Evaluation of the combination of endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension (PAH) in pathologic human pulmonary arteries in an ex-vivo organ bath model.

PURPOSE: Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH. METHODS: Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX). Contraction of pulmonary arteries (PA) was elicited by consecutive dose-response curves of endothelin-1 (ET-1) followed by norepinephrine (NE) to allow inhibition by different pathways. Forces were measured isometrically in an organ bath in the presence and absence of ERA and PDE-5 inhibitors and their combination. RESULTS: PA of 38 patients were examined between October 2016 and November 2019. Bosentan (1E-7 M) and macitentan (1E-8 M, 3E-8 M, 1E-7 M) inhibited ET-1 induced contractions, whereas vardenafil (1E-6 M, 3E-6 M, 1E-5 M) inhibited only the NE induced part of the contractions. Vardenafil enhanced bosentan-induced inhibition of vasoconstriction in a dose-dependent fashion. Combination effects exceeded single bosentan at 3E-6 M and 1E-5 M vardenafil, and they exceeded single vardenafil at the lower vardenafil concentrations. Macitentan showed a more pronounced inhibition than bosentan regardless of the lower concentrations. Accordingly, combination effects with vardenafil resembled those of macitentan alone. CONCLUSIONS: Macitentan and bosentan were potent antagonists of vasoconstriction in PA of LTX patients. The benefit of drug combinations was demonstrated at selected concentrations only owing to a narrow therapeutic range of vardenafil in this ex-vivo model. These results suggest the utility of drug combinations other than the established pair of ambrisentan and tadalafil in PAH treatment but also make a case for a further assessment of vasodilator properties of drugs complementing ERA.

[Pulmonary Tuberculosis--Is Surgery still Necessary?]. / Pulmonale Tuberkulose--ist die Chirurgie noch notwendig?

BACKGROUND: Tuberculosis is still one of the most common infectious diseases along with HIV and malaria and therefore represents a serious problem in the health sector. Due to immigrants and refugees, the disease is also present in Europe. The global increase of multidrug resistant tuberculosis leads to a highly significant and current importance of sufficient therapeutic measures. In recent years, this fact has led to a reevaluation of surgical therapy in the context of an interdisciplinary and multimodal treatment of multidrug resistant tuberculosis. In addition, despite an effective treatment of drug sensitive tuberculosis with antibiotics, there are still indications for surgery in the treatment of tuberculosis. Beside massive hemoptysis as an emergency indication for surgical intervention, secondary complications of tuberculosis such as aspergilloma, chronic hemoptysis, pneumothorax, bronchopleural fistula and destroyed lung remain indications for surgery. CONCLUSION: The indication for surgery should always be made in a multimodal therapeutic approach by an interdisciplinary team, taking patient age and functional analysis into account. Effective antibiotic therapy should be performed before and after surgery in order to achieve a sustained treatment success.

[Consequences of pneumonectomy in the early and late phases]. / Folgen der Pneumonektomie in der Früh- und Spätphase.

Pneumonectomy can represent the appropriate surgical treatment option in advanced or centrally localized non-small cell lung cancer (NSCLC). A satisfactory oncologic tumor surgery can be reached in these cases although pneumonectomy is associated with a significantly higher mortality and morbidity than less extensive resection of the lung parenchyma.The aim of this article is a systematic review and the presentation of possible postoperative consequences of pneumonectomy in the early and late phases, which depend not only on the underlying disease but are also primarily affected by the state and function of the remaining contralateral lung parenchyma. Cardiopulmonary complications, especially pneumonia, pulmonary embolism, cardiac arrhythmia or myocardial infarction lead to increased 30-day mortality in the early postoperative period. Moreover, advanced ages over 70 years can be identified as a significant risk factor for poor quality of life after pneumonectomy.

Pre- and post-treatment effect of physostigmine on soman-inhibited human erythrocyte and muscle acetylcholinesterase in vitro.

Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by de-carbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors.

