bluuebunny/crossref_metadata_2025 huggingface dataset:
Poly(A) Tail Recognition by a Viral RNA Element Through Assembly of a Triple Helix
Authors: Mitton-Fry Rachel M. , DeGregorio Suzanne J. , Wang Jimin , Steitz Thomas A. , Steitz Joan A.
Published: November 2010

Self-Protection Mechanism

Kaposi's sarcoma–associated herpesvirus (KSHV) causes an AIDS-associated cancer. During its lytic phase, the virus produces a noncoding polyadenylated nuclear RNA that accumulates to high levels in infected cells. This occurs because a helix-loop-helix element, called ENE within the RNA, that contains a uridine-rich internal loop, sequesters the poly(A) tail, preventing the initiation of RNA decay.

Mitton-Fry
et al.

(p.
1244
) have determined the 2.5 angstrom structure of the ENE core bound to the RNA. Instead of just binding to the uridine-rich loop, as was expected, the poly(A) tail interacts with the loop and lower stem to form a triple helix to prevent decay. Similar mechanisms may protect other noncoding RNAs from rapid turnover.
Modular Organic Structure-Directing Agents for the Synthesis of Zeolites
Authors: Simancas Raquel , Dari Djamal , Velamazán Noemí , Navarro María T. , Cantín Angel , Jordá José L. , Sastre Germán , Corma Avelino , Rey Fernando
Published: November 2010

Routes to Rare Zeolites

Zeolites are microporous crystalline solids with well-defined structures. Although many naturally occurring ones have been obtained in laboratory synthesis, some have remained elusive. One of these, boggsite, is of interest for catalytic reactions because it has large channels defined by rings of 10 or 12 atoms that intersect within its crystalline lattice.

Simancas
et al.

(p.
1219
) report the synthesis of boggsite by using phosphazenes as the organic groups that directed the formation of rings during synthesis. These reagents can be readily modified—a feature that should allow greater flexibility in synthesis routes.
Fixing the Planet?
The Climate Fix
What Scientists and Politicians Won't Tell You About Global Warming

by Roger Pielke Jr.

Basic Books (Perseus Books Group), New York, 2010. 288 pp. $26, C$32.95, £15.99. ISBN 9780465020522.
Hack the Planet
Science's Best Hope—or Worst Nightmare—for Averting Climate Catastrophe

by Eli Kintisch

Wiley, Hoboken, NJ, 2010. 285 pp. $25.95, C$30.95, £17.99, €20.80. ISBN 9780470524268.
Authors: Trenberth Kevin E.
Published: November 2010

Assigning climate scientists much of the blame for the failure to adequately address the challenges posed by climate change, Pielke argues that we should focus on adapting to the potential shifts. Kintisch discusses the claimed benefits and possible consequences of proposals for radical interventions to engineer the climate while also profiling people promoting or questioning such schemes.
Quantum Measurement and Control of Single Spins in Diamond
Authors: Milburn Gerard J.
Published: November 2010

Changes in the state of a single spin at a defect in diamond, read out from optical measurements, could be used in quantum sensing and computing.
Lynx for Braking Plasticity
Authors: Higley Michael J. , Strittmatter Stephen M.
Published: November 2010

Knocking out the
Lynx1
gene restores plasticity in the visual cortex of adult mice.
Protect U.S. Science Funding
Authors: Leshner Alan I.
Published: November 2010

The recent power shift in the U.S. Congress reflects in part the public's desire to get the U.S. economy quickly back on track and the federal budget under better control. In recognition, both the Obama Administration and the Republican Party leadership are considering significant budget reductions. These could result in 5 to 10% (or greater) cuts in R&D allocations for fiscal years 2011 and 2012. The consequences would be severe. Federal agencies, which often commit their funds years in advance but only pay them out in later years, would have little left for new and competing renewal grants. Agencies could see funding success rates fall to below 1 in 10 applications, and new investigators—the seeds of the future—could be hit even harder. These kinds of budget cuts work against the ultimate national goals of restoring the U.S. economy and its international prowess. It is well documented that science, engineering, and technology fuel innovation and economic growth. That is why virtually all competitor countries, including India, China, and Korea, are increasing investments in science and engineering research, development, and education. U.S. funding looks like it could be heading in the opposite direction.
New Clues About What Makes the Human Brain Special
Authors: Miller Greg
Published: November 2010

Researchers who've examined preserved samples of cerebral cortex from humans and several species of ape report that in a particular region of the prefrontal cortex, neurons have more space between them in the human brain than in the brains of apes, allowing more room for connections between neurons.
The Fight for Yasuni
Authors: Marx Eric
Published: November 2010

