bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Assembly in Natural and Engineered Tissues
Authors: HIRSCHI KAREN K. , SKALAK THOMAS C. , PEIRCE SHAYN M. , LITTLE CHARLES D.
Published: July 2009

Abstract: With the advent of molecular embryology and exploitation of genetic models systems, many genes necessary for normal blood vessel formation during early development have been identified. These genes include soluble effectors and their receptors, as well as components of cell‐cell junctions and mediators of cell‐matrix interactions. In vitro model systems (2‐D and 3‐D) to study paracrine and autocrine interactions of vascular cells and their progenitors have also been created. These systems are being combined to study the behavior of genetically altered cells to dissect and define the cellular role(s) of specific genes and gene families in directing the migration, proliferation, and differentiation needed for blood vessel assembly. It is clear that a complex spatial and temporal interplay of signals, including both genetic and environmental, modulates the assembly process. The development of real‐time imaging and image analysis will enable us to gain further insights into this process. Collaborative efforts among vascular biologists, biomedical engineers, mathematicians, and physicists will allow us to bridge the gap between understanding vessel assembly in vivo and assembling vessels ex vivo.
A Chemical Perspective on the Interplay Between NO, Reactive Oxygen Species, and Reactive Nitrogen Oxide Species
Authors: ESPEY MICHAEL G. , MIRANDA KATRINA M. , THOMAS DOUGLAS D. , XAVIER SANDHYA , CITRIN DEBORAH , VITEK MICHAEL P. , WINK DAVID A.
Published: July 2009

Abstract: Nitric oxide (nitrogen monoxide, NO) plays a veritable cornucopia of regulatory roles in normal physiology. In contrast, NO has also been implicated in the etiology and sequela of numerous neurodegenerative diseases that involve reactive oxygen species (ROS) and nitrogen oxide species (RNOS). In this setting, NO is often viewed solely as pathogenic; however, the chemistry of NO can also be a significant factor in lessening injury mediated by both ROS and RNOS. The relationship between NO and oxidation, nitrosation, and nitration reactions is summarized. The salient factors that determine whether NO promotes, abates, or interconnects these chemistries are emphasized. From this perspective of NO chemistry, the type, magnitude, location, and duration of either ROS or RNOS reactions may be predicted.
Nitric Oxide in Liver Diseases
Authors: HON WEI MIN , LEE KANG HOE , KHOO HOON ENG
Published: July 2009

Abstract:Research on the free radical gas, nitric oxide (NO), during the past twenty years is one of the most rapid growing areas in biology. NO seems to play a part in almost every organ and tissue. However, there is considerable controversy and confusion in understanding its role. The liver is one organ that is clearly influenced by NO. Acute versus chronic exposure to NO has been associated with distinct patterns of liver disease. In this paper we review and discuss the involvement of NO in various liver diseases collated from observations by various researchers. Overall, the important factors in determining the beneficial versus harmful effects of NO are the amount, duration, and site of NO production. A low dose of NO serves to maximize blood perfusion, prevent platelet aggregation and thrombosis, and neutralize toxic oxygen radicals in the liver during acute sepsis and reperfusion events. NO also demonstrates antimicrobial and antiapoptosis properties during acute hepatitis infection and other inflammatory processes. However, in the setting of chronic liver inflammation, when a large sustained amount of NO is present, NO might become genotoxic and lead to the development of liver cancer. Additionally, during prolonged ischemia, high levels of NO may have cytotoxic effects leading to severe liver injury. In view of the various possible roles that NO plays, the pharmacologic modulation of NO synthesis is promising in the future treatment of liver diseases, especially with the emergence of selective NO synthase inhibitors and cell‐specific NO donors.
Nitric Oxide (NO) and Convulsions Induced by Pentylenetetrazol
Authors: JELENKOVIĆ ANKICA , JOVANOVIĆ MARINA , NINKOVIĆ MILICA , MAKSIMOVIĆ M. , BOKONJIĆ D. , BOŠKOVIĆ B.
Published: July 2009

Abstract: Data about the role of nitric oxide (NO) in epileptogenesis are contradictory. It is found to exert both proconvulsant and anticonvulsant effects. In an attempt to elucidate the role of NO in seizures, male Wistar rats were treated intraperitoneally by pentylenetetrazol (PTZ) (60, 80, and 100 mg/kg) and by a nitric oxide synthase antagonist, N‐omega‐nitro‐l‐arginine‐methyl‐ester (l‐NAME) (10, 40, and 70 mg/kg), applied before PTZ. The time to onset and incidence of forelimb dystonia (FLD), generalized clonic convulsions (GCC), clonic‐tonic convulsions (CTC), and mortality were recorded. The most successful convulsive response and mortality prevention were found in PTZ (80 mg/kg)‐treated groups, where l‐NAME (70 mg/kg) decreased the incidence by 29, 50, 67 (p= 0.052), and 50%, respectively, and significantly prolonged the time to onset, except that for mortality. Unexpectedly, l‐NAME (40 mg/kg) increased incidence of GCC and mortality by 16%, similar to l‐NAME (10 mg/kg) in PTZ (60 mg/kg)‐treated groups, where GCC, CTC, and mortality increased by 14, 14, and 28%, respectively. Convulsive latency was prolonged in some PTZ (100 mg/kg) +l‐NAME (40 and 70 mg/kg)‐treated groups. In the experimental model and protocol used, it is concluded that (1) the effects of NO are l‐NAME‐ and PTZ‐dose dependent; (2) clonic‐tonic convulsions are more strongly influenced by NO than limbic, probably because of PTZ limbic structure overstimulation; (3) l‐NAME decreases the incidence of CTC and prolongs FLD, GCC, and CTC times to onset, indicating that NO acts as a proconvulsant; and (3) increased GCC, CTC, and mortality that suggests an anticonvulsant effect of NO needs further investigation.
Protective Effects of Glial Cell Line‐Derived Neurotrophic Factor in Ischemic Brain Injury
Authors: WANG Y. , CHANG C. F. , MORALES M. , CHIANG Y. H. , HOFFER J.
Published: July 2009

