bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation
Authors: Hsu Jun-te , Kan Wen-Hong , Hsieh Chi-Hsun , Choudhry Mashkoor A , Schwacha Martin G , Bland Kirby I , Chaudry Irshad H
Published: July 2007

Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)-1. Up-regulation of HO-1 mediates potent, anti-inflammatory effects and attenuates organ injury. Although studies have shown that 17β-estradiol (E2) prevents organ damage following trauma-hemorrhage, it remains unknown whether Akt/HO-1 plays any role in E2-mediated attenuation of hepatic injury following trauma-hemorrhage. To study this, male rats underwent trauma-hemorrhage (mean blood pressure, ∼40 mmHg for 90 min), followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body weight), E2 plus the PI-3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma-hemorrhage, plasma α-GST and hepatic tissue myeloperoxidase (MPO) activity, IL-6, TNF-α, ICAM-1, cytokine-induced neutrophil chemoattractant-1, and MIP-2 levels were measured. Hepatic Akt and HO-1 protein levels were also determined. Trauma-hemorrhage increased hepatic injury markers (α-GST and MPO activity), cytokines, ICAM-1, and chemokine levels. These parameters were markedly improved in the E2-treated rats following trauma-hemorrhage. E2 treatment also increased hepatic Akt activation and HO-1 expression compared with vehicle-treated, trauma-hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma-hemorrhage are in part mediated via an ER-related, Akt-dependent up-regulation of HO-1.
Transforming Growth Factor-β Blocks Inhibin Binding to Different Target Cell Types in a Context-Dependent Manner through Dual Mechanisms Involving Betaglycan
Authors: Farnworth Paul G. , Wang Yao , Escalona Ruth , Leembruggen Pauline , Ooi Guck T. , Findlay Jock K.
Published: July 2007

Inhibin antagonizes activin and bone morphogenetic protein actions by sequestering their type II receptors in high-affinity complexes with betaglycan, a coreceptor that inhibin shares with TGF-β. To clarify the nature and extent of interactions between inhibin and TGF-β, we therefore examined 1) the mutual competition between these ligands for binding, 2) the regulation of endogenous betaglycan expression by inhibin and TGF-β isoforms, and 3) the consequences of such betaglycan regulation for subsequent inhibin binding in mouse Leydig (TM3), Sertoli (TM4), adrenocortical cancer (AC), and gonadotroph (LβT2) cell lines, chosen to model cellular targets for local and endocrine actions of inhibin. Recognized inhibin, activin, and TGF-β binding proteins and TGF-β/activin signaling components were expressed by all four cell types, but AC and LβT2 cells notably lacked the type II receptor for TGF-β, TβRII. Overnight treatment of TM3 and TM4 cells with TGF-β1 suppressed the levels of betaglycan mRNA by 73 and 46% of control and subsequent [125I]inhibin A binding by 64 and 41% of control (IC50 of 54 and 92 pm), respectively. TGF-β2 acted similarly. TGF-β pretreatments commensurately decreased the [125I]inhibin A affinity labeling of betaglycan on TM3 and TM4 cells. TGF-β isoforms as direct competitors blocked up to 60% of specific inhibin A binding sites on TM3 and TM4 cells but with 9- to 17-fold lower potency than when acting indirectly via regulation of betaglycan. Only the competitive action of TGF-β was observed with TβRII-deficient AC and LβT2 cells. Neither inhibin A nor inhibin B regulated betaglycan mRNA or competed for binding of [125I]TGF-β1 or -β2. Thus, inhibin binding to its target cell types is controlled by TGF-β through dual mechanisms of antagonism, the operation of which vary with cell context and display different sensitivities to TGF-β. In contrast, TGF-β binding is relatively insensitive to the presence of either inhibin A or inhibin B.
Hypothalamic-Pituitary-Adrenal Axis Hyporesponsiveness to Restraint Stress in Mice Deficient for Large-Conductance Calcium- and Voltage-Activated Potassium (BK) Channels
Authors: Brunton Paula J. , Sausbier Matthias , Wietzorrek Georg , Sausbier Ulrike , Knaus Hans-Guenther , Russell John A. , Ruth Peter , Shipston Michael J.
Published: July 2007

