Meta-analysis of the results of intravenous gamma globulin treatment of coronary artery lesions in Kawasaki disease

The objective of this study was to evaluate the efficacy of intravenous gamma globulin (IVGG) therapy on the prevention of coronary artery lesions (CALs) in patients with Kawasaki disease (KD), with reference to the literature on meta-analyses in randomized controlled studies. Studies from 1984 to the end of 2000 obtained from the National Library of Medicine or from the bibliographies of these articles were used in the analysis. The total number of patients with KD covered in 17 articles was 4020. All the articles were examined for the number of doses per day, the duration of administration, and the total number of IVGG doses. The number of patients in each group was counted, and the incidence of CALs was evaluated at 30 or 60 days after onset. The results of these searches were further analyzed by meta-analytical methods. The administration of IVGG significantly decreased the incidence of CALs in a dose-dependent manner: At 30 days after onset the incidence of CALs was 29.4% without IVGG but 21.6% with a total dosage of IVGG < 1000mg/kg, 10.8% with a total dosage of 1000–2000mg/kg, and 10.2% with a total dosage of 2000mg/kg. Compared with the incidence of CALs without IVGG, the odds ratio (OR) was 0.662 [95% confidence interval (CI) 0.519–0.815)] at <1000mg/kg, 0.292 (95% CI 0.222–0.371) with 1000–2000mg/kg, and 0.274 (95% CI 0.207–0.349) with 2000mg/kg. At 60 days, the values had decreased to 17.3%, 13.8% [OR 0.767 (95% CI 0.585–1.005)], 5.8% [OR 0.296 (95% CI 0.200–0.436)], and 4.9% [OR 0.244 (95% CI 0.170–0.349)], respectively. The meta-analyses also indicated that high doses of IVGG (2000mg/kg per day) given in a single dose prevented CALs more effectively than the same dosages divided into five daily doses in the patients with KD: The incidence of CALs at 30 days after disease onset was 2.4% with a single dose versus 12.9% with divided doses. Compared with divided doses, the OR with a single dose was 0.164 (95% CI 0.064–0.393) and 2.8% versus 6.1% at 60 days [OR 0.450 (95% CI 0.206–0.956)]. We clearly confirmed that higher doses of IVGG (2000mg/kg per day) administered in a single infusion were more effective for preventing CALs, as evaluated during both the subacute and convalescent phases of KD.     

Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of β-adrenoceptor subtypes

The electrophysiological effects mediated by ₁- and ₂- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (–)-isoproterenol (IPN) and the selective agonists (–)-noradrenaline (₁) and procaterol (₂) in the absence and presence of the selective antagonists bisoprolol (₁) and ICI 118,551 (₂).IPN (0.01 mol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at –20 mV (APD –20 mV) from 96 to 154 ms, reduced the APD –70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 mol/l), diminished by bisoprolol (0.1 mol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 mol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 mol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units.Noradrenaline (0.3 mol/l) elicited similar actions as IPN. Bisoprolol (0.1 mol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 mol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 mol/l).These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of ₁. However, contribution of ₂ mediated effects could be demonstrated.Supported by Ministerium für Wissenschaft und Forschung, Nordrhein-Westfalen, Projekt-Nr, 40008786.     

Pharmacological evidence for beta3 adrenoceptors in the control of rat gastric acid secretion

The effect of the ₃-adrenoceptor agonist BRL37344 on gastric acid secretion evoked by different secretory stimuli was investigated in anaesthetized rats with lumen-perfused stomachs in comparison with the ₂-adrenoceptor agonist clenbuterol. Intravenous injections of BRL37344 (1–10 mol/kg) and clenbuterol (0.01–1 mol/kg) dose-dependently reduced 2-deoxy-D-glucose-induced acid secretion, with BRL37344 about forty times less potent than clenbuterol. BRL37344 (0.1–3 mol/kg) inhibited pentagastrin-induced acid output, whereas clenbuterol was effective only at high doses (10–100 mol/kg). The inhibitory effect of BRL37344 on pentagastrin-induced acid secretion was not modified by the nonselective –adrenoceptor antagonist propranolol, but it was prevented by bupranolol, a ₃-adrenoceptor antagonist. Furthermore, neither BRL37344 (10 mol/kg) nor clenbuterol (100 mol/kg) modified the acid secretion induced by histamine. These data suggest that ₃ adrenoceptors have an inhibitory role in the control of rat gastric acid secretion induced by indirect stimuli.     

