Typology of patients who use emergency departments for mental and substance use disorders.
Identifying profiles of people with mental and substance use disorders who use emergency departments may help guide the development of interventions more appropriate to their particular characteristics and needs. To develop a typology for the frequency of visits to the emergency department for mental health reasons based on the Andersen model. Questionnaires were completed by patients who attended an emergency department (n = 320), recruited in Quebec (Canada), and administrative data were obtained related to sociodemographic/socioeconomic characteristics, mental health diagnoses including alcohol and drug use, and emergency department and mental health service utilization. A cluster analysis was performed, identifying needs, predisposing and enabling factors that differentiated subclasses of participants according to frequency of emergency department visits for mental health reasons. Four classes were identified. Class 1 comprised individuals with moderate emergency department use and low use of other health services; mostly young, economically disadvantaged males with substance use disorders. Class 2 comprised individuals with high emergency department and specialized health service use, with multiple mental and substance use disorders. Class 3 comprised middle-aged, economically advantaged females with common mental disorders, who made moderate use of emergency departments but consulted general practitioners. Class 4 comprised older individuals with multiple chronic physical illnesses co-occurring with mental disorders, who made moderate use of the emergency department, but mainly consulted general practitioners. The study found heterogeneity in emergency department use for mental health reasons, as each of the four classes represented distinct needs, predisposing and enabling factors. As such, interventions should be tailored to different classes of patients who use emergency departments, based on their characteristics.


Interlayer coupling through a dimensionality-induced magnetic state.
Dimensionality is known to play an important role in many compounds for which ultrathin layers can behave very differently from the bulk. This is especially true for the paramagnetic metal LaNiO3, which can become insulating and magnetic when only a few monolayers thick. We show here that an induced antiferromagnetic order can be stabilized in the [111] direction by interfacial coupling to the insulating ferromagnet LaMnO3, and used to generate interlayer magnetic coupling of a nature that depends on the exact number of LaNiO3 monolayers. For 7-monolayer-thick LaNiO3/LaMnO3 superlattices, negative and positive exchange bias, as well as antiferromagnetic interlayer coupling are observed in different temperature windows. All three behaviours are explained based on the emergence of a (¼,¼,¼)-wavevector antiferromagnetic structure in LaNiO3 and the presence of interface asymmetry with LaMnO3. This dimensionality-induced magnetic order can be used to tailor a broad range of magnetic properties in well-designed superlattice-based devices.


Soybean seed 2-S globulins are not trypsin inhibitors.
Trypsin inhibitory activity found in 2-S soybean seed globulins is due to the coprecipitation of inhibitors during the isolation of globulins.


Endothelial dysfunction and vascular disease.
The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive G(i) (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive G(q) (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.


A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth.
Oncostatin M (OSM) is a member of the IL-6 family cytokines that use gp130 as a common signal transducer and exhibits both growth stimulatory as well as growth inhibitory activity depending on the cells. To analyze the mechanism of OSM function, we isolated immediate early responsive genes upon OSM stimulation. Here we describe the novel OSM-inducible gene OIG37 that is related to MyD118 and GADD45. The MyD118 gene has been described as an immediate early gene induced by IL-6 in M1 monocytic cells, and GADD45 was identified as a gene induced by UV or gamma-ray irradiation. Both are considered to function in growth arrest and/or DNA repair. Although the expression of OIG37, MyD118, and GADD45 was rather ubiquitous, it was differentially regulated. As the gp130 mutant defective for activating the STAT3 pathway showed the reduced induction of OIG37 by cytokine stimulation and expression of dominant negative STAT3 inhibited the induction of OIG37 by OSM, STAT3 is involved in OIG37 induction by IL-6 family cytokines. To examine the function of OIG37, we expressed it in NIH3T3 and IL-3-dependent BaF3 cells and found that OIG37 suppressed cell growth without any evidence of apoptosis. Whereas both MyD118 and OIG37 suppressed cell growth in both cell lines, suppression by OIG37 was more efficient than by MyD118. Immunoprecipitation experiments indicated that OIG37 associates with p21, a cyclin-dependent kinase inhibitor, and proliferating cell nuclear antigen.


Detailed Imaging of Mitochondrial Transport and Precise Manipulation of Mitochondrial Function with Genetically Encoded Photosensitizers in Adult Drosophila Neurons.
Precise distribution of mitochondria is essential for maintaining neuronal homeostasis. Although detailed mechanisms governing the transport of mitochondria have emerged, it is still poorly understood how the regulation of transport is coordinated in space and time within the physiological context of an organism. How alteration in mitochondrial functionality may trigger changes in organellar dynamics also remains unclear in this context. Therefore, the use of genetically encoded tools to perturb mitochondrial functionality in real time would be desirable. Here we describe methods to interfere with mitochondrial function with high spatiotemporal precision with the use of photosensitizers in vivo in the intact wing nerve of adult Drosophila. We also provide details on how to visualize the transport of mitochondria and to improve the quality of the imaging to attain super-resolution in this tissue.


Immediate information expected by the neonatologist from the placenta.
As the obstetrician attends to the mother and the pediatrician to the child, the placenta often tends to be ignored. Nevertheless, essential anamnestic information about the condition of a newborn infant, and especially of a premature, can be gained from careful scrutiny of the placenta and fetal membranes. This paper emphasizes the importance of gross examination of the placenta and membranes as a source of immediate information to the pediatrician within the delivery room.


Verapamil sensitive idiopathic ventricular tachycardia in an infant.
Idiopathic ventricular tachycardia is rare, especially in infants. We report here on an 8 month-old female infant who presented with tachycardia with a heart rate of 186 beats/ min. An electrocardiogram showed a right bundle branch block pattern, a QRS duration of 80 msec, a superior QRS axis, atrioventricular dissociation, and occasional fusion and capture beats. Suspected ventricular tachycardia was treated with lidocaine, propranolol and amiodarone, but in vain. The tachycardia was terminated and well controlled with the use of verapamil. According to an electrocardiogram and her clinical response, verapamil-sensitive idiopathic ventricular tachycardia was diagnosed with the arrhythmic origin in the left posterior fascicle.


CS5 pilus biosynthesis genes from enterotoxigenic Escherichia coli O115:H40.
We have sequenced the entire region of DNA required for the biosynthesis of CS5 pili from enterotoxigenic Escherichia coli O115:H40 downstream of the major subunit gene, designated csfA (for coli surface factor five A). Five more open reading frames (ORFs) (csfB, csfC, csfE, csfF, and csfD) which are transcribed in the same direction as the major subunit and are flanked by a number of insertion sequence regions have been identified. T7 polymerase-mediated overexpression of the cloned csf ORFs confirmed protein sizes based on the DNA sequences that encode them. The expression of only the csf region in E. coli K-12 resulted in the hemagglutination of human erythrocytes and the cell surface expression of CS5 pili, suggesting that the cluster contains all necessary information for CS5 pilus biogenesis and function.


[Effect of lipoic acid on tyrosine metabolism in patients with open-angle glaucoma].
Lipoic acid effects on tyrosine metabolism and ocular hydrodynamics were examined in patients with primary open-angle glaucoma. Glaucoma patients not administered the drug and patients with ocular hypertension made up two reference groups. In the majority of glaucoma patients administration of lipoic acid did not result in improvement of tyrosine metabolism, whereas hydrodynamic parameters somewhat increased. Tyrosine metabolism normalized in the patients administered lipoic acid in complex with tyrosine catabolism cofactors (pyridoxal phosphate, ascorbic acid, iron ions). The studied parameters improved in ocular hypertension patients administered lipoic acid. The authors' findings and the literature data permit recommending lipoic acid in complex with vitamins B1, B2, B5 (PP), B6 (pyridoxal phosphate), C to glaucoma patients. Judging from the reaction to lipoic acid administration, tyrosine catabolism enzyme activities in glaucoma patients are related to a peculiar sensitization of the body.


Evaluation of a (99m)Tc-labeled cyclic RGD tetramer for noninvasive imaging integrin alpha(v)beta3-positive breast cancer.
Integrin alphavbeta3 plays a critical role in tumor angiogenesis and metastasis. Radiolabeled RGD peptides that are integrin alphavbeta3-specific are very useful for noninvasive imaging of integrin expression in rapidly growing and metastatic tumors. In this study, we determined the binding affinity of E{E[c(RGDfK)]2}2 (tetramer) and its 6-hydrazinonicotinamide conjugate (HYNIC-tetramer) against the binding of 125I-echistatin to the integrin alphavbeta3-positive MDA-MB-435 breast cancer cells. The athymic nude mice bearing MDA-MB-435 xenografts were used to evaluate the potential of ternary ligand complex [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3' '-trisulfonate) as a new radiotracer for imaging breast cancer integrin alphavbeta3 expression by single photon emission computed tomography (SPECT). It was found that the binding affinity of tetramer (IC50 = 51 +/- 11 nM) was slightly higher than that of its dimeric analogue (IC50 = 78 +/- 27 nM) and is comparable to that of the HYNIC-tetramer conjugate (IC50 = 55 +/- 11 nM) within the experimental error. Biodistribution data showed that [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] had a rapid blood clearance (4.61 +/- 0.81 %ID/g at 5 min postinjection (p.i.) and 0.56 +/- 0.12 %ID/g at 120 min p.i.) and was excreted mainly via the renal route. [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] had high tumor uptake with a long tumor retention (5.60 +/- 0.87 %ID/g and 7.30 +/- 1.32 %ID/g at 5 and 120 min p.i., respectively). The integrin alphavbeta3-specificity was demonstrated by co-injection of excess E[c(RGDfK)]2, which resulted in a significant reduction in tumor uptake of the radiotracer. The metabolic stability of [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] was determined by analyzing urine and feces samples from the tumor-bearing mice at 120 min p.i. In the urine, about 20% of [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] remained intact while only approximately 15% metabolized species was detected in feces. SPECT images displayed significant radiotracer localization in tumor with good contrast as early as 1 h p.i. The high tumor uptake and fast renal excretion make [99mTc(HYNIC-tetramer)(tricine)(TPPTS)] a promising radiotracer for noninvasive imaging of the integrin alphavbeta3-positive tumors by SPECT.


Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel.
Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents.


Evidence for varied aetiologies regulating the transmission of prion disease: implications for understanding the heritable basis of prion incubation times.
Transmissible Spongiform Encephalopathies (TSEs) are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation between quantitative trait loci (QTLs) reported in mouse models is due to methodological differences between approaches or genuine differences between traits. With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits. Our data indicate a surprising degree of heritability (up to 60%). Correlations between traits are also identified. A series of QTLs on chromosomes 1, 2, 3, 4, 6, 11 and 18 accompany our heritability estimates. However, only a locus on chromosome 11 has a general effect across all 4 models explored. We have achieved some success in detecting novel and pre-existing QTLs associated with incubation time. However, aside from the general effects described, the model-specific nature of the broader host genetic architecture has also been brought into clearer focus. This suggests that genetic overlap can only partially account for the general heritability of incubation time when factors, such as the nature of the TSE agent and the route of administration are considered. This point is highly relevant to vCJD (a potential threat to public health) where the route of primary importance is oral, while the QTLs being sought derive exclusively from studies of the ic route. Our results highlight the limitations of a single-model approach to QTL-mapping of TSEs.


Comparative Metabolomic Profiles of Vascular Involvement in Behçet's Disease.
Behçet's disease is a systemic, inflammatory disease affecting multiple organs. Vascular involvement is the main cause of morbidity and mortality in Behçet's disease patients. Though clinically well-defined, there is limited information related to disease pathogenesis and vascular incidence in this patient group. The aim of this study is to investigate the unique metabolic signatures of Behçet's disease patients with vascular involvement. Metabolomic profiling was performed on serum samples of 48 Behçet's disease patients (18 with vascular involvement) and 40 healthy controls using gas chromatography-mass spectrometrybased untargeted metabolomics analysis. Multivariate and univariate statistical analyses were performed to find altered metabolites and pathways. Untargeted metabolomics results showed that a total of 168 metabolites were identified. The comparison between the groups of Behçet's disease, vascular involvement in Behçet's disease, and the healthy control group showed that altered amino acid and oxidative stress pathways, especially with glutathione synthesis, could be an important stage for developing Behçet's disease. In the present work, the untargeted metabolomics approach provided new molecular insights for a better understanding of Behçet's disease pathogenesis and also developing vascular involvement in Behçet's disease at the metabolite level. The results showed that vascular involvement in Behçet's disease could be highly linked with amino acid metabolism and also the antioxidant system, and these disease-related pathways could be evaluated with further experiments for diagnosis and prognosis of Behçet's disease and also for vascular involvement in Behçet's disease.


HIV/AIDS communication campaigns: progress and prospects.
The mass media have been the primary method for disseminating human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) prevention messages worldwide. In this article, we update previous reviews by systematically examining published articles (n = 41) of empirical evaluations of international HIV/AIDS prevention campaigns. Of the 41 studies identified, 17 countries are represented. In this review, we examine six components related to media campaign design and evaluation: target audience, communication channel(s), message content, campaign theme, exposure, and outcomes. Of the studies included in this sample, each one described the target audience; 93% reported on channel selection; 75% described message content; 63% mentioned a campaign theme; and 62% documented campaign exposure. We investigate also the extent to which HIV/AIDS prevention efforts have moved beyond media campaigns to comprehensive communitywide programs. We conclude that HIV/AIDS prevention efforts would benefit from: (1) better reporting of media campaign components and outcomes, (2) more systematic evaluation, (3) greater integration of theory, and (4) increased attention to communitywide intervention strategies.


Early growth and abdominal fatness in adult life.
The aim was to determine whether abdominal fatness in adult men is associated with retarded growth in fetal life and infancy. This was a follow up study of (1) men born during 1920-30 whose birthweights and weights at one year were recorded at the time by health visitors; and (2) men born during 1935-43 whose size at birth was measured in detail. The main outcome measure was the ratio of waist circumference to hip girth. Hertfordshire and Preston, England. Subjects were 845 men born in east Hertfordshire who still live there; and 239 men born in Preston who still live in or close to the city. After allowing for body mass index, mean waist to hip ratio fell with increasing birthweight and rose as the ratio of placental weight to birthweight increased. These trends were independent of duration of gestation and therefore reflected retarded fetal growth. Waist to hip ratio also fell with increasing weight at one year. All these trends were independent of adult height, alcohol consumption, smoking, social class, and age. The tendency to store fat abdominally, which is known to increase the risk of cardiovascular disease and diabetes independently of obesity, may be a persisting response to adverse conditions and growth failure in fetal life and infancy.


Whose quality is it? Young people report on a participatory research project to explore the involvement of children in monitoring quality of care in hospital.
While helping with the analysis of interviews about our views, we found that privacy, good technical skills, explanations, choice and friendly staff were factors that contributed to care being rated as excellent. We decided to ask years 5 and 6 and year 9 what aspects of hospital care they would use to rate 'good' or 'bad' and whether they thought they should be asked their views. (We tried to get children's nurses' views about whether children should be asked but only received II replies). 100 per cent (n=45) of the year 9s answered 'me' to the question of who should be asked about quality compared with 77.25 per cent (n=63) of the years 5 and 6. We confirmed the five quality factors we had identified and gained more understanding of what each involved. Responses indicated that privacy should be broadened and we agreed on using the term 'respect'. Based on these findings we recommend (among other things) that when drawing up your standards you should emphasise technical expertise, the attitudes of staff and the need for respect. Aim for giving choice where possible and don't forget the explanations.


Treatment of hypertension in acute ischemic stroke.
Blood pressure fluctuation early in the course of ischemic stroke is a proven independent predictor of morbidity and mortality. Both high and low systolic blood pressures have a detrimental effect on the neurologic outcome. Current guidelines support permissive hypertension in the early course of acute ischemic stroke. For patients with marked elevation in blood pressure, a reasonable goal would be to lower blood pressure by 15% during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus exists that medications should be withheld unless the systolic blood pressure is greater than 220 mm Hg or the diastolic blood pressure is greater than 120 mm Hg. For patients undergoing intravenous thrombolysis for acute ischemic stroke, it is recommended that the blood pressure be reduced and maintained below 185 mm Hg systolic for the first 24 hours. The first-line drugs for lowering of blood pressure remain labetalol, nicardipine, and sodium nitroprusside. These recommendations are based on consensus rather than evidence, however. Comorbid conditions such as myocardial infarction, left ventricular failure, aortic dissection, preeclampsia, or eclampsia would override the guidelines for permissive hypertension; a lower blood pressure would be preferred in these conditions. Children with acute strokes should be managed in the same way as adults, with extrapolated lowering of blood pressures, until further evidence emerges. Current research focuses on both hemodynamic augmentation of low blood pressures and the effects of further lowering the blood pressure after acute ischemic stroke. Until more definitive data are available, a cautious approach to the treatment of arterial hypertension is generally recommended.


A Family with Autosomal Dominant Distal Renal Tubular Acidosis Presents with Atypical Phenotype Caused by a Missence Mutation (R388C) of the Human Kidney Anion Exchanger.
Hereditary forms of distal renal tubular acidosis (dRTA) are rare and mainly caused by mutations in ATP6V1B1, ATP6V0A4 and SLC4A1. About 20 mutations in SLC4A1 gene have been found that are related to either autosomal dominant (AD) or autosomal recessive dRTA. AD dRTA often manifest as constitutional and can easily be delayed in diagnosis and treatment. A 30-year-old male patient has a history of paroxysmal paralysis for 7 years, presenting with mild hypokalemia, alkalization of urine, normal blood PH value and increased urinary calcium. Patient's father has similar presentations but never came to the hospital. We find a heterozygous mutation (c.1162C>T, p.Arg388Cys) located in exon 11 of SLC4A1 gene by utilization of next-generation sequencing technology. Both patient and his father carry the same mutation. Highly conserved R388 is located in amphipathic helix 1 of N-terminal of the kAE1 protein, which may cause AD dRTA by changing the conformation of kAE1. Expression studies provide evidence that the mutant kAE1 R388C proteins are impaired in trafficking to the cell surface.


