Small-for-gestational age and preterm birth across generations: a population-based study of Illinois births.
Small for gestational age (weight for gestational age <10th percentile, SGA) and preterm birth (<37 weeks, PTB) are the major determinants of infant mortality rates and racial disparities therein. To determine the generational inheritance patterns of SGA and PTB among non-Hispanic Whites and African-Americans. Stratified and multivariable binominal regression analyses were performed on an Illinois transgenerational dataset of White and African-American infants (1989-1991) and their mothers (1956-1976) with appended US census income information. Former SGA White mothers (N = 8,993) had a twofold greater infant SGA frequency than former non-SGA White mothers (N = 101,312); 14.4 versus 6.9 %, RR = 2.1 (2.0-2.2). Former SGA African American (N = 4,861) mothers had a SGA birth frequency of 25.7 % compared to 16.1 % for former non-SGA mothers (N = 28,090); RR = 1.5 (1.5-1.6). The adjusted (controlling for maternal age, education, marital status, parity, prenatal care usage, cigarette smoking, and hypertension) RR (95 % CI) of infant SGA for former SGA (compared to non-SGA) White and African-American mothers equaled 2.0 (1.9-2.1 and 1.5 (1.5-1.6), respectively. The adjusted RR (95 % CI) of infant preterm birth for former preterm (compared to term) White and African-American mothers were 1.1 (1.0-1.2). The findings were minimally changed among mothers with a lifelong residence in impoverished or affluent neighborhoods. In both races, approximately 8 % of SGA births were attributable to maternal SGA. There is a transgenerational association of SGA but not preterm birth among non-Hispanic Whites and African-Americans. In both races, a similar proportion of SGA births are attributable to maternal SGA.


Risk Factors for Anastomotic Leakage of Esophagojejunostomy after Laparoscopy-Assisted Total Gastrectomy for Gastric Cancer.
The study aimed to clarify the risk factors for anastomotic leakage after laparoscopy-assisted total gastrectomy (LATG) for gastric cancer. In this study, we enrolled 131 patients with preoperatively diagnosed early gastric cancer who underwent LATG by a single surgeon between June 2006 and February 2014 at the Department of Surgery, Gastroenterological Center, Yokohama City University. Risk factors for anastomotic leakage (esophagojejunostomy) after LATG were retrospectively evaluated by univariate and multivariate analyses. Anastomotic leakage of the esophagojejunostomy was observed in 13 (9.9%) of 131 patients. Univariate analysis of risk factors for anastomotic leakage revealed that the prognostic nutritional index (PNI) is a risk factor for anastomotic leakage (<55, 11 of 63 vs. ≥55, 2 of 55; p = 0.039). Multivariate analysis revealed that PNI is an independent risk factor for anastomotic leakage (OR 0.208; 95% CI 0.044-0.981; p = 0.047). Gastric cancer patients with a low PNI have a higher risk for anastomotic leakage after LATG. The results of this study must be confirmed by a study with a large cohort of patients receiving LATG reconstructed using the same method by experienced surgeons in multiple institutions.


Possible relationship between the release of calcium ions and inactivation of the potassium conductance induced by noradrenaline in smooth muscle of the guinea-pig vas deferens.
In order to examine whether any change in cytoplasmic Ca2+ concentration occurs during the noradrenaline (NA)-induced change in the membrane potential, the isometric tension of smooth muscle of the guinea-pig vas deferens was recorded together with membrane potentials using the sucrose-gap method. NA induced a depolarization and an increase in cytoplasmic Ca2+ comprising two (initial and second) phases. In time courses, the depolarization and the second phase of the increase in cytoplasmic Ca2+ were similar. Only at the phase around the onset of the depolarization, the membrane conductance was increased but then, it was decreased. Lowering the external Ca2+ concentration and application of D600 suppressed all of the NA-induced responses. In addition, D600 diminished the size of the NA-induced decrement in the membrane conductance. The present results suggest that the initial phase of the increase in the cytoplasmic Ca2+ is due to the influx of Ca2+ and the second phase, probably to the release of Ca2+ from some intracellular stores. It was discussed that the release of Ca2+ might occur at the internal surface of the membrane, and the membrane might be left less permeable to K+ as a result.


Whipple's in the valleys: a case of Whipple's with thrombocytopenia and endocarditis.
This case report details the second described case of Whipple's disease-related thrombocytopenia in the medical literature. Whipple's disease is a rare multisystem infection caused by the actinomycete Tropheryma whipplei, first described by George Whipple in 1907. The key clinical manifestations are weight loss, diarrhoea and malabsorption, but arthralgia and endocarditis are also well described. A 62-year-old Caucasian female presented with weight loss, anaemia and behavioural changes but denied any abdominal symptoms. Thrombocytopenia subsequently developed rapidly. Bone marrow examination showed abundant megakaryocytes in keeping with peripheral platelet sequestration. In addition, there was significant polyclonal plasmacytosis. She was also found to have a 1.6 cm tricuspid vegetation. The diagnosis was confirmed by presence of foamy macrophages on duodenal biopsy, positive periodic acid-Schiff staining and visualisation of T whipplei actinomycetes on electron microscopy. Tissue PCR performed mid-treatment showed traces of T whipplei DNA. The infection was treated with a 2-week intravenous course of ceftriaxone followed by 12 months of oral co-trimoxazole. The thrombocytopenia and anaemia resolved rapidly with antibiotic therapy, her behaviour returned to normal and she remains clinically well. This report confirms the association of thrombocytopenia with Whipple's disease, likely due to peripheral platelet sequestration, which resolves rapidly with treatment. In patients with a long history of unintended weight loss, Whipple's disease is a rare but important differential diagnosis as it is ultimately fatal if left untreated.


FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations.
FTY720 is a potent immunomodulator with unique effects on lymphocyte homing and has recently proved to be safe and effective in renal transplantation in man. The authors investigated the potency of FTY720 in inhibiting allograft rejection in the rat model of orthotopic allogeneic penetrating keratoplasty. Penetrating keratoplasties were performed using Fisher rats as donors and Lewis rats as recipients or donors: group 1 (n = 10), allogeneic control; group 2 (n = 10), Lewis/Lewis syngeneic control; group 3 (n = 9), mycophenolate mofetile (MMF) 40 mg/kg; group 4 (n = 10), FTY720 1.2 mg/kg; group 5 (n = 8), FTY720 0.3 mg/kg. Four animals from each group were sacrificed for immunohistological evaluation on day 14. Medication in the therapy groups was given for 18 days. The mean (SD) rejection free graft survival time was 11.3 (0.8) days for the allogeneic control (group 1), 24.6 (2.5) days for group 3 (MMF), 44.5 (5.7) days for group 4 (FTY720 1.2 mg/kg), and 35.3 (5.7) days for group 5 (FTY720 0.3 mg/kg) (p<0.05). The allogeneic control showed a dense infiltration with CD4+, CD8+, CD161+ (NK-cells), CD25+ (IL2 receptor), and macrophages. In the therapy groups the density of infiltrating CD4+, CD8+, CD161+ (NK-cells), and CD25+ (IL2 receptor) cells was notably reduced compared with the allogeneic control (p<0.05). In group 5 however, the reduction of infiltration by CD4+ cells was higher than the reduction of infiltration by CD8+ (p<0.05) and CD161+ (NK) cells. Oral immunosuppression with FTY720 significantly prolongs corneal allograft survival in this transplant model. The results suggest that FTY720 has a different effect on certain lymphocyte populations. CD4+ cells seem to be more affected than CD8+ cells and NK-cells.


Replicase, excisionase, and integrase genes of the Streptomyces element pSAM2 constitute an operon positively regulated by the pra gene.
pSAM2 is a site-specific integrative element from Streptomyces ambofaciens. The pra gene described earlier as an activator of pSAM2 replication is shown here to be also involved in the activation of its integration and excision. This was evidenced with derivatives of pSAM2 mutant B3 in which the pra gene was placed under the control of the inducible tipAp promoter. Transformation of Streptomyces lividans by these derivatives was efficient only when pra expression was induced, indicating its involvement in pSAM2 integration activation. Once established, these constructions remained integrated in the chromosome under noninduced conditions. Activation of the pra expression provoked strong activation of their excision, leading to the appearance of free forms. The results of functional, transcriptional, and sequence analyses allowed to conclude that the three genes repSA, xis, and int coding for the pSAM2 replicase, excisionase, and integrase, respectively, constitute an operon directly or indirectly activated by pra.


On the Merits of Using Angled Fiber Tips in Office-based Laser Surgery of the Vocal Folds.
Office-based endoscopic laser surgery is an increasingly popular option for the treatment of many benign and pre-malignant tumors of the vocal folds. While these procedures have been shown to be generally safe and effective, recent clinical studies have revealed that there are a number of challenging locations inside the larynx where laser light cannot be easily delivered due to line-of-sight limitations. In this paper, we explore whether these challenges can be overcome through the use of side-firing laser fibers. Our study is conducted in simulation, using three-dimensional models of the human larynx generated from X-ray microtomography scans. Using computer graphics techniques (ray-casting), we simulate the application of laser pulses with different types of laser fibers and compare the total anatomical coverage attained by each fiber. We consider four fiber types: a traditional "forward-looking" fiber - not unlike the ones currently used in clinical practice - and three side-firing fibers that emit light at an angle of 45, 70, and 90 degrees, respectively. Results show that side-firing fibers enable a ~70% increase in accessible anatomy compared to forward-looking fibers.


