Enzymuria in carboplatin nephrotoxicity

Urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is an early marker of nephrotoxicity. NAG activity was assayed by the fluorimetric method of Leaback and Walker in 17 patients treated (22 courses) with carboplatin (CBDCA, 220-550 mg/m2) before infusion and 24, 48, 72 and 96 h after. Increased excretion of NAG, a sensitive index of renal tubular damage, was observed following 10 of the 22 courses. A transient increase in plasma creatinine and/or abnormal proteinuria was observed in 6 cases. Impaired renal function prior to therapy seems to be a predisposing factor to the nephrotoxicity.     

Intracerebroventricular injection of hemicholinium-3 prevents the ACTH-induced, but not the physostigmine-induced, reversal of hemorrhagic shock in rats

In rats bled to hypovolemic shock, the intracerebroventricular injection of hemicholinium-3 (20 micrograms/rat) completely prevented the shock reversal induced by the intravenous injection of ACTH (1-24) (160 micrograms/kg), but had no influence on the shock reversal induced by the intravenous injection of physostigmine (70 micrograms/kg). These data indicate that brain cholinergic neurons are involved in the anti-shock effect of ACTH-peptides, but not in that of centrally acting cholinergic drugs.     

Influence of ovariectomy, estradiol and progesterone on the behavior of mice in an experimental model of depression

In the tail suspension test (an animal model of depression) the duration of immobility during the 6 min of observation was 56.84 +/- 6.54 sec in sham-ovariectomized mice and 113.11 +/- 7.86 sec 30-32 days after ovariectomy. Estradiol (10, 100 or 1,000 micrograms/kg) and progesterone (50, 1,000 or 10,000 micrograms/kg), subcutaneously injected daily 4 times before the test, restored the duration of immobility in ovariectomized mice to normal, while having no effect on sham-operated animals. On the other hand, desipramine (20 mg/kg IP 1 hr before testing) significantly reduced the duration of immobility both in ovariectomized and in sham-operated mice. These data indicate that ovarian sex hormones, while having no "antidepressant," desipramine-like, effect on the behavior of intact adult female mice, have such an effect in ovariectomized mice, and enable the animal to cope in a "normal" way with adverse environmental situations.     

Chronic administration ofl-sulpiride at non-neuroleptic doses reduces the duration of immobility in experimental models of “depression-like” behavior

It has been shown that long-term administration ofl-sulpiride induces a down-regulation of receptor-associated adenylate cyclase activity in the frontal cortex of rats, an adaptive response that is typically associated with the chronic administration of antidepressants. Here we show that in two animal models of depression-like behavior (forced swim in rats and tail suspension in mice), the long-term (21 days) administration ofl-sulpiride at a non-neuroleptic dose (2 mg/kg IP twice a day) significantly decreases the duration of immobility, the effect being similar to that of desipramine (20 mg/kg IP). The same dose (2 mg/kg) ofl-sulpiride, acutely administered, has no effect at all. On the other hand, either chronic (21 days) or acute administration of neuroleptic doses ofl-sulpiride have an opposite effect, and indeed increase the duration of immobility. These results are an in vivo support to the in vitro findings suggesting that low doses ofl-sulpiride may have antidepressant-like activity.     

Calculated and measured oxygen consumption in mechanically ventilated surgical patients in the early post-operative period

Oxygen consumption (VO2) measured by indirect calorimetry (Nellcor-Puritan-Bennett 7250; Carlsbad, CA, USA) has been compared with VO2 calculated by the Fick method in 22 volume-controlled ventilated general surgical patients in the early post-operative period. For 198 pairs of measurements, VO2 Fick and VO2 indirect calorimetry correlated significantly (y = 1.00x - 35.8, P = 0.0001, r = 0.77). VO2 indirect calorimetry was 212 +/- 32 mL min-1 and VO2 Fick was 177 +/- 41 mL min-1 (P = 0.0001). The bias was 35 +/- 26 mL min-1. This difference represents 16 +/- 13% of the total body VO2. VO2 calculated by the Fick method did not accurately predict VO2 measured by indirect calorimetry, and the two methods were not interchangeable. VO2 calculated by the Fick method underestimated VO2 as measured by indirect calorimetry by a systematic quantity that could be attributed, in part, to VO2 of the lung. Indirect calorimetry should be the preferred method for measuring total body VO2 in mechanically ventilated surgical patients.     

l-Sulpiride, at a low, non-neuroleptic dose, prevents conditioned fear stress-induced freezing behavior in rats

