Application of carbon isotope stratigraphy to late miocene shallow marine sediments, new zealand.
A distinct (0.5 per mil) carbon-13/carbon-12 isotopic shift in the light direction has been identified in a shallow marine sedimentary sequence of Late Miocene age at Blind River, New Zealand, and correlated with a similar shift in Late Miocene Deep Sea Drilling Project sequences throughout the Indo-Pacific. A dated piston core provides an age for the shift of 6.2 +/- 0.1 million years. Correlations based on the carbon isotopic change require a revision of the previously established magnetostratigraphy at Blind River. The carbon shift at Blind River occurs between 6.2 and 6.3 +/- 0.1 million years before present. A new chronology provides an age for the evolutionary first appearance datum of Globorotalia conomiozea at 6.1 +/- 0.1 million years, the beginning of a distinct latest Miocene cooling event associated with the Kapitean stage at 6.2 +/- 0.1 million years, and the beginning of a distinct shallowing of water depths at 6.1 +/- 0.1 million years. The Miocene-Pliocene boundary as recognized in New Zealand is now dated at 5.3 +/- 0.1 million years. Extension of carbon isotope stratigraphy to other shallow Late Miocene sequences should provide an important datum for international correlation of Late Miocene shallow and deep marine sequences.


Bucco-lingual bone remodeling around implants placed into immediate extraction sockets: a case series.
Implants placed immediately after tooth extraction have shown high percentages of clinical success. Few studies in the scientific literature have observed the horizontal bone remodeling in the buccal-lingual direction after immediate placement of implants. The aim of this study was to analyze bone healing and coronal bone remodeling around 15 implants placed immediately after tooth removal without the use of guided bone regeneration (GBR) techniques. Ten patients received a total of 15 implants placed immediately after removal of 15 single-rooted teeth. All implants were placed within the alveolar confines, limiting, in most cases, small peri-implant bone defects. After implant placement, the distance from the buccal to lingual bone plate was measured. No membranes or filling materials were used. Primary flap closure was performed in all cases. At second-stage surgery, all peri-implant defects were completely filled and the distance from buccal to lingual bone was measured again. The pattern of bone healing around the neck of immediate implants showed an absence of peri-implant defects and a narrowing of bone crest width in a buccal-lingual direction. The mean distance between buccal bone and lingual bone at the time of implant placement was 10.5 mm (+/- 1.52) and, at second-stage surgery, 6.8 mm (+/- 1.33). The coronal bone remodeling around immediate implants showed a healing pattern with new bone apposition around the neck of the implants and, at the same time, bone resorption with horizontal width reduction of the bone ridge. The small peri-implant bone defects were completely healed without the use of GBR procedures. An absence of complications during the healing period was also observed, probably due to the absence of barrier membranes and grafting materials.


Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.
Kruppel-like factor 6 (KLF6) is a ubiquitous zinc finger tumor suppressor that is often mutated in prostate cancer. Our aims were to establish the frequency of KLF6 inactivation in sporadic and inflammatory bowel disease (IBD)-associated colorectal cancers (CRC); to correlate these abnormalities with mutation and/or loss of TP53, APC, and K-RAS; and to characterize the behavior of mutant KLF6 in colon-derived cell lines. We analyzed DNA isolated from 50 microdissected CRC cases, including 35 sporadic and 15 IBD-associated tumors. Microsatellite analysis and direct sequencing were used to establish the incidence of microsatellite instability, KLF6 and TP53 allelic imbalance, and KLF6, K-RAS, TP53, and APC mutation. Loss of growth suppressive function of the CRC-derived KLF6 mutants was characterized by in vitro thymidine incorporation assays and Western blotting. KLF6 was inactivated by loss and/or mutation in most sporadic and IBD-related CRCs. The KLF6 locus was deleted in at least 55% of tumors, and mutations were identified in 44%. Rates of KLF6 loss and mutation were similar to those of TP53 and K-RAS in the same samples. KLF6 mutations were present in tumors with either microsatellite or chromosomal instability and were more common, particularly in the IBD-related cancers, in the presence of wild-type APC. Unlike wild-type KLF6, cancer-derived KLF6 mutants neither suppressed growth nor induced p21 following transfection into cultured cells. Deregulation of KLF6 by a combination of allelic imbalance and mutation may play a role in the development of CRC.


Scoliosis correction surgery for patients with McCune-Albright syndrome using pedicle screws: a report of two cases with different characteristics and a review of the literature.
Scoliosis can occur secondary to McCune-Albright syndrome (MAS); it can be progressive and sometimes requires surgical treatment. It is still unclear if pedicle screw (PS) fixation in these patients with poor bone quality can be considered an effective treatment for scoliosis. The purpose of this study is to report two MAS patients with spinal fibrous dysplasia (FD) who underwent scoliosis surgeries with the PS system. Case 1: a 12-year-old girl. Standing posteroanterior radiographs revealed a 58° right curve from T7 to L2. Computed tomography (CT) showed small areas of FD throughout the spine. A posterior spinal arthrodesis from T4 to L3 using PS fixation was performed with a CT-based navigation system. Case 2: a 26-year-old woman. Radiographs in the standing position revealed a right 87° curve from T8 to L2 and a 55° kyphosis from T8 to T12. CT images showed multiple areas of severe spinal FD causing angular deformity and collapse of vertebral bodies. The patient underwent posterior spinal arthrodesis from T8 to her pelvis using a CT-based navigation system for PS fixation. Superior scoliosis corrections were obtained using PS instrumentation, attaining complete bony union in both cases without major complications. However, Case 2 had some technical difficulties in treating due to the multiple large FD lesions. PS fixation can be considered an effective treatment for correcting scoliosis and maintaining the correction at follow-up in MAS patients with poor bone quality. However, great care must be taken when performing correction and follow-up.


Mental Health in Allergic Rhinitis: Depression and Suicidal Behavior.
A high proportion of suicides visit their medical provider in the month prior to death, but depression, suicidal thoughts, and substance use are seldom addressed. For the clinicians routinely treating a substantial patient population with allergic diseases, there are additional concerns, as allergy has been linked with both depression and suicidal behavior. While psychotropic medications may affect diagnosis of allergies, medications used to treat allergies impact mood and behavior. Thus, we present an overview of the overlap of allergic rhinitis with depression and suicidal behavior in adults, based on clinical and epidemiological data, and our research and clinical experience. In summary, we suggest: 1) inquiring among patients with allergies about personal and family history of depression, substance use disorders, suicidal ideation and attempts 2) increased mindfulness regarding the potential effects of allergy medications on mood and behavior; and 3) for people identified with certain types of depression or increased suicide risk, a systematic multilevel collaborative approach. While for practical reasons the majority of patients with depression will continue to be treated by general or family practitioners, the allergy-treating provider should always consider integrated care for bipolar, psychotic or suicidal depression and incomplete remission, or relapsing and highly recurrent course. While awaiting results of much needed basic and clinical research to guide clinical approach for patients with comorbid allergic rhinitis and depression, the simple steps recommended here are expected to improved clinical outcomes in depression, including, on a large scale, reduced premature deaths by suicide.


Delta Np63 alpha – Responsive microRNA Modulate the Expression of Metabolic Enzymes.
MicroRNAs, whose transcription is regulated by members of the tumor protein p53 family, modulate the expression of numerous metabolic enzymes, significantly altering tumor cell response to chemotherapeutic treatments. The role for ΔNp63α-regulated microRNAs in regulation of cell cycle arrest, apoptosis and autophagy in squamous cell carcinoma (SCC) cells upon cisplatin exposure has been reported. The current study indicated that the selected microRNA targets differentially regulated by ΔNp63α in cisplatin-sensitive and cisplatin-resistant SCC cells could alter the expression of a few metabolic enzymes, thereby potentially contributing to the metabolic changes in SCC cells upon cisplatin exposure. Finally, the modulation of specific targets (e.g., SREBF2, AKT2, G6PD, CPS1, FADS1, and ETNK1) using a combination of microRNA mimics and siRNA silencing has shown that a suppression of these metabolic factors/ enzymes could confer a sensitivity of SCC cells to cisplatin. Thus, the Δ Np63α-regulated microRNAs were found to regulate the levels of several metabolic factors and enzymes, thereby potentially contributing to the response of larynx and tongue-derived SCC cells to platinum chemotherapy.


Volume and dose-response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung.
To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5 Gy fractions over 6 weeks. No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose-response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2-66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5-52.0 Gy, 95% CI). The ED50 and ED5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2-53.5Gy, 95% CI) and 39.1 Gy (8.8-41.8 Gy, 95% CI) respectively. Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.


Current Practices of Live Discharge from Hospice: Social Work Perspectives.
Hospice provides holistic support for individuals living with terminal illness and to their caregivers during the bereavement period. However, some individuals who enroll in hospice services are decertified as they do not experience a decline in health as quickly as required by current regulations, a practice referred to as a live discharge. The interruption in care can affect the physical and psychosocial care needs for individuals and caregivers and leave hospice clinicians with questions about how to best support them. However, there are no formal guidelines to support this process. This qualitative study (N = 24) explored the current practices of hospice social workers across the United States engaged in the live discharge process. Results from this study emphasize the need to bridge the gaps between policy and practice. Specifically, results highlight the challenges hospice social workers face to replicate or supplement the holistic support and unique services hospice provides for individuals discharged alive, and suggest further research to develop live discharge guidelines to identify appropriate support for patients and their caregivers who no longer meet hospice eligibility requirements.


