Evaluation of PEG-L-asparaginase in asparagine suppression and anti-drug antibody development in healthy Beagle dogs: A multi-phase preclinical study.

L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma.

[Metabolic diseases in psychiatry]. / Stofwisselingsziekten binnen de psychiatrie.

Metabolic diseases can be associated with psychiatric symptoms. We present two case histories that demonstrate the importance of correctly diagnosing a metabolic disease as being the cause of psychiatric symptoms. We also discuss which symptoms or signals may indicate a metabolic disease.

The role of physical activity and physical fitness in postcancer fatigue: a randomized controlled trial.

PURPOSE: Patients suffering from postcancer fatigue have both an inferior physical activity and physical fitness compared to non-fatigued cancer survivors. The aims of this study were (1) to examine the effect of cognitive behavior therapy, an effective treatment for postcancer fatigue, on physical activity and physical fitness and (2) to examine whether the effect of cognitive behavior therapy on postcancer fatigue is mediated by physical activity and/or physical fitness. METHODS: Severely fatigued cancer survivors were randomly assigned to either the intervention (cognitive behavior therapy) or the waiting list condition. After assigning 23 patients in the intervention condition and 14 patients in the waiting list condition, they were assessed both at baseline and 6 months later. Physical activity was assessed via actigraphy and physical fitness was assessed by a maximal exercise test. A nonparametric bootstrap approach was used to test the statistical significance of the mediation effects. RESULTS: A significant increase in physical activity was observed in the intervention group from baseline to follow-up, whereas physical activity did not change from baseline to follow-up in the waiting list group. Physical fitness did not significantly change after cognitive behavior therapy or after 6 months of waiting for therapy. Fatigue decreased more significantly in the intervention group than in the waiting list group. The mediation hypotheses were rejected. CONCLUSIONS: Cognitive behavior therapy effectively reduced postcancer fatigue and increased physical activity but did not change physical fitness. The effect of cognitive behavior therapy on postcancer fatigue is not mediated by a change in physical activity or physical fitness.

Maximal exercise performance in patients with postcancer fatigue.

PURPOSE: The aim of this study is to examine whether physical fitness of severely fatigued and non-fatigued cancer survivors, as measured by maximal exercise performance, is different between both groups and, if so, whether this difference can be explained by differences in physical activity, self-efficacy regarding the exercise test, and/or social support. METHODS: Severely fatigued (n = 20) and sex- and age-matched non-fatigued (n = 20) disease-free cancer survivors, who completed treatment for a malignant, solid tumor at least 1 year earlier, participated in this case-control study. Maximal oxygen consumption was measured during an incremental cycling exercise test. Physical activity was assessed via actigraphy. Self-efficacy regarding the test and social support were assessed via questionnaires to study its relationship with physical fitness. RESULTS: Maximal oxygen consumption was significantly lower in fatigued compared to non-fatigued participants. Actual physical activity, self-efficacy regarding the test, and negative interactions of social support were significantly different between both groups. However, after inclusion of these three variables in linear regression analyses, the difference in physical fitness between fatigued and non-fatigued cancer survivors persisted. CONCLUSIONS: Maximal oxygen consumption, a measure for physical fitness, was reduced in severely fatigued compared to non-fatigued cancer survivors. The inferior maximal exercise performance cannot fully be explained by differences in physical activity, self-efficacy, or social support between both groups. Other currently still unknown factors, such as a disturbance in the cardiopulmonary circuit, may play a role.

The effect of rising and sitting trot on back movements and head-neck position of the horse.

REASON FOR PERFORMING STUDY: During trot, the rider can either rise from the saddle during every stride or remain seated. Rising trot is used frequently because it is widely assumed that it decreases the loading of the equine back. This has, however, not been demonstrated in an objective study. OBJECTIVE: To determine the effects of rising and sitting trot on the movements of the horse. HYPOTHESIS: Sitting trot has more extending effect on the horse's back than rising trot and also results in a higher head and neck position. METHODS: Twelve horses and one rider were used. Kinematic data were captured at trot during over ground locomotion under 3 conditions: unloaded, rising trot and sitting trot. Back movements were calculated using a previously described method with a correction for trunk position. Head-neck position was xpressed as extension and flexion of C1, C3 and C6, and vertical displacement of C1 and the bit. RESULTS: Sitting trot had an overall extending effect on the back of horses when compared to the unloaded situation. In rising trot: the maximal flexion of the back was similar to the unloaded situation, while the maximal extension was similar to sitting trot; lateral bending of the back was larger than during the unloaded situation and sitting trot; and the horses held their heads lower than in the other conditions. The angle of C6 was more flexed in rising than in sitting trot. CONCLUSIONS AND CLINICAL RELEVANCE: The back movement during rising trot showed characteristics of both sitting trot and the unloaded condition. As the same maximal extension of the back is reached during rising and sitting trot, there is no reason to believe that rising trot was less challenging for the back.

