bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective PTH regulation of sodium-dependent phosphate transport in NHERF-1−/−renal proximal tubule cells and wild-type cells adapted to low-phosphate media
Authors: Cunningham Rochelle , E Xiaofei , Steplock Deborah , Shenolikar Shirish , Weinman Edward J.
Published: June 2005

The present experiments using primary cultures from renal proximal tubule cells examine two aspects of the regulation of sodium-dependent phosphate transport and membrane sodium-dependent phosphate transporter (Npt2a) expression by parathyroid hormone (PTH). Sodium-dependent phosphate transport in proximal tubule cells from wild-type mice grown in normal-phosphate media averaged 4.4 ± 0.5 nmol·mg protein−1·10 min−1and was inhibited by 30.5 ± 8.6% by PTH (10−7M). This was associated with a 32.7 ± 5.2% decrease in Npt2a expression in the plasma membrane. Proximal tubule cells from Na+/H+exchanger regulatory factor-1 (NHERF-1)−/−mice had a lower rate of phosphate transport compared with wild-type cells and a significantly reduced inhibitory response to PTH. Wild-type cells incubated in low-phosphate media for 24 h had a higher rate of phosphate transport compared with wild-type cells grown in normal-phosphate media but a significantly blunted inhibitory response to PTH. These data indicate a role for NHERF-1 in mediating the membrane retrieval of Npt2a and the subsequent inhibition of phosphate transport in renal proximal tubules. These studies also suggest that there is a blunted phosphaturic effect of PTH in cells adapted to low-phosphate media.
Meprin-α in chronic diabetic nephropathy: interaction with the renin-angiotensin axis
Authors: Mathew Roy , Futterweit Stephen , Valderrama Elsa , Tarectecan Antonio A. , Bylander John E. , Bond Judith S. , Trachtman Howard
Published: June 2005

Meprin (MEP) A is a metalloendopeptidase that is present in the renal proximal tubule brush-border membrane (BBM) and that colocalizes with angiotensin-converting enzyme (ACE). The MEP β-chain gene locus on chromosome 18 has been linked to a heightened risk of diabetic nephropathy (DN) in patients with type 2 diabetes. This study evaluated 1) whether MEP-α and MEP-β gene and protein expression are altered in db/db mice before the onset of DN and 2) the role of MEP-α in the pathogenesis of DN and the impact of the renin-angiotensin system on this interaction in two experimental models of diabetes. MEP-α and MEP-β gene and protein expression were evaluated in db/db mice, 13–14 wk of age, compared with lean C57BLKS/J littermate animals. A treatment study was then performed in which db/db mice and controls were assigned to one of three groups: control (C) water, no therapy; ACE inhibitor therapy, enalapril (EN)-treated water, 50 mg/l; ANG II receptor type 1 blocker (ARB) therapy, losartan (LOS)-treated water, 500 mg/l. Treatment was started at 8 wk of age and continued for 52 wk. Male Sprague-Dawley rats with diabetes for 52 wk following a single dose of streptozocin (STZ; 60 mg/kg) were also studied. At 13.5 wk of age, MEP-α and MEP-β kidney mRNA abundance and protein expression were significantly lower in db/db mice compared with lean controls, with greater changes in MEP-β ( P < 0.05). In the treatment study, EN ameliorated and LOS exacerbated DN in db/db mice. BBM MEP A enzymatic activity and MEP-α protein content were lower in db/db mice vs. control nonobese mice at 52 wk ( P < 0.02). EN-treated db/db mice showed increased MEP A activity, MEP-α content in BBM, decreased urinary MEP-α excretion, and enhanced BBM staining for MEP-α protein vs. C and LOS-treated db/db mice. In nonobese mice, EN and LOS treatment had no effect on MEP-α expression. In rats with STZ-induced diabetes for 52 wk, urinary MEP-α excretion was increased and MEP A activity and MEP-α protein content per milligram of BBM protein were decreased compared with age-matched control animals ( P < 0.05). These results indicate that db/db mice manifest decreased MEP-α and MEP-β gene and protein expression, before the development of overt kidney disease. Moreover, in db/db mice with DN and rats with STZ-diabetes, there was an inverse relationship between renal MEP-α content and the severity of the renal injury. Treatment with an ACE inhibitor was more effective than ARB in ameliorating DN in db/db mice, a change that correlated with alterations in urinary excretion and BBM content of MEP-α. MEP-α may play a role in the pathogenesis of DN and the benefits of ACE inhibitor therapy on the progression of diabetic kidney disease may be related, in part, to its impact on renal MEP-α expression.
Vitamin D
Authors: Dusso Adriana S. , Brown Alex J. , Slatopolsky Eduardo
Published: June 2005

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.
Calcium and chloride channel activation by angiotensin II-AT1receptors in preglomerular vascular smooth muscle cells
Authors: Fuller Andrew J. , Hauschild Benjamin C. , Gonzalez-Villalobos Romer , Awayda Mouhamed S. , Imig John D. , Inscho Edward W. , Navar L. Gabriel
Published: June 2005

