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Biomedical subjects

D Heath

Publications and source records attributed to D Heath.

At least 37 records · Page 2Linked to original sources
PubMed1996

Vasopressin modulation of peritoneal, lymphatic, and plasma drug exposure following intraperitoneal administration.

i.p. administration of cytotoxic drugs for the treatment of regionally confined cancers results in a greater total drug exposure [area under the concentration x time curve (AUC)] for the peritoneal fluid and regional lymphatics than for plasma. We sought to augment the relative advantage of i.p. administration further through modulation of peritoneal clearance by reduction in splanchnic blood flow. Pigs were treated with 5-fluorouracil, etoposide (VP-16), and carboplatin (CBDCA) alone by the i.p. route or with the same drugs in combination with i.v. lypressin, a synthetic vasopressin analogue, which reduces splanchnic blood flow. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 6 h. The pharmacokinetics of 5-fluorouracil were not altered by vasopressin; however, vasopressin increased the peritoneal fluid:plasma AUC ratio for CBDCA from 30.6 +/- 5.6 to 70. 6 +/- 7.4 (P < 0.01) and increased the lymph:plasma AUC ratio from 1.1 +/- 0.4 to 2.6 +/- 0.22 (P < 0.05). In the case of VP-16, vasopressin increased the peritoneal fluid:plasma AUC ratio from 129 +/- 35 to 350 +/- 76 (P < 0.05) and the lymph:plasma AUC ratio from 2.1 +/- 0.6 to 10.6 +/- 3.5 (P < 0.05). Concurrent i.v. administration of vasopressin can increase the pharmacokinetic advantage of the i.p. route of administration of CBDCA and VP-16 markedly in the pig model. These data suggest that the strategy of concurrent i.p. administration of CBDCA or VP-16 plus an agent that reduces splanchnic blood flow may increase the dose intensity in the abdominal cavity and intraabdominal lymphatic tissue substantially without increasing systemic toxicity.

Animals↗
PubMed1995

Ultrastructure of rat pulmonary arterioles after neonatal exposure to hypoxia and subsequent relief and treatment with monocrotaline.

A group of rats was born in and spent the first 4 weeks of life at a simulated altitude of 3550 m. Two animals were killed immediately afterwards and the remaining 16 were allowed to recover for various times up to a maximum of 12 weeks at sea-level atmospheric pressure. On ultrastructural examination, the pulmonary arterioles of hypoxic rats showed muscularization, the new layer of mature smooth muscle cells containing abundant organelles and myofilaments. These cells were bounded by prominent elastic laminae. During the recovery period, the medial layer became progressively thinned, but the cells still retained some characteristics of smooth muscle by 12 weeks' recovery. When a similar group of ten hypoxic rats was allowed to recover for 12 weeks before being given monocrotaline, there was early enlargement of the residual smooth muscle cells in the media of pulmonary arterioles and within 5 weeks there was again a thick layer of medial smooth muscle. This was in contrast to the sparse, weakly muscularized arterioles seen in eight similarly treated rats born under normoxic conditions. The relevance is discussed of these findings to the rare occurrence of primary pulmonary hypertension in people who were born at high altitude but returned to sea-level during childhood.

Altitude↗
PubMed1994

Ultrastructural differences between pulmonary arteriolar muscularization induced by hypoxia and monocrotaline.

A group of Wistar rats was treated with two subcutaneous injections of monocrotaline, at 4 and 6 weeks of age. They were then killed 1 month after the initial injection. A second group of rats was born and reared in hypobaric hypoxia for 1 month before being killed. Both groups had age-matched controls. The ultrastructure of pulmonary arterioles from all groups was studied, and quantitative measurements were made of the volume densities of organelles within the cytoplasm of arteriolar smooth muscle cells. The pulmonary arterioles of rats treated with monocrotaline contained immature smooth muscle cells with coarse peripheral myofilaments and were bounded by thin indistinct elastic laminae. In contrast, the arteriolar smooth muscle cells of hypoxic rats were mature with fine myofilaments and bounded by electron dense laminae. When compared with both their respective controls and the alternative test group, the muscle cells from rats treated with monocrotaline had significantly lower volume densities of dense bodies, and the hypoxic muscle cells had significantly higher densities of mitochondria. The pulmonary arteriolar muscularization in rats would appear to be a nonuniform process producing smooth muscle cells with differing cytoplasmic features that suggest differing cellular functions.