The blocking effect of pictorial prompts on sight-word reading.

This study replicates and extends previous work showing that pictorial prompts can interfere with the learning of sight words by students with moderate mental retardation. Effects of training with 6 students were assessed during five conditions using an alternating treatments design. In four conditions, words were presented either alone or with a corresponding picture. In a fifth condition, pictures were used to provide feedback. The results showed that acquisition was achieved fastest during the word-alone conditions with 5 students.

Nucleotide sequence of a cDNA clone encoding a Caenorhabditis elegans homolog of mammalian alkyl-dihydroxyacetonephosphate synthase: evolutionary switching of peroxisomal targeting signals.

The nucleotide sequence is reported of a cDNA clone encoding a Caenorhabditis elegans homolog of guinea pig and human alkyl-dihydroxyacetonephosphate synthase. The open reading frame encodes a protein of 597 amino acids which shows extensive homology with the mammalian enzymes (52% identical and about 76% similar in the overlapping region). In contrast to the mammalian enzymes, which carry a consensus peroxisomal targeting signal type 2 in a cleavable N-terminal presequence, this Caenorhabditis elegans homolog carries a consensus peroxisomal targeting signal type 1 (CKL) at its C-terminus. Expression of this protein in an in vitro transcription/translation system yielded a 65 kDa protein. Recombinant aenorhabditis elegans alkyl-DHAP synthase expressed in the yeast Pichia pastoris was enzymatically active.

Protective efficacy of a recombinant DNA vaccine against hepatitis B in male homosexuals: results at 36 months.

An open study with a recombinant DNA yeast-derived hepatitis B vaccine (YDV) was carried out in homosexual men to assess the protective efficacy of this vaccine. A total of 278 seronegative volunteers were enrolled to receive three intramuscular doses of either 20 or 40 micrograms at months 0, 1 and 6. Serum specimens were taken at various times up to 36 months; relevant information regarding the occurrence of other sexually transmitted diseases (STDs) and sexual behaviour was also collected annually. One month after the third injection, the seroconversion rate in both groups was 99%. The geometric mean anti-HBs titre at this time was higher for subjects receiving 40 micrograms doses although a similar percentage of the vaccinees had titres greater than 10 mIU ml-1 in both groups. Compared with a historical control group in which the annual incidence of hepatitis B infection was 12%, only two vaccinees developed markers of infection during the immunization period and none thereafter. While an important increase in the use of condoms was noted during the 1984-87 study period and the incidence of some STDs declined, these changes could not solely account for the decrease in hepatitis B infection in the study population.

Immunogenicity and tolerance of a yeast-derived hepatitis B vaccine in homosexual men.

A yeast-derived recombinant DNA vaccine against hepatitis B was administered to 314 active homosexual men lacking serum markers for hepatitis B virus. Volunteers were vaccinated intramuscularly in the deltoid region at 0, 1, and 6 months with either a 20- or 40-micrograms dose per injection. Serologic tests for syphilis and human immunodeficiency virus were positive in 3.2% and 2.0%, respectively. The overall seroconversion rates for anti-HBs were 35%, 97%, and 98% after the first, second, and third injection, respectively. The geometric mean titres of anti-HBs antibodies at 7 months were 955 IU/l and 2541 IU/l, for the 20 and 40 micrograms doses, respectively. Among 183 completely vaccinated subjects, 97% had an anti-HBs titre greater than 10 IU/l. Tolerance of the vaccine was excellent. Among the 183 subjects followed up for at least 7 months, two volunteers developed HBsAg and anti-HBc within one month of the first vaccine injection and one anti-HBc just before the third dose of vaccine. However, no subject experienced clinical hepatitis or ALT elevations.