Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with homozygous beta-thalassemia show an abnormal lipoprotein profile. In asymptomatic heterozygotes the lipid pattern is less markedly affected but interestingly related to a diminished cardiovascular risk. The extent and significance of these findings are still a matter of debate and no data are available on lipoprotein(a) plasma levels. Seventy patients with homozygous beta-thalassemia (HT-P), 70 beta-thalassemia trait carriers (TT-C) and 70 sex and age-matched controls were investigated and their plasma lipoprotein profile and apo(a) phenotypes determined. In a subgroup of these same subjects (12 HT-P, 12 TT-C and 24 controls) and in 12 bone marrow-transplanted homozygous beta-thalassemic patients (BMT-P) plasma lipoprotein composition was assessed. HT-P disclosed significantly lower total-cholesterol, LDL-cholesterol, HDL-cholesterol, apo A-I, apo B plasma levels and higher triglyceride concentration than TT-C (-7, -11, -8, -8, -13 and +11%, respectively) or controls (-39, -50, -46, -32, -30 and + 35%, respectively). All lipoprotein subclasses were triglyceride-enriched, while LDLs were also protein-enriched and HDLs protein-depleted. TT-C disclosed a small but significant reduction in apo A-I and apo B plasma levels but only minor lipoprotein abnormalities with respect to the controls. BMT-P lipoprotein composition was intermediate between HT-P and normal subjects. Apo(a) plasma levels did not differ among the groups. A higher prevalence of 'small' apo(a) isoforms was present in HT-P. Within the same 'isoform group', apo(a) plasma levels were significantly lower in HT-P than in TT-C or controls. Since liver cirrhosis is almost always present in HT-P, it is conceivable that an altered hepatic apo(a) synthesis or catabolism due perhaps to diminished apolipoprotein glycation may be involved. In TT-C a partially improved cardiovascular risk profile was apparent (low hematocrit, low LDL-cholesterol and apo B), thus justifying the claim for a low prevalence of ischemic heart disease, but no Lp(a) plasma level modification could be detected.
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PMID:Plasma lipoprotein composition, apolipoprotein(a) concentration and isoforms in beta-thalassemia. 918 Feb 53

No experience has been reported to date in treating chronic hepatitis C virus (HCV) infection with interferon (IFN) therapy after BMT, mainly due to concerns related to the impact of an immunomodulatory drug in patients who are immunologic and haematologic chimeras. However, chronic inflammatory activity related to HCV infection results in a chronic fibrogenous mechanism potentially leading to liver cirrhosis and hepatocellular carcinoma. Moreover, patients transplanted for beta-thalassemia could be at greater risk because of concomitant iron overload and pre-existing fibrous liver damage. Eleven patients with serological, biochemical, histological and molecular biological evidence of HCV infection were included in the study and treated for 6-12 months with recombinant IFN 24-65 months following BMT. The serum alanine aminotransferase (ALT) was persistently elevated (range 85-1242 U/l; mean 416) for at least 1 year prior to IFN treatment. Ten patients completed the protocol; five were considered as responders to treatment. In these five patients the liver histology showed an overall reduction of inflammation and necrosis: histological inflammatory activity improved from chronic active hepatitis (CAH) to chronic persistent hepatitis (three patients) or minimal residual inflammatory activity (two patients). The Knodell total activity score varied from 5.4 (range 3-9) to 1.4 (range 1-2; P = 0.05). All responding patients revealed negativization of serum HCV-RNA, that has been persistent in four (follow-up 1-3 years). ALT level fell to 15-80 U/l (mean 52; P = 0.0027). No major complications occurred during the therapy and no influence on marrow engraftment parameters were noted. We conclude that IFN therapy does not adversely interfere with engraftment and that it is a feasible therapy for treatment of chronic hepatitis C virus after BMT.
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PMID:Alpha-interferon treatment of chronic hepatitis C after bone marrow transplantation for homozygous beta-thalassemia. 938 79

