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We identified and characterized the cDNA coding for human LANCL2, a new member of the eukaryotic LanC-like protein family which is related to the bacterial lanthionine synthetase components C (LanC). The composite nucleotide sequence revealed a coding region of 1353 bp, a 5′-UTR of 186 bp and a 3'-UTR of 2421 bp. The deduced sequence of 450 amino acids showed 57.9 % identity (74.7 % similarity) when compared with the human LANCL1 homologue. In contrast to LANCL1, a unique ATP/GTP-binding site motif A was found in LANCL2. Northern blot analysis revealed the presence of two major transcripts in the brain, 4.7 kb and 4.1 kb in size, and a major 1.8 kb transcript in testis. Accordingly, expression array analysis showed prominent signals in these tissues. Because of the structural similarity to LanC, we postulate that LANCL2 may play a role as a component of a pep-tide-modifying complex.

This study compared intravenous followed by oral clarithromycin (500mg twice daily; manufactured by Abbott Laboratories) with intravenous followed by oral erythromycin and cefuroxime (1g erythromycin three times daily, 1.5g cefuroxime three times daily intravenously, 500mg erythromycin, 500mg cefuroxime axetil orally) in the treatment of patients admitted to hospital with community-acquired pneumonia in 21 centres in Europe and Canada. 235 patients were enrolled for the study, of whom 169 (88 clarithromycin and 81 erythromycin/cefuroxime) were clinically evaluable and 47 (24 clarithromycin and 23 erythromycin/cefuroxime) were bacteriologically evaluable. All clinically evaluable patients received intravenous therapy for between 2 and 5 days. No significant differences between the treatment groups were seen regarding age, underlying disease, extent of chest x-ray shadowing and other indices of severity of pneumonia. A satisfactory clinical response was observed in 91 and 88% of clinically evaluable patients and 71 and 66% of all patients (intent-to-treat analysis) in the clarithromycin and erythromycin/cefuroxime groups, respectively, and similar bacterial cure rates were obtained (67 and 70%, respectively). There were no significant differences in the clinical and bacterial response rates between the two treatment groups. There was a significantly greater number of patients experiencing drug-related adverse events in the erythromycin/cefuroxime group (65%) than in the clarithromycin group (49%; p = 0.018), with significantly less nausea, vomiting, diarrhoea and abdominal pain occurring in the clarithromycin group. We concluded that clarithromycin is a suitable monotherapy for patients with community-acquired pneumonia who require intravenous treatment, and is associated with significantly fewer adverse effects than the combination of erythromycin and cefuroxime.

A pilot study on intraoperative radiation therapy (IORT) combined with external beam radiation therapy (EBRT) in nonresectable non-small cell lung cancer (NSCLC) was performed in 31 patients (mean age: 66.2 years, range: 51-80; 10 anatomically and functionally, 21 functionally, nonresectable; 20 squamous-cell, 11 adenocarcinoma). The tumor was exposed by lateral thoracotomy and a staging lymph node dissection was performed (final staging 7 T1, 16 T2, 8 T3; 11 nodal positive). Ten to 20 Gy IORT (energy: 7-20 MeV electrons) were delivered to the tumor. Unilateral continuous positive airway pressure ventilation of the diseased lung was used to reduce the amount of healthy lung tissue in the IORT port and to minimize the ventilatory movement. Secondary collimation and direct shielding of radio-sensitive structures within the IORT port by aluminium sheets were used to further reduce collateral damage. Four weeks after IORT, 46 Gy EBRT (2 Gy/day 5 times a week; 8-23 MeV photons) were administered to the mediastinum and to the tumor-bearing area on an outpatient basis. In nodal positive cases the mediastinal dose was increased to 56 Gy. Twenty-three patients were evaluable. In 13 complete, in 8 partial (50-97% regression) and in 2 minor response has been achieved. Five patients experienced a recurrence (local only: 2; local and distant: 1; distant only: 2). Twelve patients died of underlying cardio-respiratory disorders within 6 to 25 months after IORT; 7 died of cancer. The overall 5-year survival rate including the incidental deaths is 14.7%. The recurrence-free survival rate is 53.2%.

