3-amino thioacridone inhibits DNA synthesis and induce DNA damage in T-cell acute lymphoblastic leukemia (T-ALL) in a p16-dependent manner

In T-cell Acute Lymphocytic Leukemia (T-ALL), the inhibitors of cyclin-dependent kinases (CDK) 4 and 6, p16 and p15, are inactivated almost universally at the DNA, RNA and protein levels. This suggests that CDK-targeting may be an effective therapeutic approach for T-ALL and other cancers. In this study, we tested 3 inhibitors of CDK4, 3-aminothioacridone (3-ATA), thioacridone (TA), and oxindole, for their effects on DNA synthesis and viability in primary T-ALL. Each compound was an effective inhibitor, with overall IC(50)s in similar ranges. In colony formation assay, leukemic cells were approximately 10-fold more sensitive to 3-ATA than normal bone marrow cells. When sorted by G1 protein status of T-ALL, p16(+), p15(+) or pRb(-) samples were significantly less sensitive to 3-ATA and TA, but not to oxindole, than p16(-), p15(-) or pRb(+) samples. There was no relationship of sensitivity with ARF expression. Despite their in vitro function as inhibitors of CDK4, 3-ATA did not inhibit pRb phosphorylation or cause G1 arrest, but did cause DNA damage and result in the induction and phosphorylation of p53. We conclude that 3-ATA efficacy can be predicted by p16 status in T-ALL, but the mechanism of action may be distinct from their in vitro ability to regulate CDK4 kinase activity     

Gonarthritis due to Salmonella enteritidis in a patient with systemic lupus erythematosus

Extraintestinal manifestations of Salmonella infection occur more frequently in immunocompromised patients than in healthy persons. About 25 % present as septic arthritis. Particularly patients with SLE are predisposed. We report a case of a 16-year old girl with systemic lupus erythematosus who developed septic arthritis of the left knee. Delayed diagnosis because of similar symptoms of arthritis due to lupus and purulent arthritis led to a destruction of the joint despite systemic antibiotic treatment. Seven months later an endoprosthesis was implanted with good outcome. Early diagnosis, adequate antibiotic therapy and, if necessary, surgical intervention are essential for successful treatment. In patients with SLE suffering from fever or arthritis it is necessary to think of infections particularly due to salmonella.     

Experimental investigations onto the biocompatibility of coated vascular grafts as a function of the primary disease in various patients groups

INTRODUCTION: This work presents initial experimental results obtained with co-incubation of human neutrophilic granulocytes from patients with various diseases (5 patients each group) and collagen- or silver-coated polyester grafts (25 patients each graft). METHODS: After two-hour co-cultivation of the graft with human granulocytes of different patients (normal controls; peripheral occlusive vascular disease; diabetes mellitus; carcinoma/chemotherapy; sepsis), the following parameters were determined by flow cytometry: CD11b, CD62L, fMLP, CXCR2. RESULTS: The change in the receptor expression was taken as a measure of responsiveness, with statistically significant differences seen within and between the groups. For the silver-coated graft, such differences were mainly noted for the fMLP receptor (p=0.01). For the two-hour incubation with collagen coating, the receptors CD62L and CXCR2 were indicative of differences between the various diseases (CD62L p=0.01; CXCR2 p=0.01). Comparison between the grafts revealed statistically significant differences for the CXCR2 and the fMLP receptors (CXCR2 p=0.00; fMLP p=0.03). CONCLUSIONS: The differences noted between the grafts and between the patients groups are suggestive of an altered responsiveness of the granulocytes to the grafts. This enables new aspects with respect to the genesis of accompanying clinical symptoms.     

Warfarin and acetaminophen interaction

A 74-year-old man who was receiving warfarin for atrial fibrillation experienced an abrupt increase in his international normalized ratio (INR) after taking acetaminophen. To investigate this effect, the patient's anticoagulation therapy was stabilized, and he was given acetaminophen 1 g 4 times/day for 3 days. His INR rose from 2.3 before receiving acetaminophen to 6.4 on the day after acetaminophen was discontinued. Warfarin was stopped for 2 days, and the patient's INR returned to 2.0. Warfarin was restarted at the same dosage, and his INR remained within 2.0-3.0 for 6 months. Factor VII activity decreased from 29.4% before acetaminophen therapy to 15.5% when his INR was 6.4, and factor X activity fell from 27.0% to 20.2%. His warfarin plasma concentration was 1.54 microg/ml before acetaminophen compared with 1.34 microg/ml when his INR was 6.4. No significant changes in drug intake, clinical status, diet, or lifestyle were noted. Changes in INR of this magnitude with the addition of another drug during stable anticoagulation therapy suggest a drug interaction. The lack of an increase in warfarin plasma concentration associated with the increased INR suggests a possible pharmacodynamic mechanism for this interaction. Acetaminophen or a metabolite may enhance the effect of oral coumarin anticoagulants by augmenting vitamin K antagonism. Thus, the anticoagulant effect of warfarin may be significantly elevated after only a few days of acetaminophen therapy. Patients receiving warfarin should be counseled to have their INR monitored more frequently when starting acetaminophen at dosages exceeding 2 g/day.     

