Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study

It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 +/- 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 +/- 25.9 mL/min) was lower than for BI (78.3 +/- 27.2 mL/min), and NAI (66 +/- 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post-transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher-risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.     

Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation

Abstract:  CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 ± 22 to 59.38 ± 28.6 mL/min/1.73 m² (p = 0.04) at six months and 57.46 ± 31.1 mL/min/1.73 m² (p = 0.02) at 12 months post-withdrawal. Forty-one percent of patients experienced AR. Increased risk for AR was associated with prior AR history, lower sirolimus trough levels, and lower CNIT biopsy scores. Graft loss (24%) was associated with worse CrCl, proteinuria, and histologic chronicity. Proteinuria (spot protein/creatinine ratio) increased from 0.75 ± 1.0 to 1.71 ± 2.0 (p = 0.03), unrelated to de novo sirolimus use. Four patients returned to CNI-based immunosuppression due to AR (n = 3) and gastrointestinal side effects (n = 1). Careful selection of pediatric candidates for CNI withdrawal is recommended. Worsening graft function and graft loss may be minimized by selecting patients with high CNIT scores and low biopsy chronicity and excluding patients with prior AR history.     

Catecholestrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: protective effect of catechol-O-methyltransferase

Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E(2)) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE(2)) and 2-hydroxyestradiol (2-OHE(2)), may play an important role in estrogen carcinogenicity. CEs can be oxidized to the corresponding ortho-quinone derivatives with concomitant formation of the reactive oxygen species (ROS). Catechol-O-methyltransferase (COMT) is the major enzyme involved in the detoxification of CEs in extrahepatic tissues. We investigated the potential of E(2), 2-OHE(2) and 4-OHE(2) to induce microsatellite instability (MSI) and neoplastic transformation of immortalized human endometrial glandular (EM) cells. We also investigated the functional significance of COMT gene expression on modulating the effects of E(2) and CEs in EM cells. Our data indicated that E(2) and 4-OHE(2) induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E(2) and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE(2) > E(2) > 2-OHE(2). Knockdown of COMT expression in EM cells resulted in increased estrogenic milieu and increased estrogen-induced cell proliferation. More importantly, knockdown of COMT increased the propensity of E(2) or CEs to induce ROS, MSI and neoplastic transformation of EM cells. In contrast, overexpression of COMT in EM cells significantly reduced the cellular estrogenic milieu and protected against E(2)- or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E(2) or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E(2)-induced endometrial cancer is mediated by its metabolism into CEs. Our study clearly indicates that COMT gene expression plays a critical role in modulating the hormonal and carcinogenic effects of E(2) and CEs and, consequently, modifies the risk for E(2)-induced endometrial cancer. To the best of our knowledge, this is the first study to (i) demonstrate the potential capacity of estrogen and its catechol metabolites to induce neoplastic transformation of immortalized human endometrial glandular cells; and (ii) illustrate the important role of COMT gene expression in protecting against E(2)-induced endometrial cancer.     

Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia

Infection with high-risk human papillomavirus (HPV) plays a major role in the etiology of cervical cancer (CC). However, most infected women do not develop cancer. Therefore, exposure to other carcinogenic agents may be a contributing risk factor for CC. We investigated the hypothesis that environmental exposure to cigarette smoke and inheritance of polymorphic chemical metabolizing genes (CYP2E1, GSTM1, and mEH) significantly increase the risk for neoplasia. We selected 76 cases with high-grade cervical neoplasia or with invasive CC and 75 matched healthy controls. The collected data support the well-established observation that infection with high-risk HPV is the major risk factor for CC (OR = 75; 95% CI = 26-220). In addition, our data show that women who smoked more than 15 "pack-year" had a significant 6.9-fold increase in risk (95% CI = 1.2-40.3) after adjustment for HPV infection. The CYP2E1 variant genotype did not significantly increase the risk for neoplasia. A significant increase in risk for neoplasia was observed for the low-activity mEH 113 His allele after adjustment for smoking (OR = 3.0; 95% CI = 1.4-6.3). The GSTM1 null genotype was associated with a significant 3.3-fold increased risk for neoplasia (95% CI = 1.0-11.8) compared to women who were GSTM1-positive after adjustment for smoking and HPV infection. Our study suggests that genetic differences in the metabolism of cigarette smoke, particularly GSTM1, may confer susceptibility to CC. Further studies using larger populations will be needed to confirm our observations and to validate data for disease prevention.     

