Clinical Pharmacology of Citrus aurantium and Citrus sinensis for the Treatment of Anxiety.
The aim of this review is to analyze preclinical and clinical studies investigating the anxiety effects of Citrus aurantium or Citrus sinensis essential oils (EOs). The bibliographic research was made on the major scientific databases. Analysis included only articles written in English and published on peer-reviewed scientific journals describing preclinical experiments and clinical trials carried out to investigate the antianxiety effects of Citrus aurantium or Citrus sinensis EOs on anxiety disorders. Clinical studies reporting the antianxiety effects of products containing Citrus aurantium or Citrus sinensis EOs in combination with other active substances, including medicinal plants, were excluded. Nine clinical studies fulfilled the criteria adopted for analysis. Data show that Citrus aurantium or Citrus sinensis EOs produce anxiolytic effects both in preclinical experiments and in different clinical conditions. Citrus aurantium EO aromatherapy reduced anxiety level in the great part of stress conditions studied (subjects affected by chronic myeloid leukemia and preoperative patients) except for a sample of patients subjected to colonoscopy. Exposition to Citrus sinensis EO in clinical studies shows to be positive in reducing anxiety level in patients waiting for dental treatment as well as in healthy volunteers submitted to an anxiogenic situation. Overview of clinical trials conducted with Citrus aurantium or Citrus sinensis on people with anxiety showed that inhalation or oral administration of Citrus aurantium and inhalation of Citrus sinensis can exert beneficial effects on anxiety; however, because of incomplete accuracy in the reporting of methodology, further more complete clinical studies are warranted.


Synthesis and biological evaluation of the progenitor of a new class of cephalosporin analogues, with a particular focus on structure-based computational analysis.
We present the synthesis and biological evaluation of the prototype of a new class of cephalosporins, containing an additional isolated beta lactam ring with two phenyl substituents. This new compound is effective against Gram positive microorganisms, with a potency similar to that of ceftriaxone, a cephalosporin widely used in clinics and taken as a reference, and with no cytotoxicity against two different human cell lines, even at a concentration much higher than the minimal inhibitory concentration tested. Additionally, a deep computational analysis has been conducted with the aim of understanding the contribution of its moieties to the binding energy towards several penicillin-binding proteins from both Gram positive and Gram negative bacteria. All these results will help us developing derivatives of this compound with improved chemical and biological properties, such as a broader spectrum of action and/or an increased affinity towards their molecular targets.


Bone morphogenetic proteins and spinal fusion.
Bone morphogenetic proteins (BMPs) have increasingly become a focus of research in the laboratory, with animal models, and in human clinical trials for the treatment of spinal disorders. Basic science research has elucidated the putative mechanism of action of BMPs, and the efficacy of BMPs in inducing bone formation has been evaluated in multiple animal models of anterior and posterior spinal fusion. Not only has BMP been shown to improve the quality and amount of bone formation when used as a supplement to autograft, it has also been shown to promote superior fusion in the absence of autograft, even in high-risk fusion models involving the use of nicotine or nonsteroidal antiinflammatory agents. Both completed and ongoing clinical trials have demonstrated the efficacy of recombinant BMP, leading to the first BMP product being approved for clinical use earlier this year. Animal models and clinical trials have also been used to evaluate the safety of BMPs. Although few complications have been reported, BMPs can induce heterotopic bone formation, especially when placed adjacent to exposed neural elements. Potentially more serious, antibody formation has been seen in up to 38% of patients in some clinical trials. No clinical sequelae have been reported despite the development of antibodies against BMP, a naturally occurring human protein implicated in processes other than osteoinduction. The future directions of biological manipulation of the osteoinduction process include further understanding of the interactions of the BMP subtypes, the interactions of BMP with its receptors, and exploring other molecules capable of osteoinduction.


Cardiovascular disease prevention: Community Based Asset Mapping within religious networks in a rural Sub-Saharan African neighbourhood.
Prevalence of conditions which raise cardiovascular risk, such as hypertension and type 2 diabetes are seeing a dramatic rise in Sub Saharan Africa. A large proportion of these cases remain undiagnosed and there is limited resource to provide patients with self-management support and education once diagnosed. This study aimed to identify and catalogue community-based assets for the purposes of developing and deploying a screening and education programme for cardiometabolic risk factors (diabetes and hypertension) within religious organisations in a local community in a rural Ghanaian context. We utilised a community-based form of participatory research made up of a number of different components including community-based asset mapping and stakeholder consultation, supplemented by 18 in-depth interviews and 10 focus groups with n = 115 service users, to map existing assets with relevance to cardiometabolic health in this setting and context. Thematic analysis of interview and focus group data was performed to identify themes related to successful implementation of health screening. Two stakeholder workshops with local healthcare professionals, faith leaders and health policy makers were delivered to co-produced a prioritised list of recommendations and 'asset map' to aid deployment of mass screening within faith organisations in this context. The findings of this research highlight a number of 'hidden' community assets and motivational mechanisms at an individual, community and institutional levels; these have informed a list of recommendations which have been co-developed with the stakeholder group and local community to support the development of effective screening strategies for cardiometabolic conditions within faith organisations in this context. We have identified key mechanisms and assets which would support a sustainable screening approach designed to engage an underserved community at high CVD risk to promote general community health and well-being.


The cure: design and evaluation of a crowdsourcing game for gene selection for breast cancer survival prediction.
Molecular signatures for predicting breast cancer prognosis could greatly improve care through personalization of treatment. Computational analyses of genome-wide expression datasets have identified such signatures, but these signatures leave much to be desired in terms of accuracy, reproducibility, and biological interpretability. Methods that take advantage of structured prior knowledge (eg, protein interaction networks) show promise in helping to define better signatures, but most knowledge remains unstructured. Crowdsourcing via scientific discovery games is an emerging methodology that has the potential to tap into human intelligence at scales and in modes unheard of before. The main objective of this study was to test the hypothesis that knowledge linking expression patterns of specific genes to breast cancer outcomes could be captured from players of an open, Web-based game. We envisioned capturing knowledge both from the player's prior experience and from their ability to interpret text related to candidate genes presented to them in the context of the game. We developed and evaluated an online game called The Cure that captured information from players regarding genes for use as predictors of breast cancer survival. Information gathered from game play was aggregated using a voting approach, and used to create rankings of genes. The top genes from these rankings were evaluated using annotation enrichment analysis, comparison to prior predictor gene sets, and by using them to train and test machine learning systems for predicting 10 year survival. Between its launch in September 2012 and September 2013, The Cure attracted more than 1000 registered players, who collectively played nearly 10,000 games. Gene sets assembled through aggregation of the collected data showed significant enrichment for genes known to be related to key concepts such as cancer, disease progression, and recurrence. In terms of the predictive accuracy of models trained using this information, these gene sets provided comparable performance to gene sets generated using other methods, including those used in commercial tests. The Cure is available on the Internet. The principal contribution of this work is to show that crowdsourcing games can be developed as a means to address problems involving domain knowledge. While most prior work on scientific discovery games and crowdsourcing in general takes as a premise that contributors have little or no expertise, here we demonstrated a crowdsourcing system that succeeded in capturing expert knowledge.


Development and clinical application of COX-2-selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis.
Osteoarthritis (OA) and rheumatoid arthritis (RA) are among the most prevalent chronic illnesses and leading causes of disability in the United States. The clinical symptoms of OA and RA, pain and inflammation, are biologic processes mediated in part by prostanoids-prostaglandins, prostacyclin, and thromboxanes. The intermediate enzymes responsible for prostaglandin biosynthesis, cyclooxygenase (COX)-1 and COX-2, have been the target of arthritis therapy using nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). An understanding of the biochemistry and molecular pharmacology of COX enzymes has allowed for the development of agents that specifically inhibit COX-2. COX-2-selective inhibitors have efficacy in OA and RA that is similar to that of NSAIDs but with a lower potential for upper gastrointestinal injury, a serious side effect of nonselective NSAIDs. COX-2-selective inhibitors have been increasingly used in the treatment of OA and RA as well as other inflammatory arthropathies including ankylosing spondylitis and gout. Clinical trials with two currently available drugs, rofecoxib and celecoxib, have demonstrated efficacy comparable to nonselective NSAIDs but with a lower risk of gastrointestinal side effects. In general, these drugs are well tolerated in patients with aspirin-sensitive asthma. Rofecoxib is well tolerated in patients with sulfonamide sensitivities; further studies are needed to fully characterize the utility of celecoxib in these patients. Clinical experience shows that because of their improved GI safety, rofecoxib and celecoxib, and newer COX-2-selective inhibitors (valdecoxib, etoricoxib, parecoxib), represent a significant advance in the treatment of arthritis and other related inflammatory conditions.


Application of rare-earth elements in the agriculture of China and its environmental behavior in soil.
Rare-earth elements (REEs) have been used in fertilizers in the agriculture of China for about 20 years. They have been shown to be beneficial elements for plants. For example, they have improved the yield and quality for several kinds of crops. This paper reviews the current literature on studies of REEs being used as fertilizers. Some studies have focused on the effects of REEs on metabolic nutrients, photosynthesis and stress resistance of plants. Other studies have shown that the environmental behaviors of REEs in soil are dominated by their low solubility. Fluorides, carbonates, phosphates and hydroxides may form neutral complexes containing REEs with a low solubility. The amount of extraneous REEs demonstrate the following relationship: residual >> bound to organic matter > bound to Fe-Mn oxides > bound to carbonate >> exchangeable and water soluble forms. The adsorption capacity of REEs depends on the clay type and the content of amorphous and manganese oxides, whereas the desorption of REEs is usually very low. At the end of the paper, authors discuss the needs for future environmental research on REEs, which would shed new light on the effects of REEs on agriculture, environment and human health.


