A sustainable world is one in which human needs are met equitably and without sacrificing the ability of future generations to meet their needs. Human well-being is described by four primary elements—basic human needs, economic needs, environmental needs, and subjective well-being. These elements can interact in a myriad of ways to influence overall well-being. What makes changes in human well-being sustainable for a population or a nation? Two major interactional concepts can push changes in human well-being toward a sustainable state in space and time—social equity and intergenerational equity. The concept of social equity distributes well-being over space, ensuring the fair treatment of all members of society promoting spatial sustainability of a well-being decision. The concept of intergenerational equity distributes well-being through time, ensuring the well-being of present and future generations of a population or nation, promoting temporal sustainability of a well-being decision. The roles of social and intergenerational equity in terms of their influence on human well-being are examined with a focus on more sustainable decision-making.
Well-being; Sustainability; Social equity; Environmental justice; Intergenerational equity
Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques.
Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model.
Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model.
Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.
pancreatic cancer; radiation resistance; cholesterol; zoledronic acid; radiosensitiser
Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia.
We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008–2010 and 2011–2013). Durability of successful treatment and progression to OAC were also evaluated.
508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51).
Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2–4% at 1 year in these high-risk patients.
Trial registration number
BARRETT'S OESOPHAGUS; OESOPHAGEAL CANCER; ENDOSCOPIC PROCEDURES
Vatalanib (PTK 787/ZK22584) is an oral polytyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy.
Vatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. the primary objective of this study was to evaluate the 6-month survival rate.
Sixty-seven patients were enrolled. The median age was 64, and 66 %(N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18–41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug.
Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.
Vatalinib; Pancreatic adenocarcinoma; Tyrosine kinase inhibitor; Second-line treatment
Background and Objective
The etiology and exact incidence of infantile hemangiomas (IH) are unknown. Prior studies have noted immunohistochemical and biologic characteristics shared by IH and placental tissue. We investigated the possible association between placental anomalies and the development of IH, as well as the demographic characteristics and other risk factors for IH.
578 pregnant women were prospectively enrolled and their offspring followed for 9 months. Placental evaluations were performed and demographic data collected on all mother-infant pairs.
594 infants were evaluated: 32 hemangiomas (either IH or congenital (CH)) were identified in 27 infants, yielding an incidence of 4.5% for IH and 0.3% for CH. Placental anomalies were noted in almost 35% of hemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants. (p = 0.025). Other risk factors for IH included prematurity (p = 0.016) and low birth weight (p = 0.028). All IH were present by 3 months of age, and cessation of growth had occurred in all by 9 months of age. Most occurred on the trunk. Of note, 20% of identified IH were abortive/telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention.
This is the first prospective American study to document the incidence of IH in infants followed from birth to early infancy. The association with placental anomalies was statistically significant. The overall incidence mirrors prior estimates, but the need for treatment was lower than previously reported.
infantile hemangioma; congenital hemangioma; abortive/telangiectatic hemangioma; placental anomalies
To identify, using a longitudinal data set, parental and childhood correlates of adult television (TV) viewing time at 32-year follow-up.
Data were derived from the 1970 British Cohort Study, a longitudinal observational study of 17 248 British people born in a single week of 1970. The present analyses incorporated data from the age 10 and 42-year surveys. When participants were aged 10 years, their mothers provided information on how often participants watched TV and played sports (never/sometimes/often), and parents’ own occupation, as well as height and weight. A health visitor objectively assessed participants’ height and weight at age 10. Thirty-two years later, when participants were aged 42 years, they reported their daily TV viewing hours (none/0≤1/1<3/3<5/≥5), physical activity and health status. Associations between putative childhood and parental correlates and adult TV viewing time were investigated using logistic regression.
Valid data at both time points were available for 6188 participants. Logistic regression models showed that those who reported ‘often’ watching TV at baseline were significantly more likely to watch >3 h/days of TV at follow-up (OR 1.42, 95% CI 1.21 to 1.65), as were those whose father was from a lower socio-occupational class (intermediate, routine/manual) compared with managerial (OR 1.55, 95% CI 1.14 to 2.11; OR 2.05, 95% CI 1.47 to 2.87). Body mass index (BMI) at age 10 was inversely associated with high TV in adulthood (per unit increase; OR 0.93, 95% CI 0.90 to 0.96) although fathers BMI when the child was aged 10 was positively associated with high TV in adulthood (per unit increase; OR 1.04, 95% CI 1.02 to 1.06).
