bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: role of NOS and KATP channels
Authors: Fitzpatrick Colleen M. , Shi Yang , Hutchins William C. , Su Jidong , Gross Garrett J. , Ostadal Bohuslav , Tweddell James S. , Baker John E.
Published: August 2004

Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (KATP) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (FiO2 = 0.21) or hypoxic (FiO2 = 0.12) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts ( n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 ± 4%) than normoxic controls (43 ± 4%). At 10 days of age, NG-nitro-l-arginine methyl ester (200 μM) and glibenclamide (3 μM) abolished the cardioprotective effects of chronic hypoxia (45 ± 4% and 46 ± 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 ± 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 ± 4%). l-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 ± 4% and 39 ± 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of KATP channels.
Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model
Authors: Goldman Daniel , Bateman Ryon M. , Ellis Christopher G.
Published: August 2004

Inherent in the inflammatory response to sepsis is abnormal microvascular perfusion. Maldistribution of capillary red blood cell (RBC) flow in rat skeletal muscle has been characterized by increased 1) stopped-flow capillaries, 2) capillary oxygen extraction, and 3) ratio of fast-flow to normal-flow capillaries. On the basis of experimental data for functional capillary density (FCD), RBC velocity, and hemoglobin O2 saturation during sepsis, a mathematical model was used to calculate tissue O2 consumption (V̇o2), tissue Po2 (Pt) profiles, and O2 delivery by fast-flow capillaries, which could not be measured experimentally. The model describes coupled capillary and tissue O2 transport using realistic blood and tissue biophysics and three-dimensional arrays of heterogeneously spaced capillaries and was solved numerically using a previously validated scheme. While total blood flow was maintained, capillary flow distribution was varied from 60/30/10% (normal/fast/stopped) in control to 33/33/33% (normal/fast/stopped) in average sepsis (AS) and 25/25/50% (normal/fast/stopped) in extreme sepsis (ES). Simulations found approximately two- and fourfold increases in tissue V̇o2 in AS and ES, respectively. Average (minimum) Pt decreased from 43 ( 40 ) mmHg in control to 34 ( 27 ) and 26 ( 15 ) mmHg in AS and ES, respectively, and clustering fast-flow capillaries (increased flow heterogeneity) reduced minimum Pt to 14.5 mmHg. Thus, although fast capillaries prevented tissue dysoxia, they did not prevent increased hypoxia as the degree of microvascular injury increased. The model predicts that decreased FCD, increased fast flow, and increased V̇o2 in sepsis expose skeletal muscle to significant regions of hypoxia, which could affect local cellular and organ function.
Relative contributions of Na+/H+exchange and Na+/HCO3−cotransport to ischemic Nai+overload in isolated rat hearts
Authors: Ten Hove Michiel , Nederhoff Marcel G. J. , Van Echteld Cees J. A.
Published: August 2004

The Na+/H+exchanger (NHE) and/or the Na+/HCO3−cotransporter (NBC) were blocked during ischemia in isolated rat hearts. Intracellular Na+concentration ([Na+]i), intracellular pH (pHi), and energy-related phosphates were measured by using simultaneous23Na and31P NMR spectroscopy. Hearts were subjected to 30 min of global ischemia and 30 min of reperfusion. Cariporide (3 μM) or HCO3−-free HEPES buffer was used, respectively, to block NHE, NBC, or both. End-ischemic [Na+]iwas 320 ± 18% of baseline in HCO3−-perfused, untreated hearts, 184 ± 6% of baseline when NHE was blocked, 253 ± 19% of baseline when NBC was blocked, and 154 ± 6% of baseline when both NHE and NBC were blocked. End-ischemic pHiwas 6.09 ± 0.06 in HCO3−-perfused, untreated hearts, 5.85 ± 0.02 when NHE was blocked, 5.81 ± 0.05 when NBC was blocked, and 5.70 ± 0.01 when both NHE and NBC were blocked. NHE blockade was cardioprotective, but NBC blockade and combined blockade were not, the latter likely due to a reduction in coronary flow, because omission of HCO3−under conditions of NHE blockade severely impaired coronary flow. Combined blockade of NHE and NBC conserved intracellular H+load during reperfusion and led to massive Na+influx when blockades were lifted. Without blockade, both NHE and NBC mediate acid-equivalent efflux in exchange for Na+influx during ischemia, NHE much more than NBC. Blockade of either one does not affect the other.
Body, eye, and chorioallantoic vessel growth are not dependent on cardiac output level in day 3–4 chicken embryos
Authors: Burggren Warren , Khorrami Sheva , Pinder Alan , Sun Tiffany
Published: August 2004

