bluuebunny/crossref_metadata_2025 huggingface dataset:
Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct
Authors: Liu Wen , Morimoto Tetsuji , Woda Craig , Kleyman Thomas R. , Satlin Lisa M.
Published: March 2007

Apical low-conductance SK and high-conductance Ca2+-activated BK channels are present in distal nephron, including the cortical collecting duct (CCD). Flow-stimulated net K secretion ( JK) in the CCD is 1) blocked by iberiotoxin, an inhibitor of BK but not SK channels, and 2) associated with an increase in [Ca2+]i, leading us to conclude that BK channels mediate flow-stimulated JK. To examine the Ca2+ dependence and sources of Ca2+ contributing to flow-stimulated JK, JK and net Na absorption ( JNa) were measured at slow (∼1) and fast (∼5 nl·min−1·mm−1) flow rates in rabbit CCDs microperfused in the absence of luminal Ca2+ or after pretreatment with BAPTA-AM to chelate intracellular Ca2+, 2-aminoethoxydiphenyl borate (2-APB), to inhibit the inositol 1,4,5-trisphosphate (IP3) receptor or thapsigargin to deplete internal stores. These treatments, which do not affect flow-stimulated JNa (Morimoto et al. Am J Physiol Renal Physiol 291: F663–F669, 2006), inhibited flow-stimulated JK. Increases in [Ca2+]i stimulate exocytosis. To test whether flow induces exocytic insertion of preformed BK channels into the apical membrane, CCDs were pretreated with 10 μM colchicine (COL) to disrupt microtubule function or 5 μg/ml brefeldin-A (BFA) to inhibit delivery of channels from the intracellular pool to the plasma membrane. Both agents inhibited flow-stimulated JK but not JNa (Morimoto et al. Am J Physiol Renal Physiol 291: F663–F669, 2006), although COL but not BFA also blocked the flow-induced [Ca2+]i transient. We thus speculate that BK channel-mediated, flow-stimulated JK requires an increase in [Ca2+]i due, in part, to luminal Ca2+ entry and ER Ca2+ release, microtubule integrity, and exocytic insertion of preformed channels into the apical membrane.
Renal localization and function of the tight junction protein, claudin-19
Authors: Angelow Susanne , El-Husseini Randa , Kanzawa Sanae A. , Yu Alan S. L.
Published: March 2007

Claudins form a family of transmembrane tight junction proteins that play a key role in control and selectivity of paracellular transport. Mutations in claudin-19, which is expressed in kidney, retina, and myelinated peripheral neurons, were identified in familial hypomagnesemia with hypercalciuria and nephrocalcinosis, a hereditary disease causing renal Mg2+and Ca2+wasting. Here, we studied the distribution and possible functional role of claudin-19 in the renal tubule. By immunofluorescence staining of mouse kidney, claudin-19 was found to be expressed at the tight junction of the thick ascending limb of Henle, the major site of paracellular Mg2+reabsorption, where it colocalized with claudin-16, as well as in the thin ascending limb. The role of claudin-19 in paracellular transport was tested by stable transfection into Madin Darby canine kidney II TetOff cells to generate inducible cell lines. Claudin-19 increased the transepithelial electrical resistance and decreased permeability to monovalent and divalent cations, while anion and urea permeability were not affected. Our data suggest that claudin-19 acts as a selective cation barrier at the tight junction. This would be consistent with its physiological role to electrically seal myelinated peripheral neurons. The normal role of claudin-19 in renal tubule function remains to be determined.
Trafficking of ENaC subunits in response to acute insulin in mouse kidney
Authors: Tiwari Swasti , Nordquist Lina , Halagappa Veerendra K. Madala , Ecelbarger Carolyn A.
Published: March 2007

Studies done in cell culture have demonstrated that insulin activates the epithelial sodium channel (ENaC) via a variety of mechanisms. However, to date, upregulation of ENaC in native renal tissue by in vivo administration of insulin has not been demonstrated. To address this, we injected 6-mo-old male C57BL/CBA mice ( n = 14/group) intraperitoneally with vehicle or 0.5 U/kg body wt insulin and examined short-term (1–2 h) sodium excretion and kidney ENaC subunits (α, β, and γ) and serum and glucocorticoid-induced kinase (SGK-1) regulation. Insulin resulted in a significant reduction in urine sodium (by ∼80%) that was restored by intraperitoneal administration of the ENaC antagonist, benzamil (1.4 mg/kg body wt). Differential centrifugation followed by Western blotting of whole kidney revealed significantly increased band densities (by 26–103%) for insulin- relative to vehicle-treated mice for α- and γ-ENaC in the homogenate (H), and plasma membrane-enriched fraction (MF), with no difference in the vesicle-enriched fraction (VF). Similarly, β-ENaC was significantly increased in MF (by 45%) but no change in the H. It was, however, significantly decreased in the VF (by 28%) with insulin. In agreement, immunoperoxidase labeling demonstrated relatively stronger apical, relative to cytosolic, localization of α-, β-, and γ-ENaC with insulin, whereas, with vehicle, labeling was fairly evenly dispersed throughout collecting duct principal cells. Furthermore, Western blotting showed insulin increased SGK-1 (by 75%) and phosphorylated-SGK band densities (by 30%) but only in the MF. These studies demonstrate novel in vivo regulation of renal ENaC activity and subunit proteins and SGK-1 by insulin in the acute time frame in the mouse.
Guanylyl cyclase/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels
Authors: Zhao Di , Vellaichamy Elangovan , Somanna Naveen K. , Pandey Kailash N.
Published: March 2007

