Diagnosis and management of children with Kawasaki disease.
Significant progress has been made in understanding the epidemiology, natural history, and management of Kawasaki disease since 1967. The introduction of intravenous gamma globulin therapy as well as more vigilant care has reduced the mortality rate to well below 1%. Major goals for future research are to identify the etiology and pathogenesis of Kawasaki disease and the associated coronary artery disease and to develop more precise diagnostic techniques and therapy.


Postpartum Follow-Up of Patients with Subclinical Hypothyroidism During Pregnancy.
Background: Subclinical hypothyroidism (SCH) in pregnancy is associated with adverse pregnancy and perinatal outcomes. However, few studies have investigated the evolution of postpartum thyroid function in these women. This study aimed to determine the postpartum outcomes of SCH during pregnancy and the clinical and biochemical factors related to the evolution of long-term hypothyroidism. Methods: A total of 393 women diagnosed with SCH during pregnancy (defined as thyrotropin [TSH] >4.0 μIU/mL with normal free thyroxine levels according to the 2017 American Thyroid Association guidelines) were prospectively followed up after delivery. Among them, 216 underwent long-term follow-up [median (interquartile range) follow-up time: 11 (7-19) months] postpartum. The clinical and biochemical characteristics of the women with long-term postpartum hypothyroidism and euthyroidism were compared. Linear mixed model (LMM) was used to explore the risk factors for longitudinal changes of TSH, and logistic regression analysis was employed to identify the independent predictors of long-term postpartum hypothyroidism. Results: The probability of long-term hypothyroidism after delivery in SCH during pregnancy was 38.9%. Among the subjects with normal thyroid function 6-week postpartum, 28.2% developed hypothyroidism during long-term follow-up. The LMM showed that gestational age at the time of SCH diagnosis (estimate: -0.018, p = 0.004) and thyroid peroxidase antibodies (TPOAb) (estimate: 0.001, p = 0.020) were significantly associated with longitudinal changes of TSH. The logistic regression model showed that TPOAb positive both during pregnancy and six-week postpartum was a risk factor for long-term hypothyroidism after delivery (odds ratio = 4.686 [95% confidence interval 1.242 to 17.680], p = 0.023). Conclusions: More than one-third of patients with SCH during pregnancy had persistent hypothyroidism after delivery. We recommend that patients with TPOAb positive both during pregnancy and six-week postpartum undergo close follow-up to detect persistent hypothyroidism, especially before the next pregnancy.


Giant Cell Sarcomas in Domestic Rabbits (Oryctolagus cuniculus).
Multinucleated giant cells (MGCs) are a prominent histological feature of various mesenchymal neoplasms and are often considered a criterion of malignancy. Mesenchymal neoplasms with MGCs for which the cell lineage is unclear generally are referred to as giant cell sarcomas. Here we characterize the gross, histologic, and immunohistochemical features of 90 giant cell sarcomas in domestic pet rabbits. Based on the anatomic location and histologic and immunohistochemical findings, 18 cases were classified as histiocytic sarcomas (HS) and 72 cases as anaplastic sarcomas (AS). At postmortem examination, HS was either localized HS (n = 7) always affecting the lungs, or disseminated HS (n = 10) that affected the lungs (n = 10), liver (n = 6), kidneys (n = 4), pleura (n = 2), mediastinum (n = 2), heart (n = 4), skeletal muscle (n = 1), adipose tissue (n = 1), and lymph node (n = 1). Additionally, one cecal biopsy was consistent with HS. Microscopically, HS were characterized by sheets of neoplastic polygonal to round cells that contained single to several, often greatly enlarged nuclei as well as abundant cytoplasm. HS were always positive for CD204 and always negative for SMA and desmin. In contrast, AS arose most commonly from the skin or subcutis (n = 62) and rarely the skeletal muscle (n = 8) or abdominal organs (n = 2). In 29% of extra-abdominal AS, the tumor deeply invaded into surrounding connective tissue, skeletal muscle, tendons, and bone causing pathological fractures. Five of 9 postmortem cases metastasized to various organs often including the lungs. Microscopically, AS were characterized by sheets of spindle or pleomorphic cells admixed with variable numbers of MGCs. Immunohistochemically, AS were always negative for CD204 and often (71%) positive for SMA and/or desmin.


Stimulant medication in ADHD: what do children and their parents say?
The prescription of stimulant medication to children with attention deficit hyperactivity disorder remains topical. Few reports target children's views about taking long-term medication. The aim was to assess child and parent views of stimulant medication. To compare attitudes to medication between two groups of children, those with attention deficit hyperactivity disorder taking stimulant medication and those with epilepsy taking anti-epileptic medication. Forty children (n = 40) with attention deficit hyperactivity disorder on stimulant medication, and 40 children (n = 40) with epilepsy on anti-epileptic medication formed the study population. A semi-structured interview was carried out with each child and parent. Each parent completed the Dosage and Side-effects Questionnaire and the Attitude to Medication Questionnaire. Each child completed the Attitude to Medication Questionnaire. Sixty per cent of children (n = 24) with attention deficit hyperactivity disorder and 62.5% (n = 25) of those with epilepsy knew the name and purpose of their medication. Forty per cent (n = 16) of children in the stimulant group and 32.5% (n = 13) in the anti-epileptic group reported themselves as being non-compliant with medication. In both groups children reported positive aspects to taking medication. More children with epilepsy reported negative aspects. Only 32.5% (n = 13) of children with attention deficit hyperactivity disorder said that they would tell a friend about their medication, while 55% (n = 22) of the children with epilepsy indicated that they would do so. In both groups parents were better informed than their children were about the purpose of the medication. Parents of children with attention deficit hyperactivity disorder tended to be more positive about medication than their children and than the parents in the comparison group. The majority of children and their parents express positive views about the stimulant medication. Children's views about medication compliance and side-effects should be sought, as they may differ significantly from those of their parents. Where parents have noticed positive changes, but children have not, this information can be used therapeutically to help children feel more in control of their behaviour.


Effect of four i.v. induction agents on T-lymphocyte proliferations to PHA in vitro.
Anaesthetic agents are believed to have an adverse effect on human immunity. We have studied the effects of four i.v. induction agents, thiopentone, methohexitone, etomidate and propofol, on T-lymphocyte proliferations to phytohaemagglutinin in vitro. We found that at plasma concentrations similar to those obtained after induction doses, all drugs, with the exception of propofol, caused depression of T-lymphocyte function.


Spatial analysis of p63, K5 and K7 defines two groups of progenitor cells that differentially contribute to the maintenance of normal sebaceous glands, extraocular sebaceous carcinoma and benign sebaceous tumors.
The histogenesis of extraocular sebaceous carcinomas is - in contrast to ocular sebaceous carcinomas - unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki-67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63+ K5+ progenitors which generate the K10+ luminal cells of sebaceous ducts; and (ii) p63+ K5+ K7+ progenitors which finally generate K7+ adipophilin+ EMA+ sebocytes. Without exception, all types of sebaceous tumors contained p63+ K5+ cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin+ and/or EMA+ mature sebocytes and to K10+ ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63+ K5+ cells play a major role.


Bioactivity and pharmacological actions of carbon monoxide-releasing molecules.
Carbon monoxide (CO) is a resourceful gas as recent advances in the area of cell signaling are revealing an unexpected physiological role for CO in the cardiovascular, immune and nervous systems. Transition metal carbonyls have been lately discovered to function as CO-releasing molecules (CO-RMs) and elicit distinct pharmacological activities in biological systems. Studies currently ongoing in our laboratories are investigating both the chemical and bioactive features of a series of water-soluble CO-RMs and their specific utilization as vasoactive mediators, anti-inflammatory agents and inhibitors of cellular and tissue damage. The data presented in this review corroborate the notion that transition metal carbonyls could be used as carriers to deliver CO in mammals and highlight the bioactivity and potential therapeutic features of CO-RMs in the mitigation of cellular and organ dysfunction.


Deploying efficient net batch normalizations (BNs) for grading diabetic retinopathy severity levels from fundus images.
Diabetic retinopathy (DR) is one of the main causes of blindness in people around the world. Early diagnosis and treatment of DR can be accomplished by organizing large regular screening programs. Still, it is difficult to spot diabetic retinopathy timely because the situation might not indicate signs in the primary stages of the disease. Due to a drastic increase in diabetic patients, there is an urgent need for efficient diabetic retinopathy detecting systems. Auto-encoders, sparse coding, and limited Boltzmann machines were used as a few past deep learning (DL) techniques and features for the classification of DR. Convolutional Neural Networks (CNN) have been identified as a promising solution for detecting and classifying DR. We employ the deep learning capabilities of efficient net batch normalization (BNs) pre-trained models to automatically acquire discriminative features from fundus images. However, we successfully achieved F1 scores above 80% on all efficient net BNs in the EYE-PACS dataset (calculated F1 score for DeepDRiD another dataset) and the results are better than previous studies. In this paper, we improved the accuracy and F1 score of the efficient net BNs pre-trained models on the EYE-PACS dataset by applying a Gaussian Smooth filter and data augmentation transforms. Using our proposed technique, we have achieved F1 scores of 84% and 87% for EYE-PACS and DeepDRiD.


