Utilization of vinasse for production of poly-3-(hydroxybutyrate-co-hydroxyvalerate) by Haloferax mediterranei.
Vinasse, a highly polluting waste of the ethanol industry was utilized for the production of polyhydroxyalkanoate (PHA) by the extremely halophilic archaeon, Haloferax mediterranei in shake-flasks. Following pre-treatment through adsorption on activated carbon, 25%-50% (v/v) pre-treated vinasse was utilized leading to 70% maximum accumulation of PHA. Maximum PHA concentration of 19.7 g/l, product yield coefficient (based on total carbohydrates) of 0.87 and 0.21 g/l h volumetric productivity were achieved. Concomitant lowering of BOD5 of pre-treated vinasse by at least 78% and COD by at least 80% was attained at the end of this process. The PHA was recovered by osmotic lysis of the cells and purification by sodium hypochlorite and organic solvents. Through UV-vis spectroscopy, gas chromatography, differential scanning calorimetry and nuclear magnetic resonance spectroscopy, the PHA was identified as poly-3-(hydroxybutyrate-co-hydroxyvalerate). The 3-hydroxyvalerate content was 12.36 mol % (utilizing 25% pre-treated vinasse) and 14.09 mol % (utilizing 50% pre-treated vinasse). High salt concentration in the medium allowed this process without sterile conditions and thus reduction in costs of sterilization can be envisaged. Activated charcoal pre-treatment of vinasse is economical than competing processes such as ultrafiltration of whey, extrusion and enzymatic treatment of rice and corn starch. Without impacting sugar prices, this process can easily be integrated into a distillery that has fermentation equipment and trained personnel. High PHA content, productivity, zero-cost carbon source, low-cost isolation of a high-purity product and potential integration into ethanol manufacturing unit with concomitant wastewater treatment should merit further development of this process to higher scales.


Detailed assessment of nutritional status and eating patterns in children with gastrointestinal diseases attending an outpatients clinic and contemporary healthy controls.
In the era of modern multidisciplinary clinical management, very little is known about the prevalence and presentation of malnutrition in children with gastrointestinal disorders (GastroD) particularly employing composite, global measures of nutritional status. Anthropometry, body composition, dietary intake, eating habits and grip strength were assessed with bedside methods in 168 patients from outpatient gastroenterology clinics (n, median (IQR) years; Crohn's disease (CD): n=53, 14.2 (11.6:15.4); ulcerative colitis (UC): n=27, 12.2 (10.7:14.2); coeliac disease: n=31, 9.3 (7.5:13.6); other GastroD: n=57, 9.8 (7.2:13.8)) and compared with 62 contemporary healthy controls (n, median (IQR): 9.8 (6.9:13.8)) and the results of the recent UK, National Diet and Nutritional Survey (NDNS). Children with CD had lower BMI z-scores than controls (median (IQR): -0.3 (-0.9:0.4) vs 0.3 (-0.6:1.4); P=0.02) but only 2% were classified as thin (BMI z-score <-2 s.d.). The prevalence of obesity in children with UC was 19%, 6% in CD, 11% in children with other GastroD and 15% in controls. No difference was found in grip strength measurement between groups. Except for CD children, the proportion of patients with suboptimal micronutrient intake was similar to that of controls and the cohort of children from the latest NDNS. A higher proportion of children with CD had suboptimal intake for riboflavin, vitamin B6 and calcium and consumed significantly more meat products, juices (including carbonated drinks), spreads/jams and crisps and savoury snacks and significantly fewer portions of dairy, fish, fruits and vegetables compared with healthy controls. GastroD affect children's body composition, growth, strength, dietary intake and eating habits, particularly CD, but to a lesser extent than expected.


The Roles of the PSEUDO-RESPONSE REGULATORs in Circadian Clock and Flowering Time in Medicago truncatula.
PSEUDO-RESPONSE REGULATORs (PRRs) play key roles in the circadian rhythms and flowering in plants. Here, we identified the four members of the PRR family in Medicago truncatula, including MtPRR9a, MtPRR9b, MtPRR7 and MtPRR5, and isolated their Tnt1 retrotransposon-tagged mutants. They were expressed in different organs and were nuclear-localized. The four MtPRRs genes played important roles in normal clock rhythmicity maintenance by negatively regulating the expression of MtGI and MtLHY. Surprisingly, the four MtPRRs functioned redundantly in regulating flowering time under long-day conditions, and the quadruple mutant flowered earlier. Moreover, MtPRR can recruit the MtTPL/MtTPR corepressors and the other MtPRRs to form heterodimers to constitute the core mechanism of the circadian oscillator.


[Congenital diaphragmatic hernia. Prenatal diagnosis and neonatal outcome].
The objective of this study is to determine the management and the outcome of 17 cases of congenital diaphragmatic hernia observed, and to compare the results with the literature data. The study was made between June 1994 and June 1998 in the Department of Obstetrics and Gynecology of the University of Naples Federico II and it collected 17 pregnant women with diagnosed or suspected congenital diaphragmatic hernia, referred to our diagnostic unit from other institutes: between 18 and 37 weeks' gestation, a detailed ultrasound examination and an echocardiography were performed to confirm the diagnosis, to establish the site and contents of the hernia exactly and to detect associated structural malformations. Fetal kariotyping was made in 7 cases. When the women decided to continue pregnancy, or the legal limit for termination of pregnancy was exceeded, the pregnancy was monitored with ultrasound examination, delivery took place in our department and the baby was transferred to an intensive care unit. Ultrasound examination led to the diagnosis of 14 postero-lateral left-sided diaphragmatic hernias (82.3%), 1 antero-lateral left-sided (5.9%), 1 bilateral postero-lateral sided (5.9%) and 1 diaphragmatic eventration (5.9%). Associated structural malformation were diagnosed in 4 fetuses (27%). In 1 case only (14.3% of examinated kariotyping) an abnormal result was found. Five pregnancies (29.4%) were terminated, 2 (11.7%) are still going on and 10 fetuses (58.9%) were born alive: 5 fetuses (50%) died in the first days of life before surgical intervention, 2 (40% of operated children and 20% of born alive) died after the operation and 3 (60% of operated children and 30% of born alive) are actually alive and in good health. The total postnatal mortality was 70% and 40% after operation. From the analysis of these data and from the international literature the conclusion is drawn that congenital diaphragmatic hernia is associated with a high postnatal mortality, although potentially it can be corrected with surgery: a better postnatal management and a better knowledge of evaluable in uterus prognostic factors are necessary to improve postnatal outcome.


Menopause effect on blood Fe and Cu isotope compositions.
Iron (δ(56) Fe) and copper (δ(65) Cu) stable isotope compositions in blood of adult human include a sex effect, which still awaits a biological explanation. Here, we investigate the effect of menopause by measuring blood δ(56) Fe and δ(65) Cu values of aging men and women. The results show that, while the Fe and Cu isotope compositions of blood of men are steady throughout their lifetime, postmenopausal women exhibit blood δ(65) Cu values similar to men, and δ(56) Fe values intermediate between men and premenopausal women. The residence time of Cu and Fe in the body likely explains why the blood δ(65) Cu values, but not the δ(56) Fe values, of postmenopausal women resemble that of men. We suggest that the Cu and Fe isotopic fractionation between blood and liver resides in the redox reaction occurring during hepatic solicitation of Fe stores. This reaction affects the Cu speciation, which explains why blood Cu isotope composition is impacted by the cessation of menstruations. Considering that Fe and Cu sex differences are recorded in bones, we believe this work has important implications for their use as a proxy of sex or age at menopause in past populations.


The linkage between protein folding and functional cooperativity: two sides of the same coin?
During the course of their biological function, proteins undergo different types of structural rearrangements ranging from local to large-scale conformational changes. These changes are usually triggered by their interactions with small-molecular-weight ligands or other macromolecules. Because binding interactions occur at specific sites and involve only a small number of residues, a chain of cooperative interactions is necessary for the propagation of binding signals to distal locations within the protein structure. This process requires an uneven structural distribution of protein stability and cooperativity as revealed by NMR-detected hydrogen/deuterium exchange experiments under native conditions. The distribution of stabilizing interactions does not only provide the architectural foundation to the three-dimensional structure of a protein, but it also provides the required framework for functional cooperativity. In this review, the statistical thermodynamic linkage between protein stability, functional cooperativity, and ligand binding is discussed.


Admission patterns and risk factors linked with neonatal mortality: A hospital-based retrospective study.
This research was conducted to analyze the elements and factors that link with newborn deaths at Neonatal Intensive Care Unit (NICU) of a public teaching hospital in Jordan. A retrospective study was conducted by reviewing the medical records of all the neonates admitted to the NICU over a one- year period from 1st of March, 2018 to 28th of February, 2019 at Princess Rahma Pediatric Hospital, Jordan. Overall, the medical records of 1247 neonates were included in this study. The common causes of admission were sepsis (27.3%), followed by respiratory distress syndrome (RDS) (24.9%) and asphyxia (13.1%). The majority of the admitted neonates survived (91.9%), and the overall mortality rate was 8.1%. According to the cause-specific death rate analysis, RDS was the most common cause of death rate (35.6%), followed by sepsis (27.7%). Logistic regression analysis results show that gestational age, weight of the baby at birth, and the quick clinical assessment (Apgar) within the first five minutes were the strongest predictors of neonatal mortality (P<0.05). Sepsis, RDS, and asphyxia were the leading causes of morbidity in neonates. These diseases were also responsible for a high rate of mortality. Understanding the cause of morbidity and mortality of neonates admitted at NICU is useful for prioritizing and planning health services, re-allocating resources, and improving the quality of care.


