Physiological consequences of membrane-initiated estrogen signaling in the brain.

Many of the actions of 17beta-estradiol (E2) in the central nervous system (CNS) are mediated via the classical nuclear steroid receptors, ER(alpha) and ERbeta, which interact with the estrogen response element to modulate gene expression. In addition to the nuclear-initiated estrogen signaling, E2 signaling in the brain can occur rapidly within minutes prior to any sufficient effects on transcription of relevant genes. These rapid, membrane-initiated E2 signaling mechanisms have now been characterized in many brain regions, most importantly in neurons of the hypothalamus and hippocampus.

Synthesis and pharmacological evaluation of N-(3-(1H-indol-4-yl)-5-(2-methoxyisonicotinoyl)phenyl)methanesulfonamide (LP-261), a potent antimitotic agent.

The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency.

Navigated knee kinematics after tear of the ACL and its secondary restraints: preliminary results.

In this study we evaluated the role of the anterior cruciate ligament (ACL) and its secondary restraint in controlling knee stability using a navigation system. The purpose of this study was to evaluate the kinematics of the knee in different conditions of instability: ACL intact, after transection of the posterolateral (PL) bundle, after transection of the anteromedial (AM) bundle, and after lesion of the anterolateral femorotibial ligament (ALFTL). Anterior tibial translation and rotation were measured with a computer navigation system in 6 knees in whole fresh-frozen human cadavers by use of a manual maximum load.

Treatment of acute cough/lower respiratory tract infection by antibiotic class and associated outcomes: a 13 European country observational study in primary care.

Objectives: Acute cough/lower respiratory tract infection (LRTI) is one of the commonest reasons for consulting and antibiotic prescribing. There are theoretical reasons why treatment with particular antibiotic classes may aid recovery more than others, but empirical, pragmatic evidence is lacking. We investigated whether treatment with a particular antibiotic class (amoxicillin) was more strongly associated with symptom score resolution and time to patients reporting recovery than each of eight other antibiotic classes or no antibiotic treatment for acute cough/LRTI.

Estrogen signaling in hypothalamic circuits controlling reproduction.

It is well known that many of the actions of 17β-estradiol (E2) in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane steroid receptors for estrogen in hypothalamic and other brain neurons. Yet, it is not well understood how estrogen signals via membrane receptors and how these signals impact not only membrane excitability but also gene transcription in neurons that modulate GnRH neuronal excitability.

Administration of bovine anti-IGF-1 immunoglobulin to dietary protein deficient rats alters dietary intake and plasma IGF-1 binding profiles, but does not affect change in body mass.

The potential of antibodies raised against insulin-like growth factor-1 (IGF-1) as a treatment to enhance the anabolic actions of IGF-1 has been demonstrated in both rodent and ruminant models. We investigated whether treatment of genetically normal rats with anti-IGF-1 immunoglobulin (Ig, raised in cattle) would enhance growth and if anti-IGF-1 Ig treatment would ameliorate live-weight loss in genetically normal rats offered a severely protein-restricted diet. Scatchard analysis was used to characterise ammonium sulphate precipitated bovine anti-IGF-1 Ig.

Outcome-related metabolomic patterns from 1H/31P NMR after mild hypothermia treatments of oxygen-glucose deprivation in a neonatal brain slice model of asphyxia.

Human clinical trials using 72 hours of mild hypothermia (32°C-34°C) after neonatal asphyxia have found substantially improved neurologic outcomes. As temperature changes differently modulate numerous metabolite fluxes and concentrations, we hypothesized that (1)H/(31)P nuclear magnetic resonance (NMR) spectroscopy of intracellular metabolites can distinguish different insults, treatments, and recovery stages. Three groups of superfused neonatal rat brain slices underwent 45 minutes oxygen-glucose deprivation (OGD) and then were: treated for 3 hours with mild hypothermia (32°C) that began with OGD, or similarly treated with hypothermia after a 15-minute delay, or not treated (normothermic control group, 37°C).

Influence of CRP testing and clinical findings on antibiotic prescribing in adults presenting with acute cough in primary care.

Objective: Respiratory tract infections are the most common indication for antibiotic prescribing in primary care. The value of clinical findings in lower respiratory tract infection (LRTI) is known to be overrated. This study aimed to determine the independent influence of a point of care test (POCT) for C-reactive protein (CRP) on the prescription of antibiotics in patients with acute cough or symptoms suggestive of LRTI, and how symptoms and chest findings influence the decision to prescribe when the test is and is not used.

Contribution of a membrane estrogen receptor to the estrogenic regulation of body temperature and energy homeostasis.

The hypothalamus is a key region of the central nervous system involved in the control of homeostasis, including energy and core body temperature (Tc). 17β-Estradiol (E2) regulates Tc, in part, via actions in the basal hypothalamus and preoptic area. E2 primarily controls hypothalamic functions via the nuclear steroid receptors, estrogen receptor α/β.

17 β-estradiol rapidly increases ATP-sensitive potassium channel activity in gonadotropin-releasing hormone neurons [corrected] via a protein kinase signaling pathway.

