An absorption profile centred at 78 megahertz in the sky-averaged spectrum.

After stars formed in the early Universe, their ultraviolet light is expected, eventually, to have penetrated the primordial hydrogen gas and altered the excitation state of its 21-centimetre hyperfine line. This alteration would cause the gas to absorb photons from the cosmic microwave background, producing a spectral distortion that should be observable today at radio frequencies of less than 200 megahertz. Here we report the detection of a flattened absorption profile in the sky-averaged radio spectrum, which is centred at a frequency of 78 megahertz and has a best-fitting full-width at half-maximum of 19 megahertz and an amplitude of 0.5 kelvin. The profile is largely consistent with expectations for the 21-centimetre signal induced by early stars; however, the best-fitting amplitude of the profile is more than a factor of two greater than the largest predictions. This discrepancy suggests that either the primordial gas was much colder than expected or the background radiation temperature was hotter than expected. Astrophysical phenomena (such as radiation from stars and stellar remnants) are unlikely to account for this discrepancy; of the proposed extensions to the standard model of cosmology and particle physics, only cooling of the gas as a result of interactions between dark matter and baryons seems to explain the observed amplitude. The low-frequency edge of the observed profile indicates that stars existed and had produced a background of Lyman-α photons by 180 million years after the Big Bang. The high-frequency edge indicates that the gas was heated to above the radiation temperature less than 100 million years later.

A lower limit of Δz > 0.06 for the duration of the reionization epoch.

Observations of the 21-centimetre line of atomic hydrogen in the early Universe directly probe the history of the reionization of the gas between galaxies. The observations are challenging, though, because of the low expected signal strength (∼10 mK), and contamination by strong (>100 K) foreground synchrotron emission in the Milky Way and extragalactic continuum sources. If reionization happened rapidly, there should be a characteristic signature visible against the smooth foreground in an all-sky spectrum. Here we report an all-sky spectrum between 100 and 200 MHz, corresponding to the redshift range 6 < z < 13 for the 21-centimetre line. The data exclude a rapid reionization timescale of Δz < 0.06 at the 95% confidence level.

Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.

Identification of mosquito bloodmeals using mitochondrial cytochrome oxidase subunit I and cytochrome b gene sequences.

Primer pairs were designed and protocols developed to selectively amplify segments of vertebrate mitochondrial cytochrome oxidase subunit 1 (COI) and cytochrome b (Cyt b) mtDNA from the bloodmeals of mosquitoes (Diptera: Culicidae). The protocols use two pairs of nested COI primers and one pair of Cyt b primers to amplify short segments of DNA. Resultant sequences are then compared with sequences in GenBank, using the BLAST function, for putative host identification. Vertebrate DNA was amplified from 88% of our sample of 162 wild-caught, blood-fed mosquitoes from Oregon, U.S.A. and GenBank BLAST searches putatively identified 98% of the amplified sequences, including one amphibian, seven mammalian and 14 avian species. Criteria and caveats for putative identification of bloodmeals are discussed.

Efficient gene transfer to airway epithelium using recombinant Sendai virus.

Clinical studies of gene therapy for cystic fibrosis (CF) suggest that the key problem is the efficiency of gene transfer to the airway epithelium. The availability of relevant vector receptors, the transient contact time between vector and epithelium, and the barrier function of airway mucus contribute significantly to this problem. We have recently developed recombinant Sendai virus (SeV) as a new gene transfer agent. Here we show that SeV produces efficient transfection throughout the respiratory tract of both mice and ferrets in vivo, as well as in freshly obtained human nasal epithelial cells in vitro. Gene transfer efficiency was several log orders greater than with cationic liposomes or adenovirus. Even very brief contact time was sufficient to produce this effect, and levels of expression were not significantly reduced by airway mucus. Our investigations suggest that SeV may provide a useful new vector for airway gene transfer.

Bringing Rounds Back to the Patient: A One-Year Evaluation of the Chiefs' Service Model for Inpatient Teaching.

PURPOSE: The Chiefs' Service (CS), a structured approach to inpatient teaching rounds, focuses on resident education and patient-centered care without disrupting patient census sizes or admitting cycles. It has five key elements: morning huddles; bedside rounds; diagnostic "time-outs"; day-of-discharge rounds; and postdischarge follow-up rounds. The authors hypothesized the CS model would be well received by residents and considered more effective than more-traditional rounds. METHOD: The CS was implemented on Penn Presbyterian Medical Center's general medicine inpatient service using a quasi-experimental design. Its first year (January 2013-January 2014) was evaluated with a mixed-methods approach. Residents completed end-of-rotation evaluation questionnaires; 20 CS and 10 traditional service (TS) residents were interviewed. Measures of resident agreement on questionnaire items were compared across groups using independent sample t testing. A modified grounded theory approach was used to assess CS residents' perspectives on the CS elements and identify emergent themes. RESULTS: The questionnaires were completed by 183/188 residents (response rate 97%). Compared with TS residents, CS residents reported significantly greater satisfaction in the domains of resident education and patient care, and they rated the overall value of the rotation significantly higher. The majority of CS residents found the CS elements to be effective. CS residents described the CS as focused on resident education, patient-centered care, and collaboration with an interdisciplinary team. CONCLUSIONS: The CS approach to inpatient rounding is seen by residents as valuable and is associated with positive outcomes in terms of residents' perceptions of learning, interdisciplinary communication, and patient care.

Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group.

BACKGROUND: ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure. An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects. METHODS AND RESULTS: Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were randomly assigned to double-blind treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while receiving their usual ACE inhibitor therapy. Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy. A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg resulted in a significantly greater reduction in pulmonary capillary wedge pressure at 3, 4, and 8 hours and during the prespecified 4- to 8-hour interval after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4 to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not achieve statistical significance. After 4 weeks of therapy, net reductions in 0-hour trough pulmonary capillary wedge pressure (-4.3 mm Hg; P=0. 16), pulmonary artery diastolic pressure (-4.7 mm Hg; P=0.013), and systolic blood pressure (-6.8 mm Hg; P=0.013) were observed in the valsartan 160 mg group compared with placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80 mg BID (-52. 1 pg/mL; P=0.001) and 160 mg BID (-47.8 pg/mL; P<0.001) compared with placebo, and there was a trend for a reduction in plasma norepinephrine (-97 pg/mL; P=0.10). Seventy-four of the 83 patients completed the trial. CONCLUSIONS: Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy.

Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels.

OBJECTIVES: This study sought to determine whether neurohormonal activation occurs in isolated right heart failure. BACKGROUND: Neurohormonal activation appears to parallel the severity of left heart failure, but little is known about its role in right heart failure. METHODS: We evaluated neurohormonal activation and endothelin levels in 21 patients with primary pulmonary hypertension at the time of right heart catheterization. RESULTS: Plasma norepinephrine levels correlated significantly with pulmonary artery pressure (r = 0.66, p < 0.01), cardiac index (r = -0.56, p < 0.01) and pulmonary vascular resistance (r = 0.69, p < 0.001). Atrial natriuretic peptide levels were higher in the pulmonary artery than the right atrium and femoral artery and correlated closely with pulmonary artery oxygen saturation (r = -0.73, p < 0.0001). Plasma renin levels were not elevated. Endothelin levels were increased and correlated with right atrial pressure (r = 0.74, p < 0.0001) and pulmonary artery oxygen saturation (r = -0.070, p < 0.0004). CONCLUSIONS: Neurohormonal activation occurs in patients with isolated right ventricular failure and inherently normal left ventricles and appears to be related to the overall severity of cardiopulmonary derangements. The elevation in endothelin levels is consistent with its release in response to pulmonary hypertension.

Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with ventricular tachycardia or congestive heart failure.

Results of cardiac muscle and skeletal muscle biopsies were compared in 22 patients with cardiomyopathy; 11 patients presented with symptoms secondary to ventricular tachycardia (Group 1) and 11 had symptoms of severe congestive heart failure (Group 2). No patient had structural or ischemic cardiac disease. In Group 1 patients, hemodynamic abnormalities were subtle, but invasive study demonstrated dilated cardiomyopathy in two patients and restrictive cardiomyopathy in nine. In Group 2, eight patients had dilated cardiomyopathy and three had restrictive cardiomyopathy. Cardiac biopsy results were abnormal in all 22 patients and the abnormalities were similar for the two groups. Cardiac histologic study revealed a spectrum of abnormalities including fibrosis, dilated sarcoplasmic reticulum, increased numbers of intercalated discs and mitochondrial abnormalities. Histologic abnormalities of skeletal muscle were similar in each group, consisting of endomysial fibrosis and increased lipid deposits. Slightly more than half of the Group 1 and Group 2 patients also had a low concentration of skeletal muscle long chain acylcarnitine. These data demonstrate that abnormalities of both cardiac and skeletal muscle are common in patients with cardiomyopathy; abnormalities are similar whether initial symptoms are due to ventricular tachycardia or congestive heart failure. It is suggested that these patients with cardiomyopathy may have a generalized myopathy.

The effect of delayed reperfusion following infarction in the rat on structural changes in viable myocardium.

