Spontaneous phasic activity of the pig urinary bladder smooth muscle: characteristics and sensitivity to potassium channel modulators.
A hallmark for unstable bladder contractions is hyperexcitability and changes in the nature of spontaneous phasic activity of the bladder smooth muscle. In this study, we have characterized the spontaneous activity of the urinary bladder smooth muscle from the pig, a widely used model for studying human bladder function. Our studies demonstrate that phasic activity of the pig detrusor is myogenic and is influenced by the presence of urothelium. Denuded strips exhibit robust spontaneous activity measured as mean area under the contraction curve (AUC=188.9+/-15.63 mNs) compared to intact strips (AUC=7.3+/-1.94 mNs). Spontaneous phasic activity, particularly the amplitude, is dependent on both calcium entry through voltage-dependent calcium channels and release from ryanodine receptors as shown by inhibition of spontaneous activity by nifedipine and ryanodine respectively. Inhibition of BK(Ca) channels by iberiotoxin (100 nM) resulted in an increase in contraction amplitude (89.1+/-20.4%) and frequency (92.5+/-31.0%). The SK(Ca) channel blocker apamin (100 nM) also increased contraction amplitude (69.1+/-24.3%) and frequency (53.5+/-13.6%) demonstrating that these mechanisms are critical to the regulation of phasic spontaneous activity. Inhibition of K(ATP) channels by glyburide (10 microM) did not significantly alter myogenic contractions (AUC=18.5+/-12.3%). However, K(ATP) channel openers (KCOs) showed an exquisite sensitivity for suppression of spontaneous myogenic activity. KCOs were generally 15 fold more potent in suppressing spontaneous activity compared to contractions evoked by electrical field-stimulation. These studies suggest that potassium channel modulation, particularly K(ATP) channels, may offer a unique mechanism for controlling spontaneous myogenic activity especially those associated with the hyperexcitability occurring in unstable bladders.


Nanovesicle-Mediated Targeted Delivery of Immune Checkpoint Blockades to Potentiate Therapeutic Efficacy and Prevent Side Effects.
Despite the clinically proven efficacies of immune checkpoint blockades, including anti-cytotoxic T lymphocyte-associated protein 4 antibody (αCTLA-4), the low response rate and immune-related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA-4 therapy are mainly due to the suboptimal activation of tumor-specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA-4 is delivered by dendritic cell-derived nanovesicles presenting tumor antigens (DCNV-TAs) that exclusively interact with tumor-specific T cells, leading to selective activation of tumor-specific CTLs. Compared to conventional αCTLA-4 therapy, treatment with αCTLA-4-conjugated DCNV-TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor-bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA-4 and tumor antigens enables selective activation of tumor-specific T cells and potentiates the antitumor efficacy of αCTLA-4 without inducing systemic irAEs.


Infant eye movement asymmetries: temporal-nasal asymmetry is reversed at isoluminance in 2-month-olds.
Tested monocularly with luminance-modulated stimuli, young infants classically show a directional asymmetry of eye movements: optokinetic nystagmus (OKN) and OKN-like eye movements are more reliably elicited by temporo-nasally- (T-N) than by naso-temporally- (N-T) directed stimuli. In the present experiment, 2-month-old infants were tested with isoluminant red-green gratings. A reverse asymmetry was found: at isoluminance, directionally appropriate eye movements were more readily elicited by N-T- than by T-N-directed stimuli. The results suggest the presence of a reverse asymmetry in the ensemble of direction-selective neurons that controls young infants' immature eye movements in response to isoluminant stimuli.


A New Temperature Control Shifting Strategy for Enhanced Triterpene Production by Ganoderma lucidum G0119 Based on Submerged Liquid Fermentation.
Temperature control is a very important factor on triterpene productivity in submerged liquid fermentation. Temperature effects from 23 to 32 °C on triterpene production by Ganoderma lucidum G0119 were investigated in 6-L stirred fermentor. Logistic and Luedeking-Piret equations were used to estimate the mycelial growth and triterpene production kinetics by regression analysis. On that basis, a temperature-shifting fermentation control strategy was established. From 0 to 61 h, culturing was performed at 32 °C to get high specific mycelial growth rate. Between 62 and 127 h, the temperature was decreased stepwise from 31 to 30 °C to maintain high triterpene productivity. After 128 h, temperature was maintained at 29 °C to minimize triterpene production inhibition and sustain high productivity. Elevated triterpene level (0.269 g L-1), yield (0.0101 g g-1), and productivity (0.00207 g (L h)-1) were achieved representing 27.32, 13.94, and 37.11 % higher than submerged liquid fermentation at constant temperature of 29 °C, respectively, feasible for the industrial scale.


Mesenteric leiomyosarcoma in a 13-year-old boy.
Mesenteric leiomyosarcoma occurs most commonly in middle-aged individuals. Primary tumors of the mesentery are uncommon in pediatric and adolescent patients, and primary mesenteric leiomyosarcoma is particularly rare. Accurate preoperative diagnosis of mesenteric soft tumor is generally difficult. We describe a case of leiomyosarcoma arising from the ileal mesentery in a 13-year-old boy. The diagnosis was based on histopathologic evaluation using immunohistochemical staining and gene analysis.


Low basal levels of circulating adiponectin in patients undergoing coronary stenting predict in-stent restenosis, independently of basal levels of inflammatory markers: lipoprotein associated phospholipase A2, and myeloperoxidase.
The aim of this study was to find a pre-interventional marker with the capacity to predict in-stent restenosis (ISR). Considering the anti-atherosclerotic role of adiponectin (APO), an adipocytokine with anti-inflammatory, anti-proliferative, anti-oxidative and anti-thrombotic properties, low plasma levels of APO might be correlated with the risk of ISR. We investigated the correlations between the plasma levels of APO and two markers of inflammation: lipoprotein associated phospholipase A2 (Lp-PLA2) and myeloperoxidase (MPO). 80 patients with angiographically significant stenosis underwent percutaneous coronary intervention (PCI) with bare metal stent. Plasma APO concentration and plasma Lp-PLA2 and MPO activities were evaluated immediately before and after PCI, then followed-up at 24, 48, 72 h, and at 1, 3, 6 months, respectively. ISR was evaluated at 6 months after stenting by follow-up coronary angiograms, and it was defined as >50% stenosis of the target lesion. ISR was present in 33.75% of patients. Baseline APO plasma concentration, measured before PCI, was lower in ISR patients than those without ISR [3.97 (+/-1.05) vs 6.65 (+/-2.95) microg/mL respectively, p<0.001]. The patients with APO values less than 4.9 microg/mL at discharge were more susceptible to develop ISR (odd ratio, 4.27; 95% CI, 1.56-11.72, p<0.001). ISR rate was independent of inflammation markers Lp-PLA2 and MPO baseline values, measured before PCI. The persistence of a low APO plasma level at discharge and 6 months afterwards may be used as a clinically useful marker for ISR prediction in patients undergoing PCI.


The primary structure of rat ribosomal protein S6.
The amino acid sequence of rat ribosomal protein S6, the major phosphoprotein in the organelle, was deduced from the sequence of nucleotides in two recombinant cDNAs and confirmed from the sequence of amino acids in portions of the protein. Ribosomal protein S6 contains 249 amino acids and has a molecular weight of 28,683. The protein has 15 seryl residues; 7 are located in the carboxyl-terminal sequence of 15 amino acids and probably include most if not all of the residues that are phosphorylated. There are related repeated sequences of 10 amino acids each that occur at four separate positions in S6 and that are very basic. Rat S6 is homologous to Saccharomyces cerevisiae S10 (the extent of the identity is 75%) and most likely also to Schizosaccharomyces pombe S6.


Methylselenocysteine treatment leads to diselenide formation in human cancer cells: evidence from X-ray absorption spectroscopy studies.
The selenoamino acids methylselenocysteine (MeSeCys) and selenomethionine (SeMet) have disparate efficacies as anticancer agents. Herein, we use X-ray absorption spectroscopy to determine the chemical form of selenium in human neuroblastoma cells. Cells treated with MeSeCys contain a significant diselenide component, which is absent from SeMet-treated cells and suggests that metabolites of MeSeCys are capable of altering the redox status of the cells. The differences in the speciation of Se in the selenoamino acid-treated cells may provide insight into the differing anticancer activities of MeSeCys and SeMet.


Intrathecal clonidine reduces the incidence of ischemia-provoked ventricular arrhythmias in a canine postinfarction heart failure model.
Intrathecal clonidine (ITC) is used clinically to manage neuropathic pain but frequently causes hypotension and bradycardia due to centrally mediated sympatholytic effects. The purpose of this study was to evaluate the cardiac electrophysiologic effects of thoracic ITC and its effects on ischemia-provoked ventricular arrhythmias. Twelve mongrel dogs with healed myocardial infarctions and heart failure were evaluated. ITC was delivered locally via catheter to the T2-T4 spinal segments and was dosed to reduce heart rate (HR) by >20% to 25%. Electrophysiologic testing was performed before and after ITC. Transient (4-minute) myocardial ischemia was induced via left circumflex coronary artery occlusion on two separate occasions to provoke ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]). Ischemic episodes were separated by 1 to 2 days, and dogs were randomly assigned to receive ITC or intrathecal saline flush (control) prior to the first or the second ischemic episode. ITC produced significant decrease in HR (31%) and increases in PR interval (22%), Wenckebach cycle length (122%), and atrial and ventricular effective refractory periods (19% and 9%, respectively) but had no significant effect on systemic blood pressure. The occurrence of VT/VF was reduced from 9 of 12 to 3 of 12 dogs when ITC was administered prior to transient myocardial ischemia (P = .04). ITC also blunted ischemia-induced HR increase by 74%. ITC reduced ischemia-induced VT/VF in a canine model of healed myocardial infarction with superimposed heart failure and acute ischemia. Results from electrophysiologic testing were consistent with a clonidine-induced reduction in cardiac sympathetic activity from the spinal cord. These data suggest that ITC administration may be a novel approach to treating ventricular arrhythmias.


