Effect of nasal anti-inflammatory treatment in chronic obstructive pulmonary disease.
Sinonasal inflammation and symptoms are often underdiagnosed in chronic obstructive pulmonary disease (COPD) patients. So far, it is not known to what extent anti-inflammatory nasal treatment may reduce sinonasal symptoms in COPD patients. This study was designed to examine the effects of nasal anti-inflammatory treatment on sinonasal symptoms and cough in COPD patients. Thirty-three COPD patients on stable bronchial therapy (salmeterol/fluticasone propionate 50/500 mg b.i.d. for >6 weeks) were randomized to receive fluticasone furoate (FF) or placebo nasal spray at 110 μg once daily for 12 weeks. Sinonasal symptoms and cough were monitored at baseline, at 6 and12 weeks of treatment, and at 4 weeks after cessation of the treatment using a visual analog scale. Levels of cytokines were measured in nasal secretions. In contrast to the placebo group (n = 13), FF patients (n = 14) reported less nasal blockage (10.62 ± 4.21 mm versus 36.57 ± 8.01 mm; p = 0.0026), postnasal drip (1.46 ± 0.29 score versus 2.83 ± 0.38 score; p = 0.03), and nasal discharge (0.23 ± 0.12 score versus 1.77 ± 0.43 score; p = 0.01) after 6 weeks of treatment compared with baseline, which was still present at 12 weeks. FF patients reported less cough compared with baseline (25.54 ± 4.46 mm versus 36.79 ± 5.75 mm; p = 0.04), which was not the case in the placebo group (49.58 ± 10.44 mm versus 42.00 ± 8.05 mm; p = 0.38). Nine of 14 patients in the FF group (64%) reported slight to total relief of nasal symptoms, and this subgroup had a significant decrease in IL-8 levels in nasal secretions after 6 weeks of treatment (850.7 ± 207.2 pg/mL versus 1608 ± 696.5 pg/mL; p = 0.03) compared with baseline. Nasal FF treatment in COPD patients significantly reduced sinonasal symptoms, in parallel with reduced IL-8 in nasal secretion levels and cough.


Changes in serum conditioning profiles of glutaraldehyde-crosslinked collagen sponges after their treatment with calcification inhibitors.
The purpose of this study was to evaluate the effects of the calcification inhibitors FeCl3 and sodium dodecyl sulfate (SDS) on the morphology of glutaraldehyde-crosslinked type I collagen sponges and on their serum conditioning. Scanning electron microscopy (SEM) showed that the morphology of the sponges, already modified by glutaraldehyde crosslinking, underwent further changes after treatment of the hydrogels with inhibitors. Coral-like structures were found to branch from the bulk of the material especially in the case of SDS-treated samples. The composition and morphology of the conditioning layers was characterized after 48 h incubation in serum by SDS-polyacrylamide gel electrophoresis-immunoblot of the adsorbed proteins, by energy-dispersive X-ray analysis of the elements (EDX), and by SEM of the conditioned surfaces. All the samples showed the adsorption of proteins with molecular weights ranging from 10 to 203 kD. However, the peculiar adsorption of an approximately 10-kD band (complement C3 fragment) and of fibronectin were detected in the case of glutaraldehyde-crosslinked collagen. On the other hand, glutaraldehyde-crosslinked collagen treated with 0.1M FeCl3 showed the remarkable adsorption of a 29-kD band. The glutaraldehyde-crosslinked hydrogels showed the massive precipitation of crystals on their exposed surfaces, whereas a disordered network structure surrounding the collagen fibrils was found in the case of the samples pretreated with inhibitors. A predominant precipitation of sodium and chloride was detected in all the sponges, although the ratio between the peaks changed from from one hydrogel to another. The results reported in this article clearly indicate that the treatments with SDS and FeCl3 change the surface conditioning of collagen sponges, suggesting a possible role of deposited serum solutes in affecting mineralization processes on bioprosthesis.


Bed-blocking. Discharge of the late brigade.
Delayed discharges are seen as a litmus test for how the whole health and social care system is working. The problem has been exacerbated by delays in developing intermediate care schemes. There has been less use of the private nursing homes for intermediate care than envisaged a year ago, possibly because of NHS concerns about standards. More support should be given to people with chronic conditions to keep them out of hospital.


Coronary arteriographic study of mild angina.
The results of coronary arteriography, exercise, and pacing stress testing in 50 young patients with mild angina are analysed. There was a significant correlation between the results of stress tests and the secerity of disease. There were, however, patients with severe disease and negative tests. Fifty-six per cent of patients had disease which potentially could have been surgically treated. It is concluded that coronary arteriography is indicated in these patients with mild symptoms.


Personal predictors of consumers' food and health concerns.
Three surveys were conducted of 429 supermarket shoppers in Canberra, Australia, in order to examine factors that may influence their concerns about food and health. In each survey, a 28 item food and health concerns inventory was administered along with selected personality trait, personal values or shopping style scales. Principal components analysis of the ratings of the food and health concerns derived eight components. In order to test a number of hypotheses, a series of multiple regression analyses were carried out in which the psychological variables were entered along with demographic variables as predictors of the respondents' scores on the concerns components. Response rates for the surveys averaged 72%. The psychological variables accounted for more variance in the food and health concern scores than the demographic variables. Examples of the observed relationships showed that: (i) safety and quality concerns were positively related to social activism and nature values and to anomy, but were negatively related to age of the respondent and neuroticism; (ii) concerns about hidden additives in foods were directly linked to the quality-seeking shopping style; (iii) concerns about general food system problems were positively linked to the nature value orientation, and negatively to the self-monitoring and neuroticism personality traits; (iv) empathy for vulnerable people was positively linked to the social activism and nature values and negatively to the fashion-seeking shopping style; concern about animal welfare was directly related to the nature value. The findings show that individual difference variables have some utility in predicting responses to food and health issues. They have implications for food communicators, nutrition educators, food label designers as well as consumer and industry groups, all of whom need to recognize consumers' varied orientations.


Proton Coupled Electron Transfer and Redox Active Tyrosines: Structure and Function of the Tyrosyl Radicals in Ribonucleotide Reductase and Photosystem II.
Proton coupled electron transfer (PCET) reactions are important in many biological processes. Tyrosine oxidation/reduction can play a critical role in facilitating these reactions. Two examples are photosystem II (PSII) and ribonucleotide reductase (RNR). RNR is essential in DNA synthesis in all organisms. In E. coli RNR, a tyrosyl radical, Y122(•), is required as a radical initiator. Photosystem II (PSII) generates molecular oxygen from water. In PSII, an essential tyrosyl radical, YZ(•), oxidizes the oxygen evolving center. However, the mechanisms, by which the extraordinary oxidizing power of the tyrosyl radical is controlled, are not well understood. This is due to the difficulty in acquiring high-resolution structural information about the radical state. Spectroscopic approaches, such as EPR and UV resonance Raman (UVRR), can give new information. Here, we discuss EPR studies of PCET and the PSII YZ radical. We also present UVRR results, which support the conclusion that Y122 undergoes an alteration in ring and backbone dihedral angle when it is oxidized. This conformational change results in a loss of hydrogen bonding to the phenolic oxygen. Our analysis suggests that access of water is an important factor in determining tyrosyl radical lifetime and function. TOC graphic.


MAGE-1 gene product is a cytoplasmic protein.
MAGE-1 gene encodes a human melanoma antigen, recognized by syngeneic cytotoxic T lymphocytes (CTL). MAGE-1 transcripts are also detectable in breast cancers, in non-small-cell lung carcinomas and in central nervous system tumors. In order to identify, in cellular preparations, the protein encompassing the antigenic peptide, we generated a panel of monoclonal antibodies (MAbs) against the MAGE-1 gene product by using, as immunogen, a full-length recombinant preparation (rMAGE-1), obtained through expression cloning of the relevant gene in E. coli. Four reagents were obtained recognizing both rMAGE-1 and the 46-kDa native protein in cell lines expressing MAGE-1 mRNA. No positivity could be detected in MAGE-1-mRNA-negative melanoma lines. No surface labelling of MAGE-1-positive cell lines could be observed. In contrast, on permeabilization of MZ2 melanoma cells, all 4 MAbs induced efficient staining, as detected by cytofluorography. Fluorescence microscopy shows that MAGE-1 gene product is a cytoplasmic protein clustered in paranuclear organelle-like structures. Thus, MAGE-1 protein location closely resembles that of P91A and P198 murine-tumor antigens.


The Association Between Perceived Stress and Low Back Pain Among Eldercare Workers in Japan.
We investigated the association between perceived stress and low back pain (LBP) among Japanese eldercare workers. Self-reported questionnaires were completed regarding perceived stress (Perceived Stress Scale-14), presence of memorable LBP in the preceding month, and other relevant factors (age, sex, body mass index, smoking status, job demands, job control, and social support) among 954 eldercare workers. Univariate and multivariate logistic regression analysis were performed to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Data from 571 eldercare workers were analyzed. In the multivariate logistic regression model, higher perceived stress was significantly associated with a higher prevalence of memorable LBP (adjusted OR [95% CI] = 1.05 [1.02 to 1.08]). Higher perceived stress was independently associated with LBP among eldercare workers. Our study indicates the importance of considering perceived stress as one of the factors related to LBP.


Precise CO2 Reduction for Bilayer Graphene.
It is of great significance to explore unique and diverse chemical pathways to convert CO2 into high-value-added products. Bilayer graphene (BLG), with a tunable twist angle and band structure, holds tremendous promise in both fundamental physics and next-generation high-performance devices. However, the π-conjugation and precise two-atom thickness are hindering the selective pathway, through an uncontrolled CO2 reduction and perplexing growth mechanism. Here, we developed a chemical vapor deposition method to catalytically convert CO2 into a high-quality BLG single crystal with a room temperature mobility of 2346 cm2 V-1 s-1. In a finely controlled growth window, the CO2 molecule works as both the carbon source and the oxygen etchant, helping to precisely define the BLG nucleus and set a record growth rate of 300 μm h-1.