Normal aerobic metabolic rates persist in the early chicken embryo after elimination of cardiac output, but the dependence of tissue growth and differentiation on blood flow is unknown in these early stages. We partially ligated (25–50% occlusion) the ventricular outflow tract of Hamburger-Hamilton stage (HH) 16–18 embryos, producing a wide range of cardiac output. For the next ∼48 h (to HH 24), we measured heart rate (HR), stroke volume (SV), and cardiac output (CO), as well as these growth indicators: eye diameter, chorioallantoic vessel density, and body mass. Acutely, HR declined with partial ligation (from 108 to 98 beats/min). Paradoxically, SV and CO decreased sharply in most embryos but increased in others, collectively producing the desired large variation (up to 25-fold) in CO and permitting assessment of tissue growth over a very large range of blood perfusion. Eye diameter doubled (from 0.6 to 1.2 mm) with development from HH 16 to HH 24, but within a developmental cohort there was no significant correlation between eye diameter and CO over a 25-fold range of CO. Similarly, chorioallantoic membrane vessel index was independent of CO over the CO range at all stages. Finally, body mass increase during development was not significantly affected by partial conal truncal ligation. Collectively, these data suggest that normal eye and vessel growth and body mass accumulation occur independent of their rate of blood perfusion, supporting the hypothesis of prosynchronotropy—that the heart begins to beat and generate blood flow in advance of the actual need for convective blood flow to tissues.
Do incremental increases in blood pressure elicit neointimal plaques through endothelial injury?
Authors: Ruiz-Feria Ciro A. , Yang Yimu , Nishimura Hiroko
Published: August 2004

Fowl (males more than females) show maturation-dependent rises in blood pressure (BP) and formation of neointimal plaques (NPs), resembling balloon catheter injury-induced neointima, in the abdominal aorta (AbA) just above the bifurcation. The plaque comprises neointimal cells containing abundant endoplasmic reticulum and extracellular matrix. Hence, we investigated whether rapid incremental BP increases in male chicks trigger NP formation, possibly via endothelial injury in hemodynamically selective areas. In 6-wk-old chicks ( n = 8) treated 4 wk with solvent (Sv; minipump) or arginine supplement (Arg; 0.3% in drinking water), BP increased from 140 ± 5 to 159 ± 4 (Sv) and from 138 ± 4 to 157 ± 3 (Arg) mmHg, whereas propranolol treatment (Prop, 8 mg·kg−1·day−1; minipump) prevented the rise. Arg and Prop groups had, respectively, 73% and 77% smaller ( P < 0.05) NP areas and 19% and 25% less ( P < 0.01) AbA medial thickness than Sv controls. In 16-wk-old cockerels, established BP remained high after Sv and Arg treatments. In the Prop group, BP decreased, but neither NP area nor medial thickness was lower than in the Sv group, whereas the Arg group showed greater NP area and medial thickness. Pulse pressure, determined by intravascular transducer, increased as the pulse wave descended the aorta. The results suggest that maturation-dependent rises in BP in chicks may trigger NP formation in the lower segment of the AbA, which was prevented by inhibition of BP increase, or via a possible increase in nitric oxide availability. BP reduction exerts no effect once BP reaches a plateau. Involvement of endothelial injury leading to NP formation and hemodynamic forces selective for the lesion-prone area remain to be determined.
High-unsaturated-fat, high-protein, and low-carbohydrate diet during pregnancy and lactation modulates hepatic lipid metabolism in female adult offspring
Authors: Zhang Junlong , Wang Chunli , Terroni Paul L. , Cagampang Felino R. A. , Hanson Mark , Byrne Christopher D.
Published: August 2004

Whether a high-unsaturated-fat, high-protein (HFP), and low-carbohydrate (CHO) diet during gestation has long-lasting beneficial effects on lipid metabolism in the offspring was investigated using a mouse model. Female mice were fed either a standard (CHO rich) chow diet or a CHO HFP diet, before and during gestation and lactation. All offspring were weaned onto the same chow until adulthood. Although liver cholesterol concentration and fasting plasma triglyceride (TG), cholesterol, and free fatty acid concentrations were not affected in either male or female HFP offspring, hepatic TG concentration was reduced by ∼51% ( P < 0.05) in the female adult offspring from dams on the HFP diet, compared with females from dams on the chow diet (a trend toward reduced TG concentration was also observed in the male). Furthermore, hepatic protein levels for CD36, carnitine palmitoyltransferase-1 (CPT-1), and peroxisomal proliferator activated receptor-α (PPAR-α) were increased by ∼46% ( P < 0.001), ∼52% ( P < 0.001), and ∼14% ( P = 0.035), respectively, in the female HFP offspring. Liver TG levels were negatively correlated with protein levels of CD 36 ( r = −0.69, P = 0.007), CPT-1 ( r = −0.55, P = 0.033), and PPAR-α ( r = −0.57, P = 0.025) in these offspring. In conclusion, a maternal HFP diet during gestation and lactation reduces hepatic TG concentration in female offspring, which is linked with increased protein levels in fatty acid oxidation.
Enhanced corticosterone concentrations and attenuated Fos expression in the medial amygdala of female oxytocin knockout mice exposed to psychogenic stress
Authors: Mantella Rose C. , Vollmer Regis R. , Rinaman Linda , Li Xia , Amico Janet A.
Published: August 2004

