Traffic-derived particulate matter (PM) is associated with cardiovascular morbidity and mortality, but the mechanism of this association is unclear. Prothrombotic processes have been linked to PM in epidemiological and animal models, but have not been consistently implicated in controlled human models. Diesel exhaust (DE) is a major contributor to PM. We conducted a controlled human exposure of DE in subjects with metabolic syndrome. The study objective was to evaluate DE exposure effects on prothrombotic markers in a population vulnerable to cardiovascular disease. A randomized, crossover, double-blinded design was used: 16 subjects with metabolic syndrome exposed on 3 different days (≥2 wk washout) to DE at 0 (filtered air, FA), 100 μg PM2.5/m3 (DE100) and 200 μg PM2.5/m3 (DE200). We assessed DE-associated changes in D-dimer, von Willebrand factor (VWF), and plasmin activator inhibitor-1 (PAI-1) at 3, 7, and 22 h after exposure initiation. A DE200-attributable decrease (1.17-fold; CI 1.04 to 1.34) in VWF was noted at 7 h. Significant changes did not occur in other primary endpoints. As previously noted with healthy subjects, strong diurnal patterns in PAI-1 were observed. Thus, in a novel study, we were unable to demonstrate a prothrombotic effect of moderate-dose diesel exhaust exposure in a population at risk for cardiovascular disease.
To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.
Observational, retrospective case series.
Mayo Clinic Health System.
Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.
Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.
Main Outcome Measure
After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.
When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.
During the 2009 influenza pandemic, pregnant women were at particular risk of serious influenza illness. This concern was further complicated by questions about vaccine safety in pregnant women raised by anecdotal reports of fetal deaths following vaccination.
We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios of fetal death, with gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables.
There were 117,347 eligible pregnancies in Norway in 2009–2010. Fetal mortality was 4.9/1000. 54% of pregnant women in their second or third trimester during the pandemic were vaccinated. Vaccination in pregnancy substantially reduced the risk of influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). A clinical diagnosis of influenza in the mother increased the risk of fetal death (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). Among pregnant women, the risk of fetal death was lower with vaccination, although this reduction was not statistically significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17).
Pandemic influenza in pregnancy was associated with increased risk of fetal death. Vaccination during pregnancy reduced the risk of influenza diagnosis. Vaccination itself did not increase fetal mortality, and may have reduced the risk of influenza-related fetal death during the pandemic.
Pandemic vaccination; influenza; influenza A(H1N1)pdm09; pandemic; pregnancy; fetal death; miscarriage; abortions; stillbirth; Norway; registry; register; population
We investigated the association of sST2 with diagnostic and prognostic outcomes and assessed whether it aids B-natriuretic peptide (BNP) in diagnosing and predicting outcomes in emergency department (ED) patients with suspected AHFS.
We recruited patients who presented to the ED of 3 tertiary hospitals with signs or symptoms of AHFS and met modified Framingham criteria for AHFS. Outcome measures were a final diagnosis of AHFS and 5-and 30-day adverse events.
In the 295 subjects with sST2 available, the median sST2 was 0.20 ng/ml (IQR=0.10, 0.34). Although unadjusted analyses indicated sST2 was significantly associated with the diagnosis of AHFS (p=0.02), this was not so in the adjusted analysis (p=0.33). Moderately low diagnostic utility was noted with an AUC of 0.62 (95% CI=0.56, 0.69). Similar sST2 test characteristics were seen when BNP was restricted between 100 and 500 pg/ml. While sST2 was associated with AHFS readmission at 30-days (p=0.04), in the adjusted analyses it was not associated with adverse events.
In patients with signs or symptoms of AHFS, unadjusted analyses indicated that sST2 was significantly associated with the diagnosis of AHFS and with 30-day AHFS recidivism. However, the associations did not carry over to adjusted analyses, and sST2 did not add significant information with regard to explaining the diagnostic and prognostic variability of BNP.
