Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis.
Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.


Actualities in neonatal endocrine and metabolic screening.
Neonatal metabolic screening has proven to be an important tool for the early detection of innate metabolic errors. Despite the fact that simple and effective methods of testing for metabolic diseases have been identified since the middle of the twentieth century, no consensus has been reached so far on the content of neonatal metabolic screening panels. There are large differences between countries in the number of metabolic diseases identified through national metabolic screening programs, ranging from zero to several tens, the most common testing being for phenylketonuria and congenital hypothyroidism (including in Romania). Given the fact that rare but treatable diseases have been identified in recent decades, reducing the financial burden on the health system, it would be useful to include them in the national neonatal metabolic screening program.


Pupillometry reveals cognitive demands of lexical competition during spoken word recognition in young and older adults.
In most contemporary activation-competition frameworks for spoken word recognition, candidate words compete against phonological "neighbors" with similar acoustic properties (e.g., "cap" vs. "cat"). Thus, recognizing words with more competitors should come at a greater cognitive cost relative to recognizing words with fewer competitors, due to increased demands for selecting the correct item and inhibiting incorrect candidates. Importantly, these processes should operate even in the absence of differences in accuracy. In the present study, we tested this proposal by examining differences in processing costs associated with neighborhood density for highly intelligible items presented in quiet. A second goal was to examine whether the cognitive demands associated with increased neighborhood density were greater for older adults compared with young adults. Using pupillometry as an index of cognitive processing load, we compared the cognitive demands associated with spoken word recognition for words with many or fewer neighbors, presented in quiet, for young (n = 67) and older (n = 69) adult listeners. Growth curve analysis of the pupil data indicated that older adults showed a greater evoked pupil response for spoken words than did young adults, consistent with increased cognitive load during spoken word recognition. Words from dense neighborhoods were marginally more demanding to process than words from sparse neighborhoods. There was also an interaction between age and neighborhood density, indicating larger effects of density in young adult listeners. These results highlight the importance of assessing both cognitive demands and accuracy when investigating the mechanisms underlying spoken word recognition.


Expression of raf family proto-oncogenes in normal mouse tissues.
We have determined RNA expression patterns of raf family proto-oncogenes in a variety of normal NFS/n mouse tissues, and several murine cell lines. Tissues were collected from male and female adults, and 16 day old fetuses. Raf-1 transcripts of 3.1 kb were found to be expressed in all tissues examined with highest levels in striated muscle, cerebellum and fetal brain. In contrast, A-raf showed wider variation in its range of expression, with the 2.6 kb transcripts being most abundant in epididymis and ovary. B-raf was found to have a very restricted expression pattern, with high levels in fetal brain and adult cerebrum. In addition to the 10 and 13 kb transcripts common to all B-raf expressing tissues, alternate sized B-raf RNAs were detected in testes, placenta and fetal membranes. We found no effect of gender on raf expression in non-sex related tissues, nor does tissue germline of origin correlate with levels of expression for any of the three genes.


Neonatal reflexes and behavior in hypertensive rats of ISIAH strain.
Hypertension is one of the most common diseases in humans, and there is a special concern on the consequences of maternal hypertensive conditions for the health of newborns. An inherited stress-induced arterial hypertension (ISIAH) rat strain has been selected but only a few studies have addressed behavior in these rats. Body weight, neurodevelopmental reflexes, and neuronal density in the hippocampus were compared in ISIAH and normotensive WAG rats during their suckling period. Systolic and diastolic blood pressure (SBP, DBP), adult rat performance in the open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were evaluated at the age of 12-14weeks old. Body weight in pups did not differ significantly during the suckling period, while adult ISIAH rats were heavier than age-matched WAG rats and possessed the increased SBP and DBP. ISIAH pups were developmentally more advanced than WAG as indicated by grasp reflex and negative geotaxis reaction scores. This was associated with higher neuronal density in CA1 and CA3 hippocampal areas in ISIAH pups on postnatal day 6 as compared to WAG rats. Adult ISIAH rats demonstrated an increased locomotor and exploratory activity in the OF and EPM tests as well as low levels of anxiety. The NOR test revealed no significant difference in recognition but confirmed higher exploratory activity in ISIAH rats compared to WAG rats. The results indicate that hypertensive ISIAH rats feature accelerated development during their suckling period, and as adults, they are more active and less anxious than normotensive WAG rats.


Surgical removal of failed ruptured Sinus of Valsalva Aneurysm device.
A Sinus of Valsalva Aneurysm can cause aortic insufficiency, coronary artery flow compromise, cardiac arrhythmia, or aneurysm rupture. There are different management plans available, ranging from open surgery to percutaneous device closure, but sometimes, device closure may be life-threatening. We report a case of ruptured Sinus of Valsalva Aneurysm in a 42-year-old woman, which was managed by percutaneous device closure that failed and required surgical removal of the device.


Medico-legal issues surrounding medical countermeasures used in the Gulf War--part 1.
When the multinational force deployed to the Gulf after Iraq's invasion of Kuwait in 1990, military intelligence assessed the Iraqi's as possessing and being capable of using weapons of mass destruction. There was judged to be a real threat that chemical weapons, especially nerve agents, and certain biological weapons would be used. Coalition countries attempted to reduce the effects by the use of medical countermeasures. Since the Gulf conflict a series of medico legal problems from this policy have arisen; some of which have formed the basis of claims against MOD. In this paper I shall review how consent to treatment may have been modified in the military operational context and by the interface with military law. I shall look at the issues of clinical negligence and how duty of care may be affected. In the next article I shall look at relevant employment law; briefly review how medicines regulatory provision applies to medical countermeasures, whether they were properly licensed and whether in any case this applied to the Ministry of Defence in the context of deployment to the Gulf War.


Increased risk of influenza among vaccinated adults who are obese.
Influenza infects 5-15% of the global population each year, and obesity has been shown to be an independent risk factor for increased influenza-related complications including hospitalization and death. However, the risk of developing influenza or influenza-like illness (ILI) in a vaccinated obese adult population has not been addressed. This study evaluated whether obesity was associated with increased risk of influenza and ILI among vaccinated adults. During the 2013-2014 and 2014-2015 influenza seasons, we recruited 1042 subjects to a prospective observational study of trivalent inactivated influenza vaccine (IIV3) in adults. A total of 1022 subjects completed the study. Assessments of relative risk for laboratory confirmed influenza and ILI were determined based on body mass index. Seroconversion and seroprotection rates were determined using prevaccination and 26-35 days post vaccination serum samples. Recruitment criteria for this study were adults 18 years of age and older receiving the seasonal trivalent inactivated influenza vaccine (IIV3) for the years 2013-2014 and 2014-2015. Exclusion criteria were immunosuppressive diseases, use of immunomodulatory or immunosuppressive drugs, acute febrile illness, history of Guillain-Barre syndrome, use of theophylline preparations or use of warfarin. Among obese, 9.8% had either confirmed influenza or influenza-like-illness compared with 5.1% of healthy weight participants. Compared with vaccinated healthy weight, obese participants had double the risk of developing influenza or ILI (relative risk=2.01, 95% CI 1.12, 3.60, P=0.020). Seroconversion or seroprotection rates were not different between healthy weight and obese adults with influenza or ILI. Despite robust serological responses, vaccinated obese adults are twice as likely to develop influenza and ILI compared with healthy weight adults. This finding challenges the current standard for correlates of protection, suggesting use of antibody titers to determine vaccine effectiveness in an obese population may provide misleading information.


Sales performance and athletic outcome in young Thoroughbreds with pericarditis.
Pericarditis is a sporadic, but important cause of critical illness in horses of all ages. There is limited information on whether Thoroughbred horses that survive pericarditis are able to reach athletic potential. To determine how pericarditis affected horses that had the disease as young animals with regard to selling price in public sales and the ability to race successfully. Retrospective case series. Medical records were searched to identify pericarditis cases. Signalment and month of diagnosis were noted and Thoroughbreds with ultrasonographically confirmed pericarditis that presented from 2 months to 3 years old were identified. For this subgroup data on sales and racing performed were obtained from publicly available databases to determine long-term survival and post-treatment outcomes from these horses and their unaffected half-siblings. Horses that survived pericarditis as young animals may recover growth and maturation rates quickly enough to reach expected sales prices at public sales for horses of racing age and recovered horses can have successful racing careers. The number of horses in this case series was not sufficient to enable statistical comparisons between affected horses and unaffected half-siblings, but description of sales prices and race earnings nevertheless yields information about the chances for affected young horses to achieve their intended purposes. Young Thoroughbreds with pericarditis warrant treatment and can sell and have successful racing careers.


Spirometry and provocation tests for vocal fold dysfunction diagnosis: a retrospective case series.
Vocal cord dysfunction (VCD) is characterised by paradoxical inspiratory laryngeal motion and is often misdiagnosed as asthma. Definitive diagnosis of VCD is difficult, because laryngoscopy is positive only during symptomatic episodes or upon provocation with exercise or inhaled irritants. The aims of the study were to better characterise the symptomatology of patients with VCD and to evaluate the potential usefulness of less-invasive diagnostic tools, namely provocation tests and spirometry. Retrospective case series of 84 patients with a typical clinical history of VCD, in whom at least one of the three following diagnostic tests were performed: laryngoscopy, provocation testing, or spirometry. The mean age of the patients was 51 years and 74% were women. The principal comorbidities were rhinosinusitis (60%), gastro-oesophageal reflux disease (56%) and atopy (54%). Diagnosis of VCD was confirmed in 73/84 cases (87%), by laryngoscopy (8%), spirometry (84%) and/or provocation tests (68%). VCD remains an underdiagnosed condition. A negative finding on laryngoscopy can lead to false negative diagnosis if it is done when the patient is asymptomatic. Here we show that a clinical suspicion of VCD, evoked by medical history, can be confirmed in many cases by less invasive diagnostic tools such as spirometry and provocation tests. Future well-conducted prospective case-control studies are needed to draw firmer conclusions and to improve the diagnostic accuracy of this condition. &nbsp.


