Activism in academic internal medicine.
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Faculty, Medical↗
Biomedical subjects
J Nolan
Publications and source records attributed to J Nolan.
Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease.
Thirty-two patients with chronic cardiac failure underwent 24-hour ambulatory electrocardiographic monitoring on 2 separate occasions: 20 patients before and during treatment with captopril, and 12 acting as controls. Heart rate variability was calculated by counting the number of times successive RR interval differences were greater than 50 ms (this measurement being a reliable index of cardiac parasympathetic activity). During treatment with captopril, group mean total counts increased to 1,032 (range 48 to 7,437) from 482 (range 23 to 6,120) (p = 0.002). There was no change in mean hourly waking or sleeping heart rates. In the control group, no changes were seen: group mean total counts on the first occasion were 340 (range 120 to 3,255) and on the second occasion 400 (range 154 to 3,300) (p = not significant). These results show that treatment with angiotensin-converting enzyme inhibitors increases cardiac parasympathetic activity in patients with chronic cardiac failure. This may be relevant to the improved prognosis of this group of patients when treated with angiotensin-converting enzyme inhibitors.
Adult↗
Acute effects of intravenous phosphodiesterase inhibition in chronic heart failure: simultaneous pre- and afterload reduction with a single agent.
Intravenous phosphodiesterase inhibition with milrinone is known to have a beneficial effect on haemodynamics in chronic heart failure. Its effect on lower limb capacitance vessels has not been previously investigated. We have studied the effect of intravenous milrinone in 10 patients with severe chronic heart failure. Thirty minutes after commencement of treatment mean cardiac index had risen by 26% and pulmonary artery wedge pressure, systemic vascular resistance and right atrial pressure had fallen by 51, 24 and 89%, respectively (p less than 0.05 for all changes). These changes were maintained for the 2 h observation period with no evidence of tolerance and were accompanied by a 17% increase in venous volume (p less than 0.01) and a 42% increase in ejection fraction (p less than 0.001) at 30 min; at 120 min the improvement in ejection fraction had been maintained and a further increase in venous volume to 38% above baseline was evident. The increase in venous volume was strongly correlated with the decrease in mean pulmonary artery wedge pressure and mean right atrial pressure at 30 min and 2 h (r = -0.80 and -0.69 for mean pulmonary artery wedge pressure, r = -0.88 and -0.56 for mean right atrial pressure). Milrinone therefore has clinically important venodilating properties, in addition to its known effects as an arterial vasodilator and a positive inotrope.
Aged↗
Retention of misonidazole in normal and malignant tissues: interplay of hypoxia and reductases.
Tritiated misonidazole (MISO) was injected intravenously (iv) into mice bearing five different tumors. At 24 hr the tumors were removed for analysis of bound MISO, and at the same time three normal tissues were removed (liver, labial gland, and esophagus). The labial gland and esophagus were selected as representatives of sebaceous and stratified squamous tissues, respectively, tissues that in many parts of the body retain high levels of MISO. The tumors used were early transplant generations of spontaneous mouse tumors of mammary gland, lung, and liver. The levels (mean +/- SEM) of MISO at 24 hr for the five tumors and three normal tissues, expressed as percentage of the injected dose per gram of tissue were: A110 (0.03 +/- 0.007), A114 (0.103 +/- 0.04), A150 (0.09 +/- 0.005), A167 (0.037 +/- 0.012), A168 (0.122 +/- 0.0016), esophagus (0.507 +/- 0.09), labial gland (0.125 +/- 0.013), liver (0.11 +/- 0.004). Histochemical examination of the normal tissues showed reductase activity in all three. In the esophagus and labial gland, inhibition of the reaction by dicumarol indicated the likely presence of the reductase DT-diaphorase which, by 2-electron transfer, can be expected to reduce MISO to a reactive, locally-binding metabolite, even in the presence of oxygen.
Animals↗
The use of octadecyl-bonded microparticulate silica in the separation of free and bound fractions during saturation analysis of vitamin D metabolites.
The use of octadecyl-bonded microparticulate silica to separate free and bound fractions during the saturation analysis of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D has been investigated. A slurry of octadecyl-bonded silica in an appropriate incubation buffer was prepared and used in parallel with a conventional dextran-coated charcoal suspension in several assay procedures. Standard curves, non-specific binding and plasma values were compared. A competitive protein binding assay for 25-hydroxyvitamin D and two radioreceptor assays and one radioimmunoassay for 1,25-dihydroxyvitamin D were investigated. In most cases the octadecyl-bonded silica preparation gave the more favourable results; its action was rapid, time- and temperature-independent, and it produced low non-specific binding and higher B0 values in all the assays examined. It was in our hands easier to use than dextran-coated charcoal. The use of octadecyl-bonded silica is recommended as an efficient agent for the separation of free and bound fractions in the saturation analysis of vitamin D metabolites.
Animals↗
Atrial myxoma: tumour or trauma?
