A prospective, randomized trial of intravenous hydroxocobalamin versus whole blood transfusion compared to no treatment for Class III hemorrhagic shock resuscitation in a prehospital swine model.
The objective was to compare systolic blood pressure (sBP) over time in swine that have had 30% of their blood volume removed (Class III shock) and treated with intravenous (IV) whole blood or IV hydroxocobalamin, compared to nontreated control animals. Thirty swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged a total of 20 mL/kg over a 20-minute period. Five minutes after hemorrhage, animals were randomly assigned to receive 150 mg/kg IV hydroxocobalamin solubilized in 180 mL of saline, 500 mL of whole blood, or no treatment. Animals were monitored for 60 minutes thereafter. A sample size of 10 animals per group was determined based on a power of 80% and an alpha of 0.05 to detect an effect size of at least a 0.25 difference (>1 standard deviation) in mean sBP between groups. sBP values were analyzed using repeated-measures analysis of variance (RANOVA). Secondary outcome data were analyzed using repeated-measures multivariate analysis of variance (RMANOVA). There were no significant differences between hemodynamic parameters of IV hydroxocobalamin versus whole blood versus control group at baseline (MANOVA; Wilks' lambda; p = 0.868) or immediately posthemorrhage (mean sBP = 47 mm Hg vs. 41 mm Hg vs. 37 mm Hg; mean arterial pressure = 39 mm Hg vs. 28 mm Hg vs. 34 mm Hg; mean serum lactate = 1.2 mmol/L vs. 1.4 mmol/L vs. 1.4 mmol/L; MANOVA; Wilks' lambda; p = 0.348). The outcome RANOVA model detected a significant difference by time between groups (p < 0.001). Specifically, 10 minutes after treatment, treated animals showed a significant increase in mean sBP compared to nontreated animals (mean sBP = 76.3 mm Hg vs. 85.7 mm Hg vs. 51.1 mm Hg; p < 0.001). RMANOVA modeling of the secondary data detected a significant difference in mean arterial pressure, heart rate, and serum lactate (p < 0.001). Similar to sBP, 10 minutes after treatment, treated animals showed a significant increase in mean arterial pressure compared to nontreated animals (mean arterial pressure = 67.7 mm Hg vs. 61.4 mm Hg vs. 40.5 mm Hg). By 10 minutes, mean heart rate was significantly slower in treated animals compared to nontreated animals (mean heart rate = 97.3 beats/min vs. 95.2 beats/min vs. 129.5 beats/min; p < 0.05). Serum lactate, an early predictor of shock, continued to rise in the control group, whereas it did not in treated animals. Thirty minutes after treatment, serum lactate values of treated animals were significantly lower compared to nontreated animals (p < 0.05). This trend continued throughout the 60-minute observation period such that 60-minute values for lactate were 1.4 mmol/L versus 1.1 mmol/L versus 3.8 mmol/L. IV hydroxocobalamin produced a statistically significant increase in systemic vascular resistance compared to control, but not whole blood, with a concomitant decrease in cardiac output. Intravenous hydroxocobalamin was more effective than no treatment and as effective as whole blood transfusion, in reversing hypotension and inhibiting rises in serum lactate in this prehospital, controlled, Class III swine hemorrhage model.


Correlation Between First Morning Single Void and 24-Hour Urines: The Reliability to Quantify Niacin Status.
BACKGROUND The current common practice when using urine as a biomarker for vitamin excretion is to use a 24-hour sample for analysis. Due to the difficulty involved in this process, we attempted to find an alternative solution through the use of a single first morning void. The aim of our study was to investigate if there is a correlation between the first morning single void and the 24-hour collections of urines for the urine metabolite of niacin, N-1-methylnicotinamide (N1MN), and to test the reliability of utilizing a method using first morning single void collections corrected with the concentration of urine creatinine. MATERIAL AND METHODS All urine samples were collected from 30 healthy adult volunteers over the age of 18 years: 20 females and 10 males. Samples were collected after discarding the first morning urine and collecting every other urine voided during the next 24 hours including the first morning urine of the day after in 2 separate vessels. We analyzed the concentration of N1MN by high performance liquid chromatography and the concentration of creatinine by a commercial kit by spectrophotometry. The B3 excretion was expressed as the ratio of N1MN to creatinine. RESULTS We found a significant correlation between the ratios of first morning single void and 24-hour urines. When comparing males and females, the ratio demonstrated a significant correlation as well. CONCLUSIONS Our results demonstrated that it is possible to substitute a 24-hour collection with a first morning single void urine for the estimation of N1MN excretion.


Cholesterol Regulates Monocyte Rolling through CD44 Distribution.
Cholesterol is an important risk factor of atherosclerosis, due to its active uptake by monocytes/macrophages. Monocyte recruitment from flowing blood to atherosclerotic foci is the key first step in the development of atherosclerosis. Cholesterol content alters cell membrane stiffness, and lateral lipid and protein diffusion. We hypothesized that cholesterol content will modulate the recruitment of monocytes to inflamed endothelial surface by altering the dynamics of adhesion receptors. We depleted or enriched the cellular cholesterol levels using methyl-β-cyclodextran in freshly isolated human monocytes. We investigated the effect of these changes on the mechanics of monocyte rolling on E-selectin surfaces at 1 dyn/cm2 in microchannels. Using imaging flow cytometry and atomic force microscopy, we characterized the distribution of lipid rafts and the E-selectin counterreceptor CD44 on the monocyte surface. We observed that lower levels of cholesterol resulted in the uniform, CD44-mediated rolling of monocytes on the E-selectin-coated surfaces. We also observed that cells depleted of cholesterol had higher membrane fluidity, and more uniform distribution of CD44 counterreceptor, which resulted in smooth motion of the cells compared to cells enriched with cholesterol. This work demonstrates that cholesterol can modulate monocyte adhesion by regulating the receptor mobility, and our results provide insights into the biophysical regulation of inflammation for the better understanding of diseases like atherosclerosis and hypercholesterolemia.


Encapsulated peracetic acid as a valid broad-spectrum antimicrobial alternative, leading to beneficial microbiota compositional changes and enhanced performance in broiler chickens.
Antimicrobial alternatives are urgently needed, including for poultry production systems. In this study, we tested the potential broad-range antimicrobial alternative peracetic acid, delivered in feed via the hydrolysis of encapsulated precursors through a 28-day study using 375 Ross 308 broiler chickens. We tested two peracetic acid concentrations, 30 and 80 mg/kg on birds housed on re-used litter, and we evaluated the impact of both levels on gut microbial communities, bacterial concentration, antimicrobial resistance genes relative abundance and growth performance when compared to control birds housed on either clean or re-used litter. Body weight gain and feed conversion ratio improved in peracetic acid fed birds. At d 28, birds given 30 mg/kg of peracetic acid had a decreased Firmicutes and an increased Proteobacteria abundance in the jejunum, accompanied by an increase in Bacillus, Flavonifractor and Rombustia in the caeca, and a decreased abundance of tetracycline resistance genes. Chicken given 80 mg/kg of peracetic acid had greater caecal abundance of macrolides lincosamides and streptogramins resistance genes. Growth performance on clean litter was reduced compared to re-used litter, which concurred with increased caecal abundance of Blautia, decreased caecal abundance of Escherichia/Shigella, Anaerostipes and Jeotgalicoccus, and greater gene abundance of vancomycin, tetracycline, and macrolides resistance genes. Peracetic acid could be used as a safe broad-spectrum antimicrobial alternative in broilers. Encapsulated precursors were able to reduce the bacterial concentration in the jejunum whilst promoting the proliferation of probiotic genera in the caeca, especially at the low peracetic acid concentrations tested, and improve growth performance. Moreover, our findings offer further insights on potential benefits of rearing birds on re-used litter, suggesting that the latter could be associated with better performance and reduced antimicrobial resistance risk compared to clean litter rearing.


Decoding expectation and surprise in dementia: the paradigm of music.
Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer's disease, impaired processing of 'surprise' may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music. We studied 62 patients (24 female; aged 53-88) representing major syndromes of frontotemporal dementia (behavioural variant, semantic variant primary progressive aphasia, non-fluent-agrammatic variant primary progressive aphasia) and typical amnestic Alzheimer's disease, in relation to 33 healthy controls (18 female; aged 54-78). Participants heard famous melodies containing no deviants or one of three types of deviant note-acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). Using a regression model that took elementary perceptual, executive and musical competence into account, we assessed accuracy detecting melodic deviants and simultaneously recorded pupillary responses and related these to deviant surprise value (information-content) and carrier melody predictability (entropy), calculated using an unsupervised machine learning model of music. Neuroanatomical associations of deviant detection accuracy and coupling of detection to deviant surprise value were assessed using voxel-based morphometry of patients' brain MRI. Whereas Alzheimer's disease was associated with normal deviant detection accuracy, behavioural and semantic variant frontotemporal dementia syndromes were associated with strikingly similar profiles of impaired syntactic and semantic deviant detection accuracy and impaired behavioural and autonomic sensitivity to deviant information-content (all P < 0.05). On the other hand, non-fluent-agrammatic primary progressive aphasia was associated with generalized impairment of deviant discriminability (P < 0.05) due to excessive false-alarms, despite retained behavioural and autonomic sensitivity to deviant information-content and melody predictability. Across the patient cohort, grey matter correlates of acoustic deviant detection accuracy were identified in precuneus, mid and mesial temporal regions; correlates of syntactic deviant detection accuracy and information-content processing, in inferior frontal and anterior temporal cortices, putamen and nucleus accumbens; and a common correlate of musical salience coding in supplementary motor area (all P < 0.05, corrected for multiple comparisons in pre-specified regions of interest). Our findings suggest that major dementias have distinct profiles of sensory 'surprise' processing, as instantiated in music. Music may be a useful and informative paradigm for probing the predictive decoding of complex sensory environments in neurodegenerative proteinopathies, with implications for understanding and measuring the core pathophysiology of these diseases.


