Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery.
Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications.


Redefining Comorbid Insomnia and Sleep Apnea: The Association of Sleep Breathing Impairment and Insomnia with Incident Diabetes.
Rationale: Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is frequently comorbid with insomnia and often accompanied by metabolic diseases such as type 2 diabetes. Although the apnea-hypopnea index (AHI) is currently the diagnostic criterion for gauging the severity of OSA, the AHI has not consistently predicted incident diabetes. Objectives: To test whether a combined insomnia-OSA (COMISA) phenotype based on comorbid insomnia and sleep breathing impairment index (COMISA-SBII) predicts incident diabetes and to compare the association with an AHI definition of COMISA (COMISA-AHI) in the MrOS (Osteoporotic Fractures in Men) study. Methods: The study samples came from participants in the MrOS sleep study without diabetes at their baseline examination. The SBII was derived as the product of the duration of each respiratory event (apnea and hypopnea) and the accompanying desaturation area from baseline unattended polysomnography. A subgroup of individuals classified as having comorbid insomnia (difficulties falling asleep, waking up in the middle of the night and/or early morning awakenings >15 times per month, and daytime impairments) and sleep breathing impairment (greater than 50th percentile of SBII) were identified at baseline. The primary outcome was incident diabetes during the follow-up visits. Cox proportional models were built to assess the adjusted hazard ratios of COMISA-AHI and COMISA-SBII. Prediction model performances of incident diabetes were compared across different models. Results: A total of 2,365 men (mean age, 76 yr) without diabetes at baseline were included. During a median follow-up of 10.0 years, diabetes developed in 181. After adjusting for demographic characteristics, comorbidities, and behavioral risk factors, participants with COMISA-SBII had a higher risk of incident diabetes (hazard ratio, 1.82; 95% confidence interval, 1.15-2.89) than those without sleep disorders (those with an SBII ⩽13.17 and no insomnia). The result remained significant in the risk competing model. Compared with COMISA-AHI, the addition of COMISA-SBII to a crude model with established risk factors significantly improved the predictive value of incident diabetes. Conclusions: COMISA-SBII, but not COMISA-AHI, predicted incident diabetes after accounting for multiple covariates in a cohort of older men. A comorbid insomnia phenotype based on SBII plus insomnia symptoms may be an important clinical subtype.


A single compartment neuron model with activity-dependent conductances during NMDA induced activity.
In most neuron models the values of maximal conductances of membrane ionic currents are fixed. In our paper we investigate spiking activity of the neuron model activated tonically by NMDA synapse, when the membrane ionic currents are dynamically dependent on calcium concentration, as in a model by Abbott and coauthors (1993). A spiking neuron model (in Matlab/Simulink environment) is based on the properties of lamprey spinal neurons. The basic neuron is a one-compartment model with voltage-gated Na+, K, Ca2+, KCa+ channels. The Na+ and K+ currents are described with the dynamic equations of Hodgkin-Huxley model (Hodgkin and Huxley 1952). The Ca2+ and KCa+ channels are modeled using description of calcium dynamic introduced by Ekeberg and coauthors (1991). The model was tonically activated by NMDA synapse described by a kinetic model of synaptic transmission. We analyzed the activity of this model and showed that when only one of conductances is calcium-dependent, the cell is not able to react to and recover from external perturbations.


The role of IL-33 in gut mucosal inflammation.
Interleukin (IL)-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD). Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation.


Can ID Migraine be used as a screening test for adolescent migraine?
Although the ID Migraine has been developed and used for adults, it can also be used in adolescents. We aimed to investigate the validity of the ID Migraine in the adolescent student population. The study was performed on 1064 adolescents aged 12-17 years. A face-to-face semistructured interview was conducted with students after they had answered a 17-item questionnaire on sociodemographics and headache. Students who had had two or more headache attacks during the last 3 months then answered the ID Migraine. The sensitivity and specificity of the ID Migraine were 62.1% and 71.1%, respectively. The sensitivity was higher for patients with migraine with aura (71.1%), for girls (71.3%) and for younger adolescents (69.1%). The specificity was higher for boys (77.9%) and for older adolescents (73.3%). The kappa value was 0.316 (P < 0.001). Although the kappa value of the ID Migraine is low, the test may be a useful tool in screening adolescent migraine after some changes are made.


Epitheliocystis in Atlantic salmon, Salmo salar L., farmed in fresh water in Ireland is associated with 'Candidatus Clavochlamydia salmonicola' infection.
Intracellular inclusions containing chlamydia-like organisms are frequently observed in the gill epithelial cells of Atlantic salmon, Salmo salar L., cultured in fresh water in Ireland. In this study, the causative agent was identified in four separate freshwater sites, using 16s rRNA sequencing, as 'Candidatus Clavochlamydia salmonicola'. Histopathology and real-time (RT) PCR were used to further assess infections. The prevalence of infection ranged from 75-100% between sites and infection intensity was highly variable. No significant lesions were associated with these infections. As a diagnostic tool, RT-PCR proved marginally more sensitive than histopathology. The fate of 'Candidatus Clavochlamydia salmonicola' in Atlantic salmon post-seawater transfer was investigated in a 12-week marine longitudinal study. Both RT-PCR and histopathological examination indicate that the organism disappears from the gills 4-6 weeks post-transfer.


STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch.
Chronic itch is an intractable symptom of inflammatory skin diseases, such as atopic and contact dermatitis. Recent studies have revealed neuronal pathways selective for itch, but the mechanisms by which itch turns into a pathological chronic state are poorly understood. Using mouse models of atopic and contact dermatitis, we demonstrate a long-term reactive state of astrocytes in the dorsal horn of the spinal segments that corresponds to lesioned, itchy skin. We found that reactive astrogliosis depended on the activation of signal transducer and activator of transcription 3 (STAT3). Conditional disruption of astrocytic STAT3 suppressed chronic itch, and pharmacological inhibition of spinal STAT3 ameliorated the fully developed chronic itch. Mice with atopic dermatitis exhibited an increase in scratching elicited by intrathecal administration of the itch-inducer gastrin-releasing peptide (GRP), and this enhancement was normalized by suppressing STAT3-mediated reactive astrogliosis. Moreover, we identified lipocalin-2 (LCN2) as an astrocytic STAT3-dependent upregulated factor that was crucial for chronic itch, and we demonstrated that intrathecal administration of LCN2 to normal mice increased spinal GRP-evoked scratching. Our findings indicate that STAT3-dependent reactive astrocytes act as critical amplifiers of itching through a mechanism involving the enhancement of spinal itch signals by LCN2, thereby providing a previously unrecognized target for treating chronic itch.


Essential role of multi-element data in interpreting elevated element concentrations in areas impacted by both natural and anthropogenic influences.
This article presents a detailed analysis of a dataset consisting of 27 elements found in soils, soil eluates, and vegetables from private gardens in a region with a long history of coal mining and burning. With coal being one of the world's most significant energy sources, and previous studies highlighting elevated element levels in vegetables from this region, the objective of this study was to identify the factors that impact soil geochemistry and metal(loid) uptake in plants. Total major and trace element concentrations were analyzed in soils, soil eluates and vegetables by high resolution inductively coupled plasma mass spectrometry. The vegetable samples included six species: fennel, garlic, lettuce, parsley, onion, and radicchio. Each plant was divided into roots, stems, leaves, and/or bulbs and analyzed separately. In addition, the soil pollution status, bioavailable fractions and transfer factors from soil and soil eluates to different plant parts were determined. The comprehensive dataset revealed that, apart from the substrate enriched with various elements (Al, As, Co, Cr, Mo, Ni, Pb, Sb, Sn, Ti, U, V, and Zn), other anthropogenic factors such as the legacy of coal mining and combustion activities, associated industries in the area, transport, and agricultural practices, also influence the elevated element concentrations (Cd, Cu, Fe, Mn, and Se) in locally grown vegetables. The transfer factors based on element concentrations in aqueous soil eluates and element bioavailable fractions confirmed to be an effective tool for evaluating metal uptake in plants, emphazising to some extent the effects of plant species and revealing unique patterns for each pollution source within its environmental context (e.g., Cd, Mo, S, and Se in this case). The study highlights the crucial importance of utilizing comprehensive datasets that encompass a multitude of factors when interpreting the impacts of element uptake in edible plants.


Genes that escape from X inactivation.
To achieve a balanced gene expression dosage between males (XY) and females (XX), mammals have evolved a compensatory mechanism to randomly inactivate one of the female X chromosomes. Despite this chromosome-wide silencing, a number of genes escape X inactivation: in women about 15% of X-linked genes are bi-allelically expressed and in mice, about 3%. Expression from the inactive X allele varies from a few percent of that from the active allele to near equal expression. While most genes have a stable inactivation pattern, a subset of genes exhibit tissue-specific differences in escape from X inactivation. Escape genes appear to be protected from the repressive chromatin modifications associated with X inactivation. Differences in the identity and distribution of escape genes between species and tissues suggest a role for these genes in the evolution of sex differences in specific phenotypes. The higher expression of escape genes in females than in males implies that they may have female-specific roles and may be responsible for some of the phenotypes observed in X aneuploidy.


