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)     

Mechanism of bronchodilator effect in chronic airflow limitation.

OBJECTIVE: To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities. METHODS: Twenty-four patients with chronic airflow limitation participated in a multiple crossover, randomized, placebo-controlled trial. The effect of theophylline and salbutamol, alone or combined, on pulmonary function and dyspnea during daily activities was examined. Correlations of changes in forced expiratory volume in 1 second (FEV1) and maximum expiratory pressures (MIPs) (independent variables) and changes in dyspnea score during daily activities (dependent variable) were also examined. RESULTS: The two drugs proved to be beneficial the effects in general were additive rather than synergistic. The drugs improved the FEV1; theophylline significantly improved the MIPs. The correlation between the changes in FEV1 and those in dyspnea score, after adjustment for the changes in MIPs, was 0.55 (p less than 0.001). The correlation between the changes in MIPs and those in dyspnea score, after adjustment for the changes in FEV1, was 0.39 (p less than 0.001). CONCLUSIONS: Changes in airway calibre and in respiratory muscle strength play an independent and important role in dyspnea during daily activities in patients with chronic airflow limitation. Changes in airway calibre may be of greater importance.     

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.     

New aspects of surgical treatment of cholelithiasis

The interventional endoscopy and new knowledge about the spontaneous course of the cholelithiasis have obtained a far-reaching influence on the indication for operation and the surgical approach. Now as ever the adequate therapy of the symptomatic cholecystolithiasis consists in the early cholecystectomy. Since in the natural course the risk of lethality is small the operation for indication depending on the age and the risk factors given must be made cautiously. This in a still higher degree concerns the asymptomatic cholelithiasis in which at present no general indication for operation is regarded necessary. Due to the low lethality of circa 1% the endoscopic papillotomy has become the therapeutic method of choice in residual and recurrent calculi after cholecystectomy, but also in risk patients with cholecystocholedocholithiasis. The endoscopic papillotomy with stone extraction before the operation suggests a decrease of the operation lethality of 3 to 5% after cholecystectomy with revision of the choledochus.     

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.     

An experimental collagen-impregnated dacron graft: Potential for endothelial seeding

This study evaluates the potential for endothelial seeding of a collagen-impregnated Dacron graft with or without surface modifiers (fibronectin, heparin) to attach and retain these cells during flow. Human umbilical endothelial cells were harvested, cultured, labeled with Indium111-oxine and seeded onto 30 mm X 4 mm diameter grafts. Six graft surfaces were studied: 1) a collagen-impregnated Dacron graft, HemashieldR (C); 2) C + fibronectin (C + F); 3) C + heparin (C + H); 4) C + F + H; 5) HytrelR + F (Hyt + F); and 6) Hyt + F + H. Radioactive loss determined the percentage attachment and then percentage retention of labeled inoculum after a one-hour in vitro perfusion. Scanning electron and light microscopy demonstrated the endothelium on the graft surface following perfusion. Fibronectin-coated grafts had a significantly higher percentage attachment than those without fibronectin (ANOVA, P less than 0.05). However, the percentage retention following perfusion was similar for all Dacron grafts and statistically inferior to the HytrelR grafts studied (ANOVA, P less than 0.05). SEM evaluation of the C + F + H graft surface was qualitatively the most impressive Dacron surface for seeding, yet was inferior to the HytrelR graft. We conclude that fibronectin benefits the initial attachment of endothelium to collagen-coated Dacron rivaling the HytrelR surface. Fibronectin does not improve percentage retention of the HemashieldR surface during perfusion, therefore, some of its initial benefit is lost.