A molecular target for suppression of the evolution of antibiotic resistance: inhibition of the Escherichia coli RecA protein by N(6)-(1-naphthyl)-ADP.
We report that N(6)-(1-naphthyl)-ADP inhibits the Escherichia coli RecA protein in vitro. A novel rapid screen identified it as a potent inhibitor of RecA nucleoprotein filament formation, and further characterization established it as an ATP-competitive inhibitor of RecA-catalyzed ATP hydrolysis. This and other inhibitors of RecA activities represent a new approach for understanding the molecular targets and pathways involved in the evolution of antibiotic resistance in bacteria.


Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells.
Retinal ganglion cell (RGC) replacement holds potential for restoring vision lost to optic neuropathy. Transplanted RGCs must undergo neuroretinal integration to receive afferent visual signals for processing and efferent transmission. To date, retinal integration following RGC transplantation has been limited. We sought to overcome key barriers to transplanted human stem cell-derived RGC integration. Following co-culture ex vivo on organotypic mouse retinal explants, human RGCs cluster and extend bundled neurites that remain superficial to the neuroretina, hindering afferent synaptogenesis. To enhance integration, we increased the cellular permeability of the internal limiting membrane (ILM). Extracellular matrix digestion using proteolytic enzymes achieved ILM disruption while minimizing retinal toxicity and preserving glial reactivity. ILM disruption is associated with dispersion rather than clustering of co-cultured RGC bodies and neurites, and increased parenchymal neurite ingrowth. The ILM represents a significant obstacle to transplanted RGC connectivity and its circumvention may be necessary for functional RGC replacement.


Torque-in-base: another straight-wire myth?
The theoretical inaccuracies of straight-wire systems which incorporate torque in the bracket face are discussed, with the conclusion that this variation from the original design is unlikely to be of any practical significance.


An SV40 mutant T antigen does not bind the SV40 viral origin.
F8dl is an SV40 deletion mutant that lacks over 60% of the coding sequences for large T antigen and yet is able to immortalize early passage rat cells, to transform established cell lines, and to cause tumors in animals. We report here on the further characterization of this mutant and show that (a) transformation by F8dl is protein mediated but does not require the action of the SV40 small t antigen; (b) the F8dl T antigens have, or are associated with, an ATPase activity; (c) the 34-kDa mutant T antigen of F8dl is localized in nuclei and cell membranes of F8dl transformants and binds to double-stranded DNA; (d) the 20-25 kDa forms of the mutant T antigen are cytoplasmic; and (e) the F8dl T antigens do not bind with high affinity to the SV40 origin of viral DNA replication.


The interaction of decorin core protein fragments with type I collagen.
To further define the molecular interaction between decorin and type I collagen we generated a 20 kD fragment containing the N-terminal half of the core protein by Endoproteinase Arg C digestion and a 40 kD fragment including all leucine-rich repeats in the central part of decorin core by cleavage with 2-nitro-5-thiocyanobenzoate. The fragments did not influence collagen fibril formation, even at high concentration, and radioactive fragments showed little binding to collagen fibrils. Our observations suggest that neither the N-terminal half nor the central leucine-rich repeats of the decorin core protein can, by itself, interact fully with fibrillar collagen.


Perforated neonatal appendicitis.
We present a case of perforated appendicitis with peritonitis in a premature 920 gm neonate who survived. The incidence, etiology, and presenting signs and symptoms of appendicitis in the newborn are discussed.


Prenatal cocaine exposure in the laboratory mouse: effects on maternal water consumption and offspring outcome.
Pregnant mice were given 50 mg/kg cocaine HCl (1% solution, sc) once daily from gestation days 7 through 18 (sperm positive = day 0; term = day 19). Pair-fed and untreated control groups were also used. The pregnant cocaine-treated females showed normal weight gain and food consumption but had significantly increased water consumption. The cocaine-treated group had a significant increase in embryonic resorptions but no significant effects on stillbirths or postnatal mortality. The offspring of cocaine-treated females had significantly reduced birth weights and postnatal weight gains up to the age of 28 days. There was also a delay in their ear opening but not in other maturational milestones. Increased water consumption following cocaine treatment has been reported by other studies. We speculate that cocaine has a diuretic effect. We discuss the implications of this effect during pregnancy.


[Repair of flexor-tendon injury in children's finger using microsurgical technique].
To improve the clinical result of repair on flexor tendon injury, and recover the defected finger function in children as far as possible. From January 1990 to October 1997, 12 cases with flexor tendon injury were repaired by microsurgical technique, sutured by modified Kessler method with 3/0 or 5/0 nontraumatic thread and followed by invering suture of the gap edge with 7/0 or 8/0 nontraumatic thread after debridement. Appropriate functional practice was performed postoperatively. All the defected fingers were healed by first intention. Followed up 6 months to 1 year, there was excellent in 7 cases, better in 4 cases, moderate in 1 case and 91.67% in excellent rate according to the TAM standard of International Hand Committee. The important measures to improve the clinical result in children's flexor tendon injury are prompt and accurate diagnosis and repair of the injured tendon by microsurgical technique, and effective postoperative functional practice.


Expression and site-specific mutagenesis of phospholamban. Studies of residues involved in phosphorylation and pentamer formation.
Full-length cDNAs encoding either dog cardiac or rabbit skeletal muscle phospholamban were expressed transiently in COS-1 cells. The expressed protein displayed the mobility of a pentamer when dissolved in sodium dodecyl sulfate and separated in polyacrylamide gels, and of a monomer when boiled prior to polyacrylamide gel separation. Site-specific mutagenesis was used to analyze the roles of several amino acids in the structure and function of the protein. Ser16 and Thr17 were shown to be phosphorylated uniquely by cAMP- and calmodulin-dependent protein kinases, respectively, confirming earlier observations on the native protein (Simmerman, H. K. B., Collins, J. H., Theibert, J.L., Wegener, A.D., and Jones, L.R. (1986) J. Biol. Chem. 261, 13333-13341). Arg13 and Arg14 were shown to be essential for both types of phosphorylation, and Arg9 was shown to be essential for calmodulin-dependent phosphorylation. In studies of pentamer stability, mutation of Gln22-Gln23 to Ala-Ala or Glu-Glu, of Gln26-Asn27 to Glu-Asp, or of Gln29-Asn30 to Glu-Asp had no effect on thermal stability of the pentamer, suggesting that hydrogen bonding involving these residues in domain IB is not important for pentamer stability. By contrast, mutation of Cys36, Cys41, and Cys46 in transmembrane domain II to Ser, Ala, or Phe diminished the stability of the pentamer when microsomal proteins were dissociated in sodium dodecyl sulfate and separated by polyacrylamide gel electrophoresis. In particular, the Cys41 to Phe mutant existed as a monomer at ambient temperature. These results suggest that the intramembranous cysteine residues are important for pentamer formation even though they are not disulfide-bonded.


Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.
The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single-nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC. A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele [70% vs. 90%, univariate: hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.03-5.06, P = 0.035; multivariate: HR 2.58, 95% CI 1.15-5.76, P = 0.021]. Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95% CI 0.12-0.97, P = 0.034; multivariate: HR 0.39, 95% CI 0.13-1.11, P = 0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P = 0.007). Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.


Radionuclide cisternography in intracranial hypotension syndrome.
A 44-year-old male patient complaining of severe headache right after twisting his body during aerobic exercises in a swimming pool underwent In-111 DTPA radionuclide cisternography. Leakage of cerebrospinal fluid (CSF) was proved on the right side of T2 and T3 vertebrae. Cisternography after bed and conservative treatments demonstrated the disappearance of abnormal tracer accumulations. Radionuclide cisternography is of great value in diagnosing cerebral-spinal fluid leak and in evaluating the therapeutic effect.


N-Methyldimaprit (SK&F92054). A chemical control for the histamine H2-receptor agonist dimaprit.
Dimaprit analogues having alkyl substituents on the isothiourea group have no detectable H2-agonist activity on the guinea-pig atrium. N-Methyldimaprit [S-[3-(N,N-dimethylamino)propyl]-N'-methylisothiourea] (SK&F92054) is identified as a compound which may serve as a suitable chemical control when studying the actions of dimaprit at putative H2-histamine receptors. Concentrations of N-methyl-dimaprit (up to 3 X 10(-3) M) had no agonist activity in vitro on the guinea-pig atrium (less than 0.005% of the activity of histamine), rat uterus (up to 2 X 10(-3) M,) or as a stimulant of guinea-pig ventricular adenylate cyclase (up to 10(-3) M). N-Methyldimaprit at 10(-3) M also did not significantly stimulate acid secretion in the rat isolated stomach preparation; it was a very weak stimulant of gastric acid secretion (less than 0.2% of the activity of histamine) in vivo in the lumen-perfused stomach of the anaesthetised rat but exhibited marked tachyphylaxis on repeated administration. N-Methyldimaprit has two basic centres, macroscopic pKa values 8.31 and 9.58 at 40 degrees C.


Decrease in the phagocytic activity of peripheral monocytes in patients treated with human interferon-alpha.
The influence of daily intramuscular injections of 3 X 10(6) units of interferon-alpha (IFN-alpha) on the phagocytic activity of peripheral monocytes was studied in 28 tumor patients. One day after initiation of IFN therapy no major change in the capacity of monocytes to ingest yeast particles was observed. After 1 week, 3 months, 6 months, and 9 months of treatment, monocyte phagocytosis had decreased in the majority of the patients tested. In patients where natural killer (NK) cell activity was measured simultaneously with monocyte phagocytosis, a correlation between the degree of enhancement of NK activity and the degree of decrease in monocyte phagocytosis was observed.