A group of scientists is on the verge of winning its battle to protect an Ecuadorian forest containing record biodiversity—but will the world pay to seal the innovative deal?
Postexposure Prevention of Progressive Vaccinia in SCID Mice Treated with Vaccinia Immune Globulin
Authors: Fisher R. W. , Reed J. L. , Snoy P. J. , Mikolajczyk M. G. , Bray M. , Scott D. E. , Kennedy M. C.
Published: November 2010

A recently reported case of progressive vaccinia (PV) in an immunocompromised patient has refocused attention on this condition. Uniformly fatal prior to the licensure of vaccinia immune globulin (VIG) in 1978, PV was still fatal in about half of VIG-treated patients overall, with a greater mortality rate in infants and children. Additional therapies would be needed in the setting of a smallpox bioterror event, since mass vaccination following any variola virus release would inevitably result in exposure of immunocompromised people through vaccination or contact with vaccinees. Well-characterized animal models of disease can support the licensure of new products when human studies are not ethical or feasible, as in the case of PV. We chose vaccinia virus-scarified SCID mice to model PV. As in immunocompromised humans, vaccinia virus-scarified SCID animals develop enlarging primary lesions with minimal or no inflammation, eventual distal virus spread, and lethal outcomes if left untreated. Postexposure treatment with VIG slowed disease progression, caused local lesion regression, and resulted in the healthy survival of most of the mice for more than 120 days. Combination treatment with VIG and topical cidofovir also resulted in long-term disease-free survival of most of the animals, even when initiated 7 days postinfection. These results support the possibility that combination treatments may be effective in humans and support using this SCID model of PV to test new antibody therapies and combination therapies and to provide further insights into the pathogenesis and treatment of PV.
Identification of
Fusarium
Species in Formalin-Fixed and Paraffin-Embedded Sections by
In Situ
Hybridization Using Peptide Nucleic Acid Probes
Authors: Shinozaki Minoru , Okubo Yoichiro , Sasai Daisuke , Nakayama Haruo , Murayama Somay Yamagata , Ide Tadashi , Wakayama Megumi , Hiruta Nobuyuki , Shibuya Kazutoshi
Published: November 2010

Fusarium
has recently emerged as an opportunistic pathogen of humans, but the histological differentiation of
Fusarium
from
Aspergillus
and
Scedosporium
is particularly difficult because these fungi may induce similar clinical features and exhibit filamentous development in host tissues. Thus, there is a need to establish rapid and reliable methods that are applicable to pathological diagnoses. The aim of this study was to evaluate and establish
in situ
hybridization (ISH) using peptide nucleic acid (PNA) probes targeting the 28S rRNA to identify
Fusarium
species in tissue sections. This technique was validated using both formalin-fixed and paraffin-embedded pulmonary tissues from mice infected with seven different species of fungi and cell blocks from fungal cultures of 30 strains. As a result, strong positive signals were observed within fungal organisms present in tissues of the lung from mice infected with
Fusarium solani
. Furthermore, this probe reacted strongly with both
F. solani
and
Fusarium oxysporum
in sections from cell blocks. Although some cross-reactivity occurred with the
Pseudallescheria boydii
in sections from cell blocks, the signal intensity was low and most hyphae were not reactive. In conclusion, it was confirmed that ISH with PNA probes is accurate and is a valuable tool for identifying
Fusarium
spp. among organisms that have identical morphological features in formalin-fixed and paraffin-embedded sections.
Rapid and Sensitive Loop-Mediated Isothermal Amplification Test for Clostridium difficile Detection Challenges Cytotoxin B Cell Test and Culture as Gold Standard
Authors: Norén Torbjörn , Alriksson Ingegärd , Andersson Josefin , Åkerlund Thomas , Unemo Magnus
Published: November 2010

Compared to the composite gold standard cytotoxin B assay and toxigenic culture, the loop-mediated isothermal amplification (LAMP) test for
Clostridium difficile
had a sensitivity and specificity of 98%, positive predictive value of 92%, and negative predictive value of >99%. A one-hour turnaround time for the LAMP test provides rapid diagnosis and cost savings.
Distinct Bacteriophages Encoding Panton-Valentine Leukocidin (PVL) among International Methicillin-Resistant Staphylococcus aureus Clones Harboring PVL
Authors: Boakes E. , Kearns A. M. , Ganner M. , Perry C. , Hill R. L. , Ellington M. J.
Published: November 2010

