Short-term therapy with relatively low-dose cerivastatin improves endothelial function independently of its lipid-lowering effect: Evaluation of brachial artery vasodilatation using B-mode ultrasound imaging.
Administration of 0.4 to 0.8 mg of cerivastatin per day for 2 weeks has been reported to have pleiotropic effects and improve endothelial function. Whether low-dose cerivastatin would produce these rapid pleiotropic effects in the clinical setting remains uncertain, however. We investigated the effect of short-term therapy with relatively low-dose cerivastatin (0.15 mg/day) on endothelial function, thrombostatic parameters, and C-reactive protein (CRP) levels in hypercholesterolemic patients. Thirteen patients with LDL-cholesterol>160 mg/dl were treated with daily doses of 0.15 mg of cerivastatin for 2 weeks. Endothelial function, thrombostatic parameters (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor type 1 [PAI-1], and CRP were estimated at baseline and again after 2 weeks of treatment. Endothelial function was measured as flow-mediated vasodilation. Flow-mediated vasodilatation was assessed by measuring the percent change in the diameter of the brachial artery in response to reactive hyperemia using high-resolution ultrasound. Endothelium-independent vasodilatation was also measured using sublingual nitroglycerin. No major complications developed after the treatment. Total cholesterol decreased significantly, from 258±32 to 211±21 mg/dl, and LDL-cholesterol also decreased from 171±15 to 133±16 mg/dl after the treatment. Flow-mediated vasodilatation increased significantly, from 4.6±1.3 percent to 8.7±3.5 percent after 2 weeks of therapy, although endothelium-independent vasodilatation was not affected (9.5±2.4% vs 8.8±3.1%). No relation was found between percent change in flow-mediated vasodilatation and improvement in levels of LDL-cholesterol after therapy (r=0.07). PAI-1, t-PA, and CRP were not significantly changed by 2 weeks of therapy. (1) Evaluating vasodilation of the brachial artery with B-mode ultrasound imaging was useful in investigating the effect of statin on endothelial function. (2) Although no effect was detected in PAI-1, t-PA, or CRP, relatively low-dose cerivastatin therapy for 2 weeks improved endothelial function and lipid level independently and safely in hypercholesterolemic patients.


Intravenous urography after acute urinary retention.
The results of a 12-month prospective study of 113 patients show that intravenous urography has no place in the management of men with acute urinary retention without haematuria.


Replicate and repeat faecal immunochemical tests in symptomatic patients: A systematic review.
Faecal Immunochemical tests (FITs) in the assessment of patients presenting with symptoms have generally used a single sample. Little evidence pertains to the use of replicate, where a number of tests are done prior to decision-making or repeat FIT, where additional FIT are performed following clinical decision-making. Overwhelmingly, research has focussed on FIT to help identify colorectal cancer (CRC). The aim of this review is to assess the available literature concerning replicate and repeat FIT in symptomatic patients to help generate consensus and guide future research. The terms 'faecal immunochemical test' or 'FIT' were combined with 'multiple' or 'repeat'. EMBASE, Medline and PubMed database and other searches were conducted. All papers published in English were included with no exclusion date limits until November 2021. Of the 161 initial papers screened, seven were included for review. Qualitative and quantitative FIT outcomes were assessed in the studies. The primary aims of most related to whether replicate FIT increased diagnostic yield of CRC, with colonoscopy used as the reference standard. One publication assessed the impact of a new COVID-adapted pathway on CRC detection. No consensus on replicate FIT was apparent. Some concluded that FITs may help minimise missed CRC diagnoses: others showed no increase in diagnostic yield of CRC. Current evidence on replicate and repeat FIT is both minimal and conflicting. FIT is a superb clinical tool, but significant gaps surrounding application remain. Further studies relating to replicate and repeat FIT are required.


Photoreactivity of Bis-retinoid A2E Complexed with a Model Protein in Selected Model Systems.
The bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E) is formed as a byproduct of visual cycle in retinal pigment epithelium (RPE). It contributes to golden-yellow fluorescence of the age pigment lipofuscin, which accumulates in RPE. Lipofuscin can generate a variety of reactive oxygen species (ROS) upon blue-light excitation. Although in model systems photoreactivity of A2E has been determined to be low, this bis-retinoid exhibited significant phototoxicity in RPE cells in vitro. Although the mechanism of A2E-mediated phototoxicity remains mostly unknown, we hypothesize that formation of A2E-adducts with different biomolecules may play an important role. In this study, we investigated the photochemical reactivity of A2E and its complex with bovine serum albumin (BSA) using UV-Vis absorption and emission spectroscopy, EPR-spin trapping, EPR-oximetry, time-resolved singlet oxygen phosphorescence, and the fluorogenic CBA probe. Our data show that A2E after complexation with this model protein photogenerated an increased level of ROS, particularly singlet oxygen. We also demonstrated the ability of A2E to oxidize BSA upon excitation with blue light in aqueous model systems. The data suggest that pyridinium bis-retinoid could oxidatively modify cellular proteins under physiological conditions.


Contemporary practice of testicular prosthesis insertion.
To assess the practice of testicular prosthesis insertion (TPI) related to orchidectomy in one geographical region and to identify the difference in the rates of insertion among different age groups. Males who underwent orchidectomy between 1989 and 2009 were identified from data collected from Scottish Morbidity Records. Patients were classified into six age groups. The TPI rate and relation to original orchidectomy were analysed according to different age groups. In all, 3364 patients underwent orchidectomy in the 20-year period of the study. The most common indications for orchidectomy were atrophy, undescended testes, torsion, and tumour. In the same period, 530 patients had a TPI, with 59.4% of them (316 patients) having TPI at initial surgery, 17.3% (92) as a second surgical procedure, and 22.8% (122) having the TPI without prior history of orchidectomy. Among patients who underwent TPI, postpubertal males were more likely to have simultaneous insertion at the time of orchidectomy than prepubertal males (83% vs 32%; odds ratio 10.44, 95% confidence interval 5.23-20.82; P < 0.01). Younger males are more likely to have TPI at a later date. Paediatric urologists should be mindful of the possibility of concurrent TPI at the time of initial scrotal/groin exploration.


A urinary biomarker for monitoring exposures to 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate in rats.
2,2,4-Trimethyl-1,3-pentanediol monoisobutyrate (TMPD-MB) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TMPD-DB) are widely used primarily as surface stabilizers for water-based paints and plasticizers, respectively. Exposure to these compounds has been suspected as being associated with sick building syndrome and allergic diseases such as asthma in general populations. Therefore, it is very important to be able to know the amounts of these compounds absorbed into the body in order to evaluate its adverse effects on humans in living environments. In the present study, the urinary excretion kinetics of TMPD-MB and TMPD-DB were studied in animals to establish for urinary metabolites suitable as biomarkers for monitoring exposure. A single dose (48-750 mg/kg body weight) of TMPD-MB or TMPD-DB was administered intraperitoneally to male Sprague-Dawley rats, and their urine was collected periodically for a week. Two major metabolites, 2,2,4-trimethyl-1,3-pentanediol (TMPD) and 3-hydroxy-2,2,4-trimethylvaleric acid (HTMV), were measured in the urine samples. Their kinetics were evaluated by moment analysis of the urinary excretion rates of the metabolites versus time curves. The urinary excretion amounts of HTMV were suggested to be proportional to the absorption amounts over a wide exposure range of both TMPD-MB and TMPD-DB. The amounts of HTMV accounted for almost the same level, i.e., 4-5% of the dose at the lowest dosage, in rats tested for both TMPD-MB and TMPD-DB. Urinary HTMV was considered to be an optimal biomarker for monitoring exposure to mixtures of these compounds.


Self-awareness and Social Influences as Predictors of Body Dissatisfaction and Acceptance of Cosmetic Surgery for Social Reasons Among Men.
Body dissatisfaction and the use of surgery for purely aesthetic reasons among men is steadily increasing. Nevertheless, compared to women, few studies have focused on specific sociocultural and individual factors predicting men's body dissatisfaction and interest in cosmetic surgery procedures. The present study investigated the role of media, significant others, public and private self-awareness in predicting men's body dissatisfaction and acceptance of cosmetic surgery for social reasons. Participants were 203 men (mean-age 24 years), who completed a questionnaire containing the Sociocultural Attitudes Toward Appearance Questionnaire-4R, the Situational Self-Awareness Scale, the Muscular internalization subscale, the Male Body Attitudes Scale, and the Social subscale of the Acceptance of Cosmetic Surgery Scale. A path analysis was performed. The influence of significant others and public self-awareness predicted men's body dissatisfaction directly and indirectly, via muscularity internalization, while media was only directly associated with body dissatisfaction. A significant link between private self-awareness and body dissatisfaction was found. Moreover, media was not associated with cosmetic surgery either directly or indirectly and public self-awareness showed only a significant association with internalization. These findings provide information about the role that self-awareness and sociocultural factor play on body dissatisfaction and acceptance of surgery for social reasons among men. The study highlighted the importance of designing preventive programs aimed at enhancing men's ability to resist various forms of pressure regarding body image and its management. Moreover, the advantages of focusing one's attention on internal states and feelings can limit body dissatisfaction and can discourage consideration of cosmetic surgery for social benefits. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Neurotensin modulates human neutrophil locomotion and phagocytic capability.
Neurotensin (NT) was found to induce oriented locomotion and augment the phagocytic capability of human blood neutrophils over 10(-11) - 10(-7) M. The tridecapeptide also causes Ca2+ extrusion from neutrophils, very likely as a result of intracellular Ca2+ mobilization. It is suggested that the NT-mediated functional modulation of neutrophils correlates with the capacity of NT to affect the intracellular compartmentalization of Ca2+. Peripheral NT-elicited phenomena such as vasodilation, enhanced vascular compartmentalization of Ca2+. Peripheral NT-elicited phenomena such as vasodilation, enhanced vascular permeability, mast cell degranulation and the enhancement of directional migration and phagocytosis of neutrophils described here, classify NT as a typical mediator of inflammation.