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing ACTH from the anterior pituitary gland and glucocorticoids from the adrenal cortex. Stress also activates the sympathetic nervous system, evoking adrenaline release from the adrenal medulla. Large-conductance calcium- and voltage-activated potassium (BK) channels have been implicated in regulation of cellular excitability in these systems. Here, we examine the functional role of BK channels in HPA axis regulation in vivo using female mice genetically deficient (BK−/−) for the pore-forming subunits of BK channels. BK−/− phenotype in the HPA was confirmed by immunohistochemistry, Western blot analysis, and corticotrope patch-clamp recording. Restraint stress-induced plasma concentrations of ACTH and corticosterone were significantly blunted in BK−/− mice compared with wild type (WT) controls. This stress hyporesponsiveness was associated with reduced activation of hypothalamic paraventricular nucleus (PVN) neurons. Basal expression of CRH, but not arginine vasopressin mRNA in the PVN was significantly lower in BK−/− mice compared with WT controls. Total anterior pituitary ACTH peptide content, but not proopiomelanocortin mRNA expression or corticotrope number, was significantly reduced in BK−/− mice compared with WT. However, anterior pituitary corticotropes from BK−/− mice fully supported ACTH output, releasing a significantly greater proportion of stored ACTH in response to secretagogue in vitro compared with WT. These results support an important role for BK channels in both the neural circuitry and endocrine output of the HPA axis and indicate that the stress hyporesponsiveness in BK−/− mice primarily results from reduced activation of hypothalamic PVN neurosecretory neurons.
Abnormalities of Glucose Homeostasis and the Hypothalamic-Pituitary-Adrenal Axis in Mice Lacking Hexose-6-Phosphate Dehydrogenase
Authors: Rogoff Daniela , Ryder Jeffrey W. , Black Kelli , Yan Zheng , Burgess Shawn C. , McMillan D. Randy , White Perrin C.
Published: July 2007

Hexose-6-phosphate dehydrogenase (EC 1.1.1.47) catalyzes the conversion of glucose 6-phosphate to 6-phosphogluconolactone within the lumen of the endoplasmic reticulum, thereby generating reduced nicotinamide adenine dinucleotide phosphate. Reduced nicotinamide adenine dinucleotide phosphate is a necessary cofactor for the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (EC 1.1.1.146), which converts hormonally inactive cortisone to active cortisol (in rodents, 11-dehydrocorticosterone to corticosterone). Mice with targeted inactivation of hexose-6-phosphate dehydrogenase lack 11β-hydroxysteroid dehydrogenase type 1 reductase activity, whereas dehydrogenase activity (corticosterone to 11-dehydrocorticosterone) is increased. We now report that both glucose output and glucose use are abnormal in these mice. Mutant mice have fasting hypoglycemia. In mutant primary hepatocytes, glucose output does not increase normally in response to glucagon. Mutant animals have lower hepatic glycogen content when fed and cannot mobilize it normally when fasting. As assessed by RT-PCR, responses of hepatic enzymes to fasting are blunted; enzymes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase, tyrosine aminotransferase) are not appropriately up-regulated, and expression of glucokinase, an enzyme required for glycolysis, is not suppressed. Corticosterone has attenuated effects on expression of these enzymes in cultured mutant primary hepatocytes. Mutant mice have increased sensitivity to insulin, as assessed by homeostatic model assessment values and by increased glucose uptake by the muscle. The hypothalamic-pituitary-adrenal axis is also abnormal. Circulating ACTH, deoxycorticosterone, and corticosterone levels are increased in mutant animals, suggesting decreased negative feedback on the hypothalamic-pituitary-adrenal axis. Comparison with other animal models of adrenal insufficiency suggests that many of the observed abnormalities can be explained by blunted intracellular corticosterone actions, despite elevated circulating levels of this hormone.
Inhibition of Premature Oocyte Maturation: A Role for Bone Morphogenetic Protein 15 in Zebrafish Ovarian Follicles
Authors: Clelland Eric S. , Tan Qian , Balofsky Ari , Lacivita Rosie , Peng Chun
Published: July 2007

Bone morphogenetic protein-15 (BMP-15) is a member of the TGF-β superfamily known to regulate ovarian functions in mammals. Recently, we cloned zebrafish BMP-15 (zfBMP-15) cDNA and demonstrated that it may play a role in oocyte maturation. In this study, we further investigated the role of BMP-15 in zebrafish follicular development and oocyte maturation using an antiserum developed for zfBMP-15 and by microinjection of follicles with antisense zfBMP-15 N-morpholino oligonucleotides or an expression construct containing zfBMP-15 cDNA. Injection with antiserum caused a significant decrease in maturation-incompetent [insensitive to maturation-inducing hormone (MIH)] early growth phase follicles and a concomitant increase in mature follicles in vivo. In vitro maturation assays showed that incubation with antiserum resulted in a significant increase in oocyte maturation as compared with follicles incubated in preimmune serum or media control. Next, early growth phase follicles were collected and preincubated with either antiserum, preimmune serum, or medium control before treatment with MIH or human chorionic gonadotropin (hCG). Antiserum significantly increased oocyte maturation in response to MIH, but not to hCG, and enhanced basal maturation rate in longer-term incubations. Knockdown of BMP-15 in early growth stage follicles with a BMP-15 antisense oligonucleotide resulted in increased oocyte maturation, whereas microinjection of BMP-15 cDNA into oocytes significantly reduced MIH- and hCG-induced oocyte maturation in normally competent, mid-growth-phase follicles. Collectively, these findings suggest that BMP-15 modulates follicular growth and prevents premature oocyte maturation in zebrafish, in part, by suppressing the sensitivity of follicles to MIH.
Irradiation Causes Acute and Long-Term Spermatogonial Depletion in Cultured and Xenotransplanted Testicular Tissue from Juvenile Nonhuman Primates
Authors: Jahnukainen Kirsi , Ehmcke Jens , Nurmio Mirja , Schlatt Stefan
Published: July 2007

