Syntheses of 2, 5-dialkylfuran and tetrahydrofuran carbinols and their cytotoxic activity

2, 5-Dialkylfuran and tetrahydrofuran compounds as structural elements of Annonaceae acetogenins like Asitrocinwere synthesized starting from furfural by Grignard reactions, lithiation of the furan ring and addition of aliphatic aldehydes. Hydrogenation of the furan rings over Pd-catalyst gave the corresponding tetrahydrofurans. All resulting compounds showed no or rather less antimicrobial activity against grampositive, gram-negative bacteria and fungi compared to tetracycline or clotrimazol but high cytotoxic activity against HL 60 cell line determined in the MTT assay.     

Relation of left ventricular thickness to age and gender in hypertrophic cardiomyopathy

Left ventricular (LV) wall thickening is the most consistent clinical marker of hypertrophic cardiomyopathy (HC), and characteristically increases substantially during adolescence. In this study, we used 2-dimensional echocardiography to develop a cross-sectional profile of LV wall thicknesses in adult patients with HC. We studied a regional community-based cohort of 239 consecutively enrolled patients (aged 18 to 91 years). On average, maximum LV wall thickness decreased relative to increasing age (p = 0.007) within 4 age groups: 22.8 +/- 5.1 mm (18 to 39 years) to 22.1 +/- 5.1 mm (40 to 59 years) to 21.1 +/- 3.7 mm (60 to 74 years) to 20.8 +/- 3.6 mm (>or=75 years). The LV thickness index (summation of wall thicknesses in all 4 segments) also decreased with age (p = 0.017): 63.0 +/- 12.2 mm to 59.8 +/- 11.9 mm to 58.3 +/- 10.4 mm to 57.9 +/- 9.8 mm. Decreasing magnitude of LV hypertrophy was independently associated with increasing age, but not with other relevant disease variables, such as symptoms and outflow obstruction. However, when separated by gender, this inverse relation between age and LV wall thickness was statistically significant only for women (p = 0.007). In conclusion, in an unselected HC cohort, cross-sectional analysis showed a modest but statistically significant inverse relation between age and LV hypertrophy that was largely gender-specific for women. This association constitutes another facet of the natural history of this complex and heterogenous disease and may reflect disproportionate occurrence of premature death in young patients with HC with marked hypertrophy or possibly gradual LV remodeling.     

Human prefrontal and sensory cortical activity during divided attention tasks

In our natural environment, the ability to divide attention is essential since we attend simultaneously to a number of sensory modalities, e.g., to visual and auditory stimuli. In this study, functional magnetic resonance imaging (fMRI) was used to study brain activation while a divided attention task was performed. Brain activation was also assessed under selective attention. Fourteen healthy male subjects aged between 19 and 28 years underwent fMRI studies using gradient EPI sequences. Cingulate activation was evident in all attention tasks. Focusing attention on one modality (visual or auditory) increased the activity in the corresponding primary and secondary sensory area. When attention is divided between both modalities, the activation in the sensory areas is decreased, possibly due to a limited capacity of the system for controlled processing. Left prefrontal activation, however, was evident selectively during the divided attention task. The present results suggest that this area may be important in the execution of controlled processing when attention is divided between two sources of information. These results support the view that the prefrontal cortex is involved in the central executive system and controls attention and information flow.     

Role of Fas and granule exocytosis pathways in tumor-infiltrating T lymphocyte-induced apoptosis of autologous human lung-carcinoma cells

We have isolated a cytotoxic T lymphocyte (CTL) clone, Heu161, that reacts specifically with the human autologous lung carcinoma cell line IGR-Heu. We first demonstrated that IGR-Heu lacked Fas-receptor expression and was resistant to CD95-induced apoptosis. To further elucidate the role of Fas in tumor immune surveillance, we have stably transfected IGR-Heu with a Fas-expression vector and isolated CD95-sensitive and -resistant clones. Our data indicated that the resistance of 2 selected Fas-transfected clones to CD95-mediated lysis correlated with down-regulation of caspase-8 or its lack of cleavage and subsequent activation. All Fas transfectants, either sensitive or resistant to anti-Fas agonistic antibody, were as efficiently lysed by the CTL clone as the parental cell line. In addition, neither anti-Fas-blocking antibody nor Fas-Fc molecule inhibited T-cell lysis of Fas-sensitive tumor clone. This cytotoxicity was extracellular Ca(2+)-dependent and abolished in the presence of EGTA, indicating that it was mainly granzyme-mediated. Interestingly, although the caspase inhibitor z-VAD-fmk had no effect on tumor-cell lysis, it efficiently blocked target DNA damage triggered by autologous CTLs via the granule exocytosis pathway, indicating that the latter event was caspase-dependent. The present results suggest that lung carcinoma-specific CTLs use mainly a granule exocytosis-dependent pathway to lyse autologous target cells and that these effectors are able to circumvent alteration of the Fas-triggered intracellular signalling pathway via activation of a caspase-independent cytoplasmic death mechanism.     

