bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging and nonlinear heart rate control in a healthy population
Authors: Beckers Frank , Verheyden Bart , Aubert André E.
Published: December 2005

In recent years more studies are using nonlinear dynamics to describe cardiovascular control. Because of the large dispersion of physiological data, it is important to have large studies with both male and female participants to establish a range of physiological healthy values. This study investigated the effect of gender and age on nonlinear indexes. Nonlinear scaling properties were studied by using 1/ f slope (where f is frequency), fractal dimension, and detrended fluctuation analysis short- and long-term correlations (DFAα1 and DFAα2, respectively). Nonlinear complexity was described with correlation dimension (CD), Lyapunov exponent (LE), and approximate entropy (ApEn). The population consisted of 135 women and 141 men (age, 18–71 yr). Twenty-four hour ECG recordings were obtained by using Holter monitoring. The recordings were split into daytime (8 AM–9 PM) and nighttime (11 PM–6 AM). A day-night variation was present in all nonlinear heart rate variability (HRV) indexes, except for the CD in the female population. During the night the percentage of CD values of surrogate data files differing from the CD value of the original data increased. All nonlinear indexes were significantly correlated with age. Deeper analysis per age category of 10 yr showed a stabilization in the age decline of the fractal dimension and ApEn at the age of ≥40 yr. The vagal pathways seemed to be more involved in the generation of nonlinear fluctuations. Higher nonlinear behavior was evident during the night. No clear difference between men and women was found in the nonlinear indexes. Nonlinear indexes decline with age. This can be related to the concept of decreasing autonomic modulation with advancing age.
Cardiac microimpedance measurement in two-dimensional models using multisite interstitial stimulation
Authors: Pollard Andrew E. , Barr Roger C.
Published: December 2005

We analyzed central interstitial potential differences during multisite stimulation to assess the feasibility of using those recordings to measure cardiac microimpedances in multidimensional preparations. Because interstitial current injected and removed using electrodes with different proximities allows modulation of the portion of current crossing the membrane, we hypothesized that multisite interstitial stimulation would give rise to central interstitial potential differences that depend on intracellular and interstitial microimpedances, allowing measurement of those microimpedances. Simulations of multisite stimulation with fine and wide spacing in two-dimensional models that included dynamic membrane equations for guinea pig ventricular myocytes were performed to generate test data (∂φo). Isotropic interstitial and intracellular microimpedances were prescribed for one set of simulations, and anisotropic microimpedances with unequal ratios (intracellular to interstitial) along and across fibers were prescribed for another set of simulations. Microimpedance measurements were then obtained by making statistical comparisons between ∂φo values and interstitial potential differences from passive bidomain simulations (Δφo) in which a wide range of possible microimpedances were considered. Possible microimpedances were selected at 25% increments. After demonstrating the effectiveness of the overall method with microimpedance measurements using one-dimensional test data, we showed microimpedance measurements within 25% of prescribed values in isotropic and anisotropic models. Our findings suggest that development of microfabricated devices to implement the procedure would facilitate routine measurement as a component of cardiac electrophysiological study.
Inositol phospholipids localized to caveolae in rat heart are regulated by α1-adrenergic receptors and by ischemia-reperfusion
Authors: Lanzafame Alfred A. , Turnbull Lynne , Amiramahdi Fatemeh , Arthur Jane F. , Huynh Huy , Woodcock Elizabeth A.
Published: December 2005

Postischemic reperfusion of rat or mouse hearts causes generation of inositol ( 1 , 4 , 5 )trisphosphate [Ins( 1 , 4 , 5 )P3] and the initiation of arrhythmias. In the current study we investigated the possibility that the enhanced Ins( 1 , 4 , 5 )P3generation in postischemic reperfusion was associated with an increased availability of the precursor lipid phosphatidylinositol( 4 , 5 )bisphosphate (PIP2) for α1-adrenergic receptor-activated phospholipase C (PLC). Isolated-perfused rat hearts were labeled with [3H]inositol and subjected to ischemia-reperfusion or stimulation with norepinephrine under normoxic conditions. Caveolar fractions were prepared by buoyant density sucrose gradient centrifugation. [3H]PIP2was concentrated in caveolae, along with Gαq and PLCβ1b. Caveolae contained only 27.3 ± 6.9% (means ± SE, n = 6) of the total α1-adrenergic receptor complement of the heart. These did not migrate to PIP2-containing caveolar fractions with norepinephrine stimulation under normoxic conditions, even though caveolar PIP2was depleted. In contrast, [3H]PIP2in caveolae increased during 2 min of reperfusion, independently of norepinephrine release and thus of α1-adrenergic receptor activation. The increased PIP2in the caveolar fractions where signaling proteins are concentrated may be critical for the heightened generation of Ins( 1 , 4 , 5 )P3in early reperfusion.
Abdominal muscle activity during voiding in female rats with normal or irritated bladder
Authors: Cruz Yolanda , Downie John W.
Published: December 2005

