Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial.
Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20-4.99); p value 0.02; anastrozole 0.80 (0.36-1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment.


Herpes simplex virus type 1 amplicons and their hybrid virus partners, EBV, AAV, and retrovirus.
HSV-1 amplicons can accommodate foreign DNA of any size up to 150 kbp. Genomic sequences as well as cDNA, large transcriptional regulatory sequences for cell type-specific expression, or multiple transgenes can be inserted in a modular fashion. HSV-1 amplicon vectors deliver DNA efficiently into the cell nucleus as an extrachromosomal, non-replicating circular concatenate, which is rapidly diluted, at least in dividing cells. Consequently, transgene expression is lost within days to weeks in dividing cells, but may be retained for months in non-dividing cells. In contrast, vectors based on Epstein-Barr virus, adeno-associated virus, or retroviruses can mediate long-term transgene expression, as vector DNA is retained by episomal replication or chromosomal integration. Hybrid amplicons use genetic elements from HSV-1 that allow replication and packaging of the vector DNA into HSV-1 virions, thereby conserving the large transgene capacity of HSV-1, and genetic elements from other viruses that confer genetic stability to the vector DNA within transduced cells. Additional strategies to sustain genetic material in infected cells include the incorporation of recombinases from different bacteriophages or transposable elements of the Tc1/mariner family in the amplicon vector. Moreover, modification of the HSV-1 virion itself offers a myriad of possibilities to improve gene delivery by targeting specific cell populations or transporting foreign proteins, such as Cre recombinase or the adeno-associated virus Rep protein, which can control the fate and expression of the therapeutic transgene.


Epidemiology and spatio-temporal analysis of West Nile virus in horses in Spain between 2010 and 2016.
During the last decade, West Nile virus (WNV) outbreaks have increased sharply in both horses and human in Europe. The aims of this study were to evaluate characteristics and spatio-temporal distribution of WNV outbreaks in horses in Spain between 2010 and 2016 in order to identify the environmental variables most associated with WNV occurrence and to generate high-resolution WNV suitability maps to inform risk-based surveillance strategies in this country. Between August 2010 and November 2016, a total of 403 WNV suspected cases were investigated, of which, 177 (43.9%) were laboratory confirmed. Mean values of morbidity, mortality and case fatality rates were 7.5%, 1.6% and 21.2%, respectively. The most common clinical symptoms were as follows: tiredness/apathy, recumbency, muscular tremor, ataxia, incoordination and hyperaesthesia. The outbreaks confirmed during the last 7 years, with detection of WNV RNA lineage 1 in 2010, 2012, 2013, 2015 and 2016, suggest an endemic circulation of the virus in Spain. The spatio-temporal distribution of WNV outbreaks in Spain was not homogeneous, as most of them (92.7%) were concentrated in western part of Andalusia (southern Spain) and significant clusters were detected in this region in two non-consecutive years. These findings were supported by the results of the space-time scan statistics permutation model. A presence-only MaxEnt ecological niche model was used to generate a suitability map for WNV occurrence in Andalusia. The most important predictors selected by the Ecological Niche Modeling were as follows: mean annual temperature (49.5% contribution), presence of Culex pipiens (19.5% contribution), mean annual precipitation (16.1% contribution) and distance to Ramsar wetlands (14.9% contribution). Our results constitute an important step for understanding WNV emergence and spread in Spain and will provide valuable information for the development of more cost-effective surveillance and control programmes and improve the protection of horse and human populations in WNV-endemic areas.


Molecular Analysis of South African Ovine Herpesvirus 2 Strains Based on Selected Glycoprotein and Tegument Genes.
Ovine herpesvirus 2 (OvHV-2), is the causative agent of sheep-associated malignant catarrhal fever (SA-MCF), a generally fatal disease of cattle and other captive wild ruminants. Information on the OvHV-2 strains circulating in South Africa (SA) and other African countries with regard to genetic structure and diversity, and pattern of distribution is not available. This study aimed to characterize the OvHV-2 strains circulating in SA using selected genes encoding glycoproteins and tegument proteins. To establish the genetic diversity of OvHV-2 strains, four genes, Ov 7, Ov 8 ex2, ORF 27 and ORF 73 were selected for analysis by PCR and DNA sequencing. Nucleotide and amino acid multiple sequence analyses revealed two genotypes for ORF 27 and ORF 73, and three genotypes for Ov 7 and Ov 8 ex2, randomly distributed throughout the regions. Ov 7 and ORF 27 nucleotide sequence analysis revealed variations that distinguished SA genotypes from those of reference OvHV-2 strains. Epitope mapping analysis showed that mutations identified from the investigated genes are not likely to affect the functions of the gene products, particularly those responsible for antibody binding activities associated with B-cell epitopes. Knowledge of the extent of genetic diversity existing among OvHV-2 strains has provided an understanding on the distribution patterns of OvHV-2 strains or genotypes across the regions of South Africa. This can facilitate the management of SA-MCF in SA, in terms of introduction of control measures or safe practices to monitor and control OvHV-2 infection. The products encoded by the Ov 7, Ov 8 ex2 and ORF 27 genes are recommended for evaluation of their coded proteins as possible antigens in the development of an OvHV-2 specific serodiagnostic assay.


Do women prefer caesarean sections? A qualitative evidence synthesis of their views and experiences.
Caesarean sections (CS) continue to increase worldwide. Multiple and complex factors are contributing to the increase, including non-clinical factors related to individual women, families and their interactions with health providers. This global qualitative evidence synthesis explores women's preferences for mode of birth and factors underlying preferences for CS. Systematic database searches (MEDLINE, EMBASE, CINAHL, PsycINFO) were conducted in December 2016 and updated in May 2019 and February 2021. Studies conducted across all resource settings were eligible for inclusion, except those from China and Taiwan which have been reported in a companion publication. Phenomena of interest were opinions, views and perspectives of women regarding preferences for mode of birth, attributes of CS, societal and cultural beliefs about modes of birth, and right to choose mode of birth. Thematic synthesis of data was conducted. Confidence in findings was assessed using GRADE-CERQual. We included 52 studies, from 28 countries, encompassing the views and perspectives of pregnant women, non-pregnant women, women with previous CS, postpartum women, and women's partners. Most of the studies were conducted in high-income countries and published between 2011 and 2021. Factors underlying women preferences for CS had to do mainly with strong fear of pain and injuries to the mother and child during labour or birth (High confidence), uncertainty regarding vaginal birth (High confidence), and positive views or perceived advantages of CS (High confidence). Women who preferred CS expressed resoluteness about it, but there were also many women who had a clear preference for vaginal birth and those who even developed strategies to keep their birth plans in environments that were not supportive of vaginal births (High confidence). The findings also identified that social, cultural and personal factors as well as attributes related to health systems impact on the reasons underlying women preferences for various modes of birth (High confidence). A wide variety of factors underlie women's preferences for CS in the absence of medical indications. Major factors contributing to perceptions of CS as preferable include fear of pain, uncertainty with vaginal birth and positive views on CS. Interventions need to address these factors to reduce unnecessary CS.


Hyper-Cryptic radiation of a tropical montane plant lineage.
Species are seen as the fundamental unit of biotic diversity, and thus their delimitation is crucial for defining measures for diversity assessments and studying evolution. Differences between species have traditionally been associated with variation in morphology. And yet, the discovery of cryptic diversity suggests that the evolution of distinct lineages does not necessarily involve morphological differences. Here, we analyze 1,684,987 variant sites and over 4,000 genes for more than 400 samples to show how a tropical montane plant lineage (Geonoma undata species complex) is composed of numerous unrecognized genetic groups that are not morphologically distinct. We find that 11 to 14 clades do not correspond to the three currently recognized species. Most clades are genetically different and geographic distance and topography are the most important factors determining this genetic divergence. The genetic structure of this lineage does not match its morphological variation. Instead, this species complex constitutes the first example of a hyper-cryptic plant radiation in tropical mountains.


LoRaWAN for Smart Campus: Deployment and Long-Term Operation Analysis.
The recent years have gradually increased the value of wireless connectivity, making it the de facto commodity for both human users and the machines. In this paper, we summarize our experiences of deploying and managing for over two years the extensive indoor sensor network composed of more than three hundred devices connected over LoRaWAN low power wide area network (LPWAN) technology. We start by detailing the background and methodology of our deployment and then present the results of analyzing the network's operation over a period of two years, focusing specifically on identifying the reasons after the packet losses. Our results reveal that despite the common assumptions, in a real-life network, the packets are lost not only during the on-air transmission but also within the backbone. Among the other interesting findings are the observed nonuniform distribution of the packet transmissions by the nodes in the networks, the seasonal effects on the packet delivery, and the observed effects of the interferences on network performance. The empirical results presented in the paper provide valuable insight into the performance of a real-life extensive LoRaWAN network deployed in an indoor environment and thus may be of interest both to the practitioners and academics.


