Decreased resistance to intravenous tumour-cell challenge during reticuloendothelial depression following surgery

The influence of surgical stress on resistance to i.v. challenge with Walker 256 tumour cells was investigated in rats, with respect to the functional state of the reticuloendothelial system (RES). Phagocytic activity of the RES was evaluated by colloid (gelatinized [131I] "RE test lipid emulsion") clearance, and opsonin levels were determined by bioassay. Reticuloendothelial clearance capacity was significantly (P less than 0-05) depressed 60 min following surgery (coeliotomy plus jejunal enterotomy) as quantified by both humoral and cellular parameters of RE function. Phagocytic depression was primarily due to impaired hepatic Kupffer cell function and related to a deficiency in the phagocytic supporting capacity of plasma, also referred to as opsonic or recognition factor (RF) capacity. During the postoperative period of RES colloid clearance depression, pulmonary localization of the blood-borne test particulate matter increased. Rats challenged with 51Cr-labelled viable tumour cells at a dose of 1-0 X 106 i.v., either prior to or during the postoperative period of RE depression, manifested a significant (P less than 0-05) increment in pulmonary localization of the viable tumour cells, and a decrease (P less than 0-05) in hepatic clearance. Evaluation of survival patterns demonstrated a significant (P less than 0-01) decrease in host resistance to i.v. tumour cell challenge (2 X 103 cells) during the postoperative period of RE depression and hypo-opsonaemia. Sham-anaesthetized control animals survived 17-9 +/- 0-8 days, while animals challenged during the period of RE depression survived 7-9 +/- 0-4 days. An increased incidence of respiratory distress and nasal discharge was observed in the animals with impaired survival. Thus, surgical manipulation may transiently compromise RES systemic host defence and may be reflected in an increment in the pulmonary localization of blood-borne tumour cells. The relationship of this altered pattern of tumour cell distribution to the impaired survival remains to be determined, and warrants investigations.     

Glutamate dehydrogenase activity in the structures of the rabbit brain limbic system

The activity of glutamate dehydrogenase (EC 1.41.1.3) is studied in homogenates and subcellular fractions of five limbic structures: regio superior, regio inferior of hippocampus, fascia dentata, septum and corpora mamillaria. The lowest activity of the enzyme is found in regio superior of hippocampus. 80% of the total enzyme activity of primary fractions is found in "crude" mitochondria. After centrifugation of the latter within the linear sucrose density gradient the distribution of the enzume activity is similar for different structures and the highest activity is found in the region of sucrose molarity from 1.44 up to 1.50 M which corresponds to the mitochondria distribution region. 50% of the total found activity is in the fraction enriched by mitochondria, 30% is in the fraction enriched by nerve endings with the high activity of glutamate decarboxylase. It was found for different fractions that 1 mM of ADF with 0.2 mM NAD-H+ produces about 10-fold increase in the enzyme activity. Pyridoxal-5'-phosphate inhibits the enzyme from inactivation. The results are discussed in connection with the possible role of pyridoxal-5'-phosphate in regulation of the glutamate dehydrogenase activity in vivo.     

Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers

Urinary free cortisol excretion (UFC) was compared in 21 patients with chronic fatigue syndrome (CFS), in 10 melancholic depressives and in 15 healthy controls. Patients with depression had UFC values which were significantly higher than healthy comparison subjects, whereas UFC excretion of CFS patients was significantly lower than the comparison group. These findings are in keeping with currently held hypotheses of hyperactivity and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression and chronic fatigue syndrome respectively. Five of the 21 CFS patients had a co-morbid depressive illness. This sub-group retained the profile of UFC excretion of those with CFS alone, suggesting a different pathophysiological basis for depressive symptoms in CFS.     

Comparison of the pharmacological profile of S-nitrosothiols, nitric oxide and the nitrergic neurotransmitter in the canine ileocolonic junction