The aims of the present study were to determine in female rats whether abdominal muscle discharges during normal voiding and to describe the effect of bladder irritation on this visceromotor activity. The sensory pathway of this reflex was also determined. Electromyograms (EMGs) indicated that in awake rats, the abdominal muscle was consistently activated during spontaneous voiding and during voiding induced by saline infusion. Similarly, in anesthetized animals, the muscle discharged during urine expulsion. The abdominal EMG activity was not abolished by hypogastric (Hgnx) or sensory pudendal neurectomy (SPdnx). SPdnx dramatically decreased the intercontraction interval and voided volume. Acetic acid infusion reduced the intercontraction interval and increased bladder contraction duration. It also reduced the pressure threshold for evoking the abdominal EMG response and increased the EMG duration and amplitude. Although SPdnx and Hgnx modified some urodynamic parameters, they did not reverse the acetic acid effect on EMG activity. Thus the afferents activating the visceromotor reflex during normal voiding and the increased reflex in response to acetic acid are probably both carried by the pelvic nerve. Abdominal muscle activity induced by bladder distension has been considered to be a pain marker. However, we conclude that in female rats, the abdominal muscle is reflexively activated during physiological urine expulsion. On the other hand, bladder irritation is marked by an exaggeration of this abdominal visceromotor reflex.
Postprandial increase of oleoylethanolamide mobilization in small intestine of the Burmese python (Python molurus)
Authors: Astarita Giuseppe , Rourke Bryan C. , Andersen Johnnie B. , Fu Jin , Kim Janet H. , Bennett Albert F. , Hicks James W. , Piomelli Daniele
Published: December 2005

Oleoylethanolamide (OEA) is an endogenous lipid mediator that inhibits feeding in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α). In rodents, intestinal OEA levels increase about threefold upon refeeding, a response that may contribute to the induction of between-meal satiety. Here, we examined whether feeding-induced OEA mobilization also occurs in Burmese pythons ( Python molurus), a species of ambush-hunting snakes that consume huge meals after months of fasting and undergo massive feeding-dependent changes in gastrointestinal hormonal release and gut morphology. Using liquid chromatography/mass spectrometry (LC/MS), we measured OEA levels in the gastrointestinal tract of fasted (28 days) and fed (48 h after feeding) pythons. We observed a nearly 300-fold increase in OEA levels in the small intestine of fed compared with fasted animals (322 ± 121 vs. 1 ± 1 pmol/mg protein, n = 3–4). In situ OEA biosynthesis was suggested by the concomitant increase of N-acyl phosphatidylethanolamine species that serve as potential biosynthetic precursors for OEA. Furthermore, we observed a concomitant increase in saturated, mono- and diunsaturated, but not polyunsaturated fatty-acid ethanolamides (FAE) in the small intestine of fed pythons. The identification of OEA and other FAEs in the gastrointestinal tract of Python molurus suggests that this class of lipid messengers may be widespread among vertebrate groups and may represent an evolutionarily ancient means of regulating energy intake.
Are large amounts of sodium stored in an osmotically inactive form during sodium retention? Balance studies in freely moving dogs
Authors: Seeliger Erdmann , Ladwig Mechthild , Reinhardt H. Wolfgang
Published: December 2005

Alterations in total body sodium (TBSodium) that covered the range from moderate deficit to large surplus were induced by 10 experimental protocols in 66 dogs to study whether large amounts of Na+are stored in an osmotically inactive form during Na+retention. Changes in TBSodium, total body potassium (TBPotassium), and total body water (TBWater) were determined by 4-day balance studies. A rather close correlation was found between individual changes in TBSodium and those in TBWater ( r2= 0.83). Changes in TBSodium were often accompanied by changes in TBPotassium. Taking changes of both TBSodium and TBPotassium into account, the correlation with TBWater changes became very close ( r2= 0.93). The sum of changes in TBSodium and TBPotassium was accompanied by osmotically adequate TBWater changes, and plasma osmolality remained unchanged. Calculations reveal that even moderate TBSodium changes often included substantial Na+/K+exchanges between extracellular and cellular space. The results support the theory that osmocontrol effectively adjusts TBWater to the body's present content of the major cations, Na+and K+, and do not support the notion that, during Na+retention, large portions of Na+are stored in an osmotically inactive form. Furthermore, the finding that TBSodium changes are often accompanied by TBPotassium changes and also include Na+/K+redistributions between fluid compartments suggests that cells may serve as readily available Na+store. This Na+storage, however, is osmotically active, since osmotical equilibration is achieved by opposite redistribution of K+.
Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice
Authors: Roestenberg Peggy , van Nieuwenhoven Frans A. , Joles Jaap A. , Trischberger Claudia , Martens Paula P. , Oliver Noelynn , Aten Jan , Höppener Jo W. , Goldschmeding Roel
Published: December 2005

Connective tissue growth factor (CTGF) is overexpressed in diabetic nephropathy (DN) and has therefore been implicated in its pathogenesis. The objective of the present study was to determine the tissue distribution of increased CTGF expression and the relationship of plasma, urinary, and renal CTGF levels to the development and severity of DN. We studied the relationship between CTGF and renal pathology in streptozotocin (STZ)-induced diabetes in C57BL/6J mice. Diabetic and age-matched control mice were killed after 1, 2, 4, and 9 wk of diabetes. In addition, key parameters of diabetes and DN were analyzed in 10-mo-old diabetic ob/ob mice and their ob/+ littermates. STZ-induced diabetic mice showed a significantly increased urinary albumin excretion after 1 wk and increased mesangial matrix score after 2 wk. Increased renal fibronectin, fibronectin ED-A, and collagen IVα1expression, as well as elevated plasma creatinine levels, were observed after 9 wk. After 2 wk, CTGF mRNA was upregulated threefold in the renal cortex. By 9 wk, CTGF mRNA was also increased in the heart and liver. In contrast, transforming growth factor-β1mRNA content was significantly increased only in the kidney by 9 wk. Renal CTGF expression was mainly localized in podocytes and parietal glomerular epithelial cells, and less prominent in mesangial cells. In addition, plasma CTGF levels and urinary CTGF excretion were increased in diabetic mice. Moreover, albuminuria strongly correlated with urinary CTGF excretion ( R = 0.83, P < 0.0001). Increased CTGF expression was also demonstrated in type 2 diabetic ob/ob mice, which points to a causal relationship between diabetes and CTGF and thus argues against a role of STZ in this process. The observed relationship of podocyte and urinary CTGF to markers of DN suggests a pathogenic role of CTGF in the development of DN.
AT1receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats
Authors: Li Xiao C. , Campbell Duncan J. , Ohishi Mitsuru , Yuan Shao , Zhuo Jia L.
Published: December 2005

