Modelling the exposure to chemicals for risk assessment: a comprehensive library of multimedia and PBPK models for integration, prediction, uncertainty and sensitivity analysis - the MERLIN-Expo tool.

MERLIN-Expo is a library of models that was developed in the frame of the FP7 EU project 4FUN in order to provide an integrated assessment tool for state-of-the-art exposure assessment for environment, biota and humans, allowing the detection of scientific uncertainties at each step of the exposure process. This paper describes the main features of the MERLIN-Expo tool. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (i) the integration of multimedia (MM) models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic (PBPK) models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (ii) the incorporation of a set of functionalities for uncertainty/sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (iii) the integration of human and wildlife biota targets with common fate modelling in the environment. MERLIN-Expo is composed of a library of fate models dedicated to non biological receptor media (surface waters, soils, outdoor air), biological media of concern for humans (several cultivated crops, mammals, milk, fish), as well as wildlife biota (primary producers in rivers, invertebrates, fish) and humans. These models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Standardized documentation for each model and training material were prepared to support an accurate use of the tool by end-users. One of the objectives of the 4FUN project was also to increase the confidence in the applicability of the MERLIN-Expo tool through targeted realistic case studies. In particular, we aimed at demonstrating the feasibility of building complex realistic exposure scenarios and the accuracy of the modelling predictions through a comparison with actual measurements.

Expression of vascular endothelial growth factor and basic fibroblast growth factor receptors in lung cancer.

OBJECTIVE: To determine the expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor receptors (FGFR), in non-small cell lung carcinoma (NSCLC) in relation to tumor stage (TN0, TN1, TN2) and in association with the expression of p53 protein, a potential suppressor of tumor angiogenesis. STUDY DESIGN: The immunohistochemical (IHC) expression of VEGF and FGFR was examined in paraffin sections of 56 NSCLC in relation to the presence of lymph node metastases and p53 expression. Nodal status of NSCLC determined: 27 tumors, N0; 16, N1; and 13, N2 stage. Semiquantitative analysis with a score corresponding to IHC staining intensity and percentage of positive cells was used. Statistical analysis was performed with the chi 2 test. RESULTS: A significant association was noted between VEGF and FGFR expression in NSCLC. No relation was found between VEGF, FGFR expression and lymph node metastasis or p53 expression. CONCLUSION: We assume that VEGF and FGFR act in a synergistic manner in NSCLC and that their expression is not related to lymph node metastases. Angiogenesis is a very complex phenomenon and heterogeneous within tumors. Also, it is affected by microenviromental factors.

[LGM inferior vena cava filters--observation of 79 patients]. / Filtry LGM zakladane do zyly glównej dolnej--obserwacja 79 chorych.

The aim of the study was to assess effectiveness and safety of the LGM inferior vena cava (IVC) filters in patients with venous thromboembolic disease. In the Department of Internal Medicine of Institute of Tuberculosis and Lung Diseases in Warsaw 79 LGM IVC filters have been inserted since 1993. Indications for filters placement were as follows: recurrent pulmonary embolism (pe) despite anticoagulation--17 patients (pts), severe bleeding complications of thrombolytic or anticoagulant therapy--11 pts, contraindications for thrombolytic and/or anticoagulant treatment--5 pts, massive pe--14 pts, chronic thromboembolic-major vessel pulmonary hypertension (CTEPH)--30 pts, extensive deep vein thrombosis of lower limbs or vena cava inferior in patients with urgent indications for surgery--24 pts. Each filter placement was preceded by cavography. The diagnostic procedures (mainly ultrasonography) were performed after 3-6 and 12 months in the first year then once yearly during follow-up period. Oral anticoagulants (OA) or low-molecular-weight heparins (LMWH) were instituted in the majority of patients. 58 patients are still alive, 21 patients died. Only two non-fatal episodes of recurrent pe were documented. Other complications were rare and insignificant. We have not observed excess rate of recurrent deep venous thrombosis nor thrombosis at the filter site. The LGM IVC filters are effective and safe in such selectively chosen group of patients.

Lung carcinoids. Tumor angiogenesis in relation to clinicopathologic characteristics.

OBJECTIVE: To evaluate the prognostic value of carcinoid angiogenesis for the presence of lymph node metastases, histologic subtype and tumor size. STUDY DESIGN: The study group consisted of 72 resected primary lung carcinoids, 57 typical and 15 atypical. TNM staging was performed. The histologic criteria for carcinoids was based on the Flieder classification. Angiogenesis, expressed as tumor microvessel density, was estimated in sections stained with CD34 antibody, according to Weidner's method. RESULTS: The size of carcinoids was related to the histologic type: the average tumor diameter of typical carcinoids was significantly smaller than the average diameter of atypical carcinoids (P = .003, U = 207, Z = -3.023). Atypical carcinoids represented a more aggressive form of tumors than typical carcinoids; patients with typical carcinoids developed lymph node metastases less frequently (10% vs. 33%) as compared to patients with atypical carcinoids; the difference was statistically significant (P = .032). Tumor angiogenesis failed to distinguish the histologic type of carcinoids and did not indicate the presence or absence of regional lymph node metastases; neither did pTN stage or tumor size. CONCLUSION: Angiogenesis is not a determining factor of the metastatic potential of pulmonary carcinoids.