Good medical ethics, justice and provincial globalism.
The summer 2014 Ebola virus outbreak in Western Africa illustrates global health's striking inequalities. Globalisation has also increased pandemics, and disparate health system conditions mean that where one falls ill or is injured in the world can mean the difference between quality care, substandard care or no care at all, between full recovery, permanent ill effects and death. Yet attention to the normative underpinnings of global health justice and distribution remains, despite some important exceptions, inadequate in medical ethics, bioethics and political philosophy. We need a theoretical foundation on which to build a more just world. Provincial globalism (PG), grounded in capability theory, offers a foundation; it provides the components of a global health justice framework that can guide implementation. Under PG, all persons possess certain health entitlements. Global health justice requires progressively securing this health capabilities threshold for every person.


Inhibition of pregnancy viability in mice following IL-2 administration.
The influence of administration of interleukin-2 (IL-2) on syngeneic and allogeneic murine pregnancy has been investigated. Human or mouse recombinant IL-2 (rhIL-2 and rmIL-2), or partially purified rat IL-2, was inoculated i.p. into C57B1 mice following syngeneic mating but before embryo implantation. This inhibited subsequent fetal development in up to 100% of cases, compared with mice inoculated with control material, including recombinant human interleukin-1 alpha (IL-1 alpha), where no inhibition of pregnancy viability was observed. Similar data were obtained in both syngeneic and allogeneic matings when rhIL-2 was administered on Day 1 of pregnancy. Administration of rhIL-2 during the second pregnancy, rather than a first pregnancy, was less effective. Administration of rhIL-2 during the first pregnancy does not induce a permanent sterility. Histological examination of the endometrium further demonstrated that mice injected with rhIL-2 on Day 1 of their first pregnancy showed a complete absence of embryonic tissue.


Clinical Features and Drug Retention of TNF Inhibitors in Older Patients with Ankylosing Spondylitis: Results from the KOBIO Registry.
This study aimed to analyse the clinical features and outcomes of and reasons for discontinuing tumour necrosis factor (TNF) inhibitor therapy in older patients with ankylosing spondylitis (AS). Data were extracted from the nationwide Korean College of Rheumatology Biologics registry. Clinical variables and outcomes were compared, and drug retention rate was evaluated. Among 1524 patients with AS treated with TNF inhibitors, 306 were aged ≥ 50 years ('older patients'). Fewer patients were male, the incidence of hypertension and diabetes was higher (all p < 0.001), and the proportion of peripheral arthritis (35.6 vs. 27.1%), Ankylosing Spondylitis Disease Activity Score‒erythrocyte sedimentation rate (4.0 ± 1.1 vs. 3.6 ± 1.0), and Bath Ankylosing Spondylitis Functional Index (4.2 ± 2.6 vs. 3.3 ± 2.5) were all higher in older patients. Although the drug retention rate was lower (log-rank p = 0.018) and lack of efficacy and adverse events were more frequent in older patients (both p < 0.001), drug retention rates were not different after propensity score matching (log-rank p = 0.23). Improvements in disease activity and manifestations were comparable between groups, except for the incidence of peripheral arthritis, which decreased significantly less in older patients over 3 and 5 years. Improvements in disease-related clinical factors and drug retention rates were not different between older and younger patients with AS receiving TNF inhibitors. However, the incidence of adverse events was higher in older patients.


Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats.
N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin receptors are required for induction, but not maintenance, of pLTF. However, because NMDA and non-NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O(2)) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (+/-)-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist, 1.5 mg/kg) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA antagonist, 10 mg/kg) was systemically (ip) injected approximately 30 min before hypoxia. APV was also injected immediately after or 20 min after episodic hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1-2 days before. Regardless of being injected before or after episodic hypoxia, vehicle did not alter vLTF ( approximately 23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast, CNQX enhanced vLTF ( approximately 34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of NMDA but not non-NMDA receptors is necessary for formation and maintenance of vLTF in awake rats.


Circulating coagulation inhibitors in the acquired immunodeficiency syndrome.
Abnormal coagulation profiles were identified in ten patients with the acquired immunodeficiency syndrome (AIDS) associated with opportunistic infections and malignancies. Activated partial thromboplastin times were elevated in all patients; three of seven had elevated prothrombin times. All patients had lupus-type anticoagulants characterized by rapid prolongations of the partial thromboplastin time in mixing studies, prolonged dilute thromboplastin inhibition assays, and increased Russell viper venom clotting times. Ivy bleeding times were prolonged in three patients with defective platelet aggregation. The lupus anticoagulant was isolated from the sera of healthy heterosexual men and from patients with AIDS with and without the lupus anticoagulant, and in the presence and absence of opportunistic infections. Both polyclonal IgM and IgG lambda from plasma with lupus anticoagulant interfered with clotting studies and platelet aggregation. The inhibitors usually accompanied active opportunistic infections and tended to disappear with successful resolution of infection.


Language after temporal or frontal lobe surgery in children with epilepsy.
The purpose of this study was to compare language function in children undergoing temporal or frontal lobe surgery to control intractable epilepsy. Language measures (expressive vocabulary, receptive vocabulary, comprehension, reading, spelling, phonemic fluency, and category fluency) were administered to 9 children with frontal lobe epilepsy (mean age: 10.8 +/- 2.7 years) and 10 children with temporal lobe epilepsy (11.5 +/- 2.6 years). The results indicate that no differences exist, in language function, before and after surgery between children with frontal and temporal lobe epilepsy (all p > or = .05). Children with left hemisphere lesions had significantly lower scores than those with right on category fluency and comprehension, but laterality effects were not seen on the other measures. In both groups, language function was not significantly affected by surgery.


Population pharmacokinetics of 25-hydroxyvitamin D in healthy young adults.
The aim of our study was to develop a population pharmacokinetic (PPK) model for 25-hydroxyvitamin D clearance in a healthy young adult population in Serbia. Study sample consisted of 70 healthy young students of the Faculty of Medical Science, University of Kragujevac, Serbia, with a mean age and body mass index of 22.39 ± 1.82 years and 21.31 ± 2.69 kgm-2, respectively. Non-linear mixed-effect modeling (NONMEM) software was used for data analysis. A validation set of 16 participants was used to estimate the predictive performance of the pharmacokinetic model. In the base model (without covariates), we had parameter estimates of 0.01 L/h for apparent clearance, 0.25 L for apparent volume of distribution, while value of minimum objective function (MOF) was 383.468. The full regression model was established by estimating the effects of 12 covariates. Mean intake of vitamin D from foods (DD) and value of phosphate in serum (PHO) were covariates included in the final model, while others were excluded in this process. The estimated value in the final MOF model was 274.555. The final regression model formula was: clearance (CL) (L/h) = 0.0711 + 0.738 x DD + 0.618 x PHO. The PPK model obtained determined clearance of 25-hydroxyvitamin D in a healthy young adult population in Serbia. Mean intake of vitamin D from foods and serum phosphate level are the most important covariates that influence value of 25-hydroxyvitamin D clearance in healthy young adults.


Postkeratoplasty atopic sclerokeratitis in keratoconus patients.
To estimate the incidence of and investigate possible risk factors for postkeratoplasty atopic sclerokeratitis in keratoconus patients undergoing keratoplasty. Retrospective, noncomparative, interventional case series. Two hundred forty-seven eyes with keratoconus. We reviewed the medical records of all keratoplasty cases of keratoconus between May 2000 and December 2005 at Tokyo Dental College Ichikawa General Hospital. The incidence and clinical details of cases consistent with postkeratoplasty atopic sclerokeratitis were recorded. Cases with acute sclerokeratitis during the early postoperative period were retrospectively evaluated. A total of 247 keratoconus eyes were followed at our clinic after keratoplasty (mean follow-up, 18.5+/-13.0 months). Thirty-five eyes of 29 patients (14.2%) had a history of atopic dermatitis, of which 6 eyes of 5 patients (2.4%) developed postkeratoplasty atopic sclerokeratitis. Mean age of postkeratoplasty atopic sclerokeratitis patients was 29 years (range, 23-39). The mean period between keratoplasty and onset of postkeratoplasty atopic sclerokeratitis was 26 days (range, 11-41). Loosening of running sutures and wound leakage were observed in 3 eyes; persistent epithelial defects in 3 eyes; and graft melting in 2 eyes, 1 of which was perforated. Preoperative atopic blepharitis and corneal neovascularization were identified as risk factors for postkeratoplasty atopic sclerokeratitis. Postkeratoplasty atopic sclerokeratitis is a potentially severe complication in atopic patients undergoing keratoplasty. Systemic immunosuppression may be considered in patients with active blepharitis and corneal neovascularization.