A structure-dynamics relationship in ratcheted colloids: resonance melting, dislocations, and defect clusters.
We consider a two dimensional colloidal dispersion of soft-core particles driven by a one dimensional stochastic flashing ratchet that induces a time averaged directed particle current through the system. It undergoes a non-equilibrium melting transition as the directed current approaches a maximum associated with a resonance of the ratcheting frequency with the relaxation frequency of the system. We use extensive molecular dynamics simulations to present a detailed phase diagram in the ratcheting rate-mean density plane. With the help of a numerically calculated structure factor, solid and hexatic order parameters, and pair correlation functions, we show that the non-equilibrium melting is a continuous transition from a quasi-long range ordered solid to a hexatic phase. The transition is mediated by the unbinding of dislocations and formation of compact and string-like defect clusters.


A Prospective, Descriptive Study to Assess Nursing Staff Perceptions of and Interventions to Prevent Medical Device-related Pressure Injury.
Nurses play an important role in identifying patients at risk for medical device-related (MDR) pressure injuries and preventing their occurrence. A prospective, descriptive study was conducted across 6 hospitals in Ankara, Turkey between December 2014 and June 2015 to assess nursing perceptions about and interventions used for the pre- vention of MDR pressure ulcers. A questionnaire was used to collect demographic information and data on experience with MDR pressure ulcers; in addition, participants completed a Nursing Interventions Form that included 10 statements regarding basic nursing interventions to prevent MDR pressure ulcers; answer options were I perform, I partly perform, I do not perform. Of the 1555 nurses invited, 606 (38%) participated. Nurses who chose to volunteer completed the study instruments independently at their convenience; their responses were entered directly into the statistical analysis system by the researchers. Demographic and interventions data were analyzed using frequency and percentage distributions. Participant mean age was 30.0 ± 6.83 years, most were women (86.9%), with a mean of 8.47 ± 6.70 years of experience. Most had a bachelor's degree (55.1%), 38.2% worked in intensive care units, 50.2% participated in a scienti c program regarding the prevention/treatment of pressure ulcers after their gradu- ation, and 87.9% provided care to patients with pressure ulcers. A great majority (80.1%) of the nurses believed the use of medical devices can lead to pressure ulcers and 59.2% had experience with MDR pressure ulcers, but almost 20% did not believe medical devices can cause a pressure ulcer. The nurses identi ed 18 medical devices that posed the highest risk of causing MDR pressure ulcers; the 3 most commonly identi ed devices were endotracheal tubes (59.7%), tracheostomy ties (58.9%), and blood pressure cuffs (58.4%). The most common interventions used by these nurses included ensuring correct device positioning (87.9%) and loosening devices at least once every shift (80%) when medical conditions allowed. These ndings suggest nurses may not be aware of the risk for pressure ul- cers associated with a number of medical devices, indicating a need for comprehensive inservice training programs and research to identify optimal measures and methods to prevent MDR pressure ulcers.


Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes.
Chronic demyelination is a pathophysiologic component of compressive spinal cord injury (SCI) and a characteristic finding in demyelinating diseases including multiple sclerosis (MS). A better characterization of endogenous cells responsible for successful remyelination is essential for designing therapeutic strategies aimed at restoring functional myelin. The present study examined the spatiotemporal response of endogenous oligodendrocyte precursor cells (OPCs) following ethidium bromide (EB)-induced demyelination of the adult rat spinal cord. Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2(+) cells within the lesion was observed, none of which expressed the oligodendrocyte lineage-associated transcription factor Nkx2.2. At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2. Despite successful recruitment of Nkx2.2(+)/Olig2(+) OPCs within the lesion, demyelinated axons were not remyelinated by these OPCs in regions lacking astrocytes. Rather, Schwann cell remyelination predominated throughout the central core of the lesion, particularly around blood vessels. Oligodendrocyte remyelination was observed in the astrogliotic perimeter, suggesting a necessary role for astrocytes in oligodendrocyte maturation. In addition, reexpression of the radial glial antigen, RC-1, by reactive astrocytes and ependymal cells was observed following injury. However, these cells did not express the neural stem cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by glial progenitors. In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous remyelination following EB-induced lesions.


Genetic Ablation of Neural Progenitor Cells Impairs Acquisition of Trace Eyeblink Conditioning.
Adult-born neurons are believed to play a role in memory formation by providing enhanced plasticity to the hippocampus. Past studies have demonstrated that reduction of neurogenesis impairs associative learning, but these experiments used irradiation or neurotoxic substances, which may have had unintended off-target effects. Therefore, to investigate the role of these adult-born neurons more precisely, we used nestin-HSV-TK transgenic mice (Nes-TK) to selectively ablate newborn neurons. Nes-TK mice were fed a chow infused with valganciclovir to induce the ablation of neural progenitor cells. After being on this diet for 4 weeks, mice were trained on trace eyeblink conditioning, a hippocampus-dependent temporal associative memory task. Following the completion of training, brain sections from these animals were stained for doublecortin, a marker for immature neurons, to quantify levels of neurogenesis. We found that male transgenic mice on valganciclovir had significantly decreased amounts of doublecortin relative to male control animals, indicating a successful reduction in levels of neurogenesis. In conjunction with this reduction in neurogenesis, the male transgenic mice on valganciclovir learned at a significantly slower rate than male control mice. The female Nes-TK mice on valganciclovir showed no significant decrease in neurogenesis and no behavioral impairment relative to female control mice. Ultimately, the results are consistent with, and expand upon, prior studies that demonstrated that adult-born neurons are involved in the formation of associative memories. This study also provides a foundation to continue to explore the physiological role of newborn neurons with in vivo recordings during behavioral training.


[Obstructive jaundice after cholecystectomy].
In this article we present the case of a 72 year-old woman who three years after laparoscopic cholecystectomy develops obstructive jaundice. An MRI of the liver and biliary system revealed an hiliar mass that caused dilatation of the biliary tree. The patient underwent hepatic duct resection and reconstruction via hepaticojejunostomy. The histological examination of the surgical specimen identified an intramural biliary neuroma with no evidence of malignancy.


Chemical and physical properties of dry flue gas desulfurization products.
Beneficial and environmentally safe recycling of flue gas desulfurization (FGD) products requires detailed knowledge of their chemical and physical properties. We analyzed 59 dry FGD samples collected from 13 locations representing four major FGD scrubbing technologies. The chemistry of all samples was dominated by Ca, S, Al, Fe, and Si and strong preferential partitioning into the acid insoluble residue (i.e., coal ash residue) was observed for Al, Ba, Be, Cr, Fe, Li, K, Pb, Si, and V. Sulfur, Ca, and Mg occurred primarily in water- or acid-soluble forms associated with the sorbents or scrubber reaction products. Deionized water leachates (American Society for Testing and Materials [ASTM] method) and dilute acetic acid leachates (toxicity characteristic leaching procedure [TCLP] method) had mean pH values of >11.2 and high mean concentrations of S primarily as SO(2-)4 and Ca. Concentrations of Ag, As, Ba, Cd, Cr, Hg, Pb, and Se (except for ASTM Se in two samples) were below drinking water standards in both ASTM and TCLP leachates. Total toxicity equivalents (TEQ) of dioxins, for two FGD products used for mine reclamation, were 0.48 and 0.53 ng kg(-1). This was similar to the background level of the mine spoil (0.57 ng kg(-1)). The FGD materials were mostly uniform in particle size. Specific surface area (m2 g(-1)) was related to particle size and varied from 1.3 for bed ash to 9.5 for spray dryer material. Many of the chemical and physical properties of these FGD samples were associated with the quality of the coal rather than the combustion and SO2 scrubbing processes used.


Correlation between Microstructural Alteration, Mechanical Properties and Manufacturability after Cryogenic Treatment: A Review.
Cryogenic treatment is a supplemental structural and mechanical properties refinement process to conventional heat treatment processes, quenching, and tempering. Cryogenic treatment encourages the improvement of material properties and durability by means of microstructural alteration comprising phase transfer, particle size, and distribution. These effects are almost permanent and irreversible; furthermore, cryogenic treatment is recognized as an eco-friendly, nontoxic, and nonexplosive process. In addition, to encourage the application of sustainable techniques in mechanical and manufacturing engineering and to improve productivity in current competitive markets, cryo-treatment can be considered as a promising process. However, while improvements in the properties of materials after cryogenic treatment are discussed by the majority of reported studies, the correlation between microstructural alteration and mechanical properties are unclear, and sometimes the conducted investigations are contradictory with each other. These contradictions provide different approaches to perform and combine cryogenic treatment with pre-and post-processing. The present literature survey, mainly focused on the last decade, is aimed to address the effects of cryogenic treatment on microstructural alteration and to correlate these changes with mechanical property variations as a consequence of cryo-processing. The conclusion of the current review discusses the development and outlines the trends for the future research in this field.


Turning job finders into job keepers.
Most welfare-to-work programs designed to help single mothers leave welfare for employment focus on the challenge of finding a job. This article looks beyond the point of employment to consider the difficulty many former welfare recipients have keeping their jobs. The authors review evidence showing that many families cycle back and forth between welfare and work, losing jobs and returning to public assistance while they seek work again. Factors contributing to high rates of job loss include characteristics of the job and of the worker. Temporary jobs, frequent layoffs, low pay in relation to work expenses, lack of experience meeting employer expectations, and personal or family problems all lead to dismissals and resignations. Drawing from the experience of innovative programs, the authors recommend policy changes and program approaches that can help families overcome setbacks and stabilize their lives as they move from welfare into increasingly stable employment.