Cytotoxic effect of conjugates of doxorubicin and human chorionic gonadotropin (hCG) in breast cancer cells

Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and doxorubicin alone was investigated compared to doxorubicin in breast cancer cells with and without expression of hCG receptors. Expression of hCG receptor was determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt-PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected in MCF-7 but not in MB231 breast cancer cell line. Cytostatic effect of doxorubicin–hCG conjugates was investigated in these cell lines in comparison to unconjugated doxorubicin. The number of viable cells was determined after 24, 48, 72, 96, and 120 h. To exclude non-specific uptake of the carrier hCG from the culture media, a similar experiment was performed with albumin–doxorubicin conjugates. The number of viable cells decreased in a concentration depending manner after doxorubicin and hCG–doxorubicin conjugate treatment. However, the cytotoxic effect of hCG–doxorubicin conjugate was 10-fold increased compared to unconjugated doxorubin in hCG-receptor positive MCF-7 but not in hCG-receptor negative MB231 cells. Albumin–doxorubicin conjugates showed no increased toxicity compared to doxorubicin. We conclude that the cytotoxic effect of hCG–doxorubicin conjugates is mediated specifically via the hCG receptor. By using hCG conjugates, the development of more selective cytostatics can be achieved.     

Role of hysteroscopy in detection and extraction of endometrial polyps: results of a prospective study

OBJECTIVE: The aim of this study was to determine whether hysteroscopy improves the detection and extraction of endometrial polyps in postmenopausal women. This method was compared with curettage complemented by Randall polyp forceps. STUDY DESIGN: In a prospective study hysteroscopy was performed before and after curettage in postmenopausal women. In addition to curettage, the Randall polyp forceps was used to extract endometrial polyps. Curettage and polyp extraction by Randall forceps were performed by a second surgical team that did not know the results of hysteroscopy. RESULTS: A total of 83 patients were included in the study because of either postmenopausal bleeding (n = 40) or ultrasonographic abnormal endometrium (n = 37), or both (n = 6). Thirty-two patients received either hormone replacement therapy or tamoxifen. Hysteroscopy revealed endometrial polyps in 51 patients. Polyps were diagnosed by curettage alone in 22 (43%) cases. In 18 of these 22 cases remnants of polyps were extracted by Randall forceps, and in another 23 cases polyps were only found by use of the Randall forceps. Thus in 45 (88%) of 51 patients the detection of endometrial polyps by curettage and Randall forceps was possible. A second hysteroscopy procedure revealed remnants of polyps or polyps in 31 cases. These patients with incomplete curettage predominantly had a preoperative endometrial thickness of > or =10mm. CONCLUSIONS: Curettage alone in postmenopausal patients is not sufficient for detection and extraction of endometrial polyps. Additional use of Randall forceps improves detection of polyps considerably. However, with both procedures complete extraction of polyps was not achieved in a considerable number of patients. Hysteroscopy-controlled extraction was superior, especially in those patients with an endometrial thickness of >10 mm.     

Survey of conventional and spiral ct doses

PURPOSE: To investigate the radiation dose for conventional computed tomography (CT) and spiral CT during different CT examinations at various hospitals and practices. MATERIALS AND METHODS: CT dose index with an active length of 15 cm was measured in 16 different types of CT scanners by using ionization chamber dosimetry. Twenty-six holders (one who has legal responsibility under national law for a radiologic installation) operating a total of seven conventional and 20 spiral CT scanners were asked for their standard parameters for various CT examinations. Weighted CT dose index and dose-length product were determined for each examination. RESULTS: For most examinations, the tube current time product was significantly higher for conventional CT than for spiral CT (.002 相似文献   

Multi-slice spiral CT: 3D CT angiography for evaluating therapeutically relevant stenosis in peripheral arterial occlusive disease

PURPOSE: Evaluation of 3D multislice CT angiography for the assessment of relevant stenoses of pelvic arteries and arteries of the lower extremity in patients with peripheral artery occlusive disease compared to digital subtraction angiography. METHOD/MATERIALS: For this study we examined 31 patients with peripheral artery occlusive disease. All patients received a multislice helical CT angiography and arterial digital subtraction angiography. Multislice CT angiography was performed with a Somatom Plus 4 Volume Zoom (Siemens, Erlangen, Germany). After test bolus injection of 20 ml Ultravist 370 (Schering AG, Berlin) additional 150 ml were applied with a flow rate of 3 ml/sec and a scan delay between 20-35 sec depending on individual blood circulation time. Collimation was 4 x 2.5 mm with a pitch of 6. Reconstructed slice thickness was 3 mm. 3D reconstructions of arteries of pelvic and lower extremity arteries were performed in volume rendering technique on a 3D Virtuoso workstation (Siemens, Erlangen). RESULTS: For the assessment of therapeutically relevant stenoses (over 50% reduction of luminal diameter) multislice CT achieved the following results compared to conventional angiography for the diagnosis of stenosis: sensitivity of 86%, specificity of 86% and an accuracy of 72%. CONCLUSIONS: Multislice helical CT angiography of pelvic arteries and arteries of the thigh represents a reliable means for the detection of relevant stenoses in patients with peripheral occlusive artery disease.     

A novel,noncanonical mechanism of cytoplasmic polyadenylation operates in Drosophila embryogenesis

Cytoplasmic polyadenylation is a widespread mechanism to regulate mRNA translation that requires two sequences in the 3′ untranslated region (UTR) of vertebrate substrates: the polyadenylation hexanucleotide, and the cytoplasmic polyadenylation element (CPE). Using a cell-free Drosophila system, we show that these signals are not relevant for Toll polyadenylation but, instead, a “polyadenylation region” (PR) is necessary. Competition experiments indicate that PR-mediated polyadenylation is required for viability and is mechanistically distinct from the CPE/hexanucleotide-mediated process. These data indicate that Toll mRNA is polyadenylated by a noncanonical mechanism, and suggest that a novel machinery functions for cytoplasmic polyadenylation during Drosophila embryogenesis.