The effect of fraction time in intensity modulated radiotherapy: theoretical and experimental evaluation of an optimisation problem.

BACKGROUND AND PURPOSE: In intensity modulated radiotherapy (IMRT), the complexity and the number of treatment fields have expanded. This may imply that the delivery time for each fraction becomes prolonged. In a number of IMRT techniques used in the clinic, the delivery time per fraction is usually 10-15 min, sometimes more than 15 min. In studies on human skin, prolonged delivery time is shown to cause significant reduction of radiation effects compared with acute irradiation. In this paper the effect of changes in fraction delivery time was studied by in vitro irradiation of mammalian cells. MATERIAL AND METHODS: Chinese hamster fibroblasts (V79-379-A) were used for simulating clinical situations. Most experiments were performed with 2Gy/fraction with 4-h intervals in 40-60 replicates. Each fraction was divided into different subfractions, simulating the delivery of a complicated treatment. The effect of changing the delivery time for each fraction was studied. Parameters for the cell survival curve and repair kinetics were determined experimentally. The same methods were also used for large fraction sizes (8Gy). The validity of the most widely used models in the literature, all derived from linear-quadratic formalism, were tested against the experimental results. RESULTS: The effect of prolonging the fraction time for 2-Gy fractions was underestimated by the biological models. The experiments showed that 10-min prolonged delivery time gave a ratio between surviving fractions at 2Gy (S-ratio) of 1.054 with a 95% confidence interval (CI) 1.030-1.080, while the models predicted 1.007 and 1.009. Extending the fraction time to 20 min gave an S-ratio of 1.063 with CI of 1.045-1.080, while the models predicted 1.012 and 1.014. For 8-Gy fractions, there was a good agreement between predications and experimental results. The ratio between surviving fractions at 8Gy is 1.370 with CI of 1.300-1.440, while the models predicated 1.37 and 1.35. CONCLUSIONS: The effect of prolonging fraction time at conventional dose/fraction is underestimated by biological models. Prolonging the fraction time will spare tissues with a fast DNA repair. There is a risk for sparing tumours. This should be considered when IMRT technique is implemented in the clinic.     

Antimutagenic properties of bell and black peppers.

The wing Somatic Mutation And Recombination Test (SMART) in Drosophila melanogaster was used to study the modulating action of bell pepper (Capsicum annuum) and black pepper (Piper nigrum) in combination with the alkylating agent methyl methanesulfonate (MMS) and the promutagen agent ethyl carbamate (EC). Larvae trans-heterozygous for the third chromosome recessive markers multiple wing hairs (mwh) and flare-3 [flr(3)] were fed genotoxins alone or in combination with each of the two spices. Genetic changes induced in somatic cells of the wing's imaginal discs lead to the formation of mutant clones on the wing blade. Our results showed that bell pepper was effective in reducing the mutational events induced by EC and MMS and black pepper was only effective against EC. Pretreatment of 2-day-old larvae with the spices for 24 h followed by a treatment with EC and MMS was only effective in reducing mutations induced by EC. Suppression of metabolic activation or interaction with the active groups of mutagens could be mechanisms by which the spices exert their antimutagenic action.     

Sustained-release theophylline-uniphyllin in nocturnal asthmatics

For a period of six months, we collected 12 cases of nocturnal asthmatics (7 males, 5 females); their ages ranged from 20 to 66 (the average age is 49). We found that administration of Uniphyllin (10 mg/kg) once a day at 6 PM could maintain the blood level of theophylline within therapeutic range at least 12 to 24 hrs. The peak expiratory flow rate of the 6 cases we collected, were significantly improved. The result of pharmokinetic parameters: 1) The average of a single dose (12 cases) is AUC (ug. hr/ml) 275.1 +/- 62. k; Kel (hr-1) 0.068 +/- 0.019; Ka (hr-1) 0.33 +/- 0.07); Tmax (hr) 6.3 +/- 1.4; T 1/2 (hr) 11.2 +/- 4.4; Clearance/F (ml/kg/hr) 37.9 +/- 9.0.2). The average of steady state (12 cases) is Css (mg/L) 5. 7 +/- 2.6; Cmax-Cmin (mg/L) 10.09 +/- 1.46.3). The average of relative bioavailability (3 cases) is 82%, 83%, 102%. However, the extent of absorption data is available for only 3 subjects. There are too few subjects to draw any meaningful conclusions about this relative bioavailability. Four cases show slight symptoms, including 1 case of dizziness, 2 cases of nausea, and 1 case gaseousness. It is suggested that the drug be administered at about 6-8 PM to coincide peak levels in the early morning in nocturnal asthmatics.     