IL-7 receptor expression identifies suicide gene-modified allospecific CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors.
In allogeneic hematopoietic cell transplantation (HSCT), donor T lymphocytes mediate the graft-versus-leukemia (GVL) effect, but induce graft-versus-host disease (GVHD). Suicide gene therapy-that is, the genetic induction of a conditional suicide phenotype into donor T cells-allows dissociating the GVL effect from GVHD. Genetic modification with retroviral vectors after CD3 activation reduces T-cell alloreactivity. We recently found that alloreactivity is maintained when CD28 costimulation, IL-7, and IL-15 are added. Herein, we used the minor histocompatibility (mH) antigens HA-1 and H-Y as model alloantigens to directly explore the antileukemia efficacy of human T cells modified with the prototypic suicide gene herpes simplex virus thymidine kinase (tk) after activation with different stimuli. Only in the case of CD28 costimulation, IL-7, and IL-15, the repertoire of tk(+) T cells contained HA-1- and H-Y-specific CD8(+) cytotoxic T cells (CTL) precursors. Thymidine kinase-positive HA-1- and H-Y-specific CTLs were capable of self-renewal and differentiation into potent antileukemia effectors in vitro, and in vivo in a humanized mouse model. Self-renewal and differentiation coincided with IL-7 receptor expression. These results pave the way to the clinical investigation of T cells modified with a suicide gene after CD28 costimulation, IL-7, and IL-15 for a safe and effective GVL effect.


An Irreversibility-Based Criterion to Determine the Cost Formation of Residues in a Three-Pressure-Level Combined Cycle.
In an energy system, it is important to identify the origin of residue formation in order to implement actions to reduce their formation or to eliminate them as well as to evaluate their impact on the production costs of the system. In the exergetic cost theory, although there are several criteria to allocate the cost formation of residues to the productive components, no unique indication on the best choice has been defined yet. In this paper, the production exergy costs are determined by allocating the residue cost formation to the irreversibilities of the productive components from which they originate. This criterion, based on the Gouy-Stodola theorem, is an extension of the criterion of entropy changes, and unlike this, it avoids the existence of a negative production cost. This criterion is applied to a combined cycle of three pressure levels, and the production exergy costs are compared with the criteria of entropy changes, distributed exergy, and entropy. The results of the proposed criterion are in agreement with the compared criteria.


Concepts of Designing and Implementing Pharmacoepidemiology Studies on the Safety of Systemic Treatments in Dermatology Practice.
The U.S. Food and Drug Administration and clinical guidelines use evidence from pharmacoepidemiology studies to inform prescribing decisions and fill evidence gaps left by randomized controlled trials (RCTs). The long-term safety and infrequent adverse reactions are not well-understood when RCTs are short and involve few patients, as is the case for most systemic immunomodulating drugs in dermatology. A better understanding of the design and implementation of pharmacoepidemiology studies will help practitioners assess the accuracy of etiologic findings and use them with confidence in clinical practice. Conducting pharmacoepidemiology studies follows a structured approach, which we discuss in this article: (i) a design layer connects the research question with the appropriate study design, and considering which hypothetical RCT one ideally would want to conduct reduces inadvertent investigator errors; (ii) a measurement layer transforms longitudinal patient-level data into variables that identify the study population, patient characteristics, treatment, and outcomes; and (iii) the analysis focuses on the causal treatment effect estimation. The review and interpretation of pharmacoepidemiology studies should consider issues beyond a typical review of RCTs, chiefly the lack of baseline randomization and the use of secondary data. Well-designed and well-conducted pharmacoepidemiologic studies complement dermatology practice with critical information on prescribing systemic medications.


Scleroderma-like lesions in insulin-dependent diabetes mellitus.
We report on two patients (one female 42 years, one male 47 years) suffering from insulin-dependent diabetes mellitus (IDDM) for more than 20 years. Both patients exhibited sclerodactyly and sclerosis of the hands and lower arms as well as swelling and slight contracture of the distal interphalangeal joints. Interestingly, internal organs were not involved and autoantibodies characteristic for scleroderma were missing. Poor utilization and excess of glucose seem to be responsible for the activation of fibroblasts to produce abundant matrix proteins in the skin. Significant therapeutic improvement of the glucose metabolism was able to improve joint contractures or at least to stop the progression of skin changes in our patients. These skin changes should not be misdiagnosed as systemic sclerosis.


Epigenetic control: slow and global, nimble and local.
The regulation of gene expression involves multiple levels of control, from those that are inheritable to those that are highly responsive to environmental changes. In this issue of Genes & Development, Dong and colleagues (pp. 1159-1173) demonstrate that the dynamically controlled immune response transcription factor NF-kappaB may, in fact, have a role in regulating heterochromatin and gene expression at large distances from its actual target sequences and genes.


Marine habitats map of "Isla del Caño", Costa Rica, comparing Quickbird and Hymap images classification results.
Isla del Caño is a marine protected area on the south Pacific coast of Costa Rica, surrounded by coral reefs and coral communities. The ecology of these coral reefs has been studied for over 20 years, but they have not been mapped. Maps are considered a great research, planning, management and monitoring tool. Medium to high resolution images (HyMap 2005 and Quickbird 2007 respectively) were processed and classified in order to test and compare their accuracy in producing a marine habitat map. Manta tow surveys were performed in the field for identification of 7 marine habitats 1. Coral community; 2. Coral reef; 3. Bed rock; 4. Sand; 5. Sand with boulders; 6. Sand with rodolyths; and 7. Deep water. The overall accuracy was slightly higher using Quickbird (87%) than using Hymap (60%), however the difference was not significant. The map produced using Quickbird was selected to represent the marine habitats of Isla del Caño. This map will help to analyze the adequate size and zoning of the marine protected area.


Neurofibromatosis type 1-associated hypertension secondary to coarctation of the thoracic aorta.
Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen's disease, is an autosomal dominant genetic disorder. NF-I vasculopathy has been used to describe various vascular malformations associated with NF-1. Secondary hypertension related to NF-1 vasculopathy has been reported because of renal artery stenosis, coarctation of the abdominal aorta and other vascular lesions; however, coarctation of the thoracic aorta has seldom been reported. We report the first case, to our knowledge, of isolated coarctation of thoracic aorta in a pregnant female with NF-1. Healthcare providers caring for patients with NF-1 should be aware of associated vascular complications.


The Adaptive Learner: How Faculty and Medical Students' Perceptions of Learning Needs and Desires Differ.
Medical schools historically have utilized instructor-centered lectures to teach medical students the basic sciences. Several commercial electronic-based resources are now available to enhance lecture-based content. This study examines perceptions between students and faculty regarding the efficacy of lecture-based teaching and learning strategies used by students overall. The authors distributed surveys to medical students and basic science teaching faculty at the Medical College of Wisconsin. Survey items used categorical and 10-point scales and open-ended text response. Mean scores were compared with independent t tests and Cohen d effect sizes. Pearson (r) and Spearman rho (ρ) correlations were used for relational analysis. IBM SPSS 24.0 was used for statistical analysis, NVivo 11 was used for qualitative analysis. Faculty's perception of meeting students' learning needs was rated significantly higher (mean [SD] = 7.3 [1.3]) than students (5.9 [2.0]) (Cohen d = 1.0/P < .001). There was a significant negative correlation between lectures meeting students' learning needs and time students spent outside of lecture seeking supplemental learning resources (ρ = -0.4/P < .001). Students highlighted their use of personal learning strategies, desire for equitable access to resources, and preparation for national board examinations. Faculty emphasized their perceptions of learning resources, recognition of learning styles, time restrictions, and desire to utilize diverse teaching methods. Student and faculty perceptions regarding student learning needs were significantly different. Students use lectures extensively, but additionally add to the financial burden of medical school by personally funding supplemental resources. This study helps bridge the gap between medical students and faculty regarding what educational tools are best suited to support a student population with increasingly diverse learning needs.


Multi-level control of conductive nano-filament evolution in HfO2 ReRAM by pulse-train operations.
Precise electrical manipulation of nanoscale defects such as vacancy nano-filaments is highly desired for the multi-level control of ReRAM. In this paper we present a systematic investigation on the pulse-train operation scheme for reliable multi-level control of conductive filament evolution. By applying the pulse-train scheme to a 3 bit per cell HfO2 ReRAM, the relative standard deviations of resistance levels are improved up to 80% compared to the single-pulse scheme. The observed exponential relationship between the saturated resistance and the pulse amplitude provides evidence for the gap-formation model of the filament-rupture process.


Translation and adaptation of a questionnaire on the needs of postpartum adolescents.
Describe the processes of translation to the Portuguese language and cultural adaptation of the Postpartum Learning Needs (PLN) to the Portuguese context. Methodological study of an instrument that was constructed and validated in Jordan. Here are presented the procedures referring to linguistic, semantic and cultural validation, involving the stages of translation from English to European Portuguese, synthesis of translations, back-translation to the original language, expert committee, and pre-testing. In the translation process, some vocabulary variations were solved through consensus among translators. The expert committee found that the version translated to Portuguese presented semantic, idiomatic, cultural and conceptual equivalence, while needing some adjustments. Pre-testing was applied to 45 adolescent mothers, of whom 86.6% considered the items comprehensible. Semantic, idiomatic, cultural and conceptual equivalences were conceptually satisfactory among questionnaire versions, which is relevant for the Portuguese culture and easily understandable. It is crucial to assess the psychometric properties of the questionnaire so its adapted version can be made available.


Which Biomarkers Can Be Used as Diagnostic Tools for Infection in Suspected Sepsis?
The diagnosis of infection in patients with suspected sepsis is frequently difficult to achieve with a reasonable degree of certainty. Currently, the diagnosis of infection still relies on a combination of systemic manifestations, manifestations of organ dysfunction, and microbiological documentation. In addition, the microbiologic confirmation of infection is obtained only after 2 to 3 days of empiric antibiotic therapy. These criteria are far from perfect being at least in part responsible for the overuse and misuse of antibiotics, in the community and in hospital, and probably the main drive for antibiotic resistance. Biomarkers have been studied and used in several clinical settings as surrogate markers of infection to improve their diagnostic accuracy as well as in the assessment of response to antibiotics and in antibiotic stewardship programs. The aim of this review is to provide a clear overview of the current evidence of usefulness of biomarkers in several clinical scenarios, namely, to diagnose infection to prescribe antibiotics, to exclude infection to withhold antibiotics, and to identify the causative pathogen to target antimicrobial treatment. In recent years, new evidence with "old" biomarkers, like C-reactive protein and procalcitonin, as well as new biomarkers and molecular tests, as breathomics or bacterial DNA identification by polymerase chain reaction, increased markedly in different areas adding useful information for clinical decision making at the bedside when adequately used. The recent evidence shows that the information given by biomarkers can support the suspicion of infection and pathogen identification but also, and not less important, can exclude its diagnosis. Although the ideal biomarker has not yet been found, there are various promising biomarkers that represent true evolutions in the diagnosis of infection in patients with suspected sepsis.