Genetically diverse community-associated methicillin resistant
Staphylococcus aureus
(CA-MRSA) can harbor a bacteriophage encoding Panton-Valentine leukocidin (PVL) lysogenized into its chromosome (prophage). Six PVL phages (ΦPVL, Φ108PVL, ΦSLT, ΦSa2MW, ΦSa2USA, and ΦSa2958) are known, and single-nucleotide polymorphisms (SNPs) in the PVL genes have been reported. We sought to determine the distribution of lysogenized PVL phages among MRSA strains with PVL (PVL-MRSA strains), the PVL gene sequences, and the chromosomal phage insertion sites in 114 isolates comprising nine clones of PVL-MRSA that were selected for maximal underlying genetic diversity. The six PVL phages were identified by PCR; ΦSa2USA was present in the highest number of different lineages (multilocus sequence type clonal complex 1 [CC1], CC5, CC8, and sequence type 93 [ST93]) (
n
= 37 isolates). Analysis of 92 isolates confirmed that PVL phages inserted into the same chromosomal insertion locus in CC22, -30, and -80 but in a different locus in isolates of CC1, -5, -8, -59, and -88 and ST93 (and CC22 in two isolates). Within the two different loci, specific attachment motifs were found in all cases, although some limited inter- and intralineage sequence variation occurred. Overall, lineage-specific relationships between the PVL phage, the genes that encode the toxin, and the position at which the phage inserts into the host chromosome were identified. These analyses provide important insights into the microepidemiology of PVL-MRSA, will prove a valuable adjunct in outbreak investigation, and may help predict the emergence of new strains.
First Case of Invasive Human Infection Caused by Cupriavidus metallidurans
Authors: Langevin Stéphanie , Vincelette Jean , Bekal Sadjia , Gaudreau Christiane
Published: November 2010

We describe the first case of invasive human infection (a nosocomial septicemia) caused by
Cupriavidus metallidurans
. This metal-resistant bacterium has not been reported to be pathogenic in humans or animals.
Recombinant Infectious Bursal Disease Virus Carrying Hepatitis C Virus Epitopes
Authors: Upadhyay Chitra , Ammayappan Arun , Patel Deendayal , Kovesdi Imre , Vakharia Vikram N.
Published: November 2010

The delivery of foreign epitopes by a replicating nonpathogenic avian infectious bursal disease virus (IBDV) was explored. The aim of the study was to identify regions in the IBDV genome that are amenable to the introduction of a sequence encoding a foreign peptide. By using a cDNA-based reverse genetics system, insertions or substitutions of sequences encoding epitope tags (FLAG, c-Myc, or hepatitis C virus epitopes) were engineered in the open reading frames of a nonstructural protein (VP5) and the capsid protein (VP2). Attempts were also made to generate recombinant IBDV that displayed foreign epitopes in the exposed loops (P
BC
and P
HI
) of the VP2 trimer. We successfully recovered recombinant IBDVs expressing c-Myc and two different virus-neutralizing epitopes of human hepatitis C virus (HCV) envelope glycoprotein E in the VP5 region. Western blot analyses with anti-c-Myc and anti-HCV antibodies provided positive identification of both the c-Myc and HCV epitopes that were fused to the N terminus of VP5. Genetic analysis showed that the recombinants carrying the c-Myc/HCV epitopes maintained the foreign gene sequences and were stable after several passages in Vero and 293T cells. This is the first report describing efficient expression of foreign peptides from a replication-competent IBDV and demonstrates the potential of this virus as a vector.
Characterization of Two Substrains of Puumala Virus That Show Phenotypes That Are Different from Each Other and from the Original Strain
Authors: Sundström Karin B. , Stoltz Malin , Lagerqvist Nina , Lundkvist Åke , Nemirov Kirill , Klingström Jonas
Published: November 2010

Hantaviruses, the causative agents of two emerging diseases, are negative-stranded RNA viruses with a tripartite genome. We isolated two substrains from a parental strain of Puumala hantavirus (PUUV-Pa), PUUV-small (PUUV-Sm) and PUUV-large (PUUV-La), named after their focus size when titrated. The two isolates were sequenced; this revealed differences at two positions in the nucleocapsid protein and two positions in the RNA-dependent RNA polymerase, but the glycoproteins were identical. We also detected a 43-nucleotide deletion in the PUUV-La S-segment 5′ noncoding region covering a predicted hairpin loop structure that was found to be conserved among all hantaviruses with members of the rodent subfamily Arvicolinae as their hosts. Stocks of PUUV-La showed a lower ratio of viral RNA to infectious particles than stocks of PUUV-Sm and PUUV-Pa, indicating that PUUV-La replicated more efficiently in alpha/beta interferon (IFN-α/β)-defective Vero E6 cells. In Vero E6 cells, PUUV-La replicated to higher titers and PUUV-Sm replicated to lower titers than PUUV-Pa. In contrast, in IFN-competent MRC-5 cells, PUUV-La and PUUV-Sm replicated to similar levels, while PUUV-Pa progeny virus production was strongly inhibited. The different isolates clearly differed in their potential to induce innate immune responses in MRC-5 cells. PUUV-Pa caused stronger induction of IFN-β, ISG56, and MxA than PUUV-La and PUUV-Sm, while PUUV-Sm caused stronger MxA and ISG56 induction than PUUV-La. These data demonstrate that the phenotypes of isolated hantavirus substrains can have substantial differences compared to each other and to the parental strain. Importantly, this implies that the reported differences in phenotypes for hantaviruses might depend more on chance due to spontaneous mutations during passage than inherited true differences between hantaviruses.
Inhibition of Enveloped Virus Infection of Cultured Cells by Valproic Acid
Authors: Vázquez-Calvo Ángela , Saiz Juan-Carlos , Sobrino Francisco , Martín-Acebes Miguel A.
Published: November 2010