Hong Kong's new wave of migration: socio-political factors of individuals' intention to emigrate.
With a recent surge in the outward movement of the population, a new wave of emigration has been suggested to have started in Hong Kong. It is speculated that recent socio-political changes in Hong Kong may have contributed to this phenomenon. Therefore, five socio-political variables-mobility, sense of place, trust and confidence in the law and the legal system, global citizenship, and perception of inequality-are employed in this study as proposed determinants to investigate the intention of Hong Kong residents to migrate to mainland China and to other international destinations. A random telephone questionnaire survey representative of the local population was conducted, with a total of 801 valid samples collected. Stepwise multiple regression analysis was carried out. The results showed that all five proposed socio-political variables successfully predicted people's migration intention to mainland China and to foreign countries, with important variations between the two choices. Our results carry strong implications for understanding people's concerns behind their intention to emigrate. Further, our findings present a challenge for Hong Kong; society may gradually be failing to accommodate individuals with diverse perceptions and values, particularly in terms of trust and confidence in the law and the legal system, and individuals' sense of global citizenship.


Perineoscopic radical prostatectomy: A novel surgical technique for the treatment of prostate cancer.
The objective of this article is to discuss the technical details of perineoscopic radical prostatectomy (perineoscopic-RP), which we performed for the first time as a surgical treatment for prostate cancer (PCa), and to present the outcomes of three patients who underwent this procedure. Using a robotic scope as an optical system, we performed perineoscopic-RP in 3 patients in March 2018. Technical details of the procedure have been explained step-by-step in this article. Preoperative, perioperative, and postoperative data of all the patients was analyzed. Perineoscopic-RP was completed successfully without the need to convert to other approaches and/or techniques in all three patients. The patients were in a low-risk group for PCa. The mean time that elapsed to reach the prostate apex was 50±3.6 minutes, including the time required to install the optic and retractor system. The mean total operative time was 144.3±8.4 minutes. No intraoperative or postoperative complications were observed. Surgical margins were negative in all patients. Incontinence was observed in 2 patients after the removal of the Foley catheter. All patients achieved complete continence in the 3rd month during the follow-up. This technique, of which we presented the initial results in this article, can be successfully performed as a surgical intervention method for PCa. Prospective and comparative studies with larger patient series are required to place this method in routine practice.


Common types of microdebris affect the physiology of reef-building corals.
Marine debris, particularly microdebris (<1 mm) poses a potential threat to marine life, including reef-building corals. While previous research has mainly focused on the impact of single polymer microplastics, the effects of natural microdebris, composed of a mixture of materials, have not been explored. Therefore, this study aimed to assess the effects of different microdebris, originating from major sources of pollution, on reef-building corals. For this, we exposed two scleractinian coral species, Pocillopora verrucosa and Stylophora pistillata, known to frequently ingest microplastics, to four types of microdebris in an 8-week laboratory experiment: fragmented environmental plastic debris, artificial fibers from clothing, residues from the automobile sector consisting of tire wear, brake abrasion, and varnish flakes, a single polymer microplastic treatment consisting of polyethylene particles, and a microdebris-free control treatment. Specifically, we (I) compared the effects of the different microdebris on coral growth, necrosis, and photosynthesis, (II) investigated the difference between the microdebris mixtures and the exposure to the single polymer treatment, and (III) identified potential mechanisms causing species-specific effects by contrasting the feeding responses of the two coral species on microdebris and natural food. We show that the fibers and tire wear had the strongest effects on coral physiology, with P. verrucosa being more affected than S. pistillata. Both species showed increased volume growth in response to the microdebris treatments, accompanied by decreased calcification in P. verrucosa. Photosynthetic efficiency of the symbionts was enhanced in both species. The species-specific physiological responses might be attributed to feeding reactions, with P. verrucosa responding significantly more often to microdebris than S. pistillata. These findings highlight the effect of different microdebris on coral physiology and the need for future studies to use particle mixtures to better mimic naturally occurring microdebris and assess its effect on corals in more detail.


The threshold concept in food safety and its applicability to food allergy.
Down the years there have been many clinical reports of exquisite sensitivity to low doses of food allergens. There are many factors that may contribute to a variation of threshold in an individual exposed to an allergen during the course of his or her daily life. Some of these factors are intrinsic and unavoidable. Other factors may be predictable but not easily controllable, such as asthma, exposure to allergens during the pollen season and predicting situations that may be risky. Other factors may be out of the control of the individual. The most important one of these is the adequate training and awareness of manufacturers and caterers who aim to provide safe and nutritious meals to their allergic and non-allergic customers alike. Clinical histories of reactions in the community and the use of labial exposure during food challenge show that most non-ingestion exposures to peanut usually result in easily treated minor reactions. Formal, oral food challenges have shown that low dose reactivity is relatively common but studies have not yet had the power to investigate whether peanut allergy is more commonly associated with very low dose reactivity than other foods. This means that industry must not concentrate only on peanut and tree nuts when looking at issues of contamination just because they are associated with the majority of severe reactions. There are more milk and egg allergic children in the general population and they deserve the same protection from allergen exposure as sufferers of peanut or tree nut allergies.


Occurrence and Levels of Aflatoxins in Fish Feeds and Their Potential Effects on Fish in Nyeri, Kenya.
Aflatoxins are fungal metabolites that contaminate foods and feeds, causing adverse health effects in humans and animals. This study determined the occurrence of aflatoxins in fish feeds and their potential effects on fish. Eighty-one fish feeds were sampled from 70 farms and 8 feed manufacturing plants in Nyeri, Kenya for aflatoxin analysis using competitive enzyme-linked immunosorbent assay. Fish were sampled from 12 farms for gross and microscopic pathological examination. Eighty-four percent of feeds sampled tested positive for aflatoxins, ranging from 1.8 to 39.7 µg/kg with a mean of 7.0 ± 8.3 µg/kg and the median of 3.6 µg/kg. Fifteen feeds (18.5%) had aflatoxins above the maximum allowable level in Kenya of 10 µg/kg. Homemade and tilapia feeds had significantly higher aflatoxin levels than commercial and trout feeds. Feeds containing maize bran and fish meal had significantly higher aflatoxin levels than those without these ingredients. Five trout farms (41.7%) had fish with swollen abdomens, and enlarged livers with white or yellow nodules, which microscopically had large dark basophilic hepatic cells with hyperchromatic nuclei in irregular cords. In conclusion, aflatoxin contamination of fish feeds is prevalent in Nyeri, and may be the cause of adverse health effects in fish in this region.


[Elements of structural organization of the transcribed area of the ribosomal repeat (rDNA) in human peripheral blood lymphocytes].
The rDNA transcribed region (TR) was tested for accessibility to RsaI recognizing 15 TR sites, DNase I, and photoinducible arylazide (N-(4-azido-2-hydroxybenzoyl)-N,N'-diaminoheptane acetate) in isolated nuclei and, with arylazide, in intact cells. Arylazide entered cells well and did not appreciably affect the chromatin structure. Its photolysis products efficiently modified DNA in accessible sites. Single-strand breaks made by DNase I were not transformed in double-stranded in rDNA TR, suggesting the necessity of denaturing electrophoresis for such an analysis. About 70% of all rDNA copies proved poorly inaccessible to endonucleases and arylazide, the accessibility being higher in their 18S and 5.8S rRNA gene regions than in the regions of the external transcribed spacers (ETSs) and the 28S rRNA gene. Proteinase K disrupted this structure, and the corresponding copies were extracted from nuclei. This explained why in situ hybridization occasionally fails to reveal rDNA in the nucleolar fibrillar center (FC) on electron microscopic preparations. In other rDNA copies, TR (excluding 5'-ETS) was accessible to nucleases and arylazide. These copies were not extracted from nuclei treated with proteinase K. Some of their RsaI sites were protected by tightly bound proteins. Seven such regions were identified in TR. Possible association of the molecular structure, nucleolar location, and functional state of rDNA is discussed.


Myosin‑II heavy chain and formin mediate the targeting of myosin essential light chain to the division site before and during cytokinesis.
MLC1 is a haploinsufficient gene encoding the essential light chain for Myo1, the sole myosin‑II heavy chain in the budding yeast Saccharomyces cerevisiae. Mlc1 defines an essential hub that coordinates actomyosin ring function, membrane trafficking, and septum formation during cytokinesis by binding to IQGAP, myosin‑II, and myosin‑V. However, the mechanism of how Mlc1 is targeted to the division site during the cell cycle remains unsolved. By constructing a GFP‑tagged MLC1 under its own promoter control and using quantitative live‑cell imaging coupled with yeast mutants, we found that septin ring and actin filaments mediate the targeting of Mlc1 to the division site before and during cytokinesis, respectively. Both mechanisms contribute to and are collectively required for the accumulation of Mlc1 at the division site during cytokinesis. We also found that Myo1 plays a major role in the septin‑dependent Mlc1 localization before cytokinesis, whereas the formin Bni1 plays a major role in the actin filament-dependent Mlc1 localization during cytokinesis. Such a two‑tiered mechanism for Mlc1 localization is presumably required for the ordered assembly and robustness of cytokinesis machinery and is likely conserved across species.


Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor.
The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis.


Complete Restoration of Respiratory Muscle Function in Three Subjects With Spinal Cord Injury: Pilot Interventional Clinical Trial.
The aim of this study was to assess the safety and efficacy of complete restoration of respiratory muscle function in subjects with spinal cord injury. This was an interventional study investigating three subjects maintained on a diaphragm pacing system who were implanted with the spinal cord stimulation system to restore cough. Peak expiratory airflow and airway pressure generation were the primary physiologic outcome measures; an assessment of the degree of difficulty in raising secretions was the primary clinical outcome measure. Mean peak expiratory airflow and airway pressure generation during spontaneous efforts were 1.7 ± 0.2 L/s and 31 ± 7 cmH2O, respectively. When spinal cord stimulation was applied after pacing volume associated with the subject's maximum inspiratory effort and synchronized with the subject's maximum expiratory effort, peak expiratory airflow and airway pressure generation were 9.0 ± 1.9 L/s and 90 ± 6 cmH2O, respectively (P < 0.05). Moreover, each subject experienced much greater ease in raising secretions and marked improvement in the ease in raising secretions compared with other methods. Complete restoration of respiratory muscle function can be safely and effectively achieved in the same individuals with spinal cord injury. Spinal cord stimulation results in peak expiratory airflow and airway pressure generation characteristic of a normal cough, whereas diaphragm pacing was successful in maintaining patients off mechanical ventilation.


Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.
Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment. This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index (BMI) 31.9 kg/m(2) ; body weight 91.5 kg] inadequately controlled on metformin. Patients (N = 182) were randomly assigned 1 : 1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual-energy X-ray absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated. A total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection (UTI) and genital infection was similar in both treatment groups. Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.


Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers.
Epidemiological studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of nonneuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, Raij L. Am J Physiol Heart Circ Physiol 292: H76-H82, 2007; Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319-326, 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 μg/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (∼20%). These changes were accompanied by significant increases in NADPH oxidase 4 (∼30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers.


[Status and problems of postgraduate training of medical staff of Disaster Medicine Service].
An analysis of the postgraduate training of doctors of Disaster Medicine Service in the central and local training bases in the federal districts of Russian Federation in 2010 is performed. It was concluded that the existing Department of Emergency Medicine and mobilization training and health education can not reach those who need further training. It was proposed to create on the basis of a FSI VTSMK "Protection" Institute of Emergency Medicine to improve the training of doctors, training and methodological support of teaching and training of the teaching staff.


Changes in circulating steroids with aging in postmenopausal women.
to examine the possible effects of aging on circulating steroid hormones in postmenopausal women, blood samples were drawn from 155 women, aged 34 to 83 years, with spontaneous ovarian failure. The C-21 steroids, pregnenolone and 17-hydroxypregnenolone; the delta 4 progestins, progesterone and 17-hydroxyprogesterone; and cortisol did not change with age and were similar in concentration to the levels measured during the follicular phase of premenopausal women. The delta 5 androgens, dehydropiandrosterone and dehydroepiandrosterone sulfate, declined significantly (P less than .001) with age, whereas no change was noted in the delta 4 androgens, androstenedione and testosterone. The levels of estradiol (E2) and estrone (E1) were strongly correlated with percent ideal weight but did not change with age. The authors conclude that 1) The production of progestins does not change with age in normal adult women, other than that resulting from the loss of secretion associated with ovarian corpus luteum function. 2) The decline of delta 5 androgens without corresponding changes in their precursors suggests an age-related change of adrenal 17,20 desmolase activity. 3) The levels of E2 and E1 reflect an effect of body size but not of age on peripheral aromatization of precursor androgens.


Spread of ESC-, carbapenem- and colistin-resistant Escherichia coli clones and plasmids within and between food workers in Lebanon.
Knowledge on the dynamic of MDR Escherichia coli in the human community is still limited, especially in low- and middle-income countries. Our goal was to decipher the dynamics of E. coli lineages and plasmids resistant to ESC, carbapenem and colistin within and between food workers in Lebanon using genomic-based approaches. Eighty-four healthy adults working in three bakeries were sampled twice at a 6 monthly interval. E. coli resistant to ESC (ESC-E), carbapenem (CP-E) and colistin (CO-E) were collected on selective plates. Non-duplicate isolates were whole-genome sequenced using the Illumina technology and plasmid transmission was assessed by long-read sequencing. Data were analysed using bioinformatics tools and SNP-based phylogeny. ESC-E carriage rate reached 34.5% (t0) and 52.9% (t6), and 15 workers were positive at both t0 and t6. Carbapenem resistance (blaOXA-181, blaOXA-204, blaNDM-5) was found in five workers at t0 and two at t6, while colistin resistance (mcr-1.1) was found in five workers at t0 and one at t6. Forty-seven different STs were identified, of which three STs were predominant (ST131, n = 9; ST10, n = 5; ST69, n = 5). One worker presented the same ESC-E clone at t0 and t6. Twelve different events of clonal transmission among individuals were exemplified while plasmid transmission was only shown once. Our study revealed a high carriage rate of MDR E. coli (60.7%) and the emergence of CP and colistin resistance in the Lebanese community. Incidental and long-term ESC-E carriage was observed in 41.7% and 17.9% of the workers, respectively. The high clonal diversity suggests an important dynamic of acquisition and loss of MDR E. coli and limited plasmid spread.


Endoscopic removal of gastric and duodenal polyps.
As endoscopic surgery comes into its own, the applications of this modality are increasing. This is well illustrated by the use of endoscopic polypectomy in the colon, and more recently by endoscopic polypectomy in the stomach and duodenum. We can anticipate increased applicability of these technics as the experience widens and the margins of safety increase. The present series of six polypectomies from the stomach and duodenum confirms the applicability of endoscopic polypectomy for this portion of the gastrointestinal tract, attests to its safety, and indicates that these procedures can contribute materially to the care of patients with gastric or duodenal polyps. The real and potential problems are discussed.


Total vascular resistance and blood flow frequency during left ventricular assistance using a vibrating flow pump.
A vibrating flow pump (VFP) can generate high frequency oscillated blood flow within 10-30 Hz by the oscillation of its central tube. A totally implantable artificial heart using a VFP is being developed as a unique type of blood pump. In this study, left ventricular (LV) assist circulation was performed using a VFP. The total vascular resistance and driving frequency of the VFP were estimated from their relationship. The effect of oscillation on the vascular system was studied by the frequency analysis method and vascular impedance. Adult goats were anesthetized by halothane using an inhaler and a left fourth thoracotomy was performed. The inflow cannula was inserted into the left ventricle, and the outflow cannula was sutured to the descending aorta. The VFP and a centrifugal pump were set in parallel for alternation and comparison. The driving frequency of the VFP was changed and included 15, 20, 25, and 30 Hz. The hemodynamic parameters were continuously recorded during experiments by a digital audio tape (DAT) data recorder. The internal pressure of the left ventricular cavity and aortic pressure were monitored by the pressure manometers continuously. One hundred percent LV assistance was judged by the separation of LV and aortic pressure. The total vascular resistance was decreased by the start of operation of each pump. The decrease during flow using the VFP was not as large as that using a centrifugal pump (CP). The arterial input impedance during oscillated blood flow by the VFP showed a slow curve appearance. It was similar to the frequency characteristics curve of natural heart beats within the lower frequencies. The study of arterial impedance may be important for the estimation of the reflection of the pulsatile wave from the arterial branch, among other things.


[Prediction of the activity of rabies foci based on biotic and climatic factors].
Investigations carried out in Voronezh Province have shown that the activity of the foci of rabies is poorly related to the changes in the fox population. For the prognostication of the situation to be expected, good promise is held in the use of such data as the size of the population of murine rodents and the climatic conditions of the autumn and winter period. Rises in rabies morbidity are observed following an increase in the number of murine rodents (26% and higher) in autumn and a sharp decrease in their number by the spring of the epizootic year, and also if in the preceding year autumn began early and temperatures in winter and spring were above the average level, flood came quickly and water levels were low. It is expedient to use these regularities for the short-term prognosis of the epidemiological situation.