2-DE combined with two-layer feature selection accurately establishes the origin of oolong tea.
Taiwan is known for its high quality oolong tea. Because of high consumer demand, some tea manufactures mix lower quality leaves with genuine Taiwan oolong tea in order to increase profits. Robust scientific methods are, therefore, needed to verify the origin and quality of tea leaves. In this study, we investigated whether two-dimensional gel electrophoresis (2-DE) and nanoscale liquid chromatography/tandem mass spectroscopy (nano-LC/MS/MS) coupled with a two-layer feature selection mechanism comprising information gain attribute evaluation (IGAE) and support vector machine feature selection (SVM-FS) are useful in identifying characteristic proteins that can be used as markers of the original source of oolong tea. Samples in this study included oolong tea leaves from 23 different sources. We found that our method had an accuracy of 95.5% in correctly identifying the origin of the leaves. Overall, our method is a novel approach for determining the origin of oolong tea leaves.


The early origins of obesity and insulin resistance: timing, programming and mechanisms.
Maternal obesity is associated with an increased risk of developing gestational diabetes mellitus and it also results in an increased risk of giving birth to a large baby with increased fat mass. Furthermore, it is also contributes to an increased risk of obesity and insulin resistance in the offspring in childhood, adolescence and adult life. It has been proposed that exposure to maternal obesity may therefore result in an 'intergenerational cycle' of obesity and insulin resistance. There is significant interest in whether exposure to maternal obesity around the time of conception alone contributes directly to poor metabolic outcomes in the offspring and whether dieting in the obese mother before pregnancy or around the time of conception has metabolic benefits for the offspring. This review focusses on experimental and clinical studies that have investigated the specific impact of exposure to maternal obesity during the periconceptional period alone or extending beyond conception on adipogenesis, lipogenesis and on insulin signalling pathways in the fat, liver and muscle of the offspring. Findings from these studies highlight the need for a better evidence base for the development of dietary interventions in obese women before pregnancy and around the time of conception to maximize the metabolic benefits and minimize the metabolic costs for the next generation.


Comparison of two different vitamin D supplementation regimens with oral calcifediol in kidney transplant patients.
Vitamin D deficiency is prevalent in kidney transplant recipients (KTR) and recommendations on how to replenish vitamin D deposits are scarce. To evaluate, in KTR, the safety and efficacy of calcifediol in two different vitamin D supplementation regimens, in order to assess the most suitable dose. Prospective observational study with two calcifediol supplementation regimens randomly prescribed by clinicians in liquid form, at 266 mcg doses, monthly or biweekly. We analyzed 168 KTR with a functioning allograft for more than 6 months. Patients receiving other vitamin D forms, calcimimetics or bisphosphonates were excluded. Before calcifediol initiation (pre-treatment levels) and after at least 3 months of treatment (post-treatment levels), we measured serum levels of 25-OH vitamin D (25(OH)D), parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium (sCa), phosphate (sPO4) and creatinine (sCreat). In the monthly group (n = 72), 25(OH)D levels increased from 14 ng/ml [interquartile range, IQR 9-22] at baseline to 31 [20-38] (p = 0.000), PTH decreased from 124 pg/ml [87-172] to 114 [78-163] (p = 0.006), while sCa and sPO4 remained stable. In the biweekly group (n = 96), 25(OH)D increased from 14 ng/ml [9-20] at baseline to 39 [28-52] (p = 0), PTH decreased from 141 pg/ml [95-221] to 112 [90-180] (p = 0.000), sCa remained stable and sPO4 increased from 3.3 ± 0.6 mg/dl to 3.5 ± 0.6 (p = 0.003). Renal function remained stable in both groups. Vitamin D reposition with oral calcifediol, in a biweekly or monthly regimen, is safe and effective in improving 25(OH)D blood levels and in decreasing PTH in kidney transplant recipients.


Association of depression and anxiety disorder with the risk of mortality in breast cancer: A National Health Insurance Service study in Korea.
To examine whether depression, anxiety disorder, and their co-occurrence would increase the risk of mortality in patients with breast cancer, and whether antidepressant treatment would reduce the same. Data were retrieved from the database of the Korean National Health Insurance Service. Of 145,251 patients diagnosed with breast cancer between 2007 and 2014, 20,870 patients diagnosed with depression or anxiety disorder one year before breast cancer diagnosis were excluded. Thus, data of 124,381 patients were included in this study. Depression and anxiety disorder were associated with an increased risk of mortality [Hazard Ratio (HR) 1.26, 95% CI 1.18-1.36; HR 1.14, 95% CI 1.08-1.22, respectively] and their co-occurrence further increased the risk (HR = 1.38, 95% CI 1.24-1.54). Antidepressant treatment was related to a reduced risk of mortality. Compared to patients without any psychiatric comorbidity with no antidepressant treatment, the mortality risk increased in patients with either psychiatric comorbidity or both, but the risk seemed to attenuate with antidepressant treatments. The current findings suggest that psychiatric comorbidities are markers of increased mortality risk in patients with breast cancer, and antidepressant treatment may attenuate the risk. This underscores the need for screening and treating depression and anxiety disorders to improve survival in patients with breast cancer.


Use of iRNA in the post-transcriptional gene silencing of necrosis-inducing Phytophthora protein 1(NPP1) in Phytophthora cinnamomi.
Phytophthora cinnamomi is an Oomycetes associated with soil, this Oomycete is one of the most destructive species of Phytophthora, being responsible for the decline of more than 5000 ornamental, forest, or fruit plants. It can secrete a class of protein NPP1 (Phytophthora necrosis inducing protein 1), responsible for inducing necrosis in leaves and roots of plants, leading to their death. This work will report the characterization of the Phytophthora cinnamomi NPP1 gene responsible for the infection of Castanea sativa roots and will characterize the mechanisms of interaction between Phytophthora cinnamomi and Castanea sativa, by gene silencing NPP1 from Phytophthora cinnamomi mediated by RNAi. For silencing a part of the coding region of the NPP1 gene, was placed in the sense and antisense directions between an intron and ligated to the integrative vector pTH210. Cassette integration was confirmed by PCR and sequencing on the hygromycin-resistant Phytophthora cinnamomi transformants. Transformants obtained with the silenced gene was used to infect Castanea sativa. Plants infected with these transformants showed a great reduction in disease symptoms, confirming iRNA as a potential alternative biological tool in the study of molecular factors, and in the control and management of Phytophthora cinnamomi.


Qualitative Research as a Basis for Transforming an Annual Plague Into an Economic and Nutrition Opportunity for Youths and Their Families in Madagascar: "From Harmful to Useful Critters" for Sustainable Development.
Madagascar is among the 10 highest burden countries for malnutrition. Protein-energy malnutrition, anemia, and vitamin deficiencies are major public health problems. Hunger is exacerbated by an annual locust invasion. The current policy of large-scale government spraying of pesticides from planes is logistically complex, costly, and damaging to the environment. Our research aimed to study the feasibility of turning the locust invasion into a protein-rich food supply for families and an economic opportunity for youth. We conducted 20 focus group discussions (FGDs) with females and males aged 18-24 and 25 years or older and with female artisans in 6 swarm communes in Madagascar's south to understand enablers and barriers to collection, preparation, and consumption of locusts. Enablers include consumption by all ages in Antandroy culture and perception of locusts as a delicacy, tasty, and free. Family members have different roles in the collection and preparation of locusts. Local technologies for mass collection include digging trenches in fields and entrapment via sisal netting. Common preparations include boiling in salted water, drying, skewering, frying, and grinding locusts into flour. Disablers include pesticide contamination of locusts and the view that locusts are a famine food. Our research provided a first step in demonstrating the feasibility of transforming locust infestations into economic and nutritional opportunities in a fragile environment with high levels of poverty and malnutrition. It contributes to advocacy in Madagascar to end the use of pesticides. It responds to the government desire to address the protein-energy malnutrition burden and youth poverty in an integrated way.


Structuration of multilocus genotypes associated with insecticide resistance of the peach potato aphid, Myzus persicae (Sulzer), in potato fields in southern Belgium.
The peach potato aphid, Myzus persicae, has developed resistance to many insecticides. In Belgium, M. persicae is one of the most common aphids in potato fields and one of the most effective virus vectors. We monitored resistance mutations to pyrethroids, carbamates and neonicotinoids and related these results to microsatellite genotyping to provide information to support the choice of management tactics. Most of the 254 aphids tested (97.6%) displayed at least one mutation conferring resistance to pyrethroids (L1014F, M918L and M918T) and 36.2% additionally carried the modified acetylcholinesterase (MACE) carbamates resistance making them resistant to two insecticide action modes. Ten mutation combinations were detected, two of which were frequent and a strong linkage was found between MACE and M918L mutations. The R81T mutation conferring resistance to neonicotinoids was not detected. Microsatellites highlighted a moderate genetic diversity [69 multilocus genotypes (MLG) detected], severe deviations from Hardy-Weinberg expectations, a highly significant excess of heterozygotes and linkage disequilibrium between all pairs of loci. A structuration of MLGs in association with the mutation combinations was observed. Genetic differentiation was mainly not significant between sampling locations and most MLGs were geographically widespread. These results suggest the likely coexistence of parthenogenesis (obligatory or facultative) and sexual reproduction, and the existence of 'old' parthenogenetic overwintering asexual lineages. The results of this monitoring at a regional scale provide useful information on insecticide resistance, genetic diversity and reproductive modes, and highlight the need to reduce the insecticide selection pressure and to implement mitigating techniques.


Pharmacokinetics of TH-302: a hypoxically activated prodrug of bromo-isophosphoramide mustard in mice, rats, dogs and monkeys.
To characterize the pharmacokinetics of the prodrug, TH-302, and its active metabolite, bromo-IPM (Br-IPM), in nonclinical species. TH-302 was administered in single oral, intraperitoneal and intravenous bolus doses to mice, rats, dogs and monkeys as well as in acute and chronic safety studies in rats and dogs as a 30-min intravenous infusion given once a week for 3 weeks. Assessments were made using liquid chromatography-tandem mass spectrometry. TH-302 was extensively distributed with high systemic clearance exceeding hepatic plasma flow in all species studied, resulting in half-lives ranging between 8 min (mice) and over 4 h (rats). In rats, TH-302 exhibited linear kinetics following intravenous administration and good oral bioavailability. In acute and chronic safety studies, there was no accumulation of TH-302 following once weekly dosing for 3 weeks in the rat and dog. Br-IPM plasma concentrations were a small fraction of the TH-302 plasma concentrations with significantly smaller percentages present in dogs than in rats. Allometric scaling predicted that the systemic clearance and steady-state volume of distribution in humans would be 38.8 l/h/m(2) and 34.3 l/m(2), respectively, resulting in a terminal elimination half-life of about 36 min. These values were similar to those observed in patients with solid tumors (27.1 l/h/m(2), 23.5 l/m(2) and 47 min). TH-302 exhibited good safety, efficacy and pharmacokinetic properties in nonclinical species, translating into favorable properties in humans.