Antidepressant drugs are effective in anxiety states, including panic disorder. Both clinical and animal studies indicate that l-sulpiride, at low, non-neuroleptic doses, has antidepressant activity. The present study examined the effect of an antidepressant dose of l-sulpiride (4 mg/kg per day SC), compared with a well-established antidepressant drug (fluoxetine, 3 mg/ kg per day SC), in a rat model of anticipatory anxiety/panic behavior: conditioned fear stress-induced freezing behavior. Long-term (26 days) administration of l-sulpiride almost completely abolished freezing, a similar effect being produced by fluoxetine (freezing duration, in seconds: controls, 148.1 ± 29.6; l-sulpiride, 27.5 ± 8.3; fluoxetine, 72.0 ± 15.2). The same doses of l-sulpiride (4 mg/kg SC) and fluoxetine (3 mg/kg SC) had no effect when administered for shorter periods (1, 5, or 12 days). No effect was produced by the long-term (26 days) administration of a neuroleptic dose of l-sulpiride (20 mg/kg per day SC). These results demonstrate that long-term administration of low, non-neuroleptic doses of l-sulpiride, is highly effective in an animal model of anticipatory anxiety/panic behavior. Received: 13 March 1998/Final version: 23 July 1998     

Stroma cells: a novel target of herceptin activity.

PURPOSE: Stroma cells play a relevant role in tumor development and progression. We investigated the activity of herceptin (HER), a humanized monoclonal antibody widely used for the treatment of HER2-overexpressing epithelial cancer, toward stroma cell lines L87/4 and L88/5. EXPERIMENTAL DESIGN: We studied the antiproliferative potential of HER and role of human serum in HER activity. We also investigated the ability of HER to alter ancillary functions of L87/4 and L88/5, such as support to long-term hematopoiesis, growth factor production, breast cancer cell adhesion, and proliferation. RESULTS: Flow cytometry showed that HER2 membrane expression in L87/4 and L88/5 stroma cells was intermediate between the expression in HER2-negative/dim MCF-7 breast cancer cells and HER2-bright SK-BC3 breast cancer cells. HER2 gene amplification was not detected by fluorescence in situ hybridization in either stromal cell lines. HER significantly inhibited L87/4 and L88/5 proliferation. Mean ID(50)s were found to be 2000 and 1700 micro g/ml for L87/4 and L88/5, respectively, after 3-day exposure and 800 micro g/ml for both cell lines after 9-day exposure. The presence of 10% human serum in the culture increased HER inhibitory activity. IC(50) of stroma cells was found to be intermediate between HER2-bright breast cancer cells (SK-BC3) and HER2-negative/dim breast cancer cells (MCF-7). The drug did not significantly affect the ability of stroma cells to support long-term hematopoiesis in the cobblestone area forming cell assay. In contrast, in coculture assay, MCF7 cells demonstrated a worse adhesion and growth capability on HER-treated stroma layers when compared with untreated stroma. Moreover, HER significantly reduced vascular endothelial growth factor production by L88/5 cells. CONCLUSIONS: Our data support the novel finding that HER may have a relevant activity against stroma cells.     

Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia

One of the genetic features of the Sardinian population is the high prevalence of hemoglobin disorders. It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers. In this population, a single mutation of beta-globin gene (Q39X, beta(0) 39) accounts for >95% of beta-thalassemia cases. Because previous studies have shown that Sardinian beta-thalassemia carriers have lower total and low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether this LDL-lowering effect of the beta-thalassemia trait was also present in subjects with familial hypercholesterolemia (FH). In a group of 63 Sardinian patients with the clinical diagnosis of FH, we identified 21 unrelated probands carrying 7 different mutations of the LDL receptor gene, 2 already known (313+1 g>a and C95R) and 5 not previously reported (D118N, C255W, A378T, T413R, and Fs572). The 313+1 g>a and Fs572 mutations were found in several families. In cluster Fs572, the plasma LDL cholesterol level was 5.76+/-1.08 mmol/L in subjects with beta(0)-thalassemia trait and 8.25+/-1.66 mmol/L in subjects without this trait (P<0.001). This LDL-lowering effect was confirmed in an FH heterozygote of the same cluster who had beta(0)-thalassemia major and whose LDL cholesterol level was below the 50th percentile of the distribution in the normal Sardinian population. The hypocholesterolemic effect of beta(0)-thalassemia trait emerged also when we pooled the data from all FH subjects with and without beta(0)-thalassemia trait, regardless of the type of mutation in the LDL receptor gene. The LDL-lowering effect of beta(0)-thalassemia may be related to (1) the mild erythroid hyperplasia, which would increase the LDL removal by the bone marrow, and (2) the chronic activation of the monocyte-macrophage system, causing an increased secretion of some cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) known to affect the hepatic secretion and the receptor-mediated removal of apolipoprotein B-containing lipoproteins. The observation that our FH subjects with beta(0)-thalassemia trait (compared with noncarriers) have an increase of blood reticulocytes (40%) and plasma levels of interleukin-6 (+60%) supports these hypotheses. The lifelong LDL-lowering effect of beta(0)-thalassemia trait might slow the development and progression of coronary atherosclerosis in FH.