Frequency sixupler for millimeter-wave over fiber systems.
In this work, we propose and investigate a novel technique for the generation of millimeter-wave (mm-wave), i.e. frequency sixuplexing technique. The proposed technique is comprised of two cascaded Mach- Zehnder modulators (MZMs). The first MZM, biased at maximum transmission, is only used for even-order optical harmonic generation, and then a second MZM, biased at minimum transmission, is used for both optical carrier suppression modulation and data signal modulation. As an example, we consider an RF at 10 GHz, which carries the data signal and drives the MZMs; and an mm-wave signal at 60 GHz, i.e. a frequency sixupler, is obtained. It is found that our proposed sixupler leads to an 8-dB higher RF power at 60 GHz and a 6-dB improvement in receiver sensitivity with comparison to the conventional technique, i.e. optical carrier suppression modulation. The generated mm-wave signal is robust to fiber chromatic dispersion. The proposed technique is verified by experiments.


[Radioisotope diagnostic unit].
A diagnostic radionuclide complex is described, developed and introduced into practice in the clinical hospital, servicing 300 thousand patients. Optimal set of methods, nomenclature of instruments, system for information collection and processing as well as the tactics of application of these instruments have been developed.


Endobronchial phototoxicity of WST 09 (Tookad), a new fast-acting photosensitizer for photodynamic therapy: preclinical study in the pig.
Photodynamic therapy (PDT) has been used for many years for both palliative and curative treatment of bronchial carcinomas. However, prolonged skin phototoxicity and reduced depth of penetration has limited the widespread use of PDT. We studied the endobronchial phototoxicity of a novel photosensitizer, WST 09 (Tookad). Fourteen pairs of Large White-Landrace male piglets were given intravenous WST 09 followed by laser light illumination of the left mainstem bronchus. Different settings for light dose (fluence), fluence rate (FR), drug dose (D) and drug-light interval (DLI) were applied to each pair. Bronchial toxicity was assessed with repeat bronchoscopic photographic evaluation as well as by pathologic examination following autopsy. Animals developed no toxicity, moderate toxicity or severe toxicity. Increased toxicity was seen with increasing D and fluence and decreasing DLI, whereas no increased toxicity was seen with higher FR. PDT-related histological changes in the normal bronchus confirm the vascular effect of WST 09. Depending on the parameter settings for fluence, D and DLI, the lesions ranged from focal intramucosal ischemia to transmural infarction with subsequent acute inflammation and fibrosis. Clinically feasible parameters for drug and light dosimetry were documented. These data will be important in determining safe starting doses for human phase I/II studies.


Evolutionary dynamics of the wnt gene family: a lophotrochozoan perspective.
The wnt gene family encodes a set of secreted glycoproteins involved in key developmental processes, including cell fate specification and regulation of posterior growth (Cadigan KM, Nusse R. 1997. Wnt signaling: a common theme in animal development. Genes Dev. 11:3286-3305.; Martin BL, Kimelman D. 2009. Wnt signaling and the evolution of embryonic posterior development. Curr Biol. 19:R215-R219.). As for many other gene families, evidence for expansion and/or contraction of the wnt family is available from deuterostomes (e.g., echinoderms and vertebrates [Nusse R, Varmus HE. 1992. Wnt genes. Cell. 69:1073-1087.; Schubert M, Holland LZ, Holland ND, Jacobs DK. 2000. A phylogenetic tree of the Wnt genes based on all available full-length sequences, including five from the cephalochordate amphioxus. Mol Biol Evol. 17:1896-1903.; Croce JC, Wu SY, Byrum C, Xu R, Duloquin L, Wikramanayake AH, Gache C, McClay DR. 2006. A genome-wide survey of the evolutionarily conserved Wnt pathways in the sea urchin Strongylocentrotus purpuratus. Dev Biol. 300:121-131.]) and ecdysozoans (e.g., arthropods and nematodes [Eisenmann DM. 2005. Wnt signaling. WormBook. 1-17.; Bolognesi R, Farzana L, Fischer TD, Brown SJ. 2008. Multiple Wnt genes are required for segmentation in the short-germ embryo of Tribolium castaneum. Curr Biol. 18:1624-1629.]), but little is known from the third major bilaterian group, the lophotrochozoans (e.g., mollusks and annelids [Prud'homme B, Lartillot N, Balavoine G, Adoutte A, Vervoort M. 2002. Phylogenetic analysis of the Wnt gene family. Insights from lophotrochozoan members. Curr Biol. 12:1395.]). To obtain a more comprehensive scenario of the evolutionary dynamics of this gene family, we exhaustively mined wnt gene sequences from the whole genome assemblies of a mollusk (Lottia gigantea) and two annelids (Capitella teleta and Helobdella robusta) and examined them by phylogenetic, genetic linkage, intron-exon structure, and embryonic expression analyses. The 36 wnt genes obtained represent 11, 12, and 9 distinct wnt subfamilies in Lottia, Capitella, and Helobdella, respectively. Thus, two of the three analyzed lophotrochozoan genomes retained an almost complete ancestral complement of wnt genes emphasizing the importance and complexity of this gene family across metazoans. The genome of the leech Helobdella reflects significantly more dynamism than those of Lottia and Capitella, as judged by gene duplications and losses, branch length, and changes in genetic linkage. Finally, we performed a detailed expression analysis for all the Helobdella wnt genes during embryonic development. We find that, although the patterns show substantial overlap during early cleavage stages, each wnt gene has a unique expression pattern in the germinal plate and during tissue morphogenesis. Comparisons of the embryonic expression patterns of the duplicated wnt genes in Helobdella with their orthologs in Capitella reveal extensive regulatory diversification of the duplicated leech wnt genes.


The role of viruses in the origin of leukaemia in animals and man.
In the course of the last decade intensive research has been conducted in many laboratories on the role of viruses in the etiology of various forms of animal and human leukaemia. This research has led to the accumulation of substantial experimental material, several reviews of which have been published.This article discusses the more important data obtained from study of the etiology of leukaemia in animals and man and attempts to evaluate them and to outline the pathways of study of problems still unsolved. It also contains information on the induction of leukaemia and tumours by means of nucleic acids isolated from neoplastic tissues, and some general problems of the pathogenesis of cancer caused by viruses are discussed in this connexion.


"We sold the buffalo to pay for a brain scan" - a qualitative study of rural experiences with private mental healthcare providers in Uttar Pradesh, India.
The majority of persons with mental distress (PWMD) in India do not have access to care, and even those who seek care are pushed to attend private providers, given the weak and largely absent public mental health services framework. The aim of this study was to examine the experiences in help-seeking and with unethical health service provision among persons with mental distress in the Saharanpur and Bijnor districts of Uttar Pradesh. In-depth interviews were conducted with twenty persons with mental distress and their caregivers. Thematic analysis yielded four key findings about help-seeking: first, that it was syncretic and persistent; second, that expenditure for private care was high and often catastrophic; third, that investigations and care provided were pharmacological and predominantly irrational and excessive; and lastly, that help-seeking was abandoned. This study demonstrates that PWMD are particularly vulnerable to exploitation by private providers with illnesses that are stigmatising, poorly understood, chronic, relapsing, and disabling and that often require complex management. Responding to mental distress requires multiple empowering and interacting policy and programme initiatives that must include regulation of private and public providers, resources, and actions to strengthen public and primary mental healthcare and promotion of mental health competence in communities.


Physical activity in the prevention and management of bladder cancer.
The aim was to examine the role of physical activity in reducing the risk of bladder cancer, and in managing established disease. A systematic search of Ovid/Medline from 1996 to June 2016 coupled the term urinary bladder neoplasms (25,061 hits) with markers of physical activity (exercise, physical activity, physical education/training, athletes, and physical fitness, a total of 246,683 unique entries). Of 42 titles identified, 18 relevant abstracts were supplemented by reviewing reference lists and personal files to yield 21 articles on prevention of bladder cancer, and 8 on physical activity in disease management. Three cohort and 3 case-control studies examined occupational activity. One report found a statistically significant 40% increase in bladder cancers with a sedentary job, and 2 of 5 other reports found a non-significant trend to decreased risk with physically demanding work. Of 9 cohort and 2 case-control leisure analyses, 1 found significant benefit from physical activity, and 6 others trended to a 11-34% reduction of risk, with adverse effects in only 2 studies. After development of bladder cancer, physical activity was commonly low. However, greater physical activity decreased the risks of cystectomy and increased the quality of life following surgery. Better categorization of lifetime activity and fuller allowance for co-variates seems needed to establish conclusively that greater habitual physical activity will reduce the risk of bladder cancer. Nevertheless, an active lifestyle should be encouraged pending definitive information, because of positive trends and the more general health advantages of regular exercise.


[Effect of competitive sports on the menstrual cycle and sexuality--results of a survey of the West German team for the Olympic games in Los Angeles].
The present investigation attempts to analyse exact data on the menstruation cycle, contraception and the sexual behavior of competitive sportswomen. Since the West German participants at the Olympic Games of 1984 in Los Angeles were chosen for this investigation, the patients are unquestionably highly selected. For this reason, the results cannot claim to be representative in all respects. The objective of this study was primarily to register and to analyse the gynecological aspects of women's competitive sport, to reveal interrelationships and if appropriate to point out disadvantageous tendencies. The Olympics participants were subdivided into five different groups on the basis of the type of sport: I. take-off power/speed II. anaerobic endurance III. aerobic endurance IV. technique/dexterity V. team games. A control group was formed of middle-distance and long-distance runners. The data were analysed with regard to competitive sport and age, number of days of training and training minutes per week, menarche, duration and length as well as intensity of menstrual bleeding, menstruation symptoms, influence of menstrual bleeding on sport performance, dependence of peak performance on the menstruation cycle, sexual behavior, contraception behavior.