Free fatty acid as a marker of energy malnutrition in liver cirrhosis.
Protein-energy malnutrition is frequently observed in patients with liver cirrhosis (LC). Non-protein respiratory quotient (npRQ) measured by indirect calorimetry is a good marker to estimate energy malnutrition, and predicts the prognosis of patients with LC. However, measurement of npRQ is limited because of the high cost of indirect calorimetry. Our aim was to find out an alternative marker to npRQ that can be used in the routine clinical setting. One hundred and fifty-six patients with LC were enrolled in this study. Indirect calorimetry and blood examinations were conducted after overnight fasting, and anthropometry was performed by an expert dietician. The correlation between npRQ and other parameters were calculated by simple and multiple regression analysis. Receiver-operator curve (ROC) analysis was used to identify the cut-off value that would best predict the threshold npRQ of 0.85. Plasma levels of free fatty acid (FFA) was significantly correlated with npRQ value by simple (r = -0.39, P < 0.0001) and multiple regression analysis (t = -2.96, P = 0.0052). Free fatty acid rose in parallel with the increasing disease severity as defined by Child-Pugh classification (P < 0.05). FFA was also correlated with increasing oxidation rate of fat (r = 0.38, P < 0.0001) and decreasing oxidation rate of carbohydrate (r = -0.39, P < 0.0001). The cut-off value of FFA to predict npRQ = 0.85 was 660 μEq/L by ROC analysis. FFA is a useful alternative marker to represent npRQ in patients with LC.


Modulation of the brain activity in outcome evaluation by the presence of an audience: An electrophysiological investigation.
The audience effect refers to the phenomenon that one׳s performance on a task is affected by the presence of others. Here we investigated how the audience effect modulates the neurocognitive signatures underlying people׳s evaluation of their own task performance/outcome. Participants in our study played a gambling game in two social contexts: an "audience" condition and an "alone" condition. The presence of others modulated the feedback-related negativity (FRN), which might reflect enhanced motivational significance or increased reward processing when participants were watched compared to when they were alone. We also observed increased P300 responses to outcome feedback in the audience condition, presumably reflecting more elaborative and sustained evaluation of outcomes in the audience than alone context. This audience effect on the evaluative processes complements previous observations on the social nature of outcome evaluation and extends a traditional topic in social psychology to the neuroscientific field.


Epidermolysis bullosa: report of three cases treated with homeopathy.
Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by recurrent blistering as a result of even minor traction of epithelial lined tissues, most remarkably the skin. Associated morbidity is serious for all patients affected due to the presence of large areas of denudated skin thus susceptible to infection. There is currently no available treatment in conventional medicine. This article reports the case of 3 children successfully treated with individualized homeopathic medicines.


Derepression of carbon catabolite repression in an extractive liquid-surface immobilization (Ext-LSI) system.
An extractive liquid-surface immobilization (Ext-LSI) system with a fungal mat formed on the surface of a liquid medium effectively enabled derepression of carbon catabolite repression. In this system, a fungicidal secondary metabolite 6-pentyl-α-pyrone was efficiently produced by Trichoderma atroviride AG2755-5NM398 despite the addition of 25% glucose or fructose.


Non-adherence to ivabradine and placebo and outcomes in chronic heart failure: an analysis from SHIFT.
In heart failure, non-adherence increases events; in turn, the effect of hospitalization on adherence is incompletely understood. We explored the relationship of non-adherence to outcomes, hospitalizations with non-adherence, and the influence of non-adherence on treatment effects of heart rate lowering with ivabradine. In the randomized, controlled Systolic Heart failure treatment with the If-inhibitor ivabradine Trial (SHIFT), we studied the effect of non-adherence (n = 1287) compared with adherence (n = 5204) on cardiovascular outcomes. After adjustment, non-adherence was associated with the primary composite endpoint of cardiovascular death and heart failure hospitalization (hazard ratio 3.47, 95% confidence interval 2.91-4.13, P < 0.0001). No interaction with the treatment groups of placebo or ivabradine (P for interaction 0.54) occurred. Similar results for cardiovascular death and heart failure hospitalization, as well as for cardiovascular hospitalization, heart failure death, and total death were observed. The effect of ivabradine was maintained in patients being adherent or becoming non-adherent during the trial (P for interaction = 0.54). Patients with a previous hospitalization were more likely to become non-adherent thereafter. Non-adherence identifies a group at particularly high cardiovascular event risk independent of treatment allocation. Non-adherent patients in the ivabradine group maintain a treatment benefit. Patients with previous hospitalizations are more likely to become non-adherent and represent a group of particularly high-risk patients in whom special attention to stimulate adherence may be valuable. ISRCTN70429960.


Gamma-ray sensitivity during synchronous cell differentiation in Caulobacter crescentus.
Gamma-ray sensitivity of Caulobacter crescentus during its cell cycle was examined. Survival curves of the swarmer and stalked cells were similar and exponential in shape, whereas that of the predivisional cell was sigmoidal, with an extrapolation number of 1.8.


The adaptor molecule Trif contributes to murine host defense during Leptospiral infection.
Leptospirosis is a zoonotic disease and is caused by pathogenic species of the Leptospira genus, including Leptospira interrogans (L. interrogans). Humans, domestic and wild animals are susceptible to acute or chronic infection. The innate immune response is a critical defense mechanism against Leptospira interrogans, and has been investigated in mouse models. Murine Toll-like receptors (TLRs) have been shown to be key factors in sensing and responding to L. interrogans infection. Specifically, TLR2, TLR4 and the TLR adaptor molecule MyD88 are essential for host defense against L. interrogans; however, the role of the TLR adaptor molecule TIR-domain-containing adaptor-inducing interferon β (TRIF) in the response to L. interrogans has not been previously determined. In the present study, TRIF was found to play an important role during leptospiral infection. Following challenge with L. interrogans, Trif(-/-) mice exhibited delayed weight gain compared to wild-type mice. Moreover, Trif(-/-) mice exhibited an increase in L. interrogans burden in the kidneys, lungs, and blood at early time points (less than 7days post infection). Multiple components of the innate immune responses were dampened in response to leptospiral infection including transcription and production of cytokines, and the humoral response, which suggested that TRIF contributes to expression and production of cytokines important for the host defense against L. interrogans.


An ameloblastoma-like neoplasm of the buccal mucosa. Report of a case.
A case of an unusual neoplasm of the buccal mucosa nearly identical to an ameloblastoma is reported. The tumor probably arose from the overlying squamous epithelium in the vicinity of the parotid duct.


Non-proteinaceous hydrolase comprised of a phenylalanine metallo-supramolecular amyloid-like structure.
Enzymatic activity is crucial for various technological applications, yet the complex structures and limited stability of enzymes often hinder their use. Hence, de novo design of robust biocatalysts that are much simpler than their natural counterparts and possess enhanced catalytic activity has long been a goal in biotechnology. Here, we present evidence for the ability of a single amino acid to self-assemble into a potent and stable catalytic structural entity. Spontaneously, phenylalanine (F) molecules coordinate with zinc ions to form a robust, layered, supramolecular amyloid-like ordered architecture (F-Zn(ii)) and exhibit remarkable carbonic anhydrase-like catalytic activity. Notably, amongst the reported artificial biomolecular hydrolases, F-Zn(ii) displays the lowest molecular mass and highest catalytic efficiency, in addition to reusability, thermal stability, substrate specificity, stereoselectivity and rapid catalytic CO2 hydration ability. Thus, this report provides a rational path towards future de novo design of minimalistic biocatalysts for biotechnological and industrial applications.


Immunotherapy combination with regorafenib for refractory hepatocellular carcinoma: A real-world study.
To compare the efficacy and safety of immunotherapy plus regorafenib versus regorafenib only in patients with pretreated hepatocellular carcinoma (HCC). Immunotherapy plus regorafenib or regorafenib alone was analyzed in patients with advanced HCC with documented tumor progression on front-line therapy. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and treatment-related adverse events (TRAEs) were assessed. Of the 125 patients enrolled in this study, 50 patients received combination (pCOM) treatment as front-line treatment, and 60 patients received monotherapy (pMONO) as front-line treatment. In the pCOM cohort, median OS was significantly longer with for patients regorafenib plus immunotherapy than regorafenib alone treatment (15.0 vs. 2.0 months; P = 0.035). The DCR numerically increased in the regorafenib plus immunotherapy treatment in both cohorts (40.6 % vs. 22.2 %, 72.7 % vs. 54.7 %, respectively). There were no differences in PFS with regorafenib according to whether or not regorafenib was combined with immunotherapy in the pCOM and pMONO cohorts (PFS, P = 0.17, P = 0.91, respectively). Regarding the number of TRAEs occurred, regorafenib plus immunotherapy group was comparable to regorafenib group in the pCOM cohort (65.6 % vs. 72.2 %). In the pMONO cohort, TRAEs occurred in fewer patients receiving regorafenib than regorafenib plus immunotherapy (69.8 % vs. 95.5 %). Immunotherapy plus regorafenib may significantly improve clinical outcomes and have a manageable safety profile compared with regorafenib monotherapy in advanced HCC after front-line therapy failure. The efficacy of combination therapy needs to be validated in prospective studies with large samples.


