bluuebunny/crossref_metadata_2025 huggingface dataset:
An echolocation model for range discrimination of multiple closely spaced objects: Transformation of spectrogram into the reflected intensity distribution
Authors: Matsuo Ikuo , Kunugiyama Kenji , Yano Masafumi
Published: February 2004

Using frequency-modulated echolocation, bats can discriminate the range of objects with an accuracy of less than a millimeter. However, bats’ echolocation mechanism is not well understood. The delay separation of three or more closely spaced objects can be determined through analysis of the echo spectrum. However, delay times cannot be properly correlated with objects using only the echo spectrum because the sequence of delay separations cannot be determined without information on temporal changes in the interference pattern of the echoes. To illustrate this, Gaussian chirplets with a carrier frequency compatible with bat emission sweep rates were used. The delay time for object 1, T1, can be estimated from the echo spectrum around the onset time. The delay time for object 2 is obtained by adding T1 to the delay separation between objects 1 and 2 (extracted from the first appearance of interference effects). Further objects can be located in sequence by this same procedure. This model can determine delay times for three or more closely spaced objects with an accuracy of about 1 μs, when all the objects are located within 30 μs of delay separation. This model is applicable for the range discrimination of objects having different reflected intensities and in a noisy environment (0-dB signal-to-noise ratio) while the cross-correlation method is hard to apply to these problems.
Risk of hip fracture in protected and unprotected falls in nursing homes in Norway
Authors: Forsén L , Søgaard A J , Sandvig S , Schuller A , Røed U , Arstad C
Published: February 2004

Objectives:To compare the probability of hip fracture in protected and unprotected falls in a real world setting in nursing homes.

Design:Observational study.

Setting:Seventeen nursing homes (965 beds) in Norway.

Subjects:All residents in the nursing homes with at least one fall during the intervention period.

Intervention:Hip protectors were introduced as a regular part of the health care service for all the residents for an intervention period of 18 months. Residents who were considered high risk were especially encouraged to be regular users of hip protectors.

Main outcome measures:Hip fracture in protected and unprotected falls.

Results:At the time of the first fall within each faller, 430 were non-users of hip protectors, while 84 were registered as users, but did not wear it, and 191 were users and did wear it. The odds ratio of suffering a hip fracture was 0.31, 95% confidence interval 0.13 to 0.75 for wearers compared with non-wearers in the first fall, adjusted for age, gender, and whether they were registered as users or not.

Conclusion:The odds of suffering a hip fracture for nursing home high risk residents was reduced to less than a third in protected falls compared with unprotected falls. Or, in other words, the odds of hip fracture showed a 69% reduction in protected falls compared with unprotected falls.
Diabetes in a high secure hospital
Authors: MacFarlane I A , Gill G V , Finnegan D , Pinkney J
Published: February 2004

Aims

To determine the prevalence of diabetes mellitus and its possible causes and to assess its control in a high secure hospital.

Methods

A cross sectional survey and a prospective cohort study were conducted. The cross sectional survey included 408 patients admitted under the Mental Health Act, and the prospective study included 22 patients with known diabetes followed up for 24 months. The outcome measures evaluated were drug treatment, status of microvascular and macrovascular complications, glycated haemoglobin, and body mass index.

Results

In the cross sectional survey, 35 out of 408 patients (8.6%; 95% confidence interval 5.9% to 11.3%) had known diabetes, and all of these had type 2 diabetes. Obesity, cigarette smoking, schizophrenia, and antipsychotic drug use were frequent, and weight gain was common after hospital admission. Glycaemic control was variable, and, although a majority of patients were above recommended treatment targets, control remained stable over the follow up period.

Conclusions

Type 2 diabetes was common in this hospital. Both its prevalence and the suboptimal glycaemic control in some patients probably relate to sedentary life, dietary factors, smoking, and perhaps widespread use of antipsychotic drugs. However, regular multidisciplinary input enabled most patients to maintain relatively stable glycaemic control, with good control of blood pressure and lipids, at levels similar to those seen in community and hospital diabetic clinics. Further modification of lifestyle risk factors is probably needed to reduce the prevalence and impact of diabetes in this patient group.
Resource utilisation, length of hospital stay, and pattern of investigation during acute medical hospital admission
Authors: McMullan R , Silke B , Bennett K , Callachand S
Published: February 2004

Objectives

To describe the patient demographic characteristics and organisational factors that influence length of stay (LOS) among emergency medical admissions. Also, to describe differences in investigation practice among consultant physicians and to examine the impact of these on LOS.

Design

Prospective observational study.

Setting

General medicine department of a teaching hospital in Belfast, UK.