Centrally released oxytocin (OT) is believed to attenuate the response of the hypothalamic-pituitary-adrenal (HPA) axis to psychogenic stress. To test this hypothesis, we measured plasma corticosterone concentrations and Fos-immunoreactive protein in the paraventricular nucleus of the hypothalamus (PVN) and limbic brain areas of female wild-type and OT knockout mice that were exposed to a shaker platform, a predominantly psychogenic stress. Plasma corticosterone concentrations after shaker stress were higher in female OT knockout mice than wild-type mice. Genotypic differences in the corticosterone response after shaker stress persisted across all stages of the estrous cycle and when mice were conditioned to repeated shaker stress. Shaker stress activated Fos in OT-positive neurons of wild-type mice and corticotropin-releasing hormone-positive, but not vasopressin-positive, neurons within the PVN of wild-type and OT knockout mice. Fos expression was also increased after shaker stress in the bed nucleus of the stria terminalis, medial and central nuclei of the amygdala, medial preoptic area, and the paraventricular nucleus of the thalamus of wild-type and OT knockout mice. However, Fos expression in the medial amygdala was significantly lower in female OT knockout mice than wild-type mice. Our findings indicate heightened stress-induced corticosterone release in female OT knockout mice. Therefore, the results suggest that OT pathways play a role in attenuating the HPA axis response to psychogenic stress in female mice.
Functional organization of the bovine rumen epithelium
Authors: Graham C. , Simmons N. L.
Published: August 2004

The functional organization of the bovine rumen epithelium has been examined by electron and light microscopy combined with immunocytochemistry to define a transport model for this epithelium. Expression of connexin 43, an integral component of gap junctions, the tight-junction molecules claudin-1 and zonula occludens 1 (ZO-1), and the catalytic α-subunit of Na+-K+-ATPase was demonstrated by SDS-PAGE and Western blotting. From the lumen surface, four cell layers can be distinguished: the stratum corneum, the stratum granulosum, the stratum spinosum, and the stratum basale. Both claudin-1 and ZO-1 immunostaining showed plasma membrane staining, which was present at the stratum granulosum with decreasing intensity through the stratum spinosum to the stratum basale. The stratum corneum was negative for claudin-1 immunostaining. Transmission electron microscopy confirmed that occluding tight junctions were present at the stratum granulosum. Plasma membrane connexin 43 immunostaining was most intense at the stratum granulosum and decreased in intensity through stratum spinosum and stratum basale. There was intense immunostaining of the stratum basale for Na+-K+-ATPase, with weak staining of the stratum spinosum. Both the stratum granulosum and the stratum corneum were essentially negative. Stratum basale cells also displayed a high mitochondrial density relative to more apical cell layers. We conclude that epithelial barrier function may be attributed to the stratum granulosum and that cell-cell gap junctions allow diffusion to interconnect the barrier cell layer with the stratum basale where Na+-K+-ATPase is concentrated.
Hormonal regulation of glycogen metabolism in white muscle slices from rainbow trout (Oncorhynchus mykissWalbaum)
Authors: Frolow Jason , Milligan C. Louise
Published: August 2004

To test the hypothesis that cortisol and epinephrine have direct regulatory roles in muscle glycogen metabolism and to determine what those roles might be, we developed an in vitro white muscle slice preparation from rainbow trout ( Oncorhynchus mykiss Walbaum). In the absence of hormones, glycogen-depleted muscle slices obtained from exercised trout were capable of significant glycogen synthesis, and the amount of glycogen synthesized was inversely correlated with the initial postexercise glycogen content. When postexercise glycogen levels were <5 μmol/g, about 4.3 μmol/g of glycogen were synthesized, but when postexercise glycogen levels were >5 μmol/g, only about 1.7 μmol/g of glycogen was synthesized. This difference in the amount of glycogen synthesized was reflected in the degree of activation of glycogen synthase. Postexercise glycogen content also influenced the response of the muscle to 10−8M epinephrine and 10−8M dexamethasone (a glucocorticoid analog). At high glycogen levels (>5 μmol/g), epinephrine and dexamethasone stimulated glycogen phosphorylase activity and net glycogenolysis, whereas at low (<5 μmol/g) glycogen levels, glycogenesis and activation of glycogen synthase activity prevailed. These data clearly indicate not only is trout muscle capable of in situ glycogenesis, but the amount of glycogen synthesized is a function of initial glycogen content. Furthermore, whereas dexamethasone and epinephrine directly stimulate muscle glycogen metabolism, the net effect is dependent on initial glycogen content.
Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats
Authors: Hodges M. R. , Opansky C. , Qian B. , Davis S. , Bonis J. , Bastasic J. , Leekley T. , Pan L. G. , Forster H. V.
Published: August 2004

The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO2/H+ chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats ( n = 13), and breathing at rest (awake and asleep), breathing during exercise, as well as CO2 sensitivity were assessed repeatedly before and after sequential injections of the neurotoxins saporin conjugated to substance P [SP-SAP; neurokinin-1 receptor (NK1R) specific] and ibotenic acid (IA; nonspecific glutamate receptor excitotoxin). In all goats, microtubule implantation alone resulted in altered breathing periods, manifested as central or obstructive apneas, and fractionated breathing. The frequency and characteristics of the altered breathing periods were not subsequently affected by injections of the neurotoxins ( P > 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO2 sensitivity was reduced ( P < 0.05) by 23.8 and 26.8%, respectively, but CO2 sensitivity returned to preinjection control values >7 days postinjection. However, there was no hypoventilation at rest (awake, non-rapid eye movement sleep, or rapid eye movement sleep) or during exercise after these injections ( P > 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced ( P < 0.05) both tryptophan hydroxylase-expressing (36%) and NK1R-expressing (35%) neurons at the site of injection. We conclude that both NK1R- and glutamate receptor-expressing neurons in the medullary raphe nuclei influence CO2 sensitivity apparently through CO2/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO2 chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms.
Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats
Authors: Hodges M. R. , Martino P. , Davis S. , Opansky C. , Pan L. G. , Forster H. V.
Published: August 2004