The interplay of processivity, substrate inhibition and a secondary substrate binding site of an insect exo-beta-1,3-glucanase.
Abracris flavolineata midgut contains a processive exo-beta-glucanase (ALAM) with lytic activity against Saccharomyces cerevisiae, which was purified (yield, 18%; enrichment, 37 fold; specific activity, 1.89 U/mg). ALAM hydrolyses fungal cells or callose from the diet. ALAM (45 kDa; pI 5.5; pH optimum 6) major products with 0.6 mM laminarin as substrate are beta-glucose (61%) and laminaribiose (39%). Kinetic data obtained with laminaridextrins and methylumbelliferyl glucoside suggest that ALAM has an active site with at least six subsites. The best fitting of kinetic data to theoretical curves is obtained using a model where one laminarin molecule binds first to a high-affinity accessory site, causing active site exposure, followed by the transference of the substrate to the active site. The two-binding-site model is supported by results from chemical modifications of amino acid residues and by ALAM action in MUbetaGlu plus laminarin. Low laminarin concentrations increase the modification of His, Tyr and Asp or Glu residues and MUbetaGlu hydrolysis, whereas high concentrations abolish modification and inhibit MUbetaGlu hydrolysis. Our data indicate that processivity results from consecutive transferences of substrate between accessory and active site and that substrate inhibition arises when both sites are occupied by substrate molecules abolishing processivity.


Continuing education--the EANS concepts.
Continuing Medical Education (CME) is becoming to be an important part of professional conduct of neurosurgeons in the member countries of EANS. It is therefore a task for the EANS to harmonize various systems of CME and to offer a compatible programme of continuing education that would meet the expectations and needs of the neurosurgeons. It should help choose fields in which updating knowledge is indispensable, offer teaching and training opportunities and provide systems of evaluation and certification of progress in neurosurgical CME.


Proteasome inhibitors.
Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications.


13C CP (cross-polarization) MAS (magic angle spinning) NMR and GIAO-CHF calculations of buspirone analogues. Part 1. 3a,4,7,7a-Tetrahydro-2-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl ]-4,7-ethane-1H-isoindole-1,3(2H)-dione hydrochloride and hydrobromide.
13C CP (cross-polarization) MAS (magic angle spinning) solid state NMR spectra of buspirone analogue 3a,4,7,7a-tetrahydro-2-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-4,7-eth ane-1H-isoindole-1,3(2H)-dione were recorded. In the spectra of hydrochloride and hydrobromide, two sets of signals appeared, in agreement with single crystal X-ray diffraction data indicating that in each of the salts two independent cations were present in the crystal unit. The largest shielding differences of 3.2-4.6 ppm between two sets of signals were found for quinoline aromatic carbons C3 and C2. Ab initio calculations of the carbon and nitrogen shielding constants were performed with the use of the GIAO-CHF method for structural fragments: N-butylsuccinimide, quinoline-(N-methyl) piperazine hydrochloride and hydrobromide. Linear correlations between theoretical and solid state results were obtained, thus enabling a reasonable assignment of carbon resonances of the conformations present in the solid state. Due to the fast dynamics in solution, the carbon chemical shifts corresponded to the averaged values of the forms present in the solid state.


Yuja Juice and Concentrate Enhance Immunomodulating Effects via Increasing Immune-Related Cytokines in RAW264.7 Cells and Mouse Splenocytes.
Good immunity is highly valued in modern society. Although yuja's efficacy in immunity enhancement has been elucidated, there have been few studies on its role. In this study, we investigate the immune enhancement activity of yuja juice extracts (YJEs) and yuja concentrate extracts (YCEs). The immunoregulatory potencies of YJE and YCE were examined by determining cell viability and the expression of cytokines and immune-related molecules in RAW264.7 cells and mouse primary splenocytes. YJE and YCE induced the production of inducible nitric oxide synthase and cytokines (IL-10, IL-4, IL-6, and IFN-γ) at 1000 μg/mL concentration in RAW 264.7 cells. In addition, in mice that were orally administered 3000 or 2000 mg/kg concentrations of YJE or YCE, immune-related cytokines in splenocytes were boosted to levels higher than those in control mice. Importantly, no liver toxicity was observed at all doses. Thus, our results suggest that compounds present in YJEs and YCEs represent novel natural immune-modulatory substances.


Parametric survival densities from phase-type models.
After a brief historical survey of parametric survival models, from actuarial, biomedical, demographical and engineering sources, this paper discusses the persistent reasons why parametric models still play an important role in exploratory statistical research. The phase-type models are advanced as a flexible family of latent-class models with interpretable components. These models are now supported by computational statistical methods that make numerical calculation of likelihoods and statistical estimation of parameters feasible in theory for quite complicated settings. However, consideration of Fisher Information and likelihood-ratio type tests to discriminate between model families indicates that only the simplest phase-type model topologies can be stably estimated in practice, even on rather large datasets. An example of a parametric model with features of mixtures, multiple stages or 'hits', and a trapping-state is given to illustrate simple computational tools in R, both on simulated data and on a large SEER 1992-2002 breast-cancer dataset.


Cloning, characterization and gene expression of a metallothionein isoform in the edible cockle Cerastoderma edule after cadmium or mercury exposure.
Metallothionein (MT) genes encode crucial metal-binding proteins ubiquitously expressed in living organisms and which play important roles in homeostasis of essential metals and detoxification processes. Here, the molecular organization of the first metallothionein gene of the edible cockle Cerastoderma edule and its expression after cadmium (Cd) or mercury (Hg) exposures were determined. The resulting sequence (Cemt1) exhibits unusual features. The full length cDNA encodes a protein of 73 amino acids with nine classical Cys-X((1-3))-Cys motifs, but also one Cys-Cys not generally found in molluscan MT. Moreover, characterization of the molecular organization of the Cemt1 gene revealed two different alleles (A1 and A2) with length differences due to large deletion events in their intronic sequences involving direct Short Interspersed repeated Elements (SINE), while their exonic sequences were identical. To our knowledge, such large excision mechanisms have never before been reported in a bivalve gene sequence. After 10 days of Cd exposure at environmentally relevant doses, quantitative real-time PCR revealed a strong induction of Cemt1 in gills of C. edule. Surprisingly, neither induction of the Cemt1 gene nor of MT protein was shown after Hg exposure, despite the fact that this organism is able to bioaccumulate a high amount of this trace metal which is theoretically one of the most powerful inducers of MT biosynthesis.


Surgical Atrial Fibrillation Ablation: An Electrophysiologist's Perspective.
The experience and insight obtained during surgical ablation of all types of arrhythmias was formative for electrophysiology and catheter ablation. The early surgical ablation experience provided proof of concept as well direct operative observation of anatomy and pathophysiologic mechanisms. For atrial fibrillation (AF), surgical ablation anticipated many of the problems that catheter ablation subsequently encountered, although these lessons were not promptly appreciated. Rather than competition, greater cooperation and communication between surgeons and electrophysiologists in the future would be more likely to enhance understanding of the underlying pathophysiology of AF.


Effect of long-term ovariectomy on bone mechanical properties in young female cynomolgus monkeys.
Feral adult female cynomolgus monkeys were divided into two groups: normal controls and ovariectomized. Tibiae and trabecular bones from the femoral head, from each group, were tested using a materials testing machine. The bending stiffness of the tibiae was measured by nondestructive three-point bending tests and their maximum torque capacity by destructive torsion tests. The compressive strength of the trabecular bones was measured by compression tests. Ovariectomy caused significant decreases in elastic modulus of the tibiae (p < 0.008), measured by three-point bending tests, and in shear modulus (p < 0.015), failure shear stress (p < 0.01), and failure torque (p < 0.001) of the tibiae, measured by torsion tests. It caused a significant decrease in cortical bone density (p < 0.005), but no significant changes in tibial cross-sectional area and in cortical shaft external and internal diameters. The differences in elastic modulus, maximum compressive strength, and density of femoral trabecular bone samples between the two groups were not significant.


Neurobiology of nicotine addiction: implications for smoking cessation treatment.
Nicotine sustains addictive tobacco use, which in turn causes much premature disability and death. The essence of drug addiction is loss of control of drug use. Molecular biology studies suggest that the alpha(4)beta(2) nicotinic acetylcholine receptor subtype is the main receptor mediating nicotine dependence. Nicotine acts on these brain nicotinic cholinergic receptors to facilitate neurotransmitter release (dopamine and others), producing pleasure, stimulation, and mood modulation. Neuroadaptation develops with repeated exposure to nicotine, resulting in tolerance to many of the effects of nicotine. When a smoker stops smoking, a nicotine withdrawal syndrome ensues, characterized by irritability, anxiety, increased eating, dysphoria, and hedonic dysregulation, among other symptoms. Smoking is also reinforced by conditioning, such that specific stimuli that are psychologically associated with smoking become cues for an urge to smoke. These include the taste and smell of tobacco, as well as particular moods, situations, and environmental cues. Pharmacotherapies to aid smoking cessation should ideally reduce nicotine withdrawal symptoms and block the reinforcing effects of nicotine obtained from smoking without causing excessive adverse effects. Further, given the important role of sensory effects of smoking and psychoactive effects of nicotine, counseling and behavioral therapies are important adjuncts to and substantially augment the benefits of pharmacotherapy.


Smoking prevalence in a cohort of adolescents, including absentees, dropouts, and transfers.
This study reports daily smoking rates among older adolescents obtained by a unique follow-up of a cohort originally identified in the seventh grade. Those no longer in their original school districts were located and interviewed by telephone. Smoking rates among dropouts exceeded 70 per cent in all age-sex groups. Smoking rates among transfers were as high as those among absentees. Including these subgroups raised smoking prevalence rates among older adolescents substantially.


Ethnic neutropenia and clozapine.
The aim of the present paper was to examine the concept of benign ethnic neutropenia and to consider the implications of ethnicity in the current clozapine regulatory system. The case of a young Palestinian man who lost access to clozapine due to a fall in his neutrophil count, is presented herein, and a brief review of ethnic variations in neutrophil levels is given. This patient's clozapine was ceased, with unfortunate consequences, despite his having normal immune function. By using normative haematological data established in white populations, the Australian clozapine regulatory system places some non-white patients at a considerable disadvantage.


Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors.
One hundred and forty children with hematologic malignancies undergoing allogeneic BMT were reviewed in order to clarify the incidence, onset time, and risk factors for veno-occlusive disease (VOD) of the liver. Thirty-eight patients (27.1%) developed VOD diagnosed according to the Seattle clinical criteria. Seventeen patients developed VOD within 20 days of transplantation (early-onset) and in 21 patients developed after day 20 (late-onset) including eight patients with histological confirmation. Late-onset VOD occurred from day 21 to day 508 (median day 39). Moderate or severe VOD developed in 11 early-onset and 13 late-onset patients. Death occurred in eight early-onset and 10 late-onset patients. Serum albumin and cholinesterase levels prior to the start of pretransplant conditioning were significantly lower in early-onset VOD than in late-onset VOD. Multivariate analysis showed that low serum albumin levels (< or =3.7 g/dl) prior to the start of pretransplant conditioning was most strongly associated with the development of VOD. Donor mismatch (other than HLA-matched relatives), use of minocycline, and a long interval (> or =13 months) between diagnosis and BMT were also significantly associated with the development of VOD. In contrast, use of fosfomycin was associated with a decreased risk. Our data suggest that hepatic function reserve is important in the development and onset time of VOD. Veno-occlusive disease of the liver is a complication which may occur a long time after transplantation.


Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study.
Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models. TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses. A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma. Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745.


Low fecal rotavirus vaccine virus shedding is significantly associated with non-secretor histo-blood group antigen phenotype among infants in northern Pretoria, South Africa.
Histo-blood group antigens are recognized by rotaviruses in a P- genotype dependent manner and their frequency in a population can influence fecal virus shedding. This study investigated the rate of fecal shedding of Rotarix vaccine and its association with HBGA phenotype distribution in South Africa. Stool and saliva specimens were collected from 150 infants attending immunization on the day of both first and second doses and 7 days later. Virus shedding was detected by real-time qPCR while HBGA phenotypes in saliva were determined by enzyme linked immunosorbent assay. Vaccine virus shedding was higher (23.6%) after the first dose than the second dose (4.7%). About 77% of virus-shedding infants were secretors (OR = 129; 95% CI, 6.088 - 2733), compared with none of non-virus shedding infants. Non-secretor status was significantly associated with low vaccine virus shedding while the likelihood of shedding was significantly higher in secretors.


cDNA cloning and expression of a Talaromyces emersonii beta-glucosidase determinant in Escherichia coli.
Intact mRNA has been isolated from the thermophilic fungus Talaromyces emersonii following growth on lactose-containing media and this has been used as template to produce cDNA. This cDNA has been cloned into the Escherichia coli expression system, pUC18 and this DNA was used to transform E. coli. A 2.1 kb fragment was isolated and shown to encode functional beta-glucosidase activity in E. coli. When the fragment was sub-cloned into a leaky strain of E. coli K-12, beta-glucosidase activity was detected in culture supernatants. The fragment was characterised further using restriction enzyme analysis and was also used as a probe in Northern and Southern blotting analyses of T. emersonii mRNA and genomic DNA, respectively. Results obtained from these analyses verified that the cloned insert DNA was of T. emersonii origin.


Fingerprint and weathering characteristics of crude oils after Dalian oil spill, China.
In an attempt to analyze the chemical characterization of oil residues and examine the suitability of chemical fingerprinting methods in oil spill investigations, multiple parameters sensitive to both sources and degree of weathering were used to characterize oil residues from "7-16" Dalian oil spill, China. Oil residues collected 90 days to 120 days after the spill showed a weathering pattern where significant amounts of light to middle molecular weight normal alkanes were depleted with pristane and phytane as dominant peaks. Diagnostic ratios developed from n-alkane and selected isoprenoids (e.g. Pr/Ph, n-C17/Pr, n-C18/Ph, carbon preference index, LMW/HMW-alkanes ratio), all display obvious changes over weathering time, indicating that these ratios are not valid for oil source identification. Furthermore, the biomarker ratios of hopanes and steranes with relative standard deviations (RSDs) of 0.88-4.08% were useful for source identification even for severely weathered oil residues. In addition, RSD of δ(13)C values of individual n-alkanes in oil residue varied from 0.07% to 0.20%, which suggest that stable carbon isotope profile of n-alkanes can also be a useful tool for tracing the source of an oil spill.


The spatio-temporal partitioning of sperm by males of the prospermatogenic parasitoid Nasonia vitripennis is in line with its gregarious lifestyle.
Male fitness depends on the number of lifetime progeny of their mates and could be constrained by the chance of finding a mate, lifespan and temporal patterns of sperm production and allocation. Here, we used the parasitic wasp Nasonia vitripennis with a two-week lifespan and a gregarious lifestyle, to analyze how the reproductive system is organized to allocate spermatozoa over consecutive matings. Results show that spermatogenesis is synchronized and completed one day before emergence so that males emerge with a full sperm complement. We also found a regulation of spermatozoa transfer between testis and seminal vesicles that allows males to partition small ejaculates over multiple matings. Overall, this study shows that for N. vitripennis, male fertilization potential is determined (1) at the pupal stage, when spermatogenesis takes place to generate a complete life-long stock, (2) on emergence, when transport of spermatozoa from testes to seminal vesicles is initiated and (3) in adulthood, during which spermatozoa are partitioned over successive copulations. Such life history-traits are consistent with the gregarious lifestyle of N. vitripennis.


A histochemical study of the activity of nonspecific cholinesterase in C6 glioma cells in culture.
The activity of nonspecific cholinesterase (nChE) was revealed histochemically in a small number of C6 glioma cells under conditions of spontaneous growth in culture. The nChE-positive cells (nChE+) first appeared in 4-day-old cultures. They occurred solitarily or in small groups with a cluster- or chain-like arrangement. The incidence of nChE+ cells increased with in vitro age and/or higher population densities of cultures but it never exceeded 3% of the whole population. These results indicate the necessity of histochemical as well as biochemical data on nChE activity in glioma cells both in situ and in culture for the discovery of the heterogeneous distribution of this enzyme. db-cAMP induced a decrease in the proportion of nChE+ cells to total number of cells. These changes suggest that the original C6 glioma cell seed stock contains a small subclone of less differentiated cells exhibiting nChE activity. The greater number of nChE+ cells in older cultures is probably due to recovery and multiplication of initially scarce subclone cells. C6 glioma cells in culture form a suitable model for investigation of changes in nChE activity of glial cells provided that a histochemical method of detection is applied.


Dingkun pill alleviates metabolic abnormalities in polycystic ovary syndrome through brown adipose tissue activation.
Traditional Chinese medicine has been used for a long time to treat a variety of gynecological diseases. Among various traditional Chinese medicine, Dingkun Pill (DK) has been used for the treatment of female gynecological diseases. However, DK therapeutic effect on PCOS and the target tissue for its potential effect need to be explored. This study aims to explore the therapeutic effect of DK for PCOS in mice from three aspects: metabolism, endocrine and fertility, and determine whether the brown adipose tissue is the target organ to alleviate the PCOS phenotype. PCOS mouse model was constructed by subcutaneous injection of DHEA. The estrous cycle, ovulation, and pregnancy outcome was examined in mice. The level of hormone including the LH, FSH, estrogen and testosterone in the serum were measured by ELISA. Both the glucose sensitivity and insulin sensitivity were determined in mice with different treatment. The histomorphology and lipid contents in the brown adipose tissue were analyzed. RNA-Seq was conducted for the brown adipose tissue and different expression of critical metabolism marker genes was confirmed by real-time PCR. The data showed that the fertility in PCOS mice with DK treatment was significantly increased, and the metabolic disorder was partially restored. Both the whiten of brown adipose tissue and reduced UCP1 expression induced by DHEA was rescued by the DK. The RNA-Seq data further demonstrated both the DHEA induced downregulation of lipolysis genes and oxidative phosphorylation genes were at least partially rescued by DK in the brown adipose tissue. DK has therapeutic effect on PCOS in DHEA treated mice and the brown adipose tissue is at least one critical target organ to alleviate the PCOS. This is achieved by not only regulating the lipid mobilization of brown adipose, but also restoring its thermogenic function.


Smartphone patient monitoring post-laser resurfacing.
Patients should be monitored post-laser resurfacing for reassurance and the early detection of adverse events. Smartphone monitoring in the post-laser resurfacing setting is an efficient and convenient tool that is well accepted by patients and dermatologists. The objective was to identify the benefits and barriers of, and patient attitudes towards, smartphone monitoring in the post-laser resurfacing setting. A retrospective audit of 123 laser resurfacing patients was undertaken to determine the characteristics of this population. A web-based survey was used to determine patients' attitudes towards smartphone monitoring. The commonest indications for laser resurfacing were acne scarring and photoageing rejuvenation. 88% of patients either had no adverse outcomes or expected post-laser resurfacing side-effects such as erythema. 12% developed adverse effects requiring intervention. The survey showed that all patients who had used the smartphone monitoring service felt it was a positive initiative for post-laser patients. Of note, most patients not using the smartphone review service were simply unaware of its existence. Biases may have been introduced as staff were less likely to promote the review service to patients undergoing lower intensity procedures. Smartphone monitoring post-laser resurfacing is an efficient and convenient alternative to face-to-face review for both patients and dermatologists. As technology improves and patients' expectations increase we expect more patients will request teledermatology reviews in order to easily and rapidly access medical advice.


