Effects of a phosphocitrate analogue on osteophyte, subchondral bone advance, and bone marrow lesions in Hartley guinea pigs.

OBJECTIVES: The objectives of this study were: 1) to examine osteophyte formation, subchondral bone advance, and bone marrow lesions (BMLs) in osteoarthritis (OA)-prone Hartley guinea pigs; and 2) to assess the disease-modifying activity of an orally administered phosphocitrate 'analogue', Carolinas Molecule-01 (CM-01). METHODS: Young Hartley guinea pigs were divided into two groups. The first group (n = 12) had drinking water and the second group (n = 9) had drinking water containing CM-01. Three guinea pigs in each group were euthanized at age six, 12, and 18 months, respectively. Three guinea pigs in the first group were euthanized aged three months as baseline control. Radiological, histological, and immunochemical examinations were performed to assess cartilage degeneration, osteophyte formation, subchondral bone advance, BMLs, and the levels of matrix metalloproteinse-13 (MMP13) protein expression in the knee joints of hind limbs. RESULTS: In addition to cartilage degeneration, osteophytes, subchondral bone advance, and BMLs increased with age. Subchondral bone advance was observed as early as six months, whereas BMLs and osteophytes were both observed mainly at 12 and 18 months. Fibrotic BMLs were found mostly underneath the degenerated cartilage on the medial side. In contrast, necrotic BMLs were found almost exclusively in the interspinous region. Orally administered CM-01 decreased all of these pathological changes and reduced the levels of MMP13 expression. CONCLUSION: Subchondral bone may play a role in cartilage degeneration. Subchondral bone changes are early events; formation of osteophytes and BMLs are later events in the OA disease process. Carolinas Molecule-01 is a promising small molecule candidate to be tested as an oral disease-modifying drug for human OA therapy.Cite this article: Y. Sun, A. J. Kiraly, A. R. Sun, M. Cox, D. R. Mauerhan, E. N. Hanley Jr. Effects of a phosphocitrate analogue on osteophyte, subchondral bone advance, and bone marrow lesions in Hartley guinea pigs. Bone Joint Res 2018;7:157-165. DOI:10.1302/2046-3758.72.BJR-2017-0253.

Pesquisa de anticorpos contra maedi visna em ovinos nas microregiões de Botucatu, Campinas, Piedade e São Paulo, Estado de São Paulo / Survey for antibodies against maedi-visna virus in sheep in the regions of Botucatu, Campinas, São Paulo and Piedade, State of São Paulo, Brazil

O objetivo deste estudo foi avaliar a ocorrência da infecção pelo vírus Maedi-Visna em ovinos criados nas microrregiões de Botucatu, Campinas, Piedade e São Paulo do Estado de São Paulo. As amostras de soro sanguíneo foram colhidas de 226 ovinos e foi realizada a técnica de imunodifusão em gel de ágar para a detecção de anticorpos antivírus Maedi-Visna e verificou-se que nenhuma das amostras testadas foi sororeagente. Dessa forma, faz-se necessário um estudo mais amplo no estado, a fim de se confirmar a baixa ocorrência e importância da enfermidade no estado.

Survey for antibodies against maedi-visna virus in sheep in the regions of Botucatu, Campinas, São Paulo and Piedade, state of São Paulo, Brazil. The purpose of the study was to evaluate the occurrence of infection with maedi-visna virus in sheep raised in the regions of Botucatu, Campinas, Piedade and São Paulo, state of São Paulo, Brazil, that showed symptoms of the disease. Blood serum samples collected from 226 sheep were submitted to the agar gel immunodiffusion technique for detection of antibodies against maedi-visna virus, and none of the samples tested was serum reactive. In conclusion, the maedi-visna virus has low frequency in animals raised in the regions studied.

Microalbuminuria in inflammatory bowel diseases using immunoturbidimetry and high-performance liquid chromatography.