[Vision 2020: 100 years of river blindness research].
The early investigators of onchocerciasis from 1874 - 1930 in Africa made no mention at all of concomitant severe eye disease. Publications of the observations in Central America in 1917/1919 prompted some specialists in tropical medicine to look for eye disease associated with African onchocerciasis. However, there did not seem to be any eye disease leading to blindness. It was not until 1930/1931 that Hissette reported that 20 % of patients with onchocerciasis were blind in an onchocerciasis focus on the Sankuru river in the Belgian Congo, and that 50 % of the villagers suffered from eye troubles. Two years later, he found a second focus with the same pathology on the Uéle river. We wished to establish why African river blindness manifested itself so unusually late and what criteria must be fulfilled for it to be brought under control quickly. The following questions are examined: (1) Had the early tropical doctors overlooked river blindness? (2) Could the still low distribution and density of microfilariae in the body of the affected patients have determined whether or not eye disease is likely to occur? (3) Had the microfilariae mutated into a more aggressive variety? There are indications confirming all three points in the working hypothesis. Before 1930, cases of African onchocerciasis with ocular complications were demonstrably very localized on the Uéle river. The reason for this is likely to have been that the severity of the disease still varied from focus to focus at that time and/or because the individuals concerned still had a relatively mild microfilarial infection. In principle, onchocerciasis has reverted to the situation before occurrence of ocular complications in consequence of the ongoing control measures even though the insect destruction and mass therapy are sometimes incomplete. This appears to be sufficient to prevent blindness even if onchocerciasis is not cured. Only a few of the present-day patients with river blindness will still be left by 2030. By then, the problem of river blindness is likely to have become a thing of the past.


Autophagy-Based Unconventional Secretory for AIM2 Inflammasome Drives DNA Damage Resistance During Intervertebral Disc Degeneration.
Intervertebral disc degeneration (IDD) is the primary cause of low back pain. Stress-induced DNA damage is closely relevant to the pathogenesis of IDD; however, the underlying mechanisms remain unclear. This study investigated the role of the absent in melanoma 2 (AIM2) inflammasome as a DNA damage sensor in nucleus pulposus (NP) cells. We found that the level of AIM2 increased in degenerated discs and was correlated to the degree of IDD. Knockdown of AIM2 ameliorated H2O2-induced DNA damage and apoptosis in NP cells in vitro, and retarded the progression of IDD in vivo. Furthermore, the induction of autophagy protected against cellular DNA damage via the unconventional secretion of AIM2. We further identified the Golgi re-assembly and stacking protein 55 (GRASP55) as mediator of the transport and secretion of AIM2 via an autophagic pathway. Taken together, our researches illustrate the role and regulatory mechanism of the AIM2 inflammasome during IDD. Targeting the AIM2 inflammasome may offer a promising therapeutic strategy for patients with IDD.


A Comparison of Temporal Patterns of Fatigue in Patients on Hemodialysis.
This qualitative study describes the temporal patterns of fatigue found as part of a larger study designed to elicit a description of the experience and self-management of fatigue for patients on hemodialysis. Two patterns of fatigue were identified. The first pattern, continuous fatigue, was characterized by participants who experienced fatigue at all times, which was their normal, baseline feeling. Within this group, two subgroups were identified. The second pattern of fatigue, post-dialysis fatigue only, was characterized by participants who experienced fatigue only after their hemodialysis session. This study is unique because it expands our knowledge about hemodialysis and fatigue by describing the patterns that fatigue follows over time from one hemodialysis session to the next. Insight into these phenomena could help ameliorate fatigue and allow nurses to tailor interventions for patients on hemodialysis.


N-Nitroso(2-hydroxyethyl)glycine, a urinary metabolite of N,N-dinitrosopiperazine with potential utility as a monitor for its formation in vivo from piperazine.
Urinary metabolites in the rat of the carcinogen N,N-dinitrosopiperazine were identified as N-nitroso(2-hydroxyethyl)-glycine (22% of the dose), N-nitrosodiethanolamine (3%), 3-hydroxy-N-nitrosopyrrolidine (3%), and unchanged N,N-dinitrosopiperazine (18%). N-Nitroso(2-hydroxyethyl)glycine (1.6 mumol) was detected by gas chromatography-nitrosamine specific detection in the urine of rats treated by gavage with 19 mumol of piperazine and 191 mumol of sodium nitrite. Since sensitive methods are available to quantify N-nitroso(2-hydroxyethyl)glycine in rat urine and human urine, it has potential utility as a monitor for in vivo formation of N,N-dinitrosopiperazine.


The immunophilin FK506-binding protein modulates Ca2+ release channel closure in rat heart.
1. The nature of the signal that terminates the release of Ca2+ from the cardiac sarcoplasmic reticulum has remained elusive. This study was intended to examine whether FK506-binding protein (FKBP), which is tightly associated to the ryanodine receptor (RyR)/Ca2+ release channel, plays a role in the termination of Ca(2+)-induced Ca2+ release (CICR) in heart. 2. Confocal microscopy and the Ca2+ indicator fluo-3 were used to visualize the elementary release events, i.e. 'Ca2+ sparks' in rat ventricular myocytes under resting or voltage-clamped conditions. Additionally, electrophysiological single-channel recordings, at constant [Ca2+] or during [Ca2+] steps produced by photorelease of caged Ca2+, were obtained from rat cardiac RyRs incorporated in planar lipid bilayers. 3. Inhibition of FKBP by the immunosuppressants FK506 or rapamycin increased the duration of spontaneous or depolarization-evoked Ca2+ sparks 6- to 7-fold. In addition, Ca2+ sparks were seen with two-level amplitudes, corresponding to full and half normal spark amplitude. 4. FK506 potentiated and prolonged electrically stimulated [Ca2+]i transients and contractions, but did not affect the amplitude and kinetics of the L-type Ca2+ channel current. 5. In planar lipid bilayers, FK506 (15 microM) prolonged approximately 7-fold the mean open lifetime of reconstituted single RyRs, induced the appearance of long-lasting subconductance states, and markedly slowed the spontaneous decay of RyR activity elicited by fast and sustained Ca2+ stimuli. The time constant of the spontaneous decay of activity increased from 1.8 s in control to > or = 20 s in the presence of FK506. 6. We conclude that FKBP may afford an intrinsic mechanism to terminate RyR openings and it may thus exert a negative feedback on CICR in heart cells.


Differentiating patients with higher cerebral dysfunction from patients with psychiatric or acute medical illness using the BNI Screen for Higher Cerebral Functions.
The BNI Screen for Higher Cerebral Functions (BNIS) was administered to 41 patients with known cerebral dysfunction. 22 psychiatric patients (some of whom were psychotic) without documented brain lesions, and 22 medical inpatients without neurological or psychiatric diagnoses. Patients with cerebral dysfunction scored significantly lower than the medical and psychiatric patients (p < 0.05). Utilizing the recommended cutoff score of 47, 40 of the 41 brain-dysfunctional patients were correctly classified as impaired, but only seven of the medical and five of the psychiatric patients were correctly classified. Using age-based T-scores, 36 of the 41 brain-dysfunctional patients (87.8%) were correctly classified. Specificity improved slightly, but these numbers were still low (55%), primarily because psychotic patients performed like neurological patients (100%). This study provides further empirical validation of this screening instrument in identifying patients with brain disorders.


Treatment of myelodysplasia with oral cyclosporin.
Recent studies have shown a good response to immunosuppressive treatment with cyclosporin A (CSA) in patients with the myelodysplastic syndrome (MDS). We have treated six transfusion-dependent MDS patients with CSA for a minimum of 3 months. None of these patients showed a significant response, while the drug was withdrawn in 3/6 patients because of intolerable side-effects. Two reasons for the failure of this treatment in our patients can be advanced. Firstly, the hypoplastic variant of MDS predominated in previous studies in contrast to ours. Secondly, the concomitant use of other immunosuppressive agents in previous studies might have enhanced the effect of CSA. We suggest further therapeutic trials of CSA in MDS, selecting patients on the basis of in vitro studies that predict an immunological basis for their disease, to assess its efficacy in prolonging survival.


Measuring health promotion research impact - What researchers think?
The significant investment in health research has resulted in an increased focus to determine suitable approaches to measure health promotion research impact. This research was undertaken at the request of a nationally competitive research organisation that funds health promotion research, to explore how Chief Investigators (CIs) on their funded projects understood research impact, its measurement and associated challenges. Participants were required to be or have been a CI on an Australian competitive research (exploratory or intervention) grant focussed on health promotion. The qualitative study used thematic analysis from one-on-one interviews. Themes were created and descriptive quotes were selected to illustrate the main findings. The majority of participants were female (n = 13) working at a university (n = 13). Three themes emerged: a) defining health research impact; b) complexity and simplicity of measuring health research impact; c) challenges of measuring health research impact: i) differing language; ii) differing assessment; iii) attribution and timing; and iv) resourcing and skills. Researchers recognised that there are significant challenges in measuring the impact of health promotion research. The most significant factors identified by participants were the disciplinary background of the researchers undertaking the measurement, their skills and experience and the resources (including time) available to assess impact. SO WHAT?: Research impact assessment is complex, time consuming and requires specific skills to facilitate measurement of impact provision of funding for this activity in research grants and research impact training is required.


Chlorzoxazone 6-hydroxylase and p-nitrophenol hydroxylase as the most suitable activities for assaying cytochrome P450 2E1 in cynomolgus monkey liver.
Western blot analyses of liver microsomes from 13 male and 12 female monkeys demonstrated that in each sample a variable amount of a cytochrome P450 (P450) protein, likely monkey P450 2E1, cross-reacted with anti-rat P450 2E1 antibodies. Therefore, the involvement of monkey 2E1 in the oxidation of typical substrates for 2E1 from other species, such as dimethylnitrosamine (DMN), p-nitrophenol (pNP), chlorzoxazone (CLZ), and aniline, was investigated. Kinetic studies using microsomes from five male and five female monkeys showed that CLZ and pNP hydroxylations were monophasic, with apparent KM values of 77 and 14 microgramsM, respectively, whereas aniline hydroxylation and DMN demethylation were multiphasic, suggesting that P450s other than 2E1 were involved in catalyzing the latter two reactions. When correlation analyses were performed using several monooxygenase activities determined in male and female monkey liver specimens, it was found that immunodetectable 2E1 contents were highly correlated (r >/= 0.75) with CLZ and pNP hydroxylations, weakly correlated (r = 0.6) with aniline hydroxylation, and not correlated with DMN demethylation or other monooxygenase activities; CLZ hydroxylation was strongly correlated with pNP hydroxylation, weakly correlated with aniline hydroxylation, and not correlated with DMN demethylation. Inhibition experiments showed that CLZ and pNP hydroxylations were immunoinhibited by 60-80% by anti-rat P450 2E1 and were inhibited by the prototypical 2E1 inhibitor 4-methylpyrazole with IC50 values of 1.5 and 13 microgramsM, respectively. In conclusion, the findings provide evidence that P450 2E1 is constitutively and equally expressed in male and female monkey liver and it exerts a major role only in hydroxylation of CLZ and pNP.