Orthodontic space closure in sliding mechanics: a systematic review and meta-analysis.
The aim of this systematic review was to compare the different force delivery systems for orthodontic space closure by sliding mechanics. Multiple sources including Cochrane Central, Ovid Medline, Embase etc. were used to identify all relevant studies. Randomized controlled trials (RCT) of parallel-group and split-mouth designs were included. Orthodontic patients of any age treated with fixed orthodontic appliances and requiring space closure. Search result screening, data extraction and quality assessment were performed independently and in duplicate by 2 reviewers. The included studies were grouped into parallel-arm and split-mouth studies and subgroup analysis was then performed for the type of retraction subsets; en-masse and individual canine retraction. A traditional meta-analysis, and network meta-analysis (NMA) for direct and indirect comparisons for the rate of space closure were performed. Thirteen studies, six parallel-arm and seven split-mouth were included. The traditional meta-analysis comparing Nickel-titanium (NiTi) closed coil springs and elastomeric power chain for the rate of tooth movement showed statistically significant difference favouring NiTi springs (MD: 0.24; 95% CI, 0.03-0.45; I2 0%, P = 0.02) and the comparison between NiTi springs and active ligatures also showed statistically significant result favouring NiTi springs (MD: 0.53; 95% CI, 0.44-0.63; I2 0%, P ˂ 0.00001) for the rate of tooth movement. NMA for the rate of space closure showed fairly confident evidence for NiTi coil springs when compared with elastomeric chain and active ligatures. The NiTi coil spring ranked best between all methods of space closure. There is moderate quality evidence in favour of NiTi coil springs for the rate of space closure when compared with active ligature and low quality of evidence favouring NiTi springs when compared with elastomeric chain. The ranking from NMA showed NiTi coil springs to be the best method for space closure with 99% chance. An urgent need for standardization of study designs and the need for development of an agreed core outcome sets and core outcome instrument measurement sets is evident. PROSPERO CRD42020157811.


Design and evaluation of cyclodextrin-based delivery systems to incorporate poorly soluble curcumin analogs for the treatment of melanoma.
Various analogs of curcumin show high in vitro cytotoxic activity and are potential candidates for treating a deadly skin disease, melanoma. Due to the low solubility of the drugs, a new delivery agent, namely a cationic gemini surfactant-conjugated β-cyclodextrin, was designed to incorporate novel drug candidates of the 1,5-diaryl-3-oxo-1,4-pentadienyl family. Based on physicochemical parameters, such as particle size and zeta potential, a schematic model for the potential interaction of the drug with the delivery agent was developed. The drug formulations were highly efficient in inhibiting the growth of melanoma cells, with IC(50) values significantly lower than melphalan, the drug currently used for the treatment of in-transit melanoma. CDgemini formulations showed excellent cellular selectivity, triggering apoptosis in the A375 cell line while showing no cytotoxicity to healthy human epidermal keratinocytes. The goal is to develop this novel nanoparticle approach into a non-invasive therapy for in-transit melanoma metastasis that lacks adequate treatment to date.


Enzyme-Mineralized PVASA Hydrogels with Combined Toughness and Strength for Bone Tissue Engineering.
Enzymatic mineralization is an advanced mineralization method that is often used to enhance the stiffness and strength of hydrogels, but often accompanied by brittle behavior. Moreover, the hydrogel systems with dense networks currently used for enzymatic mineralization are not ideal materials for bone repair applications. To address these issues, two usual bone repair hydrogels, poly(vinyl alcohol) (PVA) and sodium alginate (SA), were selected to form a double-network structure through repeated freeze-thawing and ionic cross-linking, followed by enzyme mineralization. The results demonstrated that both enzymatic mineralization and double-network structure improved the mechanical and biological properties and even exhibited synergistic effects. The mineralized PVASA hydrogels exhibited superior comprehensive mechanical properties, with a Young's modulus of 1.03 MPa, a storage modulus of 103 kPa, and an equilibrium swelling ratio of 132%. In particular, the PVASA hydrogel did not suffer toughness loss after mineralization, with a high toughness value of 1.86 MJ/m3. The prepared hydrogels also exhibited superior biocompatibility with a cell spreading area about 13 times that of mineralized PVA. It also effectively promoted cellular osteogenic differentiation in vitro and further promoted the formation of new bone in the femur defect region in vivo. Overall, the enzyme-mineralized PVASA hydrogel demonstrated combined strength and toughness and great potential for bone tissue engineering applications.


The buttressing coalition of the PNGIMR: an example of international collaborative research.
Good partnerships are based on mutual benefit. This also applies to international partnerships in medical research. The Papua New Guinea Institute of Medical Research (PNGIMR) has had many successful research collaborations, from which an interactive coalition has been built that is committed to supporting the PNGIMR without jeopardizing its integrity. This coalition also involves policy-makers from the Department of Health, teachers at the Medical School of Papua New Guinea and the Medical Research Advisory Committee of PNG. The PNGIMR's Buttressing Coalition supports research and training, but also assists the process of transferring research results into policy. The concept of "buttressing" is explored and the activities of the Buttressing Coalition are briefly described here. The idea of the Buttressing Coalition is a response from the international medical research community to globalization, and could be applied elsewhere, following the model developed in PNG.


Isolation and characterization of irradiation fusion hybrids from mouse chromosome 1 for mapping Rmc-1, a gene encoding a cellular receptor for MCF class murine retroviruses.
An irradiation-reduced somatic cell hybrid mapping panel was constructed of BALB/c mouse Chromosome 1. Nineteen hybrids were selected from a pool of 292 clones to generate a fine structure physical map of the distal 40 cM of the chromosome. The hybrids contain mouse DNA fragments only from Chromosome 1, ranging from approximately 5 cM to approximately 20 cM. Utilizing a viral infectibility assay, a cellular receptor gene, Rmc-1, for the MCF class of murine retroviruses was found to be linked to Lamb2, in the region between the Lamb2 and Bxv-1 loci. In addition, analysis of the hybrid mapping panel resulted in the remapping of three loci, Atpb, Ly-5, and Pmv-24, as compared to the mouse linkage map. Two previously unmapped endogenous proviruses are also putatively assigned positions on the chromosome.


Viral safety characteristics of Flebogamma DIF, a new pasteurized, solvent-detergent treated and Planova 20 nm nanofiltered intravenous immunoglobulin.
A new human liquid intravenous immunoglobulin product, Flebogamma DIF, has been developed. This IgG is purified from human plasma by cold ethanol fractionation, PEG precipitation and ion exchange chromatography. The manufacturing process includes three different specific pathogen clearance (inactivation/removal) steps: pasteurization, solvent/detergent treatment and Planova nanofiltration with a pore size of 20 nm. This study evaluates the pathogen clearance capacity of seven steps in the production process for a wide range of viruses through spiking experiments: the three specific steps mentioned above and also four more production steps. Infectivity of samples was measured using a Tissue Culture Infectious Dose assay (log(10) TCID(50)) or Plaque Forming Units assay (log(10) PFU). Validation studies demonstrated that each specific step cleared more than 4 log(10) for all viruses assayed. An overall viral clearance between > or =13.33 log(10) and > or =25.21 log(10), was achieved depending on the virus and the number of steps studied for each virus. It can be concluded that Flebogamma DIF has a very high viral safety profile.


Autoantibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein in paediatric CNS demyelination: Recent developments and future directions.
Diagnosis and prognosis of acute inflammatory disorders of the central nervous system in both children and adults would be aided by the availability of serum biomarkers. Antibodies directed against the aquaporin-4 water channel has led to recognition of neuromyelitis optica (NMO) and NMO spectrum disorders in both children and adults and to the ability to predict a relapsing disease course in antibody-positive patients. Serum antibodies directed against myelin antigens are detectable in approximately one third of children with acute disseminated encephalomyelitis (ADEM) at the time of acute illness, and in approximately 25% of children with multiple sclerosis (MS) in whom seropositivity persists. Whether circulating antibodies contribute to disease pathogenesis or are secondary to cell damage is an area of active study. The contribution of T-cells, eosinophils, neutrophils, infection and blood brain barrier permeability are also receiving increasing attention in antibody-associated inflammatory demyelination. The present manuscript reviews the current clinical, laboratory and immunological features of acquired CNS inflammation in children.


Seasonality of birth in schizophrenia. An insufficient stratification of control population?
The seasonality of birth in 142 schizophrenics from Barcelona (Spain) has been studied, showing a pattern similar to that described by other authors, with a maximum in winter. If sample is compared with the local general population there are significant differences, but these disappear when the comparison is made with a control population properly stratified by age, sex, place of birth, place of residence and social status. The same results are obtained using statistical methods suggested by other authors. The seasonality pattern usually obtained in schizophrenia could be due to a selective stratification of the ill population based on variables that might or might not be related to illness.


Predictors of Treatment Outcome in Eating Disorders: A Roadmap to Inform Future Research Efforts.
With the current review, we provide a brief summary of recent literature that tests clinically observable characteristics at baseline that may impact treatment response, across eating disorder diagnoses. We then provide a critical discussion regarding how researchers may shift their approach to this research to improve treatment implications and generalizability of these findings. Recent work has broadly replicated prior findings suggesting a negative impact of lower weight status, poor emotion regulation, and early-life trauma on eating disorder treatment outcomes. Findings are more mixed for the relative contributions of illness duration, psychiatric comorbidity, and baseline symptom severity. Recent studies have begun to explore more specific domains of previously tested predictors (e.g., specific comorbidities) as well as previously neglected identity-related and systemic factors. However, recent research continues to use similar sampling techniques and approaches to analysis used in prior work. We propose that resolving remaining questions and illuminating predictors of treatment outcome in eating disorders requires a new approach to research sampling and study design. Suggested changes that can be applied within a traditional clinical trial framework may yield new insights with relevance across transdiagnostic eating disorder presentations.