Die computertomographischen Veranderungen im herkommlichen CT und im High-Resolution-CT (HR-CT) von 14 Patienten mit exogen allergischer Alveolitis (EAA) wurden retrospektiv analysiert. Das Patientengut setzte sich zusammen aus 8 Patienten mit klinisch subakutem Beschwerdebild, 5 Patienten im chronischen Stadium und einem Patienten im akuten Stadium der exogen allergischen Alveolitis. Der Typ der Veranderungen und deren Verteilungsmuster wurden untersucht. 7 der 8 Patienten mit klinisch subakutem Beschwerdebild zeigten milchglasartige Verschattungen („ground glass pattern”) und multiple, unter 2 mm im Durchmesser haltende Noduli. Bei allen Patienten im chronischen Stadium der EAA fand sich eine Kombination von fleckigen Opazifikationen, kleinen nodularen Densitaten und irregularen linearen Verdichtungen; eine Distraktion des Lungengewebes war in drei Fallen aufzuweisen. Ein Patient mit klinisch akuter exogen allergischer Alveolitis zeigte fleckige dichte Konsolidierungsareale in beiden Lungen sowie multiple nodulare Verschattungen und „ground glass pattern”. Das computertomographische Erscheinungsbild der EAA korreliert mit der zugrundeliegenden Makropathologie und sollte im entsprechenden klinischen Kontext eine artdiagnostische Zuordnung erlauben. The CT changes on conventional and high resolution CT in 14 patients with exogenous allergic alveolitis (EAA) were analysed retrospectively. There were 8 patients with clinically subacute disease, 5 patients in a chronic stage and 1 patient with acute EAA. The appearances and their distribution were examined. Seven of the 8 patients in the subacute stage showed a ground glass pattern and multiple nodules of less than 2 mm. All patients in the chronic stage showed a combination of fine infiltrates, small nodules and irregular linear densities; distortion of the pulmonary pattern was present in 3 cases. The patient with acute EAA showed diffuse dense areas of consolidation in both lungs as well as multiple nodules and a ground glass pattern. The CT appearances of EAA correspond with the basic micropathology and, within the clinical context, permit diagnostic classification.

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.

Antineoplastic ruthenium(III) complexes are generally regarded as prodrugs, being activated by reduction. Within a homologous series of ruthenium(III) complexes, cytotoxic potency is therefore expected to increase with increasing ease of reduction. Complexes of the general formula [Ru(III)Cl((6-n))(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind(+) or Cl(-)) and the compound trans-[Ru(II)Cl(2)(ind)(4)] have been prepared and characterized electrochemically. Lever's parametrization method predicts that a higher indazole-to-chloride ratio results in a higher reduction potential, which is confirmed by cyclic voltammetry. In vitro antitumor potencies of these complexes in colon cancer cells (SW480) and ovarian cancer cells (CH1) vary by more than 2 orders of magnitude and increase in the following rank order: [Ru(III)Cl(6)](3-)[Ru(III)Cl(4)(ind)(2)](-)[Ru(III)Cl(5)(ind)](2-)[Ru(III)Cl(3)(ind)(3)][Ru(III)Cl(2)(ind)(4)](+) approximately [Ru(II)Cl(2)(ind)(4)]. Thus, the observed differences in potency correlate with reduction potentials largely, though not perfectly, pointing to the influence of additional factors. Differences in the cellular uptake (probably resulting from different lipophilicity) contribute to this correlation but cannot solely account for it.

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.