The dark side of the moon: impact of moon phases on long-term survival, mortality and morbidity of surgery for lung cancer.

OBJECTIVE: Superstition is common and causes discomfiture or fear, especially in patients who have to undergo surgery for cancer. One superstition is, that moon phases influence surgical outcome. This study was performed to analyse lunar impact on the outcome following lung cancer surgery. METHODS: 2411 patients underwent pulmonary resection for lung cancer in the past 30 years at our institution. Intra- and postoperative complications as well as long-term follow-up data were entered in our lung-cancer database. Factors influencing mortality, morbidity and survival were analyzed. RESULTS: Rate of intra-operative complications as well as rate of post-operative morbidity and mortality was not significantly affected by moon phases. Furthermore, there was no significant impact of the lunar cycle on long-term survival. CONCLUSION: In this study there was no evidence that outcome of surgery for lung cancer is affected by the moon. These results may help the physician to quiet the mind of patients who are somewhat afraid of wrong timing of surgery with respect to the moon phases. However, patients who strongly believe in the impact of moon phase should be taken seriously and correct timing of operations should be conceded to them as long as key-date scheduling doesn't constrict evidence based treatment regimens.

Value of systematic mediastinal lymph node dissection during pulmonary metastasectomy.

BACKGROUND: Systematic mediastinal lymph node dissection is the accepted standard when curative resection of bronchial carcinoma is performed. However, mediastinal lymph node dissection is not routinely performed with pulmonary metastasectomy, in which only enlarged or suspicious lymph nodes are removed. The incidence of malignant infiltration of mediastinal lymph nodes in patients with pulmonary metastases is not known. METHODS: Sixty-three patients who underwent 71 resections through a thoracotomy for pulmonary metastases of different primary tumors were studied prospectively. Selected patients showed no evidence of tumor progression or extrathoracic metastases and pulmonary metastasectomy was planned with curative intent. All patients underwent preoperative helical computed tomography (CT) scanning. Only patients with no evidence of suspicious mediastinal lymph nodes on the CT scan (less than 1 cm in the short axis) were included in this study. A mediastinal lymph node dissection was performed routinely with metastasectomy. RESULTS: In 9 patients (14.3%) at least one mediastinal lymph node revealed malignant cells in accordance with the resected metastases. When compared with the preoperative CT scan, additional pulmonary metastases were detected in 16.9% of performed operations. There was a trend toward an improved survival rate in patients without involvement of the mediastinal lymph nodes. The number of pulmonary metastases had no influence on survival. CONCLUSIONS: On a patient-by-patient basis, the frequency of misdiagnosed mediastinal lymph node metastases is about the same as compared with non-small cell bronchial carcinomas. Systematic mediastinal lymph node dissection reveals a significant number of patients, who otherwise are assumed free of residual tumor. The knowledge of metastases to mediastinal lymph nodes after complete resection of pulmonary metastases could influence the decision for adjuvant therapy in selected cases.

Inducible nitric oxide synthase expression before and after eradication of Helicobacter pylori in different forms of gastritis.

An increased expression of inducible nitric oxide synthase (iNOS) has been observed in the inflamed human gastric mucosa as well as in some tumors. This observation suggests a pathobiological role of elevated NO production. The purpose of this study was to compare the immunohistochemical iNOS expression in the different kinds of gastritis before and after the eradication of Helicobacter pylori. We performed iNOS and H. pylori immunohistochemical staining and counted iNOS positive cells. We detected elevated expression of iNOS around sites infected with H. pylori. iNOS expression in chemical gastritis was strongly elevated in mucosal glands. After treatment, we found a significant difference in iNOS expression in patients with classical H. pylori-induced antrum predominant gastritis and in patients with active autoimmune gastritis. In the special case of progressed gastritis with intestinal metaplasia we found persistence of intestinal metaplasia, and we could not find a significant difference in the number of positive iNOS cells before and after treatment. The persistence of IM as a possibly precancerous lesion is probably at least in the antrum a source of continuous iNOS induction even after H. pylori eradication.

