bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of calcium in the secretion of leptin from white adipocytes
Authors: Cammisotto Philippe G. , Bukowiecki Ludwik J.
Published: August 2004

The mechanism by which calcium regulates leptin secretion was studied in adipocytes isolated from rat white adipose tissue. Incubation of adipocytes in a medium containing glucose, but no calcium, markedly inhibited insulin-stimulated leptin secretion (ISLS) and synthesis, without affecting basal leptin secretion or lipolysis. However, when pyruvate was used as a substrate, ISLS was insensitive to the absence of calcium. Likewise, the stimulatory effects of insulin were completely prevented by phloretin, cytochalasin B, and W-13 (3 agents that interfere with early steps of glucose metabolism) in the presence of glucose, but not in the presence of pyruvate. Thus calcium appears to be specifically required for glucose utilization. On the other hand,45Ca uptake and leptin secretion were not affected by insulin or by inhibitors of L-type calcium channels. However, agents increasing plasma membrane permeability to calcium (high calcium concentrations, A-23187, and ATP) increased45Ca uptake and concomitantly inhibited ISLS. Similarly, release of endogenous calcium stores by thapsigargin inhibited ISLS in a dose-dependent manner. ATP, A-23187, calcium, and thapsigargin inhibited ISLS, even in the presence of pyruvate. These results show that 1) extracellular calcium is necessary for ISLS, mainly by affecting glucose uptake, 2) insulin does not affect extracellular calcium uptake, and 3) increasing cytosolic calcium by stimulating its uptake or its release from endogenous stores inhibits ISLS at a level independent of glucose metabolism. Thus calcium regulates leptin secretion from adipocytes in a manner that is markedly different from its role in the exocytosis of many other polypeptidic hormones.
Overexpression of RET leads to vesicoureteric reflux in mice
Authors: Yu O. H. , Murawski I. J. , Myburgh D. B. , Gupta I. R.
Published: August 2004

RET, a tyrosine kinase receptor essential for kidney development, has recently been shown to be important for the formation of the urinary tract. When RET is overexpressed in the HoxB7/Ret transgenic mouse, kidneys are small and cystic, and in some of the mice, the ureters are grossly dilated. Here, we report that the observed ureteral dilatation is associated with the urinary tract abnormality vesicoureteric reflux (VUR), in which urine flows retrogradely from the bladder to the ureter. Reflux was determined in vitro by injecting methylene blue into the bladders of HoxB7/Ret and wild-type mice. At postnatal day 1, 30% of HoxB7/Ret mice had VUR compared with 4% of wild-type mice ( P < 0.05). The length of the intravesical ureteral tunnel was shorter in HoxB7/Ret mice compared with wild-type mice, on both the right and the left sides ( P < 0.05), suggesting a basis for the higher incidence of VUR in these mutants. At embryonic day 11, the ureteric bud was found to exit more caudally from the mesonephric duct in HoxB7/Ret mice, and this may predispose them to VUR ( P < 0.05). Wild-type and HoxB7/Ret mice were tested for reflux at embryonic day 17, and both showed a high frequency of VUR (59 and 75%, respectively). These results suggest that VUR may occur transiently during normal urinary tract development before the ureter has completed its insertion into the bladder. In the HoxB7/Ret mouse, overexpression of RET appears to delay the maturation of the distal ureter, resulting in postnatal VUR. The HoxB7/Ret mouse is thus an important model in which to examine how vesicoureteric reflux arises during urinary tract development.
What makes vessels grow with exercise training?
Authors: Prior Barry M. , Yang H. T. , Terjung Ronald L.
Published: August 2004

Exercise and muscle contractions create a powerful stimulus for structural remodeling of the vasculature. An increase in flow velocity through a vessel increases shear stress, a major stimulus for enlargement of conduit vessels. This leads to an endothelial-dependent, nitric oxide-dependent enlargement of the vessel. Increased flow within muscle, in the absence of contractions, leads to an enhanced capillarity by intussusceptive angiogenesis, a process of capillary splitting by intraluminal longitudinal divide. In contrast, sprouting angiogenesis requires extensive endothelial cell proliferation, with degradation of the extracellular matrix to permit migration and tube formation. This occurs during muscle adaptations to chronic contractions and/or muscle overload. The angiogenic growth factor VEGF appears to be an important element in angiogenesis. Recent advances in research have identified hemodynamic and mechanical stimuli that upregulate angiogenic processes, demonstrated a complexity of potent growth factors and interactions with their corresponding receptors, detected an interaction of cellular signaling events, and identified important tissue reorganization processes that must be coordinated to effect vascular remodeling. It is likely that much of this information is applicable to the vascular remodeling that occurs in response to exercise and/or muscle contractions.
A New Interpretation of Spontaneous Sway Measures Based on a Simple Model of Human Postural Control
Authors: Maurer Christoph , Peterka Robert J.
Published: August 2004