Dietary Supplement Intake and Factors Associated with Increased Use in Preadolescent Endurance Runners.
The prevalence of dietary supplement intake among preadolescent endurance runners is currently unknown. Our aim was to describe use of dietary supplements, higher-risk supplements, and sport foods among preadolescent endurance athletes and identify associated characteristics of dietary supplement users in this population. This was a retrospective, cross-sectional study. Participants were 2,113 preadolescent endurance runners (male: n = 1,255, female: n = 858; mean age ± standard deviation = 13.2 ± 0.9 years). Use of dietary supplements, higher-risk dietary supplements, and sport foods on 2 or more days per week during the past year. Mann-Whitney U tests, χ2 tests, univariate and multivariate analyses. Twenty-six percent (n = 551) of preadolescent runners used dietary supplements on 2 or more days per week during the past year; 1.3% (n = 27) reported taking higher-risk supplements. Compared with male runners, female runners reported higher use of 1 or more supplements (32.5% vs 21.7%; P < .001) and 4 or more supplements (4.0% vs 1.9%; P = 0.005), multivitamin/minerals (24.2% vs 14.4%; P < .001), vitamin D (12.4% vs 5.6%; P < .001), calcium (8.9% vs 4.8%; P < .001), iron (3.1 vs 1.1%; P < .001), probiotic supplements (8.2% vs 1.3%; P < .001), and diet pills (0.5% vs 0.0%; P = .02). Male runners reported higher use of creatine (1.3% vs 0.0%; P < .001) and sport foods, including protein bars and drinks (19.5% vs 8.4%; P < .001), energy bars (23.5% vs 9.7%; P < .001), and carbohydrate-electrolyte drinks (27.9% vs 13.3%; P < .001) than female runners. Factors independently associated with a higher likelihood for dietary supplement use included weight loss in the past year, female (vs male) gender, following a vegetarian diet, skipping meals, attempting to gain weight, and history of a running-related bone stress injury. More than one-quarter of preadolescent runners regularly consumed dietary supplements. Behaviors consistent with dietary restriction and history of bone stress injury were associated with higher likelihood for supplement use. Further work to understand supplement use patterns and potential value for nutrition education is advised to optimize health of preadolescent runners.


Association of novel and conventional obesity indices with colorectal cancer risk in older Chinese: a 14-year follow-up of the Guangzhou Biobank Cohort Study.
Visceral adiposity index (VAI) and a body shape index (ABSI) were newly developed indices for visceral fat mass. Whether they are superior to conventional obesity indices in predicting colorectal cancer (CRC) remains unclear. We examined the associations of VAI and ABSI with CRC risk, and investigated their performance in discriminating CRC risk compared with conventional obesity indices in the Guangzhou Biobank Cohort Study. A total of 28,359 participants aged 50 + years without cancer history at baseline (2003-8) were included. CRC were identified from the Guangzhou Cancer Registry. Cox proportional hazards regression was used to assess the association of obesity indices with the CRC risk. Discriminative abilities of obesity indices were assessed using Harrell's C-statistic. During an average follow-up of 13.9 (standard deviation = 3.6) years, 630 incident CRC cases were recorded. After adjusting for potential confounders, the hazard ratio (95% confidence interval) of incident CRC for per standard deviation increment in VAI, ABSI, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) was 1.04 (0.96, 1.12), 1.13 (1.04, 1.22), 1.08 (1.00, 1.17), 1.15 (1.06, 1.24), 1.16 (1.08, 1.25)and 1.13 (1.04, 1.22), respectively. Similar results for colon cancer were found. However, the associations of obesity indices with risk of rectal cancer were non-significant. All obesity indices showed similar discriminative abilities (C-statistics from 0.640 to 0.645), with WHR showing the highest whilst VAI and BMI the lowest. ABSI, but not VAI, was positively associated with a higher risk of CRC. However, ABSI was not superior to the conventional abdominal obesity indices in predicting CRC.


Superior oblique tendon damage resulting from eyelid surgery.
To describe the occurrence of superior oblique (SO) tendon damage resulting from upper eyelid surgery and to explain its cause and treatment. Retrospective, observational case series. An institution-based retrospective observational case series of seven patients in whom damage to the SO tendon secondary to eyelid surgery developed. In four of the patients, ipsilateral SO palsy developed, and three patients, a Brown syndrome pattern developed. The causative eyelid procedures consisted of surgery to correct ptosis in four patients, tumor removal in two patients, and cosmetic blepharoplasty in one patient. The SO tendon may be damaged as a result of eyelid surgery. The anatomy of the SO tendon should be kept in mind while performing surgery in the superomedial aspect of the upper eyelid.


Local hyperthermia and cartilage breakdown: histochemical and metabolic studies on rabbit articular cartilage in vitro.
The hypothesis that local hyperthermia generated in inflamed joints may cause damage to the articular cartilage was tested in vitro using histochemical and isotopic methods. We found that this could be the case. Incubation temperatures above 38 degrees C in experiments of longer duration and 39 degrees C during shorter incubation times induced a loss of metachromasia, decreased rates of synthesis, and increased degradation of cartilage matrix macromolecules. It is postulated that local synovial hyperthermia might partly account for the cartilage degeneration that frequently occurs in rheumatoid arthritis as a result of a decreased synthesis and increased catabolism of matrix macromolecules.


Evaluation of continuous flow centrifugation as an alternative technique to sample microplastic from water bodies.
The scientific and public interest regarding environmental pollution with microplastic has considerably increased within the last 15 years. Nevertheless, up to now there is no widely applied standard operation procedure for microplastic sampling, resulting in a lack of inter-study comparability. In addition, many studies on microplastic occurrences do not indicate a sound methodological validation of the applied methods and procedures. This study presents an alternative volume-reduced sampling technique to sample the entire load of suspended particulate matter including microplastic particles in natural waters, based on continuous flow centrifugation. For the lab-scale validation of the proposed instrumental setup, six different microplastic types (PE, PET, PS, PVDC, EPS and PP) were used. The particles covered a size range from 1 μm to 1 mm and a density range from 0.94 g mL-1 to 1.63 g mL-1. Recoveries ranged from 95.0% ± 2.3% - 99.1% ± 0.3% for virgin powders and from 96.1% ± 0.6% - 99.4% ± 0.2% (1 SD, n = 2 - 3) for microplastic suspended in river water for 40 days. Gravimetric and microscopic analysis of the effluent indicates efficient removal of microplastic from the suspensions. Static light scattering analysis of the microplastic suspensions prior to and after centrifugation confirmed that no change of the particle size distribution has occurred - neither through aggregation nor through size-discrimination during centrifugation. Moreover, the system was tested in the field and used twice to sample suspended particulate matter from the Elbe estuary directly on site. Based on these first lab-scale experiments, continuous flow centrifugation proves a promising technique bearing potential to alleviate drawbacks such as contamination, filter clogging and particle size-discrimination of commonly used volume-reduced microplastic sampling approaches.


Contrasting in vitro effects of retinol and mononuclear cell factor on young and old human cartilage.
Studies with young animal cartilage have shown that retinol and mononuclear cell-factor (MCF) cause in vitro breakdown of the cartilage, mediated by the living chondrocyte (indirect degradation). We studied the effects of retinol and MCF on healthy human articular cartilage of different ages, measuring the effects on proteoglycan (PG) content of the cartilage, and on PG synthesis during 8 days of culture. This study shows: Retinol and MCF induce indirect degradation of young, but not of old human cartilage of the humeral head; Both retinol and MCF suppress PG synthesis of young and stimulate PG synthesis of old cartilage; The effects of retinol and MCF on cartilage PG content and on PG synthesis are related to the metabolic state of the chondrocyte; Therefore mononuclear cell-factor may have a destructive or beneficial effect on cartilage depending on whether proteoglycan synthesizing activity is high or low, respectively.


Prevention of doxorubicin induced cardiotoxicity by catechin.
Doxorubicin (dox) is an anthracycline antibiotic which is broadly used in solid tumors. Long-term therapy with this drug is accompanied by potentially lethal, dose-dependent side effects. Several reports suggest that oxygen free radicals produced during the metabolic activation of dox may have toxic effects on heart muscle. We tried to protect dox cardiotoxicity in rats using catechin which is a known antioxidant and iron chelating agent. Different dose levels and combinations of catechin and doxorubicin have been studied in different experimental groups. Electrocardiograms, myocardial contractility, body weight and the electron microscope were used to assess the cardioprotective effect of catechin in dox-treated animals. We found significant prevention of dox-induced cardiotoxicity by catechin in rats.


Diffusion cooling of thermal neutrons in basic rock minerals by Monte Carlo simulation of the pulsed neutron experiments.
The pulsed neutron experiment (the variable geometric buckling experiment) in spherical geometry has been simulated using the MCNP code. The time decay of the thermal neutron flux has been observed as a function of the sample size. The thermal neutron diffusion cooling coefficient C with the correction F has been determined for three basic rock minerals (quartz, calcite, dolomite) at the given specific densities. The corresponding density-removed parameters have also been obtained.


Reduction of aldehydes and ketones by transfer hydrogenation with 1,4-butanediol.
1,4-Butanediol has been used as the hydrogen donor in transfer hydrogenation reactions. The equilibrium is driven by the formation of gamma-butyrolactone, and the diol is therefore not required in excess.


Isolation and screening of heterocystous cyanobacterial strains for biodiesel production by evaluating the fuel properties from fatty acid methyl ester (FAME) profiles.
This study reports on the biodiesel quality parameters of eleven heterocystous cyanobacterial strains based on fatty acid methyl esters (FAME) profiles. The biomass productivity of the tested cyanobacterial strains ranged from 9.33 to 20.67 mg L(-1) d(-1) while the lipid productivity varied between 0.65 and 2.358 mg L(-1) d(-1). The highest biomass and lipid productivity was observed for Calothrix sp. MBDU 013 but its lipid content is only 11.221 in terms of percent dry weight, next to the Anabaena sphaerica MBDU 105, whose lipid content is high. To identify the most competent isolate, a multi-criteria decision analyses (MCDA) was performed by including the key chemical and physical parameters of biodiesel calculated from FAME profiles. The isolate A.sphaerica MBDU 105 is the most promising biodiesel feed stock based on decision vector through Preference Ranking Organisation Method for Enrichment Evaluation (PROMETHEE) and Graphical Analysis for Interactive Assistance (GAIA) analysis.


