Reversibility of the acute toxic effect of Cyclosporin A on pancreatic B cells of Wistar rats

Summary. This study investigated if and to what extent the acute toxic effect of Cyclosporin A on pancreatic Wistar rat B cells is reversible. After 2 weeks of treatment rats developed marked glucose intolerance accompanied by reduced pancreatic insulin content due to a loss of B cells, diminished islet DNA synthesis and decreased B-cell insulin content. Cyclosporin A had accumulated in the pancreas. Three weeks after withdrawal of Cyclosporin A, pancreatic tissue concentrations of Cyclosporin A were still 100 times larger than in serum. Glucose tolerance, however, had already improved, associated with an increase of B-cell insulin content and apparent islet replication, and the insulin response of isolated islets was reduced. Five weeks after the withdrawal of Cyclosporin A, glucose tolerance was normal, but pancreatic insulin content and relative B-cell volume were still diminished in comparison to vehicle-treated controls. Eight weeks after withdrawal, the morphometric parameters had also been normalized. The results suggest that the loss of pancreatic B cells is caused by a toxic destruction, possibly combined with an apparent decrease of replicatory activity. The acute toxic effects of Cyclosporin A in pancreatic B cells are stepwise reversible.     

Euthanasia in the Third Reich--only a problem of psychiatry? On the development of the euthanasia debate 1933-1941 in Germany

The devastating consequences of the Fascist dictatorship in Germany for the ethical thinking of the physicians are particularly clearly recognizable by the mass killings of severely damaged children and patients with chronic psychic diseases which were performed at that time. Recent investigations of the developments which began in 1938 show that by way of intensive efforts for a juridicial legalization of the "active euthanasia" an enlargement of this killing practice has been striven after. References to a motive of compassion and the free decision of the affected persons should cover the real intention for reducing welfare services. A bill presented in 1940 for a law "on euthanasia for incurable ill persons" found the unanimous consent of the renowned physicians consulted for this purpose. Though this law finally did not become legal beginning with 1941 the medical practice showed further forms of the repressive and antihumane association with ill persons who were regarded as incurable, which must be valuated as practical consequences of an unadmissible relativation of the life-preserving task of medicine.     

Mathematical model of volume kinetics and renal function after burn injury and resuscitation

This paper presents a mathematical model of blood volume kinetics and renal function in response to burn injury and resuscitation, which is applicable to the development and non-clinical testing of burn resuscitation protocols and algorithms. Prior mathematical models of burn injury and resuscitation are not ideally suited to such applications due to their limited credibility in predicting blood volume and urinary output observed in wide-ranging burn patients as well as in incorporating contemporary knowledge of burn pathophysiology. Our mathematical model consists of an established multi-compartmental model of blood volume kinetics, a hybrid mechanistic-phenomenological model of renal function, and novel lumped-parameter models of burn-induced perturbations in volume kinetics and renal function equipped with contemporary knowledge on burn-related physiology and pathophysiology. Using the dataset collected from 16 sheep, we showed that our mathematical model can be characterized with physiologically plausible parameter values to accurately predict blood volume kinetic and renal function responses to burn injury and resuscitation on an individual basis against a wide range of pathophysiological variability. Pending validation in humans, our mathematical model may serve as an effective basis for in-depth understanding of complex burn-induced volume kinetic and renal function responses as well as development and non-clinical testing of burn resuscitation protocols and algorithms.     

Kann man balancierte Infusionslösungen verbessern?

Die Anaesthesiologie -     

Site of metastatic recurrence impacts prognosis in patients with high-grade upper tract urothelial carcinoma

