Detection of pathogenic bacteria in food samples using highly-dispersed carbon particles.
There is an unmet need for detection methods that can rapidly and sensitively detect food borne pathogens. A flow through immunoassay system utilizing highly dispersed carbon particles and an amperometric technique has been developed and optimized. A sandwich immunoassay format was utilized in which pathogenic cells were captured by antibodies immobilized onto activated carbon particles, and labeled with horseradish peroxidase (HRP) conjugated antibodies. Flow of the peroxidase substrates resulted in an amperometric signal that is proportional to the number of captured cells. Factors influencing the analytical performance of the system, such as the quantity of carbon particles and concentrations of capture antibody, enzyme labeled antibody, and enzyme substrates, were investigated and optimized. Detection and quantification of Escherichia coli, Listeria monocytogenes and Campylobacter jejuni were demonstrated with low detection limits of 50, 10, and 50 cells/ml, respectively, and an overall assay time of 30 min. Milk and chicken extract samples were spiked with various concentrations of these pathogens and were used to challenge the system. The system design is flexible enough to allow its application to the detection of viruses and proteins.


CD4+ and CD8+ T-cell kinetics in aviremic HIV-infected patients developing Hodgkin or non-Hodgkin lymphoma.
The risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is increased in HIV-infected individuals. We studied the kinetics of lymphocyte subsets in patients who subsequently developed HL or NHL while on virologically suppressive antiretroviral therapy (ART). Using a nested case-control design, cases of HIV+ HL or NHL were selected from two prospective clinical studies. Aviremia was defined as less than 200 HIV-RNA copies/ml for at least 6 months prior to lymphoma diagnosis. Each case was matched to three aviremic HIV+ controls without lymphoma. In the 81 cases (50 HL and 31 NHL), prediagnostic CD4 T cells and CD8 T cells displayed discordant kinetics compared with controls. Within the last and within the next-to-last year preceding HL diagnosis, mean CD4 T cells decreased by -168 and by -2 cells/μl, compared with an increase of +44 and +73 cells/μl in the controls, respectively. Mean CD8 T cells decreased by -352 and -115 cells/μl, compared with nonsignificant changes of -29 and ±0 cells/μl in the controls, respectively. T-cell kinetics demonstrated a marked inter-individual variability. Kinetics of CD4 and CD8 T cells were also discordant between NHL cases and controls. This study on a large number of aviremic patients developing HL and NHL who were carefully matched with controls, gives insights to prediagnostic kinetics of immune parameters. The discordant kinetics of both CD4 and CD8 T cells are already seen 1-2 years prior to lymphoma diagnosis, are more pronounced during the last year and in patients developing HL but are also seen in NHL.


Mental Health Treatment-Seeking Appraisal, Afrocentric Cultural Norms, and Mental Health Functioning: Buffering Factors of Young Black Men's Externalizing Behavior.
Depression rates are disproportionately high among Black American Men. This disparity--compounded by low mental healthcare seeking rates and high incorrect diagnosis rates in men--could be related to masculine norms, including self-reliance, restrictive emotionality, and stoicism. Furthermore, men are more likely to engage in externalized behavior, such as aggression, to cope with mental health challenges; this pattern is influenced by cultural and environmental factors. Contrary to these detrimental factors, social relationships, belief in social networks, and collectivism have been associated with positive mental health in these populations. Similarly, an Afrocentric worldview (including concepts like Ubuntu and African self-consciousness) has been hypothesized to promote positive mental health outcomes among Black American men. However, little research exists on harnessing these factors as a means of increasing health-seeking behaviors in young Black males. To elucidate the effect of region, depression, African humanism, collectivism, and help-seeking values and needs concerning aggression in young Black males. This study included Black or African American participants (n = 428) identifying as male, aged 18-25 years, who responded to a Qualtrics survey with questions on region, aggression, depression, African humanism, collectivism, and help-seeking value and need. Hierarchical linear regression revealed that collectivism, humanness, value, and the need for seeking treatment were inversely associated with aggression (p < 0.001). Highlighting the effect of cultural norms and help-seeking behaviors and the aggravating effect of depression on aggression in young Black males can help to develop aggression-mitigating interventions rooted in Afrocentric Norms.


Effect of β-N-methylamino-L-alanine on oxidative stress of liver and kidney in rat.
β-N-methylamino-(L)-alanine (L)-BMAA) is a neurotoxic amino acid, found in the majority of cyanbacterial genera tested. Evidence for implication of (L)-BMAA in neurodegenerative disorders, like amyotrophic lateral sclerosis (ALS), relies on bioaccumulation and biomagnification from symbiotic cyanobacteria. The involvement of (L)-BMAA in oxidative stress was demonstrated in several studies in the central nervous system. In the present study, we investigated the effect of (L)-BMAA on the oxidative stress responses of liver and kidney in rats treated by intraperitoneal administration with this amino acid. Oxidative stress was demonstrated by the quantification of lipid peroxidation, the measurement of both catalase and glutathione peroxidase activities, as well as the quantification of glutathione (GSH) levels and the total antioxidant capacity. It was observed that (L)-BMAA caused a significant increase in the degree of lipid peroxidation and catalase activity in both organs. A significant increase in glutathione peroxidase activity was obtained only in liver, whereas glutathione levels were also increased in both organs. The total antioxidant capacity decreased in liver and increased in kidney. These results suggest that the oxidative stress was higher in liver than in kidney, and might be crucial for (L)-BMAA toxicological action.


Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.
To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma). The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models. The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001). Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.


[Importance of dyslipidaemia in cardiovascular disease: a point of view].
The authors present their view on the prevention of cardiovascular diseases, accepting the European ESC/EAS guidelines. They consider that the aim of the lipid control, based on LDL-C goals, is essential for the prevention and treatment of cardiovascular diseases. In subjects with metabolic syndrome (mainly, abdominal obesity, pre-diabetes and diabetes), the primary objective should be apoB or Non-HDL-C, which are better associated with cardiovascular risk. The treatment must be lifestyle changes and control of other risk factors. After calculating cardiovascular risk, statins are the first therapeutic step, with the strength and dose needed to achieve LDL-C goals. If targets are not achieved, ezetimibe or resins should be added. A new group of potent cholesterol-lowering agents, the PCSK-9 monoclonal antibodies, have recently been approved in Spain. Subjects at very high cardiovascular risk that have achieved LDL-C goals, or other objectives (apoB, Non-HDL-C), other drugs (fibrates, omega-3) capable of modifying triglycerides and HDL-C could be added, if necessary. Treatment to reduce cardiovascular risk and prevent cardiovascular disease has proven effective in all populations and at all age groups. Subjects older than 80years should be individually assessed, taking into consideration possible comorbidities.


Ultrathin mesoporous BiOCl nanosheets-mediated liposomes for photoelectrochemical immunoassay with in-situ signal amplification.
Designing new biochemical sensors and achieving selectivity and high-sensitivity analysis is one of main research directions for immunoassays. Herein, a liposome-amplification photoelectrochemical (PEC) immunoassay was developed using ultrathin mesoporous bismuth chloride oxide nanosheets (BiOCl MSCN) for the highly selective and sensitive detection of carcinoembryonic antigen (CEA). Based on good photocurrent response of BiOCl MSCN toward dopamine, a liposome-conjugated secondary antibody loaded with dopamine was added for specific recognition in the presence of CEA. After the lysis treatment, the liberated dopamine was injected into the three-electrode electrolytic cell to enhance the photocurrent of BiOCl MSCN. Under the optimized conditions, the constructed liposome-mediated PEC immunoassay showed high sensitivity against CEA, with a dynamic response in the linear range of 0.05 ng mL-1 to 100 ng mL-1 and a detection limit of 35 pg mL-1. The present study proposes a new approach to the liposome-mediated PEC immunoassay constructed on ultrathin mesoporous BiOCl nanosheets, which can be used to target further the study of the sensing mechanism.


Rehabilitation Levels in Patients with COVID-19 Admitted to Intensive Care Requiring Invasive Ventilation. An Observational Study.
Rationale: Patients with severe coronavirus disease (COVID-19) have complex organ support needs that necessitate prolonged stays in the intensive care unit (ICU), likely to result in a high incidence of neuromuscular weakness and loss of well-being. Early and structured rehabilitation has been associated with improved outcomes for patients requiring prolonged periods of mechanical ventilation, but at present no data are available to describe similar interventions or outcomes in COVID-19 populations.Objectives: To describe the demographics, clinical status, level of rehabilitation, and mobility status at ICU discharge of patients with COVID-19.Methods: Adults admitted to the ICU with a confirmed diagnosis of COVID-19 and mechanically ventilated for >24 hours were included. Rehabilitation status was measured daily using the Manchester Mobility Score to identify the time taken to first mobilize (defined as sitting on the edge of the bed or higher) and highest level of mobility achieved at ICU discharge.Results: A total of n = 177 patients were identified, of whom n = 110 survived to ICU discharge and were included in the subsequent analysis. While on ICU, patients required prolonged periods of mechanical ventilation (mean 19 ± 10 d), most received neuromuscular blockade (90%) and 67% were placed in the prone position on at least one occasion. The mean ± standard deviation time to first mobilize was 14 ± 7 days, with a median Manchester Mobility Score at ICU discharge of 5 (interquartile range: 4-6), which represents participants able to stand and step around to a chair with or without assistance. Time to mobilize was significantly longer in those with higher body mass index (P < 0.001), and older patients (P = 0.012) and those with more comorbidities (P = 0.017) were more likely to require further rehabilitation after discharge.Conclusions: The early experience of the COVID-19 pandemic in the United Kingdom resembles the experience in other countries, with high acuity of illness and prolonged period of mechanical ventilation required for those patients admitted to the ICU. Although the time to commence rehabilitation was delayed owing to this severity of illness, rehabilitation was possible within the ICU and led to increased levels of mobility from waking before ICU discharge.Clinical trial registered with ClinicalTrials.gov (NCT04396197).