Disruption of the guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) gene leads to elevated arterial blood pressure and congestive heart failure in mice lacking NPRA. This study was aimed at determining whether Npr1 (coding for GC-A/NPRA) gene copy number affects adrenal ANG II and aldosterone (Aldo) levels in a gene-dose-dependent manner in Npr1 gene-targeted mice. Adrenal ANG II and Aldo levels increased in 1-copy mice compared with 2-copy mice, but decreased in 3-copy and 4-copy mice. In contrast, renal ANG II levels decreased in 1-copy (25%), 3-copy (38%), and 4-copy (39%) mice compared with 2-copy mice. The low-salt diet stimulated adrenal ANG II and Aldo levels in 1-copy (20 and 2,441%), 2-copy (15 and 2,339%), 3-copy (20 and 424%), and 4-copy (31 and 486%) mice, respectively. The high-salt diet suppressed adrenal ANG II and Aldo levels in 1-copy (46 and 29%) and 2-copy (38 and 17%) mice. On the other hand, the low-salt diet stimulated renal ANG II levels in 1-copy (45%), 2-copy (45%), 3-copy (59%), and 4-copy (48%) mice. However, the high-salt diet suppressed renal ANG II levels in 1-copy (28%) and 2-copy (27%) mice. In conclusion, NPRA signaling antagonizes adrenal ANG II and Aldo levels in a gene-dose dependent manner. Increased adrenal ANG II and Aldo levels may play an important role in elevated arterial blood pressure and progressive hypertension, leading to renal and vascular injury in Npr1 gene-disrupted mice.
Humidity-Dependent Cold Cells on the Antenna of the Stick Insect
Authors: Tichy Harald
Published: March 2007

We present the first systematic study of the response of insect “cold cells” to a variation in the partial pressure of water vapor in ambient air. The cold cells on the antenna of the stick insect respond with an increase in activity when either the temperature or the partial pressure of water vapor is suddenly reduced. This double dependency does not in itself constitute bimodality because it could disappear with the proper choice of parameters involving temperature and humidity. In this study, we demonstrate that the evaporation of a small amount of water from the sensillum surface resulting from a drop in the water vapor pressure—leading to a transient drop in temperature and thus to a brief rise in impulse frequency—is the most plausible explanation for this bimodal response. We also show with an order-of-magnitude calculation that this mechanism is plausible and consistent with the amounts of water vapor potentially present on the sensillum. We hypothesize that a film of moisture collects on the hygroscopic sensillum surface at higher humidity and then tends to evaporate when humidity is lowered. The water might even be bound loosely within the cuticular wall, a situation conceivable in a sensillum that contains two hygroreceptive cells in addition to the cold cell.
Layer- and Cell-Type-Specific Effects of Neonatal Whisker-Trimming in Adult Rat Barrel Cortex
Authors: Lee Soo-Hyun , Land Peter W. , Simons Daniel J.
Published: March 2007

Tactile deprivation in rats produced by whisker-trimming early in life leads to abnormally robust responses of excitatory neurons in layer 4 of primary somatosensory cortex when the re-grown whiskers are stimulated. Present findings from fast-spike neurons indicate that presumed inhibitory cells fire less robustly under the same conditions. These contrasting effects may reflect altered patterns of thalamocortical input to excitatory versus inhibitory cells and/or changes in the strength of intracortical connections. Despite increased excitability of layer 4, neurons in layer 2/3 respond at control levels even after full whisker re-growth. Layer 4 synapses onto supragranular neurons may be permanently depressed as a result of neonatal sensory deprivation.
Gender Differences in UVB-Induced Skin Carcinogenesis, Inflammation, and DNA Damage
Authors: Thomas-Ahner Jennifer M. , Wulff Brian C. , Tober Kathleen L. , Kusewitt Donna F. , Riggenbach Judy A. , Oberyszyn Tatiana M.
Published: March 2007

The American Cancer Society reports the incidence of squamous cell carcinoma in males to be thrice the incidence in females. This increased squamous cell carcinoma incidence has been attributed to men accumulating more sun exposure and using less sun protection than women. To date, there have been no controlled studies examining the effect of gender on skin tumor development following equal doses of UVB. Gender differences in UVB-induced skin carcinogenesis were examined using the Skh-1 mouse model. After chronic exposure to equal doses of UVB, male mice developed tumors earlier and had more tumors than female mice; tumors in male mice tended to be larger, and the total tumor burden was greater than in females. In addition, tumors in males were of more advanced histologic grade compared with those of female mice. To evaluate the contribution of differences in inflammation and DNA damage to differences in skin carcinogenesis, male and female Skh-1 mice were exposed once to 2,240 J/m2 UVB and examined 48 h after exposure. Surprisingly, male mice developed less of an inflammatory response, as determined by skin fold thickness and myeloperoxidase activity, compared with females. Interestingly, male mice showed more cutaneous oxidative DNA damage than the females and lower antioxidant levels. These results show a gender bias in skin carcinogenesis and suggest that the gender difference in tumor development is more influenced by the extent of oxidative DNA damage and antioxidant capacities than by inflammatory response. [Cancer Res 2007;67(7):3468–74]
Transitional Change in the Clinical Features of Pulmonary Tuberculosis
Authors: Kobashi Yoshihiro , Mouri Keiji , Fukuda Minoru , Yoshida Kouichiro , Miyashita Naoyuki , Oka Mikio
Published: March 2007

