Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes.

5-Amino-4-imidazolecarboxamide (AICA) riboside, the nucleoside corresponding to AICA ribotide (AICAR or ZMP), an intermediate of the de novo pathway of purine biosynthesis, was found to exert a dose-dependent inhibition on gluconeogenesis in isolated rat hepatocytes. Production of glucose from lactate-pyruvate mixtures was half-maximally inhibited by approximately 100 microM and completely suppressed by 500 microM AICA riboside. AICA riboside also inhibited the production of glucose from all other gluconeogenic precursors investigated, i.e., fructose, dihydroxyacetone, and L-proline. Measurements of intermediates of the glycolytic-gluconeogenic pathway showed that AICA riboside provoked elevations of triose phosphates and fructose-1,6-bisphosphate and decreases in fructose-6-phosphate and glucose-6-phosphate. The effects of AICA riboside persisted when the cells were washed 10 min after its addition but were suppressed by 5-iodotubercidin, an inhibitor of adenosine kinase. AICA riboside provoked a dose-dependent buildup of normally undetectable Z nucleotides. After 20 min of incubation with 500 microM AICA riboside, ZMP, ZTP, and ZDP reached 3, 0.3, and 0.1 mumol/g cells, respectively. Concentrations of ATP were not significantly modified by addition of up to 500 microM AICA riboside when the cells were incubated with lactate-pyruvate but decreased with fructose or dihydroxyacetone. The activity of rat liver fructose-1,6-bisphosphatase was inhibited by ZMP with an apparent Ki of 370 microM. It is concluded that AICA riboside exerts a suppressive effect on gluconeogenesis because it provokes an accumulation of ZMP, which inhibits fructose-1,6-bisphosphatase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereoselectivity of idarubicin reduction in various animal species and humans

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p.l.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile. 2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8-5.0%) administration of idarubicin; the same applies to rat bile and urine. 3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.     

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle

Oxygen withdrawal from myocardial cells leads to changes of the transmembrane action potential (mainly action potential shortening), to cellular uncoupling, and to changes of vascular permeability. This study was aimed at the simultaneous measurement of electrical activity and passive electrical properties (extracellular and intracellular longitudinal resistance) in arterially perfused rabbit papillary muscles under different conditions of changed oxygen supply. These included 1) complete anoxia (erythrocyte-free perfusate), 2) hypoxia (PO2 between 23-28 mm Hg, erythrocytes present) in the presence and absence of glucose, and 3) normoxia with erythrocyte-free perfusate. Similarly to myocardial ischemia, rapid cellular uncoupling occurred only after an initial stable period of approximately 17 minutes, and it required complete anoxia. The marked shortening of the action potential developed before cellular uncoupling. In six out of eight experiments, the fibers were inexcitable when uncoupling started. In severe hypoxia, no significant change of internal longitudinal resistance was observed over 35-40 minutes. The time course of the extracellular longitudinal resistance was different from the change in intracellular resistance: A marked decrease occurred almost immediately after the onset of oxygen withdrawal. This decrease was followed by a small increase in conduction velocity, which was most likely due to a change in the interstitial compartment (edema). It was observed during anoxic as well as during hypoxic perfusion. We conclude that 1) cellular uncoupling in arterially perfused tissue requires almost complete oxygen lack and occurs with a delay of more than 10 minutes, 2) marked action potential shortening precedes uncoupling, and therefore can not simply be attributed to an increase in free, intracellular calcium, and 3) vascular endothelial function is more sensitive to oxygen withdrawal than the myocyte.     