Participants

Data were recorded for patients who were admitted as emergencies and reviewed on the post-take ward rounds (PTWR) attended by the investigation coordinator.

Outcome measures

Non-laboratory investigations requested, LOS, and diagnosis on discharge.

Results

Of 830 episodes evaluated, the median LOS was 7 days (interquartile range 3–12 days); this was significantly longer for admissions on Fridays (p = 0.0011) and for patients managed on medical wards (p<0.0001). There was a positive correlation between patient age and LOS (r = 0.32, p<0.0001). Chest radiographs (p = 0.002) and echocardiography (p = 0.015) were associated with a prolonged LOS; no investigations were associated with a shortened LOS. Diagnoses of congestive heart failure, respiratory disease, and cancer were associated with a longer LOS; a diagnosis of angina was associated with a shorter LOS. Considerable variation in investigation ordering, but no difference in LOS, was observed between consultants. High use of a given medical test did not correlate with high use of other tests.

Conclusion

A systematic means of dealing with the NHS resource crisis should include an improved organisational strategy as well as social care provision. A more unified approach to investigation practice should also have a sparing effect on resources.
Attitudes of preclinical medical students towards caring for chronically ill and dying patients: does palliative care teaching make a difference?
Authors: Lloyd-Williams M , Dogra N
Published: February 2004

Introduction

Students entering medical school today will encounter an ageing population and a higher incidence of diseases affecting the elderly—for example, chronic respiratory and cardiac disease and malignancy.

Purpose

This study was carried out to determine the attitudes of preclinical medical students towards the care of patients for whom a cure is not possible.

Methods

All students were invited to complete a 23 item questionnaire prior to initial teaching and again following the second teaching session in palliative care.

Results

Overall, 149 of the 186 students (80%) completed the pre-teaching questionnaire (59 males and 90 females; median age 20 years, range 19–27 years), and 66 students (35%) completed the post-teaching questionnaire. Attitudes towards chronically ill and dying patients were generally positive. It was found that increasing age was associated with a more positive view of caring for patients with chronic or terminal illness, a more positive view of listening to patients reminisce, and a more positive view of patients dying at home (p = 0.014). The only notable result was that after palliative care teaching students had a significantly more positive view of hospices.

Conclusion

Caring for patients at the end of life can be one of the most rewarding aspects of being a doctor. This study suggests that the majority of medical students have a positive attitude towards patients with chronic incurable illness, and the trend for encouraging older students to enter medicine may be an influencing factor.
Cardiac magnetic resonance imaging
Authors: Heatlie G J , Pointon K
Published: February 2004

Recent advances in technology have allowed magnetic resonance imaging to be exploited in cardiology. It is capable of giving high definition structural and functional information. The current applications of this technique and how it may develop in the future are reviewed.
Intravenous therapy
Authors: Waitt C , Waitt P , Pirmohamed M
Published: February 2004

Intravenous administration of fluids, drugs, and nutrition is very common in hospitals. Although insertion of peripheral and central cannulae and subsequent intravenous therapy are usually well tolerated, complications that prolong hospitalisation, and in some cases cause death, can arise on occasions. Additionally, many cannulae are inserted unnecessarily. This article seeks to review this area and to outline good medical practice.
The Worshipful Society of Apothecaries of London
Authors: Hunting P
Published: February 2004

The Society of Apothecaries is both a City livery company and an examining authority for the medical profession. Founded in 1617 by the royal apothecary Gideon de Laune leading a breakaway group from the Grocers’ Company, the Society was instrumental in raising the status of apothecaries as general practitioners. Under the Apothecaries’ Act (1815) the Society examined for the LSA and it now awards the LMSSA (Licence in Medicine and Surgery of the Society of Apothecaries) and postgraduate diplomas, while maintaining the civic, charitable, and ceremonial traditions of a livery company of the City of London.
FKBP12.6 and cADPR regulation of Ca2+ release in smooth muscle cells
Authors: Wang Yong-Xiao , Zheng Yun-Min , Mei Qi-Bing , Wang Qinq-Song , Collier Mei Lin , Fleischer Sidney , Xin Hong-Bo , Kotlikoff Michael I.
Published: February 2004