Background: An aging population, increased use of immunosuppressive therapy and an increase in patients with risk factors for tuberculosis have induced changes in the clinical features of pulmonary tuberculosis in Japan. Objective: To investigate transitional changes in the clinical features of recent patients with pulmonary tuberculosis. Methods: This study analyzed 820 patients with pulmonary tuberculosis who were culture positive for Mycobacterium tuberculosis in the Kawasaki Medical School Hospital and ten associated community hospitals between January 1986 and December 2005 (406 patients between January 1986 and December 1995 and 414 patients between January 1996 and December 2005). Results: The characteristic clinical features of the latter period were as follows: (1) an increase in the percentages of patients with both malignant diseases and collagen vascular diseases, (2) a decrease in the proportion of patients with obvious clinical symptoms, (3) an increase in the number of microbiologically smear-positive patients, (4) an increase in the percentages of patients with atypical radiological findings, (5) no change in the incidence of multidrug-resistant M. tuberculosis and (6) no change in the rate of the effect of treatment or prognosis. Conclusions: The findings of an increase in atypical features may be related to the increase in immunocompromised patients and should therefore be investigated further. Performance of acid-fast bacillus examination is extremely important because a good prognosis can be achieved if an accurate diagnosis is established as soon as possible and the resistance of M. tuberculosis to antituberculous drugs has not progressed.
Infarct Tissue Heterogeneity by Magnetic Resonance Imaging Identifies Enhanced Cardiac Arrhythmia Susceptibility in Patients With Left Ventricular Dysfunction
Authors: Schmidt André , Azevedo Clerio F. , Cheng Alan , Gupta Sandeep N. , Bluemke David A. , Foo Thomas K. , Gerstenblith Gary , Weiss Robert G. , Marbán Eduardo , Tomaselli Gordon F. , Lima João A.C. , Wu Katherine C.
Published: March 2007

Background—

The extent of the peri-infarct zone by magnetic resonance imaging (MRI) has been related to all-cause mortality in patients with coronary artery disease. This relationship may result from arrhythmogenesis in the infarct border. However, the relationship between tissue heterogeneity in the infarct periphery and arrhythmic substrate has not been investigated. In the present study, we quantify myocardial infarct heterogeneity by contrast-enhanced MRI and relate it to an electrophysiological marker of arrhythmic substrate in patients with left ventricular (LV) systolic dysfunction undergoing prophylactic implantable cardioverter defibrillator placement.

Methods and Results—

Before implantable cardioverter defibrillator implantation for primary prevention of sudden cardiac death, 47 patients underwent cine and contrast-enhanced MRI to measure LV function, volumes, mass, and infarct size. A method for quantifying the heterogeneous infarct periphery and the denser infarct core is described. MRI indices were related to inducibility of sustained monomorphic ventricular tachycardia during electrophysiological or device testing. For the noninducible versus inducible patients, LV ejection fraction (30±10% versus 29±7%,
P
=0.79), LV end-diastolic volume (220±70 versus 228±57 mL,
P
=0.68), and infarct size by standard contrast-enhanced MRI definitions (
P
=NS) were similar. Quantification of tissue heterogeneity at the infarct periphery was strongly associated with inducibility for monomorphic ventricular tachycardia (noninducible versus inducible: 13±9 versus 19±8 g,
P
=0.015) and was the single significant factor in a stepwise logistic regression.

Conclusions—

Tissue heterogeneity is present and quantifiable within human infarcts. More extensive tissue heterogeneity correlates with increased ventricular irritability by programmed electrical stimulation. These findings support the hypothesis that anatomic tissue heterogeneity increases susceptibility to ventricular arrhythmias in patients with prior myocardial infarction and LV dysfunction.
Targeted Cardiac Overexpression of A20 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction
Authors: Li Hong-Liang , Zhuo Ming-Lei , Wang Dong , Wang Ai-Bing , Cai Hua , Sun Li-Hong , Yang Qinglin , Huang Yue , Wei Yu-Sheng , Liu Peter P. , Liu De-Pei , Liang Chih-Chuan
Published: March 2007

Background—

A20 was originally characterized as a tumor necrosis factor–inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-κB signaling, A20 protects against apoptosis, inflammation, and cardiac hypertrophy. In the present study, we tested the hypothesis that cardiac-specific overexpression of A20 could protect the heart from myocardial infarction.

Methods and Results—

We investigated the role of constitutive human A20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the human A20 gene under the control of the α-myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20 transgenic mice and control animals. The extent of infarction was then quantified by 2-dimensional and M-mode echocardiography and by molecular and pathological analyses of heart samples in infarct and remote heart regions 7 days after myocardial infarction. Constitutive overexpression of A20 in the murine heart resulted in attenuated infarct size and improved cardiac function 7 days after myocardial infarction. Significantly, we found a decrease in nuclear factor-κB signaling and apoptosis, as well as proinflammatory response, cardiac remodeling, and interstitial fibrosis, in noninfarct regions in the hearts of constitutive A20-expressing animals compared with control animals.

