The current status of lipoprotein (a) measurement in clinical biochemistry laboratories in the UK: Results of a 2021 national survey.
Lipoprotein(a) (Lp(a)) is now established as a causal risk factor for cardiovascular disease (CVD) and accurate laboratory measurement is of pivotal importance in reducing Lp(a) associated risk. The consensus statement by HEART UK in 2019 included recommendations to improve standardisation of clinical laboratory measurement and reporting of Lp(a). A 16 question, electronic audit survey was circulated to 190 accredited clinical biochemistry laboratories to assess the adoption of these recommendations in the UK. Responses were received from 65 of 190 laboratories (34%). Only 5 (8%) did not offer Lp(a) measurement. Of those providing the test, 23% (n = 14) offered an in-house service (IHS), the remaining laboratories (77%; n = 46) used an external referral service (ERS). The majority (10 of 14 or 71%) of IHS laboratories responded with details of their method, stating whether it minimised sensitivity to the effect of Lp(a) isoform size and used calibrators certified for traceability to the WHO/IFCC reference material, however, only a minority ERS laboratories (13 of the 46 or 28%) were able to specify the method used by their referral laboratory. Of the laboratories who specified their reporting units, 6 of 10 IHS and 7 of 23 ERS laboratories reported in nmol/L. Among the 60 laboratories who responded, the HEART UK recommendations appear to have been adopted in full by only 3 IHS laboratories. Further efforts are needed to standardise the measurement and reporting of Lp(a) so that results and interpretation are comparable across clinical biochemistry laboratories in the UK.


Causes of Artificial Urinary Sphincter Failure and Strategies for Surgical Revision: Implications of Device Component Survival.
Up to 50% of patients receiving an artificial urinary sphincter (AUS) require surgical revision after initial placement. However, the literature is heterogeneous regarding the leading causes of AUS failure and appropriate surgical management. To inform a revision approach by tabulating the causes of AUS failure, assessing AUS component survival, and examining the single-component revision efficacy. We retrospectively reviewed 168 patients receiving AUS placements carried out by a single surgeon from 2008 to 2016 at a high-volume academic institution. The median follow-up from initial placement was 2.7 yr, with 37.5% experiencing recurrent incontinence. The cuff size ranged from 4.0 to 5.5cm, with median size of 4.5cm. Patients without infection or erosion underwent systematic device interrogation and revision, starting with the pressure-regulating balloon (PRB) and then, if necessary, the urethral cuff. Device revision involved either PRB-only correction or cuff and PRB revision. We used bootstrapped intervals to estimate the mean time to failure for individual AUS components. Kaplan-Meier estimates were used to compare survival for individual components and for revised devices by revision technique. PRB malfunction most commonly caused device failure, while cuff or pump malfunction was rare. Among patients undergoing surgical revision, those with PRB-only correction had similar outcomes to those with more extensive device correction (cuff and PRB exchange; p=0.46). This study, while systematic and detailed, is limited by sample size, follow-up length, and its retrospective nature. PRB malfunction most commonly caused AUS failure in our cohort. PRB-only correction may satisfactorily restore AUS function in select patients. Consequently, initial interrogation of the PRB may avoid a second incision and urethral exposure for many patients requiring AUS revision. Artificial urinary sphincters remain prone to failure over time. In many instances, correcting only the pressure-regulating balloon may effectively restore device function, allowing for a less invasive revision.


Addressing tuberculosis through complex community-based socioeconomic interventions in low- and middle-income countries: A systematic realist review.
The established relationship between poverty and tuberculosis has led to the implementation of complex socioeconomic interventions to address poverty as both a risk factor for and consequence of tuberculosis. However, limited research to date has examined the conditions that facilitate the successful implementation of these interventions. We conducted a systematic realist review to examine how complex socioeconomic interventions for tuberculosis treatment and care were defined, implemented, and evaluated in low- and middle-income countries. We used a systematic search to identify published work that implemented complex socioeconomic interventions for tuberculosis, followed by a realist analysis informed by existing programme theories. From a total of 2825 collected records, 36 peer-reviewed articles and 17 grey literature reports were included in this review. The realist analysis identified three main contexts (sociopolitical and cultural; relational and interpersonal; operational and administrative) and ten mechanisms that facilitated successful implementation of interventions. Overall, this review highlights the importance of political commitment in shaping sustainable programme delivery, the role of healthcare and community-based provider training in creating patient-centred treatment environments, and the opportunity to leverage operational research for evidence-based decision making to address the socioeconomic needs of tuberculosis patients experiencing poverty.


A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion.
γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABA(A)R), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABA(A)R agonist and antagonist. The effect of GABA(A)R antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABA(A)R subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABA(A)R agonist induced an inward current and depolarized IEC-18. Both GABA and the GABA(A)R agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABA(A)R antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which upregulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea.


Netherton's Syndrome: A Case of Two Male Siblings Diagnosed in Adulthood.
Netherton's syndrome (NS) is a rare autosomal recessive genetic disease caused by a germline mutation in the SPINK5 gene. It is most commonly diagnosed in neonates due to the presence of congenital ichthyosiform erythroderma. Affected individuals will typically also develop a hair shaft abnormality known as trichorrhexis invaginata, severe atopy, and a migratory rash known as ichythyosis linearis circumflexa. The chronicity and severity of NS adversely affects a patient's quality of life to a large extent. It Is therefore important that this condition is identified early, and treatment to reduce cutaneous inflammation is initiated in a timely fashion. However, due to this condition being relatively rare, a lack of awareness may lead clinicians to misdiagnose it as atopic dermatitis or undifferentiated psoriasis. Clinicians should therefore be aware of the peripheral stigmata that this disease may present as in adulthood, so that a correct diagnosis can be made if it was previously missed. Here we present a case of two male siblings from Jordon who were misdiagnosed since childhood as having erythrodermic psoriasis. Clinical examination of one of the siblings, as an adult, revealed multiple peripheral features associated with NS. Genetic analysis through sanger sequencing was also able to identify a mutation in the SPINK5 gene, confirming the diagnosis.


[Shotgun injury of head and neck: case report].
A 48-year-old male was hit by a shotgun blast from behind while he was hunting. He was only 7 meters away when one of his colleagues pulled the trigger accidentally. About 180 lead pellets penetrated his head and neck. When he was brought to our hospital, he was alert and complained of occipital and nape pain, but had no apparent neurological deficits. We administered 200 mg of dimercaprol immediately and removed 77 pellets by midline suboccipital incision on the next day. Afterwords, we performed four minor operations using a fluoroscope, and removed another 70 pellets by day 29. In addition, we administered a 100 mg x 3 dose of dimercaprol every other week. He was discharged 41 days after the accident without any acute signs of lead poisoning. Though serum lead level did not rise to critical level, EDTA was continued after his discharge to prevent delayed lead poisoning from the retained pellets. Since we seldom encounter this type of patient in Japan, delayed lead poisoning by shotgun injury was discussed with reference to the literature.


The role of deformability in determining the structural and mechanical properties of bubbles and emulsions.
We perform computational studies of jammed particle packings in two dimensions undergoing isotropic compression using the well-characterized soft particle (SP) model and deformable particle (DP) model that we developed for bubbles and emulsions. In the SP model, circular particles are allowed to overlap, generating purely repulsive forces. In the DP model, particles minimize their perimeter, while deforming at fixed area to avoid overlap during compression. We compare the structural and mechanical properties of jammed packings generated using the SP and DP models as a function of the packing fraction ρ, instead of the reduced number density φ. We show that near jamming onset the excess contact number Δz = z - zJ and shear modulus G scale as Δρ0.5 in the large system limit for both models, where Δρ = ρ - ρJ and zJ ≈ 4 and ρJ ≈ 0.842 are the values at jamming onset. Δz and G for the SP and DP models begin to differ for ρ ⪆ 0.88. In this regime, Δz ∼ G can be described by a sum of two power-laws in Δρ, i.e. Δz ∼ G ∼ C0Δρ0.5 + C1Δρ1.0 to lowest order. We show that the ratio C1/C0 is much larger for the DP model compared to that for the SP model. We also characterize the void space in jammed packings as a function of ρ. We find that the DP model can describe the formation of Plateau borders as ρ → 1. We further show that the results for z and the shape factor A versus ρ for the DP model agree with recent experimental studies of foams and emulsions.


Expression and clinical significance of microRNA-376a in colorectal cancer.
The incidence of colorectal cancer (CRC) is increasing in many Asian countries and microRNAs have already been proven to be associated with tumorigenesis. Currently, microRNA-376a (miR-376a) expression and association with clinical factors in CRC remains unclear. In this study, real-time quantitative reverse transcriptase- polymerase chain reaction (qRT-PCR) was carried out on 53 matched pairs of CRC and adjacent normal mucosa to investigate the expression levels of miR-376a. According to the high or low expression of miR-376a, patients were divided into two groups. The relationship between miR-376a expression and clinicopathological factors of 53 patients was evaluated. Survival analysis of 53 CRC patients was performed with clinical follow- up information and survival curves were assessed by the Kaplan-Meier method. Immunohistochemistry (IHC) staining was performed on sections of paraffin-embedded tissue to investigate the vascular endothelial growth factor (VEGF) expression. MiR-376a showed low expression in cancer tissues compared to the adjacent normal tissues and altered high miR-376a expression tended to be positively correlated with advanced lymph node metastasis and shorter patient survival. VEGF IHC positivity was significantly more common in patients with high expression levels of miR-376a.Those results demonstrated that miR-376a may be a meaningful prognostic biomarker and potential therapeutic target in colorectal cancer.


