Determination of long-life radiocesiums Cs-134 and Cs-137 in food by gamma-ray spectrometry: summary of collaborative study

PURPOSE: The authors evaluated the ability of a confocal scanning laser ophthalmoscope to detect glaucomatous visual field loss by using their previously described discriminant formula on a prospectively obtained cohort. The relationship of optic disc size to diagnostic classification was also evaluated. METHODS: One eye was chosen randomly from each of 153 subjects. Sixty control eyes had intraocular pressure less than 21 mmHg and normal visual fields; 93 glaucomatous eyes had intraocular pressure greater than 21 mmHg and abnormal visual fields. The optic disc status purposely was not used for classification purposes. All subjects were examined with the Heidelberg Retina Tomograph (HRT; Heidelberg Engineering GMBH, Heidelberg, Germany) and Humphrey Perimeter, program 30-2 (Humphrey Instruments, Inc., San Leandro, CA). Visual fields were considered abnormal by the authors' previously published criteria. The HRT classification used age, adjusted cup shape measure, rim volume, and height variation contour to classify the optic disc as normal or glaucomatous. Then the authors assessed the sensitivity, specificity, and diagnostic precision for the entire group, and for three subsets classified by disc area: disc area less than 2 mm2, between 2 and 3 mm2, and more than 3 mm2. RESULTS: The entire group had a sensitivity, specificity, and diagnostic precision of 74%, 88%, and 80%, respectively. The specificity was 83% when disc area was less than 2 mm2 and improved to 89% when disc area was more than 2 mm2. The sensitivity tended to improve from 65% to 79%, and to 83% if the disc area increased, but the difference was not statistically significant. CONCLUSIONS: In a prospective cohort of patients, the HRT discriminant analysis formula was capable of detecting glaucomatous visual field loss with good precision. Unusually small optic discs continue to present diagnostic difficulties.     

Prospects of riboflavin carrier protein (RCP) as an antifertility vaccine in male and female mammals

MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.     

Blood trauma in plastic haemodialysis cannulae

To investigate the haemolysis in haemodialysis cannulae, an in-vitro set up is built, using a unipuncture dialysis system. This system is connected to a bag with fresh calf's blood, by the cannula under test, mounted in a large bloodline (5 mm diameter). The blood characteristics are kept constant by means of a bicarbonate dialysate in the dialyser. During a 6 h period, haematological parameters are regularly samples. Flow through the cannulae is recorded, which is about 500 mL/min. Four different cannulae are tested and compared to the results obtained without any cannula in the circuit. In all cases a linear increase in plasma free haemoglobin levels is found after 6 h. The cannulae can be ranked from 8F catheter over 13G, 14G to 16G cannula, the latter producing the highest degree of haemolysis. When using plastic cannulae at high blood flows, their haemolytic effect may not be neglected.     

Autocatalytic processing of heme by lactoperoxidase produces the native protein-bound prosthetic group

The covalently bound prosthetic group of lactoperoxidase (LPO) has been obtained by hydrolysis of the protein and identified as a dihydroxylated heme. A baculovirus expression system has been developed for LPO and used to obtain protein in which the heme is only partially covalently bound. Reaction of the purified heme. apoLPO complex with H2O2 results in both autocatalytic modification of the heme and covalent attachment to the protein. Hydrolytic experiments establish that the autocatalytically incorporated heme is bound normally. Two monohydroxylated heme intermediates have been detected. The peroxidative activity of LPO increases in proportion to the extent of covalently bound heme. The LPO results provide a paradigm for autocatalytic incorporation of heme groups into the mammalian peroxidases, including myeloperoxidase and eosinophil peroxidase, all of which exhibit strong sequence similarity with LPO and have covalently-bound heme groups.     

Drug release from hydrophilic matrices. 1. New scaling laws for predicting polymer and drug release based on the polymer disentanglement concentration and the diffusion layer

Two scaling laws for predicting polymer and drug release profiles from hydrophilic matrices were developed. They were developed on the basis of the diffusion layer and the polymer disentanglement concentration, rho p,dis, the critical polymer concentration below which polymer chains detach off a gelled matrix that is undergoing simultaneous swelling and dissolution. The relation between rho p,dis and molecular weight, M1 for (hydroxypropyl)methylcellulose (HPMC) in water was established as rho p,dis (g/mL) varies M-0.8. This power-law relationship for rho p,dis, along with the diffusion layer adjacent to the gelled matrix, leads to the scaling law of mp(t)/mp(infinity) varies Meq-1.15, where mp(t)/mp(infinity) is the fractional HPMC release. The scaling law explains the observation that polymer and drug release rates decreased sharply with M at low M and approach limiting values at high M. Experimentally, mp(t)/mp(infinity) was found to scale with Meq as mp(t)/mp(infinity) varies Meq-0.93, where Meq is the equivalent matrix molecular weight. Moreover, fractional drug release, md(t)/md(infinity), followed Meq as md(t)/md(infinity) varies Meq-0.48. These two scaling laws imply that, if the release profiles are known for one composition, release profiles for other compositions can be predicted. The above two power laws lead to two master curves for mp(t)/mp(infinity) and md(t)/md(infinity), suggesting that the release mechanism for soluble drugs from HPMC matrices is independent of matrix compositions, presumably via a diffusion-controlled process. Limitations of the power laws are discussed.     

The role of p53 and the CD95 (APO-1/Fas) death system in chemotherapy-induced apoptosis

To explore the pathway of p53 dependent cell death, we investigated if p53 dependent apoptosis following DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated cell lines of solid human tumors upon treatment with clinically relevant chemotherapeutic drugs known to act via p53 accumulation. Treatment with these cytotoxic drugs led to an upregulation of both, the CD95 receptor (CD95) and the CD95L (CD95L). Induction of the CD95L occurred in p53 wild-type (wt), p53 mutant (mt) and in cell lines lacking p53 altogether (p53-/-). Thus, the regulation of the CD95L in response to chemotherapeutic drugs clearly involves p53 independent mechanisms. Most importantly, upregulation of CD95 occurred only in cell lines with wild-type p53, thereby strongly increasing the responsiveness towards CD95 mediated apoptosis. Thus, upregulation of the CD95 receptor seems to be dependent on intact wild-type p53. Apoptosis was mediated by cleavage of the receptor proximal caspase, caspase-8 (FLICE/MACH). Caspase-8 cleavage was observed, independent of the p53 status of the tumor cells and irrespective whether or not apoptosis was dependent on the CD95 system. Hence, additional effector pathways besides CD95/CD95L signaling are likely to contribute to drug-induced apoptosis.