Prevention and diagnosis of delayed haemolytic transfusion reactions.
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Anemia↗
Biomedical subjects
T Koski
Publications and source records attributed to T Koski.
Spinal cord compression in beta-thalassemia: case report and review of the literature.
STUDY DESIGN: A case report of thoracic spinal cord compression in a 34-year-old male with beta-thalassemia is reported. OBJECTIVES: In patients with thalassemia, neurologic complaints should lead to a high index of suspicion for spinal cord compression from marrow expansion, ectopic bone formation and resultant stenosis. Initial presentation, diagnosis, radiographic findings, surgical treatment and follow-up are reviewed. SETTING: This case is reported from Chicago, Illinois. METHOD: A chart review is performed for the purposes of this case report. RESULTS: Patient underwent decompressive laminectomy with good surgical outcome. CONCLUSION: Rapid diagnosis and treatment of such a condition is essential to optimize the chances of recovery.
Adult↗
A fragment library based on Gaussian mixtures predicting favorable molecular interactions.
Here, a protein atom-ligand fragment interaction library is described. The library is based on experimentally solved structures of protein-ligand and protein-protein complexes deposited in the Protein Data Bank (PDB) and it is able to characterize binding sites given a ligand structure suitable for a protein. A set of 30 ligand fragment types were defined to include three or more atoms in order to unambiguously define a frame of reference for interactions of ligand atoms with their receptor proteins. Interactions between ligand fragments and 24 classes of protein target atoms plus a water oxygen atom were collected and segregated according to type. The spatial distributions of individual fragment - target atom pairs were visually inspected in order to obtain rough-grained constraints on the interaction volumes. Data fulfilling these constraints were given as input to an iterative expectation-maximization algorithm that produces as output maximum likelihood estimates of the parameters of the finite Gaussian mixture models. Concepts of statistical pattern recognition and the resulting mixture model densities are used (i) to predict the detailed interactions between Chlorella virus DNA ligase and the adenine ring of its ligand and (ii) to evaluate the "error" in prediction for both the training and validation sets of protein-ligand interaction found in the PDB. These analyses demonstrate that this approach can successfully narrow down the possibilities for both the interacting protein atom type and its location relative to a ligand fragment.
Algorithms↗
Longitudinal effects of high-dose chemotherapy and autologous stem cell transplantation on quality of life in the treatment of metastatic breast cancer.
This study determined the effects of high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide (CTX) and mitoxantrone (MXT), with dose escalation of paclitaxel. Longitudinal QL data were collected using the functional living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9 and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients were feelings of hardship on themselves and their families, followed by psychological functioning and physical functioning problems. The time around diagnosis of the metastatic disease and following HDCT were the worst times for all levels of quality of life, but anxiety and depression symptoms continued to increase in severity across the entire follow-up period. The symptoms that were most problematic were worry about the future, loss of sexual interest, anxiety about the treatment, general worrying, and joint pain. These data highlight the problems that women with metastatic breast cancer encounter at different stages of the disease and treatment process, and can be used to tailor psychosocial interventions appropriate for treating the relevant issues at different points in time.
Adolescent↗
Cyclosporin A-induced cell kill in vitro in various clinical-hematological types of B-cell chronic lymphocytic leukemia.
We investigated whether a known T cell modulator, Cyclosporin A (CyA) is also toxic to chronic lymphocytic leukemia (B-CLL), in vitro. In contrast to seven other drugs and two types of irradiation the dose-response curves for CyA were very steep among the 36 CLL patients investigated, and the intraindividual variation of ID(80) values was remarkably lower. The mode of CyA-induced cell death was 'apoptotic-like' as indicated by flow cytometric analysis, revealing cell condensation and annexin positivity. The partially smeary DNA fragmentation pattern together with the relatively slow process of cell death revealed a distinctive pattern of cell death in CLL. Leukemia cells from patients at an advanced clinical stage, of a diffuse histologic type and showing fast progression were the most sensitive to CyA. These new observations may have therapeutic implications in CLL.
Aged↗
Minimizing stochastic complexity using local search and GLA with applications to classification of bacteria.
In this paper, we compare the performance of two iterative clustering methods when applied to an extensive data set describing strains of the bacterial family Enterobacteriaceae. In both methods, the classification (i.e. the number of classes and the partitioning) is determined by minimizing stochastic complexity. The first method performs the minimization by repeated application of the generalized Lloyd algorithm (GLA). The second method uses an optimization technique known as local search (LS). The method modifies the current solution by making global changes to the class structure and it, then, performs local fine-tuning to find a local optimum. It is observed that if we fix the number of classes, the LS finds a classification with a lower stochastic complexity value than GLA. In addition, the variance of the solutions is much smaller for the LS due to its more systematic method of searching. Overall, the two algorithms produce similar classifications but they merge certain natural classes with microbiological relevance in different ways.