Abstract: Glial cell line‐derived neurotrophic factor (GDNF), a member of the transforming growth factor‐β (TGF‐β) superfamily, has been shown to have trophic activity on dopaminergic neurons. Recent studies indicate that GDNF can protect the cerebral hemispheres from damage induced by middle cerebral arterial ligation. We found that such neuroprotective effects are mediated through specific GDNF receptor alpha‐1 (GFRα1). Animals with a deficiency in GFRα‐1 have less GDNF‐induced neuroprotection. Ischemia also enhances nitric oxide synthase (NOS) activity, which can be attenuated by GDNF. These.data suggest that GDNF can protect against ischemic injury through a GFRα‐1/NOS mechanism. We also found that the receptor for GDNF, GFRα1, and its signaling moiety c‐Ret were upregulated, starting immediately after ischemia. This upregulation suggests that activation of an endogenous neuroprotective mechanism occurs so that responsiveness of GDNF can be enhanced at very early stages during ischemia.
Perspectives on the Relationship of Adrenal Steroids to Rheumatoid Arthritis
Authors: MASI ALFONSE T. , CHATTERTON ROBERT T. , ALDAG JEAN C. , MALAMET RAYMOND L.
Published: July 2009

Abstract: An expanded model of RA is presented that incorporates cumulative multifactorial processes operating over a prolonged physiological phase prior to initial clinical manifestations. During this phase, progressive imbalances in the homeostasis of core neuroendocrine, immunological, and microvascular systems are believed to occur. Normal adrenal function plays an essential role in helping to maintain homeostasis of core systems in health. In RA, chronic adrenal hypocompetence is suspected to occur in a minority subset of females who have younger clinical onset and males who have associated low serum testosterone levels. Chronic, relative glucocorticoid insufficiency is believed to contribute to development of inflammatory manifestations in RA patients. Androgenic deficiencies, particularly of gonadal origin in males, may also contribute to RA, particularly its decreased anabolic features. Precise influences of hypocompetent adrenal steroid function on long‐term modeling of the immunological compartment and control of microvascular activation processes are not well understood. These complex mechanisms need to be elucidated for better understanding of the physiopathogenesis of RA. Nevertheless, at a clinical level, sufficient data are currently available to endorse further controlled studies of early clinical onset patients and prospective investigations to determine more definitively the roles of adrenal (and gonadal) steroids in subsets of RA patients and unaffected susceptible persons in the population.
Fifty Years of Experience with Cortisone Therapy in the Study and Treatment of Rheumatoid Arthritis
Authors: NEECK GUNTHER
Published: July 2009

Abstract: In 1948 the U.S. rheumatologist Phillip S. Hench administered cortisone for the first time to a patient with rheumatoid arthritis (RA), thereby discovering the therapeutic effects of glucocorticoids. He published this observation together with Kendall, Slocumb, and Polly in 1949, and they received, along with Reichstein and Kendall, the Nobel Prize in Medicine or Physiology in 1950. However, as early as 1949, he rejected the idea that steroids were of etiological significance for RA, and instead stressed their unique place as a tool for pathophysiological research. The discovery of the glucocorticoid receptor and its genomic effects disclosed that there are no qualitative differences between the effects of endogenous cortisol and exogenously applied synthetic glucocorticoids, since all effects are transmitted via the same receptor. Later came the discovery that the hypothalamo‐pituitary‐adrenal axis is stimulated by cytokines after activation of the immune system. Glucocorticoids are not only the most effective antiphlogistic and immune‐suppressive substances with instant effect, but they also show, with low‐dosage long‐term treatment, clear antiproliferative effects on the cartilage and bone destroying pannus in RA. Little is still known about the precise mechanisms of actions of glucocorticoids in general, and specifically when rheumatic autoimmune diseases are involved. The high effectiveness of these substances and their direct effects via the genomic glucocorticoid receptor allows us to anticipate that uncovering their mechanisms of action will shed deeper insight into the pathomechanisms of these diseases. The use of TNFα blockers in the treatment of rheumatoid arthritis and Crohn's disease, with their dramatic immediate effects, comparable with those of the glucocorticoids but without the side effects of the latter, points us in that direction.
Glucocorticoids in Rheumatoid Arthritis
Authors: BIJLSMA JOHANNES W.J. , VAN EVERDINGEN AMALIA A. , HUISMAN MARGRIET , DE NIJS RON N.J.T.L. , JACOBS JOHANNES W.G.
Published: July 2009

Abstract: Recently, four prospective placebo‐controlled studies have further evaluated the disease‐modifying properties of glucocorticoids in the treatment of rheumatoid arthritis. These studies irrefutably show that the use of (low) doses of glucocorticoids leads to a significant retardation of the progression of erosions, especially in early rheumatoid arthritis. This effect on erosions seems more impressive and probably more persistent than the well‐known relief during low‐dose glucocorticoid therapy of symptoms, such as pain, stiffness, and joint scores. The management of the (side) effects of glucocorticoids on bone has clearly improved in the last years. These two developments lead to a further optimizing of glucocorticoid treatment in patients with rheumatoid arthritis.
Corticotropin‐Releasing Hormone Signaling in Synovial Tissue Vascular Endothelium Is Mediated through the cAMP/CREB Pathway
Authors: McEVOY ALICE N. , BRESNIHAN BARRY , FITZGERALD OLIVER , MURPHY EVELYN P.
Published: July 2009

