Gesundheit und Frühe Hilfen: Die intersektorale Kooperation im Blick der Forschung

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A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia

The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or cell death) and microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to DNA breaks to facilitate DNA strand break repair. Pre-clinical data suggest that PARP inhibitors (PARPi) may potentiate the effects of radiotherapy and chemotherapy. However, it is unclear as to whether PARPi are effective against hypoxic cells. We therefore tested the role for a novel PARPi, ABT-888, as a radiosensitizing agent under hypoxic conditions. Using human prostate (DU-145, 22RV1) and non-small cell lung (H1299) cancer cell lines, we observed that ABT-888 inhibited both recombinant PARP activity and intracellular PARP activity (86% to 92% decrease in all 3 cells lines following 2.5muM treatment). ABT-888 was toxic to both oxic and hypoxic cells. When ABT-888 was combined with ionizing radiation (IR), clonogenic radiation survival was decreased by 40-50% under oxic conditions. Under acute hypoxia, ABT-888 radiosensitized malignant cells to a level similar to oxic radiosensitivity. To our knowledge, this is the first study to demonstrate that inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of IR-PARPi has the potential to improve the therapeutic ratio of radiotherapy.     

Perfusion imaging of the kidney using contrast-enhanced phase-inversion ultrasound

PURPOSE: We evaluated different techniques of contrast-enhanced phase-inversion ultrasound to visualize renal perfusion. MATERIALS AND METHODS: Levovist contrast-enhanced phase-inversion ultrasound with different levels of mechanical index and frame rate was performed in 20 kidneys. Analysis using a software algorithm for time-resolved perfusion imaging was compared to single-image analysis performed by three independent radiologists. RESULTS: Optimal depiction of renal perfusion was achieved only by using a mechanical index which was high enough to destroy the microbubbles of the contrast agent (burst imaging) combined with a low frame rate (0.5 images/second). Renal cortex and medulla showed a homogeneous enhancement. Computer-assisted time-resolved perfusion analysis was applicable; it did not show additional Information to single-image analysis. CONCLUSION: Renal perfusion can be visualized using contrast-enhanced phase-inversion ultrasound. For depiction of bigger vessels, it is equal to B-mode ultrasound or Doppler mode techniques; however, it is superior for visualization of renal parenchymal perfusion.     

Three-dimensional imaging of the inner ear by volume-rendered reconstructions of magnetic resonance data

OBJECTIVE: To evaluate 3-dimensional inner ear visualization by volume rendering of high-resolution magnetic resonance data in patients with clinically suspected inner ear abnormality. DESIGN: Prospective comparative study of different postprocessing techniques, based on blinded film readings. SETTING: Tertiary referral hospital. SUBJECTS: Fifty patients (17 females and 33 males) aged 1 to 77 years (average age, 42 years) with sensorineural hearing loss, vertigo, and/or tinnitus. INTERVENTION: Postprocessing of magnetic resonance data to inner ear reconstructions by the use of volume rendering as well as maximum-intensity projection; caloric testing by electronystagmography. MAIN OUTCOME MEASURES: Film was read blindly by 4 radiologists using a 5-point parameter scale for image quality and diagnostic value. The assessibility of inner ear subsegments was evaluated. The specificity of volume-rendered reconstructions for detecting semicircular canal obliterations was assessed in a subgroup of 9 patients by caloric testing. The time required for data postprocessing as well as film reading was recorded by means of a stopwatch. RESULTS: Volume-rendered inner ear reconstructions were superior in image quality (P<.001), diagnostic value (P<.001), subsegment inner ear assessment (P<.01 to P<.001), and film reading time (P<.001) compared with maximum-intensity projections. The data postprocessing time was comparable for both techniques. Caloric weakness was noted in all patients assessed by electronystagmography. CONCLUSION: Volume rendering is the postprocessing technique of choice for 3-dimensional inner ear visualization, performing better than maximum-intensity projections with respect to various parameters.     

Characterization of clinical Streptococcus pneumoniae strains from Germany with decreased susceptibility to fluoroquinolones

Fourteen pneumococcal strains isolated in three nationwide studies were characterized for amino acid changes in the enzymes GyrA, GyrB, ParC and ParE, and for the in vitro activity of eight fluoroquinolones and the new non-fluorinated quinolone BMS 284756. Gemifloxacin and BMS 284756 exhibited the best in vitro activity against all 14 isolates tested. In nine of the 14 isolates mainly classical alterations in ParC (D83N/Y, S79Y/F), as well as rarer alterations such as S80P and D78N, contributed to the decreased susceptibility to fluoroquinolones. In two of the 14 isolates the classical alteration in GyrA (S81F) was found. In only one isolate did alterations in ParC and GyrA exist in parallel.     

Behavioural and microdialysis study after neurotoxic lesion of the dorsal raphe nucleus in rats

The study investigated the effects of a 5,7-dihydroxytryptamine (5,7-DHT) lesion of the dorsal raphe nucleus (DRN) on anxiety-related behaviour and neurochemical correlates in rats. Behaviour was assessed in the elevated plus maze test (X-maze). Lesion of the DRN reduced markedly 5-HT levels in projection areas by at least 60%. Destruction of the serotonergic neurons in the DRN changed neither anxiety-related behaviour on the elevated plus maze, nor aversion-induced 5-HT release in the brain. Exposure of the lesioned rats to the elevated plus maze increased extracellular 5-HT (148%) in the ventral hippocampus similar as in sham-lesioned (162%) and non-lesioned (160%) controls. The results demonstrate that lesioning of 5-HT neurons in the DRN does not abolish totally the control of anxiety-related behaviour.     

Improved Results after Repair of Complete Atrioventricular Septal Defect

Abstract  Background: This study evaluates the historical impact on the outcomes of early primary repair of complete atrioventricular septal defect (AVSD) at our institute. Methods: Since 1976, a total of 185 children with complete AVSD have been referred to our unit. Prior to 1990, 78 children received conservative therapy, and selected 51 patients underwent surgical repair (group 1). After 1990, all referred children underwent surgical repair (n = 56; group 2). Pre- and postoperative parameters were analyzed and compared among the groups. Results: Age at operation was 15.4 ± 20.4 versus 9.9 ± 18.0 months in group 1 and group 2, respectively. Association with Down syndrome (53% vs. 82%; p < 0.01) and with patent ductus arteriosus (16 vs. 34%; p < 0.05) was less frequent in group 1. No difference was seen regarding preoperative pulmonary vascular resistance index (RPI). Actuarial survival at 15 years has improved in group 2 (69.3 ± 6.7 vs. 90.8 ± 3.9%; p < 0.05). Freedom from reoperation of the left atrioventricular valve at 15 years was not significantly different (78.8 ± 6.8 vs. 90.6 ± 4.7%; p = 0.23). Risk factor analysis identified an RPI >6.0 WU/m² as a risk for early death. Conclusion: By operating on the patients with complete AVSD earlier and not excluding patients with Down syndrome, recent results had definitely improved over the last decades. Despite this positive result, a high RPI exceeding 6 WU/m² still remains a risk factor for early mortality independent of early primary repair.