Investigation on genetic thrombophilic factors in FFPE autopsy tissue from subjects who died from pulmonary embolism.
Venous thromboembolism (VTE) is a multifactorial disease determined by a combination of inherited and acquired factors. Inherited factors include mutations in the genes coding for coagulation factors, some of which seem to exert a differential influence on the risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). In post-mortem studies of subjects who have died from pulmonary embolism (PE), the analysis of the factors that may have augmented the VTE risk is often limited to acquired factors. This is due to the complexity-and sometimes the unfeasibility-of analyzing genetic factors and to insufficient knowledge of their individual roles in PE development. The present study used formalin-fixed paraffin-embedded (FFPE) tissue to investigate a panel of 12 polymorphisms-the largest ever studied-that affect the VTE risk. Tissue samples came from post-mortem examinations performed by the specialists of the Section of Legal Medicine of the Department of Pathology of Marche's Polytechnic University, and by the specialists of Health Care District Hospital of Imola, on 44 subjects who died from PE in the period 1997-2014. All individuals were found to have at least one mutation affecting the VTE risk. The present study demonstrates that genetic analysis can be performed post-mortem and the results are useful for forensic investigations, especially from MTHFR C677T and PAI-1 4G/5G polymorphisms. Broader studies using the techniques described herein are needed to determine the relative influence of the individual polymorphisms and their interaction in PE deaths.


Seasonal patterns of growth, tissue acid fluctuations, and 14CO2 uptake in the crassulacean acid metabolism epiphyte Tjllandsia usneoides L. (Spanish moss).
Seasonal patterns of growth, 14CO2 uptake, and fluctuations in tissue titratable acidity were studied over the course of a year at a study site in the coastal plain of North Carolina.Elongation rates of Spanish moss strands were maximal in the summer and minimal in the winter. Summer maximal biomass addition rates were calculated to be 3.4 mg·month-1. Mortality of the strands was greatest in the winter months. Rates of 14CO2 uptake and fluctuations in tissue acidity were greatest in the summer over a fairly broad spectrum of environmental conditions (day and night temperatures, irradiance, length of drought). Maximal 14CO2 uptake rates (1.2 mg CO2·mg Chl-1 ·h01) were measured in May 1978. Rates of 14CO2 uptake and fluctuations in titratable acidity were inhibited below 5°C and eliminated at 0°C air temperatures.Isothermal diurnal conditions resulted in low rates of 14CO2 uptake. Tissue water content did not appear to be a major factor controlling 14CO2 uptake rates. However, tissue wetting by rain severely reduced nighttime uptake yet stimulated low rates of daytime 14CO2 uptake. This was the only condition in which daytime 14CO2 uptake occurred, excluding the early morning and late afternoon 14CO2 uptake typical of many Crassulacean Acid Metabolism (CAM) plants.The results suggest that tissue water content is not the major factor controlling CO2 uptake as has been found in many other CAM species; and that low temperatures limit the growth of Spanish moss in North Carolina.


Hypoglycemic activation of focal abnormalities in the EEG of patients considered for temporal lobectomy.
EEGs were recorded in 22 patients with medically refractory complex partial epilepsy undergoing presurgical evaluation and 11 age-matched controls while subjected to moderate levels of hypoglycemia to determine if changes activated were predictive of underlying pathology. Five patients had fasting EEGs showing focal abnormalities not seen in the non-fasting state. With hypoglycemia, EEG tracings in normal individuals showed diffuse background slowing, whereas 7 of 22 patients developed focal temporal changes, including focal spike and focal slow wave activation. The development of focal changes correlated well with clinical data concerning underlying focal pathology; focal abnormalities were not evoked in patients with multifocal disease. Hypoglycemic activation of the EEG may be a useful technique for predicting the presence of pathology in patients considered for anterior temporal lobectomy.


d-Orbital steered active sites through ligand editing on heterometal imidazole frameworks for rechargeable zinc-air battery.
The implementation of pristine metal-organic frameworks as air electrode may spark fresh vitality to rechargeable zinc-air batteries, but successful employment is rare due to the challenges in regulating their electronic states and structural porosity. Here we conquer these issues by incorporating ligand vacancies and hierarchical pores into cobalt-zinc heterometal imidazole frameworks. Systematic characterization and theoretical modeling disclose that the ligand editing eases surmountable energy barrier for *OH deprotonation by its efficacy to steer metal d-orbital electron occupancy. As a stride forward, the selected cobalt-zinc heterometallic alliance lifts the energy level of unsaturated d-orbitals and optimizes their adsorption/desorption process with oxygenated intermediates. With these merits, cobalt-zinc heterometal imidazole frameworks, as a conceptually unique electrode, empowers zinc-air battery with a discharge-charge voltage gap of 0.8 V and a cyclability of 1250 h at 15 mA cm-2, outperforming the noble-metal benchmarks.


[Lymphedema after modified radical mastectomy as performed at the Bordet Institute. A report of 60 cases (author's transl)].
Three hundred and fifteen patients who underwent a radical mastectomy between 1969 and 1976 were studied. Nineteen percent developed lymphedema of the upper limb. Ten percent were resistant to all forms of therapy while the pathology gradually subsided in 9%. The causes of lymphedema as well as the preventive and curative methods were statistically studied and compared with those in the literature. Several preventive measures are proposed, in particular, the modified radical mastectomy.


Research trends in multimodal metaphor: a bibliometric analysis.
The concept of multimodal metaphor has generated a growing body of literature over the past decades. However, a systemic review of the domain seems to be lacking in relevant literature. This study, therefore, is an attempt to conduct a bibliometric analysis of the field of multimodal metaphor during 1977-2022, with a focus on 397 relevant publications retrieved from the Web of Science Core Collection (WoSCC) with the visualization tool VOSviewer. Some major quantitative findings are: (i) the number of publications in multimodal research began to surge in 2010 upon the seminal work of Forceville's (2009); (ii) USA, China and Spain are the most productive countries; (iii) journals in the field of advertising, communication and linguistics are important sources of publications; and (iv) eleven clusters of keywords are identified, such as "visual metaphor", "persuasion", "pictures", "impact", "multimodal metaphor", "model", etc., representing crucial areas of interests. We also identified, by qualitative observations, three research trends in multimodal metaphor, driven by cognitive linguistic theory, the theory of pragmatics and visual/multimodal rhetoric theory, respectively. Various theoretical perspectives may shed light on possible further research on multimodal metaphor.


A novel surgical glue composed of gelatin and N-hydroxysuccinimide activated poly(L-glutamic acid): Part 1. Synthesis of activated poly(L-glutamic acid) and its gelation with gelatin.
Although fibrin glue has been widely used as a surgical adhesive, its components, fibrinogen and thrombin, obtained from human blood are not completely free from the risk of virus infection due to acquired immune deficiency and hepatitis. Recently, we have reported that a polymer pair composed of gelatin and poly(L-glutamic acid) (PLGA) promptly forms a gel and can firmly bond to soft tissues when crosslinked with the aid of water-soluble carbodiimide (WSC). The present study was undertaken to design a new PLGA-gelatin glue without using WSC. Two kinds of PLGA with molecular weights of 71 and 22 kDa were employed to prepare N-hydroxysuccinimide (NHS) activated derivatives. The NHS-activated PLGA could be synthesized at high yields and was found to be stable for an extended time without losing the ability to crosslink with gelatin when stored under a dry-cold condition. This NHS-activated PLGA could spontaneously form a gel with gelatin in an aqueous solution within a short time, comparable to a commercial fibrin glue, when gelation was allowed to proceed at pH 8.3. The NHS-activated PLGA prepared from PLGA with the molecular weight of 22 kDa could be readily dissolved at high concentrations and its ability to form a gel was maintained for more than 10 min when an acidic 8% NHS-activated PLGA solution was used. The bonding strength of PLGA gelatin glues with natural tissue was higher than that of fibrin glue. These findings strongly suggest that this combination of gelatin and NHS-PLGA is very promising as a surgical adhesive and may possibly replace fibrin glues prepared from human blood components.


Tailoring Two Chemometric Models for Determination of Three Neuromuscular Combined Medications and Application to Spiked Human Plasma.
Prednisolone, 6-mercaptopurine, and pyridostigmine bromide are co-administered together to treat a neuromuscular autoimmune disease called myasthenia gravis. Prednisolone and 6-mercaptopurine are immunosuppressant drugs. 6-Mercaptopurine is the active form of the pro-drug azathioprine. Pyridostigmine bromide is a cholinesterase enzyme inhibitor. Curently, green characteristics are taken into account by analysts when they develop new methods. The spectra of the three compounds and plasma are highly overlapped, so this study aims to remove this overlap and determine the three components quantitatively in raw powders and spiked human plasma using green methods. Two multivariate updated chemometric models called principle component analysis and partial least-squares were developed. Three greenness assessment tools: the eco-scale, the analytical greenness metric approach, and the green analytical method index, were used to evaluate the greenness behavior of the generated models. The two models were verified in accordance with Food and Drug Administration requirements, and the results were within acceptable limits. In addition they are relatively green in accordance with the abovementioned greenness evaluation tools. The developed models succeeded in determining the proposed drugs in their tertiary combinations and spiked human plasma with satisfactory precision, accuracy, and good greenness behavior. Two ecologically evaluated, multivariate spectrophotometric methods were developed for the determination of pyridostigmine bromide, 6-mercaptopurine, and prednisolone in spiked human plasma.