Primary description of a new entity, renal cell-like carcinoma of the nasal cavity: van Meegeren in the house of Vermeer.
Few sinonasal malignancies can manifest, histologically, as clear cell neoplasia. The most likely such tumor to be encountered is metastatic renal cell carcinoma. Primary sinonasal tumors that can appear as clear cell malignancies include squamous cell carcinoma and mucoepidermoid carcinoma. Primary salivary clear cell carcinoma occurs almost exclusively in the oral cavity and has not been described in the nasal cavity. To report a unique sinonasal clear cell malignancy that mimicked metastatic renal carcinoma. Case report. Radiography, histology, histochemistry, immunohistochemistry, and electron microscopy. Histologically, the tumor was identical to renal cell carcinoma. No evidence of renal malignancy was found by abdominal computed tomographic scan or gadolinium-enhanced magnetic resonance imaging. Histochemistry confirmed the presence of tumor glycogen but no mucin. Immunohistochemistry confirmed strong expression of low- and high-molecular-weight keratin and S100, and no vimentin expression. Electron microscopy showed tumor myofibroblastic differentiation and cytoplasmic glycogen, neutral lipid vacuoles, and cholesterol. There was no clinical evidence of renal cell carcinoma. The immunohistochemical and ultrastructural findings were inconsistent with the diagnosis of renal cell carcinoma and showed features also inconsistent with the diagnosis of primary salivary clear cell carcinoma. We therefore conclude that this tumor represents a new and distinct entity, notable in its presentation as a "counterfeit renal cell carcinoma."


Alcohol-based handrub improves compliance with hand hygiene in intensive care units.
Nosocomial infection is a leading complication in intensive care units. Although hand hygiene is the single most efficient preventive measure, compliance with this simple action remains low. To assess the effect of an intervention to promote hand hygiene and to investigate risk factors for noncompliance in intensive care units. We performed 7 observational surveys and implemented a promotional campaign after baseline in medical, surgical, and pediatric intensive care units of a teaching hospital. Health care workers were observed during routine patient care. The intervention consisted of a hospitalwide promotional campaign, including observation and performance feedback, posters display, and distribution of individual bottles of alcohol-based handrub. The main outcome measure was compliance with hand hygiene through handwashing or handrubbing. We observed 2743 opportunities for hand hygiene distributed over 248 periods. Overall compliance increased from 38.4% to 54.5% during the study (P<.001). Although recourse to handwashing remained stable at around 30%, handrubbing increased from 5.4% at baseline to 21.7% at the last survey (P<.001). Compliance increased among nurses and nursing assistants, but remained stable among physicians. Handwashing compliance decreased, on average, by 4.7% for an increase of 10 opportunities for hand hygiene per hour of patient care (P<.001), whereas no such association existed for handrubbing. Our intervention induced a marked and sustained increase in compliance with hand hygiene. In intensive care units, less time-consuming handrubbing might replace standard handwashing and overcome the barrier of time constraints.


Aberrant localization of synchronous hemodynamic activity in auditory cortex reliably characterizes schizophrenia.
Among the most prominent features of schizophrenic brains are abnormalities in auditory cortex structure and function, particularly in the superior temporal gyrus (STG). In this study, we attempted to examine auditory cortex function using an intrinsic, task-uncorrelated measure. Using functional magnetic resonance imaging data, we calculated synchronous hemodynamic independent maps (SHIMs) of auditory cortex in patients with schizophrenia and matched healthy control subjects while they performed an auditory oddball task. Patient SHIMs revealed greater synchrony in ventral and medial STG regions (including auditory association Brodmann area [BA] 42); control SHIMs had greater synchrony in dorsal and lateral STG regions (which did not include BA 42). A within-participant subtractive comparison of these two sets of regions differentiated schizophrenic from healthy control subjects with 97% accuracy initially (further validated by a retest of the healthy control subjects) and performed with 94% accuracy in a confirmatory study of new subjects scanned at a different site. These results shed new light on STG functional differences in schizophrenia, suggest that aberrant patterns of coherence in temporal lobe cortical regions are a cardinal abnormality in schizophrenia, and have the potential to provide a powerful, quantitative clinical tool for the assessment of schizophrenia.


Gliding motility in Cytophaga.
Gliding motility in Cytophaga depends on a motility machinery that keeps surfaces of cells in motion and on a surface slime that allows motile cells to translocate over a substratum. The unusual nature of the moving cell surfaces appears to be responsible for several cell-surface properties being motility dependent.


Design, synthesis, and characterization of novel system xC- transport inhibitors: inhibition of microglial glutamate release and neurotoxicity.
Neuroinflammation appears to involve some degree of excitotoxicity promulgated by microglia, which release glutamate via the system xC- (SxC-) cystine-glutamate antiporter. With the aim of mitigating this source of neuronal stress and toxicity, we have developed a panel of inhibitors of the SxC- antiporter. The compounds were based on L-tyrosine, as elements of its structure align with those of glutamate, a primary physiological substrate of the SxC- antiporter. In addition to 3,5-dibromotyrosine, ten compounds were synthesized via amidation of that parent molecule with a selection of acyl halides. These agents were tested for the ability to inhibit release of glutamate from microglia activated with lipopolysaccharide (LPS), an activity exhibited by eight of the compounds. To confirm that the compounds were inhibitors of SxC-, two of them were further tested for the ability to inhibit cystine uptake. Finally, these agents were shown to protect primary cortical neurons from the toxicity exhibited by activated microglia. These agents may hold promise in reducing the neurodegenerative effects of neuroinflammation in conditions, such as encephalitis, traumatic brain injury, stroke, or neurodegenerative diseases.


Treatment of a human papillomavirus type 31b-positive cell line with benzo[a]pyrene increases viral titer through activation of the Erk1/2 signaling pathway.
Numerous epidemiological studies have implicated cigarette smoking as a cofactor in the progression to cervical cancer. Tobacco-associated hydrocarbons have been found in cervical mucus, suggesting a possible interaction with human papillomavirus (HPV)-infected cells. The polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) is a major component of cigarette smoke condensate that has received significant attention due to its ability to induce carcinogenesis. We have previously demonstrated by conventional methods for determining viral titer that high concentrations of BaP increase HPV31b titers within the context of organotypic raft cultures compared with the level for vehicle controls. However, a definitive mechanism for explaining this increase in viral titer was lacking. Here, we show that BaP treatment activates the Ras-Raf-Mek1/2-Erk1/2 signaling pathway. The importance of Erk1/2 pathway activation to the BaP-mediated increase in viral titer was determined by Erk pathway inhibition with multiple Erk1/2 pathway inhibitors. Finally, BaP treatment activated p90RSK and its downstream target CDK1. These data indicate that the Erk1/2 signaling pathway plays an important role in mediating the response to BaP treatment that ultimately leads to increased viral titers.


Prevalence of primary immunodeficiency in Korea.
This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.


Debris clearance by microglia: an essential link between degeneration and regeneration.
Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues.


Aldehyde PEGylation of laccase from Trametes versicolor in route to increase its stability: effect on enzymatic activity.
Laccase is a multicopper oxidase that catalyzes the oxidation of phenolic compounds. Laccase can be used in bioremediation, beverage (wine, fruit juice, and beer) processing, ascorbic acid determination, sugar beet pectin gelation baking, and as a biosensor. Recently, the antiproliferative activity of laccase toward tumor cells has been reported. Because of the potential applications of this enzyme, the efforts for enhancing and stabilizing its activity have increased. Thus, the PEGylation of laccase can be an alternative. PEGylation is the covalent attachment of one or more molecules of methoxy poly(ethylene glycol) (mPEG) to a protein. Normally, during the PEGylation reaction, the activity is reduced but the stability increases; thus, it is important to minimize the loss of activity. In this work, the effects of molar ratio (1:4, 1:8, and 1:12), concentration of laccase (6 and 12 mg/ml), reaction time (4 and 17 h), molecular weight, and type of mPEG (20, 30, 40 kDa and 40 kDa-branched) were analyzed. The activity was measured using three substrates: ABTS, 2,6-dimethoxyphenol, and syringaldazine. The best conditions for laccase PEGylation were 12 mg/ml of laccase, molar ratio 1:4, and 4 h reaction time. Under these conditions, the enzyme was able to maintain nearly 100% of its enzymatic activity with ABTS. The PEGylation of laccase has not been extensively explored, so it is important to analyze the effects of this bioconjugation in route to produce a robust modified enzyme.