[Impairment of social cognition in Parkinson disease--comparison of idiopathic Parkinson disease with juvenile parkinsonism].
The degeneration of mesocorticolimbic dopaminergic system is assumed to disturbed motivated behavior, intellectual impairment and depression in Parkinson's disease (PD), and there is growing interest in its role in impaired emotional and social behaviors. Patients with PD demonstrated the impairment of social cognition by the test of facial expression recognition and the Iowa gambling task (IGT). However, the result of facial expressions cognition in patients with juvenile parkinsonism (JP) is not significantly different from normal controls. In the IGT, the JP group learned better performance than the PD group. The relatively spared social cognition in JP as compared with PD could be attributed that dopaminergic depletion being more severe in the nigrostriatal system than in the mesocorticolimbic system.


Aggressive systolic blood pressure control in older subjects: benefits and risks.
Systolic hypertension, especially isolated systolic hypertension (ISH) is very common in older subjects aged ≥ 65 years and is a major risk factor for cardiovascular disease (CVD), strokes, heart failure (HF) and chronic kidney disease (CKD). It is also, directly and linearly related with these complications irrespective of sex, or ethnicity, but it is worse with the advancement of age. Effective control of systolic blood pressure (SBP), is associated with significant reduction in the incidence of these complications. Currently, there is a debate about the optimal SBP control in view of the Systolic Blood Pressure Intervention Trial (SPRINT) showing beneficial cardiovascular (CV) effects of intensive SBP of < 120 mmHg in older patients. Also, the recently released blood pressure (BP) guidelines by the American College of Cardiology, the American Heart Association and the American Society of Hypertension (ACC/AHA/ASH) recommend a SBP reduction of < 130 mmHg. These SBP treatment recommendations are in contrast with the current (JNC VIII) committee of BP treatment guidelines, which recommend a SBP reduction < 150 mmHg for the same age of patients. All these different recommendations have created a debate regarding the optimal treatment targets for the systolic hypertension of the elderly patients. To gain more information a focused Medline search was conducted from 2010 to 2017 using the terms, systolic blood pressure, aggressive control, older subjects, treatment guidelines, and 37 pertinent papers were retrieved. The findings from these studies suggest a SBP reduction of < 140 mm Hg for persons aged ≥ 60 years, with an attempt for SBP reduction to ≤130 mm Hg in healthier subjects and hose with CVD, DM, and CKD. Care should be taken not to further reduce the SBP in older subjects if their DBP is ≤60 mmHg for the fear of J-curve effect.


Use of hem-o-lok clips for laparoscopic appendectomy in children: retrospective analysis and comparison to ligature loop and endoscopic surgical stapler.
There are multiple techniques used for laparoscopic appendectomy (LA): ligature loop (LL), surgical stapler (SS) (Endopath Ets-Flex-Endoscopic Articulating Linear Cutter 33 mm Standard Ref Atb 35. Ethicon, Somerville, New Jersey, US), and hem-o-lok clips (HOL) (Weck Closure System. Triangle Park, NC, USA). The application of the LL usually demands dexterity and training, whilst using HOL may be more advantageous due to its simplicity in terms of application and its low cost in contrast with the SS. The objective of this study is to determine safety and efficacy of the different devices that can be used in the surgical procedure. From June 2016 to December 2019, 253 consecutive children aged to 1 to 18 years were retrospectively reviewed. They were divided into three groups depending on the device used to secure the appendix: (I) in the first group, the base of the appendix was secured by double LL, (II) in the second group the base of the appendix was secured with SS, and (III) in the third group the base of the appendix was secured with two non-absorbable HOL. The data collected includes age, gender, operative time, device used to ligate the base of the appendix, previous tests (blood analysis, imaging), antibiotic prophylaxis administered, length of hospital stay, intraoperative and postoperative complications, shoulder pain and histological study of the specimen. There were 253 patients that underwent laparoscopic appendectomy during the study time, with a mean age of 10.3±4.1 in the LL group, 9.4±2.7 in the SS group and 10.4±3.3 in the HOL group, P=0.165. Distribution by gender was 77.8% for males in the LL group, 65.2% in the SS group and 61.3% in the HOL group, P=0.559. The mean surgical time with IQR in brackets was 60.0 (10.0) minutes (min), in the first group in which the base of the appendix was secured with LL, in the second group in which the base of the appendix was secured with SS 60.0 (15.0) min and finally in the third in which the base of the appendix was secured with HOL 40.0 (30.0) min, P<0.001. HOL clips have a significantly lower cost than their analogues. Specifically, 5 HOL clips have a cost of EUR 26.75, while three LL have a cost of EUR 53.70 and a single SS has a cost of EUR 276.58. Postoperative complications were found in 14.3% of the LL group, 9.8% in the SS group and 4.6% in the HOL group, P=0.137. Efficacy and safety in controlling the base of appendix were the same in all groups. The HOL are safe and reduce surgical costs during laparoscopic appendectomy in children.


Lung metastasectomy in adenoid cystic cancer: Is it worth it?
Adenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning. A retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated. The cumulative survival was 66.8% at 5years and 40.5% at 10years. In patients with a disease-free interval (DFI) greater than 36months, the overall survival was 76.5% at 5years. Survival in case of complete surgical resection was 69.5% at 5years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables. Lung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies.


Influence of polymerization method, curing process, and length of time of storage in water on the residual methyl methacrylate content in dental acrylic resins.
This study compared the influence of different polymerization methods (heat, auto-, and microwave energy), different curing processes (in the case of heat- and autopolymerized specimens), and length of storage of the polymerized specimens in distilled water at 37 degrees C on the residual methyl methacrylate (MMA) content in dental acrylic resin specimens. Residual MMA of 120 resin specimens were measured using high-performance liquid chromatography. For the heat-polymerized resins, the lowest residual MMA content was obtained when they were given a long-term terminal boil and then stored in the distilled water for at least 1 day. For the autopolymerized resins, the lowest residual MMA content was obtained when they were additionally cured in water at 60 degrees C and then stored in the distilled water at least 1 day. For the microwave-polymerized resins, the lowest residual MMA content was obtained when they were stored in the distilled water at least 1 month. The lowest overall residual MMA content was obtained from heat-polymerized specimens that were given a long-term terminal boil cure and then stored in the distilled water at least 1 day. Different polymerization methods and curing processes have different effects on residual MMA content. It is thus shown that storing a dental acrylic resin specimen in distilled water at 37 degrees C is a simple but effective method of reducing its residual MMA content.


Genome segment reassortment between two serotypes of bluetongue virus in a natural host.
The occurrence of genome segment reassortment between two antigenically related orbiviruses was demonstrated in cattle. Individual virus clones were isolated by cell culture plaque assays directly from the blood of a calf infected with two serotypes of bluetongue virus. The majority (89%) of progeny viruses isolated from the calf represented reassortant viruses. A minimum of six genome segments participated in reassortment, with 16 unique reassortant constellations being identified. Such genome segment reassortment between unique, though antigenically related, orbiviruses has undoubtedly played a major role in generating the extensive phenotypic and genotypic diversity that is characteristic of this serogroup.


Prostate cancer update.
Recent advances in prostate cancer have focused on treatment strategies in patients with biochemical relapse and novel methods of androgen deprivation therapy such as intermittent therapy, the role of bisphosphonates, and immunotherapeutic approaches. Continued investigation into the mechanism of androgen independence and effective treatments for hormone-refractory disease are described. This article reviews the major advances in prostate cancer published between November 1, 2000, and October 31, 2001.


Early Kinetics of Intestinal Infection and Immune Responses to Two Toxoplasma gondii Strains in Pigs.
Toxoplasma gondii is an obligate intracellular parasite, able to infect all homeothermic animals mostly through ingestion of (oo)cysts contaminated food or water. Recently, we observed a T. gondii strain-specific clearance from tissues upon infection in pigs: while the swine-adapted LR strain persisted in porcine tissues, a subsequent infection with the human-isolated Gangji strain cleared parasites from several tissues. We hypothesized that intestinal immune responses shortly after infection might play a role in this strain-specific clearance. To assess this possibility, the parasite load in small intestinal lymph node cells and blood immune cells as well as the IFNγ secretion by these cells were evaluated at 2, 4, 8, 14, and 28 days post oral inoculation of pigs with tissue cysts of both strains. Interestingly, at day 4 post inoculation with the LR strain the parasite was detected by qPCR only in the duodenal lymph node cells, while in the jejunal and ileal lymph node cells and PBMCs the parasite was detected from day 8 post inoculation onwards. Although we observed a similar profile upon inoculation with the Gangji strain, the parasite load in the examined cells was much lower. This was reflected in a significantly higher T. gondii-specific serum IgG response in LR compared to Gangji infected pigs at day 28 post inoculation. Unexpectedly, this was not reflected in the IFNγ secretion upon re-stimulation of the cells where almost equal IFNγ secretion was observed in both groups. In conclusion, our results show that T. gondii first enters the host at the duodenum and then probably disseminates from this site to the other tissues. How the early immune response influences the clearance of parasite from tissues needs further study.


