The anti-tumor arotinoid Ro 40-8757 protects bone marrow from the toxic effects of 5-fluorouracil

We have previously shown that strychnine mimics the cytoprotective properties of glycine in renal proximal tubule (RPT) suspensions exposed to antimycin A (AA). The aims of this study were to determine whether the cytoprotective properties of strychnine applied to various types of nephrotoxicants and to examine the temporal aspects of the cytoprotection of glycine and strychnine. Tubular release of LDH activity was used as a marker of cell death. Glycine (2 mM) or strychnine (1 mM) added 5 min prior to the toxicant decreased LDH release in rabbit RPT suspensions exposed to 25 microM tetrafluoroethyl-L-cysteine (TFEC), 10 microM HgCl2, 0.5 mM t-butyl hydroperoxide (TBHP), or 0.2 mM bromohydroquinone (BHQ) for 4 hr, or 2 mM sodium cyanide (NaCN) for 2 hr. The relative rank order of effectiveness of glycine and strychnine was NaCN = TFEC > BHQ > DCVC > TBHP > HgCl2. The temporal aspects of strychnine and glycine protection were examined by exposing RPT to either AA or TFEC for 1 or 3 hr, respectively, and then adding either 1 mM glycine or 1 mM strychnine. Glycine and strychnine decreased LDH release in AA-treated RPT at 1.25 and 2 hr and TFEC-treated RPT at 4 hr. In addition, when RPT exposed to AA or TFEC and treated with strychnine or glycine were washed at either 1 or 4 hr, protection was eliminated at later time points. When glycine was added to RPT treated with either PCBC, TFEC, or DCVC 5 min prior to or 30, 60, 120, and 180 min following toxicant addition, LDH release was reduced at all time points. These results demonstrate that strychnine and glycine protect RPT from a variety of diverse nephrotoxicants, strychnine and glycine do not need to be present at the time of toxic insult, strychnine and glycine cytoprotection is reversible, and strychnine and glycine act in the late phase of necrotic cell injury.     

A study of urinary dolichols as a biological marker for alcohol abuse. Report 2: Comparison of urinary dolichols/creatinine concentrations among non-drinkers, moderate-drinkers and heavy-drinkers

We report here the comparison of urinary dolichols/creatine (D/Cr) concentration ratios in male non-drinkers, moderate-drinkers and heavy drinkers at admission and during hospitalization, and also discuss its usefulness as a biological marker for alcohol abuse. Urine samples were collected from the following four experimental groups: non-(male and female) and moderate-drinker (male) volunteers, and alcoholic heavy-drinking patients (male) at admission for psychiatric treatment and after 9-15 days hospitalization (informed consent was obtained). Urinary dolichols were determined by high performance liquid chromatography after BondElutC18 (500 mg) extraction. Due to significant differences in urinary D/Cr concentrations between male and female groups in non-drinkers and because the heavy-drinkers available for this study were exclusively male, comparison of the value of urinary D/Cr concentration ratios was subsequently limited to male only. There were no statistical differences in urinary D/Cr concentrations in the male among non-drinkers, moderate-drinkers and heavy-drinkers at admission. The accuracy of urinary D/Cr as a biological marker for alcohol abuse, calculated using the mean +/- 2 s.d. in non- and moderate-drinkers as the normal range, is only 33.3% in heavy-drinkers at admission, while their value of gamma-GTP in serum was 88.3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of tetramethrin isomers in rat: II. Identification and quantitation of metabolites

1. To examine the metabolic fate of (1RS, trans)- or (1RS, cis)-tetramethrin [3, 4, 5, 6-tetrahydrophthalimidomethyl (1RS, trans)- or (1RS, cis)-chrysanthemate], rat was administered a single oral dose of trans- or cis-[alcohol-14C]tetramethrin at dose levels of 2 or 250 mg/kg. 2. The radiocarbon was almost completely eliminated from rat within 7 days after administration in all groups. 14C-recoveries (expressed as percentages relative to the dosed 14C) in faeces and urine were 38-58 and 42-58% respectively in rat administrated trans-[alcohol-14C]tetramethrin, and in faeces and urine were 66-91 and 9-31% respectively in rat administered cis-[alcohol-14C]tetramethrin. 3. Fourteen metabolites found in excreta were purified by using several chromatographic techniques and identified by spectroanalyses (nmr and MS). Five sulphonate derivatives and three dicarboxylic acid derivatives were found. 4. The main metabolites were sulphonate derivatives in the faeces, and in the urine, alcohols, dicarboxylic acid and reduced metabolites derived from the 3,4,5,6-tetrahydrophthalimide moiety.     

