Habitat- and season-specific temperatures affect phenotypic development of hatchling lizards.
Embryonic environments influence phenotypic development, but relatively few experiments have explored the effects of natural environmental variation. We incubated eggs of the lizard Anolis sagrei under conditions that mimicked natural spatial and temporal thermal variation to determine their effects on offspring morphology and performance. Incubation temperatures mimicked two microhabitats (open, shade) at two different times of the incubation season (April, July). Egg survival, incubation duration and offspring size were influenced by interactions between habitat- and season-specific nest temperatures, and locomotor performance was influenced primarily by temporal factors. These findings highlight the importance of spatial and temporal environmental variation in generating variation in fitness-related phenotypes.


The human gut virome: composition, colonization, interactions, and impacts on human health.
The gut virome is an incredibly complex part of the gut ecosystem. Gut viruses play a role in many disease states, but it is unknown to what extent the gut virome impacts everyday human health. New experimental and bioinformatic approaches are required to address this knowledge gap. Gut virome colonization begins at birth and is considered unique and stable in adulthood. The stable virome is highly specific to each individual and is modulated by varying factors such as age, diet, disease state, and use of antibiotics. The gut virome primarily comprises bacteriophages, predominantly order Crassvirales, also referred to as crAss-like phages, in industrialized populations and other Caudoviricetes (formerly Caudovirales). The stability of the virome's regular constituents is disrupted by disease. Transferring the fecal microbiome, including its viruses, from a healthy individual can restore the functionality of the gut. It can alleviate symptoms of chronic illnesses such as colitis caused by Clostridiodes difficile. Investigation of the virome is a relatively novel field, with new genetic sequences being published at an increasing rate. A large percentage of unknown sequences, termed 'viral dark matter', is one of the significant challenges facing virologists and bioinformaticians. To address this challenge, strategies include mining publicly available viral datasets, untargeted metagenomic approaches, and utilizing cutting-edge bioinformatic tools to quantify and classify viral species. Here, we review the literature surrounding the gut virome, its establishment, its impact on human health, the methods used to investigate it, and the viral dark matter veiling our understanding of the gut virome.


Lacosamide decreases neonatal seizures without increasing apoptosis.
Many seizing neonates fail to respond to first-line anticonvulsant medications. Phenobarbital, an allosteric modulator of γ-aminobutyric acid type A (GABAA ) receptors, has low efficacy in treating neonatal seizures and causes neuronal apoptosis. Nonetheless, it is one of the most used anticonvulsants in this age group. In neonatal mice, phenobarbital's poor effectiveness is due in part to high intraneuronal chloride concentration, which causes GABA to exert depolarizing actions. Therefore, another approach to treat neonatal seizures could be to use anticonvulsants that do not rely on GABAergic modulation. We evaluated whether lacosamide decreases seizures in neonatal mice and whether it increases apoptosis in vitro and in vivo. In vitro, we measured the effect of different lacosamide concentrations on seizure-like activity induced by the pro-convulsant drug 4-aminopyridine in neocortical brain slices (layer IV/V) from neonatal (postnatal day 8-11) and adult (1-1.6 months old) C57BL/6J mice. In vivo, we recorded the effect of different lacosamide concentrations on neonatal behavioral seizures induced by kainic acid. We studied neocortical apoptosis in vitro and in vivo, measuring terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling signal and cleaved-caspase 3. Lacosamide reduced epileptiform activity in neocortical brain slices of neonates and adults in a concentration-dependent manner. In vivo, lacosamide reduced the duration and number of behavioral seizures. Lacosamide did not increase total or neuronal apoptosis in the neocortex in vitro or in vivo. Lacosamide reduces neocortical seizure-like activity in neonatal mice in vitro and in vivo without an acute increase in apoptosis. Our results support the use of lacosamide to treat neonatal seizures, with the advantage of not increasing apoptosis acutely.


Monozygotic twins concordant for intestinal Behçet's disease.
Although Behçet's disease (BD) is a multisystem disorder of unknown causes, both genetic and environmental factors have been suggested. This is the second reported case of monozygotic twins concordant for Behçet's disease and the first such report of intestinal Behçet's disease. Patient 1 was a 17-year-old man with fever, recurrent oral aphthae, and skin eruptions. He developed hematochezia and was given corticosteroid empirically. One month after he was discharged, he again developed oral ulcerations, fever, and hematochezia. Colonoscopy was performed again, showing aphthous ulcerations in the entire colon, and deep oval ulcers with marginal elevation around the ileocecal valve, which are characteristics of intestinal Behçet's disease. He was treated with colchicine and azathioprine in combination with salazosulfapyridine (SASP) and prednisolone (PSL) and achieved remission. Patient 2 was the twin brother of patient 1. He was admitted because of oral aphthous ulcerations, fever, pustules on his face and body, and genital ulcers. Two weeks later he developed hematochezia. Colonoscopic and barium enema findings were similar to those of his brother. SASP, PSL, colchicines, and azathioprine were also required to achieve remission. Both of the patients were diagnosed with intestinal Behçet's disease. Their monozygosity was confirmed by detailed genetic typing, and HLA-B51 was negative.


Measurement of varicella-zoster virus (VZV)-specific cell-mediated immunity: comparison between VZV skin test and interferon-gamma enzyme-linked immunospot assay.
Cell-mediated immunity (CMI) is critical for the prevention and control of varicella-zoster virus (VZV)-related disease. To assess CMI to VZV, a varicella skin test and interferon-gamma enzyme-linked immunospot (ELISPOT) assay were both performed in healthy volunteers, and the results were compared. A total of 151 subjects were examined: 16 aged 20-29 years, 26 aged 30-39 years, 18 aged 40-49 years, 73 aged 50-59 years, and 18 aged 60-69 years. All were seropositive by a glycoprotein antigen-based enzyme-linked immunosorbent assay (gpELISA). Skin test reactivity was significantly correlated with the ELISPOT count, and both decreased with increasing age, indicating an age-dependent decline in CMI to VZV. In contrast, the antibody titer obtained by the gpELISA did not correlate with skin test reactivity. The results suggest that the skin test and ELISPOT assay are both reliable for assessing CMI to VZV and can easily be applied to screen individuals susceptible to the development of herpes zoster.


Serum selenium is associated with plasma homocysteine concentrations in elderly humans.
Low selenium levels in humans have been associated with several pathologies; however, an earlier animal investigation found a direct association between Se intake and total plasma homocysteine (tHcy) concentrations. To date, the importance of serum selenium levels in association with tHcy in humans has not been determined. We evaluated the cross-sectional association of blood selenium concentrations with plasma tHcy and other determinants of this cardiovascular disease risk factor. We estimated protein intake and measured the blood status of selenium, tHcy, and several other related factors in serum such as folate, vitamin B-12, and creatinine. Serum selenium was inversely associated with tHcy, explaining 5.8% of tHcy variance with respect to 2.2% accounted for by serum folate. Furthermore, there was a 63% decreased risk of higher tHcy concentrations (>14 micro mol/L) for subjects with serum selenium in the highest tertile (P = 0.013). We also found an inverse association of protein intake with tHcy in men (beta = -0.144; P = 0.036), which disappeared after controlling for serum Se concentrations (beta = -0.055; P = 0.003). In conclusion, selenium should be considered as a potential factor to lower tHcy. In addition, the described association between protein intake and homocysteine levels could be mediated by this trace element.


A description of the growth of the major body components of 2 broiler chicken strains.
The objective of this work was to compare the growth and chemical composition of the main body parts of males and females of the Ross and Cobb broiler strains available in Brazil. In total, 1,920 chicks were raised in 16 floor pens, from which 4 birds of each strain and sex were sampled weekly for the required measurements. The strains and sexes were reared in separate pens, using 4 replications of 120 birds each. Four feeds, based on corn and soybeans, were used during the trial: feed 1 from 1 to 7 d, feed 2 from 8 to 28 d, feed 3 from 29 to 49 d, and feed 4 from 50 to 56 d of age (all of the birds were given the same feed for each time interval). All of the birds were weighed weekly and the 4 birds sampled from each strain and sex were weighed, fasted for 24 h, reweighed, killed, eviscerated, and dissected. The breast, drums, thighs, and wings were weighed, packed into identified plastic bags, and stored in a freezer to later be thawed and minced. They were then freeze-dried to obtain the water content, after which they were again milled before analyzing for protein, lipid, and ash using AOAC procedures. The Gompertz equation was fitted to the weights of the body parts as well as to the protein weights of the components. Using data from each individual chicken that was sampled, allometric regressions were fitted to the weights of the physical and chemical components, with ln body protein weight being the independent variable and ln component weight being the dependent variable. Although some of the allometric relationships between the various body parts and body protein weight differed statistically between strains and sexes, these differences were of little commercial significance, suggesting that the relative growth rates of the different body components of the genotypes tested in this trial have not been changed substantially by genetic selection.


Concern mounts as transfusion medicine loses its lustre.
Transfusion medicine is in trouble. Several factors, ranging from the tainted-blood scandal to changes in the way the system operates, mean that young physicians are avoiding the specialty. Dr. Antonio Giulivi of the Red Cross says the issue is serious because these specialists act as the system's overseers, and this fact won't change when the Red Cross gets out of the blood business in September.


Conservative care of urinary incontinence in the elderly.
Urinary incontinence is a common, costly and demoralizing problem among the elderly. Remedial efforts are often not attempted owing to the misconception that incontinence is an inevitable and irreversible characteristic of aging. In fact, a variety of relatively conservative methods of reducing geriatric incontinence are available. This paper reviews the categories of incontinence, outlines assessment strategies and critiques the literature on biofeedback, exercise, behavior therapy and electrical stimulation as treatments for geriatric incontinence, and briefly considers a role for the chiropractic physician.