A mass lesion developed in the right atrium at the site of a trans-septal puncture after percutaneous balloon dilatation of the mitral valve in a man aged 74. The lesion had the pathological appearance of an atrial myxoma and seemed to have developed after trauma to the intra-atrial septum. This case suggests that at least some atrial myxomas are reactive rather than neoplastic in origin.
Aged↗
Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function.
BACKGROUND: Activation of the sympathetic nervous system has been extensively studied in patients with chronic heart failure, but the parasympathetic nervous system has received relatively little attention. The objective in this study was to investigate cardiac parasympathetic activity in chronic heart failure and to explore its relation to left ventricular function. METHODS: Heart rate variability was measured from 24 hour ambulatory electrocardiograms by counting the number of times each RR interval exceeded the preceding RR interval by more than 50 ms (counts). This method provided a sensitive index of cardiac parasympathetic activity. RESULTS: Mean (range) of counts were: waking 48 (1-275)/h, sleeping 62 (0-360)/h, and total 1310 (31-7278)/24 h. These were lower than expected, and in 26 (60%) of the 43 patients counts fell below the lower 95% confidence intervals (95% CI) for RR counts in normal subjects. A significant correlation between total 24 hour RR counts and left ventricular ejection fraction was present (r = 0.49, p less than 0.05). CONCLUSIONS: These results indicate that most patients with chronic heart failure have reduced heart rate variability and therefore reduced cardiac parasympathetic activity. The degree of parasympathetic dysfunction is related to the severity of left ventricular dysfunction. This may be relevant to the high incidence of ventricular arrhythmias and poor prognosis of patients with chronic heart failure.
Adult↗
Non-rheumatic atrial fibrillation: warfarin or aspirin for all?
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Aspirin↗
Modulation of venous tone in heart failure.
Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs, we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure, the calcium channel blocker, felodipine, causes a marked reduction in systemic vascular resistance and left ventricular filling pressures, but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril, but venous volume increases by 16%, and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor, it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment, cardiac index, which was measured by thermodilution, increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Captopril↗
Factors influencing the transferability of medical decision support systems.
Transferability is a key issue in the development and implementation of medical decision support systems. Such systems have up to now tended to be confined to the development site. Transferability represents the integrated effect of several more basic attributes of Decision Support Systems. These attributes can be considered to belong to two main groups: those concerned with the Medical Domain (of the system) and those concerned with the Information Technology by which the System functions. Among the Domain issues the most important are: Epidemiology, Terminology and Methodology. Concerning the Information Technology issues the most important are: Knowledge Acquisition and Representation methods, Database design and integration with inference mechanism. The effect of each of the individual factors is considered by illustrations from the literature and by studying the results of recent experiments where databases and decision support systems from different countries are interchanged. This exercise allows some planning in the design of future systems with the aim of improving overall transferability and therefore applicability.
Artificial Intelligence↗
Pseudo preexcitation syndrome.
During the course of investigation for palpitations, a 62-year-old man underwent exercise testing using a MARQUETTE CASE 12 computerized exercise testing system. By stage III of the modified Bruce protocol, the computer-generated electrocardiogram appeared to show the development of exercise-induced preexcitation. Closer examination of the raw unfiltered data showed this to be a computer-generated artifact rather than true preexcitation. This artifact arose due to inherent limitations common to all computerized exercise testing systems and emphasizes the need to always review raw data, even when a seemingly clear-cut abnormality is present on a computer-averaged electrocardiogram.
Artifacts↗
Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice.
RB 6145 is a pro-drug of the hypoxic cell radiosensitizer RSU 1069 with reduced systemic toxicity. The maximum tolerated dose (MTD) of RSU 1069 for C3H/He mice was 80 mg/kg (0.38 mmol/kg) ip but 320 mg/kg (1.5 mmol/kg) following po administration. The MTD values of RB 6145 were 350 mg/kg (0.94 mmol/kg) ip and 1 g/kg (2.67 mmol/kg) po. Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50%. Oral administration of RSU 1069 resulted in lower spermatogenic toxicity. No loss of intestinal crypts was detected after ip or po administration of RSU 1069. Some nephrotoxicity was observed in half of the mice given the highest po dose of 1.5 mmol/kg of RSU 1069; this was not observed following the highest ip dose of drug. For RSU 1069 and RB 6145, administered by either route, the maximum hypoxic cell radiosensitization in murine KHT sarcomas, occurred when the drugs were given 45-60 min before 10 Gy of X rays. The degree of radiosensitization produced by a particular dose of either compound was largely independent of the route of administration. Preliminary pharmacokinetic studies, using 3H-RSU 1069, suggested that anti-tumor efficacy correlated with peak blood level of label and concentration in the tumor at the time of irradiation, which were not reduced by po compared with ip administration. Normal tissue toxicity tended to correlate with total exposure over time, which was reduced approximately two-fold by po administration. Oral administration of RSU 1069 or RB 6145, as well as being convenient, may give therapeutic benefit since dose-limiting toxicity in mice was reduced compared with parenteral administration, whereas radiosensitizing activity was less affected.