Down-regulated β-adrenoceptors in severely failing human ventricles: Uniform regional distribution,but no increased internalization

Summary In chronic heart failure cardiac -adrenoceptors are decreased. In this study we investigated whether a) in severely failing human ventricles -adrenoceptors are uniformly decreased or regional variations exist, and b) the -adrenoceptor decrease is caused by increased internalization or is a real loss in -adrenoceptors. For this purpose we assessed -adrenoceptor number and subtype distribution in a particulate fraction (mainly sarcolemmal plasma membranes) and a light vesicle fraction of right and left ventricular segments (obtained by cutting transversal, rings of 2 cm from the midventricular regions) of explanted hearts from 2 patients with end-stage congestive dilated cardiomyopathy (DCM) and one patient with end-stage ischemic cardiomyopathy (ICM). In all three hearts ventricular -adrenoceptor number was very low (7.5–10 and 21–26 fmol/mg protein in DCM, 15–22 fmol/mg protein in ICM compared to 68–74 fmol/mg protein in non-failing ventricles). -Adrenoceptors were uniformly decreased over the whole ventricular region and no considerable regional variations existed. The same held true for ₁- and ₂-adrenoceptors. In ICM decrease in -adrenoceptors was due to a concomitant reduction in ₁- and ₂-adrenoceptors, in DCM it was mainly caused by ₁-adrenoceptor down-regulation. In all ventricular segments investigated light vesicle -adrenoceptors amounted to about 5–7% of total ventricular -adrenoceptors and this was not significantly different from non-failing left ventricles. We conclude that a) in severely failing human ventricles -adrenoceptors are evenly down-regulated and no regional variations exist and b) the decrease in -adrenoceptors is not due to enhanced internalization but is a real loss of -adrenoceptors.Abbreviations DCM dillted cardiomyopathy - ICM ischemic cardiomyopathy - ICI 118,551 erythro-(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride - CGP 12177 (±)-4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on hydrochloride - ICYP (–) [¹²⁵I]-Iodocyanopindolol     

Coffee consumption and incidence of impaired fasting glucose,impaired glucose tolerance,and type 2 diabetes: the Hoorn Study

Aims/hypothesis Coffee contains several substances that may affect glucose metabolism. The aim of this study was to evaluate the relationship between habitual coffee consumption and the incidence of IFG, IGT and type 2 diabetes.Methods We used cross-sectional and prospective data from the population-based Hoorn Study, which included Dutch men and women aged 50–74 years. An OGTT was performed at baseline and after a mean follow-up period of 6.4 years. Associations were adjusted for potential confounders including BMI, cigarette smoking, physical activity, alcohol consumption and dietary factors.Results At baseline, a 5 cup per day higher coffee consumption was significantly associated with lower fasting insulin concentrations (–5.6%, 95% CI –9.3 to –1.6%) and 2-h glucose concentrations (–8.8%, 95% CI –11.8 to –5.6%), but was not associated with lower fasting glucose concentrations (–0.8%, 95% CI –2.1 to 0.6%). In the prospective analyses, the odds ratio (OR) for IGT was 0.59 (95% CI 0.36–0.97) for 3–4 cups per day, 0.46 (95% CI 0.26–0.81) for 5–6 cups per day, and 0.37 (95% CI 0.16–0.84) for 7 or more cups per day, as compared with the corresponding values for the consumption of 2 or fewer cups of coffee per day (p=0.001 for trend). Higher coffee consumption also tended to be associated with a lower incidence of type 2 diabetes (OR 0.69, CI 0.31–1.51 for 7 vs 2 cups per day, p=0.09 for trend), but was not associated with the incidence of IFG (OR 1.35, CI 0.80–2.27 for 7 vs 2 cups per day, p=0.49 for trend).Conclusions/interpretation Our findings indicate that habitual coffee consumption can reduce the risk of IGT, and affects post-load rather than fasting glucose metabolism.     

