The effects of leptin on placental development and function, and offspring behavior in mice

"May 2014."Dissertation Supervisor: Dr. Laura Schulz.Includes vita.The nutritional and energy status of individuals is communicated throughout the body by means of leptin. This hormone also plays a role in implantation and placental development and function, as well as programming behavior via alteration of brain function. The current research provides insight into how leptin is involved in placental and fetal development. The goal of the first study was to determine the importance of the leptin receptors of the mouse conceptus in placental development and function. We utilized a leptin receptor knockout mouse model, and found significant alterations in gene expression in placentas lacking the receptor, suggesting that placental function may be altered. The goal of the second study was to determine the effect of maternal hyperleptinemia on offspring behavior. We compared wildtype offspring from two hyperleptinemic mouse models. Adult offspring from hyperleptinemic dams weighed less, and were more active than their controls. Female offspring from these dams consumed more food and had reduced preference for palatable food compared to their controls. Maternal hyperleptinemia during pregnancy protected offspring from weight gain by increasing activity. Overall, leptin affects placental gene expression, and possibly function, and offspring behaviors that influence energy homeostasis.Includes bibliographical references (pages 91-111)

Endothelin.

The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.We (APD, JJM) thank the British Heart Foundation (PS/02/001, PG/05/127/19872, FS/12/64/130001), Wellcome Trust Programme in Metabolic and Cardiovascular Disease 096822/Z/11/Z NIHR Cambridge Biomedical Research Centre and the Pulmonary Hypertension Association UK; Wellcome Biomedical Resources Grant 099156/Z/12/Z for support for IUPHAR/BPS Guide to PHARMACOLOGY (CS). We acknowledge National Heart, Lung, and Blood Institute Grants P01 HL95499 (D.E.K., K.A.H., D.M.P., J.S.P.), P01 HL69999 (D.M.P., J.S.P.), U01HL117684 (D.M.P.).This is the final version of the article. It first appeared from the American Society for Pharmacology and Experimental Therapeutics via https://doi.org/10.1124/pr.115.01183

Relativistic mean field approximation to the analysis of 16O(e,e'p)15N data at |Q^2|\leq 0.4 (GeV/c)^2

We use the relativistic distorted wave impulse approximation to analyze data on 16O(e,e'p)15N at |Q^2|\leq 0.4 (GeV/c)^2 that were obtained by different groups and seemed controversial. Results for differential cross-sections, response functions and A_TL asymmetry are discussed and compared to different sets of experimental data for proton knockout from p_{1/2} and p_{3/2} shells in 16O. We compare with a nonrelativistic approach to better identify relativistic effects. The present relativistic approach is found to accommodate most of the discrepancy between data from different groups, smoothing a long standing controversy.Comment: 28 pages, 7 figures (eps). Major revision made. New figures added. To be published in Phys. Rev.

Prehospital amputation : an experimental comparison of techniques

"Prehospital limb amputation is a rare, but potentially lifesaving intervention. When adequate resuscitation is not possible due to difficult patient access, hemodynamically unstable patients may benefit from an emergent prehospital amputation. There have been a limited number of case reports detailing prehospital amputation. Furthermore, there has only been one experimental trial. Leech et al. explored prehospital-friendly methods of amputation on human cadavers; however, due to a small sample size of four trials, the data has limited reliability."--Introduction

Binge Drinking Effects on EEG in Young Adult Humans

Young adult (N = 96) university students who varied in their binge drinking history were assessed by electroencephalography (EEG) recording during passive viewing. Groups consisted of male and female non-binge drinkers (>1 to 5/4 drinks/ounces in under two hours), low-binge drinkers (5/4–7/6 drinks/ounces in under two hours), and high-binge drinkers (≥ 10 drinks/ounces in under two hours), who had been drinking alcohol at their respective levels for an average of 3 years. The non- and low-binge drinkers exhibited less spectral power than the high-binge drinkers in the delta (0–4 Hz) and fast-beta (20–35 Hz) bands. Binge drinking appears to be associated with a specific pattern of brain electrical activity in young adults that may reflect the future development of alcoholism

Influence of river discharge on grass carp occupancy dynamics in south‐eastern Iowa rivers

Despite the longstanding presence of grass carp Ctenopharyngodon idella in the Upper Mississippi River (UMR) watershed, information regarding their populations remains largely unknown, in part because capture is difficult. Occupancy models are a popular wildlife assessment tool to account for imperfect detections but have been slow to be adopted in fisheries. Herein, we used occupancy modelling to evaluate the influence of two environmental covariates (river discharge and water temperature) on grass carp occupancy, extinction, colonization, and detection at nine sites within south‐eastern Iowa rivers from April to October 2014 and 2015. Grass carp were detected at least once at all but one site. The most parsimonious model indicated that grass carp colonization probability increased from 0.15 to 0.67 with increases in river discharge. In contrast, occupancy (0.20), extinction (0.29), and detection (0.50) probabilities were temporally constant. Models indicated that water temperatures did not influence grass carp extinction or colonization probabilities relative to river discharge. Cumulative grass carp detection probability approached 1.0, whereas conditional occupancy estimates were less than 0.1 when using five or more sampling transects. The use of a robust design occupancy model allowed us to estimate site occupancy rates of grass carp corrected for imperfect detections, while demonstrating the importance of river discharge for site colonization. These results can be used to assess the distribution of a cryptic fish while helping to guide grass carp sampling and removal efforts