Fish Parasite Dinoflagellates Haidadinium ichthyophilum and Piscinoodinium Share a Recent Common Ancestor.
The dinoflagellate Haidadinium ichthyophilum Buckland-Nicks, Reimchen and Garbary 1997 is an ectoparasite of the spine-deficient, three-spine stickleback Gasterosteus aculeatus L. Reimchen 1984, a fish endemic to Rouge Lake, Haida Gwaii. Haidadinium ichthyophilum proved difficult to assign taxonomically because its morphology and complex life cycle exhibited defining characteristics of both autotrophic and heterotrophic dinoflagellates, and was tentatively assigned to the Phytodiniales. Here, we characterized a 492 bp fragment of the small subunit ribosomal RNA (SSU rRNA) from preserved H. ichthyophilum cysts. In SSU phylogeny, H. ichthyophilum branches with the fish parasites, Piscinoodinium sp., strongly supporting the inclusion of H. ichthyophilum within the Suessiales.


[Study on the safety and immunogenicity of group A + C meningococcal polysaccharide vaccine].
In order to evaluate the safety and immunogenicity of group A + C meningococcal polysaccharide vaccine, a controlled field trial was performed among children at 6-24 months and 5-13 years old in Longsheng county, Guangxi Zhuang Autonomous Region. More than 600 children were selected in this trial. 428 children, aged 6-24 month-old and 5-13 year-old were involved in two experimental groups and were inoculated 100 microg of group A + C meningococcal polysaccharide vaccine. 103 children in positive control group were inoculated 50 microg of group A meningococcal polysaccharide vaccine while 94 children in negative control group were inoculated 30 microg of Typhoid Vi polysaccharide vaccine. Both systemic and local reactions were observed in each group at 6 h,24 h,48 h and 72 h after inoculation. Blood samples were collected in all children before and at 1 month after inoculation. Additionally, at least 50 blood samples were taken in each experimental group at 6 and 12 months after inoculation. Serum bactericidal antibody was tested by micro bactericidal test. Both systemic and local reactions were mild in two experimental groups with only 3 children (0.7%) had > or = 37. 6 degrees C fever, 4 children (0.9%) appeared mild areola but all adverse reaction disappeared within 48 hours. In 5-13 year-old experimental group, the rates for four-fold increase of bactericidal antibody were 96.59% and 92.15% to group A and group C meningococcus respectively at 1 month after inoculation, and remained 90.91% and 90.08% at 12 months after inoculation. Group A + C meningococal polysaccharide vaccine was safe and having good immunogenicity among Chinese children.


The quality of the fossil record across higher taxa: compositional fidelity of phyla and classes in benthic marine associations.
Although the fossil record preserves a wealth of historical data about past ecosystems, the current paradigm, which postulates that fossils provide faithful archives of ecological information, stems from research primarily focused on a single group of organisms known for their high fossilization potential: molluscs. Here, we quantify the fidelity of higher taxa (six phyla and 11 classes) by comparing live communities and sympatric dead remains (death assemblages) using comprehensive surveys of benthic marine invertebrates from coastal habitats in North Carolina (U.S.A). We found that although community composition differed between the two assemblages across phyla and classes, these differences were predictable with an overabundance of robust and more preservable groups. In addition, dead molluscs appear to be an excellent proxy for all taxa when tracking spatio-temporal patterns and shifts in community structure using a variety of ecological metrics, including measures of α, γ, and β diversity/evenness. This suggests that despite filters imposed by differential preservation of taxa and time-averaging, the fossil record is likely to be reliable with respect to relative comparisons of composition and diversity in shallow benthic marine paleocommunities. This is consistent with previous work indicating that shallow marine death assemblages can yield robust ecological estimates adequate for assessing the variability of ecosystems that existed under natural, pre-anthropogenic conditions.


Inference of functional relations in predicted protein networks with a machine learning approach.
Molecular biology is currently facing the challenging task of functionally characterizing the proteome. The large number of possible protein-protein interactions and complexes, the variety of environmental conditions and cellular states in which these interactions can be reorganized, and the multiple ways in which a protein can influence the function of others, requires the development of experimental and computational approaches to analyze and predict functional associations between proteins as part of their activity in the interactome. We have studied the possibility of constructing a classifier in order to combine the output of the several protein interaction prediction methods. The AODE (Averaged One-Dependence Estimators) machine learning algorithm is a suitable choice in this case and it provides better results than the individual prediction methods, and it has better performances than other tested alternative methods in this experimental set up. To illustrate the potential use of this new AODE-based Predictor of Protein InterActions (APPIA), when analyzing high-throughput experimental data, we show how it helps to filter the results of published High-Throughput proteomic studies, ranking in a significant way functionally related pairs. All the predictions of the individual methods and of the combined APPIA predictor, together with the used datasets of functional associations are available at http://ecid.bioinfo.cnio.es/. We propose a strategy that integrates the main current computational techniques used to predict functional associations into a unified classifier system, specifically focusing on the evaluation of poorly characterized protein pairs. We selected the AODE classifier as the appropriate tool to perform this task. AODE is particularly useful to extract valuable information from large unbalanced and heterogeneous data sets. The combination of the information provided by five prediction interaction prediction methods with some simple sequence features in APPIA is useful in establishing reliability values and helpful to prioritize functional interactions that can be further experimentally characterized.


Features of a spatially constrained cystine loop in the p10 FAST protein ectodomain define a new class of viral fusion peptides.
The reovirus fusion-associated small transmembrane (FAST) proteins are the smallest known viral membrane fusion proteins. With ectodomains of only approximately 20-40 residues, it is unclear how such diminutive fusion proteins can mediate cell-cell fusion and syncytium formation. Contained within the 40-residue ectodomain of the p10 FAST protein resides an 11-residue sequence of moderately apolar residues, termed the hydrophobic patch (HP). Previous studies indicate the p10 HP shares operational features with the fusion peptide motifs found within the enveloped virus membrane fusion proteins. Using biotinylation assays, we now report that two highly conserved cysteine residues flanking the p10 HP form an essential intramolecular disulfide bond to create a cystine loop. Mutagenic analyses revealed that both formation of the cystine loop and p10 membrane fusion activity are highly sensitive to changes in the size and spatial arrangement of amino acids within the loop. The p10 cystine loop may therefore function as a cystine noose, where fusion peptide activity is dependent on structural constraints within the noose that force solvent exposure of key hydrophobic residues. Moreover, inhibitors of cell surface thioreductase activity indicate that disruption of the disulfide bridge is important for p10-mediated membrane fusion. This is the first example of a viral fusion peptide composed of a small, spatially constrained cystine loop whose function is dependent on altered loop formation, and it suggests the p10 cystine loop represents a new class of viral fusion peptides.


Implementation of occupational safety and health measures at German schools during the SARS-CoV-2 pandemic-cross-sectional results from 31,089 teachers.
The SARS-CoV-2 pandemic exacerbated existing health-related challenges in schools and created new ones. Under pandemic conditions, health risks increased, and with them the requirements for occupational safety and health (OSH) measures. The aim of the study was (a) to examine the status quo of OSH measures in German schools, (b) to analyze whether the implementation of OSH measures was associated with preferable outcomes and (c) to identify predictors for the implementation of OSH measures. A nationwide cross-sectional online survey was conducted among teachers at all school types in Germany in March 2021. Data on the implementation of OSH measures (risk assessments, infection protection instructions and instructions on occupational safety), associated health-related parameters (e.g., somatic symptoms, PHQ-15) and predictor variables (e.g., gender, age or federal states) were assessed using descriptive statistics, analysis of variance and multiple linear regression analysis. Less than 10% of surveyed teachers (N = 31,089) reported that their schools met legal requirements for occupational safety and health measures. Beneficial associations became apparent where more measures were implemented, e.g., significantly better somatic and mental health. Predictors for the implementation of OSH measures were found, especially on a systemic level (e.g., federal states schools were located in). Our study can serve as a basis for future studies. It provides a status quo regarding the implementation of, associations with and predictors for OSH measures in German schools. Our results are best understood as evidence-based arguments to encourage political decision makers to improve the implementation of OSH measures in German schools and thereby foster teachers' health.


[Lung involvement of primary Sjögren's syndrome].
To evaluate the incidence, clinical manifestations and immunological features of lung involvement in patients of primary Sjögren's syndrome (pSS). Five hundred twenty-two patients with pSS in Peking Union Medical College Hospital between 1985 and 2005 were screened retrospectively for lung involvement by either the abnormalities of chest imaging, lung function or the pulmonary artery systolic pressure estimated by ultrasonic echocardiogram > or = 40 mm Hg (1 mm Hg = 0.133 kPa), excluding infections, chronic obstructive pulmonary disease, asthma, congenital heart disease, rheumatic heart disease and other diseases. The difference was compared between patients with and without lung involvement. All patients fulfilled the 2002 international classification (criteria) for pSS. (1) The incidence of lung involvement in pSS was 42.3% (221/522) and occurred from 0 to 384 months (median, 48 months) after onset, while 25.2% occurred before the diagnosis of pSS. Only 47.1% of the patients showed respiratory symptoms. The average age of onset was older in patients with lung involvement than in those without lung involvement [(43 +/- 13) yr vs (37 +/- 14) yr, t = -5.445, P = 0.000]. Incidences of dry mouth (89.6% vs 81.1%, chi2 = 7.145, P = 0.008), dry eyes (78.7% vs 66.4%, chi2 = 9.472, P = 0.002) and rampant caries (55.2% vs 42.2%, chi2 = 8.647, P = 0.003) were higher in patients with lung involvement than those without. There was no significant difference in sex ratio between the two groups. (2) Interstitial lung disease was the most common lung involvement and occurred in 23.2% of the patients. Pulmonary artery hypertension in 12.5%, multiple pulmonary bullae in 9.2%, pleural effusion in 6.0% and multiple pulmonary nodules in 5.6%. (3) The major histopathological patterns were nonspecific interstitial pneumonia (5/11 cases), lymphocytic interstitial pneumonia (3/11 cases). (4) Incidences of Ranaud' s phenomenon (26.7% vs 13.0%, chi2 = 15.77, P = 0.000 ), low-grade fever (20.4% vs 13.0%, chi2 = 5.175, P = 0.023), arthrosis (29.4% vs 21.6%, chi2 = 4.164, P = 0.041), anti-U1RNP (18.2% vs 11.2%, 2 = 5.069, P = 0.024) and hypergammaglobulinemia (51.6% vs 39.5%, chi2 = 6.597, P = 0.01) were higher in patients with lung involvement than in those without. The incidence of renal tubule acidosis was lower in patients with lung involvement than in those without (5.4% vs 12.6% chi2 = 7.616, P = 0.006). (5) The death incidence in pSS with pulmonary involvement was 5.5 times higher than in those without. The most frequent cause of death was infection (64.3%), especially pulmonary infection. Lung involvement in pSS is common. As it is an important factor related to the prognosis of this disease, chest X-ray, HRCT, lung function and ultrasonic echocardiogram after the diagnosis are suggested.