Role of histamine H3 receptors in control of mouse intestinal motility in vivo and in vitro: comparison with alpha2-adrenoceptors

We tested drugs acting at histamine H₃ receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations. The agonist (R)--methylhistamine (100 mol/kg) caused a maximum 25% reduction of gastrointestinal transit, an effect mimicked by immepip (100 mol/kg) and antagonized by thioperamide (20 mol/kg) or clobenpropit (20 mol/kg). In the isolated ileum, (R)--methylhistamine (10–100 M) caused a slight, thioperamide-insensitive, reduction (maximum 15%) of electrically evoked cholinergic contractions. In comparison, the ₂-adrenoceptor agonist clonidine (0.1 mol/kg) caused a 35.2% inhibition of the gastrointestinal transit and almost completely reduced (maximum 82% at 1 M) the cholinergic contraction of the isolated ileum, both effects being antagonized by idazoxan (0.4 mol/kg and 1 M, respectively). These results suggest that histamine H₃ receptors, located outside the myenteric plexus, mediate an inhibition of the gastrointestinal transit in vivo. Conversely, the presence of ₂-adrenoceptors in the cholinergic nerve endings and their inhibitory role in the control of gastrointestinal propulsion is confirmed.     

Calcium channel blocker treatment of tumor cells induces alterations in the cytoskeleton,mobility of the integrin αIIbβ3 and tumor-cell-induced platelet aggregation

Summary Calcium channel blockers of the phenylalkylamine (i.e. verapamil), benzothiazepine (i.e. diltiazem) and dihydropyridine (i.e. nifedipine) classes were evaluated for effects on the tumor cell/platelet interactions using Walker 256 carcinosarcoma cells (W256 cells). When W256 cells were pretreated for 15 min with channel blockers at concentrations of 50–200 M, macroscopic tumor-cell-induced platelet aggregation was inhibited (order of potency; nifedipine>diltiazemverapamil). However, ultrastructural analysis revealed limited, focal platelet aggregates associated with tumor cell plasma membranes of verapamil- and diltiazem-treated cells. There was no evidence of platelet activation or platelet association with the tumor cell membrane in cells pretreated with nifedipine. Walker 256 cells possess the integrin _IIb3. Tumor cell _IIb3 was shown to mediate tumor cell/platelet interactions in vitro [Chopra et al. (1988) Cancer Res. 48:3787]. Patching and capping of surface _IIb3 were inhibited by nifedipine>diltiazemverapamil. The degree of inhibition of _IIb3 receptor mobility parallels the inhibition of tumor-cell-induced platelet aggregation. W256 cells are characterized by a well-developed microfilament and intermediate filament network and by the absence of a distinct microtubular network. Calcium channel blockers had no effect on the low polymerization level of tubulin. However, they induced rearrangement of microfilament stress fibers. Intermediate filaments were also rearranged but to varying degrees. The order of effectiveness for alteration of intermediate filament organization was nifedipine>diltiazem while verapamil was ineffective. We propose that the previously reported inhibition of tumor cell/platelet interaction and tumor cell metastasis by calcium channel blockers [Honn et al. (1984) Clin Exp Metastasis 1:61] is due not only to the effects of the Ca²⁺ channel blockers on platelets, but also to their effect on the tumor cell cytoskeleton resulting in an inhibition of the mobility and function of the _IIb3 receptor.Abbreviations CCB calcium channel blocker - _IIb3 platelet glycoprotein IIb/IIIa complex - TCIPA tumor cell induced platelet aggregation - W256 Walker 256 carcinosarcoma This work was supported by Public Health Service grant CA-47115, a grant from Harper Hospital and a grant from the Veterans Administration     

Bleeding duodenal ulcer and association with polymorphism of endothelial constitutive nitric oxide synthase gene