The concentration of glucose in mammalian liver.
Data on barium-zinc filtrates of liver homogenates and of boiled liver indicate that the free glucose content of liver exceeds the blood glucose level. For instance, for boiled liver, the glucose level is 10.1, compared with a blood level of 5.4 mM/kg. Method of preparation of the tissue is important for the interpretation of the final results, as has been shown in appropriate control experiments. Various methods including paper chromatography were used to show that the reducing substance in liver is glucose. The relation of the high glucose content of liver to hexokinase activity, phosphate activity, and to glucose transport between liver cell and blood is discussed.


Pemphigus IgG causes skin splitting in the presence of both desmoglein 1 and desmoglein 3.
According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1- but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting.


ModA and ModB, two ADP-ribosyltransferases encoded by bacteriophage T4: catalytic properties and mutation analysis.
Bacteriophage T4 encodes three ADP-ribosyltransferases, Alt, ModA, and ModB. These enzymes participate in the regulation of the T4 replication cycle by ADP-ribosylating a defined set of host proteins. In order to obtain a better understanding of the phage-host interactions and their consequences for regulating the T4 replication cycle, we studied cloning, overexpression, and characterization of purified ModA and ModB enzymes. Site-directed mutagenesis confirmed that amino acids, as deduced from secondary structure alignments, are indeed decisive for the activity of the enzymes, implying that the transfer reaction follows the Sn1-type reaction scheme proposed for this class of enzymes. In vitro transcription assays performed with Alt- and ModA-modified RNA polymerases demonstrated that the Alt-ribosylated polymerase enhances transcription from T4 early promoters on a T4 DNA template, whereas the transcriptional activity of ModA-modified polymerase, without the participation of T4-encoded auxiliary proteins for middle mode or late transcription, is reduced. The results presented here support the conclusion that ADP-ribosylation of RNA polymerase and of other host proteins allows initial phage-directed mRNA synthesis reactions to escape from host control. In contrast, subsequent modification of the other cellular target proteins limits transcription from phage early genes and participates in redirecting transcription to phage middle and late genes.


STEWARDSHIP: A Conceptual Imperative For Managerial Effectiveness In The Nigerian Health System.
Unacceptable health status indicators such as high infant and maternal mortality rates and low life expectancy have continued unabated inspite of government efforts to change it. This paper espouses the concept of stewardship as a selfless, ethical, cost effective and outcome oriented approach to governance. It is believed that through stewardship approach governments would improve the health status of their populations considerably. The paper implores not only government and health care managers but the Nigerian society also to imbibe the concept of stewardship to make the development of a result-oriented health system easy.


E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors.
Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1-/- breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/- murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.


Skin infections and antibiotic stewardship: analysis of emergency department prescribing practices, 2007-2010.
National guidelines suggest that most skin abscesses do not require antibiotics, and that cellulitis antibiotics should target streptococci, not community-associated MRSA (CA-MRSA). The objective of this study is to describe antimicrobial treatment of skin infections in U.S. emergency departments (EDs) and analyze potential quality measures. The National Hospital Ambulatory Medical Care Survey (NHAMCS) is a 4-stage probability sample of all non-federal U.S. ED visits. In 2007 NHAMCS started recording whether incision and drainage was performed at ED visits. We conducted a retrospective analysis, pooling 2007-2010 data, identified skin infections using diagnostic codes, and identified abscesses by performance of incision and drainage. We generated national estimates and 95% confidence intervals using weighted analyses; quantified frequencies and proportions; and evaluated antibiotic prescribing practices. We evaluated 4 parameters that might serve as quality measures of antibiotic stewardship, and present 2 of them as potentially robust enough for implementation. Of all ED visits, 3.2% (95% confidence interval 3.1-3.4%) were for skin infection, and 2.7% (2.6-2.9%) were first visits for skin infection, with no increase over time (p=0.80). However, anti-CA-MRSA antibiotic use increased, from 61% (56-66%) to 74% (71-78%) of antibiotic regimens (p<0.001). Twenty-two percent of visits were for abscess, with a non-significant increase (p=0.06). Potential quality measures: Among discharged abscess patients, 87% were prescribed antibiotics (84-90%, overuse). Among antibiotic regimens for abscess patients, 84% included anti-CA-MRSA agents (81-89%, underuse). From 2007-2010, use of anti-CA-MRSA agents for skin infections increased significantly, despite stable visit frequencies. Antibiotics were over-used for discharged abscess cases, and CA-MRSA-active antibiotics were underused among regimens when antibiotics were used for abscess. [West J Emerg Med. 2014;15(3):282-289.].


Dose-dependent embryotrophic effect of recombinant granulocyte-macrophage colony-stimulating factor and brain-derived neurotrophic factor in culture medium for mouse preimplantation embryo.
To evaluate the dose effect of recombinant mouse granulocyte-macrophage colony-stimulating factor (rmGM-CSF) or brain-derived neurotrophic factor (BDNF) in culture medium on the development of in vitro fertilized mouse embryos. Mature oocytes were retrieved from superovulated female BDF1 mice and inseminated by sperm from male BDF1 mice. On day 1, two-cell stage embryos were divided and cultured until day 5 in the embryo maintenance medium supplemented with 0, 1, 2, 5, or 10 ng/mL of rmGM-CSF or supplemented with 0, 5, 10, or 20 ng/mL of BDNF. Blastocyst formation rate and their cell numbers were assessed. The blastocyst formation rate and the total cell count in blastocyst was similar in all the rmGM-CSF treatment groups when compared with the control. However, the blastocyst formation rate and the total cell count was significantly higher in the group supplemented with 10 ng/mL of BDNF compared with the control (63.9%, 45.8±11.5 vs. 52.3%, 38.0±6.8; P<0.05, respectively). Supplementation of 10 ng/mL of BDNF enhanced the developmental potential of mouse preimplantation embryos, but supplementation of rmGM-CSF did not.


Interaction of socioeconomic status and provider practices as predictors of immunization coverage in Virginia children.
To describe the pattern of immunization in the cohort of children who entered public schools in Virginia in 1992. This was a historic cohort study using stratified cluster sampling. Three strata were created based on the socioeconomic status (SES) of the children in the catchment area of each public school in Virginia. The random sample included public elementary schools throughout Virginia. Immunization records were obtained for a randomly selected cohort of 2519 first-grade children in Virginia. Age at completion of recommended childhood vaccines was determined from birth to school entry by SES, race, and population density. Provider practices were assessed by ascertaining missed opportunities for simultaneous administration of vaccinations according to recommended schedules. Although immunization completion rates were high at school entry, low levels of immunization coverage were found in all areas of Virginia at 24 months of age regardless of SES (as measured by per capita income), population density, or race. However, under-immunization was more severe for poor children in urban areas (42.3% of children in low-SES urban areas were age-appropriately immunized at 24 months of age versus 64.0% in children in high-SES rural areas). By multivariate logistic regression, race and gender were not predictors of which children were appropriately immunized at 2 years of age after adjusting for the following: SES, population density, receiving the first DTP (diphtheria, tetanus, and pertussis) or OPV (oral polio) vaccination after 3 months of age, and failure to have the first DTP administered simultaneously with the first OPV or the second DTP administered simultaneously with the second OPV. Receiving the first DTP or OPV vaccination after 3 months of age and failure to have the first and second DTP and OPV administered simultaneously were the strongest predictors of not being age-appropriately immunized at 2 years of age. The effect of failure to vaccinate simultaneously on predicting vaccination coverage at 2 years of age was strongly modified by SES. Children who attended schools located in census tracts with per capita incomes less than $10,600 and who did not have the first and second doses of DTP and OPV administered simultaneously were 33.19 times more likely not to be age-appropriately immunized at 2 years of age compared with children who attended schools located in census tracts with per capita incomes greater than $18,800 and who received the first and second doses of DTP and OPV simultaneously (95% confidence interval: 18.29 to 60.22). Although beginning the immunization schedule at the recommended age was crucial to appropriate vaccination later in life, provider practices were important predictors of under-immunization. Failure to administer vaccinations simultaneously strongly influenced poorer children in Virginia. Serious delays in vaccine administration were observed not only for poor children in urban areas, but also in all areas of Virginia before school entry.