Intracellular Ca2+ release through ryanodine receptors (RyRs) plays important roles in smooth muscle excitation-contraction coupling, but the underlying regulatory mechanisms are poorly understood. Here we show that FK506 binding protein of 12.6 kDa (FKBP12.6) associates with and regulates type 2 RyRs (RyR2) in tracheal smooth muscle. FKBP12.6 binds to RyR2 but not other RyR or inositol 1,4,5-trisphosphate receptors, and FKBP12, known to bind to and modulate skeletal RyRs, does not associate with RyR2. When dialyzed into tracheal myocytes, cyclic ADP-ribose (cADPR) alters spontaneous Ca2+ release at lower concentrations and produces macroscopic Ca2+ release at higher concentrations; neurotransmitter-evoked Ca2+ release is also augmented by cADPR. These actions are mediated through FKBP12.6 because they are inhibited by molar excess of recombinant FKBP12.6 and are not observed in myocytes from FKBP12.6-knockout mice. We also report that force development in FKBP12.6-null mice, observed as a decrease in the concentration/tension relationship of isolated trachealis segments, is impaired. Taken together, these findings point to an important role of the FKBP12.6/RyR2 complex in stochastic (spontaneous) and receptor-mediated Ca2+ release in smooth muscle.
Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-κB, and cytokine expression
Authors: Strassheim Derek , Asehnoune Karim , Park Jong-Sung , Kim Jae-Yeol , He Qianbin , Richter Donald , Mitra Sanchayita , Arcaroli John , Kuhn Katherine , Abraham Edward
Published: February 2004

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-κB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-κB. However, production and secretion of the proinflammatory cytokine TNF-α in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-α-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-κB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-κB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-κB but rather reflected diminished degradation of IκB-α. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-κB activation and associated TNF-α expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.
PKC-β1 isoform activation is required for EGF-induced NF-κB inactivation and IκBα stabilization and protection of F-actin assembly and barrier function in enterocyte monolayers
Authors: Banan A. , Zhang L. J. , Farhadi A. , Fields J. Z. , Shaikh M. , Keshavarzian A.
Published: February 2004

Using monolayers of intestinal Caco-2 cells, we reported that activation of NF-κB is required for oxidative disruption and that EGF protects against this injury but the mechanism remains unclear. Activation of the PKC-β1 isoform is key to monolayer barrier integrity. We hypothesized that EGF-induced activation of PKC-β1 prevents oxidant-induced activation of NF-κB and the consequences of NF-κB activation, F-actin, and barrier dysfunction. We used wild-type (WT) and transfected cells. The latter were transfected with varying levels of cDNA to overexpress or underexpress PKC-β1. Cells were pretreated with EGF or PKC modulators ± oxidant. Pretreatment with EGF protected monolayers by increasing native PKC-β1 activity, decreasing IκBα phosphorylation/degradation, suppressing NF-κB activation (p50/p65 subunit nuclear translocation/activity), enhancing stable actin (increased F-actin-to-G-actin ratio), increasing stability of actin cytoskeleton, and reducing barrier hyperpermeability. Cells stably overexpressing PKC-β1 were protected by low, previously nonprotective doses of EGF or modulators. In these clones, we found enhanced IκBα stabilization, NF-κB inactivation, actin stability, and barrier function. Low doses of the modulators led to increases in PKC-β1 in the particulate fractions, indicating activation. Stably inhibiting endogenous PKC-β1 substantially prevented all measures of EGF's protection against NF-κB activation. We conclude that EGF-mediated protection against oxidant disruption of the intestinal barrier function requires PKC-β1 activation and NF-κB suppression. The molecular event underlying this unique effect of PKC-β1 involves inhibition of phosphorylation and increases in stabilization of IκBα. The ability to inhibit the dynamics of NF-κB/IκBα and F-actin disassembly is a novel mechanism not previously attributed to the classic subfamily of PKC isoforms.
Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage
Authors: Fogt Donovan L. , Pan Shujia , Lee Sukho , Ding Zhenping , Scrimgeour Angus , Lawrence John C. , Ivy John L.
Published: February 2004

Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 ± 20.5 μmol/g glycogen compared with 17.7 ± 2.6 μmol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 ± 0.3 and 3.9 ± 0.6 μmol·g-1·h-1 for transgenic and wild-type, respectively) and postcontraction (7.9 ± 0.4 and 7.0 ± 0.4 μmol·g-1·h-1 for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [14C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship.
cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue
Authors: Serazin Valérie , Dieudonné Marie-Noelle , Morot Mireille , de Mazancourt Philippe , Giudicelli Yves
Published: February 2004

The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to β-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via β-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.
Effect of low-protein diet and protein supplementation on the expressions of TNF-α, TNFR-I, and TNFR-II in organs and muscle of LPS-injected rats
Authors: Raina Nilima , Jeejeebhoy Khursheed N.
Published: February 2004

