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Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA. meiners@umdnj.edu
Our work centers on understanding how the extracellular matrix molecule tenascin-C regulates neuronal growth. We have found that the region of tenascin-C containing only alternately spliced fibronectin type-III repeat D, called fnD, when used by itself, dramatically increases neurite outgrowth in culture. We used overlapping synthetic peptides to localize the neurite outgrowth-promoting site within fnD to a 15 amino acid sequence, called D5. An antibody against D5 blocked promotion of neurite outgrowth by fnD as well as tenascin-C, indicating that this peptide sequence is functional in the context of the native molecule. Further testing of shorter synthetic peptides restricted the neurite outgrowth-promoting site to eight amino acids, VFDNFVLK. Of these,"FD" and "FV" are conserved in tenascin-C sequences derived from all the species available in the GenBank. To investigate the hypothesis that FD and FV are critical for the interaction with neurons, we tested a recombinant fnD protein and synthetic peptides with alterations in FD and/or FV. These molecules did not facilitate process extension, suggesting that the conserved amino acids are required for formation of the active site in fnD. We next investigated whether VFDNFVLK could be used as a reagent to overcome the neurite outgrowth inhibitory properties of chondroitin sulfate proteoglycans, the major inhibitory molecules in the glial scar. The peptide significantly enhanced outgrowth on proteoglycans and was more effective than laminin-1, L1-Fc, or intact tenascin-C, thus demonstrating the potential applicability of tenascin-C regions as therapeutic reagents.
Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Reactive gliosis, observed in numerous pathological states, leads to the formation of a glial scar that is believed to impede axonal regeneration. Astrocyte reactivity can be initiated both in vitro and in vivo by various cytokines. Thus, the aim of this study was to investigate if suramin, a polysulfonated napthylurea that has been shown to inhibit the binding of many different cytokines to their cell surface receptors, could attenuate the glial response after brain injury. A single dose of suramin (5 microl, 75 microM) or saline vehicle was injected intracerebrally through the same needle used to make the stab wound at the time of lesioning. Suramin-treated animals showed an obvious reduction in several parameters of CNS inflammation: cellular proliferation, GFAP levels, and tenascin-C immunoreactivity were reduced in suramin-treated as compared to control animals at early time points. GFAP immunoreactivity was strikingly reduced at 3 days after injury, as confirmed by Western blot analysis. This reduction was transient, however, in that the difference in GFAP expression between suramin-treated and control animals was less apparent at 7 days and had disappeared by 30 days after injury. Likewise, fewer BrdU-positive cells were noted in treated versus control tissue at 1 and 3 days, but this difference was not significant by 7 days. Moreover, tenascin immunoreactivity was significantly diminished at 24 h as confirmed by Western blot analysis in suramin-treated lesion areas, which is analogous to our observations that suramin can antagonize tenascin expression by cultured astrocytes treated with bFGF. In addition, examination of the corpus callosum of saline-treated animals 30 days post-trauma revealed a disruption of the fiber tract within the lesion site, while suramin-treated animals displayed numerous fibers spanning the lesion. These results demonstrate that a single injection of suramin transiently inhibits the gliotic response, which may be sufficient to ameliorate subsequent tissue damage.
Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway 08854, USA.
Department of General and Vascular Surgery, Johann-Wolfgang-Goethe University, Frankfurt/Main, Germany.
Hepatocyte growth factor (HGF) has unique morphogenic activity for several cell types. Besides its major effect upon liver regeneration, its motogenic activity to enhance motility has not been verified for smooth muscles. Therefore we evaluated the impact of HGF in an in-vitro model of human gallbladder motility. Twelve stone-diseased and eight stone-free muscle strips were preincubated with HGF (100 ng/ml, 200 ng/ml). For the analysis of motility, cholecystokinin (CCK) was added ( .1 nM, .5 nM, 2 nM, 10 nM, and 100 nM). Twelve stone-diseased and eight stone-free strips without HGF incubation served as the control group. The tone of healthy (tone/100 nM CCK: control group, 12.4 +/- 3.6 mN; HGF group, 19.5 +/- 4.5 mN) and stone-diseased (tone/100 nM CCK: control group, 10.8 +/- 3.8 mN; HGF group, 17.3 +/- 4.8 mN) muscle strips, preincubated with HGF, was increased, with a higher sensitivity to CCK. Our results suggest that there is a clear motogenic response of stone-diseased human gallbladders to HGF.