This study shows that center-of-pressure (COP) traces that closely resemble physiologically measured COP functions can be produced by an appropriate selection of model parameters in a simple feedback model of the human postural control system. Variations in the values of stiffness, damping, time delay, and noise level determine the values of 15 sway measures commonly used to characterize spontaneous sway. Results from model simulations indicate that there is a high degree of correlation among these sway measures, and the measures cluster into three different groups. Only two principal components accounted for about 92% of the variation among the different sway measures analyzed. This model can be used to formulate hypotheses regarding the cause of postural control deficits reported in the literature. This is accomplished using a multidimensional optimization procedure to estimate model parameters from a diverse set of spontaneous sway measures. These model parameters describe physiologically meaningful features of the postural control system as opposed to conventional sway measures that provide only a parametric description of sway. To show the application of this method, we applied it to published data of spontaneous sway from elderly subjects and contrasted it to the data of young healthy subjects. We found that modest increases in stiffness and damping and a fairly large increase in noise level with aging could account for the variety of sway measures reported in the literature for elderly subjects.
Off-Target Verbosity, Everyday Competence, and Subjective Well-Being
Authors: Arbuckle Tannis Y. , Pushkar Dolores , Bourgeois Sylvie , Bonneville Lucie
Published: August 2004

Background: Off-target verbosity (OTV), defined as prolific speech that is lacking in focus, is exhibited by relatively few older adults, but increases in prevalence with age. Objective/Methods: The hypothesis that a high level of OTV is associated with declining competence in other aspects of everyday life was examined in 142 older adults, previously screened for the level of OTV. Competence was assessed based on self-reported changes since age 50 years in quality and quantity of engagement in eleven domains of instrumental and voluntary activities of everyday life. Results: Path models indicated that a high level of OTV was associated with a decreased competence in everyday activities and was indirectly linked, through competence, with lower well-being and greater loneliness. With competence level controlled, a high level of OTV directly predicted less loneliness. Conclusions: These findings support the hypothesis that a high level of OTV is symptomatic of a more general decline in competence and of less successful aging. However, a high level of OTV also entails a strong motivation for talking to others and thus may offer protection against loneliness.
Falls and Depression in Older People
Authors: Turcu Alin , Toubin Sandrine , Mourey France , D’Athis Philippe , Manckoundia Patrick , Pfitzenmeyer Pierre
Published: August 2004

Background: Depression is one of the most common risk factors for falls, but links between falls and depression are still unclear. Few studies have examined the relationship between depression and gait alteration, which may increase the risk of fall. Objective: This study aims to assess a possible relationship between depression, postural and gait abnormalities, and falls. Methods: We conducted a 1-year prospective study on patients ≧70 years who were admitted to a geriatric unit for ‘spontaneous’ unexplained falls. Patients were tested for depression using the 30-item Geriatric Depression Scale (GDS). Their motor performances were assessed using the Mini Motor Test (MMT), which is an easy direct-observation test, validated in France, for assessment of frail old people who present with severe postural and gait impairment. This scale is composed of 4 categories of items: (1) abilities in bed; (2) quality of the sitting position; (3) abilities in the standing position, and (4) quality of gait. Results: Sixty-nine patients were included. Depression was found in 46 patients (66.7%). The MMT score was higher in the non-depressed fallers (NDF) group (GDS ≤10) compared to the depressed fallers (DF) group (GDS>10; p < 0.05). The 2 groups were compared for each of the 4 items of the MMT: the difference between the DF and NDF groups was mainly explained by the impairment of postural abilities in the standing position. Conclusions: Our results support the idea that depression is associated with postural abnormalities in the standing position, which may predispose to falls. In clinical practice, more attention should be given to old fallers concerning diagnosis and treatment of associated depression.
Just One Look, and Fractures and Death Can Be Predicted in Elderly Ambulatory Women
Authors: Gerdhem Paul , Ringsberg Karin , Åkesson Kristina , Obrant Karl J.
Published: August 2004

Background: The chronological age is clearly the strongest risk factor for fractures or death. Age as a concept can be described exactly as chronological age. Age in relative terms can be described as biological age. Objective: We postulated that, even without taking into account known or unknown comorbidity, an immediate and totally subjective evaluation of an individual’s biological age is predictive of forthcoming fractures and death. Methods: At baseline the biological age was estimated in 1,004 randomly recruited ambulatory 75-year-old women. All women were of the same ethnic background. Two independent observers estimated the biological age within 15 s of first sight of each woman. Based on this estimation of the biological age, the women were divided into tertiles. The women were then followed prospectively for a mean of 4.6 (range 3.0–6.5) years. All retrospective fractures and prospective fractures and deaths were registered. Results: When the tertile of the biologically oldest women was compared with all other women, their odds ratio for sustaining any type of prospective fracture was 1.71 (95% confidence interval 1.22–2.39), for hip fractures 2.69 (1.42–5.11), for clinical vertebral fractures 2.83 (1.57–5.11), and for multiple fractures 3.17 (1.64–6.10). Also, when retrospectively sustained fractures were included, the predictive ability for biological age remained. The death rate amongst the tertile of biologically oldest women was increased when compared with the rest of the women (odds ratio 4.33, CI 3.62–5.17). Conclusions: In ambulatory elderly women, without specific consideration of comorbidity, a subjective estimate of the biological age is predictive of future fractures and death. Subjective estimation of the biological age, in relation to the chronological age, is a valuable indicator of health, conveying additional information that merits its use in clinical practice.
Seasonal Changes in Blood Pressure and Frequency of Related Complications in Elderly Israeli Patients with Essential Hypertension
Authors: Charach Gideon , Rabinovich Pavel D. , Weintraub Moshe
Published: August 2004

