Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses.

In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light-breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light-breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three-compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady-state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light-breed horses.

Beneficial effects of judo training on bone mineral density of high-school boys in Korea.

Bone mineralization is strongly stimulated by weight-bearing exercise during growth and development. Judo, an Olympic combat sport, is a well-known form of strenuous and weight-bearing physical activity. Therefore, the primary goal of this study was to determine the effects of Judo practice on the bone health of male high school students in Korea. The secondary goal of this study was to measure and compare the bone mineral density (BMD) of the hands of Judo players and sedentary control subjects. Thirty Judo players (JDP) and 30 sedentary high school boys (CON) voluntarily participated in the present study, and all of the sedentary control subjects were individually matched to the Judo players by body weight. BMD was determined by using dual-energy X-ray absorptiometry (Hologic, Bedford, MA, USA). The lumbar spine, femur and forearm BMD in the JDP group were significantly greater by 22.7%, 24.5%, and 18.3%, respectively, than those in the CON group. In addition, a significant difference in the CON group was observed between the dominant hand (DH) radius (0.710 ± 0.074 g/cm(2)) and the non-dominant hand (NDH) radius (0.683 ± 0.072 g/cm(2)), but this was not observed in the JDP group (DH = 0.819 ± 0.055 g/cm(2); NDH = 810 ± 0.066 g/cm(2)) (P < 0.05). Therefore, the results of this study suggest that Judo practice during the growth period significantly improves bone health in high school male students. In addition, it seems that Judo practice could eliminate the effect of increased BMD in the dominant hand.

Immediate reinforcement increased duration of time riding the stationary bicycle in children with autism spectrum disorder: a pilot study.

The necessity of promoting physical activity in individuals with Autism Spectrum Disorder (ASD) has been emphasized for decades. One of the barriers to participate in physical activity for individuals with ASD is limited interest and motivation. Therefore, understanding the motivation to exercise in this population is important. The objective was to determine the effect of using contingent reinforcement in the form of watching a preferred DVD to increase duration of time pedalling on a stationary bicycle within their predetermined target heart rate zone (THRZ) in children with ASD. Using a crossover design, seven participants (11 2.7 years) who were diagnosed with ASD were randomly assigned to either Group A or B. Time spent pedalling on a bicycle within the THRZ was analysed using a linear mixed-effect model with Bonferroni adjustments. The results showed that the DVD intervention motivated children with ASD to exercise for more than 10 minutes in moderate to vigorous physical activity compared to when they were exercising without watching a DVD. This result is significant as number of studies have revealed that 10 minutes of exercise could bring improvements in activities of daily living such as behaviors and academic performance in school.

Evaluation of the MyWellness Key accelerometer.

OBJECTIVE: to examine the concurrent validity of the Technogym MyWellness Key accelerometer against objective and subjective physical activity (PA) measures. DESIGN: randomised, cross-sectional design with two phases. The laboratory phase compared the MyWellness Key with the ActiGraph GT1M and the Yamax SW200 Digiwalker pedometer during graded treadmill walking, increasing speed each minute. The free-living phase compared the MyWellness Key with the ActiGraph, Digiwalker, Bouchard Activity cord (BAR) and Global Physical Activity Questionnaire (GPAQ) for seven continuous days. Data were analysed using Spearman rank-order correlation coefficients for all comparisons. SETTING: laboratory and free-living phases. PARTICIPANTS: sixteen participants randomly stratified from 41 eligible respondents by sex (n=8 men; n=8 women) and PA levels (n=4 low, n=8 middle and n=4 high active). RESULTS: there was a strong association between the MyWellness Key and the ActiGraph accelerometer during controlled graded treadmill walking (r=0.91, p<0.01) and in free-living settings (r=0.73-0.76 for light to vigorous PA, respectively, p<0.01). No associations were observed between the MyWellness Key and the BAR and GPAQ (p>0.05). CONCLUSIONS: the MyWellness Key has a high concurrent validity with the ActiGraph accelerometer to detect PA in both controlled laboratory and free-living settings.

Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes?

