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Biomedical subjects

P L Jones

Publications and source records attributed to P L Jones.

At least 19 recordsLinked to original sources
PubMed1992

Intermediate endpoint biomarkers for chemoprevention.

The understanding of intermediate endpoint biomarker expression in relation to the sequential events in bladder tumorigenesis establishes a useful approach for evaluating chemopreventive agents. Biomarkers may be genotypic or phenotypic and function as biomarkers of susceptibility, exposure, effect, or disease. This paper reviews several years of research on biomarkers and their use in monitoring chemoprevention therapy. In initial animal experiments, mice were dosed with N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) while co-administering N-(4-hydroxyphenyl)retinamide (4-HPR). 4-HPR did not statistically reduce tumor incidence, but did affect tumor differentiation and, consequently, nuclear size and DNA ploidy. These results suggest that nuclear size and ploidy may function as intermediate endpoint biomarkers of effect for oncogenesis and that epigenetic as well as genetic mechanisms may be primary in the oncogenic process. Early biomarkers of effect which occur prior to genetic effects or chromosome aberration may portend a higher probability of being modulated by differentiating agents such as retinoids. In vitro studies demonstrated that RPMI-7666 cells cultured with a phorbol ester tumor promoter (12-O-tetradecanoyl-phorbol-13-acetate) could be redifferentiated with 13-cis-retinoic acid and dimethyl sulfoxide (DMSO). F-actin, a cytoskeletal biomarker with a presumed function in the epigenetic mechanisms of carcinogenesis, could also be normalized in HL-60 cells treated with 4-HPR or DMSO. A clinical evaluation of F-actin in patients with varying degrees of risk confirmed the value of F-actin as a differentiating biomarker useful for bladder cancer risk assessment. The clarification of when the phenotypic changes of F-actin occur in the oncogenic process was achieved when a variety of biochemical changes were mapped in the patients with bladder cancer. These studies confirmed that G-actin, a reciprocal form of F-actin, is increased relatively early in bladder cancer oncogenesis when multiple biomarkers are quantitated in the field, adjacent area, and the tumor. Comparison of each individual biomarker's expression from field, adjacent to tumor, and tumor, and subsequent cluster analysis of these biomarkers, indicated that the possible sequence of phenotypic expression of biomarkers in bladder cancer oncogenesis is from G-actin, to p300 antigen, to epidermal growth factor receptor (EGFR), to p185 (neu oncogene product), to DNA aneuploidy and, finally, to visual morphology.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Epidermal keratinocyte self-renewal is dependent upon dermal integrity.

The epidermis is a major site of self-renewal in which there is constant replacement by cell division in the basal layers of cells lost by desquamation in the superficial layers. Such a tissue is therefore likely to contain stem cells and in this study we have examined the role of the dermis in the maintenance of epidermal self-renewal. We have developed a mouse model to address the question of whether the maintenance of epidermal self-renewal is dependent, as in the hemopoietic system, upon a heterologous cell type. Intact epidermis separated from dermis at the dermo-epidermal junction or epidermis derived from disaggregated epidermal cells, can reconstitute a stratified squamous epithelium when grafted onto the lumbo-dermal fascia of the mouse or onto an experimentally induced granulation tissue bed. However, we have shown that, after grafting, the clonogenic capacity of the keratinocytes declines sharply and the colonies that are produced are incapable of self-renewal in vitro. Although initially hyperplastic, these epidermal grafts assume an atrophic appearance after 40-70 d and this may be related to the loss of self-renewal observed in vitro. With both experimental murine grafts and clinical grafts the failure of keratinocytes to self-renew can be alleviated, partially, by the presence of the dermis in full-thickness or split-thickness grafts, which implies that the dermis has a functional role in epidermal stem cell maintenance. The relevance of these observations to the clinical experience with cultured autologous keratinocyte sheets as wound dressings to patients is discussed.

Animals↗
PubMed1992

Ability of Proteus mirabilis to invade human urothelial cells is coupled to motility and swarming differentiation.