Energy loss and impact of various stunning devices used for the slaughtering of water buffaloes.
Stock management of the Swiss water buffalo livestock results in the slaughtering of about 350 animals per year. As the stunning of water buffaloes still is an unresolved issue, we investigated the terminal ballistics of currently used perforating stunning devices. Cartridge fired captive bolt devices, handguns and a bullet casing gun were tested in a shooting steep by firing on bisected heads, forehead plates and soap blocks. Energy loss of captive bolts confirmed their inadequacy when used for heavy water buffaloes, notably adult males. As for the free projectiles, ballistics revealed that beyond the impact energy, bullet deformation has a strong impact on the outcome. Light 9mm Luger or .38 Spl bullets as well as large deformable .44 Rem. Magnum bullets should be avoided in favor of heavier .357 Magnum deformation ammunition. These data have been translated into the development of a new stunning device for water buffaloes meeting both animal welfare and occupational safety requirements.


The non-pathogenic Escherichia coli strain W secretes SslE via the virulence-associated type II secretion system beta.
Many pathogenic E. coli strains secrete virulence factors using type II secretory systems, homologs of which are widespread in Gram-negative bacteria. Recently, the enteropathogenic Escherichia coli strain E2348/69 was shown to secrete and surface-anchor SslE, a biofilm-promoting virulence factor, via a type II secretion system. Genes encoding SslE and its associated secretion system are conserved in some non-pathogenic E. coli, including the commonly-used W (Waksman) strain. We report here that E. coli W uses its type II secretion system to export a cognate SslE protein. SslE secretion is temperature- and nutrient-dependent, being robust at 37°C in rich medium but strongly repressed by lower temperatures or nutrient limitation. Fusing either of two glycosyl hydrolases to the C-terminus of SslE prevented it from being secreted or surface-exposed. We screened mutations that inactivated the type II secretion system for stress-related phenotypes and found that inactivation of the secretion system conferred a modest increase in tolerance to high concentrations of urea. Additionally, we note that the genes encoding this secretion system are present at a hypervariable locus and have been independently lost or gained in different lineages of E. coli. The non-pathogenic E. coli W strain shares the extracellular virulence factor SslE, and its associated secretory system, with pathogenic E. coli strains. The pattern of regulation of SslE secretion we observed suggests that SslE plays a role in colonization of mammalian hosts by non-pathogenic as well as pathogenic E. coli. Our work provides a non-pathogenic model system for the study of SslE secretion, and informs future research into the function of SslE during host colonization.


Laughing as a manifestation of rapid eye movement sleep behavior disorder.
Among the range of sleep-related behavior displayed by patients with rapid eye movement (REM) sleep behavior disorder (RBD), aggressive acts are particularly common, while pleasant behaviors have rarely been reported. We aimed at identifying the frequency and characteristics of patients who displayed laughing as a pleasant, nonviolent manifestation of RBD. We reviewed 67 consecutive polysomnographic recordings of patients with RBD, obtained in our sleep laboratory between July 2004 and July 2009. We identified 14 patients (21% of our RBD patients with degenerative parkinsonism: 10 males, mean age 63 ± 11 years) who repeatedly laughed during REM sleep. Ten patients had idiopathic Parkinson's disease, 3 suffered from multisystem atrophy and 1 patient was diagnosed with dementia with Lewy bodies. Other RBD-associated behaviors included smiling, crying, aggressive behavior, screaming, and somniloquia. Nine of the 14 patients were depressed during daytime. Laughing belongs to the spectrum of behavioral manifestations of RBD. Many of our patients with RBD-associated laughter were depressed, suggesting a dissociation between emotional expression during daytime and REM sleep.


Dynamics of infectious diseases.
Modern infectious disease epidemiology has a strong history of using mathematics both for prediction and to gain a deeper understanding. However the study of infectious diseases is a highly interdisciplinary subject requiring insights from multiple disciplines, in particular a biological knowledge of the pathogen, a statistical description of the available data and a mathematical framework for prediction. Here we begin with the basic building blocks of infectious disease epidemiology--the SIS and SIR type models--before considering the progress that has been made over the recent decades and the challenges that lie ahead. Throughout we focus on the understanding that can be developed from relatively simple models, although accurate prediction will inevitably require far greater complexity beyond the scope of this review. In particular, we focus on three critical aspects of infectious disease models that we feel fundamentally shape their dynamics: heterogeneously structured populations, stochasticity and spatial structure. Throughout we relate the mathematical models and their results to a variety of real-world problems.


Probiotic modulation of dendritic cell function is influenced by ageing.
Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR.


[Echographic screening of the abdominal aorta in older men is useful].
Ultrasound detection of abdominal aortic aneurysm (AAA) in men aged 65 years or older meets the WHO criteria for screening. Evidence shows a 50% reduction of AAA-related mortality and the costs per life-year gained are acceptable. AAA-screening is not only recommended in the USA and UK but in the Netherlands as well.


Community-based medical education: is success a result of meaningful personal learning experiences?
Community-based medical education (CBME) is the delivery of medical education in a specific social context. Learners become a part of social and medical communities where their learning occurs. Longitudinal integrated clerkships (LICs) are year-long community-based placements where the curriculum and clinical experience is typically delivered by primary care physicians. These programs have proven to be robust learning environments, where learners develop strong communication skills and excellent clinical reasoning. To date, no learning model has been offered to describe CBME. The characteristics of CBME are explored by the authors who suggest that the social and professional context provided in small communities enhances medical education. The authors postulate that meaningfulness is engendered by the authentic context, which develops over time. These relationships with preceptors, patients and the community provide meaningfulness, which in turn enhances learning. The authors develop a novel learning model. They propose that the context-rich environment of CBME allows for meaningful relationships and experiences for students and that such meaningfulness enhances learning.


Comparative morphology of the pollical distal phalanx.
Functional analysis of human pollical distal phalangeal (PDP) morphology is undertaken to establish a basis for the assessment of fossil hominid PDP morphology. Features that contribute to the effectiveness of grips involving the distal thumb and finger pulp areas include: 1) distal thumb interphalangeal joint morphology, facilitating PDP conjunct pronation with flexion; 2) differentiation of a proximal, mobile pulp region from a distal, stable pulp region, providing for firm precision pinch grips and precision handling of objects; and 3) asymmetric attachment of the flexor pollicis longus (FPL) tendon fibers, favoring PDP conjunct pronation. A proportionately larger size of the ulnar vs. radial ungual spine suggests differential loading intensity of the ulnar side of the proximal ungual pulp and supporting nail bed. Stresses at the distal interphalangeal joint are indicated by the presence of a sesamoid bone within the volar (palmar) plate, which also increases the length of the flexor pollicis longus tendon moment arm. Dissections of specimens from six nonhuman primate genera indicate that these human features are shared variably with individuals in other species, although the full pattern of features appears to be distinctively human. Humans share variably with these other species all metric relationships examined here. The new data identify a need to systematically review long-standing assumptions regarding the range of precision and power manipulative capabilities that might reasonably be inferred from morphology of the distal phalangeal tuberosity and from the FPL tendon insertion site on the PDP.


Effect of moderate exercise on bowel habit.
Ten healthy volunteers (six men and four women, aged 22-41 years) were studied in a crossover trial. The study was divided into three one week periods. During each period the subjects either ran on a treadmill, cycled on a bicycle ergometer, or rested in a chair for 1 hour every day. The exercise was performed at two thirds predicted maximum heart rate (equivalent to 50% VO2 max). The sequences were rotated; no studies were performed in the perimenstrual period. Transit was measured by the method of measuring the excretion of a single dose of radio-opaque markers; all stools were collected, weighed, and x rayed after the ingestion of radio-opaque markers. Dietary fibre and fluid intake were measured on the fourth day of each test period by 24 hour record. Lifestyle was otherwise unchanged. Transit time was dramatically accelerated by moderate exercise (both jogging and cycling); however, stool weight, defecation frequency, dietary fibre intake, and fluid intake did not change significantly. Whole gut transit changed from 51.2 hours (95% confidence intervals 41.9 to 60.5) at rest to 36.6 hours (31.6 to 39.2) when riding and 34.0 hours (28.8 to 39.2) when jogging. Riding and running both differed significantly from resting (p less than 0.01); the difference between riding and running was not significant.


Optimizing the development of targeted agents in pancreatic cancer: tumor fine-needle aspiration biopsy as a platform for novel prospective ex vivo drug sensitivity assays.
At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross antitumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit.


Comparative human cell toxicogenomic analysis of monohaloacetic acid drinking water disinfection byproducts.
The monohaloacetic acids (monoHAAs), iodoacetic, bromoacetic and chloroacetic acids are toxic disinfection byproducts. In vitro toxicological end points were integrated with DNA damage and repair pathway-focused toxicogenomic analyses to evaluate monoHAA-induced alterations of gene expression in normal nontransformed human cells. When compared to concurrent control transcriptome profiles, metabolic pathways involved in the cellular responses to toxic agents were identified and provided insight into the biological mechanisms of toxicity. Using the Database for Annotation, Visualization and Integrated Discovery to analyze the gene array data, the majority of the altered transcriptome profiles were associated with genes responding to DNA damage or those regulating cell cycle or apoptosis. The major pathways involved with altered gene expression were ATM, MAPK, p53, BRCA1, BRCA2, and ATR. These latter pathways highlight the involvement of DNA repair, especially the repair of double strand DNA breaks. All of the resolved pathways are involved in human cell stress response to DNA damage and regulate different stages in cell cycle progression or apoptosis.


