Specification of the Dose to Organs at Risk in External Beam Radiotherapy

Reporting of the clinical relevant dose to organs at risk (OR) and other normal tissues is crucial in trials and protocols where the aim is to assess late complications and to increase the therapeutic ratio for external beam radiotherapy. The dose distribution in normal tissues and ORs are, however, most often heterogeneous, at least when more than two opposing beams are applied. To decide the most clinical relevant dose with respect to late occurring complications is therefore not a straight forward problem. In this work we discuss what parameters characterise the dose-volume-histogram (DVH) best by calculating normal tissue complication probabilities (NTCPs) by using the Lyman model and various sets of statistical parameters drawn out from the DVHs. These NTCPs are compared to NTCPs calculated from the full DVHs, when the sets of parameters are evaluated. Our calculations indicate that the NTCP based on the Lyman model is best correlated to the D_max value, for serially organised tissues such as the spinal cord. For organs, described largely as tissues organised in parallel, the D_median or D_mean of the DVH may be applied. Our calculations reveal that D_mean is the parameter of choice when D_meclian is quite small, but when the two parameters approach each other, D_mediarl will be a better choice, using a unity volume fraction. For ORs characterised by a mixed serial and parallel functional structure, as the heart, neither D_max, D_median, nor D_mi,_an may predict the actual NTCP.     

Toxic epidermal necrolysis; 15 years'' experience in a Dutch burns centre

BACKGROUND: Toxic epidermal necrolysis (TEN) is a severe and potentially fatal drug reaction characterized by an extensive skin rash with blisters and exfoliation, frequently accompanied by mucositis. The wounds caused by TEN are similar to second-degree burns and severe cases may involve large areas of skin loss. OBJECTIVES: Analysis of our results in patients with TEN and evaluation of the variety of therapeutic interventions that has been studied and suggested in TEN. PATIENTS/METHODS: Retrospective analysis of 19 consecutive patients with TEN treated in our burns centre between 1989 and 2004. RESULTS: Immediate withdrawal of any potentially fatal drug, maximum supportive care, and a restricted and tailored antibiotic, medical and surgical treatment regimen confined mortality to 21%, whereas prognosis scores like APACHE II and SCORTEN predicted mortality of 22 and 30%, respectively. A positive contribution of selective digestive decontamination is suggested but has yet to be established. CONCLUSIONS: Because of a potentially fatal outcome, fast referral of a patient suspected of TEN to a specialized centre (mostly a burns unit or specialized dermatology centre) for expert wound management and tailored comprehensive care is strongly advised and contributes to survival.     

Stereoselective S-oxygenation of 2-aryl-1,3-dithiolanes by the flavin-containing and cytochrome P-450 monooxygenases

The reaction of NalO4, highly purified flavin-containing monooxygenase (EC 1.14.13.8), and microsomes from hog liver with 2-aryl-1,3-dithiolanes and 2-aryl-1,3-dithiolane S-oxides was investigated. The initial rates determined for the microsome- and purified flavin-containing monooxygenase-catalyzed rate of S-oxidation of para-substituted 2-aryl-1,3-dithiolanes were similar, demonstrating that S-oxidation of these substrates occurred with similar velocities at saturating concentrations of substrate and, at least for the first S-oxidation, the reaction was insensitive to the nature of the para-substituent. The diastereoselectivity of S-oxygenation of 2-aryl-1,3-dithiolanes was determined and, in general, a marked preference for addition of oxygen to the sulfide sulfur atom was observed to occur trans to the aryl groups. In all cases examined, enantioselective enzymatic S-oxidation was observed. For S-oxide formation in microsomes, the data provided evidence for a minor role of cytochrome P-450 in S-oxide formation, but the flavin-containing monooxygenase was mainly responsible for production of S-oxide. In contrast to previous reports, the enantioselectivity of S-oxidation catalyzed by highly purified cytochrome P-450IIB-1 and cytochrome P-450IIB-10 was not always opposite to that catalyzed by hog liver flavin-containing monooxygenase activity. 2-Aryl-1,3-dithiolane S-oxides were also oxidized a second time by NalO4, microsomes, or highly purified flavin-containing monooxygenase from hog liver but not cytochrome P-450IIB-1 or P-450IIB-10. The rate of the second oxidation was 10-15-fold slower than the corresponding first S-oxidation and S,S'-dioxide formation was markedly dependent on the electronic nature of the para-substituent (Hammett correlation rho value of -1.3 and -1.1 for microsomes and highly purified flavin-containing monooxygenase from hog liver, respectively). The large dependence of the rate of S,S'-dioxide formation on the nature of the para-substituent demonstrates that velocity values at saturating concentrations of S-oxide were not the same for all 2-aryl-1,3-dithiolane S-oxides and suggests that the chemical nature of the 2-aryl-1,3-dithiolane S-oxide contributes to the rate-determining step of this enzymatic reaction.     