The hematopoietic stem cell niche in homeostasis and disease.
The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.


Spatiotemporal Dynamics of Sporadic Shiga Toxin-Producing Escherichia coli Enteritis, Ireland, 2013-2017.
The Republic of Ireland regularly reports the highest annual crude incidence rates of Shiga toxin-producing Escherichia coli (STEC) enteritis in the European Union, ≈10 times the average. We investigated spatiotemporal patterns of STEC enteritis in Ireland using multiple statistical tools. Overall, we georeferenced 2,755 cases of infection during January 2013-December 2017; we found >1 case notified in 2,340 (12.6%) of 18,641 Census Small Areas. We encountered the highest case numbers in children 0-5 years of age (n = 1,101, 39.6%) and associated with serogroups O26 (n = 800, 29%) and O157 (n = 638, 23.2%). Overall, we identified 17 space-time clusters, ranging from 2 (2014) to 5 (2017) clusters of sporadic infection per year; we detected recurrent clustering in 3 distinct geographic regions in the west and mid-west, all of which are primarily rural. Our findings can be used to enable targeted epidemiologic intervention and surveillance.


Serum Creatinine Distinguishes Duchenne Muscular Dystrophy from Becker Muscular Dystrophy in Patients Aged ≤3 Years: A Retrospective Study.
Here, we investigated correlations between serum creatinine (SCRN) levels and clinical phenotypes of dystrophinopathy in young patients. Sixty-eight patients with dystrophinopathy at the Neuromuscular Clinic, The First Affiliated Hospital, Sun Yat-sen University, were selected for this study. The diagnosis of dystrophinopathy was based on clinical manifestation, biochemical changes, and molecular analysis. Some patients underwent muscle biopsies; SCRN levels were tested when patients were ≤3 years old, and reading frame changes were analyzed. Each patient was followed up, and motor function and clinical phenotype were assessed when the same patients were ≥4 years old. Our findings indicated that in young patients, lower SCRN levels were associated with increased disease severity (p < 0.01) and that SCRN levels were the highest in patients exhibiting mild Becker muscular dystrophy (BMD) (p < 0.001) and the lowest in patients with Duchenne muscular dystrophy (DMD) (p < 0.01) and were significantly higher in patients carrying in-frame mutations than in patients carrying out-of-frame mutations (p < 0.001). SCRN level cutoff values for identifying mild BMD [18 µmol/L; area under the curve (AUC): 0.947; p < 0.001] and DMD (17 µmol/L; AUC: 0.837; p < 0.001) were established. These results suggest that SCRN might be a valuable biomarker for distinguishing DMD from BMD in patients aged ≤3 years and could assist in the selection of appropriate treatment strategies.


Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: Strategy to prevent CTLN2.
Identification of the genes responsible for adult-onset type II citrullinemia (CTLN2) and citrin protein function have enhanced our understanding of citrin deficiency. Citrin deficiency is characterized by 1) neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD); 2) adaptation/compensation stage with unique food preference from childhood to adulthood; and 3) CTLN2. The treatment of NICCD aims to prevent the progression of cholestasis, and it includes medium chain triglycerides (MCT) milk and lactose-free milk, in addition to medications (e.g., vitamin K2, lipid-soluble vitamins and ursodeoxycholic acid). Spontaneous remission around the age of one is common in NICCD, though prolonged cholestasis can lead to irreversible liver failure and may require liver transplantation. The adaptation/compensation stage (after one year of age) is characterized by the various signs and symptoms such as hypoglycemia, fatty liver, easy fatigability, weight loss, and neuropsychiatric symptoms. Some poorly-controlled patients show failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Diet therapy is the key in the adaptation/compensation stage. Protein- and fat-rich diet with a protein: fat: carbohydrate ratio being 15-25%: 40-50%: 30-40% along with the appropriate energy intake is recommended. The use of MCT oil and sodium pyruvate is also effective. The toxicity of carbohydrate is well known in the progression to CTLN2 if the consumption is over a long term or intense. Alcohol can also trigger CTLN2. Continuous intravenous hyperalimentation with high glucose concentration needs to be avoided. Administration of Glyceol® (an osmotic agent containing glycerol and fructose) is contraindicated. Because the intense treatment such as liver transplantation may become necessary to cure CTLN2, the effective preventative treatment during the adaptation/compensation stage is very important. At present, there is no report of a case with patients reported having the onset of CTLN2 who are on the diet therapy and under the appropriate medical support during the adaptation/compensation stage.


[Family prevention of drug use in Europe: a critical review of EDDRA programs].
In early adolescence, family is one of the main risk/protection agent for drug misuse. Its influence on health habits acquisition makes family a key target for prevention programs. The aim is to conduct a comparative analysis of European family prevention programs. For this purpose, 85 programs were reviewed. Programs were retrieved from EMCDDA database EDDRA (Exchange on Drug Demand Reduction Actions). No time period was delimited; hence time span was 1998-2011. 53% of all programs came from 4 countries (Ireland, Germany, Portugal and Spain). 89% were unspecific drug prevention or health promotion programs. Providing information about drugs is the main objective pursued by the majority of the programs. Over half the programs (59.7%) report having undergone an outcome evaluation process. Regarding the program objectives, 70.59% do not address any of the risk factors proposed by the main theories in international literature. Despite the solid theoretical framework that supports coherent evidence about family risk factors, prevention programs' objectives and components have a low theoretical compliance rate and the level of evaluation continues to be a challenge. Some aspects of the EDDRA functioning are reviewed.


Evaluation of pain in intravitreal bevacizumab injections.
To evaluate the correlation between pain associated with intravitreal bevacizumab injection and the location of the injection. The study included 218 eyes of 218 patients, who received an intravitreal bevacizumab injection at our institution. Pain was measured by the Visual Analog Scale (VAS). Additional parameters recorded included age, sex, indication for the injection, injection site by quadrant, number injections in the study eye, presence of diabetes mellitus, and lens status. Indications for injection included age-related macular degeneration (69.7%), diabetic macular edema (13.3%), neovascularization due to proliferative diabetic retinopathy (6.9%), and cystoid macular edema secondary to retinal vascular occlusions (10.1%). Pain scores on the VAS ranged from 0 to 84, with a mean of 17.4 ± 17.1. Pain did not correlate significantly with any of the recorded parameters, but a trend was found toward less pain associated with injection in the lower-left quadrant (p = 0.067). This is the largest series studying the pain associated with intravitreal injections and provides a thorough description of the pain associated with this procedure. Since there is no anatomical difference between quadrants, we assume the demonstrated trend indicates that less pain is associated with the location in which it is most convenient for the ophthalmologist to perform the injection.


Field evaluation of piglet vaccination with a Mycoplasma hyopneumoniae bacterin as compared to a ready-to-use product including porcine circovirus 2 and M. hyopneumoniae in a conventional French farrow-to-finish farm.
A controlled randomized trial was performed on a well-managed conventional French 180-sow farm. The trial compared the growth performances of piglets vaccinated at weaning (single shot) either with a commercial monovalent Mycoplasma hyopneumoniae bacterin vaccine or with a commercial bivalent vaccine (Porcilis® PCV M Hyo) against M. hyopneumoniae and porcine circovirus 2 (PCV2). The farm's porcine reproductive and respiratory syndrome status was stable, and most diseases (enzootic pneumonia, atrophic rhinitis, post-weaning multisystemic wasting syndrome) were controlled by routine vaccination. During the post-weaning phase, the growth performances of the piglets vaccinated with the bivalent vaccine were not significantly different from those vaccinated with the monovalent vaccine. However, during the fattening phase the group vaccinated with the bivalent vaccine had a significantly improved ADG (+34 g/d, p = 0. 047), resulting in a 5-day earlier shipment to slaughter. The group also had a shorter and lower PCV2 load in serum during the fattening period, and an improved lung lesions score. In both groups, three pigs died during the peak PCV2 viraemia (16-23 weeks of age). Immunohistochemistry of the lymph nodes showed that in the group vaccinated with the bivalent vaccine, none of these pigs had PCV2-like lesions, while 2 out of the 3 from the other group did. Results suggest that the added PCV2 valence in the vaccination protocol helps countering the negative impact of subclinical PCV2 infection on growth. The calculated return on investment of the added PCV2 vaccine valence was €1.7 extra revenue per slaughtered pig (€ 39 additional revenue per sow and per year), despite the fact that the cost of the bivalent vaccine was higher than the monovalent M. hyopneumoniae vaccine. In this healthy conventional sow farm, the combined M. hyopneumoniae and PCV2 vaccination was efficacious, convenient to administer and profitable.