Relativistic Structure of the Deuteron: 1.Electro-disintegration and y-scaling

Realistic solutions of the spinor-spinor Bethe-Salpeter equation for the deuteron with realistic interaction kernel including the exchange of pi, sigma, omega, rho, eta and delta mesons, are used to systematically investigate relativistic effects in inclusive quasi-elastic electron-deuteron scattering within the relativistic impulse approximation. Relativistic y-scaling is considered by generalising the non relativistic scaling function to the relativistic case, and it is shown that y-scaling does occur in the usual relativistic scaling variable resulting from the energy conservation in the instant form of dynamics. The present approach of y-scaling is fully covariant, with the deuteron being described by eight components, viz. the 3S_1^{++}, 3S_1^{--}, 3D_1^{++}, 3D_1^{--}, 3P_1^{+-}, 3P_1^{-+}, 1P_1^{+-}, 1P_1^{-+} waves. It is demonstrated that if the negative relative energy states 1P_1, 3P_1 are disregarded, the concept of covariant momentum distributions N(p_0,p), with p_0=M_D/2-\sqrt{p^2+m^2}, can be introduced, and that calculations of lectro-disintegration cross section in terms of these distributions agree within few percents with the exact calculations which include the 1P_1, 3P_1 states, provided the nucleon three momentum |p|\<= 1 GeV/c; in this momentum range, the asymptotic relativistic scaling function is shown to coincide with the longitudinal covariant momentum distribution.Comment: 32 LaTeX pages, 18 eps-figures. Final version to appear in Phys. Rev.

The High-Superior-Tension Technique: Evolution of Lipoabdominoplasty

Because abdominoplasty is associated with complications such as seroma and necrosis as well as epigastric bulging and a suprapubic scar located too high, the demand for this procedure is not as high as it otherwise might be. However, although these negative effects were common many years ago, their incidence has decreased dramatically with modern abdominoplastic techniques. One approach using a combination of abdominoplasty and liposuction or lipoabdominoplasty has resolved many of the problems faced with earlier techniques, offering aesthetically pleasing results and excellent reliability. The keys to successful lipoabdominoplasty, first developed as the high-superior-tension technique, are extensive liposuction, preservation of lymphatic trunks, preaponeurotic epigastric dissection, major muscle fascia plication, two high-tension paraumbilical sutures, hypogastric tension sutures, and closure of the dead spaces. The most recent updates to this technique are described in this article

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit\u27s Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?. Methods/Design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer\u27s disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson\u27s disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. Results: We found three components in the ZBI. The first was “overall burden” and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = −0.566, basic ADLs r = −0.43), (2) moderately related to cognition (MoCA r = −0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions

Performance of the GeneXpert Ebola Assay for Diagnosis of Ebola Virus Disease in Sierra Leone: A Field Evaluation Study

Background: Throughout the Ebola virus disease (EVD) epidemic in West Africa, field laboratory testing for EVD has relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays; an accurate sample-to-answer RT-PCR test would reduce time to results and potentially increase access to testing. We evaluated the performance of the Cepheid GeneXpert Ebola assay on clinical venipuncture whole blood (WB) and buccal swab (BS) specimens submitted to a field biocontainment laboratory in Sierra Leone for routine EVD testing by RT-PCR (“Trombley assay”). Methods and Findings: This study was conducted in the Public Health England EVD diagnostic laboratory in Port Loko, Sierra Leone, using residual diagnostic specimens remaining after clinical testing. EDTA-WB specimens (n = 218) were collected from suspected or confirmed EVD patients between April 1 and July 20, 2015. BS specimens (n = 71) were collected as part of a national postmortem screening program between March 7 and July 20, 2015. EDTA-WB and BS specimens were tested with Xpert (targets: glycoprotein [GP] and nucleoprotein [NP] genes) and Trombley (target: NP gene) assays in parallel. All WB specimens were fresh; 84/218 were tested in duplicate on Xpert to compare WB sampling methods (pipette versus swab); 43/71 BS specimens had been previously frozen. In all, 7/218 (3.2%) WB and 7/71 (9.9%) BS samples had Xpert results that were reported as “invalid” or “error” and were excluded, leaving 211 WB and 64 BS samples with valid Trombley and Xpert results. For WB, 22/22 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 84.6%–100%), and 181/189 Trombley-negative samples were Xpert-negative (specificity 95.8%, 95% confidence interval (CI) 91.8%–98.2%). Seven of the eight Trombley-negative, Xpert-positive (Xpert cycle threshold [Ct] range 37.7–43.4) WB samples were confirmed to be follow-up submissions from previously Trombley-positive EVD patients, suggesting a revised Xpert specificity of 99.5% (95% CI 97.0%–100%). For Xpert-positive WB samples (n = 22), Xpert NP Ct values were consistently lower than GP Ct values (mean difference −4.06, 95% limits of agreement −6.09, −2.03); Trombley (NP) Ct values closely matched Xpert NP Ct values (mean difference −0.04, 95% limits of agreement −2.93, 2.84). Xpert results (positive/negative) for WB sampled by pipette versus swab were concordant for 78/79 (98.7%) WB samples, with comparable Ct values for positive results. For BS specimens, 20/20 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 83.2%–100%), and 44/44 Trombley-negative samples were Xpert-negative (specificity 100%, 95% CI 92.0%–100%). This study was limited to testing residual diagnostic samples, some of which had been frozen before use; it was not possible to test the performance of the Xpert Ebola assay at point of care. Conclusions: The Xpert Ebola assay had excellent performance compared to an established RT-PCR benchmark on WB and BS samples in a field laboratory setting. Future studies should evaluate feasibility and performance outside of a biocontainment laboratory setting to facilitate expanded access to testing