Valproic acid (VPA) is a short-chain fatty acid commonly used for treatment of neurological disorders. As VPA can interfere with cellular lipid metabolism, its effect on the infection of cultured cells by viruses of seven viral families relevant to human and animal health, including eight enveloped and four nonenveloped viruses, was analyzed. VPA drastically inhibited multiplication of all the enveloped viruses tested, including the zoonotic lymphocytic choriomeningitis virus and West Nile virus (WNV), while it did not affect infection by the nonenveloped viruses assayed. VPA reduced vesicular stomatitis virus infection yield without causing a major blockage of either viral RNA or protein synthesis. In contrast, VPA drastically abolished WNV RNA and protein synthesis, indicating that this drug can interfere the viral cycle at different steps of enveloped virus infection. Thus, VPA can contribute to an understanding of the crucial steps of viral maturation and to the development of future strategies against infections associated with enveloped viruses.
Modulation of Stress Granules and P Bodies during Dicistrovirus Infection
Authors: Khong Anthony , Jan Eric
Published: November 2010

Stress granules (SGs) are dynamic cytosolic aggregates composed of ribonucleoproteins that are induced during cellular stress when protein synthesis is inhibited. The function of SGs is poorly understood, but they are thought to be sites for reorganizing mRNA and protein. Several viruses can modulate SG formation, suggesting that SGs have an impact on virus infection. In this study, we have investigated the relationship of SG formation inDrosophilaS2 cells infected by cricket paralysis virus (CrPV), a member of theDicistroviridaefamily. Despite a rapid shutoff of host translation during CrPV infection, several hallmark SG markers such as theDrosophilaTIA-1 and G3BP (RasGAP-SH3-binding protein) homologs, Rox8 and Rin, respectively, do not aggregate in CrPV-infected cells, even when challenged with potent SG inducers such as heat shock, oxidative stress, and pateamine A treatment. Furthermore, we demonstrate that a subset of P body markers become moderately dispersed at late times of infection. In contrast, as shown by fluorescentin situhybridization, poly(A)+RNA granules still form at late times of infection. These poly(A)+RNA granules do not contain viral RNA nor do they colocalize with P body markers. Finally, our results demonstrate that the CrPV viral 3C protease is sequestered to SGs under cellular stress but not during virus infection. In summary, we propose that dicistrovirus infection leads to the selective inhibition of distinct SGs so that viral proteins are available for viral processing.
Transcranial magnetic stimulation: a historical evaluation and future prognosis of therapeutically relevant ethical concerns
Authors: Horvath Jared C , Perez Jennifer M , Forrow Lachlan , Fregni Felipe , Pascual-Leone Alvaro
Published: November 2010

Transcranial Magnetic Stimulation (TMS) is a non-invasive neurostimulatory and neuromodulatory technique increasingly used in clinical and research practices around the world. Historically, the ethical considerations guiding the therapeutic practice of TMS were largely concerned with aspects of subject safety in clinical trials. While safety remains of paramount importance, the recent US Food and Drug Administration approval of the Neuronetics NeuroStar TMS device for the treatment of specific medication-resistant depression has raised a number of additional ethical concerns, including marketing, off-label use and technician certification. This article provides an overview of the history of TMS and highlights the ethical questions that are likely arise as the therapeutic use of TMS continues to expand.
Emergency presentations of Parkinson's disease: early recognition and treatment are crucial for optimum outcome
Authors: Ghosh R , Liddle B J
Published: November 2010

Parkinson's disease (PD) is a debilitating condition associated with significant morbidity and mortality. Pathophysiologically the illness is due to a disruption of dopamine production in the basal ganglia and leads to a wide array of symptoms. These symptoms are not restricted to the nervous system; thus, the illness often presents acutely to a wide range of specialties, many of which may have limited experience in the condition. Patients often become unwell with illnesses unrelated to their PD. However, these conditions frequently lead to a deterioration in PD control. In addition, there exist certain acute complications of PD which are often difficult to recognise and carry significant mortality. Discussing the acute presentations of the illness under the umbrella of PD is important as it enables clinicians to focus upon the specific concerns involved in managing patients with the illness. A number of conditions are extremely common in PD and include falls, orthostatic hypotension, swallowing difficulties, psychosis, and hyperkinetic movement disorders. Optimal treatment of these conditions requires the consideration of issues specific to PD. Lesser recognised acute presentations of PD include the serotonin syndrome and neuroleptic malignant-like syndrome. While encountered less commonly, these conditions have been well described in the literature and untreated may prove fatal. They require urgent management, with their importance being further highlighted by the fact they may often mimic other illnesses, making diagnosis difficult. Therapeutic interventions aimed at treating PD and preventing its complications are evolving rapidly.
Smoking among Lao medical doctors: challenges and opportunities for tobacco control
Authors: Vanphanom Sychareun , Morrow Martha , Phengsavanh Alongkone , Hansana Visanou , Phommachanh Sysavanh , Tomson Tanja
Published: November 2010

