bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperpolarization of murine small caliber mesenteric arteries by activation of endothelial proteinase-activated receptor 2
Authors: McGuire John J , Hollenberg Morley D , Bennett Brian M , Triggle Chris R
Published: February 2005

Activation of endothelial proteinase-activated receptor 2 (PAR-2) relaxes vascular smooth muscle (VSM) and causes hypotension by nitric oxide (NO)–prostanoid-dependent and -independent mechanisms. We investigated whether endothelium-dependent hyperpolarization of VSM was the mechanism whereby resistance caliber arteries vasodilated independently of NO. VSM membrane potentials and isometric tension were measured concurrently to correlate the electrophysiological and mechanical changes in murine small caliber mesenteric arteries. In uncontracted arteries, the PAR-2 agonist, SLIGRL-NH2(0.1 to 10 µmol/L), hyperpolarized the VSM membrane potential only in endothelium-intact arterial preparations. This response was unaltered by treatment of arteries with inhibitors of NO synthases (L-NAME), soluble guanylyl cyclase (ODQ), and cyclooxygenases (indomethacin). L-NAME, ODQ, and indomethacin also failed to inhibit SLIGRL-NH2-induced hyperpolarization and of cirazoline-contracted mesenteric arteries. However, in blood vessels that were depolarized and contracted with 30 mmol/L KCl, the effects of the SLIGRL-NH2on membrane potential and tension were not observed. SLIGRL-NH2-induced hyperpolarization and relaxation was inhibited completely by the combination of apamin plus charybdotoxin, but only partially inhibited after treatment with the combination of barium plus ouabain, suggesting an important role for SKCaand IKCachannels and a lesser role for Kirchannels and Na+/K+ATPases in the hyperpolarization response. We concluded that activation of endothelial PAR-2 hyperpolarized the vascular smooth muscle (VSM) cells of small caliber arteries, without requiring the activation of NO synthases, cyclooxygenases, or soluble guanylyl cyclase. Indeed, this hyperpolarization may be a primary mechanism for PAR-2–induced hypotension in vivo.Key words: proteinase-activated receptor 2, protease-activated receptor 2, endothelium, vascular smooth muscle, hyperpolarization, blood vessels, transgenic mice, vasoactive peptides.
Beyond angiogenesis: the cardioprotective potential of fibroblast growth factor-2
Authors: Detillieux Karen A , Cattini Peter A , Kardami Elissavet
Published: February 2005

In the field of cardiovascular research, a number of independent approaches have been explored to protect the heart from acute and chronic ischemic damage. Fibroblast growth factor-2 (FGF-2) recently has received considerable attention with respect to its angiogenic potential. While therapeutic angiogenesis may serve to salvage chronically ischemic myocardium, more acute treatments are in demand to increase cardiac resistance to injury (preconditioning) and to guard against secondary injury after an acute ischemic insult. Here, we look beyond the angiogenic potential of FGF-2 and examine its acute cardioprotective activity as demonstrated under experimental conditions, both as an agent of a preconditioning-like response and for secondary injury prevention at the time of reperfusion. Factors to consider in moving to the clinical setting will be discussed, including issues of dosage, treatment duration, and routes of administration. Finally, issues of safety and clinical trial design will be considered. The prospect of such a multipotent growth factor having clinical usefulness opens the door to effective treatment of both acute and chronic ischemic heart disease, something well worth the attention of the cardiovascular community.Key words: fibroblast growth factor-2, ischemia, reperfusion injury, cardioprotection, angiogenesis, apoptosis.
Higher viscosity participates in the regulation of coronary flow via nitric oxide and indomethacin-sensitive contracting factor
Authors: Kimura Akira , Okumura Kenji , Mokuno Shinji , Numaguchi Yasushi , Matsui Hideo , Murohara Toyoaki
Published: February 2005

Few studies have reported on the association of viscosity with coronary circulation. We evaluated the change in coronary flow after dextran was added to a perfusion solution to increase viscosity in isolated rat hearts. We also measured NOx– production induced by the change in shear stress in the coronary effluent, as a marker of NO synthesis. The baseline coronary flow was not influenced by the presence of either the cyclooxygenase inhibitor indo metha cin, the thromboxane A2 (TXA2)–prostaglandin H2 (PGH2) receptor antagonist ONO-3708, or the TXA2 synthase inhibitor OKY-046. After exposure to solution containing 0.5% dextran, the coronary flow first decreased and then gradually increased until 10 min. The initial decrease in coronary flow was inhibited by indomethacin, ONO-3708, and OKY-046 individually. The gradual increase was completely inhibited by the NO inhibitor L-NAME, but not by indomethacin or ONO-3708. OKY-046 partially inhibited the increase. NOx– levels in the effluent were higher after the dextran solution was administered, and the increased NOx– levels were inhibited by L-NAME. The increased NOx- levels were not inhibited by inhibitors of the cyclooxygenase pathway. It appears that a higher viscosity of perfusion solution induced a gradual increase in NO production and was associated with increased production of indomethacin-sensitive contracting factor.Key words: coronary flow, indomethacin, nitric oxide, viscosity.
Regional differences in diving behavior of harbor seals in the Gulf of Alaska
Authors: Hastings K K , Frost K J , Simpkins M A , Pendleton G W , Swain U G , Small R J
Published: February 2005