Background: Earlier studies on hypertension demonstrated seasonal variations in different age groups. However, slightly greater fluctuations were found in the hypertensive elderly. Objective: We conducted a prospective 5-year study from January 1997 to December 2001 to evaluate the seasonal variation in blood pressure and the variables of age, gender, body mass index and related complications in elderly Israeli patients with essential hypertension. Methods: Blood pressure was measured in four seasons in 182 patients (98 men and 84 women; age range 65–91 years) treated for hypertension in our outpatient clinic. Results: Both systolic and diastolic mean blood pressures were higher during winter compared to summer (165 ± 11.6 and 90 ± 13.7 and 134 ± 47.3 and 74 ± 8.5 mm Hg, respectively; p < 0.001). There were no significant seasonal differences between spring and autumn or any correlation between the seasonal winter-summer difference in blood pressure and other studied parameters. Patients aged 65–75 years were unexpectedly more sensitive to winter-summer changes than older patients. There was a correlation between a large winter-summer difference in systolic blood pressure and a body mass index between 20 and 30, but there was none in lower or higher ranges. Supplementary antihypertension treatment was required during winter in 38% of these selected patients. Complications such as myocardial infarctions and strokes occurred twice as frequently in winter than in any other season (p < 0.0001). Conclusions: Both systolic and diastolic blood pressures were highest during winter. Hypertension complications were more frequent in winter. Our results refute those of earlier studies that failed to find significant seasonal variations in blood pressure among the elderly.
Steady-State Brain Concentrations of Antihistamines in Rats
Authors: Doan Kelly Mahar , Wring Stephen A. , Shampine Larry J. , Jordan Kelly H. , Bishop James P. , Kratz John , Yang Eric , Serabjit-Singh Cosette J. , Adkison Kimberly K. , Polli Joseph W.
Published: August 2004

The purpose of this study was to measure the in vivo brain distribution of antihistamines and assess the influence of in vitro permeability, P-glycoprotein (Pgp) efflux, and plasma protein binding. Six antihistamines (acrivastine, chlorpheniramine, diphenhydramine doxylamine, fexofenadine, terfenadine) were selected based on previously reported in vitro permeability and Pgp efflux properties and dosed intravenously to steady-state plasma concentrations of 2–10 µmol/l in rats. Plasma and brain concentrations were measured by LC/MS/MS, and protein binding determined by ultrafiltration. Doxylamine, diphenhydramine and chlorpheniramine had brain-to-plasma concentration ratios of 4.34 ± 1.26, 18.4 ± 2.35 and 34.0 ± 9.02, respectively. These drugs had high passive membrane permeability (>310 nm/s), moderate protein binding (71–84%) and were not Pgp substrates; features that yield high CNS penetration. In contrast, acrivastine and fexofenadine had low brain-to-plasma ratios of 0.072 ± 0.014 and 0.018 + 0.002, consistent with low passive membrane permeability for both compounds (16.2 and 66 nm/s, respectively) and Pgp efflux. Finally, terfenadine had a brain-to-plasma ratio of 2.21 ± 1.00 even though it underwent Pgp-mediated efflux (in vitro ratio = 2.88). Terfenadine’s high passive permeability (285 nm/s) overcame the Pgp-mediated efflux to yield brain-to-plasma ratio >1. The brain-to-unbound plasma ratio was 22-fold higher suggesting that protein binding (96.3% bound) limited terfenadine’s brain distribution. In conclusion, passive membrane permeability, Pgp-mediated efflux and/or high plasma protein binding influence the in vivo brain distribution of antihistamine drugs.
Poly(ADP-Ribose) Polymerase Inhibition Prevents Homocysteine-Induced Endothelial Dysfunction in the Isolated Rat Aorta
Authors: Tasatargil Arda , Dalaklioglu Selvinaz , Sadan Gulay
Published: August 2004

Recent studies have clearly shown that there is a relationship between hyperhomocysteinemia and endothelial dysfunction. However, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on homocysteine (Hcy)-induced endothelial damage has not been investigated. In this study, we investigated whether the loss of endothelial function in rat aortic rings preincubated with Hcy is dependent upon the PARP pathway within the vasculature. Preincubation of rat aortic rings with Hcy (1 mmol/l; 180 min) significantly inhibited endothelium-dependent relaxation in this tissue. This inhibitory effect was significantly reduced in the presence of both superoxide dismutase (100 U ml–1) and catalase (100 U ml–1) together with Hcy. Similarly, preincubation for 180 min with either N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34; 3 µmol/l) or 3-aminobenzamide (3 mmol/l), structurally different PARP inhibitors, also significantly prevented the development of endothelial dysfunction induced by Hcy. Further incubation of aortic rings with these PARP inhibitors for 60 min after exposure to Hcy for 180 min, at least in part, improved the endothelium-dependent relaxation responses. Thus, our results suggest that intraendothelial PARP activation may be associated with endothelial dysfunction in hyperhomocysteinemic conditions and that inhibition of this pathway may present a novel pharmacological approach to prevent Hcy-induced endothelial damage. Suprisingly, inhibition of the PARP pathway not only prevents the endothelial dysfunction mediated by Hcy, but is also able to rapidly improve it.
S-Nitroso Human Serum Albumin Improves Oxygen Metabolism during Reperfusion after Severe Myocardial Ischemia
Authors: Dworschak Martin , Franz Maximilian , Hallström Seth , Semsroth Severin , Gasser Harald , Haisjackl Markus , Podesser Bruno K. , Malinski Tadeusz
Published: August 2004