Antidepressant and antinociceptive activities in animal models and in vitro assessment of the anti-thyroid activity of bis(DL-pyroglutamate)magnesium complex.
Magnesium is an essential element related with biochemistry of the brain and different types of depression have been associated with its deficiency. The structure of a novel magnesium bis(DL-pyroglutamate) (Mg(DL-pGlu)2) was elucidated by X-ray crystallography. Wistar rats were used in the in vivo experiments. The antidepressant-like effect was assessed by the forced swim test (FST) and the antinociceptive activity was evaluated using hot plate test. In both, non-specific effects were evaluated by the open field test. Anti-thyroid activity was examined using Lang's method. Albumin binding behavior was evaluated by 3D fluorescence spectroscopy. For the Mg(DL-pGlu)2 complex (30 mg/kg), the FST test on Wistar rats revealed a decrease of 22% in the immobility time and an increment of 106% in the swimming time. The compound alters neither the locomotor activity nor the body weight after chronic administration. At the same dose, it showed antinociceptive activity, increasing the response latency. It blocks iodination reactions generating a charge transfer complex with iodine hence indicating anti-thyroid activity (Kc = 45366.5 ± 29 M-1). Albumin 3D fluorescence spectroscopy experiments showed intensity increase of peak A and decrease of peak B. The results showed that the new compound produced a lowering of the immobility time and an increment of the swimming ability of the rats. The compound is able to increase the response latency in 70.0%, to capture iodine (anti-thyroid activity) and to interact with albumin through covalent type of interaction of the free NH groups.


Synthesis, characterization, biological screenings and interaction with calf thymus DNA of a novel azomethine 3-((3,5-dimethylphenylimino)methyl)benzene-1,2-diol.
The novel azomethine, 3-((3,5-dimethylphenylimino)methyl)benzene-1,2-diol (HL) was synthesized and characterized by elemental analysis, FT-IR, (1)H, (13)C NMR spectroscopy and single crystal analysis. The title compound has been screened for its biological activities including enzymatic study, antibacterial, antifungal, cytotoxicity, antioxidant and interaction with CTDNA, and showed remarkable activities in each area of research. The titled compound interacts with DNA via two binding modes: intercalation and groove binding. In intercalation the compound inserts itself into the base pairs of DNA and the compound-DNA complex is stabilized by π-π stacking. Interaction via groove binding may be due to hydrogen bonding to bases, typically to N3 of adenine and O2 of thymine. The synthesized compound was also found to be an effective antioxidant of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and gives percent inhibition (%I) of 90.7 at a concentration level of 31.3μg/mL.


Single-Atom Co-N4 Electrocatalyst Enabling Four-Electron Oxygen Reduction with Enhanced Hydrogen Peroxide Tolerance for Selective Sensing.
Electrocatalysis of the four-electron oxygen reduction reaction (ORR) provides a promising approach for energy conversion, storage, and oxygen monitoring. However, it is always accompanied by the reduction of hydrogen peroxide (H2O2) on most employed catalysts, which brings down the electrocatalytic selectivity. Here, we report a single-atom Co-N4 electrocatalyst for the four-electron ORR at an onset potential of 0.68 V (vs RHE) in neutral media while with high H2O2 tolerance, outperforming commercial Pt electrocatalysts. Electrochemical kinetic analysis confirms that the Co-N4 catalytic sites dominantly promote the direct four-electron pathway of the ORR rather than the two sequential two-electron reduction pathways with H2O2 as the intermediate. Density functional theory calculations reveal that H2O2 reduction is hampered by the weak adsorption of H2O2 on the porphyrin-like Co centers. This endows the electrocatalyst with improved resistance to current interference from H2O2, enabling highly selective O2 sensing as validated by the reliable sensing performance in vivo. Our study demonstrates the intriguing advantage of single-atom catalysts with high capacity for tailoring metal-adsorbate interactions, broadening their applications in environmental and life monitoring.


Homoleptic Group 13 Trimethylsilylchalcogenolato Metalates [M(ESiMe3)4]- (M = Ga, In; E = S, Se): Metastable Precursors for Low-Temperature Syntheses of Chalcogenide-Based Materials.
We communicate the synthesis and full characterization of so far unknown tetrakis(trimethylsilylsulfido) and -(trimethylsilylselenido) gallates and indates in form of their organic salts Cat+[M(ESiMe3)4]- (M = Ga, In; E = S, Se; Cat = dimethylpyrrolidinium (DMPyr+), Ph4P+, (dppe)2Cu+, (dmpe)2Cu+). These thermally metastable silylchalcogenolatometalates can act as modular precursors for an ionic-liquid- or organic-solution-based low-temperature synthesis of multinary metal chalcogenide materials such as the CIGS species Cu(InxGa1-x)(SySe1-y)2.


Triterpenoid from Styrax japonica SIEB. et ZUCC, and its effects on the expression of matrix metalloproteinases-1 and type 1 procollagen caused by ultraviolet irradiated cultured primary human skin fibroblasts.
Long term and repeated exposure of ultraviolet light on the skin often induces chronic skin diseases such as skin cancer as well as photoaging, and the mechanisms of these skin damages are closely associated with up-regulation of matrix metalloproteinase's (MMPs) activities. The methylene chloride soluble fraction of methanol extract from the stems of Styrax japonica. (Styracaceae) showed significant MMP-1 inhibition in primary human skin fibroblasts cause by ultraviolet irradiation. Four triterpenoids were isolated by column chromatography. Among them, Erythrodiol-3-acetate reduced of MMP-1 and induced of type 1 procollagen at the protein levels in a dose-dependent manner.


gamma-Aminobutyric acid uptake by rat kidney brush-border membrane vesicles.
Brush-border membrane vesicles (BBMV) from rat kidney cortex possessed two uptake systems for gamma-aminobutyric acid (GABA), a high affinity system (Km = 10.9 microM) and a low affinity system (Km = 1203 microM). Both uptake systems were inhibited by p-hydroxymercuribenzoic acid and ouabain, and by the action of neuraminidase, whereas the GABA analogs nipecotic acid, beta-alanine, 2,4-diaminobutyric acid and 4,5,6,7-tetrahydroisoxazolo-[4,5 c]-pyridin-3-ol had no effect on the GABA uptake activity. The BBMV uptake systems were clearly different from the GABA transport systems present in brain tissue.


Epidemiology and Risk Factors for Severe Delayed Drug Hypersensitivity Reactions.
Severe delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune-mediated mechanisms. Common examples are severe cutaneous adverse reactions and druginduced internal organ injuries. The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. Several risk factors have been identified for reaction severity; some are transverse, such as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work, we reviewed the epidemiology of SCARs and liver/kidney/lung drug-induced immune-mediated reactions. We focus on particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors.


Human cells experience a Zn2+ pulse in early G1.
Zinc is an essential micronutrient required for all domains of life. Cells maintain zinc homeostasis using a network of transporters, buffers, and transcription factors. Zinc is required for mammalian cell proliferation, and zinc homeostasis is remodeled during the cell cycle, but whether labile zinc changes in naturally cycling cells has not been established. We use genetically encoded fluorescent reporters, long-term time-lapse imaging, and computational tools to track labile zinc over the cell cycle in response to changes in growth media zinc and knockdown of the zinc-regulatory transcription factor MTF-1. Cells experience a pulse of labile zinc in early G1, whose magnitude varies with zinc in growth media. Knockdown of MTF-1 increases labile zinc and the zinc pulse. Our results suggest that cells need a minimum zinc pulse to proliferate and that if labile zinc levels are too high, cells pause proliferation until labile cellular zinc is lowered.


Malaria in São Tomé and Príncipe: parasite prevalences and vector densities.
A cross-sectional survey was carried out in 16 localities on the island of São Tomé and three on the island of Príncipe, at the end of the rainy season of 1997, to determine malaria prevalence and vector densities. Blood samples from 664 inhabitants of all ages were examined by optical microscopy (OM) and PCR. Mosquito collections were made by outdoor landing captures from 21:00-23:00 h. Great differences were found between OM and PCR readings. OM had a sensitivity of 66%, a specificity of 79% and failed to reveal any mixed-infections. Overall prevalence, determined by PCR, was higher in São Tomé (53%) than in Príncipe (35%). It was highest in children below 16 years-old. All four human Plasmodium species occurred in São Tomé but P. ovale was not detected in Príncipe. The human population was largely asymptomatic. Bednet users had lower prevalence than did non-users. The FOREST form of Anopheles gambiae s.s., identified by PCR and cytogenetics, was the only vector on the islands. The sporozoite rate in São Tomé, assessed by ELISA, was 0.5%. Parasite prevalence and vector densities were positively correlated in São Tomé, where malaria transmission must occur predominantly in the more populated coastal areas.


Telmisartan versus EnalapRil In heart failure with redUced ejection fraction patients with Moderately impaired kidney Functions; randomized controlled trial: "TRIUMF trial".
When heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD) co-exist, Renin angiotensin-aldosterone system inhibitors (RAASi) are often underutilized for the fear of worsening renal function (WRF). Telmisartan is a RAASi characteristic for a favorable renal profile, although data on its utility in HFrEF is limited. This study aimed to compare efficacy and tolerability of Telmisartan versus Enalapril in patients with HFrEF and CKD. This study randomized 107 patients with HFrEF and CKD to either Telmisartan (10-80 mg) or Enalapril (5-40 mg) daily. The achieved RAASi dose, dose reductions (DR) or dis-continuation (DC), death/Heart failure rehospitalization (HFH), NYHA class and 6MWT were compared at 3- and 6-months. At 3- and 6-months, 93.5% versus 68.6% and 95.2% versus 72.9% were maintaining ≥ 50% of the target dose in the Telmisartan- versus Enalapril-group, respectively. Despite the higher achieved dose by 3- and 6-months, Telmisartan versus Enalapril was associated with less WRF (6.4% vs. 22.9%, p = 0.022 and 7.3% vs. 13.6%, p = 0.28) and fewer episodes of DR-DC (31.9% vs. 55.1%, p = 0.018 and 35.7% vs. 56.5%, p = 0.041), respectively. By the end of the study, there were 5 deaths in each group, yet, HFH occurred in 34.1% versus 55.3%, p = 0.035, and NYHA class changed by - 1 [- 2, 0] versus 0 [- 1, 1], p = 0.017 in Telmisartan- versus Enalapril patients, respectively. Within-group results showed improvement in 6MWT in Telmisartan-, and increase in diuretic requirements in Enalapril-group. In patients with HFrEF and CKD, Telmisartan was better tolerated to uptitrate, caused less WRF, less HFH and showed better functional improvement compared to Enalapril. Clinical trial registration This study was prospectively registered on clinicaltrials.gov, with registration number (NCT04736329).