A randomized waitlist control community study of Social Cognition and Interaction Training for people with schizophrenia.
Social Cognition and Interaction Training (SCIT) has demonstrated effectiveness in improving social cognition and functioning of people with schizophrenia. This pilot study examines the acceptability, feasibility, and effectiveness of SCIT with individuals who have schizophrenia-spectrum disorders and are receiving care through a public mental health service. In a pragmatic randomized waitlist controlled trial, 36 participants (aged 19-55 years) with a schizophrenia spectrum disorder were randomly allocated to SCIT or treatment as usual (TAU). Measures of theory of mind, emotion perception, attributional bias, social skills, quality of life, life skills, depression, anxiety, and stress were administered pre- and post-intervention with follow-up conducted 4 months later. All wait-list controls subsequently received the intervention and a secondary within-group analysis was conducted including these participants. While no significant differences were found between groups on any outcomes, there was strong engagement with the SCIT intervention. Of the 21 participants in the intervention group, the completion rate was 85.71% with a median attendance rate of 17 sessions. Within subject analyses of SCIT participants over time showed significant improvements in quality of life, emotion recognition, social skills, and a trend towards better life skills from pre- to post-intervention. These gains were sustained at the 4-month follow-up time. Although this study showed limited benefits in outcomes associated with SCIT compared with TAU, it demonstrated the acceptability of SCIT to participants in a real world public health setting shown by high retention, attendance, and positive feedback. This pilot shows SCIT can be implemented in routine clinical practice and lays the foundation for a larger pragmatic study. SCIT can be implemented successfully in a real-world community mental health setting. SCIT had high levels of acceptability to these participants. Limitations The small sample size meant there was insufficient power to detect differences between groups on outcome measures. The study did not include measures of psychiatric symptoms or neuropsychological functioning which may have influenced participants' capacity to benefit from SCIT.


Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?
Fish and commercially available fish oil preparations are rich sources of long-chain omega-3 polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important fatty acids in fish oil. Following dietary intake, these fatty acids get incorporated into the cell membrane phospholipids throughout the body, especially in the heart and brain. They play an important role in early brain development during infancy, and have also been shown to be of benefit in dementia, depression, and other neuropsychiatric disorders. Early epidemiologic studies show an inverse relationship between fish consumption and the risk of coronary heart disease. This led to the identification of the cardioprotective role of these marine-derived fatty acids. Many experimental studies and some clinical trials have documented the benefits of fish oil supplementation in decreasing the incidence and progression of atherosclerosis, myocardial infarction, heart failure, arrhythmias, and stroke. Possible mechanisms include reduction in triglycerides, alteration in membrane fluidity, modulation of cardiac ion channels, and anti-inflammatory, anti-thrombotic, and anti-arrhythmic effects. Fish oil supplements are generally safe, and the risk of toxicity with methylmercury, an environmental toxin found in fish, is minimal. Current guidelines recommend the consumption of either one to two servings of oily fish per week or daily fish oil supplements (around 1 g of omega-3 polyunsaturated fatty acids per day) in adults. However, recent large-scale studies have failed to demonstrate any benefit of fish oil supplements on cardiovascular outcomes and mortality. Here, we review the different trials that evaluated the role of fish oil in cardiovascular diseases.


Robust modeling of differential gene expression data using normal/independent distributions: a Bayesian approach.
In this paper, the problem of identifying differentially expressed genes under different conditions using gene expression microarray data, in the presence of outliers, is discussed. For this purpose, the robust modeling of gene expression data using some powerful distributions known as normal/independent distributions is considered. These distributions include the Student's t and normal distributions which have been used previously, but also include extensions such as the slash, the contaminated normal and the Laplace distributions. The purpose of this paper is to identify differentially expressed genes by considering these distributional assumptions instead of the normal distribution. A Bayesian approach using the Markov Chain Monte Carlo method is adopted for parameter estimation. Two publicly available gene expression data sets are analyzed using the proposed approach. The use of the robust models for detecting differentially expressed genes is investigated. This investigation shows that the choice of model for differentiating gene expression data is very important. This is due to the small number of replicates for each gene and the existence of outlying data. Comparison of the performance of these models is made using different statistical criteria and the ROC curve. The method is illustrated using some simulation studies. We demonstrate the flexibility of these robust models in identifying differentially expressed genes.


Lung-volume controlled computerised tomography in real-life acute severe asthma.
It is not known how airway structure is altered during real-life acute asthma exacerbations. The aim of this study was to examine changes in airway structure during acute asthma exacerbations and at convalescence by using lung-volume controlled high resolution computerised tomography (HRCT). Eight subjects with acute asthma exacerbation admitted to hospital were recruited. HRCT was performed within 72 h of admission (n = 8) and repeated after 8 weeks of convalescence (n = 7). Individual airways were carefully matched on acute and convalescent CT data sets for comparisons of airway parameters. A novel methodology was employed for standardisation of lung volumes to permit valid comparisons of lung imaging. Measurements of bronchial cross sectional airway area (Aa) and bronchial luminal area (Ai) for each matched airway were obtained using a validated program. The airway wall thickness was analysed as wall area (WA) calculated as a percentage: WA% = WA/Aa × 100. Wilcoxon signed-rank testing was used to compare acute and convalescent asthma and Spearman's correlation to examine associations. Airway lumen (Ai) areas were similar in both acute and stable asthma phases (6.6 ± 3.1 mm(2) versus 7.2 ± 3.8 mm(2) p = 0.8). However, the airway wall was significantly thickened during acute asthma exacerbations compared to convalescence (62 ± 4% versus 55 ± 7%; p = 0.01). There was no correlation between airway structure dimensions and lung function measurements. This is the first study to demonstrate an increase in airway wall thickness during real-life acute asthma exacerbation. However, narrowing of the airway lumen area was variable and will require larger studies able to detect small differences. These results suggest that airway wall thickening linked to mucosal inflammation is likely to characterise acute asthma in vivo but that changes in the airway lumen accompanying bronchoconstriction may be more heterogeneous.


Epidemiological typing of Candida albicans from bloodstream infections by restriction enzyme analysis.
Candida albicans blood culture isolates (n = 142) from 130 patients treated in 7 acute care hospitals in Southern Finland between 1986 and 1995 were typed by restriction enzyme analysis (REA) with EcoRI and MspI. REA revealed 118 distinct DNA types: 13 were detected in > 1 patient and 105 DNA types were unique. Patients with identical DNA types were not temporally or geographically clustered. Among 11 patients with more than 1 C. albicans isolate during 1 episode of fungemia the DNA type remained the same, except in 1 patient. These results indicate that REA is a powerful tool for the epidemiological typing of C. albicans infections.


Identification of spontaneous cardiac baroreflex episodes at different timescales in rats.
To study spontaneous cardiac baroreflex at different timescales, a new method has been developed that identifies such episodes. Mean arterial pressure (MAP) and heart rate (HR) were recorded beat to beat over 1 h in freely moving control (n = 10) and acutely (1 day before study, n = 7) and chronically (2 wk before study, n = 10) sinoaortic-denervated (SAD) 12- to 14-wk-old male Sprague-Dawley rats. These beat-to-beat time series were successively low-pass filtered seven times and resampled at different time intervals from 0.1 to 6.4 s, allowing different timescales to be scanned. With the use of the Z coefficient, the statistical relationship was estimated for the associations of inverse MAP and HR variations when these inverse MAP and HR variations occurred simultaneously or were time shifted. In control rats and for timescales > or = 0.4 s, the highest Z coefficient (0.38) was obtained when MAP variations preceded inverse HR variations by one sampling interval. The baroreflex origin of this link was demonstrated by its disappearance after acute SAD. In conclusion, this method enabled spontaneous baroreflex episodes to be identified for unusually long timescales without limiting the study to fast, linear, stationary, or oscillating phenomena.


Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences.
Background: Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome. Methods: The plasma metabolomes of children with autism spectrum disorder (ASD; n = 167), idiopathic developmental delay (i-DD; n = 51), Down syndrome (DS; n = 31), and typically developing controls (TD; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child's neurodevelopmental diagnosis, child's sex, child's age, child's race/ethnicity, maternal age at child's birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population. Results: Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child's neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors. Conclusions: Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.


Is the "triple rule-out" study an appropriate indication for cardiovascular CT?
There is interest in using the fast volume coverage of 64-slice cardiovascular CT angiography (CCTA) in patients presenting with undifferentiated acute chest pain to simultaneously evaluate the coronary arteries, thoracic aorta, and pulmonary arteries during a single breathhold, the so-called "triple rule-out." However, it is not clear whether the triple rule-out study is an appropriate indication for cardiovascular CCTA. Initial studies suggest that performing a triple rule-out protocol to comprehensively evaluate patients with acute chest pain presenting to the emergency department (ED) is feasible and that quantitative parameters of image quality may be comparable to the conventional, dedicated coronary and pulmonary CTA protocols. Recent data also suggest that a triple rule-out protocol has the potential to identify a subset of patients presenting with acute chest pain who can safely be discharged from the ED. In addition, new scanner technology has also reduced the contrast and radiation doses necessary for such an examination. However, despite these early encouraging results, randomized control trials designed to determine whether this protocol is safe, cost-effective, and improves clinical decision making are necessary before routine implementation of such an examination can be justified.