After successful marrow transplantation (BMT) iron overload remains an important cause of morbidity in Thalassemia. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. Forty-one patients (mean age 16 +/- 2.9 years) with prolonged follow-up (range 2-7 years) after BMT were submitted to a moderate intensity phlebotomy program (6 ml/kg blood withdrawal at 14-day intervals) to reduce iron overload. Values are expressed as mean +/- SD or as median with a range (25th-75th percentile). Serum ferritin decreased from 2,587 (2,129-4,817) to 280 (132-920) micrograms/l (p < 0.0001), total transferrin increased from 2.34 +/- 0.37 to 2.9 +/- 0.66 g/l (p = 0.0001), transferrin saturation decreased from 90% +/- 14% to 39% +/- 34% (p < 0.0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5-28.1) to 3 (0.9-14.6) mg/g dry weight (p < 0.0001). Alanine amino-transaminase from 5.2 +/- 3.4 to 1.6 +/- 1.2 (p < 0.0001) times the upper level of normality. The histological grading for chronic hepatitis (Histology Activity Index) decreased from 4.2 +/- 2.4 to 2.3 +/- 1.8 (p < 0.0001). Phlebotomy is a safe, efficient, and widely applicable method to decrease iron overload in "ex-thalassemic."
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PMID:Treatment of iron overload in the "ex-thalassemic". Report from the phlebotomy program. 966 50

Long term effects of BMT in thalassemia were monitored in 33 patients transplanted between 1987 and 1995 and compared with 155 patients matched for age and treated during the same period with conventional therapy (CT). The incidence of fulminant sepsis and growth impairment was significantly higher in transplanted patients, whereas the occurrence of hypothyroidism, hypogonadism, and cardiopathy was higher in CT patients. For diabetes, liver disease, and severe infections, the differences were not statistically significant. After BMT we performed monthly erythrocytaferesis for iron removal in 23 (70%) patients, obtaining a complete normalization of iron stores in 91% of cases; among untreated patients, 60% had evidence of iron up to 8.3 years after BMT. Protection against poliovirus, tetanus, diphtheria, and hepatitis B has been lost in 74%, 47%, 78%, and 44%, respectively. After BMT a careful follow-up is needed to monitor and treat late transplant-related and thalassemia-related complications.
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PMID:Late effects of bone marrow transplantation for thalassemia. 966 51

Eurocord Transplant has established a registry for studying results of cord blood transplant. We have analyzed 78 patients who have received a related CBT between October 1988 and December 1996. The median follow-up time was 29 months (1-99). The median age was 5 years (0.2-20), median weight 19 kg (5-50). Forty-six patients had a malignant disease: 32 acute leukemia (AL), six chronic myeloid leukemia (CML), four myelodysplastic syndrome, two neuroblastoma and two non-Hodgkin lymphoma. Thirty-two patients were transplanted for non-malignant diseases including 17 bone marrow failure syndromes (BMFS), three sickle cell anemia, five thalassemia and seven inborn errors. The donor was an HLA-identical sibling in 60 cases and an HLA-mismatched donor in 18 cases. As conditioning, 36 patients received irradiation and 40 patients received associated busulfan-containing regimens. GVHD prophylaxis consisted of CsA alone in 36 cases, CsA associated with prednisone in eight cases, CsA, methotrexate (Mtx) with or without prednisone in 28 cases and CsA with monoclonal antibody or ATG in four cases. The median number of nucleated cells (NC) infused/kg was 3.9 x 10(7) (0.7-15). One-year survival was 63 +/- 6%. Age, weight, HLA identity and negative cytomegalovirus (CMV) serology in the recipient were significant favorable prognostic factors. Among these 78 patients, the incidence of grade > or = II GVHD was 9% in HLA-matched CBT and 50% in mismatched CBT (P < 0.001). Neutrophil engraftment was associated with age <6 years (P = 0.02) and weight <20 kg (P = 0.02). It was 73% in patients receiving <3.7 x 10(7) nucleated cells (NC) infused/kg and 85% in patients receiving more (P = 0.06). Favorable factors for platelets engraftment were age <6 years (P = 0.03), weight <20 kg (P = 0.002) and HLA identity (P < 0.0001). Related cord blood transplantation offers a good alternative to BMT. Theses results are in favor of freezing cord blood in families in whom a transplant might be indicated.
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PMID:Related cord blood transplants: the Eurocord experience from 78 transplants. Eurocord Transplant group. 971 97