Adult and subadult harbor seals (Phoca vitulina richardii (Gray, 1864); n = 108) from Southeast Alaska (SE), Kodiak Island (KO), and Prince William Sound (PWS) were instrumented with satellite data recorders to examine dive parameters for harbor seals in the Gulf of Alaska at regional and annual scales. Most dives (40%–80%) were <20 m in depth and <4 min in duration; however, dives from 50 to 150 m depth were not uncommon and dives to 508 m were recorded. PWS seals spent less time in the water during the prebreeding and breeding seasons than SE and KO seals. SE seals used a greater diversity of depths than KO and PWS seals. Only seals in PWS and SE (i) dived deeper and longer and spent more time diving in winter than during spring and summer and (ii) dived deepest during the day only in winter. Seals in all regions and seasons dived most frequently and spent the most time diving at night. Subadult seals spent more time diving, dived more often, displayed a stronger diurnal pattern with deepest dives during the day in the winter, and dived deeper than adults.
The effects of terrestrial and breeding densities on corticosterone and testosterone levels in spotted salamanders, Ambystoma maculatum
Authors: Cooperman Mark D , Reed J Michael , Romero L Michael
Published: February 2005

We examined plasma concentrations of corticosterone (CORT) and testosterone in male free-living and captive spotted salamanders, Ambystoma maculatum (Shaw, 1802), to determine if (i) they mounted significant CORT responses to conspecifics in captive enclosures during potential competition for limited burrows; (ii) artificially induced, increased breeding densities altered CORT and testosterone levels in a free-living population; and (iii) testosterone in free-living males varied seasonally. We found increased baseline CORT in captive male spotted salamanders exposed to conspecifics under high densities (4 animals with only 1 burrow). Original residents of the cage, however, had significantly higher baseline CORT titers than did newly introduced animals, and titers were significantly higher in animals cohabiting a burrow than those remaining outside the burrow. This suggests that spotted salamanders perceive con specifics as threats for burrows and become stressed when forced to share these resources. In contrast, free-living spotted salamanders during breeding showed no significant increases in baseline CORT or testosterone in high-density treatments. This suggests that increased adult density during breeding is not stressful to these salamanders. Finally, spotted salamanders had greater plasma testosterone titers in fall than in spring, suggesting that they are dissociated breeders.
Effect of testosterone on immunocompetence, parasite load, and metabolism in the common wall lizard (Podarcis muralis)
Authors: Oppliger A , Giorgi M S , Conelli A , Nembrini M , John-Alder H B
Published: February 2005

Testosterone can benefit individual fitness by increasing ornament colour, aggressiveness, and sperm quality, but it can also impose both metabolic and immunological costs. However, evidence that testosterone causes immuno suppression in freely living populations is scant. We studied the effects of testosterone on one component of the immune system (i.e., the cell-mediated response to phytohaemagglutinin), parasite load, and metabolic rate in the common wall lizard, Podarcis muralis (Laurenti, 1768). For analyses of immunocompetence and parasitism, male lizards were implanted at the end of the breeding season with either empty or testosterone implants and were returned to their site of capture for 5–6 weeks before recapture. For analyses of the effects of testosterone on metabolic rate, male lizards were captured and implanted before hibernation and were held in the laboratory for 1 week prior to calorimetry. Experimental treatment with testosterone decreased the cell-mediated response to the T-cell mitogen phytohemagglutinin and increased mean metabolic rate. No effects of testosterone on the number of ectoparasites, hemoparasites, and resting metabolic rate could be detected. These results are discussed in the framework of the immunocompetence handicap hypothesis and the immuno-redistribution process hypothesis.
Population dynamics of the northern short-tailed shrew, Blarina brevicauda: insights from a 25-year study
Authors: Getz Lowell L , Hofmann Joyce E , McGuire Betty , Oli Madan K
Published: February 2005