Long-term prognosis of women with Brugada syndrome and electrophysiological study.
A male predominance in Brugada syndrome (BrS) has been widely reported, but scarce information on female patients with BrS is available. The purpose of this study was to investigate the clinical characteristics and long-term prognosis of women with BrS. A multicenter retrospective study of patients diagnosed with BrS and previous electrophysiological study (EPS) was performed. Among 770 patients, 177 (23%) were female. At presentation, 150 (84.7%) were asymptomatic. Females presented less frequently with a type 1 electrocardiographic pattern (30.5% vs 55.0%; P <.001), had a higher rate of family history of sudden cardiac death (49.7% vs 29.8%; P <.001), and had less sustained ventricular arrhythmias (VAs) on EPS (8.5% vs 15.1%; P = .009). Genetic testing was performed in 79 females (45% of the sample) and was positive in 34 (19%). An implantable cardioverter-defibrillator was inserted in 48 females (27.1%). During mean (± SD) follow-up of 122.17 ± 57.28 months, 5 females (2.8%) experienced a cardiovascular event compared to 42 males (7.1%; P = .04). On multivariable analysis, a positive genetic test (18.71; 95% confidence interval [CI] 1.82-192.53; P = .01) and atrial fibrillation (odds ratio 21.12; 95% CI 1.27-350.85; P = .03) were predictive of arrhythmic events, whereas VAs on EPS (neither with 1 or 2 extrastimuli nor 3 extrastimuli) were not. Women with BrS represent a minor fraction among patients with BrS, and although their rate of events is low, they do not constitute a risk-free group. Neither clinical risk factors nor EPS predicts future arrhythmic events. Only atrial fibrillation and positive genetic test were identified as risk factors for future arrhythmic events.


Heparin-associated priapism.
A patient who developed priapism 7 hr after stopping an intravenous heparin infusion is described. Abnormal spontaneous platelet aggregation was demonstrated whilst on heparin treatment and is thought to play a role in the aetiology of heparin induced priapism.


CuB promotes both binding and reduction of dioxygen at the heme-copper binuclear center in the Escherichia coli bo-type ubiquinol oxidase.
A CuB-deficient mutant of the Escherichia coli bo-type ubiquinol oxidase exhibits a very low oxidase activity that is consistent with a decreased dioxygen binding rate. During the turnover, a photolabile reaction intermediate persists for a few hundred milliseconds, due to much slower heme o-to-ligand electron transfer. Thus, the lack of CuB seems to have endowed the mutant enzyme with myoglobin-like properties, thereby stabilizing the CO-bound form, too. Accordingly we conclude that CuB plays a pivotal role in preferential trapping and efficient reduction of dioxygen at the heme-copper binuclear center.


High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial.
To assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with cystic fibrosis (CF). In this multicenter, double-blinded, placebo-controlled trial, a total of 142 patients age 6 to 18 years with mild lung disease (forced expiratory volume in 1 minute [FEV1] > 60 predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 mug/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annualized rate of change in FEV1% predicted. The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 +/- 0.51 vs -1.62 +/- 0.52; P = .03), but not FEV1%. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events. High-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated.


The Structure and Function of DNA G-Quadruplexes.
Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery.


Adsorptive removal of aromatic hydrocarbons from water over metal azolate framework-6-derived carbons.
Metal azolate framework-6 (MAF-6) was pyrolyzed at 1000°C to yield MOF-derived carbons (MCs). The obtained MCs were used to eliminate aromatic hydrocarbons, including polyaromatic hydrocarbons (PAHs; e.g., naphthalene (NAP), anthracene (ATC), and pyrene (PRN)) and benzene (BZ) from water via adsorption. The adsorption results over the MCs were compared with that of pristine MAF-6 and commercial activated carbon (AC). MC obtained after 24h (MC-24) exhibited a remarkable adsorption efficiency compared to that of the other MCs (obtained after different durations), MAF-6, and AC. For example, MC-24 led to adsorptions of NAP around 17 and 2.5 times those of pristine MAF-6 and AC, respectively. Or, the maximum adsorption capacities (Q0) of MAF-6, AC and MC-24 for NAP were 14, 104 and 237mg/g, respectively. Moreover, Q0 values of MC-24 for ATC and PRN were also very high of 284 and 307mg/g, respectively. Based on the properties of PAHs and the hydrophobicity of MC-24, hydrophobic interaction was suggested as the main mechanism for the adsorption of PAHs and BZ. In addition, MC-24 can be recycled by washing with acetone with little loss in performance. Therefore, MC-24 is recommended as a competitive adsorbent for aromatic hydrocarbon removal from water.


New approach to vital analysis of functional activity in ABC transporters (markers for multidrug resistance) in solid tumors by the method of flow cytofluorometry.
We developed and described a new approach to vital analysis of functional activity of multidrug resistance markers (ABC transporters) in intact biopsy specimens from human solid tumors by the method of flow cytofluorometry. The algorithm of the study underwent revision, and the cell suspension was obtained in the final stage. Intensification of intracellular doxorubicin accumulation (fluorescence) and increase in the number of fluorescent cells and total fluorescence of doxorubicin-accumulating cells produced by ABC transporter inhibitor sodium azide served as the criteria of expression of these transporters in tumor tissue. Informative value of changes in various parameters of doxorubicin fluorescence is discussed. The increase in the count of fluorescent cells in the suspension of tumors cells after treatment with the inhibitor indicates the presence of tumor cells absolutely resistant to this preparation. The proposed method is technically simple, suitable for structurally different tumors, requires small amounts of the biopsy material and, therefore, can be used for routine analysis. The results of our analysis and spectrofluorometric assay of ABC transporters agree very closely, which suggest that this method is adequate for the purpose.


Analysis of prednisolone in plasma by high-performance liquid chromatography.
A sensitive, specific high-performance liquid chromatographic procedure for the determination of prednisolone in plasma is described. The organic solvent extract from plasma is chromatographed on a silica gel column using a mobile phase of 0.2% glacial acetic acid, 6% ethanol, 30% methylene chloride in n-hexane on a high-performance liquid chromatograph fitted with an ultraviolet dector (254 nm). Quantitation of plasma samples containing 25 ng/ml prednisolone is reported. Metabolites and endogenous hydrocortisone do not interfere with prednisolone. The determination of prednisolone concentration in plasma following administration of a 10-mg single oral dose to a human subject is described.


DNA double-strand breaks in human induced pluripotent stem cell reprogramming and long-term in vitro culturing.
Human induced pluripotent stem cells (hiPSCs) play roles in both disease modelling and regenerative medicine. It is critical that the genomic integrity of the cells remains intact and that the DNA repair systems are fully functional. In this article, we focused on the detection of DNA double-strand breaks (DSBs) by phosphorylated histone H2AX (known as γH2AX) and p53-binding protein 1 (53BP1) in three distinct lines of hiPSCs, their source cells, and one line of human embryonic stem cells (hESCs). We measured spontaneously occurring DSBs throughout the process of fibroblast reprogramming and during long-term in vitro culturing. To assess the variations in the functionality of the DNA repair system among the samples, the number of DSBs induced by γ-irradiation and the decrease over time was analysed. The foci number was detected by fluorescence microscopy separately for the G1 and S/G2 cell cycle phases. We demonstrated that fibroblasts contained a low number of non-replication-related DSBs, while this number increased after reprogramming into hiPSCs and then decreased again after long-term in vitro passaging. The artificial induction of DSBs revealed that the repair mechanisms function well in the source cells and hiPSCs at low passages, but fail to recognize a substantial proportion of DSBs at high passages. Our observations suggest that cellular reprogramming increases the DSB number but that the repair mechanism functions well. However, after prolonged in vitro culturing of hiPSCs, the repair capacity decreases.


The transition from vitellogenesis to choriogenesis triggers the downregulation of the UPR sensors IRE1 and PERK and alterations in the ER architecture in the follicle cells of the vector Rhodnius prolixus.
In insects, the follicle cells (FCs) give rise to a single-layered tissue of binucleated professional secretory cells that surround the oocytes during oogenesis. In the latest stage of oocyte development, the FCs rapidly synthesize and secrete the chorion (eggshell) immediately before degenerating through apoptosis. Here, we used RT-qPCR, electron microscopy, and RNAi silencing to explore the role of the main unfolded protein response (UPR) receptors IRE1 and PERK, as well as the ultrastructure dynamics of the FCs during oogenesis of the insect vector of Chagas disease Rhodnius prolixus. We found that IRE1 and PERK mRNAs are highly expressed in the ovaries of vitellogenic females. Interestingly, we observed that IRE1 and PERK, as well as different isoforms of the chaperones Bip and PDI, have their FCs gene expression levels decreased during the vitellogenesis to choriogenesis transition. Using transmission electron microscopy, we observed that the downregulation of the UPR gene expression is accompanied by dramatic changes in the FCs ultrastructure, with an 80% reduction in the mean area of the ER tubules, and circularization and enlargement of the mitochondria. Additionally, we found that parental RNAi silencing of both IRE1 and PERK resulted in minor changes in the chorion protein composition and ultrastructure, accessed by urea extraction of the chorion proteins and scanning electron microscopy, respectively, but did not impact the overall levels of oviposition and F1 embryo development.


SAGE advice and political decision-making: 'Following the science' in times of epistemic uncertainty.
This article presents a preliminary analysis of the advice provided by the UK government's Scientific Advisory Group for Emergencies (SAGE) held between 22 January and 23 March 2020 in response to the emerging coronavirus pandemic. Drawing on the published minutes of the group's meetings, the article examines what was known and not known, the assumptions and working practices that shaped their work, and how this knowledge was reflected in the decisions made by the government. In doing so, the article critically examines what it means for policy making to be 'led by the science' when the best available science is provisional and uncertain. Using ideas of 'externality' and 'evidential significance', the article argues that the apparent desire for high levels of certainty by both scientists and political decision-makers made early action impossible as the data needed were not, and could not be, available in time. This leads to an argument for changes to the institutions that provide scientific advice based on sociologically informed expectations of science in which expert judgement plays a more significant role.