Evaluation of the sensitivity of miniaturized liquid chromatography-electrospray ionization-mass spectrometry for pharmaceutical analysis.
LC-ESI-MS is applied frequently in pharmaceutical analysis. The sample amount is generally not restricted, however with LC-ESI-MS, a lack of sensitivity may still be observed with standard-bore LC columns in isocratic mode. Therefore, it was investigated whether increased sensitivity could be achieved by using miniaturized LC-ESI-MS. Seven columns ranging from 0.1 to 4.6 mm ID were tested using several instrument setups. For proper comparison, a sensitivity gain factor (SGF) was introduced. The SGF expresses the extra sensitivity that may be obtained on top of the normal increase of peak concentration, which can be expected when the column ID is reduced. Desogestrel, mirtazapine, and sugammadex sodium were used as test compounds. For desogestrel and sugammadex sodium, the SGF increased up to a factor of 5-13 when the column ID was reduced, indicating enhanced ionization efficiencies at lower flow rates. Optimum sensitivity was found for the 0.3 mm column coupled in combination with a microinjection valve and a dedicated low flow rate interface. For mirtazapine, no increase of SGF was observed when the column ID was decreased. Apparently, the ionization efficiency of this compound is not affected by the flow rate and the spray quality.


[Radiophysical characteristics of different detectors for use in dosimetry].
The present study investigated the radiophysical influences on the measurement of dosimetry basic data, attributable to field size, photon energy and detector type. A natural diamond detector, two ionisation chambers, different Si-diodes and a EBT-Gafchromic film were studied for this purpose. The characteristics of the detectors were investigated with regard to the measurement of output factors, lateral beam profiles and relative depth-dose curves for narrow and wide photon beams of 15 MV Significant differences in output factors were obtained with different detectors. For narrow fields, the natural diamond detector and the diodes PTW-60012 and SCX_WH-PFD measured output factors close to those of the EBT-Gafchromic film. The output facto rfor large fields was overestimated by the unshielded diode PTW 60012 and the PinPoint-chamber PTW-31006 because of their over-response to scattered photons. The relative depth dose distributions for wide beams at large depths agree well for the diamond, the ionisation chambers and the shielded Diode SCX_ WH-PFD and PTW-60008, while the measured dose was overestimated by an unshielded diode PTW-60012. Considering the influence due to the sensitive materials and the construction of the detectors the manufacturers of dosimeters have specified the application ranges for the various types of detectors.


Adrenal function as assessed by low-dose adrenocorticotropin hormone test before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate.
Low-dose adrenocorticotropin hormone (ACTH) tests (0.5 microg/L 73 m2) were done before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate in 12 patients 33-77 years old who had mild-to-severe asthma to compare the effects of these drugs on adrenal function. Low-dose ACTH tests were performed after the subjects had received inhaled beclomethasone dipropionate (200-900 microg/day) for at least 12 wk. Treatment was then switched to inhaled fluticasone propionate (200-600 microg/day) for at least 12 wk, and a second low-dose ACTH test was done. Pulmonary function was assessed on the basis of peak expiratory flow rate (PEFR, % of predicted value). After switching treatment, the daily dose of inhaled corticosteroid decreased by about 40%. Basal serum cortisol and ACTH levels were similar with both treatments. The adrenal response, as assessed by incremental rise in the serum cortisol level (peak minus basal) after ACTH challenge, improved significantly (5.6-7.9 microg/dL, p < 0.01) after switching to fluticasone. All three patients who had lower serum cortisol levels during beclomethasone treatment than during fluticasone treatment showed improvement in both the peak cortisol level and the incremental rise in cortisol. Mean morning and evening PEFRs significantly increased after switching from beclomethasone to fluticasone (morning: 71.2 to 76.0%, p < 0.01; evening: 67.3 to 72.1%, both p < 0.05). The diurnal variation of PEFR significantly decreased from 10.9% to 8.3% after switching treatment (p < 0.01). We conclude that switching from beclomethasone to fluticasone reduces the risk of adrenal dysfunction associated with inhaled steroids and improves pulmonary function.


Effect of Nano-SnS and Nano-MoS2 on the Corrosion Protection Performance of the Polyvinylbutyral and Zinc-Rich Polyvinylbutyral Coatings.
In this paper, four composite coatings of nano-SnS/polyvinylbutyral (PVB), nano-MoS2/PVB, nano-SnS-Zn/PVB, and nano-MoS2-Zn/PVB were prepared, and their anti-corrosion mechanism was analyzed by experimental and theoretical calculations. The results of the electrochemical experiments show that the effect of nano-MoS2 on the corrosion protection performance of PVB coating is better than that of nano-SnS in 3% NaCl solution, and that the addition of Zn further enhances this effect, which is consistent with the results of weight loss measurements. Furthermore, the observation of the corrosion matrix by the field emission scanning electron microscope (FESEM) further confirmed the above conclusion. At last, the molecular dynamics (MD) simulation were carried out to investigate the anti-corrosion mechanism of the nanofillers/PVB composites for the copper surface. The results show that both nano-SnS and nano-MoS2 are adsorbed strongly on the copper surface, and the binding energy of nano-MoS2 is larger than that of nano-SnS.


Enhanced cytotoxicity of prenylated chalcone against tumour cells via disruption of the p53-MDM2 interaction.
Chalcones are naturally occurring compounds with recognized anticancer activity. It was recently shown that the O-prenyl derivative (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1) had a remarkably increased cytotoxicity against human tumour cells compared to its precursor. With this study, we aimed to investigate the molecular mechanism underlying the improved tumour cytotoxicity of prenylchalcone 2. The impact of chalcones 1 and 2 on p53-MDM2 interaction was investigated using yeast growth-inhibitory and p53 transactivation assays. Their tumour growth-inhibitory effects were assessed on human colon adenocarcinoma HCT116 cell lines with wild-type p53 and its p53-null derivative, followed by analysis of cell cycle and apoptosis. In tumour cells, the activation of a mitochondrial pathway was checked by analysis of reactive oxygen species generation, Bax mitochondrial translocation and cytochrome c release. Additionally, the up-regulation of p53 transcriptional activity was investigated through Western blot analysis of p53 target expression levels, and the disruption of the p53-MDM2 interaction was confirmed by co-immunoprecipitation. The potent cell tumour growth-inhibitory activity of prenylchalcone 2 was associated with the activation of a p53 pathway involving cell cycle arrest and a mitochondria-dependent apoptosis. Furthermore, a correlation between the distinct cytotoxicity of chalcones 1 and 2 and their ability to disrupt the p53-MDM2 interaction was established. This work shows that prenylation is a determinant factor for the enhancement of chalcones tumour cytotoxicity by improving their ability to disrupt the p53-MDM2 interaction. Prenylchalcone 2 represents a starting basis for the design of new p53-MDM2 interaction inhibitors with improved antitumor properties.


M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s.
Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC). We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family. Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent.


Artificial liver support in pigs with acetaminophen-induced acute liver failure.
To establish a reversible porcine model of acute liver failure (ALF) and treat it with an artificial liver system. Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen (APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group (n = 11), in which a treatment procedure was performed, or a control group (n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased (P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h (at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group (P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution. Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment (P < 0.05). This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system (ZHJ-3) is safe and effective for the APAP-induced porcine ALF model.


Medical treatment of Cushing's disease: Overview and recent findings.
Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure <1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.


Muon reconstruction performance of the ATLAS detector in proton-proton collision data at [Formula: see text]=13 TeV.
This article documents the performance of the ATLAS muon identification and reconstruction using the LHC dataset recorded at [Formula: see text] TeV in 2015. Using a large sample of [Formula: see text] and [Formula: see text] decays from 3.2 fb[Formula: see text] of pp collision data, measurements of the reconstruction efficiency, as well as of the momentum scale and resolution, are presented and compared to Monte Carlo simulations. The reconstruction efficiency is measured to be close to [Formula: see text] over most of the covered phase space ([Formula: see text] and [Formula: see text] GeV). The isolation efficiency varies between 93 and [Formula: see text] depending on the selection applied and on the momentum of the muon. Both efficiencies are well reproduced in simulation. In the central region of the detector, the momentum resolution is measured to be [Formula: see text] ([Formula: see text]) for muons from [Formula: see text] ([Formula: see text]) decays, and the momentum scale is known with an uncertainty of [Formula: see text]. In the region [Formula: see text], the [Formula: see text] resolution for muons from [Formula: see text] decays is [Formula: see text] while the precision of the momentum scale for low-[Formula: see text] muons from [Formula: see text] decays is about [Formula: see text].


Presentation of a new method based on modern multivariate approaches for big data replication in distributed environments.
As the amounts of data and use of distributed systems for data storage and processing have increased, reducing the number of replications has turned into a crucial requirement in these systems, which has been addressed by plenty of research. In this paper, an algorithm has been proposed to reduce the number of replications in big data transfer and, eventually to lower the traffic load over the grid by classifying data efficiently and optimally based on the sent data types and using VIKOR as a method of multivariate decision-making for ranking replication sites. Considering different variables, the VIKOR method makes it possible to take all the parameters effective in the assessment of site ranks into account. According to the results and evaluations, the proposed method has exhibited an improvement by about thirty percent in average over the LRU, LFU, BHR, and Without Rep. algorithms. Furthermore, it has improved the existing multivariate methods through different approaches to replication by thirty percent, as it considers effective parameters such as time, the number of replications, and replication site, causing replication to occur when it can make an improvement in terms of access.


Alignment of molecules in pulsed resonant laser fields.
We investigate by numerical simulations the dynamics of alignment of linear molecules in resonant pulsed laser fields and its dependence on pulse length, field strength, and molecular parameters. We propose an analytical short-time approximation for the time-dependent wave packets. We provide a theoretical basis for the occurrence of saturation in the rotational pumping. We present a formula to predict the time at which the maximum alignment occurs. We discuss the magnitude of the laser-induced alignment and we relate it to a theoretical upper limit.


