Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model

Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.     

Simultaneous protective effect of a new chelating agent and zinc, on the carbon tetrachloride induced hepatic injury in squirrels

X-ray test of the osteo-articular system of upper limbs was carried out on 1231 saweyers and 272 controls as well as 50 intellectuals. Three x-ray tests were carried out on 207 sawyers and on a control group of 95 workers, to assess the progression of osseous changes. The same types od changes were found in sawyers and control group workers; besides similar frequency in the examined parts of the upper limb was found in them. The most frequent changes are: osseous cyst, osteoporosis degenerative-deformative changes and calcar of the ulnar. The greatest amounts of changes were observed in the bones and joints of the hand and next in elbow joint and acromioclavicular joint. It was observed that amoungst the sawyers and the control group workers, the greatest amounts of changes occur after 2 years of work. Progression of osseous changes after 3-4 years of work was observed in 30,9% sawyers and 12,6% control group workers.     

Tumor cell cytotoxicity of a novel metal chelator

We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity. When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 micromol/L compared with 70 micromol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration.     

Learning to predict human error: issues of acceptability, reliability and validity

Human Error Identification (HEI) techniques have been used to predict human error in high risk environments for the past two decades. Despite the lack of supportive evidence for their efficacy, their popularity remains unabated. The application of these approaches is ever-increasing, to include product assessment. The authors feel that it is necessary to prove that the predictions are both reliable and valid before the approaches can be recommended with any confidence. This paper provides evidence to suggest that human error identification techniques in general, and SHERPA in particular, may be acquired with relative ease and can provide reasonable error predictions.     

Kindling-like state occurring on periodic increases in the extracellular K+ concentration in field CA1 in rat hippocampal slices

Transient periodic increases in the extracellular K+ concentration (20 mM, 30 sec, 3-6 episodes) led to the appearance of a kindling-like state in local neuronal networks of field CA1 of rat hippocampal slices. A criterion for the appearance of this state was a reduction in the threshold for the generation of multiple population discharges and an increase in the total number of population spikes within discharges (epileptiform activity). This state correlated with potentiation of excitatory postsynaptic potentials (EPSP) (long-term increases in pyramidal neuron excitability), but not with potentiation of glutamatergic synaptic transmission in field CA1 of hippocampal slices. The role of the various Ca2+ channels in inducing and maintaining the kindling-like state in rat hippocampal sections, evoked by periodic increases in the extracellular K+ concentration, is discussed.     

Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats

Cold exposure increases TRH gene expression in hypothalamic and raphe nuclei and results in a vagal activation of gastric function. We investigated the role of medullary TRH receptors in cold (4-6 C, 90 min)-induced stimulation of gastric motor function in fasted conscious rats using intracisternal injections of TRH receptor (TRHr) antisense oligodeoxynucleotides (100 microg twice, -48 and -24 h). The gastric emptying of a methyl-cellulose solution was assessed by the phenol red method. TRH (0.1 microg) or the somatostatin subtype 5-preferring analog, BIM-23052 (1 microg), injected intracisternally increased basal gastric emptying by 34% and 47%, respectively. TRHr antisense, which had no effect on basal emptying, blocked TRH action but did not influence that of BIM-23052. Cold exposure increased gastric emptying by 64%, and the response was inhibited by vagotomy, atropine (0.1 mg/kg, i.p.), and TRHr antisense (intracisternally). Saline or mismatched oligodeoxynucleotides, injected intracisternally under similar conditions, did not alter the enhanced gastric emptying induced by cold or intracisternal injection of TRH or BIM-23052. These results indicate that TRH receptor activation in the brain stem mediates acute cold-induced vagal cholinergic stimulation of gastric transit, and that medullary TRH may play a role in the autonomic visceral responses to acute cold.     

Strain gauge plethysmography and Doppler ultrasound in the measurement of limb blood flow

The maintenance of adequate oxygen delivery (DO2) and tissue uptake (VO2) has become central dogma in the management of the critically ill. However, these parameters are derived using gas tensions measured in mixed venous blood and may not reflect changes in regional blood flow. Therefore, it has become necessary to provide estimates of blood flow to specific organs and to evaluate the most adequate techniques available. In order to define the best means of assessing blood flow to the lower limb noninvasively in normal subjects, measurements of superficial femoral arterial blood flow using Doppler ultrasound (DU) and strain gauge plethysmography (SGP) were compared in 10 normal volunteers at rest and during exercise. To evaluate the effect of strain gauge positioning, results of measurements made under four different combinations of cuff/strain gauge placement were compared in 15 other volunteers. The correlation of the limb blood flow obtained using the two methods at rest and exercise was 0.57 and 0.62 and the limits of agreement (d +/- 2SD) were 0.40 +/- 2.49 and -0.86 +/- 5.22 ml 100 ml-1 tissue min-1 at rest and on exercise, respectively. Results obtained using SGP were more reproducible (Coef. repeat. 0.45 vs. 0.94 ml 100 ml-1 tissue min-1, for SGP and DU, respectively). The various combinations of cuff/strain gauge positioning showed a tendency to over-read when the latter was placed on the thigh, but were not significantly different (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of a corpus luteum tissue extract on rabbit ovarian mesothelial cells

This study investigates rabbit ovarian mesothelial (OM) cells exposed in vitro to a crude corpus luteum extract (CLE; 60 micrograms/ml). The growth of OM cells was evaluated by measuring the change in cell number (mean % +/- standard error of mean, SEM), the number of cell population doublings (CPD +/- SEM), and the cell population doubling time in hours (CPDT +/- SEM) after 7.5 days of culture in a serum-poor medium. Quantitative estimates of surface morphology changes were obtained by analyzing the total number (mean no. +/- SEM), density (mean no./100 microns 2 +/- SEM), and length-to-diameter ratio (mean L/D +/- SEM) of microvilli. OM cells in control medium formed loosely cohesive monolayers, and grew 152.53 +/- 11.01% with a CPD of 0.59 +/- 0.08 and a CPDT of 117.29 +/- 6.43 hours. The exposed surface area of these cells was over 8,000 microns 2 and was covered in its epinuclear region by long and slender microvilli with a L/D of 6.01 +/- 0.29. The total number of microvilli in each control cell was 1977.52 +/- 120.49 with a density of 0.58 +/- 0.03/100 microns 2 in the epinuclear region and of 0.05 +/- 0.003/150 microns 2 in the remaining surface area (5,161.62 +/- 354.43 microns 2). In contrast, CLE-rich cells cultures grew 329.57 +/- 16.65%, with a CPD of 1.71 +/- 0.07 and a CPDT of 53.43 +/- 2.93 hours.(ABSTRACT TRUNCATED AT 250 WORDS)