Systematic review of genome-wide association studies of abdominal aortic aneurysm.
Abdominal aortic aneurysm (AAA) is an important cause of death worldwide and has an estimated heritability between 70 and 77%. Genome-wide association studies (GWAS) are an established way to discover genetic risk variants. The aim of this study was to systematically review the findings and quality of previous AAA GWAS. The Medline, PubMed, Web of Science and relevant genetic databases were searched to identify previous AAA GWAS. A framework was developed to grade the methodological quality of the GWAS. Data from included studies were extracted to assess methods and findings. Eight case-control studies were included. Thirty-three of the 38 total single nucleotide polymorphisms (SNPs) previously reported were associated with AAA diagnosis at genome-wide significance (p < 5.0 × 10-8). The CDKN2B antisense RNA-1 gene had the most significant association with AAA diagnosis (p = 6.94 × 10-29 and p = 1.54 × 10-33 for rs4007642 and rs10757274 respectively). Age, sex and smoking history were not reported for the complete cohort in any of the included studies, although five of the eight studies adjusted or matched for at least two confounding variables. All included studies had important design limitations including lack of sample size estimation, inconsistent case and control ascertainment and limited phenotyping of the AAAs. AAA growth was assessed in one GWAS, however, no significant associations with the reported SNPs were found. This systematic review identified 33 SNPs associated with AAA diagnosis at genome-wide significance previously validated in multiple cohorts. The association between SNPs and AAA growth was not adequately examined. Previous GWAS have a number of design limitations.


'There is always a way to living with illness'-Self-management strategies reported by Chinese hospitalized patients with cardiovascular disease: A descriptive qualitative study.
Patients living with cardiovascular diseases use different strategies to solve various problems. This study aimed to identify the category, type and specific self-management strategies reported by hospitalized patients with cardiovascular diseases. This is a qualitative descriptive study. Twenty-eight individuals with cardiovascular diseases from a Cardiology Department affiliated with a school in China were recruited by purposive sampling. Face-to-face semi-structured interviews were used. The interviews were audio-recorded, transcribed, translated and analysed by using content analysis. Five self-management strategy categories (medical and alternative therapy uptake, risk assessment and avoidance, resource seeking and utilization, maintaining normality, and optional management), and seventeen self-management strategy types, encompassing one hundred and ten specific strategies were identified. The most commonly used self-management strategy types were lifestyle adjustment (eleven strategies), self-maintenance (nine strategies) and problem-solving (nine strategies). Additionally, the most described explicit self-management strategies were receiving family/colleague support, maintaining daily routines, monitoring symptoms and managing side effects, discussing with professionals, using medicines, and improving awareness. This study identified diverse strategies reported by some Chinese cardiovascular patients. It may inform the design and development of personalized self-management interventions for health practitioners and policymakers, helping cardiovascular patients in Chinese communities worldwide receive culture-tailored services.


Non-canonical functions of the RB protein in cancer.
The canonical model of RB-mediated tumour suppression developed over the past 30 years is based on the regulation of E2F transcription factors to restrict cell cycle progression. Several additional functions have been proposed for RB, on the basis of which a non-canonical RB pathway can be described. Mechanistically, the non-canonical RB pathway promotes histone modification and regulates chromosome structure in a manner distinct from cell cycle regulation. These functions have implications for chemotherapy response and resistance to targeted anticancer agents. This Opinion offers a framework to guide future studies of RB in basic and clinical research.


Association between combined spinal-epidural analgesia and neurodevelopment at 3 years old: The Japan Environment and Children's Study.
To investigate the association between maternal combined spinal-epidural analgesia during vaginal delivery and neurodevelopment in 3-year-old children. Using data from the Japan Environment and Children's Study, a birth cohort study on pregnant women and their offspring, we described the background, perinatal outcomes, and neurodevelopmental outcomes of participants with a singleton pregnancy who received combined spinal-epidural analgesia during vaginal delivery and those who did not. The association between maternal combined spinal-epidural analgesia and abnormalities in five domains of the Ages and Stages Questionnaire, Third Edition, was analyzed using univariable and multivariable logistic regression analyses. Crude and adjusted odds ratios with 95% confidence intervals (95% CI) were calculated. Among 59 379 participants, 82 (0.1%) children (exposed group) were born to mothers who received combined spinal-epidural analgesia during vaginal delivery. In the exposed versus control groups, 1.2% versus 3.7% had communication abnormalities (adjusted odds ratio [95% CI]: 0.30 [0.04-2.19]), 6.1% versus 4.1% exhibited gross-motor abnormalities (1.36 [95% CI: 0.55-3.36]), 10.9% vs. 7.1% had fine-motor abnormalities (1.46 [95% CI: 0.72-2.96]), 6.1% vs. 6.9% showed difficulties with problem-solving (0.81 [95% CI: 0.33-2.01]), and 2.4% vs. 3.0% had personal-social problems (0.70 [95% CI: 0.17-2.85]). Exposure to combined spinal-epidural analgesia during vaginal delivery was not associated with the risk of neurodevelopmental abnormalities; however, the sample size of our study might not be appropriate for the study design.


Targeting viral-mediated transduction to the lung airway epithelium with the anti-inflammatory cationic lipid dexamethasone-spermine.
We formulated adenovirus (AdV) vectors with cationic steroid liposomes containing dexamethasone-spermine (DS)/dioleoylphosphatidylethanolamine (DOPE) in an effort to overcome the lack of apically expressed AdV vector receptors on airway epithelial cells and to reduce the inflammation associated with AdV vector exposure. An AdV vector (1 to 2.5 x 10(11) genome copies) expressing human placental alkaline phosphatase or beta-galactosidase (LacZ) was delivered alone or complexed with DS/DOPE, DC-Chol/DOPE, or dexamethasone to C57Bl/6 mice via intranasal instillation. Formulation of the AdV vector with DS/DOPE and DC-Chol/DOPE resulted in transgene expression targeted only to the airway epithelial cells with minimal expression in alveolar cells, while AdV alone caused high alveolar transduction. The DS/DOPE and dexamethasone formulations greatly reduced cellular infiltrates compared to AdV vector alone, while formulation with DC-Chol/DOPE did not. IFN-gamma was significantly elevated at day 7 in mice receiving only the AdV vector compared to the AdV vector formulated with DS/DOPE, DC-Chol/DOPE, or dexamethasone. Lipid formulation of adeno-associated virus vector expressing LacZ also produced airway epithelial targeting, similar to the AdV vector. Viral vectors can be formulated with DS/DOPE to improve targeting to the airway epithelium in vivo and to attenuate vector-induced inflammation through the pharmacological activity of DS.


Population pharmacokinetic modelling of intravenous immunoglobulin in patients with predominantly antibody deficiencies.
There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies. Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG. A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3-4-weekly dosing intervals were sufficient to maintain IgG levels of 5 g L-1 , with more frequent intervals needed to achieve higher trough levels. Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.


Prevalence and trends of coronary artery disease risk factors and their effect on age of diagnosis in patients with established coronary artery disease: Tehran Heart Center (2005-2015).
Coronary artery disease (CAD) is a universal public health challenge, more prominently so in the low- and middle-income countries. In this study, we aimed to determine prevalence and trends of CAD risk factors in patients with documented CAD and to determine their effects on the age of CAD diagnosis. We conducted a registry-based, serial cross-sectional study using the coronary angiography data bank of the Tehran Heart Center. Adult patients who had obstructive (> 50% stenosis) CAD were included in the study. The prevalence and 11-year trends of conventional CAD risk factors were analyzed by sex and age, and their adjusted effects on the age of CAD diagnosis were calculated. From January 2005 to December 2015, data for 90,094 patients were included in this analysis. A total of 61,684 (68.5%) were men and 28,410 (31.5%) were women. Men were younger at diagnosis than women, with a mean age of 60.1 in men and 63.2 in women (p < 0.001), and had fewer risk factors at the time of diagnosis. Mean age at diagnosis had an overall increasing trend during the study period. Increasing trend was seen in body-mass index, hypertension prevalence, diabetes mellitus. All lipid profile components (total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol) decreased over time. Of particular interest, opium consumption was associated with 2.2 year earlier age of CAD diagnosis. The major results of this study (lower age of CAD diagnosis in men, lower age of diagnosis associated with most risk factors, and lower prevalence of serum lipids over time) were expected. A prominent finding of this study is confirming opium use was associated with a much younger age of CAD onset, even after adjusting for all other risk factors. In addition to recommendations for control of the traditional risk factors, spreading information about the potential adverse effect of opium use, which has only recently been associated with higher risk of CAD, may be necessary.


Fluorescence Quenching/Enhancement Surface Assays: Signal Manipulation Using Silver-coated Gold Nanoparticles.
Gold nanoparticles covalently attached to the indium tin oxide coated glass slide drastically quench fluorescence of a surface immunoassay (approximately 5-fold). Silver electrochemically deposited over the gold particles leads to fluorescence amplification: signal increases approximately 7-8 times if compared to the signal on gold particles not covered with silver. This phenomenon allows enhancing of the surface immunoassays utilizing both types of nanoparticles.


Non-necrotic invasive squamous cell carcinoma associated with an inverted papilloma: MRI features.
We present the MRI findings of a carcinoma associated with an inverted papilloma located in the nasal cavity. This tumor can be divided into 2 types, those with and those without gross central necrosis. In our case, the tumor did not have any gross central necrosis, and MRI showed convoluted cerebriform patterns. We found that MRI is unable to distinguish malignant and benign regions in a central mass with no gross necrosis, since this lesion does not alter the basic morphological pattern of inverted papilloma.


Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
Nav1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Nav1.5 could progress to proliferation and metastasis through Ca2+/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.


