Ultrasensitive analysis of the intestinal absorption and compartmentalization of aluminium in uraemic rats: a 26Al tracer study employing accelerator mass spectrometry

BACKGROUND: Developments in accelerator mass spectrometry (AMS) now permit the determination of femtogram amounts of 26Al in blood and in various tissues with good precision and free of external contamination. METHODS: In the present study we used trace quantities of 26Al to investigate the intestinal absorption and compartmentalization of aluminium in rats with renal failure (Nx, 5/6 nephrectomy) and in pair- fed controls (C). Single oral doses of 20 ng 26Al were administered to six animals in each group and, subsequently, 24-h post-load 26Al was analysed in serum, urine, bone, liver, and spleen by means of AMS. RESULTS: Serum concentrations of 26Al were significantly lower in uraemic rats compared to controls, whereas urinary excretion was comparable (Nx, 7.11 +/- 5.78 pg/day vs C, 9.46 +/- 6.10 pg/day), suggesting a higher fraction of ultrafiltrable serum 26Al in uraemia. The target tissues of cellular transferrin-mediated 26Al uptake, liver and spleen, tended to show a larger degree of aluminium accumulation in controls (0.26 +/- 0.31 pg/g vs Nx, 0.14 +/- 0.10 pg/g and 0.37 +/- 0.27 pg/g vs Nx, 0.25 +/- 0.27 pg/g respectively). In contrast, in bone, a site of extracellular aluminium deposition, 26Al concentrations were more elevated in uraemia (1.22 +/- 0.59 pg/g vs C: 0.68 +/- 0.30 pg/g). Estimated total 26Al accumulation in all measured target tissues was significantly higher in uraemic rats (28.15 +/- 9.90 pg vs C: 17.03 +/- 7.03 pg) and total recovery of 26Al from tissue and urine was 26.58 +/- 6.74 pg in controls and 35.75 +/- 7.03 pg in uraemic animals, suggesting a fractional absorption of 0.133% and 0.175% respectively. CONCLUSIONS: Our data suggest that fractional absorption from a dietary level dose of 26Al is about 0.13%. Compartmentalization occurs in transferrin-dependent target tissues such as liver and spleen; however, in quantitative terms extracellular deposition in bone is more important. Uraemia has a significant effect on the intestinal absorption and compartmentalization of aluminium. It enhances fractional absorption and increases subsequent extracellular deposition of aluminium in bone. However, at the same time uraemia does not increase transferrin-dependent cellular accumulation of aluminium in liver and spleen.      

Synthesis and biological activity of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine deoxyuridine diastereomers.

The synthesis of the two diastereomers (9 and 10) of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine are described. Their antiviral and cytotoxic activities were determined, in comparison with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 5-fluoro-2'-deoxyuridine (FDU), respectively. 5-[(1R)-2,2-Difluorocyclopropyl]-2'-deoxyuridine (10) was the most active antiviral agent against HSV-1 (IC50 = 5 micrograms/ml) relative to BVDU (IC50 = 0.082 micrograms/ml), and cytotoxic agent in the CCRF-CEM (IC50 = 230 microM) screen relative to FDU (IC50 = 4.7 x 10(-3) microM). The 5-[(1S)-2,2-difluorocyclopropyl] diastereomer was inactive in both screens. Partition coefficients (P) and affinity for the mouse erythrocyte nucleoside transporter (Ki) were not determinants of antiviral or cytotoxic activities. However, the (1R)-diastereomer (10) was more resistant to glycosidic bond cleavage by thymidine phosphorylase than the (1S)-diastereomer (9).     

Synthesis of 131I, 125I and 82Br labelled (E)-5-(2-halovinyl)-2'-deoxyuridines

Radiohalogenated (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU, 4) and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, 5) were synthesized by reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridine (1) with radiolabelled iodide or bromide in the presence of chloramine-T. A "no-carrier-added" synthesis of [131I]IVDU was completed within 30 min providing a radiochemical yield of 65%. Alternatively, radioactive iodine was incorporated into IVDU using a halogen isotope exchange reaction catalyzed by cuprous ion. [82Br]BVDU was also prepared by direct neutron activation of unlabelled BVDU.     

