[The content of radon 222Rn in deep borehole water of the Pojezierze Mazurskie terrain].
Radon 222Rn in deep borehole water of Pojezierze Mazurskie region has been quantitative determined. The measurement were performed using the alpha liquid scintillation counting method. The water samples were examined from three voivodships: Elblag, Olsztyn and Suwałki. In some cases the concentrations of 222Rn in investigated water samples exceed 11 Bq/l.


Form of selenium in selenite enrichment media for isolation of salmonellae.
Selenite-F and selenite-cystine media, commercially available for the routine isolation of salmonellae, were treated by anion exchange chromatography to separate the selenium from other components of the media. A chemical assay, based on an ascorbic acid reduction, showed that the selenium was all in the form of selenite.


[The conditions for the germination of basidiomycete spores to obtain monosporic cultures].
Spore germination conditions of Basidiomycetes in a culture have been studied. Data about influence of some mineral salts, vitamins and sources of carbon on stimulation of quantity of germinating basidiospores are presented. Optimum conditions to obtain monosporous cultures from separate germinating basidiospores are analyzed in the paper.


Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.
Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. NCT01403974; NCT01317420.


Barriers physicians face when referring patients to cardiac rehabilitation: a narrative review.
While cardiac rehabilitation (CR) has been shown to be a beneficial form of secondary prevention for patients with cardiovascular disease, barriers of referral to CR still exist for patients. Barriers that specifically make it difficult for physicians to make the referral could be worthwhile to examine. This narrative review hypothesizes that increasing awareness and education on the various aspects of CR as well as simplifying the referral process could lead to increased referral rates as they target physician-related barriers. This narrative review seeks to further understand the physician-related barriers of low CR awareness and hindering referral processes. A search in Scopus was conducted with preference for articles examining CR referral strategies used by physicians; physicians' awareness of CR programs; physicians' perceptions, beliefs, or knowledge of the benefits of CR; or physicians' experience with or understanding of the selection process of CR programs, including indications for referral. Two systematic reviews and two observational studies were selected for discussion. Three of the selected studies had findings supporting the notion that increasing physicians' awareness of CR could impact referral rates. One of the studies evaluated the perceptions that physicians and CR programs had on various referral strategies. While more study is needed to assess the actual level of knowledge and awareness physicians have regarding CR, this review supports using educational interventions as well as targeting various aspects of the referral process for improving referral rates.


Reasonability and conscientious objection in medicine: a reply to Marsh and an elaboration of the reason-giving requirement.
In this paper I defend the Reasonability View: the position that medical professionals seeking a conscientious exemption must state reasons in support of their objection and allow those reasons to be subject to evaluation. Recently, this view has been criticized by Jason Marsh as proposing a standard that is either too difficult to meet or too easy to satisfy. First, I defend the Reasonability View from this proposed dilemma. Then, I develop this view by presenting and explaining some of the central criteria it uses to assess whether a conscientious objection is proper grounds for extending an exemption to a medical practitioner.


Using CRISPR-Cas9/phosphoproteomics to identify substrates of calcium/calmodulin-dependent kinase 2δ.
Ca2+/Calmodulin-dependent protein kinase 2 (CAMK2) family proteins are involved in the regulation of cellular processes in a variety of tissues including brain, heart, liver, and kidney. One member, CAMK2δ (CAMK2D), has been proposed to be involved in vasopressin signaling in the renal collecting duct, which controls water excretion through regulation of the water channel aquaporin-2 (AQP2). To identify CAMK2D target proteins in renal collecting duct cells (mpkCCD), we deleted Camk2d and carried out LC-MS/MS-based quantitative phosphoproteomics. Specifically, we used CRISPR/Cas9 with two different guide RNAs targeting the CAMK2D catalytic domain to create multiple CAMK2D KO cell lines. AQP2 protein abundance was lower in the CAMK2D KO cells than in CAMK2D-intact controls. AQP2 phosphorylation at Ser256 and Ser269 (normalized for total AQP2) was decreased. However, trafficking of AQP2 to and from the apical plasma membrane was sustained. Large-scale quantitative phosphoproteomic analysis (TMT-labeling) in the presence of the vasopressin analog dDAVP (0.1 nM, 30 min) allowed quantification of 11,570 phosphosites of which 169 were significantly decreased, while 206 were increased in abundance in CAMK2D KO clones. These data are available for browsing or download at https://esbl.nhlbi.nih.gov/Databases/CAMK2D-proteome/. Motif analysis of the decreased phosphorylation sites revealed a target preference of -(R/K)-X-X-p(S/T)-X-(D/E), matching the motif identified in previous in vitro phosphorylation studies using recombinant CAMK2D. Thirty five of the significantly downregulated phosphorylation sites in CAMK2D KO cells had exactly this motif and are judged to be likely direct CAMK2D targets. This adds to the list of known CAMK2D target proteins found in prior reductionist studies.


Pediatric Endoscopy Quality Improvement Network Quality Standards and Indicators for Pediatric Endoscopic Procedures: A Joint NASPGHAN/ESPGHAN Guideline.
High-quality pediatric gastrointestinal procedures are performed when clinically indicated and defined by their successful performance by skilled providers in a safe, comfortable, child-oriented, and expeditious manner. The process of pediatric endoscopy begins when a plan to perform the procedure is first made and ends when all appropriate patient follow-up has occurred. Procedure-related standards and indicators developed to date for endoscopy in adults emphasize cancer screening and are thus unsuitable for pediatric medicine. With support from the North American and European Societies of Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), an international working group of the Pediatric Endoscopy Quality Improvement Network (PEnQuIN) used the methodological strategy of the Appraisal of Guidelines for REsearch and Evaluation (AGREE) II instrument to develop standards and indicators relevant for assessing the quality of endoscopic procedures. Consensus was sought via an iterative online Delphi process and finalized at an in-person conference. The quality of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. The PEnQuIN working group achieved consensus on 14 standards for pediatric endoscopic procedures, as well as 30 indicators that can be used to identify high-quality procedures. These were subcategorized into three subdomains: Preprocedural (3 standards, 7 indicators), Intraprocedural (8 standards, 18 indicators), and Postprocedural (3 standards, 5 indicators). A minimum target for the key indicator, "rate of adequate bowel preparation," was set at ≥80%. It is recommended that all facilities and individual providers performing pediatric endoscopy worldwide initiate and engage with the procedure-related standards and indicators developed by PEnQuIN to identify gaps in quality and drive improvement.


Loss of rps9 in Zebrafish Leads to p53-Dependent Anemia.
Ribosome is a vital molecular machine for protein translation in the cell. Defects in several ribosomal proteins including RPS19, RPL11 and RPS14 have been observed in two types of anemia: Diamond Blackfan Anemia and 5q- syndrome. In zebrafish, deficiency of these ribosomal proteins shows similar anemic phenotype. It remains to be determined if any other ribosome proteins are similarly involved in regulating erythropoiesis. Here we generated mutations in zebrafish rps9, a rarely studied ribosomal protein gene, and investigated its function. Analysis of this mutant demonstrates that rps9 disruption leads to impairment of erythrocyte maturation, resulting in anemia. In addition, the overall phenotype including the anemic state is p53-dependent in rps9 mutants. Furthermore, this anemic state can be partially relieved by the treatment of L-leucine, and dexamethasone, which have been previously used in rescuing the phenotype of other ribosomal protein mutants. Finally, by comparing the phenotype, we show that there are considerable differences in morphology, cytomorphology, and hemoglobin levels for four ribosomal protein mutants in zebrafish. Based on the observed difference, we suggest that the level of anemic severity correlates with the delayed status of erythrocyte maturation in zebrafish models.


Characterization of recombinant fungal phytase (phyA) expressed in tobacco leaves.
The phyA gene from Aspergillus ficuum coding for a 441-amino-acid full-length phytase was expressed in Nicotiana tabacum (tobacco) leaves. The expressed phytase was purified to homogeneity using ion-exchange column chromatography. The purified phytase was characterized biochemically and its kinetic parameters were determined. When the recombinant phytase was compared with its counterpart from Aspergillus ficuum for physical and enzymatic properties, it was found that catalytically the recombinant protein was indistinguishable from the native phytase. Except for a decrease in molecular mass, the overexpressed recombinant phytase was virtually the same as the native fungal phytase. While the temperature optima of the recombinant protein remain unchanged, the pH optima shifted from pH 5 to 4. The results are encouraging enough to open the possibility of overexpressing phyA gene from Aspergillus ficuum in other crop plants as an alternative means of commercial production of this important enzyme.


Iron-binding characterization and polysaccharide production by Klebsiella oxytoca strain isolated from mine acid drainage.
To investigate Klebsiella oxytoca strain BAS-10 growth on ferric citrate under anaerobic conditions for exopolysaccharide (EPS) production and localization on cell followed by the purification and the EPS determination of the iron-binding stability constant to EPS or biotechnological applications. Klebsiella oxytoca ferments ferric citrate under anaerobic conditions and produces a ferric hydrogel, whereas ferrous ions were formed in solution. During growth, cells precipitate and a hydrogel formation was observed: the organic material was constituted of an EPS bound to Fe(III) ions, this was found by chemical analyses of the iron species and transmission electron microscopy of the cell cultures. Iron binding to EPS was studied by cyclic voltammetric measurements, either directly on the hydrogel or in an aqueous solutions containing Fe(III)-citrate and purified Fe(III)-EPS. From the voltammetric data, the stability constant for the Fe(III)-EPS complex can be assumed to have values of approx. 10(12)-10(13). It was estimated that this is higher than for the Fe(III)-citrate complex. The production of Fe(III)-EPS under anaerobic conditions is a strategy for the strain to survive in mine drainages and other acidic conditions. This physiological feature can be used to produce large amounts of valuable Fe(III)-EPS, starting from a low cost substrate such as Fe(III)-citrate. The data herein demonstrates that an interesting metal-binding molecule can be produced as a novel catalyst for a variety of potential applications and the EPS itself is a valuable source for rhamnose purification.