Role of PRDM16 in the activation of brown fat programming. Relevance to the development of obesity.
From a histological and functional point of view, two types of adipose tissue can be identified. As opposed to the mainly unilocular white adipocytes, brown adipocytes possess plenty of small multilocular lipid droplets and dissipate energy as heat. Moreover, two distinct types of brown adipose cells exist. In vivo fate mapping experiments of brown adipose tissue (BAT) precursors suggest that classical brown adipocytes and skeletal myoblasts originate from a common mesenchymal, myogenic factor 5 (Myf5)-positive precursor cell. In addition to the classical brown adipocytes, thermogenic brown-like adipocytes (brite/beige cells) may appear within white adipose tissue (WAT) depots, sharing many of the morphological and functional features of brown adipocytes, but arising from a Myf5-negative lineage. In humans, the conversion of white fat cells into brite adipocytes could be a strategy to increase energy expenditure. The zinc finger transcription factor Prdm16 controls the bidirectional fate decision between brown adipocytes and myoblasts. Prdm16 determines the brown fat-like programme and thermogenesis in both brown and white adipose tissues. Moreover, the expression of this transcriptional regulator is strongly correlated with beige cell-selective genes. From a therapeutical point of view, the potential of inducing BAT or the transdifferentiation of WAT into beige cells by enhancing Prdm16 expression, as well as the identification of mechanisms of Prdm16 function and regulation represent potentially exciting new approaches for treatment or prevention of obesity and related diseases.


State-dependent sculpting of olfactory sensory neurons is attributed to sensory enrichment, odor deprivation, and aging.
Gene-targeted deletion of the predominant Shaker potassium channel, Kv1.3, in the mitral cells of the olfactory bulb, decreases the number of presynaptic, odorant receptor (OR)-identified olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) and alters the nature of their postsynaptic connections to mitral cell targets. The current study examined whether OSN density was state-dependent by examining the impact of (1) odor enrichment, (2) sensory deprivation, and (3) aging upon the number of P2- or M72-expressing neurons. Histological approaches were used to quantify the number of OSNs across entire epithelia for wildtype (WT) vs. Kv1.3-null (KO) mice bred onto an ORtauLacZ reporter background. Following either odor enrichment or early unilateral naris-occlusion, the number of M72-expressing OSNs was significantly decreased in WT mice, but was unchanged in KO animals. Following naris-occlusion, the number of P2-expressing OSNs was decreased regardless of genotype. Animals that were reared to 2 years of age demonstrated loss of both P2- and M72-expressing OSNs in WT mice and a concomitant loss of only M72-expressing neurons in KO mice. These findings suggest that voltage-gated activity of the mitral cells is important for OSN plasticity, and can prevent neuronal loss via sensory- and OR-dependent mechanisms.


Endothelin receptor antagonists in pulmonary arterial hypertension.
The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.


Inconsistency in health care professional work: Employment in independent sector treatment centres.
The purpose of this paper is to investigate the impact of recent outsourcing and public-private partnership (PPPs) arrangements on the consistency of professional employment in health care. A case study methodology is applied. The paper finds that multiple arrangements for employment within the ISTC creates numerous sources for inconsistency in employment: across the workplace, within professional groups and with national frameworks for health care employment. These are identified as having implications for organisational outcomes, threatening the stability of current partnerships, and partially stymieing intended behavioural change. The study is a single case study of an independent sector treatment centre. Future research is required to investigate wider trends of employment in heterogeneous outsourcing and PPP arrangements. The paper informs both managers and clinical professionals of the unanticipated complexities and practical challenges that can arise in partnerships and outsourcing arrangements. The paper presents a unique in-depth investigation of employment within recently established ISTCs, and highlights important employment changes for the core health care workforce and high-status professionals in the evolving health care organisational landscape.


Repetitive transcranial magnetic stimulation and treatment of negative symptoms of schizophrenia.
One of the fundamental prerequisites of the successful schizophrenia treatment is represented by an adequately significant impact on the negative symptoms of schizophrenia. Since the present pharmacotherapy has probably reached its limit in this area, there is a logical effort to utilize other, non-pharmacological methods. One of the most promising supplements that has been for a long time verified in the clinical practice is rTMS. Most of the studies have arrived at the conclusion that rTMS is an efficient method in the treatment of negative symptoms of schizophrenia. A valuable contribution to the assessment of the rTMS application in the treatment of negative symptoms is represented by meta-analyses. The meta-analyses indicate that the effect is mild to moderate (d=0.43 to 0.68). To sum it up, there will be higher probability of the rTMS effect on negative symptoms if 10 Hz stimulating frequency and a longer stimulation period in the extent at least three, ideally four to six weeks is used.


Fish nodavirus lytic cycle and semipermissive expression in mammalian and fish cell cultures.
In this study, Dicentrarchus labrax encephalitis virus (DlEV), which causes sea bass encephalitis, was propagated in cell culture, thus allowing study of its lytic cycle. DlEV infection of mammalian and fish cells induced different patterns of expression of capsid proteins, which were assembled as virus-like particles, accumulating in the cytoplasm either as diffuse masses or in vesicles, as shown by electron microscopy. These particles correspond to virions, as shown by their ability to induce secondary infection. Fish cells proved to be more permissive for DlEV than mammalian cells, although virus yield remained low. RNA analysis of infected sea bass cells revealed DlEV RNA3, in addition to genomic RNA1 and RNA2, and the presence of the RNA2 minus strand, thus demonstrating the replication of the DlEV genome. In addition, DlEV RNA-dependent RNA polymerase was associated with mature virions even after purification by a CsCl gradient, but it was dissociated when capsids were destabilized. In addition to providing more information about the relatedness of DlEV to the members of the family Nodaviridae, this study shows that fish nodaviruses may not be able to infect as wide a variety of cells as insect nodaviruses can.


Exertional Desaturation and Prescription of Ambulatory Oxygen Therapy in Interstitial Lung Disease.
Exertional desaturation is an important predictor of mortality in patients with interstitial lung disease. We evaluated the prevalence of exertional desaturation in subjects with interstitial lung disease and determined its relationship with the prescription of ambulatory oxygen therapy. Our retrospective analysis examined prospectively collected data from interstitial lung disease registries of 2 Melbourne hospitals: Alfred Health and Austin Health. All patients with baseline the 6-min walk tests on room air were included. We evaluated the prescription of ambulatory oxygen therapy, up to 3 months after 6-min walk tests, among those with exertional desaturation. Of the 400 subjects, 214 (54%) had exertional desaturation. The prevalence of desaturation increased with the severity of lung function impairment (FVC measurement: 33% for > 75% predicted, 69% for 50-75% predicted, 86% for < 50% predicted; diffusing capacity of the lung for carbon monoxide measurement: 20% for > 55% predicted, 64% for 36-55% predicted, 93% for ≤ 35% predicted, P < .001 for both severity classifications). There was no difference in the prevalence of exertional desaturation among common disease subtypes (P = .17). Among the desaturators, 14 (7%) had resting hypoxemia and all were prescribed long-term oxygen therapy. Of the remaining 200 with exertional desaturation only, 58 (29%) were prescribed ambulatory oxygen therapy. Multiple logistic regression showed independent associations between the ambulatory oxygen therapy prescription and shorter 6-min walk distance (P < .001) as well as worse FVC (% predicted, P = .037). Exertional desaturation is common in subjects with interstitial lung disease. More severely impaired exercise capacity and worse lung function are associated with the prescription of ambulatory oxygen therapy in interstitial lung disease.


Quantitative detection of platelet aggregates in whole blood without fixation.
Platelet counting detects lesser degrees of platelet aggregation than conventional aggregometry. In order to prevent progressive platelet aggregation or disaggregation after sampling it is customary to fix blood samples. However fixation may introduce other artefacts. We first compared stability of platelet counts in EDTA-, citrate- and r-hirudin-anticoagulated blood from healthy volunteers. Second, the stability of platelet counts in unfixed EDTA- and hirudin-anticoagulated blood was compared with glutaraldehyde-fixed blood in the same anticoagulants. Third, the effect of in vivo heparin administration on platelet counts in EDTA- and hirudin-anticoagulated blood was studied. Platelet counts within 2 h of collection were significantly higher in EDTA- than in hirudin- or citrate-anticoagulated blood (P = 0.002 vs. hirudin and P = 0.001 vs. citrate). Twenty-four hour counts in hirudin and EDTA were unchanged (P = 0.3 and P = 0.2, respectively, vs. earlier counts). Counts in citrate increased significantly (P = 0.007; n = 10). Platelet counts in fixed blood did not differ significantly from those in unfixed blood. Heparin administered for cardiopulmonary bypass reduced platelet counts in hirudin-anticoagulated blood from (mean +/- 1 standard deviation) 180 +/- 45 to 162 +/- 30 x 10(9) l-1 (P = 0.01; n = 14), without significantly lowering counts with EDTA-anticoagulation, consistent with increased platelet aggregation. Hirudin and EDTA provided stable platelet counts, suggesting that fixation is unnecessary.