Modeling the Biodegradability of Chemical Compounds Using the Online CHEmical Modeling Environment (OCHEM).
Biodegradability describes the capacity of substances to be mineralized by free-living bacteria. It is a crucial property in estimating a compound's long-term impact on the environment. The ability to reliably predict biodegradability would reduce the need for laborious experimental testing. However, this endpoint is difficult to model due to unavailability or inconsistency of experimental data. Our approach makes use of the Online Chemical Modeling Environment (OCHEM) and its rich supply of machine learning methods and descriptor sets to build classification models for ready biodegradability. These models were analyzed to determine the relationship between characteristic structural properties and biodegradation activity. The distinguishing feature of the developed models is their ability to estimate the accuracy of prediction for each individual compound. The models developed using seven individual descriptor sets were combined in a consensus model, which provided the highest accuracy. The identified overrepresented structural fragments can be used by chemists to improve the biodegradability of new chemical compounds. The consensus model, the datasets used, and the calculated structural fragments are publicly available at http://ochem.eu/article/31660.


Induction of lung lysyl oxidase activity and lysyl oxidase protein by exposure of rats to cadmium chloride: properties of the induced enzyme.
Inspiration of CdCl2 results in a focally fibrotic response in rat lungs and markedly increases the activity of lung lysyl oxidase. Western blot analyses of urea-extractable rat lung proteins revealed that the levels of an immunoreactive, 32,000-Da protein were markedly increased in the cadmium-exposed rat lung tissue, consistent with the induction of lysyl oxidase protein. Anion exchange chromatography revealed low levels of multiple peaks of catalytically functional lysyl oxidase in control rat lung extracts, while the profile of cadmium-exposed rat lung extracts displayed markedly elevated levels of multiple peaks of enzyme activity indicating that the charge heterogeneity is expressed in the activated enzyme. The cadmium-induced enzyme was purified as a species of 32 kDa, without resolving individual ionic variants. The catalytic and physical properties of the isolated enzyme were very similar to those of previously well characterized basal enzyme of bovine aorta, including the presence of a pyrroloquinoline quinone-like carbonyl cofactor. The copper and cadmium content of the cadmium-induced enzyme indicated little if any replacement of tightly-bound copper by cadmium in the exposed lung.


[Insulin resistance: organ manifestations and cellular mechanisms].
Insulin resistance is an important issue in the understanding of the metabolic syndrome. Clinical insulin resistance is usually defined by reduced insulin-mediated uptake of glucose in skeletal muscle. However, new studies have shown that liver and fat cells may also develop insulin resistance in subjects with the metabolic syndrome, specifically when these subjects are hyperglycaemic. New investigations also indicate that the endothelial cell itself can be insulin-resistant, reduced blood flow and increased peripheral resistance as the outcome. Insulin resistance may not only induce hyperglycaemia, but also dyslipidaemia (increased plasma levels of free fatty acids and triglyceride, and reduced plasma HDL levels) and arterial hypertension. All these variables may provoke arteriosclerosis and ischaemic heart disease. Specifically, abdominal adiposity seems to be responsible for insulin resistance in subjects with the metabolic syndrome. The mechanism could be intracellular accumulation of acyl CoA and triglyceride. However, an increased production of peptides from the adipose tissue, such as TNF alpha and reduced production of adiponectine may also play a role. The mechanism by which FFA and triglyceride, together with the peptides mentioned, may induce insulin resistance at a cellular level, resulting in reduced glucose transport and intracellular glucose processing, is still being discussed. A change in the insulin signalling cascade is one possibility, but the results so far have been contradictory. Another possibility is, of course, that the cellular accumulation of acyl CoA itself intervenes with gene expression and with phosphorylation of proteins.


Mexicanolide-type limonoids from the seeds of Swietenia macrophylla.
Three new mexicanolide-type limonoids, 3-O-propionylproceranolide (1), 6-O-acetylswietenin B (2), and 6-deoxyswietemahonin A (3), together with 15 known limonoids, were isolated from the seeds of Swietenia macrophylla (Meliaceae). The structures of those new compounds were established by extensive analysis of MS, 1D, and 2D NMR spectral data.


An observation of assisted living environments: space use and behavior.
Assisted living facilities have become increasingly popular for older adults needing assistance. They are intended to enable privacy and provide support, but the extent to which they do so, and the degree to which these relate to residents' needs, are unknown. This observational study of 1830 residents in 182 facilities indicates that, during the mid-afternoon, the majority of residents are awake (79%), and one-half (49%) are awake and in public spaces. Residents who are cognitively and functionally impaired are more likely to be in public spaces, but less likely to be engaged. Residents who are awake and alone in private spaces are less likely to be impaired, but more likely to have medical conditions. Thus, residents needing more oversight seem to be positioned to obtain that oversight.


Nobiletin, a polymethoxylated flavonoid from citrus, shows anti-angiogenic activity in a zebrafish in vivo model and HUVEC in vitro model.
Traditional Chinese medicinal herbs are a rich source of compounds with reported anti-inflammatory and anti-carcinogenic effects. Growing evidence shows the codependence of chronic inflammation and angiogenesis, and the potential benefits of targeting angiogenesis in the treatment of chronic inflammation and targeting inflammation in the treatment of diseases with impaired angiogenesis. We hypothesized that the anti-inflammatory activity of the natural compounds may owe at least some of its efficacy to their anti-angiogenic activity and hence we investigated the anti-angiogenic activity of these compounds in vivo in zebrafish embryos and in vitro in human umbilical vein endothelial cells (HUVECs). Nobiletin, a polymethoxylated flavonoid from citrus fruits, showed anti-angiogenic activity in both assays. Nobiletin inhibited the formation of intersegmental vessels (ISVs) in live transgenic zebrafish embryos expressing green fluorescent protein (GFP) in the vasculature. Cell cycle analysis of dissociated zebrafish embryo cells showed that nobiletin induced G0/G1 phase accumulation in a dose-dependent manner in GFP-positive endothelial cells. Nobiletin also dose-dependently induced VEGF-A mRNA expression. In HUVECs, nobiletin inhibited endothelial cell proliferation and, to a greater extent, tube formation in a dose-dependent manner. As in the in vivo study, nobiletin induced G0/G1 cell cycle arrest in HUVECs. However, this arrest was not accompanied by an increase in apoptosis, indicating a cytostatic effect of nobiletin. This study, for the first time, identifies nobiletin as having potent anti-angiogenic activity and suggests that nobiletin has a great potential for future research and development as a cytostatic anti-proliferative agent.


[Possibility of uterus transplantation trial in Czech Republic - indications, research and clinical experience].
Uterus transplantation is a novel experimental method of female infertility treatment. It is an appropriate treatment modality for women with absolute uterine factor infertility - congenital uterine malformations, absent uterus, hysterectomized women and non-functional uterus.Successful animal studies confirming the safety and efficacy were performed before introduction of uterus transplantation into human medicine. The first clinical trial was performed in 2012-2013 in Gothenburg, Sweden. The first child from the transplanted womb was delivered in 2014. Concerning the promising results of Swedish trial it is essential to perform trials in some other world centers.In 2015 Czech Ministry of Health permitted uterus transplantation trial in cooperation of two Prague hospitals - namely Institute for Clinical and Experimental Medicine and University Hospital Motol. The aim of the Czech trial is to reassert feasibility, efficacy and safety of uterus transplantation in two groups of women - 10 recipients from living and 10 from deceased brain donor. We believe that detailed and precise long-term theoretic and practical preparation and perfectly arranged trial are the main conditions of the successful uterine transplantation survey. The first Czech uterus transplantation was performed in April 30, 2016.Up to December 2016 four transplantations out of planned 20 (2 in living donor and 2 in deceased brain donor arm) were carried out by our team.


In vitro and in vivo activity of 1-aryl-3-(2-chloroethyl) urea derivatives as new antineoplastic agents.
A few 1-aryl 3-(2-chloroethyl)ureas (CEU) were synthesized and screened in vitro for their cytotoxicity. Some of these derivatives were assayed for their mutagenicity, their in vivo toxicity and their antineoplastic activity. Methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tertbutyl (3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tert-butyl (3-(2-chloroethyl) ureido) benzene had an ID50 of 28, 20 and 4 microM respectively when tested on LoVo cells, while chlorambucil (CBL) and CCNU had an ID50 of 21 and 45 microM. These 3 chloroethyl urea derivatives were not toxic when injected i.p. at doses up to 220 mg/kg, whereas chlorambucil was already toxic at 18.5 mg/kg. The survival time of BDF1 mice bearing L1210 leukemia tumors was significantly enhanced by intraperitoneal injections of CBL and CEU. The most cytotoxic derivative (tert-butyl derivative) gave the best antineoplastic activity with a median survival time 1.77 times that of the control at 10 mg/kg/day and was not toxic, whereas CBL at this concentration enhanced survival time by a factor of 1.6 and presented important side effects. The 4-tert-butyl (3-(2-chloroethyl) ureido) benzene and the methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate showed no mutagenicity when assayed on TA-97, TA-98, TA-100 and TA-102, four strains of S. thyphimurium, while CBL had a weak effect on TA-102 and CCNU was highly mutagenic on TA-100 and TA-102.


High efficiency active Q-switched laser operation with a large size rectangular core crystalline waveguide.
High efficient pulse output from a large size rectangular core crystalline waveguide actively Q-switched laser was achieved experimentally. A crystalline waveguide, with a rectangular core size of 320μm×400μm by 1.0at.% Yb:YAG (core), 600μm×600μm by 0.5at.% Er:YAG (cladding), and 7mm×7mm by 4.0at.% V:YAG (outside of the cladding) was designed and fabricated. Using a continuous diode laser as an end pump, an output pulse energy 1.75mJ@10kHz, pulse width 9.9ns (peak power 175kW), optical-optical efficiency 26%, with the beam quality of Mx2=1.15, My2=1.10, were obtained in the experiment. The design method that used to suppress amplified spontaneous emission (ASE) and parasitic oscillation by cutting off the reflection and transmission paths, can be applied for various kinds of crystalline waveguide Q-switched or mode-locked lasers.