Nitric oxide (NO) exerts both protective and proinflammatory actions in the gastrointestinal tract. Enhanced gastric NO synthase (NOS) activity has been shown in duodenal ulcer patients. Recently, intron-4 polymorphism of the endothelial constitutive (ec) NOS gene has been associated with some pathological conditions. Our aim was to determine the genotype and allele frequencies of the ecNOS4 polymorphism in peptic ulcer patients. The distribution of the polymorphism ecNOS4a/b was studied in 188 ulcer patients and 120 healthy controls, from genomic DNA. Genotypes ab, bb, and aa and allele frequency were similar in both peptic ulcer patients and controls, and no differences were found when patients and controls were analyzed according to the presence of several etiological factors. However, alelle a carrier status was associated with decreased risk of bleeding in duodenal ulcer patients (OR = 0.49; 95% CI = 0.25–0.95; P = 0.03). In conclusion, this ecNOS4 polymorphism gene could be related to susceptibility of duodenal ulcer patients to bleeding.     

Stimulation of GTP hydrolysis in guinea pig bronchial membranes by mastoparan

Guanine nucleotide-binding proteins, or G proteins, play an important role in transmitting information from membrane receptors to intracellular effector systems. Activation of G proteins results in the hydrolysis of GTP, and the measurement of GTPase activity represents a means by which the role of G proteins in signal transduction can be investigated. GTPase activity of guinea pig bronchial membranes was measured as the liberation of ³²P_i from [-³²P]GTP. GTPase activity was divided into two components, one possessing a high affinity and the other a low affinity for GTP. The contribution of high- and low-affinity GTPase to total hydrolysis was dependent on Mg²⁺. In the presence of submicromolar Mg²⁺, high-affinity GTPase represented 65–80% of all activity, whereas in the presence of 26 µM Mg²⁺, all detectable hydrolysis was due to the low-affinity GTPase. High-affinity GTPase was stimulated by Mg²⁺ in the 0.15–1.1 M range (2.5-fold maximal stimulation, apparent Km for Mg²⁺ 0.31 M). Mastoparan (1–100 M) caused a concentration-dependent stimulation of high-affinity (but not low-affinity) GTPase (71 ± 13% maximal stimulation, EC₅₀ 0.38 M), suggesting that high-affinity GTPase may be due to a G protein. Carbachol (10 M) and fenoterol (10 M) had no effect on high-affinity GTP hydrolysis, suggesting that under the conditions described, GTPase activity of bronchial membranes is not activated by muscarinic or -adrenergic receptors, respectively. Offprint requests to: K. J. Rhoden     

Early and Late QRS Morphology and Width in Biventricular Pacing: Relationship to Lead Site and Electrical Remodeling

48 patients (40 Male), mean age 68 ± 8 years, in III–IV class, with intraventricular conduction delay, received a biventricular pacemaker. Heart failure aetiology was non-ischemic in 60%. Left ventricular lead positioning was inferior in 5 patients (10%), posterior in 12 (25%), lateral in 18 (37%) and anterior in 13 (27%). QRS duration and axis were evaluated in sinus rhythm, and during right ventricular pacing, left ventricular pacing and biventricular pacing, the last early after implant and late after 8.8 ± 4.3 months. QRS duration (ms) was 154 ± 29 in sinus rhythm, 175 ± 28 during right ventricular pacing, 196 ± 31 during left ventricular pacing, 122 ± 23 during biventricular pacing early and 120 ± 18 during biventricular pacing late. All the differences were statistically significant, but not between early and late biventricular pacing. Mean QRS axis (°) was –27 ± 32 in sinus rhythm, –75 ± 4 during right ventricular pacing, 112 ± 41 during left ventricular pacing, –82 ± 51 during biventricular pacing early and –80 ± 42 during biventricular pacing late. Only the difference between left ventricular pacing and all the other groups was statistically significant. QRS axis did not significantly differ according to left ventricular lead site during left and biventricular pacing. Late compared with early biventricular pacing axis showed variation >30° in 35% of patients, in spite of no significant changes in QRS duration and x-ray positioning. Conclusion: Biventricular pacing significantly reduced QRS width, which persisted long-term. Left and biventricular pacing axis was poorly related to left ventricular lead positioning. Biventricular pacing axis variability over time may suggest a role of electrical remodeling.     