To gain insight into why there are chemoreceptors at widespread sites in the brain, mircrotubules were chronically implanted at two or three sites in the medullary raphe nuclei of adult goats ( n = 7). After >2 wk, microdialysis (MD) probes were inserted into the microtubules to create focal acidosis (FA) in the awake state using mock cerebral spinal fluid (mCSF) equilibrated with 6.4% (pH = 7.3), 50% (pH = 6.5), or 80% CO2 (pH = 6.3), where MD with 50 and 80% CO2 reduces tissue pH by 0.1 and 0.18 pH unit, respectively. There were no changes in all measured variables with MD with 6.4% at single or multiple raphe sites ( P > 0.05). During FA at single raphe sites, only 80% CO2 elicited physiological changes as inspiratory flow was 16.9% above ( P < 0.05) control. However, FA with 50 and 80% CO2 at multiple sites increased ( P < 0.05) inspiratory flow by 18.4 and 30.1%, respectively, where 80% CO2 also increased ( P < 0.05) tidal volume, heart rate, CO2 production, and O2 consumption. FA with 80% CO2 at multiple raphe sites also led to hyperventilation (−2 mmHg), indicating that FA had effects on breathing independent of an increased metabolic rate. We believe these findings suggest that the large ventilatory response to a global respiratory brain acidosis reflects the cumulative effect of stimulation at widespread chemoreceptor sites rather than a large stimulation at a single site. Additionally, focal acidification of raphe chemoreceptors appears to activate an established thermogenic response needed to offset the increased heat loss associated with the CO2 hyperpnea.
Contractile responses of the rat gastrocnemius and soleus muscles to isotonic resistance exercise
Authors: Norenberg K. M. , Fitts R. H.
Published: August 2004

Male rats were divided into control and weight-trained (WT) groups. WT rats performed squat-type exercises twice daily, 5 days/wk, for 14 wk. They averaged 36 lifts/day, with an average weight of 555 g. Muscle-to-body weight ratio (mg/g) of the soleus (Sol) was not different from control, but it increased 11 and 6% in the gastrocnemius (Gast) and plantaris, respectively ( P < 0.05). The normalized twitch tension of the in situ Sol was elevated by 21%, whereas single-skinned type I fibers from the Sol showed an increased rate constant of tension redevelopment ( Ktr) but no other contractile adaptations to WT. In contrast, the Gast type I fibers showed an increase ( P < 0.05) in maximal velocity of shortening (25%), peak power (15%), Ktr (18%), and normalized tension (7%). The Ktr and normalized tension of the Gast type IIa fibers increased by 24% ( P < 0.05) and 12% ( P < 0.05), respectively, whereas velocity and power showed a tendency to increase. Fiber size, determined by myosin ATPase histochemistry, was not different for any fiber type from the Gast or Sol. These results indicate that isotonic resistance exercise of the calf targets the Gast (type I and type IIa fibers) and has little effect on the Sol.
Metabolic Complications during Regional Citrate Anticoagulation in Continuous Venovenous Hemodialysis: Single-Center Experience
Authors: Morgera Stanislao , Scholle Cornelia , Voss Gitana , Haase Michael , Vargas-Hein Ortrud , Krausch Dietmar , Melzer Christoph , Rosseau Simone , Zuckermann-Becker Heidrun , Neumayer Hans-H.
Published: August 2004

Background: Regional anticoagulation with trisodium citrate is an effective form of anticoagulation for continuous renal replacement therapy (CRRT) in patients at a high risk of bleeding. In a prospective, observational study we compared an established regional citrate anticoagulation protocol [Mehta R et al: Kidney Int 1990;38:976–981] versus a standard heparin anticoagulation protocol focusing on acid-base and electrolyte derangements as well as on cost effectiveness. Methods and Results: 209 patients were included in the study. In 37 patients, citrate was used as the sole anticoagulant, 87 patients received low-dose heparin plus citrate, and 85 patients received only heparin as anticoagulant. A customized dialysate solution was used for citrate-anticoagulated CRRT (no buffer, no calcium, reduced sodium concentration). Filter life was significantly higher during citrate anticoagulation compared to heparin anticoagulation (80.2 ± 60 vs. 30.2 ± 32 h; p < 0.001). No difference was found between citrate and citrate-heparin anticoagulation (p = 0.310). Metabolic alkalosis was observed in more than 50% of patients on citrate anticoagulation. Alkalosis developed within the first 72 h after initiating treatment and could be reversed in almost all cases by increasing the dialysate flow rate. Hypercalcemia was observed in 13 patients on citrate anticoagulation. Patients with impaired liver function were particularly at risk. Systemic hypocalcemia, hypernatremia, and anion gap acidosis were not observed. Citrate anticoagulation was well tolerated hemodynamically. A longer filter life during citrate anticoagulation translated into a significant cost reduction compared to standard heparin anticoagulation (p < 0.01). Conclusion: Regional anticoagulation with trisodium citrate in combination with a customized calcium-free dialysate is a safe and effective alternative to a heparin-based anticoagulation regimen.
Renal Vasculitis: Increasingly a Disease of the Elderly?
Authors: Satchell S.C. , Nicholls A.J. , D’Souza R.J. , Beaman M.
Published: August 2004