Changes in the coordination between respiration and swallowing from suckling through weaning.
All mammals undergo weaning from milk to solid food. This process requires substantial changes to mammalian oropharyngeal function. The coordination of swallowing and respiration is a crucial component of maintaining airway function throughout feeding and matures over infant development. However, how this coordination is affected by weaning is unknown. In this study, we ask how changes in posture, neural maturation and food properties associated with the weaning affect coordination of respiration and swallowing in a validated infant pig model. We recorded seven piglets feeding before and during the weaning age with liquid milk in a bottle and in a bowl, and solid feed in a bowl. Using videofluoroscopy synchronized with respiration, we found (i) the delay in the onset of inspiration after swallowing does not change with head position, (ii) the delay is different between solid food and bowl drinking at the same age and (iii) the delay increases over time when bottle feeding, suggesting a maturational effect. Significant changes in aerodigestive coordination occur prior to and post-weaning, resulting in distinctive patterns for liquid and solid food. The interplay of maturational timelines of oropharyngeal function at weaning may serve as a locus for behavioural and life-history plasticity.


Effects of ghrelin receptor activation on forebrain dopamine release, conditioned fear and fear extinction in C57BL/6J mice.
The ghrelin system was previously proposed to mediate an independent branch of the stress response that curbs fear processing. Interestingly, the ghrelin system was also shown to control the activity of midbrain dopamine neurons. Given that dopamine neurons of the ventral tegmental area appear to have a critical role in fear processing, we aimed to investigate their contribution to the effects of ghrelin on fear processing. Our data show that systemic administration of the ghrelin receptor agonist MK0677, in a dose that induces food intake, has no significant effect on auditory fear processing and does not significantly affect dopamine release in the nucleus accumbens of male C57BL/6J mice. Local administration of the ghrelin receptor agonist MK0677 into the ventral tegmental area significantly increases food intake and it also significantly increased dopamine release in the nucleus accumbens, the medial prefrontal cortex and the amygdala. Nevertheless, it did not significantly affect auditory fear extinction. Our data indicate that pharmacological activation of midbrain dopamine neurons using a ghrelin receptor agonist does not affect auditory fear extinction. We also investigated the effect of non-pharmacological manipulation of the ghrelin system on auditory fear processing. However, we found that neither overnight food deprivation nor genetic ablation of the ghrelin receptor had a significant effect on auditory fear extinction. We conclude that the effects of manipulation of the ghrelin system on fear processing are subject to boundary conditions that remain poorly understood.


[Expressions of oncogene products in adenoid cystic carcinomas of salivary glands: immunohistochemical study].
In 43 cases of adenoid cystic carcinomas of the salivary glands (ACC), expressions of the oncogene products such as epidermal growth factor receptor (EGF-R), erbB-2 product, c-myc product and N-myc product were investigated immunohistochemically. First, we confirmed the specificity of the antibodies used with the 13 cell lines. Of the anti-EGF-R antibodies, clone 29. 1. 1 reacted only with A431 but not with the other cell lines overexpressing EGF-R, so that it was most likely to cross-react with the blood type A antigen. Also, the anti-N-myc product antibody revealed the presence of a certain cross-reacting antigen in Lu65. Overexpression of EGF-R was observed in only one case. Nine cases (20.9%) showing tubular and cribriform patterns overexpressed the erbB-2 product, but the signals were mainly localized in the cytoplasm as a granular appearance. Eighteen cases (41.9%) with slight cellular atypia showed an overexpression of the c-myc product. The immunolocalization of the c-myc product was at the nuclei in most cases, or both the nuclei and the cytoplasm in some cases. None of the ACC expressed the N-myc product. It is speculated that the multiple oncogene expressions might be partly related to the acquirement of the differentiated or malignant phenotype in the ACC.


Can Optimal Complementary Feeding Improve Later Health and Development?
Nutrition and growth during early infancy influence later health and development, but most research has focused on the period of milk feeding, and the possibility that the timing, content or method of complementary feeding (CF) might have similar later effects has received less attention. Such effects are plausible, given that the CF period is one of rapid growth and development when infants are susceptible to nutrient deficiencies and excesses, and during which there are marked changes in diet with exposure to many new foods, tastes and feeding experiences. CF practices could influence later outcome by several potential mechanisms, including programming effects, but also direct effects on food preferences, appetite and eating behavior. Investigating these issues is challenging given the diversity and complexity of CF practices, which limit the feasibility and generalizability of randomized trials in this field. Available evidence relating CF practices to later health and development are currently limited in quantity and quality, but suggest that avoiding the introduction of solid foods before 4 months may reduce the risk of subsequent obesity and allergy. Whilst recommendations for different aspects of CF may be developed in the future based on broad principles, they will need to be tailored for different populations.


Hormesis: a response to low environmental concentrations of petroleum hydrocarbons.
Crab zoeae (Rhithropanopeus harrisii) were exposed to water-soluble fractions of jet fuel (JP5) for the first 5 days or for the duration of zoeal development (11 to 14 days). Short-term exposure or continuous exposure to low concentrations of petroleum hydrocarbons caused no increase in mortality or changes in development rate, and increased megalopal weight was characteristic of such groups. This phenomenon, termed "hormesis," is probably a generalized aspect of environmental stress etiology but has seldom been reported as such.


Comparison of a 5-mm and 10-mm vessel sealing device in an open ovariectomy model in dogs.
The objectives of this study were to compare (1) the extent of thermal damage and (2) the time between the 5-mm LigaSure V (LS5) and 10-mm LigaSure Atlas (LS10) vessel sealing devices (VSD) when performing open ovariectomy in dogs. A prospective, randomised, clinical trial was performed in 40 client-owned sexually entire female dogs. In each dog, one ovary was randomly assigned to be surgically removed using LS5 and the contralateral using LS10. The depth of thermal spread, measured on histopathological preparations, was significantly larger for LS10 (LS10 1.35±0.23 mm v LS5 0.82±0.10 mm; P<0.001). Mean ovariectomy time was significantly faster when using LS10 (LS5 2.58±1.32 minutes v LS10 2.07±1.27 minutes; P=0.008). Bodyweight was positively correlated with the time required for ovariectomy using LS5 (P=0.004), but no such correlation was present for LS10 (P=0.611). In conclusion, during open ovariectomy using VSD, LS10 causes significantly more thermal spread but surgical time is shorter compared with LS5. When using LS5, the ovariectomy time increases with increasing bodyweight.


Electrochemical reduction of horse heart ferricytochrome c at chemically derivatized electrodes.
Platinum or gold electrodes derivatized with an N,N'-dialkyl-4,4'-bipyridinium reagent can be used to reduce horse heart ferricytochrome c, whereas reduction doses does not occur at the "naked" electrodes. From 3 to 17.7 millimoles per liter, the reduction of ferricytochrome c is mass transport-limited at electrode potentials more negative than about -0.6 volt against a saturated calomel reference electrode. Data for the photoreduction of ferricytochrome c at derivatized p-type silicon photocathodes show directly that the rate of reduction is mass transport-limited. Use of derivatized electrodes may allow convenient manipulation and analysis of biological molecules that do not ordinarily respond at conventional electrodes.


Professions as the conscience of society.
Ethics is no less of a science than any other. It has its roots in conflicts of interest between human beings, and in their conflicting urges to behave either selfishly or altruistically. Resolving such conflicts leads to the specification of rules of conduct, often expressed in terms of rights and duties. In the special case of professional ethics, the paramount rule of conduct is altruism in the service of a 'noble' cause, and this distinguishes true professions from other trades or occupations. If professional ethics come into conflict with national laws, the professional today can test the legitimacy of such laws by reference to internationally agreed legal standards in the field of human rights, and so help to perform the role of 'professions as the conscience of society'.


Structural Insights into the Interaction of Coronavirus Papain-Like Proteases and Interferon-Stimulated Gene Product 15 from Different Species.
Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals. The ramifications of this sequence divergence to the recognition of ISG15 by coronavirus PLPs at a structural and biochemical level are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS-CoV, and mouse hepatitis virus was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic, and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronavirus PLP's interface with ISG15 via SARS-CoV PLpro in complex with the principle binding domain of human ISG15 (hISG15) and mouse ISG15s (mISG15s). The first X-ray structure of the full-length mISG15 protein is also reported and highlights a unique, twisted hinge region of ISG15 that is not conserved in hISG15, suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities among coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.


A Methoxydiphenylamine-Substituted Carbazole Twin Derivative: An Efficient Hole-Transporting Material for Perovskite Solar Cells.
The small-molecule-based hole-transporting material methoxydiphenylamine-substituted carbazole was synthesized and incorporated into a CH3NH3PbI3 perovskite solar cell, which displayed a power conversion efficiency of 16.91%, the second highest conversion efficiency after that of Spiro-OMeTAD. The investigated hole-transporting material was synthesized in two steps from commercially available and relatively inexpensive starting reagents. Various electro-optical measurements (UV/Vis, IV, thin-film conductivity, hole mobility, DSC, TGA, ionization potential) have been carried out to characterize the new hole-transporting material.


