bluuebunny/crossref_metadata_2025 huggingface dataset:
Moving Risk Factors into Developmental Theories of Gang Membership
Authors: Howell James C. , Egley Arlen
Published: September 2005

Several quantitative longitudinal studies of youth gang members—particularly those embedded in well-designed studies of large, representative samples of children and adolescents—have expanded interest in risk factors for gang membership. Drawing on recent research findings, this article aims to review and synthesize risk factors for gang involvement and to integrate these in a theoretical explanation of youth gang membership. Research-supported risk factors from other studies are combined with variables in Thornberry et al.’s interactional theory of gang membership to form a broader developmental theory of gang involvement. Program and policy implications are also drawn.
In Between Adolescence and Adulthood
Authors: Trulson Chad R. , Marquart James W. , Mullings Janet L. , Caeti Tory J.
Published: September 2005

This research examines the recidivism outcomes of 2,436 serious, violent, and chronic youth released from a juvenile correctional system. This group of state delinquents was followed for 5 years after their release to parole as they made the transition to young adulthood. Results of the analysis revealed that 85% of state delinquents were rearrested at least once in the follow-up period, and nearly 80% were rearrested for a felony. Generally, males, those younger at first contact with the juvenile justice system, those with a greater number of felony adjudications, gang members, institutional dangers, those in poverty, and those with mental health issues were significantly more likely to recidivate. The analyses indicate that the factors that would explain recidivism for male state delinquents may differ for female state delinquents. This article concludes with a discussion of policy implications specific to this highly select but disproportionately problematic group of delinquent offenders.
Substance Abuse and Drug Courts
Authors: Gilmore Amna Saddik , Rodriguez Nancy , Webb Vincent J.
Published: September 2005

By drawing on social control theory, this study examines the effect of juvenile drug court treatment on the desistence of delinquent behavior in Maricopa County, Arizona. Bonds to family members, school, and peers are included in the analyses to assess how they influence offenders’ treatment progress (i.e., delinquency and drug use) and program completion. Special analytical focus is placed on the additive and interactive effects such bonds have on juvenile drug court success. Results indicate social bonds (e.g., parents’ substance abuse, siblings’ substance abuse, peers’ substance abuse, and gang membership) play a significant role in the desistance of delinquent behavior and program completion. Based on these findings, the effect of juvenile court programs on delinquency and drug use will largely depend on their ability to address offenders’ weak social bonds.
Presence of bone marrow–derived circulating progenitor endothelial cells in the newly formed lymphatic vessels
Authors: Religa Piotr , Cao Renhai , Bjorndahl Meit , Zhou Zhongjun , Zhu Zhenping , Cao Yihai
Published: September 2005

Bone marrow (BM)-derived circulating endothelial precursor cells (CEPCs) have been reported to incorporate into newly formed blood vessels under physiologic and pathologic conditions. However, it is unknown if CEPCs contribute to lymphangiogenesis. Here we show that in a corneal lymphangiogenesis model of irradiated mice reconstituted with enhanced green fluorescent protein (EGFP)-positive donor bone marrow cells, CEPCs are present in the newly formed lymphatic vessels. Depletion of bone marrow cells by irradiation remarkably suppressed lymphangiogenesis in corneas implanted with fibroblast growth factor-2 (FGF-2). Further, transplantation of isolated EGFP-positive/vascular endothelial growth factor receptor-3-positive (EGFP+/VEGFR-3+) or EGFP+/VEGFR-2+ cell populations resulted in incorporation of EGFP+ cells into the newly formed lymphatic vessels. EGFP+/CEPCs were also present in peritumoral lymphatic vessels of a fibrosarcoma. These data suggest that BM-derived CEPCs may play a role in “lymphvasculogenesis.”
SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages
Authors: Ishikawa-Sekigami Tomomi , Kaneko Yoriaki , Okazawa Hideki , Tomizawa Takeshi , Okajo Jun , Saito Yasuyuki , Okuzawa Chie , Sugawara-Yokoo Minako , Nishiyama Uichi , Ohnishi Hiroshi , Matozaki Takashi , Nojima Yoshihisa
Published: September 2005

The lifespan of circulating red blood cells (RBCs) produced in bone marrow is determined by their elimination through phagocytosis by splenic macrophages. The mechanism by which RBC elimination is regulated has remained unclear, however. The surface glycoprotein SHPS-1, a member of the immunoglobulin superfamily, is abundant in macrophages. We have now examined the regulation of RBC turnover with the use of mice that express a mutant form of SHPS-1 lacking most of its cytoplasmic region. The mutant mice manifested mild anemia as well as splenomegaly characterized by expansion of the red pulp. The numbers of erythroid precursor cells in the spleen and of circulating reticulocytes were also increased in the mutant mice. In contrast, the half-life of circulating RBCs was reduced in these animals, and the rate of clearance of injected opsonized RBCs from the peripheral circulation was increased in association with their incorporation into splenic macrophages. Phagocytosis of opsonized RBCs by splenic macrophages from mutant mice in vitro was also increased compared with that observed with wild-type macrophages. These results suggest that SHPS-1 negatively regulates the phagocytosis of RBCs by splenic macrophages, thereby determining both the lifespan of individual RBCs and the number of circulating erythrocytes.
Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines
Authors: Bonig Halvard , Priestley Gregory V. , Papayannopoulou Thalia
Published: September 2005