Comparison between patient and surgeon perception of degenerative spine disease outcomes--a prospective blinded database study.
Few have studied the correlation between patients' and spine surgeons' perception on outcomes, or compared these with patient-reported outcome scores. Outcomes studies are increasingly important in evaluating costs and benefits to patients and surgeons, and in developing metrics for payer evaluation and health care policy-making. To compare patients' and surgeons' assessment of spine treatment outcome in a prospective blinded patient-driven spine surgery outcomes registry, and to correlate perceived outcomes ratings to validated outcomes scores. Patients filled out surveys at baseline, 3 months and 6 months postoperatively, including Visual Analog Scale (VAS), and Neck Disability Index (NDI) or Oswestry Disability Index (ODI). Outcome was rated independently by patients and surgeons on a 7-point Likert-type scale. Two-hundred and sixty-five consecutive adult patients were surgical candidates. Of these, 154 (58.1 %) opted for surgery, with 69 (44.8 %) cervical and 85 (55.2 %) lumbar patients. One hundred and thirty-five (87.7 %) had both patient and surgeon postoperative ratings. Surgeons' and patients' ratings correlated strongly (Spearman rho = 0.53, p < 0.0001, 45.9 % identical, 88.2 % +/- 1 grade). The surgeon rated outcomes were better than patients in 29.8 % and worse in 21.15 %. Patient rating correlated better with the most recent NDI/ODI and pain scores than with incremental change from baseline. In multivariate analysis, age, location (cervical vs lumbar), pain ratings, and functional scores (NDI, ODI) did not have significant impact on the discrepancy between patient and surgeon ratings. Patients' and surgeons' global outcome ratings for spinal disease correlate highly. Patients' ratings correlate better with most recent functional scores, rather than incremental change from baseline.


Ultrasonic characterisation of malignant melanoma of choroid.
An in-vitro study of wave spectral analysis in 8 enucleated eyes was conducted in order to differentiate histological subtypes of malignant melanoma. To obtain the backscattering coefficient for the tissues, we used a broadband focussed transducer with a frequency range of 7-12 MHz and a centre frequency of 10 MHz. Experimental measurement of backscattering coefficient and attenuation coefficient at various frequencies was done by substitution techniques. The backscattering coefficient, scatterer size, and root mean square velocity fluctuation were derived by the numerical method, while the attenuation coefficient at 1 MHz was derived from attenuation coefficient at different frequencies. This study revealed that backscattering coefficient and attenuation coefficient, over a frequency range of 7-12 MHz, show an increase in the spindle cell type compared to the mixed cell type of malignant melanoma. Particularly, the scatterer size was significantly higher in the spindle cell group (p = 0.013) in contrast to the mixed cell type. Spindle cells have uniform and compact histological pattern which contributes to an increase in scatterer size and root mean square velocity fluctuation. The ultrasonically obtained parameters have been shown to have a good correlation with the histology of malignant melanoma.


Possible involvement of an endogenous opioid in the antihypertensive effect of clonidine in patients with essential hypertension.
The effect of naloxone on the hypotensive and bradycardiac action of clonidine was studied in 27 hospitalized patients with uncomplicated mild-to-moderate essential hypertension. In a double-blind, crossover study, clonidine, 0.3 mg/day orally for 3 days, significantly reduced systolic and diastolic blood pressure and heart rate, whereas placebo was ineffective. Naloxone, 0.4 mg given intravenously on the third day of clonidine treatment, caused a rapid increase in blood pressure and heart rate in 14 patients (reacting group), but was ineffective in the remaining 13 patients (nonreacting group). Naloxone given during the placebo period was ineffective in all patients. Both the clonidine-induced hypotension and the rebound increase in blood pressure after cessation of clonidine were significantly greater in the reacting than in the nonreacting group. These observations suggest that release of an endogenous opioid contributes to the antihypertensive action of clonidine; this mechanism may be also involved in the discontinuation syndrome after cessation of clonidine.


Delivery of genes and fluorescent dyes into cells of the intact lens by particle bombardment.
The authors report the use of a particle bombardment technique to deliver exogenous genes and fluorescent dyes into living fibre cells in the intact lens. Gold particles were coated with plasmid DNA encoding green fluorescent protein (GFP) or the lipophilic fluorescent probes DiI and DiO. The particles were introduced into embryonic chicken or neonatal mouse lenses using a pressurized helium charge. A significant fraction of particles penetrated the capsule and came to rest in the superficial lens cortex. Over the range tested, varying the particle size or the pressure of the helium charge had little effect on the final distribution of particles within the lens. Particle bombardment was used initially to deliver DiI and DiO into the lens. Within a few hours, bombarded lenses exhibited multicolored membranous labelling of individual, elongating fibre cells. The particle bombardment technique was also used to introduce a plasmid encoding GFP. After overnight incubation, many fibre cells in the bow region expressed GFP. On close examination by confocal reflectance microscopy, each expressing cell was found to contain a gold particle lodged in its nucleus. The authors examined the fate of GFP-expressing fibre cells over a period of 1 week in organ culture. In the embryonic chicken lens, transfected fibres showed modest (approximately two-fold) elongation. In contrast, GFP-expressing mouse lens fibres underwent dramatic elongation, reaching the anterior and posterior sutures after 7 days in culture. These species differences may reflect the fact that mitosis continued at a near normal rate in the cultured mouse lens but declined precipitously in the cultured chicken lens. These results suggest that particle bombardment, in conjunction with appropriate cell culture conditions, may prove useful in visualizing the behaviour of differentiating fibre cells in the living intact lens in vitro.


Chlorogenic acid inhibits hepatocellular carcinoma in vitro and in vivo.
Curative treatment of patients with hepatocellular carcinoma (HCC) is poor. There is an urgent need to develop more effective strategies for the chemoprevention of HCC. Chlorogenic acid (CGA), a type of polyphenol present in the diet, especially from coffee, has many biological activities. Patients with viral hepatitis who drank coffee everyday experienced a reduction in the incidence of HCC. In the present study, we evaluated the effects of CGA on HCC. CGA inhibited the proliferation of HepG2 cells in vitro and the progression of HepG2 xenograft in vivo. CGA induced the inactivation of ERK1/2 and suppressed the expression of MMP-2 and MMP-9 in HepG2 xenograft tissue. These data demonstrate that CGA can prevent the progression of HCC through multiple pathways. CGA appears to be an effective chemopreventive agent for hepatocellular carcinoma.


A comparison of the health status and health care utilization patterns between foreigners and the national population in Spain: new evidence from the Spanish National Health Survey.
The increasing proportion of immigrants in Spanish society is placing pressure on the National Health Care System to accommodate the needs of this population group while keeping costs under control. In the year 2000, a law was approved in Spain according to which all people, regardless of their nationality, are entitled to use health care services under the same conditions as Spanish citizens, provided that they are registered in the local population census. However, empirical evidence about differences in health status and health care utilization between the immigrant and the Spanish population is insufficient. This paper uses the 2003 and 2006 Spanish National Health Surveys to explore the existence of inequalities in health and in the access to health services for the immigrant population living in Spain, relative to that of Spaniards. Our results show that there are different patterns in the level of health and the medical care use between the national and the foreign population in Spain: while immigrants' self-reported health relative to that of the Spanish population depends upon individual nationality, all immigrants, regardless of their nationality, seem to face barriers of entry to specialized care. Further research is needed to understand the nature of these barriers in order to design more effective health policies.


Extending oral health care services to underserved children through a school-based collaboration: Part 3--A cost analysis.
The purpose of this manuscript was to conduct a cost analysis of the Miles of Smiles Program, a collaboration between the University of Missouri-Kansas City School of Dentistry and the Olathe School District in Kansas. This preventive program was implemented to improve the access to oral health care for low income children within the school district. An inventory list and de-identified patient records were used to determine the costs associated with operating the program to serve 339 elementary school students during the 2008 to 2009 school term. Costs related to equipment, supplies and personnel were included. The costs were then compared to the amount of Medicaid reimbursement obtained for the services provided. Additionally, the cost of operating a similar program, if staffed by dental professionals rather than supervised dental hygiene students, was estimated. The cost of operating the program during the 2008 to 2009 school term was $107,515.74. The program received Medicaid reimbursement for approximately 1.5% of the total operating cost of and approximately 6.3% of the total billable services, however, challenges with submitting and billing Medicaid claims for the first time contributed to this low rate of reimbursement. If a similar program that utilized dental professionals was implemented and treated the same number of patients, the cost would be approximately $37,529.65 more due to higher expenses associated with personnel and supplies. The program is not self-sustainable based on Medicaid government-funded insurance reimbursement alone, and therefore continuous external sources of funding or a change in the program design would be necessary for long-term sustainability of the program.