Infertility is a serious late effect in childhood cancer survivors. Little is known about acute irradiation effects in immature primate testis. Radiation defects have previously only been studied in postpubertal primates. Here we use the juvenile rhesus monkey as a preclinical model. We expose fragments of testicular tissue to 0, 0.5, 1.0, and 4.0 Gy irradiation in vitro. We then maintain the fragments in organ culture for 24–48 h or xenograft the fragments into nude mice for 4 months. Histological endpoints were determined to explore the cellular responses to the irradiation. At the highest dose, irradiation provoked an acute depletion of A-spermatogonia and a rise of apoptotic germ and Sertoli cells in organ culture. A dose-dependent decrease in the number of seminiferous tubules containing type A dark and type A pale spermatogonia was observed in irradiated xenografts. The number of Sertoli-cell only tubules increased respectively. Outgrowth of grafts was affected by the 4-Gy dose. Our observations reveal that irradiation evoked an immediate and sustained depletion of A-spermatogonia. We conclude that spermatogonia in the juvenile primate testis are highly sensitive to irradiation and that spermatogonial depletion and cessation of proliferation is an acute response. In contrast to adult testes, where such damage is immediately visible, this damage in immature testes becomes apparent only when spermatogonial insufficiency leads to spermatogenic failure, and thus infertility, at the onset of puberty. Our methods are applicable to immature human testis and might serve as powerful tool to study irradiation toxicity in the juvenile human testis.
Verification of time-reversibility requirementfor systems satisfying the Evans-Searles fluctuation theorem
Authors: Mittag Emil , Evans Denis J. , Williams Stephen R.
Published: July 2007

The Evans-Searles fluctuation theorem (ESFT) has been shown to be applicable in the near- and far-from-equilibrium regimes for systems with both constant and time-dependent external fields. The derivations of the ESFT have assumed that the external field has a definite parity under a time-reversal mapping. In the present paper, we confirm that the time-reversibility of the system dynamics is a necessary condition for the ESFT to hold. The manner in which the ESFT fails for systems that are not time-reversible is presented, and results are shown which demonstrate that systems which fail to satisfy the ESFT may still satisfy the Crooks relation (CR).
Structure, magnetism, and thermodynamics of the novel rare earth-based R5T4 intermetallics
Authors: Pecharsky V. K. , Gschneidner K. A.
Published: July 2007

After approximately 30 years of dormancy, the binary, ternary, and multicomponent intermetallic compounds of rare earth metals (R) with the group 14 elements (T) at the R
5
T
4 stoichiometry have become a goldmine for materials science, condensed matter physics, and solid-state chemistry. In addition to providing numerous opportunities to clarify elusive structure-property relationships, the R
5
T
4 compounds may soon be developed into practical materials by exploiting their unique sensitivity toward a variety of chemical and physical triggers. The distinctiveness of this series is in the remarkable flexibility of the chemical bonding between well-defined, self-assembled, subnanometer-thick slabs and the resultant magnetic, transport, and thermodynamic properties of the R
5
T
4 compounds that can be controlled by varying either or both R and T, including mixed rare earth elements on the R-sites and different group 14 (and 13 or 15) elements occupying the T-sites. In addition to chemical means, the interslab interactions are tunable by temperature, pressure, and magnetic field. Presently, a substantial, yet far from complete, body of knowledge exists about the Gd compounds with T = Si and Ge. In contrast, only a little is known about the physics and chemistry of R
5
T
4 alloys with other lanthanides, while compounds with T = Sn and Pb remain virtually unexplored.
Three frontiers in the thermodynamics of protein solutions
Authors: Prausnitz John , Foose Loddie
Published: July 2007

Three examples illustrate the versatility and usefulness of biothermodynamics. The first example concerns calculation of a phase diagram for aqueous lysozyme with a new potential of mean force that takes the Hofmeister effect into account; such calculations may be useful for design of a separation process where addition of a salt to an aqueous protein mixture precipitates a target protein. The second example concerns thermodynamic studies to elucidate the effect of an organic cosolvent on the mechanism of crystallizing aqueous insulin. The final example concerns a thermodynamic contribution to mitigating the AIDS epidemic; it indicates how isothermal-titration-calorimetry studies are helpful for choosing an optimum inhibitor that is effective not only for the wild-type HIV protease but also for at least some of its mutants.
Protein:Creatinine Ratio in Random Urine Samples Is a Reliable Marker of Increased 24-Hour Protein Excretion in Hospitalized Women with Hypertensive Disorders of Pregnancy
Authors: Leaños-Miranda Alfredo , Márquez-Acosta Janeth , Romero-Arauz Fernando , Cárdenas-Mondragón Guadalupe M , Rivera-Leaños Roxana , Isordia-Salas Irma , Ulloa-Aguirre Alfredo
Published: July 2007

Background: The protein:creatinine ratio in random, untimed urine samples correlates with 24-h protein excretion in pregnant women with and without hypertension. Nevertheless, whether this ratio is appropriate as a screening test for proteinuria is still unclear, in part because of the paucity of large studies.