Cytoprotection of human endothelial cells from menadione cytotoxicity by caffeic acid phenethyl ester: the role of heme oxygenase-1.
Caffeic acid phenethyl ester (CAPE), derived from various plant sources, has been shown to ameliorate ischemia/reperfusion injury in vivo, and this has been attributed to its ability to reduce oxidative stress. Here we investigated the cytoprotection of CAPE against menadione-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) to evaluate potential gene expression involvement. CAPE exhibited dose-dependent cytoprotection of HUVEC. A gene screen with microarrays was performed to identify the potential cytoprotective gene(s) induced by CAPE. Heme oxygenase-1 (HO-1) was highly upregulated by CAPE and this was confirmed with reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting. Inhibition of HO-1 activity using the HO-1 inhibitor tin protoporphyrin IX (SnPPIX), resulted in loss of cytoprotection. Carbon monoxide, one of HO-1 catabolic products appeared to play a small role in CAPE protection. Caffeic acid, a potential metabolite of CAPE with similar free radical scavenging ability, however, didn't show any cytoprotective effect nor induce HO-1. These findings suggest an important role of HO-1 induction in CAPE cytoprotection against oxidant stress, which may not relate to CAPE structural antioxidant activity nor to its traditional enzymatic activity in decomposing heme but to a yet to be determined activity.


[Speech changes in dementia].
This review analyzes the spectrum of language deficits commonly encountered in dementia. A specific communication profile is found in dementia of the "cortical" type, such as Alzheimer's disease. With advancing disease lexical, comprehension and pragmatic functions deteriorate, whereas syntax and phonology tend to be preserved. This pattern bears some resemblance to aphasia types like transcortical and Wernicke's aphasia, however, a much broader range of communicative functions is impaired in Alzheimer's disease than in aphasia. Differentiation of dementia and aphasia, especially in elderly patients requires careful neuropsychological assessment of language, memory and other psychological functions. "Subcortical" dementia commonly presents with dysarthria as the leading symptom and linguistic impairment is rarely of crucial importance until late stages. Thus, the interetiologic dissociation of language and speech impairment can be used for dementia differentiation. Aphasia batteries are not sufficient to comprehend the range of language deficits in demented patients. Testing the communication impairment in dementia requires specific tasks for spontaneous speech, naming, comprehension, reading, writing, repetition and motor speech functions. Tasks for verbal learning and metalinguistic abilities should also be performed. Language deficits are frequent initial symptoms of dementia, thus language assessment may be of diagnostic relevance. Many data support the concept that the communication deficit in dementia results from a particular impairment of semantic memory.


Multiomics Provide Insights into the Key Molecules and Pathways Involved in the Physiological Adaptation of Atlantic Salmon (Salmo salar) to Chemotherapeutic-Induced Oxidative Stress.
Although chemotherapeutics are used to treat infections in farmed fish, knowledge on how they alter host physiology is limited. Here, we elucidated the physiological consequences of repeated exposure to the potent oxidative chemotherapeutic peracetic acid (PAA) in Atlantic salmon (Salmo salar) smolts. Fish were exposed to the oxidant for 15 (short exposure) or 30 (long exposure) minutes every 15 days over 45 days. Unexposed fish served as the control. Thereafter, the ability of the remaining fish to handle a secondary stressor was investigated. Periodic chemotherapeutic exposure did not affect production performance, though survival was lower in the PAA-treated groups than in the control. Increased ventilation, erratic swimming, and a loss of balance were common behavioural manifestations during the oxidant exposure. The plasma reactive oxygen species levels increased in the PAA-treated groups, particularly after the third exposure, suggesting an alteration in the systemic oxidative stress status. Plasma indicators for internal organ health were affected to a certain degree, with the changes mainly observed after the second and third exposures. Metabolomics disclosed that the oxidant altered several circulating metabolites. Inosine and guanosine were the two metabolites significantly affected by the oxidative stressor, regardless of exposure time. A microarray analysis revealed that the gills and liver were more responsive to the oxidant than the skin, with the gills being the most sensitive. Moreover, the magnitude of the transcriptomic modifications depended on the exposure duration. A functional analysis showed that genes involved in immunity and ribosomal functions were significantly affected in the gills. In contrast, genes crucial for the oxidation-reduction process were mainly targeted in the liver. Skin mucus proteomics uncovered that the changes in the mucosal proteome were dependent on exposure duration and that the oxidant interfered with ribosome-related processes. Mucosal mapping revealed gill mucous cell hypertrophy after the second and third exposures, although the skin morphological parameters remained unaltered. Lastly, repeated oxidant exposures did not impede the ability of the fish to mount a response to a secondary stressor. This study provides insights into how a chemical oxidative stressor alters salmon physiology at both the systemic and mucosal levels. This knowledge will be pivotal in developing an evidence-driven approach to the use of oxidative therapeutics in fish, with some of the molecules and pathways identified as potential biomarkers and targets for assessing the physiological cost of these treatments.


The First Chemically-Synthesised, Highly Immunogenic Anti-SARS-CoV-2 Peptides in DNA Genotyped Aotus Monkeys for Human Use.
Thirty-five peptides selected from functionally-relevant SARS-CoV-2 spike (S), membrane (M), and envelope (E) proteins were suitably modified for immunising MHC class II (MHCII) DNA-genotyped Aotus monkeys and matched with HLA-DRβ1* molecules for use in humans. This was aimed at producing the first minimal subunit-based, chemically-synthesised, immunogenic molecules (COLSARSPROT) covering several HLA alleles. They were predicted to cover 48.25% of the world's population for 6 weeks (short-term) and 33.65% for 15 weeks (long-lasting) as they induced very high immunofluorescent antibody (IFA) and ELISA titres against S, M and E parental native peptides, SARS-CoV-2 neutralising antibodies and host cell infection. The same immunological methods that led to identifying new peptides for inclusion in the COLSARSPROT mixture were used for antigenicity studies. Peptides were analysed with serum samples from patients suffering mild or severe SARS-CoV-2 infection, thereby increasing chemically-synthesised peptides' potential coverage for the world populations up to 62.9%. These peptides' 3D structural analysis (by 1H-NMR acquired at 600 to 900 MHz) suggested structural-functional immunological association. This first multi-protein, multi-epitope, minimal subunit-based, chemically-synthesised, highly immunogenic peptide mixture highlights such chemical synthesis methodology's potential for rapidly obtaining very pure, highly reproducible, stable, cheap, easily-modifiable peptides for inducing immune protection against COVID-19, covering a substantial percentage of the human population.


Conformational changes of transfer RNA. The role of magnesium(II).
Magnesium ions added to tRNAfMET1 selectively stabilize the dihydrouridine helix-tertiary structural region. Low Mg2+ levels have little direct effect on the remaining three cloverleaf helices, but these are prevented from melting independently when their intrinsic Tm is surpassed by the Tm of the tertiary structure. At high Mg2+ concentration the thermal unfolding of tRNAfMet1 is approximately a two-state, concerted transition from the globular native structure to the random coil, in contrast to the sequential unfolding observed without Mg2+. We interpret the kinetics of refolding to mean that the D helix serves as a required nucleus for the rate-limiting step of tertiary structure formation. We found that unfolding of the tertiary structure leads to loss of the tightly bound Mg2+ ions, and showed with a Mn2+-sensitive fluorescent indicator that the rate of Mn2+ release is the same as the rate of unfolding the tertiary structure. Hence the tightly bound divalent ion must be located in a site formed by the tertiary structure-D helix region of the molecule.


Methylation profiling of rectal cancer identifies novel markers of early-stage disease.
Radical surgery is the de facto treatment for early rectal cancer. Conservative surgery with transanal endoscopic microsurgery can achieve high rates of cure but the histopathological measures of outcome used to select local treatment lack precision. Biomarkers associated with disease progression, particularly mesorectal nodal metastasis, are urgently required. The aim was to compare patterns of gene-specific hypermethylation in radically excised rectal cancers with histopathological stage. Locus-specific hypermethylation of 24 tumour suppressor genes was measured in 105 rectal specimens (51 radically excised adenocarcinomas, 35 tissues adjacent to tumour and 19 normal controls) using the methylation-specific multiplex ligation-dependent probe assay (MS-MLPA). Methylation values were correlated with histopathological indices of disease progression and validated using bisulphite pyrosequencing. Five sites (ESR1, CDH13, CHFR, APC and RARB) were significantly hypermethylated in cancer compared with adjacent tissue and normal controls (P < 0·050). Methylation at these sites was higher in Dukes' A than Dukes' 'D' cancers (P = 0·013). Methylation at two sites (GSTP1 and RARB) was individually associated with localized disease (N0 and M0 respectively; P = 0·006 and P = 0·008). Hypermethylation of at least two of APC, RARB, TIMP3, CASP8 and GSTP1 was associated with early (N0 M0) disease (N0, P = 0·002; M0, P = 0·044). Methylation levels detected by MS-MLPA and pyrosequencing were concordant. Locus-specific hypermethylation was more prevalent in early- than late-stage disease. Hypermethylation of two or more of a panel of five tumour suppressor genes was associated with localized disease.


Properties of monoclonal antibodies directed against the glycoproteins of Sindbis virus.
Four monoclonal antibodies that react with Sindbis virus glycoproteins have been examined for (i) their effects on virus infectivity, (ii) their ability to recognize conformational changes in glycoprotein structure, and (iii) their cross-reaction with several different alphaviruses. Two of the monoclonal antibodies reacted with the native forms of the E1 glycoprotein but did not neutralize virus infectivity. One of the anti-E1 antibodies formed an infectious virus-antibody complex. The other two monoclonal antibodies reacted with the E2 glycoprotein in both an unfolded as well as a native structure. One of these antibodies reacted with Semliki Forest virus. The anti-E1, but not the anti-E2, antibodies cross-reacted with three serologically related equine encephalomyelitis viruses.