Reduced inflammation and cytokine production in NKLAM deficient mice during Streptococcus pneumoniae infection.
Streptococcus pneumoniae is a leading cause of pneumonia and a significant economic burden. Antibiotic-resistant S. pneumoniae has become more prevalent in recent years and many pneumonia cases are caused by S. pneumoniae that is resistant to at least one antibiotic. The ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) plays a role in innate immunity and studies using NKLAM-knockout (NKLAM-KO) macrophages have demonstrated that NKLAM positively affects the transcriptional activity of STAT1. Using an inhalation infection model, we found that NKLAM-KO mice had a significantly higher lung bacterial load than WT mice but had less lung inflammation. Coincidently, NKLAM-KO mice had fewer neutrophils and NK cells in their lungs. NKLAM-KO mice also expressed less iNOS in their lungs as well as less MCP-1, MIP1α, TNFα, IL-12, and IFNγ. Both neutrophils and macrophages from NKLAM-KO mice were defective in killing S. pneumoniae as compared to wild type cells (WT). The phosphorylation of STAT1 and STAT3 in NKLAM-KO lungs was lower than in WT lungs at 24 hours post-infection. NKLAM-KO mice were afforded some protection against a lethal dose of S. pneumoniae compared to WT mice. In summary, our novel data demonstrate a role for E3 ubiquitin ligase NKLAM in modulating innate immunity via the positive regulation of inflammatory cytokine expression and bactericidal activity.


Methodological Approaches Frame Insights into Endophyte Richness and Community Composition.
Isolating microbes is vital to study microbiomes, but insights into microbial diversity and ecology can be constrained by recalcitrant or unculturable strains. Culture-free methods (e.g., next-generation sequencing, NGS) have become popular in part because they detect greater richness than culturing alone. Both approaches are used widely to characterize microfungi within healthy leaves (foliar endophytes), but methodological differences among studies can constrain large-scale insights into endophyte ecology. We examined endophytes in a temperate plant community to quantify how certain methodological factors, such as the choice of cultivation media for culturing and storage period after leaf collection, affect inferences regarding endophyte communities; how such effects vary among plant taxa; and how complementary culturing and NGS can be when subsets of the same plant tissue are used for each. We found that endophyte richness and composition from culturing were consistent across five media types. Insights from culturing and NGS were largely robust to differences in storage period (1, 5, and 10 days). Although endophyte richness, composition, and taxonomic diversity identified via culturing vs. NGS differed markedly, both methods revealed host-structured communities. Studies differing only in cultivation media or storage period thus can be compared to estimate endophyte richness, composition, and turnover at scales larger than those of individual studies alone. Our data show that it is likely more important to sample more host species, rather than sampling fewer species more intensively, to quantify endophyte diversity in given locations, with the richest insights into endophyte ecology emerging when culturing and NGS are paired.


Linking biodiversity to ecosystem services supply: Patterns across aquatic ecosystems.
Global initiatives have been increasingly focusing on mainstreaming the values of biodiversity and ecosystem services into decision-making at all levels. Due to the accelerated rate at which biodiversity is declining and its consequences for the functioning of ecosystems and subsequently, the services they provide, there is need to develop comprehensive assessments of the services and the benefits nature delivers to society. Based on expert evaluation, we identified relevant flow linkages in the supply-side of the socio-ecological system, i.e. from biodiversity to ecosystem services supply for eight case studies across European aquatic ecosystems covering freshwater, transitional, coastal and marine waters realms. Biological mediated services were considered, as well as those reliant on purely physical aspects of the ecosystem, i.e. abiotic outputs, since both have implications for spatial planning, management and decision-making. Due to the multidimensional nature of ecosystems and their biodiversity, our approach used ecosystem components such as habitats and biota as proxies for biodiversity and as the focal point for linkage identification. Statistical analysis revealed the importance of considering mobile biota in the spatial assessment of habitats. Contrary to literature evidences so far, our results showed significantly different and complementary ecosystem services supply patterns across the continuum of aquatic realms. The implemented score of ecosystem services supply has a high potential for integrated aquatic ecosystem service supply assessments in the context of ecosystem-based management.


Innate immune and non-immune mediators of erythrocyte clearance.
Erythrocyte clearance is reviewed in the context of what is known in 2003 on clearance of apoptotic cells in vitro and in vivo. Thus, emphasis is put on the role of the innate immune system comprised of naturally occurring autoantibodies (NAbs) and complement. Oxidative damage, cellular senescence and diffusion-controlled exoplasmic cross-linking appear to generate oligomers of band 3 (anion transport protein) that are a prerequisite for anti-band 3 NAb binding to human red blood cells (RBC). Similar processes seem to be responsible for premature RBC clearance in hemoglobinopathies and membrane protein deficiencies. The review discusses why NAb binding alone is insufficient and how bound NAbs may enhance complement deposition. Clearance of RBC is not only the result of cell-bound opsonins, but is enhanced by the loss of RBC membrane constituents, such as CD47 and sialic acids. As long as these constituents are present on RBC in normal numbers and topologic arrangement, they bind to their respective receptors on macrophages, elicit a negative signal that appears to prevent the macrophage from engulfing bound RBC. Exposure of phosphatidylserine is not a primary signal for RBC removal and where exposed it initiates binding of CRP or of beta-2-glycoprotein I and NAbs.


A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.
Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in the growth medium, which extends both replicative and chronological life span (CLS). We found that conditioned media collected from stationary-phase CR cultures extended CLS when supplemented into nonrestricted (NR) cultures, suggesting a potential cell-nonautonomous mechanism of CR-induced life span regulation. Chromatography and untargeted metabolomics of the conditioned media, as well as transcriptional responses associated with the longevity effect, pointed to specific amino acids enriched in the CR conditioned media (CRCM) as functional molecules, with L-serine being a particularly strong candidate. Indeed, supplementing L-serine into NR cultures extended CLS through a mechanism dependent on the one-carbon metabolism pathway, thus implicating this conserved and central metabolic hub in life span regulation.


Compassion Fatigue in Nurses Caring for Medically Complex Children.
The number of children living with chronic, complex medical needs is steadily increasing secondary to advances in clinical technology and disease management. As a result, patient care requirements become multifaceted with the need for specific therapies and treatments that require extensive knowledge and skills. As these children are managed throughout the health care continuum, nurses are challenged to offer specialized care for complex conditions, while meeting the personnel and financial demands of the changing health care environment. It is well established that medically complex children can put a burden on family life, resulting in compassion fatigue for nonclinical caregivers. It is possible that, secondary to frequent and lengthy hospitalizations, nurses may also be affected. Therefore, a review of compassion fatigue or professional burnout in nurses caring for medically complex children was conducted. Appropriate identification of nurses at risk for compassion fatigue is imperative to provide the necessary interventions and support. Reducing compassion fatigue is likely to improve outcomes, including nursing turnover, nursing professional engagement, and job satisfaction, thus improving the care delivery experience for children with complex conditions.


13C-13C spin-coupling constants in crystalline 13C-labeled saccharides: conformational effects interrogated by solid-state 13C NMR spectroscopy.
Solid-state 13C NMR spectroscopy has been used in conjunction with selectively 13C-labeled mono- and disaccharides to measure 13C-13C spin-couplings (JCC) in crystalline samples. This experimental approach allows direct correlation of JCC values with specific molecular conformations since, in crystalline samples, molecular conformation is essentially static and can be determined by X-ray crystallography. JCC values measured in the solid-state in known molecular conformations can then be compared to corresponding JCC values calculated in the same conformations using density functional theory (DFT). The latter comparisons provide important validation of DFT-calculated J-couplings, which is not easily obtained by other approaches and is fundamental to obtaining reliable experiment-based conformational models from redundant J-couplings by MA'AT analysis. In this study, representative 1JCC, 2JCCC and 3JCOCC values were studied as either intra-residue couplings in the aldohexopyranosyl rings of monosaccharides or inter-residue (trans-glycoside) couplings in disaccharides. The results demonstrate that (a) accurate JCC values can be measured in crystalline saccharides that have been suitably labeled with 13C, and (b) DFT-calculated JCC values compare favorably with those determined by solid-state 13C NMR when molecular conformation is a constant in both determinations.


Four-Year Follow-up of Cognitive Behavioral Therapy in Persons at Ultra-High Risk for Developing Psychosis: The Dutch Early Detection Intervention Evaluation (EDIE-NL) Trial.
Previously, we demonstrated that cognitive behavior therapy for ultra-high risk (called CBTuhr) halved the incidence of psychosis over an 18-month period. Follow-up data from the same study are used to evaluate the longer-term effects at 4 years post-baseline. The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients comparing CBTuhr with treatment-as-usual (TAU) for comorbid disorders with TAU only. Of the original 196 patients, 113 consented to a 4-year follow-up (57.7%; CBTuhr = 56 vs TAU = 57). Over the study period, psychosis incidence, remission from UHR status, and the effects of transition to psychosis were evaluated. The number of participants in the CBTuhr group making the transition to psychosis increased from 10 at 18-month follow-up to 12 at 4-year follow-up whereas it did not change in the TAU group (n = 22); this still represents a clinically important (incidence rate ratio [IRR] = 12/22 = 0.55) and significant effect (F(1,5) = 8.09, P = .03), favoring CBTuhr. The odds ratio of CBTuhr compared to TAU was 0.44 (95% CI: 0.24-0.82) and the number needed to treat was 8. Moreover, significantly more patients remitted from their UHR status in the CBTuhr group (76.3%) compared with the TAU group (58.7%) [t(120) = 2.08, P = .04]. Importantly, transition to psychosis was associated with more severe psychopathology and social functioning at 4-year follow-up. CBTuhr to prevent a first episode of psychosis in persons at UHR of developing psychosis is still effective at 4-year follow-up. Our data also show that individuals meeting the formal criteria of a psychotic disorder have worse functional and social outcomes compared with non-transitioned cases. The trial is registered at Current Controlled Trials as trial number ISRCTN21353122 (http://controlled-trials.com/ISRCTN21353122/gaag).


Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach.
Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.


Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet.
Key features of diet-induced obesity are visceral fat deposition, macrophage infiltration and inflammation that can lead to metabolic disorders. This study examined the effects of bardoxolone methyl (BARD) in preventing obesity and inflammation in the visceral fat of mice fed high-fat diet. Male C57BL/6J mice were fed a high-fat diet (HFD), a low-fat diet (LFD, i.e., lab chow diet) or a high-fat diet supplemented with BARD (HFD/BARD) for 21weeks. BARD at a dosage of 10mg/kg body weight was administered orally in drinking water. Histology, immunohistochemistry and Western blot were used for the analysis of epididymal adipose tissue. Morphological results demonstrated that HFD fed mice treated with BARD had smaller adipocytes and fewer macrophages present in epididymal adipose tissue than the HFD group. Furthermore, BARD administration reduced the inflammatory profile in this tissue by increasing the expression of nuclear factor of kappa-light-polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) protein and decreasing the protein expression of tumour necrosis factor alpha (TNF-α). BARD also prevented oxidative stress reflected by a reduction in stress activated proteins, including signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). BARD administration activated the sympathetic nervous system in epididymal adipose tissue assessed by the increased synthesis of tyrosine hydroxylase (TH) and uncoupling protein 2 (UCP2). The expression of inflammatory and sympathetic nervous system proteins in BARD mice fed a HFD was equivalent to that of the LFD control mice, indicating the anti-inflammatory and anti-obesity properties of this drug. In conclusion, the oral administration of BARD in HFD mice prevented fat deposition, inflammation and oxidative stress, and improved sympathetic activity in visceral fat. This study suggests a potential therapeutic role of BARD in preventing the development of obesity.


Gallstones: advantages and disadvantages of five treatment alternatives.
Cholecystectomy is the gold standard treatment for symptomatic gallstones. However, within the last decade peroral drug chemolysis, methyl-tert-butyl ether lavage, shock wave lithotripsy, and percutaneous cholecystolithotomy have been introduced. This article compares and contrasts the presently available therapeutic modalities for gallstones and highlights the limitations of each treatment option.


Functional traits and environmental filtering drive community assembly in a species-rich tropical system.
Mechanistic models of community assembly state that biotic and abiotic filters constrain species establishment through selection on their functional traits. Predicting this assembly process is hampered because few studies directly incorporate environmental measurements and scale up from species to community level and because the functional traits' significance is environment dependent. We analyzed community assembly by measuring structure, environmental conditions, and species traits of secondary forests in a species-rich tropical system. We found, as hypothesized, that community structure shaped the local environment and that strong relationships existed between this environment and the traits of the most successful species of the regeneration communities. Path and multivariate analyses showed that temperature and leaf traits that regulate it were the most important factors of community differentiation. Comparisons between the trait composition of the forest's regeneration, juvenile, and adult communities showed a consistent community assembly pattern. These results allowed us to identify the major functional traits and environmental factors involved in the assembly of dry-forest communities and demonstrate that environmental filtering is a predictable and fundamental process of community assembly, even in a complex system such as a tropical forest.


An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer.
The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death. Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry. High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells. Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.


Toxicological deteriorations of two volatile oils of Matricaria chamomilla and Clerodendron inerme on the adult house fly Musca domestica L.
The adult stage of the house fly Musca domestica L. was treated topically with the sublethal doses of LD25, LD50 and LD75 of chamomile, Matricaria chamomilla L. flowers and jasmine, Clerodendron inerme G. leaves oils. Various biological activities of adult stage as well as the amino acids of the treated adults ovaries were determined. Amino acids determinations were achieved on newly emerged flies and on the three and four days old flies. The LD50s. of 76 and 84 ug/fly of the two oils were used for Matricaria chamomilla and Clerodendron inerme oil, respectively. Treatment with the two volatile oils induced serious effects on the biology and biotic potential of Musca domestica. Treatment was significantly increased the acidic and the aromatic amino acids during oogenesis. In contrast the quantity of aliphatic amino acids was significantly decreased while the hydroxy amino acids have inconsistent results. The hydroxy amino acids were remarkably increased in the ovaries during three days of development, and then decreased in the fourth day. Moreover, the concentration of basic and the sulfur amino acids were varied with the two treatments and the amino acid was completely disappeared in the ovaries of the treated flies.


Dl-3-n-butylphthalide Reduces Neurovascular Inflammation and Ischemic Brain Injury in Mice.
Dl-3-n-butylphthalide (NBP) is a synthetic compound that has been approved for the treatment of ischemic stroke in China. The mechanisms underlying the treatment efficacy of NBP have been reported in multiple studies and remain controversial. Here, we show that NBP treatment attenuated ischemic brain injury in mice subjected to transient middle cerebral artery occlusion or photothrombosis-induced permanent cerebral ischemia. NBP induced downregulation of intercellular adhesion molecule 1 and protease-activated receptor 1 in cerebrovascular endothelial cells after cerebral ischemia and reperfusion. This effect was associated with the reduced brain infiltration of myeloid cells and improved cerebral blood flow after reperfusion. The beneficial effects of NBP were diminished in mice subjected to the depletion of Gr1+ myeloid cells before brain ischemia. Therefore, the restriction of neurovascular inflammation is a key mode of action for NBP in ischemic stroke.


DISEASE CLASSIFICATION OF MACULAR OPTICAL COHERENCE TOMOGRAPHY SCANS USING DEEP LEARNING SOFTWARE: Validation on Independent, Multicenter Data.
To evaluate Pegasus optical coherence tomography (OCT), a clinical decision support software for the identification of features of retinal disease from macula OCT scans, across heterogenous populations involving varying patient demographics, device manufacturers, acquisition sites, and operators. Five thousand five hundred and eighty-eight normal and anomalous macular OCT volumes (162,721 B-scans), acquired at independent centers in five countries, were processed using the software. Results were evaluated against ground truth provided by the data set owners. Pegasus-OCT performed with areas under the curve of the receiver operating characteristic of at least 98% for all data sets in the detection of general macular anomalies. For scans of sufficient quality, the areas under the curve of the receiver operating characteristic for general age-related macular degeneration and diabetic macular edema detection were found to be at least 99% and 98%, respectively. The ability of a clinical decision support system to cater for different populations is key to its adoption. Pegasus-OCT was shown to be able to detect age-related macular degeneration, diabetic macular edema, and general anomalies in OCT volumes acquired across multiple independent sites with high performance. Its use thus offers substantial promise, with the potential to alleviate the burden of growing demand in eye care services caused by retinal disease.


Diversity and evolutionary patterns of bacterial gut associates of corbiculate bees.
The animal gut is a habitat for diverse communities of microorganisms (microbiota). Honeybees and bumblebees have recently been shown to harbour a distinct and species poor microbiota, which may confer protection against parasites. Here, we investigate diversity, host specificity and transmission mode of two of the most common, yet poorly known, gut bacteria of honeybees and bumblebees: Snodgrassella alvi (Betaproteobacteria) and Gilliamella apicola (Gammaproteobacteria). We analysed 16S rRNA gene sequences of these bacteria from diverse bee host species across most of the honeybee and bumblebee phylogenetic diversity from North America, Europe and Asia. These focal bacteria were present in 92% of bumblebee species and all honeybee species but were found to be absent in the two related corbiculate bee tribes, the stingless bees (Meliponini) and orchid bees (Euglossini). Both Snodgrassella alvi and Gilliamella apicola phylogenies show significant topological congruence with the phylogeny of their bee hosts, albeit with a considerable degree of putative host switches. Furthermore, we found that phylogenetic distances between Gilliamella apicola samples correlated with the geographical distance between sampling locations. This tentatively suggests that the environmental transmission rate, as set by geographical distance, affects the distribution of G. apicola infections. We show experimentally that both bacterial taxa can be vertically transmitted from the mother colony to daughter queens, and social contact with nest mates after emergence from the pupa greatly facilitates this transmission. Therefore, sociality may play an important role in vertical transmission and opens up the potential for co-evolution or at least a close association of gut bacteria with their hosts.


Synergistic effects of ACE (I/D) and Apo E (Hha I) gene polymorphisms on obesity, fat mass, and blood glucose level among the adult Asian Indians: A population-based study from Calcutta, India.
The study was aimed to determine the association of angiotensin converting enzyme (ACE) insertion/deletion (I/D) and apolipoprotein E (Apo E) Hha I gene polymorphisms with obesity, fat mass, and blood glucose levels in Asian Indian population. A total of 350 (184 men and 166 women) adult (30 years and above) Asian Indians of Calcutta and suburb participated in the study. Anthropometric measures, fat mass, and blood glucose measures were collected. Out of 350 subjects, a sample of 139 individuals was collected randomly for genotyping (adjusted for age and sex). The ACE and Apo E genotypes were determined by agarose gel electrophoresis. It was observed that neither ACE (I/D) nor Apo E (Hha I) gene polymorphisms showed any significant association with body mass index, waist circumference, fat mass, fasting, and post meal blood glucose levels. Even synergistically (ACE + Apo E), these two polymorphisms showed no significant association with obesity, fat mass, and blood glucose level. ACE (I/D), Apo E (Hha I), as well as ACE + Apo E seem to have no significant association with obesity, fat mass, and blood glucose levels in this population.


