Biomedical subjects
Publications and source records attributed to S Jones.
The dynamics of stab wounds were investigated using a load cell connected to microcomputer-based measuring equipment. Two types of knife blade were attached to the load cell to assess the characteristics of stab wounds caused in pig tissue. The results show that as the blade progresses through the tissue it is resisted mostly by the skin, but a significant secondary resistance exists in the deeper muscle layers.
Engineering a smaller lysozyme is a challenge for both random and site-directed mutagenesis. This paper illustrates the power of knowledge-based protein engineering in the design of a smaller lysozyme that folds correctly and has activity against bacterial cell walls. In this smaller lysozyme the conserved disulphide bridged loop is replaced by a short loop. The long loop was selected because it buries a predominantly hydrophilic surface. The short loop was discovered by searching for appropriate fragments in the protein databank. This approach is important in the design of small enzymes useful to the food industry.
The synthesis of a series of alkylcarbamates of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol is reported. Many of these compounds are potent acetylcholinesterase (AChE) inhibitors. The in vitro AChE inhibition, cholinergic effects, acute toxicity, and elevation of brain acetylcholine levels in vivo of this series of compounds are described. A representative compound, 1d (5.6 mg/kg, po), was able to reverse hemicolinium-3-induced amnesia in the mouse passive avoidance assay.
1. Microinjection of selective antibodies into superior cervical ganglion (SCG) neurones has identified the G-protein alpha-subunits mediating muscarinic receptor inhibition of M-type K+ current (IK(M)) and alpha-adrenoceptor inhibition of Ca2+ current (ICa). 2. Antibodies specific for G alpha q/11, but not those for G alpha o, reduced M-current inhibition by the muscarinic agonist oxotremorine-M, whereas anti-G alpha o antibodies, but not anti-G alpha q/11 or anti-G alpha i1-3 antibodies, reduced calcium current inhibition by noradrenaline. 3. Immunoblots with specific anti-G-protein antibodies demonstrated the presence of both G alpha q and G alpha 11, while G alpha o1 (but virtually no G alpha o2) was present. 4. We conclude that M1 muscarinic receptor inhibition of IK(M) is transduced by G alpha q and/or G alpha 11, and that G alpha o transduces alpha-adrenoceptor inhibition of ICa.
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The influence of angiotensin converting enzyme inhibitor therapy on elevated plasma endothelin concentrations in chronic heart failure was investigated by measuring plasma endothelin immunoreactivity in 22 patients with severe but stable chronic heart failure before and after 16 weeks of therapy with quinapril (n = 12) or captopril (n = 10). Plasma endothelin immunoreactivity in the patients (10.2 +/- 34 pg/ml) was significantly higher than a control group (5.9 +/- 1.8 pg/ml). Quinapril improved symptoms and haemodynamics but did not affect plasma endothelin immunoreactivity (11.9 +/- 2.9 pg/ml at baseline and 12.3 +/- 3.4 pg/ml after 16 weeks of quinapril). Captopril also had no effect on endothelin levels (8.1 +/- 2.9 at baseline and 8.1 +/- 3.8 pg/ml after 16 weeks of captopril). The vasodilatory effects of angiotensin converting enzyme inhibitors in heart failure are not mediated by, or associated with, changes in plasma endothelin immunoreactivity.
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Experiments were performed to establish the extent and kinetics of tumor cell repopulation in a murine sarcoma, designated SA-NH, treated with cyclophosphamide (CY). Mice bearing 8-mm leg tumors were treated with 200 mg/kg CY which caused a transient tumor regression. Changes in the absolute clonogen content of tumors was determined by the change in TCD50 values (50% tumor control) obtained under hypoxic conditions of local tumor irradiation at different times after CY treatment until tumors regrew to the pretreatment size. For comparison, hypoxic TCD50 values were determined during the growth of tumors not treated with CY. CY greatly depleted tumors of clonogenic cells as manifested by the reduction in the control TCD50 value of 64.5 Gy to 32.8 Gy 1 day after CY treatment. The reduced TCD50 value remained unchanged for 2 weeks after treatment with CY, at which time the TCD50 began to rapidly increase, continuing until the end of the observation period of 21 days when tumors reached the pretreatment size. In contrast, there was a constant but slower increase in TCD50 values during the growth of tumors not treated with CY. The daily increase in TCD50 was more than twice as high in CY-treated than in CY-untreated tumors: 4.5 Gy/day versus 2.1 Gy/day. This implies that the rate of clonogen production in CY-treated tumors was twice as high as that of unperturbed tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Mammalian cell lines that are sensitive to particular genotoxic agents have proved the most effective starting point for the cloning of human DNA-repair genes. After ethyl methanesulphonate mutagenesis of the parent murine fibroblast L-cell line, a new mammalian X-ray-sensitive cell line (WMXRS-1) was isolated. For selection of the mutant, a novel detection method was used: putative X-ray-sensitive clones were identified by their lack of incorporation of the DNA precursor, bromodeoxyuridine, after irradiation. The WMXRS-1 cell line was collaterally sensitive to ultraviolet radiation and some other agents known to be removed from DNA by the nucleotide excision repair pathway, but not to bleomycin or hydrogen peroxide. In relation to the wild-type strain, WMXRS-1 showed a similar pattern of induction of micronuclei up to an X-ray dose of 4 Gray and a similar DNA double-strand break (dsb) induction profile. The overall level of dsb rejoining was the same in the parent and mutant lines. However, WMXRS-1 demonstrated a reduced initial rate of dsb-rejoining, perhaps accounting for its radiosensitivity. WMXRS-1 also showed a greater G2 cell cycle phase accumulation after treatment with mitomycin-C. The cross-sensitivity profile and strand-break rejoining deficiency phenotype of WMXRS-1 is unique amongst previously characterised mammalian mutant cell lines.