AIM: Preoperative radiotherapy has been shown to improve local control in advanced rectal carcinoma compared with surgery alone. Several large randomized trials have confirmed that chemoradiotherapy (CRT) is better than radiotherapy alone. This pilot study was designed to increase the radiation dose using high-dose rate (HDR) brachytherapy boost following preoperative CRT to evaluate whether this strategy improves the outcome of surgery without increase in toxicity. METHOD: Since October 2004, we have used the new rectal HDR applicator for brachytherapy boost in 68 patients following CRT. The patients had CT and MRI Scans as part of staging. All had locally advanced disease either bulky low T2 or T3 with threatened circumferential resection margin and multiple suspicious lymph nodes. They were offered preoperative CRT either by 5-FU infusion 1 g/m(2) day 1-4 (week 1 + 5) or by oral capecitabine 825 mg/m(2) Monday-Friday for 5 weeks together with CT planned external beam RT 45Gy in 25 fractions over 5 weeks (CRT). Those downstage on repeat MRI scan were offered additional HDR Boost 10Gy directly to the tumour followed by surgery 6-8 weeks later [group A]. Four patients proceeded directly to surgery but because of involved resection margin had a HDR brachytherapy boost as postoperative treatment [group B]. Thirty patients were not planned for immediate surgery after CRT and brachytherapy boost, as they were either elderly or considered high risk for anaesthesia [group C]. RESULTS: There were 34 patients (median age 67 (range 39-81) years in group A, including 24 men). The PS was 0-1. The clinical stage at presentation was cT2 in five, cT3 in 23 and T4 in six patients and cN0 in 2, cN1 in 21 and N2 in 11. Thirty-three patients had CRT, and one had radiotherapy alone. All patients completed treatment without interruption. Twenty-nine patients had surgery following CRT and brachytherapy boost including anterior resection in 10 patients, Abdominoperineal excision (APR) in 18 and Hartmann's resection in one. Five patients did not have the intended surgery. Twenty-four (83%) patients had an RO resection compared with 63% having conventional preoperative CRT using bolus 5FU regimes. Pathological complete remission (pCR) was achieved in 9 (31%) compared with 12% patients having conventional CRT. There was no increase in G 3-4 toxicity from RT and no delay in wound healing or increase in anastomotic leakage. One of the four patients in group B developed local recurrence. The thirty patients in group C who had modified radical CRT followed by brachytherapy boost as a definitive treatment will be reported in a further communication. CONCLUSION: Increasing the dose of radiation by HDR brachytherapy boost appears to improve the RO resection and pCR rates compared with conventional CRT. The follow up is too short to judge its effect on disease-free survival. This study will be extended to compare this strategy in a randomized phase III trial with conventional CRT in patients who are not fit for more intensive CRT (HERCULES).

Physical fitness and carotid atherosclerosis in men.

We investigated the association between cardiorespiratory fitness (CRF) and carotid atherosclerosis in 9 871 Korean men aged 40-81 years. We measured carotid intima-media thickness by using B-mode ultrasonography, and cardiorespiratory fitness was measured by a maximal treadmill exercise test using the Bruce protocol. Carotid atherosclerosis was defined as an intima-media wall thickness greater than 1.2 mm or stenosis >25% of carotid arteries, while CRF was classified as low fit (<20%), moderately fit (20-<60%), or high fit (> or =60%) categories based on age-specific VO (2peak) (ml/kg/min) percentiles. The presence of carotid atherosclerosis across CRF categories was 11.7% (low fit), 9.6%, and 7.7%, respectively. After adjustment for age, cigarette smoking, body mass index, physical activity, there was an inverse association between CRF and carotid atherosclerosis (p for trend <0.001). The odds ratio of presence of carotid atherosclerosis in the high-fit men versus the low-fit men was 0.67 (95% CI, 0.55, 0.80). After additional adjustment for high cholesterol, hypertension, and diabetes mellitus, the results remain unchanged and the odds ratios across CRF levels were (95% CI): 1.00 (low fit, referent), 0.85 (0.71, 1.01), 0.71 (0.59, 0.85) (p for trend <0.001), respectively. High levels of cardiorespiratory fitness were associated with a lower risk of having carotid atherosclerosis in middle-aged and elderly men.