Dysmetabolism and Neurodegeneration: Trick or Treat?
Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.


A comprehensive AI-driven analysis of large-scale omic datasets reveals novel dual-purpose targets for the treatment of cancer and aging.
As aging and tumorigenesis are tightly interconnected biological processes, targeting their common underlying driving pathways may induce dual-purpose anti-aging and anti-cancer effects. Our transcriptomic analyses of 16,740 healthy samples demonstrated tissue-specific age-associated gene expression, with most tumor suppressor genes downregulated during aging. Furthermore, a large-scale pan-cancer analysis of 11 solid tumor types (11,303 cases and 4431 control samples) revealed that many cellular processes, such as protein localization, DNA replication, DNA repair, cell cycle, and RNA metabolism, were upregulated in cancer but downregulated in healthy aging tissues, whereas pathways regulating cellular senescence were upregulated in both aging and cancer. Common cancer targets were identified by the AI-driven target discovery platform-PandaOmics. Age-associated cancer targets were selected and further classified into four groups based on their reported roles in lifespan. Among the 51 identified age-associated cancer targets with anti-aging experimental evidence, 22 were proposed as dual-purpose targets for anti-aging and anti-cancer treatment with the same therapeutic direction. Among age-associated cancer targets without known lifespan-regulating activity, 23 genes were selected based on predicted dual-purpose properties. Knockdown of histone demethylase KDM1A, one of these unexplored candidates, significantly extended lifespan in Caenorhabditis elegans. Given KDM1A's anti-cancer activities reported in both preclinical and clinical studies, our findings propose KDM1A as a promising dual-purpose target. This is the first study utilizing an innovative AI-driven approach to identify dual-purpose target candidates for anti-aging and anti-cancer treatment, supporting the value of AI-assisted target identification for drug discovery.


Utilization and effectiveness of an emergency department initiated smoking cessation program
OBJECTIVE: To determine which method of intervention will best assist ED patients who smoke and are interested in quitting. METHODS: This was a prospective, controlled randomized survey of patients seen at a military ED with an annual census of approximately 30,000. All patients 18 years old or older who were medically stable and who admitted to smoking were eligible. Exclusion criteria included: predominantly psychiatric complaints, patients going directly to labor and delivery, those who left without being seen, those referred to acute care, and those who lived outside a 30 mile radius. Research assistants kept track of all patients who presented for care during four-hour time blocks representing peak census hours and asked all eligible patients if they smoked. Those who responded yes were asked if they were interested in quitting. Those who were interested were enrolled in the study and given a questionnaire. This instrument assessed demographic factors, attitudes towards quitting, and included the previously validated Fagerstrom Test for Nicotine Dependence. Once the questionnaire was complete, the subject was randomized into one of two groups. The first group was given no information or advice from the emergency department physician (EDP), but was referred to a formal smoking cessation program. The second group was not enrolled in any formal program, but was given brief counseling from the EDP. Those in the first group who completed the smoking cessation program and all patients in the second group were contacted by telephone for six-month follow-up to assess success in quitting. RESULTS: A total of 747 patients were seen during the study period, 423 of whom were eligible for the study. Of these, 86 (20%) admitted to smoking. Of these smokers, 42 (49%) were interested in quitting. These 42 patients comprised our study group and filled out questionnaires. The questionnaires showed that 35% of our study group stated they wanted to quit smoking within the next 30 days, 30% stated that they had never been advised to quit by a physician, and 43% were considered moderately to highly nicotine addicted. Twenty-one patients were randomized to each sub-group, but one was lost in each sub-group secondary to lost paper-work. This left 20 in each sub-group for data analysis. In the formal smoking cessation group, none completed the class. Of those assigned to the EDP intervention subgroup who were followed-up at six months, only one patient was able to quit smoking and stay tobacco free. However, this patient was not considered a success because she attributed her successful effort to the fact she was diagnosed with a CVA two days after enrolling in the study. Most patients who were contacted felt that other pharmacological interventions may have assisted their efforts. CONCLUSIONS: ED based smoking cessation programs in our population will likely require more than brief EDP intervention or referral to a smoking cessation program if they are going to be effective. Future studies could evaluate the possibility of initiating other medical interventions like nicotine replacement therapy, or coordination with the patient's primary care provider.


The Functional Mechanisms of Toll-Like Receptor 3 and Its Implications in Digestive System Tumors.
Toll-like receptor 3 (TLR3) is a prominent member of the Toll-like receptor (TLR) family and has the ability to recognize and bind intracellular double-stranded RNA (dsRNA). Once triggered by a viral infection or other pathological condition, TLR3 activates immune cells and induces the production of interferons and other immune response molecules. Additionally, TLR3 is considered an important immune modulator, as it can regulate cell apoptosis and promote anticancer immunity. The investigation and application of TLR3 agonists in digestive system tumors have attracted widespread attention and are regarded as a promising cancer treatment strategy with potential clinical applications. TLR3 expression levels are generally elevated in most digestive system tumors, and higher TLR3 expression is associated with a better prognosis. Therefore, TLR3 has emerged as a novel therapeutic target for digestive system tumors. It has been used in combination with chemotherapy, radiotherapy, and targeted therapy and demonstrated excellent efficacy and tolerability. This has provided new ideas and hopes for the treatment of digestive system tumors. This review discusses the mechanisms of TLR3 and its frontier research in digestive system tumors.


Identification and classification of differentially expressed genes reveal potential molecular signature associated with SARS-CoV-2 infection in lung adenocarcinomal cells.
Genomic techniques such as next-generation sequencing and microarrays have facilitated the identification and classification of molecular signatures inherent in cells upon viral infection, for possible therapeutic targets. Therefore, in this study, we performed a differential gene expression analysis, pathway enrichment analysis, and gene ontology on RNAseq data obtained from SARS-CoV-2 infected A549 cells. Differential expression analysis revealed that 753 genes were up-regulated while 746 down-regulated. SNORA81, OAS2, SYCP2, LOC100506985, and SNORD35B are the top 5 upregulated genes upon SARS-Cov-2 infection. Expectedly, these genes have been implicated in the immune response to viral assaults. In the Ontology of protein classification, a high percentage of the genes are classified as Gene-specific transcriptional regulator, metabolite interconversion enzyme, and Protein modifying enzymes. Twenty pathways with P-value lower than 0.05 were enriched in the up-regulated genes while 18 pathways are enriched in the down-regulated DEGs. The toll-like receptor signalling pathway is one of the major pathways enriched. This pathway plays an important role in the innate immune system by identifying the pathogen-associated molecular signature emanating from various microorganisms. Taken together, our results present a novel understanding of genes and corresponding pathways upon SARS-Cov-2 infection, and could facilitate the identification of novel therapeutic targets and biomarkers in the treatment of COVID-19.


[Age-related changes of the systolic and diastolic function of the left ventricle under the action of a beta adrenergic blocker, anaprilin].
Echocardiography was used to study pharmacodynamics of propranolol, a beta-adrenergic blocker, in healthy young, middle-aged and old persons. The expression and duration of a negative effect of propranolol on left ventricular contractility and pump function were shown to increase with age. Propranolol administration resulted in the deterioration of relaxation and change in phase diastolic structure causing a decrease in the contribution of rapid filling and an increase in the contribution of slow filling to left ventricular filling. A degree of shifts grows with age. A decrease in oxygen consumption by the myocardium after 40 mg of propranolol in middle-aged and old persons was accompanied by considerable suppression of contractility and end-systolic volume indicating inappropriateness of a subsequent increase in a single drug dose.


Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy.
We report changes in the genomic landscape in the development of head and neck squamous cell carcinomas HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Likely pathological mutations predominantly involved a relatively small set of genes reported previously (TP53, KMT2D, CDKN2A, PIK3CA, NOTCH1 and FAT1) but also other predicted cancer drivers (MGA, PABPC3, NR4A2, NCOR1 and MACF1). Notably, all these mutations arise early and are present in PPOLs. The most frequent genetic changes, which follow acquisition of immortality and loss of senescence, are of consistent somatic copy number alterations (SCNAs) involving chromosomal regions enriched for genes in known and previously unreported cancer-related pathways. We mapped the evolution of SCNAs in HNSCC progression. One of the earliest SCNAs involved deletions of CSMD1 (8p23.2). CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines. Modulation of CSMD1 in cell lines revealed significant suppression of proliferation and invasion by forced expression, and significant stimulation of invasion by knockdown of expression. Known cancer drivers NOTCH1, PPP6C, RAC1, EIF4G1, PIK3CA showed significant increase in frequency of SCNA in transition from PPOLs to HNSCC that correlated with their expression. In the later stages of progression, HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group.