Angiotensin IV (ANG IV), an active ANG II fragment, has been shown to induce systemic and renal cortical effects by binding to ANG IV (AT4) receptors and activating unique signaling transductions unrelated to classical type 1 (AT1) or type 2 (AT2) receptors. We tested whether ANG IV exerts systemic and renal cortical effects on blood pressure, renal microvascular smooth muscle cells (VSMCs), and glomerular mesangial cells (MC) and, if so, whether AT1receptor-activated signaling is involved. In anesthetized rats, systemic infusion of ANG II, ANG III, or ANG IV (0.01, 0.1, and 1.0 nmol·kg−1·min−1iv) caused dose-dependent increases in mean arterial pressure (MAP) and decreases in renal cortical blood flow (CBF; P < 0.01). ANG II also induced dose-dependent reductions in renal medullary blood flow ( P < 0.01), whereas ANG IV did not. ANG IV-induced pressor and renal cortical vasoconstriction were completely abolished by AT1receptor blockade with losartan (5 mg/kg iv; P < 0.05). When ANG IV (1 nmol·kg−1·min−1) was infused directly in the renal artery, CBF was reduced by >30%, and the response was also blocked by losartan ( P < 0.01). In the renal cortex, unlabeled ANG IV displaced125I-labeled [Sar1,Ile8]ANG II binding, whereas unlabeled ANG II (10 μM) inhibited125I-labeled Nle1-ANG IV (AT4) binding in a concentration-dependent manner ( P < 0.01). In freshly isolated renal VSMCs, ANG IV (100 nM) increased intracellular Ca2+concentration, and the effect was blocked by losartan and U-73122, a selective inhibitor of phospholipase C/inositol trisphosphate/Ca2+signaling (1 μM). In cultured rat MCs, ANG IV (10 nM) induced mitogen-activated protein kinase extracellular/signal-regulated kinase 1/2 phosphorylation via AT1receptor- and phospholipase C-activated signaling. These results suggest that, at nanomolar concentrations, ANG IV can increase MAP and induce renal cortical effects by interacting with AT1receptor-activated signaling.
NFAT regulates calcium-sensing receptor-mediated TNF production
Authors: Abdullah Huda Ismail , Pedraza Paulina L. , Hao Shoujin , Rodland Karin D. , McGiff John C. , Ferreri Nicholas R.
Published: December 2005

Because nuclear factor of activated T cells (NFAT) has been implicated in TNF production as well as osmoregulation and salt and water homeostasis, we addressed whether calcium-sensing receptor (CaR)-mediated TNF production in medullary thick ascending limb (mTAL) cells was NFAT dependent. TNF production in response to addition of extracellular Ca2+(1.2 mM) was abolished in mTAL cells transiently transfected with a dominant-negative CaR construct (R796W) or pretreated with the phosphatidylinositol phospholipase C (PI-PLC) inhibitor U-73122. Cyclosporine A (CsA), an inhibitor of the serine/threonine phosphatase calcineurin, and a peptide ligand, VIVIT, that selectively inhibits calcineurin-NFAT signaling, also prevented CaR-mediated TNF production. Increases in calcineurin activity in cells challenged with Ca2+were inhibited after pretreatment with U-73122 and CsA, suggesting that CaR activation increases calcineurin activity in a PI-PLC-dependent manner. Moreover, U-73122, CsA, and VIVIT inhibited CaR-dependent activity of an NFAT construct that drives expression of firefly luciferase in transiently transfected mTAL cells. Collectively, these data verify the role of calcineurin and NFAT in CaR-mediated TNF production by mTAL cells. Activation of the CaR also increased the binding of NFAT to a consensus oligonucleotide, an effect that was blocked by U-73122 and CsA, suggesting that a calcineurin- and NFAT-dependent pathway increases TNF production in mTAL cells. This mechanism likely regulates TNF gene transcription as U-73122, CsA, and VIVIT blocked CaR-dependent activity of a TNF promoter construct. Elucidating CaR-mediated signaling pathways that regulate TNF production in the mTAL will be crucial to understanding mechanisms that regulate extracellular fluid volume and salt balance.
Intracellular ANG II induces cytosolic Ca2+mobilization by stimulating intracellular AT1receptors in proximal tubule cells
Authors: Zhuo Jia L. , Li Xiao C. , Garvin Jeffrey L. , Navar L. Gabriel , Carretero Oscar A.
Published: December 2005