Animals↗
PubMed1994

Enlargement of the carotid bodies in cirrhosis of the liver.

The carotid bodies were dissected out at necropsy and weighed in seven subjects with cirrhosis of the liver and in seven control subjects of comparable age free of liver disease. The mean combined carotid body weight of the control group was 17 mg but in the cirrhotic patients it was 35 mg, a statistically significant difference (P < 0.005). Differential counts of the various types of glomic cell (progenitor, dark and light variants of chief cells and sustentacular cells) were carried out. The enlargement of the carotid bodies in the subjects with cirrhosis was associated with increased numbers of the dark variant of chief cell. The mean number of dark cells per unit area in the control group was 361 cells/mm2 but in the cirrhosis group it was 1024 cells/mm2, a statistically significant difference (P < 0.005). It is postulated that the prominence of dark cells may be associated with secretion of a natriuretic peptide in response to the hyperaldosteronism and sodium retention of cirrhosis of the liver. Alternatively, it may be a response to hypoxaemia resulting from porta-pulmonary shunts.

Adult↗
PubMed1994

Pretransplant clinicopathological correlation in end-stage primary pulmonary hypertension.

The aim of the study was to see if there was any correlation between the histopathology, ultrastructure, pulmonary endocrinology and clinical manifestations of end-stage primary pulmonary hypertension. Twenty patients undergoing heart-lung transplantation for the disease were studied. The nature and duration of symptoms and signs, results of haematological, electrocardiographic, radiographic, echocardiographic and haemodynamic studies, and the response of patients to vasodilators were compared with data from histopathological and ultrastructural study of lungs removed at transplantation. Length of clinical history and clinical evidence of severe disease were not necessarily associated with advanced histopathology, nor did the presence of small, contracted muscular pulmonary arteries imply responsiveness to vasodilators. Numbers of gastrin-releasing peptide-containing pulmonary endocrine cells were greater in lungs in which there was activity of myofibroblasts in pulmonary arterial vessels, and correlated negatively with mean pulmonary artery pressure and pulmonary artery systolic pressure. Whereas the prognosis of primary pulmonary hypertension cannot as yet be defined by other than its clinical manifestations, intimal proliferation as well as vasoconstriction may be important in its pathogenesis. The release of gastrin-releasing peptide from pulmonary endocrine cells may possibly be involved in this process.

Adolescent↗
PubMed1994

The carotid bodies enlarge in some cases of cirrhosis of the liver.

The weights of the individual carotid bodies and cardiac ventricles were obtained at necropsy in five series of subjects. The first comprised 10 cases free of cardiopulmonary disease to act as controls. The second consisted of 10 cases of pulmonary emphysema. The third was composed of 8 cases characterized by sustained alveolar hypoxia due to causes other than pulmonary emphysema. The fourth comprised 10 cases of systemic hypertension or severe left ventricular failure. The fifth was made up of 10 cases of diseases of the liver or alimentary canal. The study confirmed that enlargement of the carotid bodies is common in cases of pulmonary emphysema or sustained alveolar hypoxia with right ventricular hypertrophy. It is also common in cases of systemic hypertension with left ventricular hypertrophy. It was also revealed that enlargement of the carotid bodies may occur in cirrhosis of the liver. We believe this to be the first report of that association.

Adult↗
PubMed1993

Modulation of cisplatin cytotoxicity by permeabilization of the plasma membrane by digitonin in vitro.

Killing of human ovarian carcinoma 2008 cells by cisplatin (DDP) is in direct proportion to the amount of drug entering the cell. DDP and its analogue [3H]dichloro(ethylenediamine)platinum[II] ([3H]-DEP) enter cells relatively slowly. We found that the uptake of [3H]DEP into 2008 cells could be increased by treating the cells briefly with the plasma membrane-selective detergent digitonin. A similar effect was observed in an 11-fold DDP-resistant subline of 2008 cells, designated 2008/C13*5.25. A measurable effect was produced by concentrations as low as 5 microM, and 40 microM digitonin increased [3H]DEP accumulation at 1 hr by 4.4 +/- 0.2- and 6.5 +/- 0.7-fold (means +/- SD) in 2008 and 2008/C13*5.25 cells, respectively. The effect was rapid, occurring within 1 min. Increased [3H]DEP uptake was accompanied by increased platination of DNA (8.5-fold in 2008 cells and 18.5-fold in 2008/C13*5.25 cells), and by enhanced killing of both the DDP-sensitive and -resistant cells that was shown to be synergistic by median effect analysis. The combination index at 50% cell kill was 0.64 +/- 0.14 (values < 1 indicate synergy). We conclude that a brief exposure to digitonin can increase [3H]DEP uptake in vitro, and can overcome the impaired [3H]DEP accumulation associated with acquired DDP resistance. DDP and digitonin interact synergistically to increase tumor cell kill in vitro.