Engineering extended membrane scaffold proteins for self-assembly of soluble nanoscale lipid bilayers.
High-density lipoproteins (HDLs) play an important role in human health through the metabolism and trafficking of cholesterol as well as providing the feedstocks for steroid hormone biosynthesis. These particles contain proteins, primarily Apo-AI and phospholipid and progress through various structural forms including 'lipid-poor', 'discoidal' and 'spherical' entities as cholesterol esters and lipid are incorporated. The discoidal form of HDL is stabilized in solution by two encircling belts of Apo-AI. Previous protein engineering of the Apo-AI sequence has led to a series of amphipathic helical proteins, termed membrane scaffold proteins (MSPs), which have shown great value in assembling nanoscale soluble membrane bilayers, termed Nanodiscs, of homogeneous size and composition and in the assembly of numerous integral membrane proteins for biophysical and biochemical investigations. In this communication we document a protein engineering approach to generate and optimize an extended polypeptide MSP, which will self-assemble phospholipids into larger Nanodiscs with diameters of 16-17 nm. We extensively characterize these structures by size exclusion chromatography and solution X-ray scattering.


Time course of enhanced endothelium-mediated dilation in aorta of trained rats.
Previous work has demonstrated that 10 wk of exercise training enhances the responsiveness of rat abdominal aortas to acetylcholine (ACh), an endothelium-dependent vasodilator. The purpose of this study was to determine the time course for this training-induced adaptation of vascular endothelium. Additionally, the contribution of the cyclooxygenase and nitric oxide synthase mechanisms to the enhanced endothelium-mediated relaxation were examined. Male rats were divided into sedentary (SED) and exercise groups. Exercised animals were further subdivided into postexercise (POST-EX), 1 DAY, 1 WK, 2 WK, 4 WK and 10 WK groups. Exercise consisted of treadmill running at 30 m.min-1 (15 degrees incline) for 1 h.d-1 (5 d.wk-1 for the 1 WK, 2 WK, 4 WK, and 10 WK groups). Maximal vasodilator responses induced by 10(-4) M ACh (10(-7) M norepinephrine preconstriction) were determined on abdominal aortic rings in vitro immediately after a single exercise bout in POST-EX rats and 24 h after a single bout of exercise in 1 DAY animals. Maximal 10(-4) M ACh-induced dilation of aortas from 1 WK, 2 WK, 4 WK, and 10 WK animals was determined 24 h after the last exercise bout. Soleus muscle citrate synthase activity was greater in 2 WK (31 +/- 1 mumol.min-1.g wet wt-1), 4 WK (34 +/- 2), and 10 WK (36 +/- 1 mumol.min-1.g wet wt-1) rats than in SED (27 +/- 1 mumol.min-1.g wet wt.-1) animals. Maximal ACh-induced relaxation was greater in aorta from 4 WK (72 +/- 2%) and 10 WK (79 +/- 1%) rats than SED (61 +/- 2%) rats. ACh-mediated dilatory responses remained enhanced in the presence of the cyclooxygenase blocker indomethacin (10(-5) M), but were abolished by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (300 microM). In addition, the expression of endothelial nitric oxide synthase (ecNOS) protein in aortas from 4 WK (P = 0.057) and 10 WK (P < 0.05) rats was greater than in aortas from SED animals. These data indicate that the enhanced endothelium-dependent, ACh-mediated dilation of the rat aorta is present by 4 wk of endurance exercise training. This adaptation appears to be mediated primarily through the nitric oxide synthase pathway and is associated with an increased expression of ecNOS.


Partial Social Integration as a Predictor of COVID-19 Vaccine Rejection and Distress Indicators.
Partial social integration refers to the perceived exclusion of individuals or groups, from full participation in their society. The current study claims that perceived partial social integration (PPSI) constitutes a substantial predictor of the rejection of the COVID-19 vaccine, a significant mediator of the impact of demographic variables (such as age and level of income) on this vaccine rejection, and an important predictor of indices of psychological distress during pandemic times. Previous publications show that although vaccines constitute a very efficient means for countering pandemics, vaccine hesitancy is a prevalent public response to the COVID-19 pandemic. The present study is one of a few studies examining the impact of psychological variables on the actual behavior of vaccine rejection rather than on the cognitive element of vaccine hesitancy. A sample of 600 Israeli Jewish adults responded in February 2022 to an anonymous questionnaire exploring, among other issues, the (PPSI), the individual level of vaccine uptake, and the level of distress of these individuals. Path analyses of the variables predicted by PPSI indicated the following results: (a) PPSI score negatively predicted vaccine uptake level and significantly mediated the effects of age and family income on the level of vaccination. (b) PPSI levels significantly predicted higher levels of anxiety, depression, and a sense of danger and negatively predicted societal resilience. The discussion elaborates the contention that the PPSI is a substantial cause of psychological distress and in compliance with the pandemic vaccination guidelines, despite the potential health risk involved.


Probiotic Pediococcus pentosaceus Li05 Improves Cholestasis through the FXR-SHP and FXR-FGF15 Pathways.
Primary sclerosing cholangitis (PSC), a rare chronic cholestatic liver disease, is characterized by intrahepatic or extrahepatic strictures accompanied by biliary fibrosis. So far, there are no effective therapies to slow down the progression of this disease. Farnesoid X receptors (FXRs) are ligand-activated transcription factors involved in the control of bile acid (BA) synthesis and enterohepatic circulation. Therefore, targeting FXRs holds promise as a potential approach for treating PSC. Pediococcus pentosaceus Li05 is a probiotic that was isolated from healthy volunteers and has previously been shown to have an anti-inflammatory effect in DSS-induced colitis. In this study, we established a 3,5-diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced cholestasis mouse model and investigated the effects of Pediococcus pentosaceus Li05 on PSC. Our findings revealed that administration of Li05 significantly attenuated liver damage, hepatic inflammation, and fibrosis, as well as bile duct hyperplasia. Li05 activated the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways to decrease the expression of Cyp7a1. In addition, the Li05-modulated gut microbiota structure especially improved the abundance of 7α-dehydroxylation bacteria like Eubacterium. The intervention of Li05 also improved the intestinal barrier and reduced bacterial endotoxin translocation. Based on these findings, Li05 shows promise for future application as a therapeutic strategy for cholestasis.


Heterogeneous reovirus susceptibility in human glioblastoma stem-like cell cultures.
Glioblastoma (GB) is a devastating disease for which new treatment modalities are needed. Efficacious therapy requires the removal of stem-cell like cells, these cells drive tumor progression because of their ability to self-renew and differentiate. In glioblastoma, the GB stem-like cells (GSC) form a small population of tumor cells and possess high resistance to chemo and radiation therapies. To assess the sensitivity of GSC to reovirus-mediated cytolysis, a panel of GSC cultures was exposed to wild-type reovirus Type 3 Dearing (T3D) and its junction adhesion molecule-A (JAM-A)-independent mutant, jin-1. Several parameters were evaluated, including the fraction of cells expressing the JAM-A reovirus receptor, the fraction of cells synthesizing reovirus proteins, the number of infectious reovirus particles required to reduce cell viability, the amount of infectious progeny reovirus produced and the capacity of the reoviruses to infect the GSC in 3-dimensional (3D) tumor cell spheroids. Our data demonstrate a marked heterogeneity in the susceptibility of the cultures to reovirus-induced cytolysis. While in monolayer cultures the jin-1 reovirus was generally more cytolytic than the wild-type reovirus T3D, in the 3D GSC spheroids, these viruses were equally effective. Despite the variation in reovirus sensitivity between the different GSC cultures, our data support the use of reovirus as an oncolytic agent. It remains to be established whether the variation in the reovirus sensitivity correlates with a patient's response to reovirus therapy. Moreover, our data show that the expression of the JAM-A receptor is not a major determinant of reovirus sensitivity in 3D GSC cultures.


The microbial community composition of a nitrifying-denitrifying activated sludge from an industrial sewage treatment plant analyzed by the full-cycle rRNA approach.
The composition of the microbial community present in the nitrifying-denitrifying activated sludge of an industrial wastewater treatment plant connected to a rendering facility was investigated by the full-cycle rRNA approach. After DNA extraction using three different methods, 94 almost full-length 16S rRNA gene clones were retrieved and analyzed phylogenetically. 59% of the clones were affiliated with the Proteobacteria and clustered with the beta- (29 clones), alpha- (24), and delta-class (2 clones), respectively. 15 clones grouped within the green nonsulfur (GNS) bacteria and 11 clones belonged to the Planctomycetes. The Verrucomicrobia, Acidobacteria, Nitrospira, Bacteroidetes, Firmicutes and Actinobacteria were each represented by one to five clones. Interestingly, the highest 'species richness' [measured as number of operational taxonomic units (OTUs)] was found within the alpha-class of Proteobacteria, followed by the Planctomycetes, the beta-class of Proteobacteria, and the GNS-bacteria. The microbial community composition of the activated sludge was determined quantitatively by using 36 group-, subgroup-, and OTU-specific rRNA-targeted oligonucleotide probes for fluorescence in situ hybridization (FISH), confocal laser scanning microscopy and digital image analysis. 89% of all bacteria detectable by FISH with a bacterial probe set could be assigned to specific divisions. Consistent with the 16S rRNA gene library data, members of the beta-class of Proteobacteria dominated the microbial community and represented almost half of the biovolume of all bacteria detectable by FISH. Within the beta-class, 98% of the cells could be identified by the application of genus- or OTU-specific probes demonstrating a high in situ abundance of bacteria related to Zoogloea and Azoarcus sensu lato. Taken together, this study provides the first encompassing, high-resolution insight into the in situ composition of the microbial community present in a full-scale, industrial wastewater treatment plant.