A cryptographic key management solution for HIPAA privacy/security regulations.

The Health Insurance Portability and Accountability Act (HIPAA) privacy and security regulations are two crucial provisions in the protection of healthcare privacy. Privacy regulations create a principle to assure that patients have more control over their health information and set limits on the use and disclosure of health information. The security regulations stipulate the provisions implemented to guard data integrity, confidentiality, and availability. Undoubtedly, the cryptographic mechanisms are well defined to provide suitable solutions. In this paper, to comply with the HIPAA regulations, a flexible cryptographic key management solution is proposed to facilitate interoperations among the applied cryptographic mechanisms. In addition, case of consent exceptions intended to facilitate emergency applications and other possible exceptions can also be handled easily.

High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours: the Clatterbridge experience.

In a systemic review of 8507 patients from 22 randomised trials, radiotherapy has been shown to reduce the risk of local recurrence and death from rectal cancer compared with surgery alone. Recent large randomised trials confirmed that chemoradiotherapy was better than radiotherapy alone. Contact radiotherapy as a boost after external beam radiotherapy (without chemotherapy) has also been shown to improve local control and sphincter preservation in the Lyon 092 trial. Brachytherapy has now been used as preoperative treatment for rectal cancer and showed similar results. The Swedish and Dutch trial results of short-course preoperative radiotherapy have shown improved local control in favour of the radiotherapy group. Similar to the Scandinavian group, investigators from McGill University in Montreal adopted a short course using brachytherapy instead of external beam radiotherapy. However, surgery was delayed for 4-8 weeks to achieve downstaging. The radiation dose was delivered directly on to the tumour and the surrounding normal tissues were spared the effects of radiation. This approach has been shown to reduce the side-effects seen with external beam short-course radiotherapy, but maintains the benefit of improved local control. The Danish group used brachytherapy as a boost after external beam chemoradiotherapy for more advanced rectal tumours and have shown improved pathological complete remission and R0 resection rates. The Mount Vernon group used a similar rectal applicator for inoperable rectal cancer patients and achieved good local and symptom control. The brachytherapy group at Clatterbridge used the same approach as the Danish group, but reduced the external beam radiotherapy dose and increased the brachytherapy dose to lower the side-effects. All 16 patients (100%) had R0 resection compared with 63% with conventional preoperative chemoradiotherapy using a bolus 5-fluorouracil regimen. Pathological complete remission was achieved in seven (44%) patients compared with 2-12% with conventional chemoradiotherapy. There was no increase in grade 3-4 toxicity from radiotherapy and no delay in wound healing or anastamotic leakage. The inclusion of high dose rate brachytherapy seems to increase the pathological complete remission rates and improves the R0 resection rates with no detriment to the side-effects as the increased dose of radiation from the high dose rate boost is confined mainly to the tumour. This treatment may be particularly suitable for elderly patients where intensive chemoradiotherapy regimens are not suitable. Several trials are planned to define the role of preoperative high dose rate brachytherapy in rectal cancer and the results are awaited with interest.

A multicentre audit of HDR/PDR brachytherapy absolute dosimetry in association with the INTERLACE trial (NCT015662405).

