Thermal motions in bacteriorhodopsin at different hydration levels studied by neutron scattering: correlation with kinetics and light-induced conformational changes

Bacteriorhodopsin (BR) is a transmembrane protein in the purple membrane (PM) of Halobacterium salinarum. Its function as a light-driven proton pump is associated with a cycle of photointermediates which is strongly hydration-dependent. Using energy-resolved neutron scattering, we analyzed the thermal motions (in the nanosecond-to-picosecond time range) in PM at different hydration levels. Two main populations of motions were found that responded differently to water binding. Striking correlations appeared between these "fast" motions and the "slower" kinetic constants (in the millisecond time range) of relaxations and conformational changes occurring during the photocycle.     

Painless, red-violet skin lesions during immunosuppression

A patient with painless, bluish-red skin lesions under immunosuppressive treatment for kidney transplantation is presented. The clinical and histological diagnosis was Kaposi's sarcoma. This is a rare but serious complication in the immunocompromised patient. Human Herpes virus 8 (HHV 8) was recently found in the lesions from patients with Kaposi's sarcoma. This supports the important role of immunosuppression in the development of this tumor. Therapy consists of reduction or stopping of the immunosuppressive drugs which is usually followed by reduction in tumor mass. Local skin tumors can be treated with irradiation or laser therapy. In the case of lesions of visceral organs chemotherapeutic regimens consisting of vinicristine/bleomycin are indicated. New strategies aim to reduce the virus load with antiviral drugs or to inhibit the angiogenesis of this highly vascularized tumor.     

Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients

OBJECTIVE: To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors. DESIGN AND SETTING: Retrospective study in two German tertiary care treatment centres. PATIENTS: A total of 198 HIV-infected patients treated with protease inhibitors in 1996. MAIN OUTCOME MEASURES: Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures. RESULTS: A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001). CONCLUSION: An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.     

Development of a Cryogenic Detector for Coherent Neutrino Nucleus Scattering

In Coherent Neutrino Nucleus Scattering (CNNS) the neutrinos interact coherently with all nucleons leading to a cross section which is much larger than for all other neutrino interactions. Because of the small momentum transfer as well as the small recoil energy in CNNS, and the relatively low count rate, a low energy threshold and a large target mass (several hundred grams) are required to observe CNNS. Our aim is to build a cryodetector for that purpose. Such a cryodetector, installed in the vicinity of a nuclear power plant, could probe new physics like non-standard neutral current interactions or a neutrino magnetic moment. We describe the results of three detectors, with Ge absorbers of 0.8 and 3.2 g and with a CaWO₄ absorber of 10 g. For Ge (0.8 g) an energy threshold of 0.43 keV and an energy resolution of 0.27 keV at ∼6 keV could be reached. We demonstrate that surface roughness effects deteriorate both threshold and resolution. For the 10 g CaWO₄ absorber we obtained 0.27 keV and 0.35 keV for threshold and energy resolution at ∼6 keV respectively.      

The value of endoscopic treatment for ureteroceles during the neonatal period

PURPOSE: We report a series of 35 neonates presenting with ureterocele diagnosed during the antenatal period or during the first weeks of life. The first line treatment was an endoscopic incision. MATERIALS AND METHODS: Immediate postnatal evaluations detected 37 ureteroceles (bilateral in 2 cases), including 16 of the intravesical type and 21 that were ectopic. Endoscopic incision permitted decompression of the majority of ureteroceles and improvement in renal function in most cases. Secondary low grade vesicoureteral reflux appeared in 9 neonates (ectopic in 8 cases) and had already been present in 14 patients. RESULTS: Endoscopic treatment alone proved effective in 14 of the intravesical ureteroceles, while the other 2 cases requiring upper pole nephrectomy (1) and ureterovesical reimplantation using the Cohen technique (1). In contrast, among patients with the ectopic form additional surgery was necessary in 18 cases. Treatment comprised resection of the ureterocele with bladder reconstruction and ureteral reimplantation without remodeling according to the Cohen technique in 15 cases, total ureteronephrectomy in 1 and pole nephrectomy in 2. CONCLUSIONS: We suggest that early endoscopic incision be used for first line treatment of ureteroceles. The aim of this procedure is to ensure better urine drainage, preserve function of the parenchyma and reduce the risk of severe infection in the neonate. The principal complication remains secondary vesicoureteral reflux onset, which can be controlled well by antibiotic prophylaxis but requires regular radiological monitoring.     

Chute Aerators. I: Air Transport Characteristics

Chutes with flow velocities in excess of some 20 to 30 m/s are usually prone to cavitation damage. Therefore, these flows are aerated using chute aerators. The current literature describes the aerator efficiency mainly in terms of the air entrainment coefficient as the ratio of the entrained air and the water discharges. However, this global coefficient neither specifies the air distribution nor its detrainment rate. The present investigation focuses on the flow structure and the air transport downstream of chute aerators. Systematic hydraulic model tests were conducted including a data analysis of the spatial air concentration distribution in both the near and the far aerator fields. Based on these, three flow zones were introduced, namely: (1) jet zone; (2) reattachment and spray zone; and (3) far-field zone. It was further found that aerators have primarily an effect on the average air concentration, whereas the increase of the bottom air concentration is typically small.     