Conclusions—

Cardiac-specific overexpression of A20 improves cardiac function and inhibits cardiac remodeling, apoptosis, inflammation, and fibrosis after acute myocardial infarction.
Mechanistic Role of
I
f
Revealed by Induction of Ventricular Automaticity by Somatic Gene Transfer of Gating-Engineered Pacemaker (HCN) Channels
Authors: Xue Tian , Siu Chung-Wah , Lieu Deborah K. , Lau Chu-Pak , Tse Hung-Fat , Li Ronald A.
Published: March 2007

Background—

Although
I
f
, encoded by the hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel gene family, is known to be functionally important in pacing, its mechanistic action is largely inferential and indeed somewhat controversial. To dissect in detail the role of
I
f
, we investigated the functional consequences of overexpressing in adult guinea pig left ventricular cardiomyocytes (LVCMs) various HCN1 constructs that have been engineered to exhibit different gating properties.

Methods and Results—

We created the recombinant adenoviruses Ad-CMV-GFP-IRES (CGI), Ad-CGI-HCN1, Ad-CGI-HCN1-ΔΔΔ, and Ad-CGI-HCN1-Ins, which mediate ectopic expression of GFP alone, WT, EVY235-7ΔΔΔ, and Ins HCN1 channels, respectively; EVY235-7ΔΔΔ and Ins encode channels in which the S3–S4 linkers have been shortened and lengthened to favor and inhibit opening, respectively. Ad-CGI-HCN1, Ad-CGI-HCN1-ΔΔΔ, and Ad-CGI-HCN1-Ins, but not control Ad-CGI, transduction of LVCMs led to robust expression of
I
f
with comparable densities when fully open (≈−22 pA/pF at −140 mV;
P
>0.05) but distinctive activation profiles (V
1/2
=−70.8±0.6, −60.4±0.7, and −87.7±0.7 mV;
P
<0.01, respectively). Whereas control (nontransduced or Ad-CGI–transduced) LVCMs were electrically quiescent, automaticity (206±16 bpm) was observed exclusively in 61% of Ad-HCN1-ΔΔΔ–transduced cells that displayed depolarized maximum diastolic potential (−60.6±0.5 versus −70.6±0.6 mV of resting membrane potential of control cells;
P
<0.01) and gradual phase 4 depolarization (306±32 mV/s) that were typical of genuine nodal cells. Furthermore, spontaneously firing Ad-HCN1-ΔΔΔ–transduced LVCMs responded positively to adrenergic stimulation (
P
<0.05) but exhibited neither overdrive excitation nor suppression. In contrast, the remaining 39% of Ad-HCN1-ΔΔΔ–transduced cells exhibited no spontaneous action potentials; however, a single ventricular action potential associated with a depolarized resting membrane potential and a unique, incomplete “phase 4–like” depolarization that did not lead to subsequent firing could be elicited on simulation. Such an intermediate phenotype, similarly observed in 100% of Ad-CGI-HCN– and Ad-CGI-HCN1-Ins–transduced LVCMs, could be readily reversed by ZD7288, hinting at a direct role of
I
f
. Correlation analysis revealed the specific biophysical parameters required for
I
f
to function as an active membrane potential oscillator.

Conclusions—

Our results not only contribute to a better understanding of cardiac pacing but also may advance current efforts that focus primarily on automaticity induction to the next level by enabling bioengineering of central and peripheral cells that make up the native sinoatrial node.
Negative Regulation of Soluble Flt-1 and Soluble Endoglin Release by Heme Oxygenase-1
Authors: Cudmore Melissa , Ahmad Shakil , Al-Ani Bahjat , Fujisawa Takeshi , Coxall Heather , Chudasama Kunal , Devey Luke R. , Wigmore Stephen J. , Abbas Allyah , Hewett Peter W. , Ahmed Asif
Published: March 2007

Background—

Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 [VEGFR-1]) and soluble endoglin (sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release.

Methods and Results—

Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-γ– and tumor necrosis factor-α–induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO–releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect.

Conclusions—

The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.
Relationship Between Central Sympathetic Drive and Magnetic Resonance Imaging–Determined Left Ventricular Mass in Essential Hypertension
Authors: Burns Joanna , Sivananthan Mohan U. , Ball Stephen G. , Mackintosh Alan F. , Mary David A.S.G. , Greenwood John P.
Published: March 2007

Background—

Sympathetic activation has been implicated in the development of left ventricular hypertrophy (LVH). However, the relationship between sympathetic activation and LV mass (LVM) has not been clearly defined across a range of arterial pressure measurements. The present study was planned to determine that relationship, using cardiac magnetic resonance imaging to accurately quantify LVM, in hypertensive patients with and without LVH and in normal subjects.