Invasive Pneumococcal Disease burden and PCV coverage in children under five in Southeast Asia: implications for India.
Pneumococcal diseases, though preventable, are a major public health problem in Southeast Asia and particularly in India. Pneumococcal conjugate vaccines (PCVs) are used in the region for over a decade, but to understand their impact, invasive pneumococcal diseases (IPD) burden and PCV coverage data in the region are needed. A literature search was conducted to identify i) key evidence published between February 2008 and February 2018 on IPD burden, serotype prevalence and antibiotic resistance in Southeast Asia, and ii) PCV serotype and vaccination coverage in Southeast Asia. 49 relevant articles were included in the final analysis. Mortality in children under 5 years remains high in Southeast Asian countries, with around 25% of deaths due to IPD in India and Pakistan. There was a lack of recent data on IPD incidence. Antibiotic resistance to IPD isolates is increasing, with high resistance rates especially for meningeal isolates. Based on serotype distribution data, primarily for India, available PCVs would cover around 70-80% of IPD-causing serotypes. Vaccine coverage was around 15-20% in India to 98% in South Korea. Widespread PCV use could successfully reduce IPD burden in the region due to high serotype coverage by available PCVs; emphasis should be placed on increasing vaccination uptake, for every child, particularly in India. Reducing health system barriers and improving surveillance and awareness is essential to improve coverage and effectively prevent IPD morbidity and mortality particularly in at risk regions.


Randomized Clinical Trial to Compare Micropulse Photocoagulation Versus Half-dose Verteporfin Photodynamic Therapy in the Treatment of Central Serous Chorioretinopathy.
To evaluate subthreshold diode-laser micropulse (SDM) versus half-dose verteporfin photodynamic therapy (hd-PDT) in central serous chorioretinopathy (CSC). 62 eyes of 62 patients were prospectively followed for changes in fluorescein angiography (FA), fundus autofluorescence (FAF), central macular thickness (CMT), best-corrected visual acuity (BCVA), and contrast visual acuity (CVA) after SDM (n=20) or hdPDT (n=24). CSC observation served as control group (n=18). Both treatment groups (60% SDM vs. 66.7% hdPDT) showed significant improvement in reduction of leakage activity compared to the control group (37.5%) at 16 weeks. CMT decreased by 69.7 µm (SDM), 109.8 µm (hdPDT), and 89 µm (control). BCVA improved by +6.7 (SDM group), +8.5 (hdPDT), and +1.5 ETDRS letters (control). CVA was best improved in the hdPDT group. No secondary RPE alterations could be detected by FAF after any intervention. In comparison to the control group, hdPDT and SDM resulted in reduced leakage activity in FA and enhanced photopic and scotopic visual acuity in patients with CSC.


Effects of standardized foot positions during the execution of a submaximal pulling task.
This study examined how experimentally controlled foot positions could affect the temporal and spatial parameters of a load (20% of subject mass) during a one-handed repetitive submaximal pulling activity. Foot positions standardized relative to a frontal and sagittal plane defining a pull force vector were derived based on the preferences of 45 volunteer subjects. In general, the subjects assumed asymmetrical foot positions and on average the big toe of the foot contralateral to the hand exerting the pull was located 19% (SD = 4.4) of stature in front of the frontal plane containing the pull origin and 8.6% (SD = 4.5) of stature laterally from the sagittal plane through which the load was displaced. The big toe of the foot ipsilateral to the hand exerting the force was located at a distance of 46.7% (SD = 6.3) of stature in front of the frontal plane containing the pull origin and 0.4% (SD = 3.9) of stature laterally from the sagittal plane through which the load was displaced. The left and right feet were orientated at angles of 56.8 degrees (SD = 20.2 degrees ) and 25.9 degrees (SD = 22.7 degrees ), respectively, relative to a right horizontal of a frontal plane parallel to the plane containing the origin of pull. These foot positions were subsequently employed in a second experiment to investigate how dictating foot positions would affect the way in which 15 newly recruited subjects exerted a pull force on the same load. Results from this experiment showed that the load velocities and forces were not affected by standardized foot positions when compared to those collected when subjects were free to choose foot orientations. It is suggested that future researchers should consider the benefits of employing standardized foot positions in studies of pull exertions, particularly for methodologies similar to that described in this study.


Epigallocatechin-3-gallate Reduces Scavenger Receptor A Expression and Foam Cell Formation in Human Macrophages.
Foam cells are formed when macrophages imbibe low-density lipoprotein (LDL) through scavenger receptors. Here we examined how epigallocatechin-3-gallate (EGCG) influences foam cell formation. We found that EGCG dose-dependently reduced oxidized LDL (oxLDL) uptake in THP-1 (10 μM, 20.0 ± 0.50, p < 0.05) and primary macrophages (134.6 ± 15.6, p < 0.05) and reduced intracellular cholesterol content in these cells, respectively (10 μM, 32.6 ± 0.14, p < 0.05; 31.7 ± 1.26, p < 0.05). EGCG treatment decreased scavenger receptor A expression, but not the expression of CD36 or of reverse cholesterol transporters. Moreover, EGCG stimulated translocation of the p50 and p65 subunits of NF-κB and enhanced NF-κB DNA-binding activity, thus suppressing SR-A promoter activity. EGCG's suppression of SR-A expression was blocked by the NF-κB inhibitor Bay. The present findings suggest that EGCG regulates NF-κB activity and thus suppresses SR-A expression, oxLDL uptake, and foam cell formation.


Protein Drug Delivery Using a Novel Maxillofacial Technique Targeting the Visual Pathway in the Brain, the Optic Nerve, and the Retina.
Protein drugs are used for treating many diseases of the eye and the brain. The formidable blood neural barriers prevent the delivery of these drugs into the eye and the brain. Hence, there is a need for a protein drug delivery system to deliver large proteins across blood-neural barriers. Low half-life, poor penetration of epithelial barriers, low stability, and immunogenicity limit the use of non-invasive systemic routes for delivering proteins. In this pre-clinical study, the efficacy of a new maxillofacial route for administering protein drugs using a novel drug delivery system is compared with systemic administration through intra-peritoneal injection and ocular administration through topical eye drops and subconjunctival and intravitreal injections. Bevacizumab and retinoschisin proteins were administered using the maxillofacial technique along with systemic and ocular routes in wild-type male C57BL/6J mice. Liquid chromatography with tandem mass spectrometry and western blot was used to detect bevacizumab in tissue samples. Furthermore, immunohistochemistry was performed to detect the presence and localization of bevacizumab and retinoschisin in the retina and brain. The maxillofacial route of delivery could target the brain including regions involved in the visual pathway and optic nerve. The maxillofacial technique and intravitreal injection were effective in delivering the drugs into the retina. A new concept based on the glymphatic pathway, cerebrospinal fluid drug distribution, and the crossover of ipsilateral optic nerve fibers at optic chiasma is proposed to explain the presence of the drug in contralateral eye following maxillofacial administration and intravitreal injection.


Effects of combined epidural and general anesthesia on intraoperative hemodynamic responses, postoperative cellular immunity, and prognosis in patients with gallbladder cancer: A randomized controlled trial.
This study is supposed to investigate the effects of combined epidural and general anesthesia on intraoperative hemodynamic responses, postoperative cellular immunity, and prognosis in patients with gallbladder cancer (GBC). One hundred forty-four GBC patients were selected and randomly divided into the general anesthesia (GA) group and the combined epidural-general anesthesia (CEGA) group. Before anesthesia induction (t0), at intubation (t1), at the beginning of surgery (t2), 5 minutes after pneumoperitoneum (t3), at the end of surgery (t4), after recovery of spontaneous breathing (t5), after regaining consciousness (t6), and after extubation (t7), the heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and the depth of anesthesia (bispectral index [BIS]) were detected. Blood samples were separately collected 30 minutes before anesthesia induction (T1), 2 hours after the beginning of surgery (T2), at the end of surgery (T3), 1 day after surgery (T4), 3 days after surgery (T5). The survival rates of T cell subsets (CD3+, CD4+, CD8+, CD4+/CD8+) and natural killer (NK) cells were determined by flow cytometry. Postoperative nausea and vomiting (PONV), visual analog scale (VAS), and sedation-agitation scale (SAS) were performed to assess postoperative adverse reactions. A 3-year follow-up was conducted. Compared with the GA group, the CEGA group had significant lower SBP values at t5 and t6, lower DBP values at t1, t3, t4, and t5, lower HR values at t1 and t5, and higher BIS values at t4, t5, t6, and t7. No PONV was observed in the CEGA group. In comparison to the GA group, the VAS was markedly increased and survival rates of CD3+, CD4+, and CD4+/CD8+ cells were increased at T2, T3, T4, and T5 in the CEGA group. The 1-year, 2-year, and 3-year survival rates were not evidently different between the CEGA group and the GA group. Our study provides evidence that the combined epidural-general anesthesia might attenuate intraoperative hemodynamic responses and improve postoperative cellular immunity, so that it might be a more available anesthesia method for GBC patients.


Zigzagging: theoretical insights on climbing strategies.
Human and animal trails on steep hillsides often exhibit dramatic switchbacks and shortcuts. Helbing et al. have recently examined the emergence of human trail systems on flat terrains while Minetti and Margaria established the effect of gradients on human metabolic efficiency. In this paper we use these ideas to develop a semi-quantitative theoretical model of the behaviour of humans moving on a terrain with relief. The model determines the direction of movement by minimising metabolic cost per unit of distance in a desired direction. The structure of the theory resembles the Landau Theory of Phase Transitions, much used in theoretical physics. We find that both hairpin bends (switchbacks) and shortcuts appear as efficient strategies for downhill walkers, while uphill walkers retain switchbacks. For weakly inclined slopes, the best strategy involves walking directly uphill or downhill. For sufficiently steep slopes, however, we find that the best strategy should undergo a transition to a broken symmetry solution corresponding to the switchback trail patterns typical of rugged environments. The critical slope at which this transition takes place should be less steep for uphill and downhill walkers. The theory should be amenable to empirical investigation. Amongst other applications, this model will enable us to generalize the work of previous authors to real landscapes, eventually permitting the reconstruction of ancient patterns of movement in archaeological landscapes.