Determination of 8-oxoguanine in DNA by gas chromatography--mass spectrometry and HPLC--electrochemical detection: overestimation of the background level of the oxidized base by the gas chromatography--mass spectrometry assay.
Two analytical methods, one involving the combined use of reverse-phase HPLC and electrochemical detection (HPLC-EC) and one involving a mass spectrometric detection after gas chromatography separation (GC/MS), were developed for the detection of 8-oxoguanine in DNA. In order to obtain quantitative results, 2,6-diamino-8-oxopurine, whose chemical structure and electrochemical response are very similar to 8-oxoguanine, has been employed as an internal standard in the HPLC-EC assay. In the case of the GC/MS method, an isotopically stable (M + 4) 8-oxoguanine has been employed as an internal standard. Both methods are able to detect approximately 1 modification per 10(6) DNA bases. The background level of 8-oxoguanine in DNA as determined by GC/MS is approximately 50-fold higher than that determined by the HPLC-EC assay. The discrepancy between the two methods is due to an artifactual oxidation of guanine during the derivatization reaction as demonstrated by using pure guanine. The amount of 8-oxoguanine in guanine, determined by GC/MS, increases linearly with the time of derivatization, indicating that an oxidation occurs during the silylation reaction. Derivatization under nitrogen atmosphere reduces but does not suppress the artifactual oxidation. The amount of 8-oxoguanine in DNA, quantified by GC/MS, is comparable to that obtained by HPLC-EC when 8-oxoguanine is prepurified by HPLC or by immunoaffinity chromatography, prior to the silylation reaction. The artifactual formation of 8-oxoguanine during the derivatization reaction may explain, at least in part, why the values reported for 8-oxoguanine determination by GC/MS are generally about 1 order of magnitude higher than that determined by HPLC-EC. Prepurification of 8-oxoguanine from guanine is recommended in order to obtain reliable results by GC/MS which may be compared to HPLC-EC.


A triple mutant in the Ω-loop of TEM-1 β-lactamase changes the substrate profile via a large conformational change and an altered general base for catalysis.
β-Lactamases are bacterial enzymes that hydrolyze β-lactam antibiotics. TEM-1 is a prevalent plasmid-encoded β-lactamase in Gram-negative bacteria that efficiently catalyzes the hydrolysis of penicillins and early cephalosporins but not oxyimino-cephalosporins. A previous random mutagenesis study identified a W165Y/E166Y/P167G triple mutant that displays greatly altered substrate specificity with increased activity for the oxyimino-cephalosporin, ceftazidime, and decreased activity toward all other β-lactams tested. Surprisingly, this mutant lacks the conserved Glu-166 residue critical for enzyme function. Ceftazidime contains a large, bulky side chain that does not fit optimally in the wild-type TEM-1 active site. Therefore, it was hypothesized that the substitutions in the mutant expand the binding site in the enzyme. To investigate structural changes and address whether there is an enlargement in the active site, the crystal structure of the triple mutant was solved to 1.44 Å. The structure reveals a large conformational change of the active site Ω-loop structure to create additional space for the ceftazidime side chain. The position of the hydroxyl group of Tyr-166 and an observed shift in the pH profile of the triple mutant suggests that Tyr-166 participates in the hydrolytic mechanism of the enzyme. These findings indicate that the highly conserved Glu-166 residue can be substituted in the mechanism of serine β-lactamases. The results reveal that the robustness of the overall β-lactamase fold coupled with the plasticity of an active site loop facilitates the evolution of enzyme specificity and mechanism.


[Epidemiological trends in prostate cancer over the last years].
To analyze the evolution of prostate cancer (PCa) in our community health area over the last years, in terms of incidence, clinical-epidemiological characteristics, and cancer-specific mortality. Retrospective analysis of the medical records of patients with PCa in our hospital over the 1991-2003 period. We calculated the annual incidence rates for our community health area as well as its trend over the period of study. Changes of several clinical-epidemiological parameters over time were studied. The evolution of PCa mortality was also analyzed. 730 patients with PCa were evaluated. Median age and PSA at diagnosis were 69 years and 11.4 ng/ml, respectively. 60.5% tumors were detected in a localized clinical stage, and 18.6% were metastasic. 30.4% of PCa in the study (the most numerous group) had a Gleason score between 5 and 6. A constant increase of PCa incidence was observed with an annual percentage increase of 5.5% (p < 0.001). Standardized incidence rate for the year 2003 Spanish population pyramid was 100.9 cases/100,000 males. A significant trend to a greater proportion of PCa cases diagnosed by uncontrolled screening was observed, being the cases currently detected after symptoms only a small proportion (p < 0.001). Decreases in the age at diagnosis (p < 0.001), PSA level (p < 0.001), proportion of advanced clinical stages (p < 0.001), as well as proportion of cancers with well-differentiated Gleason score (2-4) (p < 0.001) were also detected. PCa mortality adjusted by the population pyramid was 8.7 deaths/100,000 males in the year 2003. We found an increase in the incidence of prostate cancer in our community health area over the last years, parallel to an increase in the proportion of cases detected by screening in asymptomatic population. Because of that, tumors currently detected tend to appear in younger ages, with lower PSA levels, and localized clinical stages.


Menopause hormone therapy: latest developments and clinical practice.
Menopause hormone therapy (MHT) is the most efficient treatment for symptoms of acute climacteric syndrome and for efficient prevention of long-term estrogen deficiency. Vaginal administration of low doses of estrogen is a therapy of choice for treatment and prevention of urogenital atrophy and its consequences. Systemic treatment may include estrogen, but an equally efficient alternative is tibolone. Nonhormonal therapy relies on phytoestrogens, black cohosh extract, and serotonin reuptake inhibitors.


Computerized estimation of patient setup errors in portal images based on localized pelvic templates for prostate cancer radiotherapy.
We have developed a computerized method for estimating patient setup errors in portal images based on localized pelvic templates for prostate cancer radiotherapy. The patient setup errors were estimated based on a template-matching technique that compared the portal image and a localized pelvic template image with a clinical target volume produced from a digitally reconstructed radiography (DRR) image of each patient. We evaluated the proposed method by calculating the residual error between the patient setup error obtained by the proposed method and the gold standard setup error determined by consensus between two radiation oncologists. Eleven training cases with prostate cancer were used for development of the proposed method, and then we applied the method to 10 test cases as a validation test. As a result, the residual errors in the anterior-posterior, superior-inferior and left-right directions were smaller than 2 mm for the validation test. The mean residual error was 2.65 ± 1.21 mm in the Euclidean distance for training cases, and 3.10 ± 1.49 mm for the validation test. There was no statistically significant difference in the residual error between the test for training cases and the validation test (P = 0.438). The proposed method appears to be robust for detecting patient setup error in the treatment of prostate cancer radiotherapy.


Modified control of breathing in genetically obese (ob/ob) mice.
Attenuated hypercapnic chemosensitivity and hypoventilation are characteristics periodically associated with human obesity. We tested the hypothesis that ventilatory control is altered by genetic determinants and age-dependent factors that influence the obese phenotype. To this end, the magnitude and pattern of breathing were examined before and associated with the development of obesity in C57BL/6J mice homozygous and heterozygous at the ob gene locus. Breathing frequency and tidal volume were measured using whole body plethysmography, and minute ventilation was assessed during acute hypoxic and hypercapnic challenges with intermittent room air exposures. In age- and weight-matched mice before pronounced obesity, significant (P < 0.05) reductions in hypercapnic ventilatory sensitivity occurred in mutant (ob/ob) mice relative to wild-type (+/+) homozygotes primarily because of an attenuated tidal volume. Longitudinal studies indicated that mutant ob mice developed rapid baseline breathing relative to the wild type, accompanying a twofold greater increase in body mass. Early differences between homozygotes in hypercapnic ventilatory sensitivity were maintained through 230 days. These data demonstrate that genetic determinants at or closely linked to the ob locus influence hypercapnic ventilation before the emergence of pronounced obesity, whereas changes in baseline breathing appear due to age-dependent increases in body weight.


Problem-focused coping and satisfaction with activities of daily living in individuals with muscular dystrophy and postpolio syndrome.
The problems, problem-focused coping and satisfaction with activities of daily living in a total of 119 persons with muscular weakness are described. The study encompasses three groups: 33 persons with various types of muscular dystrophy, 46 with myotonic dystrophy and 40 with symptoms relating to the post-polio syndrome. A self-report instrument for Assessment of Problem-focused Coping (APC) was used. Most of the problems reported were connected with mobility and transportation and work, but the subjects used problem-focused coping relatively infrequently and few differences were found between the different groups or between the sexes. The most widely used problem-focused coping strategy was 'Devices and tricks'. The highest degree of satisfaction was noted for personal care and the lowest for mobility and transportation. The APC provides information about patients' evaluation of everyday situations, forming a complement to functional measurements in the field of rehabilitation.