Erysipelothrix rhusiopathiae exploits cytokeratin 18-positive epithelial cells of porcine tonsillar crypts as an invasion gateway.
Tonsils are important organs for mucosal immunity and are gateways for various pathogens, including bacteria and viruses. The purpose of the present study was to reveal how Erysipelothrix rhusiopathiae, the causative agent of swine erysipelas, invades the mucosal epithelium of the tonsils of pigs. Two germ-free piglets were orally infected with E. rhusiopathiae Koganei 65-0.15, an attenuated vaccine strain in Japan, and their tonsils of the soft palate were histologically examined four weeks after infection. Bacterial organisms were observed in dilated crypt lumens and a few epithelial cells of the crypt. Immunohistochemical examination revealed that some epithelial cells of the crypt were positive for cytokeratin (CK) 18, a specific marker for M cells in the Peyer's patches of pigs. Confocal laser scanning microscopy showed that bacterial antigens were present in the cytoplasm of CK 18-positive epithelial cells. Furthermore, an ultramicroscopic examination revealed that the bacteria-containing epithelial cells did not have microfolds or microvilli, both of which are characteristic of membranous epithelial cells (M cells), and that they were in close contact with intraepithelial phagocytes. Thus, the present observations suggest that the tonsillar crypt epithelium is a site of persistent infection for orally administered E. rhusiopathiae, and the bacteria exploit cytokeratin 18-positive epithelial cells of the crypts as portals of entry into the body.


Functional analysis of different sequence elements in the Escherichia coli galactose operon P2 promoter.
Starting with a DNA fragment containing the galactose operon P2 promoter, we made a series of deletions that progressively replaced DNA sequences upstream of the transcription startpoint and determined their effects on P2 activity. The results show that specific sequences upstream of -32 are not important. Removal of the sequence 5'-CACA-3' from -32 to -28 reduces P2 activity by 50%: longer deletions to -16 further reduce activity but do not remove the information specifying the transcription startpoint. DNA sequences between -32 and -16 at gal P2 assist the isomerization of RNA polymerase from closed to open complexes rather than contributing to the initial binding of RNA polymerase. The activity of gal P2 in the absence of -35 region sequences is dependent on the sequence TG just upstream of the -10 hexamer, TATACT: a mutation at -14 changing the TG sequence to TT totally inactivates P2. However, P2 activity can be restored if the consensus -35 region sequence TTGACA is cloned 17 bp upstream of the -10 hexamer. Thus, for transcription initiation, the -10 hexamer, TATACT, must 'cooperate' with upstream sequences that may be located either around -35 or -14.


Extranodal Lymphoma of the Central Nervous System and Spine.
With a strong predilection for immunocompromised groups and a poorly explained increase in prevalence among those with normal immune status, lymphoma now accounts for approximately 6% of all primary brain tumors. Recent advances in multiagent chemotherapy and monoclonal antibody therapy have promoted longer-term survival, although a definitive cure remains elusive. Extranodal lymphoma of the spine is more often caused by secondary dissemination from systemic disease and less often the primary site of origin. This article reviews a broad spectrum of clinical, etiologic, and pathologic features that frequently intersect with common radiologic findings of this disease.


Atypical glandular cells of undetermined significance from extramammary Paget's of the bladder.
The clinical significance and appropriate diagnostic evaluation of atypical glandular cells of undetermined significance (AGCUS) on cervicovaginal Papanicolaou test have not been well established. A 53-year-old woman with AGCUS underwent colposcopy, cervical biopsy, hysteroscopy, dilation and fractional curettage, and subsequently hysterectomy with bilateral salpingo-oophorectomy without abnormal findings. A repeat vaginal Papanicolaou test revealed malignant cells. Extramammary Paget's disease and urothelial carcinoma in situ were subsequently determined to be the source of the abnormal cells interpreted as AGCUS. AGCUS may be associated with extramammary Paget's disease and urothelial carcinoma. One should maintain a high index of suspicion for extragenital causes of persistent AGCUS.


Characterizing the key genes of COVID-19 that regulate tumor immune microenvironment and prognosis in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC), a highly heterogeneous malignant tumor associated with a poor prognosis, is a common cause of cancer-related deaths worldwide, with a limited survival benefit for patients despite ongoing therapeutic breakthroughs. Coronavirus disease 2019 (COVID-19), a severe infectious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is a global pandemic and a serious threat to human health. The increased susceptibility to SARS-CoV-2 infection and a poor prognosis in patients with cancer necessitate the exploration of the potential link between the two. No studies have investigated the relationship of COVID-19 genes with the prognosis and tumor development in patients with HCC. We screened prognosis-related COVID-19 genes in HCC, performed molecular typing, developed a stable and reliable COVID-19 genes signature for predicting survival, characterized the immune microenvironment in HCC patients, and explored new molecular therapeutic targets. Datasets of HCC patients, including RNA sequencing data and clinical information, were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Prognosis-related COVID-19 genes were identified by univariate Cox analysis. Molecular typing of HCC was performed using the consensus non-negative matrix factorization method (cNMF), followed by the analysis of survival, tumor microenvironment, and pathway enrichment for each subtype. Prognostic signatures were constructed using LASSO-Cox regression models, and receiver operating characteristic (ROC) curves were used to validate the predictive performance of the signature. The same approach was used for the test and external validation sets. Seven software packages were applied to determine the abundance of immune infiltration in HCC patients and investigate its relationship with the risk scores. Gene set enrichment analysis (GSEA) was used to explore the potential mechanisms by which the COVID-19 genes affect hepatocarcinogenesis and prognosis. Three types of machine learning methods were combined to identify the most critical genes in the signature and localize their expression at the single cell level. We identified 53 prognosis-related COVID-19 genes and classified HCC into two molecular subtypes (C1, C2) by using the NMF method. The prognosis of C2 was significantly better than that of C1, and the two subtypes differed remarkably in terms of the tumor immune microenvironment and biological functions. The 17 COVID-19 genes were screened using the LASSO regression method to develop a 17 COVID-19 genes signature, which demonstrated a good predictive performance for 1-, 2- and 3-year OS of patients with HCC. The risk score as an independent prognostic factor for HCC has better predictive accuracy than traditional clinical variables. Patients in the TCGA cohort were categorized by risk score into the high- and low-risk groups, with the high-risk group mainly enriched in the immune modulation-related pathways and the low-risk group mainly enriched in the metabolism-related pathways, suggesting that the COVID-19 genes may affect disease progression and prognosis by regulating the tumor immune microenvironment and metabolism in HCC. NOL10 was identified as the most critical gene in the signature and hypothesized to be a potential therapeutic target for HCC. Objectively, the COVID-19 genes signature developed in this study, as an independent prognostic factor in HCC patients, is closely associated with the prognosis and tumor immune microenvironment of HCC patients and indicates that they may regulate the development of HCC in multiple ways, providing us with new perspectives for understanding the molecular mechanisms of HCC and finding effective therapeutic targets.


Systemic relations among the variables involved in occupational accidents of the nursing team in a psychiatric hospital.
The occupational activities carried out in hospital environments pose occupational risks to professionals. In psychiatric hospitals, due to the characteristics of the patients treated, professionals are also subjected to other risks, such as physical aggression. This research aimed to identify the systemic context, highlighting the cause-and-effect relationships that culminate in occupational accidents that occurred with the nursing staff in a psychiatric hospital in Brazil. The current study is an applied research and was divided into three stages. First, the collection of data related to the case study was made and accidents were analyzed and occupational hazards were identified. In the second stage, from the collected information, occupational safety indicators were defined. Lastly, in the third stage, the qualitative aspect of System Dynamics was applied to perform the systemic analysis and to identify how the different variables were related. The results showed that physical aggression was the main cause of accidents. Regarding safety indicators, while both the level of use of Personal Protective Equipment (PPE) by professionals and the high level of PPE protection were positive aspects, the level of training of professionals to use PPE was a negative aspect. The Causal Link Diagram (CLD) showed that the perception of risk influenced the level of use of PPE and those organizational measures influenced the accident rate. In conclusion, the systemic analysis of the system dynamics can optimize the diagnostic process of occupational accidents in psychiatric hospitals, and especially help to identify the cause and effect among the variables involved.


Impact of chronic exposure of rats to bisphenol A from perinatal period to adulthood on intraprostatic levels of 5α-reductase isozymes, aromatase, and genes implicated in prostate cancer development.
The synergetic effect of estrogens and androgens is known to play a crucial role in the physiopathology of the prostate gland. Bisphenol A (BPA) is an endocrine disrupting compound that can interfere with endocrine hormone functioning and thereby influence prostate development. The objective of this study was to examine the impact on prostate expression of aromatase, 5α-R isozymes, and prostate cancer-related genes of exposure to low doses of BPA from perinatal period to adulthood. Vehicle or BPA (2.5 μg/kg b.w./day) was administered to gestating Wistar rats from gestational day 12 (GD12) to parturition and then to their male pups from postnatal day 1 (PND1) until euthanization on PND90. Their prostate glands were examined by qRT-PCR, Western blot, PCR array, and morphological study. mRNA and protein levels of 5α-R2 were significantly reduced and mRNA and protein levels of aromatase were significantly increased in BPA-treated animals, which also showed modifications of 8 out of the 84 key genes implicated in the development of prostate cancer. Because BPA interferes with genes involved in intraprostatic androgen and estrogen production and others implicated in prostate cancer, research is warranted into the prostate disease risk associated with chronic low-dose BPA exposure throughout life.


[Studies on HPLC chromatogram of phenolic constituents of Cortex Magnoliae Officinalis].
To study the chemical characteristic, to identify the different forms and to establish the new standard for the quality control of Cortex Magnoliae Officinalis. HPLC method was used with acetonitrile-water (63:37) as the mobile phase at room temperature. The chromatographic column was Lichrospher 100 RP-18e (4.6 mm x 250 mm, 5 microm). The flow rate was 1 mL x min(-1), and the detection wavelength was 294 nm. The chromatograms of 45 individuals from 13 seed resources of Cortex Magnolia Officinalis were recorded. The chemical characteristics analysis and comparability' s calculation of seed resources were made. It was proposed that the area ratio of peak 5 to 6 (characteristic I) and the area ratio of peak 5 and 6 to the total peak areas (characteristic II) are the identification characteristics for different seed resources of Cortex Magnoliae Officinalis. This method can be used effectively to identify the high quality seed resource of Cortex Magnoliae Officinalis.