Soluble ST2; Acute heart failure; Diagnosis; Prognosis
Spectral CT is the newest advancement in CT imaging technology, which enhances traditional CT images with the capability to image and quantify certain elements based on their distinctive K-edge energies. K-edge imaging feature recognizes high accumulations of targeted elements and presents them as colorized voxels against the normal grayscale X-ray background offering promise to overcome the relatively low inherent contrast within soft tissue and distinguish the high attenuation of calcium from contrast enhanced targets. Towards this aim, second generation gold nanobeacons (GNB2), which incorporate at least five times more metal than the previous generation was developed. The particles were synthesized as lipid-encapsulated, vascularly constrained (>120 nm) nanoparticle incorporating tiny gold nanoparticles (2–4 nm) within a polysorbate core. The choice of core material dictated to achieve a higher metal loading. The particles were thoroughly characterized by physicochemical techniques. This study reports one of the earlier examples of spectral CT imaging with gold nanoparticles demonstrating the potential for targeted in vitro and in vivo imaging and eliminates calcium interference with CT. The use of statistical image reconstruction shows high SNR may allow dose reduction and/or faster scan times.
The typical dilemma with sex-ratio findings is that when they are real, they aren’t interesting, and when they are interesting, they aren’t real. In this issue of the Journal, Fernández et al. (Am J Epidemiol. 2011;174(12):1327–1331) describe a deviation of the sex ratio that is apparently both large and real. There was a temporary but distinct spike in the proportion of boys born in Cuba around the time of the collapse of the national economy during the 1990s. Although an excess of boys does not fit the prevailing biologic theory regarding maternal stress and the sex ratio, the data are consistent with results from the Dutch famine (where population-level deprivation was even more extreme). A new quandary arises in the modern era with interpretation of the sex ratio: If the decision to abort a pregnancy is influenced by the sex of the fetus, a change in the behavior of even a small proportion of women could influence the sex ratio at birth. The possible role of sex selection in the Cuban context is discussed.
abortion; sex ratio
Two new 2,2′-bipyridine (bpy) based ligands with ancillary BODIPY chromophores attached at the 4 and 4′-positions were prepared and characterized, which vary in the substitution pattern about the BODIPY periphery by either excluding (BB1) or including (BB2) a β-alkyl substituent. Both absorb strongly throughout the visible region and are strongly emissive. The basic photophysics and electrochemical properties of BB1 and BB2 are comparable to those of the BODIPY monomers on which they are based. The solid-state structures and electronic structure calculations both indicate that there is negligible electronic communication between the BODIPY moieties and the intervening bpy spacers. Electrogenerated chemiluminescence spectra of the two Bpy-BODIPY derivatives are similar to their recorded fluorescence profiles and are strongly influenced by substituents on the BODIPY chromophores. These 2,2′-bipyridine derivatives represent a new set of ligands that should find utility in applications including light-harvesting, photocatalysis, and molecular electronics.
BODIPY; bipyridine; electrochemistry; photophysics; electrogenerated chemiluminescence
Existing methods to predict the effects of climate change on the biomass and production of marine communities are predicated on modelling the interactions and dynamics of individual species, a very challenging approach when interactions and distributions are changing and little is known about the ecological mechanisms driving the responses of many species. An informative parallel approach is to develop size-based methods. These capture the properties of food webs that describe energy flux and production at a particular size, independent of species' ecology. We couple a physical–biogeochemical model with a dynamic, size-based food web model to predict the future effects of climate change on fish biomass and production in 11 large regional shelf seas, with and without fishing effects. Changes in potential fish production are shown to most strongly mirror changes in phytoplankton production. We project declines of 30–60% in potential fish production across some important areas of tropical shelf and upwelling seas, most notably in the eastern Indo-Pacific, the northern Humboldt and the North Canary Current. Conversely, in some areas of the high latitude shelf seas, the production of pelagic predators was projected to increase by 28–89%.
global environmental change; benthic–pelagic coupling; fisheries ecology; marine macroecology; marine communities; size spectrum
Engineering design often involves the determination of design variable settings to optimize competing performance requirements. In the early design stages we propose narrowing down the domain of design solutions using metamodels of principal components of the multiple performance levels that have been scaled by a multivariate quadratic loss function. The multivariate quadratic loss function is often used as the objective function in reaching optimal solutions because it utilizes the correlation structure of the design’s performance metrics and penalizes off-target performance in a symmetrical manner. We also compare the computational performance of these loss-scaled principal components when used to solve for the design with minimal expected multivariate quadratic loss under three modeling approaches: response surface methodology, multivariate adaptive regression splines, and spatial point modeling. We demonstrate the technique on the design of the mechanical frame of an electric vehicle with six desired performance levels determined simultaneously by the dimensions of eight mechanical design elements. The method is the focus in this work.