This study describes the identification of seven amino acid residues of the vascular cell adhesion molecule (VCAM-1) that influence binding to the alpha 4 beta 1 receptor. Using recombinant murine VCAM-1-IgG, which is bound by both mouse (WEHI 231) and human (Ramos) lymphoid cells, two approaches demonstrated the crucial role of the first two NH2-terminal Ig-like domains in binding: (a) blocking monoclonal anti-mouse VCAM-1 antibodies bound to only truncation variants that included the first two domains; (b) site-direct mutagenesis of the first NH2-terminal domain showed that alanine substitution of the amino acid residues R36, D40, K46, S54, N65, T72, and E81 partially or completely reduced adherence by human and/or mouse cells. Of these D40, when mutated to A, N, or K (but not E), showed complete abrogation of adherence by mouse and human cells, as well as inability to bind blocking anti-murine VCAM-1 antibody MVCAM.A429, while not inducing gross structural perturbations in VCAM-1. By molecular modeling, the D40 residue was located on a beta turn connecting two beta strands defined as C and D. The residues R36, K46, S54, N65, T72, and E81, which perturb cell adherence and caused small changes to gross structure, are conformationally near or adjacent to D40. Although these residues, identified as crucial for cell adhesion, are all located in domain 1, it is evident that there is a structural requirement for domains 1 and 2 to be intact so that cell adhesive function can occur.
Nascent DNA (nDNA) replication intermediates can be isolated and quantified by pH-step alkaline elution (L.C. Erikson et al., Chromosoma, 74, 125-139, 1979). The effects of 5-fluorouracil (FU) and 5-fluoro-2'-deoxyuridine (FdU) on the formation and persistence of nascent DNA structures were studied in Chinese hamster ovary K1 cells. Exogenous thymidine (dT) rescued FdU-induced, but had little effect on FU-induced, cytotoxicity, indicating DNA- and RNA-directed cytotoxic mechanisms respectively. Drug-treated cells were pulse labelled with [3H]dT and the percentage of total counts eluting from and retained by filters estimated at successive pH increments (11.0, 11.3, 11.5 and 12.1). A 1 min pulse of control cells resulted in > 75% of the DNA eluting at pH 12.1 or being retained by the filter. By 1 h, > 90% of the DNA was retained by the filter. FdU treatment resulted in the persistence of DNA in all four pH bands. More than 95% of total DNA synthesized during a 5 min pulse eluted as discrete peaks at each pH. This DNA was processed to higher M(r) species during a 1 h chase, but following a 24 h chase, 68% of the DNA still eluted at pH 12.1. In contrast, FU treatment caused only a transient accumulation (< or = 10 min) of the DNA (e.g. approximately 26% at 5 min) in the pH 11.0 and 11.3 bands only, indicating a selective effect of FU on the maturation of very short size classes of DNA. Neutral elution was used to assess the effect of FdU on double-strand break (dsb) formation in nDNA. Whereas no dsbs were evident in untreated cells, dsbs appeared in FdU-treated cells even following the shortest [3H]dT pulse times (1-10 min). Although these were processed into higher M(r) species with longer pulse times, dsbs were still evident at 2 h.
A two-fold decrease in the incidence of infant low birth weight, from 20.6% to 8.3%, occurred in Africa American women enrolled from 1985 to 1988 in this interdisciplinary research project conducted in an urban prenatal clinic. Nutritional, biochemical, medical, psychosocial, lifestyle, and environmental data were collected by trained Africa American interviewers. Several instruments were administered to the mother to specify the stress construct and assess body image, the social support network, and other psychosocial variables. The reduction in the incidence of low birth weight in an urban Africa American low income population admitted to the Howard University Hospital is attributed to the mediation of maternal stress by project personnel, in effect, providing an additional support system through the caring, sensitive environment provided by the project clinical staff, who met the women at each of their clinic-scheduled appointments. Women with a positive self attitude and higher self esteem were more likely to be delivered infants at term; the number of persons in the mother's social support network was directly correlated with her infant's gestational age. Maternal serum concentrations of the antioxidant vitamins, vitamin E and ascorbic acid, and the free radical scavenger, uric acid, were significantly correlated with serum folate and blood urea nitrogen. An hypothesis of low birth weight is presented.