Complementary medicine for alcohol dependence in Italian services: a mail questionnaire.
It is well known that Complementary Medicine (CM) is extensively used in western countries for the treatment of many afflictions. CM has been recently promoted in addiction treatment. To evaluate CM use in alcohol dependence we planned a mail questionnaire for Italian alcohol services. We sent out 612 questionnaires. Health services that were unable to respond to the questionnaire within a 20-day limit period were contacted by phone and if we obtained agreement to participate in the study the questionnaire was sent by fax. We obtained 312 (51.82%) completed questionnaires. Only 16.50% of Italian services use CM for alcohol dependence treatment and acupuncture is utilized more frequently than other methods (phytotherapy, homeopathy, etc.). In Italian alcohol services CM is identified as an instrument incorporated into traditional alcohol treatments (self-help groups, drug treatment, etc.) and not an alternative method. In fact, health services that use it as a principal method of treatment were a rare event in our study (1%). CM plays an integrated role with traditional forms of alcohol treatment in Italian alcohol services and this utilization could be useful to reduce drop-outs and improve alcohol treatment compliance.


Parotid gland tumors: a retrospective study of 154 patients.
Benign tumors of the parotid gland comprise the majority of salivary gland tumors. To review the clinical characteristics of parotid gland tumors submitted to surgical treatment by the same surgeon. Retrospective study with 154 patients who had parotid gland tumors. Clinical and histological data, type of surgery, and complications were assessed and described. The main manifestation was a mass with a median evolution of 12 months for benign tumors and five months for malignant tumors. Ultrasonography was the most frequent complementary exam. Pleomorphic adenoma was the most common of the benign tumors, and mucoepidermoid carcinoma was the most frequent malignant tumor. Superficial parotidectomy with preservation of the facial nerve was the most common surgical procedure and reversible paresis of branches of the facial nerve was the most common complication. Pleomorphic adenoma is the most common parotid gland tumor and superficial parotidectomy with preservation of the facial nerve is the most common and appropriate treatment for most low-morbidity tumors.


Genetic dissection of behavioral traits related to successful training of drug detection dogs.
Drug detection dogs play integral roles in society. However, the interplay between their behaviors and genetic characteristics underlying their performance remains uninvestigated. Herein, more than 120,000 genetic variants were evaluated in 326 German Shepherd or Labrador Retriever dogs to profile the genetic traits associated with various behavioral traits related to the successful training of drug detection dogs. Behavioral breed differences were observed in 'friendliness to humans' and 'tolerance to dogs.' A genome-wide association study within both breeds identified 11 regions potentially associated with drug detection dog characteristics as well as 'interest in the target' and 'friendliness to humans,' which are related to drug detection abilities. Among them, 63 protein-coding genes, including Atat1 and Pfn2 known to be associated with anxiety-related or exploration behavior in mice, respectively, were located surrounding the identified candidate polymorphisms. This study highlights genetic characteristics associated with behavioral traits that are important for the successful training of drug detection dogs. Thus, these findings may facilitate improved breeding and training of these dogs.


Study of portal vein thrombosis in patients with idiopathic portal hypertension in Japan.
The aim of this study was to elucidate the incidence and clinical manifestations of portal vein thrombosis (PVT) in patients with idiopathic portal hypertension (IPH) in Japan during long-term follow-up. Twenty-two patients with IPH were examined for PVT by sonography during a follow-up of 12+/-6 years. Clinical manifestations and patient outcome related to PVT were studied. Seventy patients with liver cirrhosis were examined by sonography as an incidence control of thrombosis. Nine IPH patients had portal thrombosis (9/22, 41%), a higher incidence than in liver cirrhosis patients (7/70, 10%). Those with thrombosis showed ascites, marked hypersplenism, and low serum albumin. Four patients with thrombosis died. Patients without thrombosis showed less clinical problems after long-term follow-up. Plasma antithrombin III and protein C activity decreased in almost half of the patients. However, there were no differences in these parameters between patients with and without thrombosis. In Japan, IPH patients had a high incidence of portal thrombosis, a significant factor for poor prognosis. Whether the management of PVT contributes to an improvement of a clinical course of IPH or not should be clarified in further study.


Experimental infections with Cooperia oncophora (Railliet, 1918) in calves. Results of single infections with two graded dose levels of larvae.
Two experiments were carried out in which calves reared parasite-free were infected with a single dose of 3rd-stage larvae of Cooperia oncophora. In the first experiment the calves received 20 000 or 200 000 infective larvae and they were autopsied 28 or 56 days after the infection. In the second experiment the doses were the same but the animals were killed 14, 84 or 140 days after infection. If a dose of 20 000 was given, clinical signs were never observed, while at a dose level of 200 000 the weight gain was less on 56 and 84 days after the infection compared with the low-infected groups or the control animals. After 170 days the differences in weight gain were compensated. Faecal egg output was higher in the 200 000 groups only in the first period of patency, thereafter the calves in the 20 000 groups produced more. No obvious differences between the two infection levels were observed with regard to the haematological data. In the low-infected groups worm counts were only slightly lower when the results after 28 days were compared with those after 56 days. Also, the worm numbers after 14 days were almost equal to those after 84 days, while at 140 days 1 animal still had the same number, the other one had lost its worm burden. In the high-infected groups the worm loss was much quicker. After 28 days a great part of the population had already been lost. Obviously, at the 200 000 level the reaction of the host against the parasite was much stronger. Adult worms were expelled at a higher rate than early 4th-larval stages. In the first experiment worm measurements revealed differences between the length of females, males and spicules of males, these being significantly longer in the low-infected groups. Analysis of the distribution of worms over the small intestine showed that in the low-infected groups worms were mainly restricted to the first 6 metres. In the high-infected groups the worm population was distributed more evenly over the whole small intestine.


Outcomes of modular proximal femoral replacement in the treatment of complex proximal femoral fractures: a case series.
The treatment of complex femur fractures poses a significant challenge. Even with current advancements and the various implements available for the fixation of femoral fractures, results are often disappointing. This study sought to identify problems associated with and examine results of modular proximal femoral replacement. Outcomes were evaluated in two groups of patients: those receiving primary modular proximal femoral replacement for fractures and those treated with salvage arthroplasty for failed internal fixation. Twelve patients who had received modular proximal femoral replacement as primary treatment for proximal femoral fractures were evaluated along with nine patients treated with salvage proximal femoral replacement for failed internal fixation. After the surgical procedure, patients were evaluated at regular follow-up intervals and contacted by phone at the conclusion of this study. Patient functional results were evaluated using the Merle D'Aubigne hip rating scale, which measures pain, motion and ambulatory status. Routine radiographs were also obtained at each patient visit. On average, patients who received modular proximal femoral replacement as the primary surgery for their femoral fractures enjoyed a high-level functional result and had few complications. Subjects who received salvage femoral replacement had a less optimal outcome and experienced more complications. Nonetheless, final post-operative MDA score was significantly increased from pre-operative levels. Modular proximal femoral replacement is a viable option in the primary fracture or revision setting, and has been shown to have a reasonable outcome, especially when the nature of initial injury is taken into account.


Assessment of factors influencing the outcome of radiotherapy for bladder cancer.
The results of treatment of 709 patients with carcinoma of the bladder are reported. Inclusion of the pelvic lymph nodes in the treatment volume failed to lead to any improvement in survival. The factors influencing survival were stage, tumour histology and differentiation. The presence of tumour at follow-up cystoscopy at 3 months was of great prognostic significance.


Acute gastroenteritis outbreaks in closed and semi-closed facilities during 2017 in Catalonia, Spain.
Acute gastroenteritis (AGE) is a leading cause of disease worldwide. The aim of this prospective observational study is to describe the epidemiology of AGE in closed and semi-closed institutions in Catalonia. In 2017, 151 outbreaks were reported; 30.5% occurred in closed and semi-closed institutions; 71.7% caused by norovirus (NoV) (1532) cases. Person-to-person transmission accounted for 75.8% of NoV outbreaks vs 46.1% in non-NoV outbreaks (p < 0.001). Attack rate for NoV outbreaks was 33.1% vs 14.3% for non-NoV outbreaks (RR = 2.3; 95%CI: 2.0-2.7). The high number of affected underscores prompt and intense preventive measures to avoid the extension and perpetuation of outbreaks in these settings.


Serum antibodies and their role in antibody-dependent cell-mediated cytotoxicity in aspergillosis.
A total of 22 sera from patients with aspergilloma and allergic bronchopulmonary aspergillosis (ABPA) were examined concomitantly for specific antibody against Aspergillus fumigatus antigen and for their activity in antibody-dependent cell-mediated cytotoxicity (ADCC) against Aspergillus antigen-coated target cells. These sera demonstrated significant precipitin bands in agar gel double diffusion test (78% of ABPA and 75% of aspergilloma sera), while in indirect immunofluorescence studies all sera showed positive reactivity with a titer distribution of 1:40 to 1:160 and 1:40 to 1:320, respectively, for ABPA and aspergilloma sera. In enzyme-linked immunosorbent assay all sera demonstrated titers varying from 1:200 to 1:6400. Several sera also displayed marked cytotoxic reactions against A. fumigatus antigen-coated SB target cells in ADCC assays using normal lymphocytes as effector cells (35% of aspergilloma and 25% of ABPA sera). These findings suggest a role for ADCC activity in patients with Aspergillus infections.


Beyond the treatment of epilepsy: new applications of vagus nerve stimulation in psychiatry.
Vagus nerve stimulation (VNS) in humans generally refers to stimulation of the left vagus nerve at the cervical level VNS is an established treatment largely devoid of severe side effect for medically refractory partial onset seizures and has been used in more than 16,000 patients. Over the past 5 years, applications in other neuropsychiatric disorders have been investigated with a special emphasis on depression. Recent data from an open-label, multi-center pilot study involving 60 patients suggest a potential clinical usefulness in the acute and maintenance treatment of drug-resistant depressive disorder. The perspective of VNS as along-term treatment with the advantage of assured compliance makes it an interesting technique to potentially treat drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large placebo-controlled trial. Results of clinical pilot studies involving patients suffering from obesity and Alzheimer's disease indicate that VNS might induce weight loss and improve cognition. Besides its clinical usefulness, VNS can be used as a research tool, allowing neurophysiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.


