Juan Montoro

Gamma-Glutamyl-Amino Acids as Signals for the Hormonal Regulation of Amino Acid Uptake by the Mammary Gland of the Lactating Rat

The mammary gland is a good model to study the hormonal regulation of amino acid uptake. Danazol, which decreases gonadotrophin release, causes a fall in gamma-glutamyltranspeptidase (GGT) and in amino acid uptake by the gland. Treatment of the rats with estrogens and progesterone partially reverts this effect. Treatment with gonadotrophins completely reverts it. gamma-Glutamyl-amino acids (GAA) increase the uptake of amino acids by the mammary gland in rats previously treated with bromocriptine. We suggest that GAA may act as signals to stimulate amino acid uptake and that the role of GGT may be to generate that signal.

Effect of specific inhibition of gamma-glutamyl transpeptidase on amino acid uptake by mammary gland of the lactating rat.

We showed [Biochem. J. (1981) 194, 99–102] that inhibition of γ‐glutamyl transpeptidase in vivo with serine‐borate decreases amino acid uptake by mammary gland. However, doubts arose about the validity of this inhibitor in metabolic studies because it must be used in very large amounts. New Inhibitors have been isolated, like anthglutin and acivicin, which are effective at low concentrations in vivo. Here, we show that treatment of lactating rats with these substances decreases the transpeptidase activity and the amino acid uptake by the gland. These results support the hypothesis that the γ‐glutamyl cycle functions as an amino acid transport system in mammary gland.

Aféresis de lipoproteínas de baja densidad en la hipercolesterolemia familiar resistente al tratamiento médico convencional intensivo

BACKGROUND AND OBJECTIVE The aim of our study is to analyze the effect and security of low-density lipoproteins (LDL) apheresis in familial hypercholesterolemia (FH) subjects who did not response to conventional intensive optimized medical treatment. PATIENTS AND METHODS Seven heterozygous FH subjects and one homozygous apoB familial defective were studied. All subjects were on secondary prevention with highest statins doses in association with other hypolipemiant drugs; the mean LDL-C reduction was 20%. All of them were treated with LDL apheresis (immunoabsorption) for a mean of 4.25 years. RESULTS LDL apheresis resulted in a 68.3% decrease in LDL-C and 58.2% in apoB plasma values (P<.001). After an average of 3 years of follow-up, the cardiovascular events disappeared in 4 out of 5 symptomatic patients while in one patient the events were reduced in 75%. Four moderate side effects were reported in 820 apheresis procedures. CONCLUSIONS LDL apheresis is a well-tolerated and safe treatment in FH patients who do not response to intensive conventional optimized medical treatment. The main limitation is its economical cost and low accessibility.

OriginalAféresis de lipoproteínas de baja densidad en la hipercolesterolemia familiar resistente al tratamiento médico convencional intensivoLow-density lipoprotein apheresis in familial hypercholesterolemia resistant to intensive medical treatment

BACKGROUND AND OBJECTIVE The aim of our study is to analyze the effect and security of low-density lipoproteins (LDL) apheresis in familial hypercholesterolemia (FH) subjects who did not response to conventional intensive optimized medical treatment. PATIENTS AND METHODS Seven heterozygous FH subjects and one homozygous apoB familial defective were studied. All subjects were on secondary prevention with highest statins doses in association with other hypolipemiant drugs; the mean LDL-C reduction was 20%. All of them were treated with LDL apheresis (immunoabsorption) for a mean of 4.25 years. RESULTS LDL apheresis resulted in a 68.3% decrease in LDL-C and 58.2% in apoB plasma values (P<.001). After an average of 3 years of follow-up, the cardiovascular events disappeared in 4 out of 5 symptomatic patients while in one patient the events were reduced in 75%. Four moderate side effects were reported in 820 apheresis procedures. CONCLUSIONS LDL apheresis is a well-tolerated and safe treatment in FH patients who do not response to intensive conventional optimized medical treatment. The main limitation is its economical cost and low accessibility.

Advances in haploidentical stem cell transplantation for hematologic malignancies

Abstract One of the most important advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the use of alternative donors and cell sources, such as haploidentical transplants (haplo-HSCT) from family donors. Several approaches have been developed to overcome the challenging bidirectional alloreactivity. We discuss these approaches, including ex vivo T-cell-depleted grafts with megadose of CD34+ cells, not requiring immunosuppression after allogeneic transplantation for graft-versus-host disease (GVHD) prophylaxis, and other strategies using unmanipulated T-cell-replete grafts with intensive immunosuppression or post-transplantation cyclophosphamide to minimize the GVHD. We also address the role of other strategies developed in the context of the haplo-HSCT platforms, such as ex vivo selective depletion of alloreactive donor T-cell subpopulations, infusion of antigen-specific T-cells against several pathogens, and infusion of regulatory T-cells, among other experimental approaches. Finally, some considerations about the selection of the most suitable donor, when more than one family member is available, are also addressed.

