bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic hypothermia increases PAI-1 expression and accelerates microvascular thrombus formation in endotoxemic mice
Authors: Lindenblatt Nicole , Menger Michael D , Klar Ernst , Vollmar Brigitte
Published: October 2006

Introduction

Hypothermia during sepsis significantly impairs patient outcome in clinical practice. Severe sepsis is closely linked to activation of the coagulation system, resulting in microthrombosis and subsequent organ failure. Herein, we studied whether systemic hypothermia accelerates microvascular thrombus formation during lipopolysacharide (LPS)-induced endotoxemia in vivo, and characterized the low temperature-induced endothelial and platelet dysfunctions.

Methods

Ferric-chloride induced microvascular thrombus formation was analyzed in cremaster muscles of hypothermic endotoxemic mice. Flow cytometry, ELISA and immunohistochemistry were used to evaluate the effect of hypothermia on endothelial and platelet function.

Results

Control animals at 37°C revealed complete occlusion of arterioles and venules after 759 ± 115 s and 744 ± 112 s, respectively. Endotoxemia significantly (p < 0.05) accelerated arteriolar and venular occlusion in 37°C animals (255 ± 35 s and 238 ± 58 s, respectively). This was associated with an increase of circulating endothelial activation markers, agonist-induced platelet reactivity, and endothelial P-selectin and plasminogen activator inhibitor (PAI)-1 expression. Systemic hypothermia of 34°C revealed a slight but not significant reduction of arteriolar (224 ± 35 s) and venular (183 ± 35 s) occlusion times. Cooling of the endotoxemic animals to 31°C core body temperature, however, resulted in a further acceleration of microvascular thrombus formation, in particular in arterioles (127 ± 29 s, p < 0.05 versus 37°C endotoxemic animals). Of interest, hypothermia did not affect endothelial receptor expression and platelet reactivity, but increased endothelial PAI-1 expression and, in particular, soluble PAI-1 antigen (sPAI-Ag) plasma levels.

Conclusion

LPS-induced endotoxemia accelerates microvascular thrombus formation in vivo, most probably by generalized endothelial activation and increased platelet reactivity. Systemic hypothermia further enhances microthrombosis in endotoxemia. This effect is associated with increased endothelial PAI-1 expression and sPAI-Ag in the systemic circulation rather than further endothelial activation or modulation of platelet reactivity.
Unraveling transcriptional control and cis-regulatory codes using the software suite GeneACT
Authors: Cheung Tom Hiu , Kwan Yin Lam , Hamady Micah , Liu Xuedong
Published: October 2006

Deciphering gene regulatory networks requires the systematic identification of functional cis-acting regulatory elements. We present a suite of web-based bioinformatics tools, called GeneACT http://promoter.colorado.edu, that can rapidly detect evolutionarily conserved transcription factor binding sites or microRNA target sites that are either unique or over-represented in differentially expressed genes from DNA microarray data. GeneACT provides graphic visualization and extraction of common regulatory sequence elements in the promoters and 3'-untranslated regions that are conserved across multiple mammalian species.
An inventory of yeast proteins associated with nucleolar and ribosomal components
Authors: Staub Eike , Mackowiak Sebastian , Vingron Martin
Published: October 2006

Background

Although baker's yeast is a primary model organism for research on eukaryotic ribosome assembly and nucleoli, the list of its proteins that are functionally associated with nucleoli or ribosomes is still incomplete. We trained a naïve Bayesian classifier to predict novel proteins that are associated with yeast nucleoli or ribosomes based on parts lists of nucleoli in model organisms and large-scale protein interaction data sets. Phylogenetic profiling and gene expression analysis were carried out to shed light on evolutionary and regulatory aspects of nucleoli and ribosome assembly.

Results

We predict that, in addition to 439 known proteins, a further 62 yeast proteins are associated with components of the nucleolus or the ribosome. The complete set comprises a large core of archaeal-type proteins, several bacterial-type proteins, but mostly eukaryote-specific inventions. Expression of nucleolar and ribosomal genes tends to be strongly co-regulated compared to other yeast genes.

Conclusion

The number of proteins associated with nucleolar or ribosomal components in yeast is at least 14% higher than known before. The nucleolus probably evolved from an archaeal-type ribosome maturation machinery by recruitment of several bacterial-type and mostly eukaryote-specific factors. Not only expression of ribosomal protein genes, but also expression of genes encoding the 90S processosome, are strongly co-regulated and both regulatory programs are distinct from each other.
Bogie frame design in consideration of fatigue strength and weight reduction
Authors: Park B H , Lee K Y
Published: October 2006