Role of virulence factors, cell components and adhesion in Helicobacter pylori-mediated iNOS induction in murine macrophages.

To investigate the mechanisms involved in Helicobacter pylori-mediated inducible nitric oxide synthase (iNOS) upregulation in mononuclear cells we cocultivated human THP-1 acute monocytic leukemia cells and murine J774A.1 professional macrophages with different H. pylori wild-type strains and mutants. We have shown that H. pylori-mediated iNOS induction in J774A.1 is independent of established virulence factors but dependent on direct interaction between bacteria and cells. In J774A.1, iNOS was equally upregulated by the wild-type strains J99, 26695, P12, and P1 as well as by mutants lacking the cag pathogenicity island, vacA, katA, alpAB genes and the hp0043 gene taking part in lipopolysaccharide biosynthesis when direct cell contact was allowed but not when bacteria and cells were separated by protein-permeable filter membranes. In contrast, iNOS was not induced in THP-1. This indicates that H. pylori-mediated iNOS induction in J774A.1 is independent of important virulence factors whereas cell contact is crucial which suggests a role of adhesion or phagocytosis.

Comparison of CXC chemokines ENA-78 and interleukin-8 expression in Helicobacter pylori-associated gastritis.

Colonization of the gastric mucosa with Helicobacter pylori is associated with a dense infiltration of granulocytes into the lamina propria in the active phase of gastritis. In this study, we investigated the involvement of epithelial cell-derived neutrophil-activating protein 78 (ENA-78) in development of H. pylori-associated gastritis. Antral biopsies from 27 patients with H. pylori-associated gastritis and 25 from H. pylori-negative individuals were first analyzed for ENA-78 and interleukin-8 (IL-8) mRNA by semiquantitative reverse transcription (RT)-PCR. In H. pylori-positive patients, significantly elevated levels were found for both chemokines (P<0.05). Only IL-8 mRNA levels differed significantly (P<0.05) in H. pylori-infected individuals who had serum antibodies for cytotoxin-associated protein CagA versus H. pylori-infected CagA-negative persons. Quantification of ENA-78 transcript levels by competitive RT-PCR yielded a significant 45-fold upregulation for ENA-78 transcripts in biopsies of H. pylori-positive versus H. pylori-negative patients (P<0.05). In contrast to earlier findings with IL-8, the degree of ENA-78 mRNA upregulation was independent of the grade of activity of gastritis. Immunofluorescence studies on tissues of antral biopsies localized ENA-78 protein expression mainly to the gastric epithelium of H. pylori-positive patients, while control tissues were negative. Upregulation of ENA-78 and IL-8 mRNA and protein expression was also observed in an in vitro system using a gastric adenocarcinoma cell line. Only viable H. pylori yielded a strong ENA-78 and IL-8 induction, while H. pylori outer membrane proteins or water-soluble proteins had no significant effect. These data provide evidence for the importance of both IL-8 and ENA-78 in the development and perpetuation of H. pylori-associated gastritis.

Long-term results after video-assisted thoracoscopic surgery for first-time and recurrent spontaneous pneumothorax.

BACKGROUND: Few investigators have reported on results after video-assisted thoracoscopic surgery (VATS) for spontaneous pneumothorax (SP) with follow-up periods longer than 24 months. The aim of this study was to evaluate VATS for first-time and recurrent SP and to follow patients long-term. METHODS: One hundred nine patients were followed long-term after treatment of SP by VATS. Ninety-five patients had primary SP and 14 had secondary SP. Sixty-two patients had a first episode and 47 had a recurrence. In 72 patients leaks or ruptured blebs were identified and excised without subsequent pleurodesis. In 37 patients showing no ruptured bullae or leaks only pleurodesis was applied. RESULTS: Median follow-up was 53.2 months. Postoperative complications were rare. Three patients (2.7%) had a prolonged air leak. The long-term recurrence rate was 4.6%. Only those patients who had not received pleurodesis at the time of first treatment by VATS experienced recurrence. CONCLUSIONS: Immediate postoperative results show VATS to be a safe and reliable method in first-time and recurrent SP to obtain quick reexpansion of the lung. Long-term recurrence rates are acceptable and compare with results after open thoracotomy. Pleurodesis should be included in each procedure for adequate recurrence prevention.

