Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks.

The emergence of effective radionuclide therapeutics, such as radium-223 dichloride, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA ligands, over the last 10 years is driving a rapid expansion in molecular radiotherapy (MRT) research. Clinical trials that are underway will help to define optimal dosing protocols and identify groups of patients who are likely to benefit from this form of treatment. Clinical investigations are also being conducted to combine new MRT agents with other anticancer drugs, with particular emphasis on DNA repair inhibitors and immunotherapeutics. In this review, the case is presented for combining MRT with external beam radiotherapy (EBRT). The technical and dosimetric challenges of combining two radiotherapeutic modalities have impeded progress in the past. However, the need for research into the specific radiobiological effects of radionuclide therapy, which has lagged behind that for EBRT, has been recognised. This, together with innovations in imaging technology, MRT dosimetry tools and EBRT hardware, will facilitate the future use of this important combination of treatments.

Extreme under-reporting of body weight by young adults with obesity: relation to social desirability.

Objective: The objective of this study was to determine whether there is an association between under-reporting of body weight and social desirability as is found with self-reports of energy intake. Methods: Twenty-seven lean individuals (mean body mass index ± standard deviation = 21.6 ± 2.0 kg m-2) and 26 individuals with obesity (mean body mass index = 35.4 ± 4.8 kg m-2) were e-mailed a questionnaire on which they had to state their body weight and conduct a home food inventory. The next day, research team members went to their homes to weigh the participants, conduct their own food inventory and administer the Marlowe-Crowne scale for social desirability. Results: Among individuals with obesity, lower social desirability scores were associated with a greater degree of under-reporting body weight (r = +0.48, p < 0.02). Among lean individuals, the correlation was negative but statistically non-significant (p = -0.22, p > 0.10). Nine individuals with obesity were extreme under-reporters (2.27 kg or more), and eight of these had social desirability scores in the bottom half of the Marlowe-Crowne scale (p < 0.01). Six under-reported on the home food inventory by three or more items. Conclusions: Individuals with obesity and low social desirability scores are more likely than others to be extreme under-reporters of body weight, possibly due to a lack of awareness of their own weight.

Chasing maximal performance: a cautionary tale from the celebrated jumping frogs of Calaveras County.

Maximal performance is an essential metric for understanding many aspects of an organism's biology, but it can be difficult to determine because a measured maximum may reflect only a peak level of effort, not a physiological limit. We used a unique opportunity provided by a frog jumping contest to evaluate the validity of existing laboratory estimates of maximum jumping performance in bullfrogs (Rana catesbeiana). We recorded video of 3124 bullfrog jumps over the course of the 4-day contest at the Calaveras County Jumping Frog Jubilee, and determined jump distance from these images and a calibration of the jump arena. Frogs were divided into two groups: 'rental' frogs collected by fair organizers and jumped by the general public, and frogs collected and jumped by experienced, 'professional' teams. A total of 58% of recorded jumps surpassed the maximum jump distance in the literature (1.295 m), and the longest jump was 2.2 m. Compared with rental frogs, professionally jumped frogs jumped farther, and the distribution of jump distances for this group was skewed towards long jumps. Calculated muscular work, historical records and the skewed distribution of jump distances all suggest that the longest jumps represent the true performance limit for this species. Using resampling, we estimated the probability of observing a given jump distance for various sample sizes, showing that large sample sizes are required to detect rare maximal jumps. These results show the importance of sample size, animal motivation and physiological conditions for accurate maximal performance estimates.

Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations.

Two premix products containing the endectocide ivermectin were compared for pharmacokinetic profiles and bioequivalence in young pigs. Test and reference articles were administered to individual pigs in-feed at 12-h intervals for a total of 14 doses. Plasma concentration-time profiles were compared after provision of the final doses of medicated feed, by which time steady-state concentrations of ivermectin had been achieved. The pharmacokinetic variables monitored were peak concentration (Cmax ), area under the curve (AUC)0-last , elimination half-life of the terminal phase (T1/2 λz) and average steady-state concentration (Css ), determined by noncompartmental analysis. Logarithmic transformation of the variables was carried out when appropriate. Analysis of data by the Classic Method yielded confidence intervals of 80.59-114.47 (for AUC0-last ), 90.38-119.68 (for Cmax ) and 84.70-111.96 (for Css ). It was concluded that the two articles were bioequivalent for ivermectin.

A comparison of the efficacy of two ivermectin formulations against larval and adult Ascaris suum and Oesophagostomum dentatum in experimentally infected pigs.