In the development of a bogie, the fatigue strength of a bogie frame is an important design criterion. In addition, weight reduction is required in order to save energy and material. In this study, the fatigue analysis of a bogie frame by using the finite-element method is performed for various loading conditions according to the UIC standards and it is attempted to minimize the weight of the bogie frame by artificial neural network and genetic algorithm.
Rapid method of stress intensity factor calculation for semi-elliptical surface breaking cracks under three-dimensional contact loading
Authors: Fletcher D I , Kapoor A
Published: October 2006

Fast methods of stress intensity factor calculation for inclined surface breaking cracks under contact loading are presented. Cracks are loaded in normal and tangential traction by a three-dimensional Hertzian elliptical contact patch, and friction between the crack faces is considered. Stress intensities are calculated from Green's functions originally developed for two-dimensional cracks through application of stresses on a plane below the three-dimensional contact patch, in place of those previously considered for a two-dimensional contact. This approach gives the method great speed advantages over fully three-dimensional methods. Both semi-circular and semi-elliptical cracks are examined. The validity of the approximations and the results are judged by validation with results from alternative fully three-dimensional cases. Very good agreement is found between trends in stress intensity factor with changes in crack size and applied tractions. Absolute values of stress intensity factor agree well for semicircular and shallow semi-elliptical cracks, but values were below those of the reference case for deep, narrow semi-elliptical cracks. Calibration of the model to overcome this under-prediction is discussed.

A case of special value in railway rail-wheel contact modelling is that of a contact offset to the side of a crack, representing the wheel running alongside rather than directly across an existing crack. This configuration results from the common procedure of grinding the rail to change or maintain its cross-sectional profile. The three-dimensional contact patch methods presented here enable this case to be modelled while retaining very fast running times for the calculations.
Coupled dynamics and control of a rotor-conical magnetic bearing system
Authors: Jing Y , Lie Y , Jing X
Published: October 2006

This paper is concerned with coupled dynamic characteristics of a conical magnetic bearing system and its influence on design of controllers. Conical electromagnetic bearings do not need additional magnetic poles to control axial motion of the rotor system and its particular structure leads to two coupled characteristics: geometry and current couplings. Because the coupled characteristics influence the design of a controller, they can not be neglected. This paper proposes the coupled dynamic characteristics of conical electromagnetic bearings for the first time and defines them. On the basis of the analysis of coupled dynamic characteristics, the dynamic model of a five-degree-of-freedom rotor-conical electromagnetic bearing system is made, and the influence of coupled characteristics on the optimal controller of the system is analyzed.
Comparison of the static and dynamic behaviour of carbon fibre composite golf club shafts
Authors: Huntley M P , Davis C L , Strangwood M , Otto S R
Published: October 2006

Golf shafts are characterized and sold by manufacturers on the basis of their static properties; however, their performance is controlled by their dynamic properties. This paper discusses the relationship between dynamic and static stiffness for a range of carbon fibre composite (CFC) shafts. In particular, the influence of ‘seams’ (specific orientations of the shaft with differing mechanical properties) on static and dynamic stiffness is considered. Vibrational frequency analysis (quasi-static testing) was used to locate the seams, and bend testing was used to determine the static stiffness of the low (seam) stiffness and high (90° to seam) stiffness positions. Dynamic stiffness values were determined by firing a golf ball from a gas cannon at a target attached to the end of the shaft and measuring the resulting deflection for different golf ball speeds. It was found that the dynamic stiffness values over a range of strain rates were similar to the static values for the sheet-laminated shafts indicating that there is no strain rate dependency for these shafts over the strain rates tested. However, for the filament wound shaft, a significant increase in dynamic stiffness, compared with the static value, was seen. This was related to the different CFC microstructure of this shaft. It was also found that the presence of seams resulted in statistically significant differences in static stiffness with respect to shaft orientation for a number of sheet-laminated shafts, whereas there was no difference in dynamic stiffness values.
Computational modelling of manually stitched soccer balls
Authors: Price D S , Jones R , Harland A R
Published: October 2006

Soccer is the major ball sport, which attracts both viewers and participants worldwide. The primary equipment requirement is the ball, and the soccer ball market is as competitive as the game itself. The global interest of the sport provides an ideal international stage for the marketing of sports equipment such as soccer balls, boots, gloves, shin guards, and apparel. Multinational sports equipment manufacturers strive for superior product performance to enable commercial advantage, and the design and development of soccer balls is a crucial activity in achieving this. This work details the development of a finite-element (FE) model of a manually stitched textile-reinforced 32-panel ball used in an elite competition. A basic icosahedron FE model was produced to describe a thin-walled isotropic homogeneous shell, and this was subsequently enhanced to include a skeletal-like stiffer stitching region. Material testing was carried out to determine the mechanical properties of the bladder, outer panel, and stitching materials and prescribed within each model by a hyperelastic strain energy potential equation. A stiffness proportional damping coefficient was also used to describe kinetic energy loss characteristics. Each model was validated by an experimental impact testing under dynamic conditions that are representative of play, evaluation of coefficient of restitution, contact time, and deformation. It was found that the advanced soccer ball model accurately represented the deformation behaviour of the ball throughout impact.
Influence of sound and vibration from sports impacts on players' perceptions of equipment quality
Authors: Roberts J R , Jones R , Rothberg S J , Mansfield N J , Meyer C
Published: October 2006