In Vivo Piggybac-Based Gene Delivery towards Murine Pancreatic Parenchyma Confers Sustained Expression of Gene of Interest.
The pancreas is a glandular organ that functions in the digestive system and endocrine system of vertebrates. The most common disorders involving the pancreas are diabetes, pancreatitis, and pancreatic cancer. In vivo gene delivery targeting the pancreas is important for preventing or curing such diseases and for exploring the biological function of genes involved in the pathogenesis of these diseases. Our previous experiments demonstrated that adult murine pancreatic cells can be efficiently transfected by exogenous plasmid DNA following intraparenchymal injection and subsequent in vivo electroporation using tweezer-type electrodes. Unfortunately, the induced gene expression was transient. Transposon-based gene delivery, such as that facilitated by piggyBac (PB), is known to confer stable integration of a gene of interest (GOI) into host chromosomes, resulting in sustained expression of the GOI. In this study, we investigated the use of the PB transposon system to achieve stable gene expression when transferred into murine pancreatic cells using the above-mentioned technique. Expression of the GOI (coding for fluorescent protein) continued for at least 1.5 months post-gene delivery. Splinkerette-PCR-based analysis revealed the presence of the consensus sequence TTAA at the junctional portion between host chromosomes and the transgenes; however, this was not observed in all samples. This plasmid-based PB transposon system enables constitutive expression of the GOI in pancreas for potential therapeutic and biological applications.


Immunoblot analysis of the serological response in systemic candidosis.
To investigate the heterogeneity in antibody response to the various antigenic determinants of Candida albicans in patients with disseminated candidosis 201 serial serum samples from 45 patients with proven systemic candidosis were examined by immunoblotting (Western blotting) for antibodies to C albicans type A NCTC 3153. 40 patients had detectable antibody. 26 different antigen bands, ranging from 104 kD to 23 kD, were identified. Despite wide variation in the antigens recognised by different patients, the antibody responses fell into six patterns (A to F). 13 patients infected during an outbreak of systemic candidosis gave the same response (A). Of a further 7 patients with this response, 2 had isolates indistinguishable from the outbreak strain. Group B responses were associated with leukaemias and lymphomas. Groups C-F responses were seen in 9 patients. Production of antibody to a 47 kD antigen, common to all six groups, occurred in all those who recovered from the infection and may therefore be of prognostic significance. Whether this antigen could be used as the basis of a vaccine remains to be determined.


Discontinuous change of shear modulus for frictional jammed granular materials.
The shear modulus of jammed frictional granular materials with harmonic repulsive interaction under an oscillatory shear is numerically investigated. It is confirmed that the storage modulus, the real part of the shear modulus, for frictional grains with sufficiently small strain amplitude γ_{0} discontinuously emerges at the jamming transition point. The storage modulus for small γ_{0} differs from that of frictionless grains even in the zero friction limit, whereas they are almost identical with each other for sufficiently large γ_{0}, where the transition becomes continuous. The stress-strain curve exhibits a hysteresis loop even for a small strain, which connects a linear region for sufficiently small strain to another linear region for larger strain. We propose a scaling law to interpolate between the states of small and large γ_{0}.


Personalized treatment in heart transplantation.
We are entering the era of personalized medicine, in which pharmacogenomics and biomarker-based assays can be used to tailor diagnostic tests and drug therapies to individual patients. This new approach to patient-specific care offers the potential to maximize the efficacy of available medical treatments while reducing the incidence of adverse side effects. Here, we present approaches to personalize the care of heart transplant recipients. Four strategies for personalized posttransplant care are described, including use of pharmacogenomic data to individualize the use of immunosuppressive drugs, immune monitoring to prevent acute rejection while reducing the long-term consequences of over immunosuppression, noninvasive surveillance for acute rejection, and targeted prophylaxis against opportunistic infections. The long-term survival of heart transplant recipients is limited by side effects of immunosuppressive drugs, including infectious complications, renal dysfunction, and malignancy. We discuss strategies to maximize the benefits of immunosuppressive and prophylactic therapies while minimizing their long-term toxicities.


Soft lithographic printing of patterns of stretched DNA and DNA/electronic polymer wires by surface-energy modification and transfer.
Aligned and stretched lambda DNA is directed to specific locations on solid substrates. Surface-energy modification of glass substrates by using patterned polydimethylsiloxane (PDMS) stamps is used to direct DNA onto the surface-energy-modified micrometer-scale pattern through molecular combing. As an alternative, patterned and nonpatterned PDMS stamps modified with polymethylmethacrylate (PMMA) are utilized to direct the stretched DNA to the desired location and the results are compared. The DNA is elongated through molecular combing on the stamp and transfer printed onto the surfaces. PMMA-modified stamps show a more defined length of the stretched DNA, as compared to bare PDMS stamps. A combination of these two methods is also demonstrated. As an application example, transfer printing of DNA decorated with a semiconducting conjugated polyelectrolyte is shown. The resulting patterned localization of stretched DNA can be utilized for functional nanodevice structures, as well as for biological applications.


A non-phenol-chloroform extraction of double-stranded RNA from plant and fungal tissues.
Double-stranded RNA (dsRNA) molecules of viruses are found in nature at a very high frequency. Their detection in plants and fungi has been carried out with difficulty due to the complicated dsRNA extraction techniques used commonly which includes phenol-chloroform extractions. In this study, an extraction method for isolation of dsRNA is described that is free of phenol and chloroform. A lysis buffer, containing beta-mercaptoethanol and polyvinylpolypyrrolidone (PVPP-40), was added to homogenised tissues and the subsequent supernatant was filtered through a cellulose CF-11 mini-column. DsRNA molecules were separated based on the differing affinity of nucleic acids for the cellulose CF-11 resin in 20% ethanol buffer. This easy, rapid and cheap technique has been successfully tested on fungi and plants containing different dsRNA virus molecules, indicating the possibility of a wide use of the method.


[The effects of grape seed and coriander oil on biochemical parameters of oral fluid in patients with periodontitis].
Biochemical changes that are taking place in patients with periodontitis 1 and 2 the quality of the individuals place in a laqtatdegidrogenazis, alkaline phosphatase activity increase and reduced activity amilazais. Therefore we can conclude that, there is an increase in superoxide substances, which causes an increase in the oral cavity patobakteriebis and quality of periodontitis. The grape seed and coriander oil is of vegetable origin and antioxidant drugs. Their action causes a statistically significant increase in the amilazis, alkaline phosphatase and laqtatdegidrogenazis reduction, while the latter leads pH - rate of return to oral fluid. It should be noted that the positive effect of coriander oil, but less effective.


Use of the orbital fat pad in eyelid reconstruction.
Eyelid reconstruction, though challenging, can produce a functional, esthetically pleasing lid. This should preferably be accomplished with a one-stage procedure, using robust, well-vascularized tissues similar to those being replaced, with minimal associated donor morbidity. According to the experience with Bichat pedicled flap in oral reconstruction, the authors propose the use of pedicle infraorbital fat pad for repair of conjunctival defect. Seven patients underwent eyelid reconstruction of full-thickness oncological or post-traumatic defects. In all cases, the reconstruction involved an orbital fat pad flap for the posterior lamella in addition to local flaps for the anterior lamella. All of the flaps survived. The transferred fat flap had a complete epithelization, histologically documented. No tumor relapse occurred in oncological cases. The results have been satisfactory both for clinical evaluation and for the patients. Reconstruction of the palpebral inner lamella with the orbital fat pad is a simple and low-morbidity procedure that has good morphological and functional results.


Antibiotic-in-Cyclodextrin-in-Liposomes: Formulation Development and Interactions with Model Bacterial Membranes.
Gram-negative bacteria possess numerous defenses against antibiotics, due to the intrinsic permeability barrier of their outer membrane (OM), explaining the recalcitrance of some common and life-threatening infections. We report the formulation of a new drug, PPA148, which shows promising activity against all Gram-negative bacteria included in the ESKAPEE pathogens. PPA148 was solubilized by inclusion complexation with cyclodextrin followed by encapsulation in liposomes. The complex and liposomal formulation presented increased activity against E. coli compared to the pure drug when assessed with the Kirby Bauer assay. The novel formulation containing 1 μg PPA148 reached similar efficacy levels equivalent to those of 30 μg of pure rifampicin. A range of biophysical techniques was used to explore the mechanism of drug uptake. Langmuir trough (LT) and neutron reflectivity (NR) techniques were employed to monitor the interactions between the drug and the formulation with model membranes. We found evidence for liposome fusion with the model Gram-negative outer membrane and for cyclodextrins acting as inner membrane (IM) permeation enhancers without presenting intrinsic antimicrobial activity. An antibiotic-in-cyclodextrin-in-liposomes (ACL) formulation was developed, which targets both the bacterial OM and IM, and offers promise as a means to breach the Gram-negative cell envelope.


[Clinical and prognostic characteristics in patients with eosinophilic granulomatosis with polyangitis].
Objective: To analyze the clinical and prognostic characteristics in patients with eosinophilic granulomatosis with polyangitis (EGPA). Methods: The clinical data of 146 EGPA patients hospitalized in Peking Union Medical College Hospital from 2000 to 2019 were analyzed retrospectively, including clinical manifestations, laboratory results, treatment, complications and outcome at discharge. Birmingham Vasculitis activity score-V3 (BVAS-V3) was used to evaluate disease activity. Results: The ratio of male to female was 1.8∶1 with average age (41.7±16.1) year-old. The median time from disease onset to diagnosis was 18(6, 60) months (0.5~450). The most common clinical manifestations were lung [121(82.9%)] and nose/paranasal sinuses [119(81.5%)] involvement. The positive rate of anti-neutrophil cytoplasmic antibody (ANCA) was 24.7%, mainly peripheral (P)-ANCA/myeloperoxidase (MPO)-ANCA. Compared with ANCA-negative patients, the ANCA-positive patients had a higher incidence of renal involvement and nervous system involvement (66.7% vs. 20.9%, 80.6% vs. 51.8%, P<0.001), fever and optic neuropathy (66.7% vs. 40.9%,8.3% vs. 0, P<0.05), more active disease [median BVAS-V3 25(18,30)vs. 19(14,24),P=0.001] and more elevated erythrocyte sedimentation rate [40.5(20.5,82.8)mm/1h vs. 25.0(13.3,50.8)mm/1h,P=0.006] and C-reactive protein [37.1(11.8,72.9)mg/L vs.13.5(3.4,66.1)mg/L,P=0.036]. More ANCA-negative patients had pleural effusion (20.9% vs. 5.6%, P<0.04) compared with ANCA-negative patients. Pulmonary infection was the most common complication. A total of 12 EGPA patients (8.2%)achieved remission and 6 patients (4.1%)died or discharged themselves from the hospital. Conclusion: EGPA is a rare small vessel vasculitis. The clinical manifestations and outcomes are heterogenous. The mortality rate of EGPA is high.