Hyperparametric Oscillation via Bound States in the Continuum.
Optical hyperparametric oscillation based on the third-order nonlinearity is one of the most significant mechanisms to generate coherent electromagnetic radiation and produce quantum states of light. Advances in dispersion-engineered high-Q microresonators allow for generating signal waves far from the pump and decrease the oscillation power threshold to submilliwatt levels. However, the pump-to-signal conversion efficiency and absolute signal power are low, fundamentally limited by parasitic mode competition and attainable cavity intrinsic Q to coupling Q ratio, i.e., Q_{i}/Q_{c}. Here, we use Friedrich-Wintgen bound states in the continuum (BICs) to overcome the physical challenges in an integrated microresonator-waveguide system. As a result, on-chip coherent hyperparametric oscillation is generated in BICs with unprecedented conversion efficiency and absolute signal power. This work not only opens a path to generate high-power and efficient continuous-wave electromagnetic radiation in Kerr nonlinear media but also enhances the understanding of a microresonator-waveguide system-an elementary unit of modern photonics.


Emergency Department Visits by Incarcerated Adults for Nonfatal Injuries - United States, 2010-2019.
During 2010-2019, U.S. correctional authorities held 1.4-1.6 million persons in state and federal prisons annually, and 10.3-12.9 million persons were admitted to local jails each year (1,2). Incarcerated persons experience a disproportionate burden of negative health outcomes, including unintentional and violence-related injuries (3,4). No national studies on injury-related emergency department (ED) visits by incarcerated persons have been conducted, but a previous study demonstrated a high rate of such visits among a Seattle, Washington jail population (5). To examine nonfatal injury-related ED visits among incarcerated adults, CDC analyzed 2010-2019 National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) data. During 2010-2019, an estimated 733,547 ED visits by incarcerated adults occurred in the United States. The proportion of ED visits resulting from assault* and self-harm among incarcerated adults was five times as high as those among nonincarcerated adults. Among incarcerated adults, men and adult persons aged <65 years had the highest proportion of assault-related ED visits. Falls accounted for the most ED visits among incarcerated adults aged ≥65 years. A higher proportion of ED visits by incarcerated women than incarcerated men were for overdose or poisoning. These findings suggest that injuries among incarcerated adults differ from those among nonincarcerated adults and might require development and implementation of age- and sex-specific prevention strategies for this population.


[Concentration of serum proteins and blood group substances in human saliva. 1. Quantitation method and variation of secreting quantities among daily life].
Immunoelectrophoretic analysis of 100 times concentrated human saliva specimens showed marked individual differences in the content of albumin (Alb), IgA, IgG and transferrin (Tf). We concluded that the planimetric measurement of the precipitated area produced by latex-agglutination or hemagglutination on microtiter plates was an appropriate method for quantitating these serum proteins or ABO and Lewis blood group substances in saliva. Nonspecific agglutinating activity caused by mucinous substances in saliva was prevented when the saliva was once stained on a filter paper then dried and extracted with a buffer solution. Quantities of the serum proteins and blood group substances in saliva decreased immediately after meals and gradually increased 2 to 3 hours thereafter. The ratios of IgA/Alb, IgA/IgG and IgG/Alb did not differ remarkably with the time of sample collection. Saliva from parotid and submaxillary-sublingual glands contained similar quantities of the serum proteins, whereas more ABO and Lewis blood group substances were found in saliva from submaxillary-sublingual glands than in that from parotid gland.


Thixotropic Supramolecular Gel Based on l-Lysine Derivatives.
The dimer l-lysine derivatives, in which two Nα,Nε-diacyl-l-lysines were crosslinked by calcium ion, were synthesized through a simply synthetic procedure and their gelation properties were examined. These compounds functioned as an organogelator; especially, the gelators possessing both a linear and a branched alkyl chains had the better organogelation ability and formed the thermally stable and rigid organogel. In addition, some organogels had a thixotropic property, which were responsive to a mechanical stimulus and reversibly underwent the gel⁻sol transition at room temperature. The thixotropic behavior was confirmed by visual contact and rheological experiments. Furthermore, it was assumed the mechanism of the thixotropic behavior.


[Artificial intraocular lenses in patients with cataracts and glaucoma].
The authors evaluated 52 glaucomatous eyes in which, after the extracapsular cataract extraction, artificial posterior lens has been implanted. In 32 patients glaucoma has been treated for 2-6 years. In 7 patients of this group, it was not possible to control the intraocular pressure before surgery and in these cases simultaneous trabeculectomy, extracapsular cataract extraction and the implantation of artificial posterior lens were performed. In 13 patients, anti-glaucomatous surgery had been performed before, and in 7 cases, glaucoma was diagnosed in the preoperative period. We considered our results as satisfactory since in 67% visual acuity was over 0.5; 29% of the patients did not require anti-glaucomatous treatment, whereas 71% took anti-glaucomatous drugs in reduced doses. In our opinion, glaucoma is not a contraindication for artificial lens implantation, although surgery can be technically more difficult.


Combining the dynamic model and deep neural networks to identify the intensity of interventions during COVID-19 pandemic.
During the COVID-19 pandemic, control measures, especially massive contact tracing following prompt quarantine and isolation, play an important role in mitigating the disease spread, and quantifying the dynamic contact rate and quarantine rate and estimate their impacts remain challenging. To precisely quantify the intensity of interventions, we develop the mechanism of physics-informed neural network (PINN) to propose the extended transmission-dynamics-informed neural network (TDINN) algorithm by combining scattered observational data with deep learning and epidemic models. The TDINN algorithm can not only avoid assuming the specific rate functions in advance but also make neural networks follow the rules of epidemic systems in the process of learning. We show that the proposed algorithm can fit the multi-source epidemic data in Xi'an, Guangzhou and Yangzhou cities well, and moreover reconstruct the epidemic development trend in Hainan and Xinjiang with incomplete reported data. We inferred the temporal evolution patterns of contact/quarantine rates, selected the best combination from the family of functions to accurately simulate the contact/quarantine time series learned by TDINN algorithm, and consequently reconstructed the epidemic process. The selected rate functions based on the time series inferred by deep learning have epidemiologically reasonable meanings. In addition, the proposed TDINN algorithm has also been verified by COVID-19 epidemic data with multiple waves in Liaoning province and shows good performance. We find the significant fluctuations in estimated contact/quarantine rates, and a feedback loop between the strengthening/relaxation of intervention strategies and the recurrence of the outbreaks. Moreover, the findings show that there is diversity in the shape of the temporal evolution curves of the inferred contact/quarantine rates in the considered regions, which indicates variation in the intensity of control strategies adopted in various regions.


Scaffold proteins IRSp53 and spinophilin regulate localized Rac activation by T-lymphocyte invasion and metastasis protein 1 (TIAM1).
The Rac exchange factor Tiam1 is involved in diverse cell functions and signaling pathways through multiple protein interactions, raising the question of how signaling and functional specificity are achieved. We have shown that Tiam1 interactions with different scaffold proteins activate different Rac-dependent pathways by recruiting specific Rac effector proteins, and reasoned that there must be regulatory mechanisms governing each interaction. Fibroblasts express at least two Tiam1-interacting proteins, insulin receptor substrate protein 53 kDa (IRSp53) and spinophilin. We used fluorescent resonance energy transfer (FRET) to measure localized Rac activation associated with IRSp53 and spinophilin complexes in individual fibroblasts to test this hypothesis. Pervanadate or platelet-derived growth factor induced localized Rac activation dependent on Tiam1 and IRSp53. Forskolin or epinephrine induced localized Rac activation dependent on Tiam1 and spinophilin. In spinophilin-deficient cells, Tiam1 co-localized with IRSp53 in response to pervanadate or platelet-derived growth factor. In IRSp53-deficient cells, Tiam1 co-localized with spinophilin in response to forskolin or epinephrine. Total cellular levels of activated Rac were affected only in cells with exogenous Tiam1, and were primarily increased in the membrane fraction. Downstream effects of Rac activation were also stimulus and scaffold-specific. Cell ruffling, spreading, and cell adhesion were dependent on IRSp53, but not spinophilin. Epinephrine decreased IRSp53-dependent adhesion and increased cell migration in a Rac and spinophilin-dependent fashion. These results support the idea that Tiam1 interactions with different scaffold proteins couple distinct upstream signals to localized Rac activation and specific downstream pathways, and suggest that manipulating Tiam1-scaffold interactions can modulate Rac-dependent cellular behaviors.


Organocatalytic entry to chiral bicyclo[3.n.1]alkanones via direct asymmetric intramolecular aldolization.
[reaction: see text] The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and endo-7-hydroxybicyclo[3.2.1]octan-2-one, featuring an alpha-amino acid catalyzed intramolecular aldolization of sigma-symmetric substrates, are described. A high enantioselectivity and a high catalytic efficiency have been exhibited by (4R,2S)-tetrabutylammonium 4-TBDPSoxy-prolinate in the aldolization of 3-(4-oxocyclohexyl)propionaldehyde to give highly enantiomerically enriched (1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one.