BACKGROUND AND STUDY AIMS: To measure urinary albumin excretion using immunoturbidimetry (IT) and high-performance liquid chromatography (HPLC) in inflammatory bowel diseases. PATIENTS AND METHODS: A cross-sectional study was carried out on 60 selected patients with Crohn's disease (CD), 57 with ulcerative colitis (UC) and 22 healthy volunteers, as controls. Urinary albumin excretion was measured by IT and HPLC, and albumin-creatinine ratio was calculated. This ratio was compared in patients with active and inactive CD and UC and in healthy volunteers. RESULTS: Patients with CD and UC had higher albumin-creatinine ratio compared to controls using both IT and HPLC (p < 0.05). We measured higher albumin-creatinine ratio in patients with active compared to inactive CD (p < 0.05). Albuminuria did not correlate with disease duration of CD or UC, but patients with more extended CD according to the Montreal classification had higher HPLC-albumin-creatinine ratio. In CD, we found a significant correlation between HPLC-albumin-creatinine ratio and some inflammatory markers i.e. white blood cells (p < 0.05) and erythrocyte sedimentation rate (p < 0.05). In UC, there was no significant correlation between HPLC-albumin-creatinine ratio and the above markers of systemic inflammation or activity of UC. Albumin-creatinine ratio measured by HPLC was higher in both active and inactive CD and UC groups than albumin-creatinine ratio measured by IT. Using a receiver operating characteristics curve analysis, in case of HPLC-albumin-creatinine ratio cut-off values of the activity of CD were 2.46 mg/mmol for men, 5.30 mg/mmol for women. CONCLUSIONS: HPLC-urinary albumin-creatinine ratio is associated with the clinical and laboratory disease activity indices in CD, but not in UC. Using HPLC we found a more sensitive method compared to IT to measure albuminuria that would be a sensitive activity marker in CD.

Computer-based System for the Virtual-Endoscopic Guidance of Bronchoscopy.

The standard procedure for diagnosing lung cancer involves two stages: three-dimensional (3D) computed-tomography (CT) image assessment, followed by interventional bronchoscopy. In general, the physician has no link between the 3D CT image assessment results and the follow-on bronchoscopy. Thus, the physician essentially performs bronchoscopic biopsy of suspect cancer sites blindly. We have devised a computer-based system that greatly augments the physician's vision during bronchoscopy. The system uses techniques from computer graphics and computer vision to enable detailed 3D CT procedure planning and follow-on image-guided bronchoscopy. The procedure plan is directly linked to the bronchoscope procedure, through a live registration and fusion of the 3D CT data and bronchoscopic video. During a procedure, the system provides many visual tools, fused CT-video data, and quantitative distance measures; this gives the physician considerable visual feedback on how to maneuver the bronchoscope and where to insert the biopsy needle. Central to the system is a CT-video registration technique, based on normalized mutual information. Several sets of results verify the efficacy of the registration technique. In addition, we present a series of test results for the complete system for phantoms, animals, and human lung-cancer patients. The results indicate that not only is the variation in skill level between different physicians greatly reduced by the system over the standard procedure, but that biopsy effectiveness increases.

Effect of MYOG genotypes on growth rate and production traits in Hungarian large white pigs.

The effect of the porcine myogenin (Myog) 3' polymorphism on birth weight, growth rate, carcass weight, lean weight, lean meat percentage and back-fat thickness has been investigated in Hungarian Large White pigs. MYOG genotypes were determined by PCR-RFLP assay. The obtained MYOGA frequency value was 0.6275. Due to the small number of BB piglets the effect of the MYOG genotypes on birth weight was not significant; however, an increasing tendency was observed from genotype AA to BB. The growth rate difference between MYOG genotypes was significant: BB animals showed the highest growth rate values during the fattening period. Since few results are available on the possible use of MYOG gene polymorphism in selection to improve carcass and growth traits, by this study the authors hope to provide additional data on this particular subject.

Gastroesophageal reflux disease progressing to achalasia.

Two achalasia patients with former complaints of heartburn were examined. Antisecretory drugs were used by the patients when dysphagia occurred. Barium X-ray and esophageal manometry were performed and achalasia was diagnosed in both patients. Twenty-four-hour pH-metry showed significant and long-lasting acid reflux during supine position. Prolonged reflux episodes can be explained not only by the swallow-unrelated transient relaxation of lower esophageal sphincter (LES) and mechanical damage of the esophageal body, but also by its chemical insensitivity. Thus preoperative detection of reflux should determinate either the operational procedure and the postoperative follow up of the patient.