Expression profiles of mouse Kell, XK, and XPLAC mRNA.
Kell and XK are related because in red cells they exist as a disulfide-bonded complex. Kell is an endothelin-3-converting enzyme, and XK is predicted to be a transporter. Absence of XK, which is accompanied by reduced Kell on red cells, results in acanthocytosis and late-onset forms of central nervous system and neuromuscular abnormalities that characterize the McLeod syndrome. In this study, expression of mouse XK, XPLAC, a homolog of XK, and Kell were compared by in situ hybridization histochemistry (ISHH) and RT-PCR. ISHH showed that Kell and XK are coexpressed in erythroid tissues. ISHH detected XK, but not Kell, mRNA in testis, but RT-PCR indicated that both Kell and XK are coexpressed. XK, but not Kell, was significantly expressed in brain, spinal cord, small intestine, heart, stomach, bladder, and kidney. ISHH did not detect XK in skeletal muscle but RT-PCR did. In brain, XK was predominantly expressed in neuronal rather than in supportive cells. By contrast, XPLAC was predominantly expressed in the thymus. Coexpression of Kell and XK in erythroid tissues and the different expressions in non-erythroid tissues suggest that XK may have a complementary hematological function with Kell and a separate role in other tissues.


Innovative approaches to treat Staphylococcus aureus biofilm-related infections.
Many bacterial infections in humans and animals are caused by bacteria residing in biofilms, complex communities of attached organisms embedded in an extracellular matrix. One of the key properties of microorganisms residing in a biofilm is decreased susceptibility towards antimicrobial agents. This decreased susceptibility, together with conventional mechanisms leading to antimicrobial resistance, makes biofilm-related infections increasingly difficult to treat and alternative antibiofilm strategies are urgently required. In this review, we present three such strategies to combat biofilm-related infections with the important human pathogen Staphylococcus aureus: (i) targeting the bacterial communication system with quorum sensing (QS) inhibitors, (ii) a 'Trojan Horse' strategy to disturb iron metabolism by using gallium-based therapeutics and (iii) the use of 'non-antibiotics' with antibiofilm activity identified through screening of repurposing libraries.


Who's afraid of growing old? Gay and lesbian perceptions of aging.
This article is a study of how gay men and lesbian individuals perceive the aging process. The findings indicate that gay men have more negative views of how gay society views growing older and how they view their own growing older than do lesbian respondents. Gay men were also found to be more ageist, have a greater fear of negative evaluation by others, and give more importance to their own physical attractiveness. Implications for social work practice with elder homosexuals are addressed.


Acquisition of granzyme B and Fas ligand proteins by human keratinocytes contributes to epidermal cell defense.
In vertebrate tissues, cell integrity is maintained by at least three mechanisms. During an immune response, injured cells are eliminated by cytotoxic lymphoid cells that produce perforin, granzyme B, and Fas ligand (FasL). Second, epithelial cells can produce FasL as an immunosuppressive protein, probably to protect the tissue against immune-mediated damage. Third, locally secreted antimicrobial peptides can be operative in the protection of animal and human epithelia. In this work, as another contribution to local mechanisms of host defense, the ability of human epidermal keratinocytes to produce cytotoxic proteins was investigated. To address this question, freshly isolated human epidermal cells and keratinocytes grown in vitro were studied. Freshly isolated epidermal cells did not express the cytolytic proteins. In contrast, keratinocyte growth to confluence was associated with granzyme B, perforin, and FasL mRNA and protein synthesis. These proteins were secreted in the culture medium. Further analysis showed that they were identical with the ones used by cytotoxic lymphocytes. Their function was then investigated with a view to a potential role in epidermal cell integrity. The data showed that activated human keratinocytes were able to protect against invading pathogens through granzyme B expression. This was demonstrated by the ability of granzyme B to greatly decrease the bacterial growth of Staphylococcus epidermidis. In addition, keratinocytes expressing FasL were found to prevent immune epidermal cell damage. Apoptosis of Fas-sensitive T cells occurred during coculture with confluent epidermal keratinocytes and was largely reduced by the addition of a FasL inhibitor. The data favor keratinocyte involvement in the regulation of dermal inflammatory responses.


Balanced scorecard-based performance evaluation of Chinese county hospitals in underdeveloped areas.
Objective Since the Guangxi government implemented public county hospital reform in 2009, there have been no studies of county hospitals in this underdeveloped area of China. This study aimed to establish an evaluation indicator system for Guangxi county hospitals and to generate recommendations for hospital development and policymaking. Methods A performance evaluation indicator system was developed based on balanced scorecard theory. Opinions were elicited from 25 experts from administrative units, universities and hospitals and the Delphi method was used to modify the performance indicators. The indicator system and the Topsis method were used to evaluate the performance of five county hospitals randomly selected from the same batch of 2015 Guangxi reform pilots. Results There were 4 first-level indicators, 9 second-level indicators and 36 third-level indicators in the final performance evaluation indicator system that showed good consistency, validity and reliability. The performance rank of the hospitals was B > E > A > C > D. Conclusions The performance evaluation indicator system established using the balanced scorecard is practical and scientific. Analysis of the results based on this indicator system identified several factors affecting hospital performance, such as resource utilisation efficiency, medical service price, personnel structure and doctor-patient relationships.


The effect of lesion filling on brain network analysis in multiple sclerosis using structural magnetic resonance imaging.
Graph theoretical network analysis with structural magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients can be used to assess subtle changes in brain networks. However, the presence of multiple focal brain lesions might impair the accuracy of automatic tissue segmentation methods, and hamper the performance of graph theoretical network analysis. Applying "lesion filling" by substituting the voxel intensities of a lesion with the voxel intensities of nearby voxels, thus creating an image devoid of lesions, might improve segmentation and graph theoretical network analysis. This study aims to determine if brain networks are different between MS subtypes and healthy controls (HC) and if the assessment of these differences is affected by lesion filling. The study included 49 MS patients and 19 HC that underwent a T1w, and T2w-FLAIR MRI scan. Graph theoretical network analysis was performed from grey matter fractions extracted from the original T1w-images and T1w-images after lesion filling. Artefacts in lesion-filled T1w images correlated positively with total lesion volume (r = 0.84, p < 0.001) and had a major impact on grey matter segmentation accuracy. Differences in sensitivity for network alterations were observed between original T1w data and after application of lesion filling: graph theoretical network analysis obtained from lesion-filled T1w images produced more differences in network organization in MS patients. Lesion filling might reduce variability across subjects resulting in an increased detection rate of network alterations in MS, but also induces significant artefacts, and therefore should be applied cautiously especially in individuals with higher lesions loads.


Indinavir Plus Methylprednisolone Ameliorates Experimental Acute Lung Injury In Vitro and In Vivo.
An abnormal HMGB1 activation plays a key role in the pathogenesis of ALI. In this study, the effects of Indinavir plus methylprednisolone on the LPS-mediated activation in human pulmonary microvascular endothelial cells (HPMECs), on the injury of AT I in vitro, and on rats with LPS-induced two-hit model with or without methylprednisolone were investigated. Indinavir treatment resulted in a reduction of HMGB1, its receptor TLR-4, and HMGB1's downstream p-NF-κB, attenuating a decrease of VE-cadherin in LPS-stimulated HPMECs. Apoptosis of AT I was attenuated with an increase of RAGE and aquaporin 5. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm and avoid GRα deficiency in LPS-stimulated HPMECs for 96 h, attenuated the increase of p-NF-κB in nucleus. Indinavir ameliorated histopathological changes of two-hit ALI model of rats with reductions in microvascular permeability, lower HMGB1, TLR4, p-NF-κB, and MPO expression, whereas higher RAGE, aquaporin 5, and VE-cadherin in LPS-instilled lungs. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm, decreased p-NF-κB in nucleus of lung tissue of two-hit ALI rats, and enhanced the anti-inflammatory effect of methylprednisolone for avoiding GRα deficiency. It demonstrated that Indinavir prevented experimental ALI model of rats by modulating the HMGB1/TLR-4 pathway to resolve systemic inflammation response in a greater degree with methylprednisolone, reduced the use time and dose of methylprednisolone, and avoided GRα deficiency in ALI and ARDS.


Modular discovery of monomeric and dimeric transcription factor binding motifs for large data sets.
In some dimeric cases of transcription factor (TF) binding, the specificity of dimeric motifs has been observed to differ notably from what would be expected were the two factors to bind to DNA independently of each other. Current motif discovery methods are unable to learn monomeric and dimeric motifs in modular fashion such that deviations from the expected motif would become explicit and the noise from dimeric occurrences would not corrupt monomeric models. We propose a novel modeling technique and an expectation maximization algorithm, implemented as software tool MODER, for discovering monomeric TF binding motifs and their dimeric combinations. Given training data and seeds for monomeric motifs, the algorithm learns in the same probabilistic framework a mixture model which represents monomeric motifs as standard position-specific probability matrices (PPMs), and dimeric motifs as pairs of monomeric PPMs, with associated orientation and spacing preferences. For dimers the model represents deviations from pure modular model of two independent monomers, thus making co-operative binding effects explicit. MODER can analyze in reasonable time tens of Mbps of training data. We validated the tool on HT-SELEX and ChIP-seq data. Our findings include some TFs whose expected model has palindromic symmetry but the observed model is directional.