Costs and cost-effectiveness of management of possible serious bacterial infections in young infants in outpatient settings when referral to a hospital was not possible: Results from randomized trials in Africa.
Serious bacterial neonatal infections are a major cause of global neonatal mortality. While hospitalized treatment is recommended, families cannot access inpatient treatment in low resource settings. Two parallel randomized control trials were conducted at five sites in three countries (Democratic Republic of Congo, Kenya, and Nigeria) to compare the effectiveness of treatment with experimental regimens requiring fewer injections with a reference regimen A (injection gentamicin plus injection procaine penicillin both once daily for 7 days) on the outpatient basis provided to young infants (0-59 days) with signs of possible serious bacterial infection (PSBI) when the referral was not feasible. Costs were estimated to quantify the financial implications of scaleup, and cost-effectiveness of these regimens. Direct economic costs (including personnel, drugs and consumable costs) were estimated for identification, prenatal and postnatal visits, assessment, classification, treatment and follow-up. Data on time spent by providers on each activity was collected from 83% of providers. Indirect marginal financial costs were estimated for non-consumables/capital, training, transport, communication, administration and supervision by considering only a share of the total research and health system costs considered important for the program. Total economic costs (direct plus indirect) per young infant treated were estimated based on 39% of young infants enrolled in the trial during 2012 and the number of days each treated during one year. The incremental cost-effectiveness ratio was calculated using treatment failure after one week as the outcome indicator. Experimental regimens were compared to the reference regimen and pairwise comparisons were also made. The average costs of treating a young infant with clinical severe infection (a sub-category of PSBI) in 2012 was lowest with regimen D (injection gentamicin once daily for 2 days plus oral amoxicillin twice daily for 7 days) at US$ 20.9 (95% CI US$ 16.4-25.3) or US$ 32.5 (2018 prices). While all experimental regimens B (injection gentamicin once daily plus oral amoxicillin twice daily, both for 7 days), regimen C (once daily of injection gentamicin injection plus injection procaine penicillin for 2 days, thereafter oral amoxicillin twice daily for 5 days) and regimen D were found to be more cost-effective as compared with the reference regimen A; pairwise comparison showed regimen D was more cost-effective than B or C. For fast breathing, the average cost of treatment with regimen E (oral amoxicillin twice daily for 7 days) at US$ 18.3 (95% CI US$ 13.4-23.3) or US$ 29.0 (2018 prices) was more cost-effective than regimen A. Indirect costs were 32% of the total treatment costs. Scaling up of outpatient treatment for PSBI when the referral is not feasible with fewer injections and oral antibiotics is cost-effective for young infants and can lead to increased access to treatment resulting in potential reductions in neonatal mortality. The trial was registered with Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.


C. elegans STK39/SPAK ortholog-mediated inhibition of ClC anion channel activity is regulated by WNK-independent ERK kinase signaling.
Mammalian Ste20-like proline/alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) kinases phosphorylate and regulate cation-coupled Cl(-) cotransporter activity in response to cell volume changes. SPAK and OSR1 are activated via phosphorylation by upstream with-no-lysine (WNK) kinases. In Caenorhabditis elegans, the SPAK/OSR1 ortholog germinal center kinase (GCK)-3 binds to and regulates the activity of the cell volume- and meiotic cell cycle-dependent ClC anion channel CLH-3b. We tested the hypothesis that WNK kinases function in the GCK-3/CLH-3b signaling cascade. CLH-3b heterologously expressed in human embryonic kidney (HEK) cells was unaffected by coexpression with the single C. elegans WNK kinase, WNK-1, or kinase-dead WNK-1 dominant-negative mutants. RNA interference (RNAi) knockdown of the single Drosophila WNK kinase had no effect on the activity of CLH-3b expressed in Drosophila S2 cells. Similarly, RNAi silencing of C. elegans WNK-1 had no effect on basal or cell volume-sensitive activity of CLH-3b expressed endogenously in worm oocytes. Previous yeast 2-hybrid studies suggested that ERK kinases may function upstream of GCK-3. Pharmacological inhibition of ERK signaling disrupted CLH-3b activity in HEK cells in a GCK-3-dependent manner. RNAi silencing of the C. elegans ERK kinase MPK-1 or the ERK phosphorylating/activating kinase MEK-2 constitutively activated native CLH-3b. MEK-2 and MPK-1 play important roles in regulating the meiotic cell cycle in C. elegans oocytes. Cell cycle-dependent changes in MPK-1 correlate with the pattern of CLH-3b activation observed during oocyte meiotic maturation. We postulate that MEK-2/MPK-1 functions upstream from GCK-3 to regulate its activity during cell volume and meiotic cell cycle changes.


Adalimumab versus infliximab in treating post-operative recurrence of Crohn's disease: a national cohort study.
Perform a comparison between adalimumab (ADA) and infliximab (IFX) in treating post-operative recurrence of Crohn's disease (a comparative analysis of efficacy and safety). From the 267 patients treated with Adalimumab or Infliximab between January 2005 and June 2014 in Romania, 44 received anti- TNF (tumor necrosis factor) therapy for prevention of post-operative recurrence. A comparison between patients treated with IFX and ADA was made with the Chi- square and t- student test, with the aid of the statistical program Mini Tab 17. Twenty-one patients received IFX and 23 ADA. This included 49% males (22/44), with a mean age of 41 years, mean disease duration of 6 years, and 84.1% had previously received azathioprine. The IFX group is comparable with the ADA group regarding most of the parameters, except for therapy duration. Mean duration of therapy was 33 months. The rate of complete response was comparable between the two groups: 67% in the IFX group vs. 78.3% in the ADA group, the same as the rate of re-resection, 19.1% vs. 4.4% and the rate of endoscopic recurrence, 29 vs. 33% at 12 months. Risk factors for postoperative recurrence (POR) (male sex, younger age, ileocolonic location, stricturing or penetrating behaviour) were studied, only ileocolonic location was found to be associated with Crohn's disease recurrence in patients treated with ADA. Overall infliximab and aalimumab are equally efficient in patients with resected Crohn's disease (CD) with a complete response of 72.7%, a rate of re-resection of 11.4 % and a rate of endoscopic recurrence of 35%. Ileocolonic location might be a predictive factor for loss of response to adalimumab in resected Crohn's disease patients.


A combined Golgi and autoradiographic study of 3H-glycine-accumulating cone bipolar cells in the cat retina.
Morphological subclasses of cone bipolar cells in the cat retina were studied in Golgi preparations and through the combination of Golgi impregnation with quantitative electron-microscopic autoradiography of 3H-glycine accumulation. Camera lucida drawings, computer-assisted rotations, and radial sections provided the morphological details used in assigning individual cells to morphologically defined subclasses. Selected Golgi-impregnated cells from retinas preloaded with 3H-glycine were sectioned for autoradiographic analysis. Grain densities were quantitated and compared on a normalized scale with the labeling of amacrine cells with 3H-glycine. Eleven types of cone bipolar cells were identified, 6 with axon terminals ramifying in sublamina a and 5 with axons terminating in sublamina b. Of these cells, types CBb2 and CBb5 showed the highest affinity for glycine, with labeling at 41 and 38% with respect to the most heavily labeled amacrine cells. Types CBb1, CBb3, CBa2, and CBa6 were labeled at approximately 20% of maximal labeling. The accumulation of glycine by these cells suggests that they may be involved in providing inhibitory input to the inner retina.


Gambling-Related Cognition Scale (GRCS): Are skills-based games at a disadvantage?
The Gambling-Related Cognition Scale (GRCS; Raylu & Oei, 2004) was developed to evaluate gambling-related cognitive distortions for all types of gamblers, regardless of their gambling activities (poker, slot machine, etc.). It is therefore imperative to ascertain the validity of its interpretation across different types of gamblers; however, some skills-related items endorsed by players could be interpreted as a cognitive distortion despite the fact that they play skills-related games. Using an intergroup (168 poker players and 73 video lottery terminal [VLT] players) differential item functioning (DIF) analysis, this study examined the possible manifestation of item biases associated with the GRCS. DIF was analyzed with ordinal logistic regressions (OLRs) and Ramsay's (1991) nonparametric kernel smoothing approach with TestGraf. Results show that half of the items display at least moderate DIF between groups and, depending on the type of analysis used, 3 to 7 items displayed large DIF. The 5 items with the most DIF were more significantly endorsed by poker players (uniform DIF) and were all related to skills, knowledge, learning, or probabilities. Poker players' interpretations of some skills-related items may lead to an overestimation of their cognitive distortions due to their total score increased by measurement artifact. Findings indicate that the current structure of the GRCS contains potential biases to be considered when poker players are surveyed. The present study conveys new and important information on bias issues to ponder carefully before using and interpreting the GRCS and other similar wide-range instruments with poker players. (PsycINFO Database Record


Reduced structural connectivity in cortico-striatal-thalamic network in neonates with congenital heart disease.
Impaired brain development has been observed in newborns with congenital heart disease (CHD). We performed graph theoretical analyses and network-based statistics (NBS) to assess global brain network topology and identify subnetworks of altered connectivity in infants with CHD prior to cardiac surgery. Fifty-eight infants with critical/serious CHD prior to surgery and 116 matched healthy controls as part of the developing Human Connectome Project (dHCP) underwent MRI on a 3T system and high angular resolution diffusion MRI (HARDI) was obtained. Multi-tissue constrained spherical deconvolution, anatomically constrained probabilistic tractography (ACT) and spherical-deconvolution informed filtering of tractograms (SIFT2) was used to construct weighted structural networks. Network topology was assessed and NBS was used to identify structural connectivity differences between CHD and control groups. Structural networks were partitioned into core and peripheral nodes, and edges classed as core, peripheral, or feeder. NBS identified one subnetwork with reduced structural connectivity in CHD infants involving basal ganglia, amygdala, hippocampus, cerebellum, vermis, and temporal and parieto-occipital lobe, primarily affecting core nodes and edges. However, we did not find significantly different global network characteristics in CHD neonates. This locally affected sub-network with reduced connectivity could explain, at least in part, the neurodevelopmental impairments associated with CHD.


