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.     

Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants

Background:  Clusterin is a ubiquitous 80 kDa heterodimeric glycoprotein previously shown to be expressed on tumor cells of systemic and, to a lesser extent, primary cutaneous anaplastic large cell lymphoma (PC-ALCL). Lymphomatoid papulosis (LyP), an important differential diagnosis of ALCL, has been studied for clusterin expression in only a small number of cases. The aim of this study was to compare clusterin immunostaining patterns in LyP and other cutaneous histologic simulants with those of PC-ALCL.
Methods:  Formalin-fixed, paraffin-embedded sections of PC-ALCL (6), LyP (20), mycosis fungoides with large cell transformation (MF-LCT, 12), pityriasis lichenoides et varioliformis acuta (PLEVA, 12), arthropod bite reaction (ABR, 12) and lymphomatoid reactions (LR, 9) were immunostained for clusterin and evaluated for staining pattern and distribution. All diagnoses were made with clinicopathologic correlation.
Results:  Characteristic dot-like Golgi staining was identified in 10/20 LyP (50%), 4/6 PC-ALCL (67%) and 9/12 MF-LCT (75%). Two of 12 PLEVA (17%), 1 of 12 ABR (8%) and 2 of 8 LR (25%) had lymphocytes (< 25%) with diffuse cytoplasmic staining. Dermal dendritic cells stained strongly for clusterin. High background staining occurred in some cases.
Conclusion:  Clusterin immunostaining does not reliably distinguish between LyP, PC-ALCL or MF-LCT, but could distinguish LyP from its reactive histologic simulants.     

Diagnostic tests in Raynaud''s phenomena in workers exposed to vibration: a comparative study.

Four objective tests to evaluate Raynaud's phenomena (RP) in workers exposed to handarm vibrations were applied on 23 exposed men with RP (vibration induced white finger 18, primary Raynaud's phenomenon 5), 56 exposed men without RP, and 15 male controls. Finger systolic blood pressure was measured by a cuff and strain gauge technique after combined body cooling and finger cooling during five minute ischaemia to 30 degrees, 15 degrees, and 6 degrees C. An attack of RP was detected as a zero pressure, FSP(0) test, whereas a pressure, reduced to a value below the normal 95% confidence limit at 6 degrees C, was regarded as an abnormal response, FSP(A) test. A hand cooling, preceded by 30 minute body precooling, was performed in water at 10 degrees C during five minute ischaemia. The finger colours after hand cooling were evaluated by a directly visual inspection, FCV test, and by a blind assessment of slides of the photographed hand, FCS test. A medical interview was used as a method of reference. The sensitivity did not differ significantly between FSP(0) (74%), FCS (61%), and FCV (57%) (p greater than 0.10). FSP(A) had a significantly higher sensitivity (96%) and lower specificity (64%) than those of FCV and FCS (p less than 0.0005) and of FSP(0) (p less than 0.05). Six of the seven men with a false positive FSP(0) had a positive FCV or FCS, and the seventh had a history of previously active RP. The six false negative FSP(0) test results did not correspond significantly to milder cases of RP (p greater than 0.20). The results indicate that a finger colour test may be as valuable as a FSP(0) test for diagnostic purposes. FSP(A) only indicates if a cold response is exaggerated and does not diagnose RP. The pressure measurements may further be of guidance in evaluating preventive measures and effects of treatments for RP.     

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.     

Treatment of the anemia of rheumatoid arthritis with recombinant human erythropoietin: clinical and in vitro studies

Two anemic patients with rheumatoid arthritis were treated with recombinant human erythropoietin (EPO) for 5 months. Both patients showed significant increases in hematocrit, red cell volumes, and marrow erythroid and megakaryocyte progenitor cells. No significant toxic effects from EPO were observed. These data indicate that EPO may be effective in overcoming the pathogenetic factors that limit erythropoiesis in rheumatoid arthritis.     

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.