The pharmacokinetics of busulphan were studied in 23 thalassaemic children undergoing BMT. Patients received busulphan at a dose of either 16 mg/kg with cyclophosphamide and ATG (Group A) or 600 mg/m2 (with cyclophosphamide alone) (Group B) in 16 divided doses every 6 h over 4 days. Busulphan levels were analyzed by a modified GC-MS method. The dose of busulphan/kg for patients in group B was 64% (range 56-71%) higher than that for patients in group A. The mean AUC, Css, Cmax and MRV were significantly higher in group B as compared with group A for both doses 1 and 13. There was no significant difference in Vd/F, T1/2 and Kel between the two groups. A significant decrease in AUC and Css was found between 1st and 13th doses in group B, but not in group A. The Cl/F values in group A were significantly higher than those in group B after dose 1, but not after dose 13. No increase in toxicity due to the higher dose of busulphan was noted. We conclude that busulphan at 600 mg/m2 results in much higher systemic exposure to the drug as compared to 16 mg/kg, without increase in toxicity in children with beta thalassaemia major.
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PMID:Pharmacokinetics of oral busulphan in children with beta thalassaemia major undergoing allogeneic bone marrow transplantation. 1043 27

Thirty-two thalassemic patients with a median age of 7.7 years (range 3.4-26 years) were given a second HLA-identical related marrow transplant (BMT2) for graft failure. Four patients were in class 1 and 28 patients in classes 2 and 3. Twenty-one patients had full thalassemia recurrence (first group) and 11 patients had aplastic marrows (second group) either with or without residual donor marrow cells after the first BMT (BMT1). As conditioning regimen for BMT2 all but five patients received BUCY or CY in association with total lymphoid irradiation (TLI) and/or anti-lymphocyte globulin (ALG), whereas nine patients received a new preparative regimen with hydroxyurea, azathioprine, fludarabine before conditioning with BUCY. Twenty one of 31 evaluable patients (67.7%) had initial, and 16 (51.6%) had sustained engraftment. Ten patients (32.3%) failed to engraft. Overall and event-free survival for the entire group of patients were 49% and 33%, respectively, with a median follow-up of 4 years (range 0.6-14 years) for surviving patients. Event-free survival was higher in the second group of patients compared with the first group (41% vs 29%). The second group of patients appeared to have less graft failure compared with the first group (30% vs 63%; P = 0.1). Transplant-related mortality was 28%. A linear stepwise regression analysis revealed that occurrence of graft failure within 60 days after BMT1 (P = 0.04) and absence of residual donor marrow cells (P = 0.009) predicted for graft failure following BMT2, whereas the occurrence of graft failure after 60 days (P = 0.03) had a positive influence on survival following BMT2. The incidence of grade >/=2 acute GVHD was low (14%). Eight of nine patients who received the new preparative regimen are alive, four without thalassemia. This study shows that BMT2 can be an effective therapy for a proportion of patients with poor survival expectancies despite conventional treatment.
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PMID:Second marrow transplants for graft failure in patients with thalassemia. 1062 38

Twenty-nine patients with thalassemia and a median age of 6 years (range 1.1-33 years) were given a BMT from an alternative donor. Six of the 29 donors were HLA-phenotypically identical and two were mismatched relatives, 13 were mismatched siblings and eight were mismatched parents. Six patients received no antigen (relatives), 15 patients one antigen, five patients two antigen and three patients three antigen disparate grafts. Twenty-three patients were in class 2 or class 3, whereas six patients were in class 1. Thirteen patients were given BUCY, nine patients BUCY plus ALG, six patients BUCY plus TBI or TLI and one patient BUCY with prior cytoreductive-immunosuppressive treatment as conditioning. As GVHD prophylaxis four patients received MTX, 22 CsA + MTX + methylprednisolone (MP) and three patients CsA + MP. Thirteen of 29 patients (44.8%) had sustained engraftment. The probability of graft failure or rejection was 55%. There were no significant differences between antigen disparities and graft failure. The incidence of grade II-IV acute GVHD was 47.3% and chronic GVHD was 37.5%. The incidence of acute GVHD was higher in patients receiving one or two antigen disparate in the GVHD direction grafts (vs no antigen) (P EQ 0.04; odds ratio 10.8; 95% CI 1.5-115). The probability of overall and event-free survival was 65% and 21%, respectively, with median follow-up of 7.5 years (range 0.6-17 years) for surviving patients. The degree of HLA disparity between patient and donor did not have a significant effect on survival. The incidence of nonhematologic toxicity was low. Transplant-related mortality was 34%. GVHD (acute or chronic) was a major contributing cause of death (50%) followed by infections (30%). We conclude that at present, due to high graft failure and GVHD rates, BMT from alternative donors should be restricted to patients who have poor life expectancies because they cannot receive adequate conventional treatment or because of alloimmunization to minor blood antigens.
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PMID:Bone marrow transplantation from alternative donors for thalassemia: HLA-phenotypically identical relative and HLA-nonidentical sibling or parent transplants. 1080 1