B cell adrenoceptors and sulphonylurea-induced insulin release in mouse islets

Summary Interactions of tolbutamide and glibenclamide with B cell adrenoceptors have been reported. This study evaluated the possible role of such interactions in the stimulation of insulin release. Mouse islets were incubated in the presence of 10 mmol/l glucose alone or with tolbutamide (10 mol/l) or glibenclamide (0.02 mol/l). At 0.01–10 mol/l, blockers of ₂-adrenoceptors (yohimbine, idazoxan) or ₁-adrenoceptors (prazosin) had practically no effect on glucose-induced insulin release and did not affect its potentiation by sulphonylureas, except for a slight increase by 10 mol/l prazosin and idazoxan. Nonspecific -blockers (phentolamine, dihydroergotamine) increased control release at 10 mol/l, but only the latter amplified the response to tolbutamide. Blockers of -adrenoceptors were tested at 0.1–100 mol/l: propranolol (₁, ₂), metoprolol (₁) and compound ICI 118-551 (₂). They increased glucose-induced insulin release at 100 mol/l but variably altered the effect of sulphonylureas. Blockers of adrenoceptors have, thus, no effect on insulin release in vitro at therapeutic concentrations. At high concentrations, they non-specifically affect the action of sulphonylureas. We conclude that an interaction with B cell adrenoceptors is not involved in the insulinotropic action of sulphonylureas.     

Local and Systemic Liberation of Proinflammatory Cytokines in Ulcerative Colitis

Determination of plasma and tissue cytokinelevels in inflammatory bowel disease have frequentlyresulted in conflicting data. In the present study wedetermined in patients with ulcerative colitis (UC), the levels of the proinflammatory cytokinesinterleukin (IL)-1, IL-6, interferon(IFN)-, and tumor-necrosis factor (TNF)-liberated by peripheral blood mononuclear cells (PBMC)and lamina propria mononuclear cells (LPMC) after 48-hrculture with pokeweed mitogen (PWM). IL-1, IL-6,IFN- and TNF- in the supernatant weredetected by ELISA. Results show low basal levels ofIL-1 secretion by PBMC and LPMC, and a considerableincrease after mitogen stimulation. Basal IL-6production by PBMC was higher in UC patients than incontrols [2029 pg/ml, CI₉ (–165 to4223) vs 572 pg/ml (–383 to 1527) respectively, P = 0.05] and also afterPWM activation [14,995 pg/ml (7759 -22230) vs 6598 pg/ml(3240-9956), respectively, P = 0.05]. In LPMC, nodifferences in IL-6 secretion were observed. TNF- in activated PBMC of patients with UC was notsignificantly increased in relation to control (P =0.09). No constitutive secretion of IFN- wasobserved in mononuclear cells. IFN- levelssecreted by activated LPMC were lower in patients withUC than in controls [1571 pg/ml (–108 to 3251) vs7953 pg/ml (3851-12,055), respectively, P = 0.03]. Theseresults suggest that IL-6, IL-1, and TNF- participate as mediators in the inflammatoryphenomena observed in UC. Further studies are necessaryto evaluate the role of IFN- in thiscondition.     

Protection by nitecapone against sodium taurocholate-induced damage to cultured gastric cells

The goal of this study was to observe if nitecapone protected against taurocholate-induced damage in primary cultured rat gastric mucosal cells, as well as in a well-differentiated human gastric epithelial cell line (MKN 28). Prostaglandins were measured to analyze the protection mechanism. In primary rat gastric mucosal cell culture, nitecapone 125–250 M protected the cells significantly against damage induced by sodidum taurocholate, increasing cell viability by 31–38%. In the human gastric epithelial cell line, in which mitochondrial activity was measured as an indication of cell viability, nitecapone (62.5–250 M) protected the cells against sodium taurocholate-induced damage by 12–20%. Prostaglandin E₂, thromboxane B₂, and 6-keto-prostaglandin F₁ measurements in the primary cultured rat gastric mucosal cells showed that nitecapone (125 M and 250 M) significantly stimulated prostaglandin E₂ production (84.7% and 61.0%, respectively), and inhibited thromboxane B₂ formation (50% at 250 M), while the 6-keto-prostaglandin F₁ formation was unaffected. Nitecapone had no effect on prostaglandin E₂ production in the MKN 28 epithelial cell line. Indomethacin or aspirin, at concentrations that did not affect cell viability, antagonized the stimulative effect of nitecapone on prostaglandin E₂ formation in the primary cultured rat gastric mucosal cells. Although the prostaglandin E₂ synthesis was blocked, nitecapone still protected against cell damage induced by taurocholate. These results demonstrated the direct and efficacious protection of nitecapone on gastric cell level and suggest that the cytoprotection by nitecapone against taurocholate may not be mediated through the mechanism of stimulated synthesis of prostaglandin E₂.     