Intracellular ANG II induces biological effects in nonrenal cells, but it is not known whether it plays a physiological role in renal proximal tubule cells (PTCs). PTCs express angiotensinogen, renin, and angiotensin-converting enzyme mRNAs, suggesting the presence of high levels of intracellular ANG II. We determined if microinjection of ANG II directly in single PTCs increases intracellular calcium concentration ([Ca2+]i) and, if so, elucidated the cellular mechanisms involved. Changes in [Ca2+]iresponses were studied by fluorescence imaging using the Ca2+indicator fluo 3. ANG II (1 nM) was microinjected directly in the cells, whereas cell-surface angiotensin type 1 (AT1) receptors were blocked by losartan (10 μM). When ANG II (1 nM) was added to the perfusate, there was a marked increase in [Ca2+]ithat was blocked by extracellular losartan. With losartan in the perfusate, intracellular microinjection of ANG II elicited a robust increase in cytoplasmic [Ca2+]ithat peaked at 30 s (basal: 2.2 ± 0.3 vs. ANG II: 14.9 ± 0.4 relative fluorescence units; P < 0.01). Chelation of extracellular Ca2+with EGTA (2 mM) did not alter microinjected ANG II-induced [Ca2+]iresponses (Ca2+free + ANG II: 12.3 ± 2.6 relative fluorescence units, not significant vs. ANG II); however, pretreatment with thapsigargin to deplete intracellular Ca2+stores or with U-73122 to inhibit phospholipase C (1 μM each) markedly attenuated microinjected ANG II-induced [Ca2+]iresponses. Combined microinjection of ANG II and losartan abolished [Ca2+]iresponses, whereas a combination of ANG II and PD-123319 had no effect. These data demonstrate for the first time that direct microinjection of ANG II in single PTCs increases [Ca2+]iby stimulating intracellular AT1receptors and releases Ca2+from intracellular stores, suggesting that intracellular ANG II may play a physiological role in PTC function.
Nitric oxide stimulates cyclooxygenase-2 in cultured cTAL cells through a p38-dependent pathway
Authors: Cheng Hui-Fang , Zhang Ming-Zhi , Harris Raymond C.
Published: December 2005

To examine the interaction of nitric oxide (NO) and cyclooxygenase (COX-2) and the signaling pathway involved, primary cultured rabbit cortical thick ascending limb (cTAL) were used. In these cells, immunoreactive COX-2 and vasodilatory prostaglandins were increased by a NO donor, S-nitros- N-acetylpenicillamine (SNAP; 2.5 ± 0.3-fold control, n = 6, P < 0.01). SNAP increased expression of phosphorylated p38 (pp38; 2.4 ± 0.3-fold control; n = 5; P < 0.01), which was inhibited by the p38 inhibitor SB-203580 (1.3 ± 0.1-fold control, n = 5, P < 0.01). SB-203580 inhibited SNAP-induced COX-2 expression [1.4 ± 0.2-fold control, n = 6, not significant (NS) vs. control] and levels of PGE2significantly. In cTAL cells transfected with a luciferase reporter driven by the wild-type mouse COX-2 promoter, SNAP stimulated luciferase activity, which was reversed by SB-203580 (control vs. SNAP vs. SNAP + SB-203580: 1.4 ± 0.2-, 8.3 ± 1.4-, and 0.4 ± 0.1-fold control, respectively, n = 4, P < 0.01). Electrophoretic mobility shift assay indicated that SNAP stimulated nuclear factor (NF)-κB binding activity in cTAL that was also inhibited by the p38 inhibitor. SNAP was not able to stimulate a mutant COX-2 promoter construct that is not activated by NF-κB (0.9 ± 0.1, 1.2 ± 0.1, and 1.0 ± 0.2 respectively, n = 4, NS). Low chloride increased COX-2 expression (2.7 ± 0.4-fold control, n = 6, P < 0.01) and pp38 expression (2.8 ± 0.3-fold; n = 5, P < 0.01), which were reversed by the specific NO synthase (NOS) inhibitor 7-nitroindazole. Administration of a low-salt diet increased immunoreactive COX-2 and neuronal NOS (nNOS) in the macula densa and surrounding cTAL of kidneys of wild-type mice but did not significantly elevate COX-2 expression in nNOS−/−mice. In summary, these studies indicate that, in cTAL, NO can increase COX-2 expression in cTAL and macula densa through p38-dependent signaling pathways via activation of NF-κB.
Relief of Synaptic Depression Produces Long-Term Enhancement in Thalamocortical Networks
Authors: Hirata Akio , Castro-Alamancos Manuel A.
Published: December 2005

Thalamocortical synapses may be able to undergo activity-dependent long-term changes in efficacy, such as long-term potentiation. Indeed, studies conducted in vivo have found that theta-burst stimulation (TBS) of the thalamus induces a long-term enhancement (LTE) of field potential responses evoked in the neocortex of adult rodents. Because the thalamus and neocortex form a complex interconnected network that is highly active in vivo, it is possible that a change in thalamic excitability would be reflected in the neocortex. To test this possibility, we recorded from barrel neocortex and applied TBS to the thalamic radiation while the somatosensory thalamus was inactivated with muscimol. Thalamocortical LTE was absent when the thalamus was inactivated, suggesting that changes in thalamic excitability are involved. Single-unit recordings from thalamocortical cells revealed that TBS causes a significant reduction in the spontaneous firing rate of thalamocortical cells. Reducing the spontaneous firing of thalamocortical cells directly enhances the efficacy of the thalamocortical pathway because it relieves the tonic depression of the thalamocortical connection caused by thalamocortical activity. Because these changes in thalamic excitability are triggered by corticothalamic activity, this may be a useful top-down mechanism to regulate afferent sensory input to the neocortex during behavior as a function of experience.
Denervation in murine fast-twitch muscle: short-term physiological changes and temporal expression profiling
Authors: Raffaello Anna , Laveder Paolo , Romualdi Chiara , Bean Camilla , Toniolo Luana , Germinario Elena , Megighian Aram , Danieli-Betto Daniela , Reggiani Carlo , Lanfranchi Gerolamo
Published: December 2005