Geographical distribution of polycyclic aromatic hydrocarbons in estuarine sediments over China: Human impacts and source apportionment.
Human activity is suggested to increase polycyclic aromatic hydrocarbons (PAHs) pollution and also cause PAHs' sources complex in estuarine environments. However, the human impacts and source apportionment of PAHs in estuarine sediments at a continental scale remains poorly understood. In this study, we investigated geographical distribution of PAHs and used the compound-specific carbon isotope approach to characterize the sources of PAHs in the sediments of estuaries along the latitudinal gradient over China. We also used human population and economic size to characterize the human impacts on PAHs pollution in the estuaries. The concentrations of total PAHs (Σ16 PAH) in wet and dry seasons ranged from 60.9 to 330.7 ng g-1 and from 103.9 to 620.6 ng g-1, respectively, across the estuaries. At the continental scale, the concentrations of PAHs were significantly higher in dry than in wet seasons. The proportions of low molecular weight (LMW, 2-3 ring PAHs), middle molecular weight (MMW, 4 ring PAH) and high molecular weight (HMW, 5-6 ring PAHs) of PAHs varied largely across the estuaries, with being in a range of 26.4-48.5%, 17.2-34.1%, 25.3-46.8% in wet season and in a range of 24.0-58.4%, 18.4-52.4%, 21.8-48.6% in dry season. The concentrations of PAHs were found to be significantly correlated with per capita GDP throughout the studied estuaries. The δ13C of individual PAH ranged from -26 to -32‰ and from -24 to -29‰ in dry and wet seasons, respectively. The main sources of PAHs indicated by the δ13C across the estuaries were coal-processing and biomass combustion. These results suggest that the increasing human activities intensity can increase the PAHs pollution in sediments of the estuaries.


The transport of esterified cholesterol in plasma high density lipoproteins of human subjects: a mathematical model.
The pattern of labeling of free and esterified cholesterol in the plasma high-density lipoproteins after an intravenous injection of [3H]-mevalonic acid has been examined in six human subjects with a variety of plasma lipoprotein phenotypes. Attempts have been made to fit these data to theoretical models of high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol transport constructed on the basis of previous experimental observation. The first model, which assumed that the high-density lipoprotein esterified cholesterol comprised a single homogeneous pool, was incompatible with the observed data. The second model assumed a two-pool model in which all of the plasma esterified cholesterol was produced in a small, rapidly turning over subfraction of the high-density lipoproteins. From this pool it was assumed that esterified cholesterol was transferred to other lipoprotein fractions, including transfer to a larger and much more slowly turning over subfraction of the high density lipoproteins. The second model was quite compatible with the observed data. Furthermore, the calculated net transport of esterified cholesterol through the fast turning over pool was in a range similar to that reported elsewhere for whole plasma. It has been concluded that the two-pool model not only fits the experimental data, but also accords well with previously documented observations of plasma esterified cholesterol transport.


Molecular crowding as a mechanism for tick secretory granule biogenesis.
During feeding ticks secrete bioactive components into the host to counter-act its immune and hemostatic defense systems. These bioactive components are stored in secretory granules that are secreted during feeding in an exocrine stimulus-response type of mechanism. All proteins destined for secretion are packaged into these granules during granule biogenesis. Up to date no mechanism for granule biogenesis has been proposed, except to note that biogenesis occurs under conditions of high protein and calcium concentrations in an acidic environment. Previously, the most abundant proteins (TSGPs) found in the salivary glands of the soft tick, Ornithodoros savignyi, were suggested to play a part in granule biogenesis, based on their high abundance. The TSGPs are part of the lipocalin family, of which numerous members have been identified in ticks. We consider here the high concentrations of the TSGPs in salivary glands and what effect this will have on the crowded environment inside the secretory granules. It is shown that the TSGPs occur at concentrations that will lead to molecular crowding of which one result is the non-specific aggregation of components to reduce crowding effects. Aggregation of proteins as a mechanism of granule biogenesis has been proposed before, but not in terms of molecular crowding. We thus propose molecular crowding as the general mechanism of granule biogenesis, in tick secretory granules, but can also be extended to other forms of secretory granules in general.


[Ways of improving chemical training of students at medical institutes].
The paper considers how to extend medical students' knowledge and to provide chemical education within the framework of routine curricula. For this, the paper proposes that the view of regarding general chemistry as chemistry of elements should be given up and that the first part of the routine course of general chemistry should be supplemented with aspects of general inorganic, organic, and physical chemistry, that course of biological organic chemistry should contain chemistry of cell elements, as generally accepted in the world, obviating its irrespective issues of general organic chemistry. The results of introducing the approaches in question into teaching practice at the author-headed Department of Medical Chemistry, Therapeutical Faculty, Tyumen Medical Institute are given.


Fundus autofluorescence patterns in subretinal haemmorhages associated with neovascular age related macular degeneration.
Submacular haemmorhage (SMH) is a vision threatening complication of neovascular age related macular degeneration (AMD). The exact treatment scheme is not established yet. The aim of the current study is to describe surgical results and fundus autofluorescence (FAF) patterns after pars plana vitrectomy ppV + subretinal tissue plasminogen activator (tPA) + anti-vascular endothelial growth factor (VEGF) and intravitreal tPA + anti-VEGF + sulfur hexafluoride (SF6) tamponade and to compare them to intravitreal TPA + anti-VEGF + SF6 in the treatment of SMH in the course of AMD. We performed FAF imaging in patients with a previous SMH in the course of AMD with a duration of <60 days treated with vitrectomy with subretinal anti-VEGF and TPA and intravitreal anti-VEGF, TPA and SF6 administration (group 1) or intravitreal TPA + anti-VEGF + SF6 (group 2). In all eyes a throughout ophthalmic examination, fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) were done for diagnosis. SD-OCT was performed monthly during treatment. Three FAF patterns were observed in both groups. Pattern one (normal autofluorescence) was observed in 5/18 in group one and 5/21 group two. Pattern two was observed in 6/18 in group one and 7/21 in group two. Pattern three was noted in 7/18 in group one and 5/21 in group two. Improvement in visual acuity (VA) was statistically significant for both groups. 0.01 Snellen (2.0 logMAR) to 0.11 Snellen (0.96 logMAR) in group one (p=0.019), and 0.11 Snellen (0.96 logMAR) to 0.33 Snellen (0.48 logMAR) in group two (p=0.0007). Central retinal thickness (CRT) also decreased with statistical significance for both groups (p<0.05). FAF patterns did not depend on the treatment used, but solely on the duration of SMH before treatment. SMH if not treated prompt enough might cause long- standing photoreceptor and retinal pigment epithelium (RPE) defect, which is represented by hypo- and hyperautofluorescence. Performing a subretinal injection of TPA and anti-VEGF does not cause any defects associated with the injection site. That might be associated with previous local internal limiting membrane (ILM) peeling, which reduces the injection pressure. Not only prompt treatment of SMH, but also further continuation of anti-VEGF treatment is mandatory to maintain vision.


Bioactive fractions and compound of Ardisia crispa roots exhibit anti-arthritic properties mediated via angiogenesis inhibition in vitro.
Ardisia crispa (Thunb.) A.DC (Primulaceae), is a medicinal herb traditionally used by Asian people as remedies to cure inflammatory related diseases, including rheumatism. The plant roots possess various pharmacological activities including antipyretic, anti-inflammation and antitumor. Previous phytochemical studies of the plant roots have identified long chain alkyl-1,4-benzoquinones as major constituents, together with other phytochemicals. Hexane fraction of the plant roots (ACRH), was previously reported with anti-angiogenic and anti-arthritic properties, while its effect on their anti-arthritic in vitro, is yet unrevealed. Considering the significance of angiogenesis inhibition in developing new anti-arthritic agent, thus we investigated the anti-arthritic potential of Ardisia crispa roots by suppressing angiogenesis, in vitro. Ardisia crispa roots hexane extract (ACRH) was prepared from the plant roots using absolute n-hexane. ACRH was fractionated into quinone-rich fraction (QRF) and further isolated to yield benzoquinonoid compound (BQ), respectively. In vitro experiments using VEGF-induced human umbilical vein endothelial cells (HUVECs) and IL-1β-induced human fibroblast-like synoviocytes for rheumatoid arthritis (HFLS-RA) were performed to evaluate the effects of these samples on VEGF-induced HUVECs proliferation and tube formation, and towards IL-1β-induced HFLS-RA proliferation, invasion, and apoptosis, respectively. Therapeutic concentrations (0.05, 0.5, and 5 μg/mL) tested in this study were predetermined based on the IC50 values obtained from the MTT assay. ACRH, QRF, and BQ exerted concentration-independent antiproliferative effects on VEGF-induced HUVECs and IL-1β-induced HFLS-RA, with IC50 values at 1.09 ± 0.18, 3.85 ± 0.26, and 1.34 ± 0.16 μg/mL in HUVECs; and 3.60 ± 1.38, 4.47 ± 0.34, and 1.09 ± 0.09 μg/mL in HFLS-RA, respectively. Anti-angiogenic properties of these samples were verified via significant inhibition on VEGF-induced HUVECs tube formation, in a concentration-independent manner. The invasiveness of IL-1β-induced HFLS-RA was also significantly inhibited in a concentration-independent manner by all samples. ACRH and BQ, but not QRF, significantly enhanced the apoptosis of IL-1β-induced HFLS-RA elicited at their highest concentration (5 μg/mL) (P < 0.05). These findings highlight the bioactive fractions and compound from Ardisia crispa roots as potential anti-arthritic agents by inhibiting both HUVECs and HFLS-RA's cellular functions in vitro, possibly mediated via their anti-angiogenic effects.


