Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.     

Use of monoclonal antibodies to identify cerebrospinal fluid lymphoblasts in children with acute lymphoblastic leukemia

The identification of small numbers of leukemic cells in the cerebrospinal fluid (CSF) presents a diagnostic problem in the treatment of children with acute lymphoblastic leukemia (ALL). We adapted a latex sphere rosetting technique to allow us to identify simultaneously cell surface markers and cell morphology in 199 CSF samples from 34 patients and 14 control subjects. In patients without leukemic meningitis, the majority of CSF lymphocytes (69%) were found to be mature T cells positive for OKT11. A much smaller number of cells (8%) were found to be B cells positive for la. In these children, only 3% of CSF lymphoid cells expressed the common acute lymphoblastic leukemia antigen (CALLA). Similar results were found in the control subjects. By contrast, 28 CSF samples from nine children with varying numbers of CSF lymphoblasts had much greater proportions of CALLA- and la-positive CSF cells (24% to 96%). Leukemic meningitis was present in one of these patients and later developed in four others. However, three patients with small numbers of lymphoblasts present but with low proportions of CALLA-positive CSF cells (less than 5%) subsequently had normal CSF examinations. We found the use of this rosetting technique valuable in providing information complementary to that obtained from cell morphology alone about the possible malignant nature of small numbers of lymphoblast-like CSF cells seen on cytocentrifuge preparations in children with ALL.     

Optical imaging and electrophysiology of rat barrel cortex. I. Responses to small single-vibrissa deflections

A study was undertaken to investigate the response of the rodent somatosensory barrel cortex to single-whisker, near-threshold vibrissal stimuli. Cortical responses to controlled whisker deflections were recorded by (i) conventional multi-unit extracellular recording within the cytochrome oxidase rich barrels centers and the interbarrel septa, and (ii) intrinsic signal optical imaging, a technique that provides a spatial view of cortical activation thought to be related to the deoxygenation of hemoglobin in activated areas. Barrel cortex neurons responded weakly to whisker deflections of 0.04 degrees. Their response to a series of small stimuli of increasing amplitude was well-fitted by a logarithmic function. Responses to larger stimuli declined monotonically with distance from the center of the barrel column, and were characterized by greater onset and offset firing rates, by greater post-excitatory reduction of firing to below spontaneous levels, and by shorter response latency. In comparison to measurements taken previously from primary vibrissal afferent fibers, we conclude that cortical cells can respond to activity in a very small fraction of first-order sensory neurons.      

Ultrasound of the whole breast utilizing a dedicated automated breast scanner

Innovations in design of a dedicated breast scanner resulted in automation of the scanning process, the production of high resolution images of the whole breast and an efficient mode of image review. The results of clinical evaluation of the prototype of this breast scanner investigating normal breasts as well as benign and malignant breast lesions are presented.     

Randomized And Parallel Algorithms For Distance Matrix Calculations In Multiple Sequence Alignment

Multiple sequence alignment (MSA) is a vital problem in biology. Optimal alignment of multiple sequences becomes impractical even for a modest number of sequences [1] since the general version of the problem is NP-hard. Because of the high time complexity of traditional MSA algorithms, even today's fast computers are not able to solve the problem for large number of sequences. In this paper we present a randomized algorithm to calculate distance matrices, which is a major step in many multiple sequence alignment algorithms. The basic idea employed is sampling (along the lines of [2]). We also illustrate how to parallelize this algorithm. In Section 1 we introduce the problem of multiple sequence alignments. In Section 2 we provide a discussion on various methods that have been employed in the literature for Multiple Sequence Alignment. In this section we also introduce our new sampling approach. We extend our randomized algorithm to the case of non-uniform length sequences as well. We show that our algorithms are amenable to parallelism in Section 3. In Section 4 we back up our claim of speedup and accuracy with empirical data and examples. In Section 5 we provide some concluding remarks.