Enlargement of the hypofluorescent post photodynamic therapy treatment spot after a combination of photodynamic therapy with an intravitreal injection of bevacizumab for retinal angiomatous proliferation.
To report a case of enlargement of the post photodynamic therapy treatment (PDT) spot in a patient with retinal angiomatous proliferation (RAP) that was treated with PDT combined with an intravitreal injection of bevacizumab. 74-year-old woman with RAP due to age-related macular degeneration was treated with one verteporfin PDT session, sequenced by a single intravitreal injection of bevacizumab (1.25 mg) after 30 minutes. The patient's visual acuity (VA) at baseline was 20/200 and is now at the 10-month follow-up visit 20/400, while the RAP has disappeared according to the indocyanine angiography (ICG) findings. The post PDT hypofluorescent treatment spot has enlarged from 1,450 microm at the day of the treatment, to 5,360 microm at the 6-week visit. The patient is now at the 10-month follow-up visit and the hypofluorescence is still persisting. The simultaneous combination of PDT with bevacizumab in patients with RAP may enhance the photochemical stress in normal choroid with prolonged and magnified hypofluorescence in ICG, due to ischemia in normal choriocapillaries.


[Case of focal convexal subarachnoid hemorrhage presenting as transient ischemic attack mimic].
An 82-year-old man was suspected to have experienced a transient ischemic attack since he developed transient weakness in the right upper limb twice. On admission, neurologic examination yielded normal findings except for mild cognitive impairment. Brain CT and images showed an unexpected finding of acute focal subarachnoid hemorrhage in the left central sulcus, although MR angiography and venography did not show any abnormality. T(2)(*) weighted images showed superficial siderosis in the bilateral frontal lobes, which indicated the possibility of a recurrent subarachnoid hemorrhage. We propose that focal subarachnoid hemorrhage should be included in the differential diagnosis of transient ischemic attack.


Are mortality differences and trends by education any better or worse in New Zealand? A comparison study with Norway, Denmark and Finland, 1980-1990s.
During the 1980s and early 1990s New Zealand experienced major social and economic change, decreasing all-cause mortality rates for the majority ethnic group, and high (but falling) cardiovascular disease (CVD) mortality rates. This paper explores whether inequalities in mortality by education were greater, and increased more, in New Zealand than in Nordic countries (Denmark, Finland, Norway), and determines the contribution of CVD to these differences and trends. We used mortality rates for 30-59 year olds by education, and slope (SII) and relative (RII) indices of inequality, calculated from comparable linked census mortality data. Mortality inequalities in New Zealand were at the high end of the Nordic range when standardised by age only, but were mid-range when also standardised by ethnicity. Over time, relative inequalities in all-cause mortality increased similarly in all countries. In New Zealand a large increase in inequality for cardiovascular disease (CVD) mortality was the major contributor. In contrast both CVD and other causes of death were important drivers of increasing inequalities in Nordic countries. Absolute inequalities in all-cause mortality were stable over time among males across all countries, and increased modestly among females. The contribution of CVD to absolute inequality was stable or decreasing over time in all countries. Overall, inequalities in mortality in New Zealand did not widen more rapidly than in northern European countries. However, rapid social and economic change may have affected trends in CVD mortality among low educated men and women, and especially the ethnic minority groups.


Prevalence of hepatitis B virus infection among women at reproductive age at a German university hospital.
Mother to infant transmission of hepatitis B virus (HBV) represents a major factor in maintaining chronic infection and depends on the degree of maternal infectivity status. To examine the seroprevalence of hepatitis B virus surface antigen (HBsAg) in women at reproductive age admitted to the Department of Gynaecology at a German university hospital. The seroprevalence of hepatitis B surface antigen (HBsAg) in 5518 women at reproductive age was examined, HBsAg-positive samples were tested for additional HBV markers to verify the infection status. Out of 5518 samples from women at reproductive age, 88 women (1.59%) were positive for HBsAg and 7 of these HBV-positive women (7.95%) were additionally positive for HBeAg. The majority of the study population were German citizens, however most HBV infected persons originated from countries with a high HBV prevalence. The HBV seroprevalence in our study group is about two times higher compared to the average seroprevalence in the German citizen adult population, thus probably resulting in an underestimation of the infection rate in a multinational setting. Screening for HBsAg during pregnancy is still necessary and important for reduction of perinatal HBV transmission even in countries with low HBV prevalence.


Understanding the impact of media viscosity on dissolution of a highly water soluble drug within a USP 2 mini vessel dissolution apparatus using an optical planar induced fluorescence (PLIF) method.
In this study, planar induced fluorescence (PLIF) was used for the first time to evaluate variability in drug dissolution data using Rhodamine-6G doped tablets within small volume USP 2 apparatus. The results were compared with tablets contained theophylline (THE) drug for conventional dissolution analysis. The impact of hydrodynamics, sampling point, dissolution media viscosity and pH were investigated to note effects on release of these two actives from the hydrophilic matrix tablets. As expected mixing performance was poor with complex and reduced velocities at the bottom of the vessel close to the tablet surface; this mixing became even worse as the viscosity of the fluid increased. The sampling point for dissolution can affect the results due to in-homogenous mixing within the vessel; this effect is exacerbated with higher viscosity dissolution fluids. The dissolution profiles of RH-6G measured via PLIF and THE measured using UV analysis were not statistically different demonstrating that RH-6G is an appropriate probe to mimic the release profile of a highly soluble drug. A linear correlation was accomplished between the release data of the drug and the dye (R(2)>0.9). The dissolution profile of the dye, obtained with the analysis of the PLIF images, can be used in order to evaluate how the viscosity and the mixing performance of USP 2 mini vessel affect the interpretation of the dissolution data of the targeted drug.


The results of microneurosurgical reconstruction in complete brachial plexus palsy. Assessing outcome and predicting results.
The outcome of microsurgical reconstruction in 114 adult patients presenting with complete traumatic brachial plexus palsy was analyzed. The authors examined the effects of age, time since injury, operative findings, and the techniques of reconstruction on the level of muscle recovery. Statistical and analytic computer programs were used in an attempt to determine what factors most influenced recovery.


Treatment of textile dyeing industry effluent using hydrodynamic cavitation in combination with advanced oxidation reagents.
Treatment of textile dyeing industry (TDI) effluent was investigated using hydrodynamic cavitation (HC) and in combination with advanced oxidation reagents such as air, oxygen, ozone and Fenton's reagent. Slit venturi was used as the cavitating device in HC reactor. The effects of process parameters such as inlet pressure, cavitation number, effluent concentration, ozone and oxygen flow rate, loading of H2O2 and Fenton's reagent on the extent of reduction of TOC, COD and color were studied. Efficiency of the hybrid treatment processes were evaluated on the basis of their synergetic coefficient. It was observed that almost 17% TOC, 12% COD, and 25% color removal was obtained using HC alone at inlet pressure of 5bar and pH of 6.8. The rate of reduction of TOC and COD decreased with dilution of the samples. HC in combination with Fenton's reagent (FeSO4·7H2O:H2O2 as 1:5) was most effective with reduction of 48%TOC and 38% COD in 15min and 120min respectively with almost complete decolorization (98%) of the TDI effluent. Whereas HC in combination with oxygen (2L/min) and ozone (3g/h) produced reduction of 48% TOC, 33% COD, 62% decolorization and 48% TOC, 23% COD, 88%, decolorization of TDI effluent respectively.


Chromatin establishes an immature version of neuronal protocadherin selection during the naive-to-primed conversion of pluripotent stem cells.
In the mammalian genome, the clustered protocadherin (cPCDH) locus provides a paradigm for stochastic gene expression with the potential to generate a unique cPCDH combination in every neuron. Here we report a chromatin-based mechanism that emerges during the transition from the naive to the primed states of cell pluripotency and reduces, by orders of magnitude, the combinatorial potential in the human cPCDH locus. This mechanism selectively increases the frequency of stochastic selection of a small subset of cPCDH genes after neuronal differentiation in monolayers, 10-month-old cortical organoids and engrafted cells in the spinal cords of rats. Signs of these frequent selections can be observed in the brain throughout fetal development and disappear after birth, except in conditions of delayed maturation such as Down's syndrome. We therefore propose that a pattern of limited cPCDH-gene expression diversity is maintained while human neurons still retain fetal-like levels of maturation.


Molecular detection of bovine Noroviruses in Argentinean dairy calves: Circulation of a tentative new genotype.
Bovine noroviruses are enteric pathogens detected in fecal samples of both diarrheic and non-diarrheic calves from several countries worldwide. However, epidemiological information regarding bovine noroviruses is still lacking for many important cattle producing countries from South America. In this study, three bovine norovirus genogroup III sequences were determined by conventional RT-PCR and Sanger sequencing in feces from diarrheic dairy calves from Argentina (B4836, B4848, and B4881, all collected in 2012). Phylogenetic studies based on a partial coding region for the RNA-dependent RNA polymerase (RdRp, 503 nucleotides) of these three samples suggested that two of them (B4836 and B4881) belong to genotype 2 (GIII.2) while the third one (B4848) was more closely related to genotype 1 (GIII.1) strains. By deep sequencing, the capsid region from two of these strains could be determined. This confirmed the circulation of genotype 1 (B4848) together with the presence of another sequence (B4881) sharing its highest genetic relatedness with genotype 1, but sufficiently distant to constitute a new genotype. This latter strain was shown in silico to be a recombinant: phylogenetic divergence was detected between its RNA-dependent RNA polymerase coding sequence (genotype GIII.2) and its capsid protein coding sequence (genotype GIII.1 or a potential norovirus genotype). According to this data, this strain could be the second genotype GIII.2_GIII.1 bovine norovirus recombinant described in literature worldwide. Further analysis suggested that this strain could even be a potential norovirus GIII genotype, tentatively named GIII.4. The data provides important epidemiological and evolutionary information on bovine noroviruses circulating in South America.