Abstract: Modulation of locally produced corticotropin‐releasing hormone (CRH) is a component of the cytokine network in human inflammatory arthritis. CRH signaling, through the CRH‐receptor subtype R1α, may play a role in both vascular changes and pathologic mechanisms associated with joint inflammation. Furthermore, the peripheral actions of CRH may be mediated in part through the NURR subfamily of nuclear orphan receptors. The aim of this study was to establish the signaling mechanisms through which CRH receptor‐mediated responses contribute to gene regulation in inflamed synovial vasculature. Immunohistochemical analysis of serial rheumatoid arthritis (RA) tissue sections demonstrates CRH and NURR1 expression in the synovial lining layer, subsynovial lining layer, and the vascular endothelium. The identical pattern of immunolocalization confirms that NURR1 is produced at the same synovial sites shown to produce CRH. The distribution of specific NURR1 staining on the synovial vasculature parallels that observed for CRH‐R1 expression. Using primary synovial tissue endothelial cells, we demonstrate that CRH induces specific CREB‐1 and ATF‐2 binding to the NURR1 promoter. We further provide evidence that CRH signaling can be mimicked by activation of cAMP/PKA/CREB using forskolin in primary human microvascular endothelial cells. These data indicate that the CRH receptor‐dependent inflammatory response in synovial tissue endothelium is mediated through the cAMP/CREB signaling pathway.
Relationships between Glucocorticoids and Gonadal Steroids in Rheumatoid Arthritis
Authors: DA SILVA JOSÉ ANTÓNIO P.
Published: July 2009

Abstract: Gender and sex hormones are strongly related to the incidence and progression of autoimmune rheumatic diseases. Although sex steroids have been shown to have direct effects on the immune system, their influence in vivo may be mediated via interactions with third party systems including the hypothalamic‐pituitary‐adrenal axis. Such interactions are well demonstrated in experimental animals. In humans, there is increasing, although indirect, evidence that these interactions also occur. Possible interactions at the cell and gene level, with mutual antagonism or synergy between cortico‐ and gonadal steroids, open new exciting hypotheses that await clarification.
Androgen Deficiency, Meibomian Gland Dysfunction, and Evaporative Dry Eye
Authors: SULLIVAN DAVID A. , SULLIVAN BENJAMIN D. , EVANS JAMES E. , SCHIRRA FRANK , YAMAGAMI HIROKO , LIU MENG , RICHARDS STEPHEN M. , SUZUKI TOMO , SCHAUMBERG DEBRA A. , SULLIVAN ROSE M. , DANA M. REZA
Published: July 2009

Abstract: Objective. We have recently discovered that women with primary and secondary Sjögren's syndrome are androgen‐deficient. We hypothesize that this hormone insufficiency contributes to the meibomian gland dysfunction, tear film instability, and evaporative dry eye that are characteristic of this autoimmune disorder. If our hypothesis is correct, we predict: (1) that androgens regulate meibomian gland function, control the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear film's lipid layer; and (2) that androgen deficiency, due to an attenuation in androgen synthesis (e.g., during Sjögren's syndrome, menopause, aging, complete androgen‐insensitivity syndrome [CAIS] and anti‐androgen use), will lead to meibomian gland dysfunction and evaporative dry eye. The following studies were designed to test these predictions. Methods. Experimental procedures included clinical studies, animal models, and histological, biochemical, molecular biological, and biomedical engineering techniques. Results. Our results demonstrate that: (1) androgens regulate the meibomian gland. This tissue contains androgen receptor mRNA, androgen receptor protein within acinar epithelial cell nuclei, and Types 1 and 2 5α‐reductase mRNAs. Moreover, androgens appear to modulate lipid production and gene expression in mouse and/or rabbit meibomian glands; and (2) androgen deficiency may lead to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, tear film instability, and evaporative dry eye. Thus, we have found that anti‐androgen therapy in men is associated with meibomian gland disease, a decreased tear film breakup time, and functional dry eye. Furthermore, we have discovered that androgen receptor dysfunction in women with CAIS is associated with meibomian gland changes and a significant increase in the signs and symptoms of dry eye. Of interest, we have also found that androgen deficiency is associated with significant and striking alterations in the neutral and polar lipid patterns of human meibomian gland secretions. Conclusions. Our findings show that the meibomian gland is an androgen target organ and that androgen deficiency may promote meibomian gland dysfunction and evaporative dry eye. Overall, these results support our hypothesis that androgen deficiency may be an important etiologic factor in the pathogenesis of evaporative dry eye in women with Sjögren's syndrome.
Post‐Menopause is the Main Risk Factor for Developing Isolated Pulmonary Hypertension in Systemic Sclerosis
Authors: SCORZA RAFFAELLA , CARONNI MONICA , BAZZI SONIA , NADOR FILIPPO , BERETTA LORENZO , ANTONIOLI RITA , ORIGGI LAURA , PONTI ALESSANDRA , MARCHINI MAURIZIO , VANOLI MASSIMO
Published: July 2009

