Biomedical subjects
Publications and source records attributed to J Maldonado.
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Although more than 50% of Hodgkin's disease patients are cured with conventional chemotherapy, many will relapse and eventually die from their disease. Many efforts have been made to identify poor prognostic factors that could be useful in selecting high-risk patients in 1st CR who may benefit from high-dose chemo/radiotherapy. However, the role of early transplantation in 1st CR remains unclear. We have retrospectively analyzed the results obtained with this procedure in 22 hospitals belonging to the Spanish GEL/TAMO cooperative group. Twenty-seven patients, of whom 19 were males, underwent autologous transplantation for Hodgkin's disease in 1st CR between January 1987 and January 1996. Remission had been achieved after one (n = 22) or two (n = 5) lines of treatment. Twenty-four patients had advanced stage disease, 12 patients bulky mediastinal disease, nine bone marrow involvement and 18 had extranodal disease. Peripheral blood was used as the source of hematopoietic stem cells in 15 patients, BM in nine, and both in three. All but three patients received chemotherapy-based conditioning regimens (16 CBV, four BEAM and four BEAC), while three were conditioned with CY and TBI. There were no transplant-related deaths. Median (range) times to recover >0.5 x 10(9)/l neutrophils and >50 x 10(9)/l platelets were 14 (8-56) days and 16 (8-240) days, respectively. With a median follow-up of 30 (8-66) months, 21 patients are alive and in continuous CR. Four patients who relapsed after transplant at 8, 17.5, 22 and 26 months achieved a second CR with conventional chemotherapy; one patient relapsed 92 months post-transplant and died 5 months afterwards. Another patient died 30.5 months post-transplant from a secondary malignancy. In conclusion, high-dose therapy in poor prognosis Hodgkin's disease in 1st CR was well tolerated with no transplant-related mortalities. Although the follow-up of this series is relatively short, our results seem promising. Nevertheless, late relapses can occur, and the role of this procedure vs conventional treatment in very high-risk patients should be assessed in prospective randomized studies.
AIMS: To study the circadian variation of BP in diabetics with chronic late complications (autonomic neuropathy, peripheral neuropathy and macroangiopathy of the lower limbs). PATIENTS AND METHODS: We studied 35 NIDDM patients, 22 male and 13 female, with a mean age of 62.17 +/- 8.66 years, all with hypertension (HBP) or with BP levels close to normal, many of them under anti-hypertensive therapy (mean BP in clinical measurements: 164 +/- 23.16 mmHg systolic and 92.14 +/- 11.06 mmHg diastolic). Twenty-four suffer from autonomic neuropathy, 23 from peripheral neuropathy and 11 from macroangiopathy of the lower limbs. The control group is composed of 10 patients with essential HBP without other observable pathology, with a mean age of 68.5 +/- 3.63 years and BP in clinical measurements: systolic 192 +/- 15.49 mmHg and diastolic 88 +/- 4.21 mmHg (without any previous therapy). The record of the BP circadian profile was made, with the use of a Spacelab monitor, model 90207, 5 days after anti-hypertensive therapy was suspended. RESULTS: The mean BPs in 24 hours were: control group-systolic BP 152.6 +/- 13 mmHg and diastolic 79.8 +/- 13 mmHg; diabetics-systolic BP 136.82 +/- 15 mmHg and diastolic 77.4 +/- 8 mmHg. The daily and nocturnal mean BPs were 158.5 +/- 8.5 and 146 +/- 8.4 mmHg (systolic) and 82.8 +/- 5.7 and 70.9 +/- 5.1 mmHg (diastolic) in the control group, while they were, in diabetics, 141.3 +/- 15.7 and 135.6 +/- 16.6 mmHg (systolic) and 79.6 +/- 7.1 and 72 +/- 8.2 mmHg (diastolic). In diabetic patients, considering the groups with and without autonomic neuropathy, the difference between daily and nocturnal mean BP was 1.6 vs 9.4 mmHg systolic and 4.9 vs 9.4 mmHg, diastolic. CONCLUSIONS: In both groups, the mean BP levels in 24 hours were notoriously lower than those obtained from the clinical measurements: the differences were 40 mmHg (control group) and 27.2 mmHg (diabetics) for systolic BP and 8.2 mmHg (control group) and 14.7 mmHg (diabetics) for diastolic. The BP circadian profiles show a lower variability, with absence of the nocturnal reduction, specially evident in diabetic patients with autonomic neuropathy versus other groups.