Findings suggest that childhood TV viewing time tracks into adulthood. Parents’ health behaviours and social position appear to be associated with their children's viewing habits, which may have important implications for the direction of future policy and practice. Specifically, findings support the case for early life interventions, particularly on socioeconomic inequalities, as a way of preventing sedentary behaviour in later life.
PREVENTION; EPIDEMIOLOGY; PUBLIC HEALTH
Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies.
Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk.
The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases.
Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
Pancreatic cancer; periampullary tumours; research registry; cancer genetics; translational research
In response to bacterial and fungal infections in insects and mammals, distinct families of innate immune pattern recognition receptors (PRRs) initiate highly complex intracellular signaling cascades. Those cascades induce a variety of immune functions that restrain the spread of microbes in the host. Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns. Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules. Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge. In this review, we summarize our current understanding of the bacterial and fungal PRRs for homologous innate signaling pathways of insects and mammals in an effort to provide a framework for future studies.
recognition receptors; innate immunity; immune signaling; insects; mammals; pathogens
The purpose of the study was to assess the pharmacokinetics of liposome-encapsulated (DPPC-C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14–28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC-C formulation (half-life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half-life of hydromorphone after SC administration of DPPC-C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (CMAX/D) ranged between 19.41–24.96 ng/mL occurring at 0.18–0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6–72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC-C hydromorphone. Liposome-encapsulated hydromorphone (DPPC-C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.
The purpose of this study was to evaluate arterial blood gases in dogs that were given hydromorphone or extended release liposome-encapsulated hydromorphone (LEH). Dogs were randomly administered LEH, n = 6, (2.0 mg kg−1), hydromorphone, n = 6, (0.2 mg kg−1) or a placebo of blank liposomes, n = 3, subcutaneously on separate occasions. Arterial blood samples were drawn at serial time points over a 6-h time period for blood gas analysis. There was no change from baseline values in PaCO2, PaO2, (HCO3−), pH, and SBEc in the dogs that received the placebo. Administration of hydromorphone resulted in significant increases in PaCO2 (maximum (mean + SD] 44.4 + 1.1 mm of Hg) and significant decreases in PaCO2 (minimum (mean + SD) 82.4 + 4.7 mm of Hg) and pH (minimum (mean + SD) 7.31 + 0.01) compared with baseline. Administration of LEH resulted in significant increases in PaCO2 (maximum (mean + SD) 44.6 + 0.9 mm of Hg) and significant decreases in PaO2 (minimum (mean + SD) 84.8 + 2.6 mm of Hg) and pH (minimum (mean + SD) 7.34 + 0.02) compared with baseline. There was no significant difference between these two groups at any time point. The changes observed in PaCO2, PaO2, and pH, however, were within clinically acceptable limits for healthy dogs. LEH was determined to cause moderate changes in arterial blood gas values similar to those caused by hydromorphone.
Hydromorphone; Extended release; Liposome; Dog; Hypercapnia; Hypoxemia
To investigate the association between objectively measured sitting and standing, using a postural allocation technique, with MRI-assessed body composition.
The present study was a cross-sectional pilot study.
Participants were examined at one centre located in London, UK.
Normal weight Caucasian women (30.9±6.1 years; body mass index (BMI), 22.9±3.4 kg/m2) with desk-bound occupations were recruited to minimise variability in body composition outcomes. A convenience sample of 12 women was recruited in January 2014 from University College London.
For each participant a number of body composition variables were attained from a single whole-body MRI session. Main outcome variables included: total and liver adiposity, visceral/subcutaneous fat ratio and BMI. Main exposure variables included: average sitting time, standing:sitting ratio and step count. Pearson correlations were carried out to examine associations between different activity categories and body composition variables.