Administration, Oral↗
Air quality in the vicinity of urban roads.
Motor vehicle emissions are a major source of CO, NOx and lead particulate concentrations to urban air quality. London urban Boroughs with high traffic densities are therefore a particular cause for concern. The air quality was monitored at an urban background site in the London Borough of Haringey for 2-years. The results of this study are assessed and their effect on human health is considered in the light of EC Directives and WHO guidelines. A desk top modelling technique based on Gaussian diffusion theory was used to predict the CO levels found at the background site. All predicted levels had a accuracy of better than 30%.
Air Pollution↗
Heavy metal levels in the near vicinity to roads in a north London Borough.
The ingestion and inhalation of heavy metals through soil, surface dust, air and food contamination may have a detrimental effect on human health. Metal levels have been measured in a Local Authority in London, UK and are discussed where possible in relation to health risk and relevant guidelines.
Child↗
Tissue distribution of 14C- and 3H-labelled misonidazole in the tumor-bearing mouse.
The retention of labelled misonidazole (MISO) was measured in a range of normal tissues in the mouse 24 hr after the intravenous injection of [14C]MISO (ring labelled) and [3H]-MISO (side-arm labelled). For [14C]MISO the 24 hr tissue retention, in order of the highest to the lowest levels (excluding pathways of excretion), was esophageal epithelium, liver, foot pad, eyelid, lung, subcutaneous lung tumor (A110), esophageal wall, uterus, eye ball, blood, salivary gland, spleen, voluntary muscle, pancreas, inguinal fat. It was assumed that the 14C represented MISO metabolite(s) bound to macromolecules. An approximately similar pattern was observed for [3H]MISO, but a higher percentage of the injected activity per gram of tissue was retained, probably due to the presence of tritiated water in the tissues. It has generally been assumed that significant levels of MISO binding are restricted to hypoxic tissues, for example tumors, but the present results show that significant levels of binding can also occur in apparently normoxic tissues. The explanation is put forward that this binding may be due to local high levels of nitroreductase capacity.
Adenocarcinoma↗
NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole.
Hack and Helmy's method for the histochemical identification of NAD(P)H nitroblue tetrazolium reductase activity was employed to pinpoint reductase activity in certain cells in the mouse. High activity was observed in the following: lower airway epithelium, liver (centrilobular zone), eyelid (meibomian and sebaceous glands), vulval gland and parotid gland (striated cells of intralobular ducts). All of these cells had previously been identified as sites of binding of the reactive metabolites formed from the enzymic reduction of misonidazole (MISO) (Cobb et al., 1989). It had previously been thought that MISO binding would only take place in significant amounts in hypoxic tissues (tumour and possibly liver) since in normoxic tissues oxygen should reverse the initial one electron enzymic reduction, thus preventing progressive reduction to reactive species. We suggest that the very high levels of reductase in the above listed, probably normoxic, tissues contribute significantly to the accumulation of bound reactive MISO metabolite(s).
Animals↗
Distribution of pimonidazole and RSU 1069 in tumour and normal tissues.
The tritium-labelled analogues of pimonidazole and RSU 1069 were injected into mice bearing the KHT murine sarcoma which has a hypoxic cell fraction of approximately 10%. The distribution of activity at 24 h was recorded using autoradiography and measurement of tissue activity. Autoradiographs with both drugs showed high activity in particular cells within tumour, eye (melanin-associated cells), eyelid (Meibomian gland), liver (centrilobular area), skin (sebaceous gland and melanin), stomach (squamous area), footpad, oesophagus, labial gland, Zymbal's gland, preputial gland, parotid gland (intralobular ducts) and airway epithelium. These tissues had previously been identified as sites of binding of misonidazole. The measurement of total tissue radioactivity showed significantly higher activity in liver, eyelid (Meibomian gland), oesophageal lining, kidney and labial gland than was found in the tumour.
Animals↗
Diet in the epidemiology of gastric cancer.
We examined the nutritional epidemiology of gastric cancer in 293 cases and neighborhood-, age-, and sex-matched controls in communities throughout the counties of Niagara, Monroe, and Erie in western New York. The interview was highly detailed, requiring two and one-half hours to complete; it attempted to provide an estimate of total calories ingested as well as of macro- and micronutrients and behaviors that could affect alimentary exposures, such as the use of refrigeration. We found that risk was enhanced by sodium, fat, and retinol. Substantial reductions in risk were associated with ingestion of carotene, especially raw vegetables (including celery, cucumbers, carrots, green peppers, tomatoes, and onions), as well as with increased use of low-temperature food storage. Both refrigeration and carotene could inhibit oxidation products that could act as carcinogens in the stomach.
Adult↗