The transition from traditional to modern materials has had a significant effect on equipment performance in many sports. As a result, governing bodies are increasingly placing performance limits on equipment and so other characteristics are becoming important to players seeking the most desirable equipment for their game. The ‘feel’ of the equipment is one such subjective characteristic, which has also been significantly affected by changes in material, but it is difficult to define. Tactile and auditory sensations from impact have been found to contribute to the feel of a shot in several sports and this paper provides further evidence of this relationship. Using golf as an example, this study presents a method for measuring and analysing players' subjective perceptions. The results are then correlated with measurements of sound, linear vibration, and torsional vibration from impact. Stronger relationships were found with the sound data rather than the vibration data, suggesting that the sound is the most significant form of feedback from impact. Psychoacoustic metrics for assessing sound quality are discussed, including perceived loudness and sharpness. Relationships were found between these metrics and the players' perceptions although similar correlations were also found with traditional metrics, such as sound pressure level. The limitations of the psycho-acoustic models for impulsive sounds are also discussed.
Dynamic association and localization of human H/ACA RNP proteins
Authors: Kittur Nupur , Darzacq Xavier , Roy Sujayita , Singer Robert H. , Meier U. Thomas
Published: October 2006

Mammalian H/ACA RNPs are essential for ribosome biogenesis, pre-mRNA splicing, and telomere maintenance. To form mature RNA–protein complexes, one H/ACA RNA associates with four core proteins. In the cell, this process is assisted by at least one nuclear assembly factor, NAF1. Here we report several unanticipated dynamic aspects of H/ACA RNP proteins. First, when overexpressed, NAF1 delocalizes to the cytoplasm. However, its nucleocytoplasmic shuttling properties remain unaffected. These observations demonstrate a subtle equilibrium between NAF1 expression levels and the availability of NAF1 nuclear binding sites. Second, although NAF1 is excluded from mature RNPs in nucleoli and Cajal bodies, NAF1 associates with mature H/ACA RNA in cell lysates. This association occurs post-lysis because it is observed even when NAF1 and the H/ACA RNA are expressed in separate cells. This documents a protein–RNP association in cell lysates that is absent from intact cells. Third, in similar experiments, all H/ACA core proteins, except NAP57, exchange with their exogenous counterparts, portraying an unexpected dynamic picture of H/ACA RNPs. Finally, the irreversible association of only NAP57 with H/ACA RNA and the conundrum that only NAP57 is mutated in X-linked dyskeratosis congenita (even though most core proteins are required for maintaining H/ACA RNAs) may be more than a coincidence.
Surgical management of petrous apex meningioma
Authors: Goin Donald W.
Published: October 2006

When centered in the petrous apex, meninglomas behave like other neoplasms occurring in that region. The petrous apex can be approached by several routes: posterior craniectomy; middle fossa craniectomy; translabyrinthine, transcochlear, and transeth‐moidosphenoid approaches. A patient harboring a malignant meningioma in her petrous apex is presented. A middle fossa craniectomy, coupled with posterior displacement of the facial nerve, allowed access to the entire temporal bone from above. The patient received postoperative irradiation.
Computed tomography in maxillofacial trauma
Authors: Rowe Lee D. , Miller Edward , Brandt‐Zawadzki Michael
Published: October 2006

Computed tomography (CT) has become the key diagnostic modality in the evaluation of head trauma. Experience with CT in the preoperative assessment of maxillofacial injuries is limited, however. Plain films and multidirectional tomography have been used until now to define fractures in the facial region. We examined 27 patients sustaining maxillofacial trauma with CT scans. Ten patients were studied in the coronal plane, 12 in the axial plane, and the reMayning 5 in both the axial and coronal planes. Polycycloidal tomography in the coronal and/or sagittal plane was obtained in 18 patients for comparison with the CT scan.