Proteus mirabilis causes serious kidney infections which can involve invasion of host urothelial cells. We present data showing that the ability to invade host urothelial cells is closely coupled to swarming, a form of cyclical multicellular behavior in which vegetative bacteria differentiate into hyperflagellated, filamentous swarm cells capable of coordinated and rapid population migration. Entry into the human urothelial cell line EJ/28 by P. mirabilis U6450 isolated at different stages throughout the swarming cycle was measured by the antibiotic protection assay method and confirmed by electron microscopy. Differentiated filaments entered urothelial cells within 30 min and were 15-fold more invasive (ca. 0.18% entry in 2 h) than an equivalent dry weight of vegetative cells isolated before differentiation, which attained only ca. 0.012% entry in the 2-h assay. The invasive ability of P. mirabilis was modulated in parallel with flagellin levels throughout two cycles of swarming. Septation and division of intracellular swarm cells produced between 50 and 300 vegetative bacteria per human cell, compared with 4 to 12 intracellular bacteria after incubation with vegetative cells. Transposon (Tn5) mutants of P. mirabilis with specific defects in motility and multicellular behavior were compared with the wild-type for the ability to invade. Mutants which lacked flagella (nonmotile nonswarming) were entirely noninvasive, and those which were motile but defective in swarm cell formation (motile nonswarming) were 25-fold less invasive than wild-type vegetative cells. Mutants with defects in the coordination of multicellular migration and the temporal control of consolidation (cyclical reversion of swarm cells to vegetative cells) were reduced ca. 3- to 12-fold in the ability to enter urothelial cells. In contrast, a nonhemolytic transposon mutant which swarmed normally retained over 80% of wild-type invasive ability. Swarm cells and early consolidation cells were at least 10-fold more cytolytic than vegetative cells as a result of their high-level production of hemolysin.

Animals↗
PubMed1991

Cellular F-actin levels as a marker for cellular transformation: correlation with bladder cancer risk.

Previous findings in cultured cells that differentiated cells had markedly higher F-actin levels than undifferentiated cells (Cancer Res., 50: 2215-2220, 1990) suggested that quantitative F-actin measurements in urinary cells might provide diagnostic or prognostic information by identifying those individuals with cells tending towards a lower degree of differentiation. The feasibility of such an approach was investigated using a risk stratification schema. Bladder wash samples were obtained from 163 symptomatic patients being evaluated for bladder cancer and 41 asymptomatic controls without hematuria or other symptoms consistent with bladder cancer. F-actin levels were evaluated by flow cytometry using a fluorescent phalloidin probe. The risk of bladder cancer was stratified according to biopsy, either DNA ploidy by flow cytometry or quantitative fluorescence image analysis cytology, previous bladder cancer history, and hematuria. A strong correlation between the presence of cells with abnormally low F-actin content in cells obtained by bladder wash from 38 patients and biopsy-proved bladder transitional cell carcinoma (P less than 0.001) was observed. A strong correlation was also observed between the presence of cells with low F-actin content and risk of bladder cancer assessed by either stratification schema (P less than 0.0001). The correlation was more consistent with the stratification by quantitative fluorescence image analysis cytology because of the 37% false-positive rate of ploidy analysis by flow cytometry among the control patients. Further evidence that low F-actin was correlated with cellular abnormality was obtained from simultaneously labeling cells for F-actin and with M344 antibody, a monoclonal antibody against a low-grade bladder tumor-related antigen. These studies showed that the F-actin content of the M344-positive cells was lower than that of the M344-negative cells. These results suggest that F-actin could be an early and sensitive marker for bladder cancer detection and risk prognostication.

Actins↗
PubMed1991

Environmental contamination during tracheal suction. A comparison of disposable conventional catheters with a multiple-use closed system device.

The extent of airborne environmental bacterial contamination which occurs following tracheal suction has been investigated in patients undergoing intermittent positive pressure ventilation in the intensive therapy unit. Two methods of performing suction, one using a conventional open technique and one using a closed system (Stericath), have been compared. Significantly lower levels of environmental contamination were observed when the closed system was used.

Air Microbiology↗
PubMed1990

Cellular F-actin levels as a marker for cellular transformation: relationship to cell division and differentiation.