The population demography of the northern short-tailed shrew, Blarina brevicauda (Say, 1823), was studied for 25 years in bluegrass, alfalfa, and tallgrass habitats in east-central Illinois. The population in bluegrass had higher over-winter population density, began increasing earlier in the year, peaked earlier in the year, had higher mean monthly densities and amplitudes of fluctuation, and remained higher for longer than did populations in alfalfa and tallgrass. Survival rates were greater in bluegrass and tallgrass than in alfalfa. The species displayed annual population fluctuations with little variation in amplitude among years in all three habitats. Seasonal reproduction appeared to be responsible for the annual fluctuations. Survival did not vary in relation to season, but was positively correlated with annual peak densities, whereas reproduction was not. There was no correlation between population densities of voles during April–August and annual peak densities of B. brevicauda. We conclude that annual fluctuations in B. brevicauda populations are driven by seasonal reproduction, while variation in mortality, most likely from predation, may explain differences in the amplitudes of annual peaks.
Fractal analysis measures habitat use at different spatial scales: an example with American marten
Authors: Nams Vilis O , Bourgeois Maryse
Published: February 2005

Habitat selection is traditionally assessed by how much time the animal spends in each habitat type; however, one can obtain additional information by analysing the structure of the movement paths. We followed and mapped snow tracks of American marten, Martes americana (Turton, 1806). The new method used to test the movement paths for deviations from a correlated random walk model show that these paths fail the test. This has led to an analysis of fractal dimension versus spatial scale, which showed a natural break in fractal dimension at a scale of approximately 3.5 m, suggesting that marten displayed different responses to their microenvironment in two regions of spatial scale. Marten travel was more direct at scales <3.5 m than at scales >3.5 m. Path tortuousity was affected by habitats at smaller scales but not at larger scales, indicating different responses by marten to their environment at these two ranges of scale. Multiple regression identified canopy closure and presence of conifer in the understory as variables that affect movement patterns at the 1- to 3.5-m scale. Fractal analysis of movement patterns provides a unique approach to examining habitat use, as well as a means to identify the spatial scales at which an animal responds to its habitat.
Movements and distribution of northern bottlenose whales,Hyperoodon ampullatus, on the Scotian Slope and in adjacent waters
Authors: Wimmer Tonya , Whitehead Hal
Published: February 2005

A small, apparently isolated, and endangered population of ~130 northern bottlenose whales (Hyperoodon ampullatus Forster, 1770) is found on the Scotian Slope south of Nova Scotia, Canada. Virtually all previous information on these animals had come from the Gully, a large submarine canyon where the northern bottlenose whales can be reliably found. A ship survey along the 1000 m depth contour in 2001 showed northern bottlenose whales only in the Gully, Shortland canyon (50 km east of the Gully), and Haldimand canyon (100 km east of the Gully). Studies in 2002 reconfirmed the presence of the whales in these other canyons, although densities were about 50% lower than in the Gully. Photo-identifications showed that individuals moved between the Gully and Shortland and Haldimand canyons over periods from days to years, with mean stays in any canyon of about 22 days. However, the population was not fully mixed: at least some individuals had preferences for particular canyons. The sex ratios were similar in all canyons, but males had higher rates of movement between canyons. These results are consistent with the expectations of optimal foraging theory, when the primary resource for females, deep-water squid of the genus Gonatus Gray, 1849, is more temporally stable than the primary resource for males, which is assumed to be receptive females. Haldimand and Shortland canyons are clearly important habitat for this species, and should receive appropriate protection.
A new method to discriminate the deer mouse (Peromyscus maniculatus) from the white-footed mouse (Peromyscus leucopus) using species-specific primers in multiplex PCR
Authors: Tessier Nathalie , Noël Sarah , Lapointe François-Joseph
Published: February 2005

Morphometric measurements or biochemical methods are often required to differentiate deer mice, Peromyscus maniculatus (Wagner, 1845), from white-footed mice, Peromyscus leucopus (Rafinesque, 1818), particularly when they are found in sympatry. However, these approaches cannot easily be applied to juveniles, or to degraded or ancient museum specimens. In this paper, we propose a rapid and non-invasive molecular approach to discriminate these cryptic species from one another. This technique relies on species-specific primers designed in the COIII mitochondrial region to amplify fragments of different lengths in each species. The method developed proved useful for the identification of ethanol-preserved, frozen, degraded, or dry museum specimens.
Inherited Susceptibility to Colorectal Cancer
Authors: Rowley Peter T.
Published: February 2005

The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is due to mutations in the APC gene. HNPCC is due to a mutation in one of at least five mismatch repair genes. Identification of individuals with these conditions is important because colon cancer will occur in ∼80% and onset is early. For FAP, protein truncation testing will identify the vast majority of mutations. For HNPCC, 80%–95% can be identified by microsatellite instability testing. A current U.S. study reports that 12% of consecutive colorectal cancers have high microsatellite instability and that, of this 12%, 25% have detectable mutations of MLH1, MSH2, or MSH6. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, offering of testing to relatives, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance.
Management of Adult Idiopathic Thrombocytopenic Purpura
Authors: Cines Douglas B. , McMillan Robert
Published: February 2005

Idiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder manifested by immune-mediated thrombocytopenia. The diagnosis remains one of exclusion, after other thrombocytopenic disorders are ruled out based on history, physical examination, and laboratory evaluation. The goal of treatment is to raise the platelet count into a hemostatically safe range. The disorder is usually chronic, although there is considerable variation in the clinical course and most patients eventually attain safe platelet counts off treatment. However, a subset of patients has severe disease refractory to all treatment modalities, which is associated with considerable morbidity and mortality. This article focuses on the management of primary ITP in adults. We discuss criteria for treatment, the roles of splenectomy and other treatment options along with their side effects, and the management of ITP during pregnancy.
Myelodysplastic Syndrome
Authors: Hofmann Wolf-K. , Koeffler H. Phillip
Published: February 2005

During the past 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndrome (MDS). MDS is a clonal disorder characterized by ineffective hematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukemia (AML). Risk-adapted treatment strategies were established because of the high median age (60–75 years) of the MDS patients and the individual history of the disease (number of cytopenias, cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplantation currently offers the only potentially curative treatment, but this form of therapy is not available for the typical MDS patient, who is >60 years of age. Therapy with erythropoietin and G-CSF has improved the quality of life of selected patients. The development of small molecules directed against specific molecular targets with minimal adverse effects is the hope for the future. Innovative uses of immunomodulatory agents and the optimizing of cytotoxic treatment should continue to help in the treatment of MDS.
Gene Therapy for Severe Combined Immunodeficiency
Authors: Cavazzana-Calvo Marina , Lagresle Chantal , Hacein-Bey-Abina Salima , Fischer Alain
Published: February 2005

Studies of severe combined immunodeficiency (SCID), a group of rare monogenic disorders, have provided key findings about the physiology of immune system development. The common characteristic of these diseases is the occurrence of a block in T cell differentiation, always associated with a direct or indirect impairment of B cell immunity. The resulting combined immunodeficiency is responsible for the clinical severity of SCID, which, without treatment, leads to death within the first year of life. Eleven distinct SCID phenotypes have been identified to date. Mutations of ten genes have been found to cause SCID. Identifying the pathophysiological basis of most SCID conditions has led to the possibility of molecular therapy as an alternative to allogeneic hematopoietic stem cell transplantation. This review discusses recent developments in SCID identification and treatment.
Stimulation of NGF expression and secretion in 3T3-L1 adipocytes by prostaglandins PGD2, PGJ2, and Δ12-PGJ2
Authors: Bulló Mònica , Peeraully Muhammad R. , Trayhurn Paul
Published: February 2005

Nerve growth factor (NGF) has recently been shown to be secreted from white adipocytes, its production being strongly stimulated by the proinflammatory cytokine tumor necrosis factor-α. In this study, we have examined whether a series of prostaglandins and other inflammation-related factors also stimulate NGF expression and secretion by adipocytes, using 3T3-L1 cells. Although interleukin (IL)-1β, IL-10, and IL-18 each induced a small decrease in NGF mRNA level in 3T3-L1 adipocytes, there was no significant effect of these cytokines on NGF secretion. A small reduction in NGF expression and/or secretion was also observed with adiponectin and prostaglandins PGE2, PGF2α, and PGI2. In marked contrast, prostaglandin PGD2induced a major, dose-dependent increase (up to 20- to 40-fold) in NGF expression and secretion. The PGD2metabolites, PGJ2and Δ12-PGJ2, also induced major increases (up to 30-fold) in NGF production. A further metabolite of PGJ2, 15-deoxy-Δ12,14-PGJ2, a peroxisome proliferator-activated receptor-γ agonist, led paradoxically to a small increase in NGF mRNA level but a fall in NGF secretion. Both PGD2and PGJ2induced significant increases in NGF gene expression by 4 h after their addition. It is concluded that PGD2and the J series prostaglandins, PGJ2and Δ12-PGJ2, can play a significant role in the regulation of NGF production by white adipocytes. These results provide support for the view that NGF is an important inflammatory response protein, as well as a target-derived neurotrophin, in white adipose tissue.
Missense mutations in Na+:HCO3−cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis
Authors: Li Hong C. , Szigligeti Peter , Worrell Roger T. , Matthews Jeffrey B. , Conforti Laura , Soleimani Manoocher
Published: February 2005