Methods: We measured protein:creatinine ratios in random urine samples and protein contents of 24-h urine samples in a cross-sectional study of 927 hospitalized pregnant women at ≥20-weeks of gestational age and in a 2nd cohort of 161 pregnant women. In the 2nd group, urine specimens were obtained before and after completion of the 24-h collections, avoiding 1st-morning void specimens.

Results: Protein excretion was ≥300 mg/24 h in 282 patients (30.4%). The urine protein:creatinine ratio and the 24-h protein excretion were significantly correlated (r = 0.98, P <0.001). The protein:creatinine ratio as an indicator of protein excretion ≥300 mg/24 h was ≥0.3. The sensitivity and specificity were 98.2% and 98.8%, respectively. Positive and negative predictive values were 97.2% and 99.2%, respectively, and positive and negative likelihood ratios were 79.2 and 0.02, respectively. The diagnostic accuracy of the urinary protein:creatinine ratio was corroborated in the 2nd cohort of patients, which also showed no statistically significant difference in protein:creatinine ratio between samples obtained >24 h apart.

Conclusions: Random urinary protein:creatinine ratio is a reliable indicator of significant proteinuria (>300 mg/day) in nonambulatory pregnant women, irrespective of sampling time during the daytime. The protein:creatinine ratio may be reasonably used as an alternative to the 24-h urine collection method.
The front line of Albion's perfidy. Inputs into the making of British policy towards Spain: The racism and snobbery of Norman king
Authors: Thomas Maria
Published: July 2007

Recent publications concerning the Spanish Civil War have shown that British policy towards Spain was governed by a fear of left wing politics, as well as class prejudice and racism towards the Spanish proletariat. This article focuses on the activities and opinions of diplomats stationed
in Spain during the conflict, revealing that their reports were decisive in forging the policy of Non-Intervention. Specifically, it examines correspondence between the Barcelona Consulate and the Foreign Office which occurred during the first six months of the war. It uses Norman King, the
Vice Consul in Barcelona as a case study, establishing that his reports serve as a pertinent example of Britain's malevolent neutrality
British counter-intelligence in Gibraltar: Deciphering Spanish neutrality during the Second World War
Authors: Cokely Megan E
Published: July 2007

Gibraltar, with its strategic position as a gateway to the Mediterranean, was also a centre for Axis espionage and sabotage during the Second World War. Although Franco proclaimed Spain's neutrality during the war, British intelligence revealed numerous examples of Spanish cooperation
with both the Germans and Italians to carry out espionage activities and acts of sabotage against British interests in Gibraltar. This intelligence provided the basis for ongoing British diplomatic protests to the Spanish authorities, who denied Spanish involvement and gave token promises
of remedial action. While British intelligence may not have eliminated belligerent activity, it clearly proved that Franco had not honoured his word: Spain was not neutral during the Second World War.
Barcelona, May, 1937
Authors: Casanova Julin
Published: July 2007

This article recounts the notorious and tragic events that occurred in May 1937 in Barcelona during the civil war, when the Republican government and revolutionary forces of the left violently confronted each other. This led to wider in-fighting, the failure of mediation, a high death
toll and the fall of the Largo Caballero government. It also gave rise to the widely held view that internal divisions fatally weakened the Republic, a view which the author re-examines here.
Identification and analysis of the promoter region of the type II transmembrane serine protease polyserase-1 and its transcript variants
Authors: Hayama Masaki , Okumura Yuushi , Takahashi Etsuhisa , Shimabukuro Aki , Tamura Manabu , Takeda Noriaki , Kubo Takeshi , Kido Hiroshi
Published: July 2007

Polyserase-1/TMPRSS9 and its alternative transcripts, serase-1B and serase-2B, are novel type II transmembrane serine proteases that may regulate physiological and pathological phenomena on the cell surface. To understand the mechanisms of gene expression and regulation of these transcripts, we cloned and characterized the 5′ promoter region of the mouse polyserase-1 (mpolyserase-1) gene. Using 5′-rapid amplification of cDNA ends, we located the transcription initiation site 272 nucleotides upstream of the translation initiation site. Luciferase reporter gene analysis revealed that the region from +186 to +272 bp in the 5′-untranslated region (UTR), containing the GATA motif (AGATAA), glucocorticoid responsible element (TGTTCT), and E-box sequence (CAGGTG), is required for maximal promoter activity. Mutations introduced into the E-box sequence but not elsewhere in the promoter region caused a selective decrease in transcriptional activity. Furthermore, a DNA probe (+229 to +255 bp) containing the E-box sequence formed a single nuclear protein complex in a sequence-specific manner. These data suggest that the expression of mpolyserase-1 and its transcript variants is positively regulated by the E-box in its 5′-UTR, which might be responsible for the binding of basic helix-loop-helix transcription factors involved in the development of various organelles.
The central domain of transcription factor FOXM1c directly interacts with itself in vivo and switches from an essential to an inhibitory domain depending on the FOXM1c binding site
Authors: Wierstra Inken , Alves Jürgen
Published: July 2007

