1,3-Propane sultone, an extremely potent experimental carcinogen: what should be expected in humans?

1,3-Propane sultone is directly alkylating, genotoxic and carcinogenic. In rats, it induces local and systemic tumours at multiple target sites. Preponderant systemic tumours occur at the central nervous system, especially gliomas. Other localisations include the mammary gland, the intestine, the haematopoietic system and the kidneys. In the German chemical industry, 1,3-propane sultone had been manufactured and used in limited amounts in the 1950s and 1960s, and for a very few purposes until the 1970s. The number of persons in contact with the compound is unknown but was limited. The medical history of some cases could be traced. As cerebral gliomas are the main systemic tumours induced by 1,3-propane sultone experimentally, the occurrence of a glioblastoma among previously exposed persons appears conspicuous. Three intestinal malignancies were recorded among the cases observed. Also noteworthy is one case of a duodenal carcinoma, normally a rare human malignancy. Two haematopoietic/lymphatic malignancies of different nature have been observed, and there was one case of a renal cell carcinoma. These malignancies observed within a group of persons exposed to 1,3-propane sultone appear surprisingly consistent with the expectations from the available animal studies. The present case studies point to long latency times (up to 30-40 years or more) after limited periods of past exposure.     

Possibilities in improvement of glucocorticoid treatments in asthma with special reference to loteprednol etabonate

Allergic conditions contribute significantly to the burden of chronic disease in the industrialized world. The increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. Despite considerable efforts of the pharmaceutical industry, the leukotriene antagonists were the only new class of asthma treatments to be licensed in the past 30 years. Topical glucocorticoids (GCs) are the most potent and effective therapy for treating allergic diseases. However, their use is limited by diverse undesired effects. Changes in pharmacokinetic parameters of GCs may be an interesting and promising approach to improve efficacy and safety of inhaled GCs. Loteprednol etabonate has been developed on the basis of the retrometabolic drug design. In animal studies, it has been demonstrated to have long-lasting anti-allergic (anti-asthmatic) effects without influencing the hypothalamic-pituitary axis (HPA). This soft steroid is now in phase III of the clinical development. Recently, loteprednol has been proven to be effective in the management of allergic rhinitis (400 microg once daily). No suppression of HPA was observed at clinically effective and higher doses. In conclusion, loteprednol as the first representative of soft steroids elicits marked anti-inflammatory effects, but has no impact on endocrine responses. It may represent a promising new therapy in the treatment of allergic rhinitis and asthma.     

Lipid effects on neutrophil calcium signaling induced by opsonized particles: platelet activating factor is only part of the story

BACKGROUND & METHODS: Total parenteral nutrition is frequently used in clinical practice to improve the nutritional status of patients. However, the risk for infectious complications remains a drawback in which immune-modulating effects of the lipid component may play a role. To characterize these lipid effects we investigated neutrophil activation by opsonized yeast particles under influence of lipid emulsions derived from fish oil (VLCT), olive oil (LCT-MUFA), soybean oil (LCT), and a physical mixture of coconut and soybean oil (LCT-MCT). RESULTS: Serum-treated zymosan (STZ) evoked a biphasic increase in cytosolic Ca2+ concentration ([Ca2+]c) with an initial slow rise that turned into a second fast rise until a plateau was reached. LCT-MCT (5 mM) pretreatment markedly increased the rate of [Ca2+]c rise during the initial phase, abolished the second phase and lowered the plateau. These effects of LCT-MCT were mimicked by the protein kinase C (PKC) activating phorbol ester PMA. LCT, LCT-MUFA and VLCT, on the other hand, decreased the rate of [Ca2+]c rise during both phases and lowered the plateau. The platelet-activating factor (PAF) receptor antagonist WEB 2086 inhibited the second phase, demonstrating that PAF acts as an intercellular messenger in STZ-induced Ca2+ mobilization, but did not interfere with the stimulatory effect of LCT-MCT or PMA on the initial rate of [Ca2+]c rise. CONCLUSIONS: Structurally different lipids act only in part through PAF to distinctively modulate neutrophil calcium signaling in response to activation by opsonized particles.     

Oncogene addiction: sometimes a temporary slavery

Tumors induced in conditional oncomice can show remarkable different responses to subsequent oncogene deprivation. Complete sustained regression, concomitant with massive differentiation and/or apoptosis, and partial regression are both observed. In the latter case, tumor growth either resumes without being dependent any longer on the oncogene, or requires reactivation of the oncogene in cells that have become dormant. These models reflect many of the features we also witness in human cancer and can therefore assist us in understanding the underlying mechanisms and in designing more effective treatment protocols.     