Inhibition of NAMPT markedly enhances plasma-activated medium-induced cell death in human breast cancer MDA-MB-231 cells.
Plasma-activated medium (PAM), which is prepared by non-thermal atmospheric pressure plasma (NTP) irradiation of cell-free medium, has been shown to exhibit tumor-specific cytotoxicity. Since PAM contains reactive oxygen species (ROS) and reactive nitrogen species (RNS), its anticancer effects are considered to be responsible for oxidative stress induced by these reactive molecules. We previously reported that PAM-induced cell death is closely related to energy failure associated with a decrease in intracellular nicotinamide adenine dinucleotide (NAD+) and ATP levels. Nicotinamide phosphoribosyltransferase (NAMPT), which is a rate-limiting enzyme for NAD+ synthesis in the salvage pathway, was shown to be overexpressed in many types of cancer cells. The NAMPT inhibitor FK866 significantly depletes NAD+ and subsequently suppresses cancer cell proliferation. In this study, we examined the effects of FK866 on PAM-induced cytotoxicity using human breast cancer MDA-MB-231 cells. FK866 dose-dependently enhanced PAM-induced cell death in MDA-MB-231 cells. The combination of PAM and FK866 markedly induced intracellular NAD+ and ATP depletion. Knockdown of NAMPT by siRNA increased the cytotoxicity of PAM. The addition of NAD+ mitigated PAM-induced cell death. In addition, cotreatment with PAM and FK866 augmented ROS production and the decrease in intracellular reduced glutathione (GSH) compared to treatment with PAM alone. FK866 had little effect on PAM-induced mitochondrial dysfunction. Furthermore, the combination of PAM and FK866 decreased the level of NADPH, which is required for GSH metabolism, compared with PAM alone. Taken together, we conclude that cotreatment with NAMPT inhibitors is beneficial for anticancer therapy using PAM.


PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1.
Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1/RAGE/TLR4) and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynurenine/tryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisin/kexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mg/kg/week subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus-pituitary-adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynurenine/tryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1/RAGE/TLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab.


Antagonistic potential of Gliocladium virens and Trichoderma longibrachiatum to phytopathogenic fungi.
Three isolates of Gliocladium virens (G1, G2 and G3) and two of Trichoderma longibrachiatum (T1 and T2) were screened against isolates of three soilborne plant pathogens namely Rhizoctonia solani, Sclerotium rolfsii and Pythium aphanidermatum. G. virens exhibited stronger hyperparasitism and wider biological spectrum than T. longibrachiatum. Further, similarities as well as variation was observed in the ability of the various isolates to invade the test pathogens in dual culture. For the hyperparasites, acidic pH range (5.0 to 5.5) favoured both growth and spore germination. The hyperparasites made direct contact with the pathogens followed by varied modes of attack invariably leading to cell disruption. Antagonists, G1 and G3 revealed strong antibiosis while T2 showed moderate effect. All the isolates produced enhanced levels of lytic enzymes adaptively and there were marked differences among them. However, no correlation was observed between these attributes and the hyperparasitic potential of the various isolates in dual culture. The relevance and the role of enzymes and toxic metabolite(s) in the antagonism of G. virens and T. longibrachiatum to these pathogens are discussed.


Functional immune monitoring in severely injured patients-A pilot study.
After severe trauma, the resulting excessive inflammatory response is countered by compensatory anti-inflammatory mechanisms. The systemic inflammatory response to trauma enhanced by inappropriately timed surgical second hits may be detrimental for the patient. On the other hand, overwhelming anti-inflammatory mechanisms may put patients at increased risk from secondary local and systemic infections. The ensuing sepsis and organ dysfunction due to immune dysregulation remain the leading causes of death after injury. To date, there are no clinically applicable techniques to monitor the pro-/anti-inflammatory immune status of the patients and the remaining ability to react to microbial stimuli. Therefore, in the present study, we used a highly standardized and easy-to-use system to draw peripheral whole blood from polytraumatized patients (ISS ≥ 32, n = 7) and to challenge it with bacterial lipopolysaccharide. Secreted cytokines were compared with those in samples from healthy volunteers. We observed a significant decrease in the release of monocyte-derived mediators. Surprisingly, we detected stable or even increased concentrations of cytokines related to T cell maturation and function. For clinical practicability, we reduced the incubation time before supernatants were collected. Even after an abbreviated stimulation period, a stable release of almost all analysed parameters in patient blood could be detected. In conclusion, the data are indicative of a clinically well-applicable approach to monitor the immune status in severely injured patients in a short time. This may be used to optimize the timing of necessary surgical interventions to avoid a boost of proinflammation and reduce risk of secondary infections.


A microscopic model of wave-function dephasing and decoherence in the double-slit experiment.
The act of measurement on a quantum state is supposed to "dephase" (dephasing refers to the phenomenon that the states lose phase coherence; then the phases get randomized in interaction with a bath of other oscillators, which is referred to as "decoherence"), then "decohere" and "collapse" (or more precisely "register" and "reduce") the state into one of several eigenstates of the operator corresponding to the observable being measured. This measurement process is sometimes described as outside standard quantum-mechanical evolution and not calculable from Schrödinger's equation. Progress has, however, been made in studying this problem with two main calculation tools-one uses a time-independent Hamiltonian, while a rather more general approach proving that decoherence occurs under some generic conditions. The two general approaches to the study of wave-function collapse are as follows. The first approach, called the "consistent" or "decoherent"' histories approach, studies microscopic histories that diverge probabilistically and explains collapse as an event in our particular history. The other, referred to as the "environmental decoherence" approach studies the effect of the environment upon the quantum system, to explain wave-function decoherence which is produced by irreversible effects of various sorts. However, as we know, wave-function collapse is not related to thermal connection with the environment, rather, it is inherent to how measurements are performed by macroscopic apparata. In the "environmental decoherence" approach, one studies decoherence using a Markovian-approximated Master equation to study the time-evolution of the reduced density matrix (post dephasing) and obtains the long-time dependence of the off-diagonal elements of this matrix. The calculation in this paper studies the evolution of a quantum system starting with "dephasing" followed by the effects of the environment with some differences from prior analyses. We start from the Schrödinger equation for the state of the system, with a time-dependent Hamiltonian that reflects the actual microscopic interactions that are occurring. Then we systematically solve (exactly) for the time-evolved state, without invoking a Markovian approximation when writing out the effective time-evolution equation, i.e., keeping the evolution unitary until the end. This approach is useful, and it shows that the system wave-function will explicitly "un-collapse" if the measurement apparatus is sufficiently small. However, in the limit of a macroscopic system, this "dephasing" quickly leads to "decoherence"-collapse is a temporary state that will simply take extremely long (of the order of multiple universe lifetimes) to reverse. This has been attempted previously and our calculation is particularly simple and calculable. We make some connections to the work by Linden et al. while doing so. The calculation in this paper has interesting implications for the interpretation of the Wigner's friend experiment, as well as the Mott experiment, which is explored in "Connection to some general theoretical results" and "Recurrence times" (especially the enumerated points in "Recurrence times"). The upshot is that as long as Wigner's friend is macroscopically large (or uses a macroscopically large measuring instrument), no one needs to worry that Wigner would see something different from his friend. Indeed, Wigner's friend does not even need to be conscious during the measurement that she conducts. It also allows one to reasonably interpret some of the more recent thought experiments proposed. In particular, as a result of the mathematical analysis, the short-time behavior of a collapsing system, at least the one considered in this paper, is not exponential. Instead, it is the usual Fermi-golden rule result. The long-term behavior is, of course, still exponential. This is a second novel feature of the paper-we connect the short-term Fermi-golden rule (quadratic-in-time behavior) transition probability to the exponential long-time behavior of a collapsing wave-function in one continuous mathematical formulation.


Mechanisms underlying input-specific expression of endocannabinoid-mediated synaptic plasticity in the dorsal cochlear nucleus.
A hallmark of brain organization is the integration of primary and modulatory pathways by principal neurons. Primary sensory inputs are usually not plastic, while modulatory inputs converging to the same principal neuron can be plastic. However, the mechanisms determining this input-specific expression of synaptic plasticity remain unknown. We investigated this problem in the dorsal cochlear nucleus (DCN), where principal cells integrate primary auditory nerve input with plastic, parallel fiber input. Our previous DCN studies have shown that parallel fiber inputs exhibit short- and long-term plasticities mediated by endocannabinoid signaling. Here we show that auditory nerve inputs to principal cells do not show short- or long-term endocannabinoid-mediated synaptic plasticity. Electrophysiological and electron microscopy studies indicate that input specificity arises from selective expression of presynaptic cannabinoid (CB1) receptors in parallel fiber terminals, but not in auditory nerve terminals. However, pairing of parallel fiber activity with auditory nerve activity elicits plasticity in parallel fiber inputs, thus suggesting a role for synaptic plasticity in multisensory integration.


Transport, weathering and pollution of plastic from container losses at sea: Observations from a spillage of inkjet cartridges in the North Atlantic Ocean.
Observations of beached polypropylene inkjet cartridges, spilled from a ship container lost in the North Atlantic Ocean, have been compiled through calls on international social media. Within a period of four years from the spillage, a total of about 1500 cartridges was reported in locations as far apart as Florida and northern Norway. The distribution of cartridges reflected the principal surface currents in the ocean, with some carried by the Azores and Canary currents around the North Atlantic Gyre, and others transported northwards with the North Atlantic and Norwegian currents. Along the shorelines of the UK and Ireland, there was a clear, preferential accumulation of cartridges on west- and south-facing coasts, consistent with the direction of the North Atlantic current and the heading of the principal winds. Dates of first sightings in various regions throughout the North Atlantic (and as reported on social media) suggested that cartridges traveled on average at around 6-13 cm s-1. These observations and estimates were largely consistent with simulations of the dispersion of free floating, neutrally buoyant particles from the spillage site derived from PlasticAdrift, an empirical model based on drifter tracking data. Microscopic and X-ray fluorescence analyses of selected cartridges revealed a high degree of exterior weathering, resulting in chalking and embrittlement of the polypropylene and the formation of microplastics rich in Ti, chemical fouling of interior ink foams (where still present) by Fe oxides, and, in some cases, the presence of an electronic chip containing Cu, Au and brominated compounds. Significantly, the latter characteristic renders cartridges as electrical and electronic waste and means that current, conventional regulations on plastic cargo lost at sea are not applicable here. More generally, the study highlights the potential usefulness of social media-led citizen science to marine research, and inadequacies in the relevance and robustness of instruments and conventions that deal with plastic waste in the ocean.


