[Exercise Therapy for Children with Cancer Related Fatigue]. / Bewegungstherapie für Kinder mit Cancer Related Fatigue.

Cancer Related Fatigue (CRF) is known as one of the strongest and incriminating side effects of cancer for adults and children. By now there is a lack of valid assessments and sufficient therapy in pediatric oncology. For children it is a tough challenge to accept this overwhelming tiredness and lower activity level in their daily life routines. First positive effects in CFR therapy were found by adults, but this specific scientific field is very young and therefore mostly unexplored. 4 databases for medical and therapeutic journals were systematically searched for RCTs, CCTs and CTs. Systematic reviews were analyzed as well. All studies were carried out in pediatric oncology and deal with exercise therapy. The enclosed studies were valued by PEDro-Scale. Only a handful papers about a potential reduction of CRF in pediatrics could be found, one RCT, 2 CCTs and one CT. No additional results could be found. To summarize the 4 papers, it can be stated that the duration of intervention depends between 2 days and 12 weeks. Also there are differences between the option inpatient and outpatient programs, as well as with or without supervising. The exercise therapy mostly consists of strength and endurance training in combination with warm-up and cool-down programs. This review underlines the importance of developing new assessments. Especially bigger groups of participants should be analyzed with the scope on individualized, supervised program. So far, CRF is underestimated in pediatric oncology and it is very crucial to identify the symptoms. This could lead to an improvement in quality of life.

C4 from C4-high and C4-low mouse strains have identical sequences in the region corresponding to the isotype-specific segment of human C4.

The human complement component C4 isotypes, C4A and C4B, show a substantial and biologically important difference in chemical reactivity. Murine C4 from different mouse strains has recently been reported to have a comparable difference in reactivity. In human C4, the difference in reactivity has been attributed to the effect(s) of one or more of only four amino acid residues, within a six-residue-long segment of the alpha subunit, which distinguish the two isotypes. In the present study, we sought to assess the role of the corresponding four amino acids in mouse C4 in the strain-specific modulation of C4 reactivity. In order to compare the sequences of the corresponding region in murine C4 among different mouse strains, we used the polymerase chain reaction method to amplify an approximately 229-bp segment of the murine gene that includes the codons for these four amino acid residues. Because the difference in chemical reactivity of murine C4 has been reported to be between C4 from strains which express different levels of C4, we examined sequences from mouse strains C57BL/6, DBA/2, C3H/He, B10.BR and CBA/J; these represent two C4-high strains and three C4-low strains. The amplified segments were cloned into the pUC19 vector and 20 independent clones from each mouse strain were sequenced. Across the entire amplified segment, our results revealed expected isotypic differences between C4 and its nonfunctional isotype in the mouse, Slp, as well as allelic differences among the C4 and Slp genes. However, all of these differences were quite distant from the amino acid residues corresponding to the human isotype-specific residues and those corresponding residues were identical in all five mouse strains. This result indicates that any strain-specific difference in chemical reactivity of murine C4 must be due to a mechanism distinct from that operating in human C4.

The murine Slp gene. Additional evidence that sex-limited protein has no biologic function.

Sex-limited protein (Slp) is a mouse serum protein of unknown function that has approximately 95% amino acid sequence identity with murine complement component C4 but is inactive in the complement pathway. The gene for Slp lies in the S region of the murine H-2 complex adjacent to the gene Cyp21 that encodes the Cytochrome P-450 enzyme steroid 21-hydroxylase. We report the sequence of a 26,307 bp long segment of the mouse genome that includes both the Slp and Cyp21 genes. The sequence reported was assembled from the sequences of three overlapping lambda phage genomic clones from mouse strain B10.WR, which carries four tandem pairs of Slp and Cyp21 genes. We also report the sequence of a fourth lambda clone, 12,539 bp in length, carrying parts of a distinct pair of Slp and Cyp21 genes from B10.WR mice. The Slp gene at 14.3 kb in length is about 1 kb shorter than the C4 gene; this difference is due primarily to absences of a simple repetitive sequence and a middle repetitive MT element in the corresponding introns 14 and 15, respectively. The gene sequence reveals an intron/exon organization identical to that of the murine C4 gene, and also that the 9 nucleotide deletion in exon 18, which appears to be directly responsible for the absence of complement activity, is unrelated to differences in intron sequences. Detailed comparisons of C4 and Slp gene sequences indicate that nucleotide substitutions in the Slp gene are occurring at approximately the same rate in both exons and introns. This implies that the murine Slp gene resembles a pseudogene and supports previously reported evidence that the Slp protein has no biologic function.

Sequence of the gene for murine complement component C4.

The gene for murine complement component C4 lies in the S region of the murine major histocompatibility (H-2) complex; in this paper, we report the nucleotide sequence of this gene. The present sequence extends from a SmaI restriction enzyme cleavage site near the 5' end of the gene to a KpnI restriction enzyme cleavage site 569 nucleotides 3' of the polyadenylation site. The sequence spans 15,956 base pairs and together with previously reported data provides a complete sequence extending from the site of transcriptional initiation to the polyadenylation site. The sequence reveals that the C4 gene has 40 introns which range from 75 to 1089 base pairs in length and which include three murine B1 middle repetitive elements, a MT repeat element, and an apparently novel repeat sequence that is also found in noncoding regions of the murine beta-glucuronidase, lymphotoxin (TNF-beta), and rat alpha-crystallin genes. An intron splits the protein coding sequence precisely at the site of proteolytic activation of C4 by complement protease C1s; however, except for this one case, the intron positions show no striking relationship to the structural features of the C4 protein. The length of the murine C4 gene relative to the isotypic C4A and C4B genes in man suggests the independent loss of a 6-kilobase intron from both murine and human C4 genes.

Mutants of complement component C3 cleaved by the C4-specific C1-s protease.

To identify some of the structural features determining specific protease recognition of complement components C3 and C4, we used site-specific mutagenesis to construct mutants of murine C3 that are cleaved by the C4-specific C1-s protease. Insertion of three amino acid residues corresponding to residues at the C1-s cleavage site of human C4 into murine C3 at the analogous C3 convertase cleavage site was adequate to render the mutant protein susceptible to C1-s cleavage. In addition, insertion of C3-specific residues at the same site or introduction of the C4-specific residues as substitutions rather than as an insertion also rendered the site susceptible to cleavage, but with 10- to 50-fold lower efficiencies, and insertion of even a single amino acid residue affected recognition by C1-s. Finally, insertion of amino acid residues into mC3 partially inhibited cleavage by the alternative-pathway C3 convertase, with insertion of C3- or C4-specific residues giving about the same level of inhibition. A simple interpretation of these data is that C1-s cleavage is dependent primarily on steric accessibility and on recognition of specific amino acid residues at the cleavage site, whereas C3 convertase cleavage is dependent primarily on specific interactions distal to the cleavage site, with only relatively weak, non-C3-specific interactions at the cleavage site itself.