[Asthma epidemiology].
Asthma is excessively common among the individuals (up to 10% in adults and 35% in children). Asthma is differently distributed in the world. Asthma incidence is 1%/y in average. Children are at greater risk of asthma than adults, which could be due to a cohort effect. Severe asthma is reported by 1-3% of the general population (children and adults respectively). Recent population-based data show that the asthma prevalence increase observed worldwide in the past 30 years has now stopped in industrialised countries. Such phenomenon has been paralleled by an increase in the use of asthma medications. The development and phenotypic expression of asthma depends on a complex interaction between genetic and environmental factors. Gene-environment interactions already in early life should be explored to understand asthma epidemiological evolution.


Insertion element IS102 resides in plasmid pSC101.
In vivo recombination was found to occur between plasmid pHS1, a temperature-sensitive replication mutant of pSC101 carrying tetracycline resistance, and plasmid ColE1 after selection for tetracycline resistance at the restrictive temperature, 42 degrees C. Extensive analysis of the physical structures of three of these recombinant plasmids, using restriction endonucleases and the electron microscope heteroduplex method, revealed that the plasmid pHS1 was integrated into different sites on ColE1. The recombinant plasmids contained a duplication of a unique 1-kilobase (kb) sequence of pHS1 in a direct orientation at the junctions between the two parental plasmid sequences. This was confirmed by comparing the nucleotide sequence of the recombinants and their parental plasmids. Nucleotide sequence analysis further revealed that nine nucleotides at the site of recombination of ColE1 were duplicated at the junction of each of the 1-kb sequences. The formation of recombinants was independent of RecA function. Based on our previous finding that a plasmid containing a deoxyribonucleic acid insertion (IS) element can recombine with a second plasmid to generate a duplication of the IS element, we conclude that the 1-kb sequence is an insertion sequence, which we named IS102. For convenience, we have also denoted the IS102 sequence as eta theta to assign the orientation of the sequence. Eighteen nucleotides at one end (eta end) were found to be repeated in an inverted orientation at the other end (theta end) of IS102. The nucleotide sequence of the eta end of the sequence was found to be identical to the sequence at the ends of the transposon Tn903, which is responsible for transposition of the kanamycin resistance gene.


The effect of administration of a single dose of T-2 toxin on blood coagulation in the rabbit.
The single intravenous administration of T-2 toxin to rabbits at a dosage of 0.5 mg per kg body weight produced an alteration in several blood coagulation parameters. The activities of factors VII, VIII, IX, X and XI were decreased by approximately 40% six hours after T-2 toxin administration. Plasma fibrinogen concentration became elevated within 24 hours after T-2 toxin exposure. Circulating platelet numbers were unaffected by T-2 toxin administration. The similarity of coagulation parameter changes induced by T-2 toxin in animals receiving daily subcutaneous injections of vitamin K (0.5 mg per kg body weight) and those in nonvitamin K supplemented animals suggests that T-2 toxin does not function as a vitamin K antagonist.


Pagan-Christian change in northeastern Hungary in the 10th-13th centuries AD--a palaeodemographic aspect.
In the present paper the authors compared skeletal populations (2421 individuals) excavated from four cemeteries, namely Hajdúdorog-Gyúlás (10th century AD), Hajdidorog-Temetöhegy (11th century AD), Hajdúdorog-Katidülö (12th-13th century AD) and Hajdúdorog-Szálldáföld (12th-13th century AD) from a micro-region of Northern Hajdúság (located in the northern part of the Great Hungarian Plain in Hungary in the Carpathian Basin) based on demographic data. The cemeteries were dated to the age of the Hungarian conquest and the Arpadian age and provided representative data for anthropological research. Previous studies based on craniological and archaeological investigations have already suggested that there was discontinuity in the population history between the 10th and the 11th centuries AD and continuity between the 11th and 12th centuries AD in this region. This hypothesis could be partially supported by demographic investigations because conclusive evidence was found that there must have been a change in the population at the turn of the 10th and 11th centuries AD, and there was certain continuity between the 11th and 12-13th centuries AD. The authors suppose that there were two crises in the examined period: the first crisis set in at the transition from the pagan era (10th century AD) to the Christian era (from the beginning of the 11th century AD, with population resettlements within the Carpathian Basin), the second might have been more moderate and meant burying the dead of the populations lacking a church in the churchyards of villages which had a church. At that time one graveyard around a church may have been used by several village populations.


Exercise echocardiography in asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction.
The management of asymptomatic patients with severe aortic stenosis (AS) remains controversial. Recent series reported that early aortic valve replacement might be associated with improved clinical outcomes. However, the risk-benefit ratio should be carefully evaluated and early surgery only be proposed to a subset of asymptomatic patients considered at higher risk. Exercise echocardiography can help unmask symptomatic patients combined with assessment of the hemodynamic consequences of AS. Recent studies have demonstrated that exercise echocardiography can provide incremental prognostic value to identify patients who may benefit most from early surgery. In "truly" asymptomatic patients, an increase in mean aortic gradient ≥ 18-20 mmHg, a limited left ventricular contractile reserve or a pulmonary hypertension during exercise are predictive parameters of adverse cardiac events. Exercise echocardiography is low-cost, safe and available in many referral centers, and does not expose patients to radiation. The purpose of this article is to describe the role of exercise testing and echocardiography in the management of asymptomatic patients with severe AS and preserved left ventricular ejection fraction.


Novel therapeutical approaches based on neurobiological and genetic strategies for diabetic polyneuropathy - A review.
Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients' quality of life. This study investigates potential novel therapeutic options that could ameliorate symptoms of DN. Research and review papers from the last 10 years were taken into consideration. There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy. Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs.


Giant arteriovenous malformation of the floor of the mouth presenting with dysarthria and difficulty in swallowing.
Arteriovenous malformation (AVM) is a vascular abnormality resulting in the development of abnormal connection between an artery and vein without capillary connections. An AVM develops mainly intracranially. Extracranial AVMs are rarely seen. Cheek, ear, nose, auricle, and forehead are the more common sites in the extracranial involvement. They cause cosmetic problems when located in the head and neck region. We report a case of a giant AVM in the floor of the mouth, which has not been specified and has not been reported until now. The lesion, in an elderly man, was supplied by multiple vessels and caused difficulty in speaking and swallowing. The lesion was totally excised after embolization of feeding vessels.


Potentiation of the adrenergic beta-receptor-mediated insulin secretion in pertussis-sensitized rats.
The increase in blood insulin level induced by adrenergic beta-stimulants, glucose and tolbutamide was strongly exaggerated in pertussis-sensitized rats. Moreover, the decrease in blood insulin caused by the alpha-receptor-mediated action of epinephrine in glucose- or tolbutamide-treated rats was effectively reversed by pertussis sensitization. The rise of blood insulin concentration due to adrenergic alpha-blockade was also enhanced by pertussis sensitization. It is concluded that the secretion of insulin resulting from the stimulation of adrenergic bate-receptor is enhanced by pertussis sensitization, probably due to activation of a process occurring in the chain of events leading to the discharge of insulin from the pancreatic beta-cell.


An empirical examination of patient room handedness in acute medical-surgical settings.
The study objective was to examine whether standardized same-handed room configurations contribute more to operational performance in comparison to standardized mirror-image room configurations. Based on a framework that physical environment standardization supports process and workflow standardization, thus contributing to safety and efficiency, the study examined the comparative effectiveness of the standardized same-handed configuration and the standardized mirror-image configuration. Patient room handedness has emerged as an important issue in inpatient unit design, with many hospitals adopting the standardized same-handed room concept at all levels of patient acuity. Although it is argued that standardized same-handed rooms offer greater levels of safety and efficiency in comparison to standardized mirror-image rooms, there is little empirical evidence either to support or refute these contentions. An experimental setting was developed where elements of the physical environment and approach to the caregiver zone were systematically manipulated. Twenty registered nurses (10 left-handed and 10 right-handed) provided three types of care to a patient-actor across nine physical design configurations, which were videotaped in 540 separate segments. Structured interviews of the subjects were conducted at the end of each individual set of simulation runs to obtain triangulation data. Video segments were coded by nursing experts. Statistical and content analyses of the data were conducted. Study data show that standardized same-handed configurations may not contribute to process and workflow standardization--hence, to safety and efficiency--any more than standardized mirror-image configurations in acute medical-surgical settings. Data suggest that a global view of the patient care environment upon entry is the most sought-after familiarization factor to reduce cognitive load.


Adsorption of plasmid DNA to mineral surfaces and protection against DNase I.
The adsorption of [3H]thymidine-labeled plasmid DNA (pHC314; 2.4 kb) of different conformations to chemically pure sand was studied in a flowthrough microenvironment. The extent of adsorption was affected by the concentration and valency of cations, indicating a charge-dependent process. Bivalent cations (Mg2+, Ca2+) were 100-fold more effective than monovalent cations (Na+, K+, NH4+). Quantitative adsorption of up to 1 microgram of negatively supercoiled or linearized plasmid DNA to 0.7 g of sand was observed in the presence of 5 mM MgCl2 at pH 7. Under these conditions, more than 85% of DNA adsorbed within 60 s. Maximum adsorption was 4 micrograms of DNA to 0.7 g of sand. Supercoil molecules adsorbed slightly less than linearized or open circular plasmids. An increase of the pH from 5 to 9 decreased adsorption at 0.5 mM MgCl2 about eightfold. It is concluded that adsorption of plasmid DNA to sand depends on the neutralization of negative charges on the DNA molecules and the mineral surfaces by cations. The results are discussed on the grounds of the polyelectrolyte adsorption model. Sand-adsorbed DNA was 100 times more resistant against DNase I than was DNA free in solution. The data support the idea that plasmid DNA can enter the extracellular bacterial gene pool which is located at mineral surfaces in natural bacterial habitats.


