Vinorelbine and ifosfamide for unresectable non-small cell lung cancer

OBJECTIVE: The diagnostic value of cine magnetic resonance imaging (CMRI) that visualizes fluid and tissue movement was evaluated in patients with spinal intradural arachnoid cysts, a rare but increasingly detected cause of spinal cord dysfunction. METHODS: Four patients with thoracic spinal intradural arachnoid cysts were investigated with conventional T1- and T2-weighted and cardiac-gated CMRI. Four normal volunteers also underwent CMRI for comparison. RESULTS: Sagittal T1- and T2-weighted imaging showed lesions as an abnormal widening of the posterior spinal subarachnoid space, but mixed high- and low-signal intensities on T2-weighted imaging suggested cystic lesions. CMRI, using 16 to 20 sagittal gradient echo images during the cardiac cycle of normal volunteers, indicated synchronous signal changes along the subarachnoid space, suggesting a smooth cerebrospinal fluid flow. CMRI of patients detected that the caudal or cranial direction of the high-signal propagation suddenly reversed at some locations (as if rebounding) in an asynchronous fashion along the lesion (asynchronous rebound phenomenon), which was well demonstrated by the closed-loop video mode. Cystectomy revealed that the cysts consisted of multiple lobules and that the asynchronous rebound phenomenon corresponded with some boundaries of cyst lobules. CMRI also visualized dynamic spinal cord compression by the cyst. CONCLUSION: CMRI can demonstrate abnormal fluid flow and spinal cord compression caused by a spinal intradural arachnoid cyst.     

Apoptotic vascular endothelial cells become procoagulant

Whereas unperturbed endothelial cells provide potent anticoagulant properties, exposure to inflammatory and atherogenic stimuli can rapidly lead to a procoagulant behavior. Because recent studies provide evidence that apoptosis of vascular cells may occur under conditions such as atherosclerosis and inflammation, we investigated whether apoptotic endothelial cells may contribute to the development of a prothrombotic state. In this report, it is shown that both adherent and detached apoptotic human umbilical vein endothelial cells (HUVECs) become procoagulant. Apoptosis was induced by staurosporine, a nonspecific protein kinase inhibitor, or by culture in suspension with serum deprivation. Both methods resulted in similar findings. As assessed by flow cytometric determination of annexin V binding, HUVECs undergoing cell death exhibited typically a more rapid exposure of membrane phosphatidylserine (PS) than DNA fragmentation. Depending on the stage of apoptosis, this redistribution of phospholipids was found to induce an increase of the activity of the intrinsic tenase complex by 25% to 60%. Although apoptotic cells did not show antigenic or functional tissue factor (TF) activity, when preactivated with lipopolysaccharide, TF procoagulant activity increased by 50% to 70%. At 8 hours after apoptosis induction, antigenic thrombomodulin, heparan sulfates, and TF pathway inhibitor decreased by about 83%, 80%, and 59%, respectively. The functional activity of these components was reduced by about 36%, 52%, and 39%, respectively. Moreover, the presence of apoptotic HUVECs led to a significant increase of thrombin formation in recalcified citrated plasma. In conclusion, apoptotic HUVECs, either adherent or in suspension, become procoagulant by increased expression of PS and the loss of anticoagulant membrane components.     

Circulating growth-regulator oncogene alpha contributes to neutrophil priming and interleukin-8-directed mucosal recruitment into chronic lesions of patients with Crohn''s disease

When alpha-hydroxytamoxifen (alpha-OHTAM) was incubated with rat liver hydroxysteroid (alcohol) sulfotransferase a (STa) and 3'-phosphoadenosine 5'-phosphosulfate, (E)-alpha-OHTAM was found to be a better substrate for STa than (Z)-alpha-OHTAM. To explore the formation of tamoxifen (TAM)-derived DNA adducts, DNA was incubated with STa and either (E)-alpha-OHTAM or (Z)-alpha-OHTAM in the presence of 3'-phosphoadenosine 5'-phosphosulfate. Using 32P-postlabeling analysis, the amount of TAM-DNA adducts resulting from (E)-alpha-OHTAM was 29 times higher than that observed with (E)-alpha-OHTAM alone. Using (Z)-alpha-OHTAM and STa, some TAM-DNA adducts were also detected but at levels 6.5 times lower than that observed with (E)-alpha-OHTAM and STa. When compared with standards of stereoisomers of 2'-deoxyguanosine 3'-monophosphate-N2-tamoxifen, the major tamoxifen adduct was identified chromatographically as an epimer of the trans form of alpha-(N2-deoxyguanosinyl)tamoxifen, and the minor adduct was identified as an epimer of the cis form. In the reaction mixture, a conversion from (E)-alpha-OHTAM to (Z)-alpha-OHTAM through the carbocation intermediate was also detected. These results show that sulfation of alpha-OHTAM catalyzed by STa results in the formation of TAM-DNA adducts.     