Previous studies had shown that increasing energy intake in anorexic TNF-α-treated rats increased morbidity due to stabilization of TNF activity by soluble and membrane TNF receptors (TNFR). Although protein supplementation reduces septic morbidity, its effect on TNF and TNFR is unknown. To determine the effect of low protein intake and supplementation on TNF and TNFR, 30 male Wistar rats weighing 250 g were fed a liquid defined-formula diet for 10 days and randomly allocated to 1) controls (C; n = 6), receiving normal energy and protein energy density of 0.047 MJ/60 ml + normal saline (NS); 2) low protein (LP; n = 6), receiving normal energy but a reduced protein-energy density of 0.012 MJ/60 ml + LPS; 3) refeeding (RF; n = 6), initially depleted on low-protein diet (10 days) and then repleted on normal protein (10 days) while receiving LPS; and 4) pair fed (P-F; n = 12), individual P-F rats being paired with individual LP or RF rats receiving NS. Protein and mRNA expression of TNF-α, TNFR-I, and TNFR-II in liver, spleen, and gastrocnemius were measured by Western blot and RT-PCR, respectively. In liver, the changes in TNF-α, TNFR-I, and TNFR-II were translational, whereas in spleen the effects were due to a combination of transcription and translation. In gastrocnemius, the effects were transcriptional/translational for TNFRs. In contrast, TNF-α mRNA was significantly increased, but TNF-α protein expression was reduced in LP rats compared with C and RF groups. In conclusion, protein deficiency in endotoxic rats increases the expression of TNFR-I and TNFR-II in all organs studied and TNF-α in selected ones. This increase is suppressed by refeeding protein. A differential pattern between translation and transcription of TNF-α and its receptors is present. Our data suggest that protein restriction may be deleterious in sepsis.
In vivo regulation of growth hormone-stimulated gene transcription by STAT5b
Authors: Woelfle Joachim , Rotwein Peter
Published: February 2004

The long-term effects of growth hormone (GH) are mediated through coordinated changes in gene expression that are the outcome of interactions between hormone-activated signal transduction pathways and specific feedback loops. Recent studies in mice have implicated the transcription factor STAT5b as part of the GH-regulated somatic growth pathway, because mice lacking this protein showed diminished growth rates. To assess the role of Stat5b in GH-stimulated gene expression, we have delivered modified versions of the protein to the liver of pituitary-deficient male rats by quantitative adenovirus-mediated gene transfer. In pilot studies in cell culture, both constitutive-active and dominant-negative STAT5b showed appropriate binding properties toward a specific DNA response element. After in vivo expression, neither protein prevented nuclear accumulation of STATs 1 and 3 in the liver. Dominant-negative STAT5b completely inhibited GH-stimulated transcription of genes encoding the growth-promoting proteins IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS), which comprise the major circulating IGF-I complex, and blocked expression of the GH inhibitors SOCS-1, SOCS-2, and CIS, but had little effect on induction of SOCS-3. Constitutive-active STAT5b stimulated robust transcription of IGF-I, ALS, and IGFBP-3 in the absence of hormone but did little to modify GH-mediated activation of SOCS family genes. An adenovirus encoding EGFP was without effect. These results, in addition to establishing STAT5b as one of the key agents of GH-stimulated gene transcription, demonstrate the feasibility of using in vivo gene transfer to target and dissect the functions of distinct components of complex hormone-activated signal transduction pathways.
Reciprocal inhibition of umbilical uptake within groups of amino acids
Authors: Jóźwik Maciej , Teng Cecilia , Wilkening Randall B. , Meschia Giacomo , Battaglia Frederick C.
Published: February 2004

Eight pregnant sheep were infused with two amino acid mixtures of different composition: essential amino acids only and the essentials plus some of the nonessentials. Uterine and umbilical uptakes of amino acids were measured before and during infusion. For most of the amino acids, the infusion increased both maternal plasma concentration and umbilical uptake. However, depending on the infusate composition, the increase in maternal concentration of some amino acids was associated with no change or a significant reduction in umbilical uptake. Data were pooled from this and other, similar studies to test the hypothesis that umbilical uptake of several amino acids can be inhibited by coinfused amino acids. The test consisted of fitting the data, by means of multiple regression analysis, to the linear transformation of a saturation kinetics equation in which uptake is assumed to depend on maternal arterial concentrations. The analysis showed significant inhibitory effects within the neutral essential amino acids group and within the lysine-arginine group, with no demonstrable interaction between the two groups. Uterine uptakes did not show clear evidence of saturability and inhibitory interactions, suggesting a large transport capacity and low transporter affinity on the maternal surface of the trophoblast. We conclude that the transport of any given amino acid from placenta to fetus is a function of both its own maternal concentration and the maternal concentration of inhibitory amino acids.
Reduced renal dopamine D1receptor function in streptozotocin-induced diabetic rats
Authors: Marwaha Aditi , Banday Anees Ahmad , Lokhandwala Mustafa F.
Published: February 2004