A UK multicentre audit to evaluate HDR and PDR brachytherapy has been performed using alanine absolute dosimetry. This is the first national UK audit performing an absolute dose measurement at a clinically relevant distance (20 mm) from the source. It was performed in both INTERLACE (a phase III multicentre trial in cervical cancer) and non-INTERLACE brachytherapy centres treating gynaecological tumours. Forty-seven UK centres (including the National Physical Laboratory) were visited. A simulated line source was generated within each centre's treatment planning system and dwell times calculated to deliver 10 Gy at 20 mm from the midpoint of the central dwell (representative of Point A of the Manchester system). The line source was delivered in a water-equivalent plastic phantom (Barts Solid Water) encased in blocks of PMMA (polymethyl methacrylate) and charge measured with an ion chamber at 3 positions (120° apart, 20 mm from the source). Absorbed dose was then measured with alanine at the same positions and averaged to reduce source positional uncertainties. Charge was also measured at 50 mm from the source (representative of Point B of the Manchester system). Source types included 46 HDR and PDR 192Ir sources, (7 Flexisource, 24 mHDR-v2, 12 GammaMed HDR Plus, 2 GammaMed PDR Plus, 1 VS2000) and 1 HDR 60Co source, (Co0.A86). Alanine measurements when compared to the centres' calculated dose showed a mean difference (±SD) of +1.1% (±1.4%) at 20 mm. Differences were also observed between source types and dose calculation algorithm. Ion chamber measurements demonstrated significant discrepancies between the three holes mainly due to positional variation of the source within the catheter (0.4%-4.9% maximum difference between two holes). This comprehensive audit of absolute dose to water from a simulated line source showed all centres could deliver the prescribed dose to within 5% maximum difference between measurement and calculation.

Role of hippocampal M2 muscarinic receptors in the estrogen-induced enhancement of working memory.

We have previously demonstrated that acetylcholine, acting at M2 muscarinic receptors, mediates the estradiol-induced increase in hippocampal N-methyl-d-aspartate receptor binding and the associated enhancement in working memory. The goal of present experiment was to investigate the role of hippocampal M2 receptors in the behavioral aspects of these effects. Ovariectomized rats were trained to locate a hidden escape platform on a matching-to-place version of the water maze in which the platform was moved to a new location for each session of four daily trials. Following 18 days of training, rats were randomly assigned to receive one of the following treatments: 1) injections of oil vehicle delivered 72 and 48 h before testing and continuous delivery of vehicle into the dorsal hippocampus via bilateral cannulae implants connected to osmotic minipumps; 2) injections of estradiol benzoate (EB) delivered 72 and 48 h before testing and continuous delivery of vehicle into the hippocampus; 3) injections of EB delivered 72 and 48 h before testing and continuous delivery of the M2 muscarinic receptor antagonist, AFDX 116, into the hippocampus; and 4) injections of EB delivered 72 and 48 h before testing and continuous delivery of AFDX 116 into a control site in the cortex. Chronic administration of AFDX 116 into the hippocampus, but not the cortex, significantly attenuated an estrogen-induced enhancement in performance on a working memory task in the water maze as indicated by increased latency and increased path length to locate an escape platform during a test trial when a 90 min delay was imposed between the first and second trials. These results indicate that acetylcholine acts at M2 muscarinic receptors located in the hippocampus to mediate the positive effects exerted by estrogen on working memory.

Hepatocytes exhibit superior transgene expression after transplantation into liver and spleen compared with peritoneal cavity or dorsal fat pad: implications for hepatic gene therapy.

For hepatic gene therapy or applications of hepatocyte transplantation in liver failure, survival and function of transplanted cells is critical. Insights into site-specific gene regulation will significantly facilitate development of appropriate strategies for transplanting hepatocytes. To assess the function of transplanted cells, we used a transgenic hepatitis B virus (HBV) hepatocyte system, which allowed analysis of cellular gene expression with HBV surface antigen (HBsAg) mRNA expression, as well as secretion of HBsAg into peripheral circulation. When congeneic HBV hepatocytes were transplanted into the liver (via spleen), serum HBsAg promptly appeared in circulation and persisted for the entire duration of the studies. In contrast, transplantation of hepatocytes into the peritoneal cavity or dorsal fat pad resulted in serum HBsAg levels that were either significantly lower or gradually rose after a lag period. HBsAg mRNA expression was several-fold greater in transplanted hepatocytes in liver or spleen versus in peritoneal cavity or dorsal fat pad. Despite persistence of transplanted hepatocytes in peritoneal cavity or dorsal fat pad, serum HBsAg was cleared by antibody to HBsAg (anti-HBs) but this was not observed after hepatocyte transplantation into spleen. As the function of transplanted hepatocytes is optimally regulated in the liver, hepatic reconstitution with cell transplantation will be most appropriate for gene therapy.

Studies on the safety of intrasplenic hepatocyte transplantation: relevance to ex vivo gene therapy and liver repopulation in acute hepatic failure.