Mitotic chromosome loss in a disomic haploid of Saccharomyces cerevisiae.
Experiments designed to characterize the incidence of mitotic chromosome loss in a yeast disomic haploid were performed; The selective methods employed utulize the non-mating property of strains disomic for linkage group III and heterozygous at the mating type locus. The principal findings are: (1) The grequency of spontaneous chromosome loss in the disome is of the order 10- minus 4 per cell; this value approximates the frequency in the same population of spontaneous mitotic exchange resulting in homozygosity at the mating type locus. (2) The recovered diploids are pure clones, and thus represent unique events in the disomic haploid. (3) Of the euploid chromosomes recovered after events leading to chromosome loss, approximately 90% retain the parental marker configuration expected from segregation alone; however, the remainder are recombinant for marker genes, and are the result of mitotic exchanges in the disome, especially in regions near the centromere. The recombinant proportion significantly exceeds that expected if chromosome loss and mitotic exchange in the disome were independent events. The data are consistent with a model proposing mitotic nondisjunction as the event responsible for chromosome loss in the disomic haploid.


Total tract nutrient digestion and milk fatty acid profile of dairy cows fed diets containing different levels of whole raw soya beans.
Whole oilseeds such as soya beans have been utilized in dairy rations to supply additional fat and protein. However, antinutritional components contained in soya beans, such as trypsin inhibitors and haemagglutinins (lectins) may alter digestibility of nutrients and consequently affect animal performance. The objective of the present experiment was to quantify the effect of different levels of whole raw soya beans in diets of dairy cows on nutrient intake, total tract digestion, nutrient balances and milk yield and composition. Sixteen mid to late-lactation cows (228 ± 20 days in milk; mean ± SD) were used in four replicated 4 × 4 Latin square design experiment with 21-d periods. Cows were assigned to each square according to milk yield and DIM. The animals were randomly allocated to treatments: control (without soya beans addition; CO), WS9, WS18 and WS27, with addition of 9%, 18% and 27% of whole raw soya bean in diet on a dry matter (DM) basis respectively. All diets contained identical forage and concentrate components and consisted of maize silage and concentrate based on ground corn and soya beans at a ratio of 60:40. There were no differences in OM, CP, NDF and NEL intakes (kg/day and MJ/day) among the treatments (p > 0.05). However, DM and NFC intakes were negatively affected (p = 0.04 and p < 0.01, respectively) and ether extract (EE) intake was positively affected (p < 0.01). Total tract digestion increased linearly with whole raw soya beans for EE (p < 0.01) and NDF (p = 0.01). The excretion (kg/day) of digested soya beans grains increased linearly according to addition of whole raw soya beans. However, the nutritive characteristics of excreted grains were not altered. Milk (kg), milk lactose (kg) and protein (kg) yield decreased linearly (p < 0.01, p < 0.01 and p = 0.04, respectively) milk fat content (%) increased linearly (p < 0.01) with whole raw soya beans inclusion. Increasing addition of whole raw soya beans affected milk fatty acid profile with a linear decrease of cis-9-trans 11CLA and total saturated FA; and linear increase of total unsaturated and C18:3 FA. Energy balance was positively affected (p = 0.03) by whole raw soya beans as well as efficiency of NEL milk/DE intake (p = 0.02). Nitrogen balance and microbial protein synthesis were not affected by whole raw soya beans. Increasing doses of whole raw soya beans decreased dry matter intake and milk yield, however, led to an increase of unsaturated acids in milk and higher milk fat concentration.


Toxicities of monoterpenes against housefly, Musca domestica L. (Diptera: Muscidae).
The development of natural plant extracts and essential oils will assist to decrease the negative effects of synthetic chemicals. Many plant extracts and essential oils contain monoterpenes, sesquiterpenes, and aliphatic compounds. In the present study, the fumigation activity of 42 pure monoterpenes against housefly, Musca domestica, was evaluated. Results from fumigation tests revealed that ρ-cymene, terpinolene, (±)-menthol, thymol, carvacrol, (-)-carvone, (+)-camphor, (+)-pulegone, (-)-menthone, citral, (±)-citronellal, cuminaldehyde, and citronellyl acetate exhibited strong fumigation activity against M. domestica. Specifically, the compounds of (+)-pulegone, cuminaldehyde, citral, and ρ-cymene had a highest toxicity toward M. domestica with LC50 values of 0.26, 0.60, 0.64, and 0.77 μl/L, respectively. The present results indicated that (+)-pulegone, cuminaldehyde, citral, and ρ-cymene are promising toxicants against M. domestica and could be useful in the search for new natural insecticides.


Effect of rearing systems on immune status, stress parameters, intestinal morphology, and mortality in conventional and local chicken breeds.
The majority of poultry meat used to be sourced from intensively housed birds. However, consumer preference has since demanded poultry producers develop more sustainable farming systems. Although free-range farming is considered beneficial for animal welfare, it is not as easy to standardize as an intensive system, which makes the choice of bird genotype appear crucial for alternative systems. In this study, we aimed to evaluate the effect of conventional and free-range rearing systems on the immune status, stress parameters, intestinal morphology and mortality in commercial hybrids (Ross 308) and local poultry strains, Bionda Piemontese (BP), Robusta Maculata (RM), BP x Sasso (BPxS), and RM x Sasso (RMxS). RNA was extracted from the jejunum and spleen to assess the mRNA expression of IL-2, IL-6, IL-10, IL-18, IL-1β, inducible nitric oxide synthase (iNOS), toll-like receptor (TLR)-4, and interferon gamma (IFN-γ). The heterophil:lymphocyte (H/L) ratio and intestinal histomorphometric evaluation were also calculated. We found that compared to the conventional system, the rearing system significantly affected the jejunum expression of IL-10, iNOS, IL-2, and IL-6, where these genes were upregulated in free-range system. A significant interaction between the rearing system and the genotype was also shown. More specifically, local breeds showed a significantly higher expression (P < 0.001) of IL-6 in the free-range system compared to the same genotypes in the conventional system. Moreover, IL-6 is constantly upregulated in local breeds within the free-range system compared to Ross hybrids. We also found significantly increased H/L and mortality rates in the latter, compared to the local breeds in the free-range reared system. The jejunum morphology also demonstrated a significantly higher villus height in BP and BPxS compared to the Ross hybrids. Overall, the results of our study confirm that the intense selection for growth in broiler chickens may have reduced their ability to react to the environmental stimuli related to free-range systems, resulting in a lower adaptability to a free-range environment, thus making them inappropriate for any farming system other than the conventional one. On the contrary, local chicken breeds are able to adapt and survive in the free-range system of rearing, and represent a genetic resource especially when adaptability to free-range conditions is required.


Modulation of Protein Fouling and Interfacial Properties at Carbon Surfaces via Immobilization of Glycans Using Aryldiazonium Chemistry.
Carbon materials and nanomaterials are of great interest for biological applications such as implantable devices and nanoparticle vectors, however, to realize their potential it is critical to control formation and composition of the protein corona in biological media. In this work, protein adsorption studies were carried out at carbon surfaces functionalized with aryldiazonium layers bearing mono- and di-saccharide glycosides. Surface IR reflectance absorption spectroscopy and quartz crystal microbalance were used to study adsorption of albumin, lysozyme and fibrinogen. Protein adsorption was found to decrease by 30-90% with respect to bare carbon surfaces; notably, enhanced rejection was observed in the case of the tested di-saccharide vs. simple mono-saccharides for near-physiological protein concentration values. ζ-potential measurements revealed that aryldiazonium chemistry results in the immobilization of phenylglycosides without a change in surface charge density, which is known to be important for protein adsorption. Multisolvent contact angle measurements were used to calculate surface free energy and acid-base polar components of bare and modified surfaces based on the van Oss-Chaudhury-Good model: results indicate that protein resistance in these phenylglycoside layers correlates positively with wetting behavior and Lewis basicity.


Oxidation--reduction midpoint potentials of the flavin, haem and Mo-pterin centres in spinach (Spinacia oleracea L.) nitrate reductase.
Oxidation-reduction midpoint potentials have been determined for the flavin, cytochrome b557 and Mo-pterin prosthetic groups of spinach (Spinacia oleracea L.) assimilatory nitrate reductase using visible, c.d. and room-temperature e.p.r. potentiometric titrations. At pH 7 and 25 degrees C, the midpoint potential for the FAD/FADH2 couple was determined by c.d. potentiometry to be -280 +/- 10 mV (n = 2). The redox potential for reduction of the haem was determined by visible potentiometry to be -123 +/- 10 mV (n = 1), significantly lower than the previously published value of -60 mV [Fido, Hewitt, Notton, Jones & Nasrulhaq-Boyce (1979) FEBS Lett. 99, 180-182]. Potentials for the Mo(VI)/Mo(V) and Mo(V)/Mo(IV) redox couples, determined by room-temperature e.p.r. potentiometry, were found to be +2 +/- 20 and -6 +/- 20 mV respectively. These values are very similar to the values previously determined for the FAD, haem and Mo-pterin centres in assimilatory nitrate reductase isolated from the unicellular green alga Chlorella vulgaris and indicate a close thermodynamic similarity between the two enzymes.


The role of contextualisation in enhancing non-communicable disease programmes and policy implementation to achieve health for all.
The September 2019 United Nations' High-Level Meeting renewed political commitments to invest in universal health coverage by strengthening health systems, programmes and policies to achieve 'health for all'. This Political Declaration is relevant to addressing the increasing global burden of non-communicable diseases, but how can evidence-based programmes and policies be meaningfully implemented and integrated into local contexts? In this Commentary, we describe how the process of contextualisation and associated tools, such as ecological frameworks, implementation research frameworks, health system indicators, effective system strengthening strategies and evidence mapping databases with priority-setting, can enhance the implementation and integration of non-communicable disease prevention and control policies and programmes. Examples across health platforms include (1) population approaches to reducing excess sodium intake, (2) fixed-dose combination therapy for cardiovascular disease prevention and control, and (3) health systems strengthening for improving the quality and safety of cardiovascular care. Contextualisation is needed to transfer evidence into locally relevant and impactful policies and programmes. The systematic and comprehensive use of contextualisation tools leverages key implementation research principles to achieve 'health for all'.