Adverse effects of lithium therapy in the acutely ill elderly patient.
The incidence of adverse effects of lithium therapy was compared between inpatients age 65 and older and those under the age of 65 to determine if the elderly patients were more susceptible to adverse effects. A retrospective chart review was utilized to determine the respective incidences. While there is no significant difference between the groups with regard to overall incidence of adverse effects, there is a significantly greater (p less than 0.02) incidence of moderate to severe adverse effects in the elderly. An attempt was made to determine what predisposes the elderly patient to this apparent increased sensitivity, but due to sample size, only trends could be determined. Methods of decreasing the frequency of lithium toxicity in the elderly are suggested.


Gaseous microemboli detection in a simulated pediatric CPB circuit using a novel ultrasound system.
The objective of this study was to evaluate the effect of flow rate and perfusion mode on the delivery of gaseous microemboli in a simulated pediatric cardiopulmonary bypass (CPB) circuit with an open arterial filter purge line using a novel ultrasound detection system. The circuit was primed with 450 ml fresh, heparinized bovine blood plus 200 ml Lactated Ringer's solution (total volume 650 ml, corrected Hct 25%). After the injection of 5 ml air into the venous line, an Emboli Detection and Classification (EDAC) Quantifier (Luna Innovations, Inc., Roanoke, VA) was used to simultaneously record microemboli counts at postpump, postoxygenator, and postarterial filter sites. Trials were conducted at four different flow rates (500, 750, 1,000, 1,250 ml/min) and two perfusion modes (pulsatile, nonpulsatile). Microemboli counts uniformly increased with increasing pump flow rates. In all trials, the majority of gaseous microemboli detected in the simulated pediatric CPB circuit were <20 microm in diameter. At the lowest flow rate tested (500 ml/min), all microemboli (>10 microm) were cleared from the circuit by the oxygenator and arterial filter. Clearance efficiency was decreased at higher flow rates (750-1,250 ml/min). Over 98% of microemboli detected at the postoxygenator site were <40 microm in diameter. In general, pulsatile flow delivered more microemboli to the circuit at postpump and postoxygenator sites than nonpulsatile flow. The results of this study confirmed that entrained air from the venous line could be delivered to the systemic circulation (as represented by our pediatric pseudo patient) at flow rates from 750 to 1,250 ml/min, despite the presence of an arterial filter and open arterial filter purge line. All of the microemboli distal to the arterial filter were smaller than the conventional detectable level of 40 microm.


[Interrelation between thrombin structure and its stability].
Temperature inactivation of human thrombin has been studied when finding out the mechanism of this enzyme stabilization by amino acids. Effect of a number of amino acids on thrombin in the conditions (pH) of the highest activity of proteinase has been investigated. It is established that most amino acids are characterized to more or less extent by the protective action, when hampering the temperature inactivation of the enzyme. The correspondence was mainly found between the stabilizing effect of amino acids and thrombin specificity. Thrombin is stabilized by L-arginine and DL-lysine more intensively than by other amino acids. A stabilizing effect of L-glutamic acid was shown in contrast to the action of the latter on trypsin that was obviously connected with the original structure of the active centre of thrombin, that is the availability of anionic binding centre which includes Lys68, Arg72, Arg77. High thrombin stabilization by such amino acids as phenylalanine, DL-serine, DL-methonine was an exception. It was established that amino acids stabilize thrombin with formation of a compound with the reactive centre of its molecule, like the compounds enzyme-substrate. The macrostructure stability probably depends, to a considerable extent, on the state of the enzyme reactive centre: thrombin molecules, which contain a free reactive centre, are more labile than those which reactive centre is bound to the reagent of more or less specific character. The inhibition of the autolysis process may be another manifestation of thrombin stabilization by amino acids.


Early suppression of the endocannabinoid degrading enzymes FAAH and MAGL alters locomotor development in zebrafish.
The fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes are the predominant catabolic regulators of the major endocannabinoids (eCBs) anadamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. The expression and roles of eCBs during early embryogenesis remain to be fully investigated. Here, we inhibited FAAH and MAGL in zebrafish embryos during the first 24 h of life and examined motor neuron and locomotor development at 2 and 5 days post fertilization (dpf). Application of the dual FAAH/MAGL inhibitor, JZL195 (2 µmol l-1), resulted in a reduction in primary and secondary motor neuron axonal branching. JZL195 also reduced nicotinic acetylcholine receptor (nAChR) expression at neuromuscular junctions. Application of URB597 (5 µmol l-1), a specific inhibitor of the FAAH enzyme, also decreased primary motor neuron branching but did not affect secondary motor neuron branching and nAChR expression. Interestingly, JZL184 (5 µmol l-1), a specific inhibitor of MAGL, showed no effects on motor neuron branching or nAChR expression. Co-treatment of the enzyme inhibitors with the CB1R inhibitor AM251 confirmed the involvement of CB1R in motor neuron branching. Disruption of FAAH or MAGL reduced larval swimming activity, and AM251 attenuated the JZL195- and URB597-induced locomotor changes, but not the effects of JZL184. Together, these findings indicate that inhibition of FAAH, or augmentation of AEA acting through CB1R during early development, may be responsible for locomotor deficiencies.


CCND1 and CDKN1B polymorphisms and risk of breast cancer.
Previous studies have shown alterations in the cell cycle regulatory proteins in breast carcinomas. However, the results of these studies remain controversial. Cyclin D1 (CCND1) and p27(KIP1) (CDKN1B) are two essential regulators of cell cycle progression. This study aimed to investigate the associations of CCND1 A870G and CDKN1B C79T polymorphisms with breast cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype and allelic frequencies of polymorphisms. Seventy-eight breast cancer patients and 84 age-matched healthy controls were included in the study. Frequencies of CT genotype and T allele of CDKN1B were found to be higher in breast cancer patients than in controls (p=0.013, OR: 1.514 95% CI: 1.086-2.114.15; p=0.007, OR=1.496; 95% CI: 1.111-2.014, respectively). The frequency of AA genotype of CCND1 was decreased in hormone receptor- (estrogen and progesterone receptors) negative patients with breast cancer (p<0.049, OR=0.286; 95% CI: 0.071-1.142) Even though CDKN1B polymorphism appears to be an important predictive factor for breast cancer risk and CCND1 polymorphism may be a prognostic biomarker for breast cancer, further investigations with larger study groups are needed to fully elucidate the role of CCND1 and CDKN1B polymorphisms in the development and prognosis of breast cancer.


Increased excitatory synaptic activity and local connectivity of hippocampal CA1 pyramidal cells in rats with kainate-induced epilepsy.
Formation of local excitatory circuits may contribute to epileptogenesis. We tested the hypothesis that epileptogenesis is associated with increased recurrent excitation in the hippocampal CA1 area of rats with kainate-induced epilepsy. Whole cell recordings were obtained during focal flash photolysis of caged glutamate, which served as a focal excitant to activate local pyramidal cells and to study possible connections between neurons. Kainate-treated rats with spontaneous seizures were studied months after status epilepticus and were compared with saline-injected control rats. Experiments were done in isolated CA1 minislices and in bicuculline to block GABA(A) receptors. Spontaneous excitatory postsynaptic currents (sEPSCs) were present in 42% of the CA1 pyramidal cells from controls and 62% from kainate-treated rats. The frequency of sEPSCs in the kainate group was significantly higher than that in the control group, but mean amplitude was not different. Flash photolysis of caged glutamate on the somatodendritic area of CA1 pyramidal neurons caused a burst of action potentials. Local excitatory connections between CA1 pyramidal cells were found in 4 of 48 neurons (8%) in slices from control animals, but in significantly more neurons (12 of 37; 32%) from rats with kainate-induced epilepsy exhibited interconnections (P < 0.001). Photoactivation of glutamate on recorded CA1 pyramidal cells in the kainate group sometimes caused afterdischarges, but not in controls. The kainate-treated rats with pyramidal cells that responded to photostimulaltion with repetitive EPSCs appeared to have experienced more severe seizures. These data provide new electrophysiological evidence for the formation of recurrent excitatory circuits in the CA1 area of rats with kainate-induced epilepsy.


Prospective memory in schizophrenia: A meta-analysis of comparative studies.
Impairment of prospective memory (PM) in schizophrenia has gained increasing attention. This meta-analysis systematically examined PM impairment in schizophrenia. Both English (PubMed, PsycINFO, EMBASE, and Cochrane Library) and Chinese (WanFang, Chinese Biomedical and China Journal Net databases) databases were systematically searched from their inception until August 14, 2017. Case-control studies of PM in schizophrenia were included. Standardized mean differences (SMDs) and their 95% confidence interval (CI) were calculated using the random-effects model. Twenty-nine case-control studies (n = 2492) were included in the analyses. The overall and three subtypes of PM were compared between patients with schizophrenia (n = 1284) and healthy controls (n = 1208). Compared to healthy controls, patients performed significantly poorer in overall (SMD = -1.125), time-based (SMD = -1.155), event-based (SMD = -1.068), and activity-based PM (SMD = -0.563). Subgroup analyses revealed significant differences between older and younger patients (SMD = -1.398 vs. -0.763), higher male predominance and no sex predominance (SMD = -1.679 vs. -0.800), lower and higher education level (SMD = -1.373 vs.-0.637), chronic and first-episode patients (SMD = -1.237 vs. -0.641) and between eco-valid and dual-task laboratory measurements (SMD = -1.542 vs. -0.725) regarding overall PM. Meta-regression analysis showed that higher negative symptom score was significantly associated with more severe overall PM impairment in patients (P = 0.022). In this meta-analysis the overall PM and all its subtypes, particularly the time-based PM, were significantly impaired in schizophrenia.