Efficient bone marrow (BM) homing is a prerequisite for successful engraftment of transplanted hematopoietic cells (HPCs). Contradictory conclusions about the contribution of SDF-1/CXCR4 have clouded our understanding of its role within the molecular pathway cooperation needed for BM homing, particularly with the well-defined hierarchic network of adhesion molecules. In the present study we sought to unravel cooperative and compensatory molecular pathways guiding BM homing. Fresh BM-HPCs, rendered either SDF-1 unresponsive or Gi-signaling refractory, homed quite efficiently, because of compensation by α4-integrin interacting with VCAM-1. The contribution of SDF-1/CXCR4- or Gi-protein-mediated signals to BM homing became apparent after their blockade was combined with deletion of α4-integrin, leading to dramatic reduction in BM homing. Similar conclusions were revealed when VCAM-1-deficient hosts were used. Cytokine incubation changed the functional properties of BM-HPCs and hierarchy of molecular pathway usage in homing, by shifting the dominance among the homing mediators: loss of CXCR4 or Gi-signaling now significantly reduced BM homing, with only partial compensation through α4/VCAM-1 and endothelial selectins. These studies depict a flexible hierarchy of cooperating homing pathways, in which dominant players are repositioned with changing cytokine milieu, and possibly source of HPCs.
Recombinant CUB-1 domain polypeptide inhibits the cleavage of ULVWF strings by ADAMTS13 under flow conditions
Authors: Tao Zhenyin , Peng Yuandong , Nolasco Leticia , Cal Santiago , Lopez-Otin Carlos , Li Renhao , Moake Joel L. , López José A. , Dong Jing-fei
Published: September 2005

The metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif) converts the hyperreactive unusually large (UL) forms of von Willebrand factor (VWF) that are newly released from endothelial cells into less active plasma forms by cleaving a peptide bond in the VWF A2 domain. Familial or acquired deficiency of this metalloprotease is associated with thrombotic thrombocytopenic purpura (TTP). ADAMTS13 belongs to the ADAMTS metalloprotease family, but, unlike other members, it also contains 2 C-terminal CUB domains (complement component Clr/Cls, Uegf, and bone morphogenic protein 1). Mutations in the CUB region have been found in congenital TTP, but deletion of the region did not impair enzyme activity in conventional in vitro assays. We investigated the functions of the CUB domain in ADAMTS13 activity under flow conditions. We found that recombinant CUB-1 and CUB-1+2 polypeptides and synthetic peptides derived from CUB-1 partially blocked the cleavage of ULVWF by ADAMTS13 on the surface of endothelial cells under flow. The polypeptide bound immobilized and soluble forms of ULVWF, and blocked the adhesion of ADAMTS13-coated beads to immobilized ULVWF under flow. These results suggest that the CUB-1 domain may serve as the docking site for ADAMTS13 to bind ULVWF under flow, a critical step to initiate ULVWF proteolysis.
The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study
Authors: Nemeth Elizabeta , Preza Gloria C. , Jung Chun-Ling , Kaplan Jerry , Waring Alan J. , Ganz Tomas
Published: September 2005

Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in mice by the induction of hypoferremia. Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when 5 N-terminal aa's were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin and did not interfere with ferroportin internalization by native hepcidin. Deletion of 2 C-terminal aa's did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not affect peptide activity in vitro. However, these peptides were less active in vivo, likely because of their decreased stability in circulation. G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations.
Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress
Authors: Gao Ning , Rahmani Mohamed , Shi Xianglin , Dent Paul , Grant Steven
Published: September 2005

Interactions between the endogenous estradiol metabolite 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors (HDACIs) have been investigated in human leukemia cells. Coadministration of subtoxic or marginally toxic concentrations of 2-ME and SAHA or sodium butyrate in diverse human leukemia-cell types resulted in a marked increase in oxidative damage (eg, generation of reactive oxygen species [ROSs]), mitochondrial injury (eg, cytochrome c release and Bax translocation), caspase activation, and apoptosis. These interactions were also noted in primary human leukemia cells but not in normal bone marrow CD34+ cells. Synergistic interactions between these agents were associated with inactivation of Akt and activation of c-Jun N-terminal kinase (JNK). Essentially all of these events were reversed by free radical scavengers such as the manganese superoxide dismutase (MnSOD) mimetic TBAP and catalase. Notably, treatment with 2-ME/HDACIs resulted in down-regulation of thioredoxin, MnSOD, and glutathione peroxidase. Enforced activation of Akt blocked 2-ME/HDACI-mediated mitochondrial injury, caspase activation, and JNK up-regulation, but not generation of ROSs. Pharmacologic or genetic (siRNA) interruption of the JNK pathway also significantly attenuated the lethality of this regimen. Together, these findings support a model in which antileukemic synergism between 2-ME and HDACIs stems primarily from induction of oxidative damage, leading in turn to Akt inactivation and JNK activation, culminating in mitochondrial injury and apoptosis. They also raise the possibility that these events may preferentially occur in leukemic versus normal hematopoietic cells.
Human mesenchymal stem cells modulate B-cell functions
Authors: Corcione Anna , Benvenuto Federica , Ferretti Elisa , Giunti Debora , Cappiello Valentina , Cazzanti Francesco , Risso Marco , Gualandi Francesca , Mancardi Giovanni Luigi , Pistoia Vito , Uccelli Antonio
Published: September 2005

Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. hMSCs isolated from the bone marrow and B cells purified from the peripheral blood of healthy donors were cocultured with different B-cell tropic stimuli. B-cell proliferation was inhibited by hMSCs through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis. A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments. hMSCs inhibited B-cell differentiation because IgM, IgG, and IgA production was significantly impaired. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B cells. B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs. These results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.
Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation
Authors: Mohty Mohamad , Blaise Didier , Faucher Catherine , Vey Norbert , Bouabdallah Reda , Stoppa Anne-Marie , Viret Frederic , Gravis Gwenaelle , Olive Daniel , Gaugler Béatrice
Published: September 2005

This study investigated the role of inflammatory cytokines in acute graft-versus-host disease (aGVHD) incidence and severity in 113 patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Among all tested cytokines in the first 3 months after allo-SCT, only interleukin-12 p70 (IL-12p70) levels in the first month were significantly associated with grades II to IV aGVHD development (P < .001). IL-12p70 levels were directly correlated with aGVHD severity grade (P < .001). Before aGVHD onset, blood monocytes, the main precursor pool of IL12p70-secreting dendritic cells, recovered more rapidly in patients with grades II to IV aGVHD (P = .005). Similarly, at the effector level, there was a more robust reconstitution of naive CD3+CD4+CD45RA+CD27+ T cells in patients developing grades II to IV aGVHD (P = .006). In multivariate analysis, IL-12p70 level measured in the first month was the strongest predictive factor for aGVHD development (P < .001). These findings, reconstituting a TH1 loop, support a model in which aGVHD reflects a type 1 alloreaction after RIC allo-SCT.
Tourette syndrome and learning disabilities
Authors: Burd Larry , Freeman Roger D , Klug Marilyn G , Kerbeshian Jacob
Published: September 2005

Background

Tourette Syndrome (TS) is a neurodevelopmental disorder of childhood. Learning disabilities are frequently comorbid with TS. Using the largest sample of TS patients ever reported, we sought to identify differences between subjects with TS only and subjects with TS and a comorbid learning disability.

Methods

We used the Tourette Syndrome International Consortium database (TIC) to compare subjects with comorbid Tourette Syndrome and learning disabilities (TS + LD) to subjects who did not have a comorbid learning disability (TS - LD). The TIC database contained 5,500 subjects. We had usable data on 5,450 subjects.

Results

We found 1,235 subjects with TS + LD. Significant differences between the TS + LD group and the TS - LD group were found for gender (.001), age onset (.030), age first seen (.001), age at diagnosis (.001), prenatal problems (.001), sibling or other family member with tics (.024), two or more affected family members (.009), and severe tics (.046). We used logistic modeling to identify the optimal prediction model of group membership. This resulted in a five variable model with the epidemiologic performance characteristics of accuracy 65.2% (model correctly classified 4,406 of 5,450 subjects), sensitivity 66.1%, and specificity 62.2%.

Conclusion

Subjects with TS have high prevalence rates of comorbid learning disabilities. We identified phenotype differences between the TS - LD group compared to TS + LD group. In the evaluation of subjects with TS, the presence of a learning disability should always be a consideration. ADHD may be an important comorbid condition in the diagnosis of LD or may also be a potential confounder. Further research on etiology, course and response to intervention for subjects with TS only and TS with learning disabilities is needed.
Methodological aspects of a GIS-based environmental health inspection program used in the Athens 2004 Olympic and Para Olympic Games
Authors: Hadjichristodoulou Christos , Soteriades Elpidoforos S , Kolonia Virginia , Falagas Matthew E , Pantelopoulos Efstathios , Panagakos Georgios , Mouchtouri Varvara , Kremastinou Jeni
Published: September 2005

Background

The use of geographical information system (GIS) technologies in public health surveillance is gradually gaining momentum around the world and many applications have already been reported in the literature. In this study, GIS technology was used to help county departments of Public Health to implement environmental health surveillance for the Athens 2004 Olympic and Para Olympic Games.

Methods

In order to assess the workload in each Olympic county, 19 registry forms and 17 standardized inspection forms were developed to register and inspect environmental health items requiring inspection (Hotels, restaurants, swimming pools, water supply system etc), respectively. Furthermore, related databases were created using Epi Info 2002 and a geographical information system (GIS) were used to implement an integrated Environmental Health inspection program. The project was conducted in Athens by the Olympic Planning Unit (OPU) of the National School of Public Health, in close cooperation with the Ministry of Health and Social Solidarity and the corresponding departments of Public Health in all municipalities that were scheduled to host events during the Athens 2004 Olympic and Para Olympic games.

