PubMed Health⌕ Search

Biomedical subjects

A M Smith

Publications and source records attributed to A M Smith.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one.

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

Aminopyridines↗
PubMed1992

Associations of social status and health-related beliefs with dietary fat and fiber densities.

BACKGROUND: Lower social status groups have higher mortality rates from some diet-related diseases and higher dietary fat and lower dietary fiber intakes. Such dietary patterns have been found to be related to social status, environmental influences, and health-related beliefs and expectations. METHODS: Associations of social status and diet-related and health-related beliefs and expectations with dietary fat and fiber densities were examined in a population sample of 874 respondents to a postal questionnaire. A food frequency listing of 172 foods was used to assess usual dietary intake. RESULTS: More positive beliefs and expectations were associated with lower dietary fat and higher dietary fiber densities in univariate models; beliefs and expectations differed little between social status groups. In multivariate models, stronger perceptions of external influences on food choices, fewer perceived barriers to eating a healthy diet, and social status were independently associated with low dietary fat density. Diet-related and health-related beliefs and perceptions of external influences on food choices, but not social status, were independently associated with high dietary fiber density. The belief that diet is a major cause of stroke, diabetes, and hypertension was weakly associated with the dietary fiber density of lower social status groups. CONCLUSIONS: Social status and perceptions of external influences on dietary choice, as well as personal beliefs, have independent associations with food intake. Although exclusive targeting of lower social status groups is not indicated, interventions to increase dietary fiber intake should address expectations, attitudes, and beliefs about dietary fiber and health and perceptions of external influences on food choices, especially among lower status groups; interventions to lower dietary fat intake should address a broad range of external and social factors, as well as personal beliefs.

Attitude to Health↗
PubMed1992

L-696,229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro.

L-696,229 (3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2 (1H)-one) is a specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity that possesses antiviral activity in cell culture (W.S. Saari, J.M. Hoffman, J.S. Wai, T.E. Fisher, C.S. Rooney, A.M. Smith, C.M. Thomas, M. E. Goldman, J. A. O'Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleif, E. A. Emini, and P. S. Anderson, J. Med. Chem. 34:2922-2925, 1991). In the present study, the RT-inhibitory activity and antiviral properties were characterized in detail. The inhibition of RT activity was template-primer dependent with 50% inhibitory concentrations of 0.018 to 0.50 microM and was noncompetitive with respect to deoxynucleoside triphosphates. L-696,229 inhibited RT activity in a mutually exclusive manner with respect to either phosphonoformate or azidothymidine triphosphate and was a weak partial inhibitor of the RNase H activity associated with HIV-1 RT. The compound did not significantly inhibit other retroviral or cellular polymerases at 300 microM.L-696,229 inhibited the spread of HIV-1 infection in cell cultures with all cell types and viral isolates tested, including human peripheral blood mononuclear cells and a virus isolate resistant to azidothymidine.

Benzoxazoles↗
PubMed1992

Public health implications of dietary differences between social status and occupational category groups.

STUDY OBJECTIVE: As there is a social status gradient in chronic disease mortality in Australia, this study aimed to establish whether there were substantial differences among socioeconomically defined groups with respect to food choice and nutrient intake, in the context of risk of nutrition related chronic diseases. DESIGN AND PARTICIPANTS: Cross sectional data were collected from a randomly selected population sample of 1500 urban Australian adults. Data were collected by postal questionnaire, which included an assessment of dietary intake and questions on sociodemographic details. Three measures of social position were collected: occupation, educational status, and income status. Occupation was interpreted both on a continuous, prestige scale, and also as categorical occupational groupings. MAIN RESULTS: The study achieved a 70% response rate. Higher social status was generally associated with healthier dietary intakes, with lower fat and refined sugar densities, and higher fibre densities, but also with higher alcohol density. No differences were found in salt, polyunsaturated fat, protein, or complex carbohydrate densities across groups. Food intake differences were also found between occupational status groups, with the upper social groups tending to consume more wholegrain cereal foods, low fat milk, and fruit, and less refined cereal foods, full cream milk, fried meat, meat products, and discretionary sugar; but also more cheese and meat dishes. CONCLUSIONS: Although this study did show statistically significant differences across social status groups in relation to nutrient and food intakes, these differences were small compared to the disparity between intakes of all groups and the recommended patterns of intake, and did not appear to be great enough to be a major explanatory variable in differences in disease risk across groups.

Adolescent↗
PubMed1992

Responses of cerebellar Purkinje cells to slip of a hand-held object.