Barriers for Early Detection of Breast Cancer among South Indian Women.
Breast cancer is one of the most common neoplasms in women across the world. Early diagnosis of breast cancer results in reduced morbidity, mortality, and improved quality of life. This study was conducted to identify the barriers among Indian women diagnosed with breast cancer in an advanced stage. A cross-sectional descriptive survey was conducted in a tertiary care teaching hospital, Southern India, among breast cancer patients. A total of 202 women with breast cancer (Stage 3 and 4) were recruited based on the predefined inclusion and exclusion criteria. The data were collected using a demographic proforma and barrier checklist and analyzed using SPSS 16.0 version. The mean age of the women was 51.5 ± 10.7 years. The majority of them were Hindu (87.6%), housewives (69.8%), with primary education (39.6%). The women have cited several barriers including financial (54.5%), lack of knowledge about breast cancer (49.5%), frightened about diagnostic test result (56.9%), afraid of anticipated surgery (54.5%), and the dearth of accessibility to health resources (52%). The presence of barriers in early diagnosis of breast cancer occurs in various contexts and should be recognized and minimized by all health-care providers to reduce the associated health-care cost, morbidity, and mortality.


Treatment of the Clinical Symptoms of Osteoarthritis in the Elbow Joints of Dogs Using Nuclear Magnetic Resonance Therapy: A Randomized, Double-Blinded Trial.
Objectives: To evaluate the effects of nuclear magnetic resonance therapy (MBST®) on the clinical symptoms of osteoarthritis (OA) in the elbow joints of dogs. Methods: In this double-blind study, 28 dogs with lameness caused by OA in the elbow joint were randomly allocated to two groups: 14 dogs received nuclear magnetic resonance (NMR) therapy [treatment group (TG)], and 14 dogs received a placebo [placebo group (PG)] over a period of 7 consecutive days. Visual and objective gait analyses were performed before treatment (M1) and at 3 (M2) and 6 months (M3) after treatment. At M2 and M3 Symmetry indices (SI) of the peak vertical force (PVFz) and the vertical impulse (IFz), lameness scores, and pain scores were compared with their values at M1 to calculate the overall treatment effectiveness (OTE) score. We also documented additional pain medication and medical physiotherapy during the time of study. Finally, we measured the range of motion (ROM) in order to evaluate the functional development of the joint. Results: The median OTE score of dogs in the TG indicates no change after 3 month and was improved after 6 months of treatment. There was an improvement of the median OTE score of dogs in the PG after 3 months of treatment. Further, the OTE scores of dogs in the PG were actually worse after 6 months. Nevertheless, there were no significance differences in SIPVFz, SIIFz, ROM, and lameness- and pain scores between the TG and PG at M1, M2, and M3. When considering all collected parameters (excluding the ROM) to calculate the OTE, no significant difference between groups was measurable for the OTE. Conclusion: There was a positive effect of NMR therapy (MBST®) on the treatment of OA in dogs. However, future studies should investigate the mechanisms underlying NMR therapy and the pathophysiology of OA to provide optimal treatments for patients. Clinical Significance: Our results demonstrated that the response to NMR treatment was individualized for each dog. As an integral way of treating dogs with chronic OA, NMR therapy may be an alternative therapeutic approach to support traditional medications.


Transforming a small midwestern city for physical activity: from the sidewalks up.
Jackson, Michigan (population 36,000) started active living interventions to help solve residents' low physical activity levels. Jackson's experience can serve as a case study for beginning similar efforts in smaller communities. In 2003, Jackson began a 3-prong community intervention utilizing the 5P model to increase safe physical activity opportunities and encourage walking and biking for short trips. The focus included work on projects at 1) elementary schools, 2) worksites, and 3) city-wide networks. Evaluation results show changes in attitudes toward active transportation (8% increase in children who thought walking to school was "safer" postintervention), intentions to try active transportation (43% of Smart Commute Day participants "would" smart commute more often postevent), and increased physical activity (the percentage of students walking to school more than doubled at 3 of 4 intervention schools). In addition, a community level observational study was conducted at 10 locations in the city in 2005 and 2006. The number of people seen using active transportation increased from 1,028 in 2005 to 1,853 people in 2006 (a 63% increase). Local community-driven projects to increase walking and biking can be effective by utilizing a variety of interventions, from the individual to the policy level.


Bacteroides chinchillae sp. nov. and Bacteroides rodentium sp. nov., isolated from chinchilla (Chinchilla lanigera) faeces.
Gram-negative anaerobic rods were isolated from chinchilla (Chinchilla lanigera) faeces and three strains, ST170(T), ST180 and ST28(T), were investigated taxonomically. On the basis of phylogenetic analyses and specific phenotypic characteristics, the three strains belonged to the genus Bacteroides. Phylogenetic analysis of their 16S rRNA gene sequences revealed that strains ST170(T) and ST180 formed a single cluster and a distinct line of descent. Strain ST170(T) exhibited 99.7 % 16S rRNA gene sequence similarity with strain ST180 and 95.1, 94.6 and 94.4 % 16S rRNA gene sequence similarity with Bacteroides massiliensis JCM 13223(T), Bacteroides dorei JCM 13471(T) and Bacteroides vulgatus JCM 5826(T), respectively. Strain ST28(T) also formed a distinct line of descent and exhibited the highest 16S rRNA gene sequence similarity with Bacteroides uniformis JCM 5828(T) (98.1 %). Low DNA-DNA relatedness (1 %) between strain ST28(T) and B. uniformis JCM 5828(T) clearly indicated that they belonged to different species. Analysis of hsp60 sequences also supported these relationships. The DNA G+C contents of strains ST170(T) and ST28(T) were 45.2 and 41.0 mol%, respectively. On the basis of phenotypic characteristics and phylogenetic data, two novel species, Bacteroides chinchillae sp. nov. (type strain ST170(T) = JCM 16497(T) = CCUG 59335(T)) and Bacteroides rodentium sp. nov. (type strain ST28(T) = JCM 16496(T) = CCUG 59334(T)), are proposed.


The bifoil photodyne: a photonic crystal oscillator.
Optical tweezers is an example how to use light to generate a physical force. They have been used to levitate viruses, bacteria, cells, and sub cellular organisms. Nonetheless it would be beneficial to use such force to develop a new kind of applications. However the radiation pressure usually is small to think in moving larger objects. Currently, there is some research investigating novel photonic working principles to generate a higher force. Here, we studied theoretically and experimentally the induction of electromagnetic forces in one-dimensional photonic crystals when light impinges on the off-axis direction. The photonic structure consists of a micro-cavity like structure formed of two one-dimensional photonic crystals made of free-standing porous silicon, separated by a variable air gap and the working wavelength is 633 nm. We show experimental evidence of this force when the photonic structure is capable of making auto-oscillations and forced-oscillations. We measured peak displacements and velocities ranging from 2 up to 35 microns and 0.4 up to 2.1 mm/s with a power of 13 mW. Recent evidence showed that giant resonant light forces could induce average velocity values of 0.45 mm/s in microspheres embedded in water with 43 mW light power.


[Dr. Voronoff's curious glandular xeno-implants].
Dr. Serge Voronoff visited Brazil during the Jornadas Médicas of 1928, where he demonstrated his xenotransplantation technique to the local medical community. The present article uses newspaper clippings from that time to illustrate how this controversial surgery and Voronoff's alleged miraculous preservation of good health and longevity was viewed in the popular imagination. Voronoff's initiative paved the way for other health professionals to report on their surgical experiences with xenotransplantation and also popularized the topic, which became the subject of Carnival songs and sardonic jokes in the press. An analysis is offered, based on current scientific parameters, along with a suggestion concerning the possible involvement of xenotransplantation in HIV epidemiology.


Cortical network underlying audiovisual semantic integration and modulation of attention: An fMRI and graph-based study.
Many neuroimaging and electrophysiology studies have suggested that semantic integration as a high-level cognitive process involves various cortical regions and is modulated by attention. However, the cortical network specific to semantic integration and the modulatory mechanism of attention remain unclear. Here, we designed an fMRI experiment using "bimodal stimulus" to extract information regarding the cortical activation related to the effects of semantic integration with and without attention, and then analyzed the characteristics of the cortical network and the modulating effect of attention on semantic integration. To further investigate the related cortical regions, we constructed a functional brain network for processing attended AV stimuli to evaluate the nodal properties using a graph-based method. The results of the fMRI and graph-based analyses showed that the semantic integration with attention activated the anterior temporal lobe (ATL), temporoparietal junction (TPJ), and frontoparietal cortex, with the ATL showing the highest nodal degree and efficiency; in contrast, semantic integration without attention involved a relatively small cortical network, including the posterior superior temporal gyrus (STG), Heschl's gyrus (HG), and precentral gyrus. These results indicated that semantic integration is a complex cognitive process that occurs not only in the attended condition but also in the unattended condition, and that attention could modulate the distribution of cortical networks related to semantic integration. We suggest that semantic integration with attention is a conscious process and needs a wide cortical network working together, in which the ATL plays the role of a central hub; in contrast, semantic integration without attention is a pre-attentive process and involves a relatively smaller cortical network, in which the HG may play an important role. Our study will provide valuable insights into semantic integration and will be useful for investigations on multisensory integration and attention mechanism at multiple processing stages and levels within the cortical hierarchy.