Background

Smoking is an increasing threat to health in low-income and middle-income countries and doctors are recognised as important role models in anti-smoking campaigns.

Objectives

The study aimed to identify the smoking prevalence of medical doctors in Laos, their tobacco-related knowledge and attitudes, and their involvement in and capacity for tobacco prevention and control efforts.

Methods

This was a cross-sectional national survey by a researcher-administered, face-to-face questionnaire implemented at provincial health facilities throughout the central (including national capital), northern and southern regions of Laos in 2007. Both descriptive and inferential statistics were used.

Results

Of the 855 participants surveyed, 9.2% were current smokers and 18.4% were ex-smokers; smoking was least common in the central region (p<0.05) and far more prevalent in males (17.3% vs 0.4%; p<0.001). Smoking was concentrated among older doctors (p <0.001). Over 84% of current smokers wanted to quit, and 74.7% had made a recent serious attempt to do so. Doctors had excellent knowledge and positive attitudes to tobacco control, although smokers were relatively less knowledgeable and positive on some items. While 78% of doctors were engaged in cessation support, just 24% had been trained to do so, and a mere 8.8% considered themselves ‘well prepared’.

Conclusion

The willingness of doctors to take up their tobacco control role and the lower smoking rates among younger respondents offers an important window of opportunity to consolidate their knowledge, attitudes, skills and enthusiasm as cessation advocates and supports.
Characterization of the histamine receptors in rabbit left atria
Authors: Polanin Alicia , McNeill John H.
Published: November 2010

The effects of selective histamine receptor analogs were studied in electrically paced rabbit left atria. Atrial tension was increased by histamine (an H1 and H2 agonist), 4-methylhistamine and impromidine (H2 agonists), and 2-pyridylethylamine (PEA) (an H1 agonist). The responses to histamine and impromidine were not altered by propranolol (1 × 10−7 M) or reserpine pretreatment. However, the responses to 4-methylhistamine and PEA were significantly decreased upon pretreatment with propranolol or reserpine. Promethazine pretreatment (H1 receptor blockade) antagonized the inotropic effects of histamine and PEA but had no effect on the responses to 4-methylhistamine or impromidine. Cimetidine pretreatment (H2 receptor antagonism) competitively blocked the positive inotropic effects of histamine, 4-methylhistamine, and impromidine. These results suggest that the left atrial inotropic response is mediated through H1 and H2 receptor stimulation.
The effect of theophylline on histamine H1 and H2 receptor mediated responses in rabbit atria
Authors: Polanin Alicia , McNeill John H.
Published: November 2010

Rabbit isolated right and left atria were exposed to theophylline and to selected doses of histamine agonists. Right atrial rate and left atrial tension were increased by theophylline (3 × 10−4 M), the H1 agonist 2-pyridylethylamine (PEA) (1 × 10−4 M), and the H2 agonists 4-methylhistamine (1 × 10−4 M) and impromidine (1 × 10−8 M). In the right atria the combined effect of theophylline (3 × 10−4 M) and any of the histamine agonists was greater than the response to either agonist alone. However, the combined effects were not significantly greater than the sum of the individual right atrial responses. In the left atria the combined effect of theophylline (3 × 10−4 M) with any one of the histamine agonists was not only greater than the response to either agonist alone but was also significantly greater than the sum of the individual responses. The potentiation of the left atrial response to the H2 agonists by theophylline was significantly decreased by the H2 antagonist cimetidine (1 × 10−5 M). However, the potentiation of the left atrial response to the H1 agonist (PEA) by theophylline was not significantly altered by the H1 antagonist promethazine (2 × 10−6 M). Reports that the cardiac effects of H1 and H2 receptor agonists are potentiated by phosphodiesterase inhibitors such as theophylline as a result of increased cyclic AMP levels are not supported by the present study.
Cyclobenzaprine: a possible mechanism of action for its muscle relaxant effect
Authors: Commissiong John W. , Karoum Farouk , Reiffenstein Rhoderick J. , Neff Norton H.
Published: November 2010