NAK-associated protein 1/NAP1 activates TBK1 to ensure accurate mitosis and cytokinesis.
Subcellular location and activation of Tank Binding Kinase 1 (TBK1) govern precise progression through mitosis. Either loss of activated TBK1 or its sequestration from the centrosomes causes errors in mitosis and growth defects. Yet, what regulates its recruitment and activation on the centrosomes is unknown. We identified that NAK-associated protein 1 (NAP1) is essential for mitosis, binding to and activating TBK1, which both localize to centrosomes. Loss of NAP1 causes several mitotic and cytokinetic defects due to inactivation of TBK1. Our quantitative phosphoproteomics identified numerous TBK1 substrates that are not only confined to the centrosomes but are also associated with microtubules. Substrate motifs analysis indicates that TBK1 acts upstream of other essential cell cycle kinases like Aurora and PAK kinases. We also identified NAP1 as a TBK1 substrate phosphorylating NAP1 at S318 to promote its degradation by the ubiquitin proteasomal system. These data uncover an important distinct function for the NAP1-TBK1 complex during cell division.


The Basal Forebrain and Motor Cortex Provide Convergent yet Distinct Movement-Related Inputs to the Auditory Cortex.
Cholinergic inputs to the auditory cortex from the basal forebrain (BF) are important to auditory processing and plasticity, but little is known about the organization of these synapses onto different auditory cortical neuron types, how they influence auditory responsiveness, and their activity patterns during various behaviors. Using intersectional tracing, optogenetic circuit mapping, and in vivo calcium imaging, we found that cholinergic axons arising from the caudal BF target major excitatory and inhibitory auditory cortical cell types, rapidly modulate auditory cortical tuning, and display fast movement-related activity. Furthermore, the BF and the motor cortex-another source of movement-related activity-provide convergent input onto some of the same auditory cortical neurons. Cholinergic and motor cortical afferents to the auditory cortex display distinct activity patterns and presynaptic partners, indicating that the auditory cortex integrates bottom-up cholinergic signals related to ongoing movements and arousal with top-down information concerning impending movements and motor planning.


Phase correlations at neighboring intensity critical points in gaussian random wave fields.
Phase correlations are studied for neighboring critical points of the intensity in an isotropic Gaussian random wave field. Significant correlations and anticorrelations are found that extend out to at least the fifth nearest neighbors. A theoretical interpretation of the empirical data is attempted within the framework of the phase autocorrelation and the probability-density functions of extended two-dimensional random phase fields. It is found, however, that adaptations of these theoretical models are unable to account satisfactorily, or even qualitatively, for the extensive phase correlations that are present in these fields.


Improvement of left ventricular diastolic function and left heart morphology in young women with morbid obesity six months after bariatric surgery.
Obesity contributes to left ventricular (LV) diastolic dysfunction (LVDD) and may lead to diastolic heart failure. Weight loss (WL) after bariatric surgery (BS) may influence LV morphology and function. Using echocardiography, this study assessed the effect of WL on LV diastolic function (LVDF) and LV and left atrium (LA) morphology 6 months after BS in young women with morbid obesity. Echocardiography was performed in 60 women with body mass index ≥ 40 kg/m², aged 37.1 ± ± 9.6 years prior to and 6 months after BS. In 38 patients, well-controlled arterial hypertension was present. Heart failure, coronary artery disease, atrial fibrillation and mitral stenosis were exclusion criteria. Parameters of LV and LA morphology were obtained. To evaluate LVDF, mitral peak early (E) and atrial (A) velocities, E-deceleration time (DcT), pulmonary vein S, D and A reversal velocities were measured. Peak early diastolic mitral annular velocities (E') and E/E' were assessed. Mean WL post BS was 35.7 kg (27%). A postoperative decrease in LV wall thickness, LV mass (mean 183.7 to 171.5 g, p = 0.001) and LA parameters (area, volume) were observed. LVDD was diagnosed in 3 patients prior to and in 2 of them subsequent to the procedure. An improvement in LVDF Doppler indices were noted: increased E/A, D and E' lateral, and decreased S/D and lateral E/E'. None of the patients showed increased LV filling pressure. No significant correlations between hypertension and echo-parameters were demonstrated. Six months after BS weight loss resulted in the improvement of LVDF and left heart morphology in morbidly obese women. (Cardiol J 2018; 25, 1: 97-105).


The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer´s Disease.
Alzheimer´s disease is a chronic neurodegenerative disorder affecting millions of people worldwide, characterized by a progressive decline in cognitive functions. Factors involved in the pathogenesis of Alzheimer´s disease include metabolic alterations such as insulin resistance and hyperglycemia, both of which are also hallmarks of type-2 diabetes mellitus. The accumulation of β-amyloid peptides in the brain of Alzheimer´s patients is responsible in part for the neurotoxicity underlying the loss of synaptic plasticity that triggers a cascade of events leading to cell death. A large number of studies revealed the key role of the hippocampus and cerebral cortex in the memory and learning deficits of Alzheimer´s disease. Although ample evidence suggests a link between altered insulin action, the dysregulation of glucose metabolism, and β-amyloid accumulation in animal models and humans with Alzheimer´s, no supporting evidence was available. In this article, we review the potential toxic effects of β-amyloid in the hypothalamus, a brain center involved in the control of insulin action and glucose metabolism. Furthermore, we discuss our recent studies unraveling a novel neurotoxic action of β-amyloid that perturbs hypothalamic glucoregulation, leading to increased hepatic glucose production and hyperglycemia. These findings provide evidence for a link between β-amyloid toxicity and altered glucose metabolism.


Advax, as a Co-adjuvant, in Combination with Poly(I:C) Elicits Enhanced Th1 Immune Responses and Parasite Growth-Inhibitory Antibodies Against Plasmodium Falciparum Merozoite Surface Protein-1 (PfMSP-142) in BALB/c Mice.
One of the main challenges in protein-based vaccines is the poor immunogenicity of antigens, which can be solved by the use of adjuvants. Advax is a novel microparticle polysaccharide adjuvant that in combination with antigens can induce both cellular and humoral immunity based on the intrinsic features of the antigen. It has been shown that poly(I:C) can be a suitable adjuvant for the PfMSP-142-based malaria vaccine. Advax is a suitable co-adjuvant for poly(I:C) to increase its half-life and reduce dose-dependent toxicity. To investigate whether advax alone or advax /poly(I:C) combination can enhance the immunogenicity with increased parasite inhibitory anti-PfMSP-142 antibodies in comparison to poly(I:C). Mice groups were inoculated with rPfMSP-142 alone or formulated in poly(I:C), poly(I:C)/advax, or advax. Then, humoral and cellular immune responses, the ratio of Th1/Th2 and growth inhibitory activity of induced antibodies were analyzed. Poly(I:C)/advax formulated PfMSP-142 induced higher levels of anti-PfMSP-142 IgG, IgG2a, and IgG2b antibodies relative to poly(I:C)-formulated PfMSP-142. The maximum ratio of IFN-?/IL-4 (50.13) and IgG2a/IgG1 (2.65), was induced in mice receivedadvax-formulated PfMSP-142. Besides, poly(I:C)/advax formulated PfMSP-142 induced a higher ratio of IFN-?/IL-4 (25.33) and IgG2a/IgG1 (1.89) when compared with poly(I:C) alone. Strong growth inhibitory activity was observed in antibodies induced in mice received poly(I:C)/advax-formulated PfMSP-142. These findings indicate that advax is a favorable adjuvant to be combined with poly(I:C), and this combination of adjuvants could induce Th1 immune responses and growth inhibitory antibodies against rPfMSP-142.


Early Response to Intravitreal Dexamethasone Implant Therapy in Diabetic Macular Edema May Predict Visual Outcome.
To determine whether early visual acuity response to intravitreal dexamethasone implant therapy in diabetic macular edema (DME) is associated with long-term outcome. Retrospective case series. Multicenter (8 sites) retrospective review of medical records of eyes with DME treated with 0.7 mg intravitreal dexamethasone implant and minimum 18-month follow-up. One hundred and two eyes were included. Eyes with vitreoretinal interface abnormalities or that had undergone vitrectomy were excluded. Eyes were categorized into 3 groups based on change in best-corrected visual acuity (BCVA) at 3 months (logMAR equivalence of <5-letter, 5-9-letter, or ≥10-letter gain). Visual acuity outcomes were determined for each early response group. The relationship between early (3-month) and overall change in BCVA was assessed using regression analysis. In the study population (102 eyes), <5-letter, 5- to 9-letter, and ≥10-letter BCVA improvements were seen in 44.1%, 18.6%, and 37.3% of eyes, respectively, at 3 months. Among suboptimal (<5-letter) responders at 3 months, 6.7% showed ≥10-letter gains at study conclusion compared to 29% in the robust (≥10-letter) early response group (P = .009). Change in BCVA at 3 months showed significant positive correlation with overall change in BCVA (coefficient = 0.44, P = .002). A similar proportion of eyes demonstrated suboptimal (<5-letter) and robust (≥10-letter) early response to treatment at 3 months. Eyes with a robust early response demonstrated ≥10-letter long-term gain in BCVA at a significantly higher rate compared to those with poor early response. Early treatment response directly correlated with overall change in BCVA.


[Dopaminergic processes in the striatum mediating corticoliberin effect on behavior of active and passive rats].
The action of intranasal corticotropin-releasing hormone (CRH) administration on open field behavior and striatal and hypothalamic levels of dopamine, noradrenaline and their metabolites has been studied in rats with different behavior strategies (KHA and KLA strains). In KLA rats, CRH administration resulted in increased locomotor and exploratory activity, while KHA rats demonstrated decreased that. The analysis of catecholamine levels did not detect any strain differences in hypothalamus, but in striatum the dopamine levels have been twice higher, while the metabolite levels (DOPAC and HVA) were significantly lower in KLA rats as compared to KHA rats. The CRH administration led to increased dopamine and noradrenaline levels in hypothalamus and decreased those in striatum in rats of both strains, but in KLA the decrease was more evident. It is probably a result of intensified mediator turnover induced by the neurohormone in KLA rats, as supported by a fact of increased dopamine metabolite levels in this structure.