Nitric oxide (NO) supplementation may modify myocardial oxygen consumption and vascular function after ischemia. We investigated the effects of the NO donor, S-nitroso human serum albumin (S-NO-HSA), on cardiac oxygen metabolism during controlled reperfusion on normothermic cardiopulmonary bypass after severe myocardial ischemia. Pigs randomly received either S-NO-HSA or human serum albumin prior to and throughout global myocardial ischemia. Myocardial oxygen utilization is impaired at the onset of reperfusion, which is not amenable to S-NO-HSA. However, NO supplementation during ongoing supply dependency of oxygen consumption eventually leads to greater myocardial oxygen delivery and consumption. In conjunction with a better washout of lactate, this indicates an improved capillary perfusion in the S-NO-HSA group during reperfusion, which results in a better contractile function post bypass.
Medical Treatment of Retinopathy of Type-2 Diabetes
Authors: Cunha-Vaz José G.
Published: August 2004

The medical treatment of retinopathy in type-2 diabetes should be considered as a major component in the overall management of diabetic retinal disease. It is clear that specific and timely interventions, such as glycemic and blood pressure control, are the basis for good management of diabetic retinopathy. The American Diabetes Association has developed specific recommendations concerning diabetic retinopathy for the primary care physician and diabetologist. The ophthalmologist must be aware of these recommendations and establish efficient communication channels with the colleagues who follow their patients and the progression of diabetes closely. The challenge for the ophthalmologist is to make sure that, when signs of retinopathy are detected, information regarding the status of the retina, prognostic factors and the rate of progression must be given to the primary care physician and diabetologist. Under these circumstances, excellent glycemic control, aggressive management of blood pressure and normalization of lipids are all needed, and the goals to be achieved must be shared between the ophthalmologist and the primary care physician or diabetologist. Appropriate medical management of diabetic retinopathy is fundamental to reduce the risk of blindness. This goal can only be achieved if the ophthalmologist is fully aware of the role of medical management and establishes an efficient flow of communication with the primary care physician or diabetologist, particularly for the diabetic patients whose eyes show signs of risk for rapid progression of their retinopathy.
Endoscopic Transnasal Dacryocystorhinostomy and Bicanalicular Silicone Tube Intubation
Authors: Apaydin K. Cemil , Fisenk Firat , Karayalcin Binnur , Akar Yusuf , Saka Osman
Published: August 2004

Purpose: To evaluate the results of endoscopic transnasal dacryocystorhinostomy (ETDCR) combined with bicanalicular silicone tube intubation (BSTI) performed in 49 patients with nasolacrimal canal obstructions secondary to chronic dacryocystitis. Material and Methods: ETDCR combined with BSTI was applied as a primary procedure in 47 cases, and as a secondary procedure in 2 cases. All patients underwent dacryocystography, and 41 patients underwent radionuclide dacryoscintigraphy before the surgery. Silicone tubes were left in place for about 6.2 months. The patency of the lacrimal passages was controlled with a clinical examination, nasolacrimal canal lavage, and dacryoscintigraphy. Results: Patients were followed up for a mean period of 25.1 months after the removal of the tubes. The epiphora symptom disappeared and a successful drainage could be maintained in 43 out of 49 cases (87.7%). The obstruction rate found in the dacryoscintigraphy performed 15 days after extubation was 22.9%, while it was found to be 14.2% in the nasolacrimal canal lavage. Conclusion: ETDCR combined with BSTI proved to be an effective surgical method in chronic dacryocystitis. The sensitivity and specificity of the postoperative dacryoscintigraphy in determining the surgical success were lower than those of the nasolacrimal canal lavage.
Ciliary Body Adenoma after Application of Mitomycin
Authors: Mietz Holger , Seifert Peter , Krieglstein Günter K.
Published: August 2004

Purpose: To describe a ciliary body tumor that was detected in a rabbit eye. Methods: For a specific experiment, the rabbit underwent trabeculectomy with mitomycin. The eye was evaluated by electron microscopy 5 weeks following surgery. Results: A ciliary body tumor was discovered in close relation to pigmented epithelial cells. The tumor cells were large with a small amount of pigment and contained prominent vesicles. Conclusions: The development of a ciliary body adenoma may be caused by the application of mitomycin. Whether the demonstrated tumor was benign or malignant could not be determined. While it could not be proven that the tumor developed related to the use of mitomycin, this possibility may be important for surgeons using this substance.
Long-Term Growth Hormone Therapy in Mitochondrial Cytopathy
Authors: Barberi Salvatore , Bozzola Elena , Berardinelli Angela , Meazza Cristina , Bozzola Mauro
Published: August 2004

Objective: To describe in a 5-year-old Caucasian male with mitochondrial cytopathy, a biochemical growth hormone (GH) deficiency associated with normal GH biological activity as evaluated by Nb2 cell bioassay and normal serum IGF-I and IGFBP3 values increasing slightly after GH administration. Method: Serum GH concentrations were measured with a commercial immunofluorometric assay and with a biological assay, which uses the Nb2 cell line. Serum IGF-I and IGFBP3 concentrations were measured with RIA. Results: The GH-supplementary therapy was initially effective in terms of growth gain, but no therapeutic benefit was observed over a long period of time. Conclusion: In patients suffering from mitochondrial cytopathy, short stature seems to be attributed more to a disease-related inadequate protein substrate than to the non-classical GH deficiency.
Darbepoetin Alfa Effectively Treats Anemia in Patients with Chronic Kidney Disease with de novo Every-Other-Week Administration
Authors: Toto Robert D. , Pichette Vincent , Navarro Jesus , Brenner Robert , Carroll Wendi , Liu Wei , Roger Simon
Published: August 2004