A case of monochorionic twin pregnancy complicated with intrauterine single fetal death with successful treatment of intrauterine blood transfusion in the surviving fetus.
We report a case of monochorionic twin pregnancy complicated with single fetal demise that received successful treatment of intrauterine transfusion for severe anemia of the surviving fetus. A single fetal demise occurred at 20 weeks of gestation and middle cerebral artery peak systolic velocity (MCA-PSV), a marker for fetal anemia, showed marked elevation in the surviving fetus. Fetal blood sampling was immediately done and severe fetal anemia (hemoglobin = 5.5 g/dl, hematocrit = 16.8%) was confirmed, and then intrauterine transfusion was performed. After transfusion, MCA-PSV rapidly decreased to the normal value and remained within normal range until delivery. A healthy 2,640 g male infant was delivered at 35 weeks of gestation without anemic status and no neurological problem was found at 1-year old. The present report supports that intrauterine rescue transfusion is a useful treatment to prevent the adverse outcome of surviving fetus in monochorionic twin pregnancy complicated with single fetal demise, and monitoring of MCA-PSV is also useful to assess anemic status of the surviving fetus.


Vasoactive intestinal peptide stabilizes intestinal immune homeostasis through maintaining interleukin-10 expression in regulatory B cells.
Rationale: Immune dysfunction is thought to play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, the underlying mechanism requires further investigation. Vasoactive intestinal peptide (VIP) has immune regulatory functions, but its role in immune regulatory activities in the intestinal mucosa is not fully understood. This study aims to elucidate the role of VIP in the regulation of regulatory B cell (Breg) function in the intestine. Methods: Peripheral blood samples were collected from UC patients and healthy control (HC) subjects. Bregs were isolated from these samples and their immune regulatory function was analyzed. A murine colitis model was established to test the role of VIP in inhibiting inflammation in the intestine. Results: Serum IL-10 and VIP levels were lower in IgE+ (≥0.35 IU/mL) UC patients than that in HC subjects. The immune suppressive function of Bregs isolated from IgE+ UC patients was impaired. IL-10 mRNA decayed spontaneously in Bregs, which was reversed by VIP added to the culture. Tristetraprolin (TTP) bound IL-10 mRNA to speed its decay, which was blocked by VIP in the culture. Administration of VIP efficiently inhibited experimental colitis. Conclusions: Insufficient VIP levels in the microenvironment speeds IL-10 mRNA decay to cause Breg dysfunction. Administration of VIP can inhibit experimental colitis, suggesting the translational potential of VIP in the treatment of IgE+ UC.


Earplugs during the first night after cardiothoracic surgery may improve a fast-track protocol.
Sleep deprivation after major surgery is common and associated with worse outcome. Noise is one important reason for sleep fragmentation, which contributes to enhanced morbidity. The purpose of this work was to evaluate the impact of earplugs on patients' sleep quality during their first night after cardiothoracic surgery to eventually improve an existing fast-track concept. Sixty-three patients undergoing cardiothoracic surgery eligible for a postoperative fast-track regimen on our cardiothoracic post anesthesia care unit (C-PACU) were prospectively included. They were randomized to either sleep with or without earplugs. Quality of sleep was measured using questionnaires for patients and nurses. Required pain medications, pain intensity, and length of hospital stay were secondary outcome variables. Twenty-seven patients were randomized to the intervention group (earplugs) and 36 to the control group. Mean (SD) age was 61 (12) years. Self-reported quality of sleep was better in the intervention group (median, IQR [range]: 3, 2-4 [1-5] vs. 4, 3-5 [1-5]; scale: 1, "excellent," to 5, "very poor"; P=0.025). Patients of the intervention group also experienced less severe pain (P=0.047) despite similar dosages of administered analgesics and expressed improved satisfaction regarding their C-PACU stay (P=0.032). Implementation of the use of earplugs in a fast-track concept following cardiothoracic surgery is efficient and easy. Earplugs improved the quality of sleep as well as patient satisfaction and attenuated pain intensity. They may thereby contribute to a faster recovery, less morbidity, and reduced costs.


Leucine catabolism in mammary tissue, liver and skeletal muscle of dam rat during lactation and weaning.
This study was designed to determine the effect of lactation and weaning on the catabolism of branched-chain amino acids (BCAA). Rates of transamination and oxidation of leucine and branched chain alpha-ketoacid dehydrogenase (BCKD) activity were measured in homogenates of mammary gland, skeletal muscle and liver on day 12 of lactation and 24 h after separation of dams from the litter (weaning). Lactating dams consumed 250% more protein than control rats, extra protein is required for protein synthesis by the mammary gland, the extent to which the excess of amino acids consumed during lactation is utilized or oxidized by different tissues is not known. The rate of transamination of [1-14C] leucine by mammary tissue of lactating dams was sixfold higher than in virgin rats. The rate of transamination remained elevated fourfold in postweaning dams. Rates of transamination were three times higher in mammary tissue than in muscle of lactating dams. Rate of oxidation [1-14C] leucine by lactating mammary tissue was tenfold higher than in control tissue. The capacity of mammary tissue for transamination and oxidation of leucine increased greatly during lactation, suggesting that the mammary gland may play an important role in the catabolism of BCAA during lactation.


The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers.
N-methyl-D: -aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience. The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion. Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation. At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels. This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.


Comparison of multipotent differentiation potentials of murine primary bone marrow stromal cells and mesenchymal stem cell line C3H10T1/2.
Murine C3H10T1/2 cells have many features of mesenchymal stem cells (MSCs). Whether or not the multipotent differentiation capability of C3H10T1/2 cells is comparable to that of primary bone marrow-derived MSCs (BM-MSCs) was investigated in this study. For in vitro osteogenic differentiation, both BM-MSCs and C3H10T1/2 cells differentiated to osteoblastic cell lineage and showed positive staining for alkaline phosphatase (ALP) and increased mRNA expression of Runx2, Col1alphaI, and osteocalcin. C3H10T1/2 cells and BM-MSCs induced similar amounts of bone formation in the biomaterials. Under chondrogenic induction in the presence of TGF-beta1, cell pellets of both BM-MSCs and C3H10T1/2 cells formed cartilage-like tissues with cartilage matrix components including proteoglycan, type II collagen, and aggrecan. However, C3H10T1/2 cells presented lower adipogenic differentiation potential, with only about 10% C3H10T1/2 cells (but about 70% of BM-MSCs) being committed to adipogenesis. In this study we confirmed that C3H10T1/2 cells coimplanted with osteoconductive scaffolds can form bone spontaneously in vivo and that C3H10T1/2 cells have a basal level of osteocalcin expression, suggesting that they may be a good alternative source of primary BM-MSCs for investigating osteogenic and chondrogenic differentiation in bone or cartilage tissue engineering studies. Caution is needed when using C3H10T1/2 cells for adipogenic studies as they appear to have lower adipogenic potential than BM-MSCs.


An unusual, giant and benign condyloma acuminatum lesion on the genital area for more than a decade.
Condyloma acuminatum, is a rare sexually transmitted disease. The virus responsible for condyloma is human papillomavirus.HPV-6 and HPV-11 are the most commonly detected HPV genotypes, but at least 20 other HPV genotypes have occasionally been found in genital wart tissue specimens. In fact genital HPV infection is common among sexually active populations. This disease may occur at any age after puberty and always seen in the mucosal area. It is characterized by slow growth. We reported here a case of a 42-year-old female patient with a 12 year history of a condyloma acuminatum lesion in her genitalia area without any medical treatment.


Ganglioside glycosyltransferases are S-acylated at conserved cysteine residues involved in homodimerisation.
Ganglioside glycosyltransferases (GGTs) are type II membrane proteins bearing a short N-terminal cytoplasmic tail, a transmembrane domain (TMD), and a lumenal catalytic domain. The expression and activity of these enzymes largely determine the quality of the glycolipids that decorate mammalian cell membranes. Many glycosyltransferases (GTs) are themselves glycosylated, and this is important for their proper localisation, but few if any other post-translational modifications of these proteins have been reported. Here, we show that the GGTs, ST3Gal-V, ST8Sia-I, and β4GalNAcT-I are S-acylated at conserved cysteine residues located close to the cytoplasmic border of their TMDs. ST3Gal-II, a GT that sialylates glycolipids and glycoproteins, is also S-acylated at a conserved cysteine located in the N-terminal cytoplasmic tail. Many other GTs also possess cysteine residues in their cytoplasmic regions, suggesting that this modification occurs also on these GTs. S-acylation, commonly known as palmitoylation, is catalysed by a family of palmitoyltransferases (PATs) that are mostly localised at the Golgi complex but also at the endoplasmic reticulum (ER) and the plasma membrane. Using GT ER retention mutants, we found that S-acylation of β4GalNAcT-I and ST3Gal-II takes place at different compartments, suggesting that these enzymes are not substrates of the same PAT. Finally, we found that cysteines that are the target of S-acylation on β4GalNAcT-I and ST3Gal-II are involved in the formation of homodimers through disulphide bonds. We observed an increase in ST3Gal-II dimers in the presence of the PAT inhibitor 2-bromopalmitate, suggesting that GT homodimerisation may be regulating S-acylation.


The relationship between service intensity and the quality of health care: an exploratory data analysis.
This paper provides an empirical check of some assumptions used to define the quality of care in the health services literature. Specifically, we test (i) whether service intensity is the only important determinant of a provider's quality and (ii) whether higher service intensity always causes higher quality. Using a panel of hospitals from Washington State, we find evidence that rejects both of these assumptions. As a result, further work is needed to postulate a more general definition that does not rely on these assumptions.


