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Biomedical subjects

M E Cabrera

Publications and source records attributed to M E Cabrera.

At least 19 recordsLinked to original sources
PubMed2006

Nasal natural killer/T-cell lymphoma and its association with type "i"/XhoI loss strain Epstein-Barr virus in Chile.

BACKGROUND: Nasal T/natural killer (NK)-cell lymphoma is an aggressive type of non-Hodking's lymphoma associated with Epstein-Barr virus (EBV) and striking geographical variations worldwide. AIM: To characterise nasal NK/T-cell lymphoma associated with genotypes of EBV in Chile, a Latin American country, where multiple strains of EBV, including two new recombinant strains, in healthy individuals were recently found. METHODS: Cases with diagnosis of primary nasal lymphoma were selected for histological and immunohistochemical analysis (CD3, CD3e, CD4, CD8, CD79a, CD56, CD57 and TIA-1) and in-situ hybridisation, serology and genotyping analysis for EBV. RESULTS: Out of 22 cases, 9 (41%) cases fulfilled the World Health Organization criteria for nasal NK/T-cell lymphoma; of these 7 (78%) cases were positive for EBV. Genotyping analysis revealed 6 cases of type 1 EBV and wildtype F at the BamHI-F region, 4 cases type "i" EBV at the BamHI-W1/I1 region; XhoI wild type was found in 2 and XhoI loss in 4 cases, respectively. Cosegregation analysis of the BamHI-W1/I1 region and XhoI restriction site showed the new recombinant strain type "i"/XhoI loss in 3 cases and type "i"/XhoI wild-type strain in 1 case. Most patients were treated with combined anthracycline-containing regimens. Half of the cases attained complete remission. CONCLUSION: Although nasal NK/T-cell lymphomas from Chile share similar clinicopathological features, high association with EBV and unfavourable prognosis with those described elsewhere, genotype analysis shows that the new recombinant type "i"/XhoI loss strain might contribute to explain the intermediate incidence of nasal NK/T-cell lymphomas in Latin America.

Adult↗
PubMed2006

Relating pulmonary oxygen uptake to muscle oxygen consumption at exercise onset: in vivo and in silico studies.

Assessment of the rate of muscle oxygen consumption, UO(2m), in vivo during exercise involving a large muscle mass is critical for investigating mechanisms regulating energy metabolism at exercise onset. While UO(2m) is technically difficult to obtain under these circumstances, pulmonary oxygen uptake, VO(2p), can be readily measured and used as a proxy to UO(2m). However, the quantitative relationship between VO(2p) and UO(2m) during the nonsteady phase of exercise in humans, needs to be established. A computational model of oxygen transport and utilization--based on dynamic mass balances in blood and tissue cells--was applied to quantify the dynamic relationship between model-simulated UO(2m) and measured VO(2p) during moderate (M), heavy (H), and very heavy (V) intensity exercise. In seven human subjects, VO(2p) and muscle oxygen saturation, StO(2m), were measured with indirect calorimetry and near infrared spectroscopy (NIRS), respectively. The dynamic responses of VO(2p) and StO(2m) at each intensity were in agreement with previously published data. The response time of muscle oxygen consumption, tauUO(2m) estimated by direct comparison between model results and measurements of StO(2m) was significantly faster (P < 0.001) than that of pulmonary oxygen uptake, tauVO(2p) (M: 13 +/- 4 vs. 65 +/- 7 s; H: 13 +/- 4 vs. 100 +/- 24 s; V: 15 +/- 5 vs. 82 +/- 31 s). Thus, by taking into account the dynamics of oxygen stores in blood and tissue and determining muscle oxygen consumption from muscle oxygenation measurements, this study demonstrates a significant temporal dissociation between UO(2m) and VO(2p) at exercise onset.

Adolescent↗
PubMed2004

Step and ramp induction of myocardial ischemia: comparison of in vivo and in silico results.

This study tested the robustness of our computational model of myocardial metabolism by comparing responses to two different inputs with experimental data obtained in pigs under similar conditions. Accordingly, an abrupt and a gradual reduction in coronary flow of similar magnitude were implemented and used as model input. After flow reductions reached 60% from control values, ischemia was kept constant for 60 min in both groups. Our hypotheses were that: (1) these two flow-reduction profiles would result in different transients (concentrations and flux rates) while having similar steady-state values and (2) our model-simulated responses would predict the experimental results in an anesthetized swine model of myocardial ischemia. The two different ischemia-induction patterns resulted in the same decrease in steady-state MVO2 and in similar steady-state values for metabolite concentrations and flux rates at 60 min of ischemia. While both the simulated and experimental results showed decreased glycogen concentration, accumulation of lactate, and net lactate release with ischemia, the onset of glycogen depletion and the switch to lactate efflux were more rapid in the experiments than in the simulations. This study demonstrates the utility of computer models for predicting experimental outcomes in studies of metabolic regulation under physiological and pathological conditions.