Prevention of maternal and developmental toxicity in rats via dietary inclusion of common aflatoxin sorbents: potential for hidden risks

The chromosomal translocation t(11;14)(q13;q32) fuses the IGH and CCND1 genes and leads to cyclin D1 overexpression. This genetic abnormality is the hallmark of mantle cell lymphoma (MCL), but is also found in some cases of atypical chronic lymphocytic leukemia (CLL), characterized by a poor outcome. For an unequivocal assessment of this specific chromosomal rearrangement on interphase cells, we developed a set of probes for fluorescence in situ hybridization (FISH). Northern blotting was performed for analysis of the cyclin D1 expression in 18 patients. Thirty-eight patients, with either a typical MCL leukemic phase (17 patients) or atypical CLL with an MCL-type immunophenotype, i.e., CD19-, CD5+, CD23-/low, CD79b/sIgM(D)++, and FMC7+ (21 patients), were analyzed by dual-color interphase FISH. We selected an IGH-specific BAC probe (covering the JH and first constant regions) and a commercially available CCND1 probe. An IGH-CCND1 fusion was detected in 28 of the 38 patients (17 typical MCL and 11 cases with CLL). Cyclin D1 was not overexpressed in two patients with typical MCL and an IGH-CCND1 fusion. In view of the poor prognosis associated with MCL and t(11;14)-positive CLL, we conclude that this set of probes is a valuable and reliable tool for a rapid diagnosis of these entities.     

Cardiovascular function before, during, and after the first and subsequent pregnancies

This study was designed to test the hypothesis that the vascular remodeling of pregnancy begins early, persists for at least 1 year after delivery, and is accentuated by a second pregnancy. Serial estimates of heart rate, arterial pressure, left ventricular volumes, cardiac output, and calculated peripheral resistance were obtained before pregnancy, every 8 weeks during pregnancy, and 12, 24, and 52 weeks postpartum in 15 nulliparous and 15 parous women using electrocardiography, automated manometry, and M-mode ultrasound. During pregnancy, body weight increased 14.5 +/- 1.8 kg and returned to prepregnancy values 1 year postpartum. Heart rate peaked at term 15 +/- 1 beat/min above prepregnancy levels (57 +/- 1 beat/min). Mean arterial pressure reached its nadir (-6 +/- 1 mm Hg) at 16 weeks, returning to baseline at term. The increases in left ventricular volumes and cardiac output (2.2 +/- 0.2 L/min) peaked at 24 weeks as did the 500 +/- 29 dynes x cm x s(-5) decrease in peripheral resistance, and their magnitude was significantly greater in the parous women. Postpartum they gradually returned toward baseline but remained significantly different from prepregnancy values in both groups at 1 year. We conclude that cardiovascular adaptations to the initial pregnancy begin early, persist postpartum, and appear to be enhanced by a subsequent pregnancy. We speculate that persistence of these changes may lower cardiovascular risk in later life.     

Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family

A novel member of the low density lipoprotein receptor (LDLR) gene family has been identified and characterized. This gene, termed LDL receptor-related protein 6 (LRP6), encodes a transmembrane protein which has 71% identity and is structurally similar to the protein encoded by LRP5, a proposed candidate gene for type 1 diabetes located on human chromosome 11q13. LRP6 maps to human chromosome 12p11-p13. Mouse Lrp6 encodes a protein that has 98% identity to human LRP6 and maps to chromosome 6. Unlike other members of the LDLR family, LRP6 and LRP5 display a unique pattern of four epidermal growth factor (EGF) and three LDLR repeats in the extracellular domain. The cytoplasmic domain of LRP6 is not similar to other members of the LDLR family, while comparison with LRP5 reveals proline-rich motifs that may mediate protein-protein interactions. Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family.     

Influence of posture and training on the endurance time of a low-level isometric contraction

Classically, the critical force of a muscle (the relative force below which an isometric contraction can be maintained for a very long time without fatigue) is comprised of between 15 and 20% of its maximum voluntary contraction (MVC). However, some authors believe that the value is below 10% MVC. If such is the case, signs that accompany the establishment of muscle fatigue (EMG changes, continuous increase in systolic blood pressure [SBP] and heart rate [HR]) would have to appear more rapidly and with a higher intensity if the muscle is already partially fatigued at the start of maintaining a contraction at 10% MVC. Twelve healthy untrained participants carried out two isometric contractions with the digit flexors: one (test A) began with a maximum contraction sustained for 4 min followed without interruption by a contraction at 10% MVC for 61 min; the other (test B) was a contraction maintained at 10% MVC for 65 min. For test B, after an initial increase of 4 bpm with respect to at rest, HR remained stable until the end of contraction, SBP progressively increased by 24 mm Hg in 28 min, then remained unchanged until the end, and there were no significant changes in EMG (absence of spectral deviation towards low frequencies). For test A, in spite of the initial maximum contraction, changes in the parameters being studied (total maintenance time, HR, SBP, EMG) during maintenance at 10% MVC were identical to those for test B. The results show that (1) when the number and intensity of the co-contractions are minimized by applying an appropriate posture, it is possible to sustain an isometric contraction at 10% MVC for at least 65 min without the appearance of signs of muscle fatigue; (2) the critical force of the digit flexors is higher than 10% MVC.