Abstract: In scleroderma patients, isolated pulmonary hypertension (PHT) has been associated with selected HLA haplotypes, severe impairment of the diffusing capacity for carbon monoxide and the diagnosis of CREST. Most patients with CREST have a late‐age onset of the disease, corresponding to the perimenopausal or postmenopausal period. We conducted a retrospective cohort study to determine the role of post‐menopause and of the other known clinical and biological markers in the development of isolated pulmonary hypertension in Italian patients with systemic sclerosis. 189 female patients with scleroderma who had no ecographic signs of pulmonary hypertension (PHT) and radiographic signs of lung fibrosis at the first visit and did not develop significant pulmonary fibrosis during the observation time were included. Sixty‐three out of 189 patients (33.3%) presented isolated pulmonary hypertension. A severe impairment of diffusing capacity for carbon monoxide at admission was found to be an early predictive element for its development. An increased risk was associated with postmenopausal condition (RR= 5.2, p= 0.000), CREST syndrome (RR= 2.8, p= 0.001) and haplotype HLA‐B35 (RR= 2.8; p= 0.002). A significant positive interaction between postmenopausal condition and either HLA‐B35 (RR= 15.2; p= 0.000) or the diagnosis of CREST (RR= 14.1; p= 0.000) was found. Postmenopausal condition alone or in combination with HLA‐B35 and CREST syndrome is the main risk‐factor for developing primary pulmonary hypertension in scleroderma patients. This suggests that hormonal replacement therapy could play a role in preventing isolated PHT in patients with systemic sclerosis.
Melatonin in Rheumatoid Arthritis
Authors: MAESTRONI GEORGES J.M. , SULLI ALBERTO , PIZZORNI CARMEN , VILLAGGIO BARBARA , CUTOLO MAURIZIO
Published: July 2009

Abstract: The pineal neurohormone melatonin is widely recognized as exerting important immunoenhancing effects that act on specific receptors in immunocompetent cells. This action results in stimulation of cytokine production in lymphocytes and macrophages. Here we report that the nocturnal plasma concentration of melatonin in rheumatoid arthritis (RA) patients is higher than in healthy controls. Furthermore, melatonin is present in the synovial fluid of RA patients and synovial macrophages express a specific binding site. We suggest that melatonin may exert a disease‐promoting role in RA.
Immunopathogenesis of Rheumatic Diseases in the Context of Neuroendocrine Interactions
Authors: WAHLE M. , KRAUSE A. , PIERER M. , HÄNTZSCHEL H. , BAERWALD C.G. O.
Published: July 2009

Abstract: Growing evidence supports the hypothesis that alterations of the stress response and interactions between the neuroendocrine and immune systems contribute to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA). In particular, the hypothalamus‐pituitary‐adrenal (HPA) axis and the autonomic nervous system (ANS) are of special interest. Polymorphisms of the corticotropin‐releasing hormone (CRH)‐regulating region have been described recently. These polymorphisms are differentially distributed in RA patients and healthy subjects of various ethnic origin, thus supporting the hypothesis that they represent a new genetic marker for RA susceptibility. The decreased expression of β2‐adrenergic receptors (β2‐R) on lymphatic cells in rheumatic diseases like RA, together with an impaired influence of catecholamines on immune function in these patients, further underlines the concept of a dysfunction of the ANS in rheumatic diseases. Results from work in this field will provide more insight into the pathogenesis of RA and help to establish novel therapies for this chronic rheumatic disease.
Neurological and Neuroendocrine‐Cytokine Inter‐relationship in the Antiphospholipid Syndrome
Authors: CHAPMAN JOAB , SHOENFELD YEHUDA
Published: July 2009

Abstract: Although many neurological deficits have been described in the antiphospholipid syndrome (APS), only stroke is well established and accepted as a diagnostic criterion in the disease. We presently review clinical data obtained from large series of cases regarding stroke, dementia, epilepsy, chorea, migraine, white‐matter disease, and behavioral changes in APS, or linked‐to‐laboratory criteria such as antiphospholipid antibodies (aPL). The contribution of animal models to our understanding of these manifestations of APS is stressed, especially regarding the cognitive and behavioral aspects for which we have established model systems in the mouse. These models utilize immunization of mice with β2‐glycoprotein1, a central autoantigen in APS, which induces persistent high levels of aPLs. These mice develop hyperactive behavior after a period of four months, as well as deficits in learning and memory, and are potentially valuable as a system in which to study the pathogenesis and treatment of cognitive and behavioral aspects of APS. We have developed another model, in which IgGs from APS patients induce depolarization of brain synaptoneurosomes, and which may serve as a model for the pathogenesis of epilepsy in APS. Hormonal changes are another potential CNS manifestation of APS and this may be potentially linked to the systemic and central effects of cytokines such as interleukin‐3. Better understanding of the link between APS and neurological or neuroendocrine manifestations other than stroke will reveal whether they can be used as clinical criteria for the diagnosis of APS and, it is hoped, lead to better treatment.
Osteoporosis with Underlying Connective Tissue Disease
Authors: PRASAD ROOPA , DE SILVA MALCOLM
Published: July 2009