Laparoscopic repair of traumatic diaphragmatic hernias.

BACKGROUND: Traumatic diaphragmatic hernias are serious complications of blunt abdominal or thoracic trauma. In the early posttraumatic period, they are often missed, and they may be followed by a variety of subacute or chronic symptoms due to pulmonary or intestinal obstruction. METHODS: We present three cases of traumatic diaphragmatic hernias. Two of them were successfully treated by laparoscopy and direct suturing during the early posttraumatic period; the other was treated 10 years after the trauma. RESULTS: We found that laparoscopy is a safe, successful, and gentle procedure not only for diagnosis but for treatment as well. The postoperative course was uneventful in all cases. All patients remained asymptomatic during long-term follow-up (42-60 months). These results are promising. We expect the same good long-term results after laparoscopic repair as after open conventional surgery. CONCLUSION: We recommend that surgeons with sufficient experience in laparoscopy use a minimally invasive approach to treat chronic as well as acute traumatic diaphragmatic hernias in hemodynamically stable patients.

[Treatment of advanced pleural empyema]. / Behandlung des fortgeschrittenen Pleuraempyems.

Despite the widespread availability of antibiotics and a declining incidence, pleural empyema still represents a serious intrathoracic disease often requiring surgical treatment for successful therapy. 104 patients with complicated pleural empyema were treated at our hospital between June 1991 and June 1997. In this retrospective study the main causes for pleural empyema were pneumonia in 41.3% and direct inoculation of the pleural space by major and minor thoracic surgery in 30.8%. Further diseases leading to an empyma of the pleural space were oesophageal perforation (11.5%), ARDS (8.7%) and hematogenous infection (7.7%). Eighty-four patients (80.8%) underwent surgery, of whom 17 patients required multiple operations. Conservative therapy with chest tube drainage and systemic application of tested antibiotics was performed in 20 patients. The overall mortality of our patients was 19.2%, but depending on the underlying disease differed considerably between 8.3% and 44.4%. Multiple operations caused by persisting empyema had a significantly higher mortality rate (58.8%) than single operations (10.5%).

Role of adherence in interleukin-8 induction in Helicobacter pylori-associated gastritis.

Active Helicobacter pylori-associated gastritis is characterized by a dense mucosal infiltration with granulocytes. Since H. pylori is noninvasive, secondary signals must induce the accumulation of granulocytes. Interleukin-8 (IL-8) has been shown to play a key role in this event. Using competitive reverse transcriptase-PCR on mRNA from gastric biopsies, we could show a clear correlation between the amount of IL-8 transcripts and the activity of H. pylori gastritis. Due to the inability of the bacterium to invade host cells, the epithelial layer is a potential candidate as an IL-8 source. To study the mechanism of IL-8 induction, established gastric carcinoma epithelial cell lines (AGS and Kato III) and well-defined H. pylori strains were used in a modified in vitro system. The experimental design enabled us to prevent direct contact of bacteria with epithelial cells by use of a filter membrane which did not block secreted bacterial products crossing the membrane. The data clearly showed that the direct contact of the bacterial cell with the epithelial cell is necessary for optimal IL-8 production because not only live bacteria, but also metabolically inactive bacteria, increased IL-8 secretion. Neither purified lipopolysaccharide nor water-soluble protein fractions of H. pylori NCTC 11637 and Tx30a nor the cytotoxin of H. pylori was able to increase IL-8 production significantly by the epithelial cells used. Furthermore, preparations of total membrane and outer membrane proteins of H. pylori were not able to stimulate IL-8 release in vitro. Accumulatively, these results imply that active metabolism is not necessary for stimulation as long as there is an intact membrane aiding the presentation of a stimulating membrane complex or aggregate on the surface of the bacteria. From these results, we conclude that whole bacteria and their direct contact with epithelial cells may be critical for IL-8 induction in vivo.