Methods and Results—

Twenty-four patients with uncomplicated and untreated essential hypertension (LVH[−]) were compared with 25 patients with essential hypertension and left ventricular hypertrophy (LVH[+]) and 24 normal control subjects. Resting muscle sympathetic nerve activity was quantified as multiunit bursts and single units. Cardiac magnetic resonance imaging–determined LVM was indexed to body surface area (LVM index); in the LVH[−] group, LVM index was 67±2.1 g/m
2
, a value between those of the LVH[+] (91±3.4 g/m
2
) and normal control (57±2.2 g/m
2
) groups, respectively. The sympathetic activity in the LVH[−] group (53±1.3 bursts per 100 cardiac beats and 63±1.6 impulses per 100 cardiac beats) was between (at least
P
<0.001) those of the LVH[+] (66±1.7 bursts per 100 cardiac beats and 77±2.2 impulses per 100 cardiac beats) and normal control (39±3.0 bursts per 100 cardiac beats and 45±3.4 impulses per 100 cardiac beats) groups. Significant positive correlation existed between sympathetic activity and LVM index in the LVH[−] and LVH[+] groups (at least
r
=0.76,
P
<0.0001) but not in the normal control group. However, no consistent relationship existed between arterial blood pressure and sympathetic activity or LVM index.

Conclusions—

These findings further support the hypothesis that central sympathetic activation is associated with the development of LVH in human hypertension.
Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction
Authors: Tsujita Kenichi , Kaikita Koichi , Hayasaki Takanori , Honda Tsuyoshi , Kobayashi Hironori , Sakashita Naomi , Suzuki Hiroshi , Kodama Tatsuhiko , Ogawa Hisao , Takeya Motohiro
Published: March 2007

Background—

Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A
−/−
) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.

Methods and Results—

Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A
−/−
and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A
−/−
mice than in WT mice (
P
=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A
−/−
mice and 12% (6 of 51 mice) in WT mice (
P
=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A
−/−
mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A
−/−
mice compared with WT mice. Furthermore, SR-A
−/−
mice showed augmented expression of tumor necrosis factor-α and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-α and decreased interleukin-10 expression in activated SR-A
−/−
macrophages.

Conclusions—

The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-α and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
The pH Hypothesis of Postconditioning
Authors: Cohen Michael V. , Yang Xi-Ming , Downey James M.
Published: March 2007

Background—

It is unclear how reperfusion of infarcting hearts with alternating cycles of coronary reperfusion/occlusion attenuates infarction, but prevention of mitochondrial permeability transition pore (MPTP) formation is crucial. Acidosis also suppresses MPTP formation. We tested whether postconditioning protects by maintaining acidosis during early reoxygenation.

Methods and Results—

After 30-minute regional ischemia in isolated rabbit hearts, reperfusion with buffer (pH 7.4) caused 34.4±2.2% of the risk zone to infarct, whereas 2 minutes of postconditioning (6 cycles of 10-second reperfusion/10-second occlusion) at reperfusion resulted in 10.7±2.9% infarction. One minute (3 cycles) of postconditioning was not protective. Hypercapnic buffer (pH 6.9) for the first 2 minutes of reperfusion in lieu of postconditioning caused equivalent cardioprotection (15.0±2.6% infarction), whereas 1 minute of acidosis did not protect. Delaying postconditioning (6 cycles) or 2 minutes of acidosis for 1 minute aborted protection. Reperfusion with buffer (pH 7.7) blocked postconditioning protection, but addition of the MPTP closer cyclosporin A restored protection. Reactive oxygen species scavenger N-2-mercaptopropionyl glycine, protein kinase C antagonist chelerythrine, and mitochondrial K
ATP
channel closer 5-hydroxydecanoate each blocked protection from 2 minutes of acidosis as they did for postconditioning.

Conclusion—

Thus, postconditioning prevents MPTP formation by maintaining acidosis during the first minutes of reperfusion as reoxygenated myocardium produces reactive oxygen species that activate protective signaling to inhibit MPTP formation after pH normalization.
A Prospective Study of
Trans
Fatty Acids in Erythrocytes and Risk of Coronary Heart Disease
Authors: Sun Qi , Ma Jing , Campos Hannia , Hankinson Susan E. , Manson JoAnn E. , Stampfer Meir J. , Rexrode Kathryn M. , Willett Walter C. , Hu Frank B.
Published: March 2007

Background—

High consumption of
trans
fat has been linked to the risk of coronary heart disease (CHD). We assessed the hypothesis that higher
trans
fatty acid contents in erythrocytes were associated with an elevated risk of CHD in a nested case-control study among US women.

Methods and Results—

Blood samples were collected from 32 826 participants of the Nurses’ Health Study from 1989 to 1990. During 6 years of follow-up, 166 incident cases of CHD were ascertained and matched with 327 controls. Total
trans
fatty acid content in erythrocytes was significantly correlated with dietary intake of
trans
fat (correlation coefficient=0.44,
P
<0.01) and was associated with increased plasma low-density lipoprotein cholesterol (
P
for trend =0.06), decreased plasma high-density lipoprotein cholesterol concentrations (
P
for trend <0.01), and increased plasma low-density lipoprotein to high-density lipoprotein ratio (
P
for trend <0.01). After adjustment for age, smoking status, and other dietary and lifestyle cardiovascular risk factors, higher total
trans
fatty acid content in erythrocytes was associated with an elevated risk of CHD. The multivariable relative risks (95% confidence intervals) of CHD from the lowest to highest quartiles of total
trans
fatty acid content in erythrocytes were 1.0 (reference), 1.6 (0.7 to 3.6), 1.6 (0.7 to 3.4), and 3.3 (1.5 to 7.2) (
P
for trend <0.01). The corresponding relative risks were 1.0, 1.1, 1.3, and 3.1 (
P
for trend <0.01) for a total of 18:1
trans
isomers and 1.0, 1.5, 2.5, and 2.8 (
P
for trend <0.01) for a total of 18:2
trans
isomers.