Successful associateship agreements.
When evaluating potential associateship agreements, dentists need to recognize and understand how status, noncompete clauses, scheduling and compensation affect the strength of an associateship agreement. Dentists should not enter an associateship agreement without fully understanding the agreement and its obligations or without the help of an accountant and an attorney.


The potential legacy of cancer nanotechnology: cellular selection.
Overexpression of oncogenes or loss of tumour suppressors can transform a normal cell to a cancerous one, resulting in uncontrolled regulation of intracellular signalling pathways and immunity to stresses, which both pose therapeutic challenges. Conventional approaches to cancer therapy, although they are effective at killing cancer cells, may still fail due to inadequate biodistribution and unwanted side effects. Nanotechnology-based approaches provide a promising alternative, with the possibility of targeting cells at an early stage, during their transformation into cancer cells. This review considers techniques that specifically target those molecular changes, which begin in only a very small percentage of normal cells as they undergo transformation. These techniques are crucial for early-stage diagnosis and therapy.


Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues.
Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis.


Nitric oxide inhibits the ATPase activity of the chaperone-like AAA+ ATPase CDC48, a target for S-nitrosylation in cryptogein signalling in tobacco cells.
NO has important physiological functions in plants, including the adaptative response to pathogen attack. We previously demonstrated that cryptogein, an elicitor of defence reaction produced by the oomycete Phytophthora cryptogea, triggers NO synthesis in tobacco. To decipher the role of NO in tobacco cells elicited by cryptogein, in the present study we performed a proteomic approach in order to identify proteins undergoing S-nitrosylation. We provided evidence that cryptogein induced the S-nitrosylation of several proteins and identified 11 candidates, including CDC48 (cell division cycle 48), a member of the AAA+ ATPase (ATPase associated with various cellular activities) family. In vitro, NtCDC48 (Nicotiana tabacum CDC48) was shown to be poly-S-nitrosylated by NO donors and we could identify Cys(110), Cys(526) and Cys(664) as a targets for S-nitrosylation. Cys(526) is located in the Walker A motif of the D2 domain, that is involved in ATP binding and was previously reported to be regulated by oxidative modification in Drosophila. We investigated the consequence of NtCDC48 S-nitrosylation and found that NO abolished NtCDC48 ATPase activity and induced slight conformation changes in the vicinity of Cys(526). Similarly, substitution of Cys(526) by an alanine residue had an impact on NtCDC48 activity. More generally, the present study identified CDC48 as a new candidate for S-nitrosylation in plants facing biotic stress and further supports the importance of Cys(526) in the regulation of CDC48 by oxidative/nitrosative agents.


The polyketide backbone of thiolactomycin is assembled by an unusual iterative polyketide synthase.
Following the in vivo investigation of thiotetronate assembly in Lentzea sp. and in S. thiolactonus NRRL 15439 (Havemann et al., Chem. Commun., 2017, DOI: 10.1039/c6cc09933e), the minimal set of genes required for thiolactomycin production was determined through heterologous expression and the mechanism for polyketide assembly was established in vitro through incubation of recombinant TlmB with its substrates in the presence of either nonhydrolysable or hydrolysable chemical probes. The results presented here constitute unequivocal evidence of enzymatic processing by an unusual iterative polyketide synthase.


Population genetic structure of Texas horned lizards: implications for reintroduction and captive breeding.
The Texas horned lizard (Phrynosoma cornutum) inhabits much of the southern Great Plains of North America. Since the 1950s, this species has been extirpated from much of its eastern range and has suffered declines and local extinctions elsewhere, primarily due to habitat loss. Plans are underway to use captive breeding to produce large numbers of Texas horned lizards for reintroduction into areas that were historically occupied by this species and that currently have suitable habitat. We used mitochondrial markers and nuclear microsatellite markers to determine levels of genetic diversity and population structure in 542 Texas horned lizards sampled from across Texas and some neighboring states to help inform these efforts. Texas horned lizards still retain high genetic diversity in many parts of their current range. We found two highly divergent mitochondrial clades (eastern and western) and three major genetic groupings at nuclear microsatellite loci: a west group corresponding to the western mitochondrial clade and north and south groups within the eastern mitochondrial clade. We also found some evidence for human-mediated movement between these genetic clusters that is probably related to the historical importance of this species in the pet trade and as an iconic symbol of the southwestern United States. We do not know, however, if there are fitness costs associated with admixture (especially for the western and eastern clades) or if there are fitness costs to moving these lizards into habitats that are distinctly different from their ancestral areas. If present, either one or both of these fitness costs would decrease the effectiveness of reintroduction efforts. We therefore recommend that reintroduction efforts should maintain current genetic structure by restricting breeding to be between individuals within their respective genetic clusters, and by reintroducing individuals only into those areas that encompass their respective genetic clusters. This cautionary approach is based on the strong divergence between genetic groupings and their correspondence to different ecoregions.


Parent hearing aid experiences in the United States.
Children born with permanent hearing loss have the opportunity to receive services earlier as a result of newborn hearing screening (NHS). We conducted a survey to address three aspects within the early hearing detection and intervention (EHDI) process: (1) timeliness of service delivery, (2) hearing device access, and (3) hearing aid management. Parent experiences provide valuable information in identifying existing challenges for these components of the EHDI system. The aim was to investigate parent experiences as they access and manage hearing aids for their child. A cross-sectional, population-based survey was used. Three hundred fifty-two completed surveys from parents of children born between 1977 and 2010 were returned from 45 states in the United States. Responses were obtained online and through the mail, and were analyzed using descriptive statistics. Over time, the age of hearing loss identification has decreased to a median of 2 mo, age of first hearing aid fitting has decreased to a median of 5 mo, and the delay between hearing loss identification and hearing aid fitting has remained the same with a median of 2 mo. For children born between 2007 and 2010, the top three challenges parents reported in obtaining hearing aids were (1) paying for hearing aids, (2) accepting the need for hearing aids, and (3) wait time for an appointment. Almost one-half (48%) of the parents reported that they did not receive adequate support from their audiologist in how to check the function of their child's hearing aids. Significant progress has been made over the past two decades in reducing the age of hearing loss identification and hearing aid fitting for children who do not pass the NHS. However, many children continue to experience delays between hearing loss diagnosis and hearing aid fitting that exceed Joint Committee on Infant Hearing recommendations. The experiences parents reported provide valuable information about areas that need further investigation to improve the process for children with hearing loss.


Nanotechnology--salvation or damnation for humans?
Nanotechnology is a term derived from the Greek word nanos, meaning dwarf. It is used to describe activities at the level of atoms and molecules. The application of this technology is aimed at controlling and manipulating the physical properties of materials with single molecule precision. Scientists use the technology to build working devices, systems and materials, molecule by molecule. This enables them to exploit the unique and powerful electrical, physical and chemical properties found at that scale. Nanotech holds the potential to revolutionise medicine, electronics and chemistry. Nanomedicine would facilitate the repair and improvement of the human body from the inside out, with a precision and delicacy far greater than the finest surgical instruments permit. Problem areas stemming from the technology include the following:- Who will benefit - just the rich or the poor as well? This paper will explore the role of law, ethics and suitable control mechanisms to limit the dangers and maximise the benefits of nanotechnology for society, especially in the field of medicine.


[Vulnerations of Human Dignity At The End of Life].
Death is constitutive of human nature and therefore it must happen naturally. But there are mainly two ways that falsify it: euthanasia and therapeutic obstinacy. Two wrong choices that do not accept the human reality of death (the first, anticipates death and the second, delays it). From the philosophical and ethical point of view, both options are rejected, because they are against human dignity at the end of life. Aside from these, this article also rejects the different names which are given to refer to euthanasia, that also go against human nature at the end of life. On the other hand, do not confuse euthanasia with sedation. Both have a common goal to prevent the patient from feeling pain and suffering. To achieve this goal, both options administer ″drugs″ to the patient. But in the administration of drugs in euthanasia involves ending patient's life. The administration of drugs in sedation aims for the patient's death to occur naturally. Finally, we briefly discuss the basic care necessary in these situations. The absence of basic care cannot become a covert euthanasia. The patient must die from his/her illness, never from a lack of care. All human actions (euthanasia, sedation, therapeutic obstinacy and basic care) should be an expression and manifestation of what human dignity demands. Such dignity is expressed in the actions performed by human beings.


The Road to Rural Primary Care: A Narrative Review of Factors That Help Develop, Recruit, and Retain Rural Primary Care Physicians.
To examine the literature documenting successes in recruiting and retaining rural primary care physicians. The authors conducted a narrative review of literature on individual, educational, and professional characteristics and experiences that lead to recruitment and retention of rural primary care physicians. In May 2016, they searched MEDLINE, PubMed, CINAHL, ERIC, Web of Science, Google Scholar, the Grey Literature Report, and reference lists of included studies for literature published in or after 1990 in the United States, Canada, or Australia. The authors identified 83 articles meeting inclusion criteria. They synthesized results and developed a theoretical model that proposes how the findings interact and influence rural recruitment and retention. The authors' proposed theoretical model suggests factors interact across multiple dimensions to facilitate the development of a rural physician identity. Rural upbringing, personal attributes, positive rural exposure, preparation for rural life and medicine, partner receptivity to rural living, financial incentives, integration into rural communities, and good work-life balance influence recruitment and retention. However, attending medical schools and/or residencies with a rural emphasis and participating in rural training may reflect, rather than produce, intention for rural practice. Many factors enhance rural physician identity development and influence whether physicians enter, remain in, and thrive in rural practice. To help trainees and young physicians develop the professional identity of a rural physician, multifactorial medical training approaches aimed at encouraging long-term rural practice should focus on rural-specific clinical and nonclinical competencies while providing trainees with positive rural experiences.