The relationships of maternal prenatal dietary intakes and anthropometric measurements to pregnancy outcomes were investigated in a prospective observational study of urban African American women. The 322 subjects, a subset of the 744 women recruited for the study using purposive sampling, were all nulliparous, free of diabetes mellitus and abnormal hemoglobins, and delivered term, singleton infants. Sociodemographic data and monthly quantitative 24-hour food recalls were collected by trained interviewers. Maternal anthropometric measurements were obtained from the subjects' hospital records. Pregnancy outcome data were obtained by physical examinations of the newborn infants by the project pediatrician. With the exception of vitamin C, average maternal dietary intakes were within the ranges of intakes obtained in previous studies. Mean intakes of protein, vitamins A and C, thiamin, riboflavin, and niacin exceeded the 1989 RDA, while those of food energy, vitamin B-6, folate, calcium, iron, magnesium, and zinc were below the RDA. Underweight prior to pregnancy and low pregnancy weight gains were found among 12.9% and 44.4% of the subjects respectively. Dietary intakes were not significantly correlated with pregnancy outcomes. Maternal anthropometric measurements significantly correlated with pregnancy outcomes included delivery weight, pregnancy weight gain, weekly weight gain, prepregnancy weight, net weight gain, height, prepregnancy body mass index, and % ideal prepregnancy body weight (P < 0.05). Using the stepwise selection procedure in multiple regression analysis, delivery weight, % ideal prepregnancy body weight, and prepregnancy body mass index were selected as being predictive of infant birth weight. It was concluded that anthropometric measurements were better nutritional predictors of pregnancy outcome than dietary intake.
The practice of pica, the compulsive ingestion of nonfood substances over a sustained period of time, was studied in 553 African American women who were admitted to prenatal clinics in Washington, D.C. Dietary, biochemical, and psychosocial correlates of the pica practices of a subset of this urban population are presented in this paper. Geophagia, compulsive eating of clay or dirt, was not observed in these women; pagophagia, or the ingestion of large quantities of ice and freezer frost, was self reported in 8.1% of the women, who consumed 1/2 to 2 cups a day from 1 to 7 days per week. Serum ferritin concentrations of pica women were significantly lower during the second and third trimesters of pregnancy; the average values for three trimesters of pregnancy for both ferritin and mean corpuscular hemoglobin were significantly lower in pica women than their nonpica counterparts (P = 0.0001 and P = 0.017, respectively). Although not significantly different, the iron (66 vs. 84% RDA) and calcium (60 vs. 75% RDA) contents of the diets of pica women were less those of nonpica women. Gestational age, body length, and body weight were not different, but head circumferences of infants delivered to pica women who consumed freezer frost and/or ice were smaller than those of nonpica women (P = 0.012). The hypothesis is presented that pica in African American women may be a mediator of stress, acting through the immune system. The size of the social support network of pica women was significantly less than that of nonpica women.(ABSTRACT TRUNCATED AT 250 WORDS)
The relationships of selected lifestyle factors (cigarette smoking, consumption of alcoholic beverages, recreational drug use, and exercise during pregnancy), all self-reported, to pregnancy outcomes, dietary intake during pregnancy, and maternal anthropometric measurements, were investigated in a group of urban African American pregnant women. The 234 subjects were aged 16-35 years and were free of diabetes and abnormal hemoglobins. The lifestyle data were collected by trained interviewers during the subjects' prenatal clinic visits, and the dietary data by monthly, quantitative 24-hour food recalls conducted during these same visits. Maternal anthropometric measurements were obtained from the subjects' hospital records, and pregnancy outcome data during physical examinations of the newborn infants. Both cigarette smoking and drug use were associated with significantly lower mean birth weight, length, and head circumference, while exercise was associated with a significantly higher mean birth weight, and head circumference (P < 0.05). Drug use during pregnancy was associated with a significantly higher intake of vitamin C, and a significantly lower intake of iron; while women reporting drug use before pregnancy had significantly higher mean intakes of food energy, protein, total and saturated fat, and zinc. Prepregnancy weight, percent ideal prepregnancy body weight, prepregnancy body mass index, and delivery weight were significantly lower among those reporting drug use before pregnancy. Multiple regression analyses indicated that smoking explained a relatively small proportion of the variance in infant birth weight compared with delivery weight and percent of ideal prepregnancy body weight.