Unlocking the potential for engaging men to improve reproductive, maternal, and neonatal health in Karnali Province, Nepal.
Adolescent girls and young women (AGYW) often experience early childbearing and have poor utilization of reproductive, maternal, and neonatal health (RMNH) services in Nepal. Involving men in such services has been increasingly recognized globally to improve gender-equitable reproductive health behaviour in husbands. This qualitative study assessed the implementation of Healthy Transitions' male engagement interventions in Karnali Province, Nepal which were implemented to improve gender-equitable attitudes, and supportive RMNH care-seeking behaviors among the husbands of young women. We conducted a summative qualitative study that included in-depth interviews with 12 AGYW as primary beneficiaries and their husbands (N = 12) and in-laws (N = 8). In addition, key informant interviews were conducted with health workers (N = 8), local government representatives (N = 4), members of Health Facility Operation and Management Committee (N = 8) and project implementers (N = 12). Due to COVID-19-related travel restrictions and lockdowns, all interviews were conducted via phone calls and online consultation. Data were analyzed using multistage coding and thematic content analysis. AGYW, their husbands, in-laws and health workers were receptive to the Healthy transitions' male engagement initiatives. They perceived that the project contributed a momentum to facilitate men's gender-responsive behaviour. Many participants reported that male engagement interventions, including home visits, community dialogues, and social events improved husbands' support for their wives during menstruation, pregnancy, and childbirth. The activities also facilitated spousal communication and improved the couple's decision-making for family planning use. Women reported that improved support from their husbands increased their self-confidence. This study sheds light on the role of male engagement strategies to improve RMNH in a context where inequitable gender norms and roles are highly prevalent. Our findings highlight the potential to improve RMNH by addressing barriers to male engagement.


Recent outcomes in European multicentre projects on ambient particulate air pollution.
The adverse health effects associated with ambient air pollution have triggered epidemiologists, toxicologists and chemists to combine their experience to investigate the toxicity of ambient PM (particulate matter) from European sites with differing traffic intensity, in order to increase the understanding of the role of fine and coarse PM, the role of chemical characteristics and relate that to health effects. Under the European Union 5th Framework Programme (FP5), the HEPMEAP, RAIAP and PAMCHAR projects have utilised high-volume samplers to collect PM in European locations with contrasting PM sources and performed a range of different laboratory investigations. The PM investigated generally induced significant biological responses, with both coarse (2.5-10 microm) and fine (0.1-2.5 microm) PM being able to induce toxic effects. The chemical composition of the PM (also reflecting the differences in the emission-source contribution) has been suggested to play an important role in these responses. Oxidative and immune effects have been demonstrated in several in vitro and animal models. Investigations have also given support for the assumption that asthmatic and elderly subjects with chronic obstructive pulmonary disease may be more susceptible to PM exposure.


Prospective associations of dietary insulin demand, glycemic index, and glycemic load during puberty with body composition in young adulthood.
Puberty is a so-called critical period for overweight development and is characterized by physiological insulin resistance during mid-puberty. This study addressed the hypothesis that habitual consumption of a diet inducing higher levels of postprandial glycemia or insulinemia during puberty may have an unfavorable effect on the body composition in young adulthood. Multivariate regression analysis was performed on 262 participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study with at least two 3-day weighed dietary records during puberty (baseline: girls 9-14 years; boys 10-15 years) and anthropometric measurements in young adulthood (18-25 years). A published dietary glycemic index was assigned to each carbohydrate-containing food. Similarly, each food was assigned a food insulin index (insulinemic response to a 1 MJ portion of food relative to 1 MJ of glucose) using 121 values measured at Sydney University. Dietary glycemic index or glycemic load during puberty was not related to body composition in young adulthood. In contrast, a higher dietary insulin index and a higher dietary insulin load during puberty were associated with higher levels of percentage of body fat (%BF) in young adulthood, even after adjustment for early life, socioeconomic and nutritional factors; %BF in energy-adjusted tertiles of dietary insulin index were 22.9 (95% confidence intervals (CI): 21.6, 24.1), 24.5 (23.2, 25.7), 24.7 (23.5, 25.9) %, P (for trend)=0.01; %BF in energy-adjusted tertiles of dietary insulin load were 22.8 (95% CI: 21.5, 24.0), 24.5 (23.2, 25.7), 24.8 (23.6, 26.0) %, P (for trend)=0.01. Adjustment for baseline %BF attenuated these relationships (P (for trend)=0.1 and=0.08, respectively). Dietary insulin demand was not related to body mass index. This study suggests a prospective adverse influence of dietary insulin demand during puberty on %BF in young adulthood. Postprandial increases in insulinemia rather than increases in glycemia appear to be implicated in an unfavorable development of body composition.


Adipocyte progenitor cells initiate monocyte chemoattractant protein-1-mediated macrophage accumulation in visceral adipose tissue.
Macrophages are important producers of obesity-induced MCP-1; however, initial obesity-induced increases in MCP-1 production precede M1 macrophage accumulation in visceral adipose tissue (VAT). The initial cellular source of obesity-induced MCP-1 in vivo is currently unknown. Preliminary reports based on in vitro studies of preadipocyte cell lines and adherent stroma-vascular fraction cells suggest that resident stromal cells express MCP-1. In the past several years, elegant methods of identifying adipocyte progenitor cells (AdPCs) have become available, making it possible to study these cells in vivo. We have previously published that global deletion of transcription factor Inhibitor of Differentiation 3 (Id3) attenuates high fat diet-induced obesity, but it is unclear if Id3 plays a role in diet-induced MCP-1 production. We sought to determine the initial cellular source of MCP-1 and identify molecular regulators mediating MCP-1 production. Id3 (+/+) and Id3 (-/-) mice were fed either a standard chow or HFD for varying lengths of time. Flow cytometry, semi-quantitative real-time PCR, ELISAs and adoptive transfers were used to assess the importance of AdPCs during diet-induced obesity. Flow cytometry was also performed on a cohort of 14 patients undergoing bariatric surgery. Flow cytometry identified committed CD45(-)CD31 (-) Ter119(-)CD29(+)CD34(+)Sca-1(+)CD24(-) adipocyte progenitor cells as producers of high levels of MCP-1 in VAT. High-fat diet increased AdPC numbers, an effect dependent on Id3. Loss of Id3 increased p21(Cip1) levels and attenuated AdPC proliferation, resulting in reduced MCP-1 and M1 macrophage accumulation in VAT, compared to Id3 (+/+) littermate controls. AdPC rescue by adoptive transfer of 50,000 Id3 (+/+) AdPCs into Id3 (-/-) recipient mice increased MCP-1 levels and M1 macrophage number in VAT. Additionally, flow cytometry identified MCP-1-producing CD45(-)CD31(-)CD34(+)CD44(+)CD90(+) AdPCs in human omental and subcutaneous adipose tissue, with a higher percentage in omental adipose. Furthermore, high surface expression of CD44 marked abundant MCP-1 producers, only in visceral adipose tissue. This study provides the first in vivo evidence, to our knowledge, that committed AdPCs in VAT are the initial source of obesity-induced MCP-1 and identifies the helix-loop-helix transcription factor Id3 as a critical regulator of p21(Cip1) expression, AdPC proliferation, MCP-1 expression and M1 macrophage accumulation in VAT. Inhibition of Id3 and AdPC expansion, as well as CD44 expression in human AdPCs, may serve as unique therapeutic targets for the regulation of adipose tissue inflammation.


Multi-target visual search organisation across the lifespan: cancellation task performance in a large and demographically stratified sample of healthy adults.
Accurate tests of cognition are vital in (neuro)psychology. Cancellation tasks are popular tests of attention and executive function, in which participants find and 'cancel' targets among distractors. Despite extensive use in neurological patients, it remains unclear whether demographic variables (that vary among patients) affect cancellation performance. Here, we describe performance in 523 healthy participants of a web-based cancellation task. Age, sex, and level of education did not affect cancellation performance in this sample. We provide norm scores for indices of spatial bias, perseverations, revisits, processing speed, and search organisation. Furthermore, a cluster analysis identified four cognitive profiles among participants, characterised by many omissions (N=18), many revisits (N=18), relatively poor search organisation (N=125), and relatively good search organisation (N=362). Thus, patient scores pertaining to search organisation should be interpreted cautiously: Given the large proportion of healthy individuals with poor search organisation, disorganised search in patients might be pre-existing rather than disorder-related.


Expression of GSK-3β in renal allograft tissue and its significance in pathogenesis of chronic allograft dysfunction.
To explore the expression of Glycogen synthase kinase 3 beta (GSK-3β) in renal allograft tissue and its significance in the pathogenesis of chronic allograft dysfunction. Renal allograft biopsy was performed in all of the renal allograft recipients with proteinuria or increased serum creatinine level who came into our hospital from January 2007 to December 2009. Among them 28 cases was diagnosed as chronic allograft dysfunction based on pahtological observation, including 21 males with a mean age of 45 ± 10 years old and 7 females with a mean age of 42 ± 9 years old. The time from kidney transplantation to biopsy were 1-9 (3.5) years. Their serum creatinine level were 206 ± 122 umol/L. Immunohistochemical assay and computer-assisted genuine color image analysis system (imagepro-plus 6.0) were used to detect the expression of GSK-3β in the renal allografts of 28 cases of recipients with chronic allograft dysfunction. Mean area and mean integrated optical density of GSK-3β expression were calculated. The relationship between expression level of GSK-3β and either the grade of inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft was analyzed. Five specimens of healthy renal tissue were used as controls. The expression level of the GSK-3β was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, compared to normal renal tissues, and GSK-3β expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue. There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3β expression in renal allograft tissue. The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/9924478946162998.