Potassium permeability of Rickettsia prowazekii.
The potassium permeability of Rickettsia prowazekii was characterized by chemical measurement of the intracellular sodium and potassium pools and isotopic flux measurements with 86Rb+ as a tracer. R. prowazekii, in contrast to Escherichia coli, did not maintain a high potassium-to-sodium ratio in their cytoplasm except when the potassium-to-sodium ratio in the extracellular medium was high or when the extracellular concentrations of both cations were low (ca. 1 mM). Both influx and efflux assays with 86Rb+ demonstrated that the rickettsial membrane had limited permeability to potassium and that incorporation of valinomycin into these cells increased these fluxes at least 10-fold. The transport of potassium showed specificity and dependence on rickettsial metabolism. The increased flux of potassium which results from the incorporation of valinomycin into the rickettsial membrane was detrimental to both lysine transport and lysis of erythrocytes by the rickettsiae.


Concorde sonic booms as an atmospheric probe.
Infrasound generated by the sonic boom from the inbound Concorde supersonic transport is recorded at Palisades, New York (Lamont-Doherty Geological Observatory), as a series of impulses from distances varying from 165 to about 1000 kilometers. Refraction effects determined by temperature and wind conditions return the signal to the surface from both stratospheric (40 to 50 kilometers) and thermospheric (100 to 130 kilometers) levels. The frequency of the recorded signal is a function of the level of reflection; the frequency decreases from impulse stretching as the atmosphere becomes more rarified relative to the sound pressure. The horizontal trace velocity of the signal across the array of instruments is equal to the acoustic velocity at the reflection level. The sonic boom can thus be used to provide temperature-wind parameters at reflection levels estimated from the signal frequency. Daily observed signal variations have indicated significant variations in these parameters.


Revolutionizing cancer immunotherapy in solid tumor: CAR engineering and single-cell sequencing insights.
The global increase in cancer incidence presents significant economic and societal challenges. While chimeric antigen receptor-modified T cell (CAR-T) therapy has demonstrated remarkable success in hematologic malignancies and has earned FDA approval, its translation to solid tumors encounters faces significant obstacles, primarily centered around identifying reliable tumor-associated antigens and navigating the complexities of the tumor microenvironment. Recent developments in single-cell RNA sequencing (scRNA-seq) have greatly enhanced our understanding of tumors by offering high-resolution, unbiased analysis of cellular heterogeneity and molecular patterns. These technologies have revolutionized our comprehension of tumor immunology and have led to notable progress in cancer immunotherapy. This mini-review explores the progress of chimeric antigen receptor (CAR) cell therapy in solid tumor treatment and the application of scRNA-seq at various stages following the administration of CAR cell products into the body. The advantages of scRNA-seq are poised to further advance the investigation of the biological characteristics of CAR cells in vivo, tumor immune evasion, the impact of different cellular components on clinical efficacy, the development of clinically relevant biomarkers, and the creation of new targeted drugs and combination therapy approaches. The integration of scRNA-seq with CAR therapy represents a promising avenue for future innovations in cancer immunotherapy. This synergy holds the potential to enhance the precision and efficacy of CAR cell therapies while expanding their applications to a broader range of malignancies.


Eye movements during search and detection in comparative visual search.
Motivated by the fact that previous visual memory paradigms have imposed encoding and retrieval constraints, the present article presents two experiments that address how observers allocate eye movements in memory and comparison processes in the absence of constraints. A comparative visual search design (Pomplun, Sichelschmidt, et al., 2001) was utilized in which observers searched for a difference between two images presented side by side. Robust time course effects were obtained, whereby search was characterized by brief fixations and a high proportion of comparative saccades. Then, upon target detection, fixations were extended, more comparative saccades were elicited, and the search focus was narrowed. The saliency and presence of differences did not guide attention, and detection was contingent upon direct fixation of the targets. The results indicate that, when full control is given, observers adopt a strategy that cuts down on memory usage in favor of restricted encoding and active scanning.


Evaluation of immunomodulatory drugs in multiple myeloma: single center experience.
Multiple myeloma (MM) comprises 1% of all cancers and 10% of hematologic malignancies and known as an incurable disease. The introduction of immunomodulatory drugs (IMiDs) has brought a major shift in therapeutic paradigm in the treatment of newly diagnosed and relapsed/refractory MM patients. The aim of this study was to evaluate the relationship between response status and hematological parameters in patients with MM treated with thalidomide or lenalidomide. Sixty-eight patients who were treated with IMiDs in Ege University, School of Medicine, Department of Hematology, between 2005 and 2012, were evaluated, retrospectively. We could not find any difference between the hematological parameters before and after the treatment neither with thalidomide nor lenalidomide. However, the heterogenity of our groups, the difference in treatment strategies and potential side effects would have an impact on this result. It is needed to perform prospective clinical trials to prove that whether correction of hematological parameters would reflect the response status in patients with myeloma that treated with IMiDs.


Prevalence of trachoma in a population of the upper Rio Negro basin and risk factors for active disease.
To determine the prevalence of trachoma in Sao Gabriel da Cachoeira (SGC), the only urban community of the upper Rio Negro Basin of the Amazon state in Brazil, near the Colombian border, and to investigate the risk factors associated with the active forms of the disease. A total of 1702 people (440 children up to 9 years and 1069 adults aged 15 years and above) were examined. The sample was selected from a probabilistic household sampling procedure based on census data and a previous study of trachoma prevalence in Sao Gabriel da Cachoeira. A two-stage probabilistic household cluster sample was drawn. Household units were randomly selected within each cluster. A variety of socioeconomic and hygiene variables were studied in order to determine the risk factors for active trachoma in a household. The total prevalence of trachoma was 8.9%. Prevalence of active trachoma (TF and/or TI) in children aged 1-9 years was 11.1% and trachomatous trichiasis in adults aged 15 years and above was 0.19%. Trachomatous scarring reached a peak of 22.4% for subjects between 50 to 60 years of age. Corneal opacity occurred in subjects aged 50 years and older with a prevalence of 2.0%. No sex effect was found on the overall prevalence of trachoma in SGC. Risk factors associated with active trachoma were mainly related to poor socioeconomic indicators. Despite the ubiquitous presence of water, the analysis of the risk factors associated with the active forms of the disease supports the idea that a low personal standard of hygiene and not water availability per se, is the key factor associated with trachoma.


Influence of the green tea leaf extract on neurotoxicity of aluminium chloride in rats.
Aluminium may have an important role in the aetiology/pathogenesis/precipitation of Alzheimer's disease. Because green tea (Camellia sinensis L.) reportedly has health-promoting effects in the central nervous system, we evaluated the effects of green tea leaf extract (GTLE) on aluminium chloride (AlCl3 ) neurotoxicity in rats. All solutions were injected into the cornu ammonis region 1 hippocampal region. We measured the performance of active avoidance (AA) tasks, various enzyme activities and total glutathione content (TGC) in the forebrain cortex (FbC), striatum, basal forebrain (BFb), hippocampus, brain stem and cerebellum. AlCl3 markedly reduced AA performance and activities of cytochrome c oxidase (COX) and acetylcholinesterase (AChE) in all regions. It decreased TGC in the FbC, striatum, BFb, hippocampus, brain stem and cerebellum, and increased superoxide dismutase activity in the FbC, cerebellum and BFb. GTLE pretreatment completely reversed the damaging effects of AlCl3 on AA and superoxide dismutase activity, markedly corrected COX and AChE activities, and moderately improved TGC. GTLE alone increased COX and AChE activities in almost all regions. GTLE reduces AlCl3 neurotoxicity probably via antioxidative effects and improves mitochondrial and cholinergic synaptic functions through the actions of (-)-epigallocatechin gallate and (-)-epicatechin, compounds most abundantly found in GTLE. Our results suggest that green tea might be beneficial in Alzheimer's disease.


Limited effects of bile acids and small heterodimer partner on hepatitis B virus biosynthesis in vivo.
Multiple nuclear receptors, including hepatocyte nuclear factor 4α (HNF4α), retinoid X receptor α (RXRα) plus peroxisome proliferator-activated receptor α (PPARα), RXRα plus farnesoid X receptor α (FXRα), liver receptor homolog 1 (LRH1), and estrogen-related receptors (ERRs), have been shown to support efficient viral biosynthesis in nonhepatoma cells in the absence of additional liver-enriched transcription factors. Although HNF4α has been shown to be critical for the developmental expression of hepatitis B virus (HBV) biosynthesis in the liver, the relative importance of the various nuclear receptors capable of supporting viral transcription and replication in the adult in vivo has not been clearly established. To investigate the role of the nuclear receptor FXR and the corepressor small heterodimer partner (SHP) in viral biosynthesis in vivo, SHP-expressing and SHP-null HBV transgenic mice were fed a bile acid-supplemented diet. The increased FXR activity and SHP expression levels resulting from bile acid treatment did not greatly modulate HBV RNA and DNA synthesis. Therefore, FXR and SHP appear to play a limited role in modulating HBV biosynthesis, suggesting that alternative nuclear receptors are more critical determinants of viral transcription in the HBV transgenic mouse model of chronic viral infection. These observations suggest that hepatic bile acid levels or therapeutic agents targeting FXR may not greatly modulate viremia during natural infection.