Conclusions—

These biomarker data provide further evidence that high
trans
fat consumption remains a significant risk factor for CHD after adjustment for covariates.
Factor analysis model evaluation through likelihood cross-validation
Authors: Knafl George J. , Grey Margaret
Published: March 2007

Medical research studies utilize survey instruments consisting of responses to multiple items combined into one or more scales. These studies can benefit from methods for evaluating those scales. Such an approach is presented for evaluating exploratory and confirmatory factor analysis models with decisions about covariance structure, including the number of factors, the factor extraction procedure, the allocation of survey items to summated scales and the extent of inter-scale dependence, made objectively using a likelihood-based form of cross-validation. This approach is demonstrated through example analyses using baseline data for three survey instruments from a clinical trial involving adolescents with type 1 diabetes.
A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation
Authors: Smida Michal , Posevitz-Fejfar Anita , Horejsi Vaclav , Schraven Burkhart , Lindquist Jonathan A.
Published: March 2007

In primary human T cells, anergy induction results in enhanced p59Fyn activity. Because Fyn is the kinase primarily responsible for the phosphorylation of PAG (the phosphoprotein associated with glycosphingolipid-enriched microdomains), which negatively regulates Src-kinase activity by recruiting Csk (the C-terminal Src kinase) to the membrane, we investigated whether anergy induction also affects PAG. Analysis of anergic T cells revealed that PAG is hyperphosphorylated at the Csk binding site, leading to enhanced Csk recruitment and inhibitory tyrosine phosphorylation within Fyn. This together with enhanced phosphorylation of a tyrosine within the SH2 domain of Fyn leads to the formation of a hyperactive conformation, thus explaining the enhanced Fyn kinase activity. In addition, we have also identified the formation of a multiprotein complex containing PAG, Fyn, Sam68, and RasGAP in stimulated T cells. We demonstrate that PAG-Fyn overexpression is sufficient to suppress Ras activation in Jurkat T cells and show that this activity is independent of Csk binding. Thus, in addition to negatively regulating Src family kinases by recruiting Csk, PAG also negatively regulates Ras by recruiting RasGAP to the membrane. Finally, by knocking down PAG, we demonstrate both enhanced Src kinase activity and Ras activation, thereby establishing PAG as an important negative regulator of T-cell activation.
Proposed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph)
Authors: Morton Lindsay M. , Turner Jennifer J. , Cerhan James R. , Linet Martha S. , Treseler Patrick A. , Clarke Christina A. , Jack Andrew , Cozen Wendy , Maynadié Marc , Spinelli John J. , Costantini Adele Seniori , Rüdiger Thomas , Scarpa Aldo , Zheng Tongzhang , Weisenburger Dennis D.
Published: March 2007

Recent evidence suggests that there is etiologic heterogeneity among the various subtypes of lymphoid neoplasms. However, epidemiologic analyses by disease subtype have proven challenging due to the numerous clinical and pathologic schemes used to classify lymphomas and lymphoid leukemias over the last several decades. On behalf of the International Lymphoma Epidemiology Consortium (InterLymph) Pathology Working Group, we present a proposed nested classification of lymphoid neoplasms to facilitate the analysis of lymphoid neoplasm subtypes in epidemiologic research. The proposed classification is based on the World Health Organization classification of lymphoid neoplasms and the International Classification of Diseases–Oncology, Third Edition (ICD-O-3). We also provide a translation into the proposed classification from previous classifications, including the Working Formulation, Revised European-American Lymphoma (REAL) classification, and ICD-O-2. We recommend that epidemiologic studies include analyses by lymphoma subtype to the most detailed extent allowable by sample size. The standardization of groupings for epidemiologic research of lymphoma subtypes is essential for comparing subtype-specific reports in the literature, harmonizing cases within a single study diagnosed using different systems, as well as combining data from multiple studies for the purpose of pooled analysis or meta-analysis, and will probably prove to be critical for elucidating etiologies of the various lymphoid neoplasms.
RSV-infected airway epithelial cells cause biphasic up-regulation of CCR1 expression on human monocytes
Authors: Morrison Paul T , Thomas Lynette H , Sharland Mike , Friedland Jon S
Published: March 2007