Fracture lines, bony fragments, and associated skeletal deformities were clearly identified by CT scan in all 27 patients permitting the diagnosis of zygomatic, orbital floor, nasoethmoidal complex, LeFort, temporal bone, frontal sinus, and mandible fractures. More importantly, concommitant intracranial injuries including epidural and intracerebral hematomas, traumatic encephalocoele, and pneumocephalus were readily seen. In addition, facial and orbital soft tissue structures including the globe, optic nerve, orbital fat, and extraocular muscles were easily examined by adjusting the CT level and window settings. Overall, CT yielded additional information not available from polytomography in 15 of 18 cases when both modalities were used. Multidirectional tomography is currently superior to CT scanning if fine, intrinsic bone detail is required. However, we have found that complex fractures with fragmentation are more easily identified on CT scans than conventional tomography because of superior contrast resolution of computed tomography. With improved spatial resolution, CT scanning may totally supplant multidirectional tomography in the evaluation of maxillofacial trauma.
Tuberculoma of the nasopharynx
Authors: Goodman Roy S. , Mattel Stephen , Kaufman David , Grant Jane M.
Published: October 2006

When a patient of oriental extraction was seen with a mass in the nasopharynx, squamous cell carcinoma appeared to be the obvious diagnosis. Histologic examination, however, proved the mass to be a tuberculoma. This condition, which was not rare in the past, is almost always secondary to pulmonary tuberculosis. It responds to antituberculous medications.
Collision tumor of the frontal sinus: Evidence of prior intrasinus instillation of thorotrast
Authors: Cantor Jerome O. , Adelglass Jeffrey , Cerreta Joseph M. , Kancherla Pushpa Latha , Samara Milhem
Published: October 2006

Carcinoma of the frontal sinus is relatively rare. We describe a case of two independent carcinomas, squamous cell and adenoid cystic, in the right frontal sinus region of a patient who received sinus irrigation with an unidentified substance 30 years previously. Radioautography performed on sections of the tumor tissue revealed linear tracks of the type produced by thorium decay, strongly suggesting that the substance was thorotrast. In addition to being the first description of a “collision tumor” of the frontal sinus, the case would represent the first reported instance of frontal sinus carcinoma following intrasinus instillation of thorotrast.
Digital subtraction angiography of lesions of the head and neck
Authors: Kinney Sam E. , Modic Michael T. , Weinstein Meredith A. , Starnes Daniel , Duchesneau Paul M.
Published: October 2006

Computer assistance with contrast angiography has yielded a new technique of intravenous Digital Subtraction Angiography (DSA). DSA has become a useful adjunct to the evaluation and treatment of patients with vascular lesions of the neck and skull base.

This paper will discuss the technique of the DSA study and the types of lesions that it will demonstrate. The combination of a DSA scan and a sector scan, performed as an outpatient, allows a complete evaluation of patients with neck vascular lesions and skull base tumors without hospitalization.
Arguments against a mediating role of the adenylate cyclase — cyclic amp system in the ototoxic action of loop diuretics.
Authors: Thalmann I. , Kobayashi T. , Thalmann R.
Published: October 2006

Previous studies in our laboratory have indicated that adenylate cyclase of the stria vascularis is strongly inhibited in vitro by ethacrynic acid and furosemide. In order to test whether the in vitro effects upon the enzyme are also present under in vivo conditions, ethacrynic acid was perfused perilymphatically for 15 min and 20 min at a concentration of 10∼3 M. Cyclic AMP of the stria vascularis was reduced by 27% and 34%, respectively, but ATP also declined significantly, suggesting unspecific effects. When ethacrynic acid was applied intravenously at a dosage of 50 mg/kg, and the endolymphatic potential allowed to decline to ‐10mV, no significant changes in cyclic AMP and ATP were seen. The absence of effects upon cyclic AMP in the early stage of systemic intoxication with ethacrynic acid is strong evidence against a mediating role of adenylate cyclase in the ototoxic action of ethacrynic acid. When a bolus of 3 × 10−2 M furosemide was applied intra‐arterially the endolymphatic potential declined at the exceedingly rapid rate of about 10 mv/sec, strongly suggesting that the action of the drug takes place in the vicinity of the capillaries of the stria vascularis. In view of the proposition that adenylate cyclase appears to be located primarily at the luminal aspect of the stria vascularis, this constitutes further evidence against a role of the enzyme in the mediation of the specific ototoxic effects of loop diuretics. Other recent evidence against a mediatory role of the adenylate cyclase — cyclic AMP system is discussed.
Improvement in speech perception and production abilities in children using a multichannel cochlear implant
Authors: Waltzman Susan , Cohen Noel L. , Spivak Lynn , Ying Elizabeth , Brackett Diane , Shapiro William , Hoffman Ronald
Published: October 2006

Nine children received the Nucleus® multichannel cochlear prosthesis. The preoperative evaluation consisted of assessments of auditory function, speech recognition, linguistic skills, and speech production. There were no surgical complications, and recovery in all patients was uneventful. The device was programmed 4 to 5 weeks following surgery, and all children were conditioned to the task. Postoperative training began immediately following device stimulation and is ongoing. Auditory skills and speech production scales were devised to monitor each child's progress. All children have shown varying degrees of improvement in auditory skills and speech production using the implant alone.
Clinical application of an implantable bone conduction hearing device
Authors: Roush Jackson , Rauch Steven D.
Published: October 2006

