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Imatinib mesylate (Gleevec, Glivec; Novartis, Basel, Switzerland) is a specific tyrosine kinase inhibitor that has become the gold-standard treatment for patients with chronic myeloid leukemia. Several tyrosine kinases inhibited by imatinib are expressed in the kidney, and although the drug is usually well tolerated, several cases of acute renal failure were reported. We describe for the first time a case of a patient treated by imatinib for chronic myeloid leukemia who developed partial Fanconi syndrome with mild renal failure, which leads to a discussion of the pathophysiological characteristics of imatinib-induced renal toxicity. Patients on long-term imatinib treatment should be monitored for renal failure, as well as proximal tubule dysfunction, including hypophosphatemia. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Background: Conflicting haemodynamic changes, suggested to be caused by vasopressin release, have been reported during carbon dioxide (CO2) pneumoperitoneum. However, peritoneal stimulations including open surgery cause both a systemic vasopressor response and a vasopressin release, which are suppressed by opiate administration. Also, a decreased venous return of blood to the heart causes vasopressin release. Furthermore, previous haemodynamic assessments of laparoscopic surgery have been conducted using various anaesthetic regimens, which are likely to have caused various haemodynamic effects. We hypothesised that intraoperative haemodynamic and/or humoral changes would not be observed in association with laparoscopic surgery provided that, (a) normovolaemia is continuously maintained using transoesophageal echocardiographic (TEE) assessment, and (b) adequate depth of general anaesthesia is continuously maintained by bispectral index (BIS) monitoring and high plasma Ievel opiate administration. Methods: Twenty ASA 1 women undergoing laparoscopic surgery received 10 ml · kg-1 lactated Ringer’s solution and thereafter were randomly allocated to receive intraoperatively either 8 ng · ml-1 or 4 ng · ml-1 plasma remifentanil concentrations while BIS was maintained at 50±5 by isoflurane alteration. The group receiving 4 ng · ml-1 remifentanil was used as control. Expired CO2 was maintained within a 32–38 kPa range throughout the investigation. Complete TEE haemodynamic investigation was performed before pneumoperitoneum (PP) (T1), and during PP horizontal (T2), with a head-up tilt (T3), with a head-down tilt (T4), horizontal (T5), and PP released (T6). Plasma vasopressin, epinephrine and norepinephrine levels were measured at T1, T3, and T6. ANOVA, Student’s t-test and Mann-Whitney U-test were used for statistical analysis. Results: Haemodynamic indices and humoral values did not change significantly within and between remifentanil groups throughout the investigation (all P<0.05). Conclusion: Continuous adequate depth of anaesthesia and normovolaemia may have prevented both a humoral and a haemodynamic response, initiated in the peritoneum by the contact with CO2 in previous investigations. [ABSTRACT FROM AUTHOR]

The effect of endogenously generated reactive oxygen metabolites on the interaction of human blood monocytes with tumour necrosis factor-alpha (TNF-α) was investigated. Pre-exposure of unactivated human blood monocytes to dimethylthiourea, a scavenger of hydroxyl radical (OH.), or to desferrioxamine (DFX), an iron chelator preventing the synthesis of OH., enhanced the specific binding of 125I-TNF-α to its receptors. Scavengers of superoxide anion or hydrogen peroxide were without effect. DFX-induced up-regulation of 125I-TNF-α binding depended on the concentration of the drug (1-5 mM) and on the duration of the treatment (1-18 h). It was not due to a reduction of receptor occupancy by endogenously generated TNF-α. Scatchard analysis of binding data revealed that DFX caused an approximately two-fold increase in the number of type II TNF-α receptors, with no change in their affinity. This up-regulation, that did not require synthesis of new proteins, was associated with a decrease in the internalization rate of TNF-α receptors, the half-life of which was doubled. Conversely, these findings suggest that OH. generation by monocytes may have a physiological role in reducing the activity of membrane-associated TNF-α receptors. [ABSTRACT FROM AUTHOR]

Previous studies have shown that desferrioxamine (DFX), an iron chelator preventing the synthesis of hydroxyl radical (OH.), up-regulates the cell-surface expression of tumour necrosis factor-α (TNF-α) receptors on unactivated human blood monocytes. In the present study, we investigated the regulatory action of DFX on 125I-TNF-α binding to monocytes upon exposure to bacterial lipopolysaccharide (LPS). Exposure to LPS (1 µg/ml) resulted in almost complete loss of 125I-TNF-α binding to the surface of monocytes. This down-regulation was reversible and the recovery observed after 18 hr was enhanced by addition of DFX (5 mM). However, binding studies on monocytes preexposed to low pH suggested that the DFX-induced increase of 125I-TNF-α binding was not due to differences in the number of receptors available but was probably due to a reduction of receptor occupancy by endogenously generated TNF-α. Time-course studies of TNF-α release from monocytes confirmed the ability of DFX to reduce the extracellular concentration of bioactive TNFα through a decrease of its synthesis and an increase of its inactivation. The latter process was associated with an increased expression of the soluble form of TNF-α receptor type II. These results indicate that, in the presence of LPS, DFX increases the release of soluble TNF-α receptors from monocytes. Thus, conversely, OH. generated in situ could reduce the shedding of soluble TNF-α receptors and, hence, increase the widespread release of bioactive TNF-α. [ABSTRACT FROM AUTHOR]

Blood monocytes from tuberculosis patients release high amounts of tumour necrosis factor-alpha (TNF-α). Because the biological efficiency of TNF-α would depend on the expression of TNF-α receptors on target cells, we thought to analyse the capacity of blood monocytes from a group of patients with pulmonary tuberculosis to binding 125I-TNF-α. We report a slight but not significant enhancement in specific binding of 125I -TNF-α on monocytes of 15 consecutively studied patients compared with 10 controls. Percent cell surface bound and internalized 125I -TNF-α was identical in the two groups. To evaluate the receptor occupancy by endogenously generated TNF-α, similar experiments were performed after cell exposure to low-pH glycine buffer. Under these conditions, specific binding of 125I-TNF-α was significantly higher on tuberculosis monocytes compared with control monocytes. Moreover, the occupancy of TNF-α receptors by endogenously generated TNF-α that was found to be significantly higher on tuberculosis monocytes than on control monocytes, was directly related to the enhanced capacity or mononuclear cells to generate TNF-α in vitro. It normalized after 3 months of antituberculous therapy, Scatchard analysis of the binding data revealed that tuberculosis infection caused a significant increase in high affinity 125I-TNF-α binding to monocytes without any significant change in the dissociation constant. Collectively, these results indicate an up-regulation of TNF-α generation and binding to blood monocytes in patients with pulmonary tuberculosis. They provide support to the hypothesis that TNF-α is of critical importance in the pathogenesis of this infection. [ABSTRACT FROM AUTHOR]

Discusses an abstract of a study published in a year 2000 issue of the 'Kidney International' regarding glomerulosclerosis in mice transgenic for human insulin-like growth factor (IGF)-binding protein-1. Role of growth hormone/IGF system in the glomerulosclerosis process; Increase in mesangial extracellular matrix area in homozygous transgenic mice.