Iatrogenic pneumothorax in mechanically ventilated children: Incidence, risk factors and other outcomes.
Determine prevalence, risk factors and outcomes of iatrogenic pneumothoraces (IPs) in a pediatric intensive care unit (PICU). Patients with IP (cases) and patients without IP (controls) were retrieved from a 5-year prospective cohort of 645 PICU patients who received mechanical ventilation (MV). Twenty cases and eighty controls were assessed. The overall prevalence of IP was 3%. Eleven IPs were procedure-related IP and 9 MV related. Performance of thoracic invasive procedures (odds ratio 11) was the significant IP predictor in the logistic regression analysis. IP incidence was higher within 12 hours. There were no differences between the groups concerning duration of MV, length of PICU and hospital stays. IP patients had a significantly higher mortality rate (p = 0.005). Performance of thoracic invasive procedures was strongly associated with IPs events in mechanically ventilated children. Many of these events may potentially be preventable with the implementation of quality improvement programs.


Establishing Quantifiable Guidelines for Antimicrobial α/β-Peptide Design: A Partial Least-Squares Approach to Improve Antimicrobial Activity and Reduce Mammalian Cell Toxicity.
Antimicrobial peptides (AMPs) are promising candidates to combat pathogens that are resistant to conventional antimicrobial drugs because they operate through mechanisms that involve membrane disruption. However, the use of AMPs in clinical settings has been limited, at least in part, by their susceptibility to proteolytic degradation and their lack of selectivity toward pathogenic microbes vs mammalian cells. We recently reported on the design of α- and β-peptide oligomers structurally templated upon the naturally occurring α-helical AMP aurein 1.2. These α/β-peptide oligomers are more proteolytically stable than aurein 1.2 and have several other attributes that render them attractive as alternatives to conventional AMPs. This study describes the influence of peptide physicochemical properties on the broad-spectrum activity of aurein 1.2-based α/β-peptide mimics against nine bacterial, fungal, and mammalian cell lines. We used a partial least-squares regression (PLSR)-supervised machine learning model to quantify and visualize relationships between experimentally determined physicochemical properties (e.g., hydrophobicity, charge, and helicity) and experimentally measured cell-type-specific activities of 21 peptides in a 149-member α/β-peptide library. Using this approach, we identified several peptides that were predicted to exhibit enhanced broad-spectrum selectivity, a measure that evaluates antimicrobial activity relative to mammalian cell toxicity compared to aurein 1.2. Experimental validation demonstrated high model predictive performance, and characterization of compounds with the highest broad-spectrum selectivity revealed peptide hydrophobicity, helicity, and helical rigidity to be strong predictors of broad-spectrum selectivity. The most selective peptide identified from the model prediction has more than a 13-fold improvement in broad-spectrum selectivity than that of aurein 1.2, demonstrating the ability of using PLSR models to identify quantitative structure-function relationships for nonstandard amino acid-containing peptides. Overall, this work establishes quantifiable guidelines for the rational design of helical antimicrobial α/β-peptides and identifies promising new α/β-peptides with significantly reduced mammalian toxicities and improved antifungal and antibacterial activities relative to aurein 1.2.


The altered mononuclear cell-derived cytokine response to glucose ingestion is not regulated by excess adiposity in polycystic ovary syndrome.
Excess adipose tissue is a source of inflammation. Polycystic ovary syndrome (PCOS) is a proinflammatory state and is often associated with excess abdominal adiposity (AA) alone and/or frank obesity. To determine the effect of glucose ingestion on cytokine release from mononuclear cells (MNC) in women with PCOS with and without excess AA and/or obesity. A cross-sectional study. Academic medical center. Twenty-three women with PCOS (seven normal weight with normal AA, eight normal weight with excess AA, eight obese) and 24 ovulatory controls (eight normal weight with normal AA, eight normal weight with excess AA, eight obese). Three-hour 75-g oral glucose tolerance test (OGTT). Body composition was measured by dual energy x-ray absorptiometry. Insulin sensitivity was derived from the OGTT (ISOGTT). TNFα, IL-6, and IL-1β release was measured in supernatants of cultured MNC isolated from blood samples drawn while fasting and 2 hours after glucose ingestion. Insulin sensitivity was lower in obese subjects regardless of PCOS status and in normal-weight women with PCOS compared with normal-weight controls regardless of body composition status. In response to glucose ingestion, MNC-derived TNFα, IL-6, and IL-1β release decreased in both normal-weight control groups but failed to suppress in either normal-weight PCOS group and in obese women regardless of PCOS status. For the combined groups, the cytokine responses were negatively correlated with insulin sensitivity and positively correlated with abdominal fat and androgens. Women with PCOS fail to suppress MNC-derived cytokine release in response to glucose ingestion, and this response is independent of excess adiposity. Nevertheless, a similar response is also a feature of obesity per se. Circulating MNC and excess adipose tissue are separate and distinct sources of inflammation in this population.


Incidence of seizures in pediatric cancer patients treated with imipenem/cilastatin.
Proconvulsive tendency of imipenem/cilastatin is one of its well-known side effects. Most studies report incidence rates ranging from 1.5 to 3%. There is no study on the incidence rate among children with systemic malignancies. Eighty-two patients with various malignancies who received imipenem/cilastatin 143 times for neutropenic fever between March 1994 and October 1999 in Department of Pediatric Oncology, Gazi University, were identified. Three of these patients had convulsions attributed to imipenem/cilastatin; 3.6% of the patients had seizure, or 2% of imipenem/cilastatin administrations was followed by a seizure attack.


Medical end-of-life decisions for children in the Netherlands.
Most end-of-life decision-making studies have, until now, involved either the general population or newborn infants. To assess the frequency of end-of-life decisions preceding child death and the characteristics of the decision-making process in the Netherlands. Two studies were performed. The first was a death certificate study in which all 129 physicians reporting the death of a child aged between 1 and 17 years in the period August to December 2001 received a written questionnaire; the second was an interview study in which face-to-face interviews were held with 63 physicians working in pediatric hospital departments. Some 36% of all deaths of children between the ages of 1 and 17 years during the relevant period were preceded by an end-of-life decision: 12% by a decision to refrain from potentially life-prolonging treatment; 21% by the alleviation of pain or symptoms with a possible life-shortening effect; and 2.7% by the use of drugs with the explicit intention of hastening death. The latter decision was made at the child's request in 0.7% and at the request of the family in 2% of cases. The interview study examined 76 cases of end-of-life decision making. End-of-life decisions were discussed with all 9 competent and 3 partly competent children, with the parents in all cases, with other physicians in 75 cases, and with nurses in 66 cases. While not inconsiderable, the percentage of end-of-life decisions was lower for children than for adults and newborn infants. Most children are not considered to be able to participate in the decision-making process. Decisions are generally discussed with parents and other caregivers and, if possible, with the child.


Report from Eurobiofilms 2011.
A considerable number of the world?s leading biofilm scientists are located in Denmark, and given the small size of Denmark it must to be the country with most biofilm researchers per capita! It was therefore appropriate that the Second European Biofilm Conference, Eurobiofilms 2011, was held in Copenhagen, Denmark. The conference was organized by the European Society of Clinical Microbiology and Infectious Diseases (ECSMID) Study Group on Biofilms (ESGB), and aimed to cover basic and clinical aspects of biofilms in order to encourage synergistic interdisciplinary interactions. Therefore, both basic biofilm science and clinically related biofilm science were presented at the joint keynote lectures, and the basic biofilm science symposia as well as clinically related biofilm science symposia were run in parallel. The main program was preceded by four workshops comprising: microfluid systems and confocal laser scanning microscopy; new techniques for visualization of biofilms; animal models of biofilm infections; and molecular diagnostics of biofilm bacteria. The number of attendees exceeded 300, who were from 31 countries on six continents, and more than 200 abstracts were submitted. The conference was opened by a warm welcome from Niels Høiby (University of Copenhagen, Denmark), the president of the conference.


Vampire bat control by systemic treatment of livestock with an anticoagulant.
The blood of beef cattle given single doses (1 milligram per kilogram of body weight) of diphenadione (2-diphenylacetyl-1,3-indandione) became toxic to vampire bats (Desmodus rotundus) and remained toxic for 3 days without harming the cattle. Cattle at three ranches in Mexico treated with single intraruminal injections of diphenadione experienced a reduction in vampire bat bites of 93 percent. Bioassays of milk and liver from cattle treated orally with diphenadione in the laboratory indicated that there were no residue problems.


Autoimmune disease--pathogenesis through molecular mimicry at the tripeptide level.
Increasingly it is being discovered that short segments of proteins can provoke an immune response. Sequential determinants are as important as conformational determinants. It is the thesis of this paper that a string of three amino acid residues (a tripeptide) is antigenic when it is located on a large carrier, that is, when it is part of a protein. Conceptually this has great explanatory power in understanding (a) autoimmune phenomena (b) the intriguing finding that monoclonal antibodies which are supposed to be exquisitely specific cross-react with disparate, non-homologous proteins. Clinical syndromes such as the neuropathies of myeloma, hepatitis and multiple sclerosis are discussed in the light of this concept by computer analysis of the putative antigenic sites of myelin basic protein, hepatitis B and A proteins and measles peptides.