Levocabastine compared with sodium cromoglygate eyedrops in children with both birch and grass pollen allergy

Fifty–five children 6–16 years old with allergic rhinoconjunctivitis due to both birch and grass pollinosis were randomized into 2 parallel groups, treated in double–blind fashion with either levocabastinc (LEV) eye–drops twice daily plus placebo eyedrops twice daily or sodium cromoglycate (SCG) eyedrops 4 times daily for 3 months. Spersallerg® (antazolini chloride + tetryzolini chloride) eyedrops were allowed as rescue medicine. All children received basic treatment with an antihistamine (terfenadine) during the complete trial period, and a local nasal corticosteroid if needed. Eye symptoms were recorded daily by the patients and at 4 visits by the investigator, at start and after 4, 10 and 13 weeks. Pollen counts were performed and a blood sample was collected at start and end of the treatment. The global evaluation of treatment was similar for the 2 groups, and there was no significant difference in any effect parameter except for the symptom, itchy eyes, which had lower score in the SCG group as evaluated by the investigator after 4 weeks. On days with low pollen counts the patients in the SCG group had fewer days with moderate or severe eye symptoms. It is concluded that even though LEV and SCG eyedrops were given in addition to systemic treatment with an antihistamine, no consistently significant differences in clinical effect were found between the 2 treatment groups, but the SCG group experienced slightly less eye symptoms throughout the trial. LEV eye–drops appear safe in long–term treatment in children, and no signs of tachyphylaxis were recorded.     

Determinants of acute respiratory infections in Soweto--a population-based birth cohort.

BACKGROUND: Acute respiratory infections (ARIs) are an important cause of infant morbidity in both developing and developed countries, and they are the leading cause of death in poorer parts of the world. Respiratory viruses appear to be the most frequent microbiological pathogens, especially respiratory syncytial virus. It has been suggested that factors such as being male, overcrowding, poor access to medical care, low level of maternal education, and passive smoking are associated with contracting ARIs. DESIGN: A fixed birth cohort of 571 children was followed from birth to 1 year of age. The children were monitored for symptoms of ARIs during regular home visits. SETTING: An urban low-income setting in Soweto, a township outside Johannesburg with an estimated 1.2 million inhabitants, including an estimated 45,000 children under 2 years of age. SUBJECTS: A total of 571 children were observed for 118,650 days. OUTCOME MEASURES: The incidence rate of ARIs. The determinants birth weight, breastfeeding, gender, crowding, passive smoking, indoor pollution, and sanitary facilities were analysed. RESULTS: A total of 489 episodes of coughing or coughing and nasal discharge combined were recorded. Only the father's level of education and the number of people living in the household remained significant in the multivariate analyses. The incidence of severe ARIs was reduced among breastfed infants. CONCLUSIONS: Our study supports previous observations suggesting that crowding and communal living conditions are important determinants of ARIs. Breastfeeding seemed protective against severe ARI. The lack of association with well-described risk factors such as low level of maternal education, gender and passive smoking could be due to lack of statistical power in this rather uniform population.     

