Evidence of a TH1-Shift of Local Vaginal Inflammatory Response During Bacterial Vaginosis

Abstract Objective: To determine the levels of pro-inflammatory and anti-inflammatory cytokines in the vagina of healthy women and in bacterial vaginosis (BV) patients. Methods: Interleukin (IL)-1α, 1β, 5 and 10 were analyzed by ELISA in vaginal wash fluids from 50 non-pregnant patients with BV and 112 healthy women. Results: Levels of IL-1β were higher and those of IL-10 lower in BV-patients than in healthy women. There was a tendency towards higher levels of IL-1α in BV patients, but these data were not statistically significant. Conclusion: We found evidence for a shift towards a TH1-dominated vaginal cytokine profile in the pathogenesis of BV. Levels of a TH1-cytokine were elevated and those of a TH2-cytokine lowered in BV-patients as compared to healthy controls. This points to a vaginal TH1-response during BV and to the importance of cell-mediated immunity in local vaginal infections.     

Inhibition of Cholecystokinin-Stimulated Pancreaticobiliary Output in Man by the Cholecystokinin Receptor Antagonist MK-329

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) Cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with ⁵¹Cr-ethylenediaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 ± 0.2 pM to levels similar to those observed postprandially, averaging 9.2 ± 1.3pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 ± 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p < 0.01), 89% (NS), and 75% (p < 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p < 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

Inhibition of Pentagastrin-induced Gastric Acid Secretion in Man by Glucagon Given Intravenously

The effect of 2 mg of glucagon given intravenously on the pentagastrininduced gastric acid secretion was studied in 8 patients with peptic ulcer disease. On the maximal acid output produced by pentagastrin glucagon induced a moderate but significant depression of the secretion. When a submaximal pentagastrin infusion of 0.0025 μg/kg/min was given, glucagon induced approximately a 50 % decrease of the gastric acid output. Glucagon inhibits the basal as well as the pentagastrin-stimulated gastric acid secretion, but not the secretion in response to a maximal dose of histamine.     

Effects of Catecholamines on the Inflammatory Response

Patients with severe sepsis are often treated with vasoactive agents in an attempt to restore cardiovascular function. Catecholamines, either administered as part of sepsis therapy or endogenously released as part of the early host response to injury, can influence the activation of inflammatory pathways during severe infection. This brief review discusses current knowledge of the interactions between exogenous and endogenous catecholamines on the one hand, and inflammatory responses activated during sepsis on the other hand.     

Leucocyte Glycogen Response in Inflammatory Exudates

S ummary . Leucocyte glycogen responses in inflammatory exudates were studied in guinea-pigs. Inflammatory exudates were produced by sterile casein injection intraperitoneally. Glycogen content, incorporation of [¹⁴C]glucose into glycogen, and activity of glycogen synthetase and glycogen phosphorylase were studied in both exudate leucocytes and blood leucocytes of the same animals. Glycogen content rises dramatically in exudate leucocytes and remains above control blood values for at least 5 days. Glycogen content of circulating blood leucocytes also rises to less extreme but significant levels during inflammation. Fasting had no effect on the ability of the animals to sustain the glycogen-loading response in the leucocytes over a 3-day period. Incorporation of [¹⁴C]glucose into glycogen was low in exudate leucocytes and high in blood leucocytes. An inverse correlation between glycogen content and glucose incorporation into leucocyte glycogen was demonstrated for exudate leucocytes. Glycogen synthetase activity was found significantly higher in exudate leucocytes than blood leucocytes, the increase being primarily in the glucose-6-phosphate-dependent (D) form of the enzyme. Glycogen phosphorylase activity was no different in blood and exudate leucocytes. The striking rise in glycogen content of inflammatory leucocytes is probably part of a normal physiologic response, and can be accounted for by a relative increase in glycogen synthesis (synthetase activity) while glycogen degradation in these constantly turning-over molecules remains constant.     

Regulation of Cellular Interferon Production: Enhancement by Antimetabolites

Cycloheximide, at a protein-inhibitory concentration, when given to rabbit kidney cell cultures that had been exposed either to UV-irradiated Newcastle Disease virus or to a complex of polyinosinic and polycytidylic acids (poly I·poly C), enhanced the production of interferon. The enhancement was greater if, in addition to cycloheximide, the cells were also treated with actinomycin D. On the basis of these findings, a mechanism, consisting primarily of the production of a control protein which normally checks interferon production, is postulated for interferons stimulated by these two substances.     

