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.     

Metastasis induced by overexpression of p185neu-T after orthotopic injection into a prostatic epithelial cell line (NbE)

The effects of the composition of bacteriological growth media on the light output in a chemiluminometric assay of beta-galactosidase in Escherichia coli using 1,2-dioxetane substrates has been studied. In this assay a basic conflict exists between conditions that promote optimal bacterial growth and those conducive to maximal chemiluminescence. Common medium ingredients such as yeast or beef extract, protein hydrolysates and lactose suppress light emission and/or lead to high backgrounds. Quenching of light emission is probably partly due to light absorption by medium ingredients such as oxgall, and partly to interference with the reaction triggering the chemiluminescent process. Elevated backgrounds are caused by the presence of high concentrations of protein hydrolysates, which interact with the alkali in the accelerator solution. Only two purposely developed media, i.e. ILM and Colicult are shown to reconcile the requirements of growth support with that of optimal luminescent properties.     

The spinal muscular atrophy gene region at 5q13.1 has a paralogous chromosomal region at 6p21.3

We have examined acetaminophen (paracetamol) dosing for outpatient management of posttonsillectomy pain in children. Forty children, 5-15 years of age, undergoing tonsillectomy and their parents were randomly assigned to use a scheduled administration of acetaminophen in weight appropriate doses, 60 mg.kg-1.24h-1 orally, 90 mg.kg-1.24h-1 rectally, or to use acetaminophen 'as needed' according to present standards (control group). Postoperative pain was assessed by the child using the poker chip tool for the first three days after discharge. The prevalence of pain amongst all the children was high. The second day after discharge 22%-64% of the children in the study group and 36%-73% of the children in the control group rated severe pain. Recommended dose ranges of acetaminophen do not provide sufficient pain relief in children following tonsillectomy. Further studies are required to determine, whether higher doses of acetaminophen or analgesics with different analgesic properties will lead to improved analgesia in children following tonsillectomy.     

Underrecognition of cervical Neisseria gonorrhoeae and Chlamydia trachomatis infections in the emergency department

OBJECTIVES: 1) To quantify the frequency of underrecognized Neisseria gonorrhoeae and Chlamydia trachomatis cervical infections in women tested in the ED, 2) to describe and compare the characteristics of those treated and not treated during the initial visit, and 3) to quantify the delay interval until treatment was provided. METHODS: A 2-year, retrospective consecutive case series was performed from June 1, 1992, to May 31, 1994. There were 148 women with > or = 1 discrete occurrence of culture-proven cervical N. gonorrhoeae or C. trachomatis infection studied. All the patients were evaluated in a university-affiliated, tertiary care hospital-based ED with a large rural referral area. The main outcome measures were the proportions of patients with positive cultures both treated and not treated in the ED, the clinical characteristics of each group, and the proportion remaining untreated or experiencing treatment delays of > 2 weeks after attempted phone, mail, and public health follow-up. RESULTS: Of 157 occurrences of positive cultures for N. gonorrhoeae or C. trachomatis, 86 (53%) were treated with a regimen suggested by the CDC prior to ED release. The proportion of women with isolated C. trachomatis infections that were underrecognized and untreated initially was larger than the proportions with isolated N. gonorrhoeae or combined infections (79% vs 27% and 53%, respectively, p < 0.0001). Women with findings suggestive of advanced disease (history of fever or chills, or examination evidence of temperature > 38 degrees C, purulent vaginal discharge, or any uterine/salpinx/ovarian tenderness) were more often recognized and treated with appropriate antibiotics initially (p = 0.02 to < 0.00001 for all). After phone, mail, and public health follow-up, treatment could not be documented for 25% of the occurrences, in all cases due to an inability to locate the patient. An additional 20% of the women did not receive treatment for 14-60 days. CONCLUSIONS: In this population, both N. gonorrhoeae and C. trachomatis cervical infections are frequently underrecognized in the ED, with isolated C. trachomatis infections associated with significantly higher proportions of underrecognition. Many affected women remain untreated for extended intervals, creating public and individual health risks. Improved point of contact detection, follow-up, and treatment policies are needed to limit these risks.     

Ultrastructure of the spermatozoa and eggs of the ocean pout (Macrozoarces americanus L.), an internally fertilizing marine fish

Ultrastructure of sperm and eggs of the ocean pout (Macrozoarces americanus L.), an internally fertilizing marine teleost, was examined by scanning and transmission electron microscopy. The results showed that the sperm do not have an acrosome but have a very long mid-piece (one to two times the sperm head length) containing numerous well-developed elongated mitochondria. The sperm also have two tails (is biflagellate) each consisting of nine peripheral and one central pair (9 +/- 2) of microtubules. This long mid-piece and the biflagellate nature of the sperm appear to be associated with the long life-span of the sperm and with sperm dispersal in the ovary to fertilize the eggs internally. The ocean pout eggs are enveloped by a porous chorionic membrane similar to that found in other teleosts but have two micropyles, a condition likely related to a mechanism of egg fertilization which increases the egg fertility in the presence of low sperm numbers. Following insemination, some biochemically undefined excretions appeared on the surface of fertilized eggs and led to the acquisition of adherent capability of the eggs which formed a tightly associated egg mass in sea water.     

Effects of high oxygen concentrations on microbial biosensor signals. Hyperoxygenation by means of perfluorodecalin

Amperometric biosensors register oxygen depletion in response to analyte catabolism, and thus are limited by the availability of dissolved oxygen. Microbial sensors containing immobilized cells of Gluconobacter oxydans were hyperoxygenated to 400% of control levels and the effects on sensor responses to glucose were determined. Oxygenated perfluorodecalin (a completely fluorinated organic substance) was as effective in hyperoxygenation as direct sparging with O2, increasing sensor base medium oxygen concentrations from 9.3 to 37 mg/l. Hyperoxygenation enhanced maximal biosensor response amplitudes, particularly at high cell loading densities. Maximal response rates were also improved, although less dramatically. Results suggest that hyperoxygenation may be a new general approach for modulating biosensor responses.