Three-dimensional path planning for virtual bronchoscopy.

Multidetector computed-tomography (MDCT) scanners provide large high-resolution three-dimensional (3-D) images of the chest. MDCT scanning, when used in tandem with bronchoscopy, provides a state-of-the-art approach for lung-cancer assessment. We have been building and validating a lung-cancer assessment system, which enables virtual-bronchoscopic 3-D MDCT image analysis and follow-on image-guided bronchoscopy. A suitable path planning method is needed, however, for using this system. We describe a rapid, robust method for computing a set of 3-D airway-tree paths from MDCT images. The method first defines the skeleton of a given segmented 3-D chest image and then performs a multistage refinement of the skeleton to arrive at a final tree structure. The tree consists of a series of paths and branch structural data, suitable for quantitative airway analysis and smooth virtual navigation. A comparison of the method to a previously devised path-planning approach, using a set of human MDCT images, illustrates the efficacy of the method. Results are also presented for human lung-cancer assessment and the guidance of bronchoscopy.

Automatic axis generation for virtual bronchoscopic assessment of major airway obstructions.

Virtual bronchoscopy (VB) has emerged as a paradigm for more effective 3D CT image evaluation. Systematic evaluation of a 3D CT chest image using VB techniques, however, requires precomputed guidance data. This guidance data takes the form of central axes, or centerlines, through the major airways. We propose an axes-generation algorithm for VB assessment of 3D CT chest images. For a typical high-resolution 3D CT chest image, the algorithm produces a series of airway-tree axes, corresponding airway cross-sectional area measurements, and a segmented airway tree in a few minutes on a standard PC. Results for phantom and human airway-obstruction cases demonstrate the efficacy of the algorithm. Also, the algorithm is demonstrated in the context of VB-based 3D CT assessment.

Otilonium bromide enhances sensory thresholds of volume and pressure in patients with irritable bowel syndrome.

UNLABELLED: Visceral hyperalgesia has been suggested to play a role in the development of symptoms presented by irritable bowel syndrome patients. Otilonium bromide was developed to block smooth muscle Ca release to control cramping pain of these patients. AIMS: to determine whether otilonium bromide can influence sensory thresholds of patients suffering from irritable bowel syndrome. METHODS: 15 patients with Rome-II positive IBS were tested by Synectics Visceral Stimulator Barostat using rapid phasic distension (870 ml/min). The sensory threshold for first sensation, stool, pain and maximum tolerable volume and pressure were measured. All of the parameters were tested before and 1 week after the initiation of otilonium bromide (Spasmomen, Berlin Chemie, 3x40 mg) therapy. RESULTS: The perceptual thresholds for first sensation, stool, pain and maximum tolerable distention were, 8.8+/-1.7 Hgmm, 19.2+/-2.1 Hgmm, 26.3+/-2.8 Hgmm, 28.7+/-2.8 Hgmm for pressure, 90+/-21 ml, 145+/-28 ml, 208+/-25 ml, 213+/-28 ml for volume, before treatment, respectively. Otilonium bromide treatment did not influence the thresholds for first sensation and stool, 7.4+/-1.4 Hgmm, 20.7+/-4.6 Hgmm and 83+/-21 ml, 178+/-35.8 ml, respectively. The pressure threshold of pain was significantly higher 1 week after treatment (26.3+/-2.8 Hgmm vs. 29.1+/-5.5 Hgmm, P<0.05), but the volume threshold of this sensation remained unchanged (208+/-25 ml vs. 234+/-39 ml, not significant). The pressure (28.7+/-2.8 Hgmm vs. 38.1+/-3.4 Hgmm, P<0.05) and volume (213+/-28 ml vs. 278+/-27 ml, P<0.05) thresholds for maximum tolerable volume were increased by 7 days otilonium bromide treatment. CONCLUSION: These data suggest that otilonium bromide enhances sensory thresholds to recto-sigmoideal distention.

Failure of capsaicin-containing red pepper sauce suspension to induce esophageal motility response in patients with Barrett's esophagus.