The potential advantage of in utero HSC transplantation over a postnatal BMT is that early curative therapy could be given to an affected fetus, thus eliminating standard intensive immunosuppressive, marrow-ablative conditioning. It is apparent from studies in animals and humans that MHC-mismatched donor HSC of either fetal or adult origin can engraft in fetal recipients if the transplants are done sufficiently early in gestation. However, except for SCID, the percentage of donor pluripotent HSC that engraft is unacceptably low. We had hoped that for diseases such as thalassemia there would be a selective survival advantage for committed donor progenitor cells resulting in a high percentage of donor cell engraftment. At least based upon the experience in human fetuses with alpha- or beta-thalassemia, this has not been the case. Furthermore, for the majority of potential recipients of in utero HSC transplants, the marrow is non-defective, and the small percentage of pluripotent donor HSC that engraft would not be expected to selectively expand post-transplant. Our own results suggest that the non-defective fetal mouse and rhesus monkey are excellent models in which to study both stem cell engraftment, rejection, and tolerance induction. In our studies in non-defective mice with normal hematopoiesis, while the percentage of donor cells that are present is quite low, in only a small number of these animals were we able to induce permanent skin graft tolerance. Thus, while we found microchimerism in approximately 75% of recipients, less than 10% became tolerant. Even when we co-injected a large number of DC precursors, similar to what has been shown to induce tolerance to allogeneic liver, most of the animals failed to become tolerant to donor skin grafts. Interestingly, donor c-kit+ cells can be recruited with cytokines into the peripheral blood in engrafted mice, although these cells do not seem to be sufficient to induce tolerance to donor skin grafts, suggesting that the type (and location) of the engrafted donor cell plays a key role in tolerance induction. Our results in the fetal monkey model parallel those in the mouse, i.e., only a small number of donor cells engraft with limited tolerance induction. Interestingly, we found in our study of DC that GVHD was induced in those murine recipients of both allogeneic marrow and DC. It is likely that there were a sufficient number of mature DC in the preparation to facilitate a donor cytotoxic response towards the host. As a consequence there was also a significant increase in the percentage of donor cells that engrafted in the survivors. Future studies will focus on ways of blocking the graft vs host reaction while still maintaining the graft-promoting role of the donor T cell.
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PMID:Tolerance induction post in utero stem cell transplantation. 1110 59

Osteoporosis and osteopenia affect up to half of patients with thalassaemia major (TM). We investigate the effects of acquired factors and BMT on bone mineral density (BMD) in these patients. In all, 53 patients on regular transfusion (BT group) and 33 patients at 5.7+/-1.9 years post transplant (BMT group) were recruited. BMD was measured by dual energy X-ray absorptiometry. Serum concentrations of osteocalcin, bone-specific alkaline phosphatase (ALP), beta-crossLap and urinary cross-linking deoxypyridinoline (DPD) were measured by chemiluminescence and enzyme immunoassay, respectively. Severe BMD deficit (Z-score <-2.5) at spine and hip were noted in 62 and 35% of BT group. Serum osteocalcin (beta=-0.463; P=0.006) was predictive of spine BMD, whereas age (beta=-0.843; P=0.007) and urine DPD (beta=-0.439; P=0.037) were associated with hip BMD in BT group. Among BMT patients, post transplant duration (beta=0.450; P=0.009) and serum bone-specific ALP (beta=-0.495; P=0.013) were associated with spine BMD. Severe BMD deficit was less common among BMT than BT patients (6 vs 35%; P=0.036). The mean (s.d.) osteocalcin levels in BMT and BT groups were 96.4 (72.7) microg and 68.9 (40.3) microg/l, respectively (P=0.037). In conclusion, severe BMD deficit is common in Chinese TM patients and BMT may reverse BMD deficit in these patients.
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PMID:Bone mineral density in children with thalassaemia major: determining factors and effects of bone marrow transplantation. 1596 88


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