Animals↗
PubMed2001

Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion.

Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across different countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (n = 266) were selected from inpatients and outpatients at hospitals serving the same populations. MLL rearrangement status was derived by Southern blot analysis, and maternal exposure data were obtained by interviews using a structured questionnaire. Apart from the use of cigarettes and alcohol, very few mothers reported exposure to known topo-II inhibitors. Significant case-control differences were apparent for ingestion of several groups of drugs, including herbal medicines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonsteroidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygon). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemias (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whether these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required.

Acute Disease↗
PubMed2001

[Clinical significance and frequency of the 11q23/MLL genetic molecular alteration in Chilean infants with acute leukemia].

BACKGROUND: Acute leukemia (AL) in infants generally shows distinctive biologic features and has a poor prognosis. AIM: To study the frequency of the cytogenetic alteration of 11q23 chromosome or the recombination of MLL gene in infants less than 18 months old, with acute leukemia. PATIENTS AND METHODS: We analyzed 37 cases of AL in infants less than 18 months of age diagnosed in Chile from 1989 to 1999. The clinical features and cytogenetic/molecular defects of 11q23MLL gene rearrangement and their influence in prognosis were determined. RESULTS: There were 18 cases of acute Lymphoblastic leukemia (ALL) characterized by female sex (67%) high presenting leukocyte count (median 99 x 109/L), blast cells with a CD10 negative phenotype (50%) and 11q23/MLL rearrangement (39%). Molecular abnormalities of 11q23 were significantly associated with adverse prognosis, with an event free survival (EFS) of only 14 +/- 12%. Interestingly, infants with germ line 11q23 had a very good outcome with an EFS of 73 +/- 11% (p < 0.025). There were 19 cases of acute myeloblastic leukemia (AML) characterized by male sex (63%) high leukocyte count (median 93 x 109/L), FAB-MS morphology (53%) and 11q23/MLL rearrangement (53%). EFS was very poor, 20 +/- 9% and 33 +/- 4% for rearranged and germinal group respectively (p = NS), due to a high mortality rate during the first month of diagnosis. CONCLUSIONS: These findings demonstrate that Chilean ALL infants with 11q23 abnormalities have a very poor prognosis. However those with germinal state can enjoy a prolonged disease free survival with the current treatment protocols.

Blotting, Southern↗
PubMed2000

[Acute myeloid leukemia in the adult. Results of the National Antineoplastic Drug Protocol at the Hospital del Salvador, 1990-1998].

BACKGROUND: The incidence of acute myeloid leukemia is 3 cases per 100,000 inhabitants/year and its five years event free survival is 15 to 20%. Since the incorporation of trans retinoic acid, event free survival of M3 acute myeloid leukemia is 80%. AIM: To report the results of acute myeloid leukemia treatment at the Hospital del Salvador, between 1990 and 1998. PATIENTS AND METHODS: The medical records of 117 patients (66 female, mean age 48.2 years), treated between 1990 and 1998 using PANDA protocol, were retrospectively reviewed. Immunophenotyping was done in 69 patients and cytogenetic studies were done in 65. RESULTS: Sixteen percent of patients had M3 acute myeloid leukemia. The most frequent phenotype was the association of DR, CD34 plus a panmyeloid marker. DR and CD34 were negative in seven of nine patients with M3 acute myeloid leukemia. Cariotype was abnormal in 78% of patients. Complete remission was achieved in 65% of cases with a 13% of failures. Early mortality was 21.3% and decreased to 6.1% in the last three years. Infections and coagulation disorders were the main causes of death. Mean survival was 10.5 months. Five years event free survival was 11%. In M3 acute myeloid leukemia, the figure is 50%. CONCLUSIONS: Treatment results are less effective than protocols that consider more aggressive chemotherapeutic protocols or bone marrow transplantation. The reduction in early mortality is due to a better management of febrile neutropenia.