Intravenously administered cyclobenzaprine (CBZ) (Flexeril), a clinically used, centrally acting muscle relaxant, abolished muscle rigidity in the intercollicular decerebrate rat. In animals in which the locus coeruleus was lesioned bilaterally previously, CBZ failed to attenuate the electromyogram. In the ventral horn of the cord, which receives a dense noradrenergic innervation from the locus coeruleus, CBZ caused an increase in the metabolism of noradrenaline. In the zona intermedia of the thoracic cord, which is not innervated by the locus coeruleus, CBZ caused only minimal effects on noradrenaline metabolism. Cells in the locus coeruleus were activated by CBZ. The results indicate that in the intercollicular decerebrate rat, an intact, coerulospinal, noradrenergic projection is essential for the muscle relaxant effect of CBZ. Muscle relaxation apparently results from an activation of locus coeruleus neurones, leading to an increased release of noradrenaline in the ventral horn of the cord and the subsequent inhibitory action of noradrenaline on α motoneurones.
Acetaldehyde concentration in rat blood and brain during the calcium carbimide – ethanol interaction
Authors: Hoover D. J. , Brien J. F.
Published: November 2010

Ethanol was administered to rats by oral intubation 3 h after intraperitoneal administration of calcium carbimide. Increased blood acetaldehyde concentration and the presence of acetaldehyde in brain were found for the calcium carbimide – ethanol interaction. There was no detectable brain acetaldehyde for ethanol administration following saline treatment. The magnitude of the acetaldehyde concentration in blood and brain during the calcium carbimide – ethanol interaction was directly dependent on the doses of calcium carbimide (0.7, 3.5, 7.0 mg/kg) and ethanol (0.5, 1.0, 1.5 g/kg). There was an exponential relationship between brain acetaldehyde concentration and blood acetaldehyde concentration. The threshold blood acetaldehyde concentration, above which acetaldehyde was found in brain, was approximately 6 μg/mL.
Distribution of radiomanganese in the rumen of sheep
Authors: Ivan M.
Published: November 2010

Twelve sheep, each prepared with a rumen fistula, were divided into three groups of four and fed three dietary levels of manganese (22, 300, and 3000 μg/g dry matter) for 11 weeks. The sheep were then dosed with radioactive manganese and samples of rumen contents were taken via the rumen fistula at 1, 7, and 13 h after dosing. The sheep were immediately killed after the last sampling and total rumen contents were mixed and sampled. Rumen fluid was separated from all samples and fractionated by centrifugation into protozoa plus plant particles, bacteria, and cell-free fraction. The bacterial cells were disrupted and fractionated into cell walls and cytoplasm. The cytoplasmic protein was precipitated with trichloroacetic acid.Although the concentration of radiomanganese in rumen fluid decreased with time after dosing from 14.4–17.8 to 6.1–9.3% of dose/L the protozoal and bacterial uptakes of radiomanganese were not significantly different and ranged from 26.5 to 40.6% and 18.9 to 31.7% of total in the rumen fluid, respectively. There was also no effect of dietary concentration of manganese on the uptake and distribution of radiomanganese in the rumen fluid fractions. However, on the average more radiomanganese was found in the bacterial cell walls (48.1–75.3% of total in bacteria) and less in the cytoplasm (51.9–24.7% of total in bacteria) with increasing dietary manganese. Very little radioactivity was found in the trichloroacetic acid precipitated cytoplasm (1.79–0.78% of total in cytoplasm). Concentrations of manganese in the bacteria and bacterial cell walls were higher than, and closely related with, those in the diet. Specific activities of radiomanganese decreased in all fractions with increasing dietary manganese. Approximately 15–17% of the total radiomanganese in the rumen contents at 13 h after dosing was found in the protozoal fraction and 10–15% was found in the bacterial fraction; only approximately 21% of the radiomanganese remained in cell-free fraction of the rumen fluid in each dietary treatment.
Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction
Authors: Shioura Krystyna M. , Farjah Mariam , Geenen David L. , Solaro R. John , Goldspink Paul H.
Published: November 2010