Aim: This multicenter, open-label study determined safety and efficacy of once-every-other-week administration of darbepoetin alfa for anemia of chronic kidney disease in erythropoietin-naive patients not on dialysis. Methods: Participants with hemoglobin levels <11.0 g/dl at baseline were administered darbepoetin alfa at an initial dosage of 0.75 µg/kg once every other week. The dose was titrated to achieve and maintain a hemoglobin response, defined as a hemoglobin range of between 11.0 and 13.0 g/dl for up to 24 weeks. The primary end point was the dose of darbepoetin alfa at initial hemoglobin response. Results: Six hundred and eight patients were enrolled, and 463 completed the study; 95% (95% confidence interval: 0.93, 0.97) of the patients who completed treatment achieved a hemoglobin response. The mean darbepoetin alfa dose at the time of response was 63.5 ± (SD) 16.9 µg, and the mean time to hemoglobin response was 5.7 ± (SD) 4.5 weeks. Oral iron therapy was administered to 60% and intravenous iron to 16% of the participants. Darbepoetin alfa was well tolerated, and adverse events were consistent with those expected in patients with chronic kidney disease. Conclusion: Darbepoetin alfa administered once every other week is effective and safe for achieving and maintaining target hemoglobin levels in anemic patients with chronic kidney disease.
Carotenoid Depletion in Serum of Young Type-1 Diabetics Fed Low-Carotenoid Diets
Authors: Granado F. , Olmedilla B. , Blanco I.
Published: August 2004

Background/Aims: Type-1 diabetics have been considered to be at risk for increased oxidative stress which has been implicated in the development of long-term diabetes complications. Evidence suggests that antioxidant activity may be an important mechanism by which carotenoids could confer protection in human health. Our aim was to compare the serum carotenoid depletion rate in type-1 diabetics and control subjects consuming low-carotenoid diets. Methods: Ten type-1 diabetics and 8 controls followed a very low-carotenoid diet for 21 days. Dietary intake was recorded daily and fasting blood samples collected at baseline and after 1, 2, 3, 6, 11, 15, 16, 17, and 21 days. Individual carotenoids in serum were analyzed by a validated HPLC method. Results: In both groups, carotenoid intake was less than 5% of the season-adjusted carotenoid reference intake. These diets resulted in decreased serum carotenoid levels in both groups, although depletion curves, final mean concentrations and the estimated half-life of carotenoids in serum revealed no differences between type-1 diabetics and controls. Levels of other minor serum carotenoids, cis-isomers and keto-carotenoids, also decreased whereas serum retinol and α- and γ-tocopherol did not change during the study. Conclusion: Upon a low-carotenoid intake, the depletion rate of carotenoids in serum in young type-1 diabetics does not differ from that observed in matched related controls.
Elimination and Tolerance of a New Parenteral Lipid Emulsion (SMOF) – A Double-Blind Cross-Over Study in Healthy Male Volunteers
Authors: Schlotzer Ewald , Kanning Ulrike
Published: August 2004

Aims: The objective of this phase I study was to investigate plasma elimination and tolerance of a new lipid emulsion based on soybean oil, medium chain triglycerides (MCT), olive oil and fish oil (SMOF). Methods: In a double-blind, randomized, cross-over study, 12 healthy male subjects received SMOF 20% and a standard soybean oil emulsion (Lipovenoes® 20%, both Fresenius Kabi). Lipid emulsions were infused at a rate of 0.125 g fat/kg body weight/h over 6 h. Before, during and up to 24 h after infusion, lipid metabolism parameters and numerous clinical, chemical and hematological parameters, vital signs and local tolerance were determined. Results: Infusion of SMOF induced a less marked increase of serum triglyceride concentration. At the end of infusion, mean serum triglyceride concentration was significantly lower with SMOF (p < 0.05). Triglyceride half-life was significantly shorter for SMOF than for Lipovenoes (p < 0.001). Infusion of SMOF was apparently associated with higher glycerol concentration (NS). Routine laboratory parameters, vital signs and local tolerance showed no evidence of infusion-related abnormalities. Conclusion: SMOF was eliminated significantly faster than the standard lipid emulsion. This is of potential benefit in patients with limited triglyceride elimination capacity. The safety evaluation revealed a good systemic and local tolerance of SMOF.
Blockade of Keratinocyte-Derived Chemokine Inhibits Endothelial Recovery and Enhances Plaque Formation After Arterial Injury in ApoE-Deficient Mice
Authors: Liehn Elisa A. , Schober Andreas , Weber Christian
Published: August 2004

Objective—

We evaluated the involvement of keratinocyte-derived chemokine (KC) in neointimal hyperplasia and endothelial repair after arterial injury.

Methods and Results—

Expression of KC was detected by immunohistochemistry in carotid arteries of apolipoprotein E–deficient (apoE−/−) mice not earlier than 2 weeks after wire-injury. Double immunofluorescence staining revealed a colocalization of KC with Mac-2–positive macrophages. Immunoreactivity for KC and its receptor CXCR2 was detectable in regenerating CD31-positive endothelial cells. Treatment of apoE−/− mice with a blocking monoclonal antibody (mAb) to KC after carotid injury for 3 weeks substantially increased neointimal plaque area compared with isotype control-treated or untreated mice. As assessed by luminal CD31 or VE-cadherin and Evans blue staining, neutralization of KC inhibited endothelial recovery in injured arteries, whereas macrophage and smooth muscle cell content were unaffected. In vitro, treatment with KC mAb, a blocking CXCR2 mAb, or the CXCR2 antagonist
8-73
GRO-α delayed KC-mediated endothelial cell chemotaxis and wound repair of endothelial monolayers after scratch injury. Conversely, addition of exogenous KC accelerated wound repair in a CXCR2-dependent manner.