Results

A total of 44,741 premises of environmental health interest were geocoded into GIS databases and several electronic maps were developed. Using such maps in association with specific criteria, we first identified the maximum workload required to execute environmental health inspections in all premises within the eleven Olympic County Departments of Public Health. Six different scenarios were created for each county, based on devised algorithms in order to design the most effective and realistic inspection program using the available inspectors from each municipality. Furthermore, GIS applications were used to organize the daily inspection program for the Olympic games, provide coloured displays of the inspection results and link those results with the public health surveillance of specific cases or outbreak investigation.

Conclusion

Our computerised program exhibited significant efficiency in facilitating the prudent use of public health resources in implementing environmental health inspections in densely populated urban areas as well as in rural counties. Furthermore, the application of simple algorithms in integrating human and other resources provided tailored and cost-effective applications to different public health agencies.
A new paradigm in respiratory hygiene: increasing the cohesivity of airway secretions to improve cough interaction and reduce aerosol dispersion
Authors: Zayas Gustavo , Dimitry John , Zayas Ana , O'Brien Darryl , King Malcolm
Published: September 2005

Background

Infectious respiratory diseases are transmitted to non-infected subjects when an infected person expels pathogenic microorganisms to the surrounding environment when coughing or sneezing. When the airway mucus layer interacts with high-speed airflow, droplets are expelled as aerosol; their concentration and size distribution may each play an important role in disease transmission. Our goal is to reduce the aerosolizability of respiratory secretions while interfering only minimally with normal mucus clearance using agents capable of increasing crosslinking in the mucin glycoprotein network.

Methods

We exposed mucus simulants (MS) to airflow in a simulated cough machine (SCM). The MS ranged from non-viscous, non-elastic substances (water) to MS of varying degrees of viscosity and elasticity. Mucociliary clearance of the MS was assessed on the frog palate, elasticity in the Filancemeter and the aerosol pattern in a "bulls-eye" target. The sample loaded was weighed before and after each cough maneuver. We tested two mucomodulators: sodium tetraborate (XL"B") and calcium chloride (XL "C").

Results

Mucociliary transport was close to normal speed in viscoelastic samples compared to non-elastic, non-viscous or viscous-only samples. Spinnability ranged from 2.5 ± 0.6 to 50.9 ± 6.9 cm, and the amount of MS expelled from the SCM increased from 47 % to 96 % adding 1.5 μL to 150 μL of XL "B". Concurrently, particles were inversely reduced to almost disappear from the aerosolization pattern.

Conclusion

The aerosolizability of MS was modified by increasing its cohesivity, thereby reducing the number of particles expelled from the SCM while interfering minimally with its clearance on the frog palate. An unexpected finding is that MS crosslinking increased "expectoration".
Household out-of-pocket medical expenditures and national health insurance in Taiwan: income and regional inequality
Authors: Chu Tu-Bin , Liu Tsai-Ching , Chen Chin-Shyan , Tsai Yi-Wen , Chiu Wen-Ta
Published: September 2005

Background

Unequal geographical distribution of medical care resources and insufficient healthcare coverage have been two long-standing problems with Taiwan's public health system. The implementation of National Health Insurance (NHI) attempted to mitigate the inequality in health care use. This study examines the degree to which Taiwan's National Health Insurance (NHI) has reduced out-of-pocket medical expenditures in households in different regions and varying levels of income.

Methods

Data used in this study were drawn from the 1994 and 1996 Surveys of Family Income and Expenditure. We pooled the data from 1994 and 1996 and included a year dummy variable (NHI), equal to 1 if the household data came from 1996 in order to assess the impact of NHI on household out-of-pocket medical care expenditures shortly after its implementation in 1995.

Results

An individual who was older, female, married, unemployed, better educated, richer, head of a larger family household, or living in the central and eastern areas was more likely to have greater household out-of-pocket medical expenditures. NHI was found to have effectively reduced household out-of-pocket medical expenditures by 23.08%, particularly for more affluent households. With the implementation of NHI, lower and middle income quintiles had smaller decreases in out-of-pocket medical expenditure. NHI was also found to have reduced household out-of-pocket medical expenditures more for households in eastern Taiwan.

Conclusion

Although NHI was established to create free medical care for all, further effort is needed to reduce the medical costs for certain disadvantaged groups, particularly the poor and aborigines, if equality is to be achieved.
Childhood obesity, prevalence and prevention
Authors: Dehghan Mahshid , Akhtar-Danesh Noori , Merchant Anwar T
Published: September 2005

Childhood obesity has reached epidemic levels in developed countries. Twenty five percent of children in the US are overweight and 11% are obese. Overweight and obesity in childhood are known to have significant impact on both physical and psychological health. The mechanism of obesity development is not fully understood and it is believed to be a disorder with multiple causes. Environmental factors, lifestyle preferences, and cultural environment play pivotal roles in the rising prevalence of obesity worldwide. In general, overweight and obesity are assumed to be the results of an increase in caloric and fat intake. On the other hand, there are supporting evidence that excessive sugar intake by soft drink, increased portion size, and steady decline in physical activity have been playing major roles in the rising rates of obesity all around the world. Consequently, both over-consumption of calories and reduced physical activity are involved in childhood obesity.