Large bowel obstruction due to gallstones: an endoscopic problem?
A 73-year-old man was admitted with symptoms of large bowel obstruction. An emergency CT scan revealed pneumobilia and large bowel obstruction at the level of the rectosigmoid due to a 4×4 cm impacted gallstone. Flexible sigmoidoscopy confirmed the diagnosis but initial attempts to drag the stone into the rectum failed. An endoscopic mechanical lithotripter was employed to repeatedly fracture the gallstone into smaller fragments, which were passed spontaneously the next day. The patient made a complete recovery avoiding the potential dangers of surgery. This case report discusses cholecystoenteric fistula and a novel minimally invasive treatment for large bowel obstruction due to gallstones.


A novel and automatic mammographic texture resemblance marker is an independent risk factor for breast cancer.
We investigated whether breast cancer is predicted by a breast cancer risk mammographic texture resemblance (MTR) marker. A previously published case-control study included 495 women of which 245 were diagnosed with breast cancer. In baseline mammograms, 2-4 years prior to diagnosis, the following mammographic parameters were analysed for relation to breast cancer risk: (C) categorical parenchymal pattern scores; (R) radiologist's percentage density, (P) computer-based percentage density; (H) computer-based breast cancer risk MTR marker; (E) computer-based hormone replacement treatment MTR marker; and (A) an aggregate of P and H. Density scores, C, R, and P correlated (tau=0.3-0.6); no other pair of scores showed large (tau>0.2) correlation. For the parameters, the odds ratios of future incidence of breast cancer comparing highest to lowest categories (146 and 106 subject respectively) were C: 2.4(1.4-4.2), R: 2.4(1.4-4.1), P: 2.5(1.5-4.2), E: non-significant, H: 4.2(2.4-7.2), and A: 5.6(3.2-9.8). The AUC analysis showed a similarly increasing pattern (C: 0.58±0.02, R: 0.57±0.03, P: 0.60±0.03, H: 0.63±0.02, A: 0.66±0.02). The AUC of the aggregate marker (A) surpasses others significantly except H. HRT-MTR (E) did not significantly identify future cancers or correlate with any other marker. Breast cancer risk MTR marker was independent of density scores and more predictive of risk. The hormone replacement treatment MTR marker did not identify patients at risk.


Strategies and challenges in Kerala's response to the initial phase of COVID-19 pandemic: a qualitative descriptive study.
To understand the structures and strategies that helped Kerala in fighting the COVID-19 pandemic, the challenges faced by the state and how it was tackled. Qualitative descriptive study using focus group discussions and in-depth interviews. State of Kerala, India. 29 participants: four focus group discussions and eight in-depth interviews. Participants were chosen purposively based on their involvement in decision-making and implementation of COVID-19 control activities, from the department of health and family welfare, police, revenue, local self-government and community-based organisations. Districts, panchayats (local bodies) and primary health centres (PHCs) were selected based on epidemiological features of the area like the intensity of disease transmission and preventive/containment activities carried out in that particular area to capture the wide range of activities undertaken in the state. The study identified five major themes that can inform best practices viz social capital, robust public health system, participation and volunteerism, health system preparedness, and challenges. This study was a real-time exploration of the intricacies of COVID-19 management in a low/middle-income country and the model can serve as an example for other states and nations to emulate or adjust accordingly. The study shows the impact of synergy of these themes towards more effective solutions; however, further research is much needed in examining the relationship between these factors and their relevance in policy decisions.


Synergistic cytotoxic effects of inorganic phosphate and chemotherapeutic drugs on human osteosarcoma cells.
Novel therapeutic approaches are required for the treatment of osteosarcoma. Combination chemotherapy is receiving increased attention in order to identify compounds that may increase the therapeutic index of clinical anticancer drugs. In this regard, naturally occurring molecules with antitumor activity and with limited toxicity to normal tissues have been suggested as possible candidates for investigation of their synergistic efficacy in combination with antineoplastic drugs. Inorganic phosphate (Pi) is an essential nutrient for living organisms. Relevantly, Pi has emerged as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. Previously, we showed that Pi inhibits proliferation and aggressiveness of U2OS human osteosarcoma cells and that Pi is capable of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner. In this study, we extended the role of Pi in the chemosensitivity of osteosarcoma cells to other anticancer drugs. Specifically, we report and compare the antiproliferative effects of a combination between Pi and doxorubicin, Taxol and 5-fluorouracil (5-FU) treatments. We found that Pi increases the antiproliferative response to both Taxol and doxorubicin to a similar extent. On the other hand, Pi did not potentiate the anticancer effects induced by 5-FU. These effects were paralleled by apoptosis induction and were cell cycle-dependent. The clinical significance of our data and their potential therapeutic applications for improving osteosarcoma treatment are discussed.


PAS IV, an integral membrane protein of mammary epithelial cells, is related to platelet and endothelial cell CD36 (GP IV).
PAS IV is a 78-kDa (bovine) to 80-kDa (human) integral membrane glycoprotein of unknown function which is found in mammary epithelial cells. We now report the purification of human PAS IV and native bovine PAS IV from the milk fat globule membrane (MFGM), a preparation of apical plasmalemma from epithelial cells of lactating mammary tissue. N-Terminal sequence analyses of human and bovine PAS IV revealed homology to the N-terminal sequence of the 88-kDa human endothelial and platelet glycoprotein CD36. The similarity of MFGM PAS IV to platelet CD36 was further established by immunoblots of purified platelet CD36 and MFGM PAS IV with MFGM PAS IV specific antiserum. The removal of N-linked oligosaccharides from PAS IV and CD36 by treatment with endoglycosidase F reduced the apparent Mr of both proteins to approximately 57,000. These data suggest that PAS IV and CD36 are similar if not identical polypeptides that undergo cell type specific glycosylation.


Posttranscriptional control of plasmid ColIb-P9 repZ gene expression by a small RNA.
The replication frequency of plasmid ColIb-P9 depends on the level of repZ gene expression, which is negatively regulated by the action of the inc gene (C. Hama, T. Takizawa, H. Moriwaki, Y. Urasaki, and K. Mizobuchi, J. Bacteriol. 172:1983-1991, 1990). To further understand the mechanism of this regulation, we analyzed transcripts of the ColIb-P9 replication control region. Four RNA species, designated RNAI to RNAIV, were observed in plasmid pCH11, which contained the whole inc gene region and the 5' portion of the repZ gene. RNAII, RNAIII, and RNAIV, with sizes of approximately 200, 500, and 1,500 bases, respectively, were identified as rightward transcripts that shared common transcription initiation sites; RNAIV was determined to be equivalent to a part of repZ mRNA, which was observed in pCH10, a plasmid that contained sufficient information for replication and control of ColIb-P9. Conversely, RNAI, with a size of about 70 bases, was transcribed leftward and was identified as the product of the inc gene and hence equivalent to inc RNA detected by in vitro RNA synthesis. This small RNA was found to be complementary to a part of repZ mRNA. These results and quantitative analyses of the transcripts in Inc- mutants indicate that the inc RNA negatively regulates repZ expression mainly at the posttranscriptional level through the possible formation of an inc RNA-repZ mRNA hybrid in the host cells.


Overconfidence in incorrect perceptual judgments in patients with schizophrenia.
Patients with schizophrenia show overconfidence in memory and social cognition errors. The present investigation examined whether this cognitive distortion also manifests in perceptual tasks. A total of 55 individuals with schizophrenia, 58 with obsessive-compulsive disorder (OCD) as well as 45 non-clinical controls were presented 24 blurry black and white pictures, half of which contained a hidden object; the other half contained ("snowy") visual noise. Participants had to judge whether the pictures depicted an object or not and how confident they were in this judgment. Participants with schizophrenia showed overconfidence in errors and an enhanced knowledge corruption index (i.e. rate of high-confident errors on all high-confident responses) relative to both control groups. In contrast, accuracy scores did not differ between clinical groups. Metacognitive parameters were correlated with self-rated levels of current paranoia. To the best of our knowledge, this is the first study to demonstrate overconfidence in errors among individuals with psychosis using a visual perception task. Speaking to the specificity of this abnormality for schizophrenia and its pathogenetic relevance, overconfidence in errors and knowledge corruption were elevated in patients with schizophrenia relative to both control groups and were correlated with paranoia.


Investigating the effects of the fixed and varying dispersion parameters of Poisson-gamma models on empirical Bayes estimates.
Traditionally, transportation safety analysts have used the empirical Bayes (EB) method to improve the estimate of the long-term mean of individual sites; to correct for the regression-to-the-mean (RTM) bias in before-after studies; and to identify hotspots or high risk locations. The EB method combines two different sources of information: (1) the expected number of crashes estimated via crash prediction models, and (2) the observed number of crashes at individual sites. Crash prediction models have traditionally been estimated using a negative binomial (NB) (or Poisson-gamma) modeling framework due to the over-dispersion commonly found in crash data. A weight factor is used to assign the relative influence of each source of information on the EB estimate. This factor is estimated using the mean and variance functions of the NB model. With recent trends that illustrated the dispersion parameter to be dependent upon the covariates of NB models, especially for traffic flow-only models, as well as varying as a function of different time-periods, there is a need to determine how these models may affect EB estimates. The objectives of this study are to examine how commonly used functional forms as well as fixed and time-varying dispersion parameters affect the EB estimates. To accomplish the study objectives, several traffic flow-only crash prediction models were estimated using a sample of rural three-legged intersections located in California. Two types of aggregated and time-specific models were produced: (1) the traditional NB model with a fixed dispersion parameter and (2) the generalized NB model (GNB) with a time-varying dispersion parameter, which is also dependent upon the covariates of the model. Several statistical methods were used to compare the fitting performance of the various functional forms. The results of the study show that the selection of the functional form of NB models has an important effect on EB estimates both in terms of estimated values, weight factors, and dispersion parameters. Time-specific models with a varying dispersion parameter provide better statistical performance in terms of goodness-of-fit (GOF) than aggregated multi-year models. Furthermore, the identification of hazardous sites, using the EB method, can be significantly affected when a GNB model with a time-varying dispersion parameter is used. Thus, erroneously selecting a functional form may lead to select the wrong sites for treatment. The study concludes that transportation safety analysts should not automatically use an existing functional form for modeling motor vehicle crashes without conducting rigorous analyses to estimate the most appropriate functional form linking crashes with traffic flow.