Understanding ADHD in AAPI College Students: Prevalence, Comorbidities, Impairments, and Treatment Utilization.
Asian American and Pacific Islander (AAPI) students with ADHD may face increased risk for college maladjustment due to cultural factors and a tendency to delay treatment. This is the first study to examine ADHD prevalence, ADHD-related impairments and comorbidities, and ADHD treatment utilization in AAPI college students. AAPI, White, Hispanic, and Black undergraduates (n = 258,005) from the American College Health Association-National College Health Assessment II survey were included in the study. AAPI students had lower ADHD prevalence rates than White and Black students, and similar prevalence to Hispanic students. AAPI students with ADHD had significantly higher risk for comorbidities and social and academic impairments, compared to White students with ADHD. Approximately half of AAPI students with ADHD did not utilize treatment despite experiencing psychiatric comorbidities and functional impairments. AAPI college students with ADHD are underutilizing treatment despite elevated psychiatric comorbidities and functional impairment.


A General Framework for Prioritizing Land Units for Ecological Protection and Restoration.
/ Past methods of prioritizing sites for protection and restoration have focused on lists of criteria or algorithms. These methods lack a common underlying framework, such that the process is explicit and repeatable, assumptions are highlighted, and commonalities and differences among prioritizations can be readily assessed. Our objective in this paper is to provide such a framework for cases where the goal of setting priorities is to maximize the ecological benefit gained from limited resources. We provide simple and general models that can be used to prioritize sites based on the projected ecological benefit per unit restoration or protection effort and to estimate the total projected benefit of restoring or protecting a set of sites. These models, which are based on an expression of the functional relationship between an end point and effort, hold up under a variety of situations and provide a common language for prioritization. We then discuss procedures for estimating model terms-calculations from regression curves when data are available, and use of judgement indicators when data are relatively limited. Finally, we present two case studies that apply the models and examine selected past prioritizations in the context of our framework.


Immediate Effect of Slow Deep Breathing Exercise on Blood Pressure and Reaction Time.
Blood pressure in our body is finely regulated through autonomic nervous system and cardiac centers and studies established that parasympathetic dominance exerted by slow deep breathing decreases blood pressure. Reaction time is an estimate of the subject's capacity for inhibiting pre-potent motor responses. Decreased reaction time indicates greater alertness, faster information processing and less distractibility. Nevertheless, there has been conflicting results about the effect of deep slow breathing on reaction time The present research targeted a community based cross sectional observational study (n=80, age=17-70 years) performed in Lalitpur Municipality, Ward number-14, Nepal from May 2019 to June 2019, to observe the immediate effect of slow deep breathing exercise on blood pressure and reaction time by using online visual reaction time test. Volunteers performed the slow breathing exercise (approximately 4seconds inhalation and 6 seconds exhalation) in Sukhasana for 5 minutes. Base-line and post-slow-breathing blood pressure and visual reaction time was recorded and compared. Decrease in systolic and diastolic pressure was recorded in all, but statistically insignificant. Among the whole study population, significant decrease (p<0.001) in reaction time was noted (90.35±13.96 msVs 76.68±9.90 ms). Among male subjects of age-group 17-28 years, and 50-70 years, significant decrease in reaction time was noted (p<0.05) whereas, among the female subjects of all age groups, reaction time decreased significantly (p<0.05). Decrease in reaction time signifies improved central neuronal processing activity. This may be due to greater arousal, faster information processing, and ability to ignore or inhibit extraneous stimuli. Hence, regular practice of slow deep breathing exercise may be beneficial to lower blood pressure and to improve concentration.


Explaining seemingly paradoxical consumer experiences: conjoining weekly road rage and church attendance.
The purposes of the current study are threefold: Provide evidence that an extreme paradoxical group exists-people frequently attending church and exhibiting road rage, profile this group, and frame possible explanations for the seemingly paradoxical behaviors. This study employs data from a national (USA) lifestyle survey conducted by Market Facts with 3,350 American respondents. The major questions asked about church participation and road-rage behavior ("giving a finger" and "flashing headlights"). Nomologically, relevant activities include 3 items for church goers and 3 items for road-rage givers. Additionally, 14 items profiled the lifestyles of the unique paradoxical behavior segment. Utilizing cross-tabulation tables, property space analyses identify the double extreme (XX) group (18 people) and other 6 groups with a significant chi-square test, confirming the extreme group exists. Analyses of variance test results show that comparing nomologically relevant activities among the seven groups is all statistically significant, indicating the nomological validity is met. Overall, the XX group tends to have more males, be younger, and have a higher proportion of people working in sales. The profile of lifestyle analyses shows the XX group members have both high ambitions and expectations, might be very frustrated individuals, and equip with the adventurous and masculine traits related to aggression. The XX behavior group's demographic and psychographic characteristics portray similar lifestyles that differ from other groups. Case-based analyses provide further contextual information of nuances to XX segment individuals. The limited energy theory, the Eagleman's theory of unconscious mind, and justification theory help to explain why people conjointly go to church and commit road rage. Addressing chronic paradoxical behaviors provides implications for social de-marketing to reduce aggressive anti-social behavior such as road rage. Frequent church attendance may help make people more sensitive to their wrongdoings and gradually revise the anti-social behavior.


Endothelin XII.
Following the initial description of endothelium-dependent vasoconstriction in the early 1980s, it has been exactly 25 years since efforts to identify the sequence of the endothelin gene and peptide began in May 1987, work which resulted in a landmark paper submitted to Nature in December 1987 and published on March 31, 1988. The paper opened an entirely new field of research, followed by the inception of the International Conferences of Endothelin, the first of which was organized by Sir John Vane as Chair and held as the "First William Harvey Workshop on Endothelin" in London, UK, in December of 1988. Endothelin receptor antagonism has now been firmly established for more than a decade as a new, orally active drug treatment for patients with pulmonary arterial hypertension. Since the discovery of endothelin, on average 1,000 papers per year have been published with more than 25,000 papers available today, many of them published in the conferences' Proceedings. The present issue of Life Sciences, Endothelin XII, represents a collection of papers of original research and invited lectures presented at the Twelfth International Conference on Endothelin held in Cambridge, UK, in September 2011.


Reactive oxygen species are involved in plant defense against a gall midge.
Reactive oxygen species (ROS) play a major role in plant defense against pathogens, but evidence for their role in defense against insects is still preliminary and inconsistent. In this study, we examined the potential role of ROS in defense of wheat (Triticum aestivum) and rice (Oryza sativa) against Hessian fly (Mayetiola destructor) larvae. Rapid and prolonged accumulation of hydrogen peroxide (H(2)O(2)) was detected in wheat plants at the attack site during incompatible interactions. Increased accumulation of both H(2)O(2) and superoxide was detected in rice plants during nonhost interactions with the larvae. No increase in accumulation of either H(2)O(2) or superoxide was observed in wheat plants during compatible interactions. A global analysis revealed changes in the abundances of 250 wheat transcripts and 320 rice transcripts encoding proteins potentially involved in ROS homeostasis. A large number of transcripts encoded class III peroxidases that increased in abundance during both incompatible and nonhost interactions, whereas the levels of these transcripts decreased in susceptible wheat during compatible interactions. The higher levels of class III peroxidase transcripts were associated with elevated enzymatic activity of peroxidases at the attack site in plants during incompatible and nonhost interactions. Overall, our data indicate that class III peroxidases may play a role in ROS generation in resistant wheat and nonhost rice plants during response to Hessian fly attacks.


Nitric oxide production by cultured human aortic smooth muscle cells: stimulation by fluid flow.
This study demonstrated that exposure of cultured human aortic smooth muscle cells (SMC) to fluid flow resulted in nitric oxide (NO) production, monitored by nitrite and guanosine 3',5'-cyclic monophosphate production. A rapid burst in nitrite production rate was followed by a more gradual increase throughout the period of flow exposure. Neither the initial burst nor the prolonged nitrite production was dependent on the level of shear stress in the range of 1.1-25 dyn/cm2. Repeated exposure to shear stress after a 30-min static period restimulated nitrite production similar to the initial burst. Ca(2+)-calmodulin antagonists blocked the initial burst in nitrite release. An inhibitor of nitric oxide synthase (NOS) blocked nitrite production, indicating that changes in nitrite reflect NO production. Treatment with dexamethasone or cycloheximide had no effect on nitrite production. Monoclonal antibodies directed against the inducible and endothelial NOS isoforms showed no immunoreactivity on Western blots, whereas monoclonal antibodies directed against the neuronal NOS gave specific products. These findings suggest that human aortic SMC express a constitutive neuronal NOS isoform, the enzymatic activity of which is modulated by flow.


Erythrocytes dynamic viscoelasticity in beta-thalassaemia minor.
Beta-thalassaemia is a hereditary hemolytic disease, in which each clinic phenotype encompasses a heterogenic group of genetic alterations resulting in beta-globin chain synthesis decrease or absence in red blood cells. Studies on beta-thalassaemia carriers suggest the existence of decreased red cell deformability. The erythrocyte deformability in the blood stream is a well-known fact regarding blood circulation efficiency. Red blood cells may be considered to be viscoelastic and their behavior may be described according to complex viscoelastic parameters when they undergo oscillatory stresses. This dynamic behavior is physiologically important due to the in vivo pulsatile blood flow. The aim of the present work was to evaluate complex erythrocyte viscoelastic parameters in patients suffering from heterozygous beta-thalassaemia in comparison with healthy individuals. Our results reveal that even though thalassaemia erythrocytes show a decreased deformability in the stationary state, in a dynamic state, hemorheological alterations are only evident at low oscillatory frequencies, i.e., at lower frequencies in contrast with the normal heart rate (60 cycles/min = 1 Hz), producing no significant alterations at increased heart rate.