Abstract: A 44‐year‐old male was initially seen by dermatologists, who noted an erythematous rash on sun‐exposed areas, the back, shoulders, and upper arms. There was associated muscle weakness and significant weight loss. Investigation revealed mildly raised aspartate and alanine transaminases but normal creatine kinase. Inflammatory indices and antinuclear antibodies (ANAs) were normal. Biopsy of the rash was reported as consistent with either dermatomyositis (DM) or acute lupus erythematosus. A diagnosis of DM was made, and prednisolone was given with improvement of the rash but deteriorating myopathy. The patient was referred to the rheumatology department, and further history revealed multiple vertebral fractures after falling from standing height; these had occurred six months prior to starting steroids. Besides smoking he had no other risk factors for osteoporosis. Examination showed normal muscle strength, no muscle tenderness, and no joint abnormality. Repeat muscle enzymes were normal, and ANAs were now 1 : 100, but dsDNA antibodies and extractable nuclear antigens were normal. Investigations for osteoporosis revealed a hypergonadotrophic hypogonadism picture. Further examination indicated scanty pubic and auxiliary hair, small testicles, and mild gynecomastia. He is married, though has no children of his own. The hormonal profile raised the possibility of Klinefelter's syndrome, which was subsequently confirmed with karyotyping of 47 XXY. Hypogonadism has been established as a cause of osteoporosis in males, and in this case would explain the occurrence of fractures in the absence of other major risk factors. Systemic lupus erythematosus has been recognized in association with Klinefelter's syndrome; in view of the normal muscle enzymes, his rash is most likely due to acute discoid lupus with androgen deficiency causing muscle weakness.
Serum Osteocalcin Levels in Premenopausal Rheumatoid Arthritis Patients
Authors: SERIOLO BRUNO , FERRETTI VALENTINO , SULLI ALBERTO , CARATTO ELISA , FASCIOLO DANIELA , CUTOLO MAURIZIO
Published: July 2009

Abstract: The objective of this study was to assess the occurrence of generalized bone loss in rheumatoid arthritis (RA) patients and to evaluate the factors influencing bone loss, in particular, the usefulness of bone turnover markers. Twenty‐five premenopausal patients (mean age, 40 × 5 years) with active RA were compared with 27 age‐matched premenopausal patients with RA but without active disease and 30 age‐matched healthy premenopausal controls. Serum concentrations of osteocalcin, intact parathyroid hormone (PTH), spot urine concentrations of crosslinked N‐telopeptidases of type 1 collagen (NTX), and deoxypyridinoline (DPD) were detected by ELISA and radioimmunoassay. Serum osteocalcin levels were found to be significantly lower (p < 0.001) in patients with active RA compared with patients without active RA and controls. Similarly, serum intact PTH was significantly lower (p < 0.01) in patients with active RA than in patients with RA without active disease and controls. Spot urine concentrations of NTX and DPD were significantly higher (p < 0.01) in active RA patients than in patients with nonactive RA and controls. Positive correlations between osteocalcin and marker of disease activity were found to be significant (p < 0.01). There were no significant correlations between serum intact PTH, urine concentrations of NTX and DPD, and markers of inflammation. This study suggests that generalized bone loss occurs in active RA and is characterized by an evident bone resorption correlated with the high levels of inflammation.
Reinventing the Wheel of Cyclic AMP
Authors: CHIN KHEW‐VOON , YANG WENG‐LANG , RAVATN ROALD , KITA TSUNEKAZU , REITMAN ELENA , VETTORI DAVID , CVIJIC MARY ELLEN , SHIN MICHAEL , IACONO LISA
Published: July 2009

Abstract: Mechanisms of cAMP signal transduction have been thoroughly investigated for more than 40 years. From the binding of hormonal ligands to their receptors on the outer surface of the plasma membrane to the cytoplasmic activation of effectors, the ensuing cAMP signaling cascades and the nuclear gene regulatory functions, coupled with the structural elucidation of the cAMP‐dependent protein kinase (PKA) and in vivo functional characterizations of each of the components of PKA by homologous recombination gene targeting, our understanding of cAMP‐mediated signal transduction has reached its pinnacle. Despite this trove of knowledge, some recent findings have emerged that suggest hitherto novel and alternative mechanisms of cAMP action that could increase the signaling bandwidth of cAMP and PKA in cell growth and transcriptional regulation. This article attempts to review some of these novel and unconventional mechanisms of cAMP and PKA signaling, and to generate further enthusiasm in investigating and validating these new frontiers of the cAMP signal transduction pathway.
Protein Kinase A as Target for Novel Integrated Strategies of Cancer Therapy
Authors: TORTORA GIAMPAOLO , CIARDIELLO FORTUNATO
Published: July 2009

Abstract: We have studied the role of protein kinase A (PKA) in neoplastic transformation, apoptosis, and angiogenesis and its relationship with other signaling molecules, as a basis for developing novel therapeutic strategies. We demonstrated the involvement of PKA type I (PKA‐I) in the transduction of mitogenic signals from different sources and demonstrated functional and structural interactions between PKA‐I and the activated epidermal growth factor receptor (EGFR). We contributed to the identification and development of several selective inhibitors of PKA‐I, such as 8‐Cl‐cAMP and a hybrid DNA/RNA antisense oligonucleotide of a novel class (AS‐PKA‐I) and of EGFR, including mAbC225 and ZD1839 (Iressa). All these agents have been investigated in cancer patients. We demonstrated the therapeutic potential of the combined blockade of PKA‐I and EGFR, reporting a synergistic antitumor effect when their inhibitors are used in combination. We have also shown that PKA‐I and EGFR inhibitors are able to cooperate with selected class of cytotoxic drugs and with ionizing radiation, causing a synergistic inhibition of tumor growth in vitro and in vivo, accompanied by inhibition of expression of growth and angiogenic factors and by suppression of vessel production. Moreover, PKA‐I is implicated in a bcl‐2‐dependent apoptotic pathway, and we have recently reported a cooperative antitumor and proapoptotic effect of AS‐PKA‐I in combination with an AS‐bcl‐2. Finally, we have shown that AS‐PKA‐I also has antitumor and antiangiogenic effects following oral administration and that they can be greatly enhanced in combination with oral ZD1839 and oral taxanes.
Protein Kinase A Signaling
Authors: ROBINSON‐WHITE AUDREY , STRATAKIS CONSTANTINE A.
Published: July 2009