Long-term outcomes after curative resection for patients with macroscopically solitary hepatocellular carcinoma without macrovascular invasion and an analysis of prognostic factors.
The long-term outcome and prognostic factors after curative in patients with single hepatocellular carcinoma (HCC) without macrovascular invasion are still unclear. The objective of this study is to evaluate the effect of curative resection on survival and analyze the prognostic clinicopathologic factors, especially the presence of microvascular invasion (MVI), in these patients. Two hundred and sixty consecutive patients with single HCC without macrovascular invasion who underwent curative resection from December 2004 to December 2007 were retrospectively reviewed in this study. Survival rates were calculated by using the Kaplan-Meier method. Univariate and multivariate analyses of 14 clinicopathologic factors were performed to determine the significant prognostic factors. No patient died within 1 month after the operation. The 1-, 3-, and 5-year overall survival rates after curative resection were 96.54, 83.46, and 74.01%, respectively. Multivariate analysis revealed that only the presence of MVI was an independent negative prognostic factor affecting overall survival. The 1-, 3-, and 5-year disease-free survival rates were 79.62, 62.69, and 56.01%, respectively. The presence of MVI was the only independent unfavorable prognostic factor for disease-free survival. According to our analysis, patients with single HCC without macrovascular invasion after curative resection can be expected to have considerable long-term survival. The presence of MVI was an independent negative prognostic factor for both overall survival and disease-free survival. To improve the prognosis, these patients should be followed up more carefully and might be good candidates for adjuvant therapy.


[Comparative study on effect of Tripterygium polyglycosides on mucous immune function of rat models of arthritis induced by collagen II and by adjuvant].
To observe the effects of Tripterygium polyglycosides (TWP) on mucous immune function in rat models of arthritis induced respectively with collagen-II induced arthritis (CIA) & adjuvant arthritis (AA). CIA and AA model rats were induced by immunization with collagen II emulsified with complete Freund's adjuvant and complete Freund's adjuvant respectively and treated with TWP. Rats' mucus, systemic immunological indexes (peripheral subsets of T cells), local inflammatory factors (IL-6, TNF-alpha, COX-2,and NF-kappaB, etc. ) were observed. In CIA model group, CD4+ in Peyer's Patch (PP), peripheral CD4+ and CD8+ positive T cells all raised, while in the AA model group, CD4+ lowered and CD8+ raised on PP, with both subsets increased. Effects of TWP on T lymphocyte subsets in PP and blood of the two models were different. High leveled IL-6, TNF-alpha, COX-2 and NF-kappaB expression could be seen in both model groups, and these inflammatory media could be inhibited by TWP. There exist similarities and differences between the two models in aspects of mucus immune response and effect of TWP on them.


Optical protein sensor for detecting cancer markers in saliva.
A surface immobilized optical protein sensor has been utilized to detect Interleukin-8 (IL-8) protein, an oral cancer marker, and can reach limit of detection (LOD) at 1.1 pM in buffer without using enzymatic amplification. Only after applying enzymatic amplification to increase the signal level by a few orders of magnitude, ELISA can reach the LOD of 1 pM level. We then develop the confocal optics based sensor for further reducing the optical noise and can extend the LOD of the surface immobilized optical protein sensor two orders in magnitude. These improvements have allowed us to detect IL-8 protein at 4.0 fM in buffer. In addition, these sensitive LODs were achieved without the use of enzymatic signal amplification, such that the simplified protocol can further facilitate the development of point-of-care devices. The ultra sensitive optical protein sensor presented in this paper has a wide number of applications in disease diagnoses. Measurements for detecting biomarkers in clinical sample are much more challenging than the measurements in buffer, due to high background noise contributed by large collections of non-target molecules. We used clinical saliva samples to validate the functionality of the optical protein sensor. Clinical detection of disease-specific biomarkers in saliva offers a non-invasive, alternative approach to using blood or urine. Currently, the main challenge of using saliva as a diagnostic fluid is its inherently low concentration of biomarkers. We compare the measurements of 40 saliva samples; half from oral cancer patients and half from a control group. The data measured by the optical protein sensor is compared with the traditional Enzyme-Linked Immunosorbant Assay (ELISA) values to validate the accuracy of our system. These positive results enable us to proceed to using confocal optical protein sensor to detect other biomarkers, which have much lower concentrations.


Patient satisfaction with pharmaceutical care: update of a validated instrument.
To develop a questionnaire for measuring patient satisfaction with pharmaceutical care and to establish its factorial composition. Single intervention, noncomparative, 20-item self-administered questionnaire. Iowa. Seven hundred seventy-five prescription patrons of eight community pharmacies whose pharmacists had received training in pharmaceutical care but who had not yet implemented it. An instrument originally developed to measure patient satisfaction with traditional community pharmacy services was modified to focus on the elements of pharmaceutical care. This revised questionnaire was mailed to participants. Participant responses to items in the questionnaire. The survey response rate was 55%. Factor analysis and item analysis identified two dimensions of pharmaceutical care. We labeled the dimensions Friendly Explanation (including items related to friendliness of care, the setting of care, and medication counseling) and Managing Therapy (items dealing with the concept of pharmaceutical care-managing drug therapy and solving therapy problems). Respondents scored items on the Managing Therapy scale lower than they did items on the Friendly Explanation scale. The scales were highly correlated. Two other hypothesized dimensions of care-Consideration/Caring Relationships and Setting-were subsumed in the final scale of Friendly Explanation. The instrument provides information on patients' satisfaction with two dimensions of pharmacy services. The instrument may be useful to practicing pharmacists, but it should be used cautiously until it is tested among patrons of pharmacies known to provide different levels of care.


Hexamethylmelamine as a single second-line agent in ovarian cancer.
Fifty-two patients with advanced ovarian cancer were treated with single-agent hexamethylmelamine (HMM), 260 mg/m2 po per day for 14 days followed by 14 days off drug. All patients had been previously treated with chemotherapy. Of these patients, 92% (48/52) received cisplatin and cyclophosphamide +/- doxorubicin prior to hexamethylmelamine. Two additional patients received other cisplatin-based regimens. Fifteen percent (8/52) were found to have no evidence of disease (NED) at the completion of treatment with HMM. Five of these patients are alive at 12 to 65 months (median follow-up of 32 months); one patient died at 41 months of an intercurrent illness with no clinical evidence of recurrence; two patients died of recurrent tumor at 21 and 31 months. The median survival of the series of 52 patients is 11 months: 9 months for patients who did not respond versus 41 months for patients with NED post-HMM (P less than 0.05). The regimen was well tolerated: moderate gastrointestinal toxicity was reported by 8 patients; only one patient reported severe gastrointestinal toxicity. Moderate neurologic toxicity (primarily sensory) was reported by 5 patients, 3 patients experienced white counts less than 2000 or platelet counts less than 100,000, and no patient sustained severe hematologic toxicity. This moderate-dose intermittent regimen was associated with moderate toxicity and was well accepted by patients. The overall response is comparable to or higher than that reported for more toxic chemotherapy regimes. Based on these data and those recently reported by other authors, hexamethylmelamine should be considered in the treatment of recurrent ovarian cancer.


Mixing and matching: the essence of plant systemic silencing?
In plants and some animals, posttranscriptional RNA silencing can be manifested beyond its sites of initiation, because of the movement of signaling molecules that must have RNA components to account for the nucleotide sequence specificity of their effects. In a recent study carried out in Arabidopsis thaliana, interesting clues were provided that suggest mechanisms by which systemic RNA silencing signals might be produced and perceived between distant plant organs.


Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo.
"Shock and kill" strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor κB (NF-κB) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.


Cytochemical duality of neurosecretory material in the hypothalamo-posthypophysial system of the rat as related to hormonal content.
Cytochemical methods using silver proteinate, silver methenamine an potassium ferrocyanide + OsO4 for ultrastructural detection of glycoproteins allow, in the posthypophysis and the magnocellular nuclei of the rat, differentiation of two types of fibres and neurons: one type containing negative granules with a homogenous content of low electron density, the second type containing granules which demonstrate a ring shaped deposit either of silver or of potassium ferrocyanide-osmium complex, likely to be related to a glycoprotein component. The difference between these two types is increased by prestaining "en bloc" with uranyl acetate before the silver proteinate reaction. A similar investigation was carried out on the vasopressin deficient Brattleboro rat; the neurosecretory material, present in some endings and neurons only, is of the nonreactive type, so that it appears justified to correlate the reactivity of granules with vasopressin, consequently to distinguish neurones and fibres containing vasopressin from those in which oxytocin is quantitatively the main hormonal peptide. This conclusion is strongly supported by the fact that percentages of reactive and negative endings, as determined on this basis in the posthypophysis of normal rats from two different strains, are in good agreement with biochemical data reported in the literature.


Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway.
Protein phosphatase 2A (PP2A) is a dephosphorylating enzyme, loss of which can contribute to prostate cancer (PCa) pathogenesis. The aim of this study was to analyse the transcriptional and translational expression patterns of individual subunits of the PP2A holoenzyme during PCa progression. Immunohistochemistry (IHC), western blot, and real-time PCR was performed on androgen-dependent (AD) and androgen-independent (AI) PCa cells, and benign and malignant prostate tissues for all the three PP2A (scaffold, regulatory, and catalytic) subunits. Mechanistic and functional studies were performed using various biochemical and cellular techniques. Through immunohistochemical analysis we observed significantly reduced levels of PP2A-A and -B'γ subunits (P<0.001 and P=0.0002) in PCa specimens compared with benign prostate. Contemporarily, there was no significant difference in PP2A-C subunit expression between benign and malignant tissues. Similar to the expression pattern observed in tissues, the endogenous levels of PP2A-A and B'γ subunits were abrogated from the low metastatic to high metastatic and AD to AI cell line models, without any change in the catalytic subunit expression. Furthermore, using in vitro studies we demonstrated that PP2A-Aα scaffold subunit has a role in dampening AKT, β-catenin, and FAK (focal adhesion kinase) signalling. We conclude that loss of expression of scaffold and regulatory subunits of PP2A is responsible for its altered function during PCa pathogenesis.