Hydrogen-dependent nitrogenase activity and ATP formation in Rhizobium japonicum bacteroids.
Rhizobium japonicum 122 DES bacteroids from soybean nodules possess an active H(2)-oxidizing system that recycles all of the H(2) lost through nitrogenase-dependent H(2) evolution. The addition of 72 muM H(2) to suspensions of bacteroids increased O(2) uptake 300% and the rate of C(2)H(2) reduction 300 to 500%. The optimal partial pressure of O(2) was increased, and the partial pressure of O(2) range for C(2)H(2) reduction was extended by adding H(2). A supply of succinate to bacteroids resulted in effects similar to those obtained by adding H(2). Both H(2) and succinate provided respiratory protection for the N(2)-fixing system in bacteroids. The oxidation of H(2) by bacteroids increased the steady-state pool of ATP by 20 to 40%. In the presence of 50 mM iodoacetate, which caused much greater inhibition of endogenous respiration than of H(2) oxidation, the addition of H(2) increased the steady-state pool of ATP in bacteroids by 500%. Inhibitor evidence and an absolute requirement for O(2) indicated that the H(2)-stimulated ATP synthesis occurred through oxidative phosphorylation. In the presence of 50 mM iodoacetate, H(2)-dependent ATP synthesis occurred at a rate sufficient to support nitrogenase activity. The addition of H(2) to H(2) uptake-negative strains of R. japonicum had no effect on ATP formation or C(2)H(2) reduction. It is concluded that the H(2)-oxidizing system in H(2) uptake-positive bacteroids benefits the N(2)-fixing process by providing respiratory protection of the O(2)-labile nitrogenase proteins and generating ATP to support maximal rates of C(2)H(2) reduction by oxidation of the H(2) produced from the nitrogenase system.


Substance use in the correctional settings: A qualitative exploration of individual and contextual characteristics and intervention strategies using the behavior change wheel framework.
Planning and implementing prison-based substance use disorder (SUD) interventions are challenging. We wanted to understand why and how people in correctional settings (CS) use drugs and to explore what policies, environmental, and interpersonal factors influence substance use among incarcerated people. Using the Behavior Change Wheel (BCW) framework, we proposed a thematic map with intervention functions to reduce substance use in CS. We used the Framework Method of qualitative analysis. We did snowball sampling for the incarcerated people with drug use (PWD) and convenience sampling for the staff. The in-depth interview sample comprised 17 adult PWD, three prison administrative, and two healthcare staff. We determined the sample size by thematic data saturation. We followed a mixed coding approach for generating categories, i.e., deductive (based on the BCW framework) and inductive. The study constructed the final theoretical framework by determining the properties of the categories and relationships among the categories. We identified eleven categories aligned with the BCW framework. The themes were prison routine, interpersonal dynamics of the incarcerated population, exposure to substance use, attitude of staff towards PWD, experience with prison healthcare, willingness (to reduce drug use) and coping, compassion, drug use harms, conflict between staff and residents, stigma, and family/peer support. The BCW framework aided the identification of potential intervention functions and their interactions with the organizational policies that could influence PWD's capability-opportunity-motivation (COM) and drug use behavior (B). There is a need to raise awareness of SUD prevention and intervention among decision-makers and revisit the prison policies.


Use of Canagliflozin in Combination With and Compared to Incretin-Based Therapies in Type 2 Diabetes.
In Brief Sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) are widely used to treat patients with type 2 diabetes. In clinical and real-world studies, canagliflozin, an SGLT2 inhibitor, has demonstrated superior A1C lowering compared to the DPP-4 inhibitor sitagliptin. Canagliflozin can also promote modest weight/fat loss and blood pressure reduction. The addition of canagliflozin to treatment regimens that include a DPP-4 inhibitor or a GLP-1 receptor agonist has been shown to further improve glycemic control, while still maintaining beneficial effects on cardiometabolic parameters such as body weight and blood pressure. Overall, the available clinical and real-world evidence suggests that canagliflozin is a safe and well-tolerated treatment option that can be considered either in addition to or instead of incretin-based therapies for patients with type 2 diabetes.


Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.
The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.


In vivo retroviral gene transfer by direct intrafemoral injection results in correction of the SCID phenotype in Jak3 knock-out animals.
Efficient retroviral gene transfer to pluripotential hematopoietic stem cells (PHSCs) requires ex vivo culture in multiple hematopoietic growth factors (HGFs) to promote cell division. While treatment of PHSCs with HGF can render stem cells viable targets for retroviral infection, HGFs can promote differentiation, loss of self-renewal potential, and affect the homing/engraftment capacity of PHSCs. To avoid the negative impacts observed with ex vivo transduction protocols, we developed a murine model for in vivo retroviral infection by direct intrafemoral injection (DII), thus abolishing the need for removal of cells from their native microenvironment and the signals necessary to maintain their unique physiology. Using this approach we have demonstrated in vivo retroviral gene transfer to colony-forming units-c (CFU-c), short-term reconstituting cells, and PHSCs. Moreover, direct intrafemoral injection of Jak3 knock-out mice with retroviral particles encoding the Jak3 gene resulted in reconstitution of normally deficient lymphocyte populations concomitant with improved immune function. In addition, DII can be used to target the delivery of other gene therapy vectors including adenoviral vectors to bone marrow cells in vivo. Taken together, these results demonstrate that in vivo retroviral gene transfer by direct intrafemoral injection may be a viable alternative to current ex vivo gene transfer approaches.


Octylphenol does not mimic diethylstilbestrol-induced oestrogen receptor-alpha expression in the newborn mouse uterine epithelium after prenatal exposure.
This study examined whether the endocrine disruptor octylphenol (OP) mimics the synthetic oestrogen diethylstilbestrol (DES) in ability to induce oestrogen receptor-alpha (ER-alpha) expression in the newborn mouse uterine epithelium after prenatal exposure. Pregnant mice were given daily s.c. injections with DES (10 or 100 microgram DES/kg maternal wt) or OP (100 or 250 mg/kg maternal wt) or with vehicle alone from day 11.5 to 16.5 of pregnancy. ER-alpha expression was evaluated on histological sections by detecting ER-alpha mRNA with the in situ hybridization technique and ER-alpha protein using immunohistochemistry. The immunostaining was quantitated using a microspectrophotometer. Oestrogen-like activity of the DES and OP batches used for in vivo exposure was confirmed in an in vitro assay based on transient gene expression of an oestrogen-dependent reporter plasmid. In mice exposed prenatally to vehicle alone, the uterine epithelium did not express either ER-alpha mRNA or protein, while both were highly expressed in the stroma. Exposure to either DES dose induced the expression of both ER-alpha mRNA and protein in the epithelium, whereas it was unchanged in the stroma. In contrast, neither OP dose induced the expression of ER-alpha mRNA or protein in the epithelium and expression was unchanged in the stroma. Our data stress the importance of in vivo studies when investigating endocrine disruptors.


Medication augmentation after the failure of SSRIs for depression.
Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).


Technical note: patient-specific quality assurance methods for TomoDirect(TM) whole breast treatment delivery.
To investigate the feasibility of implementing a novel approach for patient-specific QA of TomoDirect(TM) whole breast treatment. The most currently used TomoTherapy DQA method, consisting in the verification of the 2D dose distribution in a coronal or sagittal plane of the Cheese Phantom by means of gafchromic films, was compared with an alternative approach based on the use of two commercially available diode arrays, MapCHECK2(TM) and ArcCHECK(TM). The TomoDirect(TM) plans of twenty patients with a primary unilateral breast cancer were applied to a CT scan of the Cheese Phantom and a MVCT dataset of the diode arrays. Then measurements of 2D dose distribution were performed and compared with the calculated ones using the gamma analysis method with different sets of DTA and DD criteria (3%-3 mm, 3%-2 mm). The sensitivity of the diode arrays to detect delivery and setup errors was also investigated. The measured dose distributions showed excellent agreement with the TPS calculations for each detector, with averaged fractions of passed Γ values greater than 95%. The percentage of points satisfying the constraint Γ < 1 was significantly higher for MapCHECK2(TM) than for ArcCHECK(TM) and gafchromic films using both the 3%-3 mm and 3%-2 mm gamma criteria. Both the diode arrays show a good sensitivity to delivery and setup errors using a 3%-2 mm gamma criteria. MapCHECK2™ and ArcCHECK(TM) may fulfill the demands of an adequate system for TomoDirect(TM) patient-specific QA.


[Assessment of endoscopic, cytological and histological diagnostic methods in stomach polyps].
The results of endoscopic and morphological diagnostic methods for gastric polyps in 91 patients are analysed in detail. It is concluded that endoscopic examination makes it possible to reveal gastric polyps of any localization. However, to solve the problem of therapeutic policy it is necessary to examine the biopsy material from polyps, prior to their removal, both cytologically and histologically. This is due to the fact that small size polyps after endoscopic polypectomy are no longer suitable for morphological assay, whereas cytograms obtained from the transverse sections and surface of large polyps are equivalent diagnostically to cytograms of the biopsy specimens.