Immunohistochemical evaluation of tumour angiogenesis in adenocarcinoma and squamous cell carcinoma of lung.

Experimental studies revealed that growth and expansion of solid tumours depend on angiogenesis. Angiogenesis is very important factor for neoplastic metastasis. The presence of the metastasis is an ominous prognostic factor for many tumours, also for lung cancer. Studies of tumour microvessel density in resected non-small lung cancers have not given convincing data about value of angiogenesis. Only few reports regarded the association with angiogenesis in different histological types in lung carcinoma. Samples of 35 adenocarcinomas and 41 squamous cell resected, primary lung carcinomas were studied. Paraffin sections of tumours were stained immunohistochemically by antibody against endothelial marker CD34. Angiogenesis intensity was measured in the areas of the most active fields of tumour neovascularization. Microvessel density (MD) was higher in adenocarcinoma comparing to squamous cell cancer, but the difference was not statistically significant (p = 0,095). The groups of various stage of extension of disease in each histological type were compared-MD correlated with lymph node metastasis (p = 0,003) in the adenocarcinoma, whilst in squamous cell can cer differences between various groups of nodal involvement were not statistically significant (p = 0,53 and p = 0,22 respectively). Our results suggest that more intensive angiogenesis in adenocarcinoma could be more important factor for metastasis of adenocarcinoma than for squamous tumours. In the latter group angiogenesis may be more important for growth of squamous cell cancers, while the spread of squamous tumours may depend on other mechanisms.

[Comparison of the clinical course of pneumonia and concentration of immunoglobulin in patients treated with a standard method and with the addition of gmma-venin P]. / Porównanie przebiegu klinicznego zapalenia pluc oraz stezenia immunoglobulin w surowicy krwi u chorych leczonych metoda standardowa i w polaczeniu z Gamma-Venin P.

The therapy with immunoglobulin have been used since many years, although its clinical efficacy still is uncertain. The aim of this study was to compare the clinical course of severe pneumonia and concentration of immunoglobulin in patients admitted to the intensive care units (ICU). The patients were treated either with antibiotics only or with antibiotics and Gamma-Venin P. Investigates group consisted of 30 patients with severe pneumonia. 15 of them (group A) were treated with antibiotics only, and another 15 (group B) with antibiotics and Gamma-Venin P. Immunoglobulins were administrated intravenously in the maximum single dose 3.0 g/kg. The serum concentration of immunoglobulin were measured before and every second day after beginning of the treatment. 27 patients completed the study due to protocol (14 patients in group A and 13 patients in group B). Only two patients revealed sings of intolerance of Gamma-Venin P during the first infusion of immunoglobulin. The clinical course of pneumonia and duration of treatment in ICU were similar in both groups. Statistically significant differences in concentration of immunoglobulins in patients treated without immunoglobulin infusion in comparison with patients with Gamma-Venin P were not found. We conclude, that infusion of immunoglobulins did not improve the clinical course of the severe pneumonia.

[LGM inferior vena cava filters--follow up 50 patients]. / Filtry LGM zakladane do zyly glównej dolnej--obserwacja 50 chorych.

In the Department of Medicine at the Institute of Tuberculosis and Lung Diseases 50 LGM inferior vena cava filters have been inserted since 1993. Indications for filters placement were as follows: recurrent pulmonary embolism (PE) despite anticoagulation-16 patients (pts), severe bleeding complications of thrombolytic or anticoagulant therapy-9 pts, contraindications for thrombolytic and/or anticoagulant treatment-3 pts, massive PE-6 pts, chronic thromboembolic-major vessel pulmonary hypertension (CTEPH)-18 pts, extensive deep vein thrombosis of lower limbs or vena cava inferior in patients with urgent indications for surgery-10 pts. In every patient diagnostic procedures were performed after 1, 3, 6, 12, 24 and 36 months of follow-up period. Only one non-fatal episode of recurrent PE was documented. Other complications were rare and insignificant. The LGM inferior vena cava filters are effective and safe in such selectively chosen group of patients.

[Implantation of LGM inferior vena cava filters in patients with chronic pulmonary hypertension during a course of major vessel thromboembolism--observation of 18 patients]. / Implantacja filtrów LGM do zyly glównej dolnej u chorych z przewleklym, nadcisnieniem plucnym w przebiegu zatorowosci do duzych naczyn--obserwacja 18 chorych.