The ruthenium complex salt indazolium trans-[tetrachlorobisindazole-ruthenate(III)] (KP1019) and the analogous sodium salt KP1339 are effective tumor-inhibiting drugs in experimental therapy of autochthonous colorectal carcinomas in rats. This paper examines the cell biological mechanisms underlying their antineoplastic effects.Colorectal tumor cell lines were used to analyze uptake of the ruthenium(III) complexes into the cells and the mechanism as well as the efficacy of their cytotoxic effects.KP1019 and KP1339 are efficiently taken up into the cells: 100 microM ruthenium(III) complex in the growth medium led to the uptake of 120-160 ng ruthenium per 10(6) cells within 30 min. Uptake of KP418 was tenfold lower correlating with its lower cytotoxic efficiency. KP1019 and KP1339 induced apoptosis in SW480 and HT29 cells predominantly by the intrinsic mitochondrial pathway as indicated by loss of mitochondrial membrane potential. Correspondingly sensitivity of the cells paralleled expression of bcl(2) while it was only slightly affected by mutations in Ki-ras.Our data demonstrate that trans-[tetrachlorobisindazole-ruthenate(III)] complex salts are promising candidate drugs in the second-line treatment of colorectal cancers resistant to other cytostatic drugs and has been introduced into phase I clinical trials.

A pilot study on intraoperative radiation therapy (IORT) combined with external beam radiation therapy (EBRT) in nonresectable non-small cell lung cancer (NSCLC) was performed in 31 patients (mean age: 66.2 years, range: 51-80; 10 anatomically and functionally, 21 functionally, nonresectable; 20 squamous-cell, 11 adenocarcinoma). The tumor was exposed by lateral thoracotomy and a staging lymph node dissection was performed (final staging 7 T1, 16 T2, 8 T3; 11 nodal positive). Ten to 20 Gy IORT (energy: 7-20 MeV electrons) were delivered to the tumor. Unilateral continuous positive airway pressure ventilation of the diseased lung was used to reduce the amount of healthy lung tissue in the IORT port and to minimize the ventilatory movement. Secondary collimation and direct shielding of radio-sensitive structures within the IORT port by aluminium sheets were used to further reduce collateral damage. Four weeks after IORT, 46 Gy EBRT (2 Gy/day 5 times a week; 8-23 MeV photons) were administered to the mediastinum and to the tumor-bearing area on an outpatient basis. In nodal positive cases the mediastinal dose was increased to 56 Gy. Twenty-three patients were evaluable. In 13 complete, in 8 partial (50-97% regression) and in 2 minor response has been achieved. Five patients experienced a recurrence (local only: 2; local and distant: 1; distant only: 2). Twelve patients died of underlying cardio-respiratory disorders within 6 to 25 months after IORT; 7 died of cancer. The overall 5-year survival rate including the incidental deaths is 14.7%. The recurrence-free survival rate is 53.2%.

Between 1971 and 1992, 55 patients with grade 1 (G1) (n = 32) or grade 2 (G2) (n = 23) neuroendocrine bronchial carcinomas (males: 26, females: 29; mean age: 47.7 years, range: 13-77 years) were treated. The sexes were evenly distributed in the two groups. Patients with G1 were significantly younger than those with G2 tumors (43.3 vs 53.7 years; P0.05). There were no statistically significant differences between G1 and G2 concerning peripheral or central localization, laterality or maximum tumor diameters. Patients with G1 had a higher incidence of tumor-related symptoms and a longer mean duration of these symptoms (21.8 months) than G2 cases (14 months) but the differences were not statistically significant either. No case displayed any symptoms of hormonal activity. Fifty-two patients underwent resection, one was non-resectable for anatomical, and one for functional, reasons; a third refused an operation. We performed 8 pneumonectomies, 36 lobectomies (8 by using bronchoplasty), 2 bronchotomies and 6 segmental resections. Twelve G2 cases had N1 or N2 lymph node metastases, two intrapulmonary metastases were removed. After a median observation time of 55.7 months the 10-year survival rate for the total collective is 90.6%. For G1 it is 100%, compared with 76.4% for G2 patients, 3 of whom died of the tumor (P0.05; significant). In univariate analysis: age over 48 years, lymphatic invasion, and lymph node metastasis were also significantly correlated with a poor survival rate. Multivariate analysis proved lymphatic permeation to be the only independent prognostic factor (the survival rate was 100% where there was no invasion, but only 74% where this had occurred).

The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.