A study of zinc distribution in erythrocytes of normal humans

Summary The assignment of zinc bound to carbonic anhydrase isoenzymes (CA-I and CA-II) and Cu₂ Zn₂ superoxide dismutase (SOD₁) was investigated in the hemolysates from 21 normal male subjects.Sufficient care was taken to remove leukocytes and platelets. The following values of zinc distribution were obtained:total zinc, 1113.8±22.7 (mean±S.E.) g · 100 ml^–1; CA-I-derived zinc, 866.6±26.2 g · 100 ml^–1; CA-II-derived zinc, 99.9±3.9 g · 100 m^–1; SOD₁-derived zinc, 60.3±1.9 g · 100 ml^–1; the other zinc, 87.0±12.6 g · 100 ml^–1. Namely, 7.6% of the zinc in human erythrocytes is not bound to the carbonic anhydrases and Cu₂Zn₂ superoxide dismutase, but present in available form or attached to other enzymes.     

An evaluation of gastric hypothermia

Conclusions Gastric cooling is an acceptable, sustaining procedure beneficial in the control of upper gastrointestinal bleeding of known or obscure origin. In its present mode of application, gastric freezing is not entirely satisfactory for management of intractable duodenal ulcer. This technic inconsistently alters symptoms of ulcer, causes acute gastric mucosal damage, and may so influence some factor related to ulcer diathesis as to provide adjunctive therapy. Gastric freezing is deserving of further evaluation and development under more rigidly controlled circumstances.This study was supported by grants AM-07624 and AM-07539 from the National Institute of Arthritis and Metabolic Diseases, Bethesda, Md.Presented at a postgraduate course. Current Therapy in Gastroenterology. (Nov. 16–17, 1963) sponsored by Louisiana State University School of Medicine, New Orleans. La.Trainee in gastroenterology under a grant from the National Institute of Arthritis and Metabolic Diseases.     

REVIEW: Efficacy of Rabeprazole Once Daily for Acid-Related Disorders

Proton-pump inhibitors (PPIs) have revolutionized the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer. To evaluate the efficacy of the new PPI rabeprazole, 12 controlled clinical trials were conducted worldwide—three for each indication (erosive or ulcerative GERD healing, long-term GERD healing maintenance, duodenal ulcer healing, and gastric ulcer healing). Rabeprazole was compared to placebo, the H₂-receptor antagonist ranitidine, and the PPI omeprazole. Treatment duration ranged from 4 weeks for duodenal ulcer to 6 weeks for gastric ulcer, 8 weeks for GERD healing, and 1 year for maintenance of GERD healing. Rabeprazole was as effective as omeprazole for each indication and significantly more effective than ranitidine for healing of GERD (87% vs 66%) and duodenal ulcer (83% vs 73%). Rabeprazole was also superior to ranitidine in providing symptom relief, particularly in GERD.     

Characterization of integrin subunits,cellular adhesion and tumorgenicity of four human prostate cell lines