Three-dimensional motion of the upper cervical spine in rheumatoid arthritis

Rheumatoid arthritis frequently contributes to instability of the upper cervical spine. Rotational instability of the upper cervical spine was evaluated in rheumatoid arthritis patients using biplanar x-ray photogrammetry. Three-dimensional cervical motion and the instantaneous axis of rotation of the atlas relative to the axis were evaluated in normal and rheumatoid arthritis patients during axial rotation in the horizontal plane. Anterior atlantoaxial subluxation did not increase during axial head rotation in either the atlantoaxial subluxation or the vertical subluxation groups, while the instantaneous axes of rotation were distributed posteriorly in the dens in the RA-normal group, but were widely scattered in the atlantoaxial subluxation group.     

Structural and electrophysiological analysis of annexin V mutants. Mutagenesis of human annexin V, an in vitro voltage-gated calcium channel, provides information about the structural features of the ion pathway, the voltage sensor and the ion selectivity filter

Annexin V binds to phospholipids in a calcium-dependent manner and exhibits calcium channel activity in vitro. We prepared a variety of mutants yielding information about the structure-function relationship of the ion channel activity. All mutants were characterized by X-ray crystallography, electron microscopy and electrophysiological measurements. Their structures are insignificantly changed whereas their electrophysiological properties are drastically different. Glu95, located in the central hydrophilic pore of the molecule, is crucial for the ion selectivity filter as its exchange leads to reduced calcium and increased sodium conductance. The removal of Glu17, located on the protein surface and far from the ion conduction pathway, leads to the appearance of a second conductance level of 9 pS in addition to the conductance level of about 30 pS in the wild-type molecule. This was also the case for Glu78, which is part of a weak calcium binding site. The exchange of Glu17 and Glu78 produced a mutant retaining only the smaller conductance level. We conclude that these two residues influence the angle between the two halves of the molecule, which determines the diameter of the ion conduction pathway, thereby leading to the occurrence of a second conductance level.     

Ends,Means and Innovation Management

The management of innovation inevitably implies the management of uncertainty. Research and practise clearly indicate that judgements about the size and the nature of this are often inaccurate. This can result in poor performance against expectations and in some cases in complete failure. In this paper it is argued that prior analysis of the type of uncertainty can help to improve the success rate and/or reduce the time to completion. Early signs that discontinuation, or a significant change in direction, might be called for are also highlighted by this analysis.     

Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center

OBJECTIVES: To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY: To investigate risk factors for HPV detection apart from the correlated risk factors for cervical neoplasia. STUDY DESIGN: Cervical human papillomavirus (HPV) DNA was assessed in 357 cytologically normal women attending the University of New Mexico student health center. Cervical swab samples were obtained for HPV DNA detection and typing using a PCR-based DNA amplification system. Possible determinants of cervical HPV were examined including age, ethnicity, history of sexually transmitted disease, oral contraceptive use, smoking, age at first intercourse, lifetime number of sex partners, marital status, and history of pregnancy. RESULTS: A 44.3% overall prevalence of cervical HPV was observed. On univariate analysis, factors associated with increasing HPV prevalence included higher lifetime number of sex partners and single marital status. After adjustment for potential confounding variables, we found that HPV prevalence increased with higher lifetime number of sexual partners. CONCLUSION: These findings, along with those from the companion reports in this issue of the journal, support the sexual route of transmission of the virus.     

Analysis of bone loss with aging and menopause--using digital image processing

To study bone loss relationships to aging and menopause, cross-sectional bone mass measurements by digital image processing (DIP method), and menopause information collected by questionnaire, were analyzed on 291 women who live in Tsukude village. The results are as follows. 1) The mean DIP values (sigma GS/D, MCI) by age-stratified groups decrease with age after menopause. The rate of bone loss in sigma GS/D is almost constant, but in MCI it increases with aging. 2) In 30-year old and 40-year old age groups, the frequency distribution of DIP values is symmetrical and bell-shaped. But after the fifties the distribution is asymmetrical, with the mode of distribution deviated toward low bone mass. The change of mode with aging is larger than that of mean. This fact suggests that change of mean bone mass substantially underestimates actual bone loss from aging. 3) The change of the mean DIP values stratified by years elapsed since menopause is not especially large at start of menopause but becomes almost constant after menopause. DIP values reflect the bone loss from the aging rather than from menopause, and are beneficial to the study of bone loss in elderly women.