Respiratory syncytial virus (RSV) infection can cause extensive airway inflammation, which is orchestrated by chemokines and their receptors. RSV-infected epithelial cells secrete many cytokines and chemokines, but little is known about regulation of chemokine receptors on target cells. We investigated the effects of conditioned media (CM) from RSV-infected epithelial cells on monocyte CCR1, CCR2, and CCR5 expression. RSV-CM but not control-CM stimulated a biphasic increase in cell-surface CCR1, and levels peaked at 36 h and 96 h poststimulation. Similar CCR1 up-regulation occurred on monocyte-derived macrophages. Cytochlasin D and colchicine blocked both peaks of expression, demonstrating requirement of a functional cytoskeleton. Intracellular staining revealed little internal sequestration of CCR1 protein, and CCR1 up-regulation was inhibited by actinomycin D and cycloheximide, indicating that both waves of RSV-CM-induced surface CCR1 expression were dependent on de novo transcription and protein synthesis. Cytokine-neutralizing experiments showed that the effects of RSV-CM were decreased by blocking TNF-α (percent inhibition=51±2.3% at 36 h peak and 42±7.7% at 96 h peak) and to a lesser extent, IL-1 (percent inhibition=32±7.2% at 36 h and 23±2.9% at 96 h). In summary, RSV-CM causes a biphasic up-regulation of surface CCR1 on monocytes, which is dependent on an intact cytoskeleton, requires new gene transcription and protein synthesis, and is mediated in part by the proinflammatory cytokines TNF-α and IL-1.
MDP-induced interleukin-1β processing requires Nod2 and CIAS1/NALP3
Authors: Pan Qilin , Mathison John , Fearns Colleen , Kravchenko Vladimir V , Da Silva Correia Jean , Hoffman Hal M , Kobayashi Koichi S , Bertin John , Grant Ethan P , Coyle Anthony J , Sutterwala Fayyaz S , Ogura Yasunori , Flavell Richard A , Ulevitch Richard J
Published: April 2007

Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome 1 (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1β, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP-induced IL-1β release requires Nod2 and CIAS1/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, MDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-1β production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.
CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity
Authors: Sadhu Chanchal , Ting Harold J , Lipsky Brian , Hensley Kelly , Garcia-Martinez Leon F , Simon Scott I , Staunton Donald E
Published: March 2007

CD11c, a member of the leukointegrin family, is expressed prominently on tissue macrophages and dendritic cells and binds to complement fragment (iC3b), provisional matrix molecules (fibrinogen), and the Ig superfamily cell adhesion molecule, ICAM-1. CD11c has been proposed to function in phagocytosis, cell migration, and cytokine production by monocytes/macrophages as well as induction of T cell proliferation by Langerhans cells. Using assays to quantify CD11c-mediated cell adhesion, we demonstrate that CD11c recognizes ICAM-2 and VCAM-1. The CD11c-binding site on VCAM-1 appears to be different from that used by the integrin α4. CD11c and α4β1 contributed to monocyte capture and transmigration on inflamed human aortic endothelial cells. We discovered that the anti-mouse CD11c mAb N418 blocks CD11c binding to iC3b, ICAM-1, and VCAM-1. Treatment of mice with N418 reduced SRBC-induced delayed-type hypersensitivity significantly. CD11c appeared to contribute predominantly to the sensitization phase and somewhat less to the response to SRBC challenge. This suggests a novel role for CD11c during leukocyte recruitment, antigen uptake, and the survival of APC.
Health-Related Quality of Life in Younger Patients With Chronic Lymphocytic Leukemia Treated With Fludarabine Plus Cyclophosphamide or Fludarabine Alone for First-Line Therapy: A Study by the German CLL Study Group
Authors: Eichhorst Barbara F. , Busch Raymonde , Obwandner Tanja , Kuhn-Hallek Ingrid , Herschbach Peter , Hallek Michael
Published: March 2007

Purpose

To date, only a few studies have evaluated the health-related quality of life (HRQOL) of patients with chronic lymphocytic leukemia (CLL) receiving chemotherapy. Therefore, the German CLL Study Group assessed HRQOL in younger patients with advanced CLL receiving first-line chemotherapy with fludarabine or fludarabine plus cyclophosphamide (FC).

Patients and Methods

Three hundred seventy-five patients younger than 66 years with advanced CLL were randomly assigned to receive either fludarabine alone (fludarabine 25 mg/m2/d for 5 days intravenously [IV], repeated every 28 days) or FC (fludarabine 30 mg/m2/d for 3 days IV plus cyclophosphamide 250 mg/m2/d for 3 days, repeated every 28 days). Six courses of treatment were planned to be administered. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 was sent to all patients at baseline and after 6, 12, and 24 months.

Results

Eighty-nine percent of 362 included patients completed at least one questionnaire (163 fludarabine- and 158 FC-treated patients). Comparing the baseline levels of 249 CLL patients with the general German population, significant differences in nearly all HRQOL scales were assessed between the two groups. A multivariate analysis showed no significant differences in all HRQOL scales between both arms. In both treatment arms, symptoms such as fatigue, insomnia, and appetite loss improved to lower levels after the end chemotherapy. Except for lower physical status, no significant difference in HRQOL between male and female patients was evaluated.