Chiral stationary phase designed for beta-blockers.
A chiral stationary phase (CSP) derived from an N-3,5-dinitrobenzoyl-alpha-amino phosphonate was prepared for the direct separation of the enantiomers of underivatized beta-blockers. Structure-chromatographic activity relationships for beta-blockers and closely related analogues are reported for this CSP and are found to be consistent with the model used to design this CSP. The effect of temperature on the chromatographic behavior of beta-blocker enantiomers is unusual. A reduction in temperature reduces the retention of the less retained enantiomer and increases the retention of the more retained enantiomer without appreciable band broadening.


Lead Development of Thiazolylsulfonamides with Carbonic Anhydrase Inhibitory Action.
A series of congeners structurally related to pritelivir, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, a helicase-primase inhibitor for the treatment of herpes simplex virus infections, was prepared. The synthesized primary and secondary sulfonamides were investigated as inhibitors of six physiologically and pharmacologically relevant human (h) carbonic anhydrase (hCA, EC 126.96.36.199) isoforms, the cytosolic enzymes hCA I and II, the mitochondrial ones hCA VA and VB, and the transmembrane, tumor associated hCA IX and XII. Low nanomolar inhibition KI values were detected for all of them, with a very interesting and well-defined structure-activity relationship. As many CAs are involved in serious pathologies, among which are cancer, obesity, epilepsy, glaucoma, etc., sulfonamide inhibitors as those reported here may be of interest as drug candidates. Furthermore, pritelivir itself is an effective inhibitor of some CAs, also inhibiting whole blood enzymes from several mammalian species, which may be a favorable pharmacokinetic feature of the drug which can be transported throughout the body bound to blood CA I and II.


Atlantic salmon reovirus infection causes a CD8 T cell myocarditis in Atlantic salmon (Salmo salar L.).
Heart and skeletal inflammation (HSMI) of farmed Atlantic salmon (Salmo salar L.) is a disease characterized by a chronic myocarditis involving the epicardium and the compact and spongious part of the heart ventricle. Chronic myositis of the red skeletal muscle is also a typical finding of HSMI. Piscine reovirus (PRV) has been detected by real-time PCR from farmed and wild salmon with and without typical changes of HSMI and thus the causal relationship between presence of virus and the disease has not been fully determined. In this study we show that the Atlantic salmon reovirus (ASRV), identical to PRV, can be passaged in GF-1 cells and experimental challenge of naïve Atlantic salmon with cell culture passaged reovirus results in cardiac and skeletal muscle pathology typical of HSMI with onset of pathology from 6 weeks, peaking by 9 weeks post challenge. ASRV replicates in heart tissue and the peak level of virus replication coincides with peak of heart lesions. We further demonstrate mRNA transcript assessment and in situ characterization that challenged fish develop a CD8+ T cell myocarditis.


In vitro interactions of endometrial stromal and epithelial cells in Matrigel: reorganization of the extracellular matrix.
Fragments of human endometrial glands and dispersed endometrial stromal cells were cultured together in a thick layer of reconstituted basement membrane (Matrigel). Epithelial cells kept their glandular morphology whereas stromal cells grew into round clusters of mainly fusiform cells. Transmission electron micrographs showed collagen fibers between stromal cells as well as in surrounding extracellular matrix after 2.5 weeks. A well-defined basement membrane was found when epithelial and stromal cells were in close proximity to each other. Beneath the lamina densa there was a loose network of collagen fibers or a dense fibrillar network arranged parallel to the cell layers. Epithelial cells showed hemidesmosomes at their basal surface where they were close to stromal cells.


Safe use of pegylated interferon/ribavirin in hepatitis C virus cirrhotic patients with hypersplenism after partial splenic embolization.
Partial splenic embolization (PSE) is a non-surgical alternative for the treatment of hypersplenism. Thrombocytopenia precludes the use of pegylated interferon (peg-IFN) and ribavirin in cirrhotic patients with hepatitis C virus (HCV). We aimed to evaluate the role of PSE as a procedure allowing combined HCV therapy in this setting. A retrospective analysis of the safety and rate of sustained virological response (SVR) after a full-dose course of peg-IFN plus ribavirin in eight HCV cirrhotic patients with severe hypersplenism undergoing PSE at a tertiary centre in Madrid, Spain, from May 2002 to August 2004. Six patients (75%) were in Child-Pugh class B (median score 7). PSE significantly improved the mean platelet (P = 0.012), leucocyte (P = 0.017) and haemoglobin (P = 0.035) levels, and prothrombin activity (P = 0.012). After a mean of 20 weeks after PSE all patients started weight-adjusted ribavirin plus peg-IFN-alpha2b (n = 6) or 180 microg/week of peg-IFN-alpha2a (n = 2). Six subjects (75%) completed therapy with no peg-IFN dose reductions; the dose of ribavirin was reduced in two patients reaching haemoglobin levels of less than 10 g/dl (one also received erythropoietin and granulocyte colony-stimulating factor because of neutrophil counts < 300 cells/microl). Three patients (38%) achieved SVR. Portal vein thrombosis was observed in 50% of patients, but did not preclude antiviral therapy. The pathogenic mechanism was multifactorial. It was successfully managed with anticoagulant therapy in two cases. PSE allowed the safe use of peg-IFN plus ribavirin in HCV cirrhotic patients with severe cytopenias who otherwise would never have been treated. The rate of SVR was 38%.


Nonalcoholic fatty liver disease is associated with excessive calorie intake rather than a distinctive dietary pattern.
We aimed to assess the dietary patterns associated with nonalcoholic fatty liver disease (NAFLD) and the efficacy of dietary interventions in a real-life setting at a tertiary medical center in Northern Germany.Clinical and laboratory data as well as data obtained by a semiquantitative food frequency questionnaire of 55 consecutive patients diagnosed with NAFLD were compared to an age and gender-matched cohort of 88 healthy individuals by univariate analysis. The efficacy of the dietary intervention was assessed in a subgroup of 24 NAFLD patients 6 months after receiving dietary advice. Macronutritional components of the diet were normalized for absolute daily energy intake.NAFLD patients consumed more calories per day as compared with healthy controls (P <0.001). The absolute amounts of most nutritional components ingested by NAFLD patients were higher than those of the controls. However, there were no significant differences with regards to the relative consumption of carbohydrates (P = 0.359), fat (P = 0.416), and fructose (P = 0.353) per 1000 kcal energy intake. NAFLD patients displayed a higher intake of glucose/1000 kcal (P = 0.041) and protein/1000 kcal (P = 0.009) but a lower intake of fibers/1000 kcal (P < 0.001) and mineral nutrients/1000 kcal (P = 0.001) than healthy controls. In the longitudinal analysis patients significantly reduced their caloric intake and their ALT levels improved 6 months after the dietary counselling (P < 0.001).Our data from a German real-life cohort demonstrate that dietary patterns of patients with NAFLD display great variability and little disease specificity, while the most distinctive feature compared with healthy controls was higher energy intake in NAFLD patients.


[Scintigraphic assessment of the small intestine transit. Diagnostic investigation of dysmotility with 99mTc-HIDA].
Symptoms from the gastro-intestinal tract are common and often difficult to evaluate. Specialised examination techniques are available only at a limited number of clinics. A technique based on biliary scintigraphy when measuring the transit of contents through the small intestine has been developed. The investigation is simple to perform and convenient for the patient. It can be carried out at any clinic equipped with a gamma camera. 30 healthy individuals were examined in order to obtain reference values. 23 patients were examined with scintigraphy in combination with upper gastrointestinal manometry, 10 of whom had abdominal pain and neurogenic or myogenic pseudoobstruction disclosed by manometry. In another 4 patients, slow transit and pain prevailed in conjunction with normal manometric findings. Rapid transit and diarrhoea was found in 3 patients with various abberations on manometry. Of the remaining patients, 4 had slow transit and diarrhoea with intestinal neuropathy and pseudoobstruction, and 2 had slow transit along with endocrinopathies (diabetes, pituitary insufficiency).


Loss of mitochondrial membrane potential (ΔΨm ) in leucocytes as post-COVID-19 sequelae.
The mitochondrial membrane potential (ΔΨm ) is a parameter often used to determine mitochondrial function; therefore, it can be used to determine the integrity and functionality of cells. A decrement of ΔΨm is implicated in several inflammatory-related pathologies, such phenomena can be related to COVID-19 infection. The present work aimed to compare the ΔΨm in leucocytes (human PBMCs; HPBMC) isolated from healthy control (HC) subjects, patients with COVID-19 (C-19), recovered subjects at 40 ± 13 (R1) and 335 ± 20 (R2) days after infection (dai). Obtained data showed that ΔΨm decreased in HPBMC of subjects with C-19, R1, and R2 compared with HC. When analyzing the ΔΨm data by sex, in females, a significant decrease was observed in R1 and R2 groups versus HC. Regarding men, a significant decrease of ΔΨm was observed in R1, with respect to HC, contrary to R2 group, who reestablished this parameter. Obtained results suggest that the loss of ΔΨm could be related to the long-COVID.


A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis.
With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age <55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.


Evidence-based design for healthcare in post-katrina new orleans: current dilemmas.
New Orleans continues to struggle to rebuild from the devastation inflicted by Hurricane Katrina in 2005. More than 1,800 perished in its aftermath. Katrina stands as the costliest catastrophe in U.S. history, and the city's healthcare infrastructure is similarly striving to resuscitate itself. The incorporation of evidence-based design and research (EBD&R) in the reconstitution of the city's healthcare infrastructure offers a promising direction to improve healthcare outcomes. Recent efforts to incorporate EBD&R in New Orleans' recovery are summarized. EBD&R interventions are needed that take certain key dilemmas into consideration-embracing the adaptive reuse possibilities of historic healthcare facilities, private-public sector collaborations in acute care and in neighborhood-based outpatient care environments, and interventions to serve the city's growing population of medically underserved residents.