The CT changes on conventional and high-resolution CT in 14 patients with exogenous allergic alveolitis (EAA) were analysed retrospectively. There were 8 patients with clinically subacute disease, 5 patients in a chronic stage and 1 patient with acute EAA. The appearances and their distribution were examined. Seven of the 8 patients in the subacute stage showed a ground glass pattern and multiple nodules of less than 2 mm. All patients in the chronic stage showed a combination of fine infiltrates, small nodules and irregular linear densities; distortion of the pulmonary pattern was present in 3 cases. The patient with acute EAA showed diffuse dense areas of consolidation in both lungs as well as multiple nodules and a ground glass pattern. The CT appearances of EAA correspond with the basic micropathology and, within the clinical context, permit diagnostic classification.

Open-window thoracostomy (OWT) was performed in 21 cases of empyema. The indications were postpneumonectomy empyema with (n = 6) or without (n = 1) fistula, early recurrent empyema after decortication (n = 6), chronical empyema in ill elderly patients with (n = 5) or without fistula (n = 2), and total unilateral lung gangrene with a large fistula of the main bronchus after radiotherapy and chemotherapy (n = 1). All cases presented with severe sepsis, eight of them with acute septic shock, and six with signs of multiorgan failure. Three to five ribs were resected, the muscles and skin were sutured to the ribs confining the window located at the lowest point of the empyema cavity, while the intercostal muscles of the resected ribs were used to close fistulae. The cavity was packed with dressings every day. In all cases, the sepsis subsided immediately after OWT. With the exception of one patient with postpneumonectomy empyema, who died of contralateral pneumonia on day 36, no surgery-related complications were seen. Four further patients died of unrelated causes 2, 4, 5, and 7 months, respectively, after OWT. In one of them, the OWT had been closed. Up to this time, obliteration and closure of the cavity has been carried out in 7 cases by using thoracoplasty (n = 2) or predicted muscle flaps (n = 5) either in the early course or after a delay of 11 to 23 months, with fair functional and cosmetic results. In one further case, operative closure has been planned. In seven of the eight remaining patients, four of whom declined further operations, the cavities closed spontaneously, despite their initial size after intervals of between 11 and 21 months.

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) shows particular promise as an antitumour agent against colorectal cancer. It is known that KP1019 reacts with human serum proteins, whereby the major amount binds to albumin (present in large excess) and a smaller amount to transferrin. It has been hypothesised that transferrin-mediated uptake by transferrin receptor expressing tumour cells may in part explain the apparent tumour selectivity of this compound. Circular dichroism spectroscopy and electrospray ionisation mass spectrometry studies demonstrate that two equivalents of KP1019 bind specifically to human apotransferrin, while additional amounts of the ruthenium complex bind unspecifically. Uptake studies in the transferrin receptor-expressing human colon carcinoma cell line SW480 revealed a higher cellular accumulation of KP1019 in comparison to a KP1019-transferrin adduct (2∶1), while the uptake of a KP1019–Fe(III)-transferrin conjugate (1∶0.3∶1) significantly exceeded that of KP1019, suggesting that iron binding is necessary to obtain a protein conformation which favours recognition by the transferrin receptors on the cell surface. Our study showed that KP1019 is transported into the cell by both transferrin-independent and transferrin-dependent mechanisms. Transferrin-mediated uptake is more efficient when transferrin is saturated with iron to a physiological degree (∼30%). Cell fractionation experiments demonstrated that after a 2 h treatment of human colon cancer cells with 10 µM KP1019 on average 55% of the intracellular ruthenium is located in the cellular nucleus, while 45% remain in the cytosol and other cellular components.

New rocket data on auroral electron energy spectra are presented. Two regions of the aurora are sharply defined: the peak energy region, called the beam, and a strongly altitude-dependent tail of slowed-down secondary and backscattered electrons. It is shown that the oscillating two-stream instability described by Papadopoulos and Coffey (1974) accounts for the observed features of the tail.