Abstract: Protein kinase A (PKA) signaling, in “classic” endocrine cell functioning, is known to mediate cAMP effects, generated through adenylate cyclase as a response to the activation of G protein‐coupled receptors (GPCRs). This signaling system is highly versatile; its flexibility is supported by a number of adenylate cyclases, four PKA regulatory and three catalytic subunits, and several phosphodiesterases that close the negative feedback loop of cAMP generation, most molecules that are expressed in a tissue‐specific manner. A central question, however, remains: how do the hundreds of GPCRs mediate their specific effects? Tissue specificity of the expression of the various components of the PKA system, albeit necessary, cannot be the only answer. It helps more to view PKA as a central hub that interacts with a variety of other signaling pathways in endocrine cells, not only mediating but also communicating cAMP effects to the mitogen‐activated protein kinase (MAPK), protein kinase C and B (PKC and PKB/Akt, respectively). The net result of these complex interactions, evidence for which is reviewed in this chapter, is what we know as “cAMP effects.” It is, perhaps, because of this complexity that investigations of PKA signaling in vivo and in vitro often give contradictory results and are difficult to interpret.
Yankey's Dilemma
Authors: MURPHREE MICHAEL
Published: July 2009

Abstract: The past 20 years have seen a shift in conservation approaches to realize the importance of people in conservation and wildlife management (CWM). To this extent, in most conservation circles the concept of community involvement is no longer debated. The following factors have influenced the growth of CWM, especially in Africa: (i) recent developments in postcolonial governments have made them unable to manage and control the use of natural resources in the restrictive manner mandated by the legislation of the colonial past still in place; (ii) successes, particularly in southern Africa, of approaches that involved devolution of greater access rights and responsibilities to communities have led to these approaches being used by other countries; (iii) donor agencies, encouraged by the success of these approaches, have allocated more of their resources to community‐based projects; and (iv) changes in international perceptions have been heavily influenced by the growing voice of the “South” in international fora. While there has been some success, there have also been failures. In Ghana, there has been considerable effort to develop programs that incorporate community aspirations into specific objectives; one inherent problem with these programs—not exclusive to Ghana—is the tendency for conservation programs to try to fit community aspirations into conservation objectives as opposed to finding ways of using conservation to help fulfill community aspirations. When community‐based programs fail to recognize this, they are generally unable to deliver on their expected outputs. Some critics have used this to dismiss the community approach, which poses a dangerous reversion to a paradigm that has significantly failed in Africa, and much of the developing world, especially in regard to wildlife outside of protected areas.
Multiple Species Production Systems
Authors: UHART MARCELA , MILANO FERNANDO
Published: July 2009

Abstract: Latin America (LA) is suffering the environmental consequences of worldwide increased productivity and agricultural expansion as well as strong economic restrictions. To survive, LA landowners must turn to higher income products and/or increase productivity. Alternatives are few. But while intensification relies on unaffordable and nonsustainable subsidies, diversification is solely dependent on improved management of available resources. Diversified, multiple‐species production systems (MSPS) add wildlife use to traditional production systems, promoting economic and ecological stability. We present examples of MSPS in Latin America. Although results are technically encouraging, their future sustainability is threatened by: i) local subvaluation of wildlife and ii) restricted international markets.
Wildlife and Pastoral Society—Shifting Paradigms in Disease Control
Authors: KOCK RICHARD , KEBKIBA BIDJEH , HEINONEN RISTO , BEDANE BERHANU
Published: July 2009

Abstract:The dramatic changes in the human and animal populations in Africa over the last century demand the re‐examination of priorities and policies. The introduction of developed medical and other human technologies into the continent has contributed to increases in population and a rapid, unsustainable increase in the utilization of resources. This in turn has led to the destruction of flora and fauna on an unprecedented scale with little real improvement in the human condition. One factor in this has been the increase in livestock in line with human demographic growth, as it is a traditional livelihood of many African peoples. In recent years the growth in livestock populations has slowed owing to a cycle of degradation and disease, affecting especially traditional pastoral systems with a close physical association between people, livestock, and wild animals. Pathogens benefit hugely from the dynamic state created by animal migration, although to some extent the livestock and certainly wildlife show considerable tolerance to this. One of the grave economic consequences of this increase in disease has been collapse of the export trade. In order for Africa to fully benefit and share in world trade, the zoosanitary situation must show improvement. To do this without destroying the natural resource base and traditional pastoral systems, will require a careful, future‐oriented land‐use policy along ecologically sound criteria. Export livestock will have to be maintained in areas, probably free of ruminant wildlife, with strict veterinary controls. If this can be balanced with sufficient areas retained for traditional pastoralism and wildlife, with perhaps the main income from recreational tourism and local consumption, the benefits will be considerable. The answer may be community‐based, low‐cost, decentralized health systems for pastoral communities, with less stringent sanitary mandates, a private/parastatal sector servicing, with specialization in wildlife, dairy or export livestock and a central veterinary policy, related to surveillance and monitoring using small well‐resourced professional teams to carry out regulatory and statutory duties.
Emerging Morbillivirus Infections of Marine Mammals
Authors: SALIKI JEREMIAH T. , COOPER EMILY J. , GUSTAVSON JONATHAN P.
Published: July 2009