Equine blood serum calcium and phosphorus concentrations in progressive nutritional hyperparathyroidism.
Weekly blood serum samples from 20 yearling horses, divided into equal groups, receiving diets with total calcium to inorganic phosphorus ratios of 1,5/1 and 0,2/1, were analysed for calcium and phosphorus concentrations. This was done over a continuous 23 week period, divided into 2 sub-periods of 16 and 7 weeks each. During the first period complete diets were provided ad lib but were restricted during the second period to accentuate any effects of calcium deficiency and phosphorus excess. Falling calcium levels and rising phosphorus levels during period 1 and a reverse trend during period 2 indicated that this method can be used to detect progressive nutritional hyperparathyroidism in individual horses when a series of profiles are analysed over a period of time.


Effect of levosimendan on mortality in severe sepsis and septic shock: a meta-analysis of randomised trials.
We aim to synthesise up-to-date randomised trials to investigate the effects of levosimendan on mortality and clinical outcomes in severe sepsis and septic shock. A collection of databases including PubMed, EMBASE, Cochrane Central Register and Web of Science were searched updated to August 2017. Randomised trials were included when they pertain to the use of levosimendan in severe sepsis or septic shock compared with any category of inotropes, or as an adjunct to standard therapy with mortality reported. The primary outcome was mortality, and the secondary outcomes were clinical performances including serum lactate, cardiac function, vasopressor requirement and fluid infusion. A total of 10 studies with 1036 patients were included in this meta-analysis. The results revealed that levosimendan could not reduce mortality significantly in severe sepsis and septic shock (OR 0.89, 95% CI 0.69 to 1.16, P=0.39). Levosimendan use could reduce serum lactate more effectively, and enhance cardiac contractibility with increased cardiac index and left ventricular ejection fraction. However, its use could also increase fluid infusion but not reduce norepinephrine dose. No significant benefit in mortality could be observed of levosimendan versus dobutamine use, or in patients with proven cardiac dysfunction. Current evidence is not sufficient to support levosimendan as superior to dobutamine or as an optimal adjunct in severe sepsis and septic shock. More large-scale randomised trials are necessary to validate levosimendan use in sepsis.


MethylDetectR: a software for methylation-based health profiling.
DNA methylation is an important biological process that involves the reversible addition of chemical tags called methyl groups to DNA and affects whether genes are active or inactive. Individual methylation profiles are determined by both genetic and environmental influences. Inter-individual variation in DNA methylation profiles can be exploited to estimate or predict a wide variety of human characteristics and disease risk profiles. Indeed, a number of methylation-based predictors of human traits have been developed and linked to important health outcomes. However, there is an unmet need to communicate the applicability and limitations of state-of-the-art methylation-based predictors to the wider community. To address this need, we have created a secure, web-based interactive platform called 'MethylDetectR' which automates the calculation of estimated values or scores for a variety of human traits using blood methylation data. These traits include age, lifestyle traits and high-density lipoprotein cholesterol. Methylation-based predictors often return scores on arbitrary scales. To provide meaning to these scores, users can interactively view how estimated trait scores for a given individual compare against other individuals in the sample. Users can optionally upload binary phenotypes and investigate how estimated traits vary according to case vs. control status for these phenotypes. Users can also view how different methylation-based predictors correlate with one another, and with phenotypic values for corresponding traits in a large reference sample (n = 4,450; Generation Scotland). The 'MethylDetectR' platform allows for the fast and secure calculation of DNA methylation-derived estimates for several human traits. This platform also helps to show the correlations between methylation-based scores and corresponding traits at the level of a sample, report estimated health profiles at an individual level, demonstrate how scores relate to important binary outcomes of interest and highlight the current limitations of molecular health predictors.


Anatomy of the nail unit and the nail biopsy.
The nail unit is the largest and a rather complex skin appendage. It is located on the dorsal aspect of the tips of fingers and toes and has important protective and sensory functions. Development begins in utero between weeks 7 and 8 and is fully formed at birth. For its correct development, a great number of signals are necessary. Anatomically, it consists of 4 epithelial components: the matrix that forms the nail plate; the nail bed that firmly attaches the plate to the distal phalanx; the hyponychium that forms a natural barrier at the physiological point of separation of the nail from the bed; and the eponychium that represents the undersurface of the proximal nail fold which is responsible for the formation of the cuticle. The connective tissue components of the matrix and nail bed dermis are located between the corresponding epithelia and the bone of the distal phalanx. Characteristics of the connective tissue include: a morphogenetic potency for the regeneration of their epithelia; the lateral and proximal nail folds form a distally open frame for the growing nail; and the tip of the digit has rich sensible and sensory innervation. The blood supply is provided by the paired volar and dorsal digital arteries. Veins and lymphatic vessels are less well defined. The microscopic anatomy varies from nail subregion to subregion. Several different biopsy techniques are available for the histopathological evaluation of nail alterations.


Quadratus lumborum and erector spinae plane blocks are effective for analgesia in laparoscopic hysterectomy: a randomized controlled trial.
Total laparoscopic hysterectomy is the preferred technique for hysterectomy in obstetrics and gynecology clinics. However, patients who undergo these procedures often experience acute pain that may progress to chronic pain over time. Erector spinae plane block (ESPB) and anterior quadratus lumborum block (QLB) under ultrasound guidance are reported to be effective as part of the multi-modal analgesia protocol. Therefore, this study aimed to compare the effectiveness of erector spinae plane block and anterior quadratus lumborum block in reducing postoperative opioid consumption and pain scores in patients undergoing total laparoscopic hysterectomy. Eighty-one patients who met the inclusion criteria were divided into three groups: the erector spinae plane block, anterior quadratus lumborum block, and control groups. All patients received general anesthesia and tramadol-based patient-controlled analgesia (PCA) during the postoperative period. Tramadol consumption and pain scores during the first 24 h were evaluated by a blinded researcher. Postoperative opioid consumption was the primary outcome of the study. Postoperative tramadol consumption was lower in the erector spinae plane block and quadratus lumborum block groups than that in the control group, with no significant differences observed between the two interventional groups. Postoperative pain scores were lower for at least 12 h in both block groups, with no significant differences observed between both groups. Erector spinae plane block and quadratus lumborum block improved postoperative pain management as part of the multi-modal analgesia protocol; however, erector spinae plane block may be preferable due to its rapid procedure time. The findings suggest that incorporating erector spinae plane block and quadratus lumborum block into multi-modal analgesia protocols for laparoscopic hysterectomy would have important implications for the development and standardization of pain management protocols.


Validity of ambient levels of fine particles as surrogate for personal exposure to outdoor air pollution--results of the European EXPOLIS-EAS Study (Swiss Center Basel).
To evaluate the validity of fixed-site fine particle levels as exposure surrogates in air pollution epidemiology, we considered four indicator groups: (1) PM2.5 total mass concentrations, (2) sulfur and potassium for regional air pollution, (3) lead and bromine for traffic-related particles, and (4) calcium for crustal particles. Using data from the European EXPOLIS (Air Pollution Exposure Distribution within Adult Urban Populations in Europe) study, we assessed the associations between 48-hr personal exposures and home outdoor levels of the indicators. Furthermore, within-city variability of fine particle levels was evaluated. Personal exposures to PM2.5 mass were not correlated to corresponding home outdoor levels (n = 44, rSpearman (Sp) = 0.07). In the group reporting neither relevant indoor sources nor relevant activities, personal exposures and home outdoor levels of sulfur were highly correlated (n = 40, rSp = 0.85). In contrast, the associations were weaker for traffic (Pb: n = 44, rSp = 0.53; Br: n = 44, rSp = 0.21) and crustal (Ca: n = 44, rSp = 0.12) indicators. This contrast is consistent with spatially homogeneous regional pollution and higher spatial variability of traffic and crustal indicators observed in Basel, Switzerland. We conclude that for regional air pollution, fixed-site fine particle levels are valid exposure surrogates. For source-specific exposures, however, fixed-site data are probably not the optimal measure. Still, in air pollution epidemiology, ambient PM2.5 levels may be more appropriate exposure estimates than total personal PM2.5 exposure, since the latter reflects a mixture of indoor and outdoor sources.


Internships in Maternal and Child Protection services: Perspectives of generalists, pediatricians, and medical schools
General practitioners (GP) play a key role in children's medical care in France. Maternal and Child Protection Services (MCP) provide preventive pediatric care and may host GP interns during their curriculum. The purpose of this research is to cross stakeholders' viewpoints on MCP internships. In 2019, a declarative cross-sectional survey was conducted in metropolitan France among GP, MCP and departments of general practice (DGP) in medical schools. Data was collected concerning the organization, contents and pediatric expected results of GP internships in MCP. Questionnaires completed by 286 GP, 77 MCP and 16 DGP were collected. GP describe a non-standardized internship practice in terms of duration, the type of supervision, the medical acts carried out and the tools provided. Their answers, however, show a clear consensus on the skill in screening/prevention acts development (significantly higher for internships based on four-day weeks), on the support for parenthood, and on the awareness of the child's living environment and of the various professionals in the health, psychological and educational field. These skill acquisitions are incomplete in child protection, and insufficient in the management of acute pathologies. Links between DCP and MCP appear poor. Internships in MCP provide GPs with significant experience in prevention and daily pediatrics, but they require a better coordination between DGP and MCP and the construction of joint internships especially with hospital pediatrics.


Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole.
Azoles are important compounds for the treatment of fungal infections. This review focuses on three azoles: isavuconazole, ravuconazole and albaconazole (Stiefel). These drugs exhibit a broad spectrum of activity in vitro, including activity against several fungal isolates that are resistant to other azoles. However, poor or limited activity of these compounds has been demonstrated against species of Fusarium and Scedosporium, as well as against Zygomycetes. As isavuconazole and ravuconazole have been developed both as intravenous and oral formulations, these compounds are suitable candidates for the treatment of various invasive fungal diseases. Most clinical trials with albaconazole have targeted mucocutaneous fungal infections. Although all of these agents appear to be well tolerated, cross-resistance is a concern in the azole family of compounds.


Transcriptional enhancer elements in the mouse immunoglobulin heavy chain locus.
Two regions in the immunoglobulin heavy chain locus were tested for their ability to enhance transcription of the SV40 early promoter. A portion of the intervening sequence between the heavy chain joining region (Jh) and the constant region of the mu chain (Cmu) can enhance transcription when it is cloned either 5' or 3' to the SV40 early promoter. The region between C alpha and the alpha switch site, which occurs 5' to the translocated c-myc oncogene in many murine plasmacytomas, does not show transcriptional enhancer activity in this assay.


[Wish fulfilling medicine and wish fulfilling dentistry: -medical-ethical aspects].
Wish fulfilling medicine comprises medical procedures applied without a direct medical need. In such procedures, the medical-ethical principles can come under pressure: the autonomy of the patient, when wishes originate from social pressure; beneficence when the (underlying) aim and consequences are unclear; and 'doing no harm', when that appears to be impossible. The principle of justice, too, could come under threat when especially those with a privileged socio-economic background can take advantage of wish fulfilling medicine. Regardless of whether it concerns wish fulfilling medicine or conventional medicine, respect for human dignity and the individual integrity of the patient continue to be paramount. In care ethics and moral ethics, the qualities necessary in a proper caregiver are emphasised, such as caring, compassion, commitment, honesty and personal dedication. Wish fulfilling medicine is the subject of significant ethical debate. Important aspects arising from this debate are that the risks of harm should be limited, human dignity and integrity should be respected, people should genuinely be helped and the principle of justice should be upheld.


A diagnostic conundrum in Bardet-Biedl syndrome: when genetic diagnosis precedes clinical diagnosis.
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive, multisystem non-motile ciliopathy of progressive onset. It is primarily characterised by rod-cone dystrophy, early-onset obesity and related complications, postaxial polydactyly, renal and genitourinary abnormalities, learning disabilities, and hypogonadism. The diagnosis is based on Beales' modified diagnostic criteria. We present a case of two monozygotic female twins, 17 years of age at presentation, referred for obesity since childhood. The initial hormonal work-up was negative and no dysmorphic features were noted. They were diagnosed with exogenous obesity. However, after ophthalmologic problems became apparent, rod-cone dystrophy was observed and genetic testing was performed. A mutation in the BBS2 gene led to the diagnosis of BBS, although the full diagnostic criteria were not met. This case not only highlights the need to raise awareness for BBS but also exposes two limitations of the current diagnostic standard. The first limitation is the low sensitivity of the clinical diagnostic model, due to the progressive onset and the high variability of the syndrome. The second limitation is the unclear role of genetic testing. As genetic testing becomes more widely available, genetic diagnosis preceding clinical diagnosis will become more common, leading to a diagnostic conundrum. We propose an update of the diagnostic model. A less strict application in the presence of confirmed genetic mutations should be applied, as this could facilitate earlier diagnosis and intervention. This is important because therapeutic agents are being developed that could have a significant impact on quality of life and prognosis. Due to the low prevalence, the significant inter-and intrafamilial variation, and the slowly evolving phenotype, monogenic forms of obesity such as Bardet-Biedl syndrome are difficult to diagnose. Despite advances in the understanding of the presentation, pathophysiology and access to accurate genetic characterisation, a substantial number of diagnoses are still made by ophthalmology, as recognition of BBS in other departments of medicine, remains limited. Clinical diagnosis of BBS is based on Beales' modified diagnostic criteria which require the presence of four primary features or three primary features plus two secondary features. This model has its limitations. Due to the progressive onset of clinical symptoms, patients generally do not meet the diagnostic criteria early in life, leading to a delay in diagnosis. In addition, the role of genetic testing remains controversial. However, as it becomes more widely available, genetic diagnosis may precede a full clinical diagnosis. BBS has an impact on the quality of life and prognosis of both the patient and the family. Obesity management strategies are an important part of the multidisciplinary approach, as there is no cure available. Setmelanotide has shown promising results in a phase 3 trial, but its effect in clinical practice remains unproven.


Selenium-based metabolic oligosaccharide engineering strategy for quantitative glycan detection.
Metabolic oligosaccharide engineering (MOE) is a classical chemical approach to perturb, profile and perceive glycans in physiological systems, but probes upon bioorthogonal reaction require accessibility and the background signal readout makes it challenging to achieve glycan quantification. Here we develop SeMOE, a selenium-based metabolic oligosaccharide engineering strategy that concisely combines elemental analysis and MOE,enabling the mass spectrometric imaging of glycome. We also demonstrate that the new-to-nature SeMOE probes allow for detection, quantitative measurement and visualization of glycans in diverse biological contexts. We also show that chemical reporters on conventional MOE can be integrated into a bifunctional SeMOE probe to provide multimodality signal readouts. SeMOE thus provides a convenient and simplified method to explore the glyco-world.


Interphase cytogenetic (in situ hybridization) analysis of astrocytomas using archival, formalin-fixed, paraffin-embedded tissue and nonfluorescent light microscopy.
Astrocytomas contain nonrandom chromosomal abnormalities that recently have been correlated with shortened patient survival. Two frequently reported aberrations are trisomy 7 and monosomy 10. We assessed the numerical complement of chromosomes 7 and 10 in formalin-fixed, paraffin-embedded brain biopsy tissue from 28 diffuse astrocytomas by in situ hybridization using a nonfluorescent enzymatic detection system. Clinical follow-up of at least 5 years was available in 26 cases (93%). Monosomy 10 was identified in 7 cases (25%): astrocytoma, 1 case; anaplastic astrocytoma, 1 case; and glioblastoma, 5 cases. Trisomy 7 was identified in 11 cases (39%): astrocytoma, 5 cases; glioblastoma, 6 cases. Multivariate analysis revealed that monosomy 10 was the most statistically significant negative predictor of patient survival. Numerical chromosomal abnormalities are detectable in astrocytomas in archival tissue using interphase cytogenetics and nonfluorescent light microscopy. Although larger studies are required, our data suggest that potentially useful prognostic information may be obtained with this approach.


Arab genetic disease database (AGDDB): a population-specific clinical and mutation database.
Here we present the Arab Genetic Disease Database (AGDDB), a curated catalog of genetic disorders found in Arab populations. The first release of the database is populated primarily with information from the textbook Genetic Disorders Among Arab Populations [Teebi and Farag, 1997]. AGDDB is composed of data elements revolving around disorder reports. Other reports cover clinical, genomic, reference, and population frequency elements and their important attributes. The Arab Genetic Disease Consortium (30 investigators, 18 countries) is responsible for editing and reviewing AGDDB data. After initial indexing, AGDDB contains over 1,000 unique disorder entries. Entries are linked to their counterparts in the Online Mendelian Inheritance in Man (OMIM) database; similar associations with relevant locus-specific and central mutation databases are planned. The database can be queried by keyword across all its fields, with more focused searches allowed. The database is freely available and may be accessed at www.agddb.org. The database serves as a robust prototype for cataloging variation and disorder information within a specific population.


Dyadic Aspects of Sexual Well-Being in Men with Laser-Treated Penile Carcinoma.
Coping with cancer, its treatment and recovery are dyadic processes within a relationship. Sexual dysfunctions and problems of penile cancer may add to the demands of coping. The prospective study aimed to describe the dyadic aspects of sexual well-being and life satisfaction before and 1 year after organ-sparing laser treatment of penile carcinoma. A consecutive series of 29 patients with penile carcinoma suitable for laser treatment were included together with their partners, median age 60 (37-73) years and 57 (30-72) years, respectively. Median length of relationship was 29 years (1-54 years). The participants completed structured interviews before treatment, at 6 months' and 12 months' follow-up. The interview addressed sexual activities, sexual functions, verbal (sexual) communication, and life satisfaction. Three well-validated instruments were included: Hospital Anxiety and Depression Scale, International Index of Erectile Function-5, and Life Satisfaction checklist, LiSat-11. The interviews contained the same questions for patients and partners at all three measuring points. There was a high level of within-couple agreement on sexual activities, sexual function, and life satisfaction before and after organ-sparring treatment. No significant differences between interview data at 6 and 12 months' follow-up occurred. Before treatment, sexual dysfunctions were common among men, especially decreased sexual interest and dyspareunia. At follow-up, increased sexual function was found, with the exception of erectile function and women's orgasm. A rather high proportion was being unsatisfactory sexually inactive. Few had an ongoing verbal (sexual) mutual communication. Couples with an active sexual life at follow-up showed coherence in high satisfaction with life as a whole. A high level of within-couple agreement concerning sexuality and life satisfaction points to the necessity of including an adequate sexological case history, counseling, and treatment for this group of patients and their partners.


ATP and sensory transduction in the enteric nervous system.
ATP is a neurotransmitter in the central and peripheral nervous systems and is also involved in peripheral inflammation and transmission of the sensation of pain. Recently, the regulated release of ATP from non-neuronal sources has been shown to play a role in the activation of sensory nerve terminals. Within the enteric nervous system, which is present in the wall of the gastrointestinal tract, ATP plays three major roles. ATP acts as an inhibitory transmitter from the enteric motor neurons to the smooth muscle via P2Y receptors. ATP is released as an excitatory neurotransmitter between enteric interneurons and from the interneurons to the motor neurons via P2Y and P2X receptors. Finally, ATP may act as a sensory mediator, from epithelial sources to the intrinsic sensory nerve terminals. Thus, ATP participates in the transduction of sensory stimuli from the gut lumen and in the subsequent initiation and propagation of enteric reflexes.