Fracture-dislocation at C6-C7 level with Quadriplegia after Traditional Massage in a Patient with Ankylosing Spondylitis: A Case Report.
Ankylosing spinal disorders (ASD) tend to result in fractures and/or dislocations after minor trauma because of the altered biomechanical properties. The relative risk of traumatic vertebral fractures in patients with ankylosing spondylitis has been estimated as three times higher than in the general population. These spine traumas, which are located at cervical level in 81% of patients with ankylosing spondylitis, are complicated by neurological lesions in 65% of patients, due to the high inherent instability of these fractures. Traditional massage is an ancient practice in many parts of Asia. It has many benefits that are currently recognized world-wide. However, it can be dangerous and even lethal if practised without adequate knowledge and skill. We report a case of C6-C7 fracture-dislocation with complete neurology and neurogenic shock in a middle aged man with undiagnosed ankylosing spondylitis.


[Biochemical functions of RIB5 and RIB6 gene products participating in riboflavin biosynthesis in the yeast Pichia guilliermondii].
The biosynthesis of riboflavin precursor 6,7-dimethyl-8-ribityllumazine was studied in extracts of Pichia guilliermondii yeast mutants of rib5 and rib6 genotypes with impaired synthesis of proteins P1 and P2, respectively. It was shown that synthesis of 6,7-dimethyl-8-ribityllumazine took place in extracts of rib5 mutant (active P1 protein) in the presence of 2,4-dihydroxy-5-amino-6-ribitylaminopyrimidine and the compound formed from ribose-5-phosphate by extracts of rib6 mutant (active P2 protein). No lumazine was formed in extracts of rib6 mutant from pyrimidine substrate and ribose-5-phosphate preincubated with extracts of rib5 mutant. Hence, P1 protein (the product of RIB5 gene) participates in the biosynthesis of 6,7-dimethyl-8-ribityllumazine from 2,4-dihydroxy-5-amino-6-ribitylaminopyrimidine and aliphatic intermediate which is formed from ribose-5-phosphate, under the action of P2 protein (the product of RIB6 gene).


Stretchable Sponge-Based Electrochemical Biosensor for Real-Time Sensing of Cells in Three-Dimensional Culture.
For the study of cell biology, real-time information on cell physiological processes will be more accurate and closer to the in vivo condition in a three-dimensional (3D) culture system. Although most reported 3D cell culture scaffolds can better mimic the in vivo dynamic microenvironment, the real-time analysis technique is deficient or lacking. Herein, a stretchable and conductive 3D scaffold is developed to construct an electrochemical biosensor for real-time monitoring of cell release in 3D culture under stimulation of drug stimulant and mechanical force. In our design, the polyurethane sponge (PU) dipped with conductive carbon ink (CC/PU) was used as a conductive scaffold, and gold nanoparticles (nano-Au) were electrodeposited on the CC/PU (nano-Au CC/PU) to improve the electrochemical sensing performance. The prepared nano-Au CC/PU scaffold exhibits a good electrocatalytic ability to H2O2 with a linear range from 20 nM to 43 μM. Due to the great biocompatibility, HeLa cells can be cultured directly on the nano-Au CC/PU and the in situ and real-time tracking of H2O2 secretion from cells was achieved. The results demonstrate that both the drug stimulant and mechanical force can rapidly activate the release of reactive oxygen species. This study indicates that the stretchable 3D sensing scaffold has good potential for cell biology research in an in vivo-like microenvironment and can be extensively used in the fields of tissue engineering, drug screening, and pathological research.


Cyclen-based bismacrocycles for biological anion recognition. A potentiometric and NMR study of AMP, ADP and ATP nucleotide complexation.
The behaviour of two cyclen-based bismacrocycles linked by aromatic spacers as receptors of adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP) anions is explored. The two bismacrocycles differ from one another by the nature of their spacers, which are respectively 1,3-dimethylbenzene (BMC), or 2,6-dimethylpyridine (BPyC). Potentiometric investigations supported by (1)H and (31)P NMR measurements were performed over a wide pH range to characterize and understand the driving forces implicated in the supramolecular assemblies. A comparison is also carried out with the results presented in this work and those obtained previously with these two ligands and inorganic phosphates. The comparison exhibits the importance of pi-stacking capability of the organic anions in the binding and hydrogen-bonding network. For BPyC, NMR studies highlight two coordination schemes depending on the protonation of the nitrogen atom of the pyridinyl spacer, which acts in acidic media as a supplementary anchoring point.


Interfacial Modification of Ga-Substituted Li7La3Zr2O12 against Li Metal via a Simple Doping Method.
Garnet Li7La3Zr2O12 (LLZO) is considered a promising solid electrolyte for all-solid-state lithium-ion batteries due to its outstanding performance in which Ga-doped LLZO particularly exhibits excellent ionic conductivity. However, the application of Ga-doped LLZO is limited by the interfacial instability between Ga-doped LLZO and Li metal. In this study, Ga3+- and Sb5+-codoped LLZO is prepared using a conventional solid-state reaction method, and the effects of dual-doping on the crystal structure, microstructure, conductivity of LLZO, and battery cycle stability are investigated. The results demonstrate that the introduction of an appropriate amount of Sb5+ into Ga3+-stabilized cubic-phase LLZO promotes grain contact and enhances the total ionic conductivity. The optimized Li6.3Ga0.2La3Zr1.9Sb0.1O12 solid electrolyte exhibits the highest total ionic conductivity of 4.65 × 10-4 S cm-1 at room temperature. Additionally, the introduction of Sb5+ suppresses the formation of the LiGaO2 impurity phase, thereby improving the interface stability between Ga-doped LLZO and the Li metal. The assembled Li||Ga,Sb0.1-LLZO||Li symmetric cell demonstrates stable cycling for 500 h at room temperature under a current density of 0.13 mA cm-2. The Li||Ga,Sb0.1-LLZO||LiFePO4 full cell delivers a reversible capacity of about 140 mA h g-1, exhibiting negligible decay after 50 cycles. These findings suggest that the application of Ga-doped LLZO in all-solid-state lithium-ion batteries holds great promise by simply doping Zr sites with high-valence ions.


Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts.


Evaluation of kit-based loop-mediated isothermal amplification (TB-LAMP) assay in the diagnosis of tubercular lymphadenitis.
The rapid and accurate diagnosis of tubercular lymphadenitis remains a challenging task today. The World Health Organization (WHO) endorsed the LoopAMP MTBC kit (TB-LAMP) as a replacement for sputum smear microscopy in the diagnosis of pulmonary tuberculosis (PTB). However, no prospective diagnostic accuracy study of TB-LAMP for tubercular lymphadenitis in adults has been performed yet. The current study evaluated the diagnostic performance of TB-LAMP in tubercular lymphadenitis (LNTB). In a prospective observational study conducted at a tertiary care hospital in India, 90 subjects (age >18 years) suspected of LNTB were recruited consecutively and followed up for 6 months between January 2019 and December 2020. Samples were processed for microscopy, culture, GeneXpert, histopathology and TB-LAMP. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TB-LAMP against the composite reference standard (CRS) and culture were determined. TB-LAMP showed a sensitivity of 83.78 % (95 % CI, 73.76-90.47) and a specificity of 81.25 % (95 % CI, 56.99-93.41), respectively, against the CRS. The PPV and NPV were 95.38 % (95 % CI, 87.29-98.42) and 52.00 % (95 % CI, 33.50-69.97), respectively. TB-LAMP showed a sensitivity of 88.89 % (95 % CI, 71.94-96.15) and a specificity of 36.17 % (95 % CI, 23.97-50.46), respectively, against culture. The PPV and NPV were 44.44 % (95 % CI, 32-57.62) and 85 % (95 % CI, 63.96-94.76), respectively. TB-LAMP can be used instead of conventional microscopy for the diagnosis of TB in lymph node specimens at primary healthcare centres. It provides rapid and cost-effective diagnosis of LNTB in resource-limited settings due to good sensitivity and NPV.


US Attenuation for Liver Fat Quantification: An AIUM-RSNA QIBA Pulse-Echo Quantitative Ultrasound Initiative.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with an estimated prevalence of up to 30% in the general population and higher in people with type 2 diabetes. The assessment of liver fat content is essential to help identify patients with or who are at risk for NAFLD and to follow their disease over time. The American Institute of Ultrasound in Medicine-RSNA Quantitative Imaging Biomarkers Alliance Pulse-Echo Quantitative Ultrasound Initiative was formed to help develop and standardize acquisition protocols and to better understand confounding factors of US-based fat quantification. The three quantitative US parameters explored by the initiative are attenuation, backscatter coefficient, and speed of sound. The purpose of this review is to present the current state of attenuation imaging for fat quantification and to provide expert opinion on examination performance and interpretation. US attenuation methods that need further study are outlined.


Turning induced plasticity into refined adaptations during range expansion.
Robustness against environmental fluctuations within an adaptive state should preclude exploration of new adaptive states when the environment changes. Here, we study transitions between adaptive associations of feather structure and carotenoid uptake to understand how robustness and evolvability can be reconciled. We show that feather modifications induced by unfamiliar carotenoids during a range expansion are repeatedly converted into precise coadaptations of feather development and carotenoid accommodation as populations persist in a region. We find that this conversion is underlain by a uniform and coordinated increase in the sensitivity of feather development to local carotenoid uptake, indicative of cooption and modification of the homeostatic mechanism that buffers feather growth in the evolution of new adaptations. Stress-buffering mechanisms are well placed to alternate between robustness and evolvability and we suggest that this is particularly evident in adaptations that require close integration between widely fluctuating external inputs and intricate internal structures.