A polymorphism in the TYMP gene is associated with the outcome of HLA-identical sibling allogeneic stem cell transplantation

Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo‐SCT) from an human leukocyte antigen (HLA)‐identical sibling donor. The TYMP genotype of patients correlated with overall survival—carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.9; P = 0.004). This effect was mostly due to differences in transplant toxicity‐related mortality (HR = 2.5; P = 0.029). In addition, the TYMP genotype of donors was associated with the risk of chronic graft‐versus‐host disease (GVHD)—carriers of the minor allele being at an increased risk of developing this complication ([HR] = 1.7; P = 0.039). The impact of such polymorphism on the risk of chronic GVHD is limited to patients transplanted in early stage disease (HR = 2.2; P = 0.019). The combination of a donor harboring the minor allele with a patient homozygous for the major allele was associated with the highest risk of chronic GVHD (HR = 2.8; P = 0.008). These findings provide the first evidence of the significant impact of the TYMP genotype upon the clinical outcome of patients treated with HLA‐identical sibling allo‐SCT. Am. J. Hematol. 88:883–889, 2013.

Glutathione Metabolism Under the Influence of Hydroperoxides in the Lactating Mammary Gland of the Rat. Effect of Glucose and Extracellular ATP

Tert-butyl hydroperoxide decreases GSH and total free glutathione (GSH+2GSSG) contents of acini from lactating mammary glands. The decrease in total free glutathione can be explained by an increase in mixed disulfide formation and by excretion of GSS G to the extracellular medium, and subsequent degradation catalyzed by gamma-glutamyl transpeptidase. Low concentrations of glucose prevented the changes in glutathione levels induced by the peroxide. In the presence of extracellular ATP, glucose did not prevent these changes. However, incubations with the peroxide, did not alter the rate of other metabolic pathways by acini.

Infections of the Central Nervous System after Unrelated Donor Umbilical Cord Blood Transplantation or Human Leukocyte Antigen–Matched Sibling Transplantation

We analyzed the incidence, clinical characteristics, prognostic factors, and outcome of central nervous system (CNS) infections in consecutive patients with receiving umbilical cord blood transplantation (UCBT) (n = 343) or HLA-matched sibling donor stem cell transplantation (MST) (n = 366). Thirty-four CNS infections were documented at a median time of 116 days after transplantation (range, 7 to 1161). The cumulative incidence (CI) risk of developing a CNS infection was .6% at day +30, 2.3% at day +90, and 4.9% at 5 years. The 5-year CI of CNS infection was 8.2% after UCBT and 1.7% after MST (P < .001). The causative micro-organisms of CNS infections were fungi (35%), virus (32%), Toxoplasma spp. (12%), and bacteria (12%). Fungal infections occurred in 11 patients after UCBT and 1 after MST and were due to Aspergillus spp. (n = 8), Cryptococcus neoformans (n = 2), Scedosporium prolificans (n = 1), and Mucor (n = 1). Except for 1 patient, all died from CNS fungal infection. Viral infections occurred in 9 patients after UCBT and 1 after MST and were due to human herpes virus 6 (n = 7), cytomegalovirus (n = 2), and varicella zoster virus (n = 1). CNS toxoplasmosis was diagnosed in 3 patients after UCBT and 1 after MST. Other pathogens were Staphylococcus spp, Nocardia spp, Streptococcus pneumoniae, and Mycobacterium tuberculosis. Twenty of the 34 patients (59%) died from the CNS infection. In multivariable analysis, UCBT and disease stage beyond first complete remission were independently associated with the risk of developing CNS infections. The 5-year overall survival was 19% in patients who developed a CNS and 39% for those who did not (P = .006). In conclusion, our study showed that CNS infections are a significant clinical problem after stem cell transplantation associated with poor survival. They were more frequent after UCBT compared to MST.

Factors influencing platelet transfusion refractoriness in patients undergoing allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has been considered a risk factor for development of platelet transfusion refractoriness. The objective of this study was to assess the platelet transfusion refractoriness rate in patients undergoing allogeneic hematopoietic stem cell transplantation from different sources. We retrospectively reviewed the charts and transfusion records of patients who underwent allogeneic stem cell transplantation at our institution between 2013 and 2015. The evaluation of post-transfusion platelet count was assessed for each transfusion given, from day of progenitor infusion to day 30 after transplantation. Of 167 patients included in this study, 101 received peripheral blood stem cell transplantation (PBSCT) and 66 received umbilical cord blood transplantation (UCBT). Overall, the percentage of platelet transfusions with a 14-h CCI lower than 5000 was 59.3%, being these data significantly higher for UCBT (67.6%) than for PBSCT (31.0%). Seventy-eight percent of patients underwent UCBT become refractory, while 38.6% of patients who received PBSCT were refractory. Factors associated to platelet refractoriness were lower CD34+ cell dose infused, higher number of antibiotics used, presence of anti-HLA I antibodies, and reduced-intensity conditioning regimen. Platelet refractoriness is a frequent and complex adverse event and remains a therapeutic challenge in the management of patients undergoing HSCT. There is a higher rate of platelet refractoriness in patients who received UCBT as compared to patients who received PBSCT.

Single umbilical cord blood with or without CD34+ cells from a third-party donor in adults with leukemia

We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Español de Trasplante Hematopoyético. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.