Hereditary/familial versus sporadic prostate cancer: few indisputable genetic differences and many similar clinicopathological features.
Genetic factors and their interactions with environmental conditions and internal microenvironment influence the prostate cancer (PC) development, so that gene expression couldn't strictly occur on the basis of reductionist determinisms of DNA causality but should also conform to multifactorial and stochastic events, moreover, considering the pre-RNA alternative splicing-mediated multi-protein assemblying mechanisms. Nevertheless, after age and ethnic background, the strongest epidemiological risk factor for PC is a positive family history. However, apart from RNaseL-, ElaC2-, MSR1-genes, there are not other identified high-risk genetic variants which might be considered responsible for hereditary PC, moreover suggesting that familial PC is a genetically heterogeneous disease, many gene loci rather than a specific major susceptibility gene predisposing to it. Gene-environment interactions play a crucial role in cancer development especially when low penetrance genes, such as in case of genetic polymorphisms, are the major players. Several epidemiological studies show, in some families, a possible, either syncronous or metachronous, association of other tumors (breast, brain, gastrointestinal tumors, lymphomas) with PC, thus suggesting a common genetic background. As far as the role of androgen metabolism and androgen receptor (AR)-related genes in the development of familial PC is concerned, a small number of either guanine-guanine-cytosine (< 16) or cytosine-adenine-guanine (< 18) repeats appears to increase the AR activity, resulting in a raising PC risk. Regarding the expression of both androgen and estrogen receptor-related genes in sporadic and hereditary PC, the immunohistochemistry findings show that the percentage of AR-positive cancer cells is higher in hereditary PC than in sporadic forms, whereas the mean number of estrogen-alpha-receptor-positive stromal cells is higher in sporadic PC rather than in that hereditary. As for 5-alpha-steroid-reductase-2 gene, the dinucleotide thymine-adenine repeated 18 times on the last exon, confers an increased PC predisposition, as it is mainly shown in African-American populations. Also VDR gene, that is a component of ligand (steroid)-dependent nuclear transcription factor superfamily, shows various polymorphisms which appear to be associated with PC risk. Except an earlier age of onset, no anatomo-clinical and tumor progression peculiarities between hereditary and sporadic PC have been generally identified. Indeed, tumor progression and metastasis, both in hereditary and sporadic PC, are mainly influenced by a variety of biochemical and immune-mediated tumor microenvironmental conditions rather than by the hereditary genetic factors, thus gene expression associated with invasive ability representing a newly acquired genetic variant rather than a selection of pre-existent gene abnormalities in PC cells. It's questionable whether genetic testing of unaffected men of hereditary PC families might be actually useful. Nevertheless a suitable counselling must be proposed. Family history and/or gene profiling-guided preventive strategies for men at high risk of familial PC, range from dietary to drug measures. Cancer chemopreventive approaches may include 5-alpha-reductase inhibitors, histone deacetylase inhibitors, antioxidans, non-steroidal anti-inflammatory drugs, cholesterol-lowering statins, vitamin D analogues.


Critical incident stress debriefing in international aid workers.
Missionaries are well known to suffer the effects of stress. Patricia Miersma relates missionary stress to combat related stress. 1 Development workers too are known to be at increased risk of death whilst overseas-mostly due to traumatic incidents. Relief workers voluntarily enter high stress situations. These overseas workers are at real risk of Post Traumatic Stress Disorder (PTSD). The issue of Critical Incident Stress Debriefing (CISD, or Psychological Debriefing) has been critically examined in an editorial in the British Medical Journal.3 The first randomized, controlled study of CISD that we are aware of (for motor vehicle accident survivors) was published in 1996.4 With 54 intervention subjects, it did not demonstrate effectiveness.


Development of a Virtual Collision Sensor for Industrial Robots.
Collision detection is a fundamental issue for the safety of a robotic cell. While several common methods require specific sensors or the knowledge of the robot dynamic model, the proposed solution is constituted by a virtual collision sensor for industrial manipulators, which requires as inputs only the motor currents measured by the standard sensors that equip a manipulator and the estimated currents provided by an internal dynamic model of the robot (i.e., the one used inside its controller), whose structure, parameters and accuracy are not known. The collision detection is achieved by comparing the absolute value of the current residue with a time-varying, positive-valued threshold function, including an estimate of the model error and a bias term, corresponding to the minimum collision torque to be detected. The value of such a term, defining the sensor sensitivity, can be simply imposed as constant, or automatically customized for a specific robotic application through a learning phase and a subsequent adaptation process, to achieve a more robust and faster collision detection, as well as the avoidance of any false collision warnings, even in case of slow variations of the robot behavior. Experimental results are provided to confirm the validity of the proposed solution, which is already adopted in some industrial scenarios.


Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function.
B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS). This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement. In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS. In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.


Fine-mapping in African Americans of 8 recently discovered genetic loci for plasma lipids: the Jackson Heart Study.
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear. We genotyped 8 index single nucleotide polymorphisms (SNPs) and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared with the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, 2 with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African linkage disequilibrium patterns did not assist in narrowing association signals. We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.


The dynamics of dendritic cell: mediated innate immune regulation.
After taking up pathogen-derived antigens, dendritic cells (DCs) leave peripheral organs and migrate into sentinel lymph nodes via afferent lymphatic vessels. During this process, they undergo maturation and produce proinflammatory cytokines, which leads to efficient antigen (Ag) presentation and activation of the innate and acquired immune systems. Recent evidence indicates that DC subsets cooperate to activate the innate immune system. It is becoming clear that the total DC population is composed of a network of DC subsets with distinct functions that are critical for sensing pathogens and orchestrating immune responses.


Some endocrine aspects of affective disorders.
While frank hypothyroidism can precipitate depression, most depressed patients are euthyroid. Nevertheless, there is evidence that a resilient HPT axis favors recovery from depression. Clearly small amounts of the thyroid hormones accelerate the antidepressant action of TCA, at least in women, and usually remedy TCA failure in both men and woman. Athough TRH appears to produce mood elevation in many kinds of patients as well as in normal subjects, this property cannot presently be exploited therapeutically. The present value of TRH in psychiatry is as a psychoendocrine diagnostic tool. Used in this way it has revealed a subpopulation of depressed patients and a subpopulation of alcoholic patients who show a blunted TSH response in the absence of usual endocrinological explanations.


The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein.
Aspirin (acetylsalicylic acid) inhibits platelet prostaglandin synthesis and the ADP- and collagen-induced platelet release reaction. The mechanism of the inhibitory effect is unknown but may involve protein acetylation, since aspirin acetylates a variety of substrates, including platelet protein. We have examined the relationship between protein acetylation and aspirin's physiologic effect on platelets. Suspensions of washed human platelets were incubated at 37 degrees C with (3H)aspirin, and incorporation of radioactivity into protein was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Exposure to (acetyl-3H)aspirin but not (aromatic ring-3H)aspirin resulted in radioactive labeling of three platelet proteins, suggesting that the drug acetylates these three proteins. The acetylation of two of the proteins (located in the supernatant fraction) was not saturable, implying that these reactions may not be physiologically significant. Acetylation of the third protein, approximate mol wt 85,000 (located in the particulate fraction), saturated at an aspirin concentration of 30 muM and was complete within 20 min. Platelets prepared from aspirin-treated donors did not incorporate any (acetyl-3H)aspirin radioactivity into the particulate protein for 2 days after drug treatment and did not show full pretreatment uptake of radioactivity for 12 days thereafter. The course of increasing incorporation of (acetyl-3H)aspirin radioactivity parralleled that of platelet turnover. Therefore, in addition to its saturability, acetylation of the particulate fraction protein by aspirin was permanent. In two respects, the inhibition of platelet function by aspirin correlates well with the aspirin-mediated acetylation of the particulate fraction protein. Both persist for the life-span of the aspirin-treated platelet, and both occur at a similar saturating aspirin concentration. The evidence suggests that the physiologic effect of aspirin on human platelets is produced by acetylation of a single protein located in the particulate fraction. The acetylated protein may be related to cyclo-oxygenase, the prostaglandin G2 biosynthetic enzyme.


Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer.
The third-generation aromatase inhibitors (AIs), including anastrozole, exemestane and letrozole, have demonstrated improved efficacy versus tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer. AIs can be used in several adjuvant endocrine settings: as upfront therapy, switch to an AI after 2-3years of tamoxifen or extended therapy following 5years of tamoxifen. In the switch setting, two different types of study designs have been utilized. One is a late randomization design which randomizes patients who are disease-free after 2-3years of tamoxifen to receive an AI versus continuation of tamoxifen. In contrast, an early randomization design randomizes all patients immediately after primary treatment and prior to starting tamoxifen. Efficacy benefits with AIs have been shown in several trials evaluating the late randomization strategy, including the Intergroup Exemestane Study, the Italian Tamoxifen Anastrozole trial and the Anastrozole-Nolvadex 95 trial. Similarly, early randomization studies, including the Austrian Breast and Colorectal Cancer Study Group-8 and the Breast International Group (BIG) 1-98 trial, have demonstrated the effectiveness of receiving an AI after tamoxifen. Two trials are assessing an early switch strategy versus upfront AI therapy: the BIG 1-98 trial and the ongoing Tamoxifen Exemestane Adjuvant Multicentre trial are assessing switching from tamoxifen to an AI after 2-3years versus upfront AI therapy. This paper reviews studies that have investigated a switch strategy with AIs and considers the implications of these data on treatment choice for postmenopausal patients with hormone receptor-positive breast cancer.