Application of multielectrode array (MEA) chips for the evaluation of mixtures neurotoxicity.
Cortical neurons grown on multielectrode array (MEA) chips have been shown to be a valuable alternative method to study electrophysiological properties of the central nervous system neurons and to perform functional toxicological screening. Here we studied the effects of binary mixtures on neuronal networks cultured on MEAs. We have considered compounds with similar and different mode-of-action (MoA) to characterize and assess their combined effects. Individual and binary mixture dose-response curves based on spontaneous neuronal activity have been generated and the IC(50) has been considered as the end-point for neurotoxicity assessment. The two classical approaches of mixtures toxicity studies: concentration addition (CA) and independent action (IA) have been applied to compare calculated and experimental results. Nuclear magnetic resonance (NMR) spectroscopy has been employed to confirm no chemical reaction or complexation between mixtures components. The results suggest that both CA and IA are able to predict the toxicity of the mixture and that the combination of in vitro test methods with theoretical dose-response models has a strong potential as an alternative tool for the prediction of mixtures neurotoxicity.


The effect of frequency-specific sound signals on the germination of maize seeds.
The effects of sound treatments on the germination of maize seeds were determined. White noise and bass sounds (300 Hz) had a positive effect on the germination rate. Only 3 h treatment produced an increase of about 8%, and 5 h increased germination in about 10%. Fast-green staining shows that at least part of the effects of sound are due to a physical alteration in the integrity of the pericarp, increasing the porosity of the pericarp and facilitating oxygen availability and water and oxygen uptake. Accordingly, by removing the pericarp from the seeds the positive effect of the sound on the germination disappeared.


Toxicokinetic and toxicodynamic analyses of Androctonus australis hector venom in rats: optimization of antivenom therapy.
This paper reports the simultaneous determination of toxicokinetic and toxicodynamic properties of Androctonus australis hector venom, in the absence and presence of antivenom (F(ab')(2) and Fab), in envenomed rats. After subcutaneous injection of the venom, toxins showed a complete absorption phase from the site of injection associated with a distribution into a large extravascular compartment. The injection of Fab and F(ab')(2) induced the neutralization of venom antigens in the blood compartment, as well as the redistribution of venom components from the extravascular compartment to the blood compartment. Interestingly, F(ab')(2) and Fab showed distinct efficiencies depending on their route of injection. F(ab')(2) induced a faster venom neutralization and redistribution than Fab when injected intravenously. Fab was more effective than F(ab')(2) by the intramuscular route. The hemodynamic effects of Aah venom were further investigated. Changes in mean arterial pressure and heart rate were observed in parallel with an upper airway obstruction. Fab was more effective than F(ab')(2) for preventing early symptoms of envenomation, whatever their route of administration. Intraperitoneal injection of F(ab')(2) and Fab was similar for the prevention of the delayed symptoms, even after a late administration. Fab was more effective than F(ab')(2) in the inhibition of airway resistance, independent of the route and time of administration. These results show that the treatment for scorpion stings might be improved by the intravascular injection of a mixture of Fab and F(ab')(2). If antivenom cannot be administered intravenously, Fab might be an alternative as they are more effective than F(ab')(2) when injected intramuscularly.


Theoretical investigation of one-photon and two-photon absorption properties for multiply N-confused porphyrins.
We have theoretically investigated a series of multiply N-confused porphyrins and their Zn or Cu complexes for the first time by using DFT(B3LYP/6-31G*) and ZINDO/SOS methods. The electronic structure, one-photon absorption (OPA), and two-photon absorption (TPA) properties have been studied in detail. The calculated results indicate that the OPA spectra of multiply N-confused porphyrins are red-shifted and the OPA intensities decrease compared to normal porphyrin. The maximum two photon absorption wavelengths lambda(max) are blue-shifted and the TPA cross sections delta(max) are increased 22.7-112.1 GM when the N atoms one by one are inverted from core to beta position to form multiply N-confused porphyrins. Especially delta(max) of N3CP get to 164.7 GM. The electron donors -C6F5s at meso-position can make the TPA cross section delta(max) increase. After forming metal complexes with Cu or Zn, the TPA properties of multiply N-confused porphyrins are further increased except for N3CP, N4CP. Our theoretical findings demonstrate that the multiply N-confused prophyrins as well as their metal complexes and derivatives are promising molecules that can be assembled series of materials with large TPA cross section, and are sure to be the subject of further investigation.


Errorless reproduction of given pattern dynamics by means of cellular automata.
In this paper we propose the two methods to reproduce given binary pattern dynamics with cellular automata. The point is that one can easily find a sequence of rules or specified rules in two-state multineighbors cellular automata, which enable an errorless description and reproduction of given multiple sequences of binary patterns. Actual examples using computer experiments for one-dimensional bit-pattern data (digital sound signals, multiple sequences of cycle patterns) are given. Noise robustness and the other important dynamical properties of these methods are investigated from the perspective of "rule dynamics" and in comparison with a recurrent neural network model, which enables us to embed given binary patterns as multiple attractors in the form of fixed points or limit cycles.


A Modified Method for Purifying Gallbladder Epithelial Cells Using Fluorescence-activated Cell Sorting.
We have previously reported a procedure for isolating and culturing biliary epithelial cells (BECs). The aim of this study was to reconsider the method for obtaining pure BECs using the mouse gallbladder. Cells that were obtained from the gallbladder alone were sorted by fluorescence-activated cell sorting (FACS) for purifying based on the expression of the epithelial cell adhesion molecule (EpCAM). The viability rate was measured based on the negative expression of 7-aminoactinomycin D (7-AAD). More than 75% of cells from the gallbladder were determined to be pure BECs. An analysis of the EpCAM revealed that 73.3% of the cells were 7-AAD-negative. Finally, the 0.82×106 pure BECs that survived were obtained and seeded on a collagen gel plate. However, these pure BECs showed almost no proliferation. Pure BECs could be accumulated using FACS. However, the number of BECs was insufficient for the culturing process.


Management of bacterial and fungal infections in bone marrow transplant recipients and other granulocytopenic patients.
A review of studies on the effect of different types of gastrointestinal decontamination and protective environment on infectious complications in granulocytopenic patients is given, and the effect of these measures on graft-versus-host disease after allogeneic bone marrow transplantation is discussed. It is concluded that complete gastrointestinal decontamination of patients nursed under conditions of strict reverse isolation will maximally prevent infections, graft-versus-host disease, and lung complications and therefore is the treatment to be preferred for patients undergoing bone marrow transplantation. Since selective decontamination is as effective in preventing bacterial and fungal infections as is complete decontamination, this treatment is to be preferred for other patients with a greatly reduced resistance to these infections. The reason is that, for this type of patient, selective decontamination can be performed without the use of strict isolation facilities and in this way is less laborious and less of a burden for the patient. Besides this, the number of patients that can be treated will not be limited by the number of available facilities for strict reverse isolation, which can be reserved for bone marrow transplant patients.


Differential afferent projections to the inferior colliculus from the cochlear nucleus in the albino mouse.
The axonal projections from the cochlear nuclear complex to the inferior colliculus (IC) were examined using the retrograde transport of horseradish peroxidase. Thin sheets of neurons in the dorsal and ventral cochlear nuclei were found to project axons in a topographic fashion to restricted laminae of the central nucleus of the IC; the dorsal cochlear nucleus was also found to project axons to the external cortex. No projections were detected from the cochlear nuclear complex to the dorsal cortex of the IC.


A nutritional approach for managing irritable bowel syndrome.
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder (FGID) encountered by the pediatrician and consultant. The primary focus of this review is to provide an update on beneficial nutritional interventions for managing this patient population with discussion on gut microbiome effects. A common complaint among the pediatric population is IBS-related recurrent abdominal pain. The prevalence of IBS is estimated to range between 6 and 14% and is defined by the Rome III criteria for FGIDs. Recent studies highlight the role of nutritional interventions in mitigating symptoms of IBS. Although eliminating foods that aggravate IBS gastrointestinal symptoms have become a main nutritional approach for acute management of IBS, recent literature reflects how this may impact the gut microbiome and potentially have long-term implications. There are emerging studies suggesting IBS symptomatic improvement with different dietary interventions in the pediatric population, but most of what is known at this time has been extrapolated from the adult literature.


Congenital Cytomegalovirus Infection.
Background: Congenital cytomegalovirus (cCMV) is the leading cause of nongenetic congenital hearing loss in much of the world and a leading cause of neurodevelopmental disabilities. Infected babies can be born to women who are seropositive and seronegative prior to pregnancy, and the incidence is approximately 0.6%-0.7% in the United States. Symptoms vary from mild to severe, and hearing loss can be delayed in onset and progressive. Methods: We reviewed the literature to summarize the epidemiology, clinical manifestations, diagnosis, treatment, and future directions of cCMV. Results: The best way to diagnose the infection is with polymerase chain reaction of urine or saliva within 3 weeks after birth, followed by a repeat confirmatory test if positive. Moderately to severely symptomatic neonates should be treated for 6 months with valganciclovir, and some practitioners also choose to treat infants who have isolated hearing loss only. Treatment is not recommended for asymptomatic infants. All infected infants should be screened for hearing loss and neurodevelopmental sequelae. Universal and targeted screening may be cost effective. Currently, no vaccine is commercially available, although multiple candidates are under study. Conclusion: Congenitally acquired cytomegalovirus is found in all communities around the world with a disease burden that is greater than many other well-known diseases. Advances are being made in prevention and treatment; however, improved awareness of the disease among clinicians and patients is needed.