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Treatment of angiospasm as one of the most dangerous complications of subarachnoidal hemorrhage in the cerebral arterial aneurysm rupture constitutes an actual problem. Possibility of the cerebral vessels visualization have permitted to use intraarterial infusion of vasoactive preparations (IAIVAP) for treatment of angiospasm. Therapeutic efficacy for angiospasm, cerebral ischemia and edema depends on many factors and even in application of IAIVAP not always terminates successfully. The disease predictors studying makes possible to plan the intensive therapy tactics correctly, to prognosticate the disease course and the result of treatment. While analyzing the material there were used statistical methods of the data processing, permitting to reveal the prognostically meaningful criterions, influencing the treatment efficacy for angiospasm and its consequences. There was proved the influence of some predictors on the survival and mortality indexes, as well as on disablement and securing of ability to work in patients after application of IAIVAP. It was established, that conduction of IAIVAP had promoted the trustworthy raising of the survival indexes, as well as the lowering of mortality and the disablement rate in patients suffering angiospasm, cerebral ischemia and edema.
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, United Kingdom.
Atherosclerosis in a major leg artery leads to impaired blood supply, which normally progresses to critical limb ischemia. Atherosclerosis produces substantial alterations of structure and endothelial function in the large conduit arteries. Pressure unloading and ischemia in the distal vasculature bring about alterations in microvascular function. Resistance arteries undergo significant wall thinning and changes in their contractile regulation. Optimization of large artery dimensions by the small arteries through flow-mediated vasodilation is impaired. Angiogenesis is stimulated, which can result in the formation of major collateral feeder vessels in addition to small nutritive blood vessels. However, angiogenesis can also contribute to instability of atherosclerotic plaques, which ultimately leads to further deterioration in blood supply. Surgical bypass grafting to restore blood supply to the distal leg generates a sudden increase of pressure in the weakened resistance vasculature, leading to uncontrolled changes in capillary hydrostatic pressure, extravasation of fluid, and tissue edema. This review aims to highlight the importance of the resistance vasculature in critical limb ischemia and the interdependence of pathophysiological changes in the large conduit and small resistance arteries. The major unresolved question is why the physiological mechanisms that regulate vascular structure and function ultimately break down, leading to circulatory failure within the distal limb.
Takashi Naganuma,
Yoshiyuki Tohno,
Mineo Yamasaki,
Setsuko Tohno,
Cho Azuma,
Takeshi Minami,
Hajime Morikawa
Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
To elucidate compositional changes of the rami of the internal iliac artery with aging, the authors investigated age-related changes of the calcium content in the uterine, internal pudendal, umbilical, and obturator arteries by inductively coupled plasma-atomic emission spectrometry. After an ordinary dissection was finished, the uterine, internal pudendal, umbilical, and obturator arteries were resected from 10 female subjects, and the internal pudendal, umbilical, and obturator arteries were resected from 10 male subjects. The female subjects ranged in age from 52 to 96 yr, and the male subjects ranged in age from 63 to 88 yr. The calcium content in the uterine artery began to increase in the seventies and increased markedly in the nineties. In the internal pudendal artery, the calcium content hardly increased up to the eighties and increased significantly in the nineties. In contrast, the calcium content did not change in both the umbilical and obturator arteries with advancing age. It was found that the average content of calcium was the highest in the uterine artery and decreased in the order internal pudendal, umbilical, and obturator arteries. The average content of calcium in the uterine arteries corresponded to 46-fold the amount of the women's obturator arteries, in which it was the lowest. In the cases of men, the average content of calcium was higher in the order of the internal pudendal, umbilical, and obturator arteries. Regarding the average content of calcium, the order internal pudendal, umbilical, and obturator arteries of the men was consistent with that of the women.
