Potential influence of tacrolimus and steroid avoidance on early graft function in pediatric renal transplantation.

With the increasing adoption of steroid-sparing immunosuppression protocols in renal transplantation, it is important to evaluate any adverse effects of steroid avoidance on graft function. Early graft function, measured by CrCl was retrospectively studied in 158 consecutive pediatric renal transplant recipients from 1996 to 2005, receiving either steroid-free or steroid-based immunosuppression. Patients receiving steroid-free immunosuppression vs. steroid-based immunosuppression had no difference change in CrCl (DeltaCrCl) in the first week post-transplantation (p = 0.12). When stratified by corticosteroid usage, patients with higher tacrolimus trough levels (> or =14 ng/mL) had slower graft function recovery in the first week post-transplantation than those with lower tacrolimus trough levels (p = 0.008) in the steroid-free group only. Despite initial slower graft function recovery in this subgroup, there was no negative impact on graft function in the steroid-free group; in fact steroid-free patients trended towards better CrCl at six months (p = 0.047) and 12 months (p < 0.001) post-transplant than the steroid-based group. With the improved immunological outcomes with steroid avoidance, close surveillance should be performed of tacrolimus levels to avoid levels >14 ng/mL. In patients with slow recovery of early graft function, short-term perioperative steroids may be considered.

Absorption of hemoglobin iron: the role of a heme-splitting substance in the intestinal mucosa.

The dog behaves like man in his ability to utilize dietary hemoglobin iron and, therefore, is an excellent model in which to study the mechanisms of absorption. Heme is taken up intact into the epithelial cell of the small intestine but the iron appears in the plasma in a nonheme form. A substance is present in mucosal homogenates which is capable of releasing iron from a hemoglobin substrate in vitro. This has a molecular weight greater than 64,000, and appears to behave as an enzyme. There is no difference in the in vitro, effective concentration of the hemesplitting substance in the mucosa of iron-loaded and iron-deficient dogs to explain in vivo changes in iron absorption. However, the rate at which the heme-splitting substance works in vivo appears to be increased by the removal of the nonheme-iron-end product from the epithelial cell to the plasma. Reduction of the heme-iron content within the epithelial cell may then enhance uptake from the lumen. These studies suggest that the labile nonheme-iron content of the intestinal epithelial cell determines its ability to accept heme as well as ionized iron from the lumen.

Construction of a high-resolution physical map of the approximate 1-Mb region of human chromosome 7q31.1-q31.2 harboring a putative tumor suppressor gene.

Reports of frequent loss of heterozygosity (LOH) of markers on human chromosome 7q in malignant myeloid disorders as well as breast, prostate, ovarian, colon, head and neck, gastric, pancreatic, and renal cell carcinomas suggest the presence of a tumor suppressor gene (TSG). Functional assays have demonstrated that the introduction of an intact copy of human chromosome 7 (hchr7) can restore senescence to immortalized human fibroblast cell lines having LOH of markers within 7q31-q32 and can inhibit the tumorigenic phenotype of a murine squamous cell carcinoma cell line. To facilitate the cloning of the putative TSG, we have constructed a high-resolution physical map of this region of hchr7, specifically that encompassing the markers D7S522 and D7S677 within 7q31.1-q31.2. By using a lower resolution yeast artificial chromosome-based map as a starting framework, we established complete clone coverage of the implicated critical region in bacterial-artificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs). The resulting BAC/PAC-based contig map has provided suitable clones for the systematic sequencing of the entire interval. In addition, we have already identified 29 clusters of overlapping expressed-sequence tags (ESTs) and 4 known genes contained within these clones. Together, the physical map reported here coupled with the evolving sequence and gene maps should hasten the identification of the putative TSG residing within this region of hchr7.

Leukocyte larceny: a cause of spurious hypoxemia.