There were significant correlations between average daily sitting and liver adiposity and visceral/subcutaneous abdominal fat ratio (r=0.66 and 0.64, respectively); standing:sitting ratio was moderately correlated with liver adiposity and visceral/subcutaneous abdominal fat ratio (r=−0.53 and −0.45); average daily step count was moderately correlated with liver adiposity, total adiposity and visceral/subcutaneous abdominal fat ratio (r=−0.45, −0.46 and −0.51, respectively).
This pilot study has provided preliminary evidence of relationships between objectively measured sitting and standing and precise measures of body composition.
Preventive Medicine; Public Health
The purpose of this report is to demonstrate that a non-contact ultra-widefield dual wavelength laser camera (Optos) is able to capture high-quality images in retinopathy of prematurity (ROP).
Materials and methods
We conducted a retrospective review of patients attending the Oxford Eye Hospital with ROP between 1 August 2012 and 16 November 2012 that underwent standard clinical assessment. Anterior segment imaging, where relevant, was performed with Retcam. Retinal imaging was then performed with Optos, using a modified ‘flying baby position'.
The Optos scanning laser ophthalmoscope was able to acquire ultra-widefield fundal images in nine ROP subjects. The images obtained show clear views of the different stages of ROP features at the posterior pole and peripheral retina. Regression of ROP features were identified, following laser and intravitreal bevacizumab treatment. Additionally, ‘skip areas' missed by initial laser treatment could be identified in the peripheral retina.
The Optos ultra-widefield scanning laser ophthalmoscope is capable of acquiring clinically useful high-quality images of the fundus in ROP subjects. The imaging technique could potentially be used in monitoring ROP progression and documenting ROP regression following treatment.
retinopathy of prematurity; ultra-widefield imaging; Optos
Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra-and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.
Oxygen-induced retinopathy; OIR; Retina; Neovascularization; Quantification; SWIFT_NV
Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.
euglycemic–hyperinsulinemic clamp; GLP1; flux; stable isotopes
Radiotherapy (RT) is of critical importance in the locoregional management of early breast cancer. Over 50% of patients receive RT at some time during the treatment of their disease, equating to over 500 000 patients worldwide receiving RT each year. Unfortunately, not all patients derive therapeutic benefit and some breast cancers are resistant to treatment, as evidenced by distant metastatic spread and local recurrence. Prediction of individual responses to RT may allow a stratified approach to this treatment permitting those patients with radioresistant tumours to receive higher doses of RT (total and/or tumour cavity boost doses) and/or radiosensitising agents to optimise treatment. Also, for those patients unlikely to respond at all, it would prevent harmful side effects occurring for no therapeutic gain. More selective targeting would better direct National Health Service resources, ease the burden on heavily used treatment RT machines and reduce the economic cost of cancer treatment. Unfortunately, there are no robust and validated biomarkers for predicting RT outcome. We review the available literature to determine whether classification of breast cancers according to their molecular profile may be used to predict successful response to, or increased morbidity from, RT. Class-specific biomarkers for targeting by radiosensitising agents are also discussed.
Five laboratory-acquired brucellosis (LAB) cases that occurred in the United States between 2008 and 2011 are presented. The Centers for Disease Control and Prevention (CDC) reviewed the recommendations published in 2008 and the published literature to identify strategies to further prevent LAB. The improved prevention strategies are described.
Squamous cell carcinoma (SCC) is the most common type of malignancy affecting the oral cavity. While exposures to main risk factors for oral SCC such as smoking and alcohol use are higher amongst the Aboriginal people, little is known about oral cancer in this population. This study aimed to describe characteristics and survival of oral SCC in Aboriginal and non-Aboriginal Western Australians.
All primary oral SCC cases reported to the Western Australian Cancer Registry (WACR) between 1990 and 1999 were analysed with respect to person characteristics including: date of birth, sex and indigenous status; and disease characteristics including: date of biopsy, disease stage and site as well as date of recurrence and date of death. Exclusion criteria included diagnosis not based on incisional or excisional biopsy, diagnosis other than oral SCC or a history of another malignant neoplasm.