Anatomy of the rectourethralis muscle.
To define the true anatomic structure of the rectourethralis muscle. Cross-sectional images of fresh tissues from the Visible Human Data set were reviewed. Three-dimensional computer reconstructions of the rectourethralis and surrounding structures were generated from these data using a high speed computer and imaging software. The structure of rectourethralis was confirmed by dissection of fresh cadavers. The rectourethralis arises deep within the substance of the smooth muscle of the rectal wall as two limbs of muscle which face posterolaterally. These limbs fuse into a single thick muscle which inserts into the perineal body. In contrast to all previous descriptions in the literature, the rectourethralis is a Y-shaped muscle which arises within the substance of the rectal wall deep to the outer longitudinal smooth muscle. This shape is consistent with the muscle's embryologic origin. Knowledge of the structure of the rectourethralis muscle will help urologists avoid rectal injuries during perineal approaches to the prostate.


Medico-legal aspects of abortion in Europe.
The practice of abortion in a particular country reflects culture, economic status, religion and the law. Various aspects of abortion in Europe - laws, rates and practices - are presented. Abortion is completely prohibited in Ireland and Malta. In Poland it is permitted only to save the woman's life or protect her physical health. On the grounds of protecting the woman's mental health it is also permitted in Northern Ireland, Portugal, Spain and Switzerland. On socioeconomic grounds abortion is permitted in Finland, Great Britain and Hungary. In the other European countries it is permitted on demand. Eastern Europe has the highest abortion rate (Romania 78/1000 women aged 15-44), and Western Europe has the lowest (The Netherlands 6.5/1000); the disparity may be attributable to differences in availability and use of effective contraceptives. Within the first 12 weeks of gestation, vacuum aspiration has replaced dilatation and curettage, as the most commonly used method to perform abortion. More recently, medical abortion (mifepristone with prostaglandins) in early pregnancy has been used in several European countries. Reduction of the need for induced abortion and prevention of unsafe abortion through the provision of appropriate legislation and good family planning services should be an integral part of health care in every country.


VH mutant rabbits lacking the VH1a2 gene develop a2+ B cells in the appendix by gene conversion-like alteration of a rearranged VH4 gene.
We investigated the molecular basis for the appearance of V(H)a2 allotype-bearing B cells in mutant Alicia rabbits. The mutation arose in an a2 rabbit; mutants exhibit altered expression of V(H) genes because of a small deletion encompassing V(H)1a2, the 3'-most gene in the V(H) locus. The V(H)1 gene is the major source of V(H)a allotype because this gene is preferentially rearranged in normal rabbits. In young homozygous ali/ali animals, the levels of a2 molecules found in the serum increase with age. In adult ali/ali rabbits, 20 to 50% of serum Igs and B cells bear a2 allotypic determinants. Previous studies suggested that positive selection results in expansion of a2 allotype-bearing B cells in the appendix of young mutant ali/ali rabbits. We separated appendix cells from a 6-wk-old Alicia rabbit by FACS based on the expression of surface IgM and a2 allotype. The VDJ portion of the expressed Ig mRNA was amplified from the IgM+ a2+ and IgM+ a2- populations by reverse transcriptase-PCR. The cDNAs from both populations were cloned and sequenced. Analysis of these sequences suggested that, in a2+ B cells, the first D proximal functional gene in Alicia rabbits, V(H)4a2, rearranged and was altered further by a gene conversion-like mechanism. Upstream V(H) genes were identified as potential gene sequence donors; V(H)9 was found to be the most frequently used gene donor. Among the a2- B cells, y33 was the most frequently rearranged gene.


Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients.
Little is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in virologically suppressed patients. In this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA <50 copies/ml for 6 months or longer, negative for HBsAg and on a stable (>6 months) cART. Ninety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected. The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P < 0.0001) increment of median creatinine from 0.87 mg/dl (IQR 0.34) to 0.95 mg/dl (IQR 0.29) was observed in the first 2 months but thereafter leveled on these values (1.00 mg/dl; IQR 0.35) (P = 0.111 compared to 2 months). The lipid profile slightly improved. The daily cost of cART was significantly (P < 0.0001) reduced of 6.89 euros (SD 6.10). Switching to a dual cART regimen based on lamivudine + dolutegravir maintains virological efficacy up to week 24, and is associated to slight improvements of the immunologic and metabolic status. The strategy allows to freely using concomitant medications for associated pathologies. The dual therapy is less expensive in economic terms. Although still limited evidence exists, a dolutegravir-based dual therapy in combination with lamivudine shows promising results to be confirmed in larger controlled trials.


Levcromakalim and MgGDP activate small conductance ATP-sensitive K+ channels of K+ channel pore 6.1/sulfonylurea receptor 2A in pig detrusor smooth muscle cells: uncoupling of cAMP signal pathways.
Pharmacological studies have suggested the existence of ATP-sensitive K(+) (K(ATP)) channel as a therapeutic target in urinary bladders; however, electrical properties have not yet been shown. Patch-clamp techniques were applied to investigate the properties of K(ATP) channels in pig detrusor cells. In whole-cell configuration, levcromakalim, a K(ATP) channel opener, induced a long-lasting outward current in a concentration-dependent manner. The current-voltage curve of the levcromakalim-induced membrane current intersected at approximately -80 mV. This current was abolished by glibenclamide. Intracellular application of 0.1 mM GDP significantly enhanced the levcromakalim-induced membrane current, whereas cAMP did not. Furthermore, neurotransmitters related to cAMP signaling, such as calcitonin gene-related peptide, vasointestinal peptide, adenosine, and somatostatin, had little effect on the membrane current. In cell-attached configuration, levcromakalim activated K(+) channels with a unitary conductance of approximately 12 pS. When the patch configuration was changed to inside-out mode, the K(+) channel activity ran down. Subsequent application of 1 mM GDP reactivated the channels. The openings of the approximately 12 pS K(+) channels in the presence of 1 mM GDP was suppressed by ATP and glibenclamide. In reverse transcription-polymerase chain reaction, K(+) channel pore 6.1 and sulfonylurea receptor (SUR)2A were predominant in pig detrusor cells. The 12 pS K(+) channel activated by levcromakalim in pig detrusor smooth muscle cells is a K(ATP) channel. The predominant expression of SUR2A can account for the lack of effect of neurotransmitters related to cAMP.


The Study of Cellular and Molecular Physiological Characteristics of Sperm in Men Living in the Aral Sea Region.
Extreme environmental situation in the Aral crisis has caused a massive chemical pollution of the territory for decades with high doses of pesticides, herbicides. Discharge of industrial waste into the rivers that feed the Aral Sea has lead to the development of various pathological processes in the human body, as well as disruption of reproductive function in young men. To evaluate the performance of molecular cellular changes in the sperm of men under the influence of dust and salt aerosols in Aral Sea region. Clinical and laboratory studies were conducted in men 5 settlements (Aralsk-city, v. Aiteke-Bi, v. Zhalagash, v. Zhusaly, v. Shieli). We have studied male ejaculate obtained after 4-5 days of abstinence, and placed it in a warm tube with a glass stopper. On the investigation proceeded ejaculate within 20-30 minutes after its preparation, during which time he was subjected to liquefaction. Isolation and quantification of ASF, RNA, DNA, and determining the fraction of histones in sperm was performed by the method of Markusheva and Savina. It was found that the value of ASF in the semen of men living in the zone of ecological disaster higher compared with the values of parameters in men living in the area of environmental crisis, and this trend is observed in all age groups. The study of circulating extracellular DNA and RNA in the sperm of men registered their decline with a corresponding increase of acid precursors that can be attributed to the degradation of nucleic acids under the influence of negative factors in the complex area of ecological trouble. Also, according to a study in men residing in the areas of environmental catastrophe at the age of 18-29 years, found an increased content of the H1 histone H2A lower total fraction, H3, H4 - and a sharp increase in histone H2B content - histones. Men living in environmentally disadvantaged areas of Kyzylorda region under the influence of dust and salt aerosols and other toxicants leads to disruption of the reproductive function in men.


Expanding Opportunities for American Descendants of Slavery to Build a More Inclusive and Diverse Global Health Workforce.
Historically, the terms African American and Black have been used interchangeably to describe any person with African ancestry living in the United States. However, Black Americans are not a monolith, and legitimate differences exist between those with generational roots in the United States and either African or Caribbean immigrants. American descendants of slavery (ADOS) are underrepresented in many fields, but I have noticed during my decades long career in global health that they are acutely absent in this field. Here, I offer seven recommendations to improve recruitment, retention, and advancement of ADOS in the global health field. Immediate implementation of these recommendations will not only bring diverse perspectives and immense capacity to the field but also allow ADOS an opportunity to engage in compelling and meaningful work and to collaborate with those from their ancestral homelands.


Inbreeding and reproductive performance in standardbred horses.
The relationship between inbreeding and both conception and foaling rates in Standardbred horses (trotters and pacers) was examined for 1194 breeding years. There was a statistically significant (P less than 0.05) trend for conception and foaling rates to decrease with increased inbreeding; however, this relationship accounted for less than 2 percent of the variation. Additionally, the relationship between reproductive performance and inbreeding was not consistent between trotters and pacers. For trotters (F = 0.103) there was a trend for an increase in conception and foaling rates with increased inbreeding, while for pacers (F = 0.074), reproductive performance decreased with increased inbreeding. Overall, inbreeding does not appear to be a significant factor influencing reproductive performance of Standardbred horses.