Denervation deeply affects muscle structure and function, the alterations being different in slow and fast muscles. Because the effects of denervation on fast muscles are still controversial, and high-throughput studies on gene expression in denervated muscles are lacking, we studied gene expression during atrophy progression following denervation in mouse tibialis anterior (TA). The sciatic nerve was cut close to trochanter in adult CD1 mice. One, three, seven, and fourteen days after denervation, animals were killed and TA muscles were dissected out and utilized for physiological experiments and gene expression studies. Target cDNAs from TA muscles were hybridized on a dedicated cDNA microarray of muscle genes. Seventy-one genes were found differentially expressed. Microarray results were validated, and the expression of relevant genes not probed on our array was monitored by real-time quantitative PCR (RQ-PCR). Nuclear- and mitochondrial-encoded genes implicated in energy metabolism were consistently downregulated. Among genes implicated in muscle contraction (myofibrillar and sarcoplasmic reticulum), genes typical of fast fibers were downregulated, whereas those typical of slow fibers were upregulated. Electrophoresis and Western blot showed less pronounced changes in myofibrillar protein expression, partially confirming changes in gene expression. Isometric tension of skinned fibers was little affected by denervation, whereas calcium sensitivity decreased. Functional studies in mouse extensor digitorum longus muscle showed prolongation in twitch time parameters and shift to the left in force-frequency curves after denervation. We conclude that, if studied at the mRNA level, fast muscles appear not less responsive than slow muscles to the interruption of neural stimulation.
Effects of Artemisinin, Artemether, Arteether on the Pharmacokinetics of Carbamazepine
Authors: Sukhija Manpreet , Medhi Bikash , Pandhi P.
Published: December 2005

The effect of artemisinin, artemether and arteether on the pharmacokinetics of carbamazepine in rabbits was studied. In a cross-over study, carbamazepine 40 mg/kg/day orally was given daily for 7 days. On day 7, blood samples were taken at various time intervals between 0 and 24 h. In the artemisinin group, carbamazepine was administered for 7 days as above. On day 8, artemisinin 82 mg/kg followed by 41 mg/kg on the 9th and 10th day along with carbamazepine 40 mg/kg/day was administered and blood samples drawn as above. Artemether 10 mg/kg i.m. was given on day 8 followed by 5 mg/kg i.m. for 2 days. Arteether 10 mg/kg i.m. was given from day 8 for 3 days. Plasma carbamazepine levels were assayed by high-performance liquid chromatography and pharmacokinetic parameters calculated. In all the groups there was an increase in the AUC0–∞ when carbamazepine was co-administered with artemisinin, artemether or arteether. The increase in AUC0–∞ (22.78 ± 4.71 to 63.10 ± 12.29), Cmax (2.76 ± 0.77 to 7.02 ± 1.08), Tmax (2.83 ± 0.17 to 4.16 ± 0.40) was statistically significant when artemether was given along with carbamazepine (p < 0.05). In the other groups the increase was not significant. These results suggest artemisinin compounds alter the pharmacokinetics of carbamazepine with significant change in the bioavailability. Confirmation of these results in human studies will warrant changes in carbamazepine dose or frequency when either of these antimalarials is co-administered with it.
Effect of UVA and UVB Irradiation on the Metabolic Profile of Rabbit Cornea and Lens Analysed by HR-MAS 1H NMR Spectroscopy
Authors: Tessem May-Britt , Midelfart Anna , Čejková Jitka , Bathen Tone F.
Published: December 2005

Purpose:The aim of the study was to investigate the metabolic profiles of intact rabbit corneas and lenses exposed to UVA and UVB radiation by using high-resolution (HR) magic angle spinning (MAS) 1H nuclear magnetic resonance (NMR) spectroscopy and pattern recognition methods. Methods:Adult albino rabbits were exposed to UVA (366 nm, 0.589 J/cm2) or UVB (312 nm, 1.667 J/cm2) radiation for 8 min, once a day for 5 days. Three days after the last irradiation day, samples of corneas and lenses were dissected. HR-MAS 1H NMR spectroscopy combined with pattern recognition methods (principal component analysis and soft independent modelling of class analogy) and one-way ANOVA were applied to obtain metabolic information from intact corneal and lens tissue. Results: UVB irradiation caused statistically significant metabolic changes in the rabbit corneas. A decrease in metabolites as ascorbate (84%), myo-inositol (59%), hypotaurine (91%) and choline (76%) was observed. Exposure to UVA radiation caused no significant metabolic alteration in this tissue. The metabolic profile of the rabbit lenses showed no detectable changes after UVA or UVB exposure. Conclusions:The combination of HR-MAS 1H NMR spectroscopy and multivariate methods proved effective to analyse intact corneal and lens tissue after exposure to UV radiation of different wavelengths. By avoiding extraction methods and obtaining complete metabolic profiles from one sample, HR-MAS 1H NMR spectroscopy provided important information about metabolic alteration occurring in rabbit corneal and lens tissue after UV exposure.
Postprandial Adiponectin Levels Are Unlikely to Contribute to the Pathogenesis of Obesity in Prader-Willi Syndrome
Authors: Caixàs Assumpta , Giménez-Palop Olga , Giménez-Pérez Gabriel , Potau Neus , Berlanga Eugenio , González-Glemente José-Miguel , Arroyo Jaume , Laferrère Blandine , Mauricio Dídac
Published: December 2005