Almost all researchers agree that prevention could be the key strategy for controlling the current epidemic of obesity. Prevention may include primary prevention of overweight or obesity, secondary prevention or prevention of weight regains following weight loss, and avoidance of more weight increase in obese persons unable to lose weight. Until now, most approaches have focused on changing the behaviour of individuals in diet and exercise. It seems, however, that these strategies have had little impact on the growing increase of the obesity epidemic. While about 50% of the adults are overweight and obese in many countries, it is difficult to reduce excessive weight once it becomes established. Children should therefore be considered the priority population for intervention strategies. Prevention may be achieved through a variety of interventions targeting built environment, physical activity, and diet. Some of these potential strategies for intervention in children can be implemented by targeting preschool institutions, schools or after-school care services as natural setting for influencing the diet and physical activity. All in all, there is an urgent need to initiate prevention and treatment of obesity in children.
Complications during pharmacological stress echocardiography: a video-case series
Authors: Varga Albert , Kraft Giuliano , Lakatos Ferenc , Bigi Riccardo , Paya Rafael , Picano Eugenio
Published: September 2005

Background

Stress echocardiography is a cost-effective tool for the modern noninvasive diagnosis of coronary artery disease. Several physical and pharmacological stresses are used in combination with echocardiographic imaging, usually exercise, dobutamine and dipyridamole. The safety of a stress is (or should be) a major determinant in the choice of testing. Although large scale single center experiences and multicenter trial information are available for both dobutamine and dipyridamole stress echo testing, complications or side effects still can occur even in the most experienced laboratories with the most skilled operators.

Case presentation

We decided to present a case collection of severe complications during pharmacological stress echo testing, including a ventricular tachycardia, cardiogenic shock, transient ischemic attack, torsade de pointe, fatal ventricular fibrillation, and free wall rupture.

Conclusion

We believe that, in this field, every past complication described is a future complication avoided; what happens in your lab is more true of what you read in journals; and Good Clinical Practice is not "not having complications", but to describe the complications you had.
Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report
Authors: Jochmann Nicoline , Kiecker Felix , Borges Adrian C , Hofmann Maja A , Eddicks Stephan , Sterry Wolfram , Baumann Gert , Trefzer Uwe
Published: September 2005

background

Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare.

Case presentation

We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy.

Conclusion

This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.
Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system
Authors: Fujii Junichi , Iuchi Yoshihito , Okada Futoshi
Published: September 2005

Controlled oxidation, such as disulfide bond formation in sperm nuclei and during ovulation, plays a fundamental role in mammalian reproduction. Excess oxidation, however, causes oxidative stress, resulting in the dysfunction of the reproductive process. Antioxidation reactions that reduce the levels of reactive oxygen species are of prime importance in reproductive systems in maintaining the quality of gametes and support reproduction. While anti-oxidative enzymes, such as superoxide dismutase and peroxidase, play a central role in eliminating oxidative stress, reduction-oxidation (redox) systems, comprised of mainly glutathione and thioredoxin, function to reduce the levels of oxidized molecules. Aldo-keto reductase, using NADPH as an electron donor, detoxifies carbonyl compounds resulting from the oxidation of lipids and proteins. Thus, many antioxidative and redox enzyme genes are expressed and aggressively protect gametes and embryos in reproductive systems.
Modulation of extracellular matrix genes reflects the magnitude of physiological adaptation to aerobic exercise training in humans
Authors: Timmons James A , Jansson Eva , Fischer Helene , Gustafsson Thomas , Greenhaff Paul L , Ridden John , Rachman Jonathan , Sundberg Carl Johan
Published: September 2005

Background

Regular exercise reduces cardiovascular and metabolic disease partly through improved aerobic fitness. The determinants of exercise-induced gains in aerobic fitness in humans are not known. We have demonstrated that over 500 genes are activated in response to endurance-exercise training, including modulation of muscle extracellular matrix (ECM) genes. Real-time quantitative PCR, which is essential for the characterization of lower abundance genes, was used to examine 15 ECM genes potentially relevant for endurance-exercise adaptation. Twenty-four sedentary male subjects undertook six weeks of high-intensity aerobic cycle training with muscle biopsies being obtained both before and 24 h after training. Subjects were ranked based on improvement in aerobic fitness, and two cohorts were formed (n = 8 per group): the high-responder group (HRG; peak rate of oxygen consumption increased by +0.71 ± 0.1 L min-1; p < 0.0001) while the low-responder group (LRG; peak rate of oxygen consumption did not change, +0.17 ± 0.1 L min-1, ns). ECM genes profiled included the angiopoietin 1 and related genes (angiopoietin 2, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) and 2 (TIE2), vascular endothelial growth factor (VEGF) and related receptors (VEGF receptor 1, VEGF receptor 2 and neuropilin-1), thrombospondin-4, α2-macroglobulin and transforming growth factor β2.