Second Department of Surgery, School of Medicine, Showa University, Tokyo, Japan.
BACKGROUND/AIMS: The main aim of the study was to evaluate whether superior hypogastric plexus and hypogastric nerve can be preserved without increasing local recurrence while performing surgical treatment of rectal carcinoma. METHODOLOGY: This was a retrospective study of 129 patients with rectal carcinoma who underwent curative resection with two types of autonomic nerve-sparing operation. The superior hypogastric plexus and bilateral hypogastric nerves were resected in 61 patients and spared in 68 patients. The pelvic plexus was preserved in all the patients. Local recurrence and survival were compared between two operations. RESULTS: After three years, local recurrence cumulative rates were 13.1% after hypogastric nerve removing operation and 10.3% after hypogastric nerve preserving operation. Distant metastasis and corrected 5-year survival rates were 23. and 61.6%, respectively after hypogastric nerve-removing operation, while after hypogastric nerve-preserving operation those were 16.2 and 77.4%, respectively. There were no statistically significant differences in local recurrence, distant metastasis and survival between the two groups. CONCLUSIONS: Hypogastric nerve-preserving operation does not appear to carry an increased risk of local recurrence compared with hypogastric nerve-removing operation after an equivalent follow-up period.
Department of Diagnostic Radiology, University of Oulu and Oulu University Hospital, Oulu, Finland. markku.paivansalo@oulu.fi
PURPOSE: To compare local ophthalmic blood flow changes with flow changes in carotid and vertebral arteries in diabetic patients with retinopathy of different grades. MATERIAL AND METHODS: Ten patients with proliferative or preproliferative retinopathy, 10 with mild retinopathy, and 10 matched controls were prospectively studied with ultrasound. Color and duplex Doppler imaging was used to quantitate blood flow in the central retinal arteries (CRA), ophthalmic arteries (OA), common carotid (CCA) and vertebral arteries (VA). Peak systolic velocity (PSV), mean velocity (MV), and resistance index (RI) in CRA, OA, CCA and VA, and volume flow (VF) were measured in CCA and VA. RESULTS: There was a non-significant increase in the CRA and OA velocities in mild retinopathies, a decrease of about 30% in MV, and a slightly increased RI in proliferative or preproliferative retinopathies. There was a decrease of about 15% in the carotid MV and a 20% decrease in the vertebral MV and a decrease of about 30% in VF in the CCA and VA in severe retinopathies. The MV ratio of CRA/CCA was lower in the severe retinopathy group than in the controls. CONCLUSION: The study showed a non-significant increase of ocular blood flow velocities in mild diabetic retinopathy and a significant decrease of flow velocities in severe diabetic retinopathy. This decrease in flow primarily seems to reflect the general decrease of blood flow in the cervical arteries.
Department of Bioengineering and Whitaker Institute for Biomedical Engineering, University of California at San Diego, La Jolla, CA 92093-0412, USA.
The reversibility of tissue remodeling is of general interest to medicine. Pulmonary arterial tissue remodeling during hypertension induced by hypoxic breathing is well known, but little has been said about the recovery of the arterial wall when the blood pressure is lowered again. We hypothesize that tissue recovery is a function of the oxygen concentration, blood pressure, location on the vascular tree, and time. We measured the changes of blood pressure, vessel lumen, vessel wall thicknesses, and opening angle of each segment of the blood vessel at its zero-stress state after step changes of the oxygen concentration in the breathing gas. The zero-stress state of each vessel is emphasized because it is important to the analysis of stress and strain and in morphometry. Experimental results are presented as histories of tissue parameters after step changes of the oxygen level. Tissue characteristics are examined under the hypothesis that they are linearly related to changes in the local blood pressure. Under this linearity hypothesis, each aspect of the tissue change can be expressed as a convolution integral of the blood pressure history with a kernel called the indicial response function. It is shown the indicial response function for rising blood pressure is different from that for falling blood pressure. This difference represents a major nonlinearity of the tissue remodeling process of the blood vessels.