Algorithms↗
Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro.
The cytotoxicity of vincristine in vitro was investigated in B chronic lymphocytic leukemia (CLL) cells and in normal peripheral blood mononuclear cells. An approximately 25-fold selectivity towards leukemic vs. normal lymphocytes was demonstrated. Cells from patients having a mature subtype (CLL or CLL/mix) or a slowly progressing form of CLL were significantly more sensitive to vincristine in vitro than the cases with a CLL/PL phenotype or faster-progressing disease. Depending on the vincristine dose, the number of dead CLL cells accumulated slowly during the 4-d observation period. Our data indicate a marked individual variation in vincristine susceptibility among individual CLL cells. Vincristine induced annexin positivity, nuclear blebbing and DNA fragmentation in CLL cells. These indicate an "apoptosis-like" cell death. Since CLL cells are in the G0/G1 phase of the cell cycle, the only known mode of anticancer action of vinca alkaloids, i.e. anti-mitotic action, cannot explain the death of CLL cells. Furthermore, similar cellular uptake and efflux of vincristine by normal and CLL cells excluded pharmacokinetic differences as a cause of selectivity of vincristine towards leukemic lymphocytes. Immunostaining of filamentous structures of CLL cells revealed that vincristine brings about selective changes in alpha-tubulin but not in beta-actin or vimentin. Although the antitubulin action of vinca alkaloids in the biochemical sense is well demonstrated, this kind of anticancer effect has not previously been shown. Vincristine is used in several regimens for CLL, but its efficacy in CLL has never been demonstrated in a clinical context and its value in routine CLL chemotherapy has been questioned. The present data strongly support the need for further evaluation of the role and mode of action of vincristine in chemotherapy of CLL and other cancers as well.
Aged↗
Complex chromosomal aberrations in chronic lymphocytic leukemia are associated with cellular drug and irradiation resistance.
Drug resistance is a major problem in chemotherapy of chronic lymphocytic leukemia (CLL). The genetic basis and molecular pathogenesis of drug resistance in CLL remain poorly understood. Here, we have investigated the association between chromosomal aberrations and cellular resistance of CLL cells against seven drugs, gamma and ultraviolet irradiation. Samples were obtained from 35 patients having a classical form of B-CLL. Chromosomal aberrations were first analyzed by traditional karyotyping improved by using optimized mitogen combinations. DNA sequence copy number changes throughout the genome were next screened by comparative genomic hybridization. Finally, fluorescence in situ hybridization was used to detect trisomy 12 and loss of Rb and deletions at chromosome 11. The cellular sensitivity in vitro was assessed by the reduction of macromolecular protein synthesis measured as incorporation of radioactive L-leucine as an endpoint. The overall analysis disclosed a statistically highly significant difference in cellular drug resistance between patients having at least three aberrations compared with patients with fewer or no aberrations. This strongly indicates that complex rather than simple molecular mechanisms are responsible for the drug and irradiation resistance in CLL. According to published results, complex aberrations are constantly associated with poor prognosis in CLL. We demonstrated here that complex chromosomal aberrations were associated with cellular irradiation and drug resistance, which, on the other hand, may be responsible for the poor clinical outcome in CLL.
Aged↗
Interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-6 plasma levels and cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic parameters.
BACKGROUND AND OBJECTIVE: The growth of B-cell chronic lymphocytic leukemia (B-CLL) cells has been shown to be dependent on exogenous growth factors in vitro. We wanted to evaluate the clinical relevance of interleukin (IL)-6, IL-1 beta and interleukin-1 receptor antagonist (IL-1Ra) in B-CLL. As the plasma levels of IL-6, IL-1 beta and IL-1Ra have been suggested to be partly dependent on gene polymorphism, the previously described polymorphisms of the IL-1 complex genes and the IL-6 gene were also studied. DESIGN AND METHODS: The plasma levels of these cytokines were measured in a cohort of 36 patients with B-CLL and in 400 healthy subjects. The previously described polymorphisms of the IL-1 complex genes and the IL-6 gene were studied using PCR and RFLP. These data was correlated with other parameters associated with severity and prognosis of B-CLL and a number of clinical and laboratory findings. RESULTS: The plasma concentrations of IL-1 beta and IL-1Ra were lower in B-CLL patients than in normal controls (p < 0.001). The IL-1 beta plasma levels were dependent on the cell immunophenotype score and state of progression of the disease. Moreover, plasma concentrations of IL-6 were elevated in B-CLL patients compared with healthy subjects (p < 0.005) and correlated with disease stage, hemoglobin levels, anemia and erythrocyte sedimentation rate in the patients. The allele frequencies of the analyzed genes were similar in patients and controls. INTERPRETATION AND CONCLUSIONS: Our data demonstrate that in B-CLL, plasma levels of IL-1 beta, IL-1Ra and IL-6 differ from normal, and mechanisms other than allelic imbalance of their genes account for the distinct cytokine profiles observed in this disease.