More surprises in the global greenhouse: Human health impacts from recent toxic marine aerosol formations, due to centennial alterations of world-wide coastal food webs.
Reductions of zooplankton biomasses and grazing pressures were observed during overfishing-induced trophic cascades and concurrent oil spills at global scales. Recent phytoplankton increments followed, once Fe-, P-, and N-nutrient limitations of commensal diazotrophs and dinoflagellates were also eliminated by respective human desertification, deforestation, and eutrophication during climate changes. Si-limitation of diatoms instead ensued during these last anthropogenic perturbations of agricultural effluents and sewage loadings. Consequently, ~15% of total world-wide annual asthma trigger responses, i.e. amounting to ~45 million adjacent humans during 2004, resulted from brevetoxin and palytoxin poisons in aerosol forms of western boundary current origins. They were denoted by greater global harmful algal bloom [HAB] abundances and breathing attacks among sea-side children during prior decadal surveys of asthma prevalence, compiled here in ten paired shelf ecosystems of western and eutrophied boundary currents. Since 1965, such inferred onshore fluxes of aerosolized DOC poisons of HABs may have served as additional wind-borne organic carriers of toxic marine MeHg, phthalate, and DDT/DDE vectors, traced by radio-iodine isotopes to potentially elicit carcinomas. During these exchanges, as much as 40% of mercury poisonings may instead have been effected by inhalation of collateral HAB-carried marine neurotoxic aerosols of MeHg, not just from eating marine fish. Health impacts in some areas were additional asthma and pneumonia episodes, as well as endocrine disruptions among the same adjacent humans, with known large local rates of thyroid cancers, physician-diagnosed pulmonary problems, and ubiquitous high indices of mercury in hair, pesticides in breast milk, and phthalates in urine.


Mangifera indica (Mango): A Promising Medicinal Plant for Breast Cancer Therapy and Understanding Its Potential Mechanisms of Action.
Globally, breast cancer is the most common cancer type and is one of the most significant causes of deaths in women. To date, multiple clinical interventions have been applied, including surgical resection, radiotherapy, endocrine therapy, targeted therapy and chemotherapy. However, 1) the lack of therapeutic options for metastatic breast cancer, 2) resistance to drug therapy and 3) the lack of more selective therapy for triple-negative breast cancer are some of the major challenges in tackling breast cancer. Given the safe nature of natural products, numerous studies have focused on their anti-cancer potentials. Mangifera indica, commonly known as mango, represents one of the most extensively investigated natural sources. In this review, we provide a comprehensive overview of M. indica extracts (bark, kernel, leaves, peel and pulp) and phytochemicals (mangiferin, norathyriol, gallotannins, gallic acid, pyrogallol, methyl gallate and quercetin) reported for in vitro and in vivo anti-breast cancer activities and their underlying mechanisms based on relevant literature from several scientific databases, including PubMed, Scopus and Google Scholar till date. Overall, the in vitro findings suggest that M. indica extracts and/or phytochemicals inhibit breast cancer cell growth, proliferation, migration and invasion as well as trigger apoptosis and cell cycle arrest. In vivo results demonstrated that there was a reduction in breast tumor xenograft growth. Several potential mechanisms underlying the anti-breast cancer activities have been reported, which include modulation of oxidative status, receptors, signalling pathways, miRNA expression, enzymes and cell cycle regulators. To further explore this medicinal plant against breast cancer, future research directions are addressed. The outcomes of the review revealed that M. indica extracts and their phytochemicals may have potential benefits in the management of breast cancer in women. However, to validate its utility in the creation of innovative and potent therapeutic agents to treat breast cancer, more dedicated research, especially clinical studies are needed to explore the anti-breast cancer potentials of M. indica extracts and their phytochemicals.


An active mute for the trombone.
A mute is a device that is placed in the bell of a brass instrument to alter its sound. However, when a straight mute is used with a brass instrument, the frequencies of its first impedance peaks are slightly modified, and a mistuned, extra impedance peak appears. This peak affects the instrument's playability, making some lower notes difficult or impossible to produce when playing at low dynamic levels. To understand and suppress this effect, an active mute with embedded microphone and speaker has been developed. A control loop with gain and phase shifting is used to control the damping and frequency of the extra impedance peak. The stability of the controlled system is studied and then the effect of the control on the input impedance and radiated sound of the trombone is investigated. It is shown that the playability problem results from a decrease in the input impedance magnitude at the playing frequency, caused by a trough located on the low frequency side of the extra impedance peak. When the extra impedance peak is suppressed, the playability of the note is restored. Meanwhile, when the extra impedance peak is moved in frequency, the playability problem position is shifted as well.


Long-term experimental evolution in Escherichia coli. IX. Characterization of insertion sequence-mediated mutations and rearrangements.
As part of a long-term evolution experiment, two populations of Escherichia coli B adapted to a glucose minimal medium for 10,000 generations. In both populations, multiple IS-associated mutations arose that then went to fixation. We identify the affected genetic loci and characterize the molecular events that produced nine of these mutations. All nine were IS-mediated events, including simple insertions as well as recombination between homologous elements that generated inversions and deletions. Sequencing DNA adjacent to the insertions indicates that the affected genes are involved in central metabolism (knockouts of pykF and nadR), cell wall synthesis (adjacent to the promoter of pbpA-rodA), and ill-defined functions (knockouts of hokB-sokB and yfcU). These genes are candidates for manipulation and competition experiments to determine whether the mutations were beneficial or merely hitchhiked to fixation.


Impact of food supplements on hemoglobin, iron status, and inflammation in children with moderate acute malnutrition: a 2 × 2 × 3 factorial randomized trial in Burkina Faso.
Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplements (LNSs) or corn-soy blends (CSBs) but little is known about the impact of these supplements on hemoglobin, iron status, and inflammation. The objective of this study was to investigate the impact of supplementary foods for treatment of MAM on hemoglobin, iron status, inflammation, and malaria. A randomized 2 × 2 × 3 factorial trial was conducted in Burkina Faso. Children aged 6-23 mo with MAM received 500 kcal/d as LNS or CSB, containing either dehulled soy (DS) or soy isolate (SI) and different quantities of dry skimmed milk (0%, 20% or 50% of total protein) for 12 wk. The trial was double-blind with regard to quality of soy and quantity of milk, but not matrix (CSB compared to LNS). Hemoglobin, serum ferritin (SF), serum soluble transferrin receptor (sTfR), serum C-reactive protein (CRP), serum α1-acid glycoprotein (AGP), and malaria antigens were measured at inclusion and after supplementation. Between September 2013 and August 2014, 1609 children were enrolled. Among these, 61 (3.8%) were lost to follow-up. During the 12-wk supplementation period, prevalence of anemia, low SF adjusted for inflammation (SFAI), elevated sTfR, and iron-deficiency anemia decreased by 16.9, 8.7, 12.6 and 10.5 percentage points. Children who received LNS compared to CSB had higher hemoglobin (2 g/L; 95% CI: 1, 4 g/L), SFAI (4.2 µg/L; 95% CI: 2.9, 5.5 µg/L), and CRP (0.8 mg/L; 95% CI: 0.4, 1.2 mg/L) and lower sTfR (-0.9 mg/L, 95% CI: -1.3, -0.6 mg/L) after the intervention. Replacing DS with SI or increasing milk content did not affect hemoglobin, SFAI, sTfR, or CRP. Supplementation with LNS compared to CSB led to better hemoglobin and iron status, but overall prevalence of anemia remained high. The higher concentrations of acute-phase proteins in children who received LNSs requires further investigation. This trial was registered at www.controlled-trials.com as ISRCTN42569496.


Sediment and vegetation as reservoirs of Vibrio vulnificus in the Tampa Bay Estuary and Gulf of Mexico.
The opportunistic pathogen Vibrio vulnificus occurs naturally in estuarine habitats and is readily cultured from water and oysters under warm conditions but infrequently at ambient conditions of <15°C. The presence of V. vulnificus in other habitats, such as sediments and aquatic vegetation, has been explored much less frequently. This study investigated the ecology of V. vulnificus in water by culture and quantitative PCR (qPCR) and in sediment, oysters, and aquatic vegetation by culture. V. vulnificus samples were taken from five sites around Tampa Bay, FL. Levels determined by qPCR and culture were significantly correlated (P = 0.0006; r = 0.352); however, V. vulnificus was detected significantly more frequently by qPCR (85% of all samples) compared to culture (43%). Culturable V. vulnificus bacteria were recovered most frequently from oyster samples (70%), followed by vegetation and sediment (∼50%) and water (43%). Water temperature, which ranged from 18.5 to 33.4°C, was positively correlated with V. vulnificus concentrations in all matrices but sediments. Salinity, which ranged from 1 to 35 ppt, was negatively correlated with V. vulnificus levels in water and sediments but not in other matrices. Significant interaction effects between matrix and temperature support the hypothesis that temperature affects V. vulnificus concentrations differently in different matrices and that sediment habitats may serve as seasonal reservoirs for V. vulnificus. V. vulnificus levels in vegetation have not been previously measured and reveal an additional habitat for this autochthonous estuarine bacterium.