Hepatocytes transplanted into the host liver engraft promptly, retain normal function, and survive indefinitely. Although intrasplenic transplantation is effective in delivering hepatocytes to the liver, to define potentially limiting complications, we studied its safety in normal, cirrhotic, and partial portal vein-ligated rats. In normal rats, portal pressures increased severalfold after hepatocyte transplantation but returned to normal within 3 weeks. In contrast, in portal hypertensive rats with partial portal vein ligation or cirrhosis, portal pressures were either unchanged or increased less after hepatocyte transplantation. However, more transplanted cells migrated to the lungs along with a rise in right atrial pressures in portal hypertensive rats. Further quantitative studies using 111Indium-labeled hepatocytes showed that intrasplenic retention of transplanted hepatocytes was similar in all animal groups. Intrahepatic cell translocation was comparable in normal and cirrhotic rats, whereas fewer cells migrated to the liver in partial portal vein-ligated rats. The most remarkable difference, however, was significantly greater intrapulmonary translocation of hepatocytes in portal hypertensive rats, which was presumably related to portosystemic shunting. These results indicate that because intrasplenic hepatocyte transplantation induces only temporary portal hypertension in normal subjects, potential strategies to augment liver repopulation could include repeated cell transplantation. This should be useful for optimizing the results of ex vivo gene therapy, or other hepatocyte-based therapies. However, the hepatic and portal hemodynamic status requires careful evaluation in portal hypertensive or cirrhotic subjects if serious complications are to be avoided.

Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men.

BACKGROUND: Cardiorespiratory fitness and body fatness are both related to health, but their interrelation to all-cause and cardiovascular disease (CVD) mortality is unknown. OBJECTIVE: We examined the health benefits of leanness and the hazards of obesity while simultaneously considering cardiorespiratory fitness. DESIGN: This was an observational cohort study. We followed 21925 men, aged 30-83 y, who had a body-composition assessment and a maximal treadmill exercise test. There were 428 deaths (144 from CVD, 143 from cancer, and 141 from other causes) in an average of 8 y of follow-up (176742 man-years). RESULTS: After adjustment for age, examination year, cigarette smoking, alcohol intake, and parental history of ischemic heart disease, unfit (low cardiorespiratory fitness as determined by maximal exercise testing), lean men had double the risk of all-cause mortality of fit, lean men (relative risk: 2.07; 95% CI: 1.16, 3.69; P = 0.01). Unfit, lean men also had a higher risk of all-cause and CVD mortality than did men who were fit and obese. We observed similar results for fat and fat-free mass in relation to mortality. Unfit men had a higher risk of all-cause and CVD mortality than did fit men in all fat and fat-free mass categories. Similarly, unfit men with low waist girths (<87 cm) had greater risk of all-cause mortality than did fit men with high waist girths (> or =99 cm). CONCLUSIONS: The health benefits of leanness are limited to fit men, and being fit may reduce the hazards of obesity.

Cryopreservation and short-term storage of human lymphocytes for surface marker analysis. Comparison of three methods.

Three methods were compared for the cryopreservation and short-term storage of human lymphocytes for cell surface marker analysis with monoclonal antibodies and flow cytometry. These methods were controlled-rate freezing followed by storage in liquid nitrogen (CR), direct placement into liquid nitrogen (LN), and direct placement at -70 degrees C (-70). Our findings show that the LN and -70 methods of cryopreserving lymphocytes are as effective as the CR method for the purpose of determining T cell and large granular lymphocyte subsets within 1 month after freezing.

Evaluation of a media-based mammography program.

Reports indicate that only 15%-20% of women 50 years of age and older have had a mammogram. To promote screening mammography, the San Diego County Unit of the American Cancer Society sponsored a community-wide program that featured (1) discounted mammograms through participating clinics, (2) program promotion through television news, and (3) availability of a phone bank for obtaining referrals for mammography. Pre- and postintervention random sample phone surveys indicated that women's intentions to obtain a mammogram increased significantly after the media campaign, particularly in those aware of the program. Women's intentions after the media campaign predicted mammography compliance in the following year. A total of 3,102 women received mammograms directly through the program, with a "suspicious finding" rate of 4%. Participant satisfaction with the program was high.