Cellular adhesion to extracellular matrix proteins via integrin molecules is a major factor in the process of invasion and metastasis of human tumor cells. Four human prostate cell lines were characterized according to the presence and quantity of integrin subunits, the ability of the cells to attach to extracellular substrates and the capacity of the cells to form tumors in severe combined immunodeficient (SCID) mice. All four human prostate cell lines expressed three to five integrins on their cell surfaces. The DU145, PC3 and 431P cells expressed primarily ₃, ₅, and ₆ integrin at similar levels. These cell lines expressed the subunits ₁, ₃ and ₄ with ₁ predominant. The DU145 cells preferred attachment to fibronectin, followed by laminin and vitronectin. Approximately 50%–60% of the binding of DU145 cells to fibronectin and laminin was dependent on the function of ₅₁ and ₆ respectively. The cell line LNCaP differed in its low expression of the ₃ subunit, 95% of cellular adhesion to fobronectin and laminin being integrin-dependent and its inability to attach to vitronectin, in spite of surface expression of _v3. All the cell lines except for LNCaP readily formed tumors within SCID mice and the expression of ₃, ₆, ₁, and ₄ integrin subunits was preserved in the resulting tumor tissue. The altered adhesion properties of the LNCaP cells may explain their altered tumorigenicity.Abbreviations SCID severe combined immunodeficiency - FITC fluorescein isothiocynate - FACS fluorescence-activated cell sorting - PBS phosphate-buffered saline - FBS fetal bovine serum This work was supported in part by a grant from the Friends of the Arizona Cancer Center, Phoenix Chapter, is ACS grant PDT-388 and CH-467 and CA 56666     

Der Patient als Keimquelle in der Intensivpflegestation

Zusammenfassung 133 Patienten einer Intensivpflegestation, die bei der Aufnahme keine Symptome bakterieller Infektion zeigten und noch keine Antibiotika erhalten hatten, wurden nach dem Zufallsprinzip zwei Gruppen zugeordnet. Eine Gruppe (+Pat.) erhielt eine Antibiotikaprophylaxe mit Penicillinen oder Cephalosporinen, die zweite Gruppe (–Pat.) erhielt keine Antibiotika. Staph. aureus war bei –Pat. im Trachealsekret und in der Umgebung der häufigste potentiell pathogene Keim. Staph. aureus war im Trachealsekret und in der Umgebung der –Pat. signifikant häufiger als bei +Pat.. Klebsiella spp. standen im Trachealsekret und in der Umgebung von +Pat. an erster Stelle. Sie waren im Trachealsekret von +Pat. signifikant häufiger als bei –Pat.. In der ersten Woche des Stationsaufenthaltes traten bei +Pat. starke Veränderungen in der Keimflora der Trachealsekrete auf: die Besiedelung mit gramnegativen Keimen stieg auf fast 100% an, gleichzeitig ging die Frequenz von Staph. aureus zurück. In den Abklatschuntersuchungen aus der Patientenumgebung traten gramnegative Stäbchen bei +Pat. in signifikant höheren Koloniezahlen auf als bei –Pat.. Die paarweisen Vergleiche von Bakterienstämmen aus den Trachealsekreten und aus der Patientenumgebung ergaben, daß +Pat. gramnegative Keime und –Pat. Staph. aureus signifikant häufiger an die Umgebung abgaben. Auf die Kontamination der Patientenumgebung mit Staph. aureus wirkte sich der Faktor der trachealen Intubation nicht aus. Gramnegative Keime waren im Trachealsekret von intubierten Patienten signifikant häufiger als bei nicht intubierten. Derselbe Trend zeigte sich auch in der Patientenumgebung. Die Antibiotikaprophylaxe konnte, wie die klinischen Ergebnisse der Studie zeigten, die Patienten nicht im erwarteten Ausmaß vor Infektionen schützen. Patienten, insbesondere tracheal-intubierte, die Antibiotika erhalten, sind als Streuquellen für hochresistente gramnegative Keime anzusehen.

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The patient as a source of bacteria in intensive care units: Influence of antibiotics and tracheal intubation