Primary splenic lymphoma.
Although a number of lymphomas and leukaemias can involve the spleen and may present clinically with splenomegaly, only the B cell disorders SMZL and hepatosplenic gamma/delta T cell lymphoma can be considered true primary splenic lymphomas. The former is not uncommon and has histological features which may be to a certain extent recapitulated by other B cell lymphomas when they involve the spleen. In view of the characteristic clinically indolent behaviour of SMZL and its favourable response to splenectomy, rather than chemotherapy, the differential diagnosis from other B cell lymphomas is important. Hepatosplenic gamma/delta T cell lymphoma is rare; for the purpose of precise classification, it needs to be distinguished from other NK like T cell lymphomas and NK cells lymphomas that sometimes involve the spleen.


Cholera outbreak in Addis Ababa, Ethiopia: A case-control study.
Cholera remains a significant public health problem in more than one-third of the countries of the world. Cholera outbreak has become more common in Addis Ababa particularly in the rainy seasons; however, there is a paucity of data on risk factors associated with cholera outbreaks rendering interventions difficult. We investigated the outbreak to identify its etiology, source, risk factors and in order to control the outbreak. We compared cases with health center-based unmatched controls (1:2). Cases were patients aged ≥5 years with acute watery diarrhea, with or without vomiting while controls were persons aged ≥5 years without history of acute watery diarrhea. We interviewed our study participants using structured questionnaire to collect demographic and cholera risk factors data. We described the outbreak over time, and then tested our hypotheses using unconditional logistic regression. The outbreak began on 7 September, 2017 reaching its peak on 23 September, 2017 and ended on 01 October, 2017. We identified a total of 25 cases (Median age: 38 years; IQR: 20 years) and recruited 50 controls (Median age: 35 years; IQR: 29 years). All case-patients had acute watery diarrhea and dehydration requiring intravenous fluids. All cases were admitted to cholera treatment center but there were no deaths. Stool and water samples yielded isolates of Vibrio cholerae O1 of serological subtype Ogawa. Consumption of contaminated holy water (AOR: 20.5, 95%CI: 3.50, 119.61) and raw vegetables (AOR: 15.3, 95%CI: 3, 81.51) were independent risk factors whereas washing hands with soap after visiting latrine (AOR: 0.04, 95%CI: 0.01, 0.25) was independent protective factor. Our findings demonstrated cholera foodborne transmission via consumption of raw vegetables, and its waterborne transmission via consumption of contaminated holy water. Washing hands with soap after visiting latrine was protective. We recommended cooking of vegetables and promoting hand washing.


Homeostatic mechanisms and treatment of tinnitus.
Tinnitus, the phantom percept of sound, is a potentially debilitating disorder affecting up to ten percent of the general population. After decades of effort, we still lack an effective treatment for tinnitus, partly because of its diverse underlying etiology. Recent studies have yielded hypotheses for central mechanisms underlying hearing loss-induced tinnitus, the most common form of tinnitus. Here we review recent evidence that homeostatic down-regulation of phasic and tonic inhibition is a mechanism underlying hearing loss-induced tinnitus. We propose to treat tinnitus through novel strategies of sensory training and targeted pharmacological intervention to reverse the homeostatic changes induced by hearing loss.


Regional Heterogeneity of Perivascular Adipose Tissue: Morphology, Origin, and Secretome.
Perivascular adipose tissue (PVAT) is a unique fat depot with local and systemic impacts. PVATs are anatomically, developmentally, and functionally different from classical adipose tissues and they are also different from each other. PVAT adipocytes originate from different progenitors and precursors. They can produce and secrete a wide range of autocrine and paracrine factors, many of which are vasoactive modulators. In the context of obesity-associated low-grade inflammation, these phenotypic and functional differences become more evident. In this review, we focus on the recent findings of PVAT's heterogeneity by comparing commonly studied adipose tissues around the thoracic aorta (tPVAT), abdominal aorta (aPVAT), and mesenteric artery (mPVAT). Distinct origins and developmental trajectory of PVAT adipocyte potentially contribute to regional heterogeneity. Regional differences also exist in ways how PVAT communicates with its neighboring vasculature by producing specific adipokines, vascular tone regulators, and extracellular vesicles in a given microenvironment. These insights may inspire new therapeutic strategies targeting the PVAT.


CPPU may induce gibberellin-independent parthenocarpy associated with PbRR9 in 'Dangshansu' pear.
Parthenocarpy is a valuable trait in self-incompatible plants, such as pear. N-(2-chloro-4-pyridyl)-N'-phenylurea (CPPU), a synthetic cytokinin analog, can induce parthenocarpy in pear (Pyrus spp.), but the mechanism of induction is unclear. To investigate the role of gibberellin in CPPU-induced parthenocarpy in pear, CPPU supplemented with paclobutrazol (PAC) was sprayed onto 'Dangshansu' pear. We found that the fruit set rate of pear treated with CPPU supplemented with PAC was identical to that in a CPPU-alone treatment group. In regard to cell development, CPPU mainly promoted hypanthium cell division and expansion, and PAC application had no influence on CPPU-induced cell development. RNA sequencing revealed that gibberellin 20 oxidase and gibberellin 3 oxidase genes were not differentially expressed following CPPU treatment. According to the analysis of fruit phytohormone content, the CPPU treatments did not induce gibberellin biosynthesis. These results suggest that CPPU-induced parthenocarpy may be gibberellin independent in 'Dangshansu' pear. After CPPU treatment, the indole acetic acid (IAA) content in fruit was significantly increased, and the abscisic acid (ABA) content was significantly decreased. Similarly, RNA sequencing revealed that many genes involved in the auxin and ABA pathways were significantly differentially expressed in the CPPU treatment groups; among them, indole-3-pyruvate monooxygenase (YUCCA) was significantly upregulated and 9-cis-epoxycarotenoid dioxygenase (NCED) was significantly downregulated. IAA and ABA may thus play important roles in CPPU-induced parthenocarpy. PbTwo-component response regulator9 (PbRR9), PbYUCCA4, and PbNCED6 were then selected to further elucidate the mechanism of CPPU-induced parthenocarpy. A yeast one-hybrid assay indicated that PbRR9 can combine with the PbYUCCA4 and PbNCED6 promoters. Dual luciferase assays revealed that PbRR9 can promote and repress the activities of the PbYUCCA4 and PbNCED6 promoters, respectively. After the transient expression of PbRR9 in fruits, PbYUCCA4 expression was significantly upregulated, and PbNCED6 expression was significantly downregulated. This study uncovered a CPPU-induced parthenocarpy mechanism that is different from that in tomato. CPPU may upregulate PbYUCCA4 and downregulate PbNCED6 by upregulating PbRR9, thereby increasing IAA content and decreasing ABA content to ultimately induce parthenocarpy in 'Dangshansu' pear. However, because only a single time point was used and because 'botanical' and 'accessory' fruits have different structures, this conclusion is still preliminary.


Ineffective oesophageal motility: manometric subsets exhibit different symptom profiles.
To compare the demographic and clinical features of different manometric subsets of ineffective oesophageal motility (IOM; defined as > or = 30% wet swallows with distal contractile amplitude < 30 mmHg), and to determine whether the prevalence of gastro-oesophageal reflux differs between IOM subsets. Clinical characteristics of manometric subsets were determined in 100 IOM patients (73 female, median age 58 years) and compared to those of 100 age-and gender-matched patient controls with oesophageal symptoms, but normal manometry. Supine oesophageal manometry was performed with an eight-channel DentSleeve water-perfused catheter, and an ambulatory pH study assessed gastro-oesophageal reflux. Patients in the IOM subset featuring a majority of low-amplitude simultaneous contractions (LASC) experienced less heartburn (prevalence 26%), but more dysphagia (57%) than those in the IOM subset featuring low-amplitude propagated contractions (LAP; heartburn 70%, dysphagia 24%; both P < or = 0.01). LASC patients also experienced less heartburn and more dysphagia than patient controls (heartburn 68%, dysphagia 11%; both P < 0.001). The prevalence of heartburn and dysphagia in IOM patients featuring a majority of non-transmitted sequences (NT) was 54% (P = 0.04 vs LASC) and 36% (P < 0.01 vs controls), respectively. No differences in age and gender distribution, chest pain prevalence, acid exposure time (AET) and symptom/reflux association existed between IOM subsets, or between subsets and controls. IOM patients with LASC exhibit a different symptom profile to those with LAP, but do not differ in gastro-oesophageal reflux prevalence. These findings raise the possibility of different pathophysiological mechanisms in IOM subsets, which warrants further investigation.


Effects of TIN2 on telomeres and chromosomes in the human gastric epithelial cell line GES-1.
TERF1-interacting nuclear factor 2 (TIN2) is a key member of the protein complexes that protect telomeres. TIN2 contributes an important role in biological processes. In a previous study by the present authors, an association was reported between high TIN2 protein expression and gastric cancer. Therefore, it was hypothesized that abnormal TIN2 expression may cause the development of malignancies, including, gastric carcinomas. To investigate this hypothesis, the present study employed peptide nucleic acid fluorescence in situ hybridization technology to analyze the human gastric epithelial GES-1 cells with high TIN2 expression or inhibited TIN2 expression. The results indicated that GES-1 cell lines with high TIN2 expression exhibited greater telomere dysfunction-induced damage compared with GES-1 cell lines with inhibited TIN2 expression. Chromosome analysis indicated that GES-1 cells with high TIN2 expression exhibited 2.48±1.30 aberrant chromosomal changes per 100 cells, that may contribute to telomere DNA damage. Therefore, aberrant chromosomal alterations may provide a novel perspective for the pathogenesis of gastric cancer.


