The aminothiol WR-1065 protects T lymphocytes from ionizing radiation-induced deletions of the HPRT gene

Aminothiols, such as WR-2721 and its active free thiol, WR-1065, reduce mutations from ionizing radiation in exponentially growing cells. In this study, human noncycling G0 T lymphocytes were exposed in vitro to gamma-irradiation in the presence or absence of WR-1065. The five treatment groups were: (a) control; (b) treatment with 4 mM WR-1065; (c) treatment with 3 Gy of gamma-radiation, from a 137Cs source; and (d) and (e) treatment with WR-1065 30 min prior to or 3 h after 3 Gy of gamma-irradiaiton, respectively. A total of 224 cloned HPRT mutants representing 179 independent mutations were analyzed for genetic alterations using multiplex PCR. Ionizing radiation alone significantly increased the percentage of mutations with gross structural alterations compared to controls (P = 0.02). Although the frequency of such large structural mutations was not different from control cells treated with WR-1065 alone, this aminothiol significantly reduced their frequency among irradiated mutants (P = 0.01) when the radioprotector was present during the irradiation. Addition of WR-1065 3 h postirradiation also greatly reduced the percentage of gross structural alterations; however, due to small numbers, this was not statistically significant. This is the first demonstration that the antimutagenicity of WR-1065 in human cells specifically protects against these kinds of large-scale DNA alterations induced by ionizing radiation. WR-1065 and similar aminothiol compounds may afford protection against radiation-induced mutations through polyamine-like processes, e.g., stabilization of chromatin structure, inhibition of cell proliferation, and influences on DNA repair systems.     

Collection of peripheral blood progenitor cells after the administration of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor: an analysis of 497 patients

BACKGROUND: There is great interpatient variability in the number of peripheral blood stem cells collected, as measured by CD34+ cell content, after the administration of chemotherapy and a growth factor. The ability to predict patients who fail to yield adequate quantities of CD34+ cells would be of value. However, very few reports include large numbers of patients treated in an identical fashion. STUDY DESIGN AND METHODS: Between 1991 and 1995, 497 consecutive patients with a variety of malignant diseases received cyclophosphamide (4 g/m2), etoposide (600 mg/m2), and granulocyte-colony-stimulating factor (6 micrograms/kg/day) for mobilization and collection of a target dose > or = 2.5 x 10(8) CD34+ cells per kg. Multivariate analyses were performed to determine the factors associated with failure to achieve this target harvest. RESULTS: A median of 14.71 x 10(6) CD34+ cells per kg (range, 0.08-137.55) was harvested with a median of 2 (range, 1-11) apheresis procedures. Ninety-one percent of patients yielded > or = 2.5 x 10(5) CD34+ cells per kg. Patients with Stage II-III breast cancer, who had pretreatment platelet counts > or = 150 x 10(9) per L and patients who underwent < or = 1 prior chemotherapy regimen had improved CD34+ cell yields. However, most patients with adverse risk factors yielded > or = 2.5 x 10(6) CD34+ cells per kg. CONCLUSION: A regimen of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor led to the successful collection of adequate numbers of CD34+ cells in most patients without excessive toxicity. These observations confirm previous reports that intense prior therapy adversely affects the quantity of CD34+ cells harvested. Pretreatment and posttreatment variables did not predict with any certainty the small fraction of patients who fail to yield > or = 2.5 x 10(6) CD34+ cells per kg via multiple apheresis procedures.     

Neurotoxicity following the ingestion of a Chinese medicinal plant, Alocasia macrorrhiza

1. A case of poisoning due to the raw root tuber of a Chinese medicinal plant, Alocasia macrorrhiza is presented. 2. The patient developed neurological (severe pain and numbness in the perioral area and throat) and gastrointestinal (nausea, vomiting, abdominal pain) symptoms immediately after eating the root tuber. 3. A macrorrhiza has properties and morphology very similar to another medical plant. A. odora. The root tuber of the latter is known to contain a neurotoxin sapotoxin.     

Lipid and lipoprotein distributions in children by ethnic group, gender, and geographic location--preliminary findings of the Child and Adolescent Trial for Cardiovascular Health (CATCH)

Male and female isometric strength curves for elbow fixation, shoulder flexion, and wrist supination-pronation are obtained during systematic variation in arm configuration. The shape of a given moment-angle curve is found to be a function of the orientations of joints kinematically coupled to the primary joint. It is also found that female elbow strength curves are shifted toward flexion with respect to male elbow-strength curves, suggesting that the in situ rest length of upper-limb muscles relative to joint angle may be longer for males than for females. Experimental results were contrasted with simulation results obtained using a three-dimensional musculoskeletal model which estimates the relationships between initial joint orientations, muscle tension-length behavior, and joint moments. In most of the cases, simulation results complimented experimental data and provided insights into likely in situ muscle rest lengths and moments arms, especially for the multiarticular biceps brachii muscle. Where inconsistencies exist between simulated and experimental data, subtle biomechanical complexities within the forearm and the shoulder girdle complex are identified that require future investigation.     