Pattern of adhesion molecule expression on vascular endothelium in Helicobacter pylori-associated antral gastritis.

BACKGROUND & AIMS: The inflammatory response in Helicobacter pylori-associated gastritis (HAG) is characterized by an intense infiltrate of granulocytes and lymphocytes. The emigration of white blood cells into sites of inflammation is mediated by receptors on endothelial cells and on blood leukocytes. The aim of this study was to characterize endothelial adhesion molecule expression in HAG leading to leukocyte infiltration. METHODS: Endothelially expressed adhesion molecules were studied in situ by immunohistochemical analysis of antral mucosal biopsy specimens from 20 control patients, 10 of whom had chemical gastritis, 10 normal mucosa, and 44 HAG. Adjacent biopsies were used to evaluate messenger RNA (mRNA) transcripts for the respective adhesion molecule and its inducing cytokines. RESULTS: Constitutive expression of P-selectin was found in all groups. Intercellular adhesion molecule 1 (ICAM-1) was up-regulated in patients with HAG and chemical gastritis in contrast to normal controls. Vascular adhesion molecule 1 (VCAM-1) was only found within lymphoid aggregates present in HAG. Neither mRNA transcripts nor the protein product of E-selectin were detected in normal or inflamed mucosa, although mRNA of the E-selectin-inducing cytokines, tumor necrosis factor alpha and interleukin 1beta, were found. CONCLUSIONS: Data suggest a major role of ICAM-1 and VCAM-1 in leukocyte-endothelial interaction in HAG without E-selectin up-regulation showing a unique pattern within the gastrointestinal tract, in contrast to observations made in inflammatory bowel disease.

Granulocyte activation by Helicobacter pylori.

Helicobacter pylori-associated gastritis (HAG) is characterized by granulocytic and mononuclear cell infiltrates within infected gastric mucosa. Since the bacterium does not invade the epithelial layer, it must be assumed that components or products of the pathogen which permeate the epithelial barrier may initiate chemotaxis and activation of neutrophils. The aim of this study was to evaluate the effect of H. pylori water soluble protein (WSP) components on the induction of granulocyte adherence and activation. The results show that H. pylori WSP led to enhanced expression of the beta 2-integrin CD11b/CD18 on the granulocyte surface. Following upregulation of this adhesion molecule, activated granulocytes demonstrated increased adhesion to human endothelial cells (HUVEC) in culture. These observations support the hypothesis that in vivo neutrophil activation may be a direct result of H. pylori constituents promoting transendothelial migration into the lamina propria of infected gastric mucosa.

[Prevalence of Helicobacter pylori infection in stomach carcinoma]. / Die Prävalenz der Helicobacter pylori-Infektion beim Magencarcinom.

This report outlines the results of the first prospective case-controlled study performed within a defined geographic area of southern Germany showing a significant association between Helicobacter pylori infection and gastric carcinoma (odds ratio = 2.18, 95% confidence interval 1.04-4.56). Furthermore, it can be clearly demonstrated that no association exists between carcinoma of the gastric cardia and H. pylori infection. There is no difference in prevalence of H. pylori infection between intestinal and diffuse-type carcinoma (Lauren classification). H. pylori status determination and strain typing may be useful in identifying patient groups at risk for developing gastric carcinoma.

Characterization of lymphocytic infiltrates in Helicobacter pylori-associated gastritis.