A new alternative for reconstruction of the inferior medial canthal and nasal sidewall defects.
Reconstruction of the inferior medial canthal and nasal sidewall defects presents some particular problems resulting from the unique anatomy of this region such as the multiple contours and sigmoidal relaxed skin tension lines, differences in skin color and texture, and the anatomic limitations presented by the adjacent structures including lower eyelids, eyebrows, and lacrimal drainage system. In this study, the authors represent a new local flap as a new alternative for reconstruction of the defects of the inferior medial canthal region and nasal sidewalls. In this technique, defect closure is achieved by using 2 cutaneous flaps designed in an unequal z-plasty manner. The first flap is used to cover the defect, whereas the second flap is used for closure of the first flap's donor site. From October 2006 to May 2010, a total of 16 patients 38 to 80 years old underwent medial canthal and nasal sidewall reconstruction by using this procedure. The defect size ranged from 2.0 to 3.2 cm in width. A tension-free defect closure was achieved in all patients. Except 1 patient who had slight pseudoepicanthus, there was no patient with distortion of the surrounding anatomic structures. During a mean follow-up period of 30 months (5 months to 3½ years), all patients were satisfied with the cosmetic and functional results. Except 1 patient who underwent reoperation for tumor recurrence, no patient required further surgery. The reading man procedure was found to be a successful technique for the closure of inferior medial canthal and nasal sidewall defects. It allows tension-free closure of considerably larger defects without any additional healthy tissue excision and and/or dog ear formation. Moreover, using z-plasty principle, it avoids distortions of the surrounding mobile anatomic structures.


Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine.
We present a case of pulmonary nontuberculous mycobacterial infection (PNTM) with M. abscessus. After exclusion of genetic immune disorders known to cause NTM susceptibility, we found compound heterozygosity of two mutations, F508del and R117H in CFTR. The combination of F508del with a hypomorphic CFTR mutation can cause a mild Cystic Fibrosis (CF) phenotype with delayed CF symptoms in adulthood. Although the patient was continuously treated for her lung infection by different physicians for more than twenty years, the diagnosis CF had been missed. The forme fruste of CF should be considered in the analysis of host factors predisposing for PNTM.


Improving lactic acid yield of hemicellulose from garden garbage through pretreatment of a high solid loading coupled with semi-hydrolysis using low enzyme loading.
Byproduct (acetate and ethanol) generation and carbon catabolite repression are two critical impediments to lactic acid production from the hemicellulose of lignocellulosic biomass. To reduce byproduct generations, acid pretreatment with high solid loading (solid-liquid ratio 1:7) of garden garbage was conducted. The byproduct yield was only 0.30 g/g during in the subsequent lactic acid fermentation from acid pretreatment liquid and 40.8% lower than that of low solid loading (0.48 g/g). Furthermore, semi-hydrolysis with low enzyme loading (10 FPU/g garden garbage cellulase) was conducted to regulate and reduce glucose concentration in the hydrolysate, thereby relieving carbon catabolite repression. During the lactic acid fermentation process, the xylose conversion rate was restored from 48.2% (glucose-oriented hydrolysis) to 85.7%, eventually achieving a 0.49 g/g lactic acid yield of hemicellulose. Additionally, RNA-seq revealed that semi-hydrolysis with low enzyme loading down-regulated the expression of ptsH and ccpA, thereby relieving carbon catabolite repression.


Genetic recombination among tomato yellow leaf curl virus isolates in commercial tomato crops in Kuwait drives emergence of virus diversity: a comparative genomic analysis.
Whitefly-transmitted tomato yellow leaf curl virus (TYLCV) continues to be a major constraint to tomato production in Kuwait. However, very limited information is available about the population structure and genetic diversity of TYLCV infecting tomato in Kuwait. Whole genome sequences of 31 isolates of TYLCV, collected from commercial tomato crops grown in northern (Abdally) and southern (Al Wafra) parts of Kuwait, were deciphered. Eighteen isolates of TYLCV are identified as potential genetic recombinants. The isolates Abdally 6A and Abdally 3B reported in this study were identified to be potential recombinants. Compared to the 15 isolates from the Abdally area, and the three previously reported KISR isolates of Kuwait, six out of sixteen Al Wafra isolates showed an insertion of 19 extra nucleotides near the 5'-end. There are also four nucleotide variations before the 19-extra-nucleotides. The additional 19 nucleotides observed in nine isolates indicate that these isolates might have resulted from a single gene recombination/insertion event. Molecular phylogeny based on complete genome sequences of TYLCV isolates suggests transboundary movement of virus isolates due to geographic proximity. The information presented herein is quite useful for the comprehension of TYLCV biology, epidemiology and would aid in the management of disease in the long run.


Adsorption of arsenic(V) by activated carbon prepared from oat hulls.
The efficiency of self-manufactured activated carbon (AC) produced from oat hulls in adsorbing arsenic(V) was tested in a batch reactor. The results indicated that the adsorptive capacity of AC was affected by initial pH value, with adsorption capacity decreasing from 3.09 to 1.57 mg As g(-1) AC when the initial pH values increased from 5 to 8. A modified linear driving force model conjugated with a Langmuir isotherm was created to describe the study's kinetics. The test results show that rapid adsorption and slow adsorption exist simultaneously when AC is used to remove arsenic(V).


Body fat distribution in men with angiographically confirmed coronary artery disease.
Body fat distribution and its relationship to coronary artery disease and established cardiovascular risk factors have been studied in a cohort of 286 men aged between 30 and 74 years undergoing coronary angiography. 207 (72.4%) patients showed stenosis (greater than 30%) or occlusion of one or more coronary arteries. whereas the remaining 79 (27.6%) men were free of coronary lesions and served as a control group. 112 men with angiographically defined coronary artery disease had an additional history of myocardial infarction. Body fat distribution was assessed by determining the waist-to-hip circumference ratio. A stepwise logistic regression analysis revealed that in addition to LDL-cholesterol (P = 0.0001) and age (P = 0.0005) an abdominal type of body fat distribution (P = 0.0129) is also a significant risk indicator for the occurrence of coronary artery disease (CAD) independent of body weight and other factors such as total cholesterol, HDL-cholesterol, triglycerides, insulin, systolic and diastolic blood pressure. The results of this study suggest that an abdominal type of fat distribution is associated with an increased risk of coronary artery disease.


Characterization of the bacterial microbiome among free-ranging bottlenose dolphins (Tursiops truncatus).
Marine animals represent a dynamic and complex habitat for diverse microbial communities. The microbiota associated with bottlenose dolphins (Tursiops truncatus) are believed to influence their health status, but it remains poorly understood. We therefore characterized and compared the bacterial microbiome of bottlenose dolphins from six different anatomical sites that represent four different body systems (respiratory, digestive, reproductive, and integumentary). In this study, a total of 14 free-ranging bottlenose dolphins were sampled during the 2015 Sarasota Bay Dolphin Health Assessment. Bacterial diversity and abundance were assessed by PCR amplification of the hypervariable V3-V4 regions of the bacterial 16S rRNA gene for each sample, followed by sequencing on an Illumina MiSeq platform. Analysis showed that bottlenose dolphins harbor diverse bacterial communities with a unique microbial community at each body system. Additionally, the bottlenose dolphin bacterial microbiome was clearly distinct to the aquatic microbiome from their surrounding habitat. These results are in close agreement with other cetacean microbiome studies, while our study is the first to explore what was found to be a diverse bottlenose dolphin genital microbiome. The core bacterial communities identified in this study in apparently healthy animals might be informative for future health monitoring of bottlenose dolphins.


External Ear Anthropometry of Healthy Turkish Young Adults.
The aim of this study was to determine the external ear values in Turkish young adults with 2-dimensional photogrammetry. One hundred males and 100 females aged between 18 and 25 years were included in the study. Individuals were photographed from both sides. Ear length (superaurel-subaurel, spa-sba ), ear width (preaurel-postaurel, pra-pa ), and the angle between the vertical axis of the auricle and the line between spa and sba (ear incline angle, eia ) were measured in these photographs. Also, auricular index ( pra-pa / spa-sba ×100) was calculated. The average values of the spa-sba, pra-pa , eia , and auricular index were found as 65.46±4.68 mm, 37.89±3.61 mm, 19.40±4.83 degrees, and 57.93±4.53 in males and 60.90±5.35 mm, 35.62±3.69 mm, 17.95±4.86 degrees, and 58.65±5.29 in females, respectively. While the values of spa-sba ( P =0.001 for the right side and P =0.001 for the left side), pra-pa ( P =0.001 for the right side and P =0.001 for the left side), and eia ( P =0.024 for the right side and P =0.041 for the left side) were statistically higher for males than females, there was no statistically significant difference between the sex and the auricular index ( P =0.404 for the right side and P =0.955 for the left side). Besides, there was no statistically significant difference between the sides for these 4 parameters ( P =0.760, 0.409, 0.225, and 0.521, respectively). The authors believe that the results obtained for Turkish young adults can be used as reference values, which can be used in the diagnosis, follow, or surgical treatment of many diseases, forensic procedures, and planning esthetic surgery procedures.


Anti-virulence Strategies to Target Bacterial Infections.
Resistance of important bacterial pathogens to common antimicrobial therapies and the emergence of multidrug-resistant bacteria are increasing at an alarming rate and constitute one of our greatest challenges in the combat of bacterial infection and accompanied diseases. The current shortage of effective drugs, lack of successful prevention measures and only a few new antibiotics in the clinical pipeline demand the development of novel treatment options and alternative antimicrobial therapies. Our increasing understanding of bacterial virulence strategies and the induced molecular pathways of the infectious disease provides novel opportunities to target and interfere with crucial pathogenicity factors or virulence-associated traits of the bacteria while bypassing the evolutionary pressure on the bacterium to develop resistance. In the past decade, numerous new bacterial targets for anti-virulence therapies have been identified, and structure-based tailoring of intervention strategies and screening assays for small-molecule inhibitors of such pathways were successfully established. In this chapter, we will take a closer look at the bacterial virulence-related factors and processes that present promising targets for anti-virulence therapies, recently discovered inhibitory substances and their promises and discuss the challenges, and problems that have to be faced.