[Effort-Reward Imbalance among otolaryngology residents in Germany].
An increased psychosocial workload can have an negative impact on health. An effective way to record this is the effort reward imbalance model postulated by Siegrist. Values on this topic from ENT residents are missing, which is why the concept and corresponding questions were included in the survey on the current situation in further education. An online survey on the current situation of the ENT residency including the recording of psychosocial workload was developed by ENT physicians on the basis of a well-known questionnaire of colleagues of the Alliance of Young Physicians. The short version of the validated questionnaire on the effort reward imbalance model according to Siegrist with 16 items was used. An online survey was carried out addressing all ENT residents in Germany known to the German society of Oto-Rhino-Laryngology, Head and Neck surgery. The survey was sent by e-mail and was available from April 1st to July 31st in 2019. 92,3 % of the participants had an effort-reward imbalance. The mean value of effort reward imbalance was 1.57 ± 0.43, adjusted 2.16 ± 1.36. The effort scale was 10.71 ± 1.40 (3-12), adjusted 85.72 ± 15.52, reward scale 16.58 ± 2.86 (7-28), adjusted 45.61 ± 13.63, over commitment 17 ± 3.37, adjusted 61.14 ± 18.73. A high effort reward imbalance had positive significant correlations with regard to the duration of residency, the number of working hours per week and the number of duty hours per month. The effort and reward imbalance is comparable to other specialty physicians in residency. It is related to working hours, services and the progress of training. It can be improved through personal initiative and could be supplemented with the support of the hospital's internal stakeholders.


Insecticide resistance in Egyptian populations of the cotton whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae).
Three collections of Bemisia tabaci were taken from cotton and vegetable crops at the beginning of the growing season in Egypt. These displayed marked resistance to the carbamates carbosulfan (ca 20- to 50-fold) and aldicarb (ca 40- to 80-fold) and moderate resistance to the pyrethroids cypermethrin (ca 10- to 30-fold) and lambda-cyhalothrin (ca 10- to 25-fold). They displayed no resistance to the organophosphates profenofos and pirimiphos-methyl, or to imidacloprid. Another population, collected at the end of the growing season, differed markedly in its response. In this population, resistance to carbosulfan remained high (ca 40-fold), resistance to profenofos and cypermethrin was increased (ca 20- and 50-fold respectively) and a slight resistance to imidacloprid was detected (ca 6-fold). Resistance to cypermethrin and profenofos was shown to be similar among adults and nymphs. Irrespective of collection date, none of the populations showed resistance to pyriproxyfen. These Egyptian populations were compared with two representative Israeli populations. The differences between their resistance profiles is discussed in terms of their collection date, their geographical proximity and the patterns of insecticide use at their sites of collection.


Premenopausal Trabecular Bone Loss is Associated with a Family History of Fragility Fracture.
Although a fragility fracture family history (FFFH+) has repeatedly been shown to be associated with lower bone mineral density (BMD), its relationship to human BMD change is unclear. Animal research, however, documented that different purebred strains within rodent species have wide ranges in rates of bone acquisition during growth as well as in change post-ovariectomy. Our objective was to compare the rate of premenopausal spinal trabecular BMD change between women with and without a general family history of fragility fracture. Healthy premenopausal community women participated in prospective observational studies at two academic medical research centres: Vancouver, Canada (n = 66) and Munich, Germany (n = 20). The primary outcome was annual spinal BMD change, measured by quantitative computed tomography (QCT). The two studies employed similar methodologies for assessing QCT and FFFH. Volunteer community participants had a mean age of 36.0 (SD, 6.9) years, body mass index 22.5 (2.4) and baseline QCT of 150.2 (22.5) mg/cm3 trabecular bone. The rates of BMD change were similar in both cities: - 3.5 (5.1)/year Vancouver, - 2.0 (3.4)/year Munich (95 % CI of difference: - 3.9, 0.9). Over a third of the women (31 of the 86, 36 %) reported FFFH+. Those with and without a FFFH were similar in demographics, nutrition, exercise, menstrual cycle and luteal phase lengths and physiological measures (serum calcium, osteocalcin and estradiol). However, women with FFFH+ lost trabecular BMD more rapidly: FFFH+, - 4.9 (5.0), FFFH-, - 2.2 (4.4) mg/cm3/year (95 % CI diff - 0.7 to - 4.8, F1.83 = 7.88, p = 0.006). FFFH+ explained 7.7 % of the variance in QCT volumetric trabecular spinal bone change/year in these healthy premenopausal women. This study shows for the first time that having a history of a fragility fracture in a family member is associated with a greater rate of premenopausal spinal trabecular bone loss.


Optimal reproductive allocation in annuals and an informational constraint on plasticity.
In this computational study, we examined optimal reproductive allocation schedules in annual plants whose season lengths vary in predictability. We discuss relationships among season-length predictability, the form of the optimal allocation schedule, the degree of plasticity reflected in the optimal reaction norm, and the competitive consequences of plasticity and bet-hedging. We used an evolutionary algorithm to search the allocation-schedule space for optima, given different distributions of season length. The resulting schedules maximize geometric-mean fecundity under their selecting distributions. We then examined the relative fitness of these schedules in simulated competition among reaction norms optimized for different degrees of season-length predictability. Gradedness of optimal schedules decreases with increasing season-length predictability, and reaction norms comprising highly graded schedules reflect lesser plasticity than norms comprising schedules that are less graded. In simulations, competitively successful genotypes were those that reflected plasticity appropriate to the season-length predictability. Informational constraints in the form of low season-length predictability select for low plasticity and high bet-hedging in allocation. Because an environmental cue must mediate the relationship between environment and fitness, plasticity in reproductive allocation ought to be understood not as a direct response to the selective environment, but rather to cues that are correlated with relevant environmental parameters.


Psychometric properties and refinement of the Reproductive Coercion Scale.
Identification and refinement of psychometric properties of the Reproductive Coercion Scale (RCS) for use in survey research and clinical practice. Young women aged 16-29 years seeking services in 24 Pennsylvania and 5 California family planning clinics completed questionnaires. Data were pooled for analysis (n=4674), and underlying domains were assessed using Horn's Parallel Analysis and Exploratory Factor Analysis. Multidimensional Item Response Theory was used to refine the scale and assess reliability and validity of a short-form RCS. The full, nine-item RCS had two underlying domains: pregnancy coercion and condom manipulation. Five items were retained in the short form: three about pregnancy coercion (e.g., "told you not to use birth control…") and two for condom manipulation (e.g., "taken off the condom while you were having sex…"; one of these items is the combination of two original items on damaging the condom that were combined because of similar statistical properties and face validity and a third item on removing the condom was retained on its own). Recent reproductive coercion was reported by 6.7% and 6.3% of the sample with the full and short-form RCS, respectively. Characteristics of women reporting reproductive coercion were similar with both forms. Findings indicate that reproductive coercion includes pregnancy coercion and deliberate manipulation of condoms to promote pregnancy. Moreover, women experience reproductive coercion across a continuum of severity. We selected items that varied in RC severity and discrimination to generate a five-item short-form RCS for survey research and clinical practice. This study assesses the psychometric properties of the RCS, identifying pregnancy coercion and condom manipulation as underlying domains of reproductive coercion. Recommendations for using the RCS in research and clinical practice are discussed.


Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice.
Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ(-/-) and nNOSμ(+/+) mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor N(G)-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ(-/-) and nNOSμ(+/+) mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (~4%) were detected in muscles from nNOSμ(-/-) mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.


Adverse childhood experiences: towards a clear conceptual meaning.
To report an analysis of the concept of adverse childhood experiences. Adverse childhood experiences have been associated with negative physical and psychological health outcomes, but this phenomenon lacks the clear, consistent meaning necessary for use in nursing research, theory development and practice. Concept clarification. The literature search was not limited a priori by date and included publications with abstracts in English from PubMed, CINAHL, PsychINFO and Social Abstracts. The search retrieved 128 articles published from 1970-2013. The search term 'adverse childhood experiences' was used, with similar terms permitted. A snowball approach was used to expand the search to relevant literature. The articles were read and analysed following Norris's five steps for concept clarification to refine, elucidate and operationally define the concept and the context in which it occurred. Adverse childhood experiences were defined operationally as childhood events, varying in severity and often chronic, occurring in a child's family or social environment that cause harm or distress, thereby disrupting the child's physical or psychological health and development. This concept clarification should raise awareness and understanding of the diverse nature and shared characteristics of adverse childhood experiences that are believed to influence the health of individuals as they age. This clarified concept will help expand research on health consequences of adverse childhood experiences and interventions to improve health. We recommend promoting a model of primary care that pays attention to the social and familial influences on the health of individuals worldwide.