A role for intracellular calcium in tight junction reassembly after ATP depletion-repletion.
The integrity of the tight junction (TJ), which is responsible for the permeability barrier of the polarized epithelium, is disrupted during ischemic injury and must be reestablished for recovery. Recently, with the use of an ATP depletion-repletion model for ischemia and reperfusion injury in Madin-Darby canine kidney cells, TJ proteins such as zonula occludens-1 (ZO-1) were shown to reversibly form large complexes and associate with cytoskeletal proteins (T. Tsukamoto and S. K. Nigam, J. Biol. Chem. 272: 16133-16139, 1997). In this study, we examined the role of intracellular calcium in TJ reassembly after ATP depletion-repletion by employing the cell-permeant calcium chelator 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM (BAPTA-AM). Lowering intracellular calcium during ATP depletion is associated with significant inhibition of the reestablishment of the permeability barrier following ATP repletion as measured by transepithelial electrical resistance and mannitol flux, marked alterations in the subcellular localization of occludin by immunofluorescent analysis, and decreased solubility of ZO-1 and other TJ proteins by Triton X-100 extraction assay, suggesting that lowering intracellular calcium potentiates the interaction of TJ proteins with the cytoskeleton. Coimmunoprecipitation studies indicated that decreased solubility may partly result from the stabilization of large TJ protein-containing complexes with fodrin. Although ionic detergents (SDS and deoxycholate) appeared to cause a dissociation of ZO-1-containing complexes from the cytoskeleton, sucrose gradient analyses of the solubilized proteins suggested that calcium chelation leads to self-association of these complexes. Together, these results raise the possibility that intracellular calcium plays an important facilitatory role in the reassembly of the TJ damaged by ischemic insults. Calcium appears to be necessary for the dissociation of TJ-cytoskeletal complexes, thus permitting functional TJ reassembly and paracellular permeability barrier recovery.


Urodynamic and immunohistochemical evaluation of intravesical capsaicin delivery using thermosensitive hydrogel and liposomes.
Aqueous insolubility of the vanilloids such as capsaicin is a major disincentive in their intravesical therapy of detrusor hyperreflexia. We sought to overcome the delivery of this hydrophobic neurotoxin by entrapping it in a lipid bilayer of positively charged multilamellar lipid vesicles (liposomes) or in a hydrophobic polymer matrix of thermosensitive hydrogel. Liposomes, hydrogel and 30% ethanol/normal saline were prepared with or without 1 mM capsaicin (0.5 ml) and administered intravesically for 30 minutes to 7 groups of age matched, normal female adult Sprague-Dawley rats under halothane anesthesia. At 48 hours after intravesical instillation cystometric studies were performed using urethane anesthesia (0.04 ml per minute). The animals were subsequently sacrificed and whole bladders were harvested for histology and immunohistochemistry. In normal urethane anaesthetized rats capsaicin in 30% ethanol and liposomes completely blocked micturition reflexes. Capsaicin in hydrogel did not completely block the micturition reflex but it significantly decreased bladder contraction frequency compared with vehicle controls. The results of cystometry with capsaicin in liposomes and capsaicin in 30% ethanol correlated with a significant decrease in calcitonin gene-related peptide staining of afferent nerves in the bladder wall. Photographs taken after hematoxylin and eosin staining of the bladder treated with liposomes and hydrogel in the absence of capsaicin did not reveal any adverse histological changes. There were significant histological changes in bladders treated with 30% ethanol alone. In comparison with 30% ethanol liposomes are a superior vehicle for the intravesical administration of capsaicin, producing comparable efficacy with less tissue damage. Hydrogel can also serve as safe alternative option for capsaicin delivery.


Plasma predilution with addition of depleted plasma in a prothrombin time reagent improves the agreement between different prothrombin time methods.
The Quick (plain thromboplastins) and Owren (combined thromboplastins, with the addition of bovine plasma with vitamin K-dependent factors depleted) prothrombin time (PT) methods are used for measuring prothrombin time; for instance, in monitoring anticoagulation therapy with vitamin K antagonists. In most Quick PT methods, the final plasma dilution is 1/3 compared to Owren methods, which have a final dilution of 1/21. The Quick PT methods are associated with larger inter-laboratory variations than the Owren PT methods. We investigated whether dilution of the sample or thromboplastin has any impact on the correlation between the different PT methods. Plasma samples were analysed undiluted and prediluted in buffer, with adsorbed bovine plasma added, and by using rabbit brain or human placenta thromboplastins. Bootstrapping (re-sampling) was utilized to estimate the difference in correlations between PT of different reagents at different dilutions of plasma. We found the best correlations for combined reagents when the sample was prediluted 7-fold (r = 0.95) or more, and lowest when the sample was undiluted (r = 0.67). The source of thromboplastin had only a minor impact, if any, on the PT results. It was impossible to test whether predilution of plasma samples improved the correlation between Quick PT methods due to absence of clotting in many samples. We suggest that the Owren-style sample predilution is preferable for the harmonization of PT results and to overcome the large inter-laboratory variations that are associated with Quick PT methods to the benefit of patients on oral anticoagulation.


[Efficiency of Pulmonary Ventilation in Remote Period After Surgery in Patients With Chronic Pulmonary Thromboembolism].
to assess efficiency of pulmonary ventilation in remote period after surgical treatment of chronic pulmonary thromboembolism (CPTE). We examined 29 patients with CPTE with median age 49 (38-60) years. Pulmonary ventilation was studied by body plethysmography and its efficiency was evaluated by oxygen utilization coefficient (OUC). Comparison of OUCs before and in the remote period after surgery showed that after surgical treatment efficiency of pulmonary ventilation increased by 26% at the account of reduced hyperventilation but remained below normal. Patients' age and duration of the disease had a direct impact on the baseline bronchial conductivity as well as on recovery of the respiratory system reserve in the remote period after surgery.


The clinical effect of dentifrices containing stabilized stannous fluoride on plaque formation and gingivitis--a six-month study with ad libitum brushing.
The effects of stabilized 0.454% stannous fluoride dentifrices on supragingival plaque, gingival inflammation and gingival bleeding were studied in 549 adult male and female subjects who completed a six-month, double blind clinical study. Following an oral prophylaxis, subjects were randomly assigned to brush with one of the following dentifrices: 1) 0.454% SnF2 stabilized with 2.08% sodium gluconate, 2) 0.454% SnF2 stabilized with 4.16% sodium gluconate, 3) an experimental dentifrice, or 4) 0.243% NaF control dentifrice. Follow-up examinations were conducted at 3 and 6 months. Compared to the control dentifrice at 6 months, stannous fluoride dentifrices stabilized with 2.08% or 4.16% sodium gluconate significantly reduced gingivitis by 18.8% and 18.0%, respectively. There were no statistically significant differences between the two stabilized SnF2 groups with respect to their beneficial effects on gingival health. Gingival bleeding was also reduced, relative to the control dentifrice, for both stabilized SnF2 dentifrices. However, these differences were not statistically significant at p=0.05. The stabilized SnF2 dentifrices were not significantly different from the control dentifrice in their effects on supragingival plaque. No significant differences in adverse oral soft tissue effects were observed between the test and control groups. As expected, accumulation of extrinsic tooth stain increased in the stabilized SnF2 groups. However, the difficulty in removing accumulated dental stain was similar between the control and stabilized SnF2 dentifrices. Since use of SnF2 dentifrices has been reported to produce tooth stain, gingivitis examinations were done with and without custom-made tooth covers to evaluate the potential for examiner bias. Comparable gingivitis and gingival bleeding benefits were observed when the evaluations were conducted with or without the tooth covers. Results from this study support that 0.454% stabilized stannous fluoride dentifrices can provide an important adjunct to the prevention and control of gingivitis when used in combination with regular personal oral hygiene procedures and professional care.


Once upon Multivariate Analyses: When They Tell Several Stories about Biological Evolution.
Geometric morphometrics aims to characterize of the geometry of complex traits. It is therefore by essence multivariate. The most popular methods to investigate patterns of differentiation in this context are (1) the Principal Component Analysis (PCA), which is an eigenvalue decomposition of the total variance-covariance matrix among all specimens; (2) the Canonical Variate Analysis (CVA, a.k.a. linear discriminant analysis (LDA) for more than two groups), which aims at separating the groups by maximizing the between-group to within-group variance ratio; (3) the between-group PCA (bgPCA) which investigates patterns of between-group variation, without standardizing by the within-group variance. Standardizing within-group variance, as performed in the CVA, distorts the relationships among groups, an effect that is particularly strong if the variance is similarly oriented in a comparable way in all groups. Such shared direction of main morphological variance may occur and have a biological meaning, for instance corresponding to the most frequent standing genetic variation in a population. Here we undertake a case study of the evolution of house mouse molar shape across various islands, based on the real dataset and simulations. We investigated how patterns of main variance influence the depiction of among-group differentiation according to the interpretation of the PCA, bgPCA and CVA. Without arguing about a method performing 'better' than another, it rather emerges that working on the total or between-group variance (PCA and bgPCA) will tend to put the focus on the role of direction of main variance as line of least resistance to evolution. Standardizing by the within-group variance (CVA), by dampening the expression of this line of least resistance, has the potential to reveal other relevant patterns of differentiation that may otherwise be blurred.