Visual, cognitive, and neurodevelopmental outcome at 51/2 years in children with perinatal haemorrhagic-ischaemic brain lesions

To determine predictive values of early visual and neurocognitive assessment in children with perinatally acquired haemorrhagic or ischaemic brain lesions selected on the basis of ultrasound, 63 children (37 boys, 26 girls), who had been followed and examined until the age of 18 months, were reexamined at 5 1/2 years. Good correlations between visual and neurodevelopmental assessments at 18 months and at 5 1/2 years were found. When ultrasound abnormalities were combined with early visual and neurocognitive assessment data, good predictive values, especially for the group of children who had grade 2 to 4 leukomalacia, were found for visual acuity and neurodevelopment.     

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

1998 William J. Stickel Bronze Award. Antifungal activity of Melaleuca alternifolia (tea-tree) oil against various pathogenic organisms

Tea-tree oil (oil of Melaleuca alternifolia) has recently received much attention as a natural remedy for bacterial and fungal infections of the skin and mucosa. As with most naturally occurring agents, claims of effectiveness have been only anecdotal; however, several published studies have recently demonstrated tea-tree oil's antibacterial activity. This study was conducted to determine the activity of tea-tree oil against 58 clinical isolates: Candida albicans (n = 10), Trichophyton rubrum (n = 8), Trichophyton mentagrophytes (n = 9), Trichophyton tonsurans (n = 10), Aspergillus niger (n = 9), Penicillium species (n = 9), Epidermophyton floccosum (n = 2), and Microsporum gypsum (n = 1). Tea-tree oil showed inhibitory activity against all isolates tested except one strain of E floccosum. These in vitro results suggest that tea-tree oil may be useful in the treatment of yeast and fungal mucosal and skin infections.     

Depressive symptom reversal for women in a primary care setting: a pilot study

Our goal is to assess the viability of an in vitro preparation of bovine ciliary body/epithelium (CBE) in a small volume Ussing-type chamber. A new small volume Ussing-type chamber with continuous perfusion was developed for bovine CBE. The trans-CBE electrical parameters were monitored and the electrical responses of the CBE to ouabain (1 and 0.01 mM) were recorded. The trans-CBE fluxes of [14C]-L-ascorbate and [3H]-L-glucose were also studied. The bovine CBE preparation was stable inside the chamber in terms of its potential difference (PD), short circuit current (SCC) and trans-CBE resistance. They were -0.51+/-0.05 mV (aqueous side negative), -5.43+/-0.04 microAcm-2 and 94+/-2 Q.cm2 (mean s.e.m., n=35), respectively. The preparation hyperpolarised when 0.01 mM ouabain was administered to the aqueous side, depolarised when ouabain was applied to the stromal side. [3H]-L-glucose diffusion was about 74 nEq h(-1)cm(-2) in either direction (n=12). Taking the area magnification factor of the CBE into consideration, the diffusional L-glucose flux across the bovine CBE was comparable to other tight epithelia. A significant net ascorbate flux (0.26+/-0.05 nEq h(-1)cm(-2), n=4, p<0.01) was found in the stroma to aqueous direction. We have developed a viable in vitro bovine CBE preparation which was (1) electrically stable, (2) responsive to ouabain, (3) tight to L-glucose diffusion, and (4) capable of actively secreting ascorbate. A net trans-CBE chloride transport (0.81+/-0.30 microEq h(-1)cm(-2), n=12, p=0.01) from stromal to aqueous side was found in the present in vitro model under short-circuited conditions.     

Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL

Lysophosphatidylcholine (LPC) is formed by hydrolysis of PC in low density lipoprotein (LDL) and cell membranes by phospholipase A2 or by oxidation. Oxidized (ox) LDL activates endothelial cells, an effect mimicked by LPC. oxLDL also has the capacity to activate T and B cells, and antibody titers to oxLDL are related to the degree of atherosclerosis. The antigen in oxLDL responsible for its immune-stimulatory capacity is not well characterized, and we hypothesized that LPC was involved. We demonstrate herein the presence of antibodies against LPC, both of the IgG and IgM isotype, in 210 healthy individuals. This antibody reactivity was not specifically related to oxidation of the fatty acid moiety in LPC, since LPC containing only palmitic acid showed antibody titers equivalent to those of LPC containing unsaturated fatty acids. Antibody titers to PC were low compared with LPC, and hydrolysis of PC at the sn-2 position is thus essential for immune reactivity. There was a close correlation between anti-oxLDL and anti-LPC antibodies. Furthermore, LPC competitively inhibited anti-oxLDL reactivity, which indicates that LPC may explain a significant part of the immune-stimulatory properties of oxLDL. LPC, being a lipid, is not likely to be an antigen itself. Instead, LPC could form immunogenic complexes with peptides, which may induce and potentiate immune reactions in the vessel wall. This study adds to the evidence that LPC is an important component of oxLDL and emphasizes the potential role of phospholipase A2 in atherosclerosis.