Abstract: In the last 13 years, four viruses belonging in the Morbillivirus genus of the Paramyxoviridae family have emerged as significant causes of disease and mortality in marine mammals. The viruses involved are canine distemper virus (CDV) in seals and polar bears, dolphin morbillivirus (DMV) and porpoise morbillivirus (PMV) in cetaceans, and phocine distemper virus (PDV) in pinnipeds. The two cetacean morbilliviruses (DMV and PMV) are now considered to be the same viral species, named cetacean morbillivirus (CMV). All three morbillivirus species (CDV, CMV, and PDV) are genetically and antigenically related and cross‐react in various serological tests. The diagnosis of morbilliviral infections in marine mammal specimens poses two challenges. First, various marine mammal species can be infected by more than one closely related but distinct morbilliviruses, making definitive virus identification unattainable by classical virology methods. Second, standard immunological reagents such as anti‐species conjugates are unavailable for most marine mammal species, rendering definitive serological diagnosis difficult by classical serological techniques. The objectives of this study were to develop two diagnostic approaches that alleviate these difficulties, providing simple, rapid, and cost‐effective diagnostic methods. For nucleic acid detection, reverse transcription‐polymerase chain reaction (RT‐PCR) and restriction endonuclease digestions were used to differentiate the three viruses. For antibody detection, a monoclonal antibody‐based competitive enzyme‐linked immunosorbent assay (c‐ELISA) was used on sera from several species, thus avoiding the need for multiple anti‐species enzyme conjugates.
Molecular Immunogenetics in Susceptibility to Bovine Dermatophilosis
Authors: MAILLARD JEAN‐CHARLES , CHANTAL ISABELLE , BERTHIER DAVID , THEVENON SOPHIE , SIDIBE ISSA , RAZAFINDRAIBE HANTA
Published: July 2009

Abstract: To identify molecular genetic markers of resistance or susceptibility to dermatophilosis in cattle, we used a functional candidate gene approach to analyze the DNA polymorphisms of targeted genes encoding molecules implicated in known mechanisms of both nonspecific and specific immune responses existing in the pathogen/host interface mechanisms. The most significant results were obtained within the Major Histocompatibility Complex (MHC) where the BoLA‐DRB3 and DQB genes encode molecules involved in the antigen presentation to T cell receptors. A unique BoLA class II haplotype, made up of one DRB3 exon 2 allele and one DQB allele, highly correlates with the susceptibility character (P < 0.001). This haplotype marker of susceptibility was also found and validated in other bovine populations. A eugenic marker‐assisted selection was developed in the field by eliminating only the animals having this haplotype. The disease prevalence was thereby reduced from 0.76 to 0.02 over 5 years. A crossbreeding plan is in progress to study the genetic transmission of the genotypic and phenotypic characters of susceptibility to dermatophilosis. In conclusion, we discuss several hypotheses at the molecular and cellular levels to better define the exact role of the MHC molecules in disease control and to answer the question: How is MHC diversity selectively maintained by natural selection imposed by pathogens?
Basis for the Extraordinary Genetic Stability of Anthrax
Authors: KIEL JOHNATHAN L. , PARKER JILL E. , GIFFORD HOMER , STRIBLING LUCILLE J.V. , ALLS JOHN L. , MELTZ MARTIN L. , McCREARY R. PATRICK , HOLWITT ERIC A.
Published: July 2009

Abstract: Over 500 isolates of anthrax bacillus from around the world represent one of the most genetically homogeneous microbes. There are three possibilities for this genetic stability: (1) anthrax has an extraordinarily high fidelity repair system, (2) genetic damage to anthrax is usually lethal, and/or (3) a highly demanding and selective process exists in its environment that is necessary for the completion of its life cycle. Using probes made from genes selected by growth of an Escherichia coli expression vector Bacillus anthracis library on hypertrophic high nitrate concentration medium, genes unique to B. anthracis were isolated. High nitration conditions generated stable chromosomal mutants that displayed altered morphology and life‐cycle progression. Therefore, life‐cycle progression connected to nitration, associated with host inflammatory response, selects for mutants that show life‐cycle progression tightly coupled to progression of the inflammatory response to anthrax. Significant variation from this coupled progression leads to failure of anthrax to complete its life‐cycle at the death of its host.
Major Outer Membrane Proteins of Ehrlichia ruminantium Encoded by a Multigene Family
Authors: VAN HEERDEN H. , COLLINS N. E. , ALLSOPP M.T.E. P. , ALLSOPP B. A.
Published: July 2009

Abstract: Immune responses of infected animals and humans have been reported to be directed against variable outer membrane proteins of Ehrlichia species that are encoded by polymorphic multigene families. In Ehrlichia (= Cowdria) ruminantium, two immunodominant proteins have been identified, namely major antigenic protein 1 (MAP1) and open reading frame 2 (ORF2). The aim of the present study was to identify additional map1‐like genes in the E. ruminantium genome. A 12 kb clone that hybridized with the map1 probe was amplified using long template PCR. The PCR product was partially digested, cloned, and sequenced. Four map1‐like genes are located in tandem, namely map1−1 (orf2) and map1−2 upstream of map1 as well as map1+1 downstream of map1. A large ORF (2.4 kb) at the 3′ end is homologous to secA genes of other organisms. The sequence data in this study support other findings that outer membrane proteins are located in tandem and are encoded by a polymorphic multigene family.
Amino Acid Content of Cell Cultures Infected with Cowdria ruminantium Propagated in a Protein‐free Medium
Authors: JOSEMANS A. I. , ZWEYGARTH E.
Published: July 2009