Water-electrolyte balance in goldfish Carassius auratus, under constant and diurnally cycling temperature conditions.
1. The effects of acclimation to constant and diurnally cycling temperatures upon water-electrolyte regulation were examined in goldfish held at 20, 25, 30 and 25 +/- 5 degrees C, and sampled at 03.00, 09.00 15.00 and 21.00 h. Plasma and epaxial muscle levels of Na, K, Ca, Mg, Cl and water were determined. Using Cl space as an indicator of extracellular phase volume, mean cellular cation concentrations were estimated. 2. Fish held at constant temperature exhibited significant diurnal variations in all ions except plasma magnesium and muscle potassium. With the exception of muscle choride, however, the occurrence of peak and/or minimum concentrations tended to be inconsistent in relation to specific sampling times. Somewhat more regularity was apparent in terms of dark or light periods. 3. Under constant temperature conditions plasma Cl increased with increasing temperature, while Na declined. Plasma magnesium was consistently higher at 25 degrees C than at either 20 or 30 degrees C. This was true of muscle Mg as well and, generally, also of Na, K and Cl. Water content tended to rise at higher temperatures in these animals, as did cellular phase volume, while extracellular phase volume was reduced. 4. Exposure to cycling temperatures was associated with a number of significant departures from the pattern seen at constant temperature. Ionic concentrations tended to be lower. By comparison with animals sampled at constant temperature and comparable times, diurnal stability was greater. In several instances (e.g. muscle Cl- and K+, cellular and extracellular phase volumes) variations with temperature were significantly different. This was also the case with ion pairs such as K and Na, and Ca and Mg. 5. These observations raise obvious questions regarding the validity of earlier descriptions of water-electrolyte status in species normally exposed to fluctuating temperatures. The variations seen under cycling temperature conditions, however, appeared to be adaptively appropriate. Reductions in plasma ion levels, for example, would tend to reduce costs of ionic regulation. The stability of plasma: cellular K concentrations should desensitize muscular excitability in relation to changing temperature conditions. This was also true of cellular levels of generally stimulating (Mg, K) and generally inhibitory ions (Ca, Na) known to influence metabolic processes.


Assembly of fibronectin extracellular matrix.
In the process of matrix assembly, multivalent extracellular matrix (ECM) proteins are induced to self-associate and to interact with other ECM proteins to form fibrillar networks. Matrix assembly is usually initiated by ECM glycoproteins binding to cell surface receptors, such as fibronectin (FN) dimers binding to α5ß1 integrin. Receptor binding stimulates FN self-association mediated by the N-terminal assembly domain and organizes the actin cytoskeleton to promote cell contractility. FN conformational changes expose additional binding sites that participate in fibril formation and in conversion of fibrils into a stabilized, insoluble form. Once assembled, the FN matrix impacts tissue organization by contributing to the assembly of other ECM proteins. Here, we describe the major steps, molecular interactions, and cellular mechanisms involved in assembling FN dimers into fibrillar matrix while highlighting important issues and major questions that require further investigation.


Ionic Liquid-Silica Precursors via Solvent-Free Sol-Gel Process and Their Application in Epoxy-Amine Network: A Theoretical/Experimental Study.
This work describes the solvent-free sol-gel synthesis of epoxy-functionalized silica-based precursors in the presence of 1-butyl-3-methylimidazolium-based ionic liquids (ILs) containing different anions: chloride (Cl-) and methanesulfonate (MeSO3-). The IL-driven sol-gel mechanisms were investigated in detail using experimental characterizations (29Si NMR and ATR FTIR spectroscopy) and a theoretical computational method based on density functional theory (DFT). We observed complex IL influence on both hydrolysis and condensation steps, involving especially H-bonding and Coulomb coupling stabilization of the process intermediates. The obtained IL-silica precursors and their further xerogels were widely characterized (rheology measurements, MALDI TOF, 29Si NMR, ATR FTIR, and DFT simulation), which allowed observation of their precise silica structures and established their most energetically favorable conformations. The detected silica structures were dependent on the IL type and varied from highly condensed 3D cage-like to branched ladder-like and cyclic ones. The application of prepared IL-silica precursors as reinforcing additives into the epoxy-amine network led to an improvement in the organic/inorganic interphase interactions through chemical and physical bonding. Uniform and well-dispersed silica aggregates, in the size of ∼30 nm, were formed when ≤6.8 wt % of each IL-silica precursor was applied into the epoxy-amine network. The use of imidazolium-based ILs contributed to a significant improvement in thermomechanical properties of hybrids and reduced their UV absorption ability compared to that of the reference matrix. All hybrids exhibited an increase in energy to break (up to ∼53%), elongation at break (up to ∼43%), shear storage modulus in the rubbery region (up to 4 times), and thermo-oxidative stability.


The feline blood film.
Practical relevance: Many veterinary practices have invested in quality automated hematology instruments for use in-house. However, regardless of the specific choice of analyzer, there are important hematology findings that can only be determined by microscopic examination of stained blood films. For this reason, and also for the purpose of quality control for the analyzer, a quick blood film review should be performed alongside every automated complete blood count. Even those practices that submit their blood samples to outside diagnostic laboratories for evaluation, still require the capability to examine stained blood films in emergency situations. Series outline: This is the first of a two-part article series that aims to familiarize the practitioner with normal findings on feline blood films, with a particular focus on unique features in the cat, as well as to assist with interpretation of common abnormalities. Part 1 focuses on how to prepare and examine blood films in order to maximize the reliability of the information they convey, and describes the morphology of feline erythrocytes in health and disease. Evidence base: The information and guidance offered is based on the published literature and the author's own extensive clinical pathology research.


Long-term consequences of adolescent health behaviors: implications for adolescent health services.
The authors discuss the evidence supporting the effectiveness of adolescent preventive services to influence health outcomes, the magnitude of the long-term consequences of adolescent health-compromising behaviors, and their implications for health policies. Particular attention is given to the contribution that behaviors participated in or begun during adolescence have on long-term health, including cancer and heart disease. They postulate the health benefits that might accrue from the widespread implementation of comprehensive adolescent preventive services, assuming a conservative estimate of effectiveness, could be significant.


Ceroid lipofuscinosis in sheep. II. The major component of the lipopigment in liver, kidney, pancreas, and brain is low molecular weight protein.
Previous studies on the lipopigment from the livers of sheep affected with ceroid lipofuscinosis showed that the disease does not involve a defect in lipid metabolism or abnormal lipid peroxidation and that most of the lipopigment was proteinaceous. In this study, lipopigment was isolated from liver, kidney, pancreas, and brain of affected sheep without the use of proteolytic enzymes. Lipopigment from all tissues was two-thirds protein. Modified silver staining after sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a major band of Mr = 14,800, heterogeneous material between Mr = 5,000 and 9,000, and a major band of Mr = 3,500. These compounds did not stain for RNA or carbohydrate and were digested by a nuclease-free protease as expected for protein. They are not normal lysosomal proteins. Lipopigment levels of dolichol, ubiquinone, and cholesterol were consistent with the lipopigment being protein-enriched lysosome-derived cytosomes. The presence of the Mr = 3,500 proteins in whole affected tissue homogenates distinguished them from homogenates of normal tissues. It was concluded that low Mr proteins are specifically stored in ovine ceroid lipofuscinosis and that the ceroid lipofuscinoses may result from inherited defects in lysosomal protein catabolism.


Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease.
To study the role of occupational exposures to solvents and aluminium in the aetiology of Alzheimer's disease (AD). An industrial hygienist rated exposure. 89 subjects diagnosed with probable AD were matched by age, sex, and type of informant to 89 controls. Subjects were identified from a large health maintenance organisation in Seattle, WA. A complete occupational history was obtained from spouses of cases and controls as well as from controls themselves. After the interview an industrial hygienist, blinded to case-control status, rated exposures. Non-significant associations were found between AD and ever having been occupationally exposed to solvents (odds ratio (OR) 1.77, 95% confidence interval (95% CI) 0.81 to 3.90) and aluminium (OR 1.46, 95% CI 0.62 to 3.42). Although an increasing risk was found with increasing number of years of exposure to solvents, there was an inverse association between exposure intensity and AD, and measures of cumulative exposure taking into account both intensity and duration of exposure were not significant. Analysis of the age at which half the cumulative exposure to solvents was achieved showed that an older age incurred a greater risk of AD than a younger age. However, the total amount of exposure carried no risk. The results suggest that lifetime occupational exposure to solvents and aluminium are not likely to be important risk factors for Alzheimer's disease.


Virucidal Activity of World Health Organization-Recommended Formulations Against Enveloped Viruses, Including Zika, Ebola, and Emerging Coronaviruses.
The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations.