Differential effects of aging on the distribution of calcium-binding proteins in a pretectal nucleus of the chicken brain

The nucleus pretectalis (PT) of birds is an ovoid-shaped visuomotor cell group of the pretectum that receives tectal input and projects back to the optic tectum. We performed immunohistochemical single- and double-labeling to determine the distribution and abundance of neurons containing three calcium-binding proteins, parvalbumin (PV), calretinin (CR), and calbindin (CB), in the PT in chickens at three ages. We found that PV-positive and CR-positive cells co-localize and are largely found in the outer part of PT at all ages. The GluR4 subunit of the AMPA-type glutamate receptor was selectively localized to these neurons. CB-positive neurons, however, were largely absent from the PT in young and adult chickens. The abundance of PV-positive and CR-positive neurons in PT in old birds was indistinguishable from that in the younger birds, but CB-positive perikarya were 10-20-fold more common than in young birds, and were again mainly found in the outer part of PT. The overall abundance of neurons in PT was reduced to about 50% of its former abundance in the old birds, with this loss restricted to the central part of the nucleus. These data indicate that a cell loss process develops in PT as birds age, that parvalbuminergic and calretinergic neurons resist this process, and that this process is associated with increased expression of CB.     

Lung cancer during pregnancy involving the products of conception and a review of the literature

Approximately 1 per 1,000-1,500 pregnancies is complicated by maternal malignancies. Metastatic involvement of the products of conception is a rare event. There have been 62 cases of placental and/or fetal metastatic involvement originating from maternal cancer reported since 1866. Only 14 cases of lung cancer associated with pregnancy have been documented. We report on an additional case involving the products of conception, and the management of lung cancer in pregnancy is discussed based on an extensive review of the literature. The case of a 29-year-old woman presenting during the 31(st) week of gestation with metastatic non small-cell lung cancer to the placenta, liver and bone is described. The mother was delivered by caesarean section of a healthy baby girl during her 32(nd) week of gestation. The mother's postpartum course was complicated by disseminated pulmonary and bony metastases and malignant pericardial and pleural effusions causing the patient's death within 1 month after lung cancer was diagnosed. Malignancies spreading to the products of conception are melanoma (32%), leukemia and lymphomas (15%), breast cancer (13%), lung cancer (11%), sarcoma (8%), gastric cancer (3%) and gynecologic cancers (3%), reflecting malignancies with a high incidence in women of reproductive age. All lung cancers were diagnosed with widely disseminated, inoperable neoplastic disease, including distant metastases in 46%. The mean age was 35.1 years (range, 30-45 years) and 60% of patients had a history of tobacco use. The mean survival was 7.5 months (range: 1-42 months). Placenta involvement was present in 7 out of 15 cases. Fetal involvement was reported in only one case. Because there is no evidence of a direct adverse effect of pregnancy on the course of lung cancer, we recommend delivery at a time when enough fetal maturity can be assumed and the subsequent treatment of the mother.     

Migration and differentiation of myogenic precursors following transplantation into the developing rat brain

There is increasing evidence that muscle-derived precursor cells can, under appropriate conditions, give rise to other than myogenic cell types. Transplantation into the embryonic ventricular zone provides a unique opportunity to study the migration and differentiation of non-neural somatic progenitor cells in response to instructive cues within the developing neuroepithelium. Here, we demonstrate that myogenic cell lines grafted into the ventricles of rat embryos showed widespread migration into several host brain compartments. In contrast to incorporation patterns observed after transplantation of neural cells, grafted myoblasts incorporated virtually exclusively along endogenous blood vessels. Preferential incorporation sites included cortex, olfactory bulb, hippocampus, striatum, thalamus, hypothalamus, and tectum. While the engrafted myoblasts showed no evidence of neural differentiation, a fraction exhibited pronounced coexpression of endothelial marker antigens. These findings support the concept of a close developmental relationship between the myogenic and the endothelial lineages. Used as a delivery system, transfected myoblasts may be exploited for widespread gene transfer to the perivascular compartment of the perinatal central nervous system.     

Suicide and general elections in Austria: do preceding regional suicide rate differentials foreshadow subsequent voting behavior swings?

BACKGROUND: Suicide-epidemiological research on short-term effects of elections on national/regional suicide and parasuicide incidence has yielded contradictory evidence. Reversing the cause-effect relationship of this line of research we investigated whether preceding regional suicide rates are related to subsequent election results. METHODS: For Austria's 121 districts, we regressed averaged standardized suicide rates for the preceding period (1988-1994) on political parties' subsequent electoral gains/losses (1999-to-1995) while controlling for a set of 12 domain-relevant psychosocial/economic indices. RESULTS: Stepwise weighted multiple regression led to a significant model. The 1999-to-1995 electoral gains/losses of two opposition parties, together with the population variation caused by migration balance and by births/deaths balance, accounted for a substantial part (30%) of the variability in preceding district-level suicide rates. Various other social indices failed to contribute further substantial increments to this model. CONCLUSIONS: This finding suggests that variations in preceding regional suicide incidence might be mirrored in subsequent changes in voting behavior. A speculative post hoc explanation for the finding is offered: on a community level, suicide's aftermath might produce socially and politically alienated survivors of suicide who co-shape swings towards opposition parties in subsequent general elections. The finding calls for more research on suicide's long-term aftermath. LIMITATIONS: Within-country replicability and cross-national generalizability await further investigation. At present, the factor/mechanism accounting for this finding is neither well-established nor has been directly tested.