Incidence of congenital toxoplasmosis estimated by neonatal screening: relevance of diagnostic confirmation in asymptomatic newborn infants.
Congenital toxoplasmosis is rarely identified by routine clinical examination. The aim of this study was to estimate the incidence of the disease in the region of Ribeirão Preto, south-eastern Brazil. A definitive diagnosis was made on the basis of the persistence of anti-Toxoplasma IgG antibodies beyond 1 year of age. Blood samples obtained from 15,162 neonates and adsorbed onto filter paper were tested for anti-Toxoplasma IgM antibodies. Fifteen samples gave positive results. A definitive diagnosis was confirmed in five of the 13 infants (38.5%) who completed follow-up. These five infants presented with serum IgM and/or IgA antibodies, and clinical abnormalities. Disease incidence was estimated to be 3.3/10,000 (95% CI 1.0-7.7), indicating the need for preventive measures. Neonatal screening is feasible, but screening tests with a better performance are required; positive screening results must be carefully confirmed.


Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021.
Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.


Prevalence and clinical outcomes of pleural effusion in COVID-19 patients: A systematic review and meta-analysis.
Observational studies indicate that pleural effusion has an association with risk and the clinical prognosis of COVID-19 disease; however, the available literature on this area is inconsistent. The objective of this systematic review and meta-analysis is to evaluate the correlation between COVID-19 disease and pleural effusion. A rigorous literature search was conducted using multiple databases. All eligible observational studies were included from around the globe. The pooled prevalence and associated 95% confidence interval (CI) were calculated using the random effect model. Mantel-Haenszel odds ratios were produced to report overall effect size using random effect models for severity and mortality outcomes. Funnel plots, Egger regression tests, and Begg-Mazumdar's rank correlation test were used to appraise publication bias. Data from 23 studies including 6234 COVID-19 patients was obtained. The overall prevalence of pleural effusion in COVID-19 patients was 9.55% (95% CI, I2 = 92%). Our findings also indicated that the presence of pleural effusions associated with increased risk of severity of disease(OR = 5.08, 95% CI 3.14-8.22, I2 = 77.4%) and mortality due to illness(OR = 4.53, 95% CI 2.16-9.49, I2 = 66%) compared with patients without pleural effusion. Sensitivity analyses illustrated a similar effect size while decreasing the heterogeneity. No significant publication bias was evident in the meta-analysis. The presence of pleural effusion can assist as a prognostic factor to evaluate the risk of worse outcomes in COVID-19 patients hence, it is recommended that hospitalized COVID-19 patients with pleural effusion should be managed on an early basis.


Investigation of calcium-stimulated adenylyl cyclases 1 and 8 on toluene and ethanol neurobehavioral actions.
The abused inhalant toluene has potent behavioral effects, but only recently has progress been made in understanding the molecular pathways that mediate the action of toluene in the brain. Toluene and ethanol induce similar behavioral effects and share some targets including NMDA and GABA receptors. In studies examining neuronal actions of ethanol, mice lacking the calcium-stimulated adenylyl cyclases (ACs), AC1 and AC8 (DKO), show increased sedation durations and impaired protein kinase A (PKA) phosphorylation following acute ethanol treatment. Therefore, using DKO mice, we compared the neurobehavioral responses following toluene exposure to that of ethanol exposure to determine if these abused substances share molecular mechanisms of action. In the present study, acute sensitivity to toluene- or ethanol-induced changes in locomotor activity was evaluated in DKO and wild type (WT) mice. Mice were exposed to toluene vapor (0, 500, 1000, 2000, 6000, or 8000ppm) for 30min in static exposure chambers equipped with activity monitors. Both WT and DKO mice demonstrated increased ambulatory distance during exposure to a 2000-ppm concentration of toluene compared to respective air-exposed (0ppm) controls. Significant increases in locomotor activity were also observed during an air-only recovery period following toluene exposure in WT and DKO mice that had been exposed to 2000ppm of toluene compared to respective air controls. Sedative effects of toluene were equivalent in WT and DKO mice, both during exposure and afterwards during recovery. Although no significant differences in locomotor activity were detected in DKO compared to WT mice at individual doses tested, a significant main effect of toluene was achieved, with DKO mice demonstrating a generalized reduction in locomotor activity during the post-toluene recovery period compared to WT mice (when analyzing all doses collectively). For comparison to toluene, additional WT and DKO mice were treated with 1.0 or 2.0g/kg ethanol (i.p.) and monitored for locomotor activation. In WT mice, both doses of ethanol increased distance traveled compared to saline controls. Conversely, DKO mice demonstrated no increase in locomotor activation at 1.0g/kg, with significantly reduced distances traveled at both doses compared to ethanol-treated WT mice. These behavioral activity results suggest that acute effects of ethanol and toluene are distinct in the mechanisms by which they induce acute sedating effects with respect to AC1 and AC8 activity, but may be similar in the mechanisms subserving locomotor stimulation.


On-chip perivascular niche supporting stemness of patient-derived glioma cells in a serum-free, flowable culture.
Glioblastoma multiforme (GBM) is the most common and the most aggressive type of primary brain malignancy. Glioblastoma stem-like cells (GSCs) can migrate in vascular niches within or away from the tumour mass, increasing tumour resistance to treatments and contributing to relapses. To study individual GSC migration and their interactions with the perivasculature of the tumour microenvironment, there is a need to develop a human organotypic in vitro model. Herein, we demonstrated a perivascular niche-on-a-chip, in a serum-free condition with gravity-driven flow, that supported the stemness of patient-derived GSCs and foetal neural stem cells grown in a three-dimensional environment (3D). Endothelial cells from three organ origins, (i) human brain microvascular endothelial cells (hCMEC/D3), (ii) human umbilical vein endothelial cells (HUVECs) and, (iii) human lung microvascular endothelial cells (HMVEC-L) formed rounded microvessels within the extracellular-matrix integrated microfluidic chip. By optimising cell extraction protocols, systematic studies were performed to evaluate the effects of serum-free media, 3D cell cultures, and the application of gravity-driven flow on the characteristics of endothelial cells and their co-culture with GSCs. Our results showed the maintenance of adherent and tight junction markers of hCMEC/D3 in the serum-free culture and that gravity-driven flow was essential to support adequate viability of both the microvessel and the GSCs in co-culture (>80% viability at day 3). Endpoint biological assays showed upregulation of neovascularization-related genes (e.g., angiopoietins, vascular endothelial growth factor receptors) in endothelial cells co-cultured with GSCs in contrast to the neural stem cell reference that showed insignificant changes. The on-chip platform further permitted live-cell imaging of GSC - microvessel interaction, enabling quantitative analysis of GSC polarization and migration. Overall, our comparative genotypic (i.e. qPCR) and phenotypic (i.e. vessel permeability and GSC migration) studies showed that organotypic (brain cancer cells-brain endothelial microvessel) interactions differed from those within non-tissue specific vascular niches of human origin. The development and optimization of this on-chip perivascular niche, in a serum-free flowable culture, could provide the next level of complexity of an in vitro system to study the influence of glioma stem cells on brain endothelium.


Sister centromere fusion during meiosis I depends on maintaining cohesins and destabilizing microtubule attachments.
Sister centromere fusion is a process unique to meiosis that promotes co-orientation of the sister kinetochores, ensuring they attach to microtubules from the same pole during metaphase I. We have found that the kinetochore protein SPC105R/KNL1 and Protein Phosphatase 1 (PP1-87B) regulate sister centromere fusion in Drosophila oocytes. The analysis of these two proteins, however, has shown that two independent mechanisms maintain sister centromere fusion. Maintenance of sister centromere fusion by SPC105R depends on Separase, suggesting cohesin proteins must be maintained at the core centromeres. In contrast, maintenance of sister centromere fusion by PP1-87B does not depend on either Separase or WAPL. Instead, PP1-87B maintains sister centromeres fusion by regulating microtubule dynamics. We demonstrate that this regulation is through antagonizing Polo kinase and BubR1, two proteins known to promote stability of kinetochore-microtubule (KT-MT) attachments, suggesting that PP1-87B maintains sister centromere fusion by inhibiting stable KT-MT attachments. Surprisingly, C(3)G, the transverse element of the synaptonemal complex (SC), is also required for centromere separation in Pp1-87B RNAi oocytes. This is evidence for a functional role of centromeric SC in the meiotic divisions, that might involve regulating microtubule dynamics. Together, we propose two mechanisms maintain co-orientation in Drosophila oocytes: one involves SPC105R to protect cohesins at sister centromeres and another involves PP1-87B to regulate spindle forces at end-on attachments.


Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.
To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response. Observational analysis within the ARROW randomized trial. sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1). Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144. Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.


Evaluation of aortic arch morphologies by computed tomographic angiography in Turkish population.
The aim of this study was to evaluate the aortic arch morphologies in the Turkish population using the computed tomography angiography technique. Between August 2009 and August 2019, a total of 2,037 (1,003 males, 1,034 females; mean age: 52.8±20.3 years; range, 3 months to 100 years) thoracic computed tomography angiography scans were retrospectively analyzed. The findings were classified as described previously in the literature. The prevalence of aortic arch morphologies and possible relationship with sex were analyzed. The prevalence of variations reported in previous studies was compared with the current study. The normal aortic arch pattern (type A), observed in 1,562 cases (76.7%), was determined statistically significantly more in males than females (p<0.05). The most common variation, bovine aortic arch (type B1) which observed in a total of 315 cases (15.5%), was determined statistically significantly more in females than males (p<0.05). The second most frequent variation, in which the left vertebral artery originates directly from the aortic arch (type C1) was detected in 97 cases (4.7%). There was also observed to be aberrant right subclavian artery in 21 cases (1%), right-sided aortic arch variation in seven cases (0.4%), and double aortic arch anomaly in four cases (0.1%). In terms of the reported frequency of type B variation, a significant difference was determined between the current and previous studies in Türkiye (p<0.05). With the largest sample size to date, this study provides comparative information about the prevalence of aortic arch patterns in the Turkish population.