Thoracic spinal cord injury without radiologic abnormality in a pediatric patient case report.
Spinal Cord Injury Without Radiologic Abnormality (SCIWORA) accounts for up to 19% of spinal cord related lesions in pediatric population, mostly comprising the cervical spine. A 2-year-old patient is presented, who suffered a motor-vehicle accident. After being admitted, neither X-Ray nor spinal TC scan showed any structural abnormalities. Neurological examination showed complete sensory and motor loss under T7 as well as bladder and bowel dysfunction. Magnetic resonance imaging (MRI) showed spinal cord lesion extending from T7 to T10. The patient was treated with external immobilization and physical therapy. Thoracic SCIWORA is an uncommon diagnosis that should be considered in pediatric patients who suffer spinal trauma. Spinal cord MRI has proven to be the most accurate modality for diagnosis.


The effect of hyperbaric oxygen therapy on a burn wound model in human volunteers.
A previous nonblinded study has suggested beneficial effects from hyperbaric oxygen treatment of superficial partial-thickness radiation burns in human volunteers. This protocol was designed to either confirm or challenge these previous findings in a randomized, blinded format. Twelve healthy, nonsmoking volunteers (7 males, 5 females) participated. All were screened for contraindications to hyperbaric oxygen therapy (acute sinusitis, otitis media, pneumonia, pregnancy, active cancer, pneumothorax) and given a single test hyperbaric exposure. A standardized wound model was employed for the painless creation of a volar forearm lesion on volunteers by applying a suction device to form a blister, excising its epidermal roof, and irradiating the exposed dermis with ultraviolet light. Subjects were randomized into either a hyperbaric oxygen group (100% oxygen at 2.4 ATA, n = 6) or the sea-level air-breathing equivalent control group (8.75% oxygen at 2.4 ATA, n = 6). Both groups then underwent standard hyperbaric therapy. The subjects, the hyperbaric oxygen chamber operators, and the monitoring clinicians were all blinded to the oxygen concentration administered. Each subject received two dives per day over a 3-day period. The wounds were studied noninvasively prior to treatment and once per day over 6 days for size, hyperemia, and exudation, with epithelialization as the endpoint. The averages for each measurement of the hyperbaric oxygen group versus the control group were computed by means of a one-tail t test; p was considered significant at less than 0.05. Daily wound size, hyperemia, and exudation measurements were significantly different on day 2. The hyperbaric oxygen group showed a 42 percent reduction in wound hyperemia, a 35 percent reduction in the size of the lesion, and a 22 percent reduction in wound exudation (p values of 0.05, 0.03, and 0.04, respectively). No significant difference was noted for epithelialization. Observed differences in wound size, hyperemia, and exudation were attributable to hyperbaric oxygen therapy. This study further supports earlier conclusions that hyperbaric oxygen therapy is beneficial in a superficial dermal wound.


Intraocular complement activation is related to retinal vascular and neuronal degeneration in myopic retinopathy.
To investigate the relationship between the intraocular levels of complement proteins and myopia-related retinal neuronal and vascular degeneration. Aqueous humour from 147 myopic patients, including 60 low-myopia and 87 high-myopia were collected during Implantable Collamer Lens implantation surgery. All participants received comprehensive ophthalmic examinations, including logMAR best corrected visual acuity, axial length measurement, fundus photography and ocular B-scan ultrasonography. The myopic eyes were further classified into simple myopia (SM, n = 78), myopic posterior staphyloma (PS, n = 39) and PS with myopic chorioretinal atrophy (PS + CA, n = 30). Retinal thickness and vascular density in the macula (6 mm × 6 mm) and optic nerve head (4.5 mm × 4.5 mm) were measured using Optical Coherence Tomography (OCT) and OCT angiography (OCTA). The levels of complement proteins including C1q, C3, C3b/iC3b, C4, CFB, CFH, C2, C4b, C5, C5a, CFD, MBL and CFI in the aqueous humour were measured using the Luminex Multiplexing system. The real-time RT-PCR was conducted to examine the expression of complement genes (C1q, C2, C3, C4, CFI and CFD) in the guinea pig model of long-term form deprivation-induced myopic retinal degeneration. OCTA showed that retinal neuronal thickness and vascular density in superficial and deep layers of the macular zone as well as vascular density in the optic nerve head were progressively decreased from SM to PS and PS + CA (p < 0.05). The aqueous humour levels of C1q, C3, C3b/iC3b, C4, CFB, CFH, C2, C4b, C5 and CFI were significantly higher in high-myopic eyes compared to those in low-myopic eyes. Further subgroup analysis revealed the highest levels of complement components/fragments in the PS + CA group. The intraocular levels of complement factors particularly C3b/iC3b and C4 were negatively correlated with macular zone deep layer retinal thickness and vascular density and optic nerve head vascular density. The expression of C2, C3 and C4 genes was significantly higher in guinea pig eyes with myopic retinal degeneration compared to control eyes. The intraocular classical pathway and alternative pathway of the complement system are partially activated in pathological myopia. Their activation is related to the degeneration of retinal neurons and the vasculature in the macula and the vasculature in the optic nerve head.


The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer.
Epigenetic control of gene expression is mediated by cytosine methylation/demethylation and histone modifications including methylation, acetylation and glycosylation. The epigenetic programme is corrupted in cancer cells to maintain a pattern of gene expression that leads to their de-differentiated, rapidly proliferating phenotype. Enzymes responsible for modifying histones and cytosine are sensitive to the cellular metabolite pool and can be activated by an increase in their substrates or inhibited by an increase in their products or competitors for substrate binding. This review is based on publications identified on PubMed using a literature search of cytosine methylation, histone methylation, acetylation and glycosylation. In cancer, changes in glycolytic enzymes lead to increased production of serine, increasing the pool of S-adenosylmethionine (the major methyl donor for methylation reactions) and UDP-N-acetylglucosamine (a substrate for O-linked glycosylation of histones and cytosine methyltransferases). Mutations in tricarboxylic acid cycle enzymes lead to accumulation of fumarate, succinate and hydroxyglutarate, all of which inhibit demethylation of cytosine and histones. In contrast, proline catabolism produces α-ketoglutarate and reactive oxygen, both of which promote the activity of enzymes that remove methyl groups from cytosine and histones, and the key enzyme in proline catabolism acts as a tumour suppressor. Our emerging understanding of how the epigenetic profiles are metabolically reprogrammed in cancer cells will lead to novel diagnostic and therapeutic targets for treatment of patients.


Lipolysis and beta-adrenergic receptor binding on adipocytes of spontaneously hypertensive rats.
Adipocytes from spontaneously hypertensive rats demonstrated a blunted lipolytic response to isoproterenol and dibutyryl cyclic AMP. (-)-[3H]Dihydroalprenolol binding was examined in adipocytes from normotensive and spontaneously hypertensive rats. Increasing concentrations of isoproterenol decreased total (-)-[3H]dihydroalprenolol binding to intact cells from normotensive rats, and the efficacy of competition was decreased in adipocytes from spontaneously hypertensive rats. Scatchard analysis indicated that the number of (-)-[3H]dihydroalprenolol binding sites and the affinity of dihydroalprenolol binding were comparable between normotensive and spontaneously hypertensive rats. Isoproterenol- and Gpp(NH)p-stimulated adenylate cyclase activity was consistently depressed in adipocyte membranes from spontaneously hypertensive rats as compared to normotensive rats. No difference in fluoride-stimulated adenylate cyclase activity was observed. The blunted lipolytic and cyclic AMP response to isoproterenol in these cells suggest a postreceptor lesion of the lipolytic pathway (possibly the guanine nucleotide regulatory protein) in adipocytes from spontaneously hypertensive rats. The blunted lipolytic response to dibutyryl cyclic AMP suggests defective regulation of lipolytic enzymes at the protein kinase-hormone-sensitive lipase level.


Identification of critical genes in nucleus pulposus cells isolated from degenerated intervertebral discs using bioinformatics analysis.
Intervertebral disc (IVD) degeneration is a pathological process, which may lead to lower back pain. The present study aimed to investigate the pathogenesis of IVD degeneration. GSE42611 was downloaded from Gene Expression Omnibus, including 4 nucleus pulposus samples isolated from degenerated IVDs and 4 nucleus pulposus samples separated from normal IVDs. The differentially expressed genes (DEGs) between the degenerated and normal samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted separately for the upregulated and downregulated genes, using Database for Annotation, Visualization and Integrated Discovery software. In addition, protein‑protein interaction (PPI) networks were constructed using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. Finally, module analyses were conducted for the PPI networks using the MCODE plug‑in in Cytoscape. A total of 558 DEGs were identified in the degenerated nucleus pulposus cells: 253 upregulated and 305 downregulated. Pathway enrichment analysis revealed that downregulated thrombospondin 1 (THBS1) was enriched in extracellular matrix‑receptor interaction. Interleukin (IL)‑6 in the PPI network for the upregulated genes and vascular endothelial growth factor A (VEGFA) in the PPI network for the downregulated genes had higher degrees. Additionally, four modules (µM1, µM2, µM3 and µM4) were identified from the PPI network for the upregulated genes. Four modules (dM1, dM2, dM3 and dM4) were identified from the PPI network for the downregulated genes. In the dM2 module, collagen genes and integrin subunit α4 (ITGA4) may interact with each other. Additionally, functional enrichment indicated that collagen genes were enriched in extracellular matrix organization. In conclusion, IL‑6, VEGFA, THBS1, ITGA4 and collagen genes may contribute to the progression of IVD degeneration. These results suggested that the manipulation of these genes and their products may have potential as a novel therapeutic strategy for the treatment of patients with IVD.