The pathways responsible for the rapid and sustained increases in [Ca2+]ifollowing activation of ANG II receptors (AT1) in renal vascular smooth muscle cells were evaluated using fluorescence microscopy. Resting intracellular calcium concentration [Ca2+]iaveraged 75 ± 9 nM. The response to ANG II (100 nM) was characterized by a rapid initial increase of [Ca2+]iby 74 ± 6 nM ( n = 35) followed by a decrease to a sustained level of 12 ± 2 nM above baseline. The average time from peak to 50% reduction from the peak value (50% time point) was 32 ± 4 s. AT1receptor blockade with 1 μM candesartan ( n = 5) prevented the responses to ANG II. In nominally calcium-free conditions ( n = 8), the peak increase in [Ca2+]iaveraged 42 ± 7 nM but the sustained phase was absent and the 50% time point was reduced to 11 ± 4 s. L-type calcium channel blockade with diltiazem reduced the peak [Ca2+]ito 24 ± 8 nM and the sustained level to 4 ± 2 nM ( n = 10). In cells preincubated in low Cl−(3.0 mM), the peak response to ANG II was suppressed as was the sustained response. Blockade of chloride channels with DIDS eliminated both the peak and sustained responses ( n = 11); chloride channel blockade with DPC ( n = 17) suppressed the peak increase in [Ca2+]ito 18 ± 5 and also prevented the sustained response. IP3 receptor blockade by 10 μM TMB-8 ( n = 6) reduced the peak to 22 ± 8 and prevented the sustained response. Exposure to 10 μM TMB-8 in the presence of Ca2+-free medium prevented the ANG II response ( n = 9). In the presence of 100 μM DPC and 10 μM TMB-8 ( n = 7), the ANG II response was also prevented. Thus the rapid initial increase in [Ca2+]iis due not only to release from intracellular stores, but also to Ca2+influx from the extracellular fluid. Although Ca2+entry via L-type calcium channels is responsible for the major portion of the sustained response, other entry pathways participate. The finding that chloride channel blockers markedly attenuate both rapid and sustained responses indicates that chloride channel activation contributes to, rather than being the consequence of, the initial rapid response.
Glucocorticoids acutely increase cell surface Na+/H+exchanger-3 (NHE3) by activation of NHE3 exocytosis
Authors: Bobulescu I. Alexandru , Dwarakanath Vangipuram , Zou Lixian , Zhang Jianning , Baum Michel , Moe Orson W.
Published: June 2005

Glucocorticoids have important effects on renal function, including the modulation of renal acidification by the major proximal tubular Na+/H+exchanger, NHE3. While the chronic effect of glucocorticoids is considered to be primarily at the transcriptional level, with increases in NHE3 mRNA and protein expression driving increased transport activity, the mechanisms by which glucocorticoids activate NHE3 in an acute setting have not been investigated. Previous studies have shown that a glucocorticoid-stimulated increase in NHE3 activity can occur before any detectable change in NHE3 mRNA. The present study examines the acute effects of glucocorticoids on NHE3 using opossum kidney (OKP) cells as a cell model. In OKP cells, total NHE3 protein abundance was not changed by 3 h of treatment with dexamethasone (10−6M). However, the biotin-accessible fraction representing NHE3 at the apical membrane as well as Na+/H+exchange activity measured fluorimetrically using the pH-sensitive dye BCECF-AM were significantly increased. These effects were not prevented by the protein synthesis inhibitor cycloheximide. NHE3 insertion (biotinylatable NHE3 after sulfo-NHS-acetate blockade) was stimulated by dexamethasone incubation, with or without cycloheximide. The rate of NHE3 endocytic retrieval, assessed either by the avidin protection assay (early endocytosis) or by the sodium 2-mercaptoethane sulfonate (MesNa) cleavage assay (early and late endocytosis), was not affected by dexamethasone. These findings suggest that trafficking plays a key role in the acute stimulation of NHE3 by glucocorticoids, with exocytosis being the major contributor to the glucocorticoid-induced rapid increase in cell surface NHE3 protein abundance and Na+/H+exchange activity.
Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies
Authors: Nakhoul Farid , Ramadan Rawi , Khankin Eliyahu , Yaccob Afif , Kositch Zoya , Lewin Moshe , Assady Suheir , Abassi Zaid
Published: June 2005

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria, hypoalbuminemia, and eventual edema formation. Although the mechanisms underlying this phenomenon are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 ± 1.4 to 983.1 ± 45.8 mg/day, P < 0.01) and cumulative protein excretion (from negligible values to 22,490 ± 931 mg, P < 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 ± 82.4 mg/day, P < 0.0023) and cumulative proteinuria (15,727 ± 2,204 mg, P < 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 ± 1,042 mg, P < 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 ± 1,360 mg, P > 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in these animals. Nephrin loss is an indication of proteinuria in NS and the antiproteinuric effects of ACE inhibitors, vasopeptidase inhibitors, and mycophenolate mofetil attenuate this reduction. Not all the drugs which restore podocin reduce urinary protein in NS.
Differential serial sarcomere number adaptations in knee extensor muscles of rats is contraction type dependent
Authors: Butterfield Timothy A. , Leonard Timothy R. , Herzog Walter
Published: June 2005