Dopamine, via activation of renal D1receptors, inhibits the activities of Na-K-ATPase and Na/H exchanger and subsequently increases sodium excretion. Decreased renal dopamine production and sodium excretion are associated with type I diabetes. However, it is not known whether the response to D1receptor activation is altered in type I diabetes. The present study was designed to examine the effect of streptozotocin-induced type I diabetes on renal D1receptor expression and function. Streptozotocin treatment of Sprague-Dawley rats caused a fourfold increase in plasma levels of glucose along with a significant decrease in insulin levels compared with control rats. Intravenous administration of SKF-38393, a D1receptor agonist, caused a threefold increase in sodium excretion in control rats. However, SKF-38393 failed to produce natriuresis in diabetic rats. SKF-38393 caused a concentration-dependent inhibition of Na-K-ATPase activity in renal proximal tubules of control rats. However, the ability of SKF-38393 to inhibit Na-K-ATPase activity was markedly diminished in diabetic rats. D1receptor numbers and protein abundance as determined by [3H]SCH-23390 ligand binding and Western blot analysis were markedly reduced in diabetic rats compared with control rats. Moreover, SKF-38393 failed to stimulate GTPγS binding in proximal tubular membranes from diabetic rats compared with control rats. We conclude that the natriuretic response to D1receptor activation is reduced in type I diabetes as a result of a decrease in D1receptor expression and defective receptor G protein coupling. These abnormalities may contribute to the sodium retention associated with type I diabetes.
Microalbuminuria as a marker of cardiovascular and renal risk in type 2 diabetes mellitus: a temporal perspective
Authors: Lane James T.
Published: February 2004

Microalbuminuria is a marker for diabetic nephropathy. It also signifies cardiovascular disease, as well as nephropathy, in type 2 diabetes (DM2). Microalbuminuria may precede DM2, occurring with the insulin resistance syndrome and its components, including obesity and hypertension. Other indicators of cardiovascular risk, such as markers of inflammation, are associated with microalbuminuria in populations of patients with and without diabetes. With the rising prevalence of DM2 in minority youth, especially in Native Americans, a marker for future disease risk would allow earlier prevention strategies to be tested. Before microalbuminuria can be used in a prevention strategy, more needs to be known about the mechanism(s) of the association between elevated excretion, its relationship to glucose intolerance, and its relative contribution to cardiovascular and renal disease. These questions are especially applicable as we begin to observe the long-term complications of diabetes in youth.
Expression and relative abundance of short transient receptor potential channels in the rat renal microcirculation
Authors: Facemire Carie S. , Mohler Peter J. , Arendshorst William J.
Published: February 2004

In the resistance vessels of the renal microcirculation, store- and/or receptor-operated calcium entry contribute to the rise in vascular smooth muscle cell (VSMC) intracellular calcium concentration in response to vasoconstrictor hormones. Short transient receptor potential (TRPC) channels are widely expressed in mammalian tissues and are proposed mediators of voltage-independent cation entry in multiple cell types, including VSMCs. The seven members of the TRPC gene family (TRPC1-7) encode subunit proteins that are thought to form homo- and heterotetrameric channels that are differentially regulated depending on their subunit composition. In the present study, we demonstrate the relative abundance of TRPC mRNA and protein in freshly isolated rat renal resistance vessels, glomeruli, and aorta. TRPC1, 3, 4, 5, and 6 mRNA and protein were detected in both renal resistance vessels and aorta, whereas TRPC2 and TRPC7 mRNA were not expressed. TRPC1, 3, 5, and 6 protein was present in glomeruli. TRPC3 and TRPC6 protein levels were significantly greater in the renal resistance vessels, about six- to eightfold higher than in aorta. These data suggest that TRPC3 and TRPC6 may play a role in mediating voltage-independent calcium entry in renal resistance vessels that is functionally distinct from that in aorta.
Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation
Authors: Tierney Emily P. , Tulac Suzana , Huang Se-Te Joseph , Giudice Linda C.
Published: February 2004