Aim:To investigate fasting and postprandial adiponectin levels in PWS patients as compared to obese and lean subjects and whether they could contribute to the pathogenesis of obesity in this syndrome. Methods: We studied 7 patients with PWS, 16 obese patients and 42 lean subjects for the fasting study. From this group, we evaluated 7 patients with PWS, 7 age-sex-BMI-matched obese non-PWS patients and 7 age-sex-matched lean subjects before and after the administration of 3,139.5 kJ (750 kcal) of a standard liquid meal (53.2% carbohydrate, 30% fat, 16.7% protein) after an overnight fast. Blood samples were obtained every 15 min for the first hour and every 30 min thereafter until 6 h. Adiponectin, IGF-I, glucose, triglycerides, cholesterol, and insulin were measured. Results:Fasting plasma adiponectin levels were lower in PWS than in lean subjects (5.24 ± 2.56 vs. 8.28 ± 4.63 µg/ml, p = 0.041) but higher than in obese patients (4.01 ± 1.27 µg/ml, p = 0.047). After the meal, adiponectin concentrations mildly decreased in PWS at time point 240 min, while in obese and lean subjects no changes were observed. However, 6-hour postprandial AUC for adiponectin was similar in all three groups. Conclusion: Fasting adiponectin levels are low in PWS, but they are so mildly modulated postprandially that these changes do not seem significant for the pathogenesis of obesity in this syndrome.
Immunohistologic Attempt to Find Carcinogenesis from Hepatic Progenitor Cell in Hepatocellular Carcinoma
Authors: Yamamoto Takatsugu , Uenishi Takahiro , Ogawa Masao , Ichikawa Tsuyoshi , Hai Seikan , Sakabe Katsu , Tanaka Shogo , Kato Hiroshi , Mikami Shinichi , Ikebe Takashi , Tanaka Hiromu , Ito Satoru , Kaneda Kenji , Hirohashi Kazuhiro , Kubo Shoji
Published: December 2005

Aim: To clarify whether hepatocellular carcinoma (HCC) originates from hepatic progenitor cells and whether there is any correlation with the clinicopathologic factors of HCC, we reviewed 217 resected HCC specimens. Methods: Immunohistochemical examination of cytokeratin (CK) 7, CK19, CD34, and CD117 (c-KIT) was performed. Overexpression of CK7 and CK19 indicates differentiation from cholangiocellular and hepatic progenitor cells, while overexpression of CD34 and CD117 indicates hepatic stem cells. Fresh specimens were obtained from 20 HCC patients for mutation of the c-KIT gene. Results: CK7, CK19, and CD117 were positive in 41, 9.7, and 0.9% of the HCC specimens, respectively, and CD34 was never positive. None of the fresh HCC specimens demonstrated a c-KIT mutation. CK19 positivity was significantly correlated with a positive hepatitis B core antibody, and with poor survival outcome, and tended to correlate with poor histologic differentiation. Conclusion: These results suggest that: (i) about 10% of HCCs with typical histologic features originate from an intermediate hepatic progenitor cell, such as the canal of Hering and oval cells in the rat, or acquire the characteristics of cholangiocellular epithelium by metaplasia; (ii) HCC with typical histologic features rarely originates from hepatic stem cells, and (iii) patients with CK19-positive HCC have a poor prognosis.
Ethylene Glycol Poisoning in the Czech Republic (2000–2002)
Authors: Křenová M. , Pelclová D. , Navrátil T. , Merta M. , Tesař V.
Published: December 2005

Background: The objective of the study was to evaluate the severity of kidney damage retrospectively and to analyze prognostic factors following ethylene glycol (EG) poisonings. Methods: Data concerning the clinical course of patients with EG poisoning between 2000 and 2002 were analyzed. The χ2 test, Student’s t test, Fisher’s test and the calculation of linear correlation coefficients were used for statistical analysis. Results: Thirty-three discharge records were obtained. Three patients died, and 11 patients developed acute renal failure (mean maximum serum creatinine level 618 µmol/l). Upon discharge, serum creatinine levels were still elevated in 10 patients. In all but 1 patient, renal function completely normalized within 20 months after intoxication. Conclusion: Adult men are the most endangered segment of the population. The most important prognostic factors are the ingested dose and early antidotal treatment. EG toxic kidney damage is reversible.
Imbalance between Detached Circulating Endothelial Cells and Endothelial Progenitor Cells in Chronic Kidney Disease
Authors: Rodríguez-Ayala Ernesto , Yao Qiang , Holmén Carolina , Lindholm Bengt , Sumitran-Holgersson Suchitra , Stenvinkel Peter
Published: December 2005

Background: Patients with chronic kidney disease (CKD) display endothelial dysfunction and are at a high risk for atherosclerotic cardiovascular disease (CVD). Recent studies suggest that circulating detached endothelial cells (CECs) and stimulated endothelial progenitor cells (EPCs) from the bone marrow may reflect endothelial damage. Methods: We correlated the levels of CECs expressing the endothelial cell inflammation marker (MICA+ cells) and EPCs (Tie-2+ or VEGFR-2+ cells) in a population of 19 (55 ± 3 years; 42% males) patients with advanced CKD (median glomerular filtration rate 8 ml/min). In addition, the levels of CD-31+ cells were investigated. Twenty healthy age- (49 ± 2 years) and gender- (50% men) matched subjects served as controls. Results: CECs expressing MICA were increased (7.6 ± 2.7 vs. 1.6 ± 0.3%; p < 0.05) in CKD patients, however EPCs expressing Tie-2 or VEGFR-2 were significantly decreased (0.16 ± 0.07 vs. 0.53 ± 0.15%; p < 0.05, and 0.42 ± 0.10 vs. 2.80 ± 0.72%; p < 0.01, respectively) as compared to controls. Furthermore, we also found that the levels of CD-31+ cells were significantly elevated (22.8 ± 4.2 vs. 9.4 ± 0.8%; p < 0.01) in CKD patients. Patients on angiotensin-converting enzyme (ACE) inhibitors tended (p = 0.06) to have higher levels of VEGFR-2+ cells (0.57 ± 0.14 vs. 0.16 ± 0.11%). Conclusion: Our results suggest that there is a marked imbalance between the CEC and EPC numbers in patients with CKD. Further research is needed to evaluate the independent role of inflammatory endothelial markers as well as the effects of ACE inhibitors on mobilization of EPCs in patients with advanced CKD.
Vascular Endothelial Growth Factor Plasma Levels Are Significantly Elevated in Patients with Cerebral Arteriovenous Malformations
Authors: Sandalcioglu I. Erol , Wende Doreen , Eggert Angelika , Müller Daniela , Roggenbuck Ulla , Gasser Thomas , Wiedemayer Helmut , Stolke Dietmar
Published: December 2005