The bronchodilator effect and pharmacokinetics of theobromine in young patients with asthma.
The bronchodilator effect of a 10 mg/kg dose of theobromine (3,7-dimethylxanthine) was compared with that of 5 mg/kg of theophylline (1,3-dimethylxanthine) in young patients with asthma. Bronchodilation, as assessed by forced vital capacity, forced expiratory volume in the first second, forced expiratory flows at 25%, 50%, and 75% of vital capacity, and percent of forced expiratory volume in the first second/forced vital capacity did not differ significantly between the two drugs. After each drug bronchodilation peaked at 2 hours and lasted for 6 hours, although it was not always statistically significant for theobromine. The mean peak serum concentrations of both drugs, the time at which peak serum concentrations occurred, and elimination half-life values were similar for theobromine and theophylline.


Materials used for mastoid obliteration and its complications: a systematic review.
The objectives of this review are to identify the types of materials with their associated complications and respective considerations when used to obliterate the mastoid cavity. A systematic search was performed across PubMed, Embase, Medline and Cochrane databases from January 2009 to January 2020 for randomized controlled trials and observational studies of patients that underwent mastoid obliteration. Studies that fulfilled the inclusion criteria were screened and scored according to the MINORS and relevance scores to determine final inclusion. Types of complications were grouped into minor and major complications based on the Clavien-Dindo classification. Two thousand five hundred and seventy-eight ears were evaluated. There were a total of 165 (7.9%) minor and 142 (6.8%) major complications in the autologous group. Overall complication rate is 14.8%. The major complications were largely recurrent and residual disease requiring revision surgery. There were 10 (18.5%) minor complications and three (5.6%) major complications in the allogenic group. The cumulative complications risk is 24%. For the synthetic group, there were 39 (8.0%) minor and 34 (7.6%) major complications. The cumulative complication rate is 16.6%. Current evidence on materials for mastoid obliteration has been evolving. Each material has its strengths and limitations. The trend over the last decade favours the use of autologous materials. The principle of using a material remains being cautious of not reimplanting skin that can lead to the development of a cholesteatoma. The choice of materials is dependent on patient factors as well as the surgeons' preference and experience.


The population burden of heart failure attributable to modifiable risk factors: the ARIC (Atherosclerosis Risk in Communities) study.
The goal of this study was to estimate the population burden of heart failure and the influence of modifiable risk factors. Heart failure is a common, costly, and fatal disorder, yet few studies have evaluated the population-level influence of modifiable risk factors. From 14,709 ARIC (Atherosclerosis Risk in Communities) study participants, we estimated incidence rate differences (IRD) for the association between 5 modifiable risk factors (cigarette smoking, diabetes, elevated low-density lipoproteins, hypertension, and obesity) and heart failure. Potential impact fractions were used to measure expected changes in the heart failure incidence assuming achievement of a 5% proportional decrement in the prevalence of each risk factor. Over an average of 17.6 years of follow-up, 1 in 3 African American and 1 in 4 Caucasian participants were hospitalized with heart failure, defined as the first hospitalization with International Classification of Diseases, Ninth Revision discharge codes of 428.x. Of the 5 modifiable risk factors, the largest IRD was observed for diabetes, which was associated with 1,058 (95% confidence interval [CI]: 787 to 1,329) and 660 (95% CI: 514 to 805) incident hospitalizations of heart failure/100,000 person-years among African-American and Caucasian participants, respectively. A 5% proportional reduction in the prevalence of diabetes would result in approximately 53 and 33 fewer incident heart failure hospitalizations per 100,000 person-years in African-American and Caucasian ARIC participants, respectively. When applied to U.S. populations, this reduction may prevent approximately 30,000 incident cases of heart failure annually. Modest decrements in the prevalence of modifiable heart failure risk factors such as diabetes may substantially decrease the incidence of this major disease.


A surgical navigated cutting guide for mandibular osteotomies: accuracy and reproducibility of an image-guided mandibular osteotomy.
3D-printed cutting guides are the current standard to translate the virtual surgery plan to the intraoperative setting. The production of these patient-specific cutting guides is time-consuming and costly, and therefore, alternative approaches are currently subject of research. The aim of this study was to assess the accuracy and reproducibility of using a novel electromagnetic (EM) navigated surgical cutting guide to perform virtually planned osteotomies in mandible models. A novel 3D navigated cutting guide (dubbed Bladerunner) was designed and evaluated with a total of 20 osteotomies, performed on plaster mandibular models according to preoperative planning using EM navigation. The pre- and postoperative scans were registered, and the difference between the preoperatively planned osteotomy and the performed osteotomy was expressed as the distance between the planned and performed cutting planes, and the yaw and roll angles between the planes. The mean difference in distance between the planned osteotomy and performed osteotomy was 1.1 mm (STD 0.6 mm), the mean yaw was 1.8° (STD 1.4°), and mean roll was 1.6° (STD 1.3°). The proposed EM navigated cutting guide for mandibular osteotomies demonstrated accurate positioning of the cutting plane according to the preoperative virtual surgical plan with respect to distance, yaw and roll angles. This novel approach has the potential to make the use of 3D-printed cutting guides obsolete, thereby decreasing the interval between diagnosis and surgery, reduce cost and allow for adaptation of the virtual plan in case of rapid tumor proliferation or unanticipated in situ deviations from the preoperative CT/MR imaging.


Mesorectal lymph nodes: their location and distribution within the mesorectum.
Total mesorectal excision is an alternative surgical approach for resectable rectal cancer and is associated with favorable results and a low rate of local recurrence. Despite the popularity of this technique, few data exist regarding the location and distribution of lymph nodes within the rectal mesentery. The purpose of this study was to define the distribution, size, and location of lymph nodes within the mesorectum and on the pelvic side wall. Seven fresh cadavers at our institution's Fresh Tissue Dissection Laboratory were studied. The rectum, its mesentery, and all fatty tissue from both pelvic side walls were removed and placed in a lymph node clearing solution for 24 hours. After appropriate dissection, the distribution, size, and location of lymph nodes within the rectal mesentery and pelvic side wall tissue were documented. A total of 174 lymph nodes were identified (approximately 25 per patient). The majority (>80 percent) of lymph nodes were smaller than 3 mm in diameter. Fifty-six percent of the nodes within the rectal mesentery were located in the posterior mesentery, and most were located in the upper two-thirds of the posterior rectal mesentery. The majority of perirectal lymph nodes are small. There are few lymph nodes within the mesentery of the lower third of the rectum and relatively few in the right and left lateral portions of the mesorectum. We confirm that the majority of nodes are located in the proximal two-thirds of the posterior rectal mesentery. It is possible that removal of these nodes is responsible for the superior oncologic results found with total mesorectal excision in contrast to more traditional surgical techniques.


Presence of 'PSI free' LHCI and monomeric LHCII and subsequent effects on fluorescence characteristics in lincomycin treated maize.
The cause of the strong non-photochemical fluorescence quenching was examined in maize (Zea mays L.) plants that were treated with lincomycin during the 72 h period of greening. They were deficient in core complexes but seemed to contain the full complement of antennae. The following results were obtained: (1) High F(o) could not be attributed to the dark reduction of Q(A) but to the presence of a high amount of not properly organized antenna complexes due to the inhibited synthesis of reaction centres. (2) On illumination fluorescence intensity dropped considerably below F(o) within 20 s, and reached a steady state still below F(o). (3) Slowly relaxing part of non-photochemical quenching was significantly higher than in control plants. (4) De-epoxidation state was constant, and corresponded to the maximal value of the control. (5) Free Lhca1/4 dimers could be detected in all submembrane fractions, including the grana, obtained by digitonin fractionation. (6) Increase in the 679 and 700 nm fluorescence emissions could be attributed to the monomerisation of part of LHCII and to the presence of free Lhca2 or LHCII aggregates, respectively. (7) LHCII or PSII+LHCII and Lhca1/4 interaction may contribute to the increase of long-wavelength fluorescence in the granal fraction. We assume that the elevated fluorescence quenching of monomeric LHCII as well as the interaction between LHCII or PSII+LHCII and Lhca1/4 can be considered as an explanation for the extensive non-photochemical fluorescence quenching in lincomycin treated plants. The permanent presence of zeaxanthin may have contributed to the fast formation of quenching.


Modelling patient trajectories using multimodal information.
Electronic Health Records (EHRs) aggregate diverse information at the patient level, holding a trajectory representative of the evolution of the patient health status throughout time. Although this information provides context and can be leveraged by physicians to monitor patient health and make more accurate prognoses/diagnoses, patient records can contain information from very long time spans, which combined with the rapid generation rate of medical data makes clinical decision making more complex. Patient trajectory modelling can assist by exploring existing information in a scalable manner, and can contribute in augmenting health care quality by fostering preventive medicine practices (e.g. earlier disease diagnosis). We propose a solution to model patient trajectories that combines different types of information (e.g. clinical text, standard codes) and considers the temporal aspect of clinical data. This solution leverages two different architectures: one supporting flexible sets of input features, to convert patient admissions into dense representations; and a second exploring extracted admission representations in a recurrent-based architecture, where patient trajectories are processed in sub-sequences using a sliding window mechanism. The developed solution was evaluated on two different clinical outcomes, unexpected patient readmission and disease progression, using the publicly available Medical Information Mart for Intensive Care (MIMIC)-III clinical database. The results obtained demonstrate the potential of the first architecture to model readmission and diagnoses prediction using single patient admissions. While information from clinical text did not show the discriminative power observed in other existing works, this may be explained by the need to fine-tune the clinicalBERT model. Finally, we demonstrate the potential of the sequence-based architecture using a sliding window mechanism to represent the input data, attaining comparable performances to other existing solutions. Herein, we explored DL-based techniques to model patient trajectories and propose two flexible architectures that explore patient admissions on an individual and sequence basis. The combination of clinical text with other types of information led to positive results, which can be further improved by including a fine-tuned version of clinicalBERT in the architectures. The proposed solution can be publicly accessed at https://github.com/bioinformatics-ua/PatientTM.