Significance of high-density lipoprotein cholesterol.
The central importance of elevated blood cholesterol levels in the process of atherosclerotic heart disease (ASHD) is firmly established. Cholesterol is transported in the blood in conjunction with protein as a lipoprotein complex. The low-density lipoproteins (LDL) carry the bulk of the blood cholesterol. The high-density lipoproteins (HDL) occur in much smaller amounts. Recently it has been demonstrated that not only is the cholesterol carried in the HDL fraction not harmful, but appears to be protective against the development of ASHD. Data from Framingham and elsewhere seem consistent with this observation. The HDS apparently represent the fraction concerned with the efflux of cholesterol from the tissues, so that higher levels may represent a heightened cholesterol-riddance mechanism. Thus far, two circumstances seem to be associated with elevated levels of HDL--physical exercise and ethanol ingestion. The importance of these observations in the clinical management of the patient at risk is discussed.


A tandem liquid chromatography and tandem mass spectrometry (LC/LC-MS/MS) technique to separate and quantify steroid isomers 11β-methyl-19-nortestosterone and testosterone.
Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has become a mainstay analytical technique in pharmaceutical research and development and clinical diagnosis due to several advantages including excellent selectivity, specificity, and high sensitivity. LC-MS/MS has become the method of choice for steroids analysis due to its fast analytical time and improved specificity yet has a challenge in the separation and measurement of isomers with the same product ions. Here we describe a high-sensitivity LC/LC-MS/MS method that combines chiral chromatography and reverse-phase chromatography (LC/LC) along with MS/MS to rapidly separate and quantify steroid isomers of 11ß-methyl-19-nortestosterone (11ß-MNT) and endogenous testosterone in serum.


Biotribocorrosion of 3D-Printed silica-coated Ti6Al4V for load-bearing implants.
Laser-based 3D Printing was utilized to deposit a silica (SiO2) coating on the surface of Ti6Al4V (Ti64) alloy for implementation onto articulating surfaces of load-bearing implants. The surface laser melting (SLM) technique was implemented in 1, and 2 laser passes (1LP and 2LP) after SiO2 deposition to understand the influence of remelting on the coating's hardness and tribological performance. It was observed that compositional and microstructural features increased the cross-sectional hardness. Wear rate was observed to decrease from 2.9×10-4 in the Ti64 to 5.2 ×10-6, 3.8×10-6, and 2.1×10-7 mm3/Nm for the as-processed or zero laser-pass (0LP), 1LP, and 2LP, respectively. Coated samples displayed a positive shift in open-circuit potential (OCP) during linear wear by displaying a 368, 85, and 613 mV increase compared to Ti64 for 0LP, 1LP, and 2LP, respectively. Our results showed promising tribological performance of SiO2 coated Ti6Al4V for articulating surfaces of load-bearing implants.


Comparing roadsoils pollution patterns extracted by MOLMAP and classical three-way decomposition methods.
A recent approach based on self-organizing maps (SOMs) to extract patterns from three-way data, named MOLMAP, was applied in a four-seasons study on soil pollution and its results compared with three different conventional approaches: Parallel factor analysis (PARAFAC), matrix augmented principal components analysis (MA-PCA) and Procrustes rotation. Each sampling season comprised 92 roadsoil samples and 12 analytical variables (Cd, Co, Cu, Cr, Fe, Mn, Ni, Pb, Zn, loss on ignition, pH and humidity). It was found that all techniques yielded highly similar results as the samples became organized in two major groups, each with a differentiated pollution pattern. This confirmed MOLMAP as a reliable option to handle environmental three-way datasets and to extract accurate pollution patterns.


Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives.
The aim of this review of the literature is to report the factors which both contribute to the frailty syndrome and increase hip fracture risk in the elderly. This work is the fruit of common reflection by geriatricians, endocrinologists, gynecologists and rheumatologists, and seeks to stress the importance of detection and management of the various components of frailty in elderly subjects who are followed and treated for osteoporosis. It also sets out to heighten awareness of the need for management of osteoporosis in the frail elderly. The current literature on frailty and its links with hip fracture was reviewed and discussed by the group. The factors and mechanisms which are common to both osteoporosis and frailty (falls, weight loss, sarcopenia, low physical activity, cognitive decline, depression, hormones such as testosterone, estrogens, insulin-like growth factor-I (IGF-I), growth hormone (GH), vitamin D and pro-inflammatory cytokines) were identified. The obstacles to access to diagnosis and treatment of osteoporosis in the frail elderly population and common therapeutic pathways for osteoporosis and frailty were discussed. Future research including frail subjects would improve our understanding of how management of frailty can can contribute to lower the incidence of fractures. In parallel, more systematic management of osteoporosis should reduce the risk of becoming frail in the elderly population.


Rabbit alveolar macrophages after inhalation of soluble cadmium, cobalt, and copper: a comparison with the effects of soluble nickel.
Rabbits were exposed to aerosols of chlorides of cadmium, copper, and cobalt (0.4-0.6 mg/m3 as metal) for 1 month (5 days/weeks and 6 hr/day). The effects of alveolar macrophages were compared with earlier reported effects of nickel chloride (0.3 mg/m3 as Ni). Effects of Cd2+ exposure resembled those of Ni2+ exposure. The number of macrophages in lavage fluid and the variance of cell diameters were thus increased and many cells contained lamellated inclusions. Contrary to macrophages from Ni2+-exposed rabbits, the surface of about 50% of the cells had cytoplasmic blebs. However, such cells were rarely seen by scanning electron microscopy. There were significantly more polymorphonucleated neutrophils and small lymphocytes, suggesting lung parenchymal damage. Cells from Cd2+-exposed animals, like cells from Ni2+-exposed ones, showed an increased oxidative metabolic activity after stimulation with Escherichia coli bacteria. Bactericidal capacity, on the other hand, tended to be enhanced rather than decreased, as in the nickel experiment. After CO2+ exposure, the number of macrophages was slightly increased in the lavage fluid and the cells showed an increased metabolic activity both at rest and upon stimulation with bacteria. Cu2+ exposure gave a slight increase in lamellated inclusions in the macrophages.


The feasibility of procalcitonin and CPIS score to reduce inappropriate antibiotics use among severe-critically ill COVID-19 pneumonia patients: A pilot study.
Antibiotics have been extensively used in COVID-19 patients without a clear indication. We conducted a study to evaluate the feasibility of procalcitonin along with the "Clinical Pulmonary for Infection Score" (CPIS) as a strategy to reduce inappropriate antibiotic use. Using procalcitonin and CPIS score (PCT-CPIS) successfully reduced inappropriate antibiotics use among severe-critically ill COVID-19 pneumonia patients (45% vs 100%; P < .01). Compared to "non PCT-CPIS" group, "PCT-CPIS" group was associated with a reduction in the incidence of multidrug-resistant organisms and invasive fungal infections (18.3% vs 36.7%; P = .03), shorter antibiotic duration (2 days vs 7 days; P < .01) and length of hospital stay (10 days vs 16 days; P < .01).


Support Vector Data Descriptions and $k$ -Means Clustering: One Class?
We present ClusterSVDD, a methodology that unifies support vector data descriptions (SVDDs) and $k$ -means clustering into a single formulation. This allows both methods to benefit from one another, i.e., by adding flexibility using multiple spheres for SVDDs and increasing anomaly resistance and flexibility through kernels to $k$ -means. In particular, our approach leads to a new interpretation of $k$ -means as a regularized mode seeking algorithm. The unifying formulation further allows for deriving new algorithms by transferring knowledge from one-class learning settings to clustering settings and vice versa. As a showcase, we derive a clustering method for structured data based on a one-class learning scenario. Additionally, our formulation can be solved via a particularly simple optimization scheme. We evaluate our approach empirically to highlight some of the proposed benefits on artificially generated data, as well as on real-world problems, and provide a Python software package comprising various implementations of primal and dual SVDD as well as our proposed ClusterSVDD.


[Entomopathogenic bacteria Bacillus thuringiensis as producers of restriction endonucleases].
A total of 115 collection strains of Bacillus thuringiensis, belonging to various subspecies, have been studied for the presence of DNA restriction-modification systems. Restriction endonucleases of 13 strains have been isolated and characterized. No considerable correlations between the taxonomic positions of the bacteria and the specificities of the endonucleases isolated have been detected. It is concluded that the enzymes with identical specificities are present in both the crystalliferous and acrystalliferous strains of the same subspecies.


Transcriptional Output Transiently Spikes Upon Mitotic Exit.
The pulsatile nature of gene activity has recently emerged as a general property of the transcriptional process. It has been shown that the frequency and amplitude of transcriptional bursts can be subjected to extrinsic regulation. Here we have investigated if these parameters were constant throughout the cell cycle using the single molecule RNA FISH technique. We found evidence of transcriptional spikes upon mitotic exit in three different human cell lines. Recording of cell growth prior to hybridization and immuno-RNA FISH analysis revealed that these spikes were short-lived and subsided before completion of cytokinesis. The transient post-mitotic increase in transcriptional output was found to be the result of cells displaying a higher number of active alleles and/or an increased number of nascent transcripts per active allele, indicating that both the burst fraction and the amplitude of individual bursts can be increased upon mitotic exit. Our results further suggest that distinct regulatory mechanisms are at work shortly after mitotic exit and during the rest of interphase. We speculate that transcriptional spikes are associated with chromatin decondensation, a hallmark of post-mitotic cells that might alter the dynamics of transcriptional regulators and effectors.


Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome.
Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients' characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge-midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25-92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1-60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000-9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26-2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.Trial registration DRKS-ID DRKS00027856.