Soybean vegetable protein (Tofu) preserved with high pressure.
Tofu is a soybean vegetable protein that Asians have long consumed; its intake is increasing in other countries. Tofu was purchased at a local shop. The tofu samples were already preserved in plastic bags subjected to vacuum and storage (5 C). Tofu samples were subjected to high pressure (HP) of 400 MPa at 5 C for 5, 30, and 45 mm. Microbial analysis, sensorial evaluation, and structure were determined. HP treatment in tofu reduces the microbial population. Most of the microorganisms found in the initial population belonged to the Enterobacteriaceae family, bacteria Gram-negative (no Enterobacteriaceae), and bacteria Gram-positive. Alter HP treatment, Hafnia alvei and Bacillus cereus were found. After HP treatment, tofu is a pasteurized product, which is safer in terms of secondary pathogenic microbial contamination. Sensorial test results revealed that treated tofu was acceptable to consumers. The micrographs on the cryofracture observed with a cryoscanning electron microscope revealed a more compact structure after pressure compared with that of untreated samples, but the aggregates in the treated samples were more disperse.


Lead sequestration and species redistribution during soil organic matter decomposition.
The turnover of soil organic matter (SOM) maintains a dynamic chemical environment in the forest floor that can impact metal speciation on relatively short timescales. Here we measure the speciation of Pb in controlled and natural organic (O) soil horizons to quantify changes in metal partitioning during SOM decomposition in different forest litters. We provide a link between the sequestration of pollutant Pb in O-horizons, estimated by forest floor Pb inventories, and speciation using synchrotron-based X-rayfluorescence and X-ray absorption spectroscopy. When Pb was introduced to fresh forest O(i) samples, it adsorbed primarily to SOM surfaces, but as decomposition progressed over two years in controlled experiments, up to 60% of the Pb was redistributed to pedogenic birnessite and ferrihydrite surfaces. In addition, a significant fraction of pollutant Pb in natural soil profiles was associated with similar mineral phases (approximately 20-35%) and SOM (-65-80%). Conifer forests have at least 2-fold higher Pb burdens in the forest floor relative to deciduous forests due to more efficient atmospheric scavenging and slower organic matter turnover. We demonstrate that pedogenic minerals play an important role in surface soil Pb sequestration, particularly in deciduous forests, and should be considered in any assessment of pollutant Pb mobility.


The association between changes in urinary albumin-to-creatinine ratio and risk of abnormal ankle-brachial index in a community-based Chinese population.
To investigate the prospective association between changes in the urinary albumin-creatinine ratio (ACR) and abnormal ankle-brachial index (ABI) in a community-based Chinese population. This prospective cohort study included 799 residents aged 58.3±9.2 years and without a history of cardiovascular disease from an urban district of Beijing, China. Urinary ACR was measured at baseline, and at 4 and 6 years of follow-up. The 75th percentile of the baseline urinary ACR (5.82 mg/g) was used to define "high" ACR. The changes in urinary ACR were categorized as consistently low urinary ACR, intermittent high urinary ACR, and consistently high urinary ACR. ABI was measured at 6 years of follow-up. Multinomial logistic regression was used to evaluate the associations of changes in urinary ACR categories with the ABI categories. During 6 years of follow-up, 16.1% of participants (n= 128) had low ABI and 13.9% of participants (n= 111) had high ABI. After adjusting for potential confounders including baseline albuminuria, individuals who had consistently high urinary ACR or intermittent high urinary ACR had a significantly higher risk for low ABI than individuals who had consistently low urinary ACR, with odds ratios (OR) of 2.75 (95%CI, 1.37-5.52) and 2.06 (95%CI, 1.18-3.57), respectively. No independent association was observed between changes in urinary ACR and high ABI among participants. Changes in urinary ACR below the definition for albuminuria predict low ABI among this community-based population without a history of cardiovascular disease.


Cell Therapy of Severe Ischemia in People with Diabetic Foot Ulcers-Do We Have Enough Evidence?
This current opinion article critically evaluates the efficacy of autologous cell therapy (ACT) for chronic limb-threatening ischemia (CLTI), especially in people with diabetes who are not candidates for standard revascularization. This treatment approach has been used in 'no-option' CLTI in the last two decades and more than 1700 patients have received ACT worldwide. Here we analyze the level of published evidence of ACT as well as our experience with this treatment method. Many studies have shown that ACT is safe and an effective method for patients with the most severe lower limb ischemia. However, some trials did not show any benefit of ACT, and there is some heterogeneity in the types of injected cells, route of administration and assessed endpoints. Nevertheless, we believe that ACT plays an important role in a comprehensive treatment of patients with diabetic foot and severe ischemia.


Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates.
Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.


Lipoprotein aggregation protects human monocyte-derived macrophages from OxLDL-induced cytotoxicity.
Oxidative modifications render low density lipoprotein cytotoxic and enhance its propensity to aggregate and fuse into particles similar to those found in atherosclerotic lesions. We showed previously that aggregation of oxidized LDL (OxLDL) promotes the transformation of human macrophages into lipid-laden foam cells (Asmis, R., and J. Jelk. 2000. Large variations in human foam cell formation in individuals. A fully autologous in vitro assay based on the quantitative analysis of cellular neutral lipids. Atherosclerosis. 148: 243-253). Here, we tested the hypothesis that aggregation of OxLDL enhances its clearance by human macrophages and thus may protect macrophages from OxLDL-induced cytotoxicity. We found that increased aggregation of OxLDL correlated with decreased macrophage injury. Using 3H-labeled and Alexa546-labeled OxLDL, we found that aggregation enhanced OxLDL uptake and increased cholesteryl ester accumulation but did not alter free cholesterol levels in macrophages. Acetylated LDL was a potent competitor of aggregated oxidized LDL (AggOxLDL) uptake, suggesting that scavenger receptor A plays an important role in the clearance of AggOxLDL. Inhibitors of actin polymerization, cytochalasin B, cytochalasin D, and latrunculin A, also prevented AggOxLDL uptake and restored OxLDL-induced cytotoxicity. This suggests that OxLDL-induced macrophage injury does not require OxLDL uptake and may occur on the cell surface. Our data demonstrate that aggregation of cytotoxic OxLDL enhances its clearance by macrophages without damage to the cells, thus allowing macrophages to avoid OxLDL-induced cell injury.


Amperometric response from the glycolytic versus the pentose phosphate pathway in Saccharomyces cerevisiae cells.
The two main metabolic pathways involved in sugar metabolism, i.e., the pentose phosphate pathway (PPP) and the glycolytic pathway (GP), were amperometrically monitored using a double-mediator system composed of menadione and ferricyanide. With the use of the Saccharomyces cerevisiae deletion mutant, EBY44, lacking the gene encoding for the branch point enzyme phosphoglucose isomerize, selective amperometric monitoring of the PPP, mainly producing NADPH, and the GP, mainly producing NADH, could be achieved. It was found that the bioelectrocatalytic current was primarily originating from NADPH. This conclusion was supported by metabolite flux analysis, confirming that, in the presence of menadione, the cells increase the rate of NADPH-producing reactions although these processes might be detrimental to cell survival. The higher rate of in vivo NADPH-dependent menadione reduction can be ascribed to the fact that the intracellular NADPH/NADP(+) ratio is much higher than NADH/NAD(+) as well as that the former ratio is more tightly controlled. This tight control over the cofactor ratios is lost upon cell disintegration as observed from spectrophotometric assays using crude cell extract, and amperometric investigations of permeabilized cells indicate a higher rate of NADH- than NADPH-dependent menadione reduction. These in vitro experiments show a higher activity of NADH-dependent than NADPH-dependent menadione-reducing dehydrogenases in S. cerevisiae cells.


Ability of polymerase eta and T7 DNA polymerase to bypass bulge structures.
DNA misalignment occurs in homopolymer tracts during replication and can lead to frameshift mutations. Polymerase (pol) recognition of primer-templates containing bulge structures and the transmission of a bulge through a polymerase binding site or replication complex are important components of frameshift mutagenesis. In this report, we describe the interaction of the catalytic core of pol eta with primer-templates containing bulge structures by single round primer extension. We found that pol eta could stabilize a frayed primer terminus, which enhances its ability to extend primer-templates containing bulges. Based on methylphosphonate-DNA mapping, pol eta interacts with the single strand template but not appreciably with the template strand of the DNA stem greater than two nucleotides from the primer terminus. These latter characteristics, combined with the ability to stabilize a frayed primer terminus, may explain why primer-templates containing template bulges are extended so efficiently by pol eta. Although pol eta could accommodate large bulges and continue synthesis without obstruction, bulge structures in the template, but not in the primer, caused termination of the T7 DNA replication complex. Terminations occurred when the template bulge neared the helix-loop-helix domain of the polymerase thumb. Terminations were not observed, however, when bulge structures approached the site of interaction of the DNA with the extended thumb and thioredoxin. At low temperature, however, terminations did occur at this site.


Prevention of Overweight in Infancy (POI.nz) study: a randomised controlled trial of sleep, food and activity interventions for preventing overweight from birth.
Rapid weight gain during the first three years of life predicts child and adult obesity, and also later cardiovascular and other morbidities. Cross-sectional studies suggest that infant diet, activity and sleep are linked to excessive weight gain. As intervention for overweight children is difficult, the aim of the Prevention of Overweight in Infancy (POI.nz) study is to evaluate two primary prevention strategies during late pregnancy and early childhood that could be delivered separately or together as part of normal health care. This four-arm randomised controlled trial is being conducted with 800 families recruited at booking in the only maternity unit in the city of Dunedin, New Zealand. Mothers are randomised during pregnancy to either a usual care group (7 core contacts with a provider of government funded "Well Child" care over 2 years) or to one of three intervention groups given education and support in addition to "Well Child" care: the Food, Activity and Breastfeeding group which receives 8 extra parent contacts over the first 2 years of life; the Sleep group which receives at least 3 extra parent contacts over the first 6 months of life with a focus on prevention of sleep problems and then active intervention if there is a sleep problem from 6 months to 2 years; or the Combination group which receives all extra contacts. The main outcome measures are conditional weight velocity (0-6, 6-12, 12-24 months) and body mass index z-score at 24 months, with secondary outcomes including sleep and physical activity (parent report, accelerometry), duration of breastfeeding, timing of introduction of solids, diet quality, and measures of family function and wellbeing (parental depression, child mindedness, discipline practices, family quality of life and health care use). This study will contribute to a prospective meta-analysis of early life obesity prevention studies in Australasia. Infancy is likely to be the most effective time to establish patterns of behaviour around food, activity and sleep that promote healthy child and adult weight. The POI.nz study will determine the extent to which sleep, food and activity interventions in infancy prevent the development of overweight. Clinical Trials NCT00892983. Prospective meta-analysis registered on PROSPERO CRD420111188. Available from http://www.crd.york.ac.uk/PROSPERO.