Background/Aims: The majority of patients presenting to our district general hospital with renal vasculitis are elderly. Older patients respond less well to treatment and have a poorer prognosis. We investigated the relationship between age and outcome of renal vasculitis in our centre and examined the evidence regarding treatment of elderly patients with this condition. Methods: Patients presenting over a 2-year period with renal vasculitis were identified by clinical and histological features and by antineutrophil cytoplasmic autoantibody positivity. They were followed for a mean of 15 months and outcomes were recorded. Results were compared with published studies. Results: The mean age at presentation of 21 patients was 69 years. Forty-eight percent required dialysis and there was a 33% overall mortality. The mean age of patients in previous treatment studies has been between 50 and 55 years. Conclusions: The greater severity of disease at presentation and poorer outcome than previously described is likely to be due to the high proportion of elderly patients. The incidence of vasculitis is increasing in the elderly but as this group has been poorly represented in clinical trials in renal vasculitis, applying the findings of these trials to their treatment may be hazardous. Future research should determine which treatments are safe and effective in the elderly.
Glomerular Deposition and Urinary Excretion of Complement Factor H in Idiopathic Membranous Nephropathy
Authors: Endo Morito , Fuke Yoshinobu , Tamano Mariko , Hidaka Mutsuko , Ohsawa Isao , Fujita Takayuki , Ohi Hiroyuki
Published: August 2004

Background/Aims: The complement system plays an important role in the pathogenesis of membranous nephropathy (MN). In order to elucidate the regulatory mechanism of complement activation, we demonstrated glomerular deposition and urinary excretion of complement factor H, which controls the alternative pathway and the amplification loop at the C3 step, in patients with idiopathic MN. Methods: Renal biopsy specimens from 20 patients with idiopathic MN were studied immunohistochemically using monoclonal antibodies against complement components including factor H. SDS-PAGE and Western blotting analysis of urine samples were performed, and the urinary excretion of factor H and C5b-9 were measured by quantitative sandwich ELISA. Results: Intense glomerular deposition of factor H was observed with C3b·C3c and C5b-9 at an early stage of the disease. Factor H was detected in Western blots of urine samples, but factor H-like protein 1 (FHL-1) was not. The mean level of urinary factor H was elevated (86.30 ± 21.93 U/mg urinary creatinine) in comparison to that of normal controls (4.76 ± 1.03 U/mg urinary creatinine). Urinary factor H level exhibited no correlation with clinical parameters; however, a negative correlation was found between urinary C5b-9/factor H and creatinine clearance (r = 0.662, p < 0.01). Conclusion: The source of glomerular and urinary factor H is supposedly a 150-kD protein. There was no evidence to suggest that FHL-1 is synthesized at the site of inflammation. The urinary C5b-9 to urinary factor H ratio is indicative of the degree of ongoing complement activation in the glomeruli and complement-mediated renal injury. These findings suggest that factor H contributes to the control mechanism of in situ complement activation and prevents renal damage in idiopathic MN.
Prolonged Treatment with Low-Dose Intravenous Pulse Cyclophosphamide May Reduce Rate of Relapse in ANCA-Associated Vasculitis
Authors: Dhaygude Ajay , Griffith Megan , Cairns Thomas , McLean Adam , Palmer Andrew , Taube David
Published: August 2004

Background: Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less complications, but may lead to an increased rate of relapse. However, these studies used relatively short courses of treatment with cyclophosphamide. In this study we used a prolonged course of low-dose intravenous cyclophosphamide for 18–24 months for ANCA-associated vasculitis, evaluated the effectiveness of pCyc and analysed the outcome of a prolonged treatment on the rate of relapse. Methods: A retrospective analysis of all the patients treated with pCyc from 1995 to 2002 was performed. Results: Thirty-seven patients were followed for an average of 38 months. Thirty-four of 37 patients (91.9%) achieved complete remission at 3 months. Eight (21%) episodes of relapse occurred in 7 patients. The cyclophosphamide was well tolerated with a low rate of infections (18.9%) and 1 death (2.7%) due to sepsis whilst on cyclophosphamide. Conclusion: In this study, pCyc was effective in achieving rapid remission and had a low complication rate. If prolonged, this treatment may reduce the rate of relapse.
Oxidized ω–3 Fatty Acids Inhibit Pro-Inflammatory Responses in Glomerular Endothelial Cells
Authors: Chaudhary Ashok , Mishra Archana , Sethi Sanjeev
Published: August 2004