Stabilizing Non-Fullerene Organic Photodiodes through Interface Engineering Enabled by a Tin Ion-Chelated Polymer.
The recent emergence of non-fullerene acceptors (NFAs) has energized the field of organic photodiodes (OPDs) and made major breakthroughs in their critical photoelectric characteristics. Yet, stabilizing inverted NF-OPDs remains challenging because of the intrinsic degradation induced by improper interfaces. Herein, a tin ion-chelated polyethyleneimine ethoxylated (denoted as PEIE-Sn) is proposed as a generic cathode interfacial layer (CIL) of NF-OPDs. The chelation between tin ions and nitrogen/oxygen atoms in PEIE-Sn contributes to the interface compatibility with efficient NFAs. The PEIE-Sn can effectively endow the devices with optimized cascade alignment and reduced interface defects. Consequently, the PEIE-Sn-OPD exhibits properties of anti-environmental interference, suppressed dark current, and accelerated interfacial electron extraction and transmission. As a result, the unencapsulated PEIE-Sn-OPD delivers high specific detection and fast response speed and shows only slight attenuation in photoelectric performance after exposure to air, light, and heat. Its superior performance outperforms the incumbent typical counterparts (ZnO, SnO2 , and PEIE as the CILs) from metrics of both stability and photoelectric characteristics. This finding suggests a promising strategy for stabilizing NF-OPDs by designing appropriate interface layers.


Pituitary hyperplasia secondary to primary hypothyroidism: a case report and review of the literature.
Pituitary hyperplasia secondary to primary hypothyroidism has been reported in the literature in both adults and children. We report a case of a young woman who was diagnosed with hypothyroidism in her teenage years. Despite frequent follow-up, her TSH levels remained greater than 100 mIU/ml. A few years later, pituitary enlargement was found on an MRI at a time when her TSH was 177 mIU/ml and her free T4 was 0.2 ng/dl. Observed administration of 600 mcg of L-thyroxine was performed to determine the effectiveness of hormone absorption. Total T4 levels of 0.2 rose to 7.1 mcg/dl at two hours with a decrease in her TSH levels from 88.6 to 66.8 mIU/ml at 24 hours. With the exception of one short period, her TSH levels have remained elevated over eight years of observation without change in the size of the pituitary mass. In our review of the literature, primary uncontrolled hypothyroidism has been described as a precursor to pituitary hyperplasia. In these patients, TSH-secreting adenomas were distinguished from pituitary hyperplasia by a blunted TRH stimulation test, elevated alpha subunit concentration values, and elevated alpha subunit concentration/TSH ratios. TSH levels ranged from 98 to 732 mIU/ml in adults, and even higher values in children. Following adequate hormone replacement with L-thyroxine doses of 25 to 300 mcg/day, both symptoms and pituitary hyperplasia regressed on average within a few months.


Antigenic variants are not selected during persistent infection with Theiler's virus.
In this study, we demonstrated that non-neutralizable antigenic variants of Theiler's murine encephalomyelitis virus do not predominate during the course of chronic relapsing infection.


Prevention and treatment of allergic inflammation by an Fcγ-Der f2 fusion protein in a murine model of dust mite-induced asthma.
The immunoglobulin E (IgE) high-affinity receptor FcεRI expressed on mast cells and basophils plays a critical role in triggering allergic disease. The co-aggregation of the FcεRI and FcγRIIb receptors is inhibitory to FcεRI signaling and holds great potential for the treatment of IgE-mediated allergies. In China, Dermatophagoides farinae is a common anaphylaxis trigger. Therefore, in this study, the FcγRIIb-mediated immunomodulating activity of recombinant Fcγ-Der f2 fusion protein was tested in a Der f2-allergic murine model. Following the treatment, bronchoalveolar lavage fluid (BALF) was collected to measure the expression of several Th1/Th2-type cytokines (IL-5, TNF-α, IL-12p70, IL-4, IL-10, IFN-γ and IL-18) and histamine, while blood was used to detect the specific IgE and IgG-types anti-Der f2 antibodies, for measurement. In contrast to the saline-treated allergic mice, the levels of Der f2-specific IgE, cytokines and histamine were lowered in the Fcγ-Der f2-treated allergic mice, in addition to the rare inflammatory cell infiltration in the airways and blood vessels revealed by histopathological examination. The recombinant Fcγ-Der f2 protein was demonstrated to function as an effective immunotherapeutic agent, suggesting that chimeric human Fcγ-allergen proteins could be used in the development of antigen-specific immunotherapy for human allergic diseases.


Mapping of members of the low-copy-number repetitive DNA sequence family chAB4 within the p arms of human acrocentric chromosomes: characterization of Robertsonian translocations.
Members of the long-range, low-copy-number repetitive DNA sequence family chAB4 are located on nine different human chromosome pairs and the Y chromosome, i.e. on the short arms of all the acrocentrics. To localize the chAB4 sequences more precisely on the acrocentrics, chAB4-specific probes together with rDNA and a number of satellite sequences were hybridized to metaphase chromosomes of normal probands and of carriers of Robertsonian translocations of the frequent types rob(13q14q) and rob(14q21q). The results demonstrate that chAB4 is located on both sides of the rDNA on all the acrocentrics; the exact location, however, may be chromosome specific. Chromosome 22, most probably, is the only chromosome where chAB4 is found in the direct neighbourhood of the centromere. Fluorescence in situ hybridization analyses of metaphase chromosomes of carriers of rob(21q22q) revealed breakpoint diversity for this rare type of Robertsonian translocation chromosome. A direct involvement of chAB4 sequences in recombination processes leading to the Robertsonian translocations analysed in this study can be excluded.


Bilateral retinal ischemia in Kawasaki disease. Postmortem findings and electron microscopic observations.
A 4-month-old infant died of cardiovascular complications of Kawasaki disease (KD). At autopsy, aneurysmal dilatation with recent thromboses were found in coronary arteries, abdominal aorta, brachial and left common carotid arteries. A vasculitis with thrombosis of a branch of the ophthalmic artery was demonstrated in the right orbital apex. Light microscopy disclosed that the ocular abnormalities were confined to the retinas of both eyes that exhibited inner retinal ischemia. By electron microscopy, the inner retina showed clumping of nuclear chromatin, mitochondrial swelling, rupture of plasma membranes, and increased number of lipid figures. Müller cell processes were intact. Stereologic analysis of the mitochondria in the retinal pigment epithelium, photoreceptor inner segment, and ganglion cells in the KD infant demonstrated that identical mitochondrial changes occurred in the retina from an adult woman who had a recent central retinal artery occlusion.


Thalamic mechanisms of EEG alpha rhythms and their pathological implications.
During relaxed wakefulness, the human brain exhibits pronounced rhythmic electrical activity in the alpha frequency band (8-13 Hz). This activity consists of 3 main components: the classic occipital alpha rhythm, the Rolandic mu rhythm, and the so-called third rhythm. In recent years, the long-held belief that alpha rhythms are strongly influenced by the thalamus has been confirmed in several animal models and, in humans, is well supported by numerous noninvasive imaging studies. Of specific importance is the emergence of 2 key cellular thalamic mechanisms, which come together to generate locally synchronized alpha activity. First, a novel form of rhythmic burst firing, termed high-threshold (HT) bursting, which occurs in a specialized subset of thalamocortical (TC) neurons, and second, the interconnection of this subset via gap junctions (GJs). Because repetitive HT bursting in TC neurons occurs in the range of 2 to 13 Hz, with the precise frequency increasing with increasing depolarization, the same cellular components that underlie thalamic alpha rhythms can also lead to theta (2-7 Hz) rhythms when the TC neuron population is less depolarized. As such, this scenario can explain both the deceleration of alpha rhythms that takes place during early sleep and the chronic slowing that characterizes a host of neurological and psychiatric disorders.


Underlay mesh repair for spontaneous lumbar hernia.
Lumbar hernia is a rare condition with fewer than 300 cases reported in the literature. It arises through posterolateral abdominal wall defects, named the inferior triangle (Petit) and superior triangle (Grynfelt). It can be congenital or acquired, primary or secondary, peritoneal or extraperitoneal, reducible or complicated. We report a 63 year old female patient who presented to our hospital with a reducible right superior lumbar hernia. She underwent repair with underlay mesh after inversion of the sac and had a smooth postoperative course. In contrast to the classical procedure the underlay mesh modification saved us from enlarging the defect, and was quick and associated with minimal tissue injury. Underlay mesh repair for spontaneous lumbar hernia is feasible when the defect is small.


A novel global strain diastolic index correlates with plasma NT-proBNP levels in asymptomatic hypertensive patients with preserved left ventricular ejection fraction.
The strain imaging diastolic index (SI-DI) was reported to be a sensitive marker of regional left ventricular (LV) delayed relaxation induced by ischemia. However, the clinical usefulness of the global SI-DI has not been evaluated. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic diastolic LV dysfunction. This study investigated the ability of a novel parameter, the global SI-DI, obtained using 2D speckle tracking imaging (2DSI) to correlate with the plasma NT-proBNP levels in asymptomatic hypertensive patients with preserved LV ejection fraction. We performed 2D echocardiography and 2DSI in 83 asymptomatic hypertensive patients with preserved ejection fraction (>45 %) and in 37 control subjects. In 2DSI, the LV longitudinal peak strain and the SI-DI of 18 LV segments were measured. NT-proBNP was measured in all subjects. The data were compared between hypertensive patients and normal controls. The average peak strain and global SI-DI of 18 LV segments were significantly reduced in hypertensive patients compared with control subjects (P < 0.05); however, only the global SI-DI was significantly correlated with log10 NT-proBNP (r = -0.469, P = 0.001). In Pearson's correlation analyses, log10 NT-proBNP was significantly correlated with E/e', E/A ratio, early diastolic mitral annular velocity (e'), global peak strain, deceleration time of the E-wave, and LV ejection fraction. In the multiple stepwise regression analysis, the global SI-DI was the strongest independent determinant of log10 NT-proBNP (β = -0.386, P = 0.008). The global SI-DI derived from 2DSI correlates well with plasma NT-proBNP levels and may have prognostic value in asymptomatic hypertensive patients with preserved ejection fraction.


