A giant exoplanet orbiting a very-low-mass star challenges planet formation models.

Surveys have shown that super-Earth and Neptune-mass exoplanets are more frequent than gas giants around low-mass stars, as predicted by the core accretion theory of planet formation. We report the discovery of a giant planet around the very-low-mass star GJ 3512, as determined by optical and near-infrared radial-velocity observations. The planet has a minimum mass of 0.46 Jupiter masses, very high for such a small host star, and an eccentric 204-day orbit. Dynamical models show that the high eccentricity is most likely due to planet-planet interactions. We use simulations to demonstrate that the GJ 3512 planetary system challenges generally accepted formation theories, and that it puts constraints on the planet accretion and migration rates. Disk instabilities may be more efficient in forming planets than previously thought.

Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients.

PURPOSE: To assess whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the toxicity of chemotherapy and alters delivered dose-intensity. To assess the feasibility of dose-intensification of chemotherapy in small-cell lung cancer (SCLC) and determine whether it has an impact on outcome. MATERIALS AND METHODS: Patients with good- or intermediate-prognosis SCLC entered a prospective multicenter study that involved a 2 x 2 factorial design with randomization to six cycles of chemotherapy with ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 intravenously (I.V.) on days 1 and 2 and 240 mg/m2 orally on day 3, and vincristine 0.5 mg/m2 I.V. on day 15 (V-ICE) every 3 weeks (intensified arm) or every 4 weeks (standard arm). A second double-blind randomization to subcutaneous GM-CSF (250 microg/m2/d) or placebo for 14 days between chemotherapy cycles was made. RESULTS: Three hundred patients were entered. Myelosuppression was the main toxicity, with no significant difference in the incidence or grade between treatment groups. The incidence of febrile neutropenia and bacteriologically confirmed sepsis was unaffected by chemotherapy schedule or use of GM-CSF. Twenty-six percent greater dose-intensity was delivered in the intensified arm, with a trend for greater dose-intensity for those who received GM-CSF. Eighty-three percent of patients achieved a response (51% complete response [CR] rate), with no significant difference in response rates between treatment groups. Survival was significantly increased in the intensified compared with the standard arm (P = .0014); median survival rates were 443 versus 351 days and 2-year survival rates were 33% versus 18%, respectively. CONCLUSION: GM-CSF does not reduce the incidence of complications from myelosuppression of aggressive chemotherapy. Dose intensification of V-ICE to a 3-week schedule in SCLC is not associated with increased toxicity, but appears to improve survival significantly. Future studies should aim to deliver chemotherapy in maximal-tolerated dose-intensities.

Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

Inhibition of porcine detrusor contractility by the flavonoid fraction of Bryophyllum pinnatum--a potential phytotherapeutic drug for the treatment of the overactive bladder syndrome.

AIMS: To determine if the phytotherapeutic agent, Bryophyllum pinnatum, could serve as an alternative drug for the overactive bladder syndrome, and to characterise the fraction responsible for the inhibition of detrusor contractility. METHODS: Fractions were prepared from the MeOH extract of B. pinnatum and further analysed by HPLC-PDA-MS. Detrusor muscle strips were prepared from porcine bladders and the electrically induced muscle contractility measured by organ bath. The effect of B. pinnatum leaf press juice (2.5-10%), a flavonoid fraction (0.1-1 mg/ml), and a bufadienolide fraction (0.1-40 µg/ml) on detrusor contractility was assessed and compared with controls (polar fraction (0.5-5 mg/ml) and oxybutynin (10(-8)-10(-6) M)). RESULTS: The press juice, at a concentration of 10% led to a reduction of detrusor contractility. Bladder strips treated with the flavonoid fraction showed a significant reduction of the contractility to 21.3 ± 5.2% (1 mg/ml) while the bufadienolide fraction had no inhibitory effect in the investigated concentrations. The polar fraction showed a reduction of the contractility in a pH-dependent fashion. At 10(-6) M concentration oxybutynin reduced the detrusor contractility to 21.9 ± 4.7%. CONCLUSIONS: The flavonoid fraction of Bryophyllum pinnatum reduces the porcine detrusor contractility in a dose- and time-dependent manner. Fractions from B. pinnatum may be a new pharmacological approach for the treatment of OAB.

Prognostic relevance of aberrations in the erbB oncogenes from breast, ovarian, oral and lung cancers: double-differential polymerase chain reaction (ddPCR) for clinical diagnosis.