The glycogenolytic activity of immunoreactive pancreatic glucagon in plasma.
Conclusions concerning the physiologic role of pancreatic glucagon in health and its contribution to disorders of carbohydrate metabolism, such as diabetes mellitus, are based entirely on measurements of plasma glucagon by radioimmunoassay. The changes in plasma immunoreactive glucagon can have the metabolic and clinical significance which has been implied, only if the glucagon detected by immunoassay has biological activity. The present study was designed to determine if a relationship between the immunoassayable glucagon and glycogenolytic activity of plasma could be demonstrated. Plasma specimens obtained from normal and diabetic subjects under widely varying circumstances of alpha cell activity were extracted by a modification of the Kenny technique and the recovery of immunoreactive glucagon was calculated. Glycogenolytic activity of each extract was determined by perfusion in the Mortimore rat liver system, modified so as to detect as little as 1 ng of crystalline glucagon.A significant correlation between the calculated quantity of immunoreactive glucagon and the glycogenolytic activity of plasma extracts was observed for both normal and diabetic subjects. Most of the glycogenolytic activity was abolished by incubating the extract with antiglucagon serum. It was concluded that the glycogenolytic activity of extractable glucagon is proportional to its immunoreactivity as calculated from its original concentration in plasma. This would tend to support the view that all or most of the immunoreactive glucagon of plasma is biologically active.


Influence of diesel soot particles and sulfite on functions of polymorphonuclear leukocytes.
Aqueous suspensions of diesel soot particles in combination with sulfite influence certain functions of human polymorphonuclear neutrophils in vitro. Chemiluminescence, generated after activation by opsonized zymosan as well as oxygen uptake were decreased, whereas phagocytosis was increased. An enhancement of degranulation could not be observed. The single substances show little or no effects on the above properties. The results indicate that combinations of air pollutants such as diesel soot and sulfite may modulate vital functions of activated leukocytes in vivo.


Inter-relationships of insomnia and psychiatric symptoms with suicidal ideation among patients with chronic schizophrenia: A network perspective.
Insomnia is common in patients with schizophrenia, which contributes to worsening psychiatric symptoms and suicidality. We aimed to assess the inter-relationships of insomnia and psychopathology with suicidal ideation (SI) among 1407 Chinese patients with chronic schizophrenia via the network approach. We used Positive and Negative Syndrome Scale, Insomnia Severity Index, and Beck Scale for Suicidal Ideation to assess psychiatric symptoms, insomnia, and SI, respectively. Lifetime suicidal attempts (SA) were collected. (1) The incidence of insomnia, lifetime SI, lifetime SA, and current SI was 13.5% (n = 190), 22.8% (n = 321), 13.5% (n = 190), and 9.7% (n = 136), respectively. (2) Patients with insomnia had worse clinical symptoms and higher suicidal risk. (3) Daytime dysfunction, sleep-related distress, conceptual disorganization, delusions, anxiety, and poor rapport were the core symptoms, while late sleep onset and sleep dissatisfaction emerged as bridge symptoms connecting insomnia and psychopathology. (4) Depressive mood, hallucinations, poor impulse control, guilty feelings, insomnia-related impaired quality of life, and sleep dissatisfaction were directly associated with SI. Our findings called for formal assessment of insomnia in patients with schizophrenia, which should cover both nocturnal and daytime insomnia symptoms. Targeted interventions for key symptoms may help reduce insomnia, psychiatric symptoms, and SI in patients with schizophrenia.


Public health effects of gambling - debate on a conceptual model.
Gambling for money is a popular leisure time activity in most countries, which has major social and economic impacts not only affecting the gambler, but his/her significant others, and the society. Gambling impact studies can help researchers and policymakers compare the health and social costs and benefits of different gambling policies and can be used when considering which gambling policies will reduce or increase costs or benefits the most. In a public health approach, the impacts of gambling, negative and positive, are assessed across the entire severity spectrum of the activity. Although some studies have created basic principles for conducting impact studies, a theoretical model is currently lacking. The aim of this debate is to review complementing and contrasting views on the effects of gambling to create a conceptual model, where a public health perspective is applied. The effects of gambling can be structuralized using a conceptual model, where impacts are divided into negative and positive; costs and benefits. Costs and benefits are categorized into three classes: financial, labor and health, and well-being. These classes manifest in personal, interpersonal, and societal levels. Individual impacts cause effects on a personal level to gamblers themselves. External impacts influence the interpersonal and society/community levels and concern other people. The temporal level refers to the development, severity and scope of the gambling impact. These include general impacts, impacts of problem gambling and long-term impacts of gambling. The conceptual model offers a base on which to start building common methodology for assessing the impact of gambling on the society. While measuring monetary impacts is not always straightforward, the main issue is how to measure the social impacts, which are typically ignored in calculations, as are personal and interpersonal impacts. The reviewed empirical work largely concentrated on the costs of gambling, especially costs on the community level. The Model can be used to identify areas where research is scarce. Filling the gaps in knowledge is essential in forming a balanced evidence base on the impacts of gambling. Ideally, this evidence could be the starting point in formulating public policies on gambling.


Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND.
Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington's disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.


Persuasive Effects of Linguistic Agency Assignments and Point of View in Narrative Health Messages About Colon Cancer.
The authors explored the effects of linguistic agency and point of view on narrative force. Participants (N = 499) were randomly assigned to read one version of an article about colon cancer, defined by a 2 (disease agency: cancer, human) × 2 (temporal agency: death, human) × 2 (point of view: first person, third person) between-subjects design. Disease agency language assigned agency to cancer (e.g., "Cancer developed in me") or to humans (e.g., "I developed cancer"). Temporal agency language described death as approaching humans (e.g., "as death closes in on patients) or as being approached by humans (e.g., "as patients close in on death"). The narrative was presented from the first-person singular or third-person plural viewpoint. Participants then completed a questionnaire measuring threat perceptions, efficacy, transportation, and other study variables. Language assigning agency to humans rather than to cancer elevated susceptibility beliefs. Death-approach language led to greater fear than human-approach language without impacting efficacy perceptions. Human-approach language was rated more persuasive than death-approach language, but only in first-person point-of-view narratives. Transportation and identification were positively associated with ratings of threat severity and susceptibility, fear, efficacy, behavioral intentions, and message persuasiveness. Implications for message design are discussed.


Is compartmental surgery always mandatory in retroperitoneal liposarcoma? A case report of multifocal synchronous well-differentiated liposarcoma.
Sarcomas are rare tumors representing 0.7% of all cancer cases in adults, and approximately 15-20% of those occur in the retroperitoneum. Diagnosis is usually late. Liposarcoma and leiomyosarcoma are the most frequent forms. Liposarcomas have high local recurrence rates (35-60%) and a high metastasis rate only if dedifferentiated (30%), whereas leiomyosarcoma has a high distant metastasis rate (60%) and a low local recurrence rate (20%). A case report of multifocal synchronous well-differentiated liposarcoma is presented. The patient underwent a surgical excision of all the masses. The postoperative period was uneventful, with a postoperative hospital stay of 9 days. The patient underwent systemic chemotherapy and clinical and instrumental follow-up. A relapse of the disease was observed 24 months after surgery: a 25 mm mass was diagnosed close to the pancreatic stump, as well as a 24 mm mass in the left upper abdominal quadrant. The patient underwent a second laparotomy: recurrent lesions were identified and excised en-bloc with the body of the pancreas. Surgery is the gold standard of therapy. The best chance for curative resection is at the time of the first diagnosis of the disease. Compartmental surgery is a macroscopically complete resection through en bloc excision of adjacent structures, even if not clearly infiltrated. Many controversies still exist in the treatment of retroperitoneal liposarcoma, such as the extent of primary and secondary resections, the benefit of chemotherapy and radiation therapy, and when these treatments should be delivered. Compartmental surgery, Liposarcoma, Surgery, Retroperitoneal sarcoma.


What makes a leaf tough? Patterns of correlated evolution between leaf toughness traits and demographic rates among 197 shade-tolerant woody species in a neotropical forest.
Slow-growing juveniles of shade-tolerant plant species are predicted to have tough leaves because of the high cost of leaf replacement in shade relative to potential carbon gain. We assessed the degree of correlated evolution among eight traits associated with leaf toughness and the relationships of those traits with the growth and mortality rates of 197 tree and shrub species from the understory of the 50-ha forest dynamics plot on Barro Colorado Island, Panama. Path analysis with phylogenetically independent contrasts revealed that leaves attained material toughness (resistance to fracture per unit fracture area) through increases in tissue density, percent cellulose per unit dry mass, and vein fracture toughness. Lamina density and cellulose content evolved independently and thus represent different paths to material toughness. Structural toughness (resistance to fracture per unit fracture length) depended on material toughness and lamina thickness. Mortality rates of individuals 1-10 cm in stem diameter were negatively correlated with material toughness and lamina density but were independent of structural toughness and cell wall fiber contents. Leaf toughness traits were uncorrelated with relative growth rates. Results imply that material toughness enhances resistance to natural enemies, which increases survival and offsets the biomass allocation cost of producing tough leaves in the shaded understory.