A study was conducted to evaluate and compare the efficacy of two injectable formulations of ivermectin (IVM-1 and IVM-2) at a dose rate of 0.3 mg/kg bodyweight versus placebo in the treatment and control of larval and adult stages of Ascaris suum and Oesophagostomum spp. in experimentally infected pigs. Seventy helminth free pigs were allocated on a liveweight basis to 7 groups each comprising 10 pigs (A-G). Group A served as an untreated control group. Groups B and C were used to investigate the efficacy of both formulations against adult stages of A. suum and Oesophagostomum spp., Groups D and E for efficacy against larval stages of A. suum and Groups F and G for efficacy against larval stages of Oesophagostomum spp. Pigs of groups A, B, C, D and E were infected on Day-0 with 1000 infective A. suum eggs each. Infective larvae of Oesophagostomum spp. (10,000/pig) were given on Day-0 to pigs of Groups F and G and on Day-21 to pigs of Groups A, B and C. Treatment was given to pigs of Group A (saline as placebo) on Day-7 and -28, IVM-1 to pigs of Group F on Day-7, pigs of Group D on Day-14 and pigs of Group B on Day-49. IVM-2 was given to pigs of Group G on Day-7, Group E on Day-28 and Group C on Day-49. Pigs of Groups F and G were sacrificed on Day-28, pigs of Groups A, D and E on Day-49 and pigs of Groups B and C on Day-56. Post mortem worm counts showed the following efficacies: (IVM-1) against larval A. suum 100%, against adult A. suum 94.4%, against larval Oesophagostomum spp. 52.0% and against adult Oesophagostomum spp. 83.0%. (IVM-2) against larval A. suum 100%, against adult A. suum 90.3%, against larval Oesophagostomum spp. 94.0% and against adult Oesophagostomum spp. 94.7%.

World association for the advancement of veterinary parasitology (WAAVP): second edition of guidelines for evaluating the efficacy of equine anthelmintics.

These guidelines have been designed to assist in the planning, operation and interpretation of studies which would serve to assess the efficacy of drugs against internal parasites of horses. Although the term anthelmintic is used in the title and text, these guidelines include studies on drug efficacy against larvae of horse bot flies, Gasterophilus spp., which are non-helminth parasites commonly occurring in the stomach of horses. The advantages, disadvantages and application of critical and controlled tests are presented. Information is also provided on selection of animals, housing, feed, dose titration, confirmatory and clinical trials, record keeping and necropsy procedures. These guidelines should assist both investigators and registration authorities in the evaluation of compounds using comparable and standard procedures with the minimum number of animals.

Elimination of mucosal cyathostome larvae by five daily treatments with fenbendazole.

The efficacy of five daily treatments with 7.5 mg fenbendazole/kg bodyweight against mucosal cyathostome larvae was evaluated in 20 12- and 24-month-old ponies with naturally acquired cyathostome infections. After three weeks communal grazing on infected pasture and six weeks indoors, one group of 10 ponies were treated. Six weeks later, both groups of ponies were humanely destroyed and their burdens of large intestinal cyathostome worms, including luminal parasites and mucosal larvae, were assessed. In the control animals approximately 7 per cent of the total worm burden was present in the gut lumen and 93 per cent was present as larvae in the large intestinal mucosa. The efficacy of fenbendazole against the luminal cyathostomes was 90.7 per cent (P < 0.01). The total numbers of mucosal larvae, recovered after digestion, were reduced by 95.3 per cent (P < 0.0005); mucosal late third and fourth stage larvae were reduced by 99.4 per cent (P < 0.0001), and early inhibited third stage larvae by 91.5 per cent (P < 0.005).

Evaluation of the effect of the fenbendazole sustained-release intraruminal device on the immunity of calves to lungworm.

Each of 10 set-stocked calves was given a fenbendazole sustained-release intraruminal bolus at turnout for the control of parasitic bronchitis while a group of 10 similar calves was left untreated. The respiratory rates of the control calves were not greatly increased during the grazing season, but persistent coughing was evident from early July when they all had patent lungworm infections. Only occasional coughing was reported from the bolus-treated calves except for a transient increase in its frequency in late September. In mid-August, one of the treated calves was passing lungworm larvae and when they were housed six of the 10 had patent infections. In August tracer calves picked up an average of 23.5 lungworms per day from the control paddock but only 2.1 from the paddock grazed by the treated calves. In September the corresponding figures were 7.6 and 19.2 lungworms per day, respectively, from the control and 'treated' paddocks. After housing, the post mortem worm counts after an experimental challenge with Dictyocaulus viviparus larvae were reduced by 99.2 and 98.7 per cent (P < 0.0001), respectively, for the control and bolus-treated calves in comparison with weight-matched parasite-naive calves. Thus, despite a relatively low level of challenge during the grazing season, the treated animals had developed a considerable degree of protective immunity.

Efficacy of fenbendazole and piperazine against developing stages of toxocara and toxascaris in dogs.