Respiratory health of workers exposed to low levels of chromium in stainless steel production.
To determine whether occupational exposure to chromite, trivalent chromium, or hexavalent chromium causes respiratory diseases, an excess of respiratory symptoms, a decrease in pulmonary function, or signs of pneumoconiosis among workers in an integrated chain of stainless steel production. This cross sectional study was carried out in 1993 and the inclusion criterion was a minimum of eight years of employment in the same production department. A self administered questionnaire was collected, and spirometry, measurement of diffusing capacity, chest radiography, and laboratory tests were carried out by a mobile research unit. There were 221 workers in the exposure groups and 95 in the control group. The average duration of employment was 18 years. No significant differences in the odds ratios (ORs) of the symptoms were found between the exposure and the control groups. In a logistic regression analysis age and smoking significantly explained the occurrence of most of the respiratory symptoms. The smokers in the chromite group had significantly lower forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and diffusing capacity than the corresponding values of the control group. The analysis of variance between study groups, smoking, and exposure time, without modelling for interactions, showed that the chromite group had lower values for FVC, FEV1, and diffusing capacity than the other groups. The occurrence of small opacities was more frequent on the chest radiographs of the workers in the chromite group. An average exposure time of 18 years in ferrochromium and stainless steel production and exposure to dusts containing low concentrations of hexavalent or trivalent chromium do not lead to any respiratory changes detectable by lung function tests or radiography nor to any increase in symptoms of respiratory diseases. The lung function values were lower and the occurrence of radiological findings was more frequent among the workers from the chromite mine than among the controls. The difference was partly caused by differences in age and smoking habits, but evidently also partly by higher exposures more than two decades ago or by the fibrous components of the dust.


Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA. SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004). As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.


Three-dimensional reconstruction of a recombinant influenza virus ribonucleoprotein particle.
A three-dimensional structural model of an influenza virus ribonucleoprotein particle reconstituted in vivo from recombinant proteins and a model genomic vRNA has been generated by electron microscopy. It shows a circular shape and contains nine nucleoprotein monomers, two of which are connected with the polymerase complex. The nucleoprotein monomers show a curvature that may be responsible for the formation of helical structures in the full-size viral ribonucleoproteins. The monomers show distinct contact boundaries at the two sides of the particle, suggesting that the genomic RNA may be located in association with the nucleoprotein at the base of the ribonucleoprotein complex. Sections of the three-dimensional model show a trilobular morphology in the polymerase complex that is consistent with the presence of its three subunits.


Wasted Food, Wasted Nutrients: Nutrient Loss from Wasted Food in the United States and Comparison to Gaps in Dietary Intake.
Previous research has estimated that wasted food in the United States contains between 1,249 and 1,400 kcal per capita per day, but little is known about amounts of other nutrients embedded in the 31% to 40% of food that is wasted. This research aimed to calculate the nutritional value of food wasted at the retail and consumer levels in the US food supply, and contextualize the amount of nutrient loss in terms of gaps between current and recommended intakes and estimated food recovery potential. Data from the National Nutrient Database for Standard Reference were used to calculate the nutritional value of retail- and consumer-level waste of 213 commodities in the US Department of Agriculture Loss-Adjusted Food Availability data series for 27 nutrients in 2012. Food wasted at the retail and consumer levels of the US food supply in 2012 contained 1,217 kcal, 33 g protein, 5.9 g dietary fiber, 1.7 μg vitamin D, 286 mg calcium, and 880 mg potassium per capita per day. Using dietary fiber as an example, 5.9 g dietary fiber is 23% of the Recommended Dietary Allowance for women. This is equivalent to the fiber Recommended Dietary Allowance for 74 million adult women. Adult women in 2012 underconsumed dietary fiber by 8.9 g/day, and the amount of wasted fiber is equivalent to this gap for 206.6 million adult women. This was the first study to document the loss of nutrients from wasted food in the US food supply, to our knowledge. Although only a portion of discarded food can realistically be made available for human consumption, efforts to redistribute surplus foods where appropriate and prevent food waste in the first place could increase the availability of nutrients for Americans, while saving money and natural resources.


Neurorestorative effect of urinary bladder matrix-mediated neural stem cell transplantation following traumatic brain injury in rats.
Traumatic brain injury (TBI) is a leading cause of cell death and disability among young adults and lacks a successful therapeutic strategy. The multiphasic injuries of TBI severely limit the success of conventional pharmacological approaches. Recent successes with transplantation of stem cells in bioactive scaffolds in other injury paradigms provide new hope for the treatment of TBI. In this study, we transplanted neural stem cells (0.5x10(5) cells/µl) cultured in a bioactive scaffold derived from porcine urinary bladder matrix (UBM; 4 injection sites, 2.5µl each) into the rat brain following controlled cortical impact (CCI, velocity, 4.0 m/sec; duration, 0.5 sec; depth, 3.2mm). We evaluated the effectiveness of this strategy to combat the loss of motor, memory and cognitive faculties. Before transplantation, compatibility experiments showed that UBM was able to support extended proliferation and differentiation of neural stem cells. Together with its reported anti-inflammatory properties and rapid degradation characteristics in vivo, UBM emerged to be an ideal scaffold. The transplants reduced neuron/tissue loss and white matter injury, and also significantly ameliorated motor, memory, and cognitive impairments. Furthermore, exposure to UBM alone was sufficient to decrease the loss of sensorimotor skills from TBI (examined 3-28 days post-CCI). However, only UBMs that contained proliferating neural stem cells helped attenuate memory and cognitive impairments (examined 26-28 days post-CCI). In summary, these results demonstrate the therapeutic efficacy of stem cells in bioactive scaffolds against TBI and show promise for translation into future clinical use.


Outcome after hemorrhage following Gamma Knife surgery for cerebral arteriovenous malformations.
Although the effects of Gamma Knife surgery (GKS) on the risk of hemorrhage are poorly understood, a certain subset of patients does suffer bleeding after GKS. This study was undertaken to analyze the outcome of patients sustaining hemorrhage after GKS; it is the most feared complication of radiosurgical management of cerebral arteriovenous malformations (AVMs). Between May 1997 and June 2006, 494 cerebral AVMs in 489 patients were treated using a Leksell Gamma Knife Model B, and follow-up evaluations were conducted until June 2007 at the All India Institute of Medical Sciences in New Delhi. Fourteen patients who sustained a hemorrhage after GKS formed the study group. In most of these patients conservative management was chosen. The mortality rate was 0% and there was a 7% risk of sustaining a severe deficit following rebleeding after GKS. None of the patients sustained rebleeding after complete obliteration. Patients with Spetzler-Martin Grade III or less had increased chances of hemorrhage after GKS (p < 0.002). The presence of deep venous drainage, aneurysm, venous hypertension, or periventricular location on angiography was common in patients with hemorrhage after GKS. The risk of hemorrhage that remains following GKS for cerebral AVMs is highest in the 1st year after treatment. The present study showed a relatively good outcome even in cases with hemorrhage following GKS, with no deaths and minimal morbidity, further substantiating the safety and efficacy of the procedure.


Pneumococcal disease burden, clinical presentations and vaccine coverage in the Jamaican population.
Pneumococcal serotypes circulating in any population vary over time and between countries and impacts the effectiveness of pneumococcal vaccination. This study investigated the epidemiology of pneumococcal disease in Jamaica. Streptococcus pneumoniae isolates (n= 349) along with demographic and clinical information were collected from patients presenting at the 4 major hospitals in Jamaica over a 2-year period. Serotyping was done using latex agglutination tests and the Quellung reaction assay. Invasive pneumococcal disease (IPD) incidence was 45.4/100,000 in children under 5 yrs and 16.3/100,000 in adults over 65 yrs. Thirteen serogroups were identified among the 120 isolates subjected to grouping; the most common being serogroups: 19 (22/120,18.3%), 6 (20/120,16.7%), 14 (20/120,16.7%), 23 (18/120,15.0%), 3 (11/120,9.2%) and nontypeable (8/120,2.3%). The estimated vaccine coverage rates for the PCV7 and PCV13 vaccines in children less than 5 yrs were 82.5% and 88.7% respectively. The 23-valent PPV23 provided 100% coverage rate in adults over 65 yrs and 82.9% coverage rate for the entire population. Pneumococcal vaccine coverage rates in Jamaica are comparable to those reported in certain developed countries and higher than in other developing countries. The high incidence of IPD in the paediatric population indicates that routine vaccination would be beneficial.


Malnutrition is associated with dynamic physical performance.
Malnutrition and poor physical performance are both conditions that increase in prevalence with age; however, their interrelation in a clinically relevant population has not been thoroughly studied. This study aimed to determine the strength of the association between malnutrition and measures of both static and dynamic physical performance in a cohort of geriatric outpatients. This cross-sectional study included 286 older adults (mean age 81.8, SD 7.2 years, and 40.6% male) who were referred to geriatric outpatient mobility clinics. The presence of malnutrition was determined using the Short Nutritional Assessment Questionnaire (SNAQ, cut-off ≥ 2 points). Measures of dynamic physical performance included timed up and go (TUG), 4-m walk test, and chair stand test (CST). Static performance encompassed balance tests and hand grip strength (HGS). Physical performance was standardized into sex-specific Z-scores. The association between malnutrition and each individual measure of physical performance was assessed using linear regression analysis. 19.9% of the cohort was identified as malnourished. Malnutrition was most strongly associated with CST and gait speed; less strong but significant associations were found between malnutrition and TUG. There was no significant association between malnutrition and HGS or balance. Physical performance was associated with malnutrition, specifically, dynamic rather than static measures. This may reflect muscle power being more impacted by nutritional status than muscle strength; however, this needs to be further addressed. Malnutrition is associated with dynamic physical performance in geriatric outpatients, which should inform diagnosis and treatment/prevention strategies.