Prevalence of DSM-IV substance abuse and dependence disorders among prison inmates.
The study examined the 30-day and lifetime prevalence of DSM-IV alcohol and drug disorders among state prison inmates. A sample of 400 inmates consecutively admitted to a state prison reception center were assessed for alcohol and drug disorders using the Structured Clinical Interview for DSM-IV (SCID-IV). Test-retest reliabilities were calculated for the SCID-IV. Lifetime substance abuse or dependence disorders were detected among 74% of inmates, including over half who were dependent on alcohol or drugs. For the 30 days prior to incarceration, over half of the sample were diagnosed as having substance abuse or dependence disorders, including 46% who were dependent on alcohol or drugs. Black inmates were significantly less likely to be diagnosed as alcohol dependent than whites or Hispanics. The high rates of substance use disorders are consistent with previous findings from other studies conducted in correctional settings and reflect the need to expand treatment capacity in prisons.


Autism in the Haifa area--an epidemiological perspective.
Autism is a pervasive developmental disorder. The incidence rate and other related epidemiological characteristics of the Israeli population are not available. To assess the incidence rate of autism in the Haifa area and to compare family characteristics with previous reports from other countries. We approached facilities in the Haifa area that are involved with the diagnosis and treatment of autism. The study group comprised children born between 1989 and 1993. Records of the children were scrutinized and 69% of the mothers were interviewed. Live-birth cohorts of the same years were employed for incidence computation. An incidence rate of 1/1,000 was derived. Male to female ratio was 4.2:1. Pregnancy and perinatal periods were mostly uneventful. A low prevalence of developmental and emotional morbidity was reported for family members. The epidemiological characteristics found in the Haifa area are similar to those reported from non-Israeli communities. This finding supports an underlying biological mechanism for this disorder. These data can be used for future trend analyses in Israel.


[Monitoring parameter of respiratory biomechanics in coal miners].
Using computer spirography with registration of "flow-volume" curve for forced expiration, the authors monitored the most informative parameters of respiratory biomechanics in coal miners having preclinical chronic dust bronchitis. Revealed decrease of the ventilation values by 10-20% from the initial ones outlines the group with increased risk for chronic dust bronchitis.


Using curriculum mapping to engage faculty members in the analysis of a pharmacy program.
To develop a curriculum mapping process that supports continuous analysis and evidence-based decisions in a pharmacy program. A curriculum map based on the national educational outcomes for pharmacy programs was created using conceptual frameworks grounded in cognitive learning and skill acquisition. The curriculum map was used to align the intended curriculum with the national educational outcomes and licensing examination blueprint. The leveling and sequencing of content showed longitudinal progression of student learning and performance. There was good concordance between the intended and learned curricula as validated by survey responses from employers and graduating students. The curriculum mapping process was efficient and effective in providing an evidence-based approach to the continuous quality improvement of a pharmacy program.


The bidirectional NiFe-hydrogenase in Synechocystis sp. PCC 6803 is reduced by flavodoxin and ferredoxin and is essential under mixotrophic, nitrate-limiting conditions.
Cyanobacteria are able to use solar energy for the production of hydrogen. It is generally accepted that cyanobacterial NiFe-hydrogenases are reduced by NAD(P)H. This is in conflict with thermodynamic considerations, as the midpoint potentials of NAD(P)H do not suffice to support the measured hydrogen production under physiological conditions. We show that flavodoxin and ferredoxin directly reduce the bidirectional NiFe-hydrogenase of Synechocystis sp. PCC 6803 in vitro. A merodiploid ferredoxin-NADP reductase mutant produced correspondingly more photohydrogen. We furthermore found that the hydrogenase receives its electrons via pyruvate:flavodoxin/ferredoxin oxidoreductase (PFOR)-flavodoxin/ferredoxin under fermentative conditions, enabling the cells to gain ATP. These results strongly support that the bidirectional NiFe-hydrogenases in cyanobacteria function as electron sinks for low potential electrons from photosystem I and as a redox balancing device under fermentative conditions. However, the selective advantage of this enzyme is not known. No strong phenotype of mutants lacking the hydrogenase has been found. Because bidirectional hydrogenases are widespread in aquatic nutrient-rich environments that are capable of triggering phytoplankton blooms, we mimicked those conditions by growing cells in the presence of increased amounts of dissolved organic carbon and dissolved organic nitrogen. Under these conditions the hydrogenase was found to be essential. As these conditions close the two most important sinks for reduced flavodoxin/ferredoxin (CO2-fixation and nitrate reduction), this discovery further substantiates the connection between flavodoxin/ferredoxin and the NiFe-hydrogenase.


Air pollutant emissions from on-road vehicles in China, 1999-2011.
The on-road vehicular emission in China from 1999 to 2011 was estimated, based on the emission factors of vehicles with different emission standards calculated by the COPERT model. The CO, NMVOC, NOX, BC and OC emissions changed from 19.7 Tg, 4.4 Tg, 2.3 Tg, 47.1 Gg and 74.4 Gg in 1999 to 32.7 Tg, 4.1 Tg, 7.6 Tg, 177.6 Gg and 101.5 Gg in 2011, respectively. The general trend for CO, NOX and BC was increasing, while the tendency for NMVOC and OC was firstly increase before 2002 and then decrease from 2003. The spatial analysis results showed that high emissions occurred in developed provinces (Guangdong, Shandong, Hebei, Jiangsu and Henan). The correlation between vehicular emissions and GDP were further investigated and good linear correlation was found. The not-obvious change of the inter-annual (1999-2011) fitted straight line slope and the sustained increasing emissions for NOX and BC suggested that the challenge of mitigating vehicular NOX and BC emissions is severe in China. The contribution from different vehicle types was also analyzed. Passenger car (PC) and motorcycle (MC) was the main contributor to the CO and NMVOC emissions. However, the contribution ratio of MC was decreasing from 36.6% and 68.8% in 1999 to 15.7% and 25.7% in 2011. Heavy duty truck (HDT) was the dominant contributor to NOX, BC and OC, with proportions of 58.9%, 57.6% and 52.8% in 2011, respectively. In addition, the uncertainty of the estimated emissions was also assessed based on the Monte Carlo simulation.


Expression of IL-12, IL-10, PGE2, sIL-2R and sIL-6R in seminal plasma of fertile and infertile men.
The involvement of cytokines and other immunoregulatory factors in male infertility is still unclear. In the present study we compared the levels of IL-12, IL-10, PGE2, sIL-2R and sIL-6R in the seminal plasma (SP) of fertile and infertile men. Four groups were included: fertile donors (FERT), infertile men with azoospermia (AZOO), and infertile men with either oligoterato-asthenoazoospermia (OTA), or OTA with genital infection (OTA-INF). Cytokines and cytokine-soluble receptors in semen were evaluated by specific ELISA commercial kits. The levels of IL-12, sIL-2R and sIL-6R were similar in SP of fertile and infertile men. The mean levels of IL-10 in the SP of FERT, OTA and AZOO were 5.6 +/- 0.9, 4 +/- 2.8 and 8 +/- 3.5 pg ml-1, respectively, and did not differ significantly. The mean level of IL-10 in SP from OTA-INF (0.9 +/- 0.5 pg ml-1) was significantly lower than that for FERT (5.6 +/- 1.9 pg ml-1; P = 0.02) and AZOO (8.2 +/- 3.4 pg ml-1; P = 0.05), but not significantly different from that for OTA (3.7 +/- 2.1 pg ml-1). The mean SP level of PGE2 was significantly lower in SP of OTA-INF than FERT (7.67 +/- 2.26 and 19.67 +/- 3.69 micrograms ml-1, respectively; P < 0.02). In conclusion, the seminal plasma from fertile and infertile men contained similar levels of IL-12, sIL-2R and sIL-6R. However, the levels of IL-10 were significantly lower in SP from OTA-INF compared to FERT and AZOO. Our results indicate that specific cytokines and their soluble receptors are involved in the male reproductive system.