We have determined the average gene copy numbers (AGCN) of the erbB-1 gene, encoding the epidermal growth factor receptor (EGF-R), the erbB-2 and the erbB-3 genes in breast, ovarian, oral, and lung cancer tissue by using double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. In a retrospective study the AGCN of the erbB genes and the time up to the appearance of metastases were subjected to life-table analysis in 128 women with primary breast cancer. Patients whose breast cancer tissue showed an AGCN for erbB-1 of less than 0.4 and greater then 1.6, as expected from the literature, for erbB-2 of greater than 2.0 and for erbB-3 of less than 1.75 had decreased disease-free survival (DFS). The quotient of erbB-1 and erbB-2 AGCN was the most significant in multivariate Cox analysis followed by nodal status and progesterone receptor status. In extensive studies a similar association between erbB AGCN and metastasis was seen in ovarian cancer and oral cancer, though erbB oncogene aberrations in those entities were not as frequent as in breast cancer. The AGCN of erbB oncogenes may not be of prognostic value in untreated lung cancer patients.

Immunophenotyping of lymphocytes obtained by bronchoalveolar lavage: description of an all-purpose tricolor flow cytometric application.

A tricolor flow cytometric application is described which permits the determination of total T lymphocytes, T helper lymphocytes and cytotoxic T lymphocytes, natural killer cells and activated T lymphocytes under the same experimental conditions. Even when the lymphocyte count is low, when there is contamination by dust particles or when the cells are damaged the method works with high specificity and reliability. Lymphocytes are identified on the basis of their expression of the pan-leucocyte marker CD45, their side scatter, and plasma membrane integrity, assessed using the fluorescent DNA dye LDS 751. When lymphocyte subsets assessed by flow cytometry were compared with the standard immunoperoxidase method, a strong correlation was found for the CD3+, CD4+ and CD8+ cells. A weak correlation was found for CD25+ cells (r = 0.5). No correlation was seen for CD56+ cells. The high specificity of the procedure suggests that it could be used routinely for the analysis of lymphocytes in bronchoalveolar lavage fluid (BALF), especially when the BALF is contaminated by inorganic particles. Furthermore the application may contribute to the evaluation of lymphocyte subset analysis in the presence of low cell counts.

Immunophenotyping of lymphocytes in bronchoalveolar lavage fluid. A new flow cytometric method vs standard immunoperoxidase technique.

Characterizing lymphocyte subsets in bronchoalveolar lavage fluid (BALF) by flow cytometry (FC) proper gating of the lymphocyte subpopulation being analyzed is crucial. In order to test lymphocyte gate quality for the first time we used a DNA-dye to evaluate plasmamembrane integrity and thus to mark off fluorescent but not DNA-containing particles (eg, debris). A comparative prospective study between this newly developed FC technique and a standard peroxidase anti-peroxidase (PAP) method was performed. Samples of BALF from 50 patients with various pulmonary diseases were examined. After determination of the total cell yield, a differential cell count was performed. Subsequently, the immunophenotype of pan T lymphocyte CD3-, T-helper lymphocyte CD4-, and T-suppressor lymphocyte CD8-positive lymphocyte subsets was assessed with FC as well as with the PAP method. Both methods showed excellent correlation (CD3: r = 0.81; CD4: r = 0.97; CD8: r = 0.96; p < 0.05, respectively). Comparing the mean +/- SEM, FC tends to overestimate CD3+ cells (90.6 +/- 1.0% vs 85.8 +/- 1.3%). For CD4 (45.0 +/- 3.4% vs 44.4 +/- 3.4%) and CD8 (48.1 +/- 3.5% vs 46.7 +/- 3.5%), there was good agreement. In a clinical setting, the reliability of both methods was equivalent, and FC using a DNA-dye to test lymphocyte gate quality offered a rapid and reliable determination of lymphocyte subsets in BAL.

Hospital-acquired candida and aspergillus pneumonia--diagnostic approaches and clinical findings.

Bronchoscopy with bronchoalveolar lavage (BAL), collection of bronchial secretions (BS) and/or high resolution computed tomography (CT) of the lungs was performed in 70 patients with candida and/or aspergillus pneumonia. The sensitivity of bronchoscopy in detecting histologically proven fungal disease was 59%. Characteristic CT signs were found in 11 of 14 patients with candida pneumonia and 16 of 19 patients with aspergillosis. The more frequent use of bronchoscopy and CT scans between 1990 and 1992 compared with 1986-1989 for the differential diagnosis of new pulmonary infiltrates in immunocompromised patients resulted in earlier antifungal treatment (14 vs. nine days; P < 0 center dot 025). In the second treatment period survival was improved from 36 to 50% (not significant). Bronchoscopy and high resolution CT scans are mutually complementary diagnostic tools and should be performed as early as possible in the course of pneumonia in patients at high risk of fungal diseases.