We have previously shown that FOXM1c can transactivate its target genes by two different mechanisms, depending on the FOXM1c binding site. In the present study, by introducing a small 46-aa deletion, we confirm that the central domain of FOXM1c is essential for transactivation of the minimal c-myc P1 and P2 promoters via their TATA boxes, but functions as an inhibitory domain on conventional FOXM1c binding sites. Thus, distinct FOXM1c binding sites determine opposite functions of the central domain, suggesting allosteric control of its conformation by the DNA binding site. This is strongly supported by the identification of a direct in vivo interaction of the central domain with itself in the present study. In contrast, the DNA binding domain binds neither to itself nor to any other domain of FOXM1c. Transrepression by the central domain is unlikely to be achieved by recruitment of co-repressors, but instead seems to be mediated by direct interference with the basal transcription complex. Direct binding of the central domain to itself should be involved in transrepression. Finally, FOXM1c transactivates the chicken mim-1 promoter, whose TATA box represents a conventional FOXM1c binding site, so that transactivation follows neither of the above two mechanisms, but shows intermediate behavior.
Chemical chaperone-mediated protein folding: stabilization of P22 tailspike folding intermediates by glycerol
Authors: Mishra Rajesh , Bhat Rajiv , Seckler Robert
Published: July 2007

Polyol co-solvents such as glycerol increase the thermal stability of proteins. This has been explained by preferential hydration favoring the more compact native over the denatured state. Although polyols are also expected to favor aggregation by the same mechanism, they have been found to increase the folding yields of some large, aggregation-prone proteins. We have used the homotrimeric phage P22 tailspike protein to investigate the origin of this effect. The folding of this protein is temperature-sensitive and limited by the stability of monomeric folding intermediates. At non-permissive temperature (≥35°C), tailspike refolding yields were increased significantly in the presence of 1–4 m glycerol. At low temperature, tailspike refolding is prevented when folding intermediates are destabilized by the addition of urea. Glycerol could offset the urea effect, suggesting that the polyol acts by stabilizing crucial folding intermediates and not by increasing solvent viscosity. The stabilization effect of glycerol on tailspike folding intermediates was confirmed in experiments using a temperature-sensitive folding mutant protein, by fluorescence measurements of subunit folding kinetics, and by temperature up-shift experiments. Our results suggest that the chemical chaperone effect of polyols observed in the folding of large proteins is due to preferential hydration favoring structure formation in folding intermediates.
Alkaline Bohr effect of bird hemoglobins: the case of the flamingo
Authors: Sanna Maria Teresa , Manconi Barbara , Podda Gabriella , Olianas Alessandra , Pellegrini Mariagiuseppina , Castagnola Massimo , Messana Irene , Giardina Bruno
Published: July 2007

The hemoglobin (Hb) substitution His→Gln at position α89, very common in avian Hbs, is considered to be responsible for the weak Bohr effect of avian Hbs. Phoenicopterus ruber ruber is one of the few avian Hbs that possesses His at α89, but it has not been functionally characterized yet. In the present study the Hb system of the greater flamingo (P. ruber roseus), a bird that lives in Mediterranean areas, has been investigated to obtain further insight into the role played by the α89 residue in determining the strong reduction of the Bohr effect. Functional analysis of the two purified Hb components (HbA and HbD) of P. ruber roseus showed that both are characterized by high oxygen affinity in the absence of organic phosphates, a strong modulating effect of inositol hexaphosphate, and a reduced Bohr effect. Indeed, in spite of the close phylogenetic relationship between the two flamingo species, structural analysis based on tandem mass spectrometry of the αA chain of P. ruber roseus Hb showed that a Gln residue is present at position α89.
Alkyl-Capped Block Copolymer Surfactants for Remediation of Soil Water Repellency and Heterogeneous Rootzone Moisture
Authors: Kostka Stanley J. , Schuermann Gregor , Franklin Mica
Published: July 2007

Soil water repellency (SWR) leads to nonwettable soils, heterogeneous rootzone moisture, reduced irrigation efficiency, leaching due to preferential flow, localized dry spots, and deterioration of turfgrass quality. Nonionic hydroxyl-terminated methyl oxirane-oxirane (EO/PO triblock copolymers) copolymers are commonly employed to remediate SWR. To determine if molecular modification influenced remediation performance, C1–C4 alkyl ethers of methyl oxirane-oxirane copolymers were produced through etherification of hydroxyl-terminated methyl oxirane-oxirane copolymers. ACA 1820, an alkyl ether of methyl oxirane-oxirane copolymer (MW approximately 2500) (applied monthly at 1.9 kg ha−1) reduced SWR and maintained quality at higher levels (p=0.05) for longer periods than the hydroxyl-terminated methyl oxirane-oxirane copolymer or the control. Turf density in plots treated with the alkyl ether of methyl oxirane-oxirane copolymer was three-fold greater than the control and two-fold greater than in plots treated with the hydroxyl-terminated methyl oxirane-oxirane copolymer. Rootzone moisture was more homogeneous in plots treated with ACA1820 than other treatments. Differences in visual turf quality were observed for up to nine months after the last application of the alkyl ether of methyl oxirane-oxirane copolymer. The observed effects are proposed to be due to interfacial interactions of the alkyl caps both in solution and at hydrophobic soil surfaces.
Controlled Release Pellet Formulation
Authors: Houghton Richard
Published: July 2007