Sarcomerogenesis, or the addition of sarcomeres in series within a fiber, has a profound impact on the performance of a muscle by increasing its contractile velocity and power. Sarcomerogenesis may provide a beneficial adaptation to prevent injury when a muscle consistently works at long lengths, accounting for the repeated-bout effect. The association between eccentric exercise, sarcomerogenesis and the repeated-bout effect has been proposed to depend on damage, where regeneration allows sarcomeres to work at shorter lengths for a given muscle-tendon unit length. To gain additional insight into this phenomenon, we measured fiber dynamics directly in the vastus lateralis (VL) muscle of rats during uphill and downhill walking, and we measured serial sarcomere number in the VL and vastus intermedius (VI) after chronic training on either a decline or incline grade. We found that the knee extensor muscles of uphill walking rats undergo repeated active concentric contractions, and therefore they suffer no contraction-induced injury. Conversely, the knee extensor muscles during downhill walking undergo repeated active eccentric contractions. Serial sarcomere numbers change differently for the uphill and downhill exercise groups, and for the VL and VI muscles. Short muscle lengths for uphill concentric-biased contractions result in a loss of serial sarcomeres, and long muscle lengths for downhill eccentric-biased contractions result in a gain of serial sarcomeres.
Distinct Mechanisms of Presynaptic Inhibition at GABAergic Synapses of the Rat Substantia Nigra Pars Compacta
Authors: Giustizieri Michela , Bernardi Giorgio , Mercuri Nicola B. , Berretta Nicola
Published: June 2005

We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABAB receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist l-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 μM) and the GABAB receptor agonist baclofen (10 μM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 ± 2.7 and 79.3 ± 1.6% (means ± SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 μM) and cadmium (100 μM) were insensitive to AP4 but were reduced by baclofen to 49.7 ± 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 ± 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 ± 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 μM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of α-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 ± 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABAB receptors directly impair transmitter exocytosis.
Relationship Between Extraretinal Component of Firing Rate and Eye Speed in Area MST of Macaque Monkeys
Authors: Churchland Anne K. , Lisberger Stephen G.
Published: June 2005

We have isolated extraretinal and retinal components of firing during smooth pursuit eye movements in the medial-superior-temporal area (MST) in the extrastriate visual cortex. Awake macaque monkeys tracked spots in total darkness to eliminate image motion inputs from the background. For 300 ms during sustained tracking at different speeds, the target was stabilized on the moving eye, practically eliminating image motion inputs from the tracking target. The extraretinal component of firing rate during image stabilization was direction selective and related to eye speed but sometimes showed a different preferred speed from the retinal component of the same neuron's responses. The highly variable firing rate of individual MST neurons allowed an ideal observer to predict target speed correctly on 25% of trials. Pooling the data from 71 MST neurons improved the correct response rate to 50%. Behavioral experiments imposed brief perturbations of target velocity to assess the gain of visual-motor transmission for pursuit. The average response to perturbations increased as a function of target speed. However, the size of the responses to individual perturbations allowed an ideal observer to predict target speed correctly on only 35% of the trials. The imprecision of MST responses argues that the output of MST may be a poor candidate to drive eye velocity and so may instead regulate another component of pursuit. The good agreement between the eye velocity precision of the behavioral responses to perturbations of target motion and the firing of MST neurons raises regulation of the visual-motor gain of pursuit as one candidate component.
Visual Responses of the Human Superior Colliculus: A High-Resolution Functional Magnetic Resonance Imaging Study
Authors: Schneider Keith A. , Kastner Sabine
Published: June 2005

The superior colliculus (SC) is a multimodal laminar structure located on the roof of the brain stem. The SC is a key structure in a distributed network of areas that mediate saccadic eye movements and shifts of attention across the visual field and has been extensively studied in nonhuman primates. In humans, it has proven difficult to study the SC with functional MRI (fMRI) because of its small size, deep location, and proximity to pulsating vascular structures. Here, we performed a series of high-resolution fMRI studies at 3 T to investigate basic visual response properties of the SC. The retinotopic organization of the SC was determined using the traveling wave method with flickering checkerboard stimuli presented at different polar angles and eccentricities. SC activations were confined to stimulation of the contralateral hemifield. Although a detailed retinotopic map was not observed, across subjects, the upper and lower visual fields were represented medially and laterally, respectively. Responses were dominantly evoked by stimuli presented along the horizontal meridian of the visual field. We also measured the sensitivity of the SC to luminance contrast, which has not been previously reported in primates. SC responses were nearly saturated by low contrast stimuli and showed only small response modulation with higher contrast stimuli, indicating high sensitivity to stimulus contrast. Responsiveness to stimulus motion in the SC was shown by robust activations evoked by moving versus static dot stimuli that could not be attributed to eye movements. The responses to contrast and motion stimuli were compared with those in the human lateral geniculate nucleus. Our results provide first insights into basic visual responses of the human SC and show the feasibility of studying subcortical structures using high-resolution fMRI.
Movement Quantity and Frequency Coding in Human Motor Areas
Authors: Kim Jennifer A. , Eliassen James C. , Sanes Jerome N.
Published: June 2005