multiple response; multivariate quadratic loss function; optimal solutions; robust engineering design
Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified.
adjustment; collider; directed acyclic graph; gestational age; infant mortality; mediating variable; premature birth; stratification
Microalgae are extensively researched as potential feedstocks for biofuel production. Energy-rich compounds in microalgae, such as lipids, require efficient characterization techniques to investigate the metabolic pathways and the environmental factors influencing their accumulation. The model green alga Coccomyxa accumulates significant amounts of triacylglycerols (TAGs) under nitrogen depletion (N-depletion). To monitor the growth of TAGs (lipid) in microalgal cells, a study of microalgal cells (Coccomyxa sp. C169) using both spontaneous Raman and coherent anti-Stokes Raman scattering (CARS) spectroscopy and microscopy were carried out. Spontaneous Raman spectroscopy was conducted to analyze the components in the algal cells, while CARS was carried out to monitor the distribution of lipid droplets in the cells. Raman signals of carotenoid are greater in control microalgae compared to N-depleted cells. Raman signals of lipid droplets appear after N-depletion and its distribution can be clearly observed in the CARS microscopy. Both spontaneous Raman spectroscopy and CARS microscopy were found to be suitable analysis tools for microalgae.
(300.6365) Spectroscopy; (300.6230) Spectroscopy, coherent anti-Stokes Raman scattering; (300.6450) Spectroscopy, Raman
The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.
depression; genomics; personalized medicine; pharmacogenomics; psychiatric treatment
The molecular mechanisms regulating vascular barrier integrity remain incompletely elucidated. We have previously reported an association between the GTPase R-Ras and repeat 3 of Filamin A (FLNa). Loss of FLNa has been linked to increased vascular permeability. We sought to determine whether FLNa’s association with R-Ras affects endothelial barrier function. We report that in endothelial cells endogenous R-Ras interacts with endogenous FLNa as determined by co-immunoprecipitations and pulldowns with the FLNa-GST fusion protein repeats 1–10. Deletion of FLNa repeat 3 (FLNa 3) abrogated this interaction. In these cells FLNa and R-Ras co-localize at the plasma membrane. Knockdown of R-Ras and/or FLNa by siRNA promotes vascular permeability, as determined by TransEndothelial Electrical Resistance and FITC-dextran transwell assays. Re-expression of FLNa restored endothelial barrier function in cells lacking FLNa whereas re-expression of FLNaΔ3 did not. Immunostaining for VE-Cadherin in cells with knocked down R-Ras and FLNa demonstrated a disorganization of VE-Cadherin at adherens junctions. Loss of R-Ras and FLNa or blocking R-Ras function via GGTI-2133, a selective R-Ras inhibitor, induced vascular permeability and increased phosphorylation of VE-Cadherin (Y731) and Src (Y416). Expression of dominant negative R-Ras promoted vascular permeability that was blocked by the Src inhibitor PP2. These findings demonstrate that maintaining endothelial barrier function is dependent upon active R-Ras and association between R-Ras and FLNa and that loss of this interaction promotes VE-Cadherin phosphorylation and changes in downstream effectors that lead to endothelial leakiness.
R-Ras; Filamin A; vascular permeability; VE-Cadherin; TEER; endothelial barrier function
Non-syndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G×E) interaction simultaneously, plus a separate 1 df test for G×E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome wide significance when considered alone, markers in several genes attained or approached genome wide significance when G×E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G×E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G×E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as non-syndromic CP.