Heroin users' careers and perceptions of drug use: a comparison of smokers and injectors in the Mersey region.
To date few studies have compared heroin users who smoke heroin with those who inject it. In the present study a sample of 38 heroin users, half smokers and half injectors, was investigated using several drugs career indices. Results showed that users display preferences, with the use of some drugs being favoured over time. Injectors used all drugs more frequently than smokers. Although there was much variability in frequency of use the trend over the initial 3 years of use showed no increase in heroin use for either smokers or injectors. Although the majority of smokers had injected heroin there was no evidence that this group favoured injecting over time; rather the data suggested that smoking became the increasingly preferred method of consumption. Smokers were more likely than injectors to use other drugs post-heroin. Contrary to expectation, few periods of abstinence were reported by the subjects in either group.


Thermo-Mechanical Fatigue Crack Growth of RR1000.
Non-isothermal conditions during flight cycles have long led to the requirement for thermo-mechanical fatigue (TMF) evaluation of aerospace materials. However, the increased temperatures within the gas turbine engine have meant that the requirements for TMF testing now extend to disc alloys along with blade materials. As such, fatigue crack growth rates are required to be evaluated under non-isothermal conditions along with the development of a detailed understanding of related failure mechanisms. In the current work, a TMF crack growth testing method has been developed utilising induction heating and direct current potential drop techniques for polycrystalline nickel-based superalloys, such as RR1000. Results have shown that in-phase (IP) testing produces accelerated crack growth rates compared with out-of-phase (OOP) due to increased temperature at peak stress and therefore increased time dependent crack growth. The ordering of the crack growth rates is supported by detailed fractographic analysis which shows intergranular crack growth in IP test specimens, and transgranular crack growth in 90° OOP and 180° OOP tests. Isothermal tests have also been carried out for comparison of crack growth rates at the point of peak stress in the TMF cycles.


Integration of Motor Learning Principles Into Real-Time Ambulatory Voice Biofeedback and Example Implementation Via a Clinical Case Study With Vocal Fold Nodules.
Ambulatory voice biofeedback (AVB) has the potential to significantly improve voice therapy effectiveness by targeting one of the most challenging aspects of rehabilitation: carryover of desired behaviors outside of the therapy session. Although initial evidence indicates that AVB can alter vocal behavior in daily life, retention of the new behavior after biofeedback has not been demonstrated. Motor learning studies repeatedly have shown retention-related benefits when reducing feedback frequency or providing summary statistics. Therefore, novel AVB settings that are based on these concepts are developed and implemented. The underlying theoretical framework and resultant implementation of innovative AVB settings on a smartphone-based voice monitor are described. A clinical case study demonstrates the functionality of the new relative frequency feedback capabilities. With new technical capabilities, 2 aspects of feedback are directly modifiable for AVB: relative frequency and summary feedback. Although reduced-frequency AVB was associated with improved carryover of a therapeutic vocal behavior (i.e., reduced vocal intensity) in a patient post-excision of vocal fold nodules, causation cannot be assumed. Timing and frequency of AVB schedules can be manipulated to empirically assess generalization of motor learning principles to vocal behavior modification and test the clinical effectiveness of AVB with various feedback schedules.


Fluctuation in shear rate, with unaltered mean shear rate, improves brachial artery flow-mediated dilation in healthy, young men.
Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, -40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline (P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation (P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm (P = 0.619) or interaction effect (P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.


Validation of combined use of DWI and percentage signal recovery-optimized protocol of DSC-MRI in differentiation of high-grade glioma, metastasis, and lymphoma.
With conventional MRI, it is often difficult to effectively differentiate between contrast-enhancing brain tumors, including primary central nervous system lymphoma (PCNSL), high-grade glioma (HGG), and metastasis. This study aimed to assess the discrimination ability of the parameters obtained from DWI and the percentage signal recovery- (PSR-) optimized protocol of DSC-MRI between these three tumor types at an initial step. DSC-MRI using a PSR-optimized protocol (TR/TE = 1500/30 ms, flip angle = 90°, no preload) and DWI of 99 solitary enhancing tumors (60 HGGs, 24 metastases, 15 PCNSLs) were retrospectively assessed before treatment. rCBV, PSR, ADC in the tumor core and rCBV, and ADC in peritumoral edema were measured. The differences were evaluated using one-way ANOVA, and the diagnostic performance was evaluated using ROC curve analysis. PSR in the tumor core showed the best discriminating performance in differentiating these three tumor types with AUC values of 0.979 for PCNSL vs. others and 0.947 for HGG vs. metastasis. The ADC was only helpful in the tumor core and distinguishing PCNSLs from others (AUC = 0.897). Different from CBV-optimized protocols (preload, intermediate FA), PSR derived from the PSR-optimized protocol seems to be the most important parameter in the differentiation of HGGs, metastases, and PCNSLs at initial diagnosis. This property makes PSR remarkable and carries the need for comprehensive DSC-MRI protocols, which provides PSR sensitivity and CBV accuracy together, such as the preload use of the PSR-optimized protocol before the CBV-optimized protocol.


Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II--preclinical studies in a nude mouse model.
Preliminary studies have demonstrated that the Ras family and related guanosine triphosphate-dependent proteins are overactivated in malignant gliomas and that inhibition of the activation of such proteins, by blockade of their post-translational processing, reduces tumor cell growth in vitro. The current study evaluates the utility of this therapeutic strategy in vivo, using preclinical glioma model systems. We examined the efficacy against U-87 human malignant glioma cells, in both subcutaneous and intracranial nude mouse models, of selective peptidomimetic inhibitors of farnesyltransferase (FTI-276) and geranylgeranyltransferase (GGTI-297), which are involved in critical steps in the post-translational processing of Ras and related guanosine triphosphate-dependent proteins. For the subcutaneous model, 2 x 10(5) U-87 cells were implanted; after measurable tumors were detected on Day 7, animals were treated with either FTI-276, GGTI-297, or vehicle, administered by continuous infusion for 7 days. Differences in tumor volumes among the treatment groups were examined for significance using a Student's t test. For the intracranial model, 2 x 10(5) U-87 cells were implanted in the right frontal lobe and treatment was initiated on Day 7. In initial studies, animals received a 7-day course of either FTI-276, GGTI-297, or vehicle. In subsequent studies, a 28-day treatment period was used. Comparisons of survival times among treatment groups were performed using a rank-sum test. Although the two agents exhibited comparable antiproliferative activities in previous in vitro studies, an obvious difference in efficacy was apparent in this study. Whereas the geranylgeranyltransferase inhibitor failed to improve survival rates, compared with those observed for control animals, in either the subcutaneous or intracranial model, the farnesyltransferase inhibitor produced objective regression of tumor growth in the subcutaneous model and significant prolongation of survival times in the intracranial model, without apparent toxicity. In the subcutaneous model, tumor volumes for the control, GGTI-297-treated, and FTI-276-treated animals on Day 28 after implantation were 621+/-420, 107+/-104, and 18.5+/-12.7 mm3, respectively (P < 0.05). In the 7-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 27.7+/-2.9, 29.8+/-2.1, and 43.6+/-2.7 days, respectively (P < 0.001). In the 28-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 29.2+/-3.7, 28.3+/-3.9, and 58.7+/-6.2 days, respectively, with five of six animals in the latter group surviving more than 55 days after tumor implantation (P < 0.001). These studies demonstrate that farnesyltransferase inhibition is effective in diminishing the growth of human glioma cells in vivo. Evaluation of this treatment approach in clinical trials is warranted.


[The thymus micro-environment and T lymphocyte differentiation].
T cell precursors, which are derived from foetal liver and later from bone marrow, are obliged to colonize the thymus to differentiate into mature T cells. Multiple factors, secreted by cells of different types and origins, are involved in the constitution of a suitable micro-environment. Thymic epithelial cells have an endo-ectodermal origin, while the epithelial rudiment is secondarily colonized by mesodermal precursors of lymphocytes, macrophages and interdigitating cells. The migration of stem cells into the thymus is controlled by chemotactic factors which are derived from epithelial cells as well as from mature thymic medullary cells. Intra-thymic differentiation is controlled by thymic humoral factors secreted by epithelial cells. One of these factors, the "facteur thymique sérique" (FTS) (now called thymulin), has been isolated from the serum and also plays a role in the later extra-thymic maturation process. Thymic hormones are able to generate differentiation antigens on the surface of pre-thymic precursors. They have complex effects on the immunological function of post-thymic precursors. In addition to thymic hormones, other signals, such as interleukins, are necessary. Dendritic-shaped phagocytic cells of the thymic reticulum are able to secrete IL1 which is necessary for the secretion of IL2 by mature thymic medullary lymphocytes. MHC antigens on thymic epithelial cells and other factors, such as prostaglandins, also play important roles in intra-thymic T cell differentiation.