Oral health and health-related quality of life in type 2 diabetic patients and non-diabetic controls.
The aim of the present study was to identify factors in oral health and also diabetes-related and socio-economic components that could be associated with the subject's health-related quality of life (HRQL). One-hundred-and-two randomly sampled type 2 diabetic and 102 age-matched and gender-matched non-diabetic subjects from the same residential area were studied cross-sectionally using the SF-36 questionnaire. Although the HRQL profiles were similar in nature, the control subjects indicated a more favorable health status in their HRQL scores than did type 2 diabetic subjects. Certain oral health factors contributed to deterioration of the patient's HRQL. Multiple regression analyses including both groups were used to determine variables explaining variance in the different HRQL domains. Dissatisfaction with teeth and mouth, feeling of dry mouth and poor financial status contributed to about one-fourth of the explanation of the variance in all health domains. Having diabetes played an important role in the domains Physical Functioning, Role functioning--Physical, General Health, and Social Functioning. Age was important for Physical Functioning and Role functioning--Physical. Our study indicates that different factors may be associated with impaired HRQL, especially among type 2 diabetic subjects, although only a partial understanding of its relation to oral health could be demonstrated.


Postoperative MRI localisation of electrodes and clinical efficacy of pallidal deep brain stimulation in cervical dystonia.
Pallidal deep brain stimulation (DBS) has been shown to be effective in cervical dystonia (CD) with an improvement of about 50-60% in the Toronto Western Spasmodic Torticollis Rating (TWSTR) Scale. However, predictive factors for the efficacy of DBS in CD are missing with the anatomical location of the electrodes being one of the most important potential predictive factors. In the present blinded observational study we correlated the anatomical localisation of DBS contacts with the relative clinical improvement (CI %) in the TWSTR as achieved by DBS at different pallidal contacts in 20 patients with CD. Localisations of DBS contacts were derived from postoperative MRI-data following anatomical normalisation into the standard Montreal Neurological Institute stereotactic space. The CIs following 76 bilateral test stimulations of 24 h were mapped to stereotactic coordinates of the corresponding bilateral 152 active contacts and were allocated to low CI (<30%; n=74), intermediate CI (≥30%; <60%; n=52) or high CI (≥60%; n=26). Euclidean distances between contacts and the centroid differed between the three clusters (p<0.001) indicating different anatomical variances between clusters. The Euclidean distances between contacts and the centroid of the cluster with high CIs correlated with the individual level of CIs (r=-0.61; p<0.0001). This relationship was best fitted with an exponential regression curve (r(2)=0.41). Our data show that the clinical effect of pallidal DBS on CD displays an exponential decay over anatomical distance from an optimised target localisation within a subregion of the internal pallidum. The results will allow a comparison of future DBS studies with postoperative MRI by verifying optimised (for instance pallidal) targeting in DBS-treated patients.


Quantum integrability for three-point functions of maximally supersymmetric Yang-Mills theory.
Quantum corrections to three-point functions of scalar single trace operators in planar N=4 Super-Yang-Mills theory are studied using integrability. At one loop, we find new algebraic structures that not only govern all two-loop corrections to the mixing of the operators but also automatically incorporate all one-loop diagrams correcting the tree-level Wick contractions. Speculations about possible extensions of our construction to all loop orders are given. We also match our results with the strong coupling predictions in the classical (Frolov-Tseytlin) limit.


Complete remission of a case of hepatocellular carcinoma with tumor invasion in inferior vena cava and with pulmonary metastasis successfully treated with repeated arterial infusion chemotherapy.
We report the case of a patient having hepatocellular carcinoma with tumor invasion to the inferior vena cava and with multiple pulmonary metastases who was treated with repeated one-shot administration of epirubicin, cisplatin, and mitomycin C by hepatic artery and bronchial artery, which led to complete remission. A 72-year-old woman was diagnosed with infiltrative hepatocellular carcinoma with Vv3, multiple intrahepatic metastases, and multiple pulmonary metastases associated with compensated liver cirrhosis. One-shot infusion of epirubicin, cisplatin, and mitomycin C was performed through proper hepatic artery and bronchial artery for twice at eight weeks of intervals. Pulmonary metastases disappeared and intrahepatic lesions indicated marked shrinkage leaving a scar-like lesion with decreases in tumor markers. After six months and 20 months, tumor markers indicated increasing tendency but no evident recurrence was found by computed tomography or hepatic arteriography. One-shot infusion of the same regimens through proper hepatic artery was performed and tumor markers decreased to normal levels. After 14 months of the last therapy, no evidence of recurrence has been found on image analysis or in tumor markers. This arterial infusion therapy is well tolerated for the patients with compensated liver cirrhosis and might be promising for the effective treatment of advanced hepatocellular carcinoma with pulmonary metastases.


Iodine deficiency in northern Paris area: impact on fetal thyroid mensuration.
Iodine is essential for normal fetal and neonatal development. We studied the prevalence and impact on fetal thyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation. 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4, FT3, and TSH. Fetal thyroid gland size was assessed using ultrasonography. We found evidence of widespread iodine deficiency (mean UIE, 49.8 µg/L [standard deviation, 2.11]). Iodine deficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlation with fetal thyroid gland size (rho = 0.25, P = 0.02). Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroid gland. Clinical Trials.gov NCT00162539.


Penalized estimation of the Gaussian graphical model from data with replicates.
Gaussian graphical models are usually estimated from unreplicated data. The data are, however, likely to comprise signal and noise. These two cannot be deconvoluted from unreplicated data. Pragmatically, the noise is then ignored in practice. We point out the consequences of this practice for the reconstruction of the conditional independence graph of the signal. Replicated data allow for the deconvolution of signal and noise and the reconstruction of former's conditional independence graph. Hereto we present a penalized Expectation-Maximization algorithm. The penalty parameter is chosen to maximize the F-fold cross-validated log-likelihood. Sampling schemes of the folds from replicated data are discussed. By simulation we investigate the effect of replicates on the reconstruction of the signal's conditional independence graph. Moreover, we compare the proposed method to several obvious competitors. In an application we use data from oncogenomic studies with replicates to reconstruct the gene-gene interaction networks, operationalized as conditional independence graphs. This yields a realistic portrait of the effect of ignoring other sources but sampling variation. In addition, it bears implications on the reproducibility of inferred gene-gene interaction networks reported in literature.


Colorimetric detection of trivalent chromium in aqueous solution using tartrate-capped silver nanoparticles as probe.
This study describes a simple and highly selective method for the colorimetric detection of trivalent chromium (Cr3+) using tartrate-capped silver nanoparticles (AgNPs) as probe. The addition of tartrate to the initially prepared AgNPs gives tartrate-stabilized AgNPs ascribing to the electrostatic repulsion of the highly negatively charged tartrate ions covered on the surface of AgNPs. It is found that, in the presence of Cr3+ in aqueous solution, the aggregation of tartrate-stabilized AgNPs occurs. The color of AgNPs suspension changes from yellow to pink and the surface plasmon absorption band broadens and red shifts, which could be applied for the colorimetric detection of Cr3+ in aqueous solution. The utilization of tartrate-stabilized AgNPs as probe substantially increases the selectivity and sensitivity for colorimetric detection of Cr3+. Control experiments with the addition of over 14 other metal ions, such as Pb2+, Zn2+, Cr2O7(2-), Cd2+, Co2+, Cu2+, Al3+, Ni2+, Mn2+, Ba2+, Fe3+, Ca2+, Mg2+, Sr+ do not result in a distinct change in the color or in the spectrum of the suspension, indicating that these metal ions do not interfere with the colorimetric detection of Cr3+. Under the conditions employed here, A502/A393 (ratio of absorption value at 502 nm to 393 nm) is linear with the concentration of Cr3+ within a concentration range from 0.1 to 1.17 microM with a detection limit of 0.06 microM. This study may offer a simple, rapid and sensitive approach to colorimetric detection of Cr3+ in aqueous solution.


High-fat diet-induced obesity leads to resistance to leptin-induced cardiomyocyte contractile response.
Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low- and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca(2+) properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dl/dt), Fura-2-fluorescence intensity change (DeltaFFI), and intracellular Ca(2+) decay rate (tau). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and +/-dl/dt were depressed whereas TPS and TR(90) were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, +/-dl/dt, and DeltaFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR(90). The Janus kinase 2 (JAK2) inhibitor AG490, the mitogen-activated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca(2+) concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.