Treatment as prevention: are Argentinean HIV care providers willing to adopt earlier antiretroviral therapy?
HIV guidelines increasingly recommend antiretroviral therapy (ART) initiation at a higher CD4 levels. The extent to which these evolving standards are translated into routine clinical care has not been evaluated in Argentina. During October 2012, we conducted an online survey among Argentinean HIV clinicians to assess their attitudes and practices toward ART initiation and its potential use for HIV prevention. Of the 280 physicians included, 61% would prescribe ART at CD4 ≤ 500 cells/µL for asymptomatic patients. Although, only 11% would recommend ART irrespective of CD4 cell count, 72% would do it for serodiscordant couples, and 75% for sex workers. Most participants agreed that they would consider earlier initiation of ART if transmission risk exists, and that expansion of ART could help decrease HIV incidence. These results suggest that a large proportion of Argentinean HIV care providers are willing to adopt the recently updated Argentinean guidelines recommending earlier ART, especially when high HIV transmission risk exists.


Endoscopic study of mechanisms of failure of endotracheal tube advancement into the trachea during awake fiberoptic orotracheal intubation.
Advancing the endotracheal tube (ETT) over a flexible bronchoscope (FB) during awake fiberoptic orotracheal intubation is often impeded. The goal of this study was to identify the sites and mechanisms that inhibit the passing of the ETT into the trachea. Forty-five consenting patients underwent a clinically indicated awake fiberoptic orotracheal intubation. After topical anesthesia, nerve block, or both, an awake fiberoptic orotracheal intubation was performed. The placement of the FB and advancement of the ETT over the FB were videotaped using a second nasally inserted FB. An otolaryngologist later reviewed the videotaped data. The right arytenoid or the interarytenoid soft tissues inhibited advancement of the ETT in 42 and 11% of all patients, respectively. In all cases in which the FB was located on the right side of the larynx, failure of ETT advancement almost always occurred at the right arytenoid. Withdrawing the ETT and rotating it 90 degrees counterclockwise resulted in successful intubation on the second, third, and fourth attempts in 26.6, 20, and 0.7% of patients, respectively. The right arytenoid frequently inhibits advancement of the ETT over the FB into the trachea during awake fiberoptic orotracheal intubation. The FB position in the larynx before tube advancement and the orientation of the ETT are relevant factors in failure of advancement of the ETT into the trachea. The authors recommend positioning the FB in the center of the larynx and orienting the bevel of the ETT to face posteriorly during the first attempt at intubation.


Alpha-fetoprotein specific CD4 and CD8 T cell responses in patients with hepatocellular carcinoma.
The presence of CD8 T cell responses to tumor associated antigens have been reported in patients with different malignancies. However, there is very little information on a comparable CD8 and CD4 T cell response to a tumor antigen in liver cancer patients. Here, we re-examine the kinetic and the pattern of T helper 1 and cytotoxic T lymphocyte responses to alpha-fetoprotein (AFP), a tumor rejection antigen in hepatocellular carcinoma (HCC). Then, we discuss the possibility of using AFP-based immunotherapy in combination with necrotizing treatments in HCC patients.


Genetic counseling following the detection of hemoglobinopathy trait on the newborn screen is well received, improves knowledge, and relieves anxiety.
The primary purpose of newborn screening for hemoglobinopathies is the presymptomatic diagnosis and early treatment of sickle cell disease. Hemoglobinopathy traits detected on the newborn screening provide an opportunity for genetic counseling of families regarding the trait and information that may impact reproductive decisions of the parents. We describe the results of a study to determine the impact of newborn screening and genetic counseling on the lives of families in which an abnormal hemoglobin trait had been identified. From June 2003 to December 2009, families of children with trait attending a clinic visit and receiving professional genetic counseling were asked to participate in a semistructured follow-up survey regarding their experience and the impact of genetic counseling on their families. Of the 300 patients seen in clinic during the specified time period, 209 consented to be recontacted and 114 have completed the survey. Eighty-five percent of responders reported knowing that the newborn screen had been performed, but only 55% understood the purpose of newborn screening. When asked about the effect of finding out that trait was present in their baby, 19% reported feeling guilty or upset, whereas 4% believed that their partner blamed them for the child's results. That genetic counseling was found to be beneficial was indicated by the fact that 99% reported that their questions were answered, 82% reported feeling less anxious, and 78% discussed the trait with their partner after the appointment. Genetic counseling after newborn screening relieves anxiety, provides knowledge, facilitates dialog within families and between partners about hemoglobinopathy trait, and was seen as a positive experience for the majority of responders.


A membrane glycoprotein, Sec12p, required for protein transport from the endoplasmic reticulum to the Golgi apparatus in yeast.
SEC12, a gene that is required for secretory, membrane, and vacuolar proteins to be transported from the endoplasmic reticulum to the Golgi apparatus, has been cloned from a genomic library by complementation of a sec12 ts mutation. Genetic analysis has shown that the cloned gene integrates at the SEC12 locus and that a null mutation at the locus is lethal. The DNA sequence predicts a protein of 471 amino acids containing a hydrophobic stretch of 19 amino acids near the COOH terminus. To characterize the gene product (Sec12p) in detail, a lacZ-SEC12 gene fusion has been constructed and a polyclonal antibody raised against the hybrid protein. The antibody recognizes Sec12p as a approximately 70-kD protein that sediments in a mixed membrane fraction that includes endoplasmic reticulum. Sec12p is not removed from the membrane fraction by treatment at high pH and high salt and is not degraded by exogenous protease unless detergent is present. Glycosylation of Sec12p during biogenesis is indicated by an electrophoretic mobility shift of the protein that is influenced by tunicamycin and by imposition of an independent secretory pathway block. We suggest that Sec12p is an integral membrane glycoprotein with a prominent domain that faces the cytoplasm where it functions to promote protein transport to the Golgi apparatus. In the process of transport, Sec12p itself may migrate to the Golgi apparatus and function in subsequent transport events.


[Morphometric parameters of the bulbar conjunctiva vessels in patients with gout].
Morphometry of the bulbar conjunctiva vessels in 50 patients with gout was carried out by television capillaroscopy with videorecording. The findings indicate that microcirculatory disorders start with dilatation of the venules, after which arterioles and capillaries are involved. This results in alteration of the arteriovenular coefficient and of the bloodflow velocity in the capillaries. Hence, the metabolic form of gout may be regarded as the initial stage of disease.


Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients.
Eight patients with refractory ovarian cancer were treated on a pilot protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH). This trial was based on our previous laboratory studies which demonstrated that Adriamycin resistance in human ovarian cancer cell lines could be partially reversed by exposure of the cells to high concentrations of verapamil (3,000 ng/mL). Patients were treated in an intensive care unit with continuous cardiovascular monitoring. The dose of verapamil was escalated in each patient until hypotension or heart block developed, and this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused over 24 hours during the second day of the verapamil infusion and verapamil alone was administered on the third day in an effort to block efflux from drug-resistant cells. This intensive approach led to a median plasma verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high infusion rates of verapamil (9 micrograms/kg/min) required to achieve these plasma levels produced an unacceptable degree of cardiac toxicity. Two patients developed transient atropine-responsive complete heart block and four patients developed transient congestive heart failure with increases in pulmonary capillary wedge pressure. There was no evidence that the noncardiac toxicities of Adriamycin were enhanced by verapamil. There were no objective responses to therapy. Future studies should use less cardiotoxic calcium channel blockers that can be safely administered to produce the plasma levels required for in vitro sensitization of drug resistant cells.


[The use of fermented milk drink with topinambur for the treatment of Helicobacter infection in the liquidators of Chernobyl nuclear power plant accident].
For estimation of anti-helicobacter activity of new fermented milk drink with Helianthus tuberosus called 23 liquidators of crash after-effects of Chernobyl Nuclear Power Plant were observed. Helicobacter pylori were determined in faeces by PCR-method, immune system readings--by first-level methods. The drink was applied in 200 grams portions during 18 days. After therapy appearance of Helicobacter pylori in faeces was reduced for 3 times. Reading of HCT-test, increased up to 16% in the first test before therapy, was normalized after therapy. Listed figures prove anti-helicobacter activity of fermented milk drink with Helianthus tuberosus.


A SOA Based Solution for MDRO Surveillance and Improved Antibiotic Prescription in the Abruzzo Region.
Prevention and control of hospital and community acquired infections caused by multi drug resistant organisms (MDROs) are one major priority nowadays for health care systems worldwide. To improve actions and plans to tackle this problem, the creation of automated regional, national and international MDRO surveillance networks is a mandatory path for international health Institutions and Ministries. In this paper, the authors report on the surveillance system designed for the Abruzzo Region (Central Italy) to monitor the prevalence of MDROs in both infected and colonized patients, to verify appropriateness of antibiotic prescription in hospitalized patients and to interact with other national and sovra-national networks. Service Oriented Architecture (SOA) approach, different Healthcare Service Specification Project (HSSP) standards, local, national and international terminology and Clinical Document Architecture Release 2 (CDA R2) were adopted to design the overall architecture of this regional surveillance system. The Authors discuss the state of implementation of the project, itemizing specific design and implementation choices adopted so far and sketching next steps and reasons of some design and implementation choices, and indicate the next steps.