1. In organ bath experiments, hydroquinone (30-100 microM) and hydroxocobalamin (30-100 microM) concentration-dependently inhibited the relaxations induced by NO (0.3-30 microM) but not those by nitroglycerin (GTN, 1 microM) in the canine ileocolonic junction (ICJ). Hydroxocobalamin reduced the relaxation to low frequency (2 Hz) stimulation of the non-adrenergic, non-cholinergic (NANC) nerves, whereas hydroquinone only reduced the NANC nerve-mediated relaxations to electrical stimulation at 16 Hz, 0.5 ms. 2. Relaxations to S-nitroso-L-cysteine (CysNO, 1-30 microM), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1-30 microM) were not inhibited by hydroquinone (30-100 microM), hydroxocobalamin (30-100 microM), pyrogallol (30-100 microM) or L-cysteine (1-3 microM). Hydroquinone (100 microM) only reduced the relaxation to 10 microM CysNO. Hydroxocobalamin, but not hydroquinone, pyrogallol or L-cysteine, potentiated the relaxations to the lowest concentration (1 microM) of S-nitrosoglutathione (GSNO, 1-30 microM). 3. In the superfusion bioassay, hydroquinone (100 microM) and hydroxocobalamin (1 microM) concentration-dependently inhibited the biological activity of authentic NO (1-4 pmol) to the same extent as that of the transferable nitrergic factor, released from the canine ICJ in response to NANC nerve stimulation (8-16 Hz, 2 ms). Responses to GTN (10 pmol) or adenosine 5'-triphosphate (10 nmol) were not affected. 4. In conclusion, the nitrosothiols CysNO, SNAP and GSNO relax the canine ileocolonic junction, but these relaxations, pharmacologically, behave differently from the NANC nerve-mediated relaxations. From the bioassay experiments, we conclude that the nitrergic factor, released in response to NANCnerve stimulation of the canine ICJ, behaves pharmacologically like NO but not like a nitrosothiol.Therefore, we suggest NO, and not CysNO, SNAP or GSNO as the inhibitory NANC neurotransmitter in the canine ICJ.     

Efficacy of low-dose dopamine in preventing amphotericin B nephrotoxicity in bone marrow transplant patients and leukemia patients

This study evaluated the efficacy of low-dose dopamine for prevention of amphotericin B-induced nephrotoxicity in autologous bone marrow transplant and leukemia patients. Seventy-one patients undergoing cytoreductive therapy who required amphotericin B were randomly assigned in an unblinded fashion to a group receiving continuous-infusion low-dose dopamine (3 microgram/kg/min) or a group receiving no dopamine. Amphotericin B was dosed at 0.5 or 1.0 mg/kg/day based on computerized tomography scan results or presence of positive blood cultures. No patient received saline boluses. The rate of nephrotoxicity, severity as graded by Southwest Oncology Group toxicity criteria, and time to each grade of nephrotoxicity were compared between the two groups. Eighty percent of the no-dopamine group and 66.7% of the dopamine group developed nephrotoxicity, defined as a 1.5-fold or greater increase in baseline serum creatinine level (P = 0.20). No statistical difference was noted at any grade of nephrotoxicity between the two groups. Thirty-four percent of patients in the no-dopamine group versus 17.6% in the dopamine group had a 2.5-fold or greater increase in serum creatinine level, which was not statistically significant (P = 0.0888). Ten patients developed grade IV nephrotoxicity and were withdrawn from the study, 7 in the no-dopamine group and 3 in the dopamine group (P = 0.19). The time to each grade of nephrotoxicity was also not significantly different for the two groups. Eleven adverse drug reactions were reported in the dopamine group in comparison to one in the no-dopamine group. Thus, dopamine offers little in the way of prevention of nephrotoxicity associated with amphotericin B therapy. Although the significance of drug reactions in the dopamine group is not clearly established due to lack of cardiac monitoring in the no-dopamine group, dopamine therapy is not without complications.     

Genetic susceptibility testing: ethical and social quandaries

We have isolated a novel human C-C chemokine, MIP-1 delta from a human fetal spleen cDNA library. The human MIP-1 delta cDNA has an unusually long 400-bp 5-prime untranslated region and a predicted 113-amino acid protein of 10 kDa. The coding sequence contains a signal peptide of 21 amino acids, indicating that the mature protein has 92 amino acids (8 kDa). Recombinant human MIP-1 delta produced by transfected human embryonic kidney 293 cells produced an 8-kDa protein, which confirmed the presence of a signal peptide. Compared with other human C-C chemokines, human MIP-1 delta shows the highest homology with human HCC-1, CK beta-8, murine C10, and CCF18 (MIP-1 gamma). The human MIP-1 delta gene is localized on chromosome 17 where most of the C-C chemokine superfamily is located. Human MIP-1 delta is expressed in T and B lymphocytes, NK cells, monocytes, and monocyte-derived dendritic cells, but not in bone marrow-derived dendritic cells. Its expression can be induced by other proinflammatory cytokines in monocytes and dendritic cells. Human MIP-1 delta is chemotactic for T cells and monocytes, but not for neutrophils, eosinophils, or B cells. Human MIP-1 delta induced calcium flux in human CCR1-transfected cells.