Decidualization of endometrial stromal cells is a prerequisite for human implantation and occurs in vivo in response to progesterone and involves activation of the protein kinase A (PKA) pathway. The objective of this study was to determine the molecular signatures and patterns of gene expression during stimulation of this pathway with an analog of cAMP. Endometrial stromal cells from two subjects were treated with or without 8-Br-cAMP (1 mM) for 0, 2, 12, 24, 36, and 48 h and were processed for microarray analysis, screening for 12,686 genes and ESTs. Most abundantly upregulated genes included neuropeptides, immune genes, IGF family members, cell cycle regulators, extracellular matrix proteases, cholesterol trafficking, cell growth and differentiation, hormone signaling, and signal transduction. Most abundantly downregulated genes included activator of NF-κB, actin/tropomyosin/calmodulin binding protein, cyclin B, IGFBP-5, α1 type XVI collagen, lipocortin III, l-kynurenine hydrolase, frizzle-related protein, and cyclin E2. RT-PCR validated upregulation of IGFBP-1, preprosomatostatin, and IL-11, and Northern analysis validated their kinetic upregulation. RT-PCR confirmed downregulation of IGFBP-5, cyclin B, and TIL-4. K-means analysis revealed four major patterns of up- and downregulated genes, and genes within each ontological group were categorized into these four kinetic patterns. Within each ontological group different patterns of temporal gene expression were observed, indicating that even genes within one functional category are regulated differently during activation of the PKA pathway in human endometrial stromal cells. Overall, the data demonstrate kinetic reprogramming of genes within specific functional groups and changes in genes associated with nucleic acid binding, cell proliferation, decreased G protein signaling, increased STAT pathway signaling, structural proteins, cellular differentiation, and secretory processes. These changes are consistent with cAMP modulating early events (0–6 h) primarily involving cell cycle regulation, subsequent events (12–24 h) involving cellular differentiation (including changes in morphology and secretory phenotype), and late events (24–48 h) mediating more specialized function, including immune modulators, in the human endometrial stromal cell.
The intraclass correlation coefficient applied for evaluation of data correction, labeling methods, and rectal biopsy sampling in DNA microarray experiments
Authors: Pellis Linette , Franssen-van Hal Nicole L. W. , Burema Jan , Keijer Jaap
Published: February 2004

We show that the intraclass correlation coefficient (ICC) can be used as a relatively simple statistical measure to assess methodological and biological variation in DNA microarray analysis. The ICC is a measure that determines the reproducibility of a variable, which can easily be calculated from an ANOVA table. It is based on the assessment of both systematic deviation and random variation, and it facilitates comparison of multiple samples at once. We used the ICC first to optimize our microarray data normalization method and found that the use of median values instead of mean values improves data correction. Then the reproducibility of different labeling methods was evaluated, and labeling by indirect fluorescent dye incorporation appeared to be more reproducible than direct labeling. Finally, we determined optimal biopsy sampling by analyzing overall variation in gene expression. The variation in gene expression of rectal biopsies within persons decreased when two biopsies were taken instead of one, but it did not considerably improve when more than two biopsies were taken from one person, indicating that it is sufficient to use two biopsies per person for DNA microarray analysis under our experimental conditions. To optimize the accuracy of the microarray data, biopsies from at least six different persons should be used per group.
Boundedness of multilinear operators on Triebel‐Lizorkin spaces
Authors: Lanzhe Liu
Published: February 2004

The purpose of this paper is to study the boundedness in the
context of Triebel‐Lizorkin spaces for some multilinear operators
related to certain convolution operators. The operators include
Littlewood‐Paley operator, Marcinkiewicz integral, and Bochner‐Riesz operator.
Peroxisome Proliferator-Activated Receptor α Agonists Increase Nitric Oxide Synthase Expression in Vascular Endothelial Cells
Authors: Goya Kayoko , Sumitani Satoru , Xu Xin , Kitamura Tetsuhiro , Yamamoto Hiroyasu , Kurebayashi Shogo , Saito Hiroshi , Kouhara Haruhiko , Kasayama Soji , Kawase Ichiro
Published: February 2004

Objective—

There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor α (PPARα) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPARα activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells.

Methods and Results—

Bovine aortic endothelial cells were treated with the PPARα activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPARα action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment.

Conclusions—

PPARα activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPARα-mediated cardiovascular protection.
Evidence for a Role of Macrophage Migration Inhibitory Factor in Vascular Disease
Authors: Chen Zhiping , Sakuma Masashi , Zago Alexandre C. , Zhang Xiaobin , Shi Can , Leng Lin , Mizue Yuka , Bucala Richard , Simon Daniel I.
Published: February 2004

Objective—Inflammation plays an essential role in atherosclerosis and restenosis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is widely expressed in vascular cells. However, there is no in vivo evidence that MIF participates directly in vascular injury and repair. Therefore, we investigated the effect of MIF blockade on the response to experimental angioplasty in atherosclerosis-susceptible mice.