A qualitative study of post-settlement influences on State tobacco control funding.
State settlements with the tobacco industry increased the availability of funds that might be used for improving health outcomes and increased scrutiny of tobacco control funding overall. This research identified potential explanatory factors for state tobacco control funding and developed a conceptual framework to guide further exploration. Key informant interviews with 14 tobacco policy professionals were conducted to augment the information available in the scientific literature on funding influences. Interviews yielded a comprehensive list of 26 factors that were returned to key informants for ratings of importance using a modified Delphi process. Results indicate that the top funding influences are budgetary constraints, lobbying, advocacy, tobacco economy, legislative priorities, public opinion, and leadership by the governor or state legislators. A conceptual diagram is presented of all factors clustered into three categories. Further research is planned to quantify these factors and assess their explanatory value


Reliable typing of MERS-CoV variants with a small genome fragment.
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is an emerging pathogen that causes lower respiratory tract infection in humans. Camels are the likely animal source for zoonotic infection, although exact transmission modes remain to be determined. Human-to-human transmission occurs sporadically. The wide geographic distribution of MERS-CoV among dromedary camels and ongoing transmissions to humans provides concern for the evolution of a MERS-CoV variant with efficient human-to-human transmission capabilities. Phylogenetic analysis of MERS-CoV has occurred by analysis of full-length genomes or multiple concatenated genome fragments, which is time-consuming, costly and limited to high viral load samples. To develop a simple, reliable MERS-CoV variant typing assay to facilitate monitoring of MERS-CoV diversity in animals and humans. Phylogenetic analysis of presently known full-length MERS-CoV genomes was performed to identify genomic regions with sufficient phylogenetic content to allow reliable MERS-CoV variant typing. RT-PCR assays targeting these regions were designed and optimized. A reverse-transcription PCR assay for MERS-CoV targeting a 615 bp spike fragment provides a phylogenetic clustering of MERS-CoV variants comparable to that of full-length genomes. The detection limit corresponds to a cycle treshold value of ∼ 35 with standard upE real time PCR assays on RNA isolated from MERS-CoV EMC. Nasal swabs from RT-PCR positive camels (Ct values 12.9-32.2) yielded reliable sequence information in 14 samples. We developed a simple, reliable MERS-CoV variant typing assay which is crucial in monitoring MERS-CoV circulation in real time with relatively little investment on location.


A multicompartmental model of vitamin A kinetics in rats with marginal liver vitamin A stores.
A linear, first-order, constant-coefficient multicompartmental model is presented which describes the dynamics of [3H]retinol turnover in adult rats with normal plasma retinol concentrations but low liver stores (less than 100 micrograms of retinol equivalents). To fit plasma and tissue (liver, kidney, and rest of carcass) tracer and tracee data, eight physiological compartments were required in the model: two in plasma (proposed to correspond to the retinol transport complex, and retinyl esters in plasma lipoproteins) and two each in liver, kidneys, and other extrahepatic tissues. Extensive recycling of retinol among plasma, liver, and the rest of carcass was also required. The model predicted that 44% of whole body vitamin A (143 micrograms) was in extrahepatic tissues. The vitamin A utilization rate (system disposal rate) was 6.9 micrograms of retinol equivalents/day. The system residence time (mean sojourn time) for vitamin A was 21 days, and the fractional catabolic rate for the system was 5%/day. The mean transit time (turnover time) for vitamin A in its plasma retinol transport complex was 0.078 days (1.9 hr); the residence time was 0.98 day, versus 11 days in the liver, 9 days in carcass, and 0.54 days in kidneys. The model predicted that, of the plasma turnover, 48% recycled to the liver and 52% to extrahepatic tissues. The liver retinol secretion rate was 48 micrograms/day, more than half of which was from recycled plasma retinol. Since the plasma retinol turnover rate (87 micrograms/day) was 13 times the system disposal rate, the data suggest that this is a high response system in which changes in the dynamics of recycling of retinol allow for rapid adjustment in vitamin A distribution in response to changes in nutritional, metabolic, or physiological conditions; and in which plasma retinol levels are controlled homeokinetically by changes in hepatic and extrahepatic recycling of holo retinol-binding protein.


Physiological characterization of spinohypothalamic tract neurons in the lumbar enlargement of rats.
1. Ninety-six neurons in the lumbar enlargement of urethananesthetized rats were antidromically activated from the contralateral hypothalamus. The antidromic stimulating electrode was moved systematically within the hypothalamus until antidromic activation could be produced with currents of less than or equal to 50 microA (18.6 +/- 10.8 microA; mean +/- SD). The points at which antidromic activation thresholds were lowest were found in several regions of the hypothalamus but were concentrated in the optic tract and the supraoptic decussation. 2. The recording locations of 79 spinohypothalamic tract (SHT) neurons were marked and recovered. Twenty-nine were located in the superficial dorsal horn (SDH), 42 in the deep dorsal horn (DDH), 4 in the intermediate zone, and 2 in the gray matter surrounding the central canal. Two additional marks were located in the dorsal lateral funiculus (DLF). 3. The responses of 46 SHT neurons were examined during innocuous and noxious mechanical stimulation of their receptive fields. Forty-eight percent of recorded SHT neurons responded to both innocuous and noxious stimuli (wide dynamic range, WDR) and 39% responded only to noxious stimuli (high threshold, HT). Therefore 87% of SHT neurons responded preferentially or exclusively to noxious mechanical stimulation. Nine percent of SHT neurons responded exclusively to innocuous manipulation of joints and muscles. Four percent of SHT neurons responded only to innocuous tactile stimul (low threshold, LT). WDR, HT, and LT neurons were recorded widely throughout the dorsal horn; no relationship was found between the locations of recording sites in the dorsal horn and the response types of the neurons. SHT neurons that responded to stimulation of muscle, tendon, or joint were recorded deep in the gray matter. 4. The effects of heating the receptive fields were determined for 25 SHT neurons. Fourteen (56%) responded to thermal stimuli. Six (43%) of the responsive neurons responded at low frequencies to innocuous warming (38-41 degrees C) but more vigorously to noxious (greater than or equal to 45 degrees C) heating. The other eight responded only to noxious heat. Eighteen percent (3/17) of tested SHT neurons were activated by noxious cooling of their receptive fields. 5. Cutaneous receptive fields of most recorded SHT neurons were small, typically involving areas as small as two or three toes on the ipsilateral hindlimb; the largest receptive fields covered the entire paw. These findings indicate that relatively precise information about the location of innocuous and noxious stimuli is conveyed directly to the hypothalamus by SHT neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Air ventilation by recoil aspiration in polypterid fishes.
High-speed x-ray cine films synchronized with intra-pleuroperitoneal pressure measurements show that polypterid fishes aspiration breathe by the deformation and recoil of their bony-scaled integument. Paleozoic amphibians arose from ancient air-breathing fishes and retained piscine bony scales in V-shaped rows along the belly. These scales resemble those of modern polypterid fishes and may have contributed to inhalation by elastic recoil. The discovery that polypterid fishes breathe by recoil aspiration is the first evidence for aspiration breathing in any lower vertebrate. The use of recoil aspiration by polypterids shows that elastic storage in a stiff body wall can contribute to inhalation in animals with limited capacity for active aspiration.


Interpersonal influence among public health leaders in the United States department of health and human services.
In public health, interpersonal influence has been identified as an important factor in the spread of health information, and in understanding and changing health behaviors. However, little is known about influence in public health leadership. Influence is important in leadership settings, where public health professionals contribute to national policy and practice agendas. Drawing on social theory and recent advances in statistical network modeling, we examined influence in a network of tobacco control leaders at the United States Department of Health and Human Services (DHHS). Fifty-four tobacco control leaders across all 11 agencies in the DHHS were identified; 49 (91%) responded to a web-based survey. Participants were asked about communication with other tobacco control leaders, who influenced their work, and general job characteristics. Exponential random graph modeling was used to develop a network model of influence accounting for characteristics of individuals, their relationships, and global network structures. Higher job ranks, more experience in tobacco control, and more time devoted to tobacco control each week increased the likelihood of influence nomination, as did more frequent communication between network members. Being in the same agency and working the same number of hours per week were positively associated with mutual influence nominations. Controlling for these characteristics, the network also exhibited patterns associated with influential clusters of network members. Findings from this unique study provide a perspective on influence within a government agency that both helps to understand decision-making and also can serve to inform organizational efforts that allow for more effective structuring of leadership.


Measuring socio-economic position in dietary research: is choice of socio-economic indicator important?
To examine the association between socio-economic position (SEP) and diet, by assessing the unadjusted and simultaneously adjusted (independent) contributions of education, occupation and household income to food purchasing behaviour. The sample was randomly selected using a stratified two-stage cluster design, and the response rate was 66.4%. Data were collected by face-to-face interview. Food purchasing was examined on the basis of three composite indices that reflected a household's choice of grocery items (including meat and chicken), fruit and vegetables. Brisbane City, Australia, 2000. : Non-institutionalised residents of private dwellings located in 50 small areas (Census Collectors Districts). When shopping, respondents in lower socio-economic groups were less likely to purchase grocery foods that were high in fibre and low in fat, salt and sugar. Disadvantaged groups purchased fewer types of fresh fruits and vegetables, and less often, than their counterparts from more advantaged backgrounds. When the relationship between SEP and food purchasing was examined using each indicator separately, education and household income made an unadjusted contribution to purchasing behaviour for all three food indices; however, occupation was significantly related only with the purchase of grocery foods. When education and occupation were simultaneously adjusted for each other, the socio-economic patterning with food purchase remained largely unchanged, although the strength of the associations was attenuated. When household income was introduced into the analysis, the association between education, occupation and food purchasing behaviour was diminished or became non-significant; income, however, showed a strong, graded association with food choice. The food purchasing behaviours of socio-economically disadvantaged groups were least in accord with dietary guideline recommendations, and hence are more consistent with greater risk for the development of diet-related disease. The use of separate indicators for education, occupation and household income each adds something unique to our understanding of how socio-economic position is related to diet: each indicator reflects a different underlying social process and hence they are not interchangeable, and do not serve as adequate proxies for one another.