Lymph Edema of the Lower Extremities after Lymphadenectomy and Radiotherapy for Cervical Cancer

PURPOSE: To assess the incidence of clinical lymph edema after lymphadenectomy and postoperative radiotherapy (RT). PATIENTS AND METHODS: From 1994-2002 192 patients with risk factors for recurrence received radiotherapy with FIGO I (58.8%), II (35.4%), III (4.2%) or IV (1.6%). RT consisted of teletherapy (10.4%), brachytherapy of the vaginal vault (20.8%) or a combination of both (68.8%). Additional chemotherapy was given in 69 patients (35.9%). Surgery comprised laparoscopically assisted radical vaginal hysterectomy (LARVH) (35.4%), radical abdominal hysterectomy (RAH) (48.4%), simple hysterectomy (HE) (11.5%) or exenteration (4.7%). RESULTS: 73 patients had lymph node metastases, 119 had negative lymph nodes. In patients with LARVH 6-74 (median 30) lymph nodes were removed, with RAH 3-70 (median 21 lymph nodes), and after HE or exenteration 5-50 (median 13 lymph nodes). 90 patients had 25 or less lymph nodes removed, 83 patients more than 25 lymph nodes removed. Prognostic factors, such as age, FIGO stages, histologic grading and type of histology were well balanced in these cohorts. 45 (23.4%) of all patients developed clinically relevant lymph edema of the lower limb with a median latency of 11 (1-121) months. When 25 or less lymph nodes were removed 17.8% of patients developed leg edema, when more than 25 lymph nodes were removed 32.5% of patients were diagnosed with lymph edema (p = 0.025). Radiotherapy and chemotherapy had no influence on the incidence of leg edema. Overall survival at 5 (10) years was independent of number of lymph nodes removed. CONCLUSION: The data suggest increasing rates of leg edema with increasing number of lymph nodes dissected independent of the type of radiotherapy and chemotherapy performed. The lymph node sampling policy should be planned carefully in respect to minimize the risk of leg lymph edema.     

Measurements of HCV neutralizing antibodies and of HCV-specific CD4+ and CD8+ cells using hepatitis C virus pseudo-particles (HCVpp)

BackgroundFor the medical management, it would be of great relevance to get a diagnostic marker predicting the outcome of infection.ObjectivesFor this purpose, the envelope antigens of the individual HCV strain in a patient was tested for their capacity to induce neutralizing antibodies and cytotoxic T lymphocytes.Study designA system for the measurement of neutralizing antibodies as well as for the stimulation of a HCV-specific T-cell response using pseudo-typed HCV particles (HCVpp) was established. A report on results of a pilot study conducted with blood specimens of 19 chronically infected patients is also presented.ResultsNeutralization of HCVpp could be measured in nearly all HCV sero-positive patient samples. Nevertheless, in more than half of the patient samples (11/19), no HCV-specific CD4+ response was detectable. In addition, HCV-specific CD8+ response was measurable in most of the patients when HCVpp were used for T-cell stimulation. Although the same antigens (HCVpp) were used, there was no relevant correlation between neutralization titers and T-cell response.ConclusionOur study shows that HCVpp are appropriate antigens for specific stimulation of lymphocytes as well as for the investigation of antibody neutralization activity.     

Vergleichsstudie Soleb?der plus UVA/B versus UVA/B-Monotherapie bei Patienten mit subakuter atopischer Dermatitis

In einer kontrollierten, prospektiven Studie wurde bei Patienten mit subakuter atopischer Dermatitis (AD) die Effektivit?t einer ambulanten Therapie mit Soleb?dern und anschlie?ender UVA/B-Bestrahlung mit einer UVA/B-Monotherapie verglichen. Die Patienten der Photosolegruppe (n=16) wurden mit einer 3- bis 5%igen Solel?sung des definierten synthetischen Salzes „Psori-sal^?” behandelt. Anschlie?end wurden sie wie die UVA/B-Monotherapiegruppe (n=12) einer konventionellen UVA/B-Bestrahlung zugeführt. Nach 20 Behandlungen fand sich in der Photosolegruppe eine gegenüber der UVA/B-Monotherapiegruppe statistisch signifikante Besserung (p≤0.0015) des SCORAD von 69,5 vor auf 36,8 nach Therapie. Die UVA/B-Monotherapie führte hingegen zu keiner signifikanten Besserung des SCORAD von 50,6 vor auf 44,3 nach Therapie. Weiterhin zeigte sich in der Photosolegruppe im Vergleich zur UVA/B-Monotherapie eine deutliche Verringerung der kumulativen UVB-Dosis (Photosolegruppe 0,9 J/cm², UVA/B-Monotherapie 2,0 J/cm²). Die Photosoletherapie zeigte bei den Patienten eine hohe Akzeptanz. Es traten keine Nebenwirkungen auf, sodass diese Behandlungsform das Therapiespektrum bei der subakuten atopischen Dermatitis erweitert.