Transformation is associated with profound structural and quantitative changes in the cytoskeleton. Herein we report studies using F-actin, a major cytoskeletal protein, as a quantitative marker for transformation cells, focusing on separating the effects of the cell cycle, cell differentiation, and transformation. The model system for these studies consisted of three lymphoblastic cell lines, one untransformed line (RPMI) and two transformed lines, one (HL-60) of which can be induced to differentiate and the other (Daudi) which cannot. The relation of F-actin levels to cell cycle was studied by flow cytometry with the use of fluorescein-phalloidin to label F-actin and propidium iodide to label DNA. F-actin levels in transformed Daudi and HL-60 lines were only two-thirds that of the untransformed RPMI cells. Histograms of the distribution of F-actin showed that the transformed lines consisted of two cell populations, one having an F-actin content near that of untransformed cells and the other having much less. Cell cycle analysis showed that F-actin in untransformed cells increased 10-15% as cells entered the S compartment, remaining approximately constant through G2 + M phases of the cell cycle, but in transformed cells the major increase in F-actin occurred during G2 + M phase. Double-label studies with rhodamine-phalloidin for F-actin and KI-67 monoclonal antibody for dividing cells (cells at late G1, S, G2, and M) measured with quantitative fluorescence image analysis showed that the mean F-actin content of dividing cells was twice that of nondividing cells. These results suggested that most of the cell division-related F-actin increase occurred during late G1 phase in untransformed cells. Differentiation of HL-60 cells with dimethyl sulfoxide or retinoic acid normalized the F-actin content of the nondividing cell population, but dimethyl sulfoxide and retinoic acid produced no detectable change in F-actin in the undifferentiable Daudi cells. A tumor promoter (12-O-tetradecanoylphorphol-13-acetate) inhibits differentiation of hematopoietic cells, resulted in a 32% decrease in the mean F-actin content of RPMI cells due to the appearance of a new subpopulation of low F-actin content. The 12-O-tetradecanoylphorbol-13-acetate-induced changes reversed slowly after removal of 12-O-tetradecanolyphorbol-13-acetate but more rapidly in the presence of retinoic acid. These results indicate that F-actin quantification can serve as a marker for cellular transformation and provides a tool for studying the mechanisms of cellular differentiation that may lead to a better understanding of the oncogenic process.

Actins↗
PubMed1990

Quantitative immunofluorescence, anti-ras p21 antibody specificity, and cellular oncoprotein levels.

A general approach to investigating specificity and saturation of antibodies by quantitative immunofluorescence is applied to monoclonal antibodies generated against p21 or ras oligopeptides to quantify ras p21 oncoprotein in cultured cells. Ras 10, a panreactive mouse monoclonal antibody, appears to be a superior probe for detection of p21 in cell extracts or fixed cells because it binds a 21 kD protein on SDS-PAGE/western blots and labels the cytoplasmic membrane in a saturable and competitive manner. RAP-5, a widely used mouse monoclonal antibody generated against an oligopeptide of ras p21, does not recognize p21 in denaturing immunoblots or in immunofluorescence of cultured cells.

Animals↗
PubMed1990

Uptake and metabolism of 111In-labeled monoclonal antibody B6.2 by the rat liver.

When 111In-labeled murine monoclonal antibodies are used in radio-scintigraphic diagnostic procedures, a large fraction of the injected radionuclide is sequestered by the liver. Neither the cells responsible for the uptake nor the mechanism of uptake are known. Little is known about either the site within the liver of antibody metabolism or the form of the products of metabolism. In these studies, the uptake and metabolism of a monoclonal antibody, B6.2 radiolabeled with 111In or 125I [either intact B6.2 or F(ab')2] were determined in rats. One h after injection of either 125I- or 111In-diethylenetriaminepentaacetic acid (111In-DTPA)-labeled B6.2, the predominant liver cell in which the radionuclide was found was the parenchymal cell. At this time, the absolute uptake of 125I in the liver was 0.23 +/- 0.06% (SD) of the injected dose compared to 0.61 +/- 0.06% when the radionuclide was 111In. Removal of the Fc portion of the antibody reduced the absolute liver uptake of 125I to 0.10 +/- 0.01 and the absolute uptake of 111In to 0.16 +/- 0.06. Both radionuclides were still associated predominantly with the parenchymal cell. Using size exclusion high performance liquid chromatography analysis of liver supernatants the metabolism of radiolabeled B6.2 was followed for 24 h. Of the radioactivity recovered, 47.9% of the 125I was precipitable by centrifugation (and presumed bound to cell membranes) while 15.4% was attached to B6.2 found in the cytosol. In contrast, when 111In-DTPA-B6.2 was administered, 16.0% of 111In recovered from the liver was precipitable by centrifugation, and 6.5% was attached to B6.2 found in the cytosol. Sixty % of the 111In was recovered as a low molecular weight (less than 1000) component in the cytosol. This metabolite was not immunoreactive, nor did it comigrate with ferritin, and was resolved into four components by ion exchange high performance liquid chromatography. Of these, only a minor component cochromatographed with an 111In-DTPA standard. These data suggest that the large accretion of radionuclide by the liver is due to uptake of monoclonal antibodies by an Fc receptor-mediated mechanism and the subsequent accumulation of low molecular weight metabolites, presumably 111In-DTPA, attached to one or more amino acids. The reasons for the entrapment of metabolites in the liver are under investigation.