OBJECTIVE: Evidence indicates that patency of the infarct related artery following the completion of myocardial necrosis can attenuate ventricular remodeling. Data have also demonstrated that inhibition of infarct expansion contributes to the anti-remodeling effect of delayed reperfusion. However, the influence of a patent artery on components of the remodeling process in the viable myocardium is poorly understood. METHODS: Myocyte morphometrics (isolated cell technique) and collagen content (hydroxyproline analysis) were assessed 28 days following experimental myocardial infarction from rats with permanently ligated left coronary vessels (NRP; n = 10) compared with rats who underwent reperfusion 150 minutes after ligation (RP; n = 11) and a sham-operated group (n = 10). RESULTS: Analysis of infarct size (planimetry) in a separate group of rats demonstrated that reperfusion at this late time point did not reduce infarct size (NRP: 33 +/- 3 vs. RP: 35 +/- 5%). Myocyte length in RP rats was less than in NRP rats in viable, non-infarcted left ventricular tissue (155 +/- 3 vs. 167 +/- 4 microns, p = 0.02), in the right ventricle (154 +/- 4 vs. 167 +/- 3 microns, p = 0.02) and in the septum (158 +/- 4 vs. 169 +/- 4 microns, p = 0.05). Reperfusion also attenuated the expected increase in cell volume compared with NRP rats (left ventricle 39.4 +/- 1.7 x 10(3) vs. 44.1 +/- 1.6 x 10(3) micron 3, p = 0.06; right ventricle 36.7 +/- 1.6 x 10(3) vs. 42.7 +/- 2.0 x 10(3) micron 3, p = 0.02; septum 41.0 +/- 1.6 x 10(3) vs. 44.2 +/- 1.8 x 10(3) micron 3, p = 0.19). Hydroxyproline content increased in the viable left ventricular tissue in both the reperfused and non-reperfused groups. CONCLUSION: Reperfusion without myocardial salvage attenuates the increase in myocyte length and volume that occurs in remodeling myocardium following infarction in the rat, with no effect on the increase in collagen content. These data indicate that patency of the infarct vessel, which is known to have an inhibitory effect on infarct expansion, also has an anti-remodeling effect remote from the area perfused by this artery.

Advancing LGBT Health at an Academic Medical Center: A Case Study.

Academic health centers are strategically positioned to impact the health of lesbian, gay, bisexual and transgender (LGBT) populations by advancing science, educating future generations of providers, and delivering integrated care that addresses the unique health needs of the LGBT community. This report describes the early experiences of the Penn Medicine Program for LGBT Health, highlighting the favorable environment that led to its creation, the mission and structure of the Program, strategic planning process used to set priorities and establish collaborations, and the reception and early successes of the Program.

In vivo transfer of bacterial marker genes results in differing levels of gene expression and tumor progression in immunocompetent and immunodeficient mice.

To optimize gene delivery for the treatment of malignant mesothelioma, expression of the beta-galactosidase marker gene was examined in a murine model of intraperitoneal malignant mesothelioma. The beta-galactosidase gene was delivered to the peritoneal cavity of tumor-bearing mice by various plasmid-liposome complexes or by replication-incompetent retrovirus, used alone or complexed to liposomes. In tumor samples from immunodeficient nude mice, moderate levels of gene expression were achieved by liposome-complexed plasmids. Retroviral gene delivery was more effective, and was increased nearly 10-fold by complexing the retrovirus to liposomes. In contrast, in tumor samples from immunocompetent CBA mice treated with the same vectors, no marker gene expression was detected. In immunodeficient mice, tumor growth was not affected by beta-galactosidase gene transfer. However, immunocompetent mice showed a significant decrease in tumor size and increase in survival time after beta-galactosidase delivery. Induction of cytotoxic T cells capable of lysing beta-Gal-transfected tumor cells suggests that tumor cells transduced with the bacterial beta-galactosidase gene may be eliminated in immunocompetent hosts. Our findings also indicate that plasmid-liposome complexes, which achieve a low level of gene expression, and retrovirus-liposome complexes, which result in nearly 100 times higher levels of gene expression in tumor cells in vivo, are similarly effective in inducing an antitumor immune response.

4-[(Alkylamino)methyl]furo[3,2-c]pyridines: a new series of selective kappa-receptor agonists.

The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-pyrrolidinol analogue 17 (IC50 = 2.7 nM) was found to be approximately 5-fold more potent than the corresponding pyrrolidine analogue 16 (IC50 = 15 nM). In the rat and hamster vasa deferentia (mu-specific and delta-specific tissues, respectively), 17 showed only weak antagonist activity (pKB > 5.5), underlining its selectivity for the kappa-opioid receptor. The major activity for 17 is resident in the 4S,3'S-isomer 26 (rabbit vas deferens IC50 = 1.1 nM). Compound 26 displays excellent antinociceptive activity, as determined in the mouse acetylcholine-induced abdominal constriction test (ED50 = 0.001 mg/kg, sc).

Synthesis, characterization, and biological activity of a new potent class of anti-HIV agents, the peroxoniobium-substituted heteropolytungstates.