Antineoplastic Agents↗
PubMed1993

The earliest histopathological response to hypobaric hypoxia in rabbits in the Rifugio Torino (3370 M) on Monte Bianco.

Twelve Dutch rabbits were kept on Monte Bianco at an altitude of 3370 m. Half of the animals were killed after 3 months, the remainder after 6 months, and a further six animals maintained at sea-level acted as controls. The carotid bodies of all the rabbits were processed for light and electron microscopy and examined qualitatively and quantitatively. The lungs were processed for light microscopical assessment of small pulmonary arterial vessels; the thickness of the pulmonary trunks and aortas were measured; and the hearts were dissected to obtain ratios of the ventricular weight. There was a slight increase in the right ventricular weight in the hypoxic rabbits but no change in the thickness of the pulmonary trunk compared with that of the aorta. In particular, there was no hypoxic remodelling of the pulmonary vasculature such as muscularization of pulmonary arterioles or intimal longitudinal muscle in pulmonary arteries. The earliest histopathological response to hypoxia occurred in the carotid bodies in the form of an increase in the count of the dark variant of chief cell after 3 months which returned to normal after 6 months. It is concluded that the carotid body of the rabbit responds with a change in its population of dark chief cells to a level of hypoxia which is insufficient to affect the pulmonary arterioles. Changes in the cardiopulmonary system can no longer be considered to be the earliest histopathological response to hypobaric hypoxia.

Altitude↗
PubMed1993

Phase I and pharmacokinetic study of intraperitoneal ormaplatin.

Ormaplatin is a cisplatin analog which has demonstrated activity against cisplatin-resistant tumors in preclinical studies. We delivered 28 cycles to 14 patients in a phase I trial of intraperitoneal ormaplatin given every 28 days. The maximum tolerated dose was 88.4 mg/m2 and acute dose-limiting toxicity was abdominal pain. Other toxicities include nausea, emisis, fever, and severe neuropathy seen in 1 patient at a cumulative dose of 399 mg/m2. No objective responses were observed. Hematologic toxicity was mild. The dose recommended for future trials of intraperitoneal ormaplatin is 66.5 mg/m2. Pharmacokinetic analysis performed at a dose of 66.5 mg/m2 demonstrated that the initial phase of elimination from the peritoneal cavity follows first-order kinetics with k = 0.69 hr-1 and half-life of 1.4 hr. Plasma pharmacokinetic behavior is best described by biexponential model with k1 = 0.369 hr-1, k2 = 0.107 hr-1, and first half-life of 2.9 hr and second half-life of 8.4 hr. Pharmacologic advantage, calculated by ratio of peritoneal to plasma AUC, is 17.1. If site-specific activity is demonstrated, then the intraperitoneal route of administration of ormaplatin at 66.5 mg/m2 may be beneficial.

Adult↗
PubMed1993

Enhanced response to antigen within lymph nodes of SJL/J mice that were protected against experimental allergic encephalomyelitis by T cell vaccination.

The effects of T cell vaccination on peripheral immune responsiveness are not yet fully understood. We have induced resistance to rat spinal cord homogenate (RSCH)-induced experimental allergic encephalomyelitis (EAE) in SJL/J mice by vaccination with four T cell lines (RZ8, RZ15, RZ16, and A51) which were reactive to myelin basic protein (MBP) but not to proteolipid protein (PLP). The effect was relatively neuroantigen-specific since vaccination with ovalbumin (OVA)-reactive and alloantigen-specific cells did not prevent EAE induction. Alloantigen-reactive cells reduced the rate of relapse. The number of central nervous system (CNS) infiltrates and mean clinical EAE scores were significantly reduced. This is the first report demonstrating T cell vaccination in the SJL/J mouse, a strain in which PLP is the predominant encephalitogen in RSCH. The vaccinating cells were of the memory/effector (CD44high, CD45RBlow) surface phenotype. We examined the effect of T cell vaccination on lymph node T cell proliferative responses to MBP, encephalitogenic peptides of PLP and MBP, OVA and anti-CD3. With the exception of polyclonal cytokine responses to anti-CD3, which remained unchanged, vaccination led to a 5-10-fold augmentation in all, including background, responses. By comparison with lymph node cell (LNC) responses from naive mice and mice primed with OVA, it appeared that T cell vaccination restored cellular activation levels which had been depleted in peripheral lymphoid tissues of unvaccinated animals with EAE.