Small effective population sizes in a widespread selfing species, Lymnaea truncatula (Gastropoda: Pulmonata).
We present here a spatial and temporal population genetic survey of a common freshwater snail, also a predominantly selfing species, Lymnaea truncatula. The rate of genetic diversity loss was quantified by estimating the effective size (Ne) of the snail populations, using two different methods. A temporal survey allowed estimation of a variance effective size of the populations, and a spatial survey allowed the estimation of an inbreeding effective size, from two-locus identity disequilibria estimates. Both methods were consistent and provided low Ne values. Drift due to (i) high amounts of selfing and (ii) fluctuations in population sizes because of temporary habitats, and also selection coupled to genome-wide linkage disequilibria, could explain such reductions in Ne. The loss of genetic diversity appears to be counterbalanced only very partially by low apparent rates of gene flow.


Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity.
While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D(2)/D(3) receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [(18)F]fallypride to measure striatal dopamine D(2)/D(3) receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D(2)/D(3) receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D(2)/D(3) receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D(2)/D(3) receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D(2)/D(3) receptor availability may mediate impulsive temperament and thereby influence addiction.


Skin-contact sensor for automatic fall detection.
This paper describes an adhesive sensor system worn on the skin that automatically detects human falls. The sensor, which consists of a tri-axial accelerometer, a microcon-troller and a Bluetooth Low Energy transceiver, can be worn anywhere on a subject's torso and in any orientation. In order to distinguish easily between falls and activities of daily living (ADL), a possible fall is detected only if an impact is detected and if the subject is horizontal shortly afterwards. As an additional criterion to reduce false positives, a fall is confirmed if the user activity level several seconds after a possible fall is below a threshold. Intentional falls onto a gymnastics mat were performed by 10 volunteers (total of 297 falls); ADL were performed by 15 elderly volunteers (total of 315 ADL). The fall detection algorithm provided a sensitivity of 99% and a specificity of 100%.


Values in early-stage climate engineering: The ethical implications of "doing the research".
Calls for research on climate engineering have increased in the last two decades, but there remains widespread agreement that many climate engineering technologies (in particular, forms involving global solar radiation management) present significant ethical risks and require careful governance. However, proponents of research argue, ethical restrictions on climate engineering research should not be imposed in early-stage work like in silico modeling studies. Such studies, it is argued, do not pose risks to the public, and the knowledge gained from them is necessary for assessing the risks and benefits of climate engineering technologies. I argue that this position, which I call the "broad research-first" stance, cannot be maintained in light of the entrance of nonepistemic values in climate modeling. I analyze the roles that can be played by nonepistemic political and ethical values in the design, tuning, and interpretation of climate models. Then, I argue that, in the context of early-stage climate engineering research, the embeddedness of values will lead to value judgments that could harm stakeholder groups or impose researcher values on non-consenting populations. I conclude by calling for more robust reflection on the ethics and governance of early-stage climate engineering research.


Allosteric binding of an Ag+ ion to cerium(IV) bis-porphyrinates enhances the rotational activity of porphyrin ligands.
A series of cerium(IV) bisporphyrinate double-deckers [Ce(bbpp)2] (BBPP = 5,15-bis(4-butoxyphenyl) porphyrin dianion), [Ce(tmpp)2] (TMPP = 5,10,15,20-tetrakis(4-methoxyphenyl)-porphyrin dianion), [Ce(tfpp)2] (TFPP = 5,10,15,20-tetrakis(4-fluorophenyl)porphyrin dianion), [Ce(tmcpp)2] (TMCPP = 5,10,15,20-tetrakis(4-methoxycarbonylphenyl)porphyrin dianion), and [Ce(tmpp)(tmcpp)] was prepared. They bind three Ag+ ions to their concave porphyrin pi subunits (pi-clefts) according to a positive homotropic allosteric mechanism with Hill coefficients (nH) of 1.7-2.7. The rotation rates of the porphyrin ligands in [Ce(bbpp)2] were evaluated to be 200 s-1 at 20 degrees C (delta G++293 = 14.1 kcal mol-1) and 220 s-1 at -40 degrees C (delta G++233 = 11.0 kcal mol-1) without and with Ag+ ions, respectively. These results consistently support our unexpected finding that Ag+ binding can accelerate rotation of the porphyrin ligand. On the basis of UV-visible, 1H NMR, and resonance Raman spectral measurements, the rate enhancement of the rotational speed of the porphyrin ligands is attributed to conformational changes of the porphyrin in cerium(IV) bis-porphyrinate induced by binding of Ag+ guest ions in the clefts. This novel concept of positive homotropic allosterism is applicable to the molecular design of various supramolecular and switch-functionalized systems.


Exergaming for individuals with neurological disability: a systematic review.
Exergames have the potential to enable persons with disabilities to take part in physical activities that are of appropriate "dose-potency" and enjoyable within a relatively safe home environment. It overcomes some of the challenges regarding transportation difficulties in getting to commercial gymnasium facilities, reducing physical activities perceived as "boring" or getting access into the built environment that may be "wheelchair unfriendly". This systematic review assessed available evidence whether "exergaming" could be a feasible modality for contributing to a recommended exercise prescription according to current ACSM™ or WHO guidelines for physical activity. Strategies used to search for published articles were conducted using separate search engines (Google Scholar™, PubMed™ and Web of Science™) on cardiometabolic responses and perceived exertion during exergaming among neurologically-disabled populations possessing similar physical disabilities. Each study was categorized using the SCIRE-Pedro evidence scale. Ten of the 144 articles assessed were identified and met specific inclusion criteria. Key outcome measures included responses, such as energy expenditure, heart rate and perceived exertion. Twelve out of the 17 types of exergaming interventions met the ACSM™ or WHO recommendations of "moderate intensity" physical activity. Exergames such as Wii Jogging, Bicycling, Boxing, DDR and GameCycle reported moderate physical activity intensities. While Wii Snowboarding, Skiing and Bowling only produced light intensities. Preliminary cross-sectional evidence in this review suggested that exergames have the potential to provide moderate intensity physical activity as recommended by ACSM™ or WHO in populations with neurological disabilities. However, more research is needed to document exergaming's efficacy from longitudinal observations before definitive conclusions can be drawn. Implications for Rehabilitation Exergaming can be deployed as physical activity or exercise using commercially available game consoles for neurologically disabled individuals in the convenience of their home environment and at a relatively inexpensive cost Moderate-to-vigorous intensity exercises can be achieved during exergaming in this population of persons with neurological disabilities. Exergaming can also be engaging and enjoyable, yet achieve the recommended physical activity guidelines proposed by ACSM™ or WHO for health and fitness benefits. Exergaming as physical activity in this population is feasible for individuals with profound disabilities, since it can be used even in sitting position for wheelchair-dependent users, thus providing variability in terms of exercise options. In the context of comprehensive rehabilitation, exergaming should be viewed by the clinician as "at least as good as" (and likely more enjoyable) than traditional arm-exercise modalities, with equivalent aerobic dose-potency as "traditional" exercise in clinic or home environments.


Glucose turnover in humans in the basal state and after intravenous glucose: a comparison of two models.
This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.


Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver.
We previously showed that Dlk, a transmembrane protein containing six epidermal growth factor like repeats in its extracellular domain, is strongly expressed in hepatoblasts in murine fetal liver. Here, we examined the expression of Dlk in oval cells, which are adult hepatic progenitors, in the rat 2-acetylaminofluorene/partial hepatectomy (2AAF/PH) model. Reverse transcription polymerase chain reaction analysis showed that Dlk expression was significantly induced in the regenerating liver at day 12 and 14 after PH, when many oval cells were present in periportal areas. Immunofluoresence staining analysis revealed that Dlk(+) cells expressed oval cell markers, cytokeratin 19 (CK19) and alpha-fetoprotein, indicating that Dlk is expressed in oval cells. However, Dlk(+) cells accounted for only about 20% of total CK19(+) oval cells. Dlk(+) cells were localized more distantly from the portal vein than Dlk(-) cells, and were adjacent to mature hepatocytes, though Dlk(+) cells were surrounded by the basal membrane as other oval cells. Furthermore, at day 12 after PH, only 3% of Dlk(+) oval cells expressed Ki67, whereas about 13% of total oval cells expressed Ki67, indicating that Dlk(+) oval cells are less proliferative than Dlk(-) oval cells. Taken together, these results demonstrate that Dlk is expressed in a subpopulation of oval cells and that Dlk(+) cells represent intermediate cells between Dlk(-) oval cells and mature hepatocytes.


Association of the CTLA-4 1722TC polymorphism and systemic lupus erythematosus: a systematic review and meta analysis.
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of Tcell responses. The -1722TC polymorphism of the CTLA-4 gene may be associated with systemic lupus erythematosus (SLE) risk, but related results from previous studies have been inconsistent. We carried out a metaanalysis to assess this association more precisely. A systematic search through PubMed, Science Direct, and OVID, Iran doc, Iranmedex and SID (Scientific Information Database) databases was performed with the last search updated on December 30, 2011. The odds of ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. We evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The analyses were conducted using STATA software, version 11.0. A total of 9 independent studies on the CTLA-4 gene -1722TC polymorphism and SLE, including 1422 cases and 1417 controls were used in this meta-analysis. In the present meta-analysis, we found a significant association between -1722TC polymorphism and SLE risk in the overall analysis (TT versus OR=1.18, 95%CI 0.84-1.66, p= 0.32; TT/TC versus CC: OR = 2.06, 95%CI 1.07-3.99, p= 0.03; TT versus CC: OR = 2.32, 95%CI 1.62-3.32, p< 0.001; TC versus CC: OR = 1.99, 95%CI 1.42-2.78, p<0.001; TT versus TC: OR = 1.2, 95%CI 0.86-1.66,p= 0.28; T versus C: OR = 1.22, 95%CI 0.91-1.64,p= 0.16). In the subgroup analysis by ethnicity, -1722TC polymorphism was significantly associated with SLE risk in Asian population. This meta-analysis suggests a significant association between -1722TC polymorphism and SLE susceptibility. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.