[Retrospective analysis of complications of supracondylar fracture of humerus in children].
To investigate the causes and the measures for prevention and management of complications of supracondylar fracture of the humerus. In 203 cases of supracondylar fracture of the humerus treated from July 2002 to July 2008, 49 cases had complication, whose data were retrospectively analyzed. There were 32 males and 17 females with an average age of 9 years (range 2-14 years). Fracture was caused by tumble in 38 cases, by falling from height in 4 cases, and by traffic accident in 7 cases. All cases were closed fractures. According to Gartland typing for supracondylar fracture of the humerus, there were 10 cases of type II and 39 cases of type III. Complications included 21 cases of vascular injuries, 10 cases of neural injuries, and 3 cases of osteofascial compartment syndrome. The time from injury to operation was 1-25 days. Closed reduction was given in 13 cases, closed reduction plus percutaneous K-wire fixation in 21 cases, and open reduction plus K-wire fixation in 15 cases. After reduction, plaster external fixation was performed. The cases of manipulation which blood circulation could not improve underwent incision to exploration of blood vessel. Two cases of neural injuries were treated with incision decompression of epineurium. Three cases of osteofascial compartment syndrome were treated with incision decompression, and the incision was sutured after 7-10 days. All incisions healed by first intention. The duration of follow-up was 1-5 years with an average of 3.4 years. Fracture healing was achieved within 4-8 weeks. All vascular injuries and 9 cases of neural injures recovered thoroughly. Poor function occurred in 1 case of median nerve injury and Volkmann ischemic contracture in 1 case of osteofascial compartment syndrome. Cubitus varus deformity was found in 11 cases and myositis ossificans in 4 cases within 3 months to 1 year. According to Flynn standard of the function of elbow, the results were excellent in 21 cases, good in 7 cases, fair in 3 cases, poor in 18 cases. Early reduction is the key for prevention of further vascular injury, nerve injury and osteofascial compartment syndrome. Operation is essential when expectant treatment invalid. Satisfactory reduction, good fixation and functional rehabilitation are key points for preventing cubitus varus deformity.


[Interaction analysis between various PrP fusion proteins and the tubulin in vitro].
In order to further study the potential interaction between PrP protein and the tubulin and identify the binding region in PrP with tubulin, native tubulin was extracted from rabbit brian tissues, while various recombinant PrP proteins were expressed and purified. The possible molecular interaction between various PrP fusion proteins and tubulin was tested by pull-down and immunoprecipitation assays. Remarkable molecular interaction between the full length PrP and tubulin was observed by pull-down and immunoprecipitation assays. Subsequently, the binding regions within PrP with tubulin were firstly mapped in the aa 23 -- 91 region within N-terminus of PrP peptide. The studies of the association of PrP with tubulin may further provide insight into the unresolved mechanism of active transport of PrP protein in neurons and possible cellular pathways by which prion causes disease.


Inhibitor of DNA binding proteins: implications in human cancer progression and metastasis.
Inhibitor of DNA binding (ID) proteins are a class of helix-loop-helix (HLH) transcription regulatory factors that act as dominant-negative antagonists of other basic HLH proteins through the formation of non-functional heterodimers. These proteins have been shown to play critical roles in a wide range of tumor-associated processes, including cell differentiation, cell cycle progression, migration and invasion, epithelial-mesenchymal transition, angiogenesis, stemness, chemoresistance, tumorigenesis, and metastasis. The aberrant expression of ID proteins has not only been detected in many types of human cancers, but is also associated with advanced tumor stages and poor clinical outcome. In this review, we provide an overview of the key biological functions of ID proteins including affiliated signaling pathways. We also describe the regulation of ID proteins in cancer progression and metastasis, and elaborate on expression profiles in cancer and the implications for prognosis. Lastly, we outline strategies for the therapeutic targeting of ID proteins as a promising and effective approach for anticancer therapy.


Effect of light intensity on confinement rearing of male turkeys.
Light intensities of .11, 1.1, 11 and 33 lux of 12 hours per day duration were studied for their effect on growth rate and feed utilization efficiency. The two experiments were initiated when the birds were 3 weeks old. Up to 12-14 weeks of age, the .11 lux intensity was superior to the other treatments. After this age, the other treatments were superior. Two other experiments were conducted with a crossover design. Birds were reared under either 11 or .11 lux from 3 to 12 weeks of age, than half of each group was maintained, and half was switched to either the higher or lower, intensity. Best growth up to 12 weeks of age was associated with .11 lux. Best growth to 22 weeks was associated with 11 lux. Crossing from high to low or low to high had no beneficial effects in either experiment.


Nonpharmacological Interventions in Targeting Pain-Related Brain Plasticity.
Chronic pain is a highly prevalent and debilitating condition that is frequently associated with multiple comorbid psychiatric conditions and functional, biochemical, and anatomical alterations in various brain centers. Due to its widespread and diverse manifestations, chronic pain is often resistant to classical pharmacological treatment paradigms, prompting the search for alternative treatment approaches that are safe and efficacious. The current review will focus on the following themes: attentional and cognitive interventions, the role of global environmental factors, and the effects of exercise and physical rehabilitation in both chronic pain patients and preclinical pain models. The manuscript will discuss not only the analgesic efficacy of these therapies, but also their ability to reverse pain-related brain neuroplasticity. Finally, we will discuss the potential mechanisms of action for each of the interventions.


Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism.
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D2R-BRET functional assays.


Kinetic analysis of hyaluronidase activity using a bioactive MRI contrast agent.
One of the attractions of molecular imaging using 'smart' bioactive contrast agents is the ability to provide non-invasive data on the spatial and temporal changes in the distribution and expression patterns of specific enzymes. The tools developed for that aim could potentially also be developed for functional imaging of enzyme activity itself, through quantitative analysis of the rapid dynamics of enzymatic conversion of these contrast agents. High molecular weight hyaluronan, the natural substrate of hyaluronidase, is a major antiangiogenic constituent of the extracellular matrix. Degradation by hyaluronidase yields low molecular weight fragments, which are proangiogenic. A novel contrast material, HA-GdDTPA-beads, was designed to provide a substrate analog of hyaluronidase in which relaxivity changes are induced by enzymatic degradation. We show here a first-order kinetic analysis of the time-dependent increase in R(2) as a result of hyaluronidase activity. The changes in R(2) and the measured relaxivity of intact HA-GdDTPA-beads (r(2B)) and HA-GdDTPA fragments (r(2D)) were utilized for derivation of the temporal drop in concentration of GdDTPA in HA-GdDTPA-beads as the consequence of the release of HA-GdDTPA fragments. The rate of dissociation of HA-GdDTPA from the beads showed typical bell-shaped temperature dependence between 7 and 36 degrees C with peak activity at 25 degrees C. The tools developed here for quantitative dynamic analysis of hyaluronidase activity by MRI would allow the use of activation of HA-GdDTPA-beads for the determination of the role of hyaluronidase in altering the angiogenic microenvironment of tumor micro metastases.


Comparative analysis of binding energy of chymostatin with human cathepsin A and its homologous proteins by molecular orbital calculation.
Cathepsin A is a mammalian lysosomal enzyme that catalyzes the hydrolysis of the carboxy-terminal amino acids of polypeptides and also regulates beta-galactosidase and neuraminidase-1 activities through the formation of a multienzymic complex in lysosomes. Human cathepsin A (hCathA), yeast carboxypeptidase (CPY), and wheat carboxypeptidase II (CPW) belong to the alpha/beta-hydrolase fold family. They have structurally similar active-site clefts, but there are small differences in the amino acid residues comprising their active sites that might determine the substrate specificity and sensitivity to microbial inhibitors including chymostatin. To examine the selectivity and binding mechanism of chymostatin as to hCathA, CPY, and CPW at the atomic level, we analyzed the interaction energy between chymostatin and each protein quantitatively by semiempirical molecular orbital calculation AM1 with the continuum solvent model. We predicted the electrostatic repulsion between the P3 cyclic arginine residue of the inhibitor and the Arg344 in the S3 active subsite of hCathA. Genetic conversion of Arg344 of the wild-type hCathA to Ile also caused an increase in its sensitivity to chymostatin, which was correlated with the decrease in the interaction energy calculated with the molecular orbital method. The present results suggest that such molecular calculation should be useful for evaluating the interactions between ligands, including inhibitors and homologous enzymes, in their docking models.


Using retrospective life tables to assess the effect of extreme climatic conditions on ungulate demography.
In Mediterranean areas, severe drought events are expected to intensify in forthcoming years as a consequence of climate change. These events may increase physiological and reproductive stress of wild populations producing demographic changes and distribution shifts. We used retrospective life tables to understand demographic changes on a wild population after severe drought events. We studied the impact of two extreme events (2003 and 2005) on the population dynamics of our model species, the red deer (Cervus elaphus). During both years, population density was high (40 and 36 ind/100 ha, respectively). Thus, we reconstructed retrospectively the age structure of the female part of the population for the period 2000-2010 by using data of known-age individuals culled during the period 2000-2019 (n = 4176). Also, based on previous study results, we aimed to validate this methodology. Both extremely dry years, 2003 and 2005, produced marked and lasting cohort effects on population demography. Age pyramid the following years (2004 and 2006) revealed that the extreme drought caused the female fawn cohort to be similar or even smaller than the yearling cohort. Furthermore, these cohort effects were still perceptible 3 years after these severe events. Results agree with previous findings that showed a negative effect of severe drought events on female pregnancy rates and conception dates. Although simple, this study provides an empirical quantification of the demographic effects of severe drought events for a wild population which might be useful to understand future demographic changes under the context of climate change.