Cell cultures of bile duct epithelium and the pathogenesis of biliary atresia.
The pathogenesis of biliary atresia is unknown. The authors describe a technique for culturing extrahepatic bile duct epithelial cells of human and bovine origin in monolayer cell cultures. Light-, electron microscopy and immunohistological studies prove the epithelial nature of the cultured cells. Inoculation of the cells with reovirus 3 showed no destruction; adenovirus 6, herpes simplex and polio virus 1 and 2 destroyed the cells within 24 h. The cells produce a growth factor maintaining the integrity of the cells, even in the absence of serum.


Ocular motility problems after orbital decompression for dysthyroid ophthalmopathy.
Ocular motility problems of 50 consecutive patients following orbital decompression for dysthyroid (Graves') ophthalmopathy were analyzed retrospectively. No significant relationship to the development of postoperative diplopia was seen in the amount of retrodisplacement of the globe, the anatomical approach for orbital decompression, or the indication for decompression. Several clinical observations were made. Patients whose indication for orbital decompression was a vision-threatening ophthalmopathy were more likely (although not statistically significantly) to develop postoperative strabismus. Patients who developed changes in preoperative strabismus were more likely to develop increased esotropia and/or restrictive hypertropia. Of 32 patients who were orthotropic in the primary position before operation, 11 developed postoperative strabismus in the primary position. Only five patients had normal versions and ductions before operation. All five of these patients had normal versions and ductions after operation.


Foveal threshold of one eye when illuminated by contralateral steady light.
The effect of luminance of the contralateral steady light upon the foveal threshold was examined in the situation where both test-field and contralateral background (or surround) appeared to be completely fused when both were exposed simultaneously. The relation between the test threshold (defined as log Lt/Lto) and the luminance of the contralateral background (or surround) (I) was expressed by log (Lt/Lto) = a(1 - e-b log I), where a and b are constants.


Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4.
C4a is a small protein released from complement component C4 upon activation of the complement system's classical and lectin pathways, which are important constituents of innate immune surveillance. Despite the structural similarity between C4a and well-described anaphylatoxins C3a and C5a, the binding partner and biological function of C4a have remained elusive. Using a cell-based reporter assay, we screened C4a against a panel of both known and orphan G protein-coupled receptors and now provide evidence that C4a is a ligand for protease-activated receptor (PAR)1 and PAR4. Whereas C4a showed no activity toward known anaphylatoxin receptors, it acted as an agonist for both PAR1 and PAR4 with nanomolar activity. In human endothelial cells, ERK activation by C4a was mediated through both PAR1 and PAR4 in a Gαi-independent signaling pathway. Like other PAR1 activators, C4a induced calcium mobilization through the PAR1/Gαq/PLCβ signaling axis. Moreover, C4a increased stress fiber formation and enhanced endothelial permeability, both of which were reduced by PAR1 antagonists. In sum, our study identifies C4a as an untethered agonist for PAR1 and PAR4 with effects on cellular activation and endothelial permeability, thereby revealing another instance of cross-talk between the complement system and other host defense pathways.


MFSD12 mediates the import of cysteine into melanosomes and lysosomes.
Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions1,2. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans3,4. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation5,6. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin7-9. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.


Pro-inflammatory cytokines in patients with low back pain: A comparative study.
There are controversial results regarding the value of serum IL-8 and TNFα in patients with non-specific low back pain. This study aimed to compare pro-inflammatory cytokines between patients with non-specific back pain and pain-free controls. We conducted a case-control study including 106 participants: 46 patients with chronic non-specific low back pain (G1) and 60 pain-free controls (G0). The interleukin (IL-)6, IL-8, IL-17, IL-23, IL-22, and Tumor necrosis factor α (TNFα) were measured. We collected demographic and clinical data, including age, gender, low back pain duration and radicular pain. The pain degree was assessed using the Visual Analogic Scale. The mean age was 43.17±8.7 years in G1. Radicular pain was found in 37 cases with a Visual Analogic Scale of 3.03±2.5mm. The magnetic resonance imaging was performed in (G1), showing disk herniation and degenerative disk disease in 54.3% (n=25) and 45.7% of cases (n=21), respectively. The IL-8 was higher in G1 (18.84±44.64 versus 4.34±1.23pg/mL, p:0.033). IL-8 levels correlated with TNFα (0.942, p<10-3), IL-6 (0.490, p=0.011) and Visual Analogic ScaleRadicular-pain (r:0.297, p:0.047). IL-17 was higher in patients with restricted lumbar spine mobility (9.64±20.77 versus 1.19±2.54pg/mL, p:0.014). Our results provide evidence that IL-8 and TNFα play a role in low back pain and radicular pain due to disk degeneration or herniation. These findings could potentially be used by future studies to develop new non-specific low back pain therapeutic strategies.


Dehiscence of the superior semicircular canal: a review of the literature on its possible pathogenic explanations.
The dehiscence of superior semicircular canal is a well-known affection which is able to explain some cases of hearing loss, tinnitus and/or vertigo unexpectedly presenting in adults without previous otologic affections. Although a diagnostic algorithm has been assessed and a surgical therapy has been indicated, the review of the literature shows that a completely satisfactory explanation for the reason why symptoms of a supposed congenital condition only occur in adulthood is still lacking. A pathogenic hypothesis based on the slow metabolism of the bony labyrinth, which could in time result in a prevalence of bone re-absorption on new bone formation leading to a dehiscence, despite some controversial findings could represent a the most reliable explanation for the question.


Prucalopride for Treatment of Upper Gastrointestinal Symptoms in Children.
Upper gastrointestinal (GI) symptoms are common in pediatrics, and few prokinetics for children exist. The goal of this study was to determine the efficacy of prucalopride for treatment of upper GI symptoms and feeding difficulties in children. This was a retrospective study of patients prescribed prucalopride for upper GI symptoms at a single tertiary care center from July 2019 to January 2021. Demographic data, the indication for prucalopride, comorbidities, and feeding data were recorded. The primary outcome was improvement in the primary upper GI symptom at first follow-up after prucalopride initiation. Univariable and multivariable analyses were used to assess for factors associated with improvement. The final study population included 71 patients who received prucalopride for treatment of upper GI symptoms. The most common indications were nausea (44%), feeding difficulties (20%), and reflux (11%). Patients had a median age of 16.7 years (range 1.9-21.8 years), and they had received 4 ± 4.8 years of care in our GI clinic and trialed 3.0 ± 2.0 other GI medications by the time of the prucalopride prescription. At follow-up 3.6 ± 2.9 months after the prucalopride was prescribed, 46 patients (65%) had symptomatic improvement of the upper GI symptom. Improvement was more likely in patients with enteral tubes (p = 0.04), pulmonary comorbidities (p = 0.006), and neurologic comorbidities (p = 0.02). Amongst patients with feeding difficulties, 79% of patients showed improvements in oral or tube feeding. In this sample of children treated for refractory upper GI symptoms at a single tertiary care center, patients showed improvements in symptoms like nausea, reflux, and feeding difficulties after starting prucalopride.


The difference between interfaced and integrated systems.
The definitions of an "integrated system" and an "interfaced system" are unclear. Consequently, purchasers and developers of systems are often unable to judge the degree to which a system is integrated. This paper presents definitions of integrated systems and interfaced systems, describes the differences between the two, and reviews resulting conclusions.


Association of Ambient Particulate Matter Exposure with the Incidence of Glaucoma in Childhood.
We investigated whether exposure to air pollution, particularly to particles with a mass median aerodynamic diameter of ≤10 μm (PM10), is associated with diagnosis of childhood glaucoma. Retrospective cohort study. From the National Health Insurance Service-National Sample Cohort, a total of 9004 infants born between January 2002 and December 2002 were included and followed-up for an 11-year period (2003-2012). Patients with glaucoma were defined as International Classification of Diseases, 10th revision code H40. Exposure levels of PM10 were extrapolated using geographic information systems, and individual exposure levels were assigned. During the study period, glaucoma occurred in 85 patients (0.94%). The probability of developing childhood glaucoma increased with the increase in PM10 quartiles. Increases in 1 μg/m3 of long-term PM10 were significantly associated with increased hazard ratios (HRs) for childhood glaucoma (HR = 1.22 [95% confidence interval {CI} 1.15-1.28]). Compared with risk of the lowest PM10 exposure group (quartile 1), the adjusted HRs for childhood glaucoma were significant in the highest PM10 exposure group of quartile 4 (HR = 2.84 [95% CI 1.37-5.89]) in model 3. Regarding the long-term PM10 exposure, the estimated hazard was considerably elevated in quartile 4 (HR = 6.61 [95% CI 2.96-14.75]). Short-term and long-term exposure to PM10 was associated with the incidence of childhood glaucoma. This finding confirms previous reports on the link between air pollution and ocular disease and suggests that PM10 exposure may be a risk for childhood glaucoma.


The long-term prognosis of acute kidney injury: acute renal failure as a cause of chronic kidney disease.
There is a widespread opinion that acute kidney injury (AKI) is a rather harmless complication and that survival is determined not by renal dysfunction per se, but by the severity of the underlying disease. This opinion is in sharp contrast to evidence from several recent experimental and clinical investigations indicating that AKI is a condition which exerts a fundamental impact on the course of the disease, the evolution of associated complications and on prognosis, independently from the type and severity of the underlying condition. In conclusion, severe AKI in the critically ill patient is associated with high rates of morbidity, mortality and consumption of health care resources.


A computer program for predicting protein antigenic determinants.
A computerized method for predicting the locations of protein antigenic determinants is presented, which requires only the amino acid sequence of a protein, and no other information. This procedure has been used to predict the major antigenic determinant of the hepatitis B surface antigen, as well as antigenic sites on a series of test proteins of known antigenic structure [Hopp & Woods (1981) Proc. natn. Acad. Sci. U.S.A. 78, 3824-3828.] The method is suitable for use in smaller personal computers, and is written in the BASIC language, in order to make it available to investigators with limited computer experience and/or resources. A means of locating multiple antigenic sites on a homologous series of proteins is demonstrated using the influenza hemagglutinin as an example.