Investigations on the binding of erythrogenic toxin A of Streptococcus pyogenes on human peripheral blood lymphocytes. I. Light and electron microscopical demonstration of cell surface receptors using colloidal gold-labelled toxin.
Receptors for erythrogenic toxin A (ETA) of Streptococcus pyogenes (strain NY-5) were demonstrated on human peripheral blood lymphocytes by binding of ETA-gold conjugates to the cell surface. The specificity of the binding was proved in control experiments. The dark-red granules observed by light microscopy on unfixed cells were revealed by transmission electron microscopy to be patches of gold particles. By light microscopy on samples from 48 blood donors a mean value of 34 +/- 13% of ETA-receptor bearing lymphocytes was ascertained. The predominant part of the cells exhibited only a weak or moderate labelling. Transmission electron microscopy of prefixed cells revealed an attachment of single gold particles distributed over the whole cell surface. Counts of gold particles on serial sections yielded depending on prefixation values of 50-600 receptors/cell (1% glutaraldehyde) and 1000-7000 receptors/cell (0.26% glutaraldehyde), respectively. ETA cloned in Streptococcus sanguis as well as the toxoid of ETA exhibited a comparable binding as ETA (NY-5).


Hormonal changes following tumor transplantation: factors increasing corticosterone and the relationship of corticosterone to tumor-induced anti-inflammation.
EL-4 lymphoma cells transplanted to syngeneic C57BL/6J mice induced a biphasic decrease in inflammation and a bi-phasic increase in serum levels of corticosterone. In addition, this tumor altered serum levels of 3 other hormones, resulting in a biphasic decrease in insulin, an early decrease in prolactin, and a terminal severe deficiency in thyroxine. Early changes occurred 16 to 48 hr after tumor transplantation and were of variable duration, while late-phase defects developed during the last few days of life. Soluble factors associated with tumor growth may mediate certain hormonal changes since serum levels of corticosterone increased and insulin decreased following injection of tumorous ascites into normal mice. Further, injection of cell-free tumor culture supernatants increased corticosterone levels. Hormonal changes following injection of soluble factors occurred after a delay of 16 hr indicating that the factors acted indirectly. Surgical adrenalectomy blocked the corticosterone increase induced by tumor transplantation or ascites injection and eliminated the anti-inflammatory effect of tumor transplantation while significantly decreasing the effect associated with injection of tumorous ascites. Thus, the physiologically induced increase in serum levels of corticosterone reached anti-inflammatory levels. Further, elevated levels of corticosterone are a major contributing factor to anti-inflammation induced by tumorous ascites injection and constitute the principal mechanism of anti-inflammation following tumor transplantation.


Case study of a migraine patient with multiple extracephalic symptoms including melena due to telangiectasia of the sigmoid colon : a possible new migraine-associated symptom.
Migraine is a chronic neurological disorder characterized by headaches and extracephalic symptoms. We report a 73-year-old male patient with a history of migraines as well as several other chronic conditions including abdominal pain accompanied by nausea and vomiting, pain and ecchymosis of the limbs, dysmetropsia, syncope, and melena due to telangiectasia of the sigmoid colon. After a thorough evaluation of the migraine condition, we hypothesized that the patient's melena due to telangiectasia of the sigmoid colon might in fact be a migraine-related phenomenon. In this report, we discuss a possible mechanism for melena due to telangiectasia in migraine patients, as well as "tips" for identifying subtle and/or unreported clinical features of migraine conditions. J. Med. Invest. 70 : 298-300, February, 2023.


The influence of housing condition on autotomy following dorsal rhizotomy in rats.
Forty-four rats were subjected to unilateral intradural section of dorsal roots T13-L6. Of these, 10 were housed alone and 34 were housed with female rats. Each of the 10 animals housed alone-self-mutilated to an extreme degree, with 7 cannibalizing the denervated limb. Only of the animals housed with a female showed any sign of self-biting, and this was a minor, isolated incident. These results are discussed with particular reference to dorsal rhizotomy in rats serving as a model of chronic pain.


The impact of gut microbiota on brain and behaviour: implications for psychiatry.
The gut microbiota has become a focus of research for those interested in the brain and behaviour. Here, we profile the gut microbiota in a variety of neuropsychiatric syndromes. Multiple routes of communication between the gut and brain have been established and these include the vagus nerve, immune system, short chain fatty acids and tryptophan. Developmentally, those born by caesarean section have a distinctly different microbiota in early life to those born per vaginum. At the other extreme, individuals who age with considerable ill-heath tend to show narrowing in microbial diversity. Recently, the gut microbiota has been profiled in a variety of conditions including autism, major depression and Parkinson's disease. There is still debate as to whether or not these changes are core to the pathophysiology or merely epiphenomenal. The current narrative suggests that certain neuropsychiatric disorders might be treated by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.


Polymer-based shaft microelectrodes with optical and fluidic capabilities as a tool for optogenetics.
In this work, we describe the fabrication of a polymer-based shaft electrode which can conduct light as well as fluids to a target brain region and record electrical neural signals from the same tissue volume simultaneously. This multifunctional neural probe is intended to facilitate optogenetic in vivo experiments.


Sudden unexpected death as a result of primary aortoduodenal fistula identified with postmortem computed tomography.
Aortoenteric fistula (AEF) is an uncommon source of upper gastrointestinal (GI) tract hemorrhage, commonly occurring in persons with previous aortic surgery. Non-surgery related AEFs (primary AEFs) may occur in association with atherosclerotic lesions, infections, malignancies, or, rarely, result from penetrating/eroding foreign bodies. Given its rarity, primary AEF is not commonly considered in the pathologist's preliminary list of differential diagnoses at the commencement of an autopsy; however, the use of postmortem cross-sectional imaging may allow for the identification of primary AEF as a reasonable differential diagnoses prior to conventional autopsy. The current case outlines the forensic presentation, postmortem computed tomography (PMCT) features, and autopsy findings of a recent case of primary AEF resulting in lethal gastrointestinal hemorrhage. In such cases, PMCT features supporting primary AEF as the underlying cause of death include an atherosclerotic aneurysm abutting a segment of the GI tract with no definite soft tissue plane of separation, luminal GI contents of similar radiographic density to the aortic contents, lack of previous aortic surgery, and lack of a competing explanation for GI hemorrhage or a competing cause of death. Deaths from massive enteric hemorrhage without a medical history to suggest an underlying cause for the hemorrhage would fall under medicolegal jurisdiction and may, by examination of scene and circumstances alone, initially seem suspicious. This case demonstrates how PMCT could be used by a team of expert forensic radiologists and forensic pathologists to rapidly feedback vital information on the cause and manner of death to the criminal justice system.


Phototransformation of the fungicide tebuconazole, and its predicted fate in sunlit surface freshwaters.
The fungicide tebuconazole (TBCZ) is expected to undergo negligible direct photolysis in surface freshwaters, but it can be degraded by indirect photochemistry. TBCZ mainly reacts with hydroxyl radicals and, to a lesser extent, with the triplet states of chromophoric dissolved organic matter (3CDOM*). Indirect photochemistry is strongly affected by environmental conditions, and TBCZ lifetimes of about one week are expected in sunlit surface waters under favourable circumstances (shallow waters with low concentrations of dissolved organic carbon, DOC, during summer). In these cases, the time trend would follow pseudo-first order kinetics (mono-exponential decay). Under less favourable conditions, photoinduced degradation would span over a few or several months, and TBCZ phototransformation would depart from an exponential trend because of seasonally changing sunlight irradiance. The TBCZ phototransformation products should be less toxic than their parent compound,thus photodegradation has potential to decrease the environmental impact of TBCZ. Hydroxylation is a major TBCZ transformation route, due to either OH attack, or one-electron oxidation sensitised by 3CDOM*, followed by reaction of the oxidised transient with oxygen and water.


Suppression of an Hsp70 mutant phenotype in Saccharomyces cerevisiae through loss of function of the chromatin component Sin1p/Spt2p.
The Ssa subfamily of Hsp70 molecular chaperones in the budding yeast Saccharomyces cerevisiae has four members, encoded by SSA1, SSA2, SSA3, and SSA4. Deletion of the two constitutively expressed genes, SSA1 and SSA2, results in cells which are slow growing and temperature sensitive. In this study, we demonstrate that an extragenic suppressor of the temperature sensitivity of ssa1 ssa2 strains, EXA1-1, is a loss-of-function mutation in SIN1/SPT2, which encodes a nonhistone component of chromatin. Loss of function of Sin1p leads to overexpression of SSA3 in the ssa1 ssa2 mutant background, at a level which is sufficient to mediate suppression. In a strain which is wild type for SSA genes, we detected no effect of Sin1p on Ssa3p expression except under conditions of heat shock. Existing data indicate that expression of SSA3 in the ssa1 ssa2 mutant background as well as in heat-shocked wild-type strains is mediated by the heat shock transcription factor HSF. Our findings suggest that it is HSF-mediated induction of SSA3 which is modulated by Sin1p. The EXA1-1 suppressor mutation thus improves the growth of ssa1 ssa2 strains by selectively increasing HSF-mediated expression of SSA3.


Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS.
Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/IKr. We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization. Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes. Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STVQTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced IKs, fluoxetine and risperidone reduced IKr, resulting in additive effects on IKtotal-tail. In addition, oxytocin reduced IK1, further reducing the repolarization reserve. Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on IKs and IK1 (block by oxytocin) and IKr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS.