Results

neuropilin-1 (800%; p < 0.001) and VEGF receptor 2 (300%; p < 0.01) transcript abundance increased only in the HRG, whereas levels of VEGF receptor 1 mRNA actually declined in the LRG (p < 0.05). TIE1 and TIE2 mRNA levels were unaltered in the LRG, whereas transcription levels of both genes were increased by 2.5-fold in the HRG (p < 0.01). Levels of thrombospondin-4 (900%; p < 0.001) and α2-macroglobulin (300%, p < 0.05) mRNA increased substantially in the HRG. In contrast, the amount of transforming growth factor β2 transcript increased only in the HRG (330%; p < 0.01), whereas it remained unchanged in the LRG (-80%).

Conclusion

We demonstrate for the first time that aerobic training activates angiopoietin 1 and TIE2 genes in human muscle, but only when aerobic capacity adapts to exercise-training. The fourfold-greater increase in aerobic fitness and markedly differing gene expression profile in the HRG indicates that these ECM genes may be critical for physiological adaptation to exercise in humans. In addition, we show that, without careful demonstration of physiological adaptation, conclusions derived from gene expression profiling of human skeletal muscle following exercise may be of limited value. We propose that future studies should (a) investigate the mechanisms that underlie the apparent link between physiological adaptation and gene expression and (b) use the genes profiled in this paper as candidates for population genetic studies.
How useful is satellite positioning system (GPS) to track gait parameters? A review
Authors: Terrier Philippe , Schutz Yves
Published: September 2005

Over the last century, numerous techniques have been developed to analyze the movement of humans while walking and running. The combined use of kinematics and kinetics methods, mainly based on high speed video analysis and forceplate, have permitted a comprehensive description of locomotion process in terms of energetics and biomechanics. While the different phases of a single gait cycle are well understood, there is an increasing interest to know how the neuro-motor system controls gait form stride to stride. Indeed, it was observed that neurodegenerative diseases and aging could impact gait stability and gait parameters steadiness. From both clinical and fundamental research perspectives, there is therefore a need to develop techniques to accurately track gait parameters stride-by-stride over a long period with minimal constraints to patients. In this context, high accuracy satellite positioning can provide an alternative tool to monitor outdoor walking. Indeed, the high-end GPS receivers provide centimeter accuracy positioning with 5–20 Hz sampling rate: this allows the stride-by-stride assessment of a number of basic gait parameters – such as walking speed, step length and step frequency – that can be tracked over several thousand consecutive strides in free-living conditions. Furthermore, long-range correlations and fractal-like pattern was observed in those time series. As compared to other classical methods, GPS seems a promising technology in the field of gait variability analysis. However, relative high complexity and expensiveness – combined with a usability which requires further improvement – remain obstacles to the full development of the GPS technology in human applications.
Human herpesvirus 8 – A novel human pathogen
Authors: Edelman Daniel C
Published: September 2005

In 1994, Chang and Moore reported on the latest of the gammaherpesviruses to infect humans, human herpesvirus 8 (HHV-8) [1]. This novel herpesvirus has and continues to present challenges to define its scope of involvement in human disease. In this review, aspects of HHV-8 infection are discussed, such as, the human immune response, viral pathogenesis and transmission, viral disease entities, and the virus's epidemiology with an emphasis on HHV-8 diagnostics.
Spinal Cord NR1 Serine Phosphorylation and NR2B Subunit Suppression following Peripheral Inflammation
Authors: Caudle Robert M , Perez Federico M , Del Valle-Pinero Arseima Y , Iadarola Michael J
Published: September 2005

Background:

Spinal cord N-methyl-D-aspartate (NMDA) receptors are intimately involved in the development and maintenance of central sensitization. However, the mechanisms mediating the altered function of the NMDA receptors are not well understood. In this study the role of phosphorylation of NR1 splice variants and NR2 subunits was examined following hind paw inflammation in rats. We further examined the level of expression of these proteins following the injury.

Results:

Lumbar spinal cord NR1 subunits were found to be phosphorylated on serine residues within two hours of the induction of hind paw inflammation with carrageenan. The enhanced NR1 serine phosphorylation reversed within six hours. No phosphorylation on NR1 threonine or tyrosine residues was observed. Likewise, no NR2 subunit phosphorylation was observed on serine, threonine or tyrosine residues. An analysis of NR1 and NR2 protein expression demonstrated no change in the levels of NR1 splice variants or NR2A following the inflammation. However, spinal cord NR2B expression was depressed by the hind paw inflammation. The expression of NR2B remained depressed for more than one week following initiation of the inflammation.