Unusual presentation of sarcoidosis: solitary intracranial mass lesion mimicking an intracranial neoplasm: a case report.
Sarcoidosis is a multisystem disease of unknown cause and with a worldwide distribution. Involvement of the central nervous system occurs in a relatively small number of patients with sarcoidosis. Isolated neurosarcoidosis without signs of systemic disease however is a rare. In this report, we present an unusual case of neurosarcoidosis with intra cranial mass mimicking radiologically a glioma. Pathological examination revealed intraparenchymatous necrotising granulomatous lesions. After clinicopathological correlation, the diagnosis of a necrotizing cerebral granulomatosis (neurosarcoidosis) with atypical systemic involvement was made. Because of its non-specific clinical presentation and neuroradiological imaging characteristics, intracranial neurosarcoidosis remains a very difficult diagnosis, particularly in the absence of systemic signs of the disease.


Oral Health Status and Oral Health-related Quality of Life among Hospitalized and Nonhospitalized Geriatric Patients.
The purpose of this study was to compare the oral health status and its effect on the oral health-related quality of life (OHRQoL) of hospitalized and nonhospitalized elderly patients in a single community. The null hypothesis for the study states that there is no difference in the oral health status and OHRQoL between hospitalized and nonhospitalized elderly patients. This study was conducted at the King Khalid Hospital and College of Dentistry, King Saud University, Riyadh, Kingdom of Saudi Arabia. A total of 99 (43 - hospitalized and 56 - nonhospitalized) geriatric patients participated in this study. Oral health-related quality of life was estimated using the geriatric oral health assessment index questionnaire. Decayed, missing, and filled teeth (DMFT) index and plaque index were used to assess the oral health status of the study participants. The mean age of the study participants was 68.2 years; 17.2% were females and 82.8% were males. There was no significant difference between hospitalized and nonhospitalized patients in OHRQoL and DMFT index. However, the oral hygiene status was better among nonhospitalized patients as compared with hospitalized patients. There was a significant difference in the oral hygiene status between hospitalized and nonhospitalized geriatric patients. Caregivers must be sensitized to the importance of oral health for the elderly population, and oral health should be considered an integral component of general health.


Worries of the oldest-old.
With the emerging population of the oldest-old (those ages 85 and older), it is crucial to understand and prepare for their psychosocial needs. Worry is linked to psychological well-being and physical health, but little is known about the oldest-old's everyday worries. The authors explored four research questions: (1) What are the worries of the oldest-old? (2) What are their specific dimensions of worry? (3) How alike or different are the worry patterns over time? (4) What factors are related to variations in the pattern of change in worry? A convenience sample of 193 community-dwelling people ages 85 and older was recruited to examine various aspects of health and well-being between 1986 and 1995. This article reports on the survivors (N = 23) across three time points, waves 1, 4, and 5. The findings suggest that the very old mainly worry about health and memory and that, although worry increased over the study period, there were variations in the pattern of worry over time. Results of t tests show that at wave 4 elderly respondents with a higher level of worry reported more frequent social contact than those with a lower level of worry. Implications for social work practice and future research are discussed.


Diaphragm function during sighs in awake dogs after laparotomy.
Pulmonary complications after upper abdominal surgery are usually ascribed to temporary postoperative impairment of diaphragm function, which may not originate from intrinsic, structural injury but from reflex inhibition of diaphragm contractility. Spontaneous breathing is interrupted periodically by sighs, even after upper abdominal surgery. If postoperative dysfunction of the diaphragm arises from a reflexic inhibition, then the sigh should temporarily override the inhibition and restore normal diaphragm function. We implanted sonomicrometer and electromyogram transducers chronically in six dogs by laparotomy, then directly measured length, shortening, and electromyogram activity of costal and crural diaphragm segments, parasternal intercostal, and transversus abdominis muscles an average of 8.7 (range, 1-16) d later during resting tidal breathing and sighs. In each animal we analyzed a sequence of breaths, including a sigh, when costal or crural diaphragm contractility was abnormal. With each sigh, the shape and amplitude of costal and crural diaphragm segmental shortening improved abruptly, from 0.9 and 1.4% of baseline length (% LBL) during resting breathing to 12.1 and 11.1% LBL, respectively, during sighs. The sighs were compared to CO2-stimulated breaths of equivalent tidal volume, which did not show either pattern or amplitude of shortening equivalent to sighs. We conclude that diaphragm dysfunction after laparotomy arises from a reflex inhibition, which is overridden abruptly to return diaphragm function briefly to normal during each spontaneous sigh.


A Comparison of LASSO Regression and Tree-Based Models for Delayed Cerebral Ischemia in Elderly Patients With Subarachnoid Hemorrhage.
As a most widely used machine learning method, tree-based algorithms have not been applied to predict delayed cerebral ischemia (DCI) in elderly patients with aneurysmal subarachnoid hemorrhage (aSAH). Hence, this study aims to develop the conventional regression and tree-based models and determine which model has better prediction performance for DCI development in hospitalized elderly patients after aSAH. This was a multicenter, retrospective, observational cohort study analyzing elderly patients with aSAH aged 60 years and older. We randomly divided the multicentral data into model training and validation cohort in a ratio of 70-30%. One conventional regression and tree-based model, such as least absolute shrinkage and selection operator (LASSO), decision tree (DT), random forest (RF), and eXtreme Gradient Boosting (XGBoost), was developed. Accuracy, sensitivity, specificity, area under the precision-recall curve (AUC-PR), and area under the receiver operating characteristic curve (AUC-ROC) with 95% CI were employed to evaluate the model prediction performance. A DeLong test was conducted to calculate the statistical differences among models. Finally, we figured the importance weight of each feature to visualize the contribution on DCI. There were 111 and 42 patients in the model training and validation cohorts, and 53 cases developed DCI. According to AUC-ROC value in the model internal validation, DT of 0.836 (95% CI: 0.747-0.926, p = 0.15), RF of 1 (95% CI: 1-1, p < 0.05), and XGBoost of 0.931 (95% CI: 0.885-0.978, p = 0.01) outperformed LASSO of 0.793 (95% CI: 0.692-0.893). However, the LASSO scored a highest AUC-ROC value of 0.894 (95% CI: 0.8-0.989) than DT of 0.764 (95% CI: 0.6-0.928, p = 0.05), RF of 0.821 (95% CI: 0.683-0.959, p = 0.27), and XGBoost of 0.865 (95% CI: 0.751-0.979, p = 0.69) in independent external validation. Moreover, the LASSO had a highest AUC-PR value of 0.681 than DT of 0.615, RF of 0.667, and XGBoost of 0.622 in external validation. In addition, we found that CT values of subarachnoid clots, aneurysm therapy, and white blood cell counts were the most important features for DCI in elderly patients with aSAH. The LASSO had a superior prediction power than tree-based models in external validation. As a result, we recommend the conventional LASSO regression model to predict DCI in elderly patients with aSAH.


Efficacy of carbon monoxide laser in selectively intimal thermal welding--implications for laser balloon angioplasty.
Excessive vascular damage causes excessive vascular repair, which results in restenosis. To limit the thickness of the coagulation layer in laser balloon angioplasty, we used a carbon monoxide (CO) laser, which has high tissue absorption, as a therapy laser source instead of a Nd: YAG laser. To investigate the benefit of short-penetration CO laser light to vascular tissue, excised human abdominal aorta was irradiated with a CO laser through a 30 microns polyethylene membrane. The temperature of the vascular tissue was continuously monitored during irradiation. CO laser irradiation of 20 W/cm2 was performed in either a continuous mode or an intermittent mode with various duty ratios (exposure/interval duration). With a total fluence of 200 J/cm2, the adventitial temperature decreased as the duty ratio was reduced. The adventitial temperature at a duty ratio of 1:2 was 43 degrees C. Microscopic examination of aorta which had been intermittently irradiated duty ratio of 1:2 showed thermal coagulation localized within the intima and a flattened intimal surface. These results suggest that intermittent laser irradiation with a CO laser can be used to limit the depth of thermal coagulation, and can selectively weld the intima without excessive thermal damage. Laser balloon angioplasty using a CO laser may help to prevent restenosis.


Driver Behavior During Overtaking Maneuvers from the 100-Car Naturalistic Driving Study.
Lane changes with the intention to overtake the vehicle in front are especially challenging scenarios for forward collision warning (FCW) designs. These overtaking maneuvers can occur at high relative vehicle speeds and often involve no brake and/or turn signal application. Therefore, overtaking presents the potential of erroneously triggering the FCW. A better understanding of driver behavior during lane change events can improve designs of this human-machine interface and increase driver acceptance of FCW. The objective of this study was to aid FCW design by characterizing driver behavior during lane change events using naturalistic driving study data. The analysis was based on data from the 100-Car Naturalistic Driving Study, collected by the Virginia Tech Transportation Institute. The 100-Car study contains approximately 1.2 million vehicle miles of driving and 43,000 h of data collected from 108 primary drivers. In order to identify overtaking maneuvers from a large sample of driving data, an algorithm to automatically identify overtaking events was developed. The lead vehicle and minimum time to collision (TTC) at the start of lane change events was identified using radar processing techniques developed in a previous study. The lane change identification algorithm was validated against video analysis, which manually identified 1,425 lane change events from approximately 126 full trips. Forty-five drivers with valid time series data were selected from the 100-Car study. From the sample of drivers, our algorithm identified 326,238 lane change events. A total of 90,639 lane change events were found to involve a closing lead vehicle. Lane change events were evenly distributed between left side and right side lane changes. The characterization of lane change frequency and minimum TTC was divided into 10 mph speed bins for vehicle travel speeds between 10 and 90 mph. For all lane change events with a closing lead vehicle, the results showed that drivers change lanes most frequently in the 40-50 mph speed range. Minimum TTC was found to increase with travel speed. The variability in minimum TTC between drivers also increased with travel speed. This study developed and validated an algorithm to detect lane change events in the 100-Car Naturalistic Driving Study and characterized lane change events in the database. The characterization of driver behavior in lane change events showed that driver lane change frequency and minimum TTC vary with travel speed. The characterization of overtaking maneuvers from this study will aid in improving the overall effectiveness of FCW systems by providing active safety system designers with further understanding of driver action in overtaking maneuvers, thereby increasing system warning accuracy, reducing erroneous warnings, and improving driver acceptance.