Effect of Propranolol on the Renin Response to Frusemide in Man

Summary: The response of plasma renin activity (PRA) to frusemide, 40 mg given intravenously, was examined before and after oral propranolol 160 mg daily for seven days in normal and hypertensive subjects. Although basal PRA was reduced in many cases, the increase following frusemide was essentially unaltered by propranolol therapy. Evidence is presented that adequate beta adrenoceptor blockade was attained in these studies. Increasing the dose of propranolol to 240 mg daily for seven days in two subjects did not alter renin responsiveness to frusemide. Stimulation of renin release by oral frusemide, examined in one subject, was also unaltered by propranolol therapy. These findings indicate that enhancement of renin activity associated with diuretic use may not be prevented by concurrent propranolol administration. Limitation of the hypotensive action of combined beta blocker-diuretic therapy can therefore be expected. The fact that the renin stimulating effect of frusemide is preserved during beta blockade indicates that this procedure can be used in the investigation of hypertension even in those patients in whom discontinuation of beta blocking treatment may be undesirable.     

Inflammatory Response in Acute Viral Exacerbations of COPD

Background  Respiratory viruses are important triggers of acute exacerbations of COPD (AE-COPD). However, the inflammatory response in virus-positive exacerbations is still not fully understood. Methods  We investigated CRP, IL-6, IL-8, IL-10, IFN-γ, blood and sputum cells in patients with acute exacerbation (n = 36) and in stable disease (n = 20) and correlated these parameters to virus detection in respiratory secretions. Results  Similar to other studies we found a significant increase in systemic CRP and absolute numbers of blood leukocytes in AE-COPD patients. Sputum IL-6 levels and sputum eosinophils tended to be higher during exacerbation. In patients with detection of respiratory viruses in nasal lavage, local IL-6 production in sputum was significantly increased; FEV₁ was significantly decreased and both parameters were inversely correlated to each other. Conclusion  This study supports previous findings of both, increased local and systemic inflammation in acute exacerbation of COPD. In virus-associated exacerbations, IL-6 is significantly increased and negatively correlated to FEV₁ indicating a relation between virus-induced inflammation and airway obstruction. However, regarding our finding and previous data, it is becoming increasingly clear that the mediators investigated so far do not permit identifying the etiology of AE-COPD. Hence, further studies are needed to better define the inflammatory response in AE-COPD in general and in viral exacerbations in particular. Supported by Bundesministerium für Bildung und Forschung (BMBF) grant #01GC0101.     

Specificity in the Factor VIII Response to Vasopressin Infusion in Man

Structural requirements of the systemic factor VIII response to intravenous vasopressin in man has been investigated using vasopressin analogues. With the analogues available the receptor specificity of this phenomenon could not be distinguished from those associated with the previously described plasminogen activator release or antidiuretic effects of this hormone. Further studies using 1-desamino-[8-D-arginine]vasopressin showed a dose-related release of both procoagulant and antigenic components of the factor VIII complex. The newly released factor VIII could not be distinguished from circulating factor VIII on the basis of molecular size, electrophoretic mobility or in vitro stability despite apparent differences in the duration of response of the procoagulant and antigenic components in vivo.     

凝血酶与缺血性脑损害的炎症反应

近年的研究发现 ,凝血酶是一种多功能丝氨酸蛋白酶 ,除了参与凝血过程外 ,还刺激细胞产生各种炎症反应所必需的炎症介质 ,参与炎症反应过程 ,加重缺血性脑损害的炎症反应 ,进一步产生神经功能损害。文章综述了近年来国内外相关研究的进展和凝血酶对炎症反应的作用机制 ,旨在为临床治疗提供新的线索。     

A Study of the Pancreatic Response to Food after Gastrectomy in Man

The results of intubation tests on 50 patients before and after gastrectomy have been reviewed. Following gastrectomy, the pancreatic response to food is modified in the following manner.

(1) There is an increase in the resting volume of secretion.

(2) After a Billroth I operation, the output in one hour after a meal is some two-thirds of the pre-operative output.

(3) After a Polya gastrectomy, the pancreas continues to secrete at its resting rate after meals.

(4) Dissociation of enzymes occurs in the afferent loop after a Polya operation. Lipase is frequently absent from the intestinal contents, and trypsin occasionally so.

(5) Vagal section appears to be an important factor in the production of the new pattern of response.