Animals↗
PubMed1993

Pulmonary endocrine cells of Aymara Indians from the Bolivian Andes.

INTRODUCTION: There is evidence to suggest that life at high altitude causes changes in the population of pulmonary endocrine cells, possibly because of exposure to chronic hypoxia. A study was made of the populations of pulmonary endocrine cells in three Aymara Indians and three Mestizos of La Paz (3600 m), Bolivia, which were compared with those in four white lowlanders. METHODS: Pulmonary endocrine cells were immunolabelled for neurone specific enolase and their two major secretory products, gastrin releasing peptide and calcitonin, and their numbers expressed per cm2 of tissue section. RESULTS: No differences in morphology, number, content, or distribution of immunoreactive cells were found when the native highlanders were compared with the lowlanders. CONCLUSIONS: If chronic hypoxia as such exerts an influence on human pulmonary endocrine cells it was not apparent in this morphological study. There was no increase in gastrin releasing peptide containing pulmonary endocrine cells, such as have previously been seen in patients with pulmonary hypertension characterised by plexogenic pulmonary arteriopathy. This may be due to the fact that in plexogenic pulmonary arteriopathy there is free migration of smooth muscle cells. Although three of the highlanders in this present study showed pulmonary vascular remodelling, this was in contrast only modest.

Adolescent↗
PubMed1993

Arachnoid nodules in the lungs of high altitude Indians.

BACKGROUND: Nodules of cells showing a striking histological similarity to those of arachnoid villi have previously been found closely adjacent to pulmonary venules in several diseases associated with alveolar hypoxia or pulmonary oedema including mitral stenosis, plexogenic pulmonary arteriopathy, pulmonary thromboembolism, and chronic obstructive pulmonary disease. METHODS: Histological sections of the lungs of seven adult native highlanders from La Paz (3600 m) were examined. RESULTS: Arachnoid nodules were found in the lungs of one Aymara and one Mestizo Indian. CONCLUSIONS: These bodies may have a similar function to that of arachnoid granulations which transfer excess cerebrospinal fluid to the dural venous sinuses. In the native highlanders it is possible that they contribute to the avoidance of excessive hydration of the interstitial tissue of the alveolar walls with return of fluid into the pulmonary venules, preventing incipient pulmonary oedema.

Adolescent↗
PubMed1993

The development of the nerve network in the fetal human carotid body and its subsequent function in cardiac disease.

Carotid bodies from 17 human fetuses of gestational age ranging from 10 weeks to full term were examined in histological sections stained by the Bodian silver protargol method to demonstrate nerve axons. At 10 weeks gestation the carotid body was contacted by a single nerve bundle at its apical pole but by the 13th week a second bundle had also reached the proximal pole. Thin, pale nerve axons extended from these bundles and surrounded the carotid body to form a plexus from which several small groups of axons entered its superficial regions. With increase of gestational age beyond this point there was a progressive influx of axons to penetrate the innermost areas of glomic tissue by the 19th week. Nerve endings were not identified until 23 weeks gestation when occasional small boutons, and rarely calyces, were seen to terminate on fetal chief cells. Thus there was by this age a well-developed nerve link between glomus and brain consistent with the view that from this stage of development the carotid bodies are able to function as chemoreceptors. However, results of previous research work in our Department and in the literature lead us to believe that the fully anatomically developed nerve network of the carotid body depends on its cellular and biochemical environment to ensure that it functions efficiently as a chemoreceptor. Thus, reduction of dopamine-turnover or attenuation of chief cells in the carotid bodies is associated with increased chemosensitivity, as in the days following birth and in systemic hypertension in later life.(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid Body↗