Accumulation and persistence of cyclophosphamide-induced sister chromatid exchange in murine peripheral blood lymphocytes.
Sister chromatid exchange (SCE) responses were evaluated in lipopolysaccharide-stimulated murine peripheral blood lymphocytes assayed at various times following single or multiple injections of cyclophosphamide (3 mg/kg). Following a single injection, SCE levels in cultured lymphocytes from blood sampled at 5 min, 20 min, 35 min, 1 hr, and 3 hr postexposure were 17.1 +/- 2.0 (S.D.), 19.9 +/- 3.0, 19.3 +/- 1.8, 21.6 +/- 2.4, and 20.6 +/- 2.3, respectively. The control base-line SCE frequency was 11.2 +/- 1.2. The rapid initial increase in SCEs is consistent with the rapid increase reported previously in circulating active metabolites in rats following cyclophosphamide treatment. In peripheral blood lymphocytes cultured at 1 and 24 hr after serial injections of cyclophosphamide (3.0 mg/kg) two, four, and six times (every other day), a dose-related accumulation of SCEs occurred. Accumulation of SCEs was also observed in lymphocytes cultured at 24 and 72 hr following 12 multiple injections (three times weekly) of cyclophosphamide (3 mg/kg) (24.8 +/- 1.5 and 17.6 +/- 1.4, respectively) as compared to the single-injection group assayed at 24 and 72 hr postexposure (16.0 +/- 2.4 and 12.9 +/- 1.4, respectively). In the 12-multiple-injection study, an initial rapid decline at 72 hr was followed by a gradual decrease in SCE levels (1 week, 16.9 +/- 1.3; 2 weeks, 15.2 +/- 0.7; and 4 weeks, 13.4 +/- 1.1) which returned to near base-line (11.2 +/- 0.9) levels at 8 weeks. In the 12-multiple-injection study, successful growth of parallel concanavalin A-stimulated cultures was achieved only at 1, 2, and 4 weeks postexposure. Elevated SCE frequencies were observed at these intervals (16.2 +/- 2.1; 16.7 +/- 0.9; 14.2 +/- 0.3, respectively) relative to base-line SCE levels in concanavalin A-stimulated cells (12.1 +/- 1.8). The observed accumulation of SCEs with repeated exposure and persistence of SCE-inducing lesions parallel human data reported previously. The maximum induced (total minus baseline) SCE levels (10.2) observed in cultured lipopolysaccharide-stimulated lymphocytes from blood sampled at 1 hr after a single 3.0-mg/kg injection of cyclophosphamide were comparable or slightly higher than those (7.1) produced by the same dose of cyclophosphamide in murine bone marrow cells labeled with BrdUrd in vivo. However, in contrast to lymphocytes, bone marrow and alveolar macrophage cells did not accumulate SCEs upon repeated cyclophosphamide treatments.


Developmental patterns and variation among early theropods.
Understanding ontogenetic patterns is important in vertebrate paleontology because the assessed skeletal maturity of an individual often has implications for paleobiogeography, species synonymy, paleobiology, and body size evolution of major clades. Further, for many groups the only means of confidently determining ontogenetic status of an organism is through the destructive process of histological sampling. Although the ontogenetic patterns of Late Jurassic and Cretaceous dinosaurs are better understood, knowledge of the ontogeny of the earliest dinosaurs is relatively poor because most species-level growth series known from these groups are small (usually, maximum of n ~ 5) and incomplete. To investigate the morphological changes that occur during ontogeny in early dinosaurs, I used ontogenetic sequence analysis (OSA) to reconstruct developmental sequences of morphological changes in the postcranial ontogeny of the early theropods Coelophysis bauri and Megapnosaurus rhodesiensis, both of which are known from large sample sizes (n = 174 and 182, respectively). I found a large amount of sequence polymorphism (i.e. intraspecific variation in developmental patterns) in both taxa, and especially in C. bauri, which possesses this variation in every element analyzed. Megapnosaurus rhodesiensis is similar, but it possesses no variation in the sequence of development of ontogenetic characters in the tibia and tarsus. Despite the large amount of variation in development, many characters occur consistently earlier or later in ontogeny and could therefore be important morphological features for assessing the relative maturity of other early theropods. Additionally, there is a phylogenetic signal to the order in which homologous characters appear in ontogeny, with homologous characters appearing earlier or later in developmental sequences of early theropods and the close relatives of dinosaurs, silesaurids. Many of these morphological features are important characters for the reconstruction of archosaurian phylogeny (e.g. trochanteric shelf). Because these features vary in presence or appearance with ontogeny, these characters should be used with caution when undertaking phylogenetic analyses in these groups, since a specimen may possess certain character states owing to ontogenetic stage, not evolutionary relationships.


Visualization of genomic changes by segmented smoothing using an L0 penalty.
Copy number variations (CNV) and allelic imbalance in tumor tissue can show strong segmentation. Their graphical presentation can be enhanced by appropriate smoothing. Existing signal and scatterplot smoothers do not respect segmentation well. We present novel algorithms that use a penalty on the L(0) norm of differences of neighboring values. Visualization is our main goal, but we compare classification performance to that of VEGA.


Strengthening North Pacific Influences on United States Temperature Variability.
Changes in the frequency of occurrence of atmospheric circulation patterns under a changing climate system has important implications for regional climate variability. While many studies have focused on understanding the trends in the atmospheric pattern amplitudes and probabilities of occurrence, little attention has been given to how the linkages between climate variables and the large-scale patterns have been changing. Here we first document the strengthening relationship between an important North Pacific teleconnection - the East Pacific/North Pacific (EP/NP) pattern - and United States (US) temperature variability since the 1950s. The EP/NP pattern is linked to tropical convection, and consistently the coherence between US temperature anomalies and tropical convection anomalies has also been increasing during the same time period. This upward trend in convection-temperature alignment is most notable during autumn and winter and is absent during the summer. The relationship strengths and trends further suggest that the EP/NP pattern should be incorporated into monthly and seasonal outlooks that are of broad importance to agriculture, industry, and fisheries.


Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis.
Phospho-cofilin (p-cofilin), which has a phosphate group on Ser-3, is involved in actin polymerization. Its dephosphorylated form promotes filopodia formation and cell migration by enhancing actin depolymerization. Protein phosphatase slingshot homologs (SSHs), known as dual-specificity phosphatases, catalyze hydrolytic removal of the Ser-3 phosphate group from phospho-cofilin. Aberrant SSH activity results in cancer metastasis, implicating SSHs as potential therapeutic targets for cancer metastasis. In this study, we screened 658 natural products purified from traditional oriental medicinal plants to identify three potent SSH inhibitors with submicromolar or single-digit micromolar Ki values: gossypol, hypericin, and sennoside A. The three compounds were purified from cottonseed, Saint John's wort, and rhubarb, respectively. Sennoside A markedly increased cofilin phosphorylation in pancreatic cancer cells, leading to impaired actin dynamics in pancreatic cancer cells with or without EGF stimulation and reduced motility and invasiveness in vitro and in vivo. Collaboratively, these results demonstrate that sennoside A is a novel inhibitor of SSHs and suggest that it may be valuable in the development of pharmaceutical drugs for treating cancer metastasis.


A Cu25 Nanocluster with Partial Cu(0) Character.
Atomically precise copper nanoclusters (NCs) are of immense interest for a variety of applications, but have remained elusive. Herein, we report the isolation of a copper NC, [Cu25H22(PPh3)12]Cl (1), from the reaction of Cu(OAc) and CuCl with Ph2SiH2, in the presence of PPh3. Complex 1 has been fully characterized, including analysis by X-ray crystallography, XANES, and XPS. In the solid state, complex 1 is constructed around a Cu13 centered-icosahedron and formally features partial Cu(0) character. XANES of 1 reveals a Cu K-edge at 8979.6 eV, intermediate between the edge energies of Cu(0) and Cu(I), confirming our oxidation state assignment. This assignment is further corroborated by determination of the Auger parameter for 1, which also falls between those recorded for Cu(0) and Cu(I).


[Detection of acute infection due to legionella pneumophila in patient with community acquired pneumonia in Buenos Aires city].
Community-acquired pneumonia (CAP) is caused by different microorganisms, their frequency varying in each community. Legionella pneumophila has been reported as etiologic agent of CAP. The aim of our study was to determine the incidence of acute infection due to Legionella pneumophila in a group of adult patients in Buenos Aires city. Adults of both sexes with CAP diagnosis were included and two serum samples, acute and convalescence (2-4 weeks apart from each other), were tested to detect antibodies against Legionella pneumophila by indirect immunofluorescence (IFI) (Organon Teknica, NC, USA). Ninety-two of the enrolled patients were evaluable, average age 56 years, 55% men (males), 52.2% did not require hospitalization. Three patients (3.3%) fulfilled the serologic diagnostic criteria for Legionella pneumophila acute infection. None of them were confirmed by microorganism isolation. The actual incidence of CAP caused by Legionella pneumophila in Argentina has not yet been established. It will require studies including larger numbers of patients and the use of simple and sensitive tests, such as Legionella pneumophila urinary antigen detection, to establish the exact role of this pathogen in our community.


Will there be cold-related mortality in Spain over the 2021-2050 and 2051-2100 time horizons despite the increase in temperatures as a consequence of climate change?
Global warming is resulting in an increase in temperatures which is set to become more marked by the end of the century and depends on the accelerating pace of greenhouse gas emissions into the atmosphere. Yet even in this scenario, so-called "cold waves" will continue to be generated and have an impact on health. This study sought to analyse the impact of cold waves on daily mortality at a provincial level in Spain over the 2021-2050 and 2051-2100 time horizons under RCP4.5 and RCP 8.5 emission scenarios, on the basis of two hypotheses: (1) that the cold-wave definition temperature (T threshold) would not vary over time; and, (2) that there would be a variation in T threshold. The results of a retrospective study undertaken for Spain as a whole across the period 2000-2009 enabled us to ascertain the cold-wave definition temperature at a provincial level and its impact on health, measured by reference to population attributable risk (PAR). The minimum daily temperatures projected for each provincial capital considering the above time horizons and emission scenarios were provided by the State Meteorological Agency. On the basis of the T threshold definition values and minimum daily temperatures projected for each province, we calculated the expected impact of low temperatures on mortality under the above two hypotheses. Keeping the PAR values constant, it was assumed that the mortality rate would vary in accordance with the available data. If T threshold remained constant over the above time horizons under both emission scenarios, there would be no cold-related mortality. If T threshold were assumed to vary over time, however, then cold-related mortality would not disappear: it would instead remain practically constant over time and give rise to an estimated overall figure of around 250 deaths per year, equivalent to close on a quarter of Spain's current annual cold-related mortality and entailing a cost of approximately €1000 million per year. Given that cold waves are not going to disappear and that their impact on mortality is far from negligible and is likely to remain so, public health prevention measures must be implemented to minimise these effects as far as possible.