Chute Aerators. II: Hydraulic Design

Chute aerators are applied if cavitation damage on spillways is expected or observed. The aerator efficiency is usually described with the ratio of the air discharge entrained through the air supply ducts and the water discharge, which does however not account for the resulting air concentration distribution within the flow or for air detrainment. The present study investigates the streamwise development of the air transport along the flow downstream of chute aerators. Based on an extensive test program in which six governing parameters were systematically varied, the development of the average and the bottom air concentrations is provided up to the self-aeration point. Based on this information, an optimization of aerators in terms of increased air entrainment and reduced detrainment rates is possible, by assuming minimum required air concentrations. The main parameters influencing the air transport downstream of aerators are the approach flow Froude number, the deflector angle and the chute bottom angle.     

Junction Flow between Drop Shaft and Diversion Tunnel in Lyss, Switzerland

A diversion tunnel is planned for flood protection in the City of Lyss, Switzerland. This tunnel includes a junction, from which water from a side creek is added to the tunnel flow. The latter is sensitive to choking, so that the junction had to be optimized in a hydraulic laboratory investigation. Its setup finally consists of a drop shaft and an injector generating annular flow in the tunnel. Free surface tunnel flow then occurred for all relevant discharges. This setup is also of interest in sewer systems as well as in spillway and diversion tunnels, where similar problems may occur. The concept was optimized for a specific prototype. General recommendations may be derived for similar situations.     

Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study

PURPOSE: This multicenter, randomized phase III clinical trial evaluated the efficacy of etoposide plus carboplatin (EC) versus etoposide plus cisplatin (EP) in good-risk germ cell tumor (GCT) patients. PATIENTS AND METHODS: Between October 1986 and December 1990, 270 patients with good-risk GCTs were randomized to receive four cycles of either EP or EC. The etoposide dose in all patients was 100 mg/m2 on days 1 through 5. EP patients received cisplatin at 20 mg/m2 on days 1 through 5 and therapy was recycled at 21-day intervals. For EC patients, the carboplatin dose was 500 mg/m2 on day 1 of each cycle and the EC recycling interval was 28 days. RESULTS: Two hundred sixty-five patients were assessable: 131 patients treated with EC and 134 treated with EP. One hundred fifteen of 131 assessable patients (88%) treated with EC achieved a complete response (CR) versus 121 of 134 patients (90%) treated with EP (P = .32). Sixteen patients (12%) treated with EC relapsed from CR versus four patients (3%) treated with EP. Therefore, 32 patients (24%) who received carboplatin experienced an event (incomplete response [IR] or relapse) compared with 17 of 134 patients (13%) who received cisplatin (P = .02). At a median follow-up of 22.4 months, event-free and relapse-free survival were inferior for patients treated with EC (P = .02 and P = .005, respectively). No difference in overall survival was evident (P = .52). CONCLUSION: Two-drug therapy with EC using this dose and schedule was inferior to therapy with EP. Cisplatin remains as the standard platinum analog in the treatment of patients with good-risk GCTs. Carboplatin should be restricted to investigational trials in GCT.     

Upregulation of alpha GM-CSF-receptor in nonatopic asthma but not in atopic asthma

BACKGROUND: Intrinsic asthma is characterized by an increased number of activated eosinophils and macrophages and an increased expression of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in the bronchial mucosa. OBJECTIVE: This study was carried out to investigate the expression of alpha GM-CSF receptor (alpha GM-CSFr) messenger RNA and protein in the bronchial mucosa of patients with intrinsic or atopic asthma and of control subjects and to correlate the expression of alpha GM-CSFr to the number of EG2+ cells (eosinophils) and CD68+ cells (macrophages) and pulmonary function. METHODS: Nineteen patients with stable asthma (9 with atopic and 10 with intrinsic asthma) and 22 normal control subjects (12 atopic and 10 nonatopic subjects) were recruited, and FEV1 (percent predicted) and PC20 were measured before bronchoscopy. Endobronchial biopsy specimens were obtained and examined for membrane-bound alpha GM-CSFr by using in situ hybridization and immunocytochemistry. RESULTS: alpha GM-CSFr mRNA- and protein-positive cells were identified in biopsy specimens from all four groups studied. There was no significant difference in the number of cells expressing alpha GM-CSFr mRNA and protein in patients with atopic asthma compared with atopic and nonatopic control subjects. However, the numbers of alpha GM-CSFr mRNA- and protein-positive cells were significantly higher in nonatopic patients with asthma compared with atopic patients with asthma and atopic and nonatopic control subjects (p < 0.001). In the patients with intrinsic asthma, the number of alpha GM-CSFr mRNA-positive cells per millimeter of basement membrane correlated with numbers of CD68+ cells (r2 = 0.87, p < 0.001) but not with EG2+ cells, and colocalization studies demonstrated that 80% of the cells expressing alpha GMCSFr mRNA were CD68+. The expression of GM-CSF was also significantly increased in patients with intrinsic asthma compared with those with atopic asthma and control subjects (p < 0.05). In addition, in intrinsic asthma, there was a correlation between alpha GM-CSFr mRNA and FEV1 (r2 = 0.61, p < 0.05). CONCLUSION: These results demonstrate that elevated numbers of cells expressing alpha GM-CSFr can be detected in nonatopic asthma but not in atopic asthma and suggest that this increased expression is predominantly macrophage-associated and may play an important pathophysiologic role in intrinsic asthma.