Background: Since growth and de novo generation of cerebrovascular malformations were demonstrated, a strictly congenital model cannot be further supported as unique factor in the pathogenesis of cerebral arteriovenous malformations (AVMs). Vascular endothelial growth factor (VEGF) has previously been demonstrated to be highly expressed in AVMs by immunohistochemical methods. However, systemic VEGF levels have not been analysed previously. This study aimed to investigate VEGF plasma concentrations as a possible plasma marker for neovascularization in patients with cerebral AVMs compared to healthy controls. Methods: The study included 17 patients with cerebral AVMs and 40 healthy controls. VEGF plasma concentrations were measured by a specific enzyme immuno-assay. Results: VEGF plasma concentrations were significantly higher in patients with cerebral AVMs (mean 140.9 pg/ml, SD 148.5 pg/ml and median 63.0 pg/ml) compared to a healthy control group (mean 44.7 pg/ml, SD 36.4 pg/ml and median 35.0 pg/ml), p = 0.0003. Conclusions: Our findings suggest that VEGF plasma concentrations might play a role in the pathogenesis of cerebral AVMs. Further studies are necessary and would contribute to an improved understanding of the pathogenesis of cerebral AVMs.
Predictive Factors for Tracheostomy in Neurocritical Care Patients with Spontaneous Supratentorial Hemorrhage
Authors: Huttner Hagen B. , Kohrmann Martin , Berger Christian , Georgiadis Dimitrios , Schwab Stefan
Published: December 2005

Background: Up to 30% of patients with supratentorial intracerebral hemorrhage (ICH) require mechanical ventilation during the course of treatment. For these patients, tracheostomy is necessary in cases of protracted weaning. As only limited data exist about predictors for a tracheostomy in patients with ICH, the aim of this study was to investigate the frequency of tracheostomy and clinical findings that increase the risk for a tracheostomy in patients with supratentorial hemorrhage. Methods: A total of 392 patients with supratentorial ICH were analyzed. The parameters age, gender, chronic obstructive pulmonary disease (COPD), Glasgow Coma Scale on admission, ganglionic or non-ganglionic localization, presence of ventricular hemorrhage, hydrocephalus, hematoma volume, and hematoma evacuation were in vestigated. The effects on the end-point tracheostomy were analyzed using multivariate regression analyses. Results: The overall need for tracheostomy was 9.9% (16.3% in patients with ganglionic hemorrhage versus 2.8% in patients with non-ganglionic hemorrhages). 31% of the ventilated patients required tracheostomy. The risk for tracheostomy was increased eightfold in patients who developed hydrocephalus. The presence of ventricular blood, in general, showed no significant impact on the need for tracheostomy, whereas hemorrhage extending into the third and fourth ventricles in conjunction with hydrocephalus increased the risk for tracheostomy. The hematoma volume correlated positively with the risk for tracheostomy. Conclusions: Our study demonstrates that approximately 10% of patients with ICH require tracheostomy during the course of their disease. Presence of COPD, hematoma volume, ganglionic location of the hematoma, and the development of hydrocephalus are predisposing factors for tracheostomy.
Cardiovascular Risk Factors and 5-Year Mortality in the Copenhagen Stroke Study
Authors: Kammersgaard Lars Peter , Olsen Tom Skyhøj
Published: December 2005

Background: The treatment of cardiovascular risk factors has improved over the recent years and may have improved survival. The aim of this study was to investigate the up-to-date prognostic significance of cardiovascular risk factors for 5-year survival in a large unselected ischemic stroke population. Methods: We studied 905 ischemic stroke patients from the community-based Copenhagen Stroke Study. Patients had a CT scan and stroke severity was measured by the Scandinavian Stroke Scale on admission. A comprehensive evaluation was performed by a standardized medical examination and questionnaire for cardiovascular risk factors, age, and sex. Follow-up was performed 5 years after stroke, and data on mortality were obtained for all, except 6, who had left the country. Five-year mortality was calculated by the Kaplan-Meier procedure and the influence of multiple predictors was analyzed by Cox proportional hazards analyses adjusted for age, gender, stroke severity, and risk factor profile. Results: In Kaplan-Meier analyses atrial fibrillation (AF), ischemic heart disease, diabetes, and previous stroke were associated with increased mortality, while smoking and alcohol intake were associated with decreased mortality. No association was found for hypertension or intermittent claudication. In the final Cox proportional hazard model predictors of 5-year mortality were AF (hazard ratio, HR 1.4; 95% CI 1.1–1.7), diabetes (HR 1.3; 95% CI 1.0–1.6), smoking (HR 1.2; 95% CI 1.0–1.4), and previous stroke (HR 1.4; 95% CI 1.1–1.7), after adjustment for age, gender, and stroke severity. Conclusions: AF, diabetes, smoking, and previous stroke significantly affect long-term survival. Although smoking and daily alcohol consumption appeared to be associated with improved survival in the univariate analyses, adjustment for other factors and especially age revealed the lethal effect of smoking, while the positive effect of alcohol disappeared. More focus on secondary preventive measures, such as anticoagulation for AF, smoking cessation, and proper treatment of diabetes may significantly improve long-term survival.
rd1 Mouse Retina Shows Imbalance in Cellular Distribution and Levels of TIMP-1/MMP-9, TIMP-2/MMP-2 and Sulfated Glycosaminoglycans
Authors: Ahuja Satpal , Ahuja Poonam , Caffé A. Romeo , Ekström Per , Abrahamson Magnus , van Veen Theo
Published: December 2005