Modulation of antitumour immune responses by intratumoural Stat1 expression.
Signal transducer and activator of transcription 1 (Stat1) mediates anti-viral responses and cytokine-driven anti-proliferative, apoptotic and immunomodulatory activities. As de-regulated Stat1 function can affect tumour progression we sought to elucidate the effects of tumour cell-intrinsic Stat1 expression on immunosurveillance. Knockout of Stat1 enhanced the development of sarcomas induced by the chemical carcinogen 3-methylcholanthrene (MCA). Growth of transplanted MCA-induced Stat1⁻/⁻ sarcomas was suppressed in wild-type mice compared to growth in Stat1⁻/⁻ and immunocompromised recipients. Co-depletion of NK and CD8⁺ T cells from wild-type mice facilitated Stat1-deficient tumour growth whereas depletion of CD4⁺ T cells and CD8⁺ T cells did not. In vitro and in vivo analysis of the tumours implicated a role for NK cell-mediated, perforin-dependent killing of Stat1-deficient tumours. Interestingly, restoration of Stat1 expression in Stat1⁻/⁻ tumours resulted in diminished involvement of NK cells and increased contribution of CD8⁺ T cells in anti-tumour responses. Therefore, Stat1 expression within tumour cells modulated anti-tumour immune responses by altering the dominant immune effector cell involvement from NK cells to CD8⁺ T cells in the absence or presence of Stat1 respectively.


Microdislodgment: a likely mechanism of pacing failure with high impedence small area electrodes.
High impedance tined steroid-eluting leads, Medtronic CapSure Z family, incorporating a small surface (1.2 mm2) electrode made of porous platinum material are designed to reduce battery current drain. However, in some prior studies, an increased incidence of microdislodgment with this lead was reported thought to be due to the reduced electrode surface area. This article reports the experience that ventricular pacing failure due to microdislodgment occurred after CapSure Z lead implantation and the previous literature is reviewed. (


Graphene oxide-templated synthesis of ultrathin or tadpole-shaped au nanowires with alternating hcp and fcc domains.
Ultrathin Au nanowires (AuNWs) and tadpole-shaped nanowires are synthesized on graphene oxide (GO) sheet templates. For the first time, 1.6 nm-diameter AuNWs are shown to contain hexagonal close-packed (hcp) crystal domains, and the tadpole-shaped nanowires exhibit alternating sets of hcp and face-centered cubic (fcc) structures, associated with variation in wire thickness.


Observation of osseous healing after intraoral vertical ramus osteotomy: focus on computed tomography values.
The purpose of this study was to observe long-term osseous healing of the cleavage space between bone fragments after intraoral vertical ramus osteotomy using computed tomographic (CT) values. CT examinations were performed to observe long-term osseous healing immediately after intraoral vertical ramus osteotomy and at 6 months, 1 year, and 2 years postoperatively. Bone fragments were observed on the interior and lateral sides. CT values between bone fragments were used to measure the range of each point within a 1.7- × 1.7-mm square, and the mean of the measurements was calculated. CT values between bone fragments increased significantly over time at 1 month, 6 months, 1 year, and 2 years after surgery. Osseous healing in the cleavage between bone fragments after intraoral vertical ramus osteotomy was successful according to CT values.


Neuropsychological correlates of visual hallucinatory phenomena in Lewy body disease.
Visual hallucinations (VH) ranging from minor to complex, are the most common psychiatric feature of Lewy Body Disease (LBD). Despite their high prevalence and poor prognostic implications instigating extensive research, the precise mechanisms underlying VH remain unclear. Cognitive impairment (CI) is a risk factor and a consistent correlate of VH in LBD. To help shed light on their underlying mechanisms, this study investigates the pattern of CI across the spectrum of VH in LBD. 30 LBD patients with minor VH (MVH), 13 with complex VH (CVH) and 32 without VH were retrospectively compared on the domains of higher-order visual processing, memory, language and executive functioning. The VH groups were further stratified to investigate whether phenomenological subtypes have distinct cognitive correlates. LBD patients with CVH were impaired on the visuo-spatial and executive functioning domains relative to controls. LBD patients with MVH were also impaired on the visuo-spatial domain. No differences emerged in cognitive domains affected between patient groups endorsing specific hallucinatory phenomena. A pattern of CI indicating fronto-subcortical dysfunction in combination with posterior cortical involvement is implicated in the genesis of CVH. Moreover, this posterior cortical dysfunction may precede the occurrence of CVH as indicated by selective visuo-spatial deficits in LBD patients with MVH.


Combined use of handgrip strength and hemoglobin as markers of undernutrition in patients with stage 3-5 chronic kidney disease.
The early identification of undernourished patients with CKD could help instating appropriate nutritional intervention before the full development of the threatening condition known as Protein Energy Wasting (PEW). Handgrip strength (HGS) and blood hemoglobin (Hb) concentration are two parameters considered representative of nutritional status but not included among the criteria for PEW diagnosis. In the present work we investigated whether they could help identifying CKD patients at risk of undernutrition. We performed a two-step cluster analysis to classify a cohort of 71 stage 3-5 CKD patients, none of which with PEW, according to their Hb concentration and dominant-hand HGS. Two clusters were finely separated using this method. When we compared the two groups for main body composition and nutritional variables by using t-test statistics or Mann-Whitney test, as appropriate, we found significant differences in PhA, ECW/TBW, ASMI, serum iron. Then we stratified our population by gender and performed cluster analysis as well. PhA, ECW/TBW were still significantly different in the two clusters both in M and in F, while serum iron concentration only in males and ASMI only in females. These results suggest that either in male than in female Hb concentration and HGS may distinguish two subgroups of CKD patients with different nutritional status and disease severity. Patient belonging to either of these cluster can be easily identified by using the HGS/Hb ratio which represents the HGS normalized per gr Hb.


Systemic efficacy of ivermectin against Dermanyssus gallinae (De Geer, 1778) in fowls.
The efficacy of ivermectin on females of a laboratory strain of Dermanyssus gallinae was tested. Ivermectin produced a noticeable systemic effect on the mites when inoculated intra-abdominally into infested chickens at rates greater than 0.6 mg kg-1. The concentrations efficacious against D. gallinae (1.8-5.4 mg kg-1) were unfavourably close to those causing toxicity in experimental birds (greater than or equal to 5.4 mg kg-1). Ivermectin administered at 5.4 mg kg-1 was active for 70 h post inoculation.


Teenage parents and welfare reform: findings from a survey of teenagers affected by living requirements.
An important component of welfare reform aimed at minor teenage parents is a requirement that the teenager live in an appropriate living situation, typically with a parent or guardian. The State of Massachusetts developed Teen Living Programs as an alternate living arrangement for minor teenage parents receiving welfare who are unable to live with family members. This article reports on a survey of 199 teenage parents who lived in the Teen Living Programs. Three research questions were asked: Who are the teenagers served by these programs? What services were provided? To what extent have teenagers attained key outcomes? Outcomes measured included educational attainment, employment, welfare status, homelessness, and subsequent pregnancy. Implications for social policy, further program development, and clinical intervention are discussed.


Circadian rhythms and medical diseases: does it matter when drugs are taken?
Chronobiology is devoted to the study of biological rhythms. It is possible that a given medication may be therapeutic and safe when administered at some time, but subtherapeutic or poorly tolerated at another. We focused on some classes of drugs, widely used by the internists, performing a PubMed search with the single drugs associated with the MeSH terms "Chronotherapy", "Circadian rhythm", and "Chronobiology, phenomena". Among the studies found, we considered only those provided with discrete numerosity or clearly stated methodological characteristics. The results of available studies were given, along with a series of short take-home messages at the end of each mini-chapter devoted to: antihypertensives, statins, anticoagulants, analgesics, drugs for acid-related disorders, and anti-asthmatic drugs. In particular, evidence of morning vs. evening administration, when applicable, was given for each medication. Adequate evidence seems to support that at least ACE-inhibitors or angiotensin receptor blockers, simvastatin, corticosteroids (slow-release formulation) for arthritic patients, and ranitidine should preferably be administered in the evening. Morning dosing could be better for proton pump inhibitors, whereas time of administration is not crucial for asthma inhalation drugs. Studies are available for other drugs, but not so strong enough to draw definite conclusions. For now, we need prospective intervention trials specifically designed to investigate the long-term effects of a temporal approach to medical therapy. However, since switching to morning-evening administration or vice versa is simple and inexpensive, in some cases it could be considered, remembering that, in any case, adherence remains the crucial point.


Endovascular exclusion of patch aneurysms of intercostal arteries after thoracoabdominal aortic aneurysm repair.
Reimplantation of the largest patent intercostal arteries is usually performed during thoracoabdominal aortic aneurysm repair. This may lead to aneurysmal evolution of the intercostal arteries patch. We report the successful percutaneous endovascular repair in 4 Marfan patients of aneurysms of the intercostal arteries patch that developed after thoracoabdominal aortic aneurysm repair (Crawford type II) during a mean delay of 70 months (range, 48 to 91 months). All patients had previously undergone one or several aortic surgical procedures and had patent subclavian and hypogastric arterial networks. No in-hospital deaths or spinal cord ischemic injuries occurred, which emphasizes the importance of the vascular collateral network.


The influence of pre-warming on the physiological responses to prolonged intermittent exercise.
To examine the influence of pre-warming on the physiological responses to prolonged intermittent exercise in ambient temperatures of 21.5 +/- 0.6 degrees C and relative humidities of 35.7 +/- 5.4% (mean +/- s), six healthy men performed intermittent treadmill running (30-s bouts at 90% of maximal oxygen uptake separated by 30-s static recovery periods) to exhaustion after active pre-warming, passive pre-warming and pre-exercise rest (control). Exercise time to exhaustion was significantly different between all conditions (active, 51.8 +/- 7.2 min; passive, 38.5 +/- 11.1 min; control, 72.0 +/- 17.2 min; P < 0.05). These changes in performance time were closely associated with a significant decline in both the rate of heat storage and heat storage capacity (P < 0.05). Rectal temperature, heart rate and ratings of perceived exertion were significantly higher during exercise in the two pre-warming conditions than in the control condition (P < 0.05). Ratings of perceived exertion were also significantly higher during exercise following passive pre-warming compared with active pre-warming (P < 0.05). During exercise there were no significant differences in serum prolactin, plasma norepinephrine and plasma free fatty acid concentrations between conditions. We conclude that both active and passive pre-warming promote a reduction in prolonged intermittent exercise capacity in environmental temperatures of 21 degrees C compared with pre-exercise rest. These performance decrements were dependent upon the mode of pre-warming and closely reflected alterations in body heat content.