Obstruction to ergodicity in nonlinear Schrödinger equations with resonant potentials.
We identify a class of trapping potentials in cubic nonlinear Schrödinger equations (NLSEs) that make them nonintegrable, but prevent the emergence of power spectra associated with ergodicity. The potentials are characterized by equidistant energy spectra (e.g., the harmonic-oscillator trap), which give rise to a large number of resonances enhancing the nonlinearity. In a broad range of dynamical solutions, spanning the regimes in which the nonlinearity may be either weak or strong in comparison with the linear part of the NLSE, the power spectra are shaped as narrow (quasidiscrete), evenly spaced spikes, unlike generic truly continuous (ergodic) spectra. We develop an analytical explanation for the emergence of these spectral features in the case of weak nonlinearity. In the strongly nonlinear regime, the presence of such structures is tracked numerically by performing simulations with random initial conditions. Some potentials that prevent ergodicity in this manner are of direct relevance to Bose-Einstein condensates: they naturally appear in 1D, 2D, and 3D Gross-Pitaevskii equations (GPEs), the quintic version of these equations, and a two-component GPE system.


Practical approach to metabolic assessments in the pediatric human immunodeficiency virus outpatient clinic.
Metabolic assessment is not a routine part of the care of pediatric HIV-positive patients in the outpatient setting, although research studies are demonstrating an increasing prevalence of metabolic abnormalities in this population. Addition of metabolic assessments to routine clinic care can be hindered by the perception that collection of the data needed for the assessments will need too much clinic time and too many clinic resources to be practical. A method to provide metabolic assessments using minimal clinic resources while offering educational opportunities for university students was developed and implemented at the University of Florida Pediatric Immunology and Infectious Diseases weekly clinic. The success rate of metabolic assessment data collection from all clinic patients and the impact of data collection on the flow of clinic activity were monitored for a 12-month period. The metabolic assessment team interviewed 87% of all patients who came to the 454 clinic during the 12-month period and performed a complete metabolic assessment for 75% of the HIV-positive patients interviewed. Addition of metabolic assessments to the routine care of each patient did not result in any noticeable adverse effect on the functionality of the clinic. Addition of metabolic assessments to the routine clinic care of pediatric HIV positive patients can be an educational opportunity for university students and provide the clinic staff with changes in parameters indicative of metabolic abnormalities and without noticeable changes in maintaining the patient schedule at each clinic.


Distribution of hemokinin-1 in the rat trigeminal ganglion and trigeminal sensory nuclear complex.
A new mammalian tachykinin peptide encoded in a TAC4 gene was identified and designated as hemokinin-1 (HK-1). A representative of the tachykinin peptide family is substance P (SP), and the function of SP has been well characterized as a pain transmitter or modulator, while it is possible that HK-1 is involved in pruriceptive processing, but, as yet, the distribution of HK-1 peptide in the trigeminal sensory system is still unknown. Thus, the aim of the present study was to elucidate the distribution of HK-1, while comparing the expression of SP, in the trigeminal ganglion and trigeminal sensory nuclear complex. The trigeminal ganglion and the brain stem of male SD rats were used in the immunohistochemical study. Since the amino acid sequence in the carboxyl-terminal regions of HK-1 and SP is common, polyclonal antibodies of HK-1 and SP derived from 6 amino acids consisting of amino-terminal regions of these peptides were produced in guinea pig and rabbit, respectively. The immunohistochemical staining of HK-1 and SP was conducted using frozen sections of the trigeminal ganglion and brain stem in rats. Immunohistochemical studies revealed the expression of HK-1 in small- and medium-sized trigeminal ganglion neurons, in the paratrigeminal nucleus, and in lamina I of the trigeminal nucleus caudalis, while there was no immunoreactivity of HK-1 in the trigeminal nucleus principalis, trigeminal nucleus oralis, and trigeminal nucleus interpolaris. These findings indicate that HK-1 is a target molecule for treatment of itch in the orofaicial regions.


Controlled synthesis of (S,S)-2,7-diaminosuberic acid: a method for regioselective construction of dicarba analogues of multicystine-containing peptides.
A method to facilitate regioselective formation of multiple dicarba isosteres of cystine is described. A sequence of ruthenium-catalyzed cross metathesis and rhodium-catalyzed hydrogenation of nonproteinaceous allylglycine derivatives has been developed to achieve high-yielding and unambiguous formation of diaminosuberic acid derivatives. Allylglycine derivatives readily undergo ruthenium-catalyzed metathesis and hydrogenation to yield diaminosuberic acid derivatives in near quantitative yield. Under the same experimental conditions, prenylglycine was found to be inert to both Grubbs' and Wilkinson's catalyzed metathesis and hydrogenation, respectively, but was readily activated for metathesis via cross metathesis with Z-butene. Subsequent cross metathesis of the metathesis-formed crotylglycine derivative, followed by hydrogenation, yielded the second diaminosuberic acid derivative in excellent yield.


Perivascular infiltrate of memory lymphocytes and mature dendritic cells in MG thymomas.
In thymomas associated with myasthenia gravis (MG), the authors found that perivascular infiltrates of memory lymphocytes and mature dendritic cells (DCs) were more frequent in patients with early improvement after thymectomy than in patients without response to thymectomy. Although these findings may be limited to particular types of thymoma, thymectomy may interrupt the recruitment of mature DCs in thymus and export of activated T cells to extra-thymic tissues, thereby improving the disease.


Transport of a large oligomeric protein by the cytoplasm to vacuole protein targeting pathway.
Aminopeptidase I (API) is transported into the yeast vacuole by the cytoplasm to vacuole targeting (Cvt) pathway. Genetic evidence suggests that autophagy, a major degradative pathway in eukaryotes, and the Cvt pathway share largely the same cellular machinery. To understand the mechanism of the Cvt import process, we examined the native state of API. Dodecameric assembly of precursor API in the cytoplasm and membrane binding were rapid events, whereas subsequent vacuolar import appeared to be rate limiting. A unique temperature-sensitive API-targeting mutant allowed us to kinetically monitor its oligomeric state during translocation. Our findings indicate that API is maintained as a dodecamer throughout its import and will be useful to study the posttranslational movement of folded proteins across biological membranes.


[Epidemiological analysis of deaths occurring while taking a bath].
An epidemiological analysis of deaths occurring while taking a bath was carried out in Tochigi Prefecture. Data concerning the numbers of deaths were obtained from the Tochigi Central Police Office. Long-term assessments from 1978 to 1992 were completed for a total number of 1,348 persons (793 men and 555 women). The annual number of deaths during taking a bath increased gradually from 43 in 1978 to 140 in 1992. Death occurred 1.43 times more frequently in males than in females. The number during summer was only one eighth that of the winter peak. In addition, the increase in mortality was proportional to age. The mortality figures per 100,000 were, 10 for 40-49 age group, 31 for 50-59, 79 for 60-69, 251 for 70-79 and 469 for those 80 and over. It is concluded that the number of deaths occurring while taking a bath has increased gradually in those 80 or over.


Assimilation of metal ions bound to porphyrins or porphyrin-peptides by vibrio vulnificus, a human pathogen inhabiting estuarine and marine environments.
Vibrio vulnificus, a ubiquitous microorganism in aquatic environments, causes serious septicemia to the immunocompromised host. In addition to protoheme, this species can utilize Fe-TCPP [ferric tetrakis (4-carboxyphenyl) porphine] as an iron source. In the present study, heme c bound covalently to the protein in cytochrome c, as well as the Fe-TCPP complex formed with a nanopeptide with a high affinity, was found to be useful iron sources for V. vulnificus. This bacterium was also revealed to use Zn-TCPP as a single zinc source. However, other metalloporphyrins such as Mn-TCPP and Pt-TCPP delayed the bacterial growth in the broth containing Fe-TCPP, suggesting interference in the iron assimilation. These results indicate that V. vulnificus may acquire metal ions from both free and peptide-bound metalloporphyrins.


Correlation between the changes in the EPIC QOL scores and the dose-volume histogram parameters in high-dose-rate brachytherapy combined with hypofractionated external beam radiation therapy for prostate cancer.
To evaluate the correlations between the changes in the quality-of-life scores and the dose-volume histogram parameters in patients receiving high-dose-rate brachytherapy combined with hypofractionated external beam radiation therapy for localized prostate cancer. Among the patients who were treated with high-dose-rate brachytherapy (18 Gy in two fractions) combined with hypofractionated external beam radiation therapy (45 Gy in 15 fractions), the data of 118 consecutive patients followed up for >24 months were prospectively analyzed. The disease-specific quality of life was assessed using the expanded prostate cancer index composite, and the acute genitourinary toxicities were graded based on the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer Toxicity criteria. The median follow-up duration was 58 months (42-84 months). Thirteen patients (11%) developed Grade 2 or more severe acute genitourinary toxicities. The score for the general urinary domain of the expanded prostate cancer index composite quality-of-life scores dropped significantly at 1 month after high-dose-rate brachytherapy, and then returned to the baseline level by 3 months. Among the dose-volume histogram parameters, the reduction of the expanded prostate cancer index composite quality-of-life scores for the general urinary domain and its subscales at 12 months after high-dose-rate brachytherapy was significantly greater in the patients for whom the V150 or urethral D10 was within the upper 20% of the range than in those in whom the values of these dosimetric parameters were within the lower 20% of the range. The high-dose area of the prostate gland (V150) or urethra (D10) might influence the quality-of-life scores for the urinary domain and its subscales over the long term.