Aging reverts to juvenile conditions the synaptic connectivity of cerebral cortical pyramidal shafts.

Quantitative analysis of the total number and distribution of dendritic spines along the apical shafts of layer V cerebral cortical pyramids has been performed on aging rats (90-120 to 1,135 days old) and on rats during the period of early and late development (10-80 days). As expected from previous work, present results show that the total number of dendritic spines along the shafts increase from 10 to 80 days, after which it starts to gradually decrease until the last age studied (1,135 days). The quantitative analysis of the effect of aging on the relative decrease of dendritic spines shows that this decrease starts being homogeneous along the whole length of the apical shafts and that from a certain age onwards, estimated according to present results in 400 days, this effect is significantly more pronounced in layers IV and III-II than in deep layers. Furthermore, the comparison made between the distribution of dendritic spines along the apical shafts of pyramidal neurons of old and young animals has shown that aging produces a regression of this distribution to juvenile conditions.     

Central tumour necrosis factor-α mediates the early gastrointestinal motor disturbances induced by lipopolysaccharide in sheep

Cytokines are involved in fever and other symptoms of the acute phase response induced by endotoxins. The aim of this work was to study the involvement of central tumour necrosis factor-alpha (TNF-alpha) in the changes induced by lipopolysaccharide (LPS) on gastrointestinal (GI) motility in sheep. Body temperature and myoelectric activity of the antrum, duodenum and jejunum was recorded continuously. Intravenous (i.v.) administration of LPS (0.1 micro g kg-1)-induced hyperthermia, decreased gastrointestinal myoelectric activity and increased the frequency of the migrating motor complex (MMC). These effects started 40-50 min after LPS and lasted for 6-7 h. TNF-alpha (50 and 100 ng kg-1) mimicked these effects when injected intracerebroventricularly (i.c.v.) but not i.v. Pretreatment with soluble recombinant TNF receptor (TNFR:Fc, 10 micro g kg-1, i.c.v.) abolished the TNF-induced actions and reduced those evoked by LPS. Furthermore, the effects induced by either LPS or TNF were suppressed by prior i.c.v. injection of indomethacin (100 micro g kg-1). In contrast, the i.v. injections of TNFR:Fc or indomethacin were ineffective. Our data suggest that LPS disturbs GI motility in sheep through a central pathway that involves TNF-alpha and prostaglandins sequentially.     

The role of the posterior cricoarytenoid muscle in phonation: an electromyographic investigation in dogs

The activity of the posterior cricoarytenoid muscle during respiration has been well investigated electromyographically. Its activity during phonation, however, has not been studied systematically. We, therefore, focused our attention on the phonatory activity of the posterior cricoarytenoid muscle to confirm whether it also contracts during phonation, as has been reported by some researchers. In our series of 12 adult dogs, the posterior cricoarytenoid was active in 11 dogs and inactive in one dog during phonation. Our present study also showed that the posterior cricoarytenoid activity was stronger for phonation than for inspiration in 6, stronger for inspiration than for phonation in 3, and the same for phonation and inspiration in 2 dogs. The results obtained from the present electromyographic evaluation demonstrated that the posterior cricoarytenoid is activated during phonation. The authors believe that the posterior cricoarytenoid muscle has phonatory function and that the phonatory effect of this muscle on the vocal cord may play an important role in precise glottis control.