Conclusions—

Neutralization of KC increased plaque formation and delayed endothelial recovery after arterial injury, without affecting neointimal monocyte infiltration. As an underlying mechanism, KC was involved in promoting CXCR2-mediated endothelial chemotaxis and wound repair.
Preliminary Report of the Effects of Complement Suppression With Pexelizumab on Neurocognitive Decline After Coronary Artery Bypass Graft Surgery
Authors: Mathew Joseph P. , Shernan Stanton K. , White William D. , Fitch Jane C.K. , Chen John C. , Bell Leonard , Newman Mark F.
Published: August 2004

Background and Purpose—

Pharmacological modulation of complement activation recently has been postulated as a therapeutic target in the treatment of neurological injury. We hypothesized that pexelizumab, a humanized scFv monoclonal antibody directed against the C5 complement component, would limit deficits in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

Methods—

The Phase II Pexelizumab study was a 914-patient, double-blind, placebo-controlled, 65-center study of patients undergoing coronary artery bypass graft surgery. Patients were randomized to pexelizumab bolus, bolus plus infusion, or placebo. Neurological and neurocognitive functions were assessed as secondary endpoints at baseline and on postoperative days (POD) 4 and 30. Cognitive deficits were assessed with multivariable tests accounting for baseline cognition, age, diabetes, years of education, sex, elevated creatinine, history of myocardial infarction, neurological disorder or congestive heart failure, and cardiopulmonary bypass time.

Results—

Pexelizumab had no statistically significant effect on the primary composite endpoint or on overall cognition. When domain specific effects were examined, a decline of at least 10% in the visuo-spatial domain was observed on POD 4 in 56% of patients receiving placebo compared with 40% receiving pexelizumab by bolus and infusion (
P
=0.003). Similarly, on POD 30, a 10% decline was present in 21% of patients in the placebo group versus only 12% of the drug bolus plus infusion group (
P
=0.016). No differences were seen between treatment groups in any of the other domains.

Conclusions—

Pexelizumab administration for 24 hours perioperatively had no effect on global measures of cognition but may reduce dysfunction in the visuo-spatial domain.
NKG2D receptor–mediated NK cell function is regulated by inhibitory Ly49 receptors
Authors: Regunathan Jeyarani , Chen Yuhong , Wang Demin , Malarkannan Subramaniam
Published: August 2004

Interaction of the activating ligand H60 with NKG2D receptor constitutes a major stimulatory pathway for natural killer (NK) cells. The influence of inhibitory Ly49 receptors on NKG2D-mediated activation is not clearly understood. Here we show that the magnitude of NKG2D-mediated cytotoxicity is directly proportional to both the levels of H60 and the nature of major histocompatibility complex (MHC) class I molecules expressed on the target cells. The expression levels of H60 on the target cells determined the extent to which the inhibition by Ly49C/I receptors can be overridden. In contrast, even a higher expression of H60 molecule on the target cells failed to overcome the inhibition mediated by Ly49A/G receptors. Also, the level of interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generated by NK cells through anti-NKG2D monoclonal antibody (mAb)-mediated activation is significantly reduced by the presence of immobilized anti-Ly49A/G mAbs. Thus, NKG2D-mediated cytotoxicity and cytokine secretion results from the fine balance between activating and inhibitory receptors, thereby defining the NK cell-mediated immune responses. (Blood. 2005;105:233-240)
Physical and functional link of the leukemia-associated factors AML1 and PML
Authors: Nguyen Lan Anh , Pandolfi Pier Paolo , Aikawa Yukiko , Tagata Yusuke , Ohki Misao , Kitabayashi Issay
Published: August 2004

The AML1-CBFβ transcription factor complex is the most frequent target of specific chromosome translocations in acute myeloid leukemia (AML). The promyelocytic leukemia (PML) gene is also frequently involved in AML-associated translocation. Here we report that a specific isoform PML I forms a complex with AML1. PML I was able to recruit AML1 and coactivator p300 in PML nuclear bodies and enhance the AML1-mediated transcription in the presence of p300. A specific C-terminal region of PML I and a C-terminal region of AML1 were found to be required for both their association and colocalization in the nuclear bodies. Overexpression of PML I stimulates myeloid cells to differentiate. These results suggest that PML I could act as a mediator for AML1 and its coactivator p300/CBP to assemble into functional complexes and, consequently, activate AML1-dependent transcription and myeloid cell differentiation. (Blood. 2005;105:292-300)
Distinct homeostatic requirements of CD4+ and CD4- subsets of Vα24-invariant natural killer T cells in humans
Authors: Baev Denis V. , Peng Xiao-hui , Song Liping , Barnhart Jerry R. , Crooks Gay M. , Weinberg Kenneth I. , Metelitsa Leonid S.
Published: August 2004