[A promising search for substances, suppressing the development of the human immunodeficiency virus, among natural and semisynthetic antibiotics].
Perspectives of search, among natural and semisynthetic antibiotics, for inhibitors of different stages of the human immunodeficiency virus replication are discussed. The compounds which inhibit the virus absorbtion, reverse transcription, viral mRNA synthesis, viral protein translation or viral glycoprotein processing are presented.


Function, essentiality, and expression of cytochrome P450 enzymes and their cognate redox partners in Mycobacterium tuberculosis: are they drug targets?
This review covers the current knowledge of the cytochrome P450 enzymes (CYPs) of the human pathogen Mycobacterium tuberculosis (Mtb) and their endogenous redox partners, focusing on their biological function, expression, regulation, involvement in antibiotic resistance, and suitability for exploitation as antitubercular targets. The Mtb genome encodes twenty CYPs and nine associated redox partners required for CYP catalytic activity. Transposon insertion mutagenesis studies have established the (conditional) essentiality of several of these enzymes for in vitro growth and host infection. Biochemical characterization of a handful of Mtb CYPs has revealed that they have specific physiological functions in bacterial virulence and persistence in the host. Analysis of the transcriptional response of Mtb CYPs and redox partners to external insults and to first-line antibiotics used to treat tuberculosis showed a diverse expression landscape, suggesting for some enzymes a potential role in drug resistance. Combining the knowledge about the physiological roles and expression profiles indicates that, at least five Mtb CYPs, CYP121A1, CYP125A1, CYP139A1, CYP142A1, and CYP143A1, as well as two ferredoxins, FdxA and FdxC, can be considered promising novel therapeutic targets.


Reduced Maternal Erythrocyte Long Chain Polyunsaturated Fatty Acids Exist in Early Pregnancy in Preeclampsia.
The present prospective study examines proportions of maternal erythrocyte fatty acids across gestation and their association with cord erythrocyte fatty acids in normotensive control (NC) and preeclamptic pregnancies. We hypothesize that maternal fatty acid status in early pregnancy influences fetal fatty acid stores in preeclampsia. 137 NC women and 58 women with preeclampsia were included in this study. Maternal blood was collected at 3 time points during pregnancy (16-20th weeks, 26-30th weeks and at delivery). Cord blood was collected at delivery. Fatty acids were analyzed using gas chromatography. The proportions of maternal erythrocyte α-linolenic acid, docosahexaenoic acid, nervonic acid, and monounsaturated fatty acids (MUFA) (p < 0.05 for all) were lower while total n-6 fatty acids were higher (p < 0.05) at 16-20th weeks of gestation in preeclampsia as compared with NC. Cord 18:3n-3, 22:6n-3, 24:1n-9, MUFA, and total n-3 fatty acids (p < 0.05 for all) were also lower in preeclampsia as compared with NC. A positive association was observed between maternal erythrocyte 22:6n-3 and 24:1n-9 at 16-20th weeks with the same fatty acids in cord erythrocytes (p < 0.05 for both) in preeclampsia. Our study for the first time indicates alteration in maternal erythrocyte fatty acids at 16th weeks of gestation which is further reflected in cord erythrocytes at delivery in preeclampsia.


Zygomatico-orbital fractures: historical perspective and current surgical management.
This article presents a general historical review of zygomatico-orbital (ZO) fractures with application of contemporary surgical procedures. Two surgical cases are presented, in which the ZO fractures were approached via a transconjunctival incision with a lateral canthotomy. A two-point rigid internal fixation, combined with a porous high-density polyethylene orbital floor reconstruction, produced uniformly excellent cosmetic and functional results in a total of 42 patients with ZO fractures who were treated over a 2-year period.


An efficient process for production and purification of hyaluronic acid from Streptococcus equi subsp. zooepidemicus.
Growth of Streptococcus zooepidemicus in a 10 l bioreactor with 50 g sucrose/l and 10 g casein hydrolysate/l gave 5-6 g hyaluronic acid/l after 24-28 h. Purification of hyaluronic acid gave a recovery of 65% with the final material having an Mr of approximately 4 x 10(6) Da with less than 0.1% protein.


Comparing the nitrogen removal performance and microbial communities of flocs-granules hybrid and granule-based CANON systems.
Flocs and granules tend to coexist in a single reactor. Granules can improve microbial retention capacity, however, the role of flocs in the CANON reactor remains unclear. The changes in the nitrogen removal performance and microbial communities between flocs-granules hybrid and granule-based systems were studied in this experiment. With a reduction in the flocs ratio (35% → 10%), the nitrogen removal performance deteriorated. The average nitrogen removal efficiency and rate dropped from 81.4% to 67.2% and from 0.225 to 0.174 kg/(m3·d), respectively. The contribution of heterotrophic denitrifying bacteria decreased from 13.5% to 1%, leading to changes in the nitrogen removal pathways between the systems. Furthermore, the activities of anaerobic and aerobic ammonium oxidizing bacteria declined dramatically, which weakened the nitrogen removal performance. Thus, the hybrid system with a flocs ratio near 35% is recommended for use in a CANON reactor.


From self-assembly to charge transport with single molecules - an electrochemical approach.
Structure formation and self-assembly of physisorbed and chemisorbed organic monolayers will be describedon electrified solid-liquid interfaces employing in-situ scanning tunneling microscopy (STM) and surface-enhancedinfrared spectroscopy (SEIRAS) in combination with electrochemical techniques. We present first a casestudy on self-assembly by directional hydrogen bonding and its interplay with the electrode potential choosingaromatic carboxylic acids, with an emphasis on 1,3,5-benzene-tricarboxylic acid (TMA). Structure and electricalcharacteristics of chemisorbed organic monolayers involving the formation of covalent bonds with the substratesurface will be discussed for a series of 4-methyl-4'-(n-mercaptoalkyl)biphenylson Au(111) electrodes. In an attempt to explore single molecule properties, such as charge transport andredox-mediated tunneling, we subsequently introduce an STM-based technique to construct symmetric and asymmetricmetal/(single) molecule/metal junctions. Employing α,ω-alkanedithiols and redox-active derivatives of viologens we demonstratenovel transport and single molecule electrochemical studies, which bear unique novel perspectives for fundamentalas well as applied investigations.


Early and Mid-Term Vascular Responses to Optical Coherence Tomography-Guided Everolimus-Eluting Stent Implantation in Stable Coronary Artery Disease.
Analysis of pooled clinical data has shown the safety of 3 months of dual antiplatelet therapy with everolimus-eluting cobalt-chromium stents (Co-Cr EESs). This study evaluated early and mid-term vascular responses to Co-Cr EESs in patients with stable coronary artery disease. The Multicenter Comparison of Early and Late Vascular Responses to Everolimus-Eluting Cobalt-Chromium Stent and Platelet Aggregation Studies in Patients With Stable Angina Managed as Elective Case (MECHANISM-Elective) study (NCT02014818) is a multicenter optical coherence tomography (OCT) registry. Enrolled patients were evaluated by OCT immediately after everolimus-eluting stent implantation were prospectively allocated to 1 month (n = 50) or 3 months (n = 50) OCT follow-up and then received a 12-month OCT evaluation. The incidences of intrastent thrombus (IS-Th) and irregular protrusion (IRP) were also assessed. The percentage of uncovered struts was 6.4% ± 10.3% at 1 month (P < 0.001 vs. postprocedure) and 0.5% ± 0.9% at 12 months (P < 0.001 vs. 1 month). The corresponding values in the 3-month cohort were 2.0% ± 2.5% (P < 0.001 vs. postprocedure) and 0.5% ± 1.5% (P < 0.001 vs. 3 months). The incidence of IS-Th was 32.7% at 1 month, 5.4% at 3 months, and 2.0% at 12 months. IRP was observed in 21.8% of patients post-EES but had totally resolved at 1, 3, and 12 months. Early and mid-term vascular reactions after Co-Cr EES implantation in stable patients with coronary artery disease in the MECHANISM-Elective included dynamic resolution of IS-Th and IRP and rapid decrease in uncovered struts. Thus, EES may allow shortening of dual antiplatelet therapy duration less than 3 months in this patient subset.


N-acetylneuraminic acid and hostile mucus infertility.
A total of 39 samples of hostile mucus, as defined by postcoital examination, were examined for N-acetylneuraminic acid (NANA) deficiency, as measured by the enzymatic addition of NANA, spermatozoal penetration and immobilization. Only 56.7% of the mucus samples were deficient in NANA and this did not correlate with spermatozoal penetration or immobilization, which were negatively correlated. Thus, as the spermatozoal hostility in the mucus decreases, spermatozoal penetration increases. This finding also applies to hostile mucus not deficient in NANA. In contrast, resialylation of NANA hostile mucus, deficient and not deficient in NANA, although not enhancing spermatozoal penetration, did reduce spermatozoal immobilization. Thus, components of the mucus deficient in NANA and/or the lack of unbound NANA may contribute to mucus hostility, but it is not the only hostile factor. In addition, SEM studies of NANA-deficient mucin before and after resialylation were shown to have similar structures. Hence ultrastructural changes are not apparent in NANA-deficient mucin, and this supports the previous finding that NANA deficiency does not impede spermatozoal penetration. The spermatozoa from the husbands of the infertile couples formed three distinct groups in terms of spermatozoal penetration and immobilization in normal donor mucus. One group demonstrated normal levels of spermatozoal penetration and immobilization in donor mucus. A second group was demonstrable in which spermatozoal penetration was similar to that in the wife's hostile mucus, but had a normal level of spermatozoal immobilization. In the third group, both spermatozoal penetration and immobilization in donor mucus were similar to that in the wife's hostile mucus. The results demonstrate that not all hostile mucus is deficient in NANA, and that other unknown factors are involved. In addition, there are also male factors which may impede spermatozoal penetration and/or result in the inability of the spermatozoa to survive in normal donor mucus.