Adolescent↗
PubMed1999

Improved outcome for acute lymphoblastic leukemia in children of a developing country: results of the Chilean National Trial PINDA 87.

BACKGROUND: The National Chilean Pediatric Oncology Group, PINDA, reports the first prospective, nonrandomized trial for acute lymphoblastic leukemia (ALL), using a modified version of the Berlin-Frankfurt-Munster protocol (ALL BFM 86). The aim of this study was to classify immunophenotypes, to decrease cranial irradiation, and to assess whether this protocol would improve the survival rate. PROCEDURE: From June, 1987, to June, 1992, 444 unselected children were diagnosed with ALL. Of them, 425 were evaluable. Therapy was stratified by risk. Standard-risk (SR) and high-risk (HR) patients received protocols I, M, II, and maintenance therapy. Very-high-risk (VHR) patients received protocol E instead of protocol M. All patients received a prephase treatment consisting of prednisone and intrathecal methotrexate (MTX). HR and VHR patients received cranial irradiation (12-18 Gy). The following changes were made to the ALL BFM 86 protocol: in protocol M, MTX 1 g/m2 instead of 5 g/m2; in protocol E, citarabine 1 g/m2 instead of 2 g/m2; mithoxantrone and ifosfamide were substituted by teniposide and cyclophosphamide. RESULTS: Immunophenotypes: pro-B-ALL, 14%; common ALL, 67.4%; pre-B-ALL, 4.3%; T-ALL, 10%; undifferentiated leukemia (AUL), 4.3%. The overall 5-year event-free survival (EFS) rate was 60% +/- 2% (SE). The 5-year EFS rate for each risk group was: SR 75%, HR 62%, VHR 28%, with a median follow-up of 6.5 years (range 4.5-9.5 years). The cumulative incidence of central nervous system (CNS) relapse was 5.4%. CONCLUSIONS: We have been able successfully to perform a nationwide study. Our strategy to adapt the BFM protocol to our population of patients trial was effective in improving the EFS. The immunophenotype distribution is similar to that in other reported series.

Adolescent↗
PubMed1999

A model analysis of lactate accumulation during muscle ischemia.

PURPOSE: The mechanistic basis of the relationship between tissue [O2] and tissue or blood lactate (LA) concentration during tissue hypoxia are not fully understood. However, blood and tissue lactate accumulation are still used as indicators of tissue hypoxia in critically ill patients. To investigate this relationship, we applied a previously developed mathematical model of human bioenergetics to simulate the integrated responses (cellular, tissue, and whole body) to moderate (10% to 45%) and severe (50% to 80%) reductions in muscle blood flow. MATERIALS AND METHODS: Model simulations of muscle ischemia predicted metabolite concentration changes in muscle, splanchnic bed, and other tissues, and were compared with experimental data in humans for model validation. RESULTS: In general, simulations closely predicted the pattern of change in substrates and control metabolites to that observed experimentally. Specifically, simulations showed that most of the increase in muscle LA production during moderate ischemia was due to an increase in pyruvate (PY) and notto the change in redox state induced by a small decrease in O2 consumption. However, during severe ischemia, changes in [LA]/[PY] ratio in venous blood corresponded very closely to changes in tissue redox state. Because both blood [LA] and [LA]/[PY] tracked changes in tissue redox state very well, these can be used reliably as indices of tissue hypoxia during severe muscle ischemia. CONCLUSIONS: Based on the simulations, the commonly used threshold value for venous [LA]/[PY] = 14 as evidence of tissue hypoxia seems appropriate during severe ischemia.

Computer Simulation↗
PubMed1999

HTLV-I induced intestinal lymphoma.

We document an unusual case of HTLV-I positive adult T-cell leukaemia lymphoma (ATLL) in a 25 year old Chilean patient who presented with primary small intestinal involvement and during evolution developed a leukaemic phase. Duodenal biopsy showed infiltration by pleomorphic lymphoid cells with a CD45RO+ CD20- phenotype. Circulating lymphocytes had a convoluted nucleus and displayed a mature T-cell phenotype: CD2+, CD3+, CD4+, CD8-, CD25+, HLA-Dr+. HTLV-I serology was positive and HTLV-I retroviral sequences were demonstrated by PCR in the tissue. The patient was treated with chlorambucil and is well, disease free five years from diagnosis. Intestinal lymphoma as initial manifestation of ATLL is extremely uncommon, but when a T-cell lymphoma is detected in this localisation, in patients from a HTLV-I endemic area, retroviral studies are recommended in order to exclude an association with this retrovirus.