State-of-the-art document on optimal contemporary management of cardiomyopathies.
Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence-based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021.


Anterior Communicating Artery Aneurysm Clipping: Experience at a Tertiary Care Center with Respect to Intraoperative Rupture.
The incidence of anterior communicating artery (Acomm) aneurysm is high and it is associated with high risk of rupture. The aim is to evaluate various factors (size, wall morphology, and fundus direction) associated with intraoperative rupture (IOR) of Acomm aneurysm. Retrospective cohort study. Our study includes 25 operated patients diagnosed to have ruptured Acomm aneurysm in the Department of Neurosurgery of Institute of Medical Sciences, Banaras Hindu University, Varanasi, India, between January 2016 and July 2020. Our study included all patients with ruptured Acomm aneurysm who received clipping as method of treatment. Chi-square test was used for analysis. Values with P < 0.05 were considered statistically significant. Statistical tests were done using GraphPad Prism version 8.3.0 software. None of the patients with <4 mm, 6 patients of >4-10 mm, and 2 patients of >10 mm aneurysm size experienced IOR. IOR was seen in 2 patients with smooth wall and 6 in irregular aneurysm wall. All patients with posterior, 1 patient with inferior, 2 patients with anterior, and 1 patient with superior directing aneurysm experienced IOR. Patients with bilaterally clipped A1 experienced no IOR, while in unilaterally clipped aneurysm only 2 patients experienced IOR. Glasgow outcome score was better in patients with no IOR. The factors associated with high risk of IOR are: Aneurysm size >4 mm, multilobulated or irregular aneurysm wall, posteriorly and inferiorly directed aneurysms. Patients in whom Both A1 was temporarily clipped, experienced no IOR and better outcome.


Pharyngitis: Approach to diagnosis and treatment.
To provide family physicians with an updated approach to diagnosis and treatment of pharyngitis, detailing key symptoms, methods of investigation, and a summary of common causes. The approach described is based on the authors' clinical practice and peer-reviewed literature from 1989 to 2018. Sore throat caused by pharyngitis is commonly seen in family medicine clinics and is caused by inflammation of the pharynx and surrounding tissues. Pharyngitis can be caused by viral, bacterial, or fungal infections. Viral causes are often self-limiting, while bacterial and fungal infections typically require antimicrobial therapy. Rapid antigen detection tests and throat cultures can be used with clinical findings to identify the inciting organism. Pharyngitis caused by Streptococcus pyogenes is among the most concerning owing to its associated severe complications such as acute rheumatic fever and glomerulonephritis. Hence, careful diagnosis of pharyngitis is necessary to provide targeted treatment. A thorough history is key to diagnosing pharyngitis. Rapid antigen detection tests should be reserved for concerns about antibiotic initiation. Physicians should exercise restraint in antibiotic initiation for pharyngitis, as restraint does not delay recovery or increase the risk of S pyogenes infections.


A study on the relationship between clinical features with Ki67 expression and eosinophil cells infiltration in oral squamous cell carcinoma.
Cell proliferation is one of the most critical factors in metastasis and prognosis of the malignant tumors.Recent investigations show that the eosinophil granolosytes have an important role in developing of malignant tumors. The relation between cell proliferation and eosinophilic infiltration in oral squamous cell carcinoma (OSCS) with prognosis is unclear. The aim of this study was to investigate the relationship between the Ki67 expression and eosinophilic infiltration with the clinical features on OSCC. This study was cross sectional in which 24 paraffined embeded block of OSCC selected from the Imam Khomeini hospital; cancer institute's archive. 4 micron sections were prepared and studied for Ki67 antigen immunohistochemically. The labeling index (LI: positive epithelial cells/1000 epithelial cells) of Ki67 positive cells were obtained. In each section eosinophilic cells were counted in 10 fields with 400 (HPF). The relations between the eosinophil cells and Ki67 positive cells counts with clinical features and histopathological differentiation were achived by the linear regression and spirman statistical tests. There were no any significant relationship between gender, histopathological differentiation and the number of eosinophils and Ki67 positive cells counts (p= 0.33 and p=0.73). A significant relationship between lymph node involvement and the number of eosinophils and the Ki67 positive cells counts was found (p=0.04).There was a positive relationship between the number of Ki67 positive cells and the number of eosinophil cells (p= 0.05). A significant relationship between lymph node involvement with eosinophilc cells and Ki67 positive cells counts were exist.


[Community health centers: an alternative for the health system]
Reflecting on the current reorganization of the relationship between the state and civil society, the health care field is involved in an intense debate over the organization and use of government and private health services. The authors propose an alternative, consisting of the implementation of primary health care clinics, managed by local institutions and funded by the Unified Health System. To support this proposition, they report on the current experience at the Rocinha slum in Rio de Janeiro, where a community health center was built by the neighborhood association 12 years ago and has been managed by the community since then. The hospital referral rate at the clinic, requests for laboratory tests, and use of precriptions have been considerably limited, although these services are available. These low rates are attributed to the possibility of closer social control by the community, as well as to the geographical features of the center, favoring a broader perception of both health problems and treatment. In order to provide more substantial support to the proposed centers, some suggestions are presented, like the implementation of direct agreements between the government and neighborhood associations (not allowed under current legislation) and expanding potential sources of funding for the health centers, currently restricted to government programs.


A unique RNA Fold in the RumA-RNA-cofactor ternary complex contributes to substrate selectivity and enzymatic function.
A single base (U1939) within E. coli 23S ribosomal RNA is methylated by its dedicated enzyme, RumA. The structure of RumA/RNA/S-adenosylhomocysteine uncovers the mechanism for achieving unique selectivity. The single-stranded substrate is "refolded" on the enzyme into a compact conformation with six key intra-RNA interactions. The RNA substrate contributes directly to catalysis. In addition to the target base, a second base is "flipped out" from the core loop to stack against the adenine of the cofactor S-adenosylhomocysteine. Nucleotides in permuted sequence order are stacked into the site vacated by the everted target U1939 and compensate for the energetic penalty of base eversion. The 3' hairpin segment of the RNA binds distal to the active site and provides binding energy that contributes to enhanced catalytic efficiency. Active collaboration of RNA in catalysis leads us to conclude that RumA and its substrate RNA may reflect features from the earliest RNA-protein era.


Effect of zinc on D-galactose and L-phenylalanine uptake in rat intestine in vitro.
The effect of zinc on galactose and phenylalanine uptake was studied using rat everted jejunal rings. The rings were incubated for 2 min in oxygenated Krebs-Ringer-Tris (KRT) solution. Galactose and phenylalanine uptake was reduced by zinc in a dose-dependent manner, but not in a time-dependent way. One mM Zn2+ but not 0.5 mM Zn2+ inhibited galactose transport without modifying sugar diffusion. Na(+)-dependent phenylalanine transport was reduced by 0.5 mM and 1 mM Zn2+. However, the metal did not change phenylalanine diffusion obtained in the presence of 40 mM L-methionine or Na(2+)-independent phenylalanine transport. Therefore, zinc seems to interact only with the sodium-galactose or sodium-phenylalanine cotransporters. Zinc inhibited sugar and amino acid transport in a non-competitive way, without a significant change in the affinity of the transporters for their substrates and with a Vmax decrease. The inhibitory effect of Zn2+ on galactose and phenylalanine uptake was reversed by washing intestinal rings for 5 min with KRT solution. These results suggest that zinc might exert its inhibitory action by a weak binding to chemical groups related with sodium-substrate cotransporters and located in the luminal membrane of the enterocytes.


COVID-19 and Bangladeshi health professionals: Infection status, vaccination and its immediate health consequences.
Healthcare professionals play a pivotal role in protecting and saving the lives of general people. As health workers are more likely to be infected with COVID-19, it is inevitable to safeguard them through vaccination in advance to continue healthcare services. Hence the study aimed to explore the infection and vaccination status along with immediate health consequences among these frontiers. This was a cross-sectional, web-delivered study conducted among the 300 healthcare frontiers working at COVID-19 dedicated hospitals in eight divisions of Bangladesh. The study questionnaire encompasses infection, vaccination status with dose information, and demographical and organizational information among the respondents. A multivariate logistic regression model and Chi-square test was used for the analytical exploration. Adjusted and Unadjusted Odds Ratio with a 95% confidence interval was calculated for the specified setting indicators. The study revealed that 49% of all respondents tested positive whereas 98% of them were found vaccinated of which mostly (52.3%) had their 2nddoses and 68.7% faced immediate health consequences for having the vaccination. As predictor for COVID-19 infection status, young and senior adult group (30-39 years: AOR = 2.01/0.03; 95% CI: 1.08-3.76; >50 years: AOR = 4.36/0.01; 95% CI: 1.65-11.55) and respondents who received Sinopharm as their vaccine found to have more significant positive infection history. The predictors regarding experiencing immediate health effects after vaccination, surprisingly female (AOR = 3.31/0.01; 95% CI: 1.82-6.04) health professionals of the capital city (AOR = 1.91/0.03; 95% CI: 1.06-3.46) were observed to have health consequences on vaccination. As the older female group (>50 years) in the nursing profession was found more infected with COVID-19 and a significant number of health professionals especially the age group (30-39 years) in the nursing profession experienced immediate health effects of COVID-19 vaccination, implementation of specific strategies and policies are needed to ensure the safety precaution and effective vaccination among the health professionals of Bangladesh.