Role of BCL2-associated athanogene 1 in differential sensitivity of human endothelial cells to glucocorticoids.
Chronic therapy with synthetic glucocorticoids has been associated with cardiovascular side effects, although differential interindividual susceptibility to glucocorticoids has been observed. The objective of this study was to identify the molecular mechanisms leading to differential glucocorticoid responses in endothelial cells. We tested the sensitivity of 42 human umbilical vein endothelial cells (HUVECs) to dexamethasone as determined by changes in gene expression, promoter transactivation, and procoagulant activity. We identified that 16 HUVECs were sensitive in every test, 14 HUVECs were sensitive in at least 1 test and 12 HUVECs were resistant in every test to dexamethasone. Nuclear translocation assays revealed that Dex-sensitive HUVECs have higher basal and Dex-stimulated levels of nuclear glucocorticoid receptor compared with Dex-resistant HUVECs. Cycloheximide assays revealed that Dex-resistant HUVECs have significantly shorter glucocorticoid receptor protein half-lives than Dex-sensitive HUVECs. Dex-resistant HUVECs have a stronger interaction of glucocorticoid receptor with the proteasomal recruiting protein, BCL2-associated athanogene 1 (BAG1), as shown by immunoprecipitation assays. Silencing BAG1 expression increased Dex-sensitivity in resistant HUVECs, whereas BAG1 overexpression decreased Dex-sensitivity in sensitive HUVECs. Finally, Dex-resistant HUVECs presented higher BAG1 expression than Dex-sensitive HUVECs. In vitro endothelial sensitivity to Dex varies within individuals and is inversely proportional to BAG1 protein expression and glucocorticoid receptor protein turnover.


SPECT scatter modelling in non-uniform attenuating objects.
SPECT quantitation and image contrast are degraded by photon scatter. Water equivalent depths (WEDs) have been used by several investigators to model scatter responses in non-uniform attenuators. The drawback of this approach is the occurrence of undesired fluctuations in the shape of the scatter responses, as is shown by measurements. An improvement of the WED method is presented, based on the assumption that only a part of the scattering object (the region in the 'scatter cone') contributes significantly to the detected scatter events. The remaining part of the object is treated as a uniform medium. The extension of the WED method with extra-conical invariance (WEDECI) is evaluated by projection measurements of a phantom with a 99mTc source. Shapes of scatter responses predicted by the WEDECI method are found to agree better with the measurements than those predicted by conventional WEDs.


[Neuropathy caused by cisplatin. 7 cases including one with an autopsy study].
The clinical, electrophysiological and histopathological features in seven cases of cisplatinum peripheral neuropathy are reported and compared with the literature data. The neuropathy appears for an average intake of 500 mg/m2 of DDP. The symptoms are those of a symmetric, distal, predominantly sensitive neuropathy of an axonal type with major involvement of proprioception. Neurological improvement is poor after withdrawal of the drug. A post mortem study performed in one case showed a degeneration of the posterior column in the cord and residual nodules of Nageotte in a lumbar spinal ganglion. The systematic study of the tendon reflexes and distal pallesthesia in subjects treated with the drug, may reveal the neuropathy before the onset of the most disabling symptoms (paresthesia, ataxia, pain, Lhermitte's sign).


Suppressing versus releasing a habit: frequency-dependent effects of prefrontal transcranial magnetic stimulation.
When subjects are required to generate a random sequence of numbers they typically produce too many forward and backward 'counts' (e.g. 5-6, 4-3). This counting bias is interpreted as the consequence of an interference by overlearned tendencies to arrange numbers according to their natural order. Inhibition of such well-learned routines is known to rely on frontal lobe functioning. We examined differential effects of slow (1 Hz) and fast (10 Hz) repetitive transcranial magnetic stimulation (rTMS) over the left or right dorsolateral prefrontal cortex (DLPFC) on random number generation (RNG) performance. Eighteen healthy men performed an RNG task. Those subjects stimulated over the left DLPFC showed a frequency-dependent rTMS effect: counting bias was significantly reduced after the 1 Hz stimulation compared with baseline, but significantly exaggerated after the 10 Hz stimulation compared with 1 Hz stimulation. In contrast, the sequences of the subjects stimulated over the right DLPFC showed the well-known excess of counting in all conditions (i.e. baseline, 1 Hz and 10 Hz). These findings confirm the functional importance of specifically the left DLPFC in sequential response production and show, for the first time, that rTMS affects cognitive processing in a frequency-dependent manner.


Development of a peptide antagonist against fsr quorum sensing of Enterococcus faecalis.
Enterococcus faecalis fsr quorum sensing (QS) involves an 11-residue cyclic peptide named gelatinase biosynthesis-activating pheromone (GBAP) that autoinduces two pathogenicity-related extracellular proteases in a cell density-dependent fashion. To identify anti-pathogenic agents that target fsr QS signaling, peptide antagonists of GBAP were created by our unique drug design approach based on reverse alanine scanning. First of all, a receptor-binding scaffold (RBS), [Ala(4,5,6,8,9,11)]Z-GBAP, was created, in which all amino acids within the ring region of GBAP, except for two essential aromatic residues, were substituted to alanine. Next, the substituted alanine residues were changed back to the original amino acid one by one, permitting selection of those peptide combinations exhibiting increased antagonist activity. After three cycles of this reverse alanine scan, [Ala(5,9,11)]Z-GBAP was obtained as a maximally reverted peptide (MRP) holding the strongest antagonist activity. Then, the fifth residue in MRP, which is one of the critical residues to determine agonist/antagonist activity, was further modified by substituting with different types of amino acids including unnatural amino acids. As a result, [Tyr(Bzl)(5), Ala(9,11)]Z-GBAP, named ZBzl-YAA5911, showed the strongest antagonist activity [IC(50) = 26.2 nM and Kd against GBAP receptor (FsrC) = 39.4 nM]. In vivo efficacy of this peptide was assessed with an aphakic rabbit endophthalmitis model. ZBzl-YAA5911 suppressed the translocation of E. faecalis from the aqueous humor into the vitreous cavity by more than 1 order of magnitude and significantly reduced retinal damage. We propose that ZBzl-YAA5911 or its derivatives would be useful as anti-infective agents to attenuate virulence expression in this opportunistic pathogen.


Exclusive E-Cigarette Users Report Lower Levels of Respiratory Symptoms Relative to Dual E-Cigarette and Cigarette Users.
Exclusive e-cigarette use has been shown to be associated with reduced levels of respiratory symptoms relative to smoking combustible cigarettes; this association has been less frequently studied in smokers using advanced-generation e-cigarette devices. Advanced-generation devices generate denser vapor than either early generation or pod-style devices, and engender longer inhalations; these vaping topography patterns may contribute to respiratory symptoms. In a single-session, cross-sectional study of exclusive e-cigarette users (N = 59) and dual users of e-cigarettes and cigarettes (N = 54), participants completed questionnaires, including the American Thoracic Society Questionnaire (ATSQ) and were videotaped vaping their own device in the lab for 1 hour. Using a hierarchical regression method, we examined whether topography variables, level of nicotine concentration used in their e-cigarette device in the past month, e-cigarette dependence, amount of e-cigarette use in the past month, and smoking status (any smoking in the last month vs. none) predicted ATSQ score severity. There was a significant mean difference in ATSQ score across smoking status, with greater ATSQ scores for vapers who also smoked cigarettes (19.0, SD = 6.7) than for exclusive vapers (13.4, SD = 5.3). In the final model, of the predictors of interest, only cigarette smoking status predicted significantly greater ATSQ scores (overall F = 2.51, p = .006; R2 = .26; smoking status β = 0.39, p < .0001). Findings suggest that differences in respiratory symptoms between dual and exclusive e-cigarette users appear to be attributable to combustible cigarette smoking, rather than more intense or frequent e-cigarette use across groups. In this comparison of exclusive advanced-generation vape device users (N = 59) versus dual users of these devices and combustible cigarettes (N = 54), we set out to determine the extent to which smoking status and e-cigarette use variables predicted self-reported respiratory symptom severity. We found that dual users showed greater respiratory symptom severity (ATSQ scores) than exclusive vapers. Despite examining vaping topography and other variables, smoking status and race were the only significant predictor of respiratory symptoms. We conclude that combustible cigarette use, not individual vaping topography, likely accounts for differences in respiratory symptoms between dual users and exclusive vapers.


Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike.
The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.


[Effects of essential periodontal treatment on serum level of sCD40L and periodontal clinical parameters in patients with moderate to severe periodontitis at high risk of stroke].
To investigate the effect of periodontal treatment on patients with moderate to severe periodontitis at high risk of stroke, by detecting the level of serum soluble cell differentiation antigen 40 ligand (sCD40L) before and after periodontal non-surgical treatment. Seventy-six patients with moderate to severe periodontitis at high risk of stroke were collected and randomly divided into 2 groups, 40 patients in group A received essential periodontal treatment + routine maintenance therapy, 36 cases in group B only received routine maintenance therapy. Another 36 patients with moderate and severe periodontitis were selected as group C, and received essential periodontal treatment. Bleeding on probing (BOP), periodontal probing depth (PD) and attachment loss (AL) in 6 loci were examined by the same dentists, and enzyme linked immunosorbent assay (ELISA) was used to detect the level of serum sCD40L before treatment and 3 months after treatment. The data were analyzed by SPSS 17.0 software package. Compared with pre-treatment, serum level of sCD40L and periodontal clinical indexes of the three groups decreased. Compared with group B, serum SCD40L in group A significantly decreased(P<0.05). Periodontal treatment can reduce the serum level of sCD40L in patients with moderate to severe periodontitis at high risk of stroke, and improve the patient's inflammatory state. To a certain extent, periodontal treatment may reduce the risk of high-risk stroke population to develop stroke.