UNLABELLED: The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barrett's esophagus. METHODS: The diagnosis of Barrett's esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. RESULTS: Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barrett's esophagus. CONCLUSION: Impaired esophageal sensory motor function may serve as one etiologic role in the development of Barrett's esophagus.

Mechanisms of action of retinoids in gastrointestinal mucosal protection in animals, human healthy subjects and patients.

UNLABELLED: Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion ("nutritional gastric cytoprotection"). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. CONCLUSIONS: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.

Extraction of the hepatic vasculature in rats using 3-D micro-CT images.

High-resolution micro-computed tomography (CT) scanners now exist for imaging small animals. In particular, such a scanner can generate very large three-dimensional (3-D) digital images of the rat's hepatic vasculature. These images provide data on the overall structure and function of such complex vascular trees. Unfortunately, human operators have extreme difficulty in extracting the extensive vasculature contained in the images. Also, no suitable tree representation exists that permits straight-forward structural analysis and information retrieval. This work proposes an automatic procedure for extracting and representing such a vascular tree. The procedure is both computation and memory efficient and runs on current PCs. As the results demonstrate, the procedure faithfully follows human-defined measurements and provides far more information than can be defined interactively.

Vagus-mediated activation of mucosal mast cells in the stomach: effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue.

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.

Effect of laparoscopic antireflux operation on esophageal manometry, 24 hours pH-metry and quality of life in gastroesophageal reflux disease.

It has been suggested that laparoscopic Nissen fundoplication is an effective procedure for the treatment of gastroesophageal reflux disease (GERD). Twenty-six patients with chronic gastroesophageal reflux disease underwent laparoscopic floppy Nissen fundoplication. 24 hours pH-metry, manometry and Gastrointestinal Quality of Life Index (GIQLI) questionnaire were done preoperatively, six-month and one year after the operation. The six weeks control investigation was limited to 24 pH-metry and GIQLI interview. Adequate reflux control was obtained in all patients, with reduction in acid reflux variables at six weeks, six months as well as at one year after the operation. Preoperative reflux index and DeMeester score was significantly higher than those we found postoperatively at both time period. Preoperative lower esophageal sphincter tone and length was abnormal on average. Both parameters increased significantly at six-month and one year after the operation. GIQLI also showed characteristic changes. Compared to preoperative values we found significantly higher GIQLI at both six-month and one year following surgery. Laparoscopic Nissen fundoplication provides an excellent symptomatic and physiologic outcome in patients with esophageal reflux disease.

Effects of indomethacin, with vitamin A or beta-carotene, on the rat gastric mucosa: extra-and intracellular membrane-bound ATP mechanisms.

BACKGROUND: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory agent in the treatment of various inflammatory disorders, which causes gastrointestinal injury in humans and animal experiments. Vitamin A and beta-carotene prevent the IND-induced gastric mucosal injury. These compounds modify the membrane-bound ATP-dependent energy systems. The aims of this investigation were: (1) To study the IND-induced gastric mucosal damage and its prevention by vitamin A and beta-carotene; (2) to measure the biochemical compounds of the gastric mucosa ATP, ADP, ATP/ADP, AMP, ATP+ADP+AMP, 'energy charge' (ATP + 0.5 ADP)/(ATP+ADP+AMP), cAMP, lactate under the circumstances mentioned above; (3) to analyze the extra- and intracellular regulatory mechanisms between the membrane-bound ATP-dependent energy systems. METHODS: The observations were carried out with CFY (Sprague-Dawstrein rats, weighing 180-210 g). The gastric mucosal damage was produced by IND (20 mg/kg sc. administration) and it was prevented by vitamin A (or beta-carotene), given in doses of 0.01-0.1 to 1.0-10.0 mg/kg ig. Different biochemical compounds (ATP, ADP, AMP, cAMP, lactate) and parameters (ATP/ADP, adenylate pool, 'energy charge') were measured and calculated. RESULTS: (1) Vitamin A and beta-carotene prevented dose-dependently the IND-induced gastric mucosal damage; (2) the extent of ATP-ADP transformation was increased significantly, while the ATP-cAMP decreased in the gastric mucosa after IND-treatment; (3) vitamin A and beta-carotene enhanced the extent of ATP-cAMP transformation, while the ATP-ADP transformation was inhibited (the actions were dose-dependent responses); (4) No change was found in 'energy charge' by IND, while its value decreased significantly with vitamin A and beta-carotene. CONCLUSIONS: (1) A very complex extra- and intracellular feedback mechanism system exists in the gastric mucosa during IND, IND + vitamin A, and IND + beta-carotene treatments; (2) The gastric mucosal preventive effect of vitamin A and beta-carotene only partly depend on their scavenger properties.