Studies of movement coding have indicated a relationship between functional MRI signals and increasing frequency of movement in primary motor cortex and other motor-related structures. However, prior work has typically used block-designs and fixed-time intervals across the varying movements frequencies that may prevent ready distinction of brain mechanisms related to movement quantity and, especially, movement frequency. Here, we obtained functional MRI signals from humans working in an event-related design to extract independent activation related to movement quantity or movement frequency. Participants tapped once, twice, or thrice at 1, 2, or 3 Hz, and the tapping evoked activation related to movement quantity in the precentral and postcentral gyri, supplementary motor area, cerebellum, putamen, and thalamus. Increasing movement frequency failed to yield activation in these motor-related areas, although linear movement frequency affects occurred in nonmotor regions of cortex and subcortex. Our results do not replicate prior data suggesting movement frequency encoding in motor-related areas; instead we observed movement quantity coding in motor-related brain areas. The discrepancy between prior studies and this study likely relates to methodology concerns. We suggest that the movement quantity relationships in human motor areas and encoding of movement frequency in nonmotor areas may reflect a functional anatomical substrate for mediating distinct movement parameters.
Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells
Authors: Vengellur A. , Phillips J. M. , Hogenesch J. B. , LaPres J. J.
Published: June 2005

Cellular, local, and organismal responses to low O2availability occur during processes such as anaerobic metabolism and wound healing and pathological conditions such as stroke and cancer. These responses include increases in glycolytic activity, vascularization, breathing, and red blood cell production. These responses are mediated in part by the hypoxia-inducible factors (HIFs), which receive information on O2levels from a group of iron- and O2-dependent hydroxylases. Hypoxia mimics, such as cobalt chloride, nickel chloride, and deferoxamine, act to simulate hypoxia by altering the iron status of these hydroxylases. To determine whether these mimics are appropriate substitutes for the lower O2tension evoked naturally, we compared transcriptional responses of a Hep3B cell line using high-density oligonucleotide arrays. A battery of core genes was identified that was shared by all four treatments (hypoxia, cobalt, nickel, and deferoxamine) including glycolytic enzymes, cell cycle regulators, and apoptotic genes. Importantly, cobalt, nickel, and deferoxamine influenced transcription of distinct sets of genes that were not affected by cellular hypoxia. These global responses to hypoxia indicate a balancing act between adaptation and programmed cell death and suggest caution in the use of hypoxia mimics as substitutes for the low O2tension that occurs in vivo.
In the Face of Pain: The Relationship between Psychological Well-Being and Disability in Women with Fibromyalgia
Authors: Schleicher Holly , Alonso Carmen , Shirtcliff Elizabeth A. , Muller Daniel , Loevinger Barbara L. , Coe Christopher L.
Published: June 2005

Background: Few studies have examined the potentially beneficial role of positive psychological functioning in individuals with chronic pain. This study examined the relationship of psychological well-being (PWB) to pain and disability in women with fibromyalgia (FM) as compared to women with rheumatoid arthritis (RA) and healthy controls (HC). We targeted several domains of PWB that have been associated with health, and also tested whether PWB was related to the women’s social network. Methods: PWB, pain, and disability were assessed in 125 women (57 with FM, 20 with RA, and 48 HC) on two occasions. Results: Women with FM reported lower overall PWB than did RA and HC women. Further, greater PWB was associated with less disability and fatigue, but not pain in women with FM. Self-acceptance, environmental mastery, purpose in life, and positive relations with others emerged as four important constructs in the association between PWB and disability. In addition, PWB mediated the relationship between social network size and disability. Conclusions: This assessment of PWB provides insight into those psychological domains that should be emphasized in treatments aimed at reducing the disabling aspects of FM.
Three-Dimensional Rotational Dacryocystography for Imaging of the Lacrimal Draining System and Adjacent Anatomical Structures
Authors: Lüchtenberg Marc , Kuhli Claudia , du Mesnil de Rochemont Richard , Yan Bernard , Ohrloff Christian , Berkefeld Joachim
Published: June 2005

Purpose: A three-dimensional (3D) rotational angiography system was used to perform 3D dacryocystography (3DRD) as an adjunct to the conventional dacryocystography assisted by digital subtraction angiography (DSA). Methods:In 15 patients with severe epiphora, 3DRD was performed after inconclusive results from DSA-assisted dacryocystography. Results:3DRD was technically feasible and well tolerated in all 15 cases. In 5 out of 15 patients, 3DRD, in contrast to DSA-assisted dacryocystography, distinguished clearly between stenotic lesions of the canaliculi, lacrimal sac or nasolacrimal duct. In 10 cases, the simultaneous display of tear ducts and adjacent structures of the nasal cavity provided critical anatomical information for decision making between endoscopic and open dacryocystorhinostomy. Conclusions: 3DRD is technically feasible and adds important information to conventional DSA-assisted dacryocystography.
Improvement of Visual Functions and Fundus Alterations in Early Age-Related Macular Degeneration Treated with a Combination of Acetyl-L-Carnitine, n-3 Fatty Acids, and Coenzyme Q10
Authors: Feher J. , Kovacs B. , Kovacs I. , Schveoller M. , Papale A. , Balacco Gabrieli C.
Published: June 2005