Inhibition of protohaem ferro-lyase by N-substituted porphyrins. Structural requirements for the inhibitory effect.
N-Methyl mesoporphyrin was a powerful inhibitor of protohaem ferro-lyase in vitro, whereas N-ethyl mesoporphyrin and N-methyl coproporphyrin were not and neither was the newly described green pigment produced by giving rats ethylene. This suggests that the size of the substituent at a pyrrole nitrogen and also the number of carboxylic acid side chains of the substituted porphyrin are important for the inhibitory effect. Evidence that N-methyl mesoporphyrin inhibited the enzyme, whereas the ethylene-derived pigment did not, was also obtained in vivo.


Spatial asymmetries undermine also the short forms of the Judgement of Line Orientation test.
The Judgment of Line Orientation (JLO) test is one of the most used tasks for the assessment of visuospatial perception. However, JLO items show a left-right structural asymmetry that interacts with the ipsilesional attentional biases of brain-damaged patients, that is, the main target population for which the test is intended, and undermines the test's validity. Left hemisphere-damaged patients are favored by the way the stimulus lines are distributed in the original items, whereas right hemisphere-damaged patients are favored by the opposite distribution, obtained by mirror reversing the items (Treccani, Torri, & Cubelli, 2005). Here we aimed to analyze the short forms of JLO available in the literature, which are often presented as preferable alternatives to the full form. Characteristics of the items of these short forms were scrutinized. By reanalyzing data from Treccani et al. (2005), we also investigated the impact of these characteristics on brain-damaged patients' performance. Seven of the 8 analyzed short forms proved to be even more asymmetric than the full form (e.g., they have a different number of left and right lines), whereas the remaining one, which uses a flexible item-selection criterion, leads to unpredictable results. Like in the full form, these asymmetries affect brain-damaged patients' performance. The presence of spatial asymmetries in JLO items cannot be neglected anymore in the development of any JLO form, given their impact on performance and the resulting detrimental effect on the accuracy and validity of the measurement. We propose to select 5-10 items among those of the original set and present them together with their mirror images to obtain a left-right balanced JLO short version. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Peripheral blood lymphocytes as a biological indicator of physiologic processes in schizophrenia].
The results of studying the properties of peripheral blood lymphocytes in schizophrenic patients are reviewed. Three parameters are specified in which the patients' lymphocytes differ substantially from those of healthy donors: these are the resistance to osmotic shock and responses of the cells to stimulation with phytohemagglutinin and concanavalin A. It is shown that all the three parameters are controlled by different factors of the schizophrenics' blood serum. Two of them correlate with the clinical manifestations of the disease. It is concluded that the lymphocytes of schizophrenic patients can serve as a biological indicator of the pathophysiological processes taking place in that disease.


Regulation of mesangial cell adhesion and shape by thrombin.
Adenosine 3',5'-cyclic monophosphate (cAMP) elevation in cultured rat mesangial cells causes urokinase-dependent adhesion loss, stress-fiber fragmentation, and shape change. Thrombin cleaves single-chain urokinase (scu-PA), causing its inactivation, but not two-chain u-PA [tcu-plasminogen activator (PA)] or tissue-type PA. We tested the ability of thrombin to inhibit the effects of cAMP elevation in mesangial cells and inactivate cell-associated scu-PA. In an assay of trypsin-sensitive adhesion, 65.9% of control cells and 5.5% of cells treated with isoproterenol + methylisobutylxanthine (IM) remained adherent. In the presence of 0.01, 0.1, 1.0, and 10.0 unit/ml thrombin, 20.9, 46.6, 50.4, and 53.3%, respectively, of IM-treated cells remained attached. Thrombin also inhibited stress-fiber fragmentation and shape change. The effects of thrombin were blocked by hirudin or antithrombin III plus heparin. Direct zymography in gels containing gelatin and plasminogen revealed loss of a closely spaced pair of PA bands with thrombin treatment (1.0 unit/ml). Hirudin blocked the loss. alpha-Thrombin inactivated by diisopropyl fluorophosphate neither inhibited shape change nor caused loss of the PA bands; however, gamma-thrombin was nearly as active as native alpha-thrombin in both regards. Pretreatment of the cells with as little as 1.0 unit/ml thrombin for 1.0 min caused marked inhibition of shape change and near total loss of the slower migrating u-PA band (of the doublet). The faster migrating band was inhibited less. The results indicate that the slower migrating band represents scu-PA; the nature of the faster migrating band is less certain. Thrombin reversed the adhesion loss and shape change caused by 8-(4-chlorophenylthio)-cAMP and MIX. Thus physiological concentrations of thrombin rapidly inactivate mesangial cell scu-PA and inhibit and reverse cAMP-stimulated adhesion loss and shape change.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of manual and automated probing in an untreated periodontitis population.
Diagnosis of periodontal disease progression involves recording two probing attachment level measurements over an adequate time interval. A diagnostic instrument which exhibits less measurement variability allows for increased sensitivity and earlier disease detection. Traditionally, a manual probe with an occlusal stent of the cementoenamel junction (CEJ) as a reference landmark has been the method of choice. Automated probes that use an occlusal disk as the reference landmark have been developed as an alternative means of measure. The aim of this study was to compare the variability of these two probing methods. Four hundred eleven (411) interproximal sites in 46 untreated periodontitis patients were monitored by a single examiner over a 6-month period. Each site was measured on a monthly basis, first with an automated probe (AP) followed by a manual probe (MP) in combination with a custom-fabricated acrylic stent. Measurement variability of the two probing methods was also compared over a 7-day interval. The AP measurements were significantly more variable than the MP measurements (P < 0.001) when considering the variability between two passes at the same visit. Over the 6-month period, the MP measurements demonstrated significantly more variability than the AP measurements (P < 0.001). It was also noted that MP measurements exhibited more variability at sites with frequent bleeding during the 6 months of the study (P = 0.006). The results of this study demonstrate that AP may have less variability of attachment level measurements over a 6-month period and may be less influenced by local inflammatory changes. However, future comparison studies should include multiple examiners to reduce examiner bias and should alternate the probing method to reduce bias created by local tissue changes from multiple probings.


Aldosterone, hypertension, and beyond.
Aldosterone, a mineralocorticoid hormone, has a well-known function on water balance and blood pressure homeostasis. Recently, its role in metabolic syndrome, insulin resistance, and obesity has come into a spotlight. Aldosterone induces inflammation and oxidative stress that are attenuated by mineralocorticoid receptor blockers such as spironolactone. Aldosterone exerts its effects via the epithelial sodium channel by non-genomic pathways, including serum and glucocorticoid kinase 1, neural precursor cell-expressed developmentally downregulated (gene 4) protein, and K-Ras, and genomic pathways via epigenetic mechanisms. Beyond regulating epithelial sodium channel, aldosterone induces cardiac hypertrophy, endothelial dysfunction, podocyte injury, and fibrosis. This opens new horizons for mineralocorticoid receptor antagonists and novel therapeutic targets such as serum-glucocorticoid regulated kinase 1.


Ecosystem functioning of two marine food webs in the North-Western Ionian Sea (Central Mediterranean Sea).
The ecosystem functioning of two marine food webs covering the north-eastern (Salento) and south-western (Calabria) sectors of the North-Western Ionian Sea (NWIS) (Central Mediterranean Sea) was investigated through a food-web model. Data inputs covered a wide set of ecological information applied to 58 functional groups (FGs). The sum of consumption and the mean predation mortality rate were calculated for benthic, demersal, and pelagic subsystems indicating the predator and prey roles of the FGs. A complex system of energy and biomass exchanges characterized the investigated food webs indicating an important benthic-pelagic coupling. In the food webs of both areas, the regulation of flows between the benthic-pelagic coupling seems to occur through the benthopelagic shrimps and the small pelagics due to their wasp-waist control role. Differences were observed concerning the top predators. Odontocetes play this keystone role in the Salento food web. Anglers, bathyal squids, and sharks assume this functional role in Calabria. The geomorphology and hydrography in the NWIS could affect the biomass and energy exchanges in this coupling. The higher flows of consumption of the benthic system observed in the Calabria food web could be influenced by a widespread presence of canyons along the continental edge which increase the benthic productivity. In contrast, the flows of consumption in the Salento food web seem to be driven by the planktonic productivity supporting the pelagic, benthopelagic, and demersal compartments. This condition could be favored by the large extension of the shelf break zone. The food-web models realized for the NWIS represent ideal platforms for the development of analysis with dynamic simulations. The comparative analysis of the two food webs by means of the FGs and their functional traits allowed the general pattern of ecosystem structure and functioning in the NWIS to be identified, making it an interesting approach to investigate the marine ecosystem.


Effect of Glucose Levels on Cardiovascular Risk.
Cardiovascular diseases remain the leading cause of death and disability. The development of cardiovascular diseases is traditionally associated with various risk factors, most of which are somehow related to an unhealthy lifestyle (smoking, obesity, lack of physical activity, etc.). There are also risk factors associated with genetic predisposition, as well as the presence of concomitant diseases, especially chronic ones. One of the most striking examples is, of course, type 2 diabetes. This metabolic disorder is associated with impaired carbohydrate metabolism. The main clinical manifestation of type 2 diabetes is elevated blood glucose levels. The link between diabetes and CVD is well known, so it is logical to assume that elevated glucose levels may be important, to some extent, in the context of heart and vascular disease. In this review, we tried to summarize data on the possible role of blood glucose as a risk factor for the development of CVD.