[Experiences with early fibrinolysis in coronary infarct at an acute care hospital. Second report of experiences with 200 patients 1980 to 1985]. / Erfahrungen mit der Frühfibrinolyse bei Koronarinfarkt in einem Akutkrankenhaus. Zweiter Erfahrungsbericht an 200 Patienten der Jahre 1980 bis 1985.

Over the past two decades patients with acute myocardial infarction have been treated with intravenous streptokinase therapy at the hospital in Geldern. Based on experiences in the first study from 1970 to 1979, the second study emphasized instruction on early thrombolytic therapy. Informations were given to general practitioners and to patients at risk for acute myocardial infarction. In the study from 1980 to 1985 the percentage of patients with acute myocardial infarction being treated with thrombolytic agents within two hours after the acute event was 69%. Patients with a duration of ischemia of less than two hours had a significantly decreased in-hospital mortality compared to patients who received therapy more than two hours after onset of symptoms. We conclude that intensified information and instruction of physicians and of patients at risk for myocardial infarction enables early thrombolytic therapy and results in reduced in-hospital mortality of acute myocardial infarction.

[Incidence of ultrasound detectable liver hematomas after ultrasound controlled fine needle puncture with the 0.95 mm cutting biopsy cannula in comparison with percutaneous liver biopsy with the 1.4 mm Menghini needle]. / Inzidenz sonographisch nachweisbarer Leberhämatome nach ultraschallgezielter Feinnadelpunktion mit der 0,95-mm-Schneidbiopsiekanüle im Vergleich zur perkutanen Leberbiopsie mit der 1,4-mm-Menghini-Nadel.

BACKGROUND: Recently, a high incidence of ultrasound-detected hepatic hematomas due to percutaneous liver biopsy has been reported. Until yet, little is known about the incidence of asymptomatic hepatic hematomas following sonographically guided fine-needle biopsy. PATIENTS AND METHODS: For that reason, we carried out a prospective study with sonographic examinations before and after liver biopsy in 160 patients. 51 patients, aged 50 to 83, median 67 years, with focal liver lesions had ultrasound-guided liver biopsy using the 0.95 mm-cut biopsy-needle, in 109 patients (17 to 80, median 49 years) with diffuse liver disease percutaneous liver biopsy with the 1.4 mm-needle of Menghini was performed. RESULT: After fine-needle biopsy none of the 51 patients with focal liver lesions displayed liver hematoma on ultrasonography. In the group of patients who underwent percutaneous Menghini biopsy a liver hematoma, sized up to 12 x 5 cm in diameter, occurred four times (3.7%). CONCLUSION: The results of this study indicate that fine-needle biopsy of the liver is a particularly safe diagnostic procedure, when compared with percutaneous Menghini biopsy.

[Fever, dyspnea]. / Fieber, Atemnot.

A 52-year-old female complained about non-distinct symptoms such as fatigue, night sweats and bone pain. Because of a febrile bronchitis, chest X-ray was performed, which disclosed enlarged hilar nodes and intestinal and acinar pulmonary infiltrates. Endobronchial biopsy and cultures from bronchial aspirate permitted to diagnose infection by legionella concomitant with sarcoidosis. After antibiotic treatment for legionellosis over four weeks, immunosuppressive therapy for sarcoidosis was initiated with glucocorticoids.

[Pneumocystis carinii pneumonia in HIV-positive and HIV-negative patients]. / Pneumocystis-carinii-Pneumonien bei HIV-positiven und -negativen Patienten.

Bronchoalveolar lavage was used in 170 immunocompromised patients for detection of causative agents. Pneumocystis carinii was isolated 18 times from HIV-positive patients and 14 times from patients suffering from immunodeficiencies due to various other diseases. Patients with AIDS were in better clinical condition, had fewer infiltrates on chest x-ray, a higher oxygen partial pressure and lower LDH-plasma concentration than HIV-negative patients. In spite of the earlier stage of the disease patients with AIDS experience prodromal symptoms for a longer time and the number of isolated pneumocystis was larger. Mortality in AIDS patients was significantly lower than in patients with other causes of immunodeficiency.

Can secondary hypertension be identified by twenty-four-hour ambulatory pressure monitoring?

Circadian blood pressure rhythms were examined in subjects exhibiting various forms of secondary and essential hypertension and in normotensive subjects with and without renal disease. Indirect ambulatory blood pressure recordings were performed in 284 subjects for 24 h. In contrast to patients with essential hypertension and to normotensive healthy subjects, the circadian fluctuations of blood pressure were reduced in secondary hypertensives and in normotensive renal patients. In renal hypertensives, these alterations in the diurnal blood pressure variations were dependent on the degree of renal failure. Calculations based on comparisons of the mean sleeping and mean daytime blood pressures identified 89.8% of the essential hypertensives and 72.5% of the patients with secondary hypertension. A large proportion of the patients with secondary hypertension had very high blood pressure levels during sleep, in many cases even exceeding the daytime levels. Thus, 24-h ambulatory blood pressure curves from patients with secondary and essential hypertension can be distinguished from each other. In secondary hypertension, blood pressure monitoring during both day and night is particularly useful for evaluating frequently severe nocturnal hypertension, which may require particular treatment.