Bradykinin [corrected] B1 receptor antagonism is beneficial in renal ischemia-reperfusion injury.
Previously we have demonstrated that bradykinin B1 receptor deficient mice (B1KO) were protected against renal ischemia and reperfusion injury (IRI). Here, we aimed to analyze the effect of B1 antagonism on renal IRI and to study whether B1R knockout or antagonism could modulate the renal expression of pro and anti-inflammatory molecules. To this end, mice were subjected to 45 minutes ischemia and reperfused at 4, 24, 48 and 120 hours. Wild-type mice were treated intra-peritoneally with antagonists of either B1 (R-954, 200 microg/kg) or B2 receptor (HOE140, 200 microg/kg) 30 minutes prior to ischemia. Blood samples were collected to ascertain serum creatinine level, and kidneys were harvested for gene transcript analyses by real-time PCR. Herein, B1R antagonism (R-954) was able to decrease serum creatinine levels, whereas B2R antagonism had no effect. The protection seen under B1R deletion or antagonism was associated with an increased expression of GATA-3, IL-4 and IL-10 and a decreased T-bet and IL-1beta transcription. Moreover, treatment with R-954 resulted in lower MCP-1, and higher HO-1 expression. Our results demonstrated that bradykinin B1R antagonism is beneficial in renal IRI.


Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways.
Obesity is characterized by hypertrophy and/or by the differentiation or adipogenesis of pre-existing adipocytes. In this study, we investigated the inhibitory effects of theobromine, a type of alkaloid in cocoa, on adipocyte differentiation of 3T3-L1 preadipocytes and its mechanisms of action. Theobromine inhibited the accumulation of lipid droplets, the expression of PPARγ and C/EBPα, and the mRNA expression of aP2 and leptin. The inhibition of adipogenic differentiation by theobromine occurred primarily in the early stages of differentiation. In addition, theobromine arrested the cell cycle at the G0/G1 phase and regulated the expressions of CDK2, p27, and p21. Theobromine treatment increased AMPK phosphorylation and knockdown of AMPKα1/α2 prevented the ability of theobromine to inhibit PPARγ expression in the differentiating 3T3-L1 cells. Theobromine reduced the phosphorylation of ERK and JNK. Moreover, the secretion and the mRNA level of TNF-α and IL-6 were inhibited by theobromine treatment. These data suggest that theobromine inhibits adipocyte differentiation during the early stages of adipogenesis by regulating the expression of PPARγ and C/EBPα through the AMPK and ERK/JNK signaling pathways in 3T3-L1 preadipocytes.


A step back to the future.
The coalition government announced earlier this year that £1.4 billion would be invested in apprenticeship schemes, in the hope that 100,000 new jobs could be created from the move.


CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.
Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-γ-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-γ-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation-dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT-mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses.


How serpins change their fold for better and for worse.
The serpins differ from the many other families of serine protease inhibitors in that they undergo a profound change in topology in order to entrap their target protease in an irreversible complex. The solving of the structure of this complex has now provided a video depiction of the changes involved. Cleavage of the exposed reactive centre of the serpin triggers an opening of the five-stranded A-sheet of the molecule, with insertion of the cleaved reactive loop as an additional strand in the centre of the sheet. The drastic displacement of the acyl-linked protease grossly disrupts its active site and gives an overall loss of 40% of ordered structure. This ability to provide effectively irreversible inhibition explains the selection of the serpins to control the proteolytic cascades of higher organisms. The conformational mechanism provides another advantage in its potential to modulate activity. Sequential crystallographic structures now provide clear depictions of the way antithrombin is activated on binding to the heparans of the microcirculation, and how evolution has utilized this mobile mechanism for subtle variations in activity. The complexity of these modulatory mechanisms is exemplified by heparin cofactor II, where the change in fold is seen to trigger multiple allosteric effects. The downside of the mobile mechanism of the serpins is their vulnerability to aberrant intermolecular beta-linkages, resulting in various disorders from cirrhosis to thrombosis. These provide a well defined structural prototype for the new entity of the conformational diseases, including the common dementias, as confirmed by the recent identification of the familial neuroserpin dementias.


Genome analyses substantiate male mutation bias in many species.
In many species the mutation rate is higher in males than in females, a phenomenon denoted as male mutation bias. This is often observed in animals where males produce many more sperm than females produce eggs, and is thought to result from differences in the number of replication-associated mutations accumulated in each sex. Thus, studies of male mutation bias have the capacity to reveal information about the replication-dependent or replication-independent nature of different mutations. The availability of whole genome sequences for many species, as well as for multiple individuals within a species, has opened the door to studying factors, both sequence-specific and those acting on the genome globally, that affect differences in mutation rates between males and females. Here, we assess the advantages that genomic sequences provide for studies of male mutation bias and general mutation mechanisms, discuss major challenges left unresolved, and speculate about the direction of future studies.


Characterization and protective activity of a monoclonal antibody against a capsular epitope shared by Streptococcus suis serotypes 1, 2 and 1/2.
A monoclonal antibody (mAb Z3) was produced using BALB/c mice immunized with whole cells of Streptococcus suis serotype 2 reference strain S735. Screening by dot-ELISA showed that mAb Z3, of isotype IgG2b, reacted only with reference strains and field isolates of S. suis serotypes 1, 2 and 1/2. The recognized epitope was demonstrated to be polysaccharide in nature by periodate oxidation, and located in the capsule, since mAb Z3 reacted with purified capsular material by immunoblotting and was able to stabilize the capsule as shown by electron microscopy. Further characterization indicated that mAb Z3 may react specifically with the sialic acid moiety of the capsule, a common constituent of the polysaccharidic capsular material of the three capsular types, since sialidase-treated cells did not react with mAb Z3 in immunoblotting or indirect ELISA. Purified mAb Z3 was shown to significantly increase the rate of phagocytosis of S. suis cells by porcine monocytes and to activate the clearance of bacteria from the circulation in experimentally infected mice. However, mAb Z3 only offered partial protection to mice challenged with a minimal lethal dose. Thus, even though the capsule of S. suis seems to be an important virulence factor, the epitope recognized by mAb Z3 does not appear to be involved in complete protection against infection.


General multivariate linear modeling of surface shapes using SurfStat.
Although there are many imaging studies on traditional ROI-based amygdala volumetry, there are very few studies on modeling amygdala shape variations. This paper presents a unified computational and statistical framework for modeling amygdala shape variations in a clinical population. The weighted spherical harmonic representation is used to parameterize, smooth out, and normalize amygdala surfaces. The representation is subsequently used as an input for multivariate linear models accounting for nuisance covariates such as age and brain size difference using the SurfStat package that completely avoids the complexity of specifying design matrices. The methodology has been applied for quantifying abnormal local amygdala shape variations in 22 high functioning autistic subjects.


Gingivoperiosteoplasty in 3-to-5-year-old patients with cleft lip and palate: a preliminary communication.
Closure of the alveolar cleft and the oronasal fistulas was achieved by gingivoperiosteoplasty in 26 patients with unilateral or bilateral cleft of the lip and palate. They were divided in two groups according to whether or not functional cheiloplasty was previously performed (group I comprised 12 patients, group II--14 patients). No systemic pre- or post-surgical orthodontic treatment was administered in both groups. The malocclusions before and after gingivoperiosteoplasty, the postoperative fistulas and the speech were evaluated. Prior to gingivoperiosteoplasty malocclusions were found in 16 children (4 in group I and 12 in group II). After gingivoperiosteoplasty better occlusion was achieved in 6 patients of group II and in 3 of group I. Malocclusions remained in 6 children of group II and in one of group I. Fistulas persisted in 3 children (group II--2, group 1--1). Rhinolalia was found in 7 children of group II and in none of group I. In conclusion, we think that gingivoperiosteoplasty can be performed successfully after eruption of the deciduous teeth, that is between 3 and 5 years of age. The quality of the cheiloplasty and palatoplasty performed prior to it is of great significance. Gingivoperiosteoplasty should be included as a separate surgical stage in the management of total cleft lip and palate.


Sex differences in task performance associated with attention to ambient odor.
The effects of ambient odor (pleasant, unpleasant, none); odor suggestion (present, absent); and sex of subject on mood and performance measures were explored in a 3 x 2 x 2 experimental design. A total of 40 men and 40 women performed a clerical task and a speed and accuracy task (digit deletion), filled out self-evaluations of mood, predicted performance, and rated the odor quality of the test room. Ambient odor conditions significantly affected room smell ratings, but they had no effect on performance or mood. Odor suggestion produced a significant sex-related interaction effect on the digit deletion task, irrespective of actual ambient odor. The results are discussed with respect to sex differences observed in laboratory studies and in epidemiological investigations of multiple chemical sensitivity and sick building syndrome.