This paper is a general overview of a new controlled release formulation of imidacloprid in the form of an extruded pellet. This material delivers 50 g imidacloprid per kg of product. The formulation consists of a polymer/starch matrix which is partially biodegradable. The product consists of 2-mm-diam. spherical pellets and is available under the suSCon® trade name. This technology allows long term protection from canegrub damage with imidacloprid by controlling its release into the soil. After release from the pellets, imidacloprid acts on canegrubs in a number of ways, including: soil ingestion, soil contact and root ingestion. The pellet does not exhibit anti-feeding or repellency properties. Soil moisture appears to be the major factor controlling the release of the imidacloprid active ingredient. Under normal field conditions the pellet will release imidacloprid for 1.5–2 plus years. The pellet consistently increases cane and sugar yield in the plant and has shown to be beneficial against infestations in the first three crop cycles.
Quantitative analysis of changes in endometrial gland morphology during the bovine oestrous cycle and their association with progesterone levels
Authors: Wang C K , Robinson R S , Flint A P F , Mann G E
Published: July 2007

This study describes a digital technique for uterine morphometry and its application to endometrial structure during the bovine oestrous cycle. Neither the number nor the size of uterine gland ducts changed during the cycle but a reduction in total endometrial area from days 0 to 8 after oestrus led to an increase in the proportion of the endometrium occupied by gland ducts (gland duct density). This effect on day 8 was maintained to day 16. When endometrial morphology was related to circulating progesterone concentrations on days 5 and 8 of the luteal phase, no relationships were found on day 5, but on day 8, a high progesterone concentration was associated with an increased number of gland ducts. Furthermore, in animals slaughtered on day 8, a high progesterone concentration on day 5 was associated with decreased gland duct size, though a simultaneous decrease in endometrial area led to an increase in gland duct density. The results suggest that contrary to expectation, endometrial glands do not grow and regress during the oestrous cycle, although cyclic changes in endometrial area controlled by progesterone lead to changes in gland duct density.
Oocyte developmental competence in a bovine model of reproductive aging
Authors: Malhi Pritpal S , Adams Gregg P , Mapletoft Reuben J , Singh Jaswant
Published: July 2007

The study was designed to test the hypothesis that aging in cattle is associated with reduced developmental competence of oocytes. The hypothesis was tested by comparing embryo production and pregnancy rates between 13- to 16-year-old cows (n = 6 in Year 1 and n = 9 in Year 2) and their 3- to 6-year-old young daughters (n = 8 in Year 1 and n = 9 in Year 2) after superovulation and transfer of embryos into an unrelated group of young recipients. Embryos were transferred into 2- to 5-year-old recipient cows (n = 99) as singletons (n = 45) or in pairs (n = 54 pairs). Embryo survival in recipients was determined by ultrasonography and by the number of calves born. Between old versus young cows, the number of ovulations (31 ± 4 vs 38 ± 3; P = 0.2) and the number of corpora lutea (25 ± 3 vs 29 ± 2; P = 0.3) did not differ, but fewer (P = 0.04) embryos were recovered from old cows (6 ± 2) than their daughters (12 ± 2). A higher proportion (P < 0.0001) of unfertilized oocytes/uncleaved zygotes were recovered from old cows (222/312, 71%) than their daughters (119/316, 38%). Among the embryos recovered, the proportion of International Embryo Transfer Society Grades 1–2 embryos was similar (P = 0.9) between old (59/90, 66%) and young cows (130/194, 67%). The survival of embryos after transfer into recipients, and the proportion of calves born were also similar between old and young cows. In conclusion, recovery of fewer embryos and a greater proportion of unfertilized oocytes/uncleaved zygotes suggest reduced developmental competence of oocytes from old cows, but there was no difference between age groups in embryo survival after the morula/blastocyst stage.
Cervical remodeling during pregnancy and parturition: molecular characterization of the softening phase in mice
Authors: Read Charles P , Word R Ann , Ruscheinsky Monika A , Timmons Brenda C , Mahendroo Mala S
Published: July 2007

Cervical remodeling during pregnancy and parturition is a single progressive process that can be loosely divided into four overlapping phases termed softening, ripening, dilation/labor, and post partum repair. Elucidating the molecular mechanisms that facilitate all phases of cervical remodeling is critical for an understanding of parturition and for identifying processes that are misregulated in preterm labor, a significant cause of perinatal morbidity. In the present study, biomechanical measurements indicate that softening was initiated between gestation days 10 and 12 of mouse pregnancy, and in contrast to cervical ripening on day 18, the softened cervix maintains tissue strength. Although preceded by increased collagen solubility, cervical softening is not characterized by significant increases in cell proliferation, tissue hydration or changes in the distribution of inflammatory cells. Gene expression studies reveal a potentially important role of cervical epithelia during softening and ripening in maintenance of an immunomucosal barrier that protects the stromal compartment during matrix remodeling. Expression of two genes involved in repair and protection of the epithelial permeability barrier in the gut (trefoil factor 1) and skin (serine protease inhibitor Kazal type 5) were increased during softening and/or ripening. Another gene whose function remains to be elucidated, purkinje cell protein 4, declines in expression as remodeling progressed. Collectively, these results indicate that cervical softening during pregnancy is a unique phase of the tissue remodeling process characterized by increased collagen solubility, maintenance of tissue strength, and upregulation of genes involved in mucosal protection.
Involvement of follicular basement membrane and vascular endothelium in blood–follicle barrier formation of mice revealed by ‘in vivo cryotechnique’
Authors: Zhou Hong , Ohno Nobuhiko , Terada Nobuo , Saitoh Sei , Fujii Yasuhisa , Ohno Shinichi
Published: July 2007