In a series of controlled trials involving 59 naturally infected greyhounds, fenbendazole at a dose rate of 50 mg/kg/day for three consecutive days reduced the overall numbers of third and fourth stage Toxocara canis by 94.0 per cent and third stage, fourth stage and immature adult stages of Toxascaris leonina by 92.4 per cent. In contrast, piperazine at 100 mg/kg had little or no useful effect against the larval stages of T canis and T leonina and variable efficacy against immature adult T leonina. Fenbendazole was also 100 per cent effective against immature Trichuris vulpis. In a separate controlled experiment, puppies in three litters exposed to reinfection with T canis were treated with fenbendazole at two weeks old and again only after their mean faecal egg counts exceeded 200 epg. Between one and three doses were required to suppress the output of eggs during the puppies' first 12 weeks of life.

Influence of dietary protein on the immune responsiveness of sheep to Haemonchus contortus.

Twenty helminth-free lambs were fed diets containing either 169 g crude protein (CP) kg-1 dry matter (DM) or 88 g CP kg-1 DM from the age of seven months. One month later five lambs from each dietary group were vaccinated against Haemonchus contortus by the oral administration of 10,000 irradiated larvae on two occasions, four weeks apart. Four weeks following the administration of the second dose of irradiated larvae both the vaccinated and unvaccinated lambs were exposed to an experimental infection of 10,000 non-irradiated H contortus larvae Faecal egg output and haematological changes were monitored throughout the study. The lambs were slaughtered 28 days after challenge when worm burdens were assessed. Vaccination was equally successful in inducing a strong resistance to the challenge infection regardless of dietary status. It was concluded that dietary protein does not influence the response to vaccination with irradiated H contortus larvae of lambs more than seven months old.

Influence of dietary protein on the pathophysiology of haemonchosis in lambs given continuous infections.

Mixed-sex groups of three-month-old Finn Dorset and Dorset Horn lambs were given complete diets containing either high or low protein. A trickle infection with Haemonchus contortus of 200 larvae, given three times a week, began one month later for a 17 week period. Erythrokinetic, metabolic, digestibility and balance studies were conducted with the male lambs during weeks 12 to 14 of the infection. Clinical signs of haemonchosis became evident only in the low protein diet group. The infection was characterised by severe macrocytic anaemia, hypoproteinaemia, hypoalbuminaemia, reduced survival, high egg counts and a significantly greater worm burden. In the high protein diet group many lambs developed resistance to further infection in contrast to the low protein group in which no resistance developed. Live-weight gain was not affected by infection in the high protein diet group but decreased in the lambs given the low protein diet compared with uninfected controls. However, infection did not appear adversely to affect the digestive efficiency, nitrogen retention or iron absorption in either dietary group although loss of appetite occurred in the low protein group. Examination of a sample joint from the carcases showed infection was associated with a marked reduction in muscle mass in lambs given the low protein diet relative to the control animals.

The effect of dietary protein on the pathogenesis of acute ovine haemonchosis.

Two experiments were conducted to examine the influence of dietary protein on parasite establishment and pathogenesis in Finn Dorset/Dorset Horn lambs infected with Haemonchus contortus. The lambs were introduced to high (169 g) or low (88 g crude protein (CP) kg-1 dry matter (DM)) protein diets at 3 months of age and infected 1 month later with 350 larvae kg-1 body weight (BW). Blood and faecal samples were collected for analysis and body weights recorded weekly. In the first experiment some of the infected lambs were killed 6 weeks after infection and the remainder 5 weeks later. In the second experiment all the infected lambs were killed 4 weeks after infection. The results showed that lambs on a low protein diet were less able to withstand the pathogenic effects of infection with 350 H. contortus larvae kg-1 BW than lambs given the higher protein diet. Thus mortality was greater in the low protein group and adverse clinical signs, such as inappetence, weight loss and oedema were observed more frequently. This group also had a more severe anaemia, hypoproteinaemia and hypoalbuminaemia than the high protein group. In contrast, faecal egg counts, total daily faecal egg output and worm burdens were similar in all groups of infected lambs, indicating that the diets did not influence parasite establishment.

The effect of dietary protein on the pathophysiology of acute ovine haemonchosis.