CD1d-restricted Vα24-invariant natural killer T cells (iNKTs) are important in immunoregulation. CD4+ and CD4- iNKTs develop with similar frequencies in murine thymus and depend on interleukin-15 (IL-15) in periphery. However, homeostatic requirements of iNKTs have not been analyzed in humans. We evaluated thymic production, peripheral dynamics, and functional maturation of human iNKTs. CD4+ subset comprises 90% of iNKTs in mature thymocytes and cord blood (CB) but only 40% in adult blood. Using T-cell receptor excision circle (TREC) analysis, we directly measured in vivo replicative history of CD4+ and CD4- iNKT cells. Compared to CD4+, CD4- iNKTs contain fewer TRECs, express higher levels of IL-2Rβ, and proliferate with higher rate in response to IL-15. In contrast, CD4+ cells express higher levels of IL-7Rα and better respond to IL-7. Neither thymic nor CB iNKTs are able to produce cytokines unless they are induced to proliferate. Therefore, unlike in the mouse, human CD4+ iNKTs are mainly supported by thymic output and limited peripheral expansion, whereas CD4- cells undergo extensive peripheral expansion, and both subsets develop their functions in periphery. These findings reveal important differences in homeostatic requirements and functional maturation between murine and human iNKTs that are to be considered for clinical purposes.
CD157 is an important mediator of neutrophil adhesion and migration
Authors: Funaro Ada , Ortolan Erika , Ferranti Bruna , Gargiulo Lucia , Notaro Rosario , Luzzatto Lucio , Malavasi Fabio
Published: August 2004

CD157, a glycosylphosphatidylinositol (GPI)–anchored protein encoded by a member of the CD38 NADase/ADP-ribosyl cyclase gene family, is expressed on the surface of most human circulating neutrophils. This work demonstrates that CD157 is a receptor that induces reorganization of the cytoskeleton and significant changes in cell shape, and that signals mediated by CD157 act through modulation of cytosolic Ca2+ concentration. These signals are independent of the products of CD157's enzymatic activities (ie, cyclic adenosine diphosphate [ADP]–ribose and ADP-ribose). Indeed, the enzymatic activities of CD157 in circulating neutrophils as well as in dimethyl sulfoxide (DMSO)–differentiated (CD157+/CD38-) HL-60 cells, are hardly detectable. This work also shows that the receptorial activity relies on cross-talk between CD157 and β2 integrin. CD157 localizes in GM1-enriched lipid rafts and, upon activation, it migrates to the uropod, a structure specialized in motility and adhesive functions. Indeed, CD157 is involved in adhesion to extracellular matrix proteins and in chemotaxis induced in vitro by formyl-methionyl-leucyl-phenylalanine (fMLP). These findings were consistent with the results obtained in neutrophils from patients with paroxysmal nocturnal hemoglobinuria (PNH), in which CD157 is deficient. These neutrophils showed constant defects in adhesion and migration. Our data attribute specific and crucial roles to CD157 in the regulation of innate immunity during inflammation.
Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells
Authors: Münz Christian , Dao Tao , Ferlazzo Guido , de Cos Maria A. , Goodman Kiera , Young James W.
Published: August 2004

Natural killer (NK) cells are important effectors of innate immunity. In contrast to many studies of interleukin-2 (IL-2)-activated NK cells, the physiologic requirements for stimulating resting NK cells have only recently received attention. Given the emerging variety of dendritic cell (DC) types and their division of labor for stimulating immunity, we compared the capacity of monocyte-derived DCs (moDCs) with that of CD34+ hematopoietic progenitor cell (HPC)-derived dermal-interstitial DCs (DDC-IDCs) and Langerhans cells (LCs) to stimulate resting NK cells. MoDCs, and to a lesser extent CD34+ HPC-derived DDC-IDCs, directly stimulate NK-cell proliferation, CD56 up-regulation, and cytotoxicity. LCs, on the contrary, require exogenous IL-2 or IL-12 to activate NK cells, but they can maintain resting NK-cell viability and sustain NK-cell proliferation induced by moDCs. LCs do not secrete bioactive IL-12p70 but do produce significantly higher concentrations of IL-15 and IL-18 than either of the other 2 DC types. Despite secretion of IL-15, LCs lack IL-15R-α for surface presentation of IL-15. This together with the deficiency of IL-12p70 undermines any direct NK-cell activation by LCs. Hence, the principal myeloid DCs differ in critical ways regarding the stimulation of NK and T lymphocytes and could be used or targeted accordingly in DC-based immunotherapies. (Blood. 2005;105:266-273)
Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity
Authors: Middendorp Sabine , Zijlstra A. J. Esther , Kersseboom Rogier , Dingjan Gemma M. , Jumaa Hassan , Hendriks Rudolf W.
Published: August 2004

During B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function by phosphorylating phospholipase Cγ2, which is brought into close proximity of Btk by SLP-65. However, this model was recently challenged by the identification of a role for Btk as a tumor suppressor in the absence of SLP-65 and by the finding that Btk function is partially independent of its kinase activity. To investigate if enzymatic activity is critical for the tumor suppressor function of Btk, we crossed transgenic mice expressing the kinase-inactive K430R-Btk mutant onto a Btk/SLP-65 double-deficient background. We found that K430R-Btk expression rescued the severe developmental arrest at the pre-B-cell stage in Btk/SLP-65 double-deficient mice. Moreover, K430R-Btk could functionally replace wild-type Btk as a tumor suppressor in SLP-65- mice: at 6 months of age, the observed pre-B-cell lymphoma frequencies were approximately 15% for SLP-65- mice, 44% for Btk/SLP-65-deficient mice, and 14% for K430R-Btk transgenic mice on the Btk/SLP-65-deficient background. Therefore, we conclude that Btk exerts its tumor suppressor function in pre-B cells as an adaptor protein, independent of its catalytic activity. (Blood. 2005;105:259-265)
A mechanism of airway injury in an epithelial model of mucociliary clearance
Authors: O'Brien Darryl W , Morris Melanie I , Ding Jie , Zayas J Gustavo , Tai Shusheng , King Malcolm
Published: August 2004