1. Two monkeys were trained to grasp, lift, and hold a device between the thumb and forefinger for 1 s. The device was equipped with a position transducer and strain gauges that measured the horizontal grip force and the vertical lifting or load force. On selected blocks of 20-30 trials, a force-pulse perturbation was applied to the object during static holding to simulate object slip. The animals were required to resist this displacement by stiffening the joints of their wrists and fingers to obtain a fruit juice reward. Single cells in the hand representation area of the paravermal anterior lobe of the cerebellar cortex were recorded during perturbed and unperturbed holding. If conditions permitted, the cell discharge was also recorded during lifting of objects of various weights (15, 65, or 115 g) or different surface textures (sandpaper or polished metal), and when possible the cutaneous or proprioceptive fields of the neurons were characterized with the use of natural stimulation. 2. On perturbed trials, the force pulse was always applied to the manipulandum after it had been held stationary within the position window for 750 ms. The perturbation invariably elicited a reflexlike increase of electromyographic (EMG) activity in wrist and finger muscles, resulting in a time-locked increase in grip force that peaked at a latency between 50 and 100 ms. 3. The object-slip perturbation had a powerful effect on cerebellar cortical neurons at a mean latency of 45 +/- 14 (SD) ms. Reflexlike increases or decreases in simple spike discharge occurred in 55% (53/97) of unidentified cells and 49% (21/43) of Purkinje cells recorded in the anterior paravermal and lateral cerebellar cortex. 4. The perturbation failed to evoke complex spike responses from any of the Purkinje cells examined. All the perturbation-evoked activity changes involved modulation of the simple spike discharge. The perturbations stimulated the simple-spike receptive field of most Purkinje cells recorded here, which suggests that the short-latency unit responses were triggered by afferent stimulation. Only one Purkinje cell was found with a distinct complex-spike receptive field on the thumb, but this neuron did not respond to the perturbation. It appears that simple- and complex-spike to receptive fields are not always identical or even closely related. 5. The majority of Purkinje and unidentified neurons that responded to the perturbation had cutaneous receptive fields, although some had proprioceptive fields. Seventy-seven neurons were examined for peripheral receptive fields and were also tested with the perturbation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Primary motor cortical activity related to the weight and texture of grasped objects in the monkey.

1. Two monkeys were trained to grasp an object between the thumb and index finger and lift it to a vertical distance of 12-25 mm. Up to 12 different conditions defined by different combinations of object weights (15, 65, and 115 g) and four surface textures (oiled metal, smooth metal, fine and coarse sandpaper) were used. The apparatus was equipped to measure grip (prehensile) force, vertical (load) force, and object displacement. 2. The monkeys appropriately scaled the grip force for the weight and the coefficient of friction of the object. However, during the dynamic phase of the task (grasping and lifting), the monkeys increased the prehensile force in multiple steps, suggesting that they relied on sensory feedback from the fingers to attain an adequate grip force to lift the object rather than programming the lift in advance. 3. Single-unit activity of 248 neurons was recorded in the hand area of the primary motor cortex while the monkeys performed the task. Of 208 neurons tested for cutaneous and proprioceptive receptive fields (RFs), 96 were sensitive to cutaneous stimulation of the glabrous skin of the hand, whereas 82 received proprioceptive input from wrist and finger muscles. The concentration of neurons with cutaneous input was significantly greater in the rostral bank of the central sulcus compared with cells with proprioceptive RFs, which were more concentrated in the convexity of the precentral gyrus. 4. From the global sample, 199 cells were tested with the three object weights, and 128 of these with at least two surface textures were used in combination with the object weights. The discharge of 58/199 (29%) cells was modulated with the object weight. Cells with cutaneous (20/84, 24%) and proprioceptive (23/71, 32%) RFs were about equally responsive to the object weight. 5. A greater number of motor cortical neurons were influenced by surface texture than by object weight. Of 128 cells tested with at least two surface textures, 67 (52%) showed a modulation of their activity as a function of texture. A significantly greater proportion of neurons with cutaneous RFs (40/63, 63%) showed differential activity as a function of object texture than cells receiving proprioceptive input (21/47, 45%). 6. Weight- and texture-related neurons were not distributed equally in the rostrocaudal dimension of the motor cortex. Only 8% of texture-related cells were located in the convexity of the precentral gyrus, whereas 30% of weight-related neurons were recorded from this rostral zone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Primary motor cortical responses to perturbations of prehension in the monkey.

