Public versus private hospital maternity length of stay: a gamma mixture modelling approach.

Application of a gamma mixture model to obstetrical diagnosis-related groups (DRGs) revealed heterogeneity of maternity length of stay (LOS). The proportion of long-stay subgroups identified, which can account for 30% of admissions, varied between DRGs. The burden of long-stay patients borne was estimated to be much higher in private hospitals than public hospitals for normal delivery, but vice versa for Caesarean section. Such differences highlights the impact of DRG-based casemix funding on inpatient LOS and have significant implications for health insurance companies to integrate casemix funding across the public and private sectors. The analysis also benefits hospital administrators and managers to budget expenditures accordingly.

In vitro and in vivo responses of doxorubicin ion exchange microspheres to hyperthermia.

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43 degrees C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43 degrees C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2.3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p less than 0.01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p less than 0.05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Lack of synergy between 5-fluorouracil and interferon-gamma in the treatment of malignancy in the rat.

Numerous in vivo studies have reported synergism between 5-fluorouracil (5-FU) and interferon-gamma (IFN-gamma) but this has not been the case in clinical trials. As the immunomodulatory effects of IFN may be of greater importance in vivo than its direct anti-proliferative activities, it was of interest to determine whether the myelosuppressive effects of high dose 5-FU were responsible for the lack of enhanced activity of the combined drug treatment in the clinical setting. Using an animal model, the anti-tumour activity of three doses of 5-FU (5, 10 and 20 mg/kg/day, continuous intravenous infusion of 7 days) and concurrent IFN-gamma (5 x 10(5) U/kg/day, bolus IV for 5 days) were compared to 5-FU alone. IFN-gamma treatment alone produced a significant anti-tumour response relative to control. No synergism was observed at any dose of 5-FU when combined with IFN-gamma treatment despite white blood cell counts being similar to that in the IFN-gamma group at the lowest dose of 5-FU treatment. Thus, a lack of synergism in vivo is unlikely to be due to myelosuppression resulting in diminished immune response. However, other factors such as tumour type, size and location may be important in determining the final outcome.

Changes in hepatic blood flow during regional hyperthermia.

The influence of liver hyperthermia on hepatic arterial and portal venous blood flow to tumour and normal hepatic tissue was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450 MHz microwave generator to exteriorized livers in 18 rabbits. Blood flow was measured in both portal vein and hepatic artery using radioactive tracer microspheres before, during and 5 min after intense (greater than 43 degrees C) hyperthermia. During hyperthermia a decrease in total liver blood flow was composed primarily of a decrease in hepatic arterial blood flow to tumour tissue. Tumours were supplied almost exclusively by the hepatic artery and thus total tumour blood flow was significantly depressed during heating. The decreased tumour blood flow persisted after the cessation of hyperthermia and was indicative of vascular collapse in the tumour tissue. Temperature differentials in tumour compared to normal tissue ranged from 5 degrees C to 8 degrees C during hyperthermia because of the lower tumour blood flow. The portal vein exerted minimal influence on temperatures attained in the tumour tissue during hyperthermia but would have mediated normal liver tissue heat loss.

Low-dose systemic doxorubicin in combination with regional hepatic hyperthermia.

The influence of regional liver hyperthermia in conjunction with systemic doxorubicin administration was examined in a rabbit VX2 tumour model. Hyperthermia was delivered by 2450MHz microwave generator to the exteriorised livers of the rabbits to provide a thermal dose equivalent of 43 degrees C for 30 minutes. Animals receiving doxorubicin infusion were treated with a total of 1.2 mg/kg over a 3 day protocol through an ear vein. Rabbits were divided into 4 groups; a no treatment control, hyperthermia alone, doxorubicin alone and hyperthermia immediately preceded by doxorubicin. The tumour mass, 10 days post treatment was significantly (P less than 0.0001) reduced in all treatment groups. However, the mean tumour mass in the combination treatment group was also significantly lower than both treatments alone (P less than 0.001). This increased response was not accompanied by any signs of increased systemic or local toxicity associated with any treatment.

Effect of dietary fish oils on the formation of leukotriene B4 and B5, thromboxane and platelet activating factor by rat leukocytes.