BACKGROUND: This study evaluated the specific subset composition of lymphocytes present in Helicobacter pylori-associated gastritis (HAG), since reports so far have led to inconclusive and conflicting results. METHODS: Endoscopic biopsy specimens from 56 patients were studied by quantitative immunohistochemistry using monoclonal antibodies against the lymphocyte markers CD3, CD22, CD4, CD8, CD45RO, CD1O3, TCR alpha/beta, and TCR gamma/delta. Lamina propria and intraepithelial compartments were evaluated separately. Grade, activity, and density of bacterial colonisation were assessed histologically and with Warthin-Starry stain. RESULTS: Evaluation showed a significant increase in CD4+, CD45RO+, TCR alpha/beta+ activated lamina propria lymphocytes in HAG which correlated with grade and activity of gastritis and degree of bacterial colonisation, whereas subsets of intraepithelial lymphocytes did not change significantly. TCR gamma/delta+ T cells were not found to be increased in HAG. CONCLUSIONS: Selective expansion of CD4+, CD45RO+ memory-type T cells could reflect an antigen-specific and/or chemokine-mediated effect in HAG. Locally produced CC chemokines such as RANTES have been detected in HAG.

[Technique and results of laparoscopic vagotomy in chronic duodenal ulcer]. / Technik und Ergebnisse der laparoskopischen Vagotomie beim chronischen Ulcus Duodeni.

Advances made in the medical treatment of duodenal ulcer disease have lead to a sharp decrease in the number of patients who are referred for operative therapy. Today surgery may be indicated in patients with chronic and recurrent ulceration following failure of H. pylori eradication regimens and in patients with no or reduced compliance. Laparoscopic vagotomy procedures may offer this select group of patients an additional benefit and comfort, if their short-term and long-term results are comparable to those achieved following conventional open vagotomy. This is a prospective study on patients who underwent laparoscopic vagotomy using two different adapted methods evaluating short-term clinical and functional results. From October 1991 through April 1994 8 patients were studied. 3 patients received an anterior seromyotomy with posterior truncal vagotomy (according to Taylor) and 5 patients underwent anterior linear strip gastrectomy with posterior truncal vagotomy (according to Gomez-Ferrer and Morris). All patients had gastroduodenoscopy, secretory analysis of basal acid output (BAO) and maximal acid output (MAO) and evaluation of their H. pylori status performed pre- and postoperatively. Median follow-up was 15 months. 5 patients were completely asymptomatic, 2 patients complained of mild bloating or reflux and 1 patient had mild diarrhea up to 6 months postoperatively. None suffered an ulcer recurrency. All remained H. pylori positive following surgery. Secretory analysis of acid production showed a 50-70% drop in BAO and MAO after vagotomy. Both vagotomy procedures described have been specifically adapted and are well suited for a laparoscopic approach. They are expedient and easy to employ. As clinical and functional data demonstrate they achieve short-term results comparable to those seen after conventional surgery.

Intestinal adaptation during lactation in the mouse. II. Altered intestinal processing of a dietary protein.

We previously demonstrated in lactating mice a six- to eightfold increase in the intestinal uptake of the dietary protein, ovalbumin (OVA), administered by gavage. In this study, we tested the possibility that alterations in intestinal morphology, transit time, reduced luminal proteolysis, and enhanced association with the intestinal surface might account for the increased uptake of the protein observed in lactating mice. We found that these animals had a significant increase in length, wet weight, and surface area of the small intestine. No change in the number of Peyer's patches was noted. Intestinal transit was assessed by gavage administration of 125I-OVA and 10 mg OVA and localization of the peak of radioactivity 15, 30, and 60 min after feeding. Although motility (distance traveled per unit time) was not different in lactating and control mice at 15 and 30 min, the fraction of the small intestine traversed by the peak of radioactivity was less in lactating mice. Digestion of 125I-OVA administered by gavage with 10 mg unlabeled OVA was examined by trichloroacetic acid precipitation and gel permeation of the resulting fragments. Lactating and control mice did not show differences in digestion of 125I-OVA by either measurement. The association of 125I-OVA with small intestinal segments, however, was enhanced in lactating mice, especially in the second and third segments of the small intestine. Thus several factors including an increase in length and surface area of the small intestine, prolonged contact of protein with the small intestinal absorptive surface, and enhanced association of the protein with the intestinal surface contribute to increased uptake.(ABSTRACT TRUNCATED AT 250 WORDS)