Background: ω–3 fatty acids have beneficial effects in chronic inflammatory diseases that are characterized by accumulation of leukocytes and leukocyte-mediated tissue injury. Accumulation of leukocytes occurs, in part, due to pro-inflammatory responses in endothelial cells, such as increase in expression of leukocyte adhesion receptors and chemokines, such as MCP-1 and IL-8. Methods: ω–3 fatty acids, such as EPA, are highly polyunsaturated and readily undergo auto-oxidation. We studied the effect of oxidized EPA and unoxidized (native) EPA on leukocyte-glomerular endothelial cell interactions using adhesion assays, ELISA assays and transmigration assays. We used electrophoresis mobility shift assays to determine the effect of oxidized and unoxidized EPA on cytokine-induced nuclear factor-ĸB (NF-ĸB) activation. Results: Oxidized EPA but not unoxidized EPA dose-dependently inhibits cytokine-induced leukocyte adhesion receptors on glomerular endothelial cells, which correlates with inhibition of leukocyte-glomerular endothelial cell interactions. Oxidized EPA but not unoxidized EPA inhibits cytokine-induced glomerular endothelial and mesangial cell expression of MCP-1, and to a lesser extent IL-8. Transmigration assays show that oxidized EPA but not unoxidized EPA inhibits leukocyte transmigration across glomerular endothelial cells. Oxidized EPA but not unoxidized EPA potently inhibited cytokine-induced activation of NF-ĸB in glomerular endothelial and mesangial cells. Conclusions: These studies show that the beneficial effects of fish oil in chronic inflammatory diseases, including IgA nephropathy, may result from the inhibitory effects of oxidized ω–3 fatty acids on pro-inflammatory events in endothelial cells via inhibition of NF-ĸB activation.
Rate of False-Positive Results for Threshold Shifts during Initial Treatment with Aminoglycosides
Authors: Schmuziger Nicolas , Gürtler Nicolas , Jungi Manuel , Gratwohl Alois , Probst Rudolf
Published: August 2004

Specific recommendations from the American Speech-Language Hearing Association (1994) exist for the audiometric surveillance of patients receiving aminoglycoside therapy. However, these recommendations are not based primarily on test-retest repeatability in often seriously ill patients. The probability of ototoxicity is very low during the first three days of aminoglycoside therapy, and significant threshold shifts can be assumed to represent a false-positive result. Baseline thresholds were measured in 28 patients before or not later than 24 h after the beginning of aminoglycoside therapy. These measurements were repeated in 22 patients during the first three days of the drug administration. Three out of 22 patients fulfilled the American Speech-Language-Hearing Association’s (1994) criteria for cochleotoxicity making up a false-positive rate of 13%. In actual patients, the false-positive rate of audiometric surveillance during ototoxic drug administration may be substantially higher than in healthy subjects when these criteria are used.
Mechanisms of Apoptosis Induced by Cisplatin in Marginal Cells in Mouse Stria Vascularis
Authors: Lee Ji Eun , Nakagawa Takayuki , Kita Tomoko , Kim Tae Soo , Iguchi Fukuichiro , Endo Tsuyoshi , Shiga Atsushi , Lee Sang Heun , Ito Juichi
Published: August 2004

Degeneration of the stria vascularis (SV) is amongst the major causes of cisplatin (CDDP)-induced hearing impairment. The pathways of apoptosis occurring in the SV due to CDDP were examined using a mouse experimental model. Temporal bones of adult C57BL/6 mice were collected on days 3, 7 and 14 after the local application of CDDP. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunostaining for apoptosis-related proteins or reactive radical species were employed for analysis. Local application of CDDP caused apoptotic cell death of marginal cells 3 days after CDDP treatment. Immunohistochemical analyses demonstrated activation of caspase-3 and -9, but not -8, and redistribution of cytochrome c in affected marginal cells, indicating a caspase-dependent, mitochondrion-mediated apoptotic pathway in marginal cells. Temporary expression of hydroxynonenal, nitrotyrosine and inducible nitric oxide synthase in the SV was observed at the induction of apoptosis in marginal cells. CDDP toxicity generates reactive radical species in the SV, which causes mitochondrial membrane permeabilization leading to apoptosis of marginal cells.
Analysis of Ceiling Effects Occurring with Speech Recognition Tests in Adult Cochlear-Implanted Patients
Authors: Helms Jan , Weichbold Viktor , Baumann Uwe , von Specht Hellmut , Schön Franz , Müller Joachim , Esser Barbara , Ziese Michael , Anderson Ilona , D’Haese Patrick
Published: August 2004

This article presents a simple method of analysing speech test scores which are biased through ceiling effects. Eighty postlingually deafened adults implanted with a MED-EL COMBI 40/40+ cochlear implant (CI) were administered a numbers test and a sentence test at initial device activation and at 1, 3, 6, 12 and 24 months thereafter. As a measure for speech recognition performance, the number of patients who scored at the ‘ceiling level’ (i.e. at least 95% correct answers) was counted at each test interval. Results showed a quick increase in this number soon after device activation as well as a continuous improvement over time (numbers test: 1 month: 51%; 6 months: 73%; 24 months: 88%; sentence test: 1 month: 33%; 6 months: 49%; 24 months: 64%). The new method allows for the detection of speech recognition progress in CI patient samples even at late test intervals, where improvement curves based on averaged scores are usually assuming a flat shape.
Ultrasonically Activated Scalpel Compared with Electrocautery in Tonsillectomy
Authors: Schrey Aleksi , Pulkkinen Jaakko , Fremling Christian , Kinnunen Ilpo
Published: August 2004