Coherent octave spanning near-infrared and visible supercontinuum generation in all-normal dispersion photonic crystal fibers.
We present the first detailed demonstrations of octave-spanning SC generation in all-normal dispersion photonic crystal fibers (ANDi PCF) in the visible and near-infrared spectral regions. The resulting spectral profiles are extremely flat without significant fine structure and with excellent stability and coherence properties. The key benefit of SC generation in ANDi PCF is the conservation of a single ultrashort pulse in the time domain with smooth and recompressible phase distribution. For the first time we confirm the exceptional temporal properties of the generated SC pulses experimentally and demonstrate their applicability in ultrafast transient absorption spectroscopy. The experimental results are in excellent agreement with numerical simulations, which are used to illustrate the SC generation dynamics by self-phase modulation and optical wave breaking. To our knowledge, we present the broadest spectra generated in the normal dispersion regime of an optical fiber.


Conservation analysis in biochemical networks: computational issues for software writers.
Large scale genomic studies are generating significant amounts of data on the structure of cellular networks. This is in contrast to kinetic data, which is frequently absent, unreliable or fragmentary. There is, therefore, a desire by many in the community to investigate the potential rewards of analyzing the more readily available topological data. This brief review is concerned with a particular property of biological networks, namely structural conservations (e.g. moiety conserved cycles). There has been much discussion in the literature on these cycles but a review on the computational issues related to conserved cycles has been missing. This review is concerned with the detection and characterization of conservation relations in arbitrary networks and related issues, which impinge on simulation simulation software writers. This review will not address flux balance constraints or small-world type analyses in any significant detail.


Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients.
To evaluate the efficacy and safety of tolvaptan to treat refractory ascites in decompensated liver cirrhosis patients with or without further complications, such as hepatorenal syndrome and/or hepatocellular carcinoma. Thirty-nine patients (mean age 55 years, males: 32) with decompensated liver cirrhosis and refractory ascites were enrolled. All patients received a combination of tolvaptan (15 mg/d for 5-14 d) and diuretics (40-80 mg/d of furosemide and 80-160 mg/d of spironolactone). The etiology of cirrhosis included hepatitis B (69.2%), hepatitis C (7.7%) and alcohol-induced (23.1%). Changes in the urine excretion volume, abdominal circumference and edema were assessed. The serum sodium levels were also measured, and adverse events were recorded. A follow-up assessment was conducted 1 mo after treatment with tolvaptan. Tolvaptan increased the mean urine excretion volume (1969.2 ± 355.55 mL vs 3410.3 ± 974.1 mL, P < 0.001), and 89.7% of patients showed improvements in their ascites, 46.2% of whom showed significant improvements. The overall efficacy of tolvaptan in all patients was 89.7%; the efficacies in patients with hepatocellular carcinoma and hepatorenal syndrome were 84.2% and 77.8%, respectively. The incidence of hyponatremia was 53.8%. In patients with hyponatremia, the serum sodium levels increased after tolvaptan treatment (from 128.1 ± 4.22 mEq/L vs 133.1 ± 3.8 mEq/L, P < 0.001). Only mild drug-related adverse events, including thirst and dry mouth, were observed. Tolvaptan is a promising aquaretic for the treatment of refractory ascites in patients with decompensated liver cirrhosis.


Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells.
Helicobacter pylori infection is the main risk factor for intestinal metaplasia (IM) and gastric cancer development. IM is a pre-neoplastic lesion, induced by the transcription factor CDX2, where the gastric mucosa is converted to an intestinal phenotype. We previously demonstrated that key elements of the bone morphogenetic protein (BMP) pathway co-localize with CDX2 in IM and upregulate CDX2 expression in gastric cell lines. These observations, together with the hypothesis that CDX2 could be repressed by SOX2, led us to test whether H. pylori, through BMPs, SOX2 and CDX2 could participate in a molecular network critical for the development of IM. AGS cells with and without SMAD4 knock-down were co-cultured with H. pylori or BMP2 to assess the expression of BMP pathway members as well as CDX2 and SOX2 by qPCR and western blot. Proximity ligation assay (PLA) was also performed to evaluate SMAD proteins interaction. Immunohistochemistry and western blot were performed in gastric samples from mice infected with Helicobacter spp. to measure Smad4, pSmad1/5/8, Cdx2 and Sox2 expression in vivo. Increased expression and activity of the BMP pathway accompanied by CDX2 upregulation and SOX2 downregulation were observed in AGS cells co-cultured with H. pylori or BMP2. These effects were impaired by downregulation of the BMP pathway. Finally, infected mice present BMP pathway upregulation, focal Cdx2 expression and decreased Sox2. These results provide a novel link between H. pylori infection and the BMP pathway in the regulation of intestinal and gastric-specific genes that might be relevant for gastric IM.


Monoclonal antibody-mediated cytotoxicity of human myeloid leukemia cells: an in vitro model for estimating efficiency and optimal conditions for cytolysis.
Monoclonal antibodies (MoAbs) to myeloid differentiation antigens have a potential use in purging bone marrow of leukemia cells in autologous bone marrow transplantation (ABMT) therapy for acute myelogenous leukemia (AML). Because the efficiency of purging by MoAb and complement (C) is important to the success of ABMT, we have designed an assay to determine optimal conditions for leukemia cell lysis. In order to mimic the conditions of remission bone marrow, normal buffy coat cells were mixed with cells from the HL-60 promyelocytic leukemia cell line at a concentration that approximated the normal-leukemia cell ratio found in remission marrow. The cell mixture was treated at variable times and temperatures in the presence of C and PM-81, an IgM MoAb that reacts with both normal granulocytes and monocytes as well as with HL-60 cells. PM-81 binds to the majority of cells from 90% of patients with AML yet does not react significantly with normal stem cell populations. Because of the potential use of PM-81 in ABMT, it seemed especially important to show that the antibody was capable of mediating cytotoxicity of HL-60 cells in the presence of an excess of antigen-positive cells. A clonogenic assay that permitted the growth of HL-60 cell colonies but not normal progenitor cells in methylcellulose cultures was used to measure the efficiency of HL-60 cell lysis. We found that under certain conditions, PM-81 was capable of removing the small percentage of HL-60 clonogenic cells admixed with normal buffy coat cells. This information was useful for determining the optimal conditions for purging bone marrow of leukemia cells for ABMT.


Evolution in stressful environments. I. Phenotypic variability, phenotypic selection, and response to selection in five distinct environmental stresses.
Considerable debate has accompanied efforts to integrate the selective impacts of environmental stresses into models of life-history evolution. This study was designed to determine if different environmental stresses have consistent phenotypic effects on life-history characters and whether selection under different stresses leads to consistent evolutionary responses. We created lineages of a wild mustard (Sinapis arvensis) that were selected for three generations under five stress regimes (high boron, high salt, low light, low water, or low nutrients) or under near-optimal conditions (control). Full-sibling families from the six selection histories were divided among the same six experimental treatments. In that test generation, lifetime plant fecundity and six phenotypic traits were measured for each plant. Throughout this greenhouse study, plants were grown individually and stresses were applied from the early seedling stage through senescence. Although all stresses consistently reduced lifetime fecundity and most size- and growth-related traits, different stresses had contrasting effects on flowering time. On average, stress delayed flowering compared to favorable conditions, although plants experiencing low nutrient stress flowered earliest and those experiencing low light flowered latest. Contrary to expectations of Grime's triangle model of life-history evolution, this ruderal species does not respond phenotypically to poor environments by flowering earlier. Most stresses enhanced the evolutionary potential of the study population. Compared with near-optimal conditions, stresses tended to increase the opportunity for selection as well as phenotypic variance, although both of these quantities were reduced in some stresses. Rather than favoring traits characteristic of stress tolerance, such as slow growth and delayed reproduction, phenotypic selection favored stress-avoidance traits: earlier flowering in all five stress regimes and faster seedling height growth in three stresses. Phenotypic correlations reinforced direct selection on these traits under stress, leading to predicted phenotypic change under stress, but no significant selection in the control environment. As a result of these factors, selection under stress resulted in an evolutionary shift toward earlier flowering. Environmental stresses may drive populations of ruderal plant species like S. arvensis toward a stress-avoidance strategy, rather than toward stress tolerance. Further studies will be needed to determine when selection in stressful environments leads to these alternative life-history strategies.


Near-field-induced tunability of surface plasmon polaritons in composite metallic nanostructures.
We numerically study near-field-induced coupling effects in metal nanowire-based composite nanostructures. Our multi-layer system is composed of individual gold nanowires supporting localized particle plasmons at optical wavelengths, and a spatially separated homogeneous silver slab supporting delocalized surface plasmons. We show that the localized plasmon modes of the composite structure, forming so-called magnetic atoms, can be controlled over a large spectral range by changing the thickness of the nearby metal slab. The optical response of single-wire and array-based metallic structures are compared. Spectral shifts due to wire-mirror interaction as well as the coupling between localized and delocalized surface plasmon modes in a magnetic photonic crystal are demonstrated. The presented effects are important for the optimization of metal-based nanodevices and may lead to the realization of metamaterials with novel plasmonic functionalities.


[Healthcare rights and conditional cash transfers in Latin America].
Conditional cash transfer programs in Latin America impose specific requirements and responsibilities on beneficiary households, in order to upgrade education levels, improve drop-out rates and eliminate child labor, while enhancing health and nutrition indicators. Although counterpart healthcare conditions are common to all these programs, government strategies differ in terms of reaching their goals, at times even undermining improvements in the living conditions of more vulnerable segments of the population. Instead of upholding rights to healthcare, such initiatives may well trigger a new cycle of tightly-focused basic care through provisional programs.