Intracranial neurothekeoma--a rare parenchymal nerve sheath myxoma of the middle cranial fossa.
Neurothekeomas are rare, benign nerve sheath tumors, usually arising from cutaneous nerves in the head and neck region. So far, only 4 cases of the intracranial counterpart have been reported and these were located in the posterior fossa, sellar and parasellar region. We report here the first case of neurothekeoma located deep inside the brain parenchyma. Histologically, the tumor had lobular appearance with bland morphology in spite of cellular pleomorphism, myxoid background and variable S-100 positivity, characteristics of neurothekeomas. The schwannian origin was further confirmed ultrastructurally by demonstrating basal lamina and Luse bodies. Because of its benign nature, the lesion does not need postoperative radiotherapy. Histogenesis of neurothekeoma arising in the parenchyma remains enigmatic. The probable cell of origin could be the Schwann cell or perineurial cell of the nerve twigs around the blood vessels or by extreme differentiation of the precursor cell resting in a suitable microenvironment to the schwannian phenotype.


Thioredoxin peroxidases from Brugia malayi.
Parasite-derived antioxidant proteins have been implicated in playing an important role in protection against the oxygen radicals that are generated during aerobic metabolism and in defense against host immune cell attack. Here we report that filarial nematodes include the thioredoxin peroxidase/thiol-specific antioxidant (TPx/TSA) family of antioxidant proteins as part of their complex defense against radical-mediated damage. At the protein level, the TPx/TSA from Brugia malayi (Bm-TPx-1) was approximately 50% identical and approximately 60% similar to TPx/TSAs from mammals, amphibians and yeast. Bm-TPx-1 was also approximately 60% identical to putative TPx proteins from a related filarial nematode, Onchocerca volvulus, and from the free-living nematode Caenorhabditis elegans. That B. malayi may express multiple forms of molecules with TPx/TSA activity was indicated by the identification of a B. malayi gene encoding a second, distinct member of the TPx/TSA family (Bm-tpx-2). Bm-tpx-1 was found to be transcribed in all stages of the parasite present in the mammalian host and the 25 kDa translation product was present in all of the developmental stages studied. The results of immunohistochemical, immunofluorescent and immunoprecipitation studies showed Bm-TPx-1 to be localized in the cells of the hypodermis/lateral chord in adult parasites and not to be present at the surface or in excretory/secretory products. The distribution in the parasite suggests that Bm-TPx-1 may play its major role in countering radicals produced within cells. A recombinant form of Bm-TPx-1 was biologically active and capable of protecting DNA from oxygen radical-mediated damage. Thioredoxin peroxidases may prove to be a critical component in the parasite's defense against injury caused by oxygen radicals derived from endogenous and exogenous sources.


Syllable acoustics, temporal patterns, and call composition vary with behavioral context in Mexican free-tailed bats.
Recent research has shown that some bat species have rich vocal repertoires with diverse syllable acoustics. Few studies, however, have compared vocalizations across different behavioral contexts or examined the temporal emission patterns of vocalizations. In this paper, a comprehensive examination of the vocal repertoire of Mexican free-tailed bats, T. brasiliensis, is presented. Syllable acoustics and temporal emission patterns for 16 types of vocalizations including courtship song revealed three main findings. First, although in some cases syllables are unique to specific calls, other syllables are shared among different calls. Second, entire calls associated with one behavior can be embedded into more complex vocalizations used in entirely different behavioral contexts. Third, when different calls are composed of similar syllables, distinctive temporal emission patterns may facilitate call recognition. These results indicate that syllable acoustics alone do not likely provide enough information for call recognition; rather, the acoustic context and temporal emission patterns of vocalizations may affect meaning.


Use of fast absorption material for skin closure in young children.
In pediatric surgery, skin closure is an important problem, given the need to avoid soiling by feces and urine and to have a good cosmetic result. Furthermore, the increasing number of surgical operations on outpatients or with a short period of hospitalization significantly reduce the number of medical consultations. Personal experience with a fast absorption material for skin closure in 65 children demonstrated a perfectly watertight suture, a satisfactory cosmetic result and a low cost. This procedure has another advantage: no removal of the stitches, eliminating the need for medical or paramedical care.


Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites.
We describe the comprehensive characterization of homeodomain DNA-binding specificities from a metazoan genome. The analysis of all 84 independent homeodomains from D. melanogaster reveals the breadth of DNA sequences that can be specified by this recognition motif. The majority of these factors can be organized into 11 different specificity groups, where the preferred recognition sequence between these groups can differ at up to four of the six core recognition positions. Analysis of the recognition motifs within these groups led to a catalog of common specificity determinants that may cooperate or compete to define the binding site preference. With these recognition principles, a homeodomain can be reengineered to create factors where its specificity is altered at the majority of recognition positions. This resource also allows prediction of homeodomain specificities from other organisms, which is demonstrated by the prediction and analysis of human homeodomain specificities.


Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner.
Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.


Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet.
Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1(-/-)) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1(-/-) mice exhibited higher serum alanine aminotransferase levels compared with Xbp1(fl/fl) controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1(-/-) mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1(-/-) mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1(-/-) compared with Xbp1(fl/fl) mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.


Numerical architecture.
The idea that there is a "Number Sense" (Dehaene, 1997) or "Core Knowledge" of number ensconced in a modular processing system (Carey, 2009) has gained popularity as the study of numerical cognition has matured. However, these claims are generally made with little, if any, detailed examination of which modular properties are instantiated in numerical processing. In this article, I aim to rectify this situation by detailing the modular properties on display in numerical cognitive processing. In the process, I review literature from across the cognitive sciences and describe how the evidence reported in these works supports the hypothesis that numerical cognitive processing is modular. I outline the properties that would suffice for deeming a certain processing system a modular processing system. Subsequently, I use behavioral, neuropsychological, philosophical, and anthropological evidence to show that the number module is domain specific, informationally encapsulated, neurally localizable, subject to specific pathological breakdowns, mandatory, fast, and inaccessible at the person level; in other words, I use the evidence to demonstrate that some of our numerical capacity is housed in modular casing.


Marine Pseudovibrio sp. as a novel source of antimicrobials.
Antibiotic resistance among pathogenic microorganisms is becoming ever more common. Unfortunately, the development of new antibiotics which may combat resistance has decreased. Recently, however the oceans and the marine animals that reside there have received increased attention as a potential source for natural product discovery. Many marine eukaryotes interact and form close associations with microorganisms that inhabit their surfaces, many of which can inhibit the attachment, growth or survival of competitor species. It is the bioactive compounds responsible for the inhibition that is of interest to researchers on the hunt for novel bioactives. The genus Pseudovibrio has been repeatedly identified from the bacterial communities isolated from marine surfaces. In addition, antimicrobial activity assays have demonstrated significant antimicrobial producing capabilities throughout the genus. This review will describe the potency, spectrum and possible novelty of the compounds produced by these bacteria, while highlighting the capacity for this genus to produce natural antimicrobial compounds which could be employed to control undesirable bacteria in the healthcare and food production sectors.


Research into biocompatibility and cytotoxicity of daptomycin, gentamicin, vancomycin and teicoplanin antibiotics at common doses added to bone cement.
This study aims to investigate the biocompatibility and cytotoxicity of daptomycin, gentamicin, vancomycin and teicoplanin at commonly-used dose intervals added to polymethylmethacrylate (PMMA) in vitro. This prospective study was conducted between February 2016 and June 2016. Antibiotics were added to PMMA at doses frequently used in clinical practice. The antibiotic doses added were teicoplanin (2 g, 3 g, 4 g), gentamicin (0.5 g, 0.75 g, 1 g), daptomycin (0.5 g.) and vancomycin (2 g, 3 g, 4 g). Standard cement balls (10 mm) were created. Activated L929 mouse fibroblast cell culture was used for incubation. Agar diffusion, Cell Proliferation Kit II (XTT) test and electron microscope investigations were performed to examine biocompatibility and cytotoxicity. In the cytotoxicity test, teicoplanin at 4 g and daptomycin at 0.5 g doses were observed to cause reductions in viability percentages. The same doses caused 20% and 20-40% cell lysis indices during the agar diffusion test. On electron microscope images, cytotoxic effects in fibroblast cells and involvement with the surface of cement balls were observed. Gentamicin, vancomycin and teicoplanin were observed to be non-toxic and biocompatible at commonly-used dose intervals. Teicoplanin at 4 g and daptomycin at 0.5 g doses were identified to be cytotoxic and not biocompatible. When selecting antibiotics to be added to bone cement, care should be taken that the antibiotic is non-toxic and biocompatible.


Adsorption of Water and Ammonia on Graphene: Evidence for Chemisorption from X-ray Absorption Spectra.
While the bonding of molecular adsorbates to graphene has so far been characterized as physisorption, our study of adsorbed ammonia and water using near-edge X-ray absorption spectroscopy provides unambiguous evidence for a chemical contribution to the adsorption bond. We use the situation, unique to graphene, to characterize the unoccupied valence band states of the partners in the bond on the basis of the complementary adsorbate and substrate X-ray absorption K edges. New adsorbate-induced features on the substrate (carbon) K edge are interpreted as hybrid states in terms of a simple model of chemical interaction.