Young drivers' optimism bias for accident risk and driving skill: Accountability and insight experience manipulations.
This study aimed to determine whether two brief, low cost interventions would reduce young drivers' optimism bias for their driving skills and accident risk perceptions. This tendency for such drivers to perceive themselves as more skillful and less prone to driving accidents than their peers may lead to less engagement in precautionary driving behaviours and a greater engagement in more dangerous driving behaviour. 243 young drivers (aged 17-25 years) were randomly allocated to one of three groups: accountability, insight or control. All participants provided both overall and specific situation ratings of their driving skills and accident risk relative to a typical young driver. Prior to completing the questionnaire, those in the accountability condition were first advised that their driving skills and accident risk would be later assessed via a driving simulator. Those in the insight condition first underwent a difficult computer-based hazard perception task designed to provide participants with insight into their potential limitations when responding to hazards in difficult and unpredictable driving situations. Participants in the control condition completed only the questionnaire. Results showed that the accountability manipulation was effective in reducing optimism bias in terms of participants' comparative ratings of their accident risk in specific situations, though only for less experienced drivers. In contrast, among more experienced males, participants in the insight condition showed greater optimism bias for overall accident risk than their counterparts in the accountability or control groups. There were no effects of the manipulations on drivers' skills ratings. The differential effects of the two types of manipulations on optimism bias relating to one's accident risk in different subgroups of the young driver sample highlight the importance of targeting interventions for different levels of experience. Accountability interventions may be beneficial for less experienced young drivers but the results suggest exercising caution with the use of insight type interventions, particularly hazard perception style tasks, for more experienced young drivers typically still in the provisional stage of graduated licensing systems.


Multifaceted realities of scrub typhus: a case series from southern India.
Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi, a Gram-negative bacillus, commonly occurring in the Asia-Pacific region. It is transmitted to humans by the bite of an infected Leptotrombidium mite and the bacterium causes endothelial dysfunction resulting in widespread vasculitis and the possible development of thrombocytopenia, meningitis, acute respiratory distress syndrome, and infrequently, myocarditis. Early diagnosis and prompt treatment are crucial in managing scrub typhus. Here, we present four cases of scrub typhus with a comprehensive literature review. This study highlights the significance of considering scrub typhus as a possible diagnosis in patients of all ages from endemic regions who exhibit symptoms such as fever, thrombocytopenia, or transaminitis, even in the absence of typical clinical features. Two cases exhibited the characteristic lesion of eschar at the site of mite feeding. One case involved a middle-aged woman who was diagnosed with typhus-induced myocarditis with left ventricular dysfunction. Another case involved a 23-day-old neonate with poor feeding and seizures, who was diagnosed with late-onset sepsis with meningitis. Scrub typhus was confirmed in all cases using a positive qualitative IgM ELISA. However, it is preferred to use paired (ELISA before and after antibiotic therapy) or quantitative titers for confirmation. Healthcare providers must consider the patient's exposure history and clinical presentation to diagnose and treat scrub typhus promptly.


Monkeys and mug shots: cues used by rhesus monkeys (Macaca mulatta) to recognize a human face.
We investigated the cues rhesus monkeys (Macaca mulatta) use to recognize a familiar human face. To manipulate facial cues, schematic faces were constructed with Identi-Kit materials derived from mug shots. The monkeys (N = 4) spontaneously classed Identi-Kit as faces on initial presentations. The monkeys then learned to distinguish one Identi-Kit face, the standard, from others. Panel presses indicated recognition of the standard face. Eye movement recordings revealed that the monkeys predominantly fixated on the eyes of the standard face. When the standard face was transformed by removing, altering, or reorienting its features, only alterations of eyes or brows lowered recognition; removal of eyes, brows, nose, or lips did not. Responses to rotated, inverted, and scrambled versions of the standard face varied but generally disrupted recognition. We concluded that features and configuration were used to recognize the human face.


Exosomes provide unappreciated carrier effects that assist transfers of their miRNAs to targeted cells; I. They are 'The Elephant in the Room'.
Extracellular vesicles (EV), such as exosomes, are emerging biologic entities that mediate important newly recognized functional effects. Exosomes are intracellular endosome-originating, cell-secreted, small nano-size EV. They can transfer cargo molecules like miRNAs to act intracellularly in targeted acceptor cells, to then mediate epigenetic functional alterations. Exosomes among EV, are universal nanoparticles of life that are present across all species. Some critics mistakenly hold exosomes to concepts and standards of cells, whereas they are subcellular nanospheres that are a million times smaller, have neither nuclei nor mitochondria, are far less complex and currently cannot be studied deeply and elegantly by many and diverse technologies developed for cells over many years. There are important concerns about the seeming impossibility of biologically significant exosome transfers of very small amounts of miRNAs resulting in altered targeted cell functions. These hesitations are based on current canonical concepts developed for non-physiological application of miRNAs alone, or artificial non-quantitative genetic expression. Not considered is that the natural physiologic intercellular transit via exosomes can contribute numerous augmenting carrier effects to functional miRNA transfers. Some of these are particularly stimulated complex extracellular and intracellular physiologic processes activated in the exosome acceptor cells that can crucially influence the intracellular effects of the transferred miRNAs. These can lead to molecular chemical changes altering DNA expression for mediating functional changes of the targeted cells. Such exosome mediated molecular transfers of epigenetic functional alterations, are the most exciting and life-altering property that these nano EV bring to virtually all of biology and medicine. .Abbreviations: Ab, Antibody Ag Antigen; APC, Antigen presenting cells; CS, contact sensitivity; DC, Dendritic cells; DTH, Delayed-type hypersensitivity; EV, extracellular vesicles; EV, Extracellular vesicle; FLC, Free light chains of antibodies; GI, gastrointestinal; IP, Intraperitoneal administration; IV, intravenous administration; OMV, Outer membrane vesicles released by bacteria; PE, Phos-phatidylethanolamine; PO, oral administration.


Serpiginous choroiditis treated in a stepladder approach.
We present a case of serpiginous choroiditis in a 46-year-old graphic designer. The development of multiple scotomata urged the use of immunosuppressants although his visual acuity remained 20/20. A successful combination of corticosteroids, azathioprine and methotrexate was used in a stepladder approach. No new retinal lesions developed until the end of follow-up (18 months). Thanks to his profession, the patient enabled us to give an unique representation of his visual symptoms.


Percutaneous treatment of simple renal cysts with n-butyl cyanoacrylate and iodized oil.
The aim of this study was to demonstrate the efficacy of n-butyl cyanoacrylate (NBCA) and iodized oil mixture in treatment of simple renal cysts. Twenty-three patients with 27 symptomatic or large ( > 3 cm) simple cysts were treated by computed tomography (CT)-guided percutaneous aspiration and injection of NBCA and iodized oil mixture. The patients (17 men and 6 women, mean age, 57.2 +/- 10.5 years) were treated with as out-patients. The volume of the treated cysts was calculated with periodic noncontrast enhanced CT examinations 1 and 6 months after the procedure. The procedure was considered successful during follow-up when the diameter of the cyst was measured less than 50% of the initial diameter in CT . The sclerotherapy was technically successful in all patients. The diameter of the cysts ranged between 3.5 and 8 cm (mean, 5.6 +/- 1.3 cm), and 1 and 3.4 cm (mean, 2.1 +/- 0.6 cm) before and after sclerotherapy, respectively (P < 0.001). Average diameter reduction was 62.5% during the follow-up period. The mean follow- up lasted 9.1 months (6-14 months). Flank pain resolved in 20 of 23 symptomatic patients (87%). In three patients, the symptoms decreased slightly. At follow-up CT, the procedure was successful in 25 of 27 cysts (93%). We did not observe any complications related to the procedure. Percutaneous sclerotherapy with NBCA and iodized oil mixture was found to be a simple, safe, effective, well tolerated alternative technique for management of simple renal cysts.


Molecular genetic alterations in the laser-capture-microdissected stroma adjacent to bladder carcinoma.
Urothelial carcinoma commonly manifested loss of heterozygosity (LOH) at different regions of chromosomes 17p, 3p, and 9q. Recent studies suggested that bladder stromal cells may be implicated in the growth and progression of urothelial carcinoma. To better understand the genetic alterations in the stromal cells in patients with bladder carcinoma, the authors evaluated the prevalence of allelic loss at three microsatellite polymorphic markers on chromosomes 17p13 (TP53), 3p25-26 (D3S3050), and 9q32-33 (D9S177). In addition, the pattern of X-chromosome inactivation of the stromal cells was evaluated by analyzing the DNA methylation pattern at a polymorphic site on the androgen receptor gene. The authors studied 18 female patients who underwent either transurethral resection (n = 2) or radical cystectomy (n = 16) for high-grade muscle-invasive urothelial carcinoma of the urinary bladder. Genomic DNA samples from the stromal cells immediately adjacent to the tumor and the tumor itself were prepared from formalin-fixed, paraffin-processed tissues using laser-assisted microdissection and LOH was determined. The stromal cells showed a high frequency of LOH on chromosomes 17p13 (29%), 3p25-26 (61%), and 9q32-33 (47%) with no clear concordance with the adjacent tumor cells. Fourteen specimens (78%) showed LOH in the stroma in at least 1 of 3 markers examined. Nonrandom X-chromosome inactivation was frequent in the stromal cells (50% of informative specimens). The current study revealed that some of the genetic changes that commonly occur with invasive urothelial carcinoma were frequently found in the adjacent stroma and suggested that the stroma of urothelial carcinoma may play an important role in bladder carcinogenesis.


Four cases of adhered permanent double lumen hemodialysis catheters (Permcath).
Between September 2010 and January 2012, four patients in our hospital were observed to have permanent dialysis catheters that adhered to either the SVC or right atrium. The first patient underwent intraoperative fluoroscopy and was scheduled for cardiac surgery. Unfortunately due to metabolic disturbances, the patient's condition deteriorated and she died before surgery. The second patient underwent cardio-thoracic surgery with mid-sternotomy and cardio-pulmonary bypass. The catheter was removed and another access route for hemodialysis was established. The third case was scheduled for interventional venocavagraphic exploration of the adhered Permcath. An endovascular snare was passed through the guide wire, which separated the catheter from the SVC. Finally, the fourth patient was a known case of Von Willebrand disease who was scheduled for interventional angiographic Permcath removal. Unfortunately, a few hours following the attempt at surgical removal of the Permcath, her condition deteriorated and she died. Several methods have been used to manage an adherent Permcath. It is assumed that the longer the catheter is in place, the probability of adhesion to the central veins increases. Histological changes have been demonstrated in the venous wall adjunct to the catheter. Interventional venacavagraphic exploration of the catheter and snaring the adherent site of the catheter seems to be a valuable option.