For some patients, the transcutaneous bone‐conduction implant offers a viable alternative to conventional amplification. However, this option should be employed only after considering the relative advantages and disadvantages of conventional medical management and, when feasible, the fitting of air‐conduction amplification. The cases presented here illustrate some important factors to consider in the selection and fitting of bone‐implant candidates.
Perceptual characteristics of tracheoesophageal voice produced using four prosthetic/occlusion combinations
Authors: Williams Sarah E. , Scanio Tom S. , Ritterman Stuart I.
Published: October 2006

This study examined and compared perceptual characteristics of tracheoesophageal (TE) voice produced using four different prosthetic/occlusion combinations in 15 tracheoesophageal speakers: 1. using the Blom‐Singer duckbill prosthesis and digital occlusion of the tracheostoma; 2. using the Blom‐Singer duckbill prosthesis and valve occlusion of the tracheostoma; 3. using the Blom‐Singer low‐pressure prosthesis and digital occlusion of the tracheostoma; and 4. using the Blom‐Singer low‐pressure prosthesis and valve occlusion of the tracheostoma. Characteristics of speech produced in each condition were also compared to those of 19 normal speakers. Differences in perceptual ratings made by judges who varied in knowledge about laryngectomees were examined. Results revealed a number of speaking parameters that discriminated among normals and the four TE speaking conditions, and that differed according to the judge's expertise level. Clinical implications are emphasized.
Circulating immune complexes in patients with nasopharyngeal carcinoma
Authors: Wolf Gregory T. , Wolfe Robert A.
Published: October 2006

Studies of the serum of patients with nasopharyngeal carcinoma (NFC) demonstrate increased levels of immu‐noglobulins (Igs), Epstein‐Barr virus (EBV) antibodies, and specific immunosuppressive acute‐phase proteins (hapto‐globin, α1‐acid glycoprotein). Recent correlations of the levels of acute‐phase and immune‐reactive proteins with tumor extent, immune reactivity, and circulating immune complex (CIC) levels in patients with head and neck squa‐mous carcinoma prompted an investigation of the relationship of CICs to those protein factors characteristically altered in the serum of patients with NPC.

In 70 untreated NPC patients and 21 normal participants, levels of CIC, Igs, immune‐reactive proteins, and EBV antibody titers were measured and correlations with tumor extent and clinical stage determined. In patients with advanced tumors (stages III and IV), levels of CIC, immu‐noglobulin A (IgA), immunoglobulin M (IgM), and acute‐phase proteins (haptoglobin, α1‐acid glycoprotein, α1‐anti‐trypsin) were significantly increased compared to stage I, stage II patients, or normals. In patients with elevated CIC levels, levels of IgA and IgM were significantly increased compared to normals or patients with normal CIC levels. Uniquely, serum IgA levels correlated directly with CIC levels among patients but not controls. EBV antibody titers were increased in the NPC patients and were not significantly related to tumor extent or CIC levels.

The immunosuppressive properties of CICs might account, in part, for the immune suppression previously reported in patients with NPC. Thus, the increased levels of CICs demonstrated in these patients provide a rationale for evaluating the effects of removing CICs, since such therapeutic manipulations have been associated with tumor regressions in patients with other tumor types.
Polite behavior within relational work: The discursive approach to politeness
Authors: Locher Miriam A
Published: October 2006

Ever since Brown and Levinson's (1978, 1987) seminal work, politeness research in linguistics has been thriving. It is only in the last couple of years, however, that alternative ways of looking at politeness have been investigated in more detail and have gained more followers. This paper aims at explaining one of these ways – the discursive approach to politeness – and argues for employing the notion of relational work to move away from a dichotomy between politeness and impoliteness. Instead, it is argued that relational work comprises negatively marked behavior (impoliteness/rudeness), positively marked behavior (politeness), as well as nonmarked, politic behavior which is merely appropriate to the interaction in question and not polite as such. The interactants' assessments of linguistic behavior with respect to norms of appropriateness in social interaction is argued to be at the heart of politeness considerations rather than knowledge of prefabricated inherent linguistic devices. These theoretical considerations are illustrated with a discussion of non-elicited, written data.
Functional Genomic Analysis of Oligodendrocyte Differentiation
Authors: Dugas Jason C. , Tai Yu Chuan , Speed Terence P. , Ngai John , Barres Ben A.
Published: October 2006

To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cellsin vitro. By comparing gene expression in these OLs to OLs generatedin vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell–cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.
Central Administration of a Cytochrome P450-7B Product 7α-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats
Authors: Yau Joyce L. W. , Noble June , Graham Mags , Seckl Jonathan R.
Published: October 2006

Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7α-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7α-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7α-hydroxylated metabolite 7α-hydroxyPREG is not known. We investigated this by treating memory-impaired aged rats (identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7α-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue (percentage conversion of [14C]DHEA to [14C]7α-hydroxyDHEA) was decreased selectively in memory-impaired aged rats compared with both young and memory-intact aged rats. 7α-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory-impaired aged rats for 11 d enhanced spatial memory retention (after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7α-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory-impaired aged rats may, in part, be overcome by administration of 7α-hydroxyPREG.
Alexander Disease-Associated Glial Fibrillary Acidic Protein Mutations in Mice Induce Rosenthal Fiber Formation and a White Matter Stress Response
Authors: Hagemann Tracy L. , Connor Jolien X. , Messing Albee
Published: October 2006

Mutations in the gene for the astrocyte specific intermediate filament, glial fibrillary acidic protein (GFAP), cause the rare leukodystrophy Alexander disease (AxD). To study the pathology of this primary astrocyte defect, we have generated knock-in mice with missense mutations homologous to those found in humans. In this report, we show that mice with GFAP-R76H and -R236H mutations develop Rosenthal fibers, the hallmark protein aggregates observed in astrocytes in AxD, in the hippocampus, corpus callosum, olfactory bulbs, subpial, and periventricular regions. Astrocytes in these areas appear reactive and total GFAP expression is elevated. Although general white matter architecture and myelination appear normal, when crossed with an antioxidant response element reporter line, the mutant mice show a distinct pattern of reporter-gene induction that is especially prominent in the corpus callosum, and histochemical staining reveals accumulation of iron in the same region. The mutant mice have a normal lifespan and show no overt behavioral defects, but are more susceptible to kainate-induced seizures. Although these mice demonstrate increased GFAP expression by themselves, further elevation of GFAP via crosses to GFAP transgenic animals leads to a shift in GFAP solubility, an increased stress response, and ultimately death. The mice do not display the full spectrum of pathology observed in human infantile AxD, but may more closely resemble the adult form of the disease. These studies provide formal proof linking GFAP mutations with Rosenthal fibers and oxidative stress, and correlate gliosis and GFAP protein levels to the severity of the disease.
IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes
Authors: Yazdanpanah Mojgan , Sayed-Tabatabaei Fakhredin A , Janssen Joop A M J L , Rietveld Ingrid , Hofman Albert , Stijnen Theo , Pols Huibert A P , Lamberts Steven W J , Witteman Jacqueline C M , van Duijn Cornelia M
Published: October 2006

Objective: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes.

Design: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older.

Methods: The study was embedded in the Rotterdam Study, a prospective population-based cohort study. At baseline, 668 patients with type 2 diabetes were diagnosed, among which, 55 incident MI were ascertained during follow-up. For the present study, we used two genotype groups: non-variant carriers (homozygous for 192, 194, or 192/194 bp genotypes), and variant carriers.

Results: During a median follow-up of 8.8 years, 396 out of the 668 patients with type 2 diabetes (59.3%) died of various causes. The frequency of type 2 diabetes variant carrier and non-variant carriers was 28.7 and 71.3% respectively. The survival in patients with type 2 diabetes without an MI did not differ between the IGF-I genotype groups (hazard ratio (HR) = 0.8, 95% confidence interval (CI): 0.7–1.1, P = 0.1). In contrast, in those who developed an MI, variant carriers had a 2.4 times higher risk of mortality than non-variant carriers (95% CI: 1.2–4.8, P = 0.01).

Conclusion: Our study suggests that genetically determined low IGF-I activity is an important determinant of survival in patients with type 2 diabetes who developed an MI. The IGF-I promoter polymorphism, therefore, may help to predict the future mortality risk in this group of patients.
Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease
Authors: Nobili Valerio , Manco Melania , Ciampalini Paolo , Diciommo Vincenzo , Devito Rita , Piemonte Fiorella , Comparcola Donatella , Guidi Roberto , Marcellini Matilde
Published: October 2006

Objective: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children.

Design and methods: In 72 biopsy-proven NAFLD children (aged 9–18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients.

Results: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 ± 1.39 and 4.4 ± 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 ± 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 ± 6.3 in score 1 to 17.4 ± 6.9 in score 2 (P = 0.01) and 22.2 ± 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 ± 1.40, 3.57 ± 0.34, 4.45 ± 0.64 respectively (P = 0.05)); ballooning (from 13.7 ± 6.7 in score 1 to 17 ± 7.5 in score 2 (P = 0.001) and 22.1 ± 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 ± 1.50, 3.40 ± 1.65, 4.57 ± 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 ± 7 to18.3 ± 6.9; P = 0.03; FLI 3.03 ± 1.57 vs 3.92 ± 077; P < 0.05) and NAS score (score 1–2: 12.9 ± 6.9; score 3–4: 17 ± 6.9 (P = 0.01); score 5–7: 22.9 ± 7.5 ng/ml (P = 0.03); FLI 2.70 ± 1.53, 3.12 ± 1.53, 4.58 ± 1.57 P = 0.01 and P = 0.05 between 1–2 vs 3–4 and 3–4 vs 5–7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r0 = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r0 = 0.4, P < 0.0001), steatosis (r0 = 0.5, P < 0.0001) and NAS score (r0 = 0.5, P < 0.0001).