Conclusion

Fludarabine-based treatment seems to improve HRQOL little to moderately in younger patients with advanced CLL. No significant difference between fludarabine- and FC-treated patients was observed.
Plasma Cytokine and Soluble Receptor Signature Predicts Outcome of Patients With Classical Hodgkin's Lymphoma: A Study From the Groupe d'Etude des Lymphomes de l'Adulte
Authors: Casasnovas René-Olivier , Mounier Nicolas , Brice Pauline , Divine Marine , Morschhauser Franck , Gabarre Jean , Blay Jean-Yves , Voillat Laurent , Lederlin Pierre , Stamatoullas Aspasia , Bienvenu Jacques , Guiguet Michel , Intrator Liliane , Grandjean Monique , Brière Josette , Ferme Christophe , Salles Gilles
Published: March 2007

Purpose

Approximately 15% of patients with localized and 30% with disseminated classical Hodgkin's lymphoma fail to respond or relapse after first-line treatment. Usual prognosis scoring systems are actually unable to identify this small subset of patients with good confidence, pointing out the need for additional prognostic biomarkers.

Patients and Methods

We prospectively analyzed the prognosis value of plasma levels of tumor necrosis factor (TNF), its soluble receptors TNF-R1 and TNF-R2, IL-10, IL1-RA, IL-6, and soluble CD30 (sCD30) when taken before any treatment in 519 consecutive patients with a first diagnosis of classical Hodgkin's lymphoma.

Results

Levels of TNFα higher than 46 pg/mL, TNF-R1 higher than 3 ng/mL, TNF-R2 higher than 5 ng/mL, IL-10 higher than 30 pg/mL, IL1-RA higher than 668 pg/mL, IL-6 higher than 30 pg/mL, and sCD30 higher than 80 U/mL were associated with poor event-free and overall survival. In multivariate analysis, high levels of IL1-RA, IL-6, and sCD30 were independent poor prognosis factors, and the cytokine signature based on their combination allowed the stratification of patients in four prognosis classes, reaching a 5-year event-free survival probability of 92%, 85%, 76%, and 15%, respectively. This index was more potent than other scoring systems to predict patient event-free survival, and remained independent from the international prognostic score (P < .001), adding significant prognostic information to its predictive power.

Conclusion

Plasma cytokine signature is sufficient to predict disease-related outcome in classical Hodgkin's lymphoma, and allows the identification of patients with very high risk of treatment failure.
Effect of Lugol Solution on Thyroid Gland Blood Flow and Microvessel Density in the Patients with Graves’ Disease
Authors: Erbil Yeşim , Ozluk Yasemin , Giriş Murat , Salmaslıoglu Artur , Issever Halim , Barbaros Umut , Kapran Yersu , Özarmağan Selçuk , Tezelman Serdar
Published: March 2007

Context: Although some endocrine surgeons administer Lugol solution to decrease thyroid gland vascularity, there is still not an agreement on its effectiveness.

Objective: The aims of this clinical trial are to evaluate thyroid blood flow and microvessel density in patients with Graves’ disease who received Lugol solution treatment preoperatively.

Design: This was a prospective clinical trial.

Setting: This clinical trial took place at a tertiary referral center.

Method: Thirty-six patients were randomly assigned to receive either preoperative treatment with Lugol solution (group 1, n = 17) or no preoperative treatment with Lugol solution (group 2, n = 19).

Main Outcome Measures: Blood flow through the thyroid arteries of patients with Graves’ disease was measured by color flow Doppler ultrasonography. The microvessel density (MVD) was assessed by immunohistochemical and Western blot analysis of the level of expression of CD-34 in thyroid tissue. The weight and blood loss of the thyroid gland were measured in all patients.

Results: The mean blood flow, MVD, CD-34 expression, and blood loss in group 1 patients were significantly lower than those in group 2 patients. There was a negative correlation between Lugol solution treatment and blood flow (rs = −0.629; P = 0.0001), blood loss (rs = −0.621; P = 0.0001), MVD (rs = −0.865; P = 0.0001), and CD-34 expression (rs = −0.865; P = 0.0001). According to logistic regression analysis, Lugol solution treatment resulted in a 9.33-fold decreased rate of intraoperative blood loss.

Conclusion: Preoperative Lugol solution treatment decreased the rate of blood flow, thyroid vascularity, and intraoperative blood loss during thyroidectomy.
The microtubule destabilizer stathmin mediates the development of dendritic arbors in neuronal cells
Authors: Ohkawa Noriaki , Fujitani Kazuko , Tokunaga Eri , Furuya Shigeki , Inokuchi Kaoru
Published: March 2007

The regulation of microtubule dynamics is important for the appropriate arborization of neuronal dendrites during development, which in turn is critical for the formation of functional neural networks. Here we show that stathmin, a microtubule destabilizing factor, is downregulated at both the expression and activity levels during cerebellar development, and this down-regulation contributes to dendritic arborization. Stathmin overexpression drastically limited the dendritic growth of cultured Purkinje cells. The stathmin activity was suppressed by neural activity and CaMKII-dependent phosphorylation at Ser16, which led to dendritic arborization. Stathmin phosphorylation at Ser16 was mediated by the activation of voltage-gated calcium channels and metabotropic glutamate receptor 1. Although overexpression of SCG10, a member of the stathmin family, also limited the dendritic arborization, SCG10 did not mediate the CaMKII regulation of dendritic development. These results suggest that calcium elevation activates CaMKII, which in turn phosphorylates stathmin at Ser16 to stabilize dendritic microtubules. siRNA knockdown of endogenous stathmin significantly reduced dendritic growth in Purkinje cells. Thus, these data suggest that proper regulation of stathmin activity is a key factor for controlling the dendritic microtubule dynamics that are important for neuronal development.