CTEPH have not been widely recognised until recently. Introduction of the new, sophisticated, non-invasive diagnostic tools accounts for rapid progress in that field. Patients with high pulmonary hypertension have a very poor prognosis. Medical treatment (vasodilators, anticoagulants) does not change outcome. Pulmonary thromboendarterectomy is the only therapeutic option for the patients. It is essential to prevent further episodes of pulmonary embolism both over the long term and during the high risk perioperative period by means of inferior vena cava filters. In the Department of Medicine, Institute of Tuberculosis and Lung Diseases 18 LGM ivc filters have been inserted in patients with CTEPH since 1994. In 7 patients PTE was performed-in 5 cases good result was achieved, 2 patients died after surgery. In the latter group 5 patients died mainly because of severe heart failure. Only one non-fatal episode of pulmonary embolism was observed. It should be concluded that the LGM ivc filters are safe and effective in preventing episodes of pulmonary embolism in patients with CTEPH.

[Role of heparin in neoplastic angiogenesis]. / Rola heparyny w angiogenezie nowotworowej.

Angiogenesis, the growth of new capillary blood vessels, is a multistep process required for tumor growth and metastasis. The significant correlation between density of microvessels and occurrence of metastasis was shown in cutaneous melanoma, cancers of breast, lung (non-small-cell), and bladder. It has been shown that heparin play a crucial role in angiogenesis. In this review the mechanism of this regulation was summarized, and it was compared to action of specific antagonists of heparin in angiogenesis. It is known that heparin can promote this process, but some fractions may not. Knowing the complex action of heparin in the angiogenesis, the exact role of heparin in tumor growth and metastasis is unknown. Therefore, we suggest that it is needed to confirm if an use of heparin for treating patients with cancer can prolong their survival.

[Outcome of patients with clinically acute massive pulmonary embolism]. / Losy chorych z klinicznie ostrym masywnym zatorem tetnicy plucnej.

Acute massive pulmonary embolism (AMPE) is an event that places the recipient at an unusually high risk of sudden death. Among 183 patients with thromboembolic disease, AMPE has been diagnosed clinically in 58 cases (32%). Diagnostic criteria: cardiac arrest (24 cases--41%), shock (12--21%) acute cor pulmonale (ACP 15--26%) and ACP with shock (7 cases--12%). There were 33 women and 25 men aged 22-88 years in this group. In 25 patients heparin (H), in 7 streptokinase (S), in 1 tPA, in 7 S after H have been used, 26 patients (45%) survived, 32 (55%) died: there were 20 sudden deaths. Advanced underlying cardiopulmonary diseases or/and recurrent pulmonary embolism seem to be the most important predictors of fatal outcome of AMPE.

[Effect of large doses of nifedipine on pulmonary hypertension in patients with recurrent pulmonary thromboembolism]. / Wplyw duzych dawek nifedypiny na nadcisnienie plucne u chorych z nawracajaca zatorowoscia plucna.

Thromboembolic pulmonary hypertension is an uncommon condition with poor prognosis. Vasodilators may be effective in some patients with that disease. The effect of nifedipine on hemodynamics was investigated in two patients with thromboembolic pulmonary hypertension treated with acenocoumarol. Nifedipine was administered in 20 mg doses hourly during right cardiac catheterization and was repeated after 1 hour until a decrease in systemic pressure occurred. Patients received 80 mg and 120 mg of nifedipine. Pulmonary artery pressures decreased in both cases. An increase of cardiac output and decrease of pulmonary vascular resistance were observed after 60-80 mg of nifedipine and continued to the end of the investigation. No effect on heart rate was observed. We suggest that high doses of nifedipine may be--in some patients--effective in reducing thromboembolic pulmonary hypertension.

[Multi-organ failure syndrome. Clinical picture: report of 2 cases]. / Zespól niewydolnosci wielonarzadowej. Obraz kliniczny: opis 2 przypadków.

Two cases of MOFS (multi-organ-failure-syndrome) are presented. Pulmonary embolism was an initial presentation in one case, acute pneumonia in the other. In both cases intensive supportive treatment including mechanical ventilation was instituted because of acute respiratory failure. Sequential dysfunction and/or failure of other organs were observed. Both patients died despite 3 and 7 weeks of intensive treatment, respectively. In both cases MOFS was confirmed by autopsy.

[Pulmonary hypertension during the course of chronic pulmonary thromboembolism--case report]. / Nadcisnienie plucne w przebiegu przewleklej nawracajacej zatorowosci plucnej--opis przypadku.

