Adjuvant treatment of pancreatic carcinoma in a clinically adapted mouse resection model.

BACKGROUND: The high rate of local recurrence after radical resection of pancreatic adenocarcinoma fosters intensive efforts to develop new approaches for adjuvant treatment. The established animal models show significant limitations in simulating an adjuvant therapeutic setting. For optimal approximation to the clinical situation we therefore improved a murine orthotopic human xenotransplantation model. METHODS: Subtotal pancreatectomy in mice was performed after orthotopic inoculation of human pancreatic cancer cells and manifestation of solid tumours. The natural course of disease, tumour growth and metastases were analysed. Gemcitabine as a cytotoxic drug was tested in vitro on the cell line used in this model and the effect of adjuvant treatment with gemcitabine in vivo was investigated. RESULTS: All tumour-resected animals showed local recurrence. Organ metastases occurred in 67% in resected compared to 25% of non-resected animals. Gemcitabine in vitro was ineffective, but as adjuvant monotherapy resulted in a highly significant reduction of tumour weight and metastatic events. CONCLUSION: Subtotal pancreatectomy for xenotransplanted pancreatic cancer in SCID beige mice is feasible. Due to high rates of local recurrence and increased organ metastases, this model offers a relevant option for preclinical adjuvant testing, especially as in vitro and in vivo effects of cytotoxic drugs differ enormously.     

Family help--a critical analysis of the concept of "disability"

This article discusses relevant aspects of the psychological situation of being nursed and refers to the psychosocial conception of competence, and its importance in a differential approach to the multidimensional process of developing rehabilitation programs. The report is based on an empirical study of the coping-styles of the chronically diseased elderly and their relatives. Our purpose is to give an expanded definition of competence and to identify some characteristic conditions causing trouble for the diseased and his family. With regard to inter- and intraindividual differences, some ideas of intervention and help are suggested.     

Reactions of stroke patients to their health status

Coping patterns of two groups of stroke patients related to their health condition are compared: one group participated in a rehabilitation programme, while the consisted of long-term care patients who had suffered a stroke ten to twenty years before the interview was second group. Similarities and differences between the response hierarchies of the two groups are demonstrated and discussed with special emphasis on the complex cognition and motivation interactions determining success and failure in coping.     

Continuous measurement of gastric blood flow by laser-Doppler flowmetry during gastroscopy

Endoscopic laser-Doppler flowmetry (LDF) of gastric blood flow (GBF) was performed simultaneously with intragastric manometry to detect a possible correlation between GBF and luminal pressure during gastroscopy. By increasing luminal air pressure from 10 to 20 cm H2O a significant reduction in GBF was observed. Regional differences in GBF were also demonstrated. Variations in luminal air pressure have a significant influence on GBF as measured by LDF, and therefore intragastric manometry and standardization of intraluminal air pressure is necessary in endoscopic LDF measurements.     

Analyzing age-specific genetic effects on human extreme age survival in cohort-based longitudinal studies

The analysis of age-specific genetic effects on human survival over extreme ages is confronted with a deceleration pattern in mortality that deviates from traditional survival models and sparse genetic data available. As human late life is a distinct phase of life history, exploring the genetic effects on extreme age survival can be of special interest to evolutionary biology and health science. We introduce a non-parametric survival analysis approach that combines population survival information with individual genotype data in assessing the genetic effects in cohort-based longitudinal studies. Our approach is characterized by non-parametric analysis of late age survival to capture the observed pattern of mortality deceleration and frailty modeling to account for individual heterogeneity in unobserved frailty. The method is applied to ApoE genotype data in the Danish 1905 birth cohort to estimate effect of the e4 allele. Our results revealed an age-specific relative risk of the allele that increases nonlinearly with age and non-proportional patterns in hazard of death for carriers and non-carriers of the allele, suggesting that the e4 mutation preserves its deleterious effect that progressively affect human survival even at extreme ages.     

Phosphorylation of human cardiac troponin I G203S and K206Q linked to familial hypertrophic cardiomyopathy affects actomyosin interaction in different ways

cAMP-dependent protein kinase (PKA)-dependent phosphorylation of the two serine residues in the amino terminal region unique to cardiac troponin I (cTnI) is known to cause two effects: (i) decrease of the maximum Ca2+-controlled thin filament-activated myosin S1-ATPase (actoS1-ATPase) activity and mean sliding velocity of reconstituted thin filaments; (ii) rightward shift of the Ca2+ activation curves of actoS1-ATPase activity, filament sliding velocity, and force generation. We have studied the influence of phosphorylation of human wild-type cTnI and of two mutant cTnI (G203S and K206Q) causing familial hypertrophic cardiomyopathy (fHCM) on the secondary structure by circular dichroism spectroscopy and on the Ca2+ regulation of actin-myosin interaction using actoS1-ATPase activity and in vitro motility assays. Both mutations slightly influence the backbone structure of cTnI but only the secondary structure of cTnI-G203S is also affected by bis-phosphorylation of cTnI. In functional studies, cTnI-G203S behaves similarly to wild-type cTnI, i.e. the mutation itself has no measurable effect and bis-phosphorylation alters the actoS1-ATPase activity and the in vitro thin filament motility in the same way as does bis-phosphorylation of wild-type cTnI. In contrast, the mutation K206Q leads to a considerable increase in the maximum actoS1-ATPase activity as well as filament motility compared to wild-type cTnI. Bis-phosphorylation of this mutant cTnI still suppresses the maximum actoS1-ATPase activity and filament sliding velocity but does no longer affect the Ca2+ sensitivity of these processes. Thus, these two fHCM-linked cTnI mutations, although reflecting similar pathological situations, exert different effects on the actomyosin system per se and in response to bis-phosphorylation of cTnI.