An experiment was conducted to examine the effect of dietary protein on the pathophysiology of acute haemonchosis in Finn Dorset/Dorset Horn lambs. Erythrokinetic and metabolic studies using 51Cr-red cells, 59Fe-transferrin and 125I-albumin and digestive efficiency and nitrogen balance measurements were conducted between 19 and 39 days after infection. Identical radioisotopic and nutritional studies were conducted later on pair-fed control lambs. The results demonstrated that lambs on a low protein diet (88 g crude protein (CP) kg-1 dry matter (DM)) were less able to withstand the pathophysiological consequences of infection with 350 Haemonchus contortus larvae kg-1 body weight than lambs given a high protein (170 g CP kg-1 DM) diet, despite similar worm burdens. Erythrokinetic studies indicated that abomasal blood loss was similar in both groups of infected lambs, and circulating red cell volumes were reduced and plasma volumes were expanded to a similar degree in both groups. The majority of infected lambs in both dietary groups responded equally well to the gastric haemorrhage by increasing the rate of red cell production and their absorption of dietary iron was greater than in the control lambs. Albumin catabolism was increased in both groups of infected lambs, particularly in those given the low protein diet. Within each dietary group there were no differences in the digestibilities of the various proximate fractions of the experimental diets and no differences in the urinary or faecal nitrogen losses between infected lambs and their pair-fed controls. However, loss of appetite was a major feature of the disease, particularly in the lambs given the low protein diet and this feature appeared to be crucial in determining the ability of the infected sheep to withstand the pathophysiological effects of the parasite.

Influence of dietary protein on the pathophysiology of ovine haemonchosis in Finn Dorset and Scottish Blackface lambs given a single moderate infection.

Two experiments were conducted to examine the influence of dietary protein on the pathophysiology of Haemonchus contortus in lambs of two breeds, namely Finn Dorset and Scottish Blackface. Erythrokinetic and metabolic studies using 51Cr-red cells, 59Fe-transferrin and 125I-albumin, and digestive efficiency and nitrogen balance measurements were conducted between four and six weeks after infection. Identical radioisotopic and nutritional studies were also conducted on pair-fed control lambs of both breeds. The results demonstrated that in normal control animals, there were no significant effects of diet or breed on any of the erythrokinetic, metabolic or nutritional parameters, with the possible exception of red cell survival which was considerably longer in the Finn Dorset lambs. However, in the infected animals diet and breed did influence those parameters. The severest effects were seen in the infected Finn Dorset lambs given the low protein diet. These animals had the highest level of abomasal blood loss and this was associated with low red cell volumes and high levels of both albumin catabolism and plasma iron turnover. These animals were also in negative nitrogen balance which was partly accounted for by a significantly greater urinary nitrogen loss compared with their pair-fed controls and partly due to the poorer digestibility of the crude protein fraction of the diet. In contrast, although the infected Scottish Blackface lambs had high levels of blood loss and associated pathophysiological changes, these did not differ between dietary treatments and were similar to the changes in the infected Finn Dorset lambs given the high protein diet.

Influence of dietary protein on parasite establishment and pathogenesis in Finn Dorset and Scottish Blackface lambs given a single moderate infection of Haemonchus contortus.

An experiment was conducted to examine the influence of dietary protein on parasite establishment and pathogenesis of Haemonchus contortus in lambs of two breeds. Finn Dorset and Scottish Blackface. The lambs were introduced to high protein (170 g crude protein (CP) kg-1 dry matter (DM) or low protein (88 g CP kg-1 DM) diets at three months old and infected one month later with 125 larvae (kg bodyweight)-1. Blood and faecal samples were collected for analysis and bodyweights recorded weekly. The lambs were killed 20 weeks after infection. A second experiment was conducted in Blackface lambs solely to determine the influence on parasite establishment of the high and low protein diets following infection with 125 larvae kg-1. These lambs were killed five or 14 weeks after infection. Results showed that in Scottish Blackface lambs dietary protein did not significantly influence the establishment of H contortus. However, in Finn Dorset lambs dietary protein may have influenced parasite establishment since lambs on the low protein diet had a higher faecal egg output four weeks after infection and more severe clinical signs than infected lambs of the same breed on a high protein diet.

Studies on the pathophysiology of chronic ovine haemonchosis in Merino and Scottish blackface lambs.

An experiment was conducted to examine, under laboratory conditions, the pathophysiology of chronic ovine haemonchosis. In the present study, groups of Merino and Scottish Blackface lambs were maintained on a low plane of nutrition and infected with 50 Haemonchus contortus larvae/kg live weight. The parasitized lambs along with respective breed controls were examined over a 27-week period. In addition to the body weight, haematological and parasitological parameters, erythrokinetic, metabolic, digestibility and nitrogen balance studies were conducted in the early stages of the infection. The results demonstrated that a low level of infection with H. contortus in lambs on a poor plane of nutrition caused the development of a normochromic normocytic anaemia which was associated with a modest but significant increase in abomasal blood loss and slightly elevated erythropoiesis in both breeds relative to the controls. The level of anaemia, hypoproteinaemia and pathophysiological changes were more marked in the Merino lambs and they also had higher faecal egg counts than the Blackface lambs.