Feedback-controlled LED photobioreactor for photophysiological studies of cyanobacteria.
A custom photobioreactor was designed to enable automatic light adjustments using computerized feedback control. The system consisted of a 7.5-L cylindrical vessel and an aluminum enclosure housing quantum sensors and light-emitting diode arrays, which provide 630 or 680 nm light to preferentially excite the major cyanobacterial pigments, phycocyanin and/or chlorophyll a, respectively. Custom-developed software rapidly measures light transmission and subsequently adjusts the irradiance to maintain a defined light profile to compensate for culture dynamics, biomass accumulation, and pigment adaptations during physiological transitions, thus ensuring appropriate illumination across batch and continuous growth modes. In addition to chemostat cultivation, the photobioreactor may also operate as a turbidostat, continuously adjusting the media dilution to achieve maximal growth at a fixed culture density. The cultivation system doubles as an analytical device, using real-time monitoring to avoid sampling bias (e.g., in-situ light-saturation response), determine conditions for optimal growth, and observe perturbation responses at high time-resolution.


The American Dental Association and the value of membership.
The Chair of the ADA Council on Membership presents a snapshot of current membership numbers and trends and association membership initiatives. ADA programs include advocacy, science to enhance care, a portfolio of member benefits, attention to the concerns of young professionals, and a tripartite organizational structure.


Evaluation of emergency department visits prior to an HIV diagnosis: Missed opportunities.
There is a high rate of occult infection and late diagnosis in HIV. Hospital emergency departments (ED) are an important point of health care. The present work aims to know the number of missed opportunities for HIV diagnosis occurring in the ED. Retrospective multicenter cohort study that included all patients diagnosed with HIV infection in 2019 in 27 Spanish hospitals in 7 different autonomous communities. All ED consultation episodes in the 5 years prior to diagnosis were reviewed to find out the reason for consultation and whether this represented a missed opportunity for HIV diagnosis. Seven hundred twenty-three patients were included, and 352 (48.7%, 95%CI: 45.1%-52.3%) had at least one ED visit during the 5 years prior to diagnosis (median 2, p25-p75: 1-4). One hundred and eighteen patients (16.3%, 95%CI: 13.8%-19.2%) had a missed diagnostic opportunity. The main consultations were drug use [145 (15%)], sexually transmitted infections [91 (9.4%)] and request for post-exposure HIV prophylaxis [39 (4%)]. One hundred and fifty-five (42.9%) of the 352 had less than 350 CD4/mm3 when the HIV diagnosis was established. In patients with previous ED visits, the mean time to diagnosis from this visit was 580 (SD 647) days. Sixteen percent of patients diagnosed with HIV missed the opportunity to be diagnosed in the 5 years prior to diagnosis, highlighting the need to implement ED screening measures different from current ones to improve these outcomes.


Dietary Supplementation with γ-Aminobutyric Acid Improves Growth, Digestive Enzyme Activity, Non-Specific Immunity and Disease Resistance against Streptococcus iniae in Juvenile Olive Flounder, Paralichthys olivaceus.
Recent research is increasingly shedding light on the important role that microbial metabolites such as γ-aminobutyric acid (GABA) play in the context of nutrition, cognition, immune function, and the modulation of the gut microbiome. Yet, very few trials were conducted to assess the effects of its supplementation on biomarkers of fish health. Therefore, an eight-week feeding trial was devised to evaluate GABA supplementation in juvenile olive flounder, (Paralichthys olivaceus). A total of 630 fish with an average weight of 4.90 ± 0.10 g (±SD) were randomly assigned to one of seven triplicate groups and fed a non-GABA supplemented diet (CON, with 92 mg/kg GABA content), a positive control with 4 g/kg oxytetracycline (OTC), and five other diets supplemented with 50, 100, 150, 200 and 250 mg/kg GABA (corresponding to a total GABA content of 154, 229, 282, 327 and 352 mg/kg, respectively). Growth, blood chemistry, nonspecific immunity, digestive enzyme activity and disease resistance were assessed. The results showed that 100 and 150 mg/kg GABA supplementation consistently yielded significant improvements (p < 0.05) in growth, intestinal amylase, serum lysozyme, and survival against infection with Streptococcus iniae. Based on polynomial analysis, the optimal supplementation level was determined to be 237 mg/kg. These results support GABA as an important functional feed additive in juvenile olive flounder.


A scenario modelling analysis to anticipate the impact of COVID-19 vaccination in adolescents and children on disease outcomes in the Netherlands, summer 2021.
BackgroundSince the roll-out of COVID-19 vaccines in late 2020 and throughout 2021, European governments have relied on mathematical modelling to inform policy decisions about COVID-19 vaccination.AimWe present a scenario-based modelling analysis in the Netherlands during summer 2021, to inform whether to extend vaccination to adolescents (12-17-year-olds) and children (5-11-year-olds).MethodsWe developed a deterministic, age-structured susceptible-exposed-infectious-recovered (SEIR) model and compared modelled incidences of infections, hospital and intensive care admissions, and deaths per 100,000 people across vaccination scenarios, before the emergence of the Omicron variant.ResultsOur model projections showed that, on average, upon the release of all non-pharmaceutical control measures on 1 November 2021, a large COVID-19 wave may occur in winter 2021/22, followed by a smaller, second wave in spring 2022, regardless of the vaccination scenario. The model projected reductions in infections/severe disease outcomes when vaccination was extended to adolescents and further reductions when vaccination was extended to all people over 5 years-old. When examining projected disease outcomes by age group, individuals benefitting most from extending vaccination were adolescents and children themselves. We also observed reductions in disease outcomes in older age groups, particularly of parent age (30-49 years), when children and adolescents were vaccinated, suggesting some prevention of onward transmission from younger to older age groups.ConclusionsWhile our scenarios could not anticipate the emergence/consequences of SARS-CoV-2 Omicron variant, we illustrate how our approach can assist decision making. This could be useful when considering to provide booster doses or intervening against future infection waves.


Evidence for a relationship between mitochondrial Complex I activity and mitochondrial aldehyde dehydrogenase during nitroglycerin tolerance: effects of mitochondrial antioxidants.
The medical use of nitroglycerin (GTN) is limited by patient tolerance. The present study evaluated the role of mitochondrial Complex I in GTN biotransformation and the therapeutic effect of mitochondrial antioxidants. The development of GTN tolerance (in rat and human vessels) produced a decrease in mitochondrial O(2) consumption. Co-incubation with the mitochondria-targeted antioxidant mitoquinone (MQ, 10(-6)mol/L) or with glutathione ester (GEE, 10(-4)mol/L) blocked GTN tolerance and the effects of GTN on mitochondrial respiration and aldehyde dehydrogenase 2 (ALDH-2) activity. Biotransformation of GTN depended on the mitochondria being functionally active, particularly mitochondrial Complex I. Tolerance induced mitochondrial ROS production and oxidative stress, though these effects were not detected in HUVECρ(0) cells or Complex I mutant cells. Experiments performed to evaluate Complex I-dependent respiration demonstrated that its inhibition by GTN was prevented by the antioxidants in control samples. These results point to a key role for mitochondrial Complex I in the adequate functioning of ALDH-2. In addition, we have identified mitochondrial Complex I as one of the targets at which the initial oxidative stress responsible for GTN tolerance takes place. Our data also suggest a role for mitochondrial-antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use.


An effective dual sensor for Cu2+ and Zn2+ with long-wavelength fluorescence in aqueous media based on biphenylacrylonitrile Schiff-base.
Although some sensors for Cu2+ and Zn2+ had been reported, the sensor with long-wavelength emission in aqueous media for in-situ detecting Cu2+ and Zn2+ was always expected. Herein, a biphenylacrylonitrile Schiff-base (OPBS) with large aromatic conjugated system was designed and synthesized in yield of 82%. OPBS possessed excellent long-wavelength fluorescence at 550-750 nm in aqueous media, which selectively response to sense Cu2+ with quenched fluorescence and Zn2+ with chromotropic fluorescence from red to yellow. The detection of Cu2+ and Zn2+ were realized without mutual interference in their coexistence system by means of the assistance of ATP. The detection limits were 2.3 × 10-7 M for Cu2+ and 1.8 × 10-6 M for Zn2+, respectively. The sensing mechanism was elucidated by binding MS spectra, fluorescence Job's plot and 1H NMR spectra. Moreover, OPBS exhibited good bioimaging performance and the in-situ sensing abilities for Cu2+ and Zn2+ in living cells, suggesting the application potential for detecting Cu2+ and Zn2+ in both vitro assay and vivo environment.


The anticancer activity of an air-stable Pd(I)-NHC (NHC = N-heterocyclic carbene) dimer.
A new dinuclear Pd(i) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin.


Interactions between methanotrophs and ammonia oxidizers modulate the response of in situ methane emissions to simulated climate change and its legacy in an acidic soil.
Methane (CH4) is one of the most important greenhouse gases which can be formed by methanogens and oxidized by methanotrophs, as well as ammonia oxidizers. Agricultural soils can be both a source and sink for atmospheric CH4. However, it is unclear how climate change, will affect CH4 emissions and the underlying functional guilds. In this field study, we determined the impact of simulated climate change (a warmer and drier condition) and its legacy effect on CH4 emissions and the methanogenic and methanotrophic communities, as well as their relationships with ammonia oxidizers in an acidic soil with urea application. The climate change conditions were simulated in a greenhouse, and the legacy effect was simulated by removing the greenhouse after twelve months. Simulated climate change significantly decreased the in situ CH4 emissions in the urea-treated soils while the legacy effect significantly decreased the in situ CH4 emissions in the control plots, but had very little effect in the urea-treated soils. This indicates that the impact of simulated climate change and its legacy on CH4 emissions was significantly modified by nitrogen fertilization. Methanotrophs were more sensitive than methanogens in response to simulated climate change and its legacy effect, especially in the urea treated soil. Significant negative correlations were observed between the abundances of ammonia oxidizers and methanotrophs. Additionally, results of partial least path modeling (PLS-PM) indicated that the interactions of methanogens and methanotrophs with ammonia oxidizing archaea (AOA) had significant positive relationships with in situ CH4 emissions under the simulated climate change condition. Our work highlights the important role of AOA for CH4 emissions under climate change conditions. Further research is needed to better understand this effect in other ecosystems.