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The purposes of the present study have been to analyse the presenting features, response to therapy and survival of myeloma patients aged 70 years or more, in comparison to younger patients. From January 1985 to December 1989, 487 patients with multiple myeloma (MM) were randomized to receive melphalan and prednisone (MP) versus alternating cycles of vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) and vincristine, BCNU, adriamycin, and prednisone (VBAP). The subset of 178 patients who were 70 or more years is the subject of this study, whereas the 309 patients younger than 70 years were used as a control group. The presenting features and response to chemotherapy of older patients were no different to those of the younger population. However, the survival of elderly patients was significantly shorter (median 23.4 vs. 33.5 months, p < 0.001). The overall response rate to MP in older patients was 50% (28% objective plus 22% partial response) compared with 61% (44% objective plus 17% partial response) to combination chemotherapy (p = not significant). Myelosuppression was moderate in both arms, although MP produced a higher degree of thrombocytopenia. There were no significant differences in survival between patients given MP versus VCMP/ VBAP (median, 20 vs. 27 months, p = 0.2). Response to treatment was associated with a significantly longer survival. Older patients with symptomatic myeloma tolerate chemotherapy and should be offered treatment.
From May 1985 to May 1989, 175 patients with previously untreated aggressive non-Hodgkin's lymphoma were randomized to receive CHOP or ProMACE-CytaBOM. Eligibility criteria included follicular large-cell diffuse small cleaved-cell, diffuse mixed, diffuse large-cell and immunoblastic lymphoma with an Ann Arbor stage II, III or IV. One hundred and forty-eight patients were evaluable. There were no significant differences between the 2 treatments in response rate (83.5% [57.5% CR] for CHOP vs. 88% [62% CR] for ProMACE-CytaBOM), time to treatment failure (29% vs. 31% at 5 yr), or overall survival (42% in both groups at 5 yr). Furthermore, there were no significant differences between the 2 regimens when response rates and outcome were analyzed for different prognostic subgroups. Toxicity was not significantly different between the 2 regimens, although only 1 patient died as result of treatment-related toxicity in the CHOP arm compared to 6 patient in the ProMACE-CytaBOM group (p = 0.126). In conclusion, in this study ProMACE-CytaBOM has not proved to be superior to CHOP in aggressive lymphomas. This trial gives support to the notion that CHOP still is the standard chemotherapy for aggressive lymphomas, and that new treatment approaches for these lymphomas should be compared to CHOP.
The lactational changes in content and distribution of gangliosides in human milk from Spanish and Panamanian mothers delivering term newborns were studied. There were no statistically significant differences in the concentration of gangliosides between Spanish and Panamanian milk. The ganglioside content expressed as a function of total milk lipids tended to decrease as lactation progressed in both types of milk. There was a significant correlation (r = 0.5896; p = 0.0062) between ganglioside and total lipid contents in Panamanian milk. However, in Spanish milk, the correlation was not significant (r = 0.1516; p = 0.3439). We did not detect important differences in the relative concentrations of individual gangliosides during lactation among milk samples from Spanish and Panamanian mothers. For both of them, GD3 was the most abundant ganglioside in colostrum, whilst in mature milk it was GM3.
PURPOSE: To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy. PATIENTS AND METHODS: From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report. RESULTS: Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis. CONCLUSION: The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients.
OBJECTIVE: To analyse the relationships between arterial distensibility and blood pressure level and its circadian variability assessed by non-invasive ambulatory blood pressure monitoring. DESIGN: One hundred and six patients (69 men, 37 women; aged 20-72 years) without any cardiovascular complication or treatment underwent 24 h ambulatory blood pressure monitoring. Aortic distensibility was evaluated by carotid-femoral artery pulse-wave velocity measurements performed with a validated automatic device (Complior). RESULTS: The pulse-wave velocity correlated significantly with age (P < 0.001), systolic blood pressure (P < 0.01) and heart rate (P < 0.05). Subjects with higher pulse-wave velocities (above the median value) had higher ambulatory blood pressure and heart rate values, mainly during night-time, and present a smaller nocturnal fall both in systolic and in diastolic blood pressure than do those with lower pulse-wave velocities (below the median). The pulse-wave velocity was revealed to be an independent predictor of the nocturnal fall in systolic blood pressure (multiple r = 0.272, P < 0.02) whereas age and, to a lesser extent, mean 24 h diastolic blood pressure were independent predictors of the nocturnal fall in diastolic blood pressure (multiple r = 0.387, P < 0.001). CONCLUSION: Reductions in arterial distensibility are associated with increased blood pressure and heart rate levels whereas perturbations of the circadian blood pressure profile are associated with increased nocturnal values. The increased risk of end-organ damage and vascular events in the presence of higher nocturnal blood pressure values suggests that a study of arterial distensibility in the normal follow-up of hypertensive patients might be of benefit.