Atorvastatin induces T cell anergy via phosphorylation of ERK1.
Modulation of T cell response is a novel property of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors. Previously we reported the benefits of atorvastatin treatment in experimental autoimmune encephalomyelitis, the murine model of the T cell-mediated autoimmune disorder multiple sclerosis, in which a blockade of the T cell cycle by atorvastatin was attributed to an accumulation of the negative regulator p27(Kip1). We show in this report that, in line with the documented role of p27(Kip1) in T cell anergy, treatment with atorvastatin results in a deficient response to a second productive stimulus in human T cells. This effect of atorvastatin was dependent on HMG-CoA reduction and required IL-10 signaling. Importantly, atorvastatin induced an early and sustained phosphorylation of ERK1, but not ERK2, which was crucial for the induction of anergy. On the basis of the therapeutic impact of HMG-CoA reductase inhibitors, the present findings should pave the way for future therapeutic concepts related to tolerance induction in neuroinflammatory disorders such as multiple sclerosis.


Interleukin-22 attenuates double-stranded RNA-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism.
Double-stranded RNA derived from viruses induces host immune responses. PD-L1, also known as B7-H1, is an immune-checkpoint molecule associated with the escape of viruses from host immune systems, which plays a role in the persistence of viral infection, resulting in exacerbations of underlying diseases such as asthma and chronic obstructive pulmonary disease. Interleukin (IL)-22 is produced from various immune cells and has protective properties on mucosal tissue. The binding of IL-22 to IL-22 receptor induces STAT3 activation. We investigated the effect of IL-22 on the expression in airway epithelial cells in vitro and in mouse lungs in vivo after the stimulation with an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C). Stimulation with poly I:C upregulated PD-L1 expression on BEAS-2B cells. This upregulation of PD-L1 was attenuated by IL-22 administration. STAT3 phosphorylation was induced by IL-22 and poly I:C. Treatment of cells with STAT3 siRNA abolished the effect of IL-22 on the poly I:C-induced upregulation of PD-L1. This upregulation of PD-L1 was also attenuated by IL-11, a cytokine inducing STAT3 phosphorylation, in BEAS-2B cells. In mouse lung cells in vivo, IL-22 suppressed poly I:C-induced upregulation of PD-L1. These results suggest that IL-22 attenuates virus-induced upregulation of PD-L1 in airway epithelial cells via a STAT3-dependent mechanism.


Prediction of ubiquitin proteins using artificial neural networks, hidden markov model and support vector machines.
Ubiquitin functions to regulate protein turnover in a cell by closely regulating the degradation of specific proteins. Such a regulatory role is very important, and thus I have analyzed the proteins that are ubiquitin-like, using an artificial neural network, support vector machines and a hidden Markov model (HMM). The methods were trained and tested on a set of 373 ubiquitin proteins and 373 non-ubiquitin proteins, obtained from Entrez protein database. The artificial neural network and support vector machine are trained and tested using both the physicochemical properties and PSSM matrices generated from PSI-BLAST, while in the HMM based method direct sequences are used for training-testing procedures. Further, the performance measures of the methods are calculated for test sequences, i.e. accuracy, specificity, sensitivity and Matthew's correlation coefficients of the methods are calculated. The highest accuracy of 90.2%, specificity of 87.04% and sensitivity of 94.08% was achieved using the support vector machine model with PSSM matrices. While accuracies of 86.82%, 83.37%, 80.18% and 72.11% were obtained for the support vector machine with physicochemical properties, neural network with PSSM matrices, neural networks with physicochemical properties, and hidden Markov model, respectively. As the accuracy for SVM model is better both using physicochemical properties and the PSSM matrices, it is concluded that kernel methods such as SVM outperforms neural networks and hidden Markov models.


Escherichia coli bacteriophage T1 DNA methyltransferase appears to interact with Escherichia coli enolase.
Infection of Escherichia coli cells with bacteriophage T1 induces synthesis of a bacteriophage-specific DNA methyltransferase (M.EcoT1, EC No: 220.127.116.11) with a specificity for adenine residues in the sequence 5'-GATC-3'. Purification of M.EcoT1 allowed the determination of the coding sequence of the gene (Schneider-Scherzer et al., 1990). The peptide of the entire coding sequence was over-expressed as a histidine-hexapeptide tagged protein in E. coli. Affinity purification using a Ni2+ chelating (Ni-NTA) resin yielded a recombinant enzyme with almost the same enzymatic properties as the protein purified from T1 infected E. coli cells. Interestingly, in both purification procedures, a protein with a molecular weight of 50000 was found to copurify with M.EcoT1. The N-terminal amino acid sequence identified these proteins in both cases as E. coli enolase (EC No: 22.214.171.124).


Cloning of mglB, the structural gene for the galactose-binding protein of Salmonella typhimurium and Escherichia coli.
From libraries of EcoRI fragments of Salmonella typhimurium and Escherichia coli DNA in lambda gt7, phages could be isolated that carry mglB, the structural gene of the galactose-binding protein as well as other mgl genes. Lysogenization of an E. coli mutant carrying a defective galactose-binding protein with lambda gt7 mglB (Salmonella) restores full galactose transport and galactose chemotaxis. Both the E. coli mutant protein as well as the wild-type Salmonella galactose-binding protein are synthesized in this strain. The EcoR1 fragments of both organisms carrying the mgl genes were 6 Kb long. They were subcloned into the multicopy plasmid pACYC184. The hybrid plasmid containing the Salmonella mgl DNA gives rise to the synthesis of large amounts of galactose-binding protein in the periplasm of E. coli. The protein can be precipitated by antibodies against the E. coli binding protein and is identical to the fully processed protein isolated from Salmonella typhimurium LT2. In vitro protein synthesis (Zubay-system) with either lambda gt7 mgl phages as well as the hybrid plasmid as DNA matrix produces the galactose-binding protein mainly in precursor form that is precipitable by specific antibodies.


Cigarette smoke induces mitochondrial metabolic reprogramming in lung cells.
Cellular transformation owing to cigarette smoking is due to chronic exposure and not acute. However, systematic studies to understand the molecular alterations in lung cells due to cigarette smoke are lacking. To understand these molecular alterations induced by chronic cigarette smoke exposure, we carried out tandem mass tag (TMT) based temporal proteomic profiling of lung cells exposed to cigarette smoke for upto 12months. We identified 2620 proteins in total, of which 671 proteins were differentially expressed (1.5-fold) after 12months of exposure. Prolonged exposure of lung cells to smoke for 12months revealed dysregulation of oxidative phosphorylation and overexpression of enzymes involved in TCA cycle. In addition, we also observed overexpression of enzymes involved in glutamine metabolism, fatty acid degradation and lactate synthesis. This could possibly explain the availability of alternative source of carbon to TCA cycle apart from glycolytic pyruvate. Our data indicates that chronic exposure to cigarette smoke induces mitochondrial metabolic reprogramming in cells to support growth and survival.


Dynamic internal compliance of a vascular prosthesis.
A new technique was used to measure dynamic internal compliance of a blood vessel or vascular graft subjected to dynamic internal pressure. The internal compliance can be broken into three categories: the volumetric compliance (CV), defined as (dV/V)/dP; the longitudinal compliance (CL), defined as (dL/L)/dP; and radial compliance (CR), defined as (dR/R)/dP. It can be shown mathematically that CV = 2 CR + CL. Thus, measuring any two of the three entities will also give the value for the third. A Dynatek DCT1 dynamic compliance tester was used for measuring the compliance of DenaflexTM biologic grafts and fresh bovine internal thoracic arteries, from which the Denaflex grafts were obtained by fixation. Volumetric compliance was obtained with the test sample mounted in a loose loop that allowed the sample to move both radially and longitudinally. By mounting the sample in a straight fashion that limited longitudinal movement, the radial compliance was determined. The longitudinal compliance was then calculated from the above relationship. Test results show that the fresh bovine artery had an average volumetric compliance of 26.1%/100 mmHg, radial compliance of 9.5%/100 mmHg, and longitudinal compliance of 7.2%/100 mmHg. The Denaflex vascular graft showed a reduction in longitudinal and radial compliance, compared to the fresh raw artery, as a result of extensive fixation.


The alpha integrin cytoplasmic motif KXGFFKR is essential for integrin-mediated leukocyte adhesion.
During the development of autoimmune and inflammatory diseases, infiltration by multiple leukocyte types is commonly observed at the site of inflammation. These cells are chemotactically recruited via activated integrins expressed on their cell surfaces. However, the detailed mechanism of integrin activation has not been fully elucidated. A specific and highly conserved cytoplasmic amino acid sequence, lysine-x-glycine-phenylalanine-phenylalanine-lysine-arginine (KXGFFKR), is located in the immediate vicinity of the membrane-spanning domain of all alpha integrins. In this study, we investigated the role of the KXGFFKR motif in the adhesion of leukocytes to human umbilical-vein endothelial cells (HUVEC). Pre-treatment of human neutrophils with a membrane-permeable peptide-linked KVGFFKR decreased cell adhesion to HUVEC induced by a complement activation product, C5a and formyl-methionine-leucine-phenylalanine. Similar inhibitory efficacies of this peptide were observed in T cell adhesion. Our data therefore demonstrate that a highly conserved sequence in the alpha integrins, KXGFFKR, is pharmacologically essential for integrin activation during leukocyte adhesion by both neutrophils and T cells.