Mechanisms of Photoreceptor Death in Retinitis Pigmentosa.
Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.


Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease.
To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test. We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates. We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.


Learning higher-order structures in natural images.
The theoretical principles that underlie the representation and computation of higher-order structure in natural images are poorly understood. Recently, there has been considerable interest in using information theoretic techniques, such as independent component analysis, to derive representations for natural images that are optimal in the sense of coding efficiency. Although these approaches have been successful in explaining properties of neural representations in the early visual pathway and visual cortex, because they are based on a linear model, the types of image structure that can be represented are very limited. Here, we present a hierarchical probabilistic model for learning higher-order statistical regularities in natural images. This non-linear model learns an efficient code that describes variations in the underlying probabilistic density. When applied to natural images the algorithm yields coarse-coded, sparse-distributed representations of abstract image properties such as object location, scale and texture. This model offers a novel description of higher-order image structure and could provide theoretical insight into the response properties and computational functions of lower level cortical visual areas.


Characterization of hobo element copy number and integrity in Brasilian populations of Drosophila melanogaster.
We have determined the copy number and the presence of full-size hobo transposable elements in eight Brasilian strains of Drosophila melanogaster. Genomic DNA was digested with AvaII and XhoI restriction enzymes, respectively, and probed with a 963 bp sequence of the hobo element. Variable numbers of full-sized and defective elements were detected in all strains. The range of the copy number was 22.13 +/- 4.52. Blots showed the presence of a 2.6 kb fragment, corresponding to the complete element, in all strains exception of one and the 1.0 kb sequence, correponding to the Th1 and Th2 repressor elements. There was neither association among copy numbers of hobo elements and latitude nor the mean annual temperatures in the original geographical region of each strain.


[Ouabain-insensitive K+ and Na+ fluxes in frog muscle].
Potassium and sodium fluxes in frog muscles incubated in K- and Na-free Mg2+ or choline-substituted Ringer solution were studied. Ouabain (10(-4) M) increased the potassium and decreased the sodium efflux. It was shown, that the increase of the potassium efflux was not due to changes in membrane electrical properties of inhibition of "back pumping" of potassium ions leaking out of the cells. It is supposed that potassium ions are translocated by K-carrier phosphorylated with inorganic phosphate. As known, ouabain accelerates this type of phosphorylation, that is why the potassium efflux increases. In a medium with or without ouabain sodium ions are translocated by Na-ATPase without participation of external potassium ions. Thus sodium and potassium fluxes carried out by membrane ATPase systems are not coupled.


Silicon Nanowire Field Effect Transistor Sensors with Minimal Sensor-to-Sensor Variations and Enhanced Sensing Characteristics.
Silicon nanowire field effect transistor (FET) sensors have demonstrated their ability for rapid and label-free detection of proteins, nucleotide sequences, and viruses at ultralow concentrations with the potential to be a transformative diagnostic technology. Their nanoscale size gives them their ultralow detection ability but also makes their fabrication challenging with large sensor-to-sensor variations, thus limiting their commercial applications. In this work, a combined approach of nanofabrication, device simulation, materials, and electrical characterization is applied toward identifying and improving fabrication steps that induce sensor-to-sensor variations. An enhanced complementary metal-oxide-semiconductor-compatible process for fabricating silicon nanowire FET sensors on 8 in. silicon-on-insulator wafers is demonstrated. The fabricated nanowire (30 nm width) FETs with solution gates have a Nernst limit subthreshold swing (SS) of 60 ± 1 mV/decade with ∼1.7% variations, whereas literature values for SS are ≥80 mV/decade with larger (>10 times) variations. Also, their threshold voltage variations are significantly (∼3 times) reduced, compared to literature values. Furthermore, these improved FETs have significantly reduced drain current hysteresis (∼0.6 mV) and enhanced on-current to off-current ratios (∼106). These improvements resulted in nanowire FET sensors with the lowest (∼3%) reported sensor-to-sensor variations, compared to literature studies. Also, these improved nanowire sensors have the highest reported sensitivity and enhanced signal-to-noise ratio with the lowest reported defect density of 2.1 × 1018 eV-1 cm-3, in comparison to literature data. In summary, this work brings the nanowire sensor technology a step closer to commercial products for early diagnosis and monitoring of diseases.


Laser-based micromanipulation for separation and identification of individual Frankia vesicles.
In studies of symbiotic efficiency it is of great importance to identify and separate individual Frankia strains from a nodule. Therefore, a new laser-based micromanipulation technique has been developed in which individual vesicles from root nodules of two Frankia-Alnus symbioses have been successfully cut loose and separated from clusters of vesicles in sterile conditions under light microscopy using a laser scalpel and optical tweezers. Vesicles from the Alnus incana-Frankia AvCI1 symbiosis were successfully isolated and grown in culture using this technique. The DNA from both Frankia sources was amplified by polymerase chain reaction (PCR). The work shows that a combination of laser-based manipulation techniques and PCR can be used for the separation and study of individual vesicles. This novel laser-based micromanipulation technique opens up various new possibilities, for instance, to study whether several Frankia strains can grow simultaneously in the same root nodule.


HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.
Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.


Thiophene based europium β-diketonate complexes: effect of the ligand structure on the emission quantum yield.
The synthesis and the molecular and photophysical characterization, together with solid state and solution structure analysis, of a series of europium complexes based on β-diketonate ligands are reported. The Eu(III) complex emission, specifically its photoluminescence quantum yield (PL-QY), can be tuned by changing ligands which finely modifies the environment of the metal ion. Steady-state and time-resolved emission spectroscopy and overall PL-QY measurements are reported and related to geometrical features observed in crystal structures of some selected compounds. Moreover, paramagnetic NMR, based on the analogous complexes with other lanthanides, are use to demonstrate that there is a significant structural reorganization upon dissolution, which justifies the observed differences in the emission properties between solid and solution states. The energy of the triplet levels of the ligands and the occurrence of nonradiative deactivation processes clearly account for the luminescence efficiencies of the complexes in the series.


Aging-Related Concerns of People Living with HIV Referred for Geriatric Consultation.
People with HIV (PWH) are living longer lives and likely experiencing accentuated aging. Comprehensive geriatric assessment (CGA) has been proposed as a way to identify and help meet each individual patient's needs. We performed a retrospective review of the results of CGA in an HIV clinic in New York City. CGA included assessment of basic and instrumental activities of daily living, screens for depression, anxiety, frailty, cognition, and quality of life, along with general discussion of concerns and goals. We compared the group of PWH referred for CGA to those of comparable age who were not referred to determine the factors that were associated with referral. We carried out a descriptive analysis of those undergoing CGA, along with regression to determine factors associated with poorer PHQ-2 depression scores and higher VACS score. A total of 105 patients underwent full CGA during the study period. Mean age of referred patients was 66.5 years, ranging from 50 to 84 years (SD 7.99). More than 92% were virally suppressed. Compared with their non-referred counterparts over 50, referred patients were older and had more functional comorbidities like cerebrovascular disease, neuropathy, and urinary incontinence. More than half complained of fatigue, and 2/3 noted poor memory. Almost 60% were frail or prefrail. Ninety patients were asked about their goals, and the most commonly cited were related to health or finances; fifteen patients were unable to articulate any goals. Having fewer goals and noting weight loss or fatigue were predictive of higher scores on the PHQ-2 depression screen. Although most older PWH undergoing CGA can manage their ADL, many have concerns and deficits beyond their comorbidities. CGA offers an important window into the psychosocial concerns and needs of older PWH.