Aboriginal individuals were more likely to reside in rural areas. No statistically significant differences in oral SCC characteristics and survival were noted between Aboriginal and non-Aboriginal Western Australians.
This study provides new information on person and disease characteristics of Aboriginal Western Australians diagnosed with oral SCC.
Aboriginality; epidemiology; oral cancer; survival analysis.
Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown.
To determine whether genistein blocks eosinophil leukotriene C4 (LTC4) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients.
Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC4 synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FENO) and ex vivo eosinophil LTC4 production were assessed before and after the soy isoflavone treatment period.
Genistein inhibited eosinophil LTC4 synthesis (IC50 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC4 synthesis decreased by 33% (N = 11, P = 0.02) and FENO decreased by 18% (N = 13, P = 0.03).
At physiologically relevant concentrations, genistein inhibits eosinophil LTC4 synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC4 synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.
asthma; eosinophils; genistein; 5-lipoxygenase; soy isoflavones
The National Research Council has consistently recommended housing densities for animals used in science and agriculture. For mice, the recommended density is 77.4 cm2 (12 in2) for a 15–25 gm mouse. The Council noted that its recommendations were based on “best professional judgment” and encouraged alternatives that were data driven. As part of a continual effort of The Jackson Laboratory to ensure the health and well-being of production and research mice while promoting cost-effective, state-of-the-art research, several density-driven studies have been conducted by lab researchers. The objectives of this study were to determine the effect of housing density on parameters related to mouse physiology and air quality in the cages and to assess the value of specific measured parameters in such studies. The study discussed in this report monitored C57BL/6J mice in individually ventilated cages from weaning until 9 months of age. Housing densities were equivalent to 66.4 and 36.8 cm2/mouse (10.3 and 5.7 in2), representing increases in density of 17% and 110%, respectively, over the National Research Council recommendation. Clinical physiological parameters representing general health and well-being were measured. Hematological traits, plasma lipids and glucose, growth, bone mineral density and percent body fat did not differ between densities. In the more densely housed mice, however, adrenal glands were significantly smaller, heart rates were significantly lower, and food consumption was less. Cage air microenvironment was evaluated for ammonia, carbon dioxide, temperature and humidity in cages changed weekly or every 2 weeks. The cage microenvironment remained within acceptable limits at the higher density of mice at both cage-changing frequencies. The results suggest that mice housed in individually ventilated cages for up to 9 months at up to twice the density currently recommended by the National Research Council show no measurable adverse effects. Continued re-evaluation of the recommendation by measuring additional relevant parameters of health and general well-being and studying additional strains is warranted.
adrenal weight; animal husbandry; cage air microenvironment; heart rate; mouse housing density; animal well-being
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a measure of mitochondrial function, were obtained in children 3.5 to 17.3 years old treated for seizure disorders with valproic acid (VPA; n=52). Age-matched patients treated with carbamazepine (CBZ; n=50) and untreated healthy children (n=22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although untreated and CBZ control subjects were not distinguished by the principal component analysis (PCA) scores plot, a distinct boundary was apparent between the VPA and control/CBZ groups. Inter-individual variability in VPA-induced alterations in endogenous pathways reflecting branched chain amino acid metabolism and oxidative stress was observed. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.
Comparative analysis of the sea urchin genome has broad implications for the primitive state of deuterostome host defense and the genetic underpinnings of immunity in vertebrates. The sea urchin has an unprecedented complexity of innate immune recognition receptors relative to other animal species yet characterized. These receptor genes include a vast repertoire of 222 Toll-like receptors, a superfamily of more than 200 NACHT domain–leucine-rich repeat proteins (similar to nucleotide-binding and oligomerization domain (NOD) and NALP proteins of vertebrates), and a large family of scavenger receptor cysteine-rich proteins. More typical numbers of genes encode other immune recognition factors. Homologs of important immune and hematopoietic regulators, many of which have previously been identified only from chordates, as well as genes that are critical in adaptive immunity of jawed vertebrates, also are present. The findings serve to underscore the dynamic utilization of receptors and the complexity of immune recognition that may be basal for deuterostomes and predicts features of the ancestral bilaterian form.