Students' perception of a problem-based learning scenario in dental nurse education.
In July 2008, The General Dental Council implemented mandatory registration for Dental Nurses in the United Kingdom, recognising them as legally responsible for patient care. As dentistry comes to terms with the impact registration has on dental nurses, sustained advances in the teaching of students in other healthcare disciplines demonstrate the way in which the role of pedagogy in dental nurse education has been underdeveloped. In an attempt to see dental nursing stand in line with other progressive healthcare professionals, the authors have implemented Problem-Based Learning (PBL) into a dental nurse program in NHS Education for Scotland, Glasgow. The aim of the research is to assess the perceptions of dental nurse students with regard to participation in active learning. The study is facilitated by a short PBL package which offers introductory exposure to this method of learning. A qualitative approach has been taken to gather experiential data using a questionnaire. Thematic analysis took place to reveal emergent themes. Analysis reveals that the participants found PBL to be an enjoyable experience that could be valuable in the acquisition of deep knowledge and improved patient care. The participants raised concerns with regard to confidence in their own knowledge acquisition in PBL sessions and highlighted a need for improved feedback. While the participants enjoyed the self directed nature of PBL, it is important to note that the need for facilitator guidance was considered imperative, especially where the students had little or no experience of PBL, as in this study.


Pursuitworthiness between daring conservatism and procrastination: Wheeler and the path towards black holes.
This paper follows the story of how John A. Wheeler became the enthusiastic baptizer and popularizer of black holes, after he overcame his own initial resistance and protracted skepticism about earlier results. However, the present work is not only historical, since its aim is to suggest as well that the notion of pursuitworthiness can but benefit from a close confrontation with actual heuristic paths, examined in their complexity. This specific case, moreover, may suggest some historical-critical insights on the current situation at the most speculative frontiers of theoretical physics.


Evaluation of the intramolecular basis set superposition error in the calculations of larger molecules: [n]helicenes and Phe-Gly-Phe tripeptide.
Correlated ab initio calculations on large systems, such as the popular MP2 (or RI-MP2) method, suffer from the intramolecular basis set superposition error (BSSE). This error is typically manifested in molecules with folded structures, characterized by intramolecular dispersion interactions. It can dramatically affect the energy differences between various conformers as well as intramolecular stabilities, and it can even impair the accuracy of the predictions of the equilibrium molecular structures. In this study, we will present two extreme cases of intramolecular BSSE, the internal stability of [n]helicene molecules and the relative energies of various conformers of phenylalanyl-glycyl-phenylalanine tripeptide (Phe-Gly-Phe), and compare the calculated data with benchmark values (experimental or high-level theoretical data). As a practical and cheap solution to the accurate treatment of the systems with large anticipated value of intramolecular BSSE, the recently developed density functional method augmented with an empirical dispersion term (DFT-D) is proposed and shown to provide very good results in both of the above described representative cases.


Corrigendum: Intermediate English as a Foreign Language learners' formulaic language speaking proficiency: Where does the teaching of lexical chunks figure?
[This corrects the article DOI: 10.3389/fpsyg.2022.949675.].


Predictors of attrition from a weight loss program. A study of adult patients with obesity in a community setting.
Obesity unit attrition is frequent and contributes to treatment failure. Many studies evaluating attrition predictors were part of randomized trials, and different terminology and criteria were used in the engagement field. We aimed to investigate the factors potentially implicated in early (< 12 weeks) and late (> 12 weeks) attrition from an obesity unit in a community setting METHODS: This was a retrospective cohort study of 250 patients with obesity who were followed-up at our obesity unit. Our program included at least 6 meetings in 12 months. Sociodemographic and anthropometric data, and psychometric questionnaires were collected from all participants. One-hundred thirty-four (53.6%) participants dropped out. Those individuals showed lower BMI, lower overall health status, and increased depression scores. In a multiple regression model, BMI (inversely; OR = 0.90; 95%CI 0.84-0.96) and depression score (directly, OR = 1.05; 1.00-1.10) were associated with attrition risk. Early dropouts (n = 47) had lower weights, smaller waist circumferences and worse mental health scores than late dropouts (n = 87) and more frequently lived alone. When compared to completers, early dropouts had lower weights, BMIs, waist circumferences, overall health and mental status scores, increased depression scores and percentage of individuals living alone. In a multiple regression, lower BMI (OR = 0.83; 0.75-0.92), lower mental status score (OR = 3.17; 1.17-8.59) and living alone (OR = 2.25; 1.02-4.97) were associated with early attrition risk. Lower BMI and increased depression score were associated with attrition. Early attrition was associated with lower weight, decreased mental well-being, and living alone. Individuals with these characteristics might need tailored approaches to enhance their engagement. Level V, retrospective descriptive study.


[Family caregivers and their support at home].
Home support for carers is a cross-cutting theme running through all the areas of focus of the strategy for the integration of care and assistance services. Thanks to this strategy a health care territory has visibility, legibility and accessibility to the respite care and assistance available to family carers provided by local professionals, notably by those in charge of complex situations, the case managers.


Dietary diversity, physical activity and depressive symptoms among middle-aged women: A cross-sectional study of 48,637 women in China.
Depression is the leading cause of mental health-related disease burden. This study aimed to investigate the relationship among dietary diversity, physical activity and depressive symptoms in middle-aged women. Based on the WHO guidelines on physical activity, subjects who meet moderate-intensity aerobic physical exercise of 150-300 min per week were qualified or otherwise unqualified. The dietary diversity scores (DDS) were developed according to the balanced diet pagoda and assessed the consumption of nine food groups. The total scores ranged from 0 to 9 and could divide into three levels: insufficient [DDS-1] (score of 1-5), moderate [DDS-2] (score of 6-7), and sufficient [DDS-3] (score of 8-9). An age at menarche ≥12 years old (OR = 0.94; 95 % CI: 0.89-1.00; p < 0.05), a higher dietary diversity score [DDS-3] (OR = 0.59; 95 % CI: 0.55-0.63; p < 0.001), drinking coffee (OR = 0.88; 95 % CI: 0.84-0.92; p < 0.001), and qualified physical activity (OR = 0.69; 95 % CI: 0.66-0.72; p < 0.001) were protective factors for depressive symptoms, while an age at first birth ≤20 years old (OR = 1.23; 95 % CI: 1.12-1.36; p < 0.001) or ≥30 years old (OR = 1.18; 95 % CI: 1.11-1.26; p < 0.001), eating late-night snacks (OR = 1.44; 95 % CI: 1.36-1.52; p < 0.001), drinking sugar-sweetened beverages (OR = 1.15; 95 % CI: 1.06-1.24; p < 0.001), and overeating (OR = 2.30; 95 % CI: 2.069-2.56; p < 0.001) were risk factors. This study suggested that dietary diversity and physical activity are associated with depressive symptoms in middle-aged women. To improve dietary diversity, attention should be given to dietary patterns and dietary habits, instead of simply increasing the amount of food.


Low serum miR-223 expression predicts poor outcome in patients with acute myeloid leukemia.
Identification of biomarkers for acute myeloid leukemia (AML) is important for treating this malignancy. Recent studies have reported that microRNAs (miRNAs) are stably detectable in the blood/plasma and can be used as biomarkers for various types of cancer including AML. The aim of this study was to analyze miR-223 level in serum as a potential indicator for AML diagnosis and prognosis prediction. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the levels of miR-223 in the serum samples from 131 patients and 70 healthy individuals. The results revealed that serum miR-223 was underexpressed in AML patients, particularly those in intermediate and unfavorable cytogenetic risk groups. Further analysis revealed that serum miR-223 could yield a receiver operating characteristic (ROC) area under the curve (AUC) of 0.849 with 83.2% sensitivity and 81.4% specificity. Moreover, a significant increase in serum miR-223 level was observed in AML subjects after their treatment. Reduced serum miR-223 level was highly associated with aggressive clinical variables and shorter survival of patients. Furthermore, miR-223 expression was identified to be an independent prognostic predictor of worse overall survival. In conclusion, miR-223 may be a reliable diagnostic and prognostic biomarker for AML.


Screening and isolation of an organic solvent-tolerant bacterium for high-yield production of organic solvent-stable protease.
Forty-three strains were screened from crude oil-contaminated samples by toluene and cyclohexane enrichment in medium. Ten of these strains demonstrated high protease activity on skim-milk agar. Among them, the PT121 isolate, identified as Pseudomonas aeruginosa, was selected based on its extracellular protease stability in the presence of hydrophilic organic solvents. The crude protease also retained most of its activity up to at least 14 days in the presence of various organic solvents at 50% concentration, and the protease activity in production medium was 10,876U/ml after 72h incubation. This protease showed high activity as a catalyst for aspartame precursor Cbz-Asp-Phe-NH2 synthesis in the presence of 50% dimethylsulfoxide (DMSO).


Outcome of transurethral prostatectomy for the palliative management of lower urinary tract symptoms in men with prostate cancer.
To investigate the efficacy of palliative transurethral prostatectomy (TURP) for lower urinary tract symptoms (LUTS) in men with prostate cancer. The surgical outcome of TURP performed in 46 men with prostate cancer was studied. A poor outcome was defined as the development of urinary incontinence, repeat surgery and placement of a long-term catheter (LTC) within 1 year of surgery. A cohort of 47 men who underwent TURP for benign prostatic hyperplasia (BPH) was used as a control population. Initial catheter removal failed in a larger number of cancer patients compared to men with BPH (43% and 10%, respectively, P = 0.0001). Using objective endpoints, 37% (17/46) of cancer patients were defined as having a poor outcome because of repeat surgery, placement of a LTC or urinary incontinence following TURP. These events occurred in only 12% (6/47) of the control cohort (P = 0.004). In multiple regression analysis a good outcome was associated with presentation in acute urinary retention (AUR; P = 0.01) while a poor outcome was associated with surgery in the context of hormone refractory disease (P = 0.004). Requirement for a LTC despite surgery (12/46) was also associated with the absence of AUR at presentation (P = 0.01) and hormone refractory disease (P = 0.01). A significant number of men with prostate cancer and LUTS may not derive a good palliative benefit from TURP. Patients with hormone refractory disease in particular are more likely to have poorer outcomes.