Kaposi's sarcoma. CT-radiographic correlation

The role of CT in the diagnosis of intrathoracic Kaposi's sarcoma (KS) was evaluated retrospectively in 24 patients, in the absence of coexistent opportunistic infections. In all cases the diagnosis of KS was initially established by histologic evaluation of extrathoracic disease: 15 patients had verified parenchymal KS and nine patients endobronchial KS. (Chest roentgenograms were analyzed separately for each group: in 14 patients serial films were available for review. The predominant radiographic findings was the presence of nonspecific, bilateral, perihilar infiltrates in 22 of 24 cases (92 percent). Corresponding CT scans documented the presence of abnormal hilar densities characteristically extending into the adjacent pulmonary parenchyma along distinctly perivascular and peribronchial pathways. Discrete, poorly marginated nodules were identified radiographically in ten cases (42 percent); these proved to be randomly distributed throughout the parenchyma on CT. Radiographic evidence of mediastinal adenopathy was distinctly unusual, seen in only two cases (8 percent). While CT typically demonstrated shotty adenopathy, significantly enlarged nodes (greater than 1 cm) were rarely identified. We concluded that CT is more specific than routine roentgenograms for identifying pulmonary KS. While not pathognomonic, peribronchial and perivascular disease is sufficiently characteristic to obviate more invasive diagnostic procedures, especially in patients with established KS.     

Improving primary health care through technological innovation.

As a result of policy changes and developments on the demand side, the importance of technology in primary health care will grow fast. An approach to the implementation of new technologies in primary health care is presented in this article. First we describe the main problems in Dutch primary health care. The second step is to identify new technologies which are becoming available. Subsequently, the interface between these problems and their possible technological resolution has to be found. The fact that a technological innovation appears to be a solution is not sufficient reason for introducing it. There are all kinds of reasons why an innovation that has proved useful in the hospital situation, for example, might be of doubtful use in primary health care. Accordingly, the next step is to assess whether a technological solution to a problem in primary health care is indeed an improvement. To acknowledge the particular situation of primary health care, a scheme has been developed that may be used to determine criteria of evaluation.     

Intact parathyroid hormone, ionized calcium and calcium infusion test in the evaluation of hyperparathyroidism in chronic renal failure

We studied the parathyroid function in patients with advanced renal failure by determining their plasma concentrations of ionized calcium (iCa), intact parathyroid hormone (PTH) and its inactive metabolites (PTH-MM). The suppressibility of the parathyroidism was studied with a calcium infusion test. The intact PTH values of the nondialysis and dialysis patients did not statistically differ from each other. The concentrations of PTH-MM were, however, higher in the dialysis patients than in the nondialysis patients (p less than 0.05). The ratio of PTH-MM to intact PTH was lowest in healthy reference subjects and highest in dialysis patients (p less than 0.01), and did not correlate with the degree of intact PTH elevation in the patient groups. The calcium infusion test was carried out on 15 patients. All showed suppression in the elevated plasma intact PTH concentration and in 6 the intact PTH value normalized. The PTH-MM value did not normalize in any of the patients. During oral calcium treatment the degree of intact PTH suppression at an achieved concentration of plasma iCa was predictable from the infusion test. Three patients were parathyroidectomized after the calcium infusion test. In 2 of these elevated intact PTH normalized within 24 h while in 1 no change took place. In this latter case on clinical improvement was noted. We conclude that the determination of plasma intact PTH concentration especially of combined with plasma iCa value is a reliable means of studying the hyperparathyroidism associated with chronic renal failure.     

The effect of atrial natriuretic peptide on human isolated resistance arteries.

1. The action of (1-28) alpha-human atrial natriuretic peptide (ANP) was studied on human isolated resistance arteries. 2. Renal, skeletal muscle, omental and subcutaneous resistance arteries were taken from tissue removed at surgery and isometric tension responses were measured with a myograph. 3. ANP (10(-9)-10(-6) M) relaxed precontracted segments of renal and skeletal muscle arteries in a concentration-dependent manner. ANP failed to relax isolated omental or subcutaneous arteries. 4. The effect of ANP on human isolated resistance arteries varies depending on the site of origin of the artery.     

Value of approach to the cervical spine by bilateral anterolateral route

The authors report their experience of anterolateral bilateral approach of cervical spine. They underline the advantages and inconvenience of this route and discuss the indications.