Adult↗
PubMed1999

Lactate metabolism during exercise: analysis by an integrative systems model.

To provide a framework for quantitative analysis of metabolic and transport processes associated with ATP production during exercise, we adapted a recently developed model that links cellular metabolism and its control to whole body responses at rest. The enhanced model is based on dynamic mass balances for glycogen, glucose, pyruvate (PY), lactate (LA), O(2), and CO(2) and is solved numerically to simulate responses to acute (<20 min), moderate exercise (i.e., below the LA threshold, less than approximately 60% maximal rate of O(2) uptake). Simulations of responses to a step change in muscle ATP turnover predict substrate changes in muscle, splanchnic, and other tissues compartments, as well as changes in other metabolites (e.g., NADH, ADP) whose reactions are coupled to the main reactions. Even a significant (64%) decrease in muscle O(2) concentration (C(m, O(2))) did not affect muscle O(2) consumption. Model simulations of moderate exercise show that 1) muscle oxygenation is sufficient (C(m, O(2)) >2 mM) even during the transient state; 2) transient increases in concentration of muscle LA and arterial concentration of LA are associated with increases in glycolysis from increases in ADP/ATP and in LA production associated with a rise in NADH/NAD; 3) muscle ADP/ATP reaches a higher steady state that stimulates glycolysis, glycogenolysis, and oxidative phosphorylation to match the ATP demand; and 4) muscle NADH/NAD reaches a lower steady state that stimulates LA oxidation. It is suggested that the continuous stimulation of ATP synthesis processes during moderate exercise is mainly due to a higher ADP/ATP, not to a higher NADH/NAD. Critical measurements needed to quantify metabolic control mechanisms are identified.

Adenosine Triphosphate↗
PubMed1999

[Adult T cell leukemia lymphoma in Chile. A clinical pathologic and molecular study of 26 patients].

BACKGROUND: Adult T cell leukemia lymphoma is a lymphoproliferative syndrome etiologically associated to human T cell lymphotropic virus type I. AIM: To describe the clinical and laboratory features of 26 Caucasian Chilean patients, with HTLV-I positive adult T-cell leukemia lymphoma (ATLL). MATERIAL AND METHODS: Diagnostic criteria included clinical features, cell morphology, immunophenotype, HTLV-I serology and/or DNA analysis by Southern blot or PCR. RESULTS: According to the clinical presentation, 12 cases had the acute ATLL form, 6 had a lymphoma, 4 the chronic form and 4 had smoldering ATLL. The median presentation age was 50 years, younger than the Japanese patients, but significantly older than patients from other South American countries (e.g. Brasil, Jamaica, Colombia). The main clinical features: lymphadenopathy, skin lesions and hepatosplenomegaly, were similar in frequency to those of patients from other countries, except for the high incidence of associated neurological disease. Tropical Spastic Paraparesis (TSP) in our series of ATLL, was seen in one third of the patients (8/26). A T-cell immunophenotype was shown in all 26 cases and HTLV-I serology was positive in 25/26 patients. Molecular analysis on the seronegative patient showed clonal integration of proviral HTLV-I DNA into the lymphocytes DNA, and thus he may have been a poor responder to the retroviral infection. Proviral DNA integration was also demonstrated in 15/16 patients being clonal in 10, polyclonal in 3 (all smoldering cases) and oligoclonal in one. CONCLUSIONS: ATLL in Chile has similar clinical and laboratory features than the disease in other parts of the world, except for a younger age than Japanese patients but older than those from other Latin American countries and a high incidence of patients with associated TSP. Detailed morphological and immunophenotypic analysis of the abnormal circulating lymphocytes, together with the documentation of HTLV-I by serology and/or DNA analysis are key tests for the identification of this disease.

Acute Disease↗
PubMed1998

[Priapism in a patient with chronic myeloid leukemia].

Priapism is a rare complication of hematological diseases. Among leukemia, it is most frequently seen in patients with chronic myeloid leukemia, due to the high leukocyte counts that these patients achieve. We report a 22 years old male who presented with a priapism lasting more than 24 hours. Thirty six hours after admission and subsequent to a leukopheresis, penile relaxation was obtained. Despite good hematological response to therapy, an extensive penile and uretral necrosis, associated to an Acinetobacter infection, ensued between the fourth and fifth day of admission, that required surgical treatment.