Conclusions: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.
Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases
Authors: Reimer Raylene A
Published: October 2006

Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue released from L-cells in the intestine. Meat hydrolysate (MH) is a powerful activator of GLP-1 secretion in the human enteroendocrine NCI-H716 cell line, but the mechanisms involved in nutrient-stimulated GLP-1 secretion are poorly understood. The objective of this study was to characterize the intracellular signalling pathways regulating MH- and amino acid-induced GLP-1 secretion. Individually, the pharmacological inhibitors, SB203580 (inhibitor of p38 mitogen-activated protein kinase (MAPK)), wortmannin (inhibitor of phosphatidyl inositol 3-kinase) and U0126 (inhibitor of mitogen activated or extracellular signal-regulated protein kinase (MEK1/2) upstream of extracellular signal-regulated kinase (ERK)1/2) all inhibited MH-induced GLP-1 secretion. Further examination of the MAPK pathway showed that MH increased the phosphorylation of ERK1/2, but not p38 or c-Jun N-terminal kinase over 2–15 min. Incubation with SB203580 resulted in a decrease in phosphorylated p38 MAPK and a concomitant increase in the phosphorylation of ERK1/2. Phosphorylation of ERK1/2 was augmented by co-incubation of MH with SB203580. Inhibitors of protein kinase A and protein kinase C did not inhibit MH-induced GLP-1 secretion. In contrast to non-essential amino acids, essential amino acids (EAAs) increased GLP-1 secretion and similar to MH, activated ERK1/2. However, they also activated p38-suggesting type of protein may affect GLP-1 secretion. In conclusion, there appears to be a crosstalk between p38 and ERK1/2 MAPK in the human enteroendocrine cell with the activation of ERK1/2 common to both MH and EAA. Understanding the cellular pathways involved in nutrient-stimulated GLP-1 secretion has important implications for the design of new treatments aimed at increasing endogenous GLP-1 release in type-2 diabetes and obesity.
Central and peripheral interleukin-1β and interleukin-1 receptor I expression and their role in the acute stress response of common carp, Cyprinus carpio L.
Authors: Metz Juriaan R , Huising Mark O , Leon Karin , Verburg-van Kemenade B M Lidy , Flik Gert
Published: October 2006

In fish, the hypothalamus–pituitary–interrenal axis (HPI-axis), the equivalent of the hypothalamus–pituitary–adrenal axis (HPA-axis) in mammals, is activated during stress and leads to production and release of cortisol by the interregnal cells in the head kidney. In mammals, the cytokine interleukin-1β (IL-1β) takes a key position in the innate immune and inflammatory responses and influences the HPA-axis. In fish, studies that address the effects of cytokines on HPI-axis activation are limited. We quantitatively assessed expression of IL-1β and its receptor, IL-1RI (the latter was cloned and sequenced), in an acute restraint stress paradigm in common carp, Cyprinus carpio. We also considered expression of the pituitary hormones prolactin (PRL) and GH that have been shown to be structurally related to cytokines and have immunomodulatory actions. Pituitary PRL expression increased fourfold during stress; GH mRNA levels were unaffected. Following restraint, hypothalamic IL-1β expression was upregulated; in head kidney and pituitary pars intermedia, IL-1RI expression significantly increased. We suggest that during acute stress IL-1β signalling in the HPI-axis becomes more sensitive, since both ligand and receptor expressions are enhanced. In vitro, recombinant carp IL-1β stimulates release of α-MSH and N-Ac β-endorphin from the pituitary gland. This observation concurs with increased in vivo plasma levels of α-MSH and N-Ac β-endorphin following restraint. Our findings combined lead us to conclude that IL-1β affects the activity of the HPI-axis and, in turn, expression profiles of genes encoding IL-1β and its receptor are modified during acute stress. Our study provides convincing evidence for bi-directional communication of the HPI-axis and the immune system in fish.
Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells
Authors: Yu Run , Cruz-Soto Martha , Calzi Sergio Li , Hui Hongxiang , Melmed Shlomo
Published: October 2006