A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
Myofiber necrosis without prominent inflammation is a nonspecific finding in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure, and the question of which patients would benefit from immunosuppression remains unanswered. The aim of this study was to identify novel autoantibodies in patients with necrotizing myopathy. Muscle biopsy specimens and serum samples were available for 225 patients with myopathy. Antibody specificities were determined by performing immunoprecipitations from (35)S-methionine-labeled HeLa cell lysates. Selected biopsy specimens were stained for membrane attack complex, class I major histocompatibility complex (MHC), and endothelial cell marker CD31. Muscle biopsy specimens from 38 of 225 patients showed predominantly myofiber necrosis. Twelve of these patients had a known autoantibody association with or other etiology for their myopathy. Sixteen of the remaining 26 sera immunoprecipitated 200-kd and 100-kd proteins; this specificity was observed in only 1 of 187 patients without necrotizing myopathy. Patients with the anti-200/100 autoantibody specificity had proximal weakness (100%), high creatine kinase levels (mean maximum 10,333 IU/liter), and an irritable myopathy on electromyography (88%). Sixty-three percent of these patients had been exposed to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy, and many experienced a relapse of weakness when the medication was tapered. Immunohistochemical studies showed membrane attack complex on small blood vessels in 6 of 8 patients and on the surface of non-necrotic myofibers in 4 of 8 patients. Five of 8 patients had abnormal capillary morphology, and 4 of 8 patients expressed class I MHC on the surface of non-necrotic myofibers. An anti-200/100-kd specificity defines a subgroup of patients with necrotizing myopathy who previously were considered to be autoantibody negative. We propose that these patients have an immune-mediated myopathy that is frequently associated with prior statin use and should be treated with immunosuppressive therapy.


Automatic cell electrorotation measurements: studies of the biological effects of low-frequency magnetic fields and of heat shock.
A computer-aided automatic imaging technique has been developed for measuring the electrorotation spectra of up to 256 particles at the same time. This offers advantages over the conventional manual method, especially when rapidly acquired statistical data are necessary in investigations of the response of cells or test beads to chemical exposure, for example. We have applied this technique to investigate the biological effects of heat shock and low-frequency EM fields reported by others for yeast cells. Although heat shock effects were observed, no changes of the electrorotational behaviour could be detected after exposing the cells to 50 Hz, 8 and 80 microT fields. Although this does not rule out the possibility that the cells were influenced by the magnetic fields, it does limit the number of possible physicochemical changes that might have occurred to their cell walls and membranes.


Prenatal diagnosis for detecting congenital malformations: acceptance among Israeli Arab women.
A high rate of consanguineous marriages exists within the Israeli Arab community, with approximately half occurring between first cousins. This contributes towards a high incidence of congenital malformations and autosomal recessive diseases, many of which are detectable at prenatal diagnosis. To assess the levels of both awareness and acceptance regarding prenatal diagnosis and termination of pregnancy among a group of Arab women in order to devise the optimal means of providing genetic counseling and general health services. A total of 231 Arab women of childbearing age were interviewed 3 days postpartum to assess their knowledge of prenatal diagnosis and termination of pregnancy, their willingness to undergo prenatal diagnosis, and their opinions on termination of pregnancy in the event of a severely affected fetus. Half the women believed that prenatal testing is not an effective (or accurate) tool for diagnosing an affected fetus. A quarter had poor knowledge on prenatal diagnosis, and a quarter believed that prenatal diagnosis does provide the correct diagnosis. Ninety-five percent said they would agree to undergo prenatal diagnosis; and in the event of a severely affected fetus, 36% said they would agree to a termination of pregnancy, 57% said they would not, and 7% were undecided. There is a need for special intervention programs, with guidance by health professionals, geneticists and religious authorities, that will inform this population on the increased risk associated with consanguinity, stress the importance and effectiveness of prenatal testing to identify severe congenital malformations, and help them to accept prenatal diagnosis and termination of pregnancy if indicated.


Representativeness of a roster of volunteer North American twins with chronic disease.
To identify large numbers of twins affected by chronic disease as potential subjects for studies of environmental and genetic chronic disease determinants, we advertised for affected twins over the period 1980-91 in newspapers across North America. Responses were received from 17 245 twin pairs in which cases of cancer or other chronic disease had occurred. To assess the representativeness of affected twins identified by advertising, we evaluated the pattern of reporting, compared the cases identified to the number of cases estimated to be prevalent among all North American twins, compared the cases to population-based singleton case series, compared the healthy co-twins to population-based samples of healthy persons, assessed the impact on ascertainment of opinions about disease causation, compared the pattern of prospective to retrospective ascertainment of disease in the originally unaffected co-twins of cases, and compared the results of the prospective ascertainment of disease in co-twins to comparable published estimates. Youth, gender, zygosity, education, and disease concordance were found to be overall determinants of ascertainment. Disease-discordant DZ twins appeared to be modestly underascertained. While somewhat better educated, both concordant and discordant pairs were judged to be reasonably representative of affected non-Hispanic white North American twin pairs of comparable status, ie of comparable age, sex, race, and zygosity. If interpreted with caution, the concordance patterns of such twins can be used to generate genetic hypotheses, but should not be the basis of definitive heritability analyses. We conclude that advertising offers a method of identifying pairs of twins that can serve as subjects for studies designed to identify disease determinants.


Time to Open Repair of Mandibular Fractures and Associated Complications.
The aim of this study was to determine whether a correlation exists between the time from injury to repair of mandibular fractures and the development of postoperative complications. We also sought to assess whether a delay in treatment manifests in an increased surgical time. We performed a retrospective cohort study and enrolled a sample (N = 64) derived from patients treated with open repair of mandibular fractures at Augusta University Medical Center by the oral and maxillofacial surgery service from July 2015 to June 2018. Time from injury to surgical repair was analyzed as a continuous variable, and the primary outcome was the presence of any of the following postoperative complications: infection, mechanical complication, cranial nerve V3 deficit, or cranial nerve VII deficit. Secondary outcome variables included the presence of substance abuse, surgical approach, and surgery time. Logistical regression was performed. Among 64 patients, there were 27 patients with a total of 32 complications, including infection (n = 9), mechanical complications (n = 3), cranial nerve V3 deficits (n = 13), and cranial nerve VII deficits (n = 7). The mean time to fixation was 13.26 days in patients without complications versus 17.52 days in patients with complications. The association between time to surgical repair and complication rate was not statistically significant (P = .203). No association was found between time to surgical repair and surgery time (P = .699). Our study did not find a significant association between the timing of repair of mandibular fractures and complications. Our study also failed to show a correlation between a delay in surgical intervention and increased technical challenges manifested by an increased surgical time.


Tanshinone IIA attenuates demyelination and promotes remyelination in A. cantonensis-infected BALB/c mice.
Angiostrongylus cantonensis infection can cause demyelination in the central nervous system, and there is no effective treatment. We used dexamethasone, Tanshinone IIA (TSIIA) and Cryptotanshinone(Two traditional Chinese medicine monomers) in combination with albendazole (AB, a standard anti-helminthic compound) to observe their therapeutic effect on demyelination in A. cantonensis-infected mice. Luxol fast blue staining and electron microscope of myelin sheath, Oligodendrocyte (OL) number and myelin basic protein (MBP) expression in brain was detected in above groups. TSIIA+AB facilitated OL proliferation and significantly increased both myelin sheath thickness and the population of small-diameter axons. In addition, TSIIA treatment inhibited the expression of inflammation-related factors (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, inducible nitric oxide synthase [iNOS]) rather than inhibiting eosinophil infiltration in brain. TSIIA also decreased microglial activation and shifted their phenotype from M1 to M2. Taken together, these results provide evidence that TSIIA combined with AB may be an effective treatment for demyelination caused by A. cantonensis infection and other demyelinating diseases.


The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: A Real-World Study.
The aim of this retrospective study was to investigate the efficacy and safety of ramucirumab treatment under real-world conditions and to clarify the role of albumin-bilirubin (ALBI) score in predicting outcomes. Between June 2019 and May 2020, a total of 16 patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab in Gunma Saiseikai Maebashi Hospital and its affiliated hospitals was included. The median age was 71 (interquartile range [IQR] 65-74) years old, and 12 patients (75.0%) were male. The modified ALBI (mALBI) grade was 1, 2a, and 2b at baseline in 4 (25.0%), 3 (18.8%), and 9 patients (56.3%), respectively. The Barcelona Clinic Liver Cancer stage was intermediate and advanced stage in 1 (6.3%) and 15 patients (93.8%), respectively. The serum α-fetoprotein at baseline was 4,911 (IQR 2,091-17,377) ng/mL. The disease control rate in patients with mALBI grade1 + 2a was significantly higher than in those with mALBI grade 2b (100 vs. 28.6%, p = 0.028). The patients with mALBI grade 1 + 2a had a significantly better overall survival (OS) and longer progression-free survival (PFS) than those with mALBI grade 2b (median OS 6.7 vs. 3.0 months; p = 0.036, median PFS 7.5 vs. 1.4 months; p = 0.002). The number of cycles of ramucirumab treatment was significantly correlated with the ALBI score (r = -0.452, p = 0.030). The patients with mALBI grade 1 + 2a showed a low incidence of adverse events (AEs) and discontinuation due to AEs. Advanced HCC patients with mALBI grade 1 + 2a may be a good indication for ramucirumab treatment.