1. Two monkeys were trained to grasp, lift, and hold an object within a vertical position window. A downward force-pulse perturbation was delivered during stationary object holding to simulate slip of the object due to gravity. The responses evoked by the perturbation were studied in 189 neurons of the hand area of the primary motor cortex. In addition, the slip-evoked responses were compared with the modulation of neural discharge with textures and weights described in the previous paper. 2. The perturbation evoked responses with sharp onsets in the majority of motor cortical neurons (115/189, 61%) active during the task. The majority of the responses were of sufficiently short latency (43.17 +/- 17.24 ms, mean +/- SD) to have participated in the reflex grip force increase that followed at latencies from 50 to 100 ms. 3. Although a similar proportion of neurons with cutaneous (43/70) or proprioceptive (35/59) receptive fields (RFs) were responsive to the perturbation, the cutaneous afferents provided a stronger excitation of motor cortical cells than the feedback originating from proprioceptive receptors. 4. The covariation of the neural discharge related to the surface texture of the grasped object and the responsiveness to object slip was studied in 89 cells tested with the perturbation and with more than one surface texture on unperturbed trials. Within this population, motor cortical cells with cutaneous RFs were more sensitive to the perturbation (25/31) than neurons receiving proprioceptive input (8/16). Furthermore, all (17/17) neurons with cutaneous RFs that were more active with the smooth than with the rough surface textures showed a vigorous response to the perturbation. 5. A detectable downward displacement of the object was not always necessary to excite neurons with cutaneous RFs and whose activity increased with the smooth textures. Their sensitivity to the perturbation was consistent with the hypothesis that the cutaneous afferent activity generated by object slips or shear forces on the skin contributed to the increased discharge when lifting objects of slippery surface textures. The activity of these slip- or shear-sensitive cells may have contributed to the reflex grip force increases and to the greater sustained muscular activity needed to lift smooth objects. 6. Ten cells that were excited by stroking of the glabrous skin of the hand decreased their discharge frequency during the task even though their RFs were in direct contact with the object. Most of these neurons (7/10) did not respond to the object slip, and three cells had very weak responses to the perturbation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

NeuN, a neuronal specific nuclear protein in vertebrates.

A battery of monoclonal antibodies (mAbs) against brain cell nuclei has been generated by repeated immunizations. One of these, mAb A60, recognizes a vertebrate nervous system- and neuron-specific nuclear protein that we have named NeuN (Neuronal Nuclei). The expression of NeuN is observed in most neuronal cell types throughout the nervous system of adult mice. However, some major cell types appear devoid of immunoreactivity including cerebellar Purkinje cells, olfactory bulb mitral cells, and retinal photoreceptor cells. NeuN can also be detected in neurons in primary cerebellar cultures and in retinoic acid-stimulated P19 embryonal carcinoma cells. Immunohistochemically detectable NeuN protein first appears at developmental timepoints which correspond with the withdrawal of the neuron from the cell cycle and/or with the initiation of terminal differentiation of the neuron. NeuN is a soluble nuclear protein, appears as 3 bands (46-48 x 10(3) M(r)) on immunoblots, and binds to DNA in vitro. The mAb crossreacts immunohistochemically with nervous tissue from rats, chicks, humans, and salamanders. This mAb and the protein recognized by it serve as an excellent marker for neurons in the central and peripheral nervous systems in both the embryo and adult, and the protein may be important in the determination of neuronal phenotype.

Animals↗
PubMed1992

Terminology for drug injection practices among intravenous drug users in Baltimore.

Terms for four discrete drug injection practices were obtained by presenting photographs and a brief description of practices to intravenous drug users who enrolled in a longitudinal study of HIV infection in Baltimore. The 2,921 respondents were predominantly male (81%) and Black (90%), the median age was 34 years (range: 18-68 years), and the median duration of intravenous drug use was 13 years (range 0-50 years). Forty-six different terms were used to characterize direct injection into a vein, 51 for the practice of repeatedly withdrawing and reinjecting one's own blood following injection of drug, 39 for subcutaneous injection, and 45 for transferring drug between different syringes. Terms tended to cluster by race and duration of drug use. These data indicate substantial variation in terminology for drug injection practices. Further, they augment prior research showing that photographs may be used as a useful aid in survey research on drug experiences in the population.

Adolescent↗
PubMed1992

Modification of the behavioural effects of ethanol by nifedipine.

Nifedipine (10.0 mg/kg) was administered to mice together with graded doses of ethanol (0, 2.5, 3.0, 3.5, 4.0 and 4.5 g/kg), and activity measured over a 2-hr period following administration. Low ethanol doses increased activity, whereas the highest dose decreased it. By itself, nifedipine had no effect on activity, but when combined with ethanol it produced a consistent decrease in comparison with ethanol alone. This occurred irrespective of whether the ethanol dose alone increased or decreased activity. These results demonstrate a clear interaction between nifedipine and ethanol which cannot be characterized as simple potentiation or antagonism. Time-course data showed that the effects of nifedipine were apparent within 10-20 min of drug administration, but, in the case of the highest ethanol dose, increased toward the end of the 2-hr period. Retardation of the development of acute tolerance may contribute to the interaction between ethanol and nifedipine.