Natural ecosystems perform fundamental life-support services upon which human civilization depends. However, many people believe that nature provides these services for free and therefore, they are of little or no value. While we do not pay for them, we pay significantly for their loss in terms of wastewater treatment facilities, moratoriums on greenhouse gases, increased illnesses, reduced soil fertility and losses in those images of nature that contribute to our basic happiness. Little is understood about the well-being benefits of the natural environment and its ecosystem services. The interwoven relationship of ecosystems and human well-being is insufficiently acknowledged in the wider philosophical, social, and economic well-being literature. In this article, we discuss an approach to examine human well-being and the interactions of its four primary elements—basic human needs, economic needs, environmental needs, and subjective well-being—and ecosystem services.
Ecosystem services; Human well-being; Sustainability; Ecological economics; Subjective happiness
Development of protocols and media for culturing immune cells from marine invertebrates has not kept pace with advancements in mammalian immune cell culture, the latter having been driven by the need to understand the causes of and develop therapies for human and animal diseases. However, expansion of the aquaculture industry and the diseases that threaten these systems creates the need to develop cell and tissue culture methods for marine invertebrates. Such methods will enable us to better understand the causes of disease outbreaks and to develop means to avoid and remedy epidemics. We report a method for the short-term culture of phagocytes from the purple sea urchin, Strongylocentrotus purpuratus, by modifying an approach previously used to culture cells from another sea urchin species. The viability of cultured phagocytes from the purple sea urchin decreases from 91.6% to 57% over six days and phagocyte morphology changes from single cells to aggregates leading to the formation of syncytia-like structures. This process is accelerated in the presence of lipopolysaccharide suggesting that phagocytes are capable of detecting this molecular pattern in culture conditions. Sea urchin immune response proteins, called Sp185/333, are expressed on the surface of a subset of phagocytes and have been associated with syncytia-like structures. We evaluated their expression in cultured phagocytes to determine their possible role in cell aggregation and in the formation of syncytia-like structures. Between 0 and 3 hr, syncytia-like structures were observed in cultures when only ∼10% of the cells were positive for Sp185/333 proteins. At 24 hr, ∼90% of the nuclei were Sp185/333-positive when all of the phagocytes had aggregated into syncytia-like structures. Consequently, we conclude that the Sp185/333 proteins do not have a major role in initiating the aggregation of cultured phagocytes, however the Sp185/333 proteins are associated with the clustered nuclei within the syncytia-like structures.
Recent expeditions have revealed high levels of biodiversity in the tropical deep-sea, yet little is known about the age or origin of this biodiversity, and large-scale molecular studies are still few in number. In this study, we had access to the largest number of solariellid gastropods ever collected for molecular studies, including many rare and unusual taxa. We used a Bayesian chronogram of these deep-sea gastropods (1) to test the hypothesis that deep-water communities arose onshore, (2) to determine whether Antarctica acted as a source of diversity for deep-water communities elsewhere and (3) to determine how factors like global climate change have affected evolution on the continental slope. We show that although fossil data suggest that solariellid gastropods likely arose in a shallow, tropical environment, interpretation of the molecular data is equivocal with respect to the origin of the group. On the other hand, the molecular data clearly show that Antarctic species sampled represent a recent invasion, rather than a relictual ancestral lineage. We also show that an abrupt period of global warming during the Palaeocene Eocene Thermal Maximum (PETM) leaves no molecular record of change in diversification rate in solariellids and that the group radiated before the PETM. Conversely, there is a substantial, although not significant increase in the rate of diversification of a major clade approximately 33.7 Mya, coinciding with a period of global cooling at the Eocene–Oligocene transition. Increased nutrients made available by contemporaneous changes to erosion, ocean circulation, tectonic events and upwelling may explain increased diversification, suggesting that food availability may have been a factor limiting exploitation of deep-sea habitats. Tectonic events that shaped diversification in reef-associated taxa and deep-water squat lobsters in central Indo-West Pacific were also probably important in the evolution of solariellids during the Oligo-Miocene.
Biogeography; deep sea; Eocene–Oligocene transition; phylogeny