Disease progression in a murine model of bcr/abl leukemogenesis.
We have developed a system for expressing bcr/abl genes in the mouse hematopoietic system utilizing retroviral gene transfer and bone marrow transplantation. Expression of the P210bcr/abl gene in mice gives rise to a spectrum of hematological malignancies, most prominently a myeloproliferative syndrome which closely resembles human chronic myelogenous leukemia (CML). Studies of this system and related systems in other laboratories have begun to yield insights into the pathophysiology of the human bcr/abl leukemias. The CML-like syndrome appears to be a consequence of infection of a multipotential hematopoietic progenitor target cell. The leukemic clone is difficult to transplant to secondary recipients, but undergoes evolution to acute leukemia. The P190 form of bcr/abl appears to be more potent in leukemogenesis than P210, but may also be associated with a CML-like picture upon infection of a multipotential target cell. There may be a spectrum of different chronic phase duration associated with different Bcr/Abl proteins, with bcr sequences influencing the rate of disease progression. In mice, duplication or alterations of the bcr/abl gene itself may constitute a major mechanism of disease progression.


Radial collateral ligament of the elbow: sonographic characterization with cadaveric dissection correlation and magnetic resonance arthrography.
An abnormality of the radial collateral ligament (RCL) in the setting of lateral epicondylitis can indicate a poor clinical outcome; therefore, accurate assessment is important. The purpose of this study was to characterize the proximal RCL attachment, or footprint, as seen on sonography using cadaveric dissection correlation and magnetic resonance arthrography. For the first part of this study, 4 cadaveric elbow specimens were imaged with sonography before and after dissection to characterize the RCL. After Institutional Review Board approval with consent waived, 26 consecutive magnetic resonance (MR) arthrograms of the elbow were identified. The sonograms and MR arthrograms were retrospectively reviewed to measure the length of the RCL footprint and its percentage of the combined RCL and common extensor tendon (CET) humeral footprints. The mean RCL footprint length and percentage of the combined RCL and CET footprints were 8.4 mm (range, 7.4-10.0 mm) and 54% as measured from the elbow specimen sonograms and 9.1 mm (range, 6.4-12.5 mm) and 54% as measured from the MR arthrograms. The mean RCL footprint length combining data from specimens and MR arthrograms was 8.9 mm (range, 6.4-12.5 mm), covering 54% of the combined RCL and CET footprints. The RCL can be differentiated from the CET on sonography with knowledge of the RCL humeral footprint extent, which measured 8.9 mm in length and comprised 54% of the combined RCL and CET footprints.


Circulating microRNA profiles in different arterial territories of stable atherosclerotic disease: a systematic review.
Atherosclerosis is associated with altered circulating microRNA profiles. It is yet unclear whether the expression of these potential biomarkers differs according to the location of atherosclerosis. We assessed whether atherosclerosis of different arterial territories, except the coronary, is associated with specific circulating microRNA profiles. A systematic search in PubMed, Web of Science, Embase, and Cochrane Library was carried out using a retrieval strategy including MESH and non-MSH terms. Eligible studies have compared circulating microRNA profiles between individuals with and without stable atherosclerotic disease of large or medium size arteries. The review protocol was registered in PROSPERO database (reference CRD42017073846). Eighteen studies were selected for qualitative synthesis: ten focused on carotid, six on lower limbs, and two on renal arteries atherosclerosis, none reporting on other locations. A common microRNA profile to different atherosclerotic disease locations was identified, including deregulation of miR-21, miR-30, miR-126, and miR-221-3p. Specific microRNA profiles for each territory were also identified, with consistency across studies, such as deregulation of miR-21 and miR-29 in carotid atherosclerosis, and let 7e, miR-27b, miR-130a, and miR-210 in lower limbs atherosclerosis. The robustness of the results was very high for let 7e, miR-29, miR-30, considering both the adjustment of microRNA expression for baseline variables and the replication of results in different studies (miR-29 in carotid, let 7e in lower limbs, and miR-30 in carotid and lower limbs atherosclerosis). Globally, the deregulated microRNAs are associated with control of angiogenesis, endothelial cell function, inflammation, cholesterol metabolism, oxidative stress and extracellular matrix composition. A common microRNA profile to different atherosclerotic disease locations and specific microRNA profiles for each territory were identified. These findings may provide insights into pathophysiology and be useful for selecting potential biomarkers for clinical practice. To the best of our knowledge, no systematic data on this subject has been reported.


Ensemble Statistics Can Be Available before Individual Item Properties: Electroencephalography Evidence Using the Oddball Paradigm.
Behavioral studies have shown that statistical properties of object groups are perceived accurately with brief exposure durations. This finding motivated the hypothesis that ensemble perception occurs rapidly in vision. However, the precise timing of ensemble perception remains unclear. Here, we used the superior temporal resolution of electroencephalography to directly compare the timing of ensemble processing to that of individual object processing. The P3b was chosen as a particular component of interest, as it is thought to measure the latency of stimulus evaluation. Participants performed a simple "oddball" task in which sets of 51 lines with varied orientations sequentially flashed briefly on the display. In these sequences, there was a 20% chance of an individual oddball, wherein one marked object tilted clockwise, and a 20% chance of an ensemble oddball, wherein the average orientation of the set tilted clockwise. In counterbalanced blocks, participants were instructed to respond to either individual or ensemble oddballs. ERP analysis was performed to test the timing of this processing. At parietal electrodes, P3b components were found for both individual and ensemble oddballs. Ensemble P3b components were found to occur significantly earlier than individual P3b components, as measured with both 50% area latency and 50% onset latency. Using multivariate pattern analysis, ensemble oddball trials were classifiable from standard trials significantly earlier in their timecourse than individual oddball trials. Altogether, these results provide compelling evidence that ensemble perception occurs rapidly and that ensemble properties can be available earlier than individual object properties.


The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.
Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.


Diabetes aggravates heat stress-induced blood-brain barrier breakdown, reduction in cerebral blood flow, edema formation, and brain pathology: possible neuroprotection with growth hormone.
The possibility that diabetes influences the outcome of heat stress-induced brain pathology was examined in our experimental rat model. Because growth hormone (GH) deficiency is an important factor in diabetes, the possible neuroprotective role of GH supplements was also examined in diabetic rats following heat stress. Rats receiving streptozotocine once daily for three days (50 mg/kg, i.p.) and allowed to survive four weeks resulted in diabetes (blood glucose level 18 and 20 mMol/L) compared to controls (blood glucose 4-6 mMol/L). Control or diabetic rats when subjected to four hours' heat stress at 38 degrees C in a biological oxygen demand incubator (BOD) showed profound disruption of the blood-brain barrier (BBB), reduction in cerebral blood flow (CBF), brain edema formation, and cell injury. These effects were most pronounced in diabetic rats. Pretreatment with GH (50 microg/kg/min for 10 min before heat stress) significantly attenuated brain pathology in normal animals subjected to hyperthermia. On the other hand, almost a double dose of the growth hormone (80 to 120 microg/g/min for 10 min) is needed in diabetic rats to induce considerable neuroprotection following heat stress. These observations are the first to suggest that diabetic rats are more vulnerable to heat stress-induced brain pathology and further show that the efficacy of neuroprotective drugs is also severely reduced in diabetic rats. Taken together, our results demonstrate that the dosage of neuroprotective drugs requires adjustment to enhance neuroprotection depending on the patient's endocrine or metabolic status, for example, diabetes mellitus, a finding not reported earlier.


DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association.
The ETS protein TEL, a transcriptional repressor, contains a PNT domain that, as an isolated fragment in vitro, self-associates to form a head-to-tail polymer. How such polymerization might affect the DNA-binding properties of full-length TEL is unclear. Here we report that monomeric TEL binds to a consensus ETS site with unusually low affinity (K(d) = 2.8 x 10(-8) M). A deletion analysis demonstrated that the low affinity was caused by a C-terminal inhibitory domain (CID) that attenuates DNA binding by approximately 10-fold. An NMR spectroscopically derived structure of a TEL fragment, deposited in the Protein Data Bank, revealed that the CID consists of two alpha-helices, one of which appears to block the DNA binding surface of the TEL ETS domain. Based on this structure, we substituted two conserved glutamic acids (Glu-431 and Glu-434) with alanines and found that this activated DNA binding and enhanced trypsin sensitivity in the CID. We propose that TEL displays a conformational equilibrium between inhibited and activated states and that electrostatic interactions involving these negatively charged residues play a role in stabilizing the inhibited conformation. Using a TEL dimer as a model polymer, we show that self-association facilitates cooperative binding to DNA. Cooperativity was observed on DNA duplexes containing tandem consensus ETS sites at variable spacing and orientations, suggesting flexibility in the region of TEL linking its self-associating PNT domain and DNA-binding ETS domain. We speculate that TEL compensates for the low affinity, which is caused by autoinhibition, by binding to DNA as a cooperative polymer.


Three-component nanorotors generated from fusion of complexes and post-fusion metal-metal exchange.
The fusion of two homoleptic complexes quantitatively created a novel three-component nanorotor. The intra-supramolecular rotational dynamics leads to a rapid exchange (k298 = 24.0 ± 2.5 kHz) of two degenerate Npy → ZnPor interactions. Metal exchange at the remote HETTAP complexation site provided a faster nanorotor (k298 = 34.0 ± 3.0 kHz).