Adult↗
PubMed1992

A regional autologous bone marrow transplant network: transfers to designated centers on the day after transplant.

Autologous bone marrow transplantation (ABMT) is becoming increasingly prevalent for treatment of advanced malignant disease. In order to increase the availability and utility of this therapy, we assessed the feasibility of transferring patients to their regional referral centers on the day after marrow infusion (day 1), for management post-transplant. This prospective study compares the outcome of 77 patients either transferred the day after marrow transplant for subsequent management at one of six selected Canadian regional centers closest to their domicile, or treated entirely at The Toronto Hospital, according to a common protocol. Study end-points included frequency of complications during transfer, transplant-related morbidity and mortality and hematopoietic recovery. Assessment of eligibility for transplant, bone marrow harvesting, autograft cryopreservation, administration of intensive therapy and marrow infusion were conducted in all cases at The Toronto Hospital. Thirty patients received marrow transplants and were transferred on day 1. There were no complications during transfer. Compared with 47 consecutive patients treated entirely at The Toronto Hospital, there were no differences in treatment-related morbidity or mortality, use of intravenous antifungal therapy or total days of hospitalization. We conclude that day 1 transfer of patients after ABMT to designated centers is feasible and safe. The operation of a regional ABMT network appears to benefit patients, relatives, referring physicians, the transplant center and may also improve health care delivery.

Adolescent↗
PubMed1991

The antigenic surface of staphylococcal nuclease. I. Mapping epitopes by site-directed mutagenesis.

The analysis of the antigenic surface of staphylococcal nuclease was begun by generating and characterizing a panel of mAb. Twelve mAb were selected from a large number of anti-nuclease mAb and characterized for affinity and isotype, by their ability to block enzyme activity, and by complementation and competitive inhibition assays for the relative location of epitopes. The mAb were placed in complementation groups based on their distinct binding patterns. These groups define a series of eight overlapping epitopes that are estimated to cover a large portion of the nuclease surface. Four mAb blocked the enzyme activity of nuclease. The epitopes defined by two of these four mAb were localized on the surface of nuclease using single amino acid variant Ag generated by site-directed mutagenesis of the cloned nuclease coding sequence. mAb-25 maps to residue 46 which is located at the edge of the enzyme active site consistent with its ability to inhibit enzyme activity. mAb-19, which also blocks enzyme activity and belongs to the same complementation group as mAb-25, was unaffected by the substitution at position 46. This suggests that mAb-19 and mAb-25, if they do react with the same epitope, have differences in fine specificity. mAb-22 blocks enzyme activity and belongs to an overlapping complementation group. The fourth mAb, mAb-1, which belongs to a distinct, nonoverlapping, complementation group, does not blocks enzyme activity, and is directed to a region of nuclease that includes the amino acid at position 133. This residue is located a short distance from the active site in a region that has been suggested to participate in binding of DNA, a substrate for nuclease. Therefore, the four epitopes defined by these mAb are localized at or near the enzyme active site.

Animals↗
PubMed1991

The antigenic surface of staphylococcal nuclease. II. Analysis of the N-1 epitope by site-directed mutagenesis.

Previous studies in our laboratory on the production and isolation of a panel of mAb to staphylococcal nuclease allowed us to define a series of eight overlapping epitopes. Using site-directed mutagenesis of the nuclease coding sequences we were able to map the nonoverlapping epitopes recognized by two members of this panel. In the study reported here, we report the generation and analysis of a number of single amino acid substitutions for seven surface residues predicted to lie within one of these two epitopes. Immunochemical analysis showed that one or more substitutions at each of these seven positions had a major effect on mAb binding, whereas other substitutions had none. Based on the nature of these substitutions and the chemical and physical properties of the variant molecules, we believe that any structural effects induced by these substitutions are local and do not result in long-range structural alterations that indirectly influence antibody reactivity. Therefore, we conclude that disruption of mAb binding can be directly attributed to changes in amino acid side chains and that not only are all seven of the residues studied part of the epitope but all seven make contact with the antibody combining site. These studies demonstrate the advantages of using site-directed mutagenesis to study antigen structure and emphasize the importance of constructing the examining multiple substitutions for any given amino acid.

Animals↗