Effects of prolonged cycle ergometer exercise on maximal muscle power and oxygen uptake in humans

Summary The mechanical power (W_tot, W·kg^–1) developed during ten revolutions of all-out periods of cycle ergometer exercise (4–9 s) was measured every 5–6 min in six subjects from rest or from a baseline of constant aerobic exercise [50%–80% of maximal oxygen uptake (VO_2max)] of 20–40 min duration. The oxygen uptake [VO₂ (W·kg^–1, 1 ml O₂ = 20.9 J)] and venous blood lactate concentration ([la]_b, mM) were also measured every 15 s and 2 min, respectively. During the first all-out period, W_tot decreased linearly with the intensity of the priming exercise (W_tot = 11.9–0.25·VO₂). After the first all-out period (i greater than 5–6 min), and if the exercise intensity was less than 60% VO_2max, W_tot, VO₂ and [la]_b remained constant until the end of the exercise. For exercise intensities greater than 60% VO_2max, VO₂ and [la]_b showed continuous upward drifts and W_tot continued decreasing. Under these conditions, the rate of decrease of W_tot was linearly related to the rate of increase of V [(d W_tot/dt) (W·kg^–1·s^–1) = 5.0·10^–5 –0.20·(d VO₂/dt) (W·kg^–1·s^–1)] and this was linearly related to the rate of increase of [la]_b [(d VO₂/dt) (W·kg^–1·s^–1) = 2.310^–4 + 5.910^–5·(d [la]_b/dt) (mM·s^–1)]. These findings would suggest that the decrease of W_tot during the first all-out period was due to the decay of phosphocreatine concentration in the exercising muscles occurring at the onset of exercise and the slow drifts of VO₂ (upwards) and of W_tot (downwards) during intense exercise at constant W_tot could be attributed to the continuous accumulation of lactate in the blood (and in the working muscles).     

Isolation of mutants of CHO cells resistant to 6(p-hydroxyphenylazo)-uracil I. A novel BrdU cross-resistant phenotype

Three classes of mutants resistant to the drug 6(p-hydroxyphenylazo)-uracil have been isolated from mutagenized cultures of CHO cells. One class of these mutants designated HPU ^R A exhibits a unique form of cross-resistance to bromodeoxyuridine in that it is resistant to this drug only in the presence of thymidine. The molecular basis of the BrdU resistance is unknown but does not appear to involve the known targets of the drug. An interesting feature of these mutants is that they give rise, at a high frequency, to a subpopulation of cells which are much more resistant to BrdU.     

Isolation of mutants of CHO cells resistant to 6 (p-hydroxyphenylazo)-uracil II. Mutants auxotrophic for deoxypyrimidines

Two classes of CHO mutants resistant to the drug 6(p-hydroxyphenylazo)-uracil have been characterized. Both classes exhibited a nutritional requirement that could be satisfied by deoxypyrimidines and uridine but not other ribopyrimidines. A biochemical investigation of these mutants revealed a structural defect in ribonucleotide reductase resulting in a two- to fourfold increase in the K_m for UDP and CDP. As a consequence of this lesion, the cells had imbalanced deoxypyrimidine pools and showed an increase in the rate of spontaneous mutation to 6-thioguanine resistance but not emetine resistance.     

Multiple endocrine cell types in thyroid medullary carcinoma

Summary 10 cases of thyroid medullary carcinoma (TMC) have been studied ultrastructurally and histochemically. Well differentiated calcitonin-producing C cells were present in all tumours, being prevalent in 9 cases. 5-Hydroxytryptamine (5HT) storing cells were found in two cases, somatostatin immunoreactive cells in at least 5 cases and ACTH-immunoreactive cells in 4 cases. Ultrastructurally, at least 3 types of apparently non-C cells were observed. Type 1 cells with large, poorly osmiophilic granules resembling those of gastroenteropancreatic D cells, were present in 6 cases; they appeared to correlate well with somatostatin immunoreactive cells. Type 2 cells with large osmiophilic granules were found in 5 cases; they resembled ACTH-MSH cells of the human pituitary and may correspond to the ACTH-immunoreactive cells of light microscopy. Type 3 cells with small granules and an unknown function were found in 6 cases, always in scarce number. It is concluded that TMC, although mainly made up of C cells, usually contains large proportions of other endocrine cell types.Supported in part by grant N. 75.00630.04 from the Italian National Research Council (C.N.R.). P.F. is a fellow of the Fondazione Anna Villa Rusconi, Varese     