PurposeMetastatic recurrence occurs in over 25% of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. While metastatic recurrence suggests poor prognosis, the impact of the specific site of recurrence on prognosis is not well documented.Materials and methodsWe retrospectively analyzed 188 patients who underwent radical nephroureterectomy for high-grade, node-negative upper tract urothelial carcinoma at our institution from 2003 to 2018 without receiving neoadjuvant or adjuvant chemotherapy. Competing-risks survival analysis was performed to evaluate the cumulative incidence and predictors of metastatic recurrence. The Kaplan-Meier method and log-rank test were used to estimate and compare recurrence site-specific survival probabilities following metastatic recurrence. Cox regression analyses were performed to assess site-specific prognoses.ResultsOf the 188 patients, 47 (25%) developed metastatic recurrence over a median follow-up of 30 months (interquartile range: 10.5–58.5 months). The 1- and 2-year cumulative incidences of metastatic recurrence were 13.6% and 23.6%, respectively. On multivariable analysis, lymphovascular invasion was significantly predictive of metastatic recurrence (subhazard ratio: 2.6, P = 0.01). Of the 47 patients who developed recurrence, 38 (80.9%) died over a median follow-up of 10 months (interquartile range: 5–20 months). Metastatic recurrence was most common in the lungs (n= 13, 28%) and at multiple sites (n= 14, 30%). Median time to recurrence was shorter for recurrences at multiple sites (6.5 months) and those in the liver (13 months) and bone (18 months) compared to other sites. Patients who recurred in the liver (hazard ratio: 6.3, P = 0.007), bone (hazard ratio: 4.9, P = 0.02), and multiple sites (hazard ratio: 4.6, P = 0.01) had significantly worse prognosis compared to those who recurred in lymph nodes. Statistical significance persisted after adjusting for treatment with salvage therapy.ConclusionsA significant proportion of high-grade upper tract urothelial carcinoma patients recur systemically after radical nephroureterectomy. Lymphovascular invasion is a predictor of metastatic recurrence and may inform decisions regarding perioperative chemotherapy. Hepatic and osseous recurrences have relatively quicker onset and less favorable prognosis compared to other sites. These findings may benefit future efforts to develop recurrence site-specific treatment plans and highlight the necessity of subsequent endeavors to explore the genetic associations of recurrence in upper tract urothelial carcinoma.     

Dynamics of T cells of L3T4 and Ly 2 phenotype within granulomas in murine listeriosis.

Monoclonal antibodies anti-Ly 1, anti-Ly 2 and GK1.5 were applied to determine phenotypes of T cells within granulomas formed as a result of infection of mice with the facultative intracellular bacterium Listeria monocytogenes. Early in granuloma formation, equal numbers of Ly 1+, Ly 2+ and L3T4+ cells were found, T cells of different phenotypes being evenly distributed over the lesions. In mature granulomas, numbers of Ly 1+ and L3T4+ cells about doubled as compared to incipient granulomas, Ly 2+ cells, however, remained constant. Whereas Ly 1+ and L3T4+ cells within mature granulomas still were evenly distributed, Ly 2+ cells were predominantly localized in the periphery of the lesions. The data indicate that both, specific Ly 2+ and L3T4+ T cells, display characteristic dynamics within granulomas: Ly 2+ T cells which most likely mature from Ly 1+2+ T cells over time locate to the periphery. Concomitantly, L3T4+ T cells are enriched maintaining their distribution all over the lesions.     

Genetic and Developmental Influences on Infant Mouse Ultrasonic Calling. III. Patterns of Inheritance in the Calls of Mice 3–9 Days of Age

Infant mice produce ultrasonic calls that may elicit retrieval by adult mice. Age-related differences and genetic effects, such as additivity and directional dominance, have been found for most call characteristics at 3 days of age. Significant maternal effects have been reported for calling rate. However, little is known about how the influence of these genetic effects changes with age. This study explored developmental-genetic patterns of inheritance of seven ultrasonic call characteristics at ages 3–9 days, from groups of mice derived from a complete 4 × 4 diallel cross. The results indicate that additive variance contributes significantly to all characteristics for all ages. Maternal effects have a small effect on call characteristics. Dominance effects decrease with age for rate, range, and length of calls, suggesting less selective pressure toward higher rates, greater range, and longer calls as pups become more competent thermoregulators.     

Detection of proinsulin, C-peptide, insulin-A-chain, and glicentin in pancreatic islet cells of early human fetogenesis.

The presence of C-peptide, proinsulin, insulin-A-chain, and glicentin in human fetal pancreatic cells by using the PAP-technique was investigated and the results obtained compared with the occurrence of insulin or glucagon immunoreactive cells. In pancreatic sections obtained from 10 weeks old human fetuses we could identify cells reacting with antibodies directed against C-peptide, proinsulin, and insulin-A-chain. The majority of the cells were found in the duct epithelium and their number increased from the 10th to 14th week forming clusters near the ducts. The number and localization of the cells correspond exactly to the insulin positive cells. The presence of proinsulin and insulin-A-chains is a further proof of biological activity already in an early step of fetal development. The presence of glicentin-positive cells in the 10th week of gestational age as well as cells reacting with glucagon antibodies provide evidence for active glucagon biosynthesis. The number of these cells increased markedly in the 14th week of gestational age.