Human-induced alteration of natural habitats has the potential to impact on the genetic structuring of remnant populations at multiple spatial scales. Species from higher trophic levels, such as snakes, are expected to be particularly susceptible to land-use changes. We examined fine-scale population structure and looked for evidence of sex-biased dispersal in smooth snakes (Coronella austriaca), sampled from 10 heathland localities situated within a managed coniferous forest in Dorset, United Kingdom. Despite the limited distances between heathland areas (maximum <6 km), there was a small but significant structuring of populations based on eight microsatellite loci. This followed an isolation-by-distance model using both straight line and ‘biological' distances between sampling sites, suggesting C. austriaca's low vagility as the causal factor, rather than closed canopy conifer forest exerting an effect as a barrier to dispersal. Within population comparisons of male and female snakes showed evidence for sex-biased dispersal, with three of four analyses finding significantly higher dispersal in males than in females. We suggest that the fine-scale spatial genetic structuring and sex-biased dispersal have important implications for the conservation of C. austriaca, and highlight the value of heathland areas within commercial conifer plantations with regards to their future management.
colubridae; forestry; genetic diversity; isolation-by-distance; microsatellites; habitat loss
The quality of polyp level data in a population-based registry depends on the ability to match each polypectomy recorded by the endoscopist to a specific diagnosis on the pathology report.
To review impediments encountered in matching colonoscopy and pathology data in a population-based registry.
New Hampshire Colonoscopy Registry data from August 2006 to November 2008 was analyzed for prevalence of missing reports, discrepancies between colonoscopy and pathology reports, and the proportion of polyps that could not be matched because of multiple polyps submitted in the same container.
New Hampshire Colonoscopy Registry.
All consenting patients during the study period.
Develop an algorithm for capturing number, size, location, and histology of polyps and for defining and flagging discrepancies to ensure data quality.
Main Outcome Measurements
The proportion of polyps with no assumption or discrepancy and the proportion of patient records eligible for determining the adenoma detection rate (ADR) and the number of patients with ≥3 adenomas.
Only 50% polyps removed during this period were perfectly matched with no assumption or discrepancy. Records from only 69.9% and 29.7%% of eligible patients could be used to determine the ADR and the number of patients with ≥3 adenomas, respectively.
Rates of missing reports may have been higher in the early phase of establishment of the registry.
This study highlights the impediments in collecting polyp level data in a population-based registry and provides useful parameters for evaluating the quality and accuracy of data obtained from such registries.
The value and appropriateness of universal postpartum depression (PPD) screening remains controversial in the United States. To date, several PPD screening programs have been introduced and a few have been evaluated. Among those programs that have been evaluated, most report screening rates, diagnosis rates, or treatment initiation rates. Only four studies included patient outcomes such as the level of depressive symptoms at 6 to 12 months postpartum, and only two reported success in improving outcomes. Program characteristics that appear to result in low rates of diagnosis and followup after PPD screening include requirements for a formal psychiatric evaluation, the need to refer women to another site for therapy, and failure to integrate the PPD screening into the care provided at the woman's or her child's medical home. The two programs that reported improved outcomes were both self-contained within primary care and included specific followup, management, and therapy procedures. Both resulted in the need for outside referrals in less than 10% of women diagnosed with postpartum depression. Future studies should be based on the successful programs and their identified facilitators while avoiding identified barriers. To affect policies, the future program must report maternal outcomes going beyond the often reported process outcomes of screening, referral, and therapy initiation rates.
Based on a nanocolloidal suspension of lipid-encapsulated, organically-soluble bivalent copper, a new site-targeted molecular imaging contrast agent has been developed. Concentrating high payload of bivalent copper ions per nanoparticle, this agent provides a high per-particle r1 relaxivity allowing sensitive detection on T1-weighted MRI as is demonstrated herein targeted to fibrin clots in vitro. The particle also exhibits a defined clearance and safety profile in vivo.
Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers.
We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample.
The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.
Preterm delivery has a variety of causes, with each of these presumably carrying its own mortality risk. To the extent that they add to the risk of mortality, the various pathologic factors triggering preterm delivery will confound the causal contribution of gestational age to mortality, inflating the observed rates of gestational-age-specific mortality. We have previously estimated that about half of the mortality of US preterm singletons may be due to unmeasured pathologies that increase mortality risk and also cause preterm birth. In this paper, we examine the impact that rare factors may have, at least in theory, on preterm mortality.