Molecular mechanisms of the positive reinforcing effect of nicotine.
Animal models of nicotine dependence are fundamental experimental tools for the understanding of the neurobiological and molecular processes underlying smoking behaviour. Substance use is controlled by four main processes: positive reinforcing effects, aversive effects, discriminative effects and stimulus-conditioned effects of the drug. In this article, the molecular and neural bases of the positive reinforcing effects of nicotine are summarized, focusing on data obtained in experiments including unambiguous and objective measurements of the reinforcing properties of nicotine. Operant behaviour paradigms, in particular intravenous nicotine self-administration, offer such a possibility within a solid theoretical framework. Nicotine self-administration produces changes in the mesocorticolimbic DA system, a key component of the reward system, as do other addictive drugs. The role of the mesocorticolimbic DA system as the main substrate of the reinforcing properties of nicotine is supported by converging experiments, including the evidence that nicotine self-administration is attenuated in mutant mice lacking the beta2 subunit of neural acetylcholine nicotinic receptor. The long-term adaptive molecular changes in the target neurons of the terminal fields of the mesocorticolimbic DA system, including transcriptional regulation mediated by c-fos family gene products on other genes, suggest that the mesolimbic DA projection to the nucleus accumbens is mainly involved in the stimulus-reward learning process. These data represent an initial set of information only, which may help to develop a more complete and reliable model of the molecular dynamics underlying the reinforcing effects of nicotine.


Similar bacterial communities on healthy and injured skin of black tip reef sharks.
Sharks are in severe global decline due to human exploitation. The additional concern of emerging diseases for this ancient group of fish, however, remains poorly understood. While wild-caught and captive sharks may be susceptible to bacterial and transmissible diseases, recent reports suggest that shark skin may harbor properties that prevent infection, such as a specialized ultrastructure or innate immune properties, possibly related to associated microbial assemblages. To assess whether bacterial community composition differs between visibly healthy and insulted (injured) shark skin, we compared bacterial assemblages of skin covering the gills and the back from 44 wild-caught black-tip reef sharks (Carcharhinus melanopterus) from the Amirante Islands (Seychelles) via 16S rRNA gene amplicon sequencing. Shark skin-associated bacterial communities were diverse (5971 bacterial taxa from 375 families) and dominated by three families of the phylum Proteobacteria typical of marine organisms and environments (Rhodobacteraceae, Alteromonadaceae, Halomonadaceae). Significant differences in bacterial community composition of skin were observed for sharks collected from different sites, but not between healthy or injured skin samples or skin type (gills vs. back). The core microbiome (defined as bacterial taxa present in ≥50% of all samples) consisted of 12 bacterial taxa, which are commonly observed in marine organisms, some of which may be associated with animal host health. The conserved bacterial community composition of healthy and injured shark skin samples suggests absence of severe bacterial infections or substantial pathogen propagation upon skin insult. While a mild bacterial infection may have gone undetected, the overall conserved bacterial community implies that bacterial function(s) may be maintained in injured skin. At present, the contribution of bacteria, besides intrinsic animal host factors, to counter skin infection and support rapid wound healing in sharks are unknown. This represents clear knowledge gaps that should be addressed in future work, e.g. by screening for antimicrobial properties of skin-associated bacterial isolates.


Brief Report: Alternative Splicing of Extra Domain A (EIIIA) of Fibronectin Plays a Tissue-Specific Role in Hematopoietic Homeostasis.
Fibronectin (FN) is a major extracellular matrix protein implicated in cell adhesion and differentiation in the bone marrow (BM) environment. Alternative splicing of FN gene results in the generation of protein variants containing an additional EIIIA domain that sustains cell proliferation or differentiation during physiological or pathological tissue remodeling. To date its expression and role in adult hematopoiesis has not been explored. In our research, we demonstrate that during physiological hematopoiesis a small fraction of BM derived FN contains the EIIIA domain and that mice constitutively including (EIIIA(+/+) ) or excluding (EIIIA(-/-) ) the EIIIA exon present comparable levels of hematopoietic stem cells, myeloid and lymphoid progenitors within BM. Moreover, only minor alterations were detected in blood parameters and in hematopoietic frequencies of BM granulocytes/monocytes and B cells. As opposed to other tissues, unique compensatory mechanisms, such as increased FN accumulation and variable expression of the EIIIA receptors, Toll like receptor-4 and alpha9 integrin subunit, characterized the BM of these mice. Our data demonstrate that FN is a fundamental component of the hematopoietic tissue and that the EIIIA exon may play a key role in modulating hematopiesis in conditions of BM stress or diseases. Stem Cells 2016;34:2263-2268.


The Influence of a Warm-Up on Vigilance in University Students.
The present study aimed to analyze the effects of conducting a warm-up (WC) or not (WWC) on students of the Science Degree in Physical Activity and Sport before starting a practical class. Thirty-two students of the Science Degree in Physical Activity and Sport (age: 22.38 ± 1.81 years; height: 176.09 ± 8.52 cm; weight: 22.38 ± 1.81 kg; body fat: 25.17 ± 3.20%) participated in a counterbalanced cross-sectional study in which three conditions were tested: (a) basal lineal, (b) WC, and (c) WWC. Participants recorded longer times (worse performance) in the Illinois dribbling test (basal lineal condition [20.17 ± 1.35], WWC [20.13 ± 1.37], and WC [19.32 ± 1.35]) and the Psychomotor Vigilance Task test (basal lineal condition [397.88 ± 75.98 ms]; WWC [412.19 ± 91.39 ms], and WC [368.53 ± 68.65 ms]). The warm-up prior to physical activity classes had positive effects on vigilance linked to executive functioning, and physical performance. In this sense, more research on different types of warm-up may be in order to contrast them with each other, as well as to carry out attention measurements according to the content to be imparted after the warm-ups. The present study represents a big opportunity for all physical education teachers due to warm-up is a crucial aspect that occurs in all practical sessions, also linked to the attention processes and motivational factors of the students.


Immunologic cross-reactivity in the pathogenesis of ocular onchocerciasis.
Onchocerca volvulus, a filarial worm, is a major cause of infectious blindness and inflammatory eye disease. An autoimmune cause for ocular onchocerciasis has been suggested since the identification of a recombinant antigen of O. volvulus that shows immunologic cross-reactivity with a host ocular component of 44,000 M(r). The aim of this study was to establish the distribution of the cross-reactive antigens in both host tissues and the parasite, and to determine if significant autoantibody responses to the host antigen could be detected in infected persons. The tissue and organ distribution of the 44,000 M(r) antigen was determined by immunocytochemistry and Western blot analysis. Human autoantibody responses to the ocular antigen were demonstrated by Western blot analysis using sera collected from persons with onchocerciasis, with and without posterior segment pathology, Bancroftian filariasis, and Europeans with no filarial infection. The tissue distribution of the 44,000 M(r) antigen correlates with the sites of pathology in onchocerciasis and antibody reactivity against this antigen could be detected in all persons with onchocerciasis and posterior segment pathology. The antigen is also recognized by sera from persons with Bancroftian filariasis, but not from normal persons. A role is proposed for immunologic cross-reactivity in the pathogenesis of onchocerciasis and it is suggested that intraocular presentation of the cross-reactive parasite antigen by microfilariae is essential for the development of disease.


3.0T ¹H magnetic resonance spectroscopy for assessment of steatosis in patients with chronic hepatitis C.
To investigate the utility of (1)H magnetic resonance spectroscopy ((1)H MRS) as a noninvasive test for steatosis in patients infected with hepatitis C virus. Ninety patients with chronic hepatitis C and pathology data underwent 3.0T (1)H MRS, and the results of MRS and pathological analysis were compared. This group of patients included 26 people with mild fatty liver (28.89%), 16 people with moderate fatty liver (17.78%), 18 people with severe fatty liver (20.0%), and 30 people without fatty liver (33.33%). The water peak was near 4.7 parts per million (ppm), and the lipid peak was near 1.3 ppm. Analysis of variance revealed that differences in the lipid peak, the area under the lipid peak, ratio of the lipid peak to the water peak, and ratio of the area under the lipid peak to the area under the water peak were statistically significant among the groups. Specifically, as the severity of fatty liver increased, the value of each index increased correspondingly. In the pairwise comparisons, the mean lipid peak, area under the lipid peak, ratio of the lipid peak to the water peak, and ratio of the area under the lipid peak to the area under the water peak were significantly different between the no fatty liver and moderate fatty liver groups, whereas no differences were noted between the severe fatty liver group and the mild or moderate fatty liver group. Area under the ROC curve (AUC) of area ratio in lipid and water and ratio in lipid and water in the no fatty liver group to mild fatty liver group, mild fatty liver group to moderate fatty liver group, and moderate fatty liver disease group to severe fatty liver group, were 0.705, 0.900, and 0.975, respectively. (1)H MRS is a noninvasive technique that can be used to provide information on the effect of liver steatosis on hepatic metabolic processes. This study indicates that the (1)H MRS can be used as an indicator of steatosis in patients with chronic hepatitis C.