American Cardiovascular Research Institute, 3155 Northwoods Place, Norcross, GA 30071, USA.
PURPOSE: Endovascular irradiation inhibits neointimal hyperplasia in ballooned and stented arteries but impacts both diseased and adjacent normal tissue. Little is known about the effects of irradiation on downstream vasculature. In this study, we investigated vascular function and structure of pig coronary arteries distal to sites of endoluminal irradiation. MATERIALS AND METHODS: Vasomotor responses of distal arteries to contraction of KCl and PGF2alpha and endothelium-dependent (substance P and A23187) and -independent (sodium nitroprusside) relaxation were studied in naïve, sham-treated, irradiated, stented, and stented plus irradiated vessels. Light and scanning electron microscopy were used to assess vascular morphology. RESULTS: Relaxations to substance P and A23187 at 1 month post treatment were significantly decreased in the irradiated group, whereas contractile response to PGF2alpha was significantly increased. Hemorrhage, mural thrombus, and inflammation were present at the upstream-irradiated site; inflammatory cells were also present adherent to the endothelium in the distal segments. CONCLUSIONS: Distal vasomotor function reflects an influence from the nature of a proximal intervention. The effect of irradiation on downstream conduit arteries to increase the threshold of contractility and suppress endothelium-dependent relaxation may be related to the presence of inflammatory cells at both the upstream-instrumented site as well as the distal location.
Institute of Veterinary Pathology, University of Zurich, CH-8057 Zurich, Switzerland. tsyd@vetpath.unizh.ch
Lung biopsy in cattle for the diagnosis of lung diseases is rarely used or described. The clinical effects and the gross findings in lung and pleura after ultrasonic-guided percutaneous lung biopsy in the upright animal of healthy cattle were reported previously (Braun et al., 1999). This report describes the yield of attained lung tissue and the local tissue reaction in 60 healthy adult cows slaughtered 24 h (50 animals) and 10 days (10 animals) after invasion. The yield of lung tissue in the biopsies was high (85.5%) in 90 histologically examined biopsy specimens and judged 'good to excellent'. The local tissue reaction and the extent of haemorrhage in the lung parenchyma, both 24 h and 10 days after the biopsy, were minimal. In the latter group, the scar tissue had approximately the same dimensions as the tissue cylinders punched 10 days before. There were no local adhesions between the pleural surfaces. Previously published data concerning clinical reactions and complications, macroscopically examined local tissue bleeding and the histologically evaluated minimal local inflammatory reaction, following lung biopsy of cattle, indicate that this procedure is safe and satisfactory for sampling of accurate lung material. The results of this study concur and indicate that local complications in the animal were minimal to absent.
Centre for Burns and Reconstructive Surgery, Central Tissue Bank, Ruzinov General Hospital, Ruzinov 6, 826 06, Bratislava, Slovakia (E-mail: koller@nspr.sk)
The use of glycosaminoglycans (GAGs) as the second macromolecular component with collagen for the membrane preparation is based on the idea to create a biodegradable scaffold for new tissue. A hybrid collagen/hyaluronan membrane with specific bubble macrostructure was designed to serve as a synthetic dermal substitute. The objectives were to explain the two questions: what is the local biological response to the implanted membrane, and what is its reconstruction rate in tissue. The histological study proved low irritability, good compatibility, ingrowth of autologous tissue starting on day 7 post implantation, and resorption within four weeks. The major part of the implant was replaced by autologous tissue at the end of three weeks post implantation. The overall local biological response to implant was very good.