The pathogenesis of molybdenum cofactor deficiency, its delay by maternal clearance, and its expression pattern in microarray analysis

Molybdenum cofactor (Moco)-deficiency is a lethal autosomal recessive disease, for which until now no effective therapy is available. The biochemical hallmark of this disorder is the inactivity of the Moco-dependent sulfite oxidase, which results in elevated sulfite and diminished sulfate levels throughout the organism. In humans, Moco-deficiency results in neurological damage, which is apparent in untreatable seizures and various brain dysmorphisms. We have recently described a murine model for Moco-deficiency, which reflects all enzyme and metabolite changes observed in the patients, and an efficient therapy using a biosynthetic precursor of Moco has been established in this animal model. We now analyzed these mice in detail and excluded morphological brain damage, while expression analysis with microarrays indicates a massive cell death program. This neuronal damage appears to be triggered by elevated sulfite levels and is ameliorated in affected embryos by maternal clearance.     

Hyperbaric oxygenation mitigates focal cerebral injury and reduces striatal dopamine release in a rat model of transient middle cerebral artery occlusion

The usefulness of the administration of hyperbaric oxygen (HBO) in the treatment of acute focal cerebral ischemia remains debatable. A significant association exists between focal cerebral injury and an excessive release of extracellular dopamine (DA). In vivo microdialysis was used in the present study to examine the effect of HBO on DA release in the striatum during ischemia and reperfusion in rats. The histological changes occurring were also evaluated. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery (MCA) using a surgically placed intraluminal filament. Control rats (n=8) were subjected to 1 h of ischemia, whilst the study rats (n=8) were in addition treated with HBO (2.8 atmospheres of absolute pressure 100% O₂) during ischemia. Both groups were returned to breathing room air at normal pressure during reperfusion. Microdialysis samples were continuously collected at 15 min intervals at 2 μl·min^–1. The [mean (SE)] increase in release of striatal DA attained significance after 30 min of occlusion of MCA [170 (24)%], and continued to increase [268 (26)% at 45 min] reaching a peak level at 60 min [672 (59)%] before returning to the baseline level during the late reperfusion phase. There was no significant change in the level of DA in HBO treated rats during the period of ischemia. A significant reduction in edema and neuronal shrinkage were observed by histological examination in HBO treated rats when compared to the control rats. The results showed that HBO, when administered during ischemia, offered significant neuroprotection in our experimental model of transient focal cerebral ischemia in the rat. The mechanism seems to imply, at least in part, a reduced level of DA. Electronic Publication     

Detection of Leishmania infantum kinetoplast DNA in laryngeal tissue from an immunocompetent patient

Mucosal leishmaniasis of the upper respiratory tract is usually associated with the visceral form or is found in immunosuppressed individuals. This report presents a case of isolated mucosal leishmaniasis in an immunocompetent patient, whose diagnosis mainly rested on histology and positive polymerase chain reaction result for Leishmania donovani in the laryngeal tissue. A 59-year-old man, who never lived outside Italy, showed a subglottic mucosal polypoid-like lesion. The typical morphological picture and positive polymerase chain reaction result for L donovani by DNA extracted from laryngeal biopsy specimens allowed the diagnosis of mucosal leishmaniasis. Specific amphotericin B therapy was started, resulting in clinical and endoscopic improvement. Increased knowledge about the histological and molecular tissue analysis of Leishmania enhances the diagnostic testing for mucosal leishmaniasis, as primary mucosal leishmaniasis may occur in both immunosuppresed and immunocompetent patients who travel to or reside in areas endemic for Leishmania.