Animals↗
PubMed1990

Physiology of monoclonal antibody accretion by tumors.

During the past 8 years numerous patients have been injected with radiolabeled monoclonal antibodies for both the diagnosis and treatment of cancer. In general the results, while somewhat promising, have failed to fulfill initial expectations. It is now clear that there are many physiologic barriers that antibodies face in their trek toward their tumor-binding site. Use of terms such as antibody-guided delivery or antibody-guided targeting do not take into account the fact that the antibodies are subject to the same physiologic rules as drugs and hormones. Antibodies are no more 'guided' than any drug or hormone. They reach their binding site via the same delivery mechanisms and accumulate in proportion to their 'receptor's' (antigen's) density. Our knowledge and understanding of the physiologic barriers to the uptake of tumor-associated monoclonal antibodies is limited. To date very few studies have been reported that shed light on this problem. For radiolabeled monoclonal antibodies to fulfill their promise, a greater understanding of these physiologic barriers is needed in order to devise ways in which they may be overcome.

Antibodies, Monoclonal↗
PubMed1990

Molecular and cellular biological approaches and techniques in the detection of bladder cancer and enhanced risk for bladder cancer in high-risk groups.

Recent advances in molecular cell biology, immunology, and toxicology enhance detection of actual and incipient disease and the definition of risk. Tumor-associated antigens may greatly improve detection of low-grade tumor cells. Several new strategies depend upon detecting molecular lesions of the genes controlling cell growth (oncogenes) at either the gene or protein levels. Highly sensitive techniques detecting DNA adducts are refining the ability to detect specific DNA damage shortly after exposure. The recognition of controls that actively stop proliferation (tumor suppressor genes), regulate differentiation or of relationships between metabolism and carcinogenesis may lead to new ways to identify persons genetically at increased risk from carcinogenic exposure. Current technologies, those on the near horizon, and long-term research needs are analyzed critically in terms of screening objectives.

Biomarkers, Tumor↗
PubMed1990

Wound healing and the aged patient.

The aged patient is more susceptible to wound healing problems because of the interactions of body systems, environmental stresses, and disease with an aging process that takes place over many years. The multifactorial nature of wound healing in the elderly makes it difficult to determine whether observed healing problems are attributable to results of aging or other factors. Healing is affected by multiple factors in addition to patient age, which itself is not a dependable indicator of physiologic health. Some of these factors are disease, nutrition, perfusion, skin quality, environment, and individual responses to life events. It is particularly difficult for the aged patient to sustain the motivation to participate in care required during the healing process when cascading problems are allowed to build on the decreasing functions and reserve capacities of aging body systems and deplete available energy levels. Assessment of each individual is required because of the wide variety of aging changes and healing responses seen in aged patients. Compared with a younger adult, the aged patient generally heals well, following the same healing process but at a slower rate. Wound healing for the aged can be optimized through techniques of energy conservation, correction of existing problems, and management of risks related to aging and the individual patient. Healing problems are usually the result of decreases in systemic and local perfusion, decreases in the ability to ward off infection, and fragility of aging skin. The aged patient requires the same care as younger patients. It is more critical that this care be meticulously delivered with particular attention to care of intact skin, effects of chronic disease and medications, motivation, social habits, and discharge planning. Nurses can promote improved healing through the care they provide and by studying the progression of healing in aged patients.

Aged↗
PubMed1989

Schistosomiasis: role of endogenous opioids in suppression of gonadal steroid secretion.

1. Radioimmunoassay of the opiate, beta-endorphin, in mouse sera, indirect measurement of estrogen by examination of vaginal smears and indirect measurement of androgens by electrophoresis of major urinary proteins (MUP) revealed that beta-endorphin increases while estrogen and androgen levels decrease in mice with chronic Schistosoma mansoni infection. 2. Injections of the opiate antagonist, naltrexone, reversed the effects of schistosomiasis on estrogen and androgen levels. 3. Because opiates are known to inhibit the secretion of releasing hormones by the hypothalamus, the data suggest that the inhibition of hypothalamic-pituitary-gonadal function that occurs in chronically infected male and female mice results from excessive beta-endorphin. 4. It is also suggested that the excessive beta-endorphin may be secreted by T-lymphocytes and possibly macrophages involved in the cell-mediated immune response (CMIR) to the ova.

