Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.     

Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney

Although the full mechanisms are not yet elucidated, research into the mechanism of toxicity of aluminum (Al) on bone formation and remodeling and on hematopoietic tissue is ongoing. In contrast little information exists on the interactive effects of systemic Al and the kidney. In bone, both clinically and experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and osteoclast activities and producing osteomalacia and adynamic bone disease. In contrast, while very low levels of Al are mitogenic in bones of experimental animals, the effect of low levels of Al in humans is unknown. Aluminum has been shown to have its mitogenic action at the osteoblast, but whether the effect on resorption is viz osteoblast-directed changes in osteoclast activity has not yet been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans and animals. Whether altered PTH levels play a major or even a minor role in Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated with Al have been reported to accumulate excess iron, without incorporating it into ferritin or heme. It is not yet known which steps in iron metabolism are disrupted by Al, if they involve a single mechanism of action, or even if this disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In kidney, research is needed to evaluate Al nephrotoxicity; there are almost no studies in this area. Furthermore, research is needed to evaluate mechanisms of renal Al excretion, presently shown by one study to occur at the distal tubule. Such studies might well throw light on whether Al plays a role in aggravating renal insufficiency, or whether the role of the kidney in Al toxicosis is limited to the causative effect of renal compromise on Al accumulation. In summary, while a number of mechanisms have been proposed for the toxic action of Al, no single mechanism emerges to explain these diverse effects of systemic Al. Recommendations for future research are presented and summarized in Table 1.     

From hospital to municipal cogeneration systems: an Italian case study

A mixed integer linear programming model combined with a more traditional design by scenarios is proposed to optimize facilities size and operation mode of a municipal energy system involving significant civil centres and a hospital. Moving from the need of a new heat and power station for the local hospital due to the construction of new pavilions, the opportunity of involving other centres in the neighbourhood in a distributed cogeneration system is analysed, increasing system complexity step by step. Smaller cogeneration units tailored to hospital needs are rewarding ventures with relatively low risks but, in a country whose traditional power generation systems heavily rely on fossil fuels and where energy policy and market conditions can make it profitable to sell surplus power, district heating systems foster the installation of larger cogenerators and lead thereby to higher profits and to better performance as for primary energy savings and greenhouse gases emission reduction. Copyright © 2006 John Wiley & Sons, Ltd.     

Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sj?gren's syndrome

PURPOSE: Previous research has demonstrated that testosterone therapy causes a profound suppression of autoimmune disease in lacrimal glands of female mouse models of Sj?gren's syndrome. The aim of the present study was to determine whether other anabolic androgens, nonandrogenic steroids, or immunosuppressive agents might duplicate this hormonal effect. For comparative purposes, we also evaluated the influence of these various pharmacologic compounds on the tear volume, the magnitude of lymphocyte infiltration in the submandibular gland, and the extent of mucosal and peripheral lymphadenopathy. METHODS: Female MRL/MpJ-lpr/lpr mice were administered vehicle, steroids, or immunosuppressive compounds for 21 days after the onset of disease. Lacrimal glands and tears, as well as submandibular glands, spleens, and superior cervical and mesenteric lymph nodes were collected immediately before or after treatment and then processed for analysis. RESULTS: Our results showed that: (1) the immunosuppressive impact of testosterone on lymphocyte infiltration in lacrimal tissue was reproduced by the administration of 19-nortestosterone or cyclophosphamide, but not by therapy with 17 beta-estradiol, danazol, the experimental steroid Org 4094, cyclosporine A or dexamethasone; (2) treatment with testosterone, 19-nortestosterone, cyclophosphamide, or dexamethasone significantly reduced the extent of inflammation in salivary glands; (3) exposure to cyclophosphamide markedly diminished the size of lymphatic and splenic tissues, whereas glucocorticoid treatment only decreased the weight of superior cervical lymph nodes; and (4) administration of 17 beta-estradiol, Org 4094, or dexamethasone led to a significant decrease in tear volume. CONCLUSIONS: Overall, these results demonstrate that androgen or cyclophosphamide therapy may successfully ameliorate autoimmune expression in lacrimal and salivary glands of a female mouse model of Sj?gren's syndrome.     

Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington''s disease

During oogenesis in Drosophila, germ cells appear in sequential clusters of 16 interconnected cells. The events surrounding the differentiation of these cells are not fully understood. Here we present genetic and morphological analysis of mutations in the gene stand still (stil). Through complementation analyses we have refined the location of this gene to cyological region 49B-C. Our analyses of ovaries from ethylmethane sulfonate (EMS)-induced mutant alleles of this gene suggest that mutations in the stil gene produce a wide range of phenotypic abnormalities, from the absence of germ cells in the most severe alleles, to egg chambers with cytoskeletal defects in the less severe alleles. Our results suggest a role for this gene in specifying or maintaining a cytoskeletal component, with consequences during oogenesis and possibly during germ line sex determination.     

A new method of intestinal salvage for severe small bowel ischemia

The morbidity and mortality in short bowel syndrome are directly related to the length of the remaining small bowel and to the duration of total parenteral nutrition. We describe the successful salvage of an infant with extensive small bowel infarction for whom a new technique was used to preserve all viable mucosal surfaces. The infant, with gastroschisis, was found to have a tight volvulus of the extruded bowel and extensive small bowel ischemia at the time of delivery. Forty-eight hours after reduction of the volvulus and abdominal decompression, a second-look laparotomy was performed. Although only the terminal 13 cm of ileum was completely viable, 25% of the circumference of a further 23 cm of proximal jejunum/ileum was considered salvageable. After debridement of the dead tissue, the remaining gutter of jejunum was divided at its midpoint, and the two halves were anastomosed longitudinally to provide a "neojejunum" of 12 cm in length, which was anastomosed between the duodenum and terminal ileum. Full enteral feeding was tolerated from day 47. Although the neojejunum was excised on day 149, after becoming dilated and atonic, by that time the remaining small bowel had elongated to 30 cm. Because of the early institution of full enteral feeding, there were no long-term complications related to total parenteral nutrition.