Multiple H-2 linked immune response gene control of H-2 D-associated T-cell-mediated lympholysis to trinitrophenyl-modified autologous cells: Ir-like genes mapping to the left of I-A and within the I region.
One of the more recent associations of the murine H-2 major histocompatibility complex (MHC) with immune function has been the finding that cytotoxic T-effector cells generated by sensitization with viral-infected (1-6), chemically modified (7-9), or weak transplantation antigen-associated (10,11) syngeneic cells can efficiently lyse target cells which express the same viral, chemical, or weak antigenic agent, and which share the H-2K and/or H-2D regions of the MHC with the responding and/or stimulating cells. Furthermore, an additional contribution of a gene(s) within the H-2 complex has been demonstrated which controls immune response potential (Ir genes) in the generation of cytotoxic effector cells to trinitrophenyl (TNP)-modified self components (12,13). In such studies it was found that certain B10 congenic strains generated good cytotoxic responses to both TNP- modified H-2K and H-2D region products, whereas other B10 congenic strains exhibited preferential or exclusive reactivity against TNP-modified H-2K region products. Some of these recombinant strains differing in response potential to TNP- modified H-2D products expressed the same haplotype at the D end, but differed at the K end of H-2. The low responsiveness observed in the B10.A strain to TNP-modified H-2D(d) when compared to B10.D2 and (B10.A x B10.D2)F(1) for the same specificity, suggested a role of dominant Ir genes which map in K, I-A, I-B, I-J, and/or I-E (12, 14). In the present report an attemnpt was made to further map within the MHC the Ir gene(s) controlling cell-mediated lympholysis (CML) to TNP-modified H-2D(d), by using recombinant mouse strains on the A and B10 backgrounds. Irrespective of the genetic background, the s and k haplotypes at the K end generated high and low cytotoxic responses, respectively, to H-2D(d)-TNP. The intermediate responder and low responder status of the A.TL and A.AL strains, respectively, indicated that a gene mapping in the K region of H-2 influences response potential. Furthermore, the differences in the levels of cytotoxicity detected in the A.TH and A.TL strains suggested an additional I region influence. Taken together these findings raise the possibility that multiple genes mapping within different regions of the MHC control the level of T-cell-mediated cytotoxicity to chemically modified autologous cells.


Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.
Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.


The needs of siblings of children with a life-threatening illness, part 1: Conceptualization and development of a measure.
The presence of a child afflicted with a life-threatening illness is a difficult situation for the child's siblings, especially when their own needs are left unmet. The present article describes the first three phases of research involved in the conceptualization, development, and content validation of an initial version of the Inventaire des Besoins de la Fratrie d'Enfants Malades Sévèrement (IBesFEMS) [Needs Inventory for Siblings of Critically ill Children]. The first phase of the development of this instrument was conducted using qualitative methodology (focus groups: 6 siblings, 8 parents). The second phase consisted of validating the content of a pool of items developed according to the needs identified in the first phase. Some 21 participants (3 psychometricians, 3 researchers, 9 clinicians, and 6 siblings) evaluated each item for relevance and clarity. Finally, during the third phase, the acceptability and administration procedures of the preliminary version of the instrument were assessed qualitatively by five siblings. The first phase led to production of a typology made up of 43 needs in 10 different environments. The second phase allowed for selection of the items that were clearest and most relevant, based on expert opinion. This procedure gave rise to a first version of the IBesFEMS, which consisted of 48 items. The IBesFEMS appears to be a promising tool for specifically assessing the needs of the adolescent siblings of seriously ill children.


Characterization of the anthranilate degradation pathway in Geobacillus thermodenitrificans NG80-2.
Anthranilate is an important intermediate of tryptophan metabolism. In this study, a hydroxylase system consisting of an FADH(2)-utilizing monooxygenase (GTNG_3160) and an FAD reductase (GTNG_3158), as well as a bifunctional riboflavin kinase/FMN adenylyltransferase (GTNG_3159), encoded in the anthranilate degradation gene cluster in Geobacillus thermodenitrificans NG80-2 were functionally characterized in vitro. GTNG_3159 produces FAD to be reduced by GTNG_3158 and the reduced FAD (FADH(2)) is utilized by GTNG_3160 to convert anthranilate to 3-hydroxyanthranilate (3-HAA), which is further degraded to acetyl-CoA through a meta-cleavage pathway also encoded in the gene cluster. Utilization of this pathway for the degradation of anthranilate and tryptophan by NG80-2 under physiological conditions was confirmed by real-time RT-PCR analysis of representative genes. This is believed to be the first time that the degradation pathway of anthranilate via 3-HAA has been characterized in a bacterium. This pathway is likely to play an important role in the survival of G. thermodenitrificans in the oil reservoir conditions from which strain NG80-2 was isolated.


A Neurodynamic Model of Saliency Prediction in V1.
Lateral connections in the primary visual cortex (V1) have long been hypothesized to be responsible for several visual processing mechanisms such as brightness induction, chromatic induction, visual discomfort, and bottom-up visual attention (also named saliency). Many computational models have been developed to independently predict these and other visual processes, but no computational model has been able to reproduce all of them simultaneously. In this work, we show that a biologically plausible computational model of lateral interactions of V1 is able to simultaneously predict saliency and all the aforementioned visual processes. Our model's architecture (NSWAM) is based on Penacchio's neurodynamic model of lateral connections of V1. It is defined as a network of firing rate neurons, sensitive to visual features such as brightness, color, orientation, and scale. We tested NSWAM saliency predictions using images from several eye tracking data sets. We show that the accuracy of predictions obtained by our architecture, using shuffled metrics, is similar to other state-of-the-art computational methods, particularly with synthetic images (CAT2000-Pattern and SID4VAM) that mainly contain low-level features. Moreover, we outperform other biologically inspired saliency models that are specifically designed to exclusively reproduce saliency. We show that our biologically plausible model of lateral connections can simultaneously explain different visual processes present in V1 (without applying any type of training or optimization and keeping the same parameterization for all the visual processes). This can be useful for the definition of a unified architecture of the primary visual cortex.


Electronic transitions of the Soret band of reaction centers from Rhodobacter sphaeroides studied by femtosecond transient absorbance spectroscopy.
The Soret band of reaction centers from Rhodobacter sphaeroides has been systematically studied using femtosecond transient absorption spectroscopy. When the excitation wavelength was scanned over the entire Soret band, the approximate absorption spectra of the bacteriochlorophyll dimer, the monomer bacteriochlorophylls, and the bacteriopheophytins within the Soret band were determined by analyzing the ground state bleaching with about 100 fs resolution. The main contribution of H is on the blue end of the spectrum, peaking near 350 nm, P absorbs mostly on the red side of the spectrum, but probably has multiple bands, and the main absorbance of B likely lies between H and P, overlapping with P on the red side (particularly near 390 nm). The energy transfer from B to P in the QY band takes about 300 fs when Soret-band excitation is used and the time constant of overall energy transfer from H to B to P in the QY band when H is specifically excited near 350 nm is about 500 fs. Internal conversion after Soret-band excitation is the rate-limiting step for the energy-transfer process. The time constant of internal conversion for B and P is less than 300 fs, and for H it is about 500 fs.


Coordinated regulation of anthocyanin biosynthesis in Chinese bayberry (Myrica rubra) fruit by a R2R3 MYB transcription factor.
Chinese bayberry (Myrica rubra) is a fruit crop with cultivars producing fruit ranging from white (Shuijing, SJ) to red (Dongkui, DK) and dark red-purple (Biqi, BQ), as a result of different levels of anthocyanin accumulation. Genes encoding the anthocyanin biosynthesis enzymes chalcone synthase, chalcone isomerase, flavanone 3-hydroxylase (F3H), flavonoid 3'-hydroxylase (F3'H), dihydroflavonol 4-reductase (DFR), anthocyanidin synthase (ANS) and UDPglucose: flavonoid 3-O-glucosyltransferase (UFGT), as well as MrMYB1, a R2R3 MYB transcription factor homologous to known activators of anthocyanin biosynthesis, were isolated from ripe fruit of BQ. Differences in mRNA abundance of MrF3H, MrF3'H, MrDFR1, MrANS and MrUFGT were highly correlated with differential accumulation of anthocyanins between cultivars, suggesting coordinated regulation by transcription factors. The transcript level of MrMYB1 was strongly associated with the anthocyanin content in ripe fruit of the three cultivars, as well as different anthocyanin containing tissues of BQ fruit. Fruit bagging strongly inhibited anthocyanin accumulation in fruit as well as the expression of all anthocyanin biosynthetic genes and MrMYB1. Overexpression of MrMYB1 stimulated both anthocyanin accumulation and activated an Arabidopsis-DFR promoter in tobacco (Nicotiana tabacum). MrMYB1d, an allele with a 1 bp deletion at nucleotide 30 of coding sequence, was observed in SJ and DK fruit, suggesting that a nonsense mutation of the MYB1 protein may be responsible for no or low expression of MYB1 in the white and red fruit. These results show that coordinated expression of multiple biosynthetic genes is involved in anthocyanin accumulation in Chinese bayberry fruit, and this is regulated by MrMYB1.


Oxygen supplementation during exercise improves leg muscle fatigue in chronic fibrotic interstitial lung disease.
Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease (f-ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O2) supplementation can ameliorate these abnormalities. Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO2)). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue. Patients showed severe hypoxaemia (lowest O2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O2 was associated with a significant increase in muscle (HbO2), leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O2 significantly improved leg discomfort (p=0.005). O2 supplementation during exercise improves leg muscle oxygenation and fatigue in f-ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.


The influence of concomitant use of alcohol, tobacco, cocaine, and anabolic steroids on lipid profiles of Brazilian recreational bodybuilders.
Anabolic-androgenic steroids (AAS) are used to enhance physical performance and/or appearance. The aim of this study was to evaluate the influence of the concomitant use of alcohol, tobacco, cocaine, and AAS on blood lipid profiles of 145 asymptomatic male bodybuilders from the Northeast region of Brazil. Interviews, clinical exams, and serological evaluations were performed on all participants between 2007 and 2009. All subjects' self-reported use of testosterone or its derivatives, 118 individuals reported alcohol intake, 27-reported cigarette smoking, and 33 confirmed cocaine use. Four subjects were users of all drugs at the same time. Higher levels of total cholesterol and LDL-cholesterol were observed among concomitant users of alcohol, tobacco, cocaine, and AAS. The study's limitations are noted.