Summary 133 patients in an intensive care unit, who prior to admission had not shown any signs of bacterial infection and had not received antibiotic treatment, were assigned to two groups at random. One group received antibiotic prophylaxis with penicillins or cephalosporins (+Pat.), the other group did not receive antibiotics (–Pat.). Staph. aureus was the most frequent facultative pathogen in tracheal secretions and in the environment of –Pat.. This organism was significantly more frequent in –Pat. than in +Pat. in both the tracheal secretions and the enviroment. Klebsiella spp. outnumbered all other species in +Pat.. They were significantly more frequent in tracheal secretions of +Pat. than of –Pat.. In the first week of hospitalisation marked changes were seen in bacterial flora of tracheal secretions of +Pat.. Colonization with gramnegative bacteria rose to nearly 100%, the frequency of Staph. aureus diminishing at the same time. Monitoring by contact cultures revealed that gramnegative rods were significantly more numerous in the environment of +Pat. than of –Pat.. Matching bacterial strains cultured from tracheal secretions and from the environment of the patients proved that +Pat. spread significantly higher numbers of their gramnegative bacteria into the environment. The same is true of –Pat. for Staph. aureus. Intubation had no noticeable effect on the degree of contamination of the surroundings with Staph. aureus. Gramnegative rods were significantly more frequent in tracheal secretions of patients with intubation than in patients without. The same trend was observed for environmental contamination. As the clinical results of this study have shown, antibiotic prophylaxis does not protect patients from infections to the extent expected. Patients, and particularly intubated patients, receiving antibiotic treatment have to be considered as sources of highly resistant gramnegative organisms.

     

The influence of cardiac cholinergic activation on the induction and maintenace of ventricular fibrillation

Summary The influence of cardiac cholinergic activation was studied in rats and cats on the induction and maintenance of ventricular fibrillation (VF). Acetylcholine (ACH 2–25 g/kg), in doses which did not cause bradycardia or hypotension, induced appearance of spontaneous VF (duration 2–60 sec.) in 9/20 rats which have a high sympathetic autoregulation and in 3/6 cats only, 20–40 secs after the latter had been given adrenaline. ACh (10–45 g/kg) and methacholine (10–40g/kg) also significantly prolonged the fibrillatory period induced electrically in cats and rats with and without atrial or ventricular pacing. The induction or prolongation of VF did not occur when higher doses of ACh (50–100 g/kg) were given to rats. The influence of moderate amounts of cholinergic agents on the heart may be due to localised effects resulting in asynchronous activity. Alternatively, they may produce a discharge of multiple ectopic pacemakers or a disturbance in impulse conduction. Higher doses of ACh depress the S-A and ventricular ectopic activity node thereby decreasing the probability of inducing VF.It is concluded that under conditions of raised cardiac adrenergic activity, a moderate increase in cholinergic influence can both induce and prolong VF. The relevance of these findings to the sudden infant death syndrome is discussed.     

Abciximab is Rapidly Effective in Preventing and Arresting Established Platelet Aggregation

Background: Abciximab reduces the thrombotic complications of angioplasty. It is also used, as a 'bail out' treatment when angioplasty is complicated by thrombus but its speed of action is not known. This study sought to establish how quickly abciximab blocks the aggregation of both quiescent and activated platelets to explain this rapid efficacy. Methods: Optical aggregometry (OA) and whole blood electrical impedance platelet aggregometry (WBEA) were performed with blood from 10 healthy volunteers. Abciximab 5 g/ml was added in each case with saline control 5 minutes before agonist, 10 seconds before agonist and during aggregation. Results: (1) Abciximab administered 5 minutes before agonist, completely inhibited aggregation with OA: (medians and ranges) 0% (all 0), control: 71% (50–95%) p < 0.001. and with WBEA: 0 (all 0 ), control: 7.5 (4.8–12.5 ) p = 0.016. (2) When administered 10 s before agonist with OA a small initial degree of aggregation occurred but this was rapidly reversed (time to reversal: 2 mins (1–4.5 mins) to low levels of aggregation 16.5% (0–22%), control 72.5% (55–95%) p = 0.002. With WBEA aggregation was completely inhibited: 0 (all 0 ), control: 7.5 (4.8–12.3 ) p = 0.016. (3) When administered during aggregation, with OA the rise in the aggregometry tracing was rapidly arrested (time to arrest: 1.5 mins (0.1–3 mins)) with no further aggregation occurring: 42% (30–57%), control: 80% (60–100%) p = 0.002. With WBEA the findings were similar: (time to arrest 1.5 mins (1–2 mins)) 6.3 (1.5–11.3 ), control: 10 (3–12 ) p = 0.031. Conclusions: These data suggest that when administered during a procedure in which thrombus has occurred, aggregation may be rapidly arrested. This applies to quiescent platelets but also activated platelets undergoing aggregation.