Androgens↗
PubMed1988

Correlation of vascular permeability and blood flow with monoclonal antibody uptake by human Clouser and renal cell xenografts.

The specific uptake of 125I-A6H antibody by xenografts of the human renal cell carcinoma (RCC) TK177G in the athymic mouse was considerably greater than that seen for other human tumor xenografts and their associated antibodies (e.g., 125I-B6.2 uptake by the human breast carcinoma, Clouser). In addition the A6H-RCC model also demonstrated both greater localization indices and absolute amount of antibody bound than did the B6.2-Clouser model. Several physiological factors were studied to assess whether they might play a role in this greater specific uptake. Vascular volume was determined using the in situ labeling of red blood cells with 99mTc. Vascular permeability was determined by measuring the amount of 125I-labeled bovine serum albumin and 131I-labeled nonspecific IgG1 (anti-horseradish peroxidase) extravasated out of the tumor vasculature during 1 hr. Relative blood flow to the tumor was determined using the 86Rb method. Blood flow and vascular permeability were found to be significantly greater in the RCC tumor xenografts than in Clouser tumors. Differences in vascular permeability were especially dramatic, showing the vasculature of the RCC xenograft was twice as permeable as that of the Clouser tumor. Animals bearing either RCC or Clouser xenografts were injected with a monoclonal antibody to human major histocompatibility complexes (125I-labeled anti-human histocompatibility complex A, B, C). Tumor uptake of 125I-labeled anti-human histocompatibility complex A, B, C was found to be 5 times greater in RCC than Clouser xenografts. These results, therefore, suggest that the differences seen in the physiological factors studied can account for some of the greater specific 125I-A6H uptake by the RCC tumor than 125I-B6.2 uptake by the Clouser xenograft.

Animals↗
PubMed1988

A comparison of oxygen therapy devices used in the postoperative recovery period.

Seventy-one patients scheduled to undergo upper or lower abdominal surgical procedures were allocated at random to one of seven treatment groups: in the recovery room they were to receive oxygen via a 40% Ventimask with 10 litres/minute oxygen flow, or via either a Hudson mask or a nasal cannula with 3, 6 or 9 litres/minute oxygen flow. The 40% Ventimask gave the most consistent, satisfactory postoperative values of PaO2 but the much cheaper nasal cannula at 6 or 9 litres/minute was generally adequate in conscious patients. The performance of the intermediately priced Hudson mask was similar to that of the nasal cannula at these flows. The unconscious state was associated with a 45% lower PaO2 than the rousable or awake states. Differences between the treatments with regard to postoperative PaCO2 were small and non-significant. The nasal cannula with 6 litres/minute humidified oxygen flow is recommended for routine treatment, and the Ventimask for unconscious patients.

Abdomen↗
PubMed1979

The ultrastructure of the endolymphatic sac in Ménière's disease.

Meniere's disease is a well recognized clinical entity, yet the etiology and pathophysiology of the disease is not fully understood. Impaired endolymphatic sac function resulting in faulty reabsorption of endolymph has been implicated in the production of the disease. The histopathological findings from biopsied sac specimens and observed by transmission (TEM) and scanning (SEM) electronmicroscopy in two patients with early Meniere's disease are presented and discussed. Extensive subepithelial fibrosis with loss of vascularity and obliteration of portions of the lumen of the endolymphatic sac by an ingrowth of collagen is noted in both specimens. The implications of these findings are discussed and the need for more TEM and SEM studies of inner ear disorders is stressed.

Adult↗
PubMedDate not supplied

The flomasta. A new anaesthetic ventilator.

A new ventilator for use during anaesthesia is described. It operates as a minute-volume divider and derives its power from the energy stored in a distended reservoir bag. The unit is autoclavable, suitable for use with explosive anaesthetics and has a rational control system which avoids many of the hazards associated with other ventilators when the mode of ventilation is changed. The nature of the inspired gas mixture is known accurately because the internal volume of the ventilator is small and the system is non-rebreathing. The design of the exhaust system facilitates ventilation monitoring, the use of positive end-expiratory pressure and connection to ducted pollution-control systems.

Airway Resistance↗