Multiple blood specimens with different leukocyte counts from two patients with extreme leukocytosis secondary to leukemia and unexplained hypoxemia were tonometered with a gas of known oxygen concentration and the decay of oxygen tension (PO2) was measured over time. The decay in PO2 in the first 2 minutes for blood with leukocyte counts of between 55.2 X 10(3)/mm3 and 490.0 X 10(3)/mm3 ranged from 13 to 72 torr. The degree of PO2 decay was blunted by placing the blood on ice and was obliterated by adding potassium cyanide. Thus, extreme leukocytosis secondary to leukemia can cause spurious hypoxemia and spurious lowering of the mixed venous PO2 due to oxygen consumption by leukocytes ("leukocyte larceny").

Late postsplenectomy recurrence of thrombotic thrombocytopenic purpura responding to removal of accessory spleen.

The present report describes a patient who experienced recurrence of thrombotic thrombocytopenic purpura 10 years after the initial episode. The patient had been successfully treated with steroids and splenectomy and had complete clinical and hematologic remission. Thrombotic thrombocytopenic purpura recurred 10 years later and did not respond to steroids and plasmapheresis. The presence of an accessory spleen was demonstrated by technetium scanning. Surgical removal of the accessory spleen resulted again in prompt and complete recovery.

Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.

Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.

Is splenectomy more dangerous for massive spleens?

BACKGROUND: Reports vary about whether risks are greater for removal of massive (> or = 1500 g) spleens than for smaller (< 1500 g) spleens. We sought to determine the hazards of splenectomy. METHODS: We reviewed 223 consecutive adults with elective splenectomies for hematologic diseases. Morbidity and mortality rates were combined with published data to create a meta-analysis. RESULTS: Patients with massive spleens are more likely to have postoperative complications (relative risk [RR] 2.1, 95% confidence interval [CI] 1.3 to 3.4; P = 0.003) and death (RR 4.7, 95% CI, 1.5 to 15.1; P = 0.01). However, when the investigation is restricted to comparable diagnoses, patients with massive spleens do not differ from those with smaller spleens regarding complications (RR 1.4, 95% CI, 0.8 to 2.7; P = 0.3) or mortality (RR 2.1, 95% CI, 0.5 to 9.7; P = 0.4). These observations are confirmed by metaanalysis. Furthermore, multivariate analysis indicts age as a critical risk of complications and death. CONCLUSIONS: Increased age and underlying illness are the predominant factors associated with morbidity and mortality following splenectomy for hematologic disease. Adjusting for age and diagnosis, spleen size is not a hazard.

Renal failure in Burkitt's lymphoma.

A case of Burkitt's lymphoma with renal failure due to massive infiltration of the kidney is reported. There was a striking initial response to chemotherapy with a parallel improvement in renal function and decrease in renal size. The rare occurrence of renal failure due to lymphomatous infiltration of the kidney parenchyma in the absence of urinary tract obstruction is reviewed.

Levels of salivary cystatins in periodontally healthy and diseased older adults.

Cystatins are cysteine protease inhibitors present in a variety of tissues and body fluids, including saliva. One possible function of these molecules may be to modulate tissue destruction in periodontal diseases. To investigate the potential role of salivary cystatins in these events, the levels of cystatins in saliva from periodontally healthy and diseased individuals were measured by enzyme-linked immunosorbent assay. Flow rates and total protein content were determined in all the samples collected, while cysteine protease inhibitory activity was assessed in submandibular-sublingual secretions. Statistical analysis showed no significant differences in the levels and activity of salivary cystatins in periodontally healthy and diseased individuals. These findings suggest that comparing the levels of cystatins in glandular salivas may not be a suitable indicator of periodontal disease status.

Quantification of P-32 removed during leukapheresis by bremsstrahlung counting.

The activity of P-32 removed during leukapheresis of a patient previously administered P-32 for therapy of chronic myelogenous leukemia (CML) was determined. The bremsstrahlung produced by P-32 beta rays in the pheresis bags allowed the quantitation of radioactivity by well counting in a sodium iodide detector and by a gamma camera. Bremsstrahlung counting demonstrated that leukapheresis removes such a small amount of radioactivity that the therapeutic effect of a previously administered P-32 dose was still valid. Bremsstrahlung counting offers advantages to a Nuclear Medicine Department over the conventional use of a liquid scintillation counter to detect P-32 beta rays in that it is simpler and more readily available.