[Descemet's membrane endothelial keratoplasty for treatment of patients with corneal endothelial decompensation].
Objective: To evaluate the clinical outcomes of Descemet's membrane endothelial keratoplasty (DMEK) for treatment of patients with corneal endothelial decompensation in China. Methods: Interventional case series. Ten patients (10 eyes) with the diagnosis of corneal endothelial decompensation received DMEK during July 2016 and September 2016 in Zhongshan Ophthalmic Center. Descemet's membrane of the donor tissue was carefully stripped from the underlying stroma manually and cut with a 7.75- or 8.0-mm-diameter donor punch. After stained with 0.06% typan blue, the donor disc loaded on an inserter was gently inserted into the anterior chamber of the recipient. When the rolled graft was unfolded, air was carefully injected into the anterior chamber underneath the graft, so that the graft attached to the stroma of the recipient. All patients were followed up for 3-6 months. The best spectacle corrected visual acuity, the status of donor disc, corneal thickness and corneal endothelial cell density were documented and analyzed. Results: At 1 day after surgery, 1 donor disc presented a rolled edge, and repeated DMEK surgery was performed for this patient. The remaining 9 donor discs presented in place well. At 1 month after surgery, 7 donor discs were found to well attach to the back surface of the recipient stroma with normal corneal posterior surface using anterior segment optical coherence tomography. The average corneal thickness reduced to (620±67) μm from preoperative (680±78.3) μm (t=2.677, P=0.025). At 3 months after surgery, 6 patients achieved clear corneas with best spectacle corrected visual acuity ranging from 0.4 to 0.8. The endothelial cell density was 1 342.3±436.5 (872 to 1 933) cells/mm(2) in the patients with clear corneas. The average corneal thickness reduced to (612±70) μm (t=2.971, P=0.016). Conclusions: DMEK could improve visual acuity for corneal endothelial decompensation, but there were more technical difficulties in Chinese eyes. (Chin J Ophthalmol, 2017, 53: 534-539).


Endoscopic Transmural Therapy of Pancreatic Fistulas in an Interdisciplinary Setting-A Retrospective Data Analysis.
Pancreatic fistulas belong to the most feared complications after surgery on or near the pancreas, abdominal trauma, or severe pancreatitis. The majority occur in the setting of operative interventions and are called postoperative pancreatic fistulas (POPF). They can lead to various complications, including abscesses, delayed gastric emptying or hemorrhages with a significant impact on morbidity and mortality. Several risk factors have been identified, including smoking, high BMI, male gender, and age. Prophylactic measures and treatment options have been explored but with limited success. This study aimed to analyze the incidence and management of pancreatic fistulas treated in a tertiary referral center, particularly focusing on an endoscopic approach. The data of 60 patients with clinically relevant pancreatic fistulas were analyzed between 2018 and 2021. Different treatment approaches, including conservative management, percutaneous drainage, transpapillary stenting, and endoscopic transmural drainage, were evaluated. An endoscopic transmural approach using lumen-apposing metal stents (LAMS) was used in almost half of this cohort showing promising results, with a high rate of fistula closure in refractory cases and a mean time until closure of 2.7 months. The findings suggest that an endoscopic approach, particularly using LAMS, can be effective in the management of pancreatic fistulas.


Non-random assembly of bacterioplankton communities in the subtropical north pacific ocean.
The exploration of bacterial diversity in the global ocean has revealed new taxa and previously unrecognized metabolic potential; however, our understanding of what regulates this diversity is limited. Using terminal restriction fragment length polymorphism (T-RFLP) data from bacterial small-subunit ribosomal RNA genes we show that, independent of depth and time, a large fraction of bacterioplankton co-occurrence patterns are non-random in the oligotrophic North Pacific subtropical gyre (NPSG). Pair-wise correlations of all identified operational taxonomic units (OTUs) revealed a high degree of significance, with 6.6% of the pair-wise co-occurrences being negatively correlated and 20.7% of them being positive. The most abundant OTUs, putatively identified as Prochlorococcus, SAR11, and SAR116 bacteria, were among the most correlated OTUs. As expected, bacterial community composition lacked statistically significant patterns of seasonality in the mostly stratified water column except in a few depth horizons of the sunlit surface waters, with higher frequency variations in community structure apparently related to populations associated with the deep chlorophyll maximum. Communities were structured vertically into epipelagic, mesopelagic, and bathypelagic populations. Permutation-based statistical analyses of T-RFLP data and their corresponding metadata revealed a broad range of putative environmental drivers controlling bacterioplankton community composition in the NPSG, including concentrations of inorganic nutrients and phytoplankton pigments. Together, our results suggest that deterministic forces such as environmental filtering and interactions among taxa determine bacterioplankton community patterns, and consequently affect ecosystem functions in the NPSG.


Losartan protects human stem cell-derived cardiomyocytes from angiotensin II-induced alcoholic cardiotoxicity.
Alcoholic cardiomyopathy (ACM) is a myocardial injury caused by long-term heavy drinking. Existing evidence indicates that high levels of oxidative stress are the key to pathological cardiomyopathy caused by long-term exposure to high concentrations of alcohol, while angiotensin II (AngII) and its type 1 receptor (AT1R) play an important role in excessive drinking. Whether oxidative stress-induced damage in ACM is related to AngII and AT1R is unclear, and the effects of alcohol on the electrophysiology of myocardial cells have not been reported. Most existing studies have used animal models. This study established an in vitro model of ACM based on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The transcriptional profiling of alcohol treatment was performed by RNA-seq analysis. The role of oxidative stress, the expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX), and the role of AngII and AT1R in the overactivation of oxidative stress were studied using fluorescent labeling, Western blotting, and high-content quantitative analysis. Real-time cell analysis(RTCA) and microelectrode array (MEA) were used to continuously monitor myocardial beating, observe the effects of alcohol on myocardial electrophysiological activity, and clarify the protective effects of the AT1R blocker losartan on ACM. We found that AngII and AT1R contribute to the effects of alcohol on the myocardium through oxidative stress damage, the mechanism of which may be achieved by regulating NOX.


An experimental analysis to monitor and manage stress among engineering students using Galvanic Skin Response meter.
This paper studies the impact of musical religious songs (hymns) for managing stress of Indian Engineering students through Galvanic Skin Response (GSR). The objective of the paper is to find out, whether listening to hymns is able to reduce the value of GSR. Sample students were selected through initial screening and the students who reported high mental stress during the interview were selected for the main drills. All the readings were taken using a GSR meter. Statistical t-test was used for the purpose of hypothesis testing. The study examines the relation between GSR and stress. The results indicated that listening to hymns had a significant effect on the value of GSR. The results highlight that GSR decreased at t = 300 seconds for the experimental group, who listened to hymns, as compared to control group (not exposed to the same). It is recommended that, this amazingly effortless and yet highly efficient traditional technique of listening to hymns be made a part of student's routine curriculum. The paper aims at spreading awareness of listening to hymns as one of the modes of Stress Management amongst Indian Engineering Students.


[Cerebellar ataxia and absence epilepsy: genes, channels, neurons and mice].
To briefly review the most significant progress made in the fields of molecular genetics and cellular electrophysiology that have contributed to reveal that some paroxysmal disorders including epilepsy, are linked to voltage gated Ca2+ (CaV) channel abnormalities. Recent studies showed that the gene encoding the P/Q type Ca2+ channel is altered in a number of mutant mice strains. Phenotypic alterations of these mice include cerebellar dysfunction and absence epilepsy. These mutant mice offer a unique opportunity to elucidate the molecular, developmental, and physiological mechanisms underlying CaV channel activity in the brain, and provide the possibility to link specific CaV channel subunits to cellular disease processes, including altered excitability, synaptic signaling, and cell death.


Two-dimensional correlated spectroscopy records reduced neurotransmission in blast-exposed artillery soldiers after live fire training.
There is a requirement for an objective method to determine a safe level of low-level military occupational blast, having recognised it can lead to neurological damage. The purpose of the current study was to evaluate the effect of artillery firing training on the neurochemistry of frontline soldiers using two-dimensional (2D) COrrelated SpectroscopY (2D COSY) in a 3-T clinical MR scanner. Ten men considered to be of sound health were evaluated before and after a week-long live firing exercise in two ways. Prior to the live fire exercise, all participants were screened by a clinical psychologist using a combination of clinical interviews and psychometric tests, and were then scanned with 3-T MRI. The protocols included T1- and T2-weighted images for diagnostic reporting and anatomical localisation and 2D COSY to record any neurochemical effects from the firing. No changes to the structural MRI were recorded. Nine substantive and statistically significant changes in the neurochemistry were recorded as a consequence of firing training. Glutamine and glutamate, glutathione, and two of the seven fucose-α (1-2)-glycans were significantly increased. N-acetyl aspartate, myo-inositol + creatine, and glycerol were also increased. Significant decreases were recorded for the glutathione cysteine moiety and tentatively assigned glycan with a 1-6 linkage (F2: 4.00, F1: 1.31 ppm). These molecules are part of three neurochemical pathways at the terminus of the neurons providing evidence of early markers of disruption to neurotransmission. Using this technology, the extent of deregulation can now be monitored for each frontline defender on a personalised basis. The capacity to monitor early a disruption in neurotransmitters, using the 2D COSY protocol, can observe the effect of firing and may be used to prevent or limit these events.