Contractile dysfunction is common to many forms of cardiovascular disease. Approaches directed at enhancing cardiac contractility at the level of the myofilaments during heart failure (HF) may provide a means to improve overall cardiovascular function. We are interested in gender-based differences in cardiac function and the effect of sarcomere activation agents that increase contractility. Thus, we studied the effect of gender and time on integrated arterial-ventricular function (A-V relationship) following myocardial infarction (MI). In addition, transgenic mice that overexpress the slow skeletal troponin I isoform were used to determine the impact of increased myofilament Ca2+sensitivity following MI. Based on pressure-volume (P-V) loop measurements, we used derived parameters of cardiovascular function to reveal the effects of sex, time, and increased myofilament Ca2+sensitivity among groups of post-MI mice. Analysis of the A-V relationship revealed that the initial increase was similar between the sexes, but the vascular unloading of the heart served to delay the decompensated stage in females. Conversely, the vascular response at 6 and 10 wk post-MI in males contributed to the continuous decline in cardiovascular function. Increasing the myofilament Ca2+sensitivity appeared to provide sufficient contractile support to improve contractile function in both male and female transgenic mice. However, the improved contractile function was more beneficial in males as the concurrent vascular response contributed to a delayed decompensated stage in female transgenic mice post-MI. This study represents a quantitative approach to integrating the vascular-ventricular relationship to provide meaningful and diagnostic value following MI. Consequently, the data provide a basis for understanding how the A-V relationship is coupled between males and females and the enhanced ability of the cardiovascular system to tolerate pathophysiological stresses associated with HF in females.
Prolonged poststimulation inhibition of bladder activity induced by tibial nerve stimulation in cats
Authors: Tai Changfeng , Shen Bing , Chen Mang , Wang Jicheng , Roppolo James R. , de Groat William C.
Published: November 2010

Inhibition of bladder activity by tibial nerve stimulation was investigated in α-chloralose-anesthetized cats with an intact spinal cord. Short-duration (3–5 min) tibial nerve stimulation at both low (5 Hz) and high (30 Hz) frequencies applied repeatedly during rhythmic isovolumetric bladder contractions was effective in inhibiting reflex bladder activity. Both frequencies of stimulation were also effective in inducing inhibition that persisted after the termination of the stimulation. The poststimulation inhibitory effect induced by the short-duration stimulation significantly increased bladder capacity to 181.6 ± 24.36% of the control capacity measured before applying the stimulation. Thirty-minute continuous stimulation induced prolonged poststimulation inhibition of bladder activity, which lasted for more than 2 h and significantly increased bladder capacity to 161.1 ± 2.9% of the control capacity. During the poststimulation periods, 5-Hz stimulation applied during the cystometrogram elicited a further increase (∼30% on average) in bladder capacity, but 30-Hz stimulation was ineffective. These results in cats support the clinical observation that tibial nerve neuromodulation induces a long-lasting poststimulation inhibitory effect that is useful in treating overactive bladder symptoms.
Temporal Coding of Intensity of NaCl and HCl in the Nucleus of the Solitary Tract of the Rat
Authors: Chen Jen-Yung , Victor Jonathan D. , Di Lorenzo Patricia M.
Published: November 2010

Sensory neurons are generally tuned to a subset of stimulus qualities within their sensory domain and manifest this tuning by the relative size of their responses to stimuli of equal intensity. However, response size alone cannot unambiguously signal stimulus quality, since response size also depends on stimulus intensity. Thus a common problem faced by sensory systems is that response size (e.g., spike count) confounds stimulus quality and intensity. Here, using the gustatory system as a model, we asked whether temporal firing characteristics could disambiguate these axes. To address this question, we recorded taste responses of single neurons in the nucleus of the solitary tract (NTS, the first central gustatory relay) in anesthetized rats to a range of concentrations of NaCl and HCl and their binary mixtures. To assess the contribution of the temporal characteristics of the response to discrimination among tastants, a family of metrics that quantifies the similarity of two spike trains in terms of spike count and spike timing was used. Results showed that the spike count produced by different taste qualities and different concentrations overlapped in most cells, implying that information conveyed by spike count is imprecise. Multidimensional scaling analysis of taste responses using similarity of temporal characteristics showed that different taste qualities, intensities, and mixtures formed distinct clusters in this “temporal coding” taste space and were arranged in a logical order. Thus the temporal structure of taste responses in single cells in the NTS can simultaneously convey information about both taste quality and intensity.
Revealing the Kinematics of the Oculomotor Plant With Tertiary Eye Positions and Ocular Counterroll
Authors: Klier Eliana M. , Meng Hui , Angelaki Dora E.
Published: November 2010

Retinal information is two-dimensional, whereas eye movements are three-dimensional. The oculomotor system solves this degrees-of-freedom problem by constraining eye positions to zero torsion (Listing's law) and determining how eye velocities change with eye position (half-angle rule). Here we test whether the oculomotor plant, in the absence of well-defined neural commands, can implement these constrains mechanically, not just in a primary position but for all eye and head orientations. We stimulated the abducens nerve at tertiary eye positions and when ocular counterroll was induced at tilted head orientations. Stimulation-induced eye velocities follow the half-angle rule, even for tertiary eye positions, and microstimulation at tilted head orientations elicits eye positions that adhere to torsionally shifted planes, similar to naturally occurring eye movements. These results support the notion that oculomotor plant can continuously apply these three-dimensional rules correctly and appropriately for all eye and head orientations that obey Listing's law, demonstrating a major role of peripheral biomechanics in motor control.
Sensor Placement for Urban Homeland Security Applications
Authors: Hamel David , Chwastek Matthew , Garcia Saturnino , Farouk Bakhtier , Kam Moshe , Dandekar Kapil R.
Published: November 2010