[Choroid neovascularization in senile macular degeneration. 1 hear follow-up after radiotherapy]. / Choroidale Neovaskularisation bei altersbezogener Makuladegeneration. Einjahresergebnisse nach Strahlentherapie.

UNLABELLED: Choroidal neovascularization (CNV) associated with age-related macular degeneration is the major cause of legal blindness in Europe and the USA in patients aged more than 65 years, but Chakravarthy et al. has reported that radiotherapy has a beneficial effect on visual acuity. METHODS: Since March 1996 we have treated 56 patients in cooperation with the Department of Radiotherapy at the Technical University in Munich. The total dose with external beam radiotherapy was 16 Gy in 8 fractions, delivered through an anterior oblique axis to spare the lens. Before the treatment and 3, 6 and 12 months after therapy, we performed a standardized visual acuity and contrast-sensitivity test (ETDRS, Pelli Robson Chard) and fluorescin angiography 6 and 12 months after therapy. RESULTS: Twenty-five angiograms showed well-defined CNV and 31 not well-defined CNV. Six months after the treatment 15 patients had stable visual acuity within one line. Twenty-seven patients had lost more than one line of visual acuity. There was no difference between well and not well defined CNV's. One year after treatment the visual acuity remained stable within one line in 4 patients, no patient had an increase of two lines or more and 17 patients lost more then 2 lines of vision. We saw no side effects other than sicca symptoms in 3 patients. CONCLUSION: In our opinion, these results do not show that radiation treatment has a real beneficial effect on visual acuity. Further randomized studies are needed to demonstrate the efficiency of this treatment for choroidal neovascularization in AMD.

Peripheral mediators involved in gastric hyperemia to vagal activation by central TRH analog in rats.

Mechanisms mediating the increase in gastric mucosal blood flow (GMBF) induced by the stable thyrotropin-releasing hormone (TRH) analog RX-77368 injected intracisternally at a gastric acid secretory dose (30 ng) were investigated using hydrogen gas clearance in urethan-anesthetized rats. The histamine H1 receptor antagonist pyrilamine (intravenously), capsaicin (subcutaneously, 10 days), and NG-nitro-L-arginine methyl ester (L-NAME, intracisternally) failed to impair the 150% rise in GMBF induced by intracisternal injection of RX-77368. By contrast, atropine (subcutaneously) and NG-monomethyl-L-arginine (intravenously) completely inhibited the increase in GMBF evoked by intracisternal RX-77368. L-NAME (intravenously) blocked the intracisternal RX-77368-induced increase in GMBF in capsaicin-pretreated rats, and the L-NAME effect was reversed by intravenous L- but not D-arginine. These findings indicate that vagal efferent activation induced by TRH analog injected intracisternally at a gastric acid secretory dose increases GMBF through atropine-sensitive mechanisms stimulating L-arginine-nitric oxide pathways, whereas H1 receptors and capsaicin-sensitive afferent fibers do not play a role.

Growth hormone receptor gene expression on human lymphocytic and monocytic cell lines.

The potential effect of growth hormone (GH) in tumorigenesis, particularly in acute leukemia is controversial. Human growth hormone has the ability to influence certain immune functions; the majority of immune cells express growth hormone receptor (GHR) on plasma membranes. We determined GHR gene expression on different human lymphocyte (JURKAT, CESS) and monocyte (U937, THP1) cell lines by reverse transcriptase polymerase chain reaction analysis of GHR mRNA after stimulating the cells with phytohaemagglutinin or phorbolester, human growth hormone and with a combination of these. The receptor gene expression showed differences; in the U937 and CESS cell lines only the stimulants were able to induce GHR mRNA expression; in the case of JURKAT cells even the hormone alone had the ability to express its own receptor gene. Both the increased TNF-alpha production of U937 (but not that of THP1 cells), and the decreased proliferation of JURKAT cells in response to GH stimuli also prove the presence of biologically active GHR on the cell surface. Our data suggest asymmetric interaction between GH or phorbolester-induced signal pathways in U937 cells sharply depending on the temporal sequence of treatments. THP1 monocytes showed no gene expression in response to any of the stimulants. The phenomenon that certain human lymphoid and monocytoid cell lines at different levels of cell differentiation are able to express the GH receptor gene could have importance in the rhGH therapy.