An in vivo 19F NMR study of isoflurane elimination as a function of age in rat brain.

In vivo 19F NMR at 4.7 T has shown that the biphasic elimination of the vapor anesthetic isoflurane from rat brain is ca 15% slower in old (23-24 months) animals compared with young (5-6 months) animals. The fast kinetic component has a t1/2 of ca 7-9 min and the slow event, 100-115 min. Gas chromatographic measurement of arterial blood elimination displays age attenuation to the same extent, although a monophasic kinetic process (6-7 min). The slow wash-out from brain is thought to involve elimination from intracranial fatty tissue as postulated by others in rabbit brain. Longitudinal relaxation time measurements show monoexponential recovery and essentially identical values for young (1.09 + 0.11 s) and old (1.04 +/- 0.09 s) animals. For dipalmitoylphosphatidylcholine vesicles the monoexponential recovery also suggests rapidly exchanging averaged homogeneous lipid environments for the anesthetic, but the longer T1s (2.75 +/- 0.25 s) imply less restricted mobility compared with brain. Single T2 values were obtained in vivo, indicating either a single compartment or rapid exchange between multiple environments. These measurements were inconsistent, undoubtedly as a result of B1 inhomogeneity. The age-attenuated elimination kinetics for isoflurane are consistent with poorer cardiopulmonary function, whereas the T1 data suggest similar environments for the anesthetic in young and old brain tissue.     

Effect of glycated albumin on phenytoin binding in elderly patients with type II diabetes mellitus

We evaluated the effect of glycated albumin on phenytoin protein binding in 36 elderly (age range 63-94 yrs) patients with type II diabetes mellitus (DM) under diet management. Serum was spiked with 15 mg/L phenytoin and incubated. A serum ultrafiltrate was obtained from each sample for determining total and free phenytoin concentrations. Glycated hemoglobin was determined by boronate-affinity chromatography, and glycated albumin was separated from nonglycated fractions with boronate-agarose gel. Glycated hemoglobin in the study group ranged from 4.3-14.6% (mean 7.8 +/- SD 2.1%) and glycated albumin ranged from 3.7-12.5% (7.4 +/- SD 2.6%). We observed no correlation between glycated albumin and the percentage of free phenytoin (r2 = -0.14; p = 0.419). The concentration of nonglycated albumin ranged from 0.66-4.28 g/dl (mean 3.45 +/- 0.67 g/dl) and was calculated from measured total and glycated albumin concentrations. A correlation between the free fraction of phenytoin and nonglycated albumin was not demonstrated (r2 = 0.22, p = 0.22). In addition, a correlation was not observed between total glycated albumin and the free fraction of phenytoin (r2 = -0.095; p = 0.58). We conclude that elderly patients with type II DM under diet control do not have significant alterations in phenytoin protein binding. The use of total serum phenytoin levels therefore appears appropriate for determining phenytoin dosages in elderly patients with well controlled type II DM.     

Review of chemosystematics: multivariate approaches to oral bacteria and yeasts.

There are several problems related to the classification and identification of bacterial and yeast species assigned to the genera Actinobacillus, Haemophilus, Pasteurella, Bacteroides, Prevotella, Porphyromonas, Campylobacter, Wolinella, Treponema, Candida, Torulopsis, and Saccharomyces, most of which belong to the resident oral microflora. The present review was written to demonstrate how multivariate analyses of data on cellular fatty acids, sugars, enzyme activities, and lysis kinetics during ethylenediaminetetraacetic acid (EDTA) and EDTA plus lysozyme treatment can be used to distinguish closely related species of these bacterial and yeast genera. With the exception of the Actinobacillus-Haemophilus-Pasteurella group, fatty acids were more discriminating than sugars. Enzymes from whole cells and outer membrane vesicles also contributed to taxonomic distinction. Apparently, chemosystematics, involving multivariate analyses, is a useful adjunct in oral microbial taxonomy.