We studied the action of sodium metabisulphite on mucociliary transport in a frog palate epithelial injury model, hypothesizing that it may be useful for the study of mechanisms of airway injury. Sodium metabisulphite (MB) releases SO2 on contact with water. SO2 is a pollutant in automobile fumes and may play a role in the exacerbation of airway disease symptoms. We first investigated its effect on mucociliary clearance. MB 10-1 M, increased mucociliary clearance time (MCT) by 254.5 ± 57.3% of control values, (p < 0.001, n = 7). MB 10-4 and 10-2 M did not interfere with mucus clearance time compared to control values. In MB-treated frog palates, MCT did not return to control values after one hour (control, 97.3 ± 6.3% vs. MB, 140.9 ± 46.3%, p < 0.001, n = 7). Scanning EM images of epithelial tissue were morphometrically analyzed and showed a 25 ± 12% loss of ciliated cells in MB palates compared to controls with an intact ciliary blanket. Intact cells or groups of ciliated cells were found in scanning EM micrographs of mucus from MB-treated palates. This was associated with increased matrix metalloproteinase (MMP-9) activity in epithelial tissue and mucus. We suggest that the loss of ciliated cells as a result of MMP-9 activation prevented full recovery of MCT after MB 10-1 M. The mechanism of action may be on epithelial cell-cell or cell-matrix attachments leading to cell loss and a disruption of MCT. Further studies are warranted to determine whether this is an inflammatory mediated response or the result of a direct action on epithelial cells and what role this mechanism may play in the progression to chronic airway diseases with impaired mucociliary clearance.
The aminoguanidine carboxylate BVT.12777 activates ATP-sensitive K+ channels in the rat insulinoma cell line, CRI-G1
Authors: Kinsella Jackie M , Laidlaw Hilary A , Tang Teresa , Harvey Jenni , Sutherland Calum , Ashford Michael LJ
Published: August 2004

Background

3-guanidinopropionic acid derivatives reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, the aminoguanidine carboxylate BVT.12777, opens KATP channels in rat insulinoma cells, by the same mechanism as leptin.

Results

BVT.12777 hyperpolarized CRI-G1 rat insulinoma cells by activation of KATP channels. In contrast, BVT.12777 did not activate heterologously expressed pancreatic β-cell KATP subunits directly. Although BVT.12777 stimulated phosphorylation of MAPK and STAT3, there was no effect on enzymes downstream of PI3K. Activation of KATP in CRI-G1 cells by BVT.12777 was not dependent on MAPK or PI3K activity. Confocal imaging showed that BVT.12777 induced a re-organization of cellular actin. Furthermore, the activation of KATP by BVT.12777 in CRI-G1 cells was demonstrated to be dependent on actin cytoskeletal dynamics, similar to that observed for leptin.

Conclusions

This study shows that BVT.12777, like leptin, activates KATP channels in insulinoma cells. Unlike leptin, BVT.12777 activates KATP channels in a PI3K-independent manner, but, like leptin, channel activation is dependent on actin cytoskeleton remodelling. Thus, BVT.12777 appears to act as a leptin mimetic, at least with respect to KATP channel activation, and may bypass up-stream signalling components of the leptin pathway.
Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system
Authors: Bougras Gwenola , Cartron Pierre-François , Gautier Fabien , Martin Stéphane , LeCabellec Marité , Meflah Khaled , Gregoire Marc , Vallette François M
Published: August 2004

Background

The relative role of anti apoptotic (i.e. Bcl-2) or pro-apoptotic (e.g. Bax) proteins in tumor progression is still not completely understood.

Methods

The rat glioma cell line A15A5 was stably transfected with human Bcl-2 and Bax transgenes and the viability of theses cell lines was analyzed in vitro and in vivo.

Results

In vitro, the transfected cell lines (huBax A15A5 and huBcl-2 A15A5) exhibited different sensitivities toward apoptotic stimuli. huBax A15A5 cells were more sensitive and huBcl-2 A15A5 cells more resistant to apoptosis than mock-transfected A15A5 cells (pCMV A15A5). However, in vivo, in syngenic rat BDIX, these cell lines behaved differently, as no tumor growth was observed with huBax A15A5 cells while huBcl-2 A15A5 cells formed large tumors. The immune system appeared to be involved in the rejection of huBax A15A5 cells since i) huBax A15A5 cells were tumorogenic in nude mice, ii) an accumulation of CD8+ T-lymphocytes was observed at the site of injection of huBax A15A5 cells and iii) BDIX rats, which had received huBax A15A5 cells developed an immune protection against pCMV A15A5 and huBcl-2 A15A5 cells.

Conclusions

We show that the expression of Bax and Bcl-2 controls the sensitivity of the cancer cells toward the immune system. This sensitization is most likely to be due to an increase in immune induced cell death and/or the amplification of an anti tumour immune response