Adult↗
PubMed1998

[Results of the National Protocol for Antineoplastic Drugs in the treatment of adult acute lymphoblastic leukemia. Experience at the Hospital del Salvador, 1990-1997].

BACKGROUND: Acute lymphoblastic leukemia has a different evolution in children and adults. Complete remission is achieved in 70-85% of the latter, but only 25 to 35% have a prolonged disease-free survival. AIM: To assess the treatment outcome of adults with acute lymphoblastic leukemia in Chile. PATIENTS AND METHODS: A retrospective review of the medical files of 51 adults with acute lymphoblastic leukemia treated according to the national protocol for antineoplastic drugs, in a public hospital of Santiago. RESULTS: Mean age of patients was 35.9 years old and 53% were younger than 20 years old. Complete remission was achieved in 64%. Early mortality occurred in 22%, mostly due to infections. Treatment failure occurred in 16%. Global survival was 17 months and global survival at 5 years was 24%. Prognostic criteria of the protocol, defined a low risk group that had a complete remission of 100%, no early deaths and 5 year disease-free survival of 53%. The group defined as having high risk had a complete remission of 47%, a 29% early mortality and a 5 years disease-free survival of 6%. CONCLUSIONS: Aiming to improve treatment results in acute lymphoblastic leukemia, efforts should be made to improve the management of febrile neutropenic patients and to intensify chemotherapy.

Adult↗
PubMed1996

Discordant clinical presentation and outcome in infant twins sharing a common clonal leukaemia.

We report the different presentation features and clinical outcome between two identical infant twins with acute lymphoblastic leukaemia with a shared clonal disease and MLL gene rearrangement. One twin relapsed and died, but the other is in complete remission > 4 years after diagnosis. These data, and similar observations on other twin infants with leukaemia, suggest that despite a common clonal in utero, post-natally these leukaemias can evolve independently, at different rates, in the twinned individuals, and that the usually fatal leukaemia associated with t(4;11) MLL gene rearrangement can be effectively treated when the leukaemic burden is small.

Bone Marrow↗
PubMed1996

On the existence of a lactate threshold during incremental exercise: a systems analysis.

The relationship between blood lactate concentration ([La]) and O2 uptake (VO2) during incremental exercise remains controversial: does [La] increase smoothly as a function of VO2 (continuous model), or does it begin to increase abruptly above a particular metabolic rate (threshold model)? The dynamic characteristics of the underlying physiological system are investigated using system identification analysis techniques. A multivariate deterministic time series model of the [La] and VO2 response to incremental changes in work rate was fitted to simulated and experimental data. Time-varying system response parameters were determined through the application of a weighted recursive least squares algorithm. The model, using the identified time-varying parameters, provided a good fit to the data. The variation of these parameters over time was then examined. Two major transitions in the parameters were found to occur at intensity levels equivalent to 53 +/- 8% and 77 +/- 9% maximal VO2 (experimental data). These changes in the model parameters indicate that the best linear dynamic model that fits the observed system behavior has changed. This implies that the system has changed its operation in some way, by altering its structure or by moving to a different operating region. The identified parameter changes over time suggest that the exercise intensity range (from rest to maximal VO2) is divided into three main intensity domains, each with distinct dynamics. Further study of this three-phase system may help in the understanding of the underlying physiological mechanisms that affect the dynamics of [La] and VO2 during exercise.

Exercise↗
PubMed1996

Analysis of the complementary determining region III of the immunoglobulin heavy chain locus in acute lymphoblastic leukemia in Chilean children.

We have analyzed the sequence of 40 VDJ rearrangements of the immunoglobulin heavy chain gene locus on 32 unselected children from Chile with precursor B cell ALL at diagnosis. Rearrangements were derived by PCR with VH gene family-specific primers and sequenced directly. The number of VDJ rearrangements, and the pattern of VH, DH and JH gene usage was identical to the one reported by groups from developed countries. CDR3 regions represented an unbiased repertoire; VH to JH joinings were in frame in 36% of cases. Absent N nucleotides in the DJ border, suggestive of fetal origin of ALL, were seen in 9/40 rearrangements but they did not correlate with younger age. More than one rearrangement was sequenced in six patients, representing independent events with no signs of clonal evolution. One patient was analyzed at first bone marrow relapse showing persistence of one rearrangement and evolution of a second one which conserved the DJ border. The subset of B cell precursors which suffer malignant transformation to ALL appear to be common in different parts of the world.

Adolescent↗