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Biomedical subjects

M Witten

Publications and source records attributed to M Witten.

At least 19 recordsLinked to original sources
PubMed2003

Aerosolized substance P protects against cigarette-induced lung damage and tumor development.

Both first-hand and second-hand [i.e. side-stream cigarette smoke (SSCS)] exposure to cigarette smoke is known to damage the lungs, alter the immune system, and predispose individuals to the development of emphysema and lung cancer. Previous work from these laboratories has demonstrated that administration of aerosolized substance P (SP) was capable of protecting the pulmonary and immune systems from damage due to environmental toxicants (e.g. hydrocarbon exposures). In the present study, the effects of SP on SSCS exposure were examined. Treatment of mice exposed to SSCS with aerosolized SP prevented pathological cellular and functional changes in the lung as reflected by prevention of damage to airway basement membranes/endothelial cells and preservation of normal airway dynamic compliance. Further, SP treatment reduced and/or prevented the occurrence of micronuclei formation in cells isolated from mice exposed in vivo to SSCS (an indicator of DNA/genetic damage). Finally, in an experimental in vivo lung cancer model, SP therapy significantly reduced the numbers of lung tumors, increased animal survival, and activated pulmonary immune defense mechanisms. Thus, aerosolized SP therapy appears to be capable of inhibiting preventing and/or reversing the cellular and genetic precursors of emphysema and malignancy that often result from exposure to cigarette smoke.

Administration, Inhalation↗
PubMed2000

Increased immunoreactivity of glutathione-S-transferase in the retina of Swiss Webster mice following inhalation of JP8 + 100 aerosol.

The current study was designed to determine whether exposure of mice to aerosolized jet fuel (JP8 + 100) resulted in changes in the cellular distribution or immunoreactivity of the enzyme glutathione S-transferase (GST), a biomarker of toxicant exposure. Male mice were exposed to JP8 + 100 at 1000 mg/m3 or 2500 mg/m3 in aerosol for 1 h per day for 7 days and then sacrificed. The retinas were studied by immunohistochemical methods. The JP8 + 100 exposure caused a marked increase in the immunoreactivity of anti-GSTM antibodies with the radial glial cells of the retina, the Müller cells. These results are consistent with the hypothesis that JP8 + 100 acts as a toxicant to mouse retina by permitting the flux of materials across the blood-retina barrier. The findings are relevant to humans because recent studies indicate that Air Force personnel assigned to clean and maintain fuel pods may be exposed to concentrations of JP8 + 100 exceeding 1000 mg/m3.

Aerosols↗
PubMed2000

Effects of short-term JP-8 jet fuel exposure on cell-mediated immunity.

The U.S. Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to environmental toxicants such as JP-8 may have significant effects on host physiology. Jet fuel exposure has been shown to cause human liver dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss of immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). In the current study, an in-depth analysis of the effects of JP-8 exposure on cellular immunity was performed. Short-term (7 days, 1 h/day), low-concentration (1000 mg/m3) exposures were conducted in mice, and T cell and natural killer (NK) cell functions were analyzed 24 h after the last exposure. The exposure regimen was found to almost completely ablate NK cell function, as well as significantly suppress the generation of lymphokine-activated killer (LAK) cell activity. Furthermore, JP-8 exposure suppressed the generation of cytotoxic T lymphocyte (CTL) cells from precursor T cells, and inhibited helper T cell activity. These findings demonstrate that JP-8 jet fuel exposure has significant detrimental effects on immune functions of exposed individuals. JP-8 jet fuel should be considered a potential and significant immunotoxicant. Chronic exposure to JP-8 may have serious implications to the long-term health of exposed individuals.

Administration, Inhalation↗
PubMed2000

Substance P as prophylaxis for JP-8 jet fuel-induced immunotoxicity.

Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system that persisted for extended periods of time. It was found that administration of aerosolized substance P (SP) was able to protect exposed animals from JP-8-induced immune changes, whereas administration of SP antagonists compounded the deleterious effects ofjet fuel exposure. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure. In the current study, aerosolized SP was analyzed for its potential prophylactic ability to counteract JP-8-induced immunotoxicity. It was observed that concentrations as low as 1 nM were effective in ameliorating the effects of JP-8 exposure on the immune system. SP administered before JP-8 exposure could prophylactically protect both the spleen and thymus from significant organ weight loss, but could not completely restore immune cell numbers to normal, baseline levels. Furthermore, SP treatment could be delayed as long as 1 h postexposure and reverse the effects of jet fuel exposure on immune organ weight loss and immune cell recovery. Significantly, SP could be given 15 min pre-JP-8 exposure but neither 1 nor 6 h pre-JP-8 exposure, and prevent immune dysfunction as measured in mitogenesis assays. However, SP could be delayed up to 6 h post-JP-8 exposure and still almost completely restore immune function. Thus, SP appears able to both prevent and reverse the immunotoxicological effects associated with JP-8 exposure. These results also provide insight into the manner in which JP-8 jet fuel mediates its effects on the immune system.

Animals↗
PubMed2000

Jet fuel-induced immunotoxicity.

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

Animals↗
PubMed1998

L-DOPA exacerbates amphetamine-induced dopamine depletion.

Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

A gerontological distance metric for analysis of survival dynamics.

A metric for quantifying a gerontological mapping 'distance' or displacement consistent with the historical concept of velocity of aging and with the more recent concept of acceleration of aging, is introduced using the paradigm of a simple linear dynamics system of elementary physics. This analysis is extended to recent analytical methods utilizing intrinsic or internal time scaling so that biological or gerontological similarity can be distinguished from chronological age similarity, not only among various intraspecies populations but also among interspecies populations which may not even have the same underlying mechanisms of senescence or survival distributions. Illustrative examples are provided and discussed. Also, applications involving the comparison of an individual from one population to an individual from another population, when both can be assessed with respect to their respective group properties, are considered.

Age Factors↗
PubMed1995

Estimating parametric survival model parameters in gerontological aging studies: methodological problems and insights.

Studies of the biology of aging (both experimental and evolutionary) frequently involve the estimation of parameters arising in various multi-parameter survival models such as the Gompertz or Weibull distribution. Standard parameter estimation methodologies, such as maximum likelihood estimation (MLE) or nonlinear regression (NLR), require knowledge of the actual life spans or their explicit algebraic equivalents in order to provide reliable parameter estimates. Many fundamental biological discussions and conclusions are highly dependent upon accurate estimates of these survival parameters (this has historically been the case in the study of genetic and environmental effects on longevity and the evolutionary biology of aging). In this article, we examine some of the issues arising in the estimation of gerontologic survival model parameters. We not only address issues of accuracy when the original life-span data are unknown, we consider the accuracy of the estimates even when the exact life spans are known. We examine these issues as applied to known experimental data on diet restriction and we fit the frequently used, two-parameter Gompertzian survival distribution to these experimental data. Consequences of methodological misuse are demonstrated and subsequently related to the values of the final parameter estimates and their associated errors. These results generalize to other multiparametric distributions such as the Weibull, Makeham, and logistic survival distributions.

Aging↗
PubMed1995

Survival estimates and sample size: what can we conclude?

Attempts to understand aging processes often involve life-span measurements from which a survival curve is constructed and model parameters estimated. The parameter estimates are then compared, and conclusions concerning the underlying biological processes are subsequently deduced, based upon the magnitude of the parameter differences. In this article we discuss the role of sample size and sample fluctuation on the parameter estimates and the profound effect that these factors may play in our arrival at meaningful biological conclusions. We then extend this discussion to examine one methodology that can help select sample sizes for specific parametric survival models.

Aging↗
PubMed1995

A biologically based explanation for mortality crossover in human populations.