Human pituitary tumor-transforming gene 1 (PTTG1) encodes a securin protein critically important in regulating chromosome separation. Murine PTTG (mPTTG) is 66% homologous to human PTTG1 and PTTG-null (PTTG−/−) mice exhibit pancreatic β-cell hypoplasia and abnormal nuclear morphology with resultant diabetes. As we show that ductal β-cell neogenesis is intact in PTTG−/− mice, we explored mechanism for defective β-cell replication. We tested whether mPTTG exhibits securin properties in mouse insulin-secreting insulinoma MIN6 cells, using a live-cell system to monitor mitosis in cells transfected with an enhanced green fluorescent protein (EGFP)-tagged mPTTG conjugate (mPTTG-EGFP). To fulfill the criteria for securin properties, the protein should undergo degradation immediately before the metaphase-to-anaphase transition when expression levels are low, and should inhibit metaphase-to-anaphase transition when expression levels are high. EGFP itself did not undergo degradation throughout mitosis and high levels of EGFP per se did not affect normal mitosis progression (n=25). However, mPTTG-EGFP was degraded 2 min before the metaphase-to-anaphase transition when expression levels were low (n=19), and high mPTTG-EGFP levels blocked metaphase-to-anaphase transition in 13 cells. mPTTG-EGFP inhibited MIN6 cell proliferation and caused apoptosis. Immunocoprecipitation demonstrated binding of mPTTG-EGFP and separase. These results show that mPTTG exhibits properties consistent with a murine securin in insulin-secreting mouse cells and mPTTG overexpression inhibits cell proliferation, suggesting that defective β-cell proliferation observed in PTTG−/− mice is likely due to abnormal cell-cycle progression.
Hypertensive effect of calcilytic NPS 2143 administration in rats
Authors: Rybczynska Apolonia , Lehmann Artur , Jurska-Jasko Anna , Boblewski Konrad , Orlewska Czeslawa , Foks Henryk , Drewnowska Krystyna
Published: October 2006

Secretion of parathormone (PTH), the main parathyroid hormone, which is under the control of the calcium sensing receptor, might be inhibited by calcimimetics and stimulated by calcilytics. Parathyroid glands also secrete parathyroid hypertensive factor. Recently, it was shown that calcimimetic NPS R-568 induced decreased blood pressure in spontaneously hypertensive rats (SHR) in the presence of parathyroid glands. Therefore, the aim of this study was to determine whether administration of the calcilytic NPS 2143 provoked an increase of mean arterial blood pressure (MAP) in normotensive rats. We used male Wistar rats anaesthetized with thiopental. Clearance experiments were performed and the effect of bolus, 1 mg/kg body weight i.v. of NPS 2143 on MAP in the presence and absence of thyroparathyroidectomy (TPTX) was monitored continuously. Calcilytic properties of NPS 2143 were confirmed directly by a significant (P < 0.05) increase of plasma PTH concentration, and indirectly by a rise of plasma Ca2+ concentration and urinary fractional phosphate excretion (FE Pi). NPS 2143 administration markedly (P < 0.05) increased MAP, calculated as the difference ( Δ ) in MAP between sequential measurements and the time of bolus injection of calcilytic. The observed increase of blood pressure in the NPS 2143 group was also significant (P < 0.05) compared with the control group. Performance of TPTX prevented the hypertensive effect of NPS 2143. We conclude that NPS 2143 is responsible for increased blood pressure in rats in the presence of parathyroid glands.
Developmental aspects of adipose tissue in GH receptor and prolactin receptor gene disrupted mice: site-specific effects upon proliferation, differentiation and hormone sensitivity
Authors: Flint David J , Binart Nadine , Boumard Stephanie , Kopchick John J , Kelly Paul
Published: October 2006

Direct metabolic effects of GH on adipose tissue are well established, but effects of prolactin (PRL) have been more controversial. Recent studies have demonstrated PRL receptors on adipocytes and effects of PRL on adipose tissue in vitro. The role of GH in adipocyte proliferation and differentiation is also controversial, since GH stimulates adipocyte differentiation in cell lines, whereas it stimulates proliferation but inhibits differentiation of adipocytes in primary cell culture. Using female gene disrupted (ko) mice, we showed that absence of PRL receptors (PRLRko) impaired development of both internal and s.c. adipose tissue, due to reduced numbers of adipocytes, an effect differing from that of reduced food intake, where cell volume is decreased. In contrast, GHRko mice exhibited major decreases in the number of internal adipocytes, whereas s.c. adipocyte numbers were increased, even though body weight was decreased by 40–50%. The changes in adipose tissue in PRLRko mice appeared to be entirely due to extrinsic factors since preadipocytes proliferated and differentiated in similar fashion to wild-type animals in vitro and their response to insulin and isoproterenol was similar to wild-type animals. This contrasted with GHRko mice, where s.c. adipocytes proliferated, differentiated, and responded to hormones in identical fashion to controls, whereas parametrial adipocytes exhibited markedly depressed proliferation and differentiation potential and failed to respond to insulin or noradrenaline. Our results provide in vivo evidence that both GH and PRL stimulate differentiation of adipocytes but that the effects of GH are site specific and induce intrinsic changes in the precursor population, which are retained in vitro.