Diffuse peritoneal chlamydial infection presenting as possible ovarian peritoneal carcinomatosis in an adolescent female.
A 17-year-old girl presented with significant abdominal ascites associated with periumbilical pain. On examination, her abdomen was found to be soft and moderately distended with left lower quadrant tenderness. Abdominal computed tomographic scan demonstrated not only ascites but also diffuse peritoneal enhancement, a left-sided enhancing adnexal mass displacing the uterus to the right, as well as omental caking. Alpha fetoprotein level was normal, whereas carcinoembryonic antigen (3.4 ng/mL) and cancer antigen 125 (315 U/mL) were mildly elevated. Based on these findings, a presumptive diagnosis of peritoneal carcinomatosis of ovarian origin was made. However, intraoperative biopsy of the left adnexal mass showed only a lymphoplasmacytic infiltrate. Chlamydial polymerase chain reaction of an intraoperative cervical sample was positive, and the final diagnosis was complicated pelvic inflammatory disease. The patient responded well to a prolonged course of antibiotics.


Rewilding the cityUrban Jungle Ben Wilson Doubleday, 2023. 304 pp.
Urban environments can and should be rich reservoirs of biodiversity.


Trends in postpartum hemorrhage: United States, 1994-2006.
The purpose of this study was to estimate the incidence of postpartum hemorrhage (PPH) in the United States and to assess trends. Population-based data from the 1994-2006 National Inpatient Sample were used to identify women who were hospitalized with postpartum hemorrhage. Data for each year were plotted, and trends were assessed. Multivariable logistic regression was used in an attempt to explain the difference in PPH incidence between 1994 and 2006. PPH increased 26% between 1994 and 2006 from 2.3% (n = 85,954) to 2.9% (n = 124,708; P < .001). The increase primarily was due to an increase in uterine atony, from 1.6% (n = 58,597) to 2.4% (n = 99,904; P < .001). The increase in PPH could not be explained by changes in rates of cesarean delivery, vaginal birth after cesarean delivery, maternal age, multiple birth, hypertension, or diabetes mellitus. Population-based surveillance data signal an apparent increase in PPH caused by uterine atony. More nuanced clinical data are needed to understand the factors that are associated with this trend.


The Effects of Sports Drinks During High-Intensity Exercise on the Carbohydrate Oxidation Rate Among Athletes: A Systematic Review and Meta-Analysis.
Background: This study examines the effects of sports drinks ingestion during high-intensity exercise for carbohydrate oxidation rate (CHO-O) among athletes. Methods: PubMed, Embase, and the Cochrane library were searched for available papers published up to November 2019. The primary outcome is the carbohydrate oxidation rate (CHO-O), and the secondary outcome is the fat oxidation rate (Fat-O). Statistical heterogeneity among the included studies was evaluated using Cochran's Q test and the I2 index. The random-effects model was used for all analyses, regardless of the I2 index. Results: Five studies are included, with a total of 58 participants (range, 8-14/study). All five studies are randomized crossover trials. Compared to the control beverages, sports drinks have no impact on the CHO-O of athletes [weighted mean difference (WMD) = 0.29; 95% CI, -0.06 to 0.65, P = 0.106; I2 = 97.4%, P < 0.001] and on the Fat-O of athletes (WMD = -0.074; 95% CI, -0.19 to 0.06, P = 0.297; I2 = 97.5%, P < 0.001). Carbohydrate-electrolyte solutions increase CHO-O (WMD = 0.47; 95% CI, 0.08-0.87, P = 0.020; I2 = 97.8%, P < 0.001) but not Fat-O (WMD = -0.14; 95% CI, -0.31 to 0.03, P = 0.103; I2 = 98.2%, P < 0.001). Caffeine has a borderline effect on Fat-O (WMD = 0.05; 95% CI, 0.00-0.10, P = 0.050). Conclusions: Compared with the control beverages, sports drinks show no significant improvement in CHO-O and Fat-O in athletes. Carbohydrate-electrolyte solutions increase CHO-O in athletes but not Fat-O.


D-Tyrosine enhancement of microbiocide mitigation of carbon steel corrosion by a sulfate reducing bacterium biofilm.
Microbiocides are used to control problematic microorganisms. High doses of microbiocides cause environmental and operational problems. Therefore, using microbiocide enhancers to make microbiocides more efficacious is highly desirable. 2,2-dibromo-3-nitrilopropionamide (DBNPA) is a popular biodegradable microbiocide. D-Amino acids have been used in lab tests to enhance microbiocides to treat microbial biofilms. In this investigation, D-tyrosine was used to enhance DBNPA against Desulfovibrio vulgaris biofilm on C1018 carbon steel. After 7 days of incubation, the mass loss of coupons without treatment chemicals in the ATCC 1249 culture medium was found to be 3.1 ± 0.1 mg/cm2. With 150 ppm (w/w) DBNPA in the culture medium, the mass loss was reduced to 1.9 ± 0.1 mg/cm2 accompanied by a 1-log reduction in the sessile cell count. The 150 ppm DBNPA + 1 ppm D-tyrosine combination attained an extra 3-log reduction in sessile cell count and an additional 30% reduction in mass loss compared with 150 ppm DBNPA only treatment. The combination also led to a smaller maximum pit depth. Linear polarization resistance (LPR), electrochemical impedance spectrometry (EIS), and potentiodynamic polarization (PDP) tests corroborated the enhancement effects.


Bronchial challenges and respiratory symptoms in elite swimmers and winter sport athletes: Airway hyperresponsiveness in asthma: its measurement and clinical significance.
This study was aimed at the following: (1) the prevalence of airway hyperresponsiveness (AHR) and exercise-induced bronchoconstriction (EIB) in swimmers and winter sport athletes according to the previously recommended regulatory sport agencies criteria, (2) the relationship between respiratory symptoms and AHR/EIB, (3) the impact of the chosen cutoff value for AHR on its prevalence, and (4) the effect on the prevalence of the positive eucapnic voluntary hyperpnea (EVH) test of using the highest vs the lowest spirometric post-EVH values to calculate the magnitude of the airway response. We compared the prevalence of respiratory symptoms with responses to methacholine challenge and EVH in 45 swimmers, 45 winter sport athletes, and 30 controls. Two methacholine challenge cutoffs for AHR were analyzed: <or= 4 mg/mL (the sport agencies' criteria for AHR) and <or= 16 mg/mL. Sixty percent of swimmers, 29% of winter sport athletes, and 17% of controls had evidence of EIB or AHR (with the <or= 4 mg/mL criteria). Among athletes with a methacholine provocative concentration inducing a 20% decrease in the FEV(1) between 4 and 16 mg/mL, 43% of swimmers and 100% of winter sport athletes were symptomatic (P < .05). Prevalence of positive EVH tests were 39% in swimmers, 24% in winter sport athletes, and 13% in controls when the highest FEV(1) value measured at each time point post-EVH was used to identify maximal response for calculation of airway response, although these prevalences were higher if we used the lowest value. This study suggests that AHR/EIB is frequent in swimmers, whereas the frequently reported respiratory symptoms in winter sport athletes are often not related to AHR/EIB. Furthermore, the choice of methods for assessing methacholine challenge and EVH responses influences the prevalences of AHR and EIB. clinicaltrials.gov; Identifier NCT 00686491 and NCT 00686452.


Effects of hydraulic retention time on adsorption behaviours of EPS in an A/O-MBR: biofouling study with QCM-D.
Extra-cellular polymeric substances (EPS) are a major cause of membrane fouling in membrane bioreactors (MBRs). In this study, an anoxic-oxic membrane bioreactor (A/O-MBR) was run continuously for 98 days. The runs were divided into three stages according to hydraulic retention time (HRT) (11.8, 12.5 and 14.3 h, respectively). EPS were extracted from the reactor under the different HRTs. A quartz crystal microbalance with dissipation monitoring (QCM-D) and Fourier transform infrared (FT-IR) were used to study the adherence layer structures and the adsorption behaviours of EPS on the membrane surface. The results indicated that the removal rate of TN was more susceptible to HRT than NH3-N. The observations in the QCM-D suggested that at the lowest HRT (11.8 h), the structure of the adsorption layer is loose and soft and the fluidity was better than for HRTs of 12.5 or 14.3 h. It is likely one of the major reasons for the rapidly blocking of the membrane pores. Furthermore, the higher EPS adherence as analyzed in the QCM-D and EPS concentration could induce a higher osmotic pressure effect, leading to a rapid membrane-fouling rate.


GABAA Receptors and Maternally Derived Taurine Regulate the Temporal Specification of Progenitors of Excitatory Glutamatergic Neurons in the Mouse Developing Cortex.
Temporal specification of the neural progenitors (NPs) producing excitatory glutamatergic neurons is essential for histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPs, transit to radial glia (RG). To coincide with the transition, NPs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPs produce layer-specific neurons in a defined order with precise timing. Here, we show that GABAA receptors (GABAARs) and taurine are involved in this regulatory mechanism. Foetal exposure to GABAAR-antagonists suppressed the transition to RG, switch to asymmetric division, and differentiation into upper-layer neurons. Foetal exposure to GABAAR-agonists caused the opposite effects. Mammalian foetuses are dependent on taurine derived from the mothers. GABA and taurine function as endogenous ligands for GABAARs. Ca2+ imaging showed that NPs principally responded to taurine but not GABA before E13. The histological phenotypes of the taurine transporter knockout mice resembled those of the mice foetally exposed to GABAAR-antagonists. Foetal exposure to GABAAR-modulators resulted in considerable alterations in offspring behavior like core symptoms of autism. These results show that taurine regulates the temporal specification of NPs and that disrupting the taurine-receptor interaction possibly leads to neurodevelopmental disorders.