     

炎症反应在急性冠状动脉综合征中的作用

目的 :研究炎症细胞及其介质在急性冠状动脉综合征 (ACS)发病机制中的作用。　　方法 :45例急性心肌梗塞患者和 30例不稳定性心绞痛患者 ,共 75例为 ACS组 ,2 5例稳定性心绞痛患者为稳定性心绞痛组 ,40例健康者为对照组。采用流式细胞技术检测白细胞粘附分子 (CD11b、CD18)和血小板表面活化标志蛋白 α-颗粒膜蛋白 140 (CD6 2 P)、溶酶体膜蛋白 GP5 3(CD6 3)和人血小板凝血酶敏感蛋白 (TSP) ,采用夹心酶联免疫方法检测肿瘤坏死因子 -α,放射性同位素标记单抗检测内皮素。　　结果 :ACS组 CD18、CD6 2 P、CD6 3、TSP、内皮素、肿瘤坏死因子 -α显著高于稳定性心绞痛组和对照组 (P<0 .0 5和P<0 .0 1) ,稳定性心绞痛组和对照组比较 ,各检测指标均无显著差异。　　结论 :炎症细胞及其介质参与 ACS早期的发病过程 ,评价、筛选抗炎药物对急性心肌梗塞和不稳定性心绞痛的预防和治疗将具有重要临床意义。     

Adrenergic Mechanisms in the Systemic Plasminogen Activator Response to Adrenaline in Man

S ummary . The effect of propranolol, ICI 50172 and a combination of propranolol and phentolamine, on the plasminogen activator response to a 30 mm intravenous infusion of adrenaline hydrochloride (0.1 μg/kg/min) has been studied in five healthy subjects. Plasma factor VIII, serum free fatty acids, blood glucose and pulse rate changes were also monitored to confirm the efficacy of adrenergic blockade. Propranolol blocked the plasminogen activator response by a factor of 29% whereas ICI 50172 had no effect. The addition of phentolamine to propranolol failed to influence further the degree of blockade already present with propranolol alone. It is postulated that the plasminogen activator response to adrenaline is derived from two separate components, and that the relatively minor one may be secondary to vasoactive changes whereas the second and major component is quite independent of this phenomenon. It is also proposed that both components may share a common adrenergic receptor site.     

Comparison of Hematologic and Febrile Response to Endotoxin in Man

The infusion of endotoxin in man is followed by a fall in mononuclear cellcount and subsequent granulocytosis. Significant granulocytopenia was notobserved, nor were changes in plasma fibrinogen levels or platelet countsnoted. Although a correlation was demonstrated between dose of endotoxinadministered and hematologic response, there was no correlation between themagnitude of fever and hematologic changes. Hematologic responsivenesswas unchanged following the development of febrile tolerance to endotoxin.

Submitted on September 22, 1964 Accepted on November 11, 1964     

Golimumab Ameliorates Pancreatic Inflammatory Response in the Cerulein-Induced Acute Pancreatitis in Rats

Background:The aim of the study was to evaluate whether a new and successful treatment opportunity can be provided in acute pancreatitis and may prevent symptomatic treatments and show its effect through etiopathogenesis. Therefore, we want to investigate the efficacy of golimumab in an experimental rat model of cerulein-induced acute pancreatitis.Methods:A total of 35 rats, including 7 rats in each group, were distributed into 5 groups (sham, acute pancreatitis, placebo, acute pancreatitis + golimumab 5 mg/kg, and acute pancreatitis + golimumab 10 mg/kg). An experimental cerulein-induced acute pancreatitis model was accomplished by intraperitoneal cerulein injections. After sacrification, rat blood samples were collected for amylase, IL-6, and IL-1beta measurements. Histopathological analysis of the pancreas was performed with Tunel and hematoxylin & eosin staining.Results:Amylase, IL-6, and IL-1beta levels were found to be increased in the acute pancreatitis group. IL-1beta, amylase, IL-6 levels, and pancreatic inflammation were all significantly decreased in golimumab groups (P < .01). Moreover, in both golimumab groups, golimumab treatment significantly reduced apoptosis in pancreatic tissues (P < .05). Golimumab treatment was found to significantly reduce edema formation, inflammation, vacuolization, and fat necrosis of pancreatic tissues (P < .05).Conclusion:Firstly in the literature, we investigated the efficacy of golimumab in the experimental acute pancreatitis model. In the light of our findings, it could be suggested that golimumab may be an effective and safe therapeutic option in the treatment of patients with acute pancreatitis.