The occurrence of postoperative bleeding, the quantity of operative bleeding and the duration of operation were retrospectively evaluated in 407 patients who underwent tonsillectomy within a 32-month period. They were operated on with either an ultrasonically activated scalpel (UAS), bipolar diathermy (BPD) or blunt dissection with monopolar diathermy (MPD) with the following results. (1) Primary bleeding was more common with MPD: MPD 7.1% vs. BPD 2.4% (p < 0.01) vs. UAS 1.0% (p < 0.001). Secondary bleeding was more common with UAS: UAS 19.6% vs. MPD 14.5% (p < 0.001) vs. BPD 14.5% (p < 0.01). There was no statistical significance in the differences between overall postoperative bleeding rates. (2) There was statistically significantly less operative bleeding with UAS:UAS 24.8 ml vs. MPD 58.7 ml vs. BPD 43.8 ml. (3) On the other hand, the operation time was on average longer with UAS: UAS 32.3 min vs. MPD 18.4 min vs. BPD 22.1 min. Our results suggest that UAS offers no significant advantage over MPD or BPD in tonsillectomy other than minimal operative bleeding possibly due to longer duration of operation.
BRCA1/2 Mutation Carriers: Living with Susceptibility
Authors: Hagoel Lea , Neter Efrat , Dishon Sara , Barnett Ofra , Rennert Gad
Published: August 2004

Objectives: To examine whether being a BRCA1/2 mutation carrier affects a wide array of aspects of life, and if so, how. Methods: Participants were grouped according to their carrier status (carrier and noncarrier status), health status (affected or unaffected by cancer), and their enrollment at the counseling service (probands and other family members). One hundred and sixty-five women completed a self-administered questionnaire following their genetic consultation session. Results: Probands/nonprobands and carriers/noncarriers did not differ with regard to demographic characteristics, health behaviors including medical checkups, the distress they experience or their resources (sense of coherence, social integration, religiosity). Individuals affected by cancer did differ on some of these aspects from participants without cancer. Conclusions: From the results of this study, being a carrier could not be considered a psychosocial risk factor, nor does it seem to have an effect on carriers’ resources and lifestyle.
A Cytokine-Based Neuroimmunologic Mechanism of Cancer-Related Symptoms
Authors: Lee Bang-Ning , Dantzer Robert , Langley Keith E. , Bennett Gary J. , Dougherty Patrick M. , Dunn Adrian J. , Meyers Christina A. , Miller Andrew H. , Payne Richard , Reuben James M. , Wang Xin Shelley , Cleeland Charles S.
Published: August 2004

While many of the multiple symptoms that cancer patients have are due to the disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive dysfunction and affective symptoms are treatment related, and may lead to treatment delays or premature treatment termination. This symptom burden, a subjective counterpart of tumor burden, causes significant distress. Progress in understanding the mechanisms that underlie these symptoms may lead to new therapies for symptom control. Recently, some of these symptoms have been related to the actions of certain cytokines that produce a constellation of symptoms and behavioral signs when given exogenously to both humans and animals. The cytokine-induced sickness behavior that occurs in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines has much in common with the symptoms experienced by cancer patients. Accordingly, we propose that cancer-related symptom clusters share common cytokine-based neuroimmunologic mechanisms. In this review, we provide evidence from clinical and animal studies that correlate the altered cytokine profile with cancer-related symptoms. We also propose that the expression of coexisting symptoms is linked to the deregulated activity of nuclear factor-kappa B, the transcription factor responsible for the production of cytokines and mediators of the inflammatory responses due to cancer and/or cancer treatment. These concepts open exciting new avenues for translational research in the pathophysiology and treatment of cancer-related symptoms.
Growth Hormone Stimulates the Selective Trafficking of Thymic CD4+CD8– Emigrants to Peripheral Lymphoid Organs
Authors: Smaniotto Salete , Ribeiro-Carvalho Marilza Moura , Dardenne Mireille , Savino Wilson , de Mello-Coelho Valéria
Published: August 2004

Growth hormone (GH) has been shown to stimulate T cell development. However, its mechanisms of action on the peripheral T cell pool remain unknown. To address this question, intrathymic injection of GH in combination with fluorescein isothiocyanate (FITC) was used to assess the effects of GH on T cell trafficking from the thymus to the periphery. GH promoted a significant increase in the percentage and differential distribution of thymic CD4+CD8–FITC+ cells in secondary lymphoid organs. A significantly higher percentage of CD4+CD8–FITC+ cells was observed in the lymph nodes, while a relative decrease of these cells was found in the spleen. Moreover, we verified that GH treatment resulted in increased numbers of CD62L+CD4+CD8–FITC+ T cells in the lymph nodes, while the same treatment resulted in a decline in the percentage of VLA-6+CD4+CD8–FITC+ T cells in the spleen. Together, these findings suggest that GH is a potent immunoregulatory molecule which selectively stimulates the preferential homing of CD4+CD8– thymic emigrants to the subcutaneous lymph nodes possibly via the differential expression of CD62L and VLA-6.
Splenic Norepinephrine and Serum Corticosterone Level Fluctuations Associated with Bacteria-Induced Stress
Authors: Kim Dongsoo , Seegal Richard F. , Lawrence David A.
Published: August 2004