Effect of a micronutrient fortificant mixture and 2 amounts of calcium on iron and zinc absorption from a processed food supplement

BACKGROUND: Iron, zinc, and calcium can interact with each other in a way that inhibits their respective absorption. On the other hand, mineral fortification has been used to improve simultaneous iron and zinc absorption from food supplements. OBJECTIVE: We evaluated the effect of a novel fortificant mixture consisting of NaFeEDTA, zinc methionine, ascorbic acid, and citric acid on iron and zinc absorption from a dry food supplement designed for preschool children. DESIGN: The standard food supplement contained cereal and legume flour, dried milk, and a mixture of micronutrients including ferrous sulfate and zinc sulfate as sources of supplemental iron and zinc, respectively. Standard and novel food products were prepared as porridge with or without the addition of 200 mg Ca as calcium phosphate. Iron absorption and zinc absorption from the food products were evaluated simultaneously in 13 nonpregnant, adult women by extrinsically labeling the products with radioisotopes of iron and zinc and carrying out whole-body counting 7 d after the food products were consumed in random order. RESULTS: The absorption of iron from the NaFeEDTA-containing (novel) food product was 1.7 times that from the ferrous sulfate-containing (standard) product (P = 0.015). There was no significant effect of dietary calcium on iron absorption. Zinc absorption was not associated with the form of zinc consumed, but higher dietary calcium was marginally associated with lower zinc absorption (P = 0.071). CONCLUSIONS: A mixture of fortificants containing NaFeEDTA, zinc sulfate or zinc methionine, ascorbic acid, and citric acid, but without calcium, can improve iron and zinc absorption from food products. A cost-benefit analysis of the novel fortificant mixture needs to be performed.     

Theoretical study of catalytic mechanism for single-site water oxidation process

Water oxidation is a linchpin in solar fuels formation, and catalysis by single-site ruthenium complexes has generated significant interest in this area. Combining several theoretical tools, we have studied the entire catalytic cycle of water oxidation for a single-site catalyst starting with [Ru^II(tpy)(bpm)(OH₂)]²⁺ (i.e., [Ru^II-OH₂]²⁺; tpy is 2,2^′∶6^′,2^′′-terpyridine and bpm is 2,2′-bypyrimidine) as a representative example of a new class of single-site catalysts. The redox potentials and pK_a calculations for the first two proton-coupled electron transfers (PCETs) from [Ru^II-OH₂]²⁺ to [Ru^IV = O]²⁺ and the following electron-transfer process to [Ru^V = O]³⁺ suggest that these processes can proceed readily in acidic or weakly basic conditions. The subsequent water splitting process involves two water molecules, [Ru^V = O]³⁺ to generate [Ru^III-OOH]²⁺, and H₃O⁺ with a low activation barrier (∼10 kcal/mol). After the key O---O bond forming step in the single-site Ru catalysis, another PECT process oxidizes [Ru^III-OOH]²⁺ to [Ru^IV-OO]²⁺ when the pH is lower than 3.7. Two possible forms of [Ru^IV-OO]²⁺, open and closed, can exist and interconvert with a low activation barrier (< 7 kcal/mol) due to strong spin-orbital coupling effects. In Pathway 1 at pH = 1.0, oxygen release is rate-limiting with an activation barrier ∼12 kcal/mol while the electron-transfer step from [Ru^IV-OO]²⁺ to [Ru^V - OO]³⁺ becomes rate-determining at pH = 0 (Pathway 2) with Ce(IV) as oxidant. The results of these theoretical studies with atomistic details have revealed subtle details of reaction mechanisms at several stages during the catalytic cycle. This understanding is helpful in the design of new catalysts for water oxidation.     

Ventilatory responses to hypercapnia during bupivacaine spinal anesthesia

The effect of spinal anesthesia with isobaric 0.5% bupivacaine on ventilatory responsiveness to CO2 rebreathing was studied in ten unpremedicated patients. Minute ventilation (VE) at end-tidal PCO2 = 55 mm Hg increased from 18.7 +/- 6.7 L/min (mean +/- SD) to 22.3 +/- 10.1 L/min after induction of spinal anesthesia (P less than 0.05). Occlusion pressure (P0.1) at PCO2 = 55 mm Hg also increased, from 3.8 +/- 1.5 to 5.0 +/- 1.7 cm H2O (P less than 0.05). Spinal anesthesia was not associated with significant changes in vital capacity, maximal inspiratory pressure, resting end-tidal PCO2, or the slopes or intercepts of the lines relating VE or P0.1 to PCO2. These results show an increased ventilatory responsiveness to CO2 with bupivacaine spinal anesthesia.