Intermittent maintenance therapy in chronic hand eczema with clobetasol propionate and flupredniden acetate.
The clinical effect of two topical corticosteroids, one of very strong potency (clobetasol propionate), and one of medium potency (flupredniden acetate), was studied in the maintenance therapy of 55 patients with chronic hand eczema. Initially, 61 patients were treated on both hands continuously for 1 to 3 weeks with clobetasol only which brought about healing in 90% of cases (mean time to healing: 11 days). In a subsequent double-blind left/right study, the capacity of the two corticosteroids for keeping the dermatitis in remission was compared using an intermittent schedule of 2 applications a week. The protocol was followed by 46 patients and the mean observation period was 138 days. Treatment with clobetasol kept patients free from relapses during the entire observation period in 70%, with flupredniden in 30%. Relapses occurred with clobetasol after a mean of 66 days, with flupredniden after 36 days. Side-effects, occurring with similar frequency with both drugs, were few and mild. It is suggested that an intermittent schedule is advantageous when using a corticosteroid of high potency.


Cholesterol Esterification Inhibition Suppresses Prostate Cancer Metastasis by Impairing the Wnt/β-catenin Pathway.
Dysregulation of cholesterol is a common characteristic of human cancers including prostate cancer. This study observed an aberrant accumulation of cholesteryl ester in metastatic lesions using Raman spectroscopic analysis of lipid droplets in human prostate cancer patient tissues. Inhibition of cholesterol esterification in prostate cancer cells significantly suppresses the development and growth of metastatic cancer lesions in both orthotopic and intracardiac injection mouse models. Gene expression profiling reveals that cholesteryl ester depletion suppresses the metastatic potential through upregulation of multiple regulators that negatively impact metastasis. In addition, Wnt/β-catenin, a vital pathway for metastasis, is downregulated upon cholesteryl ester depletion. Mechanistically, inhibition of cholesterol esterification significantly blocks secretion of Wnt3a through reduction of monounsaturated fatty acid levels, which limits Wnt3a acylation. These results collectively validate cholesterol esterification as a novel metabolic target for treating metastatic prostate cancer. Mol Cancer Res; 16(6); 974-85. ©2018 AACR.


Titratable transmembrane residues and a hydrophobic plug are essential for manganese import via the Bacillus anthracis ABC transporter MntBC-A.
All extant life forms require trace transition metals (e.g., Fe2/3+, Cu1/2+, and Mn2+) to survive. However, as these are environmentally scarce, organisms have evolved sophisticated metal uptake machineries. In bacteria, high-affinity import of transition metals is predominantly mediated by ABC transporters. During bacterial infection, sequestration of metal by the host further limits the availability of these ions, and accordingly, bacterial ABC transporters (importers) of metals are key virulence determinants. However, the structure-function relationships of these metal transporters have not been fully elucidated. Here, we used metal-sensitivity assays, advanced structural modeling, and enzymatic assays to study the ABC transporter MntBC-A, a virulence determinant of the bacterial human pathogen Bacillus anthracis. We find that despite its broad metal-recognition profile, MntBC-A imports only manganese, whereas zinc can function as a high-affinity inhibitor of MntBC-A. Computational analysis shows that the transmembrane metal permeation pathway is lined with six titratable residues that can coordinate the positively charged metal, and mutagenesis studies show that they are essential for manganese transport. Modeling suggests that access to these titratable residues is blocked by a ladder of hydrophobic residues, and ATP-driven conformational changes open and close this hydrophobic seal to permit metal binding and release. The conservation of this arrangement of titratable and hydrophobic residues among ABC transporters of transition metals suggests a common mechanism. These findings advance our understanding of transmembrane metal recognition and permeation and may aid the design and development of novel antibacterial agents.


Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae.
We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.


"I've never asked one question." Understanding the barriers among orthopedic surgery residents to screening female patients for intimate partner violence.
Intimate partner violence (IPV) is a global public health problem. Orthopedic surgery residents may identify IPV among injured patients treated in fracture clinics. Yet, these residents face a number of barriers to recognizing and discussing IPV with patients. We sought to explore orthopedic surgery residents' knowledge of IPV and their preparedness to screen patients for IPV in academic fracture clinic settings with a view to developing targeted IPV education and training. We conducted focus groups with junior and intermediate residents. Discussions explored residents' knowledge of and experiences with IPV screening and preparedness for screening and responding to IPV among orthopedic patients. Data were analyzed iteratively using an inductive approach. Residents were aware of the issue of abuse generally, but had received no specific information or training on IPV in orthopedics. Residents did not see orthopedics faculty screen patients for IPV or advocate for screening. They did not view IPV screening or intervention as part of the orthopedic surgeon's role. Residents' clinical experiences emphasized time management and surgical intervention by effectively "getting through clinic" and "dealing with the surgical problem." Communication with patients about other health issues was minimal or nonexistent. Orthopedic surgery residents are entering a career path where IPV is well documented. They encounter cultural and structural barriers preventing the incorporation of IPV screening into their clinical and educational experiences. Hospitals and academic programs must collaborate in efforts to build capacity for sustainable IPV screening programs among these trainees.


Low-Cost Online Monitoring System for the Etching Process in Fiber Optic Sensors by Computer Vision.
The present research exposes a novel methodology to manufacture fiber optic sensors following the etching process by Hydrofluoric Acid deposition through a real-time monitoring diameter measurement by computer vision. This is based on virtual instrumentation developed with the National Instruments® technology and a conventional digital microscope. Here, the system has been tested proving its feasibility by the SMS structure diameter reduction from its original diameter of 125 μ until approximately 42.5 μm. The results obtained have allowed us to demonstrate a stable state behavior of the developed system during the etching process through diameter measurement at three different structure sections. Therefore, this proposal will contribute to the etched fiber optic sensor development that requires reaching an enhanced sensitivity. Finally, to demonstrate the previously mentioned SMS without chemical corrosion, and the etched manufactured SMS, both have been applied as glucose concentration sensors.


Perspectives on window of opportunity trials in head and neck cancer: lessons from the EORTC 90111-24111-NOCI-HNCG study.
Assessing tumour response using a traditional phase I, II and III trial approach is not without limitations, particularly when targeted therapies are involved. Window of opportunity trials, performed presurgically but differing from neoadjuvant studies, were developed in an attempt to overcome the limitations of the traditional approach. A recent window of opportunity trial, the EORTC 90111-24111-NOCI-HNCG study, evaluated afatinib in treatment-naive patients with squamous cell carcinoma of the head and neck. While this study was the first to demonstrate the activity of afatinib in this setting and to define its potential predictive biomarkers, it also highlighted the challenges associated with the window of opportunity trial design, including the impact of patient selection, tumour site, and other organisational issues. This report details the key learnings from the EORTC 90111-24111-NOCI-HNCG study and provides recommendations to overcome the challenges of this particular trial design.


Neutralizing cross-reactive and non-neutralizing monoclonal antibodies to HIV-1 gp120.
Amino acid sequences inducing neutralizing antibodies to HIV-1 were sought. Murine monoclonal antibodies (MAbs) were characterized by their reactivity with the envelope precursor gp160 or the Escherichia coli recombinant DNA products pB1 and pE3 representing the carboxy- and amino-terminal halves of mature envelope gp120. Fine mapping of the MAb determinants was performed using defined 15-mer synthetic peptides spanning the entire envelope gp120 region of HIV-1. One group of MAbs recognizes epitopes (amino acids 304-323) occurring in a small region with variable and conserved amino acid sequences of gp120. These MAbs mediate neutralization of the HIV-1 strain HTLV-IIIB (HIV-1IIIB) which was used for immunization. Nine out of 11 primary HIV-1 isolates were neutralized well or moderately well. In addition, prominent serological reactivity was noted with peptide sequences of strains of various European or American origins, but not with two HIV-1 strains of African origin. The cross-reactivity contrasts with previously described type-specific reactions to other sequences of this region. The reactivity to the short conserved site GPGR with its flanking amino acids may explain the broad sequence cross-reactivity seen with our neutralizing MAbs. Two other MAbs recognize conserved epitopes (amino acids 79-103) situated in the amino-terminal region of gp120. These MAbs did not neutralize HIV-1IIIB.


Relationship between asthma and severe COVID-19: a national cohort study.
We aimed to determine whether children and adults with poorly controlled or more severe asthma have greater risk of hospitalisation and/or death from COVID-19. We used individual-level data from the Office for National Statistics Public Health Data Asset, based on the 2011 census in England, and the General Practice Extraction Service data for pandemic planning and research linked to death registration records and Hospital Episode Statistics admission data. Adults were followed from 1 January 2020 to 30 September 2021 for hospitalisation or death from COVID-19. For children, only hospitalisation was included. Our cohort comprised 35 202 533 adults and 2 996 503 children aged 12-17 years. After controlling for sociodemographic factors, pre-existing health conditions and vaccine status, the risk of death involving COVID-19 for adults with asthma prescribed low dose inhaled corticosteroids (ICS) was not significantly different from those without asthma. Adults with asthma prescribed medium and high dosage ICS had an elevated risk of COVID-19 death; HRs 1.18 (95% CI 1.14 to 1.23) and 1.36 (95% CI 1.28 to 1.44), respectively. A similar pattern was observed for COVID-19 hospitalisation; fully adjusted HRs 1.53 (95% CI 1.50 to 1.56) and 1.52 (95% CI 1.46 to 1.56) for adults with asthma prescribed medium and high-dosage ICS, respectively. Risk of hospitalisation was greater for children with asthma prescribed one (2.58 (95% CI 1.82 to 3.66)) or two or more (3.80 (95% CI 2.41 to 5.95)) courses of oral corticosteroids in the year prior to the pandemic. People with mild and/or well-controlled asthma are neither at significantly increased risk of hospitalisation with nor more likely to die from COVID-19 than adults without asthma.