1. This study investigates the effect of dietary eicosapentaenoic acid (EPA), in the form of 'Max EPA' fish oil, on leukotriene B4 (LTB4) production in ionophore-stimulated rat leukocytes. Male Wistar rats (200-250 g) were fed for 3 weeks on a synthetic chow supplemented with either 10% by weight Max EPA oil or a coconut oil/safflower oil mixture. 2. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids and decreased the arachidonic acid level by 35% (P less than 0.001) compared with the control diet. 3. The concentration of leukotrienes in the ionophore (A23187) stimulated leukocytes was measured by reverse-phase HPLC using prostaglandin B2 as the internal standard. The EPA-supplemented diet caused a 50% decrease in LTB4 production (P less than 0.001) and a concomitant increase in the formation of the biologically less active LTB5 compared with the control diet. The amount of LTB4 and LTB5 produced by stimulated leukocytes closely resembled the changes in arachidonic acid and EPA content of leukocyte phospholipids. 4. Thromboxane B2 (TxB2) production in stimulated leukocytes from the EPA-fed animals was also decreased compared with the control group. 5. Although the formation of platelet activating factor by stimulated leukocytes was not altered by dietary treatment, the ability of an EPA-rich diet to decrease LTB4 and TxB2 production suggests that these diets may attenuate leukocyte activity and have useful anti-inflammatory effects.

Hypercholesterolaemic effect of fish oil in insulin-dependent diabetic patients.

The effect of the daily administration of Max EPA fish oil (equivalent to 2.7 g per day of eicosapentaenoic acid) on serum lipid levels was examined in insulin-dependent male diabetic patients with cholesterol levels of less than 6.5 mmol/L. After three weeks of fish-oil supplementation there was a significant rise in total cholesterol levels, which was due largely to increases in low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)- cholesterol levels. The increase in HDL-cholesterol levels was accounted for by its HDL2 subclass. There was a decrease in serum triglyceride levels, but this was also observed in a control group of diabetic patients who did not receive fish oil and is probably explained by weight loss in this group. Similar changes in lipid levels were found in a subgroup of diabetic patients with retinopathy. The possible detrimental effect of the increase in total cholesterol and LDL-cholesterol levels after Max EPA fish oil at this dose may be offset by the selective rise in the protective HDL2 subclass.

New findings in the fatty acid composition of individual platelet phospholipids in man after dietary fish oil supplementation.

Nine healthy male volunteers were given 15 Max EPA fish oil capsules providing 2.67 g of eicosapentaenoic acid (EPA, 20:5 omega 3) and 1.72 g of docosahexaenoic acid (DHA, 22:6 omega 3) daily for 3 wk. Measurements were taken at baseline, at the end of the fish-oil period, and at 2 and 6 wk postsupplementation. The effect of fish oil on plasma lipids and the fatty acid composition of individual platelet phospholipids was studied. In general, the proportions of 20:5 omega 3 and 22:6 omega 3 in platelet phosphoglycerides were substantially increased mainly at the expense of arachidonic acid (AA, 20:4 omega 6). A large and significant increase in the relative EPA content of phosphatidylcholine (PC) (P less than 0.001) and phosphatidylethanolamine (PE) (P less than 0.001) was noted at the end of the 3 wk supplementation. We have also shown for the first time a small but significant (P less than 0.001) incorporation of EPA in phosphatidylserine (PS). Incorporation of DHA was also detected in PC, PE and PS, whereas the relative AA content of these phospholipids was significantly reduced. Fish oil supplementation led to a significant increase of 22:5 omega 3 in PS and decreases of 20:3 omega 6 in PC and 22:4 omega 6 in PE. Postsupplementation measurements showed a gradual return of all fatty acids to baseline levels. The fatty acid composition of the phosphatidylinositol (PI) fraction remained unchanged throughout the trial period. We conclude that in humans omega 3 fatty acids are incorporated into platelet membrane phospholipid subclasses with a high degree of specificity.

The effect of dietary fish oil and salt on blood pressure and eicosanoid metabolism of spontaneously hypertensive rats.

This study was designed to investigate the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats under conditions of normal and elevated salt intake. Forty rats from both strains were placed on either a two-series PG inhibitory diet of Max eicosapentaenoic acid (EPA) fish oil or a control diet of saturated fat for an initial period of 4 weeks. The groups were then divided into two, so that half of each received 1.5% saline in place of their drinking water for 1 week. Blood pressure of the SHR and WKY were unaffected by dietary fat before the addition of saline, but with salt loading, the Max EPA-fed SHRs showed a mean blood pressure increase of 21 mmHg relative to the EPA-fed SHR with access to water. Rats fed EPA showed impaired ability to generate serum thromboxane (TXB2) and in the groups with access to water, diminished excretion of urinary 6-keto-PGF1 alpha and PGE2. Salt loading increased prostanoid synthesis and excretion. Spontaneously hypertensive rats had greater serum TXB2 generating capacity than WKYs, but diminished urinary PGE2 excretion in those animals with access to water. The increased blood pressure observed in the salt-loaded SHR on the Max EPA-diet may be explained by reduced PG synthesis resulting in either mild sodium retention and/or increased vascular reactivity.

Can the synthesis of platelet-activating factor, a potent vasodilator and pro-aggregatory agent, be altered by dietary marine oils?