Conclusion:

These data suggest that NR1 serine phosphorylation leads to an initial increase in NMDA receptor activity in the spinal cord following peripheral injury. The suppression of NR2B expression suggests compensation for the enhanced nociceptive activity. These data indicate that spinal cord NMDA receptors are highly dynamic in the development, maintenance and recovery from central sensitization following an injury. Thus, chronic pain therapies targeted to NMDA receptors should be designed for the exact configuration of NMDA receptor subunits and post-translational modifications present during specific stages of the disease.
Gonadotropin-Releasing Hormone Pulse Frequency-Dependent Activation of Extracellular Signal-Regulated Kinase Pathways in Perifused LβT2 Cells
Authors: Kanasaki Haruhiko , Bedecarrats Gregoy Y. , Kam Kyung-Yoon , Xu Shuyun , Kaiser Ursula B.
Published: September 2005

The pattern of GnRH release is associated with differential synthesis and release of LH and FSH. Using a perifusion system, we previously reported that stimulation of the LβT2 cell line with varying GnRH pulse frequencies resulted in differential stimulation of LHβ and FSHβ gene transcription, analogous to previous observations in primary gonadotropes. In the present study, we investigated the patterns of MAPK activation by GnRH and the role of MAPK in mediating the frequency-dependent effects. In static culture, ERK activation in LβT2 cells stimulated with continuous GnRH (10 nm) was maximal by 10 min and persisted for up to 6 h, with a return to basal levels by 20 h. In contrast, stimulation with continuous GnRH (10 nm) in perifused cells resulted in a more sustained activation of ERK. To investigate the effects of GnRH pulse frequency on ERK activation, perifused LβT2 cells were stimulated with pulsatile GnRH at a frequency of one pulse every 30 min or one pulse every 2 h for 20 h (10 nm, 5 min/pulse). After the final GnRH pulse, cells were lysed at frequent intervals and levels of ERK phosphorylation were measured. Under high-frequency conditions, ERK activation was maximal 10 min after the GnRH pulse and returned to baseline levels by 20 min. In contrast, under lower GnRH pulse frequency conditions, ERK activation occurred more rapidly and activation was more sustained, with a slower rate of ERK dephosphorylation. These changes resulted in different levels of nuclear phosphorylated ERK. Blockade of ERK activation abolished GnRH-dependent activation of LHβ and FSHβ transcription at both high and low pulse frequencies. These results demonstrate that in perifused LβT2 cells, distinct patterns of ERK activation/inactivation are regulated by GnRH pulse frequency, and the difference in ERK activation may be important for GnRH pulse frequency-dependent differential stimulation of LHβ and FSHβ gene expression.
Involvement of Corticotropin-Releasing Hormone- and Interleukin (IL)-6-Dependent Proopiomelanocortin Induction in the Anterior Pituitary during Hypothalamic-Pituitary-Adrenal Axis Activation by IL-1α
Authors: Chida Dai , Imaki Toshihiro , Suda Toshihiro , Iwakura Yoichiro
Published: September 2005

IL-1α/β and IL-6 are endogenous modulator of hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. Here, we show IL-1α induced a normal HPAA activation in IL-1α/β knockout (KO) and IL-6 KO mice at 1 h; however, at 6 h HPAA activation was reduced relative to wild-type mice, indicating a role for endogenous IL-1α/β and IL-6 in prolonged HPAA activation. We found that the induction of proopiomelanocortin (POMC) transcript in the anterior pituitary (AP) at 6 h in response to IL-1α was reduced in IL-1α/β KO and IL-6 KO mice, as well as in CRH KO mice, suggesting IL-1α/β, IL-6, and CRH are all required for POMC induction. The induction of CRH transcript in the paraventricular nucleus at 6 h and plasma IL-6 levels, in response to IL-1α, were reduced in IL-1α/β KO mice. Because IL-1α-induced activation of signal transducer and activator of transcription 3 in the AP was also suppressed in IL-6 KO mice, we suggest that plasma IL-6 is first induced by IL-1α, and IL-6 activates signal transducer and activator of transcription 3 in the AP, leading to the induction of POMC in concert with CRH. Our results suggest a role for IL-1α/β in the induction of POMC in the AP through the induction of two independent pathways, CRH and IL-6.
Selective Tissue Uptake of Agouti-Related Protein(82–131) and Its Modulation by Fasting
Authors: Pan Weihong , Kastin Abba J. , Yu Yongmei , Cain Courtney M. , Fairburn Tammy , Stütz Adrian M. , Morrison Christopher , Argyropoulos George
Published: September 2005

The blood concentration of agouti-related protein (AgRP), a protein related to hyperphagia and obesity, is increased in obese human and fasted lean subjects. Because there is no saturable transport system at the blood-brain barrier for circulating AgRP to reach its central nervous system target, uptake of AgRP by peripheral organs might be physiologically meaningful. Using the biologically active fragment AgRP(82–131), we determined the pharmacokinetics of its radioactively labeled tracer after iv bolus injection and compared it with that of the vascular marker albumin. AgRP enters peripheral organs at different influx rates, all of which were higher than into brain and spinal cord. At 10 min after iv injection, the radioactivity recovered in the liver, which had the fastest influx rate for AgRP, represented intact 125I-AgRP. The adrenal gland had a moderately fast uptake (but the highest initial volume of distribution), followed by the heart, lungs, and skeletal muscle. By comparison, epididymal fat, testis, and pancreas had low permeability to AgRP. Saturation of influx was determined by coadministration of excess unlabeled AgRP and was shown to be present in the liver and adrenal gland. The influx rate and initial volume of distribution did not show a linear correlation with vascular permeability or regional blood flow. AgRP uptake by the liver and epididymal fat was significantly increased by overnight fasting, whereas that by the adrenal gland was significantly decreased in fasted mice. Thus, the differential uptake of AgRP by peripheral organs could be a regulated process that is modulated by food deprivation.
Disruption of Growth Hormone Signaling Retards Early Stages of Prostate Carcinogenesis in the C3(1)/T Antigen Mouse
Authors: Wang Zhuohua , Prins Gail S. , Coschigano Karen T. , Kopchick John J. , Green Jeffrey E. , Ray Vera H. , Hedayat Samad , Christov Konstantin T. , Unterman Terry G. , Swanson Steven M.
Published: September 2005