The molecular sieve with size- and charge selectivity in ovarian follicles, the so-called blood–follicle barrier (BFB), was examined during follicular development under physiological conditions to reveal ovarian structures responsible for the BFB by using our ‘in vivo cryotechnique’ (IVCT). Mouse ovary specimens were prepared with different methods including IVCT, immersion, or perfusion chemical fixation and quick-freezing following resection or perfusion. Their paraffin sections or cryosections were stained with hematoxylin–eosin or immunostained for serum proteins with different molecular weights: albumin, immunoglobulin (Ig) G1 heavy chain, inter-α-trypsin inhibitor (IαI), fibrinogen, and IgM. Their immunoreactivity was better preserved with IVCT. The immunostaining for albumin was clearly observed in blood vessels, interstitium, and developing follicles, but that of IgG1, IαI, or fibrinogen was significantly decreased inside the follicles. IgM was immunohistochemically decreased throughout the interstitium outside blood vessels. The immunoreactivities of IgG1 and IgM, as compared with albumin, were clearly changed along follicular basement membranes and around vascular endothelial cells respectively. These findings indicate that BFB functions throughout follicular development, and the follicular basement membrane and the vascular endothelium could play some significant roles in the permselectivity for such soluble proteins with intermediate and high molecular weight respectively.
Bone morphogenetic protein-6 enhances gonadotrophin-dependent progesterone and inhibin secretion and expression of mRNA transcripts encoding gonadotrophin receptors and inhibin/activin subunits in chicken granulosa cells
Authors: Al-Musawi Sara L , Gladwell Richard T , Knight Philip G
Published: July 2007

The aims were to examine ovarian expression of bone morphogenetic protein (BMP) ligands/receptor mRNAs in the chicken and to test the hypothesis that theca-derived BMP(s) modulates granulosa cell function in a paracrine manner. RT-PCR revealed expression of multiple BMPs in granulosa and theca cells from prehierarchical and preovulatory follicles with greater expression in theca cells; both cell types expressed BMP receptors-IA, -IB and -II consistent with tissue responsiveness. Preovulatory granulosa cells (F1, F2 and F3/4) were cultured with BMP-6 (expressed by theca but not granulosa) in the presence/absence of LH, FSH or 8-Br-cAMP. BMP-6 increased ‘basal’ and gonadotrophin-induced inhibin-A and progesterone secretion by each cell type but did not enhance the effect of 8-Br-cAMP. This indicates that the observed synergism between BMP-6 and gonadotrophin might involve BMP-induced up-regulation of gonadotrophin receptors. In support of this, BMP-6 alone increased LH-receptor (LHR) mRNA in F1 cells and FSH-receptor (FSHR) mRNA in F1, F2 and F3/4 cells. BMP-6 also enhanced LH/FSH-induced LHR transcript amount in each cell type but did not raise FSHR transcript amounts above those induced by BMP-6 alone. To further explore BMP-6 action on inhibin-A secretion, we quantified inhibin/activin subunits (α, βA, βB) mRNAs. Consistent with its effect on inhibin-A secretion, BMP-6 enhanced ‘basal’ expression of α- and βA-subunit mRNA in F1, F2 and F3/4 cells, and βB-subunit mRNA in F3/4 cells. BMP-6 markedly enhanced FSH/LH-induced expression of α-subunit in all follicles and FSH-induced βA-subunit in F2 and F3/4 follicles but not in F1 follicles. Neither BMP-6 alone, nor FSH/LH alone, affected ‘basal’ βB mRNA abundance. However, co-treatment with gonadotrophin and BMP-6 greatly increased βB-subunit expression, the response being lowest in F1 follicles and greatest in F3/4 follicles. Collectively, these results support the hypothesis that intraovarian BMPs of thecal origin have a paracrine role in modulating granulosa cell function in the chicken in a preovulatory stage-dependent manner.
Secretory and cytosolic phospholipase A2 activities and expression are regulated by oxytocin and estradiol during labor
Authors: Farina Mariana Gabriela , Billi Silvia , Leguizamón Gustavo , Weissmann Carina , Guadagnoli Tamara , Ribeiro Maria Laura , Franchi Ana Maria
Published: July 2007