In four patients with immunologic and laboratory findings consistent with allergic bronchopulmonary aspergillosis a CT of the chest was performed. CT revealed central bronchiectasis in all patients. Other features of the condition revealed by CT were mucoid impaction, peripheral alveolar infiltrates, and segmental or subsegmental atelectasis. Owing to their central location the bronchiectatic bronchi always appear parallel to the image plane. This means they can generally be visualized by CT.

Aguila, a small-rocket experiment addressing the structuring of ionospheric plasmas, is described. A Terrier-Malemute two-stage rocket will be launched approximately north from Kauai Test Facility after sunset between October 8 and October 21, 1979, universal time. Aguila will deposit three barium clouds: before apogee at about 360 and 520 km, and just after apogee at 560 km. These clouds will be photoionized by the sun and observed using intensified-camera and television systems and photometers that are sensitive to barium line radiations. These observations will be made from ground stations on Mt. Haleakala, Maui, and at the launch site. Each cloud's striation time and subsequent behavior will elucidate mechanisms believed to drive ionospheric-plasma morphology.

Bronchioloalveolar lavage (BAL) enables diffuse interstitial lung disease to be divided into lymphocytic and granulocytic alveolitis. The combination of BAL and transbronchial lung biopsies using modern flexible fiberoptic bronchoscopes allows the subdivision of lymphocytic alveolitis into sarcoidosis, exogenic allergic alveolitis (synonym: hypersensitivity pneumonitis: EAA) and granulomatous pneumonias caused by infectious agents. The use of immunohistochemical surface markers of lymphocytes in conjunction with BAL provides further differentiation of lymphocytes into T- and B-, T-helper and T-suppressor types, natural killer cells (NK cells) and cytotoxic T-cells. A predominance of T-suppressor lymphocytes is an indication of EAA, whereas a predominance of T-helper lymphocytes is positively correlated with sarcoidosis. Other markers, e.g. HLA-DR, when expressed on the surface of alveolar macrophages, merely indicate activation unrelated to a specific type of lymphocytic alveolitis. BAL is also a new and promising diagnostic tool for pneumoconioses and other types of lung disease caused by inhaled industrial pollutants. Ferruginous bodies and silica crystals, free or ingested by alveolar macrophages, can be found more easily than by scraping tissue blocks or from multiple sections of transbronchial biopsies. BAL cells can easily be processed for electron microscopy and inhaled foreign material can be analysed in an electron microscope using X-ray diffraction analysis (EDAX) or electron spectroscopic imaging (ESI). BAL is also of value in the diagnosis of peripheral lung carcinomas, in addition to cytological sputum analysis, brush smears, transthoracic fine needle aspiration and transbronchial biopsies. BAL is a valuable diagnostic tool in cases of unusual pneumonia where fungi can be visualized by silver impregnation techniques and viruses by antibodies using immunofluorescence microscopy.

From 1980 through 1984, 72 patients with small cell bronchial carcinomas were treated by radiotherapy. Twenty-one patients who were in a limited disease stage (LD) received chemotherapy according to the ACO scheme and high-dose radiotherapy with 50 Gy. These patients had a complete remission rate of 67% and a partial remission rate of 33%. The median control period was 37 months. At the time of diagnosis, patients had a median survival time of ten months (six to 36 months). A recurrence in the irradiated region was seen in none of the patients, however, 14% of patients developed a recurrence beyond the irradiation field. The results are compared to literature and discussed.

A case of severe therapy-resistant asthma in a young girl with a duration of two years prior to death is reported. At autopsy antibodies of the IgA2-subtype were demonstrated in the lungs on the alveolar basement membranes. We were able to demonstrate intracellular virus-like structures by electron microscopy; this virus infection is taken to be the cause of antibody production. Following antigen-antibody reaction a non-complement-mediated eosinophilic pneumonia with numerous macrophages developed. This inflammatory reaction showed the injurious effect of eosinophilic granulocytes causing fibrinoid necrosis; this is confirmed by the pronounced depletion of the Charcot-Leyden-granules, equivalent to the release of the major basic protein and the Charcot-Leyden crystal protein. Death was caused by IgA2 deposition in the myocardial vessels with consequent eosinophilic myocarditis.