Tenolysis rate after zone 2 flexor tendon repairs.
This study aims to evaluate the tenolysis rates of zone 2 flexor digitorum profundus (FDP) with flexor digitorum superficialis (FDS) tendon repairs using four-strand technique and early passive motion exercises. In this retrospective study, we performed zone 2 flexor tendon repairs in 149 patients (117 males, 32 females, mean age 33.3±12.9 years; range, 13 to 72 years) (82 right and 67 left hands) between November 2014 and January 2019. A total of 194 FDP and FDS tendons were repaired primarily by using modified Kessler and Bunnell methods. Patients underwent pure passive motion protocols after surgery according to modified Duran's protocol. No active flexion components were added until postoperative fourth week. Twenty-three out of 149 patients and 28 out of 194 fingers (14.43%) had tenolysis. There was no significant relationship between the number of operated fingers, gender, and tenolysis rate (p=0.836, p=0.584, respectively). The repair of the FDP with FDS tendon increases the tenolysis rate in zone 2. The tenolysis rate does not change according to the number or distribution of injured fingers and gender of the patient.


Microbial Secondary Metabolites via Fermentation Approaches for Dietary Supplementation Formulations.
Food supplementation formulations refer to products that are designed to provide additional nutrients to the diet. Vitamins, dietary fibers, minerals and other functional compounds (such as antioxidants) are concentrated in dietary supplements. Specific amounts of dietary compounds are given to the body through food supplements, and these include as well so-called non-essential compounds such as secondary plant bioactive components or microbial natural products in addition to nutrients in the narrower sense. A significant social challenge represents how to moderately use the natural resources in light of the growing world population. In terms of economic production of (especially natural) bioactive molecules, ways of white biotechnology production with various microorganisms have recently been intensively explored. In the current review other relevant dietary supplements and natural substances (e.g., vitamins, amino acids, antioxidants) used in production of dietary supplements formulations and their microbial natural production via fermentative biotechnological approaches are briefly reviewed. Biotechnology plays a crucial role in optimizing fermentation conditions to maximize the yield and quality of the target compounds. Advantages of microbial production include the ability to use renewable feedstocks, high production yields, and the potential for cost-effective large-scale production. Additionally, it can be more environmentally friendly compared to chemical synthesis, as it reduces the reliance on petrochemicals and minimizes waste generation. Educating consumers about the benefits, safety, and production methods of microbial products in general is crucial. Providing clear and accurate information about the science behind microbial production can help address any concerns or misconceptions consumers may have.


Calcium sequestration by fungal melanin inhibits calcium-calmodulin signalling to prevent LC3-associated phagocytosis.
LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway regulated by Rubicon, with an emerging role in immune homeostasis and antifungal host defence. Aspergillus cell wall melanin protects conidia (spores) from killing by phagocytes and promotes pathogenicity through blocking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of LAP. However, the signalling regulating LAP upstream of Rubicon and the mechanism of melanin-induced inhibition of this pathway remain incompletely understood. Herein, we identify a Ca2+ signalling pathway that depends on intracellular Ca2+ sources from endoplasmic reticulum, endoplasmic reticulum-phagosome communication, Ca2+ release from phagosome lumen and calmodulin (CaM) recruitment, as a master regulator of Rubicon, the phagocyte NADPH oxidase NOX2 and other molecular components of LAP. Furthermore, we provide genetic evidence for the physiological importance of Ca2+-CaM signalling in aspergillosis. Finally, we demonstrate that Ca2+ sequestration by Aspergillus melanin inside the phagosome abrogates activation of Ca2+-CaM signalling to inhibit LAP. These findings reveal the important role of Ca2+-CaM signalling in antifungal immunity and identify an immunological function of Ca2+ binding by melanin pigments with broad physiological implications beyond fungal disease pathogenesis.


Elevation of Serum SSCCAII in Cutaneous and Oral Lichen Planus: Missing Link for Hidden Carcinogenic Potential?
Lichen planus (LP) is an immune mediated inflammatory condition. SCCAII is a useful biomarker reflecting Th17 type inflammation. It is also a tumour marker, especially for Squamous cell carcinoma (SCC) Mechanism of carcinogenesis in LP is still unknown. Chronic inflammation may facilitate the development of cellular clones in the epidermis. Estimation of serum level of SCCA II in patients with cutaneous and oral LP (OLP) to detect its role in LP pathogenesis, and to reveal the missing link in understanding mechanism of carcinogenesis in LP. A case control study, where 100 subjects were included; 80 LP patients (40 cutaneous & 40 oral) and 20 apparently healthy controls. We obtained an informed written consent from each subject prior the participation. Cutaneous and oral LP were diagnosed clinically, SCCA II level was measured by ELISA technique. Statistical analysis was done using SPSS vs.25. (IBM, Armonk, New York, United states). Numerical data was summarized as means and standard deviations or medians and ranges. Median SSCCAII level was significantly higher in LP cases compared to controls (P < 0.001) and was significantly higher in patients with OLP compared to patients with cutaneous LP (P ≤ 0.001). Post hoc analysis revealed that median SSCCAII was significantly higher in patients with ulcerative type compared to both reticular type and others. It was also significantly higher in patients with actinic type compared to both hypertrophic type and classic type. Median SSCCAII was significantly higher in patients with ulcerative OLP compared to actinic LP (P < 0.001). Our study revealed that serum SCCAII level was higher in patients with cutaneous and OLP. This might be linked to the pathogenesis of LP, especially actinic and erosive OLP. SCCAII level could facilitate the screening and early detection of patients at risk, a potential alarm to launch accurate assessment and continue follow up of cutaneous as well as O LP patients.


Vertebral Endplate Defect as Initiating Factor in Intervertebral Disc Degeneration: Strong Association Between Endplate Defect and Disc Degeneration in the General Population.
Cross-sectional study of spine magnetic resonance in a population, predominantly female, sample. To determine the relationship between vertebral endplate defect and intervertebral disc degeneration (DD) in general population. Precise understanding of the mechanisms leading to DD development is lacking. In a degenerating disc, mechanical and structural changes lead to further worsening of disc integrity. Increasing attention has been paid to vertebral endplate defects as having a possible role in the etiopathogenesis of DD. The study population comprised 831 twin volunteers from TwinsUK (mean age 54 ± 8 yr, 95.8% female). Lumbar T2-weighted magnetic resonance images were coded for endplate defects from 8310 endplates into six grades. Total endplate score (TEP score) was achieved by summing both endplate defect grades from the same disc level. DD was evaluated using two different classifications; Pfirrmann grading, and a quantitative trait for DD based on a 4-point grading system. Multivariable regression analysis was used to determine relationships between the traits of interest and the known risk factors for DD, age, and body mass index (BMI). A receiver operator curve for TEP score predicting DD was generated, and survival analysis paired with Cox proportional hazards models analysis performed. There was statistically significant association between DD and age and BMI. These associations lost significance when TEP score was included as predictor in multivariable model. TEP score was strongly and independently associated at every lumbar disc level with DD (Pfirmann P≤0.001; 4-point grading systems P < 1e-16). A cut-off point score of 5 for TEP score was found above which there was a higher DD prevalence. Across all age subgroups, probabilities of having DD were significantly increased in those considered TEP score positive (≥5). Our large, population-based study has shown that endplate defect was strongly and independently associated with DD at every lumbar disc level. These results provide a mechanism by which increasing age and BMI predispose to DD. 2.


[Dissociation between the development of myocardial contracture and heart damage in the "calcium paradox"].
The interrelationship between contracture development and heart damage during the calcium paradox under different sodium concentration in Ca-free media was studied on isolated rat hearts. It had been shown that calcium paradox development accompanied contracture development, intensive membrane disruption and alteration of tissue energy state. We had not found relation between contracture magnitude and degree of myocardial alterations in calcium paradox. Our dates confirm so-called intracellular hypothesis of calcium paradox. The experiments had shown close correlation between transmembrane sodium gradient in Ca-free media and degree of cellular damage and energy state alterations during calcium readmission in solution.


Evaluation of coronary collateral circulation in early ischemia in rat hearts. A morphological study.
Histological changes were examined in the left ventricular free wall of the heart in 40 rats after ligation of the distal anterior descending coronary artery for 15, 30 minutes and 1, 2, 3, 4, 5, 6 hours. Auto-injection of tracers for light microscopy was used to examine the development of collateral circulation. Morphological changes of the ischemic myocardium were observed by PAS staining and transmission electron microscopy. Fifteen minutes after coronary occlusion, the dye was observed in the vein of the ischemic zone; however, 30 minutes after coronary occlusion, the dye appeared in the capillaries of the outer-third layer. These findings suggested that the collateral circulation becomes functional between 15 and 30 minutes after coronary occlusion. Collateral circulation increased gradually in the capillaries of the ischemic zone. Thirty minutes after coronary occlusion the dye was seen only in the outer-third layer of the ventricular ischemic zone. One hour after occlusion, the dye appeared in the superficial space and the middle-third layer. Three hours after occlusion, the dye was seen in all layers of the ischemic zone. The dye appeared in the ischemic zone, where myocardium damage was not homogeneous. The positive reaction obtained by PAS staining corresponded with the capillaries, veins and superficial spaces in which the dye was evident. These results suggest that collateral circulation, verural back flow and superficial space flow are able to prevent myocardial infarction in early ischemia.