Lung cancer among rock and slag wool production workers.
Previous cohort studies have found an elevated risk of lung cancer among rock and slag wool (RSW) production workers. The aim of the present study was to investigate the risk of lung cancer associated with exposure to RSW while controlling for other occupational exposures and tobacco smoking. Since 1971, a total of 196 lung cancer cases occurred among men who worked in seven plants in Denmark, Norway, Sweden, and Germany, with start of production between 1937 and 1950. We obtained information on occupational history and extra-occupational factors from either the subject or the next of kin for 133 cases and 513 matched controls. We assessed occupational exposure on the basis of interview data combined with information from expert panels set up in each factory. For cumulative exposure to RSW assessed with a 15-year lag, the smoking-adjusted odds ratios in the second, third, and fourth quartiles of exposure were 1.3 (95% confidence interval [CI] = 0.7-2.3), 1.0 (CI = 0.5-1.9), and 0.7 (CI = 0.3-1.3). Similar results were obtained when we included only those workers employed for more than 1 year, when we included other indicators of RSW exposure, and after control for co-exposures. This study provides no evidence of a carcinogenic effect on the lung of rock and slag wool under exposure circumstances in the production industry during the last four to five decades.


Submolecular recognition profiles in two mouse strains of non-protective and protective antibodies against botulinum neurotoxin A.
We have used a set of synthetic overlapping peptides encompassing the entire heavy (H) chain of botulinum neurotoxin serotype A (BoNT/A) to map, in two mouse strains (BALB/c, H2d, and SJL, H2S), the regions on the H-chain recognized by Abs in the last bleed of non-protective anti-BoNT/A antisera and in the bleed of protective antisera immediately following it in the bleeding schedule. Although the protective antisera bound slightly higher amounts of total (IgG+IgM) Abs, non-protective and protective BALB/c antisera showed similar peptide-binding profiles involving peptides N6/N7, N25, C2/C3, C9/C10/C11, C15, C18, C24, C30, and C31 and, at lower amounts of bound Abs, peptides N19, C6/C7, and C28. IgG+IgM antibodies of the protective SJL antisera recognized peptides N5, N22, and C21, and these peptides were only slightly recognized (N22, C21) or unrecognized (N5) by the non-protective antisera. Additionally, peptides N7/N8, N25, C11, C15, and less so N27/N28 bound two-fold or more Abs from the SJL protective antisera than the non-protective antisera. The Abs bound to peptides C4 and C29 were of relatively lower affinity. Peptides C2/C3, C7, C18/C19, C24, C30, and C31 bound higher amounts of Abs in the SJL protective versus the non-protective antisera, but the differences were less than double. We also mapped the binding profiles of the IgG Abs in these sera. BALB/c and SJL had 13-36-fold higher of IgG Abs that bound to BoNT/A in the protective antisera relative to non-protective antisera. The IgG Abs in the protective antisera of each mouse haplotype bound to the same peptides that bound total Abs in the correlate antiserum. But in both mouse strains, the non-protective Abs showed little or no IgG Abs that bound to these peptides. In the SJL haplotype, the IgG response to peptide N5 was transient, appearing strongly in early protective Abs and disappearing by day 70. It is not clear whether the response to region N5 plays a role in initiating and contributing to the protective activity of the toxin in the SJL strain in the early stages but is not needed in later hyperimmune stages of the Ab response. It is concluded that the switch in BALB/c and SJL mice from non-protective to protective Abs is not associated with major changes in the epitope-recognition profiles. Although some slight differences between non-protective and protective antisera appeared in their levels of Abs that were bound by some peptides, these differences are not sufficient to explain differences in the protection properties. Protection was mostly associated with the immunoglobulin class of the antibodies. IgM antibodies were non-protective, while IgG Abs produced after the switch were protective.


Anaerobic Membrane Bioreactors for Municipal Wastewater Treatment: A Literature Review.
Currently, there is growing scientific interest in the development of more economic, efficient and environmentally friendly municipal wastewater treatment technologies. Laboratory and pilot-scale surveys have revealed that the anaerobic membrane bioreactor (AnMBR) is a promising alternative for municipal wastewater treatment. Anaerobic membrane bioreactor technology combines the advantages of anaerobic processes and membrane technology. Membranes retain colloidal and suspended solids and provide complete solid-liquid separation. The slow-growing anaerobic microorganisms in the bioreactor degrade the soluble organic matter, producing biogas. The low amount of produced sludge and the production of biogas makes AnMBRs favorable over conventional biological treatment technologies. However, the AnMBR is not yet fully mature and challenging issues remain. This work focuses on fundamental aspects of AnMBRs in the treatment of municipal wastewater. The important parameters for AnMBR operation, such as pH, temperature, alkalinity, volatile fatty acids, organic loading rate, hydraulic retention time and solids retention time, are discussed. Moreover, through a comprehensive literature survey of recent applications from 2009 to 2021, the current state of AnMBR technology is assessed and its limitations are highlighted. Finally, the need for further laboratory, pilot- and full-scale research is addressed.


Characterization of a high-dose-rate 90Sr-90Y source for intravascular brachytherapy by using the Monte Carlo code PENELOPE.
Radiation treatment with catheter-based beta-emitter sources is currently under clinical trial to prevent restenosis. In the present paper, we address the characterization of the high-dose-rate 90Sr-90Y seeds of the Beta-Cath system supplied by Novoste Corporation, one of the commercially available sources for intravascular brachytherapy. The Monte Carlo code PENELOPE has been used to simulate the transport of electrons emitted by the encapsulated 90Sr-90Y seeds. The calculated radial dose function and anisotropy function for a single seed in water are compared with simulation results from other authors. Regarding g(r), the present result lies between the ITS3 and EGS4 curves, being somewhat closer to ITS3, while in the case of F(r, theta) some differences appear for certain angular intervals and radial distances. In order to put the observed differences into perspective, we have calculated radial doses for point isotropic sources in water. Our results for 0.5 and 1 MeV electrons are in good agreement with simulations using EGSnrc, and an excellent agreement is obtained with ITS for point 90Sr-90Y emitters. Dose distributions in water are calculated for source 'trains' consisting of 1, 2, 3, 4, 5, 9 and 12 seeds. The dose at the source midplane is enhanced if the number of seeds is up to 4, and saturates for trains with 5 or more seeds. We also compare the dose distribution obtained by simply adding the contributions of individual seeds with the simulation of the complete source train. It is found that both calculation procedures yield essentially the same result for distances greater than about 2 mm. Finally, the contribution of bremsstrahlung photons to the dose is briefly analysed.


Protein adsorption to surface chemistry and crystal structure modification of titanium surfaces.
To observe the early adsorption of extracellular matrix and blood plasma proteins to magnesium-incorporated titanium oxide surfaces, which has shown superior bone response in animal models. Commercially pure titanium discs were blasted with titanium dioxide (TiO2) particles (control), and for the test group, TiO2 blasted discs were further processed with a micro-arc oxidation method (test). Surface morphology was investigated by scanning electron microscopy, surface topography by optic interferometry, characterization by X-ray photoelectron spectroscopy (XPS), and by X-ray diffraction (XRD) analysis. The adsorption of 3 different proteins (fibronectin, albumin, and collagen type I) was investigated by an immunoblotting technique. The test surface showed a porous structure, whereas the control surface showed a typical TiO2 blasted structure. XPS data revealed magnesium-incorporation to the anodic oxide film of the surface. There was no difference in surface roughness between the control and test surfaces. For the protein adsorption test, the amount of albumin was significantly higher on the control surface whereas the amount of fibronectin was significantly higher on the test surface. Although there was no significant difference, the test surface had a tendency to adsorb more collagen type I. The magnesium-incorporated anodized surface showed significantly higher fibronectin adsorption and lower albumin adsorption than the blasted surface. These results may be one of the reasons for the excellent bone response previously observed in animal studies.


Resource competition triggers the co-evolution of long tongues and deep corolla tubes.
It is normally thought that deep corolla tubes evolve when a plant's successful reproduction is contingent on having a corolla tube longer than the tongue of the flower's pollinators, and that pollinators evolve ever-longer tongues because individuals with longer tongues can obtain more nectar from flowers. A recent model shows that, in the presence of pollinators with long and short tongues that experience resource competition, coexisting plant species can diverge in corolla-tube depth, because this increases the proportion of pollen grains that lands on co-specific flowers. We have extended the model to study whether resource competition can trigger the co-evolution of tongue length and corolla-tube depth. Starting with two plant and two pollinator species, all of them having the same distribution of tongue length or corolla-tube depth, we show that variability in corolla-tube depth leads to divergence in tongue length, provided that increasing tongue length is not equally costly for both species. Once the two pollinator species differ in tongue length, divergence in corolla-tube depth between the two plant species ensues. Co-evolution between tongue length and corolla-tube depth is a robust outcome of the model, obtained for a wide range of parameter values, but it requires that tongue elongation is substantially easier for one pollinator species than for the other, that pollinators follow a near-optimal foraging strategy, that pollinators experience competition for resources and that plants experience pollination limitation.