Background: The rd1 mouse retina displays fast degeneration of photoreceptors resulting in a depletion of almost all rod photoreceptors by postnatal day 21 (PN21). To evaluate the role of proteinases in the pathophysiology of this animal model of retinitis pigmentosa, C3H rd1 and congenic wild-type (wt) mice retinas were analyzed. Material and Methods: The cellular localization and levels of proteins, matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), total sulfated glycosaminoglycans (sGAG) and nature of saccharides in rd1 and wt retinal extracts were compared. Results: MMP-2/TIMP-2 and MMP-9/TIMP-1 were predominantly localized in the interphotoreceptor matrix (IPM) of both genotypes, but MMP-2/TIMP-2 also appeared in the Müller cell fibers of rd1 retina. In rd1 retinal extracts the levels of total proteins were lower and those of active MMP-9, MMP-2, TIMP-1 and total sGAG were higher than those of wt extracts. Despite an increase in TIMP-1, active MMP-9/MMP-2 were disproportionately elevated in rd1 compared to wt retina. With increasing age, MMPs in wt retinas were decreased but were increased in rd1. The sialylation of proteoglycans in PN2 and PN7 rd1 retinas was lower, and galactosylation was higher than that in wt retinas. Conclusions: MMP-9/MMP-2 and TIMP-1/TIMP-2 are associated with IPM, possibly after secretion by retinal pigmented epithelial cells. In degenerating rd1 retina, MMP-2/TIMP-2 are associated with the Müller cell fibers, which apparently play a central role in modifying the balance between MMPs and TIMPs. Elevated sGAG and proteolysis due to an imbalance in the levels of TIMPs and active MMP-9/MMP-2 in rd1 retina possibly contribute to retinal degeneration in the rd1 mouse.
Serum Lipoprotein Lipase Concentration and Risk for Future Coronary Artery Disease
Authors: Rip Jaap , Nierman Melchior C. , Wareham Nicholas J. , Luben Robert , Bingham Sheila A. , Day Nicholas E. , van Miert Joram N.I. , Hutten Barbara A. , Kastelein John J.P. , Kuivenhoven Jan Albert , Khaw Kay-Tee , Boekholdt S. Matthijs
Published: December 2005

Background—

Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD.

Methods and Results—

LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43–85] versus 66 [46–92] ng/mL;
P
<0.0001). Those in the highest LPL concentration quartile had a 34% lower risk for future CAD compared with those in the lowest quartile (odds ratio [OR] 0.66; confidence interval [CI], 0.53 to 0.83;
P
<0.0001). This effect remained significant after adjustment for blood pressure, diabetes, smoking, body mass index, and low-density lipoprotein (LDL) cholesterol (OR, 0.77; CI, 0.60–0.99;
P
=0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size.

Conclusions—

Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C levels.
Atherosclerosis Susceptibility Loci Identified From a Strain Intercross of Apolipoprotein E–Deficient Mice via a High-Density Genome Scan
Authors: Smith Jonathan D. , Bhasin Jeffrey M. , Baglione Julie , Settle Megan , Xu Yaomin , Barnard John
Published: December 2005

Objective—

Apolipoprotein (apo) E-deficient mice are hypercholesterolemic and develop atherosclerosis on low-fat chow diets; however, the genetic background strain has a large effect on atherosclerosis susceptibility. This study aimed to determine the genetic regions associated with strain effects on lesion area.

Methods and Results—

We performed a strain intercross between atherosclerosis sensitive DBA/2 and atherosclerosis resistant AKR apoE-deficient mice. Aortic root lesion area, total cholesterol, body weights, and complete blood counts were ascertained for 114 male and 95 female F
2
progeny. A high-density genome scan was performed using a mouse single nucleotide polymorphism chip yielding 1967 informative polymorphic markers. Quantitative trait locus (QTL) statistical analyses were performed. Novel loci associated with lesion or log lesion area were identified for the female and male F
2
cohorts. The atherosclerosis QTLs in female mice reside on chromosomes 15, 5, 3, and 13, and in male mice on chromosomes 17, 18, and 2. QTL were also identified for body weight, total cholesterol, and blood count parameters.

Conclusions—

Loci were identified for atherosclerosis susceptibility in a strain intercross study. The identity of the responsible genes at these loci remains to be determined.
Applications of Nanotechnology to Atherosclerosis, Thrombosis, and Vascular Biology
Authors: Wickline Samuel A. , Neubauer Anne M. , Winter Patrick , Caruthers Shelton , Lanza Gregory
Published: December 2005

The role of nanotechnology in cardiovascular diagnosis is expanding rapidly. The goal of this brief review is to illustrate selected examples of nanosystems that have been applied to the arenas of atherosclerosis, thrombosis, and vascular biology. The technologies for producing targeted nanosystems are multifarious and reflect end uses in many cases. The results to date indicate rapid growth of interest and capability in the field. The future of cardiovascular diagnosis already is being impacted by nanosystems that can both diagnose pathology and treat it with targeted delivery systems.