Chronic thromboembolic pulmonary hypertension is a rare condition. There are two forms of that disease: major vessel thromboembolic pulmonary hypertension (CTEPH) and a "silent form": recurrent microembolism leading to extensive obstruction of the peripheral pulmonary vasculature and resulting also in severe pulmonary hypertension. On the base of case report the new approaches to the management of patients with two mentioned subgroups of thromboembolic pulmonary hypertension are discussed.

[Multi-organ failure syndrome. Pathophysiology, prevention, treatment]. / Zespól niewydolnosci wielonarzadowej. Patofizjologia, zapobieganie, leczenie.

MOFS Multi-Organ-Failure-Syndrome has not been recognized until past 10 to 20 years. There are many different causes that may lead to MOFS. Recently it has become clear that MOFS is the clinical endstage of the systemic hypermetabolic response to injury that is heralded by acute lung injury and followed by hepatic and renal failure and often by death. The lung injury may range from relatively slight increase of pulmonary small vessels leakage to the adult respiratory distress syndrome (ARDS). In the first part of the following paper there are presented two clinical cases resulted in MOFS. Pathophysiology, current therapy and prophylaxis of MOFS are reviewed in the second part.

[Urinary excretion of magnesium and calcium in patients with pulmonary squamous cell carcinoma treated by ionizing radiation]. / Wydalanie magnezu i wapnia w moczu u chorych na raka plaskonablonkowego pluca leczonych promieniami jonizujacymi.

Radiotherapy in patients with squamous cell lung cancer produced an increase of urinary magnesium and calcium secretion. This is probably due to the cytolysis of malignant cells and shifting of the acid--base balance toward acidity values. This interpretation is justified by the significant correlation between the regression of tumor and increased secretion of the intercellular cation--magnesium.

[Treatment of primary pulmonary hypertension with high doses of nifedipine controlled by Doppler echocardiography]. / Próba leczenia pierwotnego nadcisnienia plucnego wysokimi dawkami nifedypiny pod kontrola echokardiografii dopplerowskiej.

In a 22 year old female with primary pulmonary hypertension Doppler echocardiography revealed a systolic gradient between the right atrium and ventricle of 11.3 kPa (85 mmHg). A trial of high dose nifedipine therapy was started. It's efficacy was assessed by monitoring the tricuspid gradient. During therapy variations of the gradient were seen but without a favorable, steady, decrease trend. Although nifedipine did not produce any improvement during the "acute trial"--nifedipine therapy was continued--initially 60 mg, followed by 80 mg and finally 100 mg per day. Efficacy of this therapy was also controlled by Doppler echocardiography. Nifedipine was discontinued after 8 months due to lack of improvement in the patient's state. The patient died 30 months from the initial symptoms. Pathomorphological examination confirmed the clinical diagnosis. The use of Doppler echocardiography in assessing the vasodilators in primary pulmonary hypertension is discussed.

[Intensive treatment of respiratory failure--personal experiences]. / Intensywne leczenie niewydolnosci oddychania--doswiadczenia wlasne.

Controlled oxygen-therapy was used in 30 out of 49 patients (61%) with the acute respiratory failure or exacerbations of the chronic respiratory failure treated at ICU (Group Y), while artificial ventilation in the remaining 19 patients (39%; Group B). An improvement was achieved in 70% of patients of Group A and 42% in Group B. Overall improvement was achieved in 59% of the treated patients. There were 69% of treated patients with infections. Totally 41% of the treated patients died (30% of Group A and 58% of Group B). An analysis of the results has been carried out in various subgroups of the treated patients, i.e. the acute and exacerbated respiratory failure as well as partial and complete respiratory insufficiency. The result of high risk patients have also been analysed. This subgroup included sudden cardiac arrest, shock and non-compensated acidosis. Favourable effects of the intensive care of patients with infections have been discussed with particular reference to the life hazard in case of septic complications. Emphasis is on the unfavorable effects of therapy in patients with respiratory failure complicated with pulmonary embolism. Indications to the use of respirator and complications of the artificial ventilation have been discussed.

[Attitudes to tobacco smoking among Warsaw's physicians]. / Postawy wobec nalogu palenia tytoniu w warszawskim srodowisku lekarskim.

Physicians in the majority of countries in which tobacco-smoking has successfully been reduced stopped smoking themselves as the first professional group. Physician's attitude towards smoking patients plays an important role. Sometimes a single medical consultation helps some tobacco-abused patients to quit smoking for ever. However, the time of such a consultation should be adequately long. Out of all methods to control smoking such a consultation has the widest social extend and produces the most favourable effect; about 3% of the tobacco abusers quit smoking. These results are even better if physician consultation is supplemented with other activities such as supply with proper literature, reference to antinicotine center and return to the subject at any further consultation. It means that half a million smokers would quit this habit if every physician employed in the primary carek in Poland would have consulted each smoking patient. We attempted to check physician's attitude towards tobacco-smoking and their activity in this field.