Deep annotation of mouse iso-miR and iso-moR variation.
With a dataset of more than 600 million small RNAs deeply sequenced from mouse hippocampal and staged sets of mouse cells that underwent reprogramming to induced pluripotent stem cells, we annotated the stem-loop precursors of the known miRNAs to identify isomoRs (miRNA-offset RNAs), loops, non-preferred strands, and guide strands. Products from both strands were readily detectable for most miRNAs. Changes in the dominant isomiR occurred among the cell types, as did switches of the preferred strand. The terminal nucleotide of the dominant isomiR aligned well with the dominant off-set sequence suggesting that Drosha cleavage generates most miRNA reads without terminal modification. Among the terminal modifications detected, most were non-templated mono- or di-nucleotide additions to the 3'-end. Based on the relative enrichment or depletion of specific nucleotide additions in an Ago-IP fraction there may be differential effects of these modifications on RISC loading. Sequence variation of the two strands at their cleavage sites suggested higher fidelity of Drosha than Dicer. These studies demonstrated multiple patterns of miRNA processing and considerable versatility in miRNA target selection.


Association of physical workload and leisure time physical activity with incident mobility limitations: a follow-up study.
To examine individual as well as joint associations of physical workload and leisure time physical activity with incident mobility limitations in initially well-functioning middle-aged workers. This study is based on 6-year follow-up data of the Danish Longitudinal Study on Work, Unemployment and Health. Physical workload was reported at baseline and categorised as light, moderate or heavy. Baseline leisure time physical activity level was categorised as sedentary or active following the current recommendations on physical activity. Incidence of mobility limitations in climbing stairs and running among initially well-functioning workers (n=3202 and n=2821, respectively) was assessed during follow-up. Higher workload increased whereas active leisure time decreased the risk of developing mobility limitations. The incidence of limitations increased progressively with higher workload regardless of level of leisure time physical activity, although the risks tended to be higher among those with sedentary leisure time compared with their active counterparts. All in all, the risk for onset of mobility limitations was highest among those with heavy workload combined with sedentary leisure time and lowest among those with light workload combined with active leisure time. Although leisure time physical activity prevents development of mobility decline, high workload seems to accelerate the progression of mobility limitations among both those with active and sedentary leisure time. Therefore, efforts should be made to recommend people to engage in physical activity regardless of their physical workload.


Effects of interleukin-13 and montelukast on the expression of zonula occludens-1 in human podocytes.
The aim of this study was to investigate whether pathologic changes in zonula occludens-1 (ZO-1) are induced by interleukin-13 (IL-13) in the experimental minimal-change nephrotic syndrome (MCNS) model and to determine whether montelukast, a leukotriene receptor antagonist, has an effect on ZO-1 restoration in cultured human podocytes. Human podocytes cultured on bovine serum albumin-coated plates were treated with different doses of IL-13 and montelukast and then examined for distribution using confocal microscopy and for ZO-1 protein levels using Western blotting. ZO-1 was internalized and shown to accumulate in the cytoplasm of human podocytes in an IL-13 dose-dependent manner. High doses (50 and 100 ng/mL) of IL-13 decreased the levels of ZO-1 protein at 12 and 24 h (both p<0.01; n=3), which were significantly reversed by a high dose (0.5 μM) montelukast treatment (p<0.01; n=3). Our results suggest that IL-13 alters the expression of ZO-1, and such alterations in the content and distribution of ZO-1 may be relevant in the pathogenesis of proteinuria in the MCNS model.


Memory in multiple sclerosis: contextual encoding deficits.
Long-term memory (LTM) is one of the diverse cognitive functions adversely affected by multiple sclerosis (MS). The LTM deficits have often been attributed to failure of retrieval, whereas encoding processes are presumed intact. However, support for this view comes primarily from studies in which encoding and retrieval operations were not investigated systematically. In the current study, we used an encoding specificity paradigm to examine the robustness of encoding in MS and to specifically evaluate the impact of the disease on contextual memory. We hypothesized that persons with MS would exhibit a selective impairment in retrieving items from LTM when required to generate new cue-target associations at encoding, but not when cues held a strong preexisting relationship to the targets. The findings supported the hypotheses. We conclude that the mnemonic deficits associated with MS affect both encoding and retrieval. Specifically, problems with binding of contextual information at encoding impair effective retrieval of memories. Nonetheless, access to these memories can be gained through preexisting associations organized in the semantic network.


Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta-analysis of animal studies.
Obesity before and during pregnancy leads to reduced offspring cardiometabolic health. Here, we systematically reviewed animal experimental evidence of maternal obesity before and during pregnancy and offspring anthropometry and cardiometabolic health. We systematically searched Embase and Medline from inception until January 2018. Eligible publications compared offspring of mothers with obesity to mothers with a normal weight. We performed meta-analyses and subgroup analyses. We also examined methodological quality and publication bias. We screened 2543 publications and included 145 publications (N = 21 048 animals, five species). Essential methodological details were not reported in the majority of studies. We found evidence of publication bias for birth weight. Offspring of mothers with obesity had higher body weight (standardized mean difference (SMD) 0.76 [95% CI 0.60;0.93]), fat percentage (0.99 [0.64;1.35]), systolic blood pressure (1.33 [0.75;1.91]), triglycerides (0.64 [0.42;0.86], total cholesterol (0.46 [0.18;0.73]), glucose level (0.43 [0.24;0.63]), and insulin level (0.81 [0.61;1.02]) than offspring of control mothers, but similar birth weight. Sex, age, or species did not influence the effect of maternal obesity on offspring's cardiometabolic health. Obesity before and during pregnancy reduces offspring cardiometabolic health in animals. Future intervention studies should investigate whether reducing obesity prior to conception could prevent these detrimental programming effects and improve cardiometabolic health of future generations.


Thermodynamic studies on solvent effects in molecularly imprinted polymers. 2. Concentration of the organic modifier.
The effects of the organic modifier concentration on the isotherm parameters of the two enantiomers of Fmoc-tryptophan (Fmoc-L,D-Trp) on an Fmoc-L-Trp-imprinted polymer were investigated over a wide concentration range (0.005-100 mM), using frontal analysis. The modifier was acetic acid; concentrations of 0.2, 0.9, 1.7, and 3.7 M in an acetonitrile-based mobile phase were studied. At each concentration, adsorption isotherm data were acquired for each enantiomer. From these data, the isotherm parameters of each compound were derived from nonlinear isotherm fitting and the affinity energy distributions were calculated independently. We found that three types of sites coexist for Fmoc-L-Trp but only two types of sites for Fmoc-D-Trp, except at the lowest acetic acid concentration (0.2 M), at which three types of sites coexist. Increasing the acetic acid concentration decreases the selectivity and the overall affinity of both enantiomers. The overall affinity of Fmoc-L-Trp is dominated by the contribution of the low-density highest energy sites while that of Fmoc-D-Trp is dominated by the most abundant, low-energy sites. For the low-energy sites, increasing the acetic acid concentration affects the association constant of the enantiomers more than the number of corresponding sites. In contrast, for the highest energy sites (sites that exist only for Fmoc-L-Trp), increasing the concentration of acetic acid affects significantly the number of sites but hardly changes the association constant.


Calcium does not inhibit iron absorption or alter iron status in infant piglets adapted to a high calcium diet.
The purpose of this study was to investigate whether a dietary calcium:iron ratio similar to that often consumed by premature human infants inhibits iron absorption in infant piglets adapted to a high calcium diet. Male Yorkshire piglets were randomized at 3 to 4 d of age to a high calcium diet (4.67 g/L = HC) or a normal calcium diet (2.0 g/L = NC) and fed for 2 to 2.5 wk. An iron dextran injection was administered in amounts to achieve a marginal state of iron repletion to simulate iron status of premature infants. In vivo iron absorption from the diet was determined using the radiotracers 55Fe and 59Fe and whole body counting. Calcium:iron interactions at absorption sites in piglets fed HC and NC were investigated by measurements of time-dependent 59Fe uptake in response to different calcium:iron ratios in vitro in brush border membrane vesicles (BBMV). In vivo iron absorption from the diet did not differ between NC and HC diet groups [57 +/- 8% versus 55 +/- 17% (mean +/- SD), respectively]. Iron status and iron contencentrations in spleen, liver, intestine, kidney and heart did not differ between diet groups. Iron uptake in BBMV was significantly reduced by calcium in both HC and NC (P < 0.001); but there were no significant differences in iron uptake in response to different calcium:iron ratios between HC and NC. With feeding a HC diet for 2 wk there may be an adaptive response to counteract the inhibitory effects of calcium on iron absorption, thus resulting in similar in vivo iron absorption and iron status irrespective of the 1.3-fold difference in dietary calcium:iron ratio between piglet groups. However, future studies are needed to determine the specific sites of calcium:iron interactions and adaptation mechanisms. Since the calcium:iron ratios used in this study reflect the usual calcium:iron ratios in diets for premature infants, it is unlikely that interactive effects of calcium with iron will compromise iron status in this infant population when diets are supplemented with calcium.


Artery of Percheron Infarction: A Short Review.
One uncommon type of ischemic stroke is occlusion of the artery of Percheron (AOP) leading to infarction of the paramedian thalami and mesencephalon. There are several variants of thalamic blood supply, and identifying the potential presence and infarction of an AOP is important in diagnosis and treatment of ischemic strokes affecting the thalami and mesencephalon, especially because of the unusual and variable presentation of these forms of ischemic strokes. This short review includes and discusses the case of a 58-year-old woman with an AOP infarct and indicates the importance of recognizing an AOP infarct early despite its clinical variations in order to treat the stroke in a timely fashion. This short review also includes a discussion of imaging modalities in such cases and clinical differential diagnoses to consider with management strategies.