Dark states in monomeric red fluorescent proteins studied by fluorescence correlation and single molecule spectroscopy.
Monomeric red fluorescent proteins (mRFPs) have become indispensable tools for studying protein dynamics, interactions and functions in the cellular environment. Their emission spectrum can be well separated from other fluorescent proteins, and their monomeric structure preserves the natural function of fusion proteins. However, previous photophysical studies of some RFPs have shown the presence of light-induced dark states that can complicate the interpretation of cellular experiments. In this article, we extend these studies to mRFP1, mCherry, and mStrawberry by means of fluorescence correlation spectroscopy and prove that this light-driven intensity flickering also occurs in these proteins. Furthermore, we show that the flickering in these proteins is pH-dependent. Single molecule spectroscopy revealed reversible transitions from a bright to a dark state in several timescales, even up to seconds. Time-resolved fluorescence spectroscopy showed multiexponential decays, consistent with a "loose" conformation. We offer a structural basis for the fluorescence flickering using known crystal structures and point out that the environment of Glu-215 is critical for the pH dependence of the flickering in RFPs. We apply dual-color fluorescence correlation spectroscopy inside live cells to prove that this flickering can seriously hamper cellular measurements if the timescales of the flickering and diffusion are not well separated.


Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury.
Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the patho-physiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.


Geographic and temporal dynamics of a global radiation and diversification in the killer whale.
Global climate change during the Late Pleistocene periodically encroached and then released habitat during the glacial cycles, causing range expansions and contractions in some species. These dynamics have played a major role in geographic radiations, diversification and speciation. We investigate these dynamics in the most widely distributed of marine mammals, the killer whale (Orcinus orca), using a global data set of over 450 samples. This marine top predator inhabits coastal and pelagic ecosystems ranging from the ice edge to the tropics, often exhibiting ecological, behavioural and morphological variation suggestive of local adaptation accompanied by reproductive isolation. Results suggest a rapid global radiation occurred over the last 350 000 years. Based on habitat models, we estimated there was only a 15% global contraction of core suitable habitat during the last glacial maximum, and the resources appeared to sustain a constant global effective female population size throughout the Late Pleistocene. Reconstruction of the ancestral phylogeography highlighted the high mobility of this species, identifying 22 strongly supported long-range dispersal events including interoceanic and interhemispheric movement. Despite this propensity for geographic dispersal, the increased sampling of this study uncovered very few potential examples of ancestral dispersal among ecotypes. Concordance of nuclear and mitochondrial data further confirms genetic cohesiveness, with little or no current gene flow among sympatric ecotypes. Taken as a whole, our data suggest that the glacial cycles influenced local populations in different ways, with no clear global pattern, but with secondary contact among lineages following long-range dispersal as a potential mechanism driving ecological diversification.


The use of tenoxicam to prevent symptoms of discomfort induced by vagotonia during uterus manipulation in cesarean sections.
Symptoms such as nausea, vomiting, tightness of the chest, bradycardia, and shoulder or abdominal discomfort, caused by vagotonia occurring during uterus manipulation, have concerned healthcare professionals for some time. Patients sometimes report these symptoms when undergoing spinal anesthesia for cesarean sections (CSs). We designed a prospective, double-blind study to investigate the effectiveness of tenoxicam in preventing these symptoms of discomfort. A total of 105 American Society of Anesthesiologists (ASA) class I-II nulliparous pregnant women, who were scheduled for a CS, were enrolled into this prospective, double-blind study. Spinal anesthesia was conducted to reach a peak dermatome level of no more than T3. The 100 patients were randomly divided into 2 groups having completed study course: Group T (N = 50) received a 20 mg dose of tenoxicam in 5 mL of normal saline (NS) immediately after skin incision and Group N (N = 50) only received 5 mL NS. The incidence and severity of the symptoms experienced by the patients were recorded by a nurse anesthetist who was blinded to the injection regimen the patients were receiving. A chi-square test was used for statistical analysis t test and P < .05 was defined as significant. The incidence and degree of severity of nausea and vomiting were same in both the groups. The incidence and degree of severity of bradycardia, nausea, vomiting, tightness of the chest, shoulder discomfort, and abdominal discomfort were lower in Group T than in Group N. Tenoxicam might theoretically block the parasympathetic vagus pathway and decrease the visceral pain or visceral-specific symptoms, alleviating the symptoms caused by vagotonia. However, the prophylactic effect of tenoxicam in reducing the incidence and severity of nausea and vomiting was not statistically significant. This could be because nausea and vomiting are not solely caused by vagotonia, but also by other mechanisms.


Behavior and performance of weanling pigs in pens equipped with hide areas.
Two-hundred eighty crossbred pigs were used to determine the efficacy of hide areas (hides) in reducing young pigs' aggressive activity during social stress and the effect of access to hides on young pigs' productive performance. In Exp. 1, 80 pigs were kept in littermate groups of five/pen in 16 home pens. Then one pig was randomly selected from each of four pens, and the four were regrouped in either a control pen or a pen equipped with three hides (each a 20 X 23 X 25 cm box) in one of the walls. Behavior was time-lapse video-recorded for 90 min. Time spent either eating (head-in-feeder) or lying was not affected by access to hides. Pigs with hides to use in escaping attack fought less during the initial 30 min after regrouping. They spent an average of 5.5% of the time with heads hidden during the entire 90-min observation period. Experiment 2 employed 200 pigs in a performance study designed to evaluate effects of regrouping and access to hides on body weight gain and feed conversion efficiency. There were 10 replicates of each of four treatments: (a) regrouped-control pen, (b) regrouped-hide pen, (c) littermates-control pen and (d) littermates-hide pen. During the first 7 d of the 21-d trial, treatments tended to interact in affecting both average daily gain and feed conversion efficiency; littermates in control pens had the highest performance, those regrouped in hide pens were intermediate and those in regrouped-control pen and littermates-hide pen treatment groups had the poorest performance.(ABSTRACT TRUNCATED AT 250 WORDS)


Serum matrix metalloproteinase-9 is elevated in men with a history of myocardial infarction.
Elevated serum inflammatory markers have been reported in coronary heart disease. Levels of serum matrix metalloproteinase-9 (MMP-9), C-reactive protein (CRP), C3-complement (C3) and autoantibodies against oxidized low-density lipoprotein (oxLDL) in 120 male subjects with a history of myocardial infarction (MI) were compared with those in 250 age-matched controls, both groups from a large cross-sectional population survey, the FINRISK study. The concentrations of serum MMP-9 and autoantibodies against oxLDL were measured by enzyme-linked immunosorbent assay, CRP and C3 by immunonephelometry. MMP-9, CRP and C3 concentrations were higher in the subjects with a history of MI than in the controls (p=0.037, p=0.004, and p=0.006, respectively). There was no difference between the groups in serum levels of autoantibodies against oxLDL. In other background characteristics, men in the MI group had higher body mass index (BMI) and serum triglyceride values and lower serum HDL cholesterol values compared to controls (p=0.009, p=0.001, and p<0.001, respectively). When analyzed by stepwise multiple logistic regression using BMI, HDL cholesterol, triglycerides, CRP, C3 and MMP-9 as independent variables, the significant predictors for MI were HDL cholesterol (p=0.002) and MMP-9 (p=0.015). These results suggest that increased serum MMP-9 may reflect inflammatory pathologic processes that are related to progression of atherosclerosis.


Anaerobic killing of oral streptococci by reduced, transition metal cations.
Reduced, transition metal cations commonly enhance oxidative damage to cells caused by hydroperoxides formed as a result of oxygen metabolism or added externally. As expected, the cations Fe2+ and Cu+ enhanced killing of Streptococcus mutans GS-5 by hydroperoxides. However, unexpectedly, they also induced lethal damage under fully anaerobic conditions in a glove box with no exposure to O2 or hydroperoxides from initial treatment with the cations. Sensitivities to anaerobic killing by Fe2+ varied among the organisms tested. The oral streptococci Streptococcus gordonii ATCC 10558, Streptococcus rattus FA-1, and Streptococcus sanguis NCTC 10904 were approximately as sensitive as S. mutans GS-5. Enterococcus hirae ATCC 9790, Actinomyces viscosus OMZ105E, and Actinomyces naeslundii WVU45 had intermediate sensitivity, while Lactobacillus casei ATCC 4646 and Escherichia coli B were insensitive. Killing of S. mutans GS-5 in response to millimolar levels of added Fe2+ occurred over a wide range of temperatures and pH. The organism was able to take up ferrous iron, but ferric reductase activity could not be detected. Chelators, uric acid, and thiocyanate were not effective inhibitors of the lethal damage. Sulfhydryl compounds, ferricyanide, and ferrocyanide were protective if added prior to Fe2+ exposure. Fe2+, but not Fe3+, acted to reduce the acid tolerance of glycolysis by intact cells of S. mutans. The reduction in acid tolerance appeared to be related directly to Fe2+ inhibition of F-ATPase, which could be assayed with permeabilized cells, isolated membranes, or F1 enzyme separated from membranes. Cu+ and Cu2+ also inhibited F-ATPase and sensitized glycolysis by intact cells to acid. All of these damaging actions occurred anaerobically and thus did not appear to involve reactive oxygen species.