The aim of this randomized, double-blind, placebo-controlled clinical trial was to determine the efficacy of a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10 (Phototrop®) on the visual functions and fundus alterations in early age-related macular degeneration (AMD). One hundred and six patients with a clinical diagnosis of early AMD were randomized to the treated or control groups. The primary efficacy variable was the change in the visual field mean defect (VFMD) from baseline to 12 months of treatment, with secondary efficacy parameters: visual acuity (Snellen chart and ETDRS chart), foveal sensitivity as measured by perimetry, and fundus alterations as evaluated according to the criteria of the International Classification and Grading System for AMD. The mean change in all four parameters of visual functions showed significant improvement in the treated group by the end of the study period. In addition, in the treated group only 1 out of 48 cases (2%) while in the placebo group 9 out of 53 (17%) showed clinically significant (>2.0 dB) worsening in VFMD (p = 0.006, odds ratio: 10.93). Decrease in drusen-covered area of treated eyes was also statistically significant as compared to placebo when either the most affected eyes (p = 0.045) or the less affected eyes (p = 0.017) were considered. These findings strongly suggested that an appropriate combination of compounds which affect mitochondrial lipid metabolism, may improve and subsequently stabilize visual functions, and it may also improve fundus alterations in patients affected by early AMD.
Lidocaine Gel versus Combined Topical Anesthesia Using Bupivacaine, Oxybuprocaine and Diclofenac Eyedrops in Cataract Surgery
Authors: Thill Michelle , Zeitz Oliver , Richard Ines , Richard Gisbert
Published: June 2005

Purpose: To assess the safety and efficacy of two topical anesthesia regimes for cataract surgery. Methods: 21 patients received a combination of 4 times bupivacaine 0.5, oxybuprocaine and diclofenac eyedrops, 18 patients were given a single topical application of lidocaine gel 2%. A single intracameral injection of lidocaine 1% was administered to all subjects. Results: The extent to which the surgeon was bothered by patient motility was graded as low in about two thirds of all procedures. Patients reported lower intraoperative pain levels with a single application of lidocaine gel supplemented with intracameral lidocaine than with a fourfold application of the combination topical anesthesia plus intracameral anesthesia. Conclusions: A single application of lidocaine gel 2% combined with intracameral anesthesia provides at least as good analgesia than multiple administration of combined topical anesthesia supplemented with intracameral anesthesia and is equally safe.
Relationship between C-Reactive Protein and the Electrocardiographic Pattern on Admission in Patients with Acute Coronary Syndrome
Authors: Sánchez Pedro L. , Palacios Igor F. , Pabón Pedro , Santos Ignacio , Rodríguez M.Victoria , Villacorta Eduardo , Martin-Moreiras Javier , Cruz Ignacio , Martin-Luengo Candido
Published: June 2005

Background: In patients with acute coronary syndrome (ACS), the prevalence of a primary inflammatory pathogenic component of coronary instability, as detectable by elevated C-reactive protein (CRP), varies considerably. The aim of the present study was to assess the prevalence of inflammation in patients with ACS according to the different electrocardiographic (ECG) patterns on admission. Methods: Hundred and thirty-six consecutive patients with the diagnosis of acute myocardial infarction were divided in three groups according to the ECG pattern on admission. Group 1 included 59 patients with ST segment elevation, group 2 included 50 patients with ST depression and/or T wave inversion and group 3 included 27 patients with no ECG changes. CRP was measured on admission in all patients. For the prevalence of inflammation analysis, we used a cutoff value of 3 mg/l. Results: CRP was above cutpoint significantly more often in patients with ST depression and/or T wave inversion (44.1% in group 1, 70% in group 2 and 40.7% in group 3; p = 0.009). Patients with similar ECG pattern and CRP levels above the cutpoint presented a poorer outcome (coronary death, myocardial infarction and recurrence of instability) at one-year follow-up: 54 versus 27% for group 1, 74 versus 27% for group 2 and 45 versus 31% for group 3. Conclusions: Patients with ST depression and/or T wave inversion on admission exhibit a higher prevalence of elevated CRP than those with ST elevation or no ECG changes, suggesting an important heterogeneity of the role of inflammatory triggers of the clinical syndromes of coronary instability.
Clinical Epidemiology of Cardiovascular Disease in Chronic Kidney Disease
Authors: Kundhal K. , Lok C.E.
Published: June 2005