Aged↗
Calcium antagonists potentiate P-glycoprotein-independent anticancer drugs in chronic lymphocytic leukemia cells in vitro.
BACKGROUND AND OBJECTIVES: A major obstacle to the successful use of chemotherapy in the treatment of leukemia and other cancers is the emergence of drug resistance. One of the most studied resistance mechanisms is mediated by P-glycoprotein, which can be modulated by calcium channel blockers. Here we investigated whether the Ca(2+) channel blockers verapamil and nifedipine are toxic alone and in combination with P-glycoprotein-independent anticancer drugs against chronic lymphocytic leukemia (CLL) cells in vitro. DESIGN AND METHODS: Verapamil cytotoxicity was investigated in peripheral blood samples of 35 patients with B-cell CLL and 10 healthy control subjects. Cytotoxicity was assessed in in vitro 4-day cultures using 14C-leucine incorporation as an indicator of cell viability. Interactions were tested with Ca2+ channel blockers and cyclosporine or 7 anticancer drugs: (i) chlorambucil, (ii) 2-chlorodeoxyadenosine, (iii) cisplatin, (iv) fludarabine, (v) prednisolone, (vi) adriamycin, and (vii) vincristine. The mode of cell death was assessed by annexin binding and DNA ladder formation. RESULTS: Verapamil induced dose- and time -dependent death of CLL cells in vitro. A statistically significant effect (p = 0.0085) was noted with as little as 4 microM verapamil. The mode of cell death was apoptotic as determined by annexin positivity and condensation of verapamil-treated cells. Verapamil effectively potentiated the toxicity of cyclosporine and all the anticancer drugs mentioned above. Furthermore, nifedipine, a more specific L-type calcium channel antagonist, significantly potentiated the effect of chlorambucil against CLL cells. Interpretation and Conclusions. Calcium channel blockers enhance the effect of P-glycoprotein-independent anticancer drugs remarkably. This indicates that the death signals initiated by calcium depletion and anticancer drugs together facilitate cell death. This novel finding opens a new avenue to modulate, by using calcium channel antagonists, the effect of traditional anticancer drugs having different mechanisms of P-glycoprotein-independent action.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Bayesian predictive identification and cumulative classification of bacteria.
In this paper we give a mathematically precise formulation of an old idea in bacterial taxonomy, namely cumulative classification, where the taxonomy is continuously updated and possibly augmented as new strains are identified. Our formulation is based on Bayesian predictive probability distributions. The criterion for founding a new taxon is given a firm theoretical foundation based on prediction and it is given a clear-cut interpretation. We formulate an algorithm for cumulative classification and apply it to a large database of bacteria belonging to the family Enterobacteriaceae. The resulting taxonomy makes microbiological sense.
Bacteria↗
Chemosensitivity in vitro to 2-chlorodeoxyadenosine and 9-beta-D-arabinofuranosyl-2-fluoroadenine in previously unexposed cases of chronic lymphocytic leukemia.
The chemosensitivity of leukemia cells, obtained from the peripheral blood of 35 patients with B-cell chronic lymphocytic leukemia, was determined by a leucine-incorporation assay in vitro. There was good correlation between the sensitivities to two purine analogs, 2-chlorodeoxyadenosine and 9-beta-D-arabinofuranosyl-2-fluoroadenine among previously untreated patients when tested at the 80% inhibition level. Previous exposure to chlorambucil did not affect the sensitivity to these compounds.
Antineoplastic Agents↗
Stochastic complexity as a taxonomic tool.