Differentiation of ingested and endogenous bifidobacteria by DNA fingerprinting demonstrates the survival of an unmodified strain in the gastrointestinal tract of humans.
Consumption of bifidobacteria as a dietary adjunct has received considerable attention for its possible role in the maintenance of gastrointestinal health. However, speculation exists about these presumed health benefits because of an inability to assess the fate and mechanism of action of ingested bifidobacteria. Thus, our objective was to examine the fate of ingested bifidobacteria through the gastrointestinal tract. Variations in the highly conserved 16S ribosomal DNA (rDNA) of bifidobacteria from six male subjects (18 to 35 y old) were assessed by restriction fragment length polymorphism (RFLP) analysis. During the 16-d study, 10(10) colony-forming units (CFU) of a commercially available bifidobacteria were delivered to subjects in fluid milk for each of 8 d. During the remaining 8 d, subjects consumed milk without bifidobacteria. Feces were collected at 4-d intervals and plated on selective media. For each subject, 10-15 colonies were randomly selected and used as template for PCR-amplification of 16S rDNA. 16S rDNA was restriction digested and resolved by electrophoresis. The 16S rDNA-RFLP of the ingested bifidobacteria was unique compared with bifidobacteria found in subjects prior to the feeding study. When subjects consumed bifidobacteria, a 16S rDNA-RFLP identical to that of the ingested bifidobacteria was observed in feces. The concentration of the ingested bifidobacteria in feces increased to 67.2 +/- 8.5% (mean +/- SEM) of total bifidobacteria. After feeding stopped, the ingested bifidobacteria diminished and became undetectable. Using this molecular approach to monitor ingested bifidobacteria, we demonstrate the kinetics of passage of this organism through the gastrointestinal tract of healthy humans.


Cell colony counter called CoCoNut.
Clonogenic assays are powerful tools for testing cell reproductive death after biological damage caused by, for example, ionizing radiation. Traditionally, the methods require a cumbersome, slow and eye-straining manual counting of viable colonies under a microscope. To speed up the counting process and minimize those issues related to the subjective decisions of the scoring personnel, we developed a semi-automated, image-based cell colony counting setup, named CoCoNut (Colony Counter developed by the Nutech department at the Technical University of Denmark). It consists in an ImageJ macro and a photographic 3D-printed light-box, conceived and demonstrated to work together for Crystal Violet-stained colonies. Careful attention was given to the image acquisition process, which allows background removal (i.e. any unwanted element in the picture) in a minimally invasive manner. This is mainly achieved by optimal lighting conditions in the light-box and dividing the image of a flask that contains viable colonies by the picture of an empty flask. In this way, CoCoNut avoids using aggressive background removal filters that usually lead to suboptimal colony count recovery. The full method was tested with V79 and HeLa cell survival samples. Results were compared to other freely available tools. CoCoNut proved able to successfully distinguish between single and merged colonies and to identify colonies bordering on flask edges. CoCoNut software calibration is fast; it requires the adjustment of a single parameter that is the smallest colony area to be counted. The employment of a single parameter reduces the risk of subjectivity, providing a robust and user-friendly tool, whose results can be easily compared over time and among different bio-laboratories. The method is inexpensive and easy to obtain. Among its advantages, we highlight the possibility of combining the macro with a perfectly reproducible 3D-printed light-box. The CoCoNut software and the 3D-printer files are provided as supporting information (S1 CoCoNut Files).


Comparison of phage-mediated and conjugative transfer of staphylococcal plasmids in vitro and in vivo.
A strain of Staphylococcus aureus was constructed with which to compare transfer of resistance plasmids by the mechanisms of phage-mediated conjugation and conjugation. Transfer by each mechanism could be distinguished by the patterns of resistances transferred. Conjugation was favoured on dry absorbent surfaces, e.g., human skin, tissue and surgical gauze, whereas phage-mediated conjugation was favoured in fluids, e.g., milk and urine. The degree of hydration of the mating cells is postulated as one factor determining whether plasmids are transferred by phage-mediated conjugation or conjugation. Preliminary evidence indicates that topical creams and ointments affect the conjugative transfer of plasmids.


Heterosis.
Heterosis refers to the phenomenon that progeny of diverse varieties of a species or crosses between species exhibit greater biomass, speed of development, and fertility than both parents. Various models have been posited to explain heterosis, including dominance, overdominance, and pseudo-overdominance. In this Perspective, we consider that it might be useful to the field to abandon these terms that by their nature constrain data interpretation and instead attempt a progression to a quantitative genetic framework involving interactions in hierarchical networks. While we do not provide a comprehensive model to explain the phenomenology of heterosis, we provide the details of what needs to be explained and a direction of pursuit that we feel should be fruitful.


Chapter 17: Immunomodulation of allergic sinonasal disease.
IgE hypersensitivity is important to the pathogenesis of allergic diseases and the development and persistence of airway inflammation. Allergic immunomodulation encompasses various therapies that attempt to suppress or modify the immune mechanisms responsible for IgE-mediated disease. These include allergy immunotherapy (AIT) in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), as well as the emergence of biological agents, such as anti-IgE, for allergic respiratory disease. Clinical evidence strongly supports the efficacy and safety of AIT for the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, but for chronic rhinosinusitis evidence is lacking. In allergic rhinitis, the decision to initiate AIT depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, the adverse effects of medication, the severity and duration of symptoms, and their effect on quality of life. AIT has the potential to produce sustained long-lasting immune modulation and possibly avoid or reduce lifelong requirements for medical therapy. Although SLIT is currently being evaluated, SCIT remains the preferred form of AIT in the United States because of robust efficacy data, availability of allergen extracts, and current Food and Drug Administration approval. However, SLIT holds the potential for greater patient safety and convenience. Other immunomodulators such as anti-IgE also hold promise, but require further investigation.


Self-Assembly and Multifaceted Bioactivity of a Silver(I) Quinolinate Coordination Polymer.
Coordination polymers have emerged as a new class of potent biologically active agents due to a variety of important characteristics such as the presence of bioactive metal centers and linkers, low toxicity, stability, tailorable structures, and bioavailability. The research on intermediate metabolites has also been explored with implications toward the development of selective anticancer, antimicrobial, and antiviral therapeutic strategies. In particular, quinolinic acid (H2quin) is a recognized metabolite in kynurenine pathway and potent neurotoxic molecule, which has been selected in this study as a bioactive building block for assembling a new silver(I) coordination polymer, [Ag(Hquin)(μ-PTA)]n·H2O (1). This product has been prepared from silver oxide, H2quin, and 1,3,5-triaza-7-phosphaadamantane (PTA), and fully characterized by standard methods including single-crystal X-ray diffraction. Compound 1 has revealed distinctive bioactive features, namely (i) a remarkable antiviral activity against herpes simplex virus type 1 (HSV-1) and adenovirus 36 (Ad-36), (ii) a significant antibacterial activity against clinically important bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), and (iii) a selective cytotoxicity against HeLa (human cervix carcinoma) cell line. The present work widens a growing family of bioactive coordination polymers with potent antiviral, antibacterial, and antiproliferative activity.


Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families: The Lifelines Cohort Study.
Dysregulation of the cardiac autonomic nervous system, as indexed by reduced heart rate variability (HRV), has been associated with the development of high blood pressure (BP). However, the underlying pathological mechanisms are not yet fully understood. This study aimed to estimate heritability of HRV and BP and to determine their genetic overlap. We used baseline data of the 3-generation Lifelines population-based cohort study (n=149 067; mean age, 44.5). In-house software was used to calculate root mean square of successive differences and SD of normal-to-normal intervals as indices of HRV based on 10-second resting ECGs. BP was recorded with an automatic BP monitor. We estimated heritabilities and genetic correlations with variance components methods in ASReml software. We additionally estimated genetic correlations with bivariate linkage disequilibrium score regression using publicly available genome-wide association study data. The heritability (SE) estimates were 15.6% (0.90%) for SD of normal-to-normal intervals and 17.9% (0.90%) for root mean square of successive differences. For BP measures, they ranged from 24.4% (0.90%) for pulse pressure to 30.3% (0.90%) for diastolic BP. Significant negative genetic correlations (all P<0.0001) of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (-0.20/-0.16) and with diastolic BP (-0.15/-0.13) were observed. LD score regression showed largely consistent genetic correlation estimates of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (range, -0.08 to -0.23) and diastolic BP (range, -0.20 to -0.27). Our study shows a substantial contribution of genetic factors in explaining the variance of HRV and BP measures in the general population. The significant negative genetic correlations between HRV and BP indicate that genetic pathways for HRV and BP partially overlap.


Effects of arctic shrub expansion on biophysical vs. biogeochemical drivers of litter decomposition.
Climate warming in arctic tundra may shift dominant vegetation from graminoids to deciduous shrubs, whose functional traits could, in turn, alter biotic and abiotic controls over biogeochemical cycling of carbon (C) and nitrogen (N). We investigated whether shrub-induced changes in microclimate have stronger effects on litter decomposition and nutrient release than changes in litter quality and quantity. In arctic tundra near Toolik Lake, Alaska, USA, we incubated a common substrate in a snow-addition experiment to test whether snow accumulation around arctic deciduous shrubs altered the environment enough to increase litter decomposition rates. We compared the influence of litter quality on the rate of litter and N loss by decomposing litter from four different plant functional types in a common site. We used aboveground net primary production values and estimated decay constant (k) values from our decomposition experiments to calculate community-weighted mass loss for each site. Snow addition had no effect on decomposition of the common substrate, and the site with the highest abundance of shrubs had the lowest decomposition rates. Species varied in their decomposition rates, with species from the same functional type not always following similar patterns. Community-weighted mass loss was 1.5 times greater in the high shrub site, and only slightly decreased when adjusted for soil environment, suggesting that litter quality and quantity are the primary drivers of community decomposition. Our findings suggest that on a short time scale, the changes in soil environment associated with snow trapping by shrubs are unlikely to influence litter nutrient turnover enough to drive positive snow-shrub feedbacks. The mechanisms driving shrub expansion are more likely to do with shrub-litter feedbacks, where the higher growth rates and N uptake by shrubs allows them to produce more leaves, resulting in a larger litter N pool and faster internal cycling of nutrients.