Cellular mechanisms of beta-carotene-induced gastric cytoprotection in indomethacin-treated rats.

Indomethacin (IND) is a non-steroidal anti-inflammatory agent which is widely used in the treatment of various inflammatory disorders. The drug causes gastrointestinal injury in humans and experimental animals. The aim of these studies was to examine the time course correlation between the macroscopic appearance of mucosal damage, tissue level of PGE(2) and adenosine nucleotide metabolism during the development of indomethacin (IND)-induced mucosal damage and its prevention by beta-carotene.The observations were carried out on both sexes of CFY-strain rats, weighing 180-200 g. Gastric mucosal damage was produced by subcutaneous administration of IND (20 mg/kg). beta-Carotene (Hoffman-La Roche, Switzerland) was given intragastrically at the time of IND administration at doses of 0.01, 0.1, 1 and 10 mg/kg. The animals were sacrificed at 0, 1, 2, 3 and 4 h after IND administration when the number and severity of mucosal lesions were noted and the tissue levels of ATP, ADP, AMP, cAMP, lactate and PGE(2) were measured from the total homogenate of gastric mucosa. The ratio of ADP/ATP, the values of the adenylate pool (ATP+ADP+AMP), and 'energy charge' [(ATP+0.5ADP)/(ATP+ADP+AMP)] were calculated.It was found that: (a) gastric mucosal lesions appear macroscopically 2 h after IND administration; (b) the tissue level of ATP decreased, while ADP was increased 1 h after administration; (c) the most significant decrease in cAMP was found 1 h after IND administration, and thereafter its level returned to baseline; (d) beta-carotene dose-dependently prevented the IND-induced mucosal damage and elevated the cAMP level, but it did not alter the mucosal PGE(2) level 3 or 4 h after IND administration; (e) beta-carotene produced an elevation in ATP and a decrease in ADP level; (f) no significant changes were found in 'energy charge' of the gastric mucosa in IND-treated animals.The development of gastric mucosal damage due to IND was associated with increased energy liberation, i.e. transformation of ATP into ADP, and decreased ATP-cAMP transformation. The significant decrease in cAMP preceded the macroscopic appearance of mucosal damage. The increase in ATP-cAMP transformation is involved in the development of beta-carotene-induced gastric cytoprotection.

Central and peripheral vagal mechanisms involved in gastric protection against ethanol injury.

Activation of medullary thyrotropin-releasing hormone (TRH), at a dose subthreshold to increase gastric acid secretion, protects the gastric mucosa against ethanol injury through vagal cholinergic pathways in urethane-anaesthetized rats. Peripheral mediators involve the efferent function of capsaicin-sensitive splanchnic afferents leading to calcitonin gene-related peptide (CGRP)- and nitric oxide (NO)-dependent gastric vasodilatory mechanisms. In addition, gastric prostaglandins participate in gastric protection through mechanisms independent of the stimulation of gastric mucosal blood flow and mucus secretion. Medullary TRH has physiological relevance in the vagal-dependent adaptive gastric protection induced by mild (acid or ethanol), followed by strong, irritants. Additional neuropeptides, namely peptide YY (PYY), somatostatin analogues, CGRP and adrenomedullin, also act in the brainstem to induce a vagal-dependent gastric protection against ethanol through interactions with their specific receptors in the medulla. Central PYY and adrenomedullin act through vagal cholinergic prostaglandins and NO pathways, while somatostatin analogue acts through vagal non-adrenergic, non-cholinergic vasoactive intestinal peptide and NO mechanisms. Although their biological relevance is still to be established, these peptides provide additional tools to investigate the multiple vagal-dependent mechanisms which increase the resistance of the gastric mucosa to injury.