We consider the impact of a genetically predetermined maximum life span (or upper bound on life span of a species) on patterns of human mortality. In particular, we consider the implication of a predetermined maximum life span on two distinct population subgroups: one group advantaged, the other group disadvantaged. We show that the existence of a genetically predetermined maximum life span imposes the condition that the two subgroup mortality rates must cross. We further observe that proportional mortality must be associated with divergent mortality differences over the life course. We illustrate these arguments via some simulated examples.

Adolescent↗
PubMed1994

Might stochasticity and sampling variation be a possible explanation for variation in clonal population survival curves.

Biogerontological survival analysis attempts to understand, through the use of mathematical and computer models, how biological and environmental processes affect the dynamics of survival. The survival model parameters are assumed to reflect an average or mean response to some intervention. Further, these parameters are usually assumed to be constant over the time course of the experiment and across the elements of the experimental cohort. In this paper, we introduce stochastic (random) features to the survival curve parameters and we observe how this might affect our interpretation of the biology; as reflected in the estimates of the model parameters. In particular, we provide a possible explanation for variation in parameter estimates within sample populations drawn from a population of genetic clones.

Computer Simulation↗
PubMed1994

Cyclooxygenase and lipoxygenase inhibition by BW-755C reduces acrolein smoke-induced acute lung injury.

Inhalation of smoke containing acrolein, the most common toxin in urban fires after carbon monoxide, causes vascular injury with non-cardiogenic pulmonary edema containing potentially edematogenic eicosanoids such as thromboxane (Tx) B2, leukotriene (LT) B4, and the sulfidopeptide LTs (LTC4, LTD4, and LTE4). To determine which eicosanoids are important in the acute lung injury, we pretreated sheep with BW-755C (a combined cyclooxygenase and lipoxygenase inhibitor), U-63557A (a specific Tx synthetase inhibitor), or indomethacin (a cyclooxygenase inhibitor) before a 10-min exposure to a synthetic smoke containing carbon particles (4 microns) with acrolein and compared the results with those from control sheep that received only carbon smoke. Acrolein smoke induced a fall in arterial PO2 and rises in peak inspiratory pressure, main pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and the blood-free wet-to-dry weight ratio. BW-755C delayed the rise in peak inspiratory pressure and prevented the fall in arterial PO2, the rise in lymph flow, and the rise in wet-to-dry weight ratio. Neither indomethacin nor U-63557A prevented the increase in lymph flow or wet-to-dry weight ratio, although they did blunt and delay the rise in airway pressure and did prevent the rises in pulmonary arterial pressure and pulmonary vascular resistance. Thus, cyclooxygenase products, probably Tx, are responsible for the pulmonary hypertension after acrolein smoke and to some extent for the increased airway resistance but not the pulmonary edema. Prevention of high-permeability pulmonary edema after smoke with BW-755C suggests that LTB4, may be etiologic, as previous work has eliminated LTC4, LTD4, and LTE4.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1992

Smoke aldehyde component influences pulmonary edema.

The pulmonary edema of smoke inhalation is caused by the toxins of smoke and not the heat. We investigated the potential of smoke consisting of carbon in combination with either acrolein or formaldehyde (both common components of smoke) to cause pulmonary edema in anesthetized sheep. Seven animals received acrolein smoke, seven animals received a low-dose formaldehyde smoke, and five animals received a high-dose formaldehyde smoke. Pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output were not affected by smoke in any group. Peak airway pressure increased after acrolein (14 +/- 1 to 21 +/- 2 mmHg; P less than 0.05) and after low- and high-dose formaldehyde (14 +/- 1 to 21 +/- 1 and 20 +/- 1 mmHg, respectively; both P less than 0.05). The partial pressure of O2 in arterial blood fell sharply after acrolein [219 +/- 29 to 86 +/- 9 (SE) Torr; P less than 0.05] but not after formaldehyde. Only acrolein resulted in a rise in lung lymph flow (6.5 +/- 2.2 to 17.9 +/- 2.6 ml/h; P less than 0.05). Lung lymph-to-plasma protein ratio was unchanged for all three groups, but clearance of lymph protein was increased after acrolein. After acrolein, the blood-free extravascular lung water-to-lung dry weight ratio was elevated (P less than 0.05) compared with both low- and high-dose formaldehyde groups (4.8 +/- 0.4 to 3.3 +/- 0.2 and 3.6 +/- 0.2, respectively). Lymph clearance (ng/h) of thromboxane B2, leukotriene B4, and the sulfidopeptide leukotrienes was elevated after acrolein but not formaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrolein↗
PubMed1991