Single-cell protein from methanol with Enterobacter aerogenes.
An identifiedEnterobacter aerogenesutilizing methanol as a sole carbon source was studied for the optimization of biomass production and the reduction of its nucleic acid content. Results indicated that the highest yield and conversion were obtained at 0.5% methanol. The addition of seawater as a source of trace elements has an adverse effect. However, the addition of urea as source of nitrogen enhanced the growth of E. aerogenes. Heat shock at 60 degrees C for 1 min followed by incubation at 50 degrees C for 2 h caused 72.6% reduction in the nucleic acid.


HUMAN CAPITAL GROWTH AND POVERTY: EVIDENCE FROM ETHIOPIA AND PERU.
In this paper we use high quality data from two developing countries, Ethiopia and Peru, to estimate the production functions of human capital from age 1 to age 15. We characterize the nature of persistence and dynamic complementarities between two components of human capital: health and cognition. We also explore the implications of different functional form assumptions for the production functions. We find that more able and higher income parents invest more, particularly at younger ages when investments have the greatest impacts. These differences in investments by parental income lead to large gaps in inequality by age 8 that persist through age 15.


The effect of subcutaneously administered terbutaline on serum potassium in asymptomatic adult asthmatics.
Several recent reports have linked the administration of beta-adrenergic agents to the development of hypokalemia. This led us to study, under controlled conditions, the effects of a subcutaneous injection of 0.25 mg terbutaline sulfate on serum potassium (K+), sodium (Na+), glucose, and insulin in a group of asymptomatic asthmatics. Heart rate (HR), blood pressure (BP), and forced expiratory volume in one second (FEV) were measured as parameters of beta-adrenergic stimulation. Each of 7 subjects was studied on 2 separate mornings after an overnight fast. Measurements were obtained before and at various time intervals after 0.25 mg) of terbutaline sulfate or 0.25 ml of a normal saline solution (placebo) were injected subcutaneously in a double-blind randomized crossover fashion. Terbutaline injection significantly increased HR and FEV and lowered diastolic BP for a period in excess of 3 h, indicating a prolonged beta stimulatory action of the drug. Significant effects on glucose, K+, and insulin were observed as early as 15 min after terbutaline injection; serum glucose and insulin increased and remained elevated for at least 2 h. Serum K+ fell significantly, reached a peak decline of 14% from the control value at 30 min after the injection and remained decreased for a period in excess of after subcutaneous terbutaline injection should be interpreted in the light of these effects of the drug and that terbutaline should be used with caution in patients prone to hypokalemia.


Overview of Ocular Side Effects of Selinexor.
The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator-initiated trial. We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed. A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment-related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment-related adverse event was the progression of age-related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation. Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation. Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.


The effect of changes to MOLLI scheme on T1 mapping and extra cellular volume calculation in healthy volunteers with 3 tesla cardiovascular magnetic resonance imaging.
Diffuse myocardial fibrosis may be quantified with magnetic resonance (MR) by calculating extracellular volume (ECV) fraction from native and post-contrast T1 values. The ideal modified look-locker inversion recovery (MOLLI) sequence for deriving T1 values has not been determined. This study aims to establish if systematic differences exist between suggested MOLLI schemes. Twelve phantom gels were studied with inversion recovery spin echo MR at 3.0 tesla to determine reference T1. Gels were then scanned with six MOLLI sequences (3s)3b(3s)5b; 4b(3s)3b(3s)2b; 5b(3s)3b with flip angles of both 35° and 50° at a range of heart rates (HRs). In 10 healthy volunteers MOLLI studies were performed on two separate occasions. Mid ventricular native and post contrast T1 was measured and ECV (%) calculated. In phantoms, the co-efficient of variability at simulated HR [40-100] with a flip angle of 35° ranged from 6.77 to 9.55, and at 50° from 7.71 to 11.10. T1 was under-estimated by all MOLLI acquisitions. Error was greatest with longer T1, and increased as HR increased. The 10 volunteers had normal MR studies. Native T1 time was similar for all acquisitions but highest with the 5b(3s)3b 35° scheme (1,189.1±33.46 ms). Interstudy reproducibility was similar for all MOLLIs. The 5b(3s)3b MOLLI scheme agreed best with reference T1, without statistical difference between the six schemes. The shorter breath-hold time of 5b(3s)3b scheme may be preferable in clinical studies and warrants further investigation.


Myosin expression and contractile function are altered by replating stem cell-derived cardiomyocytes.
Myosin heavy chain (MyHC) is the main determinant of contractile function. Human ventricular cardiomyocytes (CMs) predominantly express the β-isoform. We previously demonstrated that ∼80% of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) express exclusively β-MyHC after long-term culture on laminin-coated glass coverslips. Here, we investigated the impact of enzymatically detaching hESC-CMs after long-term culture and subsequently replating them for characterization of cellular function. We observed that force-related kinetic parameters, as measured in a micromechanical setup, resembled α- rather than β-MyHC-expressing myofibrils, as well as changes in calcium transients. Single-cell immunofluorescence analysis revealed that replating hESC-CMs led to rapid upregulation of α-MyHC, as indicated by increases in exclusively α-MyHC- and in mixed α/β-MyHC-expressing hESC-CMs. A comparable increase in heterogeneity of MyHC isoform expression was also found among individual human induced pluripotent stem cell (hiPSC)-derived CMs after replating. Changes in MyHC isoform expression and cardiomyocyte function induced by replating were reversible in the course of the second week after replating. Gene enrichment analysis based on RNA-sequencing data revealed changes in the expression profile of mechanosensation/-transduction-related genes and pathways, especially integrin-associated signaling. Accordingly, the integrin downstream mediator focal adhesion kinase (FAK) promoted β-MyHC expression on a stiff matrix, further validating gene enrichment analysis. To conclude, detachment and replating induced substantial changes in gene expression, MyHC isoform composition, and function of long-term cultivated human stem cell-derived CMs, thus inducing alterations in mechanosensation/-transduction, that need to be considered, particularly for downstream in vitro assays.


Portal venous tumor thrombosis associated with gastric adenocarcinoma.
Tumor thrombosis of the portal vein was identified retrospectively with computed tomography (CT) in four patients aged 66-77 years with gastric adenocarcinoma. Surgical, clinical, histopathologic, laboratory, and imaging findings were analyzed. Three patients showed an elevated alpha-fetoprotein (AFP) level (230-1,560 ng/mL [230-1,560 micrograms/L]). Immunohistochemical study revealed that AFP was produced by gastric carcinoma in two patients. Multiple metastatic foci in the liver appeared on CT and ultrasound (US) scans in all four patients. Echogenic thrombus was identified in three. There were no CT or US features that enabled differentiation of neoplastic from nonneoplastic thromboses. Angiography showed tumor vessels in only one patient: The thrombus was hypervascular in the arteriocapillary phase of celiac angiography but could not be differentiated from a much more common tumor thrombus seen in hepatocellular carcinoma. Nevertheless, gastric carcinoma should be considered a possibility in the diagnosis of portal venous tumor thrombosis, even if the serum AFP level is elevated and a liver tumor is identified.


Simulations of time-dependent fluorescence in nano-confined solvents.
The time-dependent fluorescence of a model diatomic molecule with a charge-transfer electronic transition in confined solvents has been simulated. The effect of confining the solvent is examined by comparing results for solutions contained within hydrophobic spherical cavities of varying size (radii of 10-20 angstroms). In previous work [J. Chem. Phys. 118, 6618 (2002)] it was found that the solute position in the cavity critically affects the absorption and fluorescence spectra and their dependence on cavity size. Here we examine the effect of cavity size on the time-dependent fluorescence, a common experimental probe of solvent dynamics. The present results confirm a prediction that motion of the solute in the cavity after excitation can be important in the time-dependent fluorescence. The effects of solvent density are also considered. The results are discussed in the context of interpreting time-dependent fluorescence measurements of confined solvent systems.


[Rapid screening of a hotspot variant c.609G>A in MMACHC gene by using PCR-high-resolution melting curve analysis].
To carry out genetic testing for two families affected with cobalamin C (cblC) and establish a rapid method for the detection of a hotspot pathogenic variant c.609G>A of the MMACHC gene by using a PCR-high-resolution melting curve (PCR-HRM) method. Genomic DNA was extracted from peripheral blood samples of the probands and their parents. Potential variants of the MMACHC gene was analyzed by Sanger sequencing. The c.609G>A variant of the MMACHC gene was screened among 100 healthy children with the PCR-HRM method. Sanger sequencing revealed that proband 1 carried compound heterozygous variants c.394C>T and c.609G>A of the MMACHC gene, while proband 2 carried compound heterozygous variants c.482G>A and c.609G>A of the same gene. PCR-HRM analysis of the two probands and the 100 healthy children were consistent with the Sanger sequencing. c.609G>A is a hotspot pathogenic variant of the MMACHC gene. The diagnosis of cblC may be rapidly attained through detection by PCR-HRM.


[Optoelectronic PCB Wastewater Treatment by Partial Nitrification-ANAMMOX Integrative Reactor].
The feasibility and operating characteristics of treatment of printed circuit board (PCB) wastewater by using autotrophic nitrogen removal process in partial nitrification and ANAMMOX integrative reactor were investigated. The reactor had startup successfully and achieved the stable nitrogen removal efficiency. The results showed that, after 80d operation, the nitrogen removal rate increased and was up to 1. 29 kg . (m3 . d)-1, the effluent NH4+-N and NO2- -N were decreased and stabilized at 4. 0 mg . L -1, 9. 8 mg . L-1 respectively, when the influent concentration of NH4+-N maintained at 220 mg . L -1. At the same time, the concentration of total nitrogen was less than 50 mg . L-1 in effluent, which meet the quality emissions requirements. The NO2- -N production rate was up to 2. 05 kg . (m3 . d)-1 by nitrite bacteria in aerobic zone, and the highest nitrogen removal rate was 2. 91 kg . (m3 . d) -1 by ANAMMOX. bacteria in anaerobic zone, which illuminated functional bacteria were steadily grown in the corresponding region. The inorganic ammmonia in PCB wastewater could be removed by autotrophic nitrogen removal process in nitrification and ANAMMOX integrative reactor.