We studied changes during lactation in the relative concentration of individual gangliosides in human milk from mothers delivering preterm and term infants. The relative content of G(D3) was higher in colostrum than in mature milk, and tended to be higher in preterm colostrum than in term colostrum, whereas the relative content of G(M3) was higher in mature milk than in colostrum, and was also higher in term than in preterm milk. As G(D3) is usually detected in developing tissues whereas G(M3) is more abundant in mature tissues, these results suggest a relationship between the presence of individual gangliosides in human milk and immaturity of the mammary gland in mothers of preterm infants.
The activity of lecithin cholesterol acyl transferase (LCAT), a key enzyme in lipoprotein metabolism, is low in newborn preterm infants. It has been suggested that a normal gastrointestinal function might be necessary to induce a postnatal increase of LCAT activity because apoproteins A-I and A-IV (apoA-I and apoA-IV) synthesized in considerable amounts in the intestine are known activators of LCAT. Dietary nucleotides have been reported to enhance intestinal growth and maturation; therefore, we hypothesized that nucleotide supplementation to formulas for preterm infants may influence LCAT activity. To investigate this hypothesis, two groups of preterm infants were fed either a nucleotide-free formula or a nucleotide-supplemented formula during the first month of life. The plasma LCAT activity, plasma levels of apoA-I and apoA-IV, plasma cholesteryl esters, and plasma fatty acid composition of cholesteryl esters and phospholipids were then determined. Infants receiving nucleotides had higher LCAT activities and apoA-IV levels than those receiving the nucleotide-free formula for a few weeks. The changes in apoA-IV levels were highly correlated with those of the LCAT activities. However, there were no significant correlations between changes in LCAT activity and plasma cholesteryl esters or phospholipids. These findings indicate that nucleotide supplementation to formulas for preterm infants may improve dietary lipid tolerance by enhancing plasma LCAT activity, probably as a result of an increase in apoA-IV plasma concentrations; they also suggest that nucleotides may enhance apoA-IV synthesis in the intestine during the neonatal period.
The content and distribution of gangliosides, and total lipid content, were studied in human milk samples from different periods of lactation. We found a significant correlation (r = 0.5564; p = 0.0165) between ganglioside and total lipid contents. There was a selective change in the relative concentrations of GD3 and GM3 during lactation. The most abundant ganglioside in samples from the first three weeks of lactation was GD3, whereas after the first month, GM3 was the major ganglioside. In addition to GD3 and GM3, previously known to be present in human milk, we detected several previously unreported highly polar gangliosides.
Experimentally, superoxide dismutase (SOD) protects against cytotoxological and histotoxological effects of superoxide anions, which play a fundamental role where inflammatory processes are involved. Currently, only bovine copper containing SOD (Cu-SOD) is available for clinical application in the treatment of patients with various arthritic diseases. The intramuscular route is the principal route to administer usual dosages of bovine Cu-SOD 4 to 32mg, 2 or 3 times weekly. A single dose corresponds to an optimal dose ranging from 30 to 200 micrograms/kg, determined from an established dose-response curve. After intramuscular injection of bovine Cu-SOD 8, 16 and 32mg the peak plasma concentration occurs 4 to 8 hours postdose and is 0.05, 0.16 and 0.39 mg/L, respectively. Clinically this metallo-protein is particularly effective for the treatment of inflammation and toxicity resulting from ionising irradiations, ischaemia and tumours. The major advantages of liposomally encapsulated bovine Cu-SOD are its improved pharmacokinetic characteristics, leading to a longer plasma half-life and a slower release of free bovine Cu-SOD. In humans, bovine Cu-SOD (free or liposomal), although a foreign protein, is well tolerated and produces no acute or delayed toxic effects.
We identified 40 patients with malignant lymphoproliferative diseases (MLD) and HIV infection (seropositive) at a single Spanish university hospital. Thirty-two patients had non-Hodgkin's lymphoma (NHL), 6 primary central nervous system lymphoma (PCL) and 8 patients Hodgkin's disease (HD). Median age at presentation was 32 years. Four histopathological groups had distinct presenting clinical features: in 93% of the Burkitt-type lymphomas, the lymphoma itself was the AIDS defining criterion, while high and intermediate grade NHL other than Burkitt-like tended to have a more advanced HIV infection, demonstrated by antecedent AIDS criteria in 58% of these patients and a median CD4 positive cell count of 291 mm3; HD occurred in some patients without previous opportunistic infections (7/8 patients) but with median CD4 cells of 105 mm3; PCL occurred in a terminal stage of HIV infection, in patients with a low performance status, and frequent antecedent AIDS criteria. Objective response to chemotherapy could be seen in 62% of NHL patients and 100% of HD. Survival was adversely related to an antecedent diagnosis of AIDS, low performance status, and a primary localization in the central nervous system. Overall median survival was 5 months, but patients without the mentioned three adverse prognostic factors had a median survival of 10 months.