The waste-product theory of aging: simulation of metabolic waste production.

A mathematical model of cellular metabolism is used to relate the rates of cell division and waste production to the concentrations of oxygen and glucose in the medium in which a normal diploid cell culture is grown. The metabolic model in tandem with an earlier waste-content model based on the waste-product theory of aging provides a unified cell-culture model with which population size and intracellular waste content can be calculated. Population size is measured by the number of population doublings which have been achieved. After suitable adjustment of parameters in the metabolic model, maximum values of population size are calculated numerically with the use of the unified model. Results show that the population maxima are related in a plausible way to the oxygen and glucose concentrations. The effects of temperature changes and contact inhibition of growth are also simulated. Small changes in the cell-division and waste-production rates can cause transformation to unlimited growth in the waste-content model, but the unified model is not correspondingly sensitive to changes in the oxygen and glucose concentrations or to changes in temperature.

Cell Division↗
PubMed1990

Slow mortality rate accelerations during aging in some animals approximate that of humans.

A general measure of the rate of senescence is the acceleration of mortality rate, represented here by the time required for the mortality rate to double (MRD). Rhesus monkeys have an MRD close to that of humans, about 8 years; their shorter life-span results mainly from higher mortality at all ages. In contrast, some groups with short life-spans (rodents and galliform birds) have shorter MRDs and faster senescence. On the basis of the Gompertz mortality rate model, one may estimate the MRD from the maximum life-span (tmax) and the overall population mortality rate. Such calculations show that certain birds have MRDs that are as long as that of humans. These results show that high overall mortality rates or small body sizes do not preclude slow rates of senescence.

Adolescent↗
PubMed1989

A quantitative model for lifespan curves.

"This paper addresses the issue of a model for the total lifespan survival curve, with particular interest in the later life or geriatric years. This new model is based upon the basic premise that the population under study is a mixture of individuals comprising three major subgroups: (1) neonatal deaths, (2) standard Gompertzian-like survival, (3) geriatric survival. It is demonstrated that a standard mixture model, mixing three survival distributions, more than adequately describes survival over the entire lifespan of the population. Further, this newer model has the desirable added virtue that the model parameters may be interpreted in a biological manner."

Adult↗
PubMed1989

The waste-product theory of aging: transformation to unlimited growth in cell cultures.

A differential equation governing intracellular waste content is solved numerically to determine the circumstances under which the growth of an in vitro cell population is limited. Parameter values derived from data on human glial cell cultures are employed. It is assumed that a) waste accumulation depresses the rate of cellular reproduction and b) intracellular waste is diluted by cell division, but is not otherwise eliminated. Population size depends upon two parameters: the rate of waste production and the rate of cell division in the absence of waste. If the rate of waste production is sufficient, the population size approaches an asymptote as in phase III growth in vitro. If a lower rate of waste production allows the cells to outmultiply the waste, growth is unlimited as in a transformed cell population. The asymptotic population size and the threshold for unlimited growth are remarkably sensitive to small changes in the values of the two rate parameters unless the ratio of their values is constant. This suggests that there may be a cellular mechanism that relates the waste production and cell division rates.

Aging↗