Corticosterone (CORT) and norepinephrine (NE), two effector molecules of the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-lymphoid (SL) axes, respectively, differentially influence murine host resistance to Listeria monocytogenes (LM). Serum CORT and splenic NE levels early (≤24 h) after infection correlated positively with host resistance, as long as the LM burden did not exceed approximately 106 cfu LM per spleen. As previously reported, mice with right-circling preference (R-mice) have significantly greater host resistance to LM than those with left-circling preference (L-mice) and early after infection, R-mice had significantly higher serum CORT levels than L-mice. However, rapid pathogenesis with a high bacterial burden induced high activation of the HPA and SL axes, which prevented observable differences in the defense against LM, especially later in infection. With the high bacterial inoculum (105 LM), the splenic NE levels significantly increased, but no differences among R- and L-mice were discernible. We suggest that endogenous asymmetry of neuroimmune circuits contributes to differential host resistance, but the level of stress (bacterial inoculum) is critical. With regard to the neuroendocrine factors assessed, CORT, but not NE, levels significantly correlated with the enhanced defenses of R-mice in comparison to L-mice. The differential host resistance based on brain laterality seems to be more a function of the HPA axis and possibly other CNS effects on peripheral immunity than neurotransmitter release by the sympathetic innervation of the spleen.
Somatostatin and Gamma-Aminobutyric Acid Inhibit Interleukin-1β-Stimulated Release of Interleukin-6 from Rat C6 Glioma Cells
Authors: Spangelo Bryan L. , Horrell Scott , Goodwin Amy L. , Shroff Sachin , Jarvis W. David
Published: August 2004

Objective: We investigated the ability of inhibitory neurotransmitters to alter the interleukin-1β (IL-1β)-stimulated release of interleukin-6 (IL-6) from cultured glial tumor cells. Methods: C6 rat glioblastoma cells were exposed to either IL-1β or its putative second messenger lysophosphatidylcholine (LPC) in the absence or presence of the inhibitory neurotransmitters somatostatin (SRIF) or γ-aminobutyric acid (GABA). Alternatively, C6 cells were pretreated with selective inhibitors of JNK or p38 and then exposed to either IL-1β or LPC to determine the relative involvement of these terminal stress kinases in the stimulation of IL-6 release. Results: IL-1β promoted the release of IL-6 with a maximally effective concentration of 25 ng/ml. Both SRIF-14 and SRIF-28 comparably suppressed stimulated IL-6 release with an ED50 of ∼50 nM. GABA also prevented IL-1β-driven IL-6 release (ED50 = 100 µM). IL-1β and LPC synergistically enhanced release of IL-6 in the presence of the β-adrenergic receptor agonist isoproterenol (ISO); these effects were largely reversed by SRIF or GABA. The pyridinylimidazole inhibitor of p38, SB-203580, completely blocked stimulation of IL-6 release by IL-1β or LPC; conversely, the anthrapyrazolone JNK inhibitor, SP-600125, was ineffective in modifying stimulated IL-6 release. Conclusions: The effects of IL-1β and LPC on IL-6 release from glioma cells are effectively antagonized by the inhibitory neurotransmitters SRIF and GABA. On the basis of correlative studies, we propose that the ability of inhibitory transmitters such as SRIF and GABA to counter the induction of IL-6 release may entail suppression of p38 activity.
First-Line Chemotherapy with Irinotecan plus Capecitabine for Advanced Colorectal Cancer
Authors: Park Se Hoon , Bang Soo-Mee , Cho Eun Kyung , Baek Jeong Heum , Oh Jae Hwan , Im Seock Ah , Park Young Suk , Shin Dong Bok , Lee Jae Hoon
Published: August 2004

Objective: The aim of this study was to evaluate efficacy and safety of the combination chemotherapy with irinotecan plus capecitabine in patients with advanced colorectal adenocarcinoma. Methods: Patients with histologically proven advanced colorectal adenocarcinoma received a first-line chemotherapy with irinotecan 240 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day as an intermittent regimen of 2 weeks of treatment followed by a 1-week rest. Treatment was repeated every 3 weeks. Results: Thirty-nine patients were registered, and 36 were assessable for responses. Sixteen objective responses (44%) were observed with a median response duration of 6.9 months. Stable disease was documented in 14 cases (39%). The median time to progression was 6.7 months. The median overall survival was not reached at the time of analysis, and the 1-year survival rate was 67%. Two patients died: 1 due to sepsis not complicating myelosuppression, and 1 patient, known as a hepatitis B virus carrier prior to chemotherapy, died of hepatic failure, the cause of which was not clinically verified. Frequently encountered therapy-related events were leukopenia and gastrointestinal side effects including diarrhea. Severe hand-and-foot syndrome was observed in only 1 patient. Conclusions: The combination chemotherapy of irinotecan and capecitabine is an active and tolerable regimen for advanced colorectal adenocarcinoma, but the observed deaths suggest a future randomized trial that requires a cautious patient selection.