Methods and Results—Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDL receptor-deficient mice treated with a neutralizing anti-MIF or isotype control monoclonal antibody. After 7 days and 28 days, intimal and medial sizes were measured and intima/media area ratio (I/M) was calculated. Intimal thickening and I/M were reduced significantly by anti-MIF compared with control antibody. Vascular injury was accompanied by progressive vessel enlargement or “positive remodeling” that was comparable in both treatment groups. MIF blockade was associated with reduced inflammation and cellular proliferation and increased apoptosis after injury.

Conclusion—Neutralizing MIF bioactivity after experimental angioplasty in atherosclerosis-susceptible mice reduces vascular inflammation, cellular proliferation, and neointimal thickening. Although the molecular mechanisms responsible for these effects are not yet established, these data prompt further research directed at understanding the role of MIF in vascular disease and suggest novel therapeutic interventions for preventing atherosclerosis and restenosis.
Urinary 8-iso-Prostaglandin F
2α
as a Risk Marker in Patients With Coronary Heart Disease
Authors: Schwedhelm Edzard , Bartling Asja , Lenzen Henrike , Tsikas Dimitrios , Maas Renke , Brümmer Jens , Gutzki Frank-Mathias , Berger Jürgen , Frölich Jürgen C. , Böger Rainer H.
Published: February 2004

Background—

Oxidative stress is involved in the pathophysiology of atherosclerosis, diabetes mellitus, hypertension, obesity, and cigarette smoking, all of these being risk factors for coronary heart disease (CHD). We tested the hypothesis that risk factors of CHD are associated with abundant systemic oxidative stress.

Methods and Results—

We conducted a case-control study with 93 CHD patients and 93 control subjects frequency-matched by age and sex. Urinary excretion of the F
2
-isoprostane 8-iso-prostaglandin (PG) F
2α
and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF
2α
, were measured by gas chromatography–tandem mass spectrometry. Body mass index, systolic blood pressure, and C-reactive protein were elevated in CHD patients (
P
<0.01). Urinary 8-iso-PGF
2α
and 2,3-dinor-5,6-dihydro-8-iso-PGF
2α
also differed, from 77 (interquartile range, 61–101) to 139 (93–231) pmol/mmol creatinine and from 120 (91–151) to 193 (140–275) pmol/mmol in control subjects and case subjects, respectively (
P
<0.001). 8-iso-PGF
2α
and its metabolite were highly correlated (Spearman’s ρ=0.664,
P
<0.001). HDL cholesterol was diminished in CHD patients (
P
<0.001). All of these characteristics predicted CHD in univariate analysis. In a multivariate model, the odds ratios were increased only for 8-iso-PGF
2α
(≥131 pmol/mmol,
P
<0.001) and C-reactive protein (>3 mg/L,
P
<0.01), ie, by 30.8 (95% CI, 7.7–124) and 7.2 (1.9–27.6), respectively. 8-iso-PGF
2α
was found to be a novel marker in addition to known risk factors of CHD, ie, diabetes mellitus, hypercholesterolemia, hypertension, and smoking. Urinary excretion of 8-iso-PGF
2α
correlated with the number of risk factors for all subjects (
P
<0.001 for trend).

Conclusions—

8-iso-PGF
2α
is a sensitive and independent risk marker of CHD.
Role of Nrf2 in the Regulation of CD36 and Stress Protein Expression in Murine Macrophages
Authors: Ishii Tetsuro , Itoh Ken , Ruiz Emilio , Leake David S. , Unoki Hiroyuki , Yamamoto Masayuki , Mann Giovanni E.
Published: February 2004

CD36 is an important scavenger receptor mediating uptake of oxidized low-density lipoproteins (oxLDLs) and plays a key role in foam cell formation and the pathogenesis of atherosclerosis. We report the first evidence that the transcription factor Nrf2 is expressed in vascular smooth muscle cells, and demonstrate that oxLDLs cause nuclear accumulation of Nrf2 in murine macrophages, resulting in the activation of genes encoding CD36 and the stress proteins A170, heme oxygenase-1 (HO-1), and peroxiredoxin I (Prx I). 4-Hydroxy-2-nonenal (HNE), derived from lipid peroxidation, was one of the most effective activators of Nrf2. Using Nrf2-deficient macrophages, we established that Nrf2 partially regulates CD36 expression in response to oxLDLs, HNE, or the electrophilic agent diethylmaleate. In murine aortic smooth muscle cells, expressing negligible levels of CD36, both moderately and highly oxidized LDL caused only limited Nrf2 translocation and negligible increases in A170, HO-1, and Prx I expression. However, treatment of smooth muscle cells with HNE significantly enhanced nuclear accumulation of Nrf2 and increased A170, HO-1, and Prx I protein levels. Because PPAR-γ can be activated by oxLDLs and controls expression of CD36 in macrophages, our results implicate Nrf2 as a second important transcription factor involved in the induction of the scavenger receptor CD36 and antioxidant stress genes in atherosclerosis.
Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans
Authors: Díaz Mary E. , O’Neill Stephen C. , Eisner David A.
Published: February 2004