The mono- and trisubstituted peroxyniobium polyoxotungstates of formulas [(CH3)3NH]7[Si-(NbO2)3W9O37], Cs7[Si(NbO2)3W9O37], alpha-K5[Si(NbO2)W11O39] and alpha-[(CH3)3NH]5[Si(NbO2)-W11O39], have been prepared, purified, and characterized spectroscopically by 29Si NMR, 183W NMR, and IR. The presence of peroxo groups was verified by the yellow color of the product and quantified by iodometric titration. The potency of both the complexes and the precursor complexes was evaluated in human peripheral blood mononuclear cells (PBMC) acutely infected with human immunodeficiency virus type 1 (HIV-1). Hexaniobate (K7H[Nb6O19]) was the least effective with a median effective concentration (EC50) of > 100 microM, while Cs7[Si(NbO2)3W9O37] was one of the most effective compounds with an EC50 of 1.0 microM. None of the compounds were toxic to uninfected PBMC with the exception of alpha-K8[SiW11O39], which had a median inhibitory concentration (IC50) of 79 microM. The potency and selectivity of the complexes against HIV-1 reverse transcriptase was also evaluated and shown to be quite high (IC50 values from 0.03 to 0.06 microM). The trimethylammonium salts of the complexes were tested for their ability to inhibit the interaction between gp120 and CD4 using a cell-free system. The complex [(CH3)3NH]7[Si(NbO2)3W9O37] inhibited this interaction by 70% at 25 microM.

Synthesis, antinociceptive activity, and opioid receptor profiles of substituted trans-3-(decahydro- and octahydro-4a-isoquinolinyl)phenols.

A series of trans-3-(6- and 7-substituted-decahydro-4a-isoquinolinyl)phenols and trans-3-(octahydro-4a-isoquinolinyl)phenols have been synthesized as potential opioid analgesics. Using a combination of in vitro and in vivo test systems, the receptor profiles of selected compounds have been assessed and in some instances distinguish between mu- and kappa-receptor agonists. In general, introduction of a 6-exocyclic methylene group into the trans-3-(decahydro-4a-isoquinolinyl)phenol system enhanced both antinociceptive activity and kappa-opioid receptor selectivity. For each series, analogues bearing an N-cyclopropylmethyl substituent exhibited greater kappa-receptor selectivity while N-methyl derivatives showed greater mu-receptor selectivity. The 7-substituted compounds (3b) were significantly less potent antinociceptive agents than their 6-substituted counterparts (3a), the octahydroisoquinoline analogues exhibiting intermediate activity. The axial 8-methyl-6-exocyclic methylene isoquinoline (20) is the most potent compound in the mouse abdominal constriction assay (ED50 = 0.05 mg/kg sc), whereas the equatorial 8-methyl isomer (16) was significantly less potent (ED50 = 3.3 mg/kg sc).

A potent new class of kappa-receptor agonist: 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines.

The synthesis of 4-substituted 1-(arylacetyl)-2-[(alkylamino)methyl]piperazines (10-22, 26, 27, and 30-33) and their activities as kappa-opioid receptor agonists are described. This includes a range of 4-acyl and 4-carboalkoxy derivatives with the latter series showing the greatest kappa-agonist activity. In particular, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (18) displays exceptional potency and selectivity. It showed the following activities in functional in vitro assays: rabbit vas deferens (kappa-specific tissue) IC50 = 0.041 nM, rat vas deferens (mu-specific tissue) IC50 > 10,000 nM, and hamster vas deferens (delta-specific tissue) IC50 > 10,000 nM. Compound 18 is also a highly potent antinociceptive agent, as determined in the mouse acetylcholine-induced abdominal constriction test: ED50 = 0.000 52 mg/kg, sc. The activity of 18 resides solely in its 3(R)-enantiomer. The kappa-agonist activity in both the 4-acyl and the 4-carbamate series is sensitive to the size of the 4-substituent. In addition, it would appear that an appreciable negative electrostatic potential in this region of the molecule is an important requirement for optimal potency.

New kappa-receptor agonists based upon a 2-[(alkylamino)methyl]piperidine nucleus.

The syntheses of some 1-[(3,4-dichlorophenyl)acetyl]-2- [(alkylamino)methyl]piperidines and their activities as kappa-opioid receptor agonists are described. Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated. As a result, some highly potent and selective kappa-receptor agonists have been identified. In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain. Thus, 1-[(3,4-dichlorophenyl)acetyl]- 2-[[1-(3-oxopyrrolidinyl)]methyl]piperidine (10) possesses high activity in the rabbit vas deferens (LVD, kappa-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc). The spirocyclic analogue 8-[(3,4-dichlorophenyl)acetyl]-7-(1-pyrrolidinylmethyl)-1,4-dio xa-8- azaspirol4.5]decane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc. Both 10 and 39 displayed high selectivity for kappa-opioid receptors over both mu- and delta-opioid receptor subtypes.

Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability.

We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.