Mexican-Origin Women's Construction and Navigation of Racialized Identities: Implications for Health Amid Restrictive Immigrant Policies.
This study examines how Mexican-origin women construct and navigate racialized identities in a postindustrial northern border community during a period of prolonged restrictive immigration and immigrant policies, and it considers mechanisms by which responses to racialization may shape health. This grounded theory analysis involves interviews with 48 Mexican-origin women in Detroit, Michigan, who identified as being in the first, 1.5, or second immigrant generation. In response to institutions and institutional agents using racializing markers to assess their legal status and policing access to health-promoting resources, women engaged in a range of strategies to resist being constructed as an "other." Women used the same racializing markers or symbols of (il)legality that had been used against them as a malleable set of resources to resist processes of racialization and to form, preserve, and affirm their identities. These responses include constructing an authorized immigrant identity, engaging in immigration advocacy, and resisting stigmatizing labels. These strategies may have different implications for health over time. Findings indicate the importance of addressing policies that promulgate or exacerbate racialization of Mexican-origin communities and other communities who experience growth through migration. Such policies include creating pathways to legalization and access to resources that have been invoked in racialization processes, such as state-issued driver's licenses.


In vitro susceptibility of Haemophilus ducreyi to several antibiotics.
Haemophilus ducreyi was isolated from 59 (52%) of 113 men with a clinical diagnosis of chancroid. The following MIC50 (MIC90) values for H. ducreyi were obtained: erythromycin 0.14 (0.5) micrograms/ml, trimethoprim 0.25 (8.0) micrograms/ml, ceftriaxone 0.009 (0.14) micrograms/ml, and ciprofloxacin 0.007 (0.04) micrograms/ml. These data indicate that all isolates appear to be fully susceptible to erythromycin and the other antimicrobial agents tested, although ciprofloxacin was the most effective antibiotic.


"It's not an issue at the moment": a qualitative study of mothers about childhood obesity.
To explore childhood obesity through mothers' perceptions, attitudes, beliefs, and behaviors. Descriptive qualitative study using in-depth interviews. Sixteen in-depth interviews were conducted with primiparous mothers of children aged 0-2 years. The questions focused on nutrition, the context of eating in the family, physical activity, television viewing, and the responsibility of parents as role models. Thematic analysis was used to identify regular patterns of meaning regarding the major issues pertaining to childhood obesity, nutrition, and physical activity. Five themes were identified: (1) developing eating habits, (2) developing active and sedentary habits, (3) differences between age groups, (4) sources of information, and (5) response to information. Although awareness about the need to provide a nutritious diet and opportunities for children to be active was high among the mothers, this was not always reflected in their behaviors. For many mothers, obesity became a concern only if excessive weight gain occurred. Prevention through establishing good habits early, although considered, was not always actively pursued. Interventions to prevent overweight and obesity need to focus on equipping parents with the skills to translate their knowledge into behavior and lay the foundations early for their children to develop healthy habits.


Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects.
Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reduction of basal and insulin-stimulated glucose uptake activities in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Insulin responsiveness of uptake was also reduced. There was no change in total membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While glucosamine treatment had no significant effects on hexokinase activity measured in cell extracts, glucose phosphorylation in intact cells was impaired after treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucosamine treatment. These effects were similar in nondiabetic and type 2 cells. In summary: 1) Chronic treatment with glucosamine reduces glucose transport/phosphorylation and storage into glycogen in skeletal muscle cells in culture and impairs insulin responsiveness as well. 2) Down-regulation of glucose transport/phosphorylation occurs at a posttranslational level of GLUTs. 3) Glycogen synthase activity increases with glucosamine treatment. 4) Nondiabetic and type 2 muscle cells display equal sensitivity and responsiveness to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucose metabolism at multiple sites and can contribute to insulin resistance in this tissue.


[Children born with ambiguous genitalia].
For 10 - 12 children born with ambiguous genitalia in Norway annually, the sex cannot be decided directly after birth. The condition is now termed "Disorders of Sex Development" (DSD). Severely undervirilised chromosomal and gonadal boys (46,XY DSD) represent the greatest challenge; the sex assignment has traditionally been female. This review focuses on challenges within diagnostics and treatment and provides an update on the scientific basis for sex assignment in 46,XY DSD children. The article is based on articles retrieved from Pub Med and own clinical experience. During the last decade the scientific basis for sex assignment in children born with ambiguous genitalia has been increasingly questioned. The traditional DSD management has been dominated by the belief that DSD children will develop into the assigned sex regardless of the underlying cause as long as the external genitalia are "normalised" before two years of age. The most severely undervirilised 46,XY DSD children were surgically assigned as females, based on an emphasis of the size and functionality of the phallus being important for later psychosexual development into men. New guidelines for DSD management are now being developed based on recent knowledge about prenatal cerebral exposure to critical sex chromosome genes and hormones that influence foetal brain predisposition for later psychosexual development. Assignment of a sex should be based on a precise diagnosis of the condition's underlying cause and thereby a best possible prediction of future gender identity.


Electron transfer reaction of light harvesting zinc naphthalocyanine-subphthalocyanine self-assembled dyad: spectroscopic, electrochemical, computational, and photochemical studies.
Electron transfer reaction of a self-assembled donor-acceptor dyad formed by axial coordination of zinc naphthalocyanine, ZnNc, and subphthalocyanine appended with pyridine coordinating ligand, SubPc(py), was investigated in the present study. The SubPc(Py) : ZnNc self-assembled dyad absorbs the light in a wide section of the UV/Vis/NIR spectra. The formation constant of SubPc(py) : ZnNc in o-dichlorobenzene was found to be 1.2 × 10(5) M(-1) from the steady-state absorption and emission measurements, suggesting stable complex formation. The geometric and electronic calculations by using ab initio B3LYP/6-311G methods showed the majority of the highest occupied frontier molecular orbital (HOMO) on the zinc naphthalocyanine entity, while the lowest unoccupied molecular orbital (LUMO) was on the subphthalocyanine entity, suggesting that the charge-separated state of the supramolecular complex is (SubPc(py))˙(-) : ZnNc˙(+). The electrochemical results suggest the exothermic charge-separation process via the singlet states of both SubPc(py) and ZnNc entities. Upon coordination the pyridine appended subphthalocyanine to ZnNc; the main quenching pathway involved charge separation via the singlet excited states of ZnNc and SubPc(py). A clear evidence of the intramolecular electron transfer from the singlet state of ZnNc to SubPc(py) was monitored by femtosecond laser photolysis in o-dichlorobenzene by observing the characteristic absorption band of the ZnNc radical cation in the NIR region at 960 nm. The rate of charge-separation process was found to be 1.3 × 10(10) s(-1), indicating fast and efficient charge separation. The rate of charge recombination and the lifetime of the charge-separated state were found to be 1.0 × 10(9) s(-1) and 1 ns, respectively. The absorption in a wide section of the solar spectrum and high charge-separation/charge-recombination ratio suggests the usefulness of self-assembled SubPc(Py) : ZnNc for being a photosynthetic model.


Risk assessment of mercury exposure from dental amalgams.
Much attention is being focused upon the issue of mercury exposure from dental amalgam restorations and the potential for adverse health effects. This controversy has grown beyond the confines of the dental profession itself and is becoming an emotional public health issue. In hope of regaining good health, many dental patients with chronic systemic diseases are considering replacement of their amalgams. Dentists are increasingly being challenged to prove the safety of amalgams. Recently, systematic methods have been established for quantitative evaluation of environmental risks. This study brings together the quantitative methodologies of risk assessment and the knowledge of mercury exposure from dental amalgams to estimate the safety of dental amalgam restorative therapy. Analysis concludes that the margin of safety for mercury toxicity in humans from dental amalgams is approximately 8- to 30-fold. There are many uncertainties involved in this estimate, and further studies are warranted to improve its precision.


The M2 muscarinic G-protein-coupled receptor is voltage-sensitive.
G-protein coupled receptors are not considered to exhibit voltage sensitivity. Here, using Xenopus oocytes, we show that the M2 muscarinic receptor (m2R) is voltage-sensitive. The m2R-mediated potassium channel (GIRK) currents were used to assay the activity of m2R. We found that the apparent affinity of m2R toward acetylcholine (ACh) was reduced upon depolarization. Binding experiments of [3H]ACh to individual oocytes expressing m2R confirmed the electrophysiological findings. When the GIRK channels were activated either by overexpression of Gbetagamma subunits or by injection of GTPgammaS, the ratio between the currents measured at -60 mV and +40 mV was the same as for the basal activity of the GIRK channel. Thus, the steps downstream to agonist activation of m2R are not voltage-sensitive. We further found that, in contrast to m2R, the apparent affinity of m1R was increased upon depolarization. We also found that the voltage sensitivity of binding of [3H]ACh to oocytes expressing m2R was greatly diminished following pretreatment with pertussis toxin. The cumulative results suggest that m2R is, by itself, voltage-sensitive. Furthermore, the voltage sensitivity does not reside in the ACh binding site, rather, it most likely resides in the receptor region that couples to the G-protein.


FOXO3A Expression in Upper Tract Urothelial Carcinoma.
Epidemiological studies have reported various results regarding whether FOXO3A is related to various carcinomas. However, the prognostic significance of FOXO3A in upper tract urothelial carcinoma (UTUC) remains unclear. The purpose of this study was to validate the correlation between FOXO3A expression and oncological outcomes in UTUC. The expression levels of FOXO3A in 107 UTUC patients were examined by immunohistochemistry (IHC). We examined the prognostic role of FOXO3A by using the Cox proportional hazard model. The results indicated that FOXO3A expression was notably decreased in UTUC tissue compared with control tissue. Decreased expression of FOXO3A was also related to advanced pathologic stage (P = 0.026), lymph node metastasis (P = 0.040), lymphovascular invasion (P < 0.001), and adjuvant therapy (P = 0.048). In addition, UTUC patients with low FOXO3A expression had a significantly shorter survival time, including both overall survival (OS) [hazard ratio (HR) 2.382, P = 0.004] and recurrence-free survival (RFS) (HR 2.385, P = 0.004), than those with high expression. Multivariate analyses showed that FOXO3A was a significant predictor for OS (HR 2.145, P = 0.014) and RFS (HR 2.227, P = 0.010) in UTUC patients. Our results indicate that FOXO3A may be involved in the recurrence of UTUC and that it has certain clinical value in the therapeutic targeting and prognostic evaluation of UTUC.