Serotonin syndrome in a child associated with erythromycin and sertraline.

Serotonin syndrome is an uncommon, serious adverse reaction that is usually associated with the interaction of two or more serotonergic agents. A 12-year-old boy receiving sertraline developed the syndrome after erythromycin was added to his regimen. The proposed mechanism involves erythromycin inactivation of cytochrome P450 3A4 inhibition of sertraline metabolism, accumulation of the drug, and precipitation of the syndrome. It is important for clinicians to consider both pharmacokinetic and pharmacodynamic interactions to minimize the risk of the reaction.

Late development of umbilical metastasis after laparoscopic cholecystectomy for a gallbladder carcinoma.

A periumbilical mass developed 47 months after laparoscopic cholecystectomy. Pathologic examination of this mass showed features of moderately differentiated papillary adenocarcinoma, similar to that identified within the previously removed early stage (pT1b) gallbladder carcinoma. The cause of this at the laparoscope port is unclear. after laparoscopic cholecystectomy for gallbladder carcinoma has not been reported previously. We reported a case with late periumbilical tumor seeding at the navel trocar insertion site in a 65-year-old female. A review of the preventative information of tumor recurrence and management is discussed. The use of gasless laparoscopy, slow desufflation, trocar site washout, wound protector and specimen bags are recommended.

Bilateral radical radiotherapy in a patient with uterus didelphys.

We report a case of congenital abnormality of uterus didelyphys in a patient who developed invasive carcinoma of the cervix. She received radical radiotherapy by a combination of external beam pelvic radiotherapy and high dose rate brachytherapy by insertion of afterloading catheters into both uterine canals. A newly defined prescription point was used midway between the two catheters and 2 cm above the mean cervical os position. The classical point A was regarded as inappropriate in this patient with a rare condition. Acute toxicity was minor and the patient is tumour free with no significant normal tissue late effects after follow-up of nearly 3 years.

Cardiorespiratory fitness determined by exercise heart rate as a predictor of mortality in the Aerobics Center Longitudinal Study.

This paper reviews the association of cardiorespiratory fitness to all-cause and cardiovascular disease mortality. Data are presented from the Aerobics Center Longitudinal Study (ACLS), which is a prospective study of 25,341 men and 7080 women. These individuals completed a health screening examination and were followed for more than 8 years for mortality. Low cardiorespiratory fitness was one of the strongest predictors of mortality in this study, with the risk of low fitness being comparable to smoking. Risk of low fitness persisted after adjustment for a long list of other risk factors and other potential confounders. Previously unpublished data on metabolic and cardiovascular responses to the exercise test used in the ACLS are also provided. This additional information further characterizes this cohort, and gives additional data and methods that can be used by others for risk assessment and stratification.

Recent developments and best practice in brachytherapy treatment planning.

Brachytherapy has evolved over many decades, but more recently, there have been significant changes in the way that brachytherapy is used for different treatment sites. This has been due to the development of new, technologically advanced computer planning systems and treatment delivery techniques. Modern, three-dimensional (3D) imaging modalities have been incorporated into treatment planning methods, allowing full 3D dose distributions to be computed. Treatment techniques involving online planning have emerged, allowing dose distributions to be calculated and updated in real time based on the actual clinical situation. In the case of early stage breast cancer treatment, for example, electronic brachytherapy treatment techniques are being used in which the radiation dose is delivered during the same procedure as the surgery. There have also been significant advances in treatment applicator design, which allow the use of modern 3D imaging techniques for planning, and manufacturers have begun to implement new dose calculation algorithms that will correct for applicator shielding and tissue inhomogeneities. This article aims to review the recent developments and best practice in brachytherapy techniques and treatments. It will look at how imaging developments have been incorporated into current brachytherapy treatment and how these developments have played an integral role in the modern brachytherapy era. The planning requirements for different treatments sites are reviewed as well as the future developments of brachytherapy in radiobiology and treatment planning dose calculation.