Cardiovascular disease (CVD) is the most common cause of death in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). The clinical epidemiology of CVD in CKD is challenging due to a prior lack of standardized definitions of CKD, inconsistent measures of renal function, and possible alternative effects of ‘traditional’ CVD risk factors in patients with CKD. These challenges add to the complexity of the role of renal impairment as the cause or the consequence of cardiovascular disease. The goal of this review is to summarize the current evidence on: (1) the incidence and prevalence of CVD in chronic renal insufficiency and in ESRD, (2) risk factors for CVD in CKD, (3) the outcomes of patients with renal failure with CVD, and (4) CKD as a risk factor for CVD. The epidemiological associations implicating the huge burden of CVD throughout all stages of CKD highlight the need to better understand and implement adequate screening, and diagnostic and treatment strategies.
Treatment of Uremic Hyperparathyroidism with Percutaneous Ethanol Injection
Authors: Fassi Juliana , Lambertini Roberto , Farias Patricia , Blejman Oscar , Rosa Diez Guillermo , Algranati Salomon , Plantalech Luisa
Published: June 2005

The percutaneous ethanol injection (PEI) with ultrasound guidance has been suggested for the treatment of patients with hyperparathyroidism who are on dialysis, with the aim of selectively treating the parathyroid glands with nodular hyperplasia. We present our experience in 25 patients with chronic renal failure followed during 13.4 ± 10.6 months. A decrease in the levels of parathormone (PTH) (1,236.32 ± 129.8 vs. 721.66 ± 142.24 pg/ml), phosphatemia (6.16 ± 0.35 vs. 4.93 ± 0.36 mg/dl) and calcium-phosphorous product (60.82 ± 3.81 vs. 46.47 ± 3.46 mg2/dl2) was verified. In 56% of patients, PTH levels decreased (>50% of the baseline value) and 36% had final values <300 pg/ml. Patients in whom ultrasound showed a single gland responded better than those with more than one gland (83.3 vs. 30.8% of responders in each group). The procedures performed had a 4.9% complication rate: hematoma, symptomatic hypocalcemia, temporary paresis of the vocal cords. In summary, treatment with PEI is useful for the management of patients with hyperparathyroidism who are on dialysis, and the results achieved are better in patients who have a single gland identified by ultrasonography.
Cyclosporine Prolongs Delayed Graft Function in Kidney Transplantation: Are Rabbit Anti-Human Thymocyte Globulins the Answer?
Authors: Cravedi Paolo , Codreanu Igor , Satta Antonio , Turturro Marta , Sghirlanzoni MariaChiara , Remuzzi Giuseppe , Ruggenenti Piero
Published: June 2005

Background: Cyclosporine (CsA) nephrotoxicity may prolong duration of anuria in renal transplant patients with delayed graft function (DGF). Thus, many Transplant Centers tend to delay CsA treatment in order to accelerate renal function recovery. Methods: In this single-center, retrospective analysis we compared the outcomes of 40 renal transplant patients with DGF given a CsA-based (n = 17) regimen since the day of transplant or a CsA-sparing regimen (n = 23) based on early treatment with rabbit anti-human thymocyte globulin (RATG) and delayed CsA administration. We studied all patients with DGF who received a first or second graft at the Bergamo Transplant Center from January 1992 to March 2000. Results: Patients given RATG as compared to those on CsA had significantly shorter duration of anuria (11.0 ± 5.6 vs. 19.6 ± 8.9 days; p < 0.005) and of initial hospitalization (17.4 ± 4.3 vs. 27.4 ± 10.4 days; p < 0.001). Throughout the whole study period, 4 patients on RATG as compared to 6 on CsA had an acute rejection episode (p > 0.05). However, no patient on RATG as compared to 4 on CsA had an acute rejection during the anuria period (p < 0.05). Costs including hospitalization, dialysis treatment and study drugs were significantly lower in RATG than in CsA patients (EUR 29,944 ± 7,281 vs. 36,795 ± 13,656; p < 0.05). Conclusions: In renal transplant patients with DGF, early RATG treatment with delayed CsA administration accelerated renal function recovery and patient discharge, prevented occult rejections throughout the anuria period and significantly decreased the treatment costs.
Serum IgA/C3 Ratio May Be a Useful Marker of Disease Activity in Severe Henoch-Schönlein Nephritis
Authors: Shin Jae Il , Park Jee Min , Shin Youn Ho , Lee Jae Seung , Jeong Hyeon Joo , Kim Hyon Suk
Published: June 2005