Recent epidemiological studies suggest that elevated serum titers of IGF-I, which are, to a large degree, regulated by GH, are associated with an increase in prostate cancer risk. The purpose of the current study was to develop the first animal models to directly test the hypothesis that a normal, functional GH/IGF-I axis is required for prostate cancer progression. The GH receptor (GHR) gene-disrupted mouse (Ghr−/−), which has less than 10% of the plasma IGF-I found in GHR wild-type mice, was crossed with the C3(1)/T antigen (Tag) mouse, which develops prostatic intraepithelial neoplasia driven by the large Tag that progress to invasive prostate carcinoma in a manner similar to the process observed in humans. Progeny of this cross were genotyped and Tag/Ghr+/+ and Tag/Ghr−/− mice were killed at 9 months of age. Seven of eight Tag/Ghr+/+ mice harbored prostatic intraepithelial neoplasia lesions of various grades. In contrast, only one of the eight Tag/Ghr−/− mice exhibited atypia (P < 0.01, Fischer’s exact test). Disruption of the GHR gene altered neither prostate androgen receptor expression nor serum testosterone titers. Expression of the Tag oncogene was similar in the prostates of the two mouse strains. Immunohistochemistry revealed a significant decrease in prostate epithelial cell proliferation and an increase in basal apoptotic indices. These results indicate that disruption of GH signaling significantly inhibits prostate carcinogenesis.
Decidual Differentiation of Stromal Cells Promotes Proprotein Convertase 5/6 Expression and Lefty Processing
Authors: Tang Meiyi , Mikhailik Anatoly , Pauli Ilse , Giudice Linda C. , Fazelabas Asgerally T. , Tulac Suzana , Carson Daniel D. , Kaufman David G. , Barbier Claire , Creemers John W. M. , Tabibzadeh Siamak
Published: September 2005

Lefty/Ebaf polypeptides, novel members of the TGF-β superfamily, are involved in endometrial differentiation and embryo implantation. Recently, we showed that, during undisturbed estrous cycle, lefty is present in mouse uterine horn primarily in a precursor form. Here, we show that decidual differentiation of endometrial stroma leads to increased lefty (∼3.1- to 3.6-fold in vivo and 5- to 8-fold in vitro) and processing of its precursor primarily to its long form. This event occurs on d 5 of pregnancy, and is paralleled by proprotein convertase (PC)5/6 up-regulation (∼6-fold increase for PC5A and 3-fold increase for PC5B) in decidualized uterine horn, independent of embryo implantation. Among the known convertases, only PC5/6A processes lefty to its long form. Taken together, the findings show that decidualized differentiation of stroma, which is a prerequisite for embryo implantation, leads to processing of lefty by PC5/6A.
The Development of a Mouse Model of Ovarian Endosalpingiosis
Authors: Bristol-Gould Sarah K. , Hutten Christina G. , Sturgis Charles , Kilen Signe M. , Mayo Kelly E. , Woodruff Teresa K.
Published: September 2005

Pelvic pain is a common presenting ailment in women often linked to ovulation, endometriosis, early pregnancy, ovarian cancer, and cysts. Clear differential diagnosis for each condition caused by these varied etiologies is difficult and may slow the delivery of therapy that, in the case of ovarian cancer, could be fatal. Ovarian endosalpingiosis, a pelvic condition typified by the presence of cystic glandular structures lined by benign tubal/salpingeal epithelium, is also associated with pelvic pain in women. The exact cellular antecedents of these epithelial lined cystic structures are not known, nor is there a known link to ovarian cancer. A mouse model of ovarian endosalpingiosis has been developed by directing a dominant-negative version of the TGF-β transcription factor, Smad2, to the ovary using the Müllerian-inhibiting substance promoter (MIS-Smad2-dn). Female mice develop an ovarian endosalpingeal phenotype as early as 3 months of age. Importantly, cysts continuous with the ovarian surface epithelial have been identified, indicating that these cyst cells may be derived from the highly plastic ovarian surface epithelial cell layer. A second transgenic mouse model that causes loss of activin action (inhibin α-subunit transgenic mice) develops similar cystic structures, supporting a TGF-β/activin/Smad2 dependence in the onset of this disease.