We simulated a sensor network that detects and tracks the release of harmful airborne contaminants in an urban environment. The simulation determines sensor placement in that environment. The effort required integration of models from computational fluid dynamics (CFDs), combinatorial optimization, and population mobility dynamics. These CFD models, coupled with population mobility models, facilitate estimation of the effect of released contaminant on civilian populations. We studied the effects of a contaminant, chlorine gas, as a function of urban environment, prevailing winds, and likely attack locations. The models predictions optimized sensor node locations, providing mitigation of contaminant effects on human population. Results show that higher fidelity dispersal predictions increase sensor placement effectiveness. Incorporation of civilian evacuation models helps to minimize the overall impact of an attack when compared to a static population. Moreover, results show the benefits of using seasonal sensor configurations to maximize detection capabilities, taking into account prevailing seasonal wind conditions.
Relationship between Painful Crisis and Serum Zinc Level in Children with Sickle Cell Anaemia
Authors: Temiye Edamisan Olusoji , Duke Edem Samuel , Owolabi Mbang Adeyemi , Renner James Kweku
Published: November 2010

Sickle cell anaemia (SCA) is associated with zinc deficiency; zinc supplementation may ameliorate some of its clinical manifestations including the relief of painful crisis.Subjects and Methods. Serum zinc levels were determined in 71 children with SCA and painful crisis and in equal numbers in steady state. Seventy-one children with AA genotype acted as controls. Qualitative assessment of zinc content of 24-hour dietary recall and the last meal consumed before blood was drawn was taken. Serum zinc was determined using atomic absorption spectrophotometer. Haemoglobin concentration and packed cell volume (PCV) were determined using standard methods.Results. The mean serum zinc concentration in the study was less than international reference range. The controls had significantly higher serum zinc concentrations than the SCA group (42.7±13.6versus32.3±14.0 μg/dL,P<.000); this difference was due to the significantly lower values of serum zinc in SCA with painful crisis compared with the remaining two groupsF=30.9,P<.000. There was a positive correlation between serum zinc and haemoglobin concentration only in the control group (r=0.4;P=.001).Conclusion. The serum zinc levels in this study were low. Painful crisis in SCA may exert greater demand for zinc utilization in children with SCA thereby resulting in lower serum levels.
Vandetanib Improves Anti-Tumor Effects of L19mTNFα in Xenograft Models of Esophageal Cancer
Authors: Crescenzi Marika , Persano Luca , Esposito Giovanni , Zulato Elisabetta , Borsi Laura , Balza Enrica , Ruol Alberto , Ancona Ermanno , Indraccolo Stefano , Amadori Alberto
Published: November 2010

Purpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer.

Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling.

Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity.

Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR.
Tumor Regression and Growth Rates Determined in Five Intramural NCI Prostate Cancer Trials: The Growth Rate Constant as an Indicator of Therapeutic Efficacy
Authors: Stein Wilfred D. , Gulley James L. , Schlom Jeff , Madan Ravi A. , Dahut William , Figg William D. , Ning Yang-min , Arlen Phil M. , Price Doug , Bates Susan E. , Fojo Tito
Published: November 2010

Purpose: In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).

Experimental Design: Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.

Results: Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10−3.17) relative to single-agent thalidomide (log g = 10−2.08) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.

Conclusion: Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials. Clin Cancer Res; 17(4); 907–17. ©2010 AACR.
A Phase I Study of the Combination of Intravenous Reovirus Type 3 Dearing and Gemcitabine in Patients with Advanced Cancer
Authors: Lolkema Martijn P. , Arkenau Hendrik-Tobias , Harrington Kevin , Roxburgh Patricia , Morrison Rosemary , Roulstone Victoria , Twigger Katie , Coffey Matt , Mettinger Karl , Gill George , Evans T.R. Jeffry , de Bono Johann S.
Published: November 2010

Purpose: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.

Experimental Design: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 1010 TCID50. Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay.

Results: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response.

Conclusions: Reovirus at the dose of 1 × 1010 TCID50 can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule. Clin Cancer Res; 17(3); 581–8. ©2010 AACR.
Extended Dose Ipilimumab with a Peptide Vaccine: Immune Correlates Associated with Clinical Benefit in Patients with Resected High-Risk Stage IIIc/IV Melanoma
Authors: Sarnaik Amod A. , Yu Bin , Yu Daohai , Morelli Dawn , Hall MacLean , Bogle Dilip , Yan Lulu , Targan Stephan , Solomon Jolie , Nichol Geoff , Yellin Michael , Weber Jeffrey S.
Published: November 2010

Purpose: To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit.

Experimental Design: In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment.

Results: Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035).

Conclusions: Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse. Clin Cancer Res; 17(4); 896–906. ©2010 AACR.