1. Diets enriched with n-3 polyunsaturated fish oils, predominantly eicosapentaenoic acid, are associated with a lower risk of atherosclerotic vascular disease. These oils purportedly reduce plasma triglycerides, total cholesterol and impair platelet aggregation. Recently, the present authors reported that rats fed a marine oil-enriched diet had significantly reduced levels of lyso-PAF, the immediate precursor of platelet-activating factor (PAF). As PAF has potent vasodilator and pro-aggregatory properties, the purpose of this study was to examine the hypothesis that fish oils affect the biosynthesis of PAF in man. 2. Supplementation of a normal diet for 3 weeks with fish oil containing the equivalent of 2.7 g of eicosapentaenoic acid daily, increased the eicosapentaenoic acid content of platelet phospholipids as well as depleting the arachidonic acid. Platelet aggregation to PAF (measured in whole blood by impedance aggregometry) was significantly impaired and whole blood thromboxane suppressed. 3. Two weeks after ceasing supplements, platelet aggregation remained impaired although thromboxane had reverted to baseline levels. There was a transient but significant fall in whole blood lyso-PAF apparent within 2 days of commencing supplements but returning to baseline levels by the end of the treatment period. Whole blood PAF followed a similar trend. 4. The effects of dietary fish oil on whole blood aggregations to PAF, on thromboxane and plasma lyso-PAF levels may be relevant to the prevention of vascular disease and the treatment of disorders in which PAF could be an inflammatory mediator.

Dietary fish oil prevents dexamethasone induced hypertension in the rat.

This study was designed to examine the effect of dexamethasone treatment on tissue and urinary prostanoids, and to determine whether inhibition of prostaglandin biosynthesis by manipulation of dietary fatty acids accelerates the development of glucocorticoid hypertension. Forty-eight rats were placed on either a 2-series prostaglandin 'inhibitory' diet (cod liver oil/linseed oil) or a control diet of saturated fat for an initial period of 4 weeks. The groups were then divided into two so that half of each received dexamethasone in their drinking water (2.5 mg/l) for 1 week whilst continuing their respective dietary regimens. Rats on the cod liver oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid, and significantly impaired ability to generate serum thromboxane B2 (33%), aortic 6-oxo-prostaglandin F1 alpha (44%), renal homogenate prostaglandin E2 (45%) and 6-oxo-prostaglandin F1 alpha (74%) and urinary prostaglandin E2 (84%) and 6-oxo-prostaglandin F1 alpha (79%). Despite the diminished levels of vasodilator 2-series prostaglandins, the cod liver oil diet prevented the development of glucocorticoid induced hypertension. Relative to their respective dietary controls, dexamethasone treatment resulted in decreased serum thromboxane B2 (20%) but increased aortic 6-oxo-prostaglandin F1 alpha (186%), renal homogenate prostaglandins (127-230%) and urinary excretion of prostaglandin E2 (640-860%) and 6-oxo-prostaglandin F1 alpha (230-365%) in both dietary groups. It therefore seems unlikely that glucocorticoid induced hypertension is a consequence of inhibition of vasodilator prostaglandin synthesis.

Changes in prostanoid synthesis in response to diet and hypertension in one-kidney, one clip rats.

This study was designed to examine the effects of diets that alter prostaglandin biosynthesis on the blood pressure in one-kidney, one clip rats with established hypertension and to compare the prostanoid generating capacity of hypertensive animals with those that remained normotensive. Rats attaining blood pressures of at least 180 mm Hg within 8 weeks of nephrectomy and renal artery stenosis were paired by weight and blood pressure and then placed on either a safflower oil or a prostaglandin I2 inhibitory diet (cod liver oil-linseed oil mix) for 4 weeks. Animals with blood pressures of less than 150 mm Hg were also paired for the same two dietary regimens. Comparison between the two blood pressure groups revealed that on both dietary regimens hypertensive rats produced significantly more aortic 6-keto-prostaglandin F1 alpha and serum thromboxane B2. Rats on the cod liver oil-linseed oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid and significantly impaired ability to generate serum thromboxane B2 (36%), aortic 6-keto-prostaglandin F1 alpha (65%), renal homogenate 6-keto-prostaglandin F1 alpha (64%) and prostaglandin E2 (58%), and urinary prostaglandin E2 (70%) and 6-keto-prostaglandin F1 alpha (52%). Despite these differences in prostanoid synthesizing capacity, no differences in blood pressure were observed between the safflower oil-fed rats and rats fed cod liver oil-linseed oil within either the hypertensive or normotensive groups. These results suggest that prostanoids do not play a major role in maintaining blood pressure in established one-kidney, one clip hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of diet and drug interactions on prostanoid metabolism.

To study the extent to which combinations of different dietary lipids stimulate or inhibit prostanoid synthesis groups of 12 rats were fed