The release of arachidonic acid from membrane glycerophospholipids through the action of phospholipases (PLs) is the first step in the biosynthesis of prostaglandins (PGs). In reproductive tissues, the most important PLs are cytosolic PLA2 (cPLA2) and types IIA and V of the secretory isoform (sPLA2). The aim of this work was to investigate the role of ovarian steroid hormones and oxytocin (OT) in the regulation of rat uterine PLA2 activity and expression during pregnancy and labor. The activity of sPLA2 increased near labor, whereas cPLA2 activity augmented towards the end of gestation. The levels of sPLA2 IIA and cPLA2 mRNA showed an increase before labor (P<0.05, day 21), whereas sPLA2 V mRNA was not regulated during pregnancy. The administration of atosiban (synthetic OT antagonist) together with tamoxifen (antagonist of estrogen receptors) was able to decrease cytosolic and secretory PLA2 activities, diminish the expression of sPLA2 IIA and cPLA2, as well as decrease PGF2α production before the onset of labor (P<0.01). The ovarian steroid did not affect PLA2 during pregnancy. Collectively, these findings indicate that in the rat uterus, both 17β-estradiol and OT could be regulating the activity and the expression of the secretory and the cytosolic isoforms of PLA2, thus controlling PGF2α synthesis prior to the onset of labor.
Antimicrobial Dosing Considerations in Obese Adult Patients
Authors: Pai Manjunath P. , Bearden David T.
Published: July 2007

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance. Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring. These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of β‐lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram‐positive organisms— quinupristin‐dalfopristin, linezolid, and daptomycin—reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials. An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.
Absence of Food Effect on the Extent of Alprazolam Absorption from an Orally Disintegrating Tablet
Authors: Erdman Keith , Stypinski Daria , Combs Michelle , Witt Patricia , Stiles Mark , Pollock Steve
Published: July 2007

Study Objective. To evaluate the effect of a standardized meal on the bioavailability of alprazolam formulated as an immediate‐release orally disintegrating tablet (ODT) in healthy volunteers.

Design. Single‐dose, randomized, open‐label, two‐period crossover study.

Setting. Contract research organization clinic.

Subjects. Sixteen healthy volunteers (seven men, nine women), aged 20–50 years.

Intervention. Subjects were administered a single dose of alprazolam ODT 1.0 mg during two treatment periods—under fasting conditions and after a standard high‐fat breakfast—separated by a 7‐day washout period.

Measurements and Main Results. Blood samples for determination of alprazolam pharmacokinetics were collected by venipuncture up to 72 hours after dosing. A validated liquid chromatography with tandem mass spectrometry detection method was used to quantify the alprazolam plasma concentration. The overall extent of alprazolam absorption from the ODT formulation, as measured by area under the concentration‐time curve, was unaffected during fed conditions. However, the rate of alprazolam absorption was slower after administration during fed relative to fasted conditions. The mean maximum observed plasma concentration (Cmax) decreased approximately 25%, and time to Cmax (Tmax) was delayed approximately 1.5 hours when food was administered before dosing.

Conclusion. Coadministration of food was shown to have no effect on extent of absorption of immediate‐release alprazolam ODT 1.0 mg when compared with drug administration in the fasted condition; however, the rate of drug absorption was decreased. The clinical significance of the difference in rate of alprazolam absorption is unknown but thought to be minimal.
Sorafenib and Sunitinib: Novel Targeted Therapies for Renal Cell Cancer
Authors: Grandinetti Cheryl A. , Goldspiel Barry R.
Published: July 2007

Renal cell cancer (RCC) is a relatively uncommon malignancy with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High‐dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low‐dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia‐inducible factor and the Ras‐Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first‐ and second‐line therapy in patients with cytokine‐refractory metastatic RCC who have clear‐cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression‐free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first‐ and second‐line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand‐foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
Dipeptidyl Peptidase IV Inhibitors and the Incretin System in Type 2 Diabetes Mellitus
Authors: Langley Alissa K. , Suffoletta Terri J. , Jennings Heath R.
Published: July 2007

As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged—the dipeptidyl peptidase IV (DPP‐IV) inhibitors. Unlike conventional oral antidiabetic agents, these agents promote glucose homeostasis through inhibition of DPP‐IV, the enzyme responsible for degradation of two key glucoregulatory hormones: glucagon‐like peptide‐1 (GLP‐1), which extends the action of insulin while also suppressing the release of glucagon, and glucose‐dependent insulinotropic peptide (GIP). Other proposed mechanisms of action of GLP‐1 and thus DPP‐IV inhibitors include satiety, increased β‐cell production, and inhibition of apoptosis of β cells. Clinical studies have evaluated the potential for DPP‐IV inhibition to reduce glucagon levels, delay gastric emptying, and stimulate insulin release. The DPP‐IV inhibitors appear to have excellent therapeutic potential in the management of type 2 diabetes as monotherapy or in combination with existing agents, such as metformin. Their pharmacokinetic and pharmacodynamic profiles support once‐daily dosing, with sustainable reductions in glycosylated hemoglobin levels and relatively few adverse effects. Their distinctive mechanism of action and adverse‐event profiles may offer advantages over existing therapies, including low risk for hypoglycemia and possible augmentation of pancreatic β‐cell regeneration.