Viral acute lower respiratory infections impair CD8+ T cells through PD-1.
Viruses are leading causes of severe acute lower respiratory infections (LRIs). These infections evoke incomplete immunity, as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid pulmonary CD8+ cytotoxic T lymphocyte (TCD8) functional impairment via programmed death-1/programmed death ligand-1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated TCD8 impairment occurred acutely in mice following infection with human metapneumovirus or influenza virus. Viral antigen was sufficient for PD-1 upregulation, but induction of PD-L1 was required for impairment. During secondary viral infection or epitope-only challenge, memory TCD8 rapidly reexpressed PD-1 and exhibited severe functional impairment. Inhibition of PD-1 signaling using monoclonal antibody blockade prevented TCD8 impairment, reduced viral titers during primary infection, and enhanced protection of immunized mice against challenge infection. Additionally, PD-1 and PD-L1 were upregulated in the lungs of patients with 2009 H1N1 influenza virus, respiratory syncytial virus, or parainfluenza virus infection. These results indicate that PD-1 mediates TCD8 functional impairment during acute viral infection and may contribute to recurrent viral LRIs. Therefore, the PD-1/PD-L1 pathway may represent a therapeutic target in the treatment of respiratory viruses.


A multiplier-free Rulkov neuron under memristive electromagnetic induction: Dynamics analysis, energy calculation, and circuit implementation.
Establishing a realistic and multiplier-free implemented biological neuron model is significant for recognizing and understanding natural firing behaviors, as well as advancing the integration of neuromorphic circuits. Importantly, memristors play a crucial role in constructing memristive neuron and network models by simulating synapses or electromagnetic induction. However, existing models lack the consideration of initial-boosted extreme multistability and its associated energy analysis. To this end, we propose a multiplier-free implementation of the Rulkov neuron model and utilize a periodic memristor to represent the electromagnetic induction effect, thereby achieving the biomimetic modeling of the non-autonomous memristive Rulkov (mRulkov) neuron. First, theoretical analysis demonstrates that the stability distribution of the time-varying line equilibrium point is determined by both the parameters and the memristor's initial condition. Furthermore, numerical simulations show that the mRulkov neuron can exhibit parameter-dependent local spiking, local hidden spiking, and periodic bursting firing behaviors. In addition, based on the periodic characteristics of the memductance function, the topological invariance of the mRulkov neuron is comprehensively proved. Therefore, local basins of attraction, bifurcation diagrams, and attractors related to extreme multistability can be boosted by switching the memristor's initial condition. Significantly, the novel boosted extreme multistability is discovered in the Rulkov neuron for the first time. More importantly, the energy transition associated with the boosting dynamics is revealed through computing the Hamilton energy distribution. Finally, we develop a simulation circuit for the non-autonomous mRulkov neuron and confirm the effectiveness of the multiplier-free implementation and the accuracy of the numerical results through PSpice simulations.


Customizing microarrays for neuroscience drug discovery.
Microarray-based gene profiling has become the centerpiece of gene expression studies in the biological sciences. The ability to now interrogate the entire genome using a single chip demonstrates the progress in technology and instrumentation that has been made over the last two decades. Although this unbiased approach provides researchers with an immense quantity of data, obtaining meaningful insight is not possible without intensive data analysis and processing. Custom developed arrays have emerged as a viable and attractive alternative that can take advantage of this robust technology and tailor it to suit the needs and requirements of individual investigations. The ability to simplify data analysis, reduce noise and carefully optimize experimental conditions makes it a suitable tool that can be effectively utilized in neuroscience drug discovery efforts. Furthermore, incorporating recent advancements in fine focusing gene profiling to include specific cellular phenotypes can help resolve the complex cellular heterogeneity of the brain. This review surveys the use of microarray technology in neuroscience paying special attention to customized arrays and their potential in drug discovery. Novel applications of microarrays and ancillary techniques, such as laser microdissection, FAC sorting and RNA amplification, have also been discussed. The notion that a hypothesis-driven approach can be integrated into drug development programs is highlighted.


Cardiovascular effects of nociceptin in unanesthetized mice.
We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted <10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114+/-3 to 97+/-2 mm Hg at 10 minutes, P<0.01). The latter dose reduced heart rate from 542+/-43 to 479+/-31 beats/min (P<0.05) and increased aortic blood flow by 41+/-5% (P<0.05). Hypotension and bradycardia were also evoked by NC(1-17)NH2 and NC(1-13)NH2 fragments, whereas NC(1-13)OH and NC(1-9)NH2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1-13)NH2 and revealed the ability of NC(1-13)OH to decrease mean blood pressure. [F/G]NC(1-13)NH2, a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1-13)NH2 did not alter the hypotension induced by bradykinin or endomorphin-1 (a micro-receptor agonist), and the bradycardia induced by leu-enkephalin (a delta-receptor agonist) or U504885 (a synthetic kappa-receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice, with the NC(1-13) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1-13)NH2 is a potent and selective antagonist of the NC receptor in vivo.


Dietary fructans modulate polyamine concentration in the cecum of rats.
Nondigestible but fermentable dietary fructans such as oligofructose exert many effects on gut physiology through their fermentation end products such as short-chain fatty acids. Could other metabolites be produced in the gut and contribute to the physiologic effects of dietary fructans? The aim of the study was to evaluate the influence of oligofructose on putrescine, spermidine and spermine concentrations in the cecum, the portal vein and the liver of rats and to assess their involvement in cecal enlargement and the modulation of hepatic lipid metabolism. Putrescine, spermidine and spermine were quantified by HPLC in samples obtained from male Wistar rats fed a nonpurified standard diet (controls) or the same diet enriched with 10 g/100 g oligofructose (OFS) for 4 wk. OFS-fed rats had significantly greater cecal content and tissue weights. OFS almost doubled the concentration of putrescine in the cecal contents. The concentration of all three polyamines in the cecal tissue was significantly greater than in controls. The concentration of spermidine in portal plasma was lower in rats fed OFS, whereas the treatment did not affect the polyamine concentrations in the liver. The fermentation of dietary fructans contributed to an increase in the concentration of putrescine in the gut without modifying putrescine concentration in either the portal blood or liver. Moreover, the greater levels of polyamines in cecal tissue may be related to the cell proliferation resulting from OFS fermentation in the gut.


Insights on the anticancer potential of plant-food bioactives: A key focus to prostate cancer.
Prostate cancer is an international health problem and represents one of the most encountered malignancies among men. In this complex and heterogeneous disease, androgens and their receptors play a crucial role in both progression and development. Although the search for its effective treatment is still ongoing, among other priorities it requires developing better anticancer agents with greater efficacy and fewer side effects. In this regard, herbal medicines, which have been used in cancer treatment, represent a large source of new and bioactive chemical entities for the development of chemotherapeutic agents, many of them exhibiting favorable side effect and toxicity profiles compared to conventional chemotherapeutic agents. In fact, more than 50% of the current anticancer drugs originate from natural sources. Thus, the present review aims to provide an overview of the past and recent trends in the research, the role of secondary metabolites in urogenital disorders, and phytochemical assays in prostate cancer management.


What is hypertension in chronic haemodialysis? The role of interdialytic blood pressure monitoring.
Hypertension in chronic haemodialysis patients contributes significantly to morbidity and mortality. Treatment decisions are usually based on predialysis readings, which may not accurately reflect control during the interdialytic period. We studied 40 randomly selected subjects on haemodialysis and compared readings by different methods at set times during the dialysis session with the 48-h interdialytic ambulatory readings. Conventional sphygmomanometer, automated Dinamap and Tm 2421(A&D) ambulatory monitor were used for BP measurements. Conventional sphygmomanometry and self measured automatic readings (Dinamap) were highly correlated (systolic r=0.93, P<0.001; diastolic r=0.90, P<0.001). Mean blood pressure on arrival ((PreC(0)) 158 mmHg systolic, 80 mmHg diastolic and 106 mmHg mean) significantly overestimated the mean ambulatory reading during the 6 h prior to attendance ((preAm(6h)) systolic 147 (P<0.01), diastolic 75 (P<0.01), mean 99 (P<0.01)). Fifteen patients (41%) demonstrated a marked difference (>20/10 mmHg) between the PreC(0) and preAm(6h) (white-coat effect) persisting in seven patients (19%) after a period of rest 10 min predialysis (preC(10)) and present even in self-recorded Dinamap readings. There was a significant negative relationship between the systolic rise and the number of months on dialysis (P<0.05). Mean ambulatory BP on interdialytic day 2 was significantly greater than on day 1 whereas the awake-sleep differences were less on day 2 than day 1, both perhaps reflecting differences in volume status. The 20 min post-dialysis measurement (PoC(20)) for systolic, diastolic, and mean, unlike predialysis (PreC(0) and preC(10)), onset (onC) and end of dialysis readings (enC) did not differ significantly from 48 h interdialytic means. The best representation of interdialytic pressure was the 20-min post-dialysis reading. Walk-in predialysis pressures overestimate mean interdialytic pressures due to a high incidence of white-coat effect, which shows some habituation with time on dialysis. Ambulatory monitoring has a role in evaluating persistent poor blood pressure control in haemodialysis patients.


Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise.
The goal of this study was to determine whether the stress of forced exercise would result in injury to the myocardium. Male rats with 8% of body weight attached to the tail were forced to swim 3.5 h (3.5S), forced to swim 5 h (5S), or pretrained for 8 days and then forced to swim 5 h (T5S). Rats were killed immediately after they swam (0 h PS) and at 3 h (3 h PS), 24 h (24 h PS), and 48 h after they swam (48 h PS). Tissue homogenates of the left ventricle were analyzed by Western blot analysis for cardiac troponin T (cTnT). Serum cTnT was quantified by immunoassay. Results indicated that, in the 3.5S, 5S, and T5S groups, serum cTnT was significantly (P < 0.01) increased at 0 and 3 h PS. The 5S group demonstrated a greater increase in serum cTnT than the 3.5S group (P < 0.01) and the T5S group (P < 0.01) at 0 h PS. Western blot analysis indicated significant decreases (P < 0. 01) in myocardial cTnT in the 5S group only at 0 h PS (P < 0.01) and 3 h PS (P < 0.05). Histological evidence of localized myocyte damage demonstrated by interstitial inflammatory infiltrates consisting of neutrophils, lymphocytes, and histiocytes, as well as vesicular nuclei-enlarged chromatin patterns, was observed in left ventricle specimens from the 5S group at 24 and 48 h PS. Our findings demonstrate that stressful, forced exercise induces alterations in myocardial cTnT and that training before exercise attenuates the exercise-induced heart damage.


Production of a nisin-like bacteriocin by Lactococcus lactis subsp. lactis A164 isolated from Kimchi.
Lactococcus lactis subsp. lactis A164 was isolated from Kimchi (Korean traditional fermented vegetables). The bacteriocin produced by strain A164 was active against closely related lactic acid bacteria and some food-borne pathogens including Staphylococcus aureus, Listeria monocytogenes and Salmonella typhimurium. The antimicrobial spectrum was nearly identical to that of nisin. Bacteriocin activity was not destroyed by exposure to elevated temperatures at low pH values, but the activity was lost at high pH values. This bacteriocin was inactivated by pronase E and alpha, beta-chymotrypsin, but not by trypsin, pepsin, and alpha-amylase. Cultures of L. lactis subsp. lactis A164 maintained at a constant pH of 6.0 exhibited maximum production of the bacteriocin. It was purified to homogeneity by ammonium sulphate precipitation, sequential ion exchange chromatography, and ultrafiltration. Tricine-SDS-PAGE of purified bacteriocin gave the same molecular weight of 3.5 kDa as that of nisin. The gene encoding this bacteriocin was amplified by PCR with nisin gene-specific primers and sequenced. It showed identical sequences to the nisin gene. These results indicate that bacteriocin produced by Lactococcus lactis A164 is a nisin-like bacteriocin.


The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88.
BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.


Shedding light on baryonic dark matter.
Halo dark matter, if it is baryonic, may plausibly consist of compact stellar remnants. Jeans mass clouds containing 10(6) to 10(8) solar masses could have efficiently formed stars in the early universe and could plausibly have generated, for a suitably top-heavy stellar initial mass function, a high abundance of neutron stars as well as a small admixture of long-lived low mass stars. Within the resulting clusters of dark remnants, which eventually are tidally disrupted when halos eventually form, captures of neutron stars by non-degenerate stars resulted in formation of close binaries. These evolve to produce, by the present epoch, an observable x-ray signal associated with dark matter aggregations in galaxy halos and galaxy cluster cores.


Phylogeography of a game species: the red-crested pochard (Netta rufina) and consequences for its management.
Western European populations of red-crested pochard (Netta rufina) are characterized by low size and high fragmentation, which accentuate their sensitivity to hunting. Uncertainties regarding the demographic trends of these populations highlight the need for pertinent hunting regulations. This requires identification of the limits of the populations under exploitation, i.e. delimiting a management unit. We used the left domain of the mitochondrial control region and seven nuclear loci (four microsatellites and three introns) to assess the level of genetic structure and demographic independence between the fragmented Western European and the large Central Asian populations. The second objective was to investigate the colonization history of the Western European populations. This study demonstrated that the Western European populations of red-crested pochard constitute a separate demographic conservation unit relative to the Asian population as a result of very low female dispersal (mitochondrial DNA: PhiST = 0.152). A morphometric analysis further suggested that Central Asian and Western European specimens of both sexes originate from different pools of individuals. Male dispersal seems higher than female dispersal, as suggested by the lack of clear genetic structure for the nuclear markers at this continental scale. Genetic data, in conjunction with historical demographic data, indicate that the current Western European populations probably originate from a recent colonization from Central Asia. As numbers of red-crested pochards in Western Europe cannot be efficiently supplemented by immigration from the larger Asian populations, a management plan regulating the harvest in Western Europe is required.


Antenatal screening for candidiasis, trichomoniasis, and gonorrhoea.
Gonorrhoea was not found to be a problem in antenatal patients. It was found in only one out of 625 women, thus confirming other British surveys which do not agree with the North American figures. Candidiasis is commoner than trichomoniasis (27.4 and 4.7 per cent. prevalence respectively) and culture of a high vaginal swab is more effective as a means of diagnosis than a cervical cytology smear. The two conditions seldom occur together. The detection rate for Candida increases with gestation, but not with age, parity, or premarital and extramarital conception. The species isolated was predominantly Candida albicans. Trichomonads are detected in culture of a high vaginal swab more often than in a cervical cytology smear. Detection does not increase with age, parity, or gestation, but does increase with premarital and extramarital conception. It is difficult to diagnose clinically the cause of vaginal discharge in a pregnant woman.


[Effect of pulse and prolonged x-rays in air and in nitrogen on the frequency of sex-linked recessive lethal mutations in Drosophila melanogaster].
The effect of X-irradiation on the frequency of recessive lethal mutations in Drosophila melanogaster sperm cells is studied. Drosophila males were X-irradiated in air and nitrogen in three units with doses rates of 4 X 10(9), 10(11) and 1.7 rad/sec at a dose of 2000 rad. It is found that the mutation frequency after the pulse irradiation was almost twice as low as that after prolonged irradiation. The oxygen effect is eliminated under pulse irradiation, and the data on pulse irradiation in air are similar to those on irradiation at a low dose rate in nitrogen. The data obtained are explained by the presence of short-lived oxygen-dependent damages which are not realized under pulse irradiation due to the lack of oxygen in the track volume.


Analysis of immunosuppressive molecules associated with murine in vitro fertilized embryos.
Supernatants from mouse in vitro fertilized (IVF) oocyte cultures may suppress in vitro lymphocyte proliferation stimulated by concanavalin A (Sigma, St. Louis, MO). Supernatants conditioned by incubation with mouse epididymal sperm alone were even more inhibitory. Thin-layer chromatography suggested the polyamines spermine in sperm and spermine plus spermidine in IVF embryo supernatants were responsible. Putrescine was not suppressive. In vitro fertilized oocytes from old CBA/J-strain mice (greater than 20 weeks) that suffer age onset infertility lacked suppression and manifest cleavage arrest that could be partially reversed by adding spermine to the cultures. The failure of IVF oocytes to produce adequate quantities of polyamines could lead to failure of implantation due to division arrest. A possible in vivo role of polyamines as immunosuppressor factors is discussed.


Immunomodulatory activity of recombinant Ricin toxin binding Subunit B (RTB).
Ricin toxin binding subunit B (RTB) is one of the subunits of the ricin protein. RTB has been used as adjuvant, but little is known about its mechanism. In this study, we found that RTB increased not only nitric oxide (NO) release, but also tumor necrosis factor (TNF)-α and interleukin (IL)-6 production in mouse macrophage cell line RAW264.7 cells. They subsequently exhibited enhanced ConA-induced T-cell and LPS-induced B-cell proliferative responses. We also examined the cytokines that were produced from splenocytes following in vitro RTB administration. Increased levels of IL-2, interferon (IFN)-γ and TNF-α were observed, while IL-4 and IL-5 were unaffected. These results demonstrate that recombinant RTB can act on the immune system and activate T-cells by introducing a Th1 immune response. Th1 cells might be the primary cellular target affected by RTB. Our results suggest that the recombinant RTB can promote the activation of macrophages and has a beneficial effect on immunomodulatory activity.


Differential regulation of the variations induced by environmental richness in adult neurogenesis as a function of time: a dual birthdating analysis.
Adult hippocampal neurogenesis (AHN) augments after environmental enrichment (EE) and it has been related to some of the anxiolytic, antidepressant and neuroprotective effects of EE. Indeed, it has been suggested that EE specifically modulates hippocampal neurogenic cell populations over the course of time. Here we have used dual-birthdating to study two subpopulations of newborn neuron in mice (Mus musculus): those born at the beginning and at the end of enrichment. In this way, we demonstrate that while short-term cell survival is upregulated after an initial 1 week period of enrichment in 2 month old female mice, after long-term enrichment (2 months) neither cell proliferation nor the survival of the younger newly born cell populations are distinguishable from that observed in non-enriched control mice. In addition, we show that the survival of older newborn neurons alone (i.e. those born at the beginning of the enrichment) is higher than in controls, due to the significantly lower levels of cell death. Indeed, these parameters are rapidly adjusted to the sudden cessation of the EE conditions. These findings suggest both an early selective, long-lasting effect of EE on the neurons born in the initial stages of enrichment, and a quick response when the environment again becomes impoverished. Therefore, EE induces differential effects on distinct subpopulations of newborn neurons depending on the age of the immature cells and on the duration of the EE itself. The interaction of these two parameters constitutes a new, specific regulation of these neurogenic populations that might account for the long-term enrichment's behavioral effects.