Background/Aims: This study was designed to investigate whether the serum IgA/C3 ratio can be a serologic marker of disease activity in children with severe Henoch-Schönlein nephritis (HSN). Methods: Twelve HSN patients who were treated with steroids and cyclosporine were examined. The levels of serum IgA and C3 were measured using an international reference preparation (IFCC/CRM470) and a renal biopsy was performed in all patients before and after therapy. After therapy, patients were divided into 3 groups: complete remission (n = 6, group I), mild urinary abnormalities (n = 3, group II), and active renal disease (n = 3, group III). Results: The serum IgA/C3 ratio decreased significantly in groups I and II after therapy (2.62 ± 0.82 vs. 2.02 ± 0.52, p = 0.02), whereas the ratio in group III increased, although it was not statistically significant (2.13 ± 0.93 vs. 4.67 ± 1.71, p = 0.25). A follow-up renal biopsy revealed that the activity index was reduced in groups I and II (7.0 ± 2.4 vs. 3.6 ± 1.6, p = 0.016), and not changed in group III (7.3 ± 2.1 vs. 9.3 ± 2.5, p = 0.25). The activity index at a follow-up renal biopsy correlated positively with the changes of the serum IgA/C3 ratio: posttherapy activity index = 1.20 × ΔIgA/C3 + 4.78 (r = 0.635, p = 0.027); where ΔIgA/C3 is posttherapy IgA/C3 – pretherapy IgA/C3. Conclusion: These findings suggest that the serum IgA/C3 ratio may be a useful marker to predict disease activity and histologic severity in HSN.
Thrombin Is a Pro-Fibrotic Factor for Rat Renal Fibroblasts in vitro
Authors: Hewitson T.D. , Martic M. , Kelynack K.J. , Pagel C.N. , Mackie E.J. , Becker G.J.
Published: June 2005

Background: Generation of thrombin occurs in response to parenchymal injury. Thrombin not only converts plasma fibrinogen into an insoluble fibrin clot, but also potentially augments inflammation through receptor-mediated activity. This study examines whether thrombin may potentially exacerbate fibrosis by upregulating the function of interstitial fibroblasts in vitro. Methods: Fibroblasts were isolated by explant outgrowth culture of rat kidneys. Subcultured cells were grown in DMEM+10% FCS supplemented with 0.1–0.5 U/ml thrombin. Functional parameters examined included kinetics (thymidine incorporation and change in cell number), differentiation (Western blotting for α-smooth muscle actin; αSMA), expression of procollagen α1(I) (Northern blotting) and contraction of collagen I lattices. RT-PCR was used to characterise expression of protease-activated receptors (PAR) previously implicated in thrombin’s cellular effects. Results: Cell population growth was increased 66 ± 41 and 47 ± 41% by 0.1 and 0.5 U/ml thrombin respectively (both p < 0.05 vs. basal). Likewise, 0.5 U/ml thrombin increased corrected procollagen α1(I) expression 2.4-fold (p < 0.05 vs. basal) and exacerbated the ability of fibroblasts to contract collagen matrix (p < 0.05 vs. basal). These effects were not associated with any change in expression of the myofibroblast marker αSMA. Effects on cell number were inhibited by treatment with (D)-Phe-Pro-Arg-chloromethylketone HCl (PPACK) suggesting that functional effects were mediated by serine protease activity. PAR-1 was the only fully functional known thrombin receptor expressed by these cells. Conclusion: Thrombin is a potential unrecognised fibroblast agonist in renal disease. Further studies of thrombin and its receptors may yield valuable insights into the pathogenesis of interstitial fibrosis.
The Scandinavian Stroke Scale Predicts Outcome in Patients with Mild Ischemic Stroke
Authors: Christensen Hanne , Boysen Gudrun , Truelsen Thomas
Published: June 2005

Background: The prognostic value of the Scandinavian Stroke Scale (SSS) in patients with mild ischemic stroke has not previously been examined. We investigated if differences in SSS score predicted risk of death or dependency within 12 months after stroke onset. Patients and Methods: The analysis included 353 patients with acute cerebral infarction and SSS of at least 40 points on admission, 157 of whom with SSS of at least 50 points. Patients with 40–49 points on the SSS were compared with patients with 50–58 points; and patients with SSS 50–53 were compared to patients with 54–58 points on the SSS. Death or dependency was defined as 3–6 points on the modified Rankin scale (MRS), 3 and 12 months after stroke onset. The frequencies of death or dependency were compared between groups by χ2; the risk of death or dependency 1 year after stroke was calculated by multiple logistic regression analysis, adjusting for age, gender, prestroke MRS, arterial hypertension and tobacco smoking. Results: The risk of death or dependency 1 year after stroke onset was higher in patients with SSS 40–49 than with SSS 50–58, OR 2.0 (CI 95% 1.2–3.5). Three months after stroke, 46.5% of patients with SSS 40–49 were dead or dependent in comparison with 23.9% of patients with SSS > 49, p < 0.001. One year after stroke, 53.6% of patients with SSS 40–49 were dead or dependent in comparison with 30.1% of patients with SSS > 49, p <0.001. A significant 15% difference in living in own home was observed 1 year after stroke onset between patients with SSS 40–49 and SSS > 49. In very mild stroke, 32.7% of patients with SSS 50–53 were dead or dependent 3 months after stroke in comparison with 18.1% of patients with SSS 54–58 on admission, p = 0.048. Conclusions: The SSS predicts death and dependence in patients with mild ischemic stroke.
Sertoli Cell Tumor Causing Prepubertal Gynecomastia in a Boy with Peutz-Jeghers Syndrome: The Outcome of 1-Year Treatment with the Aromatase Inhibitor Testolactone
Authors: Kara Cengiz , Kutlu Alev Oguz , Tosun Mahya Sultan , Apaydın Sema , Senel Ferda
Published: June 2005

Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by benign intestinal hamartomatous polyps and mucocutaneous pigmentation, and with an increased risk for intestinal and extra-intestinal neoplasms. Sertoli cell tumors in boys with PJS have been increasingly recognized as a cause of prepubertal gynecomastia. However, an association between nephrocalcinosis and PJS has not been reported before. We report on a 7.25-year-old boy with PJS, bilateral gynecomastia, Sertoli cell tumor and nephrocalcinosis, and present the outcome of 1-year treatment with the aromatase inhibitor testolactone. The patient presented with bilateral breast and testis enlargement, and mucocutaneous pigmentation. Testicular ultrasound revealed parenchymal multiple microcalcifications. Histopathological examination was consistent with Sertoli cell tumors. Nephrocalcinosis due to idiopathic renal hypercalciuria was also detected. The aromatase inhibitor testolactone was begun in an attempt to prevent acceleration in skeletal maturation. One-year treatment with testolactone reduced the breast base diameter from 7 to 3 cm, and bone age advanced 1.2 years during this period. Our case demonstrates that waiting for the effect of aromatase inhibitors on gynecomastia before making a decision for mastectomy may be a reasonable option. We also consider that the association between PJS and nephrocalcinosis may be a coincidence.
Are Remnant-Like Particles Independent Predictors of Coronary Heart Disease Incidence?
Authors: Imke Claudia , Rodriguez Beatriz L. , Grove John S. , McNamara Judith R. , Waslien Carol , Katz Alan R. , Willcox Bradley , Yano Katsuhiko , Curb J. David
Published: June 2005

Background—Remnant-like particles have been proposed as a new risk factor for coronary heart disease (CHD). This is the first long-term prospective investigation of the relationship between remnant-like particles and a cardiovascular disease outcome in healthy men.

Methods and Results—A cohort of 1156 Japanese-American men aged 60 to 82 from the Honolulu Heart Program was followed for 17 years. During that period 164 incident cases of CHD were identified. In multivariate Cox regression analyses, baseline remnant-like particle cholesterol (RLP-C) and triglyceride (RLP-TG) levels were significantly related to CHD incidence independently of nonlipid cardiovascular risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. Total triglyceride levels were an independent predictor of CHD incidence. However, in models including RLP and triglyceride level simultaneously, neither variable was significant when adjusted for the other. This finding can be attributed to the strong correlation between RLP-C and RLP-TG levels and total triglycerides. When individuals with normal triglyceride levels (n=894) were separated from those with elevated triglycerides (n=260), the association between RLPs and CHD relative risk was only significant for the group with elevated triglyceride levels.

Conclusions—RLP levels predicted CHD incidence independently of nonlipid risk factors and of total cholesterol or high-density and low-density lipoprotein cholesterol levels. However, RLP levels did not provide additional information about CHD incidence over and above total triglyceride levels. Therefore, this study does not support the need for testing of remnants in men if measures of fasting triglycerides are available.
Pre–B-Cell Colony–Enhancing Factor Regulates NAD
+
-Dependent Protein Deacetylase Activity and Promotes Vascular Smooth Muscle Cell Maturation
Authors: van der Veer Eric , Nong Zengxuan , O’Neil Caroline , Urquhart Brad , Freeman David , Pickering J. Geoffrey
Published: June 2005

Conversion of vascular smooth muscle cells (SMCs) from a proliferative state to a nonproliferative, contractile state confers vasomotor function to developing and remodeling blood vessels. Using a maturation-competent human SMC line, we determined that this shift in phenotype was accompanied by upregulation of pre–B-cell colony–enhancing factor (PBEF), a protein proposed to be a cytokine. Knockdown of endogenous PBEF increased SMC apoptosis and reduced the capacity of synthetic SMCs to mature to a contractile state. In keeping with these findings, human SMCs transduced with the PBEF gene had enhanced survival, an elongated bipolar morphology, and increased levels of h-caldesmon, smoothelin-A, smoothelin-B, and metavinculin. Notwithstanding some prior reports, PBEF did not have attributes of a cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity. Intracellular nicotinamide adenine dinucleotide (NAD
+
) content was increased in PBEF-overexpressing SMCs and decreased in PBEF-knockdown SMCs. Furthermore, NAD
+
-dependent protein deacetylase activity was found to be essential for SMC maturation and was increased by PBEF. Xenotransplantation of human SMCs into immunodeficient mice revealed an increased capacity for PBEF-overexpressing SMCs to mature and intimately invest nascent endothelial channels. This microvessel chimerism and maturation process was perturbed when SMC PBEF expression was lowered. These findings identify PBEF as a regulator of NAD
+
-dependent reactions in SMCs, reactions that promote, among other potential processes, the acquisition of a mature SMC phenotype.