Folic Acid-Targeted Etoposide Cubosomes for Theranostic Application of Cancer Cell Imaging and Therapy.
BACKGROUND The aim of this study was to develop a novel Poloxamer-based drug delivery system featuring a tumor-targeting folate moiety, which was expected to provide better targeting properties and therapeutic effects compared with the traditional cubosomes (Cubs). MATERIAL AND METHODS Both folate-modified Cubs containing etoposide (ETP-Cubs-FA) and normal cubic nanoparticles loaded with etoposide (ETP-Cubs) were prepared through the fragmentation of bulk gels under the homogenization condition of 1500 bar, and a mean particle size of around 180 nm was obtained with a narrow size distribution. The cubosomes were further characterized by differential scanning calorimetry (DSC) and Polarized light microscopy (PLM). The release of ETP in vitro from these nanoparticles was found to be 82.5% at 36 h, showing a sustained release property compared with the free drug administration. RESULTS Folate-modified cubosomes exhibited best anti-proliferative activity followed by normal cubosomes and the free drug. A further cell uptake study of Rhodamine B-loaded Cubs-FA (Rh-B-Cubs-FA) showed a marked increase of cellular accumulation compared with free Rh-B and Rh-B-loaded Cubs (Rh-B-Cubs). In vivo Rh-B-based tumor imaging demonstrated that Cubs-FA specifically targeted the tumor tissue. CONCLUSIONS The folate-modified cubosomes containing ETP may be a promising drug candidate for antitumor treatment.


Defining the molecular signatures of human right heart failure.
Right ventricular failure (RVF) varies significantly from the more common left ventricular failure (LVF). This study was undertaken to determine potential molecular pathways that are important in human right ventricular (RV) function and may mediate RVF. We analyzed mRNA of human non-failing LV and RV samples and RVF samples from patients with pulmonary arterial hypertension (PAH), and post-LVAD implantation. We then performed transcript analysis to determine differential expression of genes in the human heart samples. Immunoblot quantification was performed followed by analysis of non-failing and failing phenotypes. Inflammatory pathways were more commonly dysregulated in RV tissue (both non-failing and failing phenotypes). In non-failing human RV tissue we found important differences in expression of FIGF, TRAPPAC, and CTGF suggesting that regulation of normal RV and LV function are not the same. In failing RV tissue, FBN2, CTGF, SMOC2, and TRAPP6AC were differentially expressed, and are potential targets for further study. This work provides some of the first analyses of the molecular heterogeneity between human RV and LV tissue, as well as key differences in human disease (RVF secondary to pulmonary hypertension and LVAD mediated RVF). Our transcriptional data indicated that inflammatory pathways may be more important in RV tissue, and changes in FIGF and CTGF supported this hypothesis. In PAH RV failure samples, upregulation of FBN2 and CTGF further reinforced the potential significance that altered remodeling and inflammation play in normal RV function and failure.


[Change in the content of salicylic acid and activities of phenylalanine ammonia-lyase and catalase in wheat seedling roots under the influence of Azospirilium lectins].
The time course of changes in the endogenous content of salicylic acid, the ratio between the acid's free and bound forms, and changes in the activities of phenylalanine ammonia-lyase and catalase in wheat seedling roots under the effect of lectins of two strains of the associative nitrogen-fixing bacterium Azospirillum (A. brasilense Sp7 and its mutant defective in lectin activity, A. brasilense Sp7.2.3) is investigated. Differences in plant response to the action of the lectins from these two strains are established. On the basis of the obtained data, a model is proposed for lectin-assisted induction of resistance, according to which the lectin effect on the roots of seedlings results in the accumulation of free salicylic acid, which inhibits catalase activity, ultimately leading to accumulation of hydrogen peroxide and formation of induced resistance.


Diagnostic and therapeutical management of supine hypertension in autonomic failure: a review of the literature.
: Supine hypertension is defined as a blood pressure at least 140 mmHg systolic or at least 90 mmHg diastolic in the supine position; supine hypertension is present in over 50% of patients with autonomic failure and orthostatic hypotension, but it is often overlooked. It may be related to antihypotensive drugs, but its presence in untreated patients suggests a neurogenic origin. Supine hypertension is often asymptomatic although it is associated with multiple organ damage. There are no official guidelines on its treatment and long-term benefits have never been proved. The present review is focused on the management of supine hypertension, including nonpharmacological and pharmacological approach. All the tested drugs have been individually revised, focusing on their hypotensive effect and their ability to act on ancillary targets, such as morning orthostatic tolerance or sodium urine excretion. Moreover, the main pathogenic mechanisms and the correct approach to the diagnosis of supine hypertension have been resumed.


Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium.
Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α , NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture.


Alteration of Hemostatic Parameters in Patients with Different Levels of Subclinical Hypothyroidism and the Effect of L-thyroxine Treatment.
Subclinical hypothyroidism (SH) is associated with hypercoagulability and hypofibrinolysis. The objective of this study was to assess the effect of L-thyroxine (L-T4) treatment and to evaluate changes in the hemostatic abnormalities of patients with varying severities of SH. We measured tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer (DDI), fibrinogen (FIB), platelet counts (PLT), mean platelet volume (MPV), platelet distribution width (PDW), activated partial thromboplastin time (APTT), and prothrombin time (PT) in 149 female subjects. The prospective study included 54 patients in the control group, 53 patients with 4.2 μIU/mL<TSH<10 μIU/mL (mild SH), and 42 patients with TSH≥10 μIU/mL (severe SH). All patients with a TSH value of ≥10 μIU/mL were given L-T4 replacement therapy, titrated to normalize their TSH levels. There were significant differences in the triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and serum uric acid (UA) levels, and in the MPV, PDW, APTT, FIB, PAI-1, t-PA, and DDI (P<0.05) measurements among three groups. These data were further tested using the least significant difference method for multiple comparisons. Patients in the severe SH group showed higher FIB, PAI-1 and t-PA levels, lower DDI levels and shorter APTT compared with the control group, whereas the hemostatic parameters in the mild SH patients were not different compared with those of the control group. After 6 months of L-T4 treatment, a significant decrease in FIB, PAI-1 and t-PA levels and an increase in APTT and DDI were observed in the severe SH group. In conclusion, SH patients displayed a distinct pattern of alteration of hemostatic parameters that was dependent on the severity of the disease. Patients with TSH levels ≥10 μIU/mL displayed hypercoagulability, which was reversed by 6 months of L-T4 treatment.


Perceived attitudes and barriers towards medical research: a survey of Jordanian interns, residents, and other postgraduates.
We investigated research barriers among Jordanian medical postgraduates to understand the current context of the local health research landscape and improve scholarly output. Using a validated questionnaire, Jordanian interns, residents, specialists, and consultants were examined for their perceived attitudes and barriers towards research. Participants were conveniently sampled from public, university, military, and private institutions. Differences in responses were examined using the Student t-test and analysis of variance. Binary logistic regression was utilized to examine predictors of being able to publish. A total of 1,141 Jordanian medical postgraduates were recruited, of which 61.3% were junior postgraduates (i.e., interns and residents in their first 2 years of residency) while 38.7% were senior postgraduates (i.e., senior residents, specialists, and consultants). Around 76.0% of participants had no peer-reviewed publications. Of those with least one publication (n=273), only 31.1% had first authorships. Participants portrayed dominantly positive attitudes towards the importance of research. There were no significant differences between junior and senior postgraduates for overall attitudes (p=0.486) and knowledge barriers scores (p=0.0261). Conversely, senior postgraduates demonstrated higher mean organizational barriers (p<0.001). Seniority (odds ratio [OR], 5.268; 95% confidence interval [CI], 3.341-8.307), age (OR, 1.087; 95% CI, 1.019-1.159), academic standing (OR, 1.730; 95% CI, 1.103-2.715), and confidence (OR, 1.086; 95% CI, 1.009-1.169) were positive predictors of publication in peer reviewed journals. The Jordanian medical research landscape is riddled with all forms of different barriers. The reworking of current and integration of new research training programs are of utmost importance.


Trial-level fluctuations in pupil dilation at encoding reflect strength of relational binding.
Eye-tracking methodologies have revealed that eye movements and pupil dilations are influenced by our previous experiences. Dynamic fluctuations in pupil size during learning reflect in part the formation of memories for learned information, while viewing behavior during memory testing is influenced by memory retrieval and drawn to previously learned associations. However, no study to date has linked fluctuations in pupil dilation at encoding to the magnitude of viewing behavior at test. The current investigation involved monitoring eye movements both in single item recognition and relational recognition tasks. In the item task, all faces were presented with the same background scene and memory for faces was subsequently tested, whereas in the relational task each face was presented with its own unique background scene and memory for the face-scene association was subsequently tested. Pupil size changes during encoding predicted the magnitude of preferential viewing during test, as well as future recognition accuracy. These effects emerged only in the relational task, but not in the item task, and were replicated in an additional experiment in which stimulus luminance was more tightly controlled. A follow-up experiment and additional analyses ruled out differences in orienting instructions or number of fixations to the encoding display as explanations of the observed effects. The results shed light on the links between pupil dilation, memory encoding, and eye movement patterns during recognition and suggest that trial-level fluctuations in pupil dilation during encoding reflect relational binding of items to their context rather than general memory formation or strength. (PsycInfo Database Record (c) 2023 APA, all rights reserved).