The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca
2+
transient (Ca
2+
alternans) is due to changes of sarcoplasmic reticulum (SR) Ca
2+
content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca
2+
content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca
2+
transient. Confocal measurements showed that the larger transients resulted from propagation of Ca
2+
waves. SR Ca
2+
content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca
2+
transient amplitude. After a large transient, if SR Ca
2+
content was elevated by brief exposure of the cell to a Na
+
-free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca
2+
content are sufficient to produce alternans. The dependence of Ca
2+
transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca
2+
efflux from the cell was also a steeper function of SR Ca
2+
content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca
2+
content. In conclusion, alternans of systolic Ca
2+
appears to depend on alternation of SR Ca
2+
content. This, in turn results from the steep dependence on SR Ca
2+
content of Ca
2+
release and therefore Ca
2+
efflux from the cell as a consequence of wave propagation.
Association of Infratentorial Brain Arteriovenous Malformations With Hemorrhage at Initial Presentation
Authors: Khaw A.V. , Mohr J.P. , Sciacca R.R. , Schumacher H.C. , Hartmann A. , Pile-Spellman J. , Mast H. , Stapf C.
Published: February 2004

Background and Purpose—

The goal of this study was to analyze the association of hemorrhagic presentation with infratentorial brain arteriovenous malformations (AVMs).

Methods—

The 623 consecutive, prospectively enrolled patients from the Columbia AVM Databank were analyzed in a cross-sectional study. Clinical presentation (diagnostic event) was categorized as intracranial hemorrhage or nonhemorrhagic presentation. From brain imaging and cerebral angiography, AVM location was classified as either infratentorial or supratentorial. Univariate and multivariate statistical models were applied to test the effect of age, sex, AVM size and location, venous drainage pattern, and associated (ie, feeding artery or intranidal) arterial aneurysms on the likelihood of hemorrhage at initial AVM presentation.

Results—

Of the 623 patients, 72 (12%) had an infratentorial and 551 (88%) had a supratentorial AVM. Intracranial hemorrhage was the presenting symptom in 283 patients (45%), and infratentorial AVM location was significantly more frequent (18%) among patients who bled initially (6%; odds ratio [OR], 3.60; 95% confidence interval [CI], 2.09 to 6.20). This difference remained significant (OR, 1.99; 95% CI, 1.07 to 3.69) in the multivariate logistic regression model controlling for age, sex, AVM size, deep venous drainage, and associated arterial aneurysms. In the same model, the effect of other established determinants for AVM hemorrhage—ie, AVM size (in 1-mm increments; OR, 0.95; 95% CI, 0.94 to 0.96), deep venous drainage (OR, 3.09; 95% CI, 1.87 to 5.12), and associated aneurysms (OR, 2.78; 95% CI, 1.76 to 4.40)—remained significant.

Conclusions—

Our findings suggest that infratentorial AVM location is independently associated with hemorrhagic AVM presentation.
The small oligomerization domain of gephyrin converts MLL to an oncogene
Authors: Eguchi Mariko , Eguchi-Ishimae Minenori , Greaves Mel
Published: February 2004

The MLL (mixed lineage leukemia) gene forms chimeric fusions with a diverse set of partner genes as a consequence of chromosome translocations in leukemia. In several fusion partners, a transcriptional activation domain appears to be essential for conferring leukemogenic capacity on MLL protein. Other fusion partners, however, lack such domains. Here we show that gephyrin (GPHN), a neuronal receptor assembly protein and rare fusion partner of MLL in leukemia, has the capacity as an MLL-GPHN chimera to transform hematopoietic progenitors, despite lack of transcriptional activity. A small 15–amino acid tubulin-binding domain of GPHN is necessary and sufficient for this activity in vitro and in vivo. This domain also confers oligomerization capacity on MLL protein, suggesting that such activity may contribute critically to leukemogenesis. The transduction of MLL-GPHN into hematopoietic progenitor cells caused myeloid and lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target multipotent progenitor cells. Our results, and other recent data, provide a mechanism for oncogenic conversion of MLL by fusion partners encoding cytoplasmic proteins.