We constructed a simple model of gestational-age specific mortality, in which we arbitrarily selected a function to represent the mortality due to immaturity alone (“baseline” risk). We then added “unmeasured” confounding factors that cause mortality and also cause preterm birth. This construct allowed us to calculate, in simple scenarios, the proportion of preterm mortality that could be caused by unmeasured confounding.
We found that rare pathologies with moderate-to-strong effects can substantially contribute to preterm mortality. The presence of such rare factors can also produce an intersection of gestational-age-specific mortality curves when stratifying by known risk factors.
It is possible that a few relatively rare factors may account for a large fraction of preterm mortality. The search for such factors should be a primary focus of future research on preterm delivery.
We investigated associations between stress and mental health (positive affect, depressive symptoms) among HIV-negative and HIV-positive midlife and older gay-identified men, along with the mediating and moderating effects of mastery and emotional support. We also studied the mental health effects of same-sex marriage.
We obtained data from self-administered questionnaires completed in 2009 or 2010 by a subsample (n=202; average age=56.91 years; age range= 44–75 years) of participants in the University of California, Los Angeles component of the Multicenter AIDS Cohort Study, one of the largest and longest-running natural-history studies of HIV/AIDS in the United States.
Both sexual minority stress (perceived gay-related stigma, excessive HIV bereavements) and aging-related stress (independence and fiscal concerns) appeared to have been detrimental to mental health. Sense of mastery partially mediated these associations. Being legally married was significantly protective net of all covariates, including having a domestic partner but not being married. Education, HIV status, and race/ethnicity had no significant effects.
Sexual minority and aging-related stress significantly affected the emotional lives of these men. Personal sense of mastery may help to sustain them as they age. We observed specific mental health benefits of same-sex legal marriage.
Despite numerous and diverse theoretical models for the indirect benefits of polyandry, empirical support is mixed. One reason for the difficulty in detecting indirect benefits of polyandry may be that these are subtle and are mediated by environmental effects, such as maternal effects. Maternal effects may be especially important if females allocate resources to their offspring depending on the characteristics of their mating partners. We test this hypothesis in the burying beetle Nicrophorus vespilloides, a species that provides extensive and direct parental care to offspring. We used a fully factorial design and mated females to one, two, three, four or five different males and manipulated conditions so that their offspring received reduced (12 h) or full (ca 72 h) maternal care. We found that average offspring fitness increased with full maternal care but there was no significant effect of polyandry or the interaction between the duration of maternal care and the level of polyandry on offspring fitness. Thus, although polyandry could provide a mechanism for biasing paternity towards high quality or compatible males, and variation in parental care matters, we found no evidence that female N. vespilloides gain indirect benefits by using parental care to bias the allocation of resources under different mating conditions.
burying beetles; indirect benefits; maternal effects; Nicrophorus vespilloides; parental care; polyandry
The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.
Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN).
PI was administered weekly in cohorts of 3–6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity.
Thirty patients (median age 9.3 years, range 1.9–34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 μg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 μg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 μg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 μg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%–22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage.
The RP2D of PI for pediatric patients with PN is 1 μg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur.
Classification of evidence:
This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.
Previous studies of hormone patterns after clinical miscarriage suggest reduced pituitary function. Hormonal effects of very early pregnancy loss (before six weeks gestation) have not been described. We used within-woman differences between menstrual cycles in urinary hormone measurements from women in the North Carolina Early Pregnancy Study to describe hormonal changes after very early pregnancy loss (n=28 early losses; 80 non-conception comparison cycles). We found lower pre-ovulatory luteinizing hormone and shorter luteal phase length after very early pregnancy loss, but the differences were non-significant (p>0.3) and smaller than those reported in the spontaneous miscarriage literature. Consistent with the reduced pituitary function reported post-spontaneous miscarriage, we found a slower rate of estrogen rise (p=0.08). There was no evidence of lower midluteal steroid levels as has been suggested for post-spontaneous miscarriage cycles. Very early pregnancy losses do not appear to influence subsequent menstrual cycles to the same degree as spontaneous miscarriages.
early pregnancy loss; hormone; estrogen; luteinizing hormone