In this paper we propose a method of constructing a hierarchical classification based on the notion of stochastic complexity. Minimization of stochastic complexity amounts to maximization of the information content of the classification. A dendrogram is obtained by first finding the classification which minimizes stochastic complexity and then by step-wise merging of groups such that at each step there is a minimum loss of information. The method was applied to a database containing 5313 strains of Enterobacteriaceae. The results are in reasonable accordance with present-day views on the taxonomy of Enterobacteriaceae.
Enterobacteriaceae↗
A phase I trial of high-dose paclitaxel, cyclophosphamide and mitoxantrone with autologous blood stem cell support for the treatment of metastatic breast cancer.
The aim of this phase I study was to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of a new combination of cyclophosphamide (6 g/m2), mitoxantrone (70 mg/m2), with dose escalation of paclitaxel (TaxolR) at a starting dose of 250 mg/m2 given intravenously over 3 h in a transplantation setting. Patients with metastatic breast cancer and chemosensitive disease were eligible. The autologous blood stem cell re-infusion and subsequent recovery occurred in an out-patient setting. 50 patients were enrolled, but 10 withdrew. 40 completed the entire protocol. At 400 mg/m2 paclitaxel administered over 3 h, 3 of 6 patients experienced serious adverse events: approximately 20-40 min after completion of infusion, diaphoresis, bradycardia mild hypotension and diarrhoea occurred; 2 patients lost consciousness for a few minutes. An extended infusion schedule delivering 400 mg/m2 paclitaxel over 6 h rather than 3 h was initiated at this level without patients experiencing this DLT. At the next dose of 450 mg/m2 paclitaxel over 6 h, the same DLT was seen as at 400 mg/m2 paclitaxel over 3 h and, therefore, MTD was reached. Time to recovery for the absolute neutrophil count > or = 0.5 x 10(9)/l was 10-19 days (median 12 days); and for platelets > or = 20 x 10(9)/l was 18-20 days (median 11.5 days). 21 patients developed neutropenic fever that required intravenous antibiotics and re-admission; the transfusion frequency for packed red blood cell was 0-5 units (median 2 units) and for platelets, 1-5 encounters (median 2). 13 complete responses, 1 patient with no evidence of disease and 19 partial remissions were documented. The dose of 400 mg/m2 at an infusion rate of 6 h will be used for the ongoing phase II study to evaluate efficacy and toxicity further.
Adult↗
[Heparin induced thrombocytopenia and thrombosis].
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Coronary Artery Bypass↗
Bi-weekly vincristine, epirubicin and methylprednisolone in alkylator-refractory multiple myeloma.
Nine patients with poor-prognosis, alkylator-refractory stage III multiple myeloma (MM) were treated with a 23-h continuous infusion (CI) of a compatible mixture of vincristine (VCR) and epirubicin (EPI) daily for 4 days along with a daily 1-h infusion of high-dose methyl prednisolone (MP) to total of 5 days (VEMP); cycles were repeated every 2 weeks when possible, usually on an outpatient basis. WHO grade 3 or 4 neutropenia and infection were the predominant toxicities encountered, necessitating some treatment delays and dose reductions. Two patients died during treatment. Peripheral neuropathy necessitated discontinuation of the VCR in six patients without obvious loss of efficacy of the regimen. Skeletal muscle dysfunction and cardiomyopathy did not occur; trivial ECG abnormalities occurred during a minority of infusions but were of indeterminate relationship to the chemotherapy. Confusion occurred in two patients; alopecia was frequent but reversible, and mild/moderate dyspepsia and stomatitis were common but easily managed. Eight patients achieved a partial response (PR); another patient experienced early death during his second cycle before response assessment. The median survival from the first VEMP administration was 9 months (range, 1-64 + months), the median response duration was 7 months (range, 1-64 + months). Two patients experienced responses too short to be clinically relevant (< or = 2 months). An analysis of weekly paraprotein estimations suggests that the intended bi-weekly cycle length may be optimal. Six of these nine patients derived major benefit from this bi-weekly regimen, which deserves further exploration.
Aged↗
Port-a-caths in cancer patients.
We report on 91 patients with cancer who underwent the insertion of 89 venous and 4 hepatic arterial, implanted vascular ports (Port-a-caths) for periods of up to 33 months (total 1,525 patient-months). There were 1 fatal, 9 serious and 8 minor complications in 18 patients which are described and discussed. In this series, complications were more common in younger patients, and infection was rare. Port-a-caths are extremely useful for vascular access, and have a low complication rate. However, the occasional occurrence of serious and even fatal complications suggests that the decision to insert a device should be judiciously weighed.
Adolescent↗
About familial defective release of t-PA.
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Adult↗