Tumor uptake of radiolabelled pyrimidine bases and pyrimidine nucleosides in animal models: VI. 1-(3'-[36Cl]-chloro-, 1-(3'-[82Br]-bromo- and 1-(3'-[123I]-Iodo-3'-deoxy-beta-D-arabinofuranosyl)uracil

3'-Radiohalogenated (36Cl, 82Br and 123I) "arabino" pyrimidine nucleosides were evaluated as potential tumor diagnostic agents in tumor bearing animals. No preferential tissue uptake was observed. The compounds were excreted mainly unchanged in the urine. The 3'-[36Cl]- and 3'-[82Br]-3'-deoxyarabino nucleosides exhibited biliary uptake. The low uptake of injected radioactivity by the tumor was probably due to the combined effects of the lack of a C-3' hydroxyl group in the "ribo" configuration, the presence of a halogen, the structural rigidity imposed by the presence of a halogen and the short biological half-lives of the compounds.     

The expanding role of ICU medical directors: from patient management to unit management

Over the past three decades the focus of physicians delivering intensive care has been on patient management whereas the management of critical care units has been done primarily by nurses. This article reviews existing literature and the arguments supporting a more active role for physicians in the management of critical care units.     

An evaluation of outcome from intensive care in major medical centers

We prospectively studied treatment and outcome in 5030 patients in intensive care units at 13 tertiary care hospitals. We stratified each hospital's patients by individual risk of death using diagnosis, indication for treatment, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. We then compared actual and predicted death rates using group results as the standard. One hospital had significantly better results with 69 predicted but 41 observed deaths (p less than 0.0001). Another hospital had significantly inferior results with 58% more deaths than expected (p less than 0.0001). These differences occurred within specific diagnostic categories, for medical patients alone and for medical and surgical patients combined, and were related more to the interaction and coordination of each hospital's intensive care unit staff than to the unit's administrative structure, amount of specialized treatment used, or the hospital's teaching status. Our findings support the hypothesis that the degree of coordination of intensive care significantly influences its effectiveness.     

Identification of low-risk monitor admissions to medical-surgical ICUs

A total of 5,790 intensive care unit (ICU) admissions from 13 tertiary care institutions were studied to identify patients who were at such low risk of receiving unique ICU therapies that admission might have been avoided or the length of ICU stay reduced. We used acute severity of disease on admission to the ICU along with the type of disease or surgery to risk stratify individual ICU patients. Among 1,941 patients who only received monitoring services on admission to the ICU, 1,358 (70 percent) were predicted to have less than a 10 percent risk of requiring subsequent active ICU treatment. Only 58 (4.3 percent) of these low-risk patients actually received active treatment. The identification of low-risk patients was equally accurate in estimation and validation data sets. Our methods should allow physicians and hospitals to assess their current ICU utilization and, if appropriate, guide reductions in use.     

Acute toxicity and first clinical results of intensive postinduction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia [see comments]

The combination of high-dose busulfan (16 mg/kg) and 200 mg/kg cyclophosphamide is gaining increasing significance as a preparative regimen prior to autologous, syngeneic, or allogeneic marrow transplantation. A new regimen of high-dose busulfan in conjunction with a reduced dose of 120 mg/kg cyclophosphamide has recently been described as a preparative regimen prior to allogeneic transplantation. To determine the drug-related nonhematologic toxic effects of this new regimen without confounding factors associated with allogeneic transplantation, we conducted a pilot study using this new regimen in 20 patients with acute myeloid leukemia (AML) in first remission prior to autologous unpurged marrow transplantation. All patients experienced transient non-life-threatening acute drug-related toxicity with skin reactions in 20 (100%), nausea and vomiting in 20 (100%), oral mucositis in 18 (90%), hepatic functional impairment in 17 (85%), hemorrhagic cystitis in three (15%), and generalized seizures in two (10%) of these patients, respectively. Two procedural, fatal complications resulted from infectious causes that were not directly related to the speed of hematopoietic reconstitution or the toxicity of the preparative regimen. The 3-year event-free survival estimate (55% +/- 11%) and probability of leukemic recurrence (38% +/- 11%) attained with this new regimen in recipients of autografts in first remission of AML are promising and challenge comparisons with preparative regimens employing combinations of cytotoxic agents or total body irradiation (TBI).