Abstract: The in vitro culture of Cowdria ruminantium, the causative agent of heartwater in domestic ruminants, was first achieved in 1985. Culture media were usually supplemented with serum and tryptose phosphate broth, both undefined components, contributing to great variability. Recently, we reported about the propagation of stocks of C. ruminantium in a protein‐free culture medium referred to as SFMC‐23, which is chemically fully defined. To clarify whether the amino acid composition in SFMC‐23 is adequate for the in vitro propagation of Cowdria, the Welgevonden stock was propagated in SFMC‐23 medium. After a 3‐day culture period, samples were taken from uninfected and infected bovine endothelial cell cultures. They were analyzed for free amino acids by the Pico Taq reversed‐phase HPLC precolumn derivatization method. Eighteen different amino acids were examined. A considerable decrease in concentration was observed with proline (29%) and glutamine (62%). Further dramatic changes were observed with amino acids which accumulated in the culture medium: aspartic acid, serine, asparagine, tryptophane, glycine, and alanine. The concentration of alanine increased by approximately 660%. The concentrations of all other amino acids analyzed remained within a 25% range, either increasing or decreasing. These results suggest that only glutamine may run short during in vitro cultivation. It seems more likely that accumulation of various amino acids may impact negatively on long‐term Cowdria propagation.
Genetic Immunization with Ehrlichia ruminantium GroEL and GroES Homologues
Authors: PRETORIUS ALRI , VAN STRIJP F. , BRAYTON K. A. , COLLINS N. E. , ALLSOPP B. A.
Published: July 2009

Abstract: Ehrlichia ruminantium GroEL and GroES genes were amplified from E. ruminantium Welgevonden genomic DNA and were cloned into genetic vaccine and Salmonella expression vectors. These constructs were used to inoculate Balb/c and C57BL/6J mice. Both GroEL and GroES induced low levels of protection in Balb/c and C57BL/6J mice immunized with the Salmonella expression vectors. None of the mice inoculated with the genetic vaccine survived. Immunological memory was also tested in these mice and a correlation between splenocyte proliferation and the survival rate was observed.
Sequence Analysis of Three Ehrlichia ruminantium LambdaGEM‐11 Clones
Authors: PRETORIUS ALRI , COLLINS N. E. , STEYN H. C. , ALLSOPP B. A.
Published: July 2009

Abstract: Three Lambda GEM11 clones were isolated from a large‐insert Ehrlichia ruminantium Welgevonden library. The inserts were amplified, sequenced, and analyzed. A total of 39 827 bp was obtained, and 18 different open reading frames (ORFs) were identified. Long repeats (100‐200 kbp) were found in all three sequences. These repeats may play a role in the induction of antigenic variation. Along with a 20‐kbp sequence of a clone from the E. ruminantium cosmid library, these sequences are the first large sequences to be yielded by the E. ruminantium genome sequencing project.
Development of Resistance to Nymphs of Amblyomma cajennense Ticks (Acari:Ixodidae) in Dogs
Authors: MUKAI LUCIANA S. , NETTO A. CASTRO , SZABÓ M. P.J. , BECHARA G. H.
Published: July 2009

Abstract: Ticks have long been regarded as constraints to humans and domestic animals, but hosts often develop resistance to ticks after repeated infestations. The purpose of this investigation was to study the possible acquisition of immunity in domestic dogs to nymphs of A. cajennense by determining the tick alimentary performance after successive controlled infestations. Mean engorged weight of nymphs was not significantly different among the three infestations; molting rate from nymph to adult ticks, and the percentage of nymph recovery were also very close in all infestations. These results are similar to those obtained in studies of the dog‐adult Rhipicephalus sanguineus interface. It is concluded that domestic dogs do not develop resistance against nymphs of A. cajennense ticks.
Hypersensitivity Induced in Dogs by Nymphal Extract of Amblyomma cajennense Ticks (Acari:Ixodidae)
Authors: MUKAI LUCIANA S. , NETTO A. CASTRO , SZABÓ M. P.J. , BECHARA G. H.
Published: July 2009

Abstract: In general, hosts develop resistance to ticks after repeated infestations; nevertheless, several studies on naturally occurring host‐tick interactions were unable to detect resistance of hosts to ticks even after repeated infestations. The purpose of this investigation was to study the type of cutaneous hypersensitivity to unfed nymphal extract of A. cajennense in dogs, which, unlike guinea pigs, do not develop resistance. A first, but no second, peak in skin reaction was observed, suggesting that cellular immunity is an important mechanism of resistance to ticks. This may partially explain why guinea pigs, but not dogs, develop resistance against ticks.
The Evolving Transmission Pattern of Rift Valley Fever in the Arabian Peninsula
Authors: FAGBO SHAMSUDEEN F.
Published: July 2009

Abstract: Vector‐borne viruses are no respecters of international boundaries. The recent outbreak of Rift Valley fever (RVF) in the Kingdom of Saudi Arabia (KSA) and Yemen in September 2000 clearly sends a message that once pathogens cross their known geographic limits, they tend to adapt to the local ecology in order to survive and maintain transmission. This paper examines the various factors that may contribute to the establishment of RVF in the Arabian Peninsula (AP) and its possible spread to other countries. The annual influx of over 2 million pilgrims for the Hajj (annual pilgrimage for Muslims) in the KSA, as well as the large migrant population in this region, generates high human and animal traffic that presents a challenging agenda for public health. The potential risks within this period as well as other peculiar ecological factors are discussed.