PURPOSE: To evaluate the toxic extramedullary morbidity of the conditioning treatment with BuCy for BMT, as well as the usefulness of pentoxyphyllin (PTX) and methylprednisolone (MP) in the prophylaxis of mucositis. PATIENTS AND METHODS: Forty-eight patients with blood malignancies (AML, 19; ALL, 14; indifferentiated AL, 1; CML, 9; lymphoblastic lymphoma, 3; RAEB, 1; RAEBT, 1), subjected to BMT (16 autologous and 32 allo-BMT) were retrospectively revised. They all had been treated with BuCy as conditioning regimen. The GVHD prophylaxis was made in allo-BMT with cyclosporin and short-term methotrexate. Twelve patients received PTX-MP as mucositis prophylaxis. RESULTS: Some kind of toxicity was found in 47 of the 48 patients, mostly grade I-II (45 cases). The commonest sites involved were the mouth (87.5%) and the liver (30.23%). Neither veno-occlusive liver disease nor pulmonary toxicity were present in any case. Heart toxicity was seen only in 2 cases, while 3 had haemorrhagic cystitis due to Cy. The severity of the mucositis was lesser in those patients receiving PTX-MP, so the requirements of NPT were lower in them (p = 0.02). CONCLUSIONS: The toxicity of the BuCy conditioning regimen was lesser than that of Cy+total body irradiation, with the same eradicating capability. Prophylaxis with PTX-MP could prove effective in reducing mucositis.
OBJECTIVE: To evaluate the influence of hypercholesterolaemia on arterial distensibility. MATERIAL AND METHODS: 43 male New Zealand White rabbits, with similar ages and weights, were included in the present study. The animals were divided in two groups: Group A (n = 15) was fed a normal diet; Group B (n = 28) was fed normal diet plus 0.1% cholesterol. at the beginning and after 6 and 9 months, blood samples were obtained for determination of serum cholesterol (total, esterified, LDL) and Triglyceride levels. Pulse wave velocity (PWV) was also evaluated, by mecanography, after 6 and 9 months of the beginning of the experiment. After 6 months (Group A = 4 and Group B = 7) and 9 months (Group A = 6 and Group B = 7) of the experiment, some animals were killed for anatomopathological studies. RESULTS: Major differences were obtained between the two groups, specially in what concerns to LDL and cholesterol levels (p < 0.001). There was also a remarkable difference in PWV between the two groups (6.078 +/- 0.162/9.002 +/- 0.196 m/s at 6 months and 7.639 +/- 0.590/9.557 +/- 0.543 m/s at 9 months) from the rabbits fed normal or cholesterol diet, respectively. The anatomical lesions were only significant after 9 months. However there was a decrease in aorta internal diameters at thoracic and renal levels at 6 months (34% and 53%) and at 9 months (29% and 33%), without significant changes in their thickness. In the heart, the left ventricle (LV) had a significant thickness increase after 6 months (about 43%). CONCLUSIONS: These data indicate that even before anatomical lesions had occurred, important functional changes are present, in the arterial wall. Then, the evaluation of the PWV could be a promising non-invasive diagnostic method of early atherosclerosis, with obvious implications concerning its prophylaxis and therapy.
Single strand conformation polymorphism (SSCP) analysis of exon 7 of the protein C gene has identified a novel splice site missense mutation (184, Q-->H), in a newborn child with purpura fulminans and undetectable protein C levels. The mutations, seen in the homozygous state in the child and in the heterozygous state in her mother, was characterized and found to be a G to C nucleotide substitution at the -1 position of the donor splice site of intron 7 of the protein C gene, which changes histidine 184 for glutamine (184, Q-->H). According to analysis of the normal and mutated sequences, this mutation should also abolish the function of the donor splice site of intron 7 of the protein C gene. Since such a mutation is compatible with the absence of gene product in plasma and since DNA sequencing of all protein C gene exons in this patient did not reveal any other mutation, we postulate that mutation 184, Q-->H results in the absence of protein C gene product in plasma, which could be the cause of the severe phenotype observed in this patient.
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