inorganic-organic hybrid monomers of MAImC₁-PW12. The synthetic procedure of MAImC₁-PW12 was a simple ion-exchange reaction, being generally applicable to several polyoxometalates, in principle. MAImC₁-PW12 was obtained as single crystals, and its molecular and crystal structures were clearly revealed. Additionally, the hybrid monomer of MAImC₁-PW12 was polymerized by a radical polymerization using AIBN as an initiator. Some of the resulting inorganic-organic hybrid polymers exhibited conductivity of 10-4 S·cm-1 order under humidified conditions at 313 K.


Hydroxyzine distribution in postmortem cases and potential for redistribution.
Hydroxyzine is an antihistaminic with sedative properties used in the control of anxiety and emesis. Peripheral blood hydroxyzine concentrations are compared to central blood and liver concentrations in 10 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by GC-FID headspace analysis, ELISA for drugs of abuse, and alkaline drugs by GC/MS. Hydroxyzine, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a specific GC-NPD procedure. Data suggest that postmortem peripheral blood hydroxyzine concentrations may be considered therapeutic to at least 0.24 mg/L and corresponding liver concentrations to at least 4.9 mg/kg. Hydroxyzine concentrations ranged 0.07-3.0mg/L in peripheral blood, 0.04-3.8 mg/L in central blood, and 0.88-55 mg/kg in liver. Hydroxyzine central blood to peripheral blood ratios averaged 0.92±0.25 (±standard deviation; N=6). Liver to peripheral blood ratios, on the other hand, were higher and averaged 13.8±6.2 (±standard deviation; N=10). Given that a liver to peripheral blood ratio less than 5 is consistent with little to no postmortem redistribution while exceeding 20-30 is indicative of propensity for significant postmortem redistribution, these data suggest that hydroxyzine is prone to a moderate degree of postmortem redistribution.


Elective single-vessel percutaneous coronary intervention in a vegetative state patient.
A 73-year-old male in a persistent vegetative state underwent percutaneous coronary intervention (PCI) for unstable angina with multiple-vessel stenosis. The maximum dose pharmaceutical therapy was ineffective in controlling his symptoms. The goal of the procedure was to alleviate the patient's severe chest pain and vomiting with minimal invasion and risk. The procedure was effective despite treating only the culprit artery. Symptoms disappeared immediately after PCI and the patient remained attack free for 12 months. With the consent of the patient's family and support of medical staff, elective single-vessel PCI can be a practical and effective treatment option for refractory angina in patients with impaired consciousness.


Epilepsy Detection Based on Variational Mode Decomposition and Improved Sample Entropy.
Epilepsy detection based on electroencephalogram (EEG) signal is of great significance to diagnosis and treatment of epilepsy. The denoised EEG signal is adopted by most traditional epilepsy detection methods. But due to nonideal denoising ability, the loss of local information and residual noise will occur, resulting in detection performance degradation. To solve the problem, the paper proposed an epilepsy detection method in noisy environment. Although epileptic signals and nonepileptic signals have some discrimination, they need to overcome the interference of noise. Hence, the improved sample entropy and phase synchronization indexes of corresponding 2 intrinsic mode functions (IMFs) caused by variational mode decomposition (VMD) are proposed as features, which can reduce the impact of noise on detection performance. The experimental results show that the accuracy, sensitivity, and specificity are 91.78%, 91.27%, and 93.61%, respectively. It can be used as an auxiliary method for clinical treatment of epilepsy.