CT findings and outcomes of acute cholecystitis: is additional ultrasound necessary?
While ultrasound is often the preferred imaging modality for suspected acute cholecystitis (AC), CT is often the first line study when patients are being evaluated for abdominal pain. The diagnostic value of CT in the setting of AC is controversial, given the prevalent use of additional imaging. To evaluate the positive predictive value (PPV) of CT for diagnosing acute cholecystitis (AC) when used as a first line imaging study for evaluating abdominal pain and assess if additional imaging with ultrasound studies provides additional clinically useful information. Abnormal gallbladder findings in CT imaging studies were queried in a retrospective study over a 25-month period within a large urban health system. Sonographic (US) studies performed within 72 h of the initial CT were also included. Outcomes were determined by surgical pathology, fluid analysis, and clinical outcomes. Cases were stratified by the interpreting radiologist's subjective confidence level of diagnosing AC, and the PPVs were compared between cases using CT without US and cases with both CT and US. Of the 468 CT studies meeting criteria, 192 were read as concerning for AC. PPV of CT was 44.7% without US and 50.5% when US was positive, which amounted to an insignificant gain (p = 0.41). When subdividing by confidence level, high-confidence positive CTs demonstrated no significant difference without ultrasound (80%) compared to with ultrasound (75%). Less confident reads in CT demonstrated potential gain from ultrasound; in the case of a "probable" CT impression, PPV increased from 45% without US to 90% with a high-confidence ultrasound impression. Based on current practice within a large health system, CT examinations with high suspicion for AC demonstrated little gain from follow-up ultrasound. However, ultrasound may be of benefit when CT interpretations are less confident but still suspicious for AC.


Kinetic mechanism and structural requirements of the amine-catalyzed decarboxylation of oxaloacetic acid.
The kinetic and chemical mechanism of amine-catalyzed decarboxylation of oxaloacetic acid at pH 8.0 has been reevaluated using a new and versatile assay. Amine-catalyzed decarboxylation of oxaloacetic acid proceeds via the formation of an imine intermediate, followed by decarboxylation of the intermediate and hydrolysis to yield pyruvate. The decrease in oxaloacetic acid was coupled to NADH formation by malate dehydrogenase, which allowed the rates of both initial carbinolamine formation (as part of the imination step) and decarboxylation to be determined. By comparing the rates observed for a variety of amines and, in particular, diamines, the structural and electronic requirements for diamine-catalyzed decarboxylation at pH 8.0 were identified. At pH 8.0, monoamines were found to be very poor catalysts, whereas some diamines, most notably ethylenediamine, were excellent catalysts. The results indicate that the second amino group of diamines enhances the rate of imine formation by acting as a proton shuttle during the carbinolamine formation step, which enables diamines to overcome high levels of solvation that would otherwise inhibit carbinolamine, and thus imine, formation. The presence of the second amino group may also enhance the rate of the carbinolamine dehydration step. In contrast to the findings of previous reports, the second amino group participates in the reaction by enhancing the rate of decarboxylation via hydrogen-bonding to the imine nitrogen to either stabilize the negative charge that develops on the imine during decarboxylation or preferentially stabilize the reactive imine over the unreactive enamine tautomer. These results provide insight into the precise catalytic mechanism of several enzymes whose reactions are known to proceed via an imine intermediate.


Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against gram-positive pathogens.
Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.


Central administration of endocannabinoids exerts bimodal effects in food intake of rainbow trout.
The endocannabinoid system (ECs) is known to participate in several processes in mammals related to synaptic signaling including regulation of food intake, appetite and energy balance. In fish, the relationship of ECs with food intake regulation is poorly understood. In the present study, we assessed in rainbow trout Oncorhynchus mykiss the effect of intracerebroventricular administration (ICV) of low and high doses of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake. We assessed endocannabinoid levels in hypothalamus, telencephalon and plasma as well as the effect of AEA and 2-AG administration at central level on gene expression of receptors involved in ECs (cnr1, gpr55 and trpv1) and markers of neural activity (fos, ntrk2 and GABA-related genes). The results obtained indicate that whereas high doses of endocannabinoids did not elicit changes in food intake levels, low doses of the endocannabinoids produce an orexigenic effect that could be due to a possible inhibition of gabaergic neurotransmission and the modulation of neural plasticity in brain areas related to appetite control, such as hypothalamus and telencephalon.


Mac-1+ cells are the predominant subset in the early hepatic lesions of mice infected with Francisella tularensis.
The cell composition of early hepatic lesions of experimental murine tularemia has not been characterized with specific markers. The appearance of multiple granulomatous-necrotic lesions in the liver correlates with a marked increase in the levels of serum alanine transferase and lactate dehydrogenase. Francisella tularensis, detected by specific antibodies, can be first noted by day 1 and becomes associated with the lesions by 5 days postinoculation. These lesions become necrotic, with some evidence of in situ apoptosis. The lesions do not contain B, T, or NK cells. Rather, the lesions are largely composed of two subpopulations of Mac-1(+) cells that are associated with the bacteria. Gr-1(+) Mac-1(+) immature myeloid cells and major histocompatibility complex class II-positive (MHC-II(+)) Mac-1(+) macrophages were the most abundant cell phenotypes found in the granuloma and are likely major contributors in controlling the infection in its early stages. Our findings have shown that there is an early development of hepatic lesions where F. tularensis colocalizes with both Gr-1(+) Mac-1(+) and MHC-II(+) Mac-1(+) cells.


Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ1-42-induced neurotoxicity via activating the JAK2/STAT3 axis.
The neurotoxicity of aggregated amyloid beta (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, Aβ-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by Aβ in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-mediated neuroprotective activity, this study extensively evaluated whether activation of the JAK2/STAT3 axis by CNTF was responsible for the neuroprotective effect of this protein against Aβ1-42-induced cytotoxicity, oxidative injury and cell apoptosis in human SH-SY5Y neuroblastoma cells. Our data showed that CNTF could attenuate or restore cell injury induced by Aβ1-42 in human SH-SY5Y neuroblastoma cells through activating the JAK2/STAT3 signaling pathway. Furthermore, CNTF strikingly prevented Aβ1-42-induced mitochondrial dysfunction and activation of mitogen-activated protein kinases (MAPKs), an effect that could be potently attenuated by the specific JAK2 inhibitor AG490. In summary, this study confirmed the detailed mechanism accounting for CNTF's protective effect against Aβ1-42-induced cytotoxic events in human SH-SY5Y neuroblastoma cells - information which might significantly contribute to better understanding of the mechanism of action of CNTF as well as providing a novel target in AD therapy.


Gender-dependent regulation of anxiety-like behavior by δ subunit-containing GABAA receptor during postnatal development.
The δ subunit-containing GABAA receptor [GABAA(δ)R], which is exclusively situated in the extrasynaptic space, has considerable influence on emotion and behavior. Although the expression of this receptor experiences dramatic fluctuation during postnatal development, it remains unknown whether it regulates emotion in a development-dependent manner. Here, by using mice with genetic deletion of GABAA(δ)R (knockout) and their wild-type littermates, we examined the role of GABAA(δ)R in regulating anxiety-like behavior, as measured with open field test (OFT) and elevated plus maze during the transition from puberty to adulthood. We observed that for female mice, the knockout ones at puberty but not adulthood showed increased anxiety-like behavior in the OFT relative to their wild-type littermates. However, such increase was not observed in elevated plus maze. For male mice, no between-genotype differences were observed in both tests at the above two developmental stages. Our results suggest that GABAA(δ)R preferentially affects the anxiety-like behavior in OFT in a development-dependent manner, but only in female mice.


The COVID-19 vaccination experience of non-English speaking immigrant and refugee communities of color: A community co-created study.
In this community-partnered study we conducted focus groups with non-English speaking immigrant and refugee communities of color in 4 languages to understand their perspectives on COVID-19 vaccines, barriers to accessing vaccines, and recommendations for healthcare providers. We used a mixed deductive-inductive thematic analysis approach and human centered design to guide data analysis. 66 individuals participated; 85% were vaccinated. The vaccination experience was often positive; however, participants described language inaccessibility, often relying on family members for interpretation. Community-based organizations played a role in connecting participants to vaccines. Unvaccinated participants expressed fear of side effects and belief in natural immunity. Participants shared recommendations to providers around increasing vaccine access, improving language accessibility, and building trust. Results from our study show numerous barriers immigrant and refugee communities of color faced getting their COVID-19 vaccine, but also highlights opportunities to engage with community partners. Future implications for research, policy, and practice are described.


The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations.
Hallucinations remains one of the most intriguing phenomena in psychopathology. In the past two decades the advent of neuroimaging techniques have allowed researchers to investigate what is happening in the brain of those who experience hallucinations. In this article we review both structural and functional neuroimaging studies of patients with auditory and visual hallucinations as well as a small number of studies that have assessed cognitive processes associated with hallucinations in healthy volunteers. The current literature suggests that in addition to secondary (and occasionally primary) sensory cortices, dysfunction in prefrontal premotor, cingulate, subcortical and cerebellar regions also seem to contribute to hallucinatory experiences. Based on the findings of these studies we tentatively propose a neurocognitive model in which both bottom-up and top-down processes interact to produce these erroneous percepts. Finally, directions for future work are discussed.


Reproductive hormone sensitivity and risk for depression across the female life cycle: a continuum of vulnerability?
Throughout most of their lives, women are at greater risk for depression than men. Hormones and neurotransmitters share common pathways and receptor sites in areas of the brain linked to mood, particularly through the hypothalamic-pituitary-gonadal axis. It has been hypothesized that women presenting with episodes of depression associated with reproductive events (i.e., premenstrual, postpartum, menopausal transition) may be particularly prone to experiencing depression, in part because of a heightened sensitivity to intense hormonal fluctuations. The menopausal transition, for example, appears to represent a window during which some women might be more vulnerable to the development of first onset or recurrent depressive symptoms and major depressive episodes. In this review, we examine the association between hormone changes and increased risk of developing depression. Some of the underlying mechanisms that may contribute to such an increased risk are discussed critically, with a special emphasis on the events occurring during the menopausal transition. Last, we explore some of the clinical and therapeutic implications of hormone-modulated depression in women.