Forbidden directions for the fracture of thin anisotropic sheets: an analogy with the Wulff plot.
It is often postulated that quasistatic cracks propagate along the direction allowing fracture for the lowest load. Nevertheless, this statement is debated, in particular for anisotropic materials. We performed tearing experiments in anisotropic brittle thin sheets that validate this principle in the case of weak anisotropy. We also predict the existence of forbidden directions and facets in strongly anisotropic materials, through an analogy with the description of equilibrium shapes in crystals. However, we observe cracks that do not necessarily follow the easiest direction but can select a harder direction, which is only locally more advantageous than neighboring paths. These results challenge the traditional description of fracture propagation, and we suggest a modified, less restrictive criterion compatible with our experimental observations.


Early-stage responses to Plasmodiophora brassicae at the transcriptome and metabolome levels in clubroot resistant and susceptible oilseed Brassica napus.
Clubroot, a devastating soil-borne root disease, in Brassicaceae is caused by Plasmodiophora brassicae Woronin (P. brassicae W.), an obligate biotrophic protist. Plant growth and development, as well as seed yield of Brassica crops, are severely affected due to this disease. Several reports described the molecular responses of B. napus to P. brassicae; however, information on the early stages of pathogenesis is limited. In this study, we have used transcriptomics and metabolomics to characterize P. brassicae pathogenesis at 1-, 4-, and 7-days post-inoculation (DPI) in clubroot resistant (CR) and susceptible (CS) doubled-haploid (DH) canola lines. When we compared between inoculated and uninoculated groups, a total of 214 and 324 putative genes exhibited differential expression (q-value < 0.05) at one or more time-points in the CR and CS genotypes, respectively. When the inoculated CR and inoculated CS genotypes were compared, 4765 DEGs were differentially expressed (q-value < 0.05) at one or more time-points. Several metabolites related to organic acids (e.g., citrate, pyruvate), amino acids (e.g., proline, aspartate), sugars, and mannitol, were differentially accumulated in roots in response to pathogen infection when the CR and CS genotypes were compared. Several DEGs also corresponded to differentially accumulated metabolites, including pyrroline-5-carboxylate reductase (BnaC04g11450D), citrate synthase (BnaC02g39080D), and pyruvate kinase (BnaC04g23180D) as detected by transcriptome analysis. Our results suggest important roles for these genes in mediating resistance to clubroot disease. To our knowledge, this is the first report of an integrated transcriptome and metabolome analysis aimed at characterizing the molecular basis of resistance to clubroot in canola.


Transcatheter mitral valve-in-valve implantation for failed bioprosthesis.
This study is a report of clinical and echocardiographic outcomes of experience with transapical mitral valve-in-valve (VIV) replacement. Eleven patients with a mean age of 63.7±13.0 years who underwent transapical mitral VIV implantation for a failed bioprosthesis at a single institution were enrolled. All of the patients were considered high-risk for surgical intervention, with a Society of Thoracic Surgery predicted risk of mortality of 14.2±17.6%, and a mean European System for Cardiac Operative Risk Evaluation (EuroSCORE II) of 10.5±6.1%. Transapical mitral VIV implantation was successful in all of the patients. Edwards, Sapien XT and Sapien 3 valves (Edwards Lifesciences Corp., Irvine, CA, USA) were used in 8 (73%), 2 (18%), and 1 (9%) patients, respectively. Size 26 valves were used in 6 (55%) patients while size 29 valves were used in 5 (45%) patients. All of the patients (11, 100%) had no or only trace mitral regurgitation at the end of the procedure. The mean length of hospital stay was 19±8.0 days. The survival was 100% at 14 days, and 90% at 30 days and at 4 years. One patient died as a result of multiorgan failure on day 16 of intensive care unit stay. The mean mitral valve gradient across the percutaneous valve was 2.26±1.047 mmHg, and the mean valve area was 2.20±0.14 cm2. Through the 4 years follow up, the New York Heart Association class of the 10 patients remaining improved to class II with no readmission for heart failure. All of the patients were on coumadin with a target international normalized ratio of 2-3. In high-risk patients, transapical mitral VIV implantation can be performed with a high success rate and considerable improvement in clinical status.


Stimulus requirements for pregnancy initiation in the golden hamster (Mesocricetus auratus) change with time of mating during the receptive period.
When maintained under a 14L:10D photoperiod, the duration of behavioural receptivity in female golden hamsters was about 18-21 h depending on age and/or parity. The effectiveness of mating stimuli in initiating pregnancy was shown to be a function of when in the receptive period (early, middle, late) that mating occurred. During the 9-h period before ovulation, 5 ejaculatory series were sufficient to produce a nearly 100% pregnancy rate and maximum litter size. During the ovulation period, however, high pregnancy rates were achieved only when mating continued to satiety (12-15 ejaculatory series plus 10-24 long intromissions). Late in the receptive period even mating to satiety failed to result in a pregnancy. In general, pregnancy rates were significantly higher for young virgin than for older multiparous females when mating occurred during or after the ovulation period. The reduced fecundity of females mating during or after ovulation was due to insufficient vaginocervical stimulation to induce functional luteal activity and not to lack of spermatozoa. Females mating late in the receptive period did not show a cessation of oestrous cycles which characteristically follows the induction of a luteal phase. Greater amounts of vaginocervical stimulation during this time increased the number of females which delivered litters but had no significant effect on litter size. These results suggest that levels of male copulatory behaviour considered 'excessive' when mating occurs early in the receptive period are essential for pregnancy initiation when mating occurs later.


The Association Between Sequence Learning on the Serial Reaction Time Task and Social Impairments in Autism.
It is assumed that learning on the Serial Reaction Time (SRT) task is related to learning involved in social skill development affected in autism, but this assumption has hardly been investigated. We have therefore examined associations between SRT task learning and social impairment measured by the Social Responsiveness Scale in 72 autistic and non-autistic adults. Results revealed a positive correlation between deterministic sequence learning, putatively involving explicit learning, and social impairment in autistic adults but not in non-autistic adults. No correlations with probabilistic learning were found. These results suggest that the type of learning that helps autistic adults during a deterministic SRT task hinders them during social development, and call for further investigating the ecological validity of the SRT task.


Targeting Cancer Stem Cells Pathways for the Effective Treatment of Cancer.
Resistance to chemotherapy and relapse are major hurdles for the effective treatment of cancer. Major reason for this is a small sub population of cancer stem cells (CSCs) and its microenvironment. CSCs are critical driving force for several types of cancer, such as gastric, colon, breast and many more. Hence, for the complete eradication of cancer, it is necessary to develop therapeutic approaches that can specifically target CSCs. Chemical agents that target different proteins involved in CSC signaling pathways, either as single agent or simultaneously targeting two or more proteins have generated promising pre-clinical and clinical results. In the current review article, we have discussed various targets and cellular pathways that can be explored for the effective and complete eradication of CSCs. Some latest developments in the field of design, synthesis and screening of ligands to target cancer stem cells have been summarized in the current review article.


Acquired color vision changes in glaucoma. Use of 100-hue test and Pickford anomaloscope as predictors of glaucomatous field change.
A five-year follow-up of eyes with elevated intraocular pressures, but without field defects, in which the color vision had been assessed by the 100-Hue test and an anomaloscope was carried out. Field defects developed in eight of 42 eyes with a low 100-Hue score, whereas field defects developed in ten of 13 eyes with a high abnormality in the 100-Hue test score. In the case of the anomaloscope (Pickford Nicholson) scores, field defects developed in four of five eyes with poor yellow-blue scores, whereas similar field defects developed in only nine of 40 years with a normal yellow-blue scores. With regard to blue-green scores, field defects developed in six of 11 eyes with a poor blue-green score, whereas field defects developed in only seven of 40 eyes with a normal blue-green score. These differences are statistically significant, and the probabilities of an abnormal color vision the results in subsequent field defects have been worked out. The red-green scores were not predictive.


[Endogenous counterinflammation and immunostimulation].
It is known since a century that inflammation is the cornerstone of the resistance against pathogens at the site of penetration. Recently, it has been shown that this beneficial effect can be found in a remote site. Furthermore, it is known that, at a distance from the site of inflammation, a decreased inflammatory reaction is observed: a counterinflammation. Concerning this counterinflammation it was found, at least in mice, that this antiinflammatory effect is equivalent or even superior to those of glucocorticoids. In mice, this counterinflammation effect is observed only 6 hours following the primo-inflammation, occurs in absence of T lymphocytes and is not mediated with bioproducts of the arachidonic metabolism. The increased host resistance against pathogens occurs later (3-10 days). It is observed against fungi, bacteria, parasites and even tumour cells. Among the possible effectors of such an increased resistance, a protein was purified to homogeneity (MW = 56 Kd, pI = 5, electrophoretic mobility of the alpha 1 globulins. This protein is with interferon gamma the more potent immunostimulant. Other effectors are presently under investigation: there are proteins involved in hematopoiesis and the cytostasis of tumour cells. It is therefore evident that in the course of certain inflammatory reactions, several substances may act as potent endogenous drugs: they are true phlogautacoïds.