Effect of IL-2-Bax, a novel interleukin-2-receptor-targeted chimeric protein, on bleomycin lung injury

The role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro-fibrotic effect for lymphocytes. The high-affinity interleukin-2 receptor (haIL-2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL-2R provides the basis for therapeutic strategies that target IL-2R-expressing cells. We hypothesized that elimination of activated lymphocytes by IL-2R-targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL-2-Bax, a novel apoptosis-inducing IL-2R-targeted chimeric protein, on bleomycin-induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice-daily intraperitoneal injections of IL-2-Bax; (ii) intratracheal bleomycin and intraperitoneal IL-2-PE66(4Glu), an older-generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi-quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL-2-Bax and IL-2-PE66(4Glu). However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL-2-Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis.     

Exercise motivation and adherence in cancer survivors after participation in a randomized controlled trial: An attribution theory perspective

The purpose of this study was to examine postprogram exercise motivation and adherence in cancer survivors who participated in the Group Psychotherapy and Home-Based Physical Exercise (GROUP-HOPE; Courneya, Friedenreich, Sela, Quinney, & Rhodes, 2002) trial. At the completion of the GROUP-HOPE trial, 46 of 51 (90%) participants in the exercise group completed measures of attribution theory constructs. A5-week follow-up self-report of exercise wasthen completed by 30 (65%) participants. Correlational analyses indicated that program exercise, perceived success, expected success, and affective reactions were strong predictors of postprogram exercise. In multivariate stepwise regression analyses, program exercise and perceived successwere the strongest predictors of postprogram exercise. Additionally, perceived success was more important than objective success in understanding the attribution process, and it interacted with personal control to influence expected success and negative affect. Finally, postprogram quality of life and changes in physical fitness were correlates of perceived success. We concluded that attribution theory may have utility for understanding postprogram exercise motivation and adherence in cancer survivors.     

Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus

A quantitative autoradiographic histological study was carried out to examine mechanisms underlying the reduction in the rates of growth and of cell acquisition, including that of granule cells, in the dentate gyrus of hypothyroid rats. Thyroid deficiency in early life had no effect on the replication of intrinsic cells present in the polymorph and granular layers. The pyknotic index was also normal in the "proliferative zone", polymorph layer and granule cell layer, indicating that thyroid hormone had no effect on the survival of replicating, migrating or maturing granule cells. By contrast, the arrival of migrating cells from the "proliferative zone" to the granular layer was severely retarded in thyroid deficiency. This deficit was rapidly restored after a physiological dose of thyroxine given to hypothyroid rats. The present findings are consistent with our previous proposal that the role of thyroid hormone in the formation and/or the maintenance of nerve cells is related to changes in either cell migration or maturation, rather than to alterations in the replication of germinal cells.     

Bi-allelic loss of function variants in SLC30A5 as cause of perinatal lethal cardiomyopathy

Perinatal mortality is a heavy burden for both affected parents and physicians. However, the underlying genetic causes have not been sufficiently investigated and most cases remain without diagnosis. This impedes appropriate counseling or therapy. We describe four affected children of two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. In the four patients, we found the following homozygous loss of function (LoF) variants in SLC30A5 NM_022902.4:c.832_836del p.(Ile278Phefs*33) and NM_022902.4:c.1981_1982del p.(His661Tyrfs*10). Knockout of SLC30A5 has previously been shown a cardiac phenotype in mouse models and no homozygous LoF variants in SLC30A5 are currently described in gnomAD. Taken together, we present SLC30A5 as a new gene for a severe and perinatally lethal form of cardiomyopathy.Subject terms: Cardiovascular diseases, Development, Medical genetics, Medical genomics     

Differential effects of scopolamine on neuronal survival in ischemia and glutamate neurotoxicity: relationships to the excessive vulnerability of the dorsoseptal hippocampus

The neurodegeneration in the CA1 subfield of hippocampus exhibited a dorsal-ventral gradient of susceptibility in global ischemia (82% dorsoseptally and only 16% ventrotemporally). Scopolamine (SCOP) did not improve the neuronal damage caused by the global ischemic challenge in rats and did not reduce the infarct area after the focal MCA-occlusion in mice. No differences were observed between saline and SCOP-treated animals in the physiologic parameters, except for a slight increase in rectal temperature. In contrast, treatment of hippocampal cultures with increasing concentrations of SCOP (1 nM to 1 mM) under glutamate incubation had a beneficial effect on neuronal viability. These data show that (1) there is substantial gradient of vulnerability of the hippocampus from dorsal to ventral in global ischemia and (2) that interactions between the NMDA, muscarinic receptors and their corresponding neurotransmitter inputs to hippocampal neurons are evident in vitro and may play a crucial role in neuronal neurodegeneration. However, the mechanisms underlying the high vulnerability of dorsal hippocampus still remain enigmatic.     

Postprandial glycaemia after regular and lispro insulin in children and adolescents with diabetes

We compared the postprandial blood glucose (BG)-levels following preprandial regular insulin or lispro insulin before and after eating in adolescents with diabetes. Lispro is a rapidly absorbed insulin analogue. Lispro insulin injected immediately before breakfast reduced the postprandial BG-rise significantly compared to the 20 min preprandially administered regular insulin (P<0.01). Postprandial lispro injection resulted in similar BG values as the standard treatment with regular insulin 20 min preprandially. Conclusion Lispro insulin injected immediately before the meal leads to lower postprandial BG levels and seems to be an option for teenagers who use multiple preprandial insulin injections. Postprandial lispro administration could be a benefit in certain situations since it resulted in similar BG values to preprandial regular insulin. Received: 13 March 1997 / Accepted: 26 May 1997