17Beta-estradiol (E2) both inhibits and excites GnRH neurons via presynaptic as well as postsynaptic mechanisms. Although it has been demonstrated that E2 can alter the excitability of GnRH neurons via direct actions, the intracellular signaling cascades mediating these actions are not well understood. Previously we have shown that the activity of one of the critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state, the ATP-sensitive potassium channel (K(ATP)) channel, is augmented by E2 in ovariectomized females.

18 F-FDG PET/CT influences management in patients with known or suspected pancreatic cancer.

Background: The aims of this study were (i) to assess and validate the incremental information of positron emission tomography/computed tomography (PET/CT) over conventional staging investigations (CSI) and (ii) to assess the management impact of PET/CT in patients with known or suspected pancreatic cancer.

Methods: Between October 2007 and September 2008, 22 PET/CT scans were performed using a dedicated PET/CT scanner in 21 patients with known or suspected pancreatic cancer. Follow up was used to reconcile discordance between PET/CT and CSI.

Gender, socioeconomic status, and self-rated health in a transitional middle-income setting: evidence from Thailand.

Poor self-rated health (SRH) correlates strongly with mortality. In developed countries, women generally report worse SRH than males. Few studies have reported on SRH in developing countries.

Genotype x environment interaction as it relates to egg production in turkeys (Meleagris gallopavo).

Genotype x environment (GxE) interactions can reduce the accuracy of a model to predict the performance of an animal and have an undesirable influence if not accounted for when estimating breeding values. Consequently, identification of these GxE is necessary when considering a turkey breeding program. Reranking based on the genetic prediction of turkey egg production, fertility, and hatchability in different seasons was indicative of a potential GxE interaction.

Energy efficiency, resilience to future climates and long-term sustainability: the role of the built environment.

Just under half of all energy consumption in the UK today takes place indoors, and over a quarter within our homes. The challenges associated with energy security, climate change and sustainable consumption will be overcome or lost in our existing buildings. A background analysis, and the scale of the engineering challenge for the next three to four decades, is described in this paper.

Leptin excites proopiomelanocortin neurons via activation of TRPC channels.

Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice.

Stomas: ethnicity and quality of life.

Aim: Stoma formation is believed to have a more significant effect on quality of life in Asian patients than in non-Asian patients, but this has never been formally demonstrated. This study examined factors which may influence quality of life following stoma formation with particular reference to ethnicity.

Method: Quality of life was measured (using an established questionnaire) in consecutive patients undergoing stoma formation under the care of two colorectal surgeons.

Acute administration of non-classical estrogen receptor agonists attenuates ischemia-induced hippocampal neuron loss in middle-aged female rats.

Background: Pretreatment with 17beta-estradiol (E2) is profoundly neuroprotective in young animals subjected to focal and global ischemia. However, whether E2 retains its neuroprotective efficacy in aging animals, especially when administered after brain insult, is largely unknown.

Methodology/principal Findings: We examined the neuroprotective effects of E2 and two agonists that bind to non-classical estrogen receptors, G1 and STX, when administered after ischemia in middle-aged rats after prolonged ovarian hormone withdrawal.

Are smokers with acute cough in primary care prescribed antibiotics more often, and to what benefit? An observational study in 13 European countries.

Little is known about actual clinical practice regarding management of smokers compared with ex-smokers and nonsmokers presenting with acute cough in primary care, and whether a lower threshold for prescribing antibiotics benefits smokers. This was a multicentre 13-country European prospective observational study of primary care clinician management of acute cough in consecutive immunocompetent adults presenting with an acute cough of View Article and Find Full Text PDF

Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child.

Undifferentiated embryonal sarcoma of the liver is a rare hepatic malignancy of childhood with a historically poor prognosis. Recent improvements in outcomes have been reported in small numbers of cases with the use of combination therapy involving aggressive surgical resection and chemotherapy. Complete surgical resection is frequently difficult to achieve when the location of the tumor is along the margins of the major hepatic vessels (portal vein, hepatic vein, and hepatic artery).

The association of lifetime education with the prevalence of myocardial infarction: an analysis of the 2006 Behavioral Risk Factor Surveillance System.

Socioeconomic status is likely an independent risk factor for coronary heart disease but little research has been done in the United States to study this association in a nationally representative sample. We sought to determine the association between lifetime education and the prevalence of myocardial infarction (MI) among adults over the age of 39 in the US. A cross sectional study was conducted using the 2006 Behavioral Risk Factor Surveillance System (BRFSS).

Bacteremia in febrile nonneutropenic pediatric oncology patients.

Background: We sought to determine the risk of bacteremia in a cohort of outpatient febrile nonneutropenic pediatric oncology patients and to assess clinical characteristics that may influence decisions regarding empiric antibiotic therapy.

Procedure: A single institution retrospective cohort study was performed of outpatient pediatric oncology patients presenting with fever, a central venous catheter, and an absolute neutrophil count (ANC) of >/=500/microl over a 6-year period. We also collected data regarding the presence of clinically evident infections, antibiotics prescribed, and the sensitivity of bacteria to specific antibiotics.