[Central sleep apnea syndrome as a cause of impaired wakefulness in multiple myeloma]. / Zentrales Schlafapnoesyndrom als Ursache von Vigilanzstörungen bei multiplem Myelom.

Progressive day-time sleepiness developed in a 73-year-old man for 3 years known to have kappa-light-chain myeloma, treated with radio- and chemotherapy. His powers of concentration and intellectual performance were diminished. Neither clinical nor biochemically was there any indication of abnormal water and electrolyte metabolism or hyperviscosity syndrome. The neurological examination was unremarkable. His wife's observation of nocturnal breathing pauses suggested sleep-related abnormal breathing. Polysomnography showed severe central sleep apnoea: an apnoea index of 60/h and blood oxygen saturations as low as 78%. On biphasic positive airway pressure (BIPAP) ventilation by nasal mask at night the apnoea index fell to 6/h and the symptoms improved. During a break in treatment the day-time sleepiness again increased and regressed once again with BIPAP ventilation. There is a 1-5% prevalence of sleep-related impaired breathing among adults. This condition should thus be considered in the differential diagnosis of characteristic day-time sleepiness.

[Computerized tomography diagnosis of opportunistic lung mycoses]. / Computertomographische Diagnostik der opportunistischen Pneumomykosen.

In 11 patients with opportunistic pneumo-mycosis, computed tomography revealed a predominantly nodular infiltration pattern of the lungs, which revealed particular features that showed a dependence on the species of pathogen involved and the stage of the disease. Computed tomography of the chest proved to be superior to conventional chest films in the clarification of unclear fungal pneumonia in patients on immunosuppressive treatment.

Decrease in arterial oxygen partial pressure within the first 24 h of rhGM-CSF administration in AML patients.

GM-CSF may induce pulmonary complications, such as dyspnea with temporary decreases in oxygen saturation described as first dose effect for higher dosages of intravenous rhGM-CSF. This study investigated possible pulmonary disturbances in adult de novo AML patients receiving yeast rhGM-CSF 24 h prior to chemotherapy under phase II/III conditions. Eighteen patients were monitored for 22 treatment episodes. GM-CSF was given s.c. 1 q.d., 2 q.d. or continuously i.v. at 250 micrograms/m2/d 24 h prior to induction chemotherapy (TAD9, n = 18) and consolidation (TAD9, n = 4). Spirometry, bodyplethysmography, single breath-diffusion capacity (DLCO) and arterial blood gas analyses were obtained prior to GM-CSF, and repeated after 24 h. Pulse oxymetric oxygen saturation (saO2) was registered continuously for the first 16 h within day 1 of rhGM-CSF treatment. Patients were aged 21-75 years. The saO2 monitoring did not reveal any first dose effect. PaO2 values decreased from 78.9 mmHg before GM-CSF to 72.8 mmHg after 24 h (p < 0.01, maximum shift 15 mmHg). PaO2 shifts occurred mainly with pre-existing lowered paO2, but otherwise were independent of age, the route of GM-CSF administration, leukocyte levels, or increase of leukocytes with GM-CSF. Increases in AaDO2 reflected the paO2 shifts (p < 0.05). No dyspnea corresponded to these changes. DLCO values did not decrease significantly after 24 h. Summarily, contemporary dosage of yeast rhGM-CSF avoids short-term oxygen desaturations, but leads to clinically benign impairment in oxygen tension, based on ventilation/perfusion mismatches. This should be taken into account for patients starting at subnormal paO2.

[Bronchoscopic diagnosis of lung infiltrates in immunocompromised patients]. / Bronchoskopische Diagnostik von Lungeninfiltraten bei Patienten mit zellulärer Abwehrschwäche.

Bronchoscopy with bronchoalveolar lavage was undertaken in 21 immunocompromised patients for microbiological and cytological diagnosis. In all of these patients radiologically confirmed pneumonic lesions had developed which, under empirical antibiotic treatment, had progressed or not clearly regressed. In four patients each the causative organisms of the pneumonia were identified as Pneumocystis carinii and Legionella, respectively, and Aspergilla in a further three. Proof of the causative organism in these patients resulted in a change of the antibiotic treatment. The pneumonia was healed in 11 patients. Ten patients died. Early bronchoscopy to identify the causative organism is recommended in immunocompromised patients so that, by administering microorganism-specific treatment, the at present high mortality in this group may be reduced.