An electrochemical impedance spectroscopy investigation of the overpotentials in Li-O2 batteries.
Lithium-O2 (Li-O2) batteries are currently limited by a large charge overpotential at practically relevant current densities, and the origin of this overpotential has been heavily debated in the literature. This paper presents a series of electrochemical impedance measurements suggesting that the increase in charge potential is not caused by an increase in the internal resistance. It is proposed that the potential shift is instead dictated by a mixed potential of parasitic reactions and Li2O2 oxidation. The measurements also confirm that the rapid potential loss near the end of discharge ("sudden death") is explained by an increase in the charge transport resistance. The findings confirm that our theory and conclusions in ref 1, based on experiments on smooth small-area glassy carbon cathodes, are equally valid in real Li-O2 batteries with porous cathodes. The parameter variations performed in this paper are used to develop the understanding of the electrochemical impedance, which will be important for further improvement of the Li-air battery.


Mutagenicity assay in Salmonella for thirteen 2-substituted-1 H-phenanthro (9,10-d) imidazoles.
Some 2-substituted-1 H-phenanthro [9,10-d] imidazole compounds synthesized as a predrugs were tested in mutagenicity assays in Salmonella strains TA97, TA98, and TA100 using a plate incorporation assay both with and without S9 mix. The 10 substances were mutagenic in TA97 and five of them were mutagenic only with metabolic activation, whereas one of them did not require the addition of S9. The eight substances were mutagenic in TA98 only with S9. For TA100, seven substances showed positive results both with and without S9, however another four required S9, whereas only one of them did not required metabolic activation. In summary, all of 13 substances derived from phenanthro [9,10-d] imidazole were found to be mutagenic for at least one or two of the three strains and their mutagenicity are discussed.


Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands.
Human D-type prostanoid (DP) and E-type prostanoid 2 (EP2) receptors are G protein-coupled receptors and are regarded as the most closely related receptors among prostanoid receptors because they are generated by tandem duplication. The DP receptor-cognate ligand, prostaglandin D2 (PGD2 ) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor-cognate ligand, prostaglandin E2 (PGE2 ) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation. However, since PGD2 and/or PGE2 activate DP and EP2 receptors to similar maximal levels, that is, their similar efficacies, differences between the ligands in each receptor have not yet been determined in detail except for their different affinities. Herein we demonstrated, using an in silico simulation to predict binding patterns among DP or EP2 receptors and PGD2 , PGE2 , or prostaglandin F2α as the reference prostanoid, that DP and EP2 receptors plausibly take on distinct forms depending on the diverse binding of different ligands. Since these ligands have the potential to make these receptors form distinct conformations with discrete signaling pathways, they are consequently regarded as endogenous biased ligands. Moreover, by using functional assays, the susceptibilities of the DP receptors to the noncognate ligands were approximately 10 times lower than those of EP2 receptors. Thus, EP2 receptors seem to be able to distinguish endogenous ligands better than DP receptors, thereby both receptors are plausibly gaining role-sharing functions with respect to one another as the copies of duplicated gene.


Changes in ocular globe-to-orbital rim position with age: implications for aesthetic blepharoplasty of the lower eyelids.
Changes in the relationship of the anterior globe to the orbital rim, orbital fat, and cheek mass are examined in the present study. Two groups of individuals (N = 28) were studied, young versus old, using three-dimensional computer tomography. A computer-derived soft tissue reformat of the data allowed the anterior-posterior changes to be evaluated at the midpupillary plane. Analysis of the data brings to light two important changes which occur with aging. First, the orbital rim moves posteriorly relative to the anterior cornea with age (p = 0.0007). This is important because overresection of orbital fat during lower blepharoplasty accentuates the proptotic appearance of the eye which occurs naturally with age due to orbital remodeling. A second finding is that there is a tendency for the cheek mass to move posteriorly with age relative to the anterior cornea (p = 0.0038). The negative vector, a warning sign for lower blepharoplasty, becomes more common with advancing age. It is suggested that the presence of a negative vector is a sign of generalized maxillary hypoplasia. Certain individuals with a negative vector can be further identified preoperatively by the clinical triad of scleral show, prominent medial fat, and a prominent nasojugal crease. These individuals likewise exhibit maxillary hypoplasia and may be more prone to complications after blepharoplasty. Lastly, a summated model of skeletal remodeling is presented. The significant points are as follows: (1) contrary to previous work, the craniofacial skeleton remodels throughout adulthood, (2) changes in the skeletal architecture impart their effects on the overlying soft tissues, and (3) facial aging is a summation of both hard and soft tissue changes which occur throughout life.


[The comprehensive assessment of studies of the microbiological and cytological indices of the implant-epithelial area].
Microbiological and cytological study of the subgingival deposit at the site of introduction of intraosseous cylindrical nickelide-titanium dental implants and comparison of the findings with similar values for the adjacent teeth showed that such studies help assess the status of the implant-epithelial zone.


The molecular basis of memory. Part 3: tagging with "emotive" neurotransmitters.
Many neurons of all animals that exhibit memory (snails, worms, flies, vertebrae) present arborized shapes with many varicosities and boutons. These neurons, release neurotransmitters and contain ionotropic receptors that produce and sense electrical signals (ephaptic transmission). The extended shapes maximize neural contact with the surrounding neutrix [defined as: neural extracellular matrix (nECM) + diffusible (neurometals and neurotransmitters)] as well as with other neurons. We propose a tripartite mechanism of animal memory based on the dynamic interactions of splayed neurons with the "neutrix." Their interactions form cognitive units of information (cuinfo), metal-centered complexes within the nECM around the neuron. Emotive content is provided by NTs, which embody molecular links between physiologic (body) responses and psychic feelings. We propose that neurotransmitters form mixed complexes with cuinfo used for tagging emotive memory. Thus, NTs provide encoding option not available to a Turing, binary-based, device. The neurons employ combinatorially diverse options, with >10 NMs and >90 NTs for encoding ("flavoring") cuinfo with emotive tags. The neural network efficiently encodes, decodes and consolidates related (entangled) sets of cuinfo into a coherent pattern, the basis for emotionally imbued memory, critical for determining a behavioral choice aimed at survival. The tripartite mechanism with tagging of NTs permits of a causal connection between physiology and psychology.


Are Bioceramics the Dernier Cri in the Management of Stage 4 Developed Root? A Finite Element Analysis.
To compare the stress distribution of four modalities of reinforcing the radicular space of a pulpless central incisor exhibiting stage 4 root development. The model of a pulpless immature central incisor with a stage 4 of root development supporting periodontium was generated based on the properties. The longitudinal growth of the root was completed. Four such models were developed. Then, the radicular space was rehabilitated as follows: Model 1: Ceramicrete; Model 2: Biomimetic Mineralization; Model 3: Biodentine; Model 4: Bioaggregate. They were subjected to three different loading conditions. One was to mimic the mastication by applying a load of 70 N applied at 45° angle. Second loading condition was a vertical load of 100 N to mimic bruxism. The third loading condition was to mirror the impact of a frontal trauma. A load of 100 N was applied labially. It was observed that during mastication, Model 2 has exhibited the lowest concentration of von Mises stresses, followed by Model 3 and then Model 4 followed by Model 1; this could be because the modulus of elasticity of Model 2 is comparable to that of Dentin. During bruxism and horizontal impact, the maximal stress concentration was found in Model 4, Model 3, Model 2, followed by Model 1. The closer the elasticity of modulus of the primary endodontic replacement monoblock was to that of dentin, the lower were the stresses generated. However, as the increase in stress values was minimal between groups, these obturating materials can be viable reinforcement materials for the rehabilitation of cases of stage 4 developing root. Biomimetic mineralization strategies can be a viable treatment option for managing cases of the open apex. Biomimetic mineralization strategies and bioceramics can be used for obturation of root canals with open apex, instead of utilizing these bioceramics as apical plugs.


Lixisenatide for type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is an increasing health problem worldwide. Glucagon-like peptide-1 (GLP-1) receptor agonists are an expanding drug class that target several of the pathophysiological traits of T2DM. Lixisenatide is a GLP-1 receptor agonist in development for once-daily treatment of T2DM. Pharmacological, preclinical and clinical evidence demonstrating the applicability of lixisenatide for the treatment of T2DM are reviewed. Available data and pending clinical development are summarized, critically appraised and compared to competitor drugs. The most relevant papers and meeting abstracts published up to November 2010 are used as sources for this review. Efficacy and safety in T2DM are demonstrated with lixisenatide in monotherapy and in combination with metformin. However, limited data with the intended once-daily 20 μg subcutaneous dosing necessitate further evaluation of lixisenatide as add-on to various antidiabetic treatments. It remains to be established whether the slightly differing chemical properties compared to other GLP-1 receptor agonists including a rather short duration of action will be a disadvantage or maybe even an advantage, for example, when combined with long-acting insulin.


Cumulative trauma disorder of the upper limb.
The current status of cumulative trauma disorder of the upper limb is examined from the standpoint of its long history, its current controversies, and the philosophic basis of the present laws, which control management of the condition. The future needs that should permit cumulative trauma disorders to be better understood, better managed, and better legislated are also addressed.