The kidney Na+:HCO3−cotransporter NBC1 is located exclusively on the basolateral membrane of kidney proximal tubule cells and is responsible for the reabsorption of majority of filtered bicarbonate. Two well-described missense mutations in NBC1, R510H and S427L, are associated with renal tubular acidosis (RTA). However, the exact relationship between these mutations and NBC1 dysregulation remains largely unknown. To address this question, cDNAs for wild-type kidney NBC1 and its mutants R510H and S427L were generated, fused in frame with NH2terminally tagged GFP, and transiently expressed in Madin-Darby canine kidney cells. In parallel studies, oocytes were injected with the wild-type and mutant NBC1 cRNAs and studied for membrane expression and activity. In monolayer cells grown to polarity, the wild-type GFP-NBC1 was exclusively localized on the basolateral membrane domain. However, GFP-NBC1 mutant R510H was detected predominantly in the cytoplasm. GFP-NBC1 mutant S427L, on the other hand, was detected predominantly on the apical membrane with residual cytoplasmic retention and basolateral membrane labeling. In oocytes injected with the wild-type or mutant GFP-NBC1 cRNAs, Western blot analysis showed that wild-type NBC1 is predominantly localized in the membrane fraction, whereas NBC1-R510H mutant was predominantly expressed in the cytoplasm. NBC1-S427L mutant was mostly expressed in the membrane fraction. Functional analysis of NBC1 activity in oocytes by membrane potential recording demonstrated that compared with wild-type GFP-NBC1, the GFP-NBC1 mutants H510R and S427L exhibited significant reduction in activity. These findings suggest that the permanent isolated proximal RTA in patients with H510R or S427L mutation resulted from a combination of inactivation and mistargeting of kidney NBC1, with H510R mutant predominantly retained in the cytoplasm, whereas S427L mutant is mistargeted to the apical membrane.
Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx
Authors: Leung Fung Ping , Yao Xiaoqiang , Lau Chi-Wai , Ko Wing-Hung , Lu Limin , Huang Yu
Published: February 2005

Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of the endothelium and Ca2+ channels in rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U-46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl2 were studied. Changes in intracellular Ca2+ concentration levels ([Ca2+]i) of vascular smooth muscle (VSM) were measured by fura 2 fluorescence. Raloxifene or 17β-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17β-estradiol. Endothelial denudation did not affect raloxifene- or 17β-estradiol-induced relaxation. NG-nitro-l-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI-182, 780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U-46619 and high K+. Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl2-induced contractions. K+ (80 mM) stimulated an increase in VSM [Ca2+]i, and raloxifene attenuated this effect. Raloxifene-induced reduction of contraction and increase in VSM [Ca2+]i were insensitive to ICI-182, 780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182, 780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca2+]i in response to CaCl2, indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca2+ influx via Ca2+ channels. There is little sex difference in raloxifene-induced relaxation.
Testing Bayesian Models of Human Coincidence Timing
Authors: Miyazaki Makoto , Nozaki Daichi , Nakajima Yasoichi
Published: February 2005

A sensorimotor control task often requires an accurate estimation of the timing of the arrival of an external target (e.g., when hitting a pitched ball). Conventional studies of human timing processes have ignored the stochastic features of target timing: e.g., the speed of the pitched ball is not generally constant, but is variable. Interestingly, based on Bayesian theory, it has been recently shown that the human sensorimotor system achieves the optimal estimation by integrating sensory information with prior knowledge of the probabilistic structure of the target variation. In this study, we tested whether Bayesian integration is also implemented while performing a coincidence- timing type of sensorimotor task by manipulating the trial-by-trial variability (i.e., the prior distribution) of the target timing. As a result, within several hundred trials of learning, subjects were able to generate systematic timing behavior according to the width of the prior distribution, as predicted by the optimal Bayesian model. Considering the previous studies showing that the human sensorimotor system uses Bayesian integration in spacing and force-grading tasks, our result indicates that Bayesian integration is fundamental to all aspects of human sensorimotor control. Moreover, it was noteworthy that the subjects could adjust their behavior both when the prior distribution was switched from wide to narrow and vice versa, although the adjustment was slower in the former case. Based on a comparison with observations in a previous study, we discuss the flexibility and adaptability of Bayesian sensorimotor learning.
Tissue-specific transcriptome responses in rats with early streptozotocin-induced diabetes
Authors: Knoll Kristen E. , Pietrusz Jennifer L. , Liang Mingyu
Published: February 2005

The understanding of common and tissue-specific molecular alterations in diabetes, particularly at early stages, is limited and fragmental. In the present study, we systematically compared transcriptome responses in four important diabetic target tissues in rats with 2 wk of streptozotocin (STZ)-induced diabetes. At this stage of diabetes, the skeletal muscle exhibited the highest transcriptome sensitivity to the STZ treatment with nearly 17% of the transcriptome being altered (false discovery rate, 1.6%) compared with ∼3% in the cardiac left ventricle, renal cortex, and retina. Similarity in transcriptome response among tissues was low, with the highest similarity being 2.2% between skeletal muscle and the left ventricle. Several biological processes or cellular components, such as lipid metabolism in the left ventricle and collagen in the renal cortex, were significantly overrepresented in the responsive genes than in the entire array. Particularly interesting cases of common or tissue-specific regulation included decorin and CD36, which were upregulated in several tissues, and serum/glucocorticoid-regulated kinase and four and a half LIM domains 2, which were upregulated only in the renal cortex. Further biochemical analyses indicated that the thiol and oxidative stress pathway was altered in a tissue-specific manner at several levels including transcript abundance, content of reduced thiols, and lipid peroxidation, providing an example of the potential biological relevance of tissue-specific transcript regulation. These results provided a transcriptome-wide view of the molecular alterations across several key tissues in early diabetes. It appears that both common pathways and, perhaps more importantly, tissue-specific mechanisms are involved in the adaptation to diabetes or the initiation of diabetic complications.
Functional characterization of human SLC41A1, a Mg2+transporter with similarity to prokaryotic MgtE Mg2+transporters
Authors: Goytain Angela , Quamme Gary A.
Published: February 2005

We have begun to identify and characterize genes that are differentially expressed with low magnesium. One of these sequences conformed to the solute carrier SLC41A1. Real-time RT-PCR of RNA isolated from renal distal tubule epithelial [mouse distal convoluted tubule (MDCT)] cells cultured in low-magnesium media relative to normal media and in the kidney cortex of mice maintained on low-magnesium diets compared with those animals consuming normal diets confirmed that the SLC41A1 transcript is responsive to magnesium. Mouse SLC41A1 was cloned from MDCT cells, expressed in Xenopus laevis oocytes, and studied with two-electrode voltage-clamp studies. When expressed in oocytes, SLC41A1 mediates saturable Mg2+uptake with a Michaelis constant of 0.67 mM. Transport of Mg2+by SLC41A1 is rheogenic, voltage dependent, and not coupled to Na+or Cl−. Expressed SLC41A1 transports a range of other divalent cations: Mg2+, Sr2+, Zn2+, Cu2+, Fe2+, Co2+, Ba2+, and Cd2+. The divalent cations Ca2+, Mn2+, and Ni2+and the trivalent ion Gd3+did not induce currents nor did they inhibit Mg2+transport. The nonselective cation La3+abolished Mg2+uptake. The SLC41A1 transcript is present in many tissues, notably renal epithelial cells, and is upregulated in some tissues with magnesium deficiency. These studies suggest that SLC41A1 is a regulated Mg2+transporter that might be involved in magnesium homeostasis in epithelial cells.
Remarks relevant to classical maximum principles
Authors: Danet Cristian-Paul
Published: February 2005

We extend, sharpen, or give independent proofs of classical maximum principles. We also concentrate on maximum principles for equations of higher order. All proofs (except for one) are derived via comparison principles. The two parts maybe read independently, but the whole paper is not self‐contained.
Solvability of initial boundary value problems for equations describing motions of linear viscoelastic fluids
Authors: Karazeeva N. A.
Published: February 2005

The nonlinear parabolic equations describing motion of incompressible media are investigated. The rheological equations of most general type are considered. The deviator of the stress tensor is expressed as a nonlinear continuous positive definite operator applied to the rate of strain tensor. The global‐in‐time estimate of solution of initial boundary value problem is obtained. This estimate is valid for systems of equations of any non‐Newtonian fluid. Solvability of initial boundary value problems for such equations is proved under some additional hypothesis. The application of this theory makes it possible to prove the existence of global‐in‐time solutions of two‐dimensional initial boundary value problems for generalized linear viscoelastic liquids, that is, for liquids with linear integral rheological equation, and for third‐grade liquids.
Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis
Authors: Dotti Gianpietro , Savoldo Barbara , Pule Martin , Straathof Karin C. , Biagi Ettore , Yvon Eric , Vigouroux Stephane , Brenner Malcolm K. , Rooney Cliona M.
Published: February 2005

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Faslow and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (Blood. 2005;105:4677-4684)
Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)
Authors: De Keersmaecker Kim , Graux Carlos , Odero Maria D. , Mentens Nicole , Somers Riet , Maertens Johan , Wlodarska Iwona , Vandenberghe Peter , Hagemeijer Anne , Marynen Peter , Cools Jan
Published: February 2005

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib. (Blood. 2005;105:4849-4852)
Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure
Authors: Wong Connie , Stearns Tim
Published: February 2005

Background

Mammalian cells have been reported to have a p53-dependent tetraploidy checkpoint that blocks cell cycle progression in G1 in response to failure of cell division. In most cases where the tetraploidy checkpoint has been observed cell division was perturbed by anti-cytoskeleton drug treatments. However, other evidence argues against the existence of a tetraploidy checkpoint. Cells that have failed to divide differ from normal cells in having two nuclei, two centrosomes, a decreased surface to volume ratio, and having undergone an abortive cytokinesis. We tested each of these to determine which, if any, cause a G1 cell cycle arrest.

Results

Primary human diploid fibroblasts with intact cell cycle checkpoints were used in all experiments. Synchronized cells exhibited G1 arrest in response to division failure caused by treatment with either cytochalasin or the myosin II inhibitor blebbistatin. The role of tetraploidy, aberrant centrosome number, and increased cell size were tested by cell/cell and cell/cytoplast fusion experiments; none of these conditions resulted in G1 arrest. Instead we found that various drug treatments of the cells resulted in cellular damage, which was the likely cause of the arrest. When cytokinesis was blocked in the absence of damage-inducing drug treatments no G1 arrest was observed.

Conclusions

We show that neither tetraploidy, aberrant centrosome number, cell size, nor failure of cytokinesis lead to G1 arrest, suggesting that there is no tetraploidy checkpoint. Rather, certain standard synchronization treatments cause damage that is the likely cause of G1 arrest. Since tetraploid cells can cycle when created with minimal manipulation, previous reports of a tetraploidy checkpoint can probably be explained by side effects of the drug treatments used to observe them.
Medicinal herb use among asthmatic patients attending a specialty care facility in Trinidad
Authors: Clement Yuri N , Williams Arlene F , Aranda Derick , Chase Ronald , Watson Nadya , Mohammed Rochelle , Stubbs Odia , Williamson Deneil
Published: February 2005

Background

There is an increasing prevalence of asthma in the Caribbean and patients remain non-compliant to therapy despite the development of guidelines for management and prevention. Some patients may self-medicate with medicinal herbs for symptomatic relief, as there is a long tradition of use for a variety of ailments. The study assessed the prevalence of use and the factors affecting the decision to use herbs in asthmatic patients attending a public specialty care clinic in Trinidad.

Methods

A descriptive, cross-sectional study was conducted at the Chest Clinic in Trinidad using a de novo, pilot-tested, researcher-administered questionnaire between June and July 2003.

Results

Fifty-eight out of 191 patients (30.4%) reported using herbal remedies for symptomatic relief. Gender, age, ethnicity, and asthma severity did not influence the decision to use herbs; however, 62.5% of patients with tertiary level schooling used herbs, p = 0.025. Thirty-four of these 58 patients (58.6%) obtained herbs from their backyards or the supermarket; only 14 patients (24.1%) obtained herbs from an herbalist, herbal shop or pharmacy. Relatives and friends were the sole source of information for most patients (70.7%), and only 10.3% consulted an herbalist. Ginger, garlic, aloes, shandileer, wild onion, pepper and black sage were the most commonly used herbs.

Conclusions

Among patients attending the Chest Clinic in Trinidad the use of herbal remedies in asthma is relatively common on the advice of relatives and friends. It is therefore becoming imperative for healthcare providers to become more knowledgeable on this modality and to keep abreast with the latest developments.
Comparison of artificial neural network and logistic regression models for prediction of mortality in head trauma based on initial clinical data
Authors: Eftekhar Behzad , Mohammad Kazem , Ardebili Hassan Eftekhar , Ghodsi Mohammad , Ketabchi Ebrahim
Published: February 2005

Background

In recent years, outcome prediction models using artificial neural network and multivariable logistic regression analysis have been developed in many areas of health care research. Both these methods have advantages and disadvantages. In this study we have compared the performance of artificial neural network and multivariable logistic regression models, in prediction of outcomes in head trauma and studied the reproducibility of the findings.

Methods

1000 Logistic regression and ANN models based on initial clinical data related to the GCS, tracheal intubation status, age, systolic blood pressure, respiratory rate, pulse rate, injury severity score and the outcome of 1271 mainly head injured patients were compared in this study. For each of one thousand pairs of ANN and logistic models, the area under the receiver operating characteristic (ROC) curves, Hosmer-Lemeshow (HL) statistics and accuracy rate were calculated and compared using paired T-tests.

Results

ANN significantly outperformed logistic models in both fields of discrimination and calibration but under performed in accuracy. In 77.8% of cases the area under the ROC curves and in 56.4% of cases the HL statistics for the neural network model were superior to that for the logistic model. In 68% of cases the accuracy of the logistic model was superior to the neural network model.

Conclusions

ANN significantly outperformed the logistic models in both fields of discrimination and calibration but lagged behind in accuracy. This study clearly showed that any single comparison between these two models might not reliably represent the true end results. External validation of the designed models, using larger databases with different rates of outcomes is necessary to get an accurate measure of performance outside the development population.
Transcriptional slippage in bacteria: distribution in sequenced genomes and utilization in IS element gene expression
Authors: Baranov Pavel V , Hammer Andrew W , Zhou Jiadong , Gesteland Raymond F , Atkins John F
Published: February 2005

Background

Transcription slippage occurs on certain patterns of repeat mononucleotides, resulting in synthesis of a heterogeneous population of mRNAs. Individual mRNA molecules within this population differ in the number of nucleotides they contain that are not specified by the template. When transcriptional slippage occurs in a coding sequence, translation of the resulting mRNAs yields more than one protein product. Except where the products of the resulting mRNAs have distinct functions, transcription slippage occurring in a coding region is expected to be disadvantageous. This probably leads to selection against most slippage-prone sequences in coding regions.

Results

To find a length at which such selection is evident, we analyzed the distribution of repetitive runs of A and T of different lengths in 108 bacterial genomes. This length varies significantly among different bacteria, but in a large proportion of available genomes corresponds to nine nucleotides. Comparative sequence analysis of these genomes was used to identify occurrences of 9A and 9T transcriptional slippage-prone sequences used for gene expression.

Conclusions

IS element genes are the largest group found to exploit this phenomenon. A number of genes with disrupted open reading frames (ORFs) have slippage-prone sequences at which transcriptional slippage would result in uninterrupted ORF restoration at the mRNA level. The ability of such genes to encode functional full-length protein products brings into question their annotation as pseudogenes and in these cases is pertinent to the significance of the term 'authentic frameshift' frequently assigned to such genes.
Novel monoclonal antibodies detect elevated levels of the chemokine CCL18/DC-CK1 in serum and body fluids in pathological conditions
Authors: Van der Voort Robbert , Kramer Matthijs , Lindhout Ernst , Torensma Ruurd , Eleveld Dagmar , Van Lieshout Antoine W T , Looman Maaike , Ruers Theo , Radstake Timothy R D J , Figdor Carl G , Adema Gosse J
Published: February 2005

CC chemokine ligand 18/dendritic cell-chemokine 1 (CCL18/DC-CK1) is a CC chemokine, preferentially expressed by DC, which acts as a chemoattractant for naive T cells and mantle zone B cells. Applying a newly developed CCL18/DC-CK1 sandwich enzyme-linked immunosorbent assay, we demonstrate that DC secrete high amounts of CCL18/DC-CK1 and that this expression can be increased by interleukin-10. High levels of CCL18/DC-CK1 were also detected in human serum (average of 88 ng/ml). Moreover, elevated CCL18/DC-CK1 levels were detected in synovial fluid from rheumatoid arthritis patients and in drain fluid (average of 254 ng/ml and 122 ng/ml, respectively). Immunoprecipitation experiment using anti-CCL18/DC-CK1 monoclonal antibodies revealed a protein of 6–7 kDa in serum and drain fluid that was indistinguishable from recombinant CCL18/DC-CK1 on Western blot and in re-aggregation assays. The concentration of CCL18/DC-CK1 found in human serum is in the same order of magnitude as was previously reported to completely inhibit CCL11/eotaxin-induced CC chemokine receptor 3 (CCR3) activation and consequent migration of eosinophils. CCL18/DC-CK1 may therefore function as an agonist (for naive T and B cells) and as an antagonist for CCR3-expressing leukocytes such as eosinophils.
Joint Attention, Self‐Recognition, and Neurocognitive Function in Toddlers
Authors: Nichols Kate E. , Fox Nathan , Mundy Peter
Published: February 2005

Recent studies have attempted to understand the processes involved in joint attention because of its relevance to both atypical and normal development. Data from a recent study of young children with autism suggests that performance on a delay nonmatch to sample (DNMS) task associated with ventromedial prefrontal functions, but not an A‐not‐B/delayed response task associated with dorsolateral prefrontal cortex, was related to joint attention skills (Dawson et al., 2002). Recent research also suggests that joint attention is associated with dorsalmedial brain systems linked to self‐monitoring (Mundy, 2003). This study investigated the relations among joint attention, DNMS, and self‐recognition performance in a longitudinal study of 39 normally developing toddlers from 14 to 18 months. The results indicated that development on the DNMS and self‐recognition tasks, but not a means end task, predicted joint attention at 18 months. Further analysis showed that the model was only significant for initiating joint attention (IJA). The implications of these results for the neuro‐development of IJA are discussed.
12‐Month‐Old Infants Represent Probable Endings of Motion Events
Authors: Wagner Laura , Carey Susan
Published: February 2005

This experiment investigated 12‐month‐old infants' ability to link an event's beginning to its probable ending. Following Csibra, Biro, Koos, and Gergely (2003), infants were habituated to a simple chasing event involving animated balls, and at test saw 2 possible endings: either 1 ball caught the other or failed to do so. Two controls were added to the previous work. First, the total amount of motion was controlled in the test endings; second, the endings were paired with a nonchasing beginning to ensure that behavior at test reflected representation of the event beginning itself. The results replicated Csibra et al.'s finding that infants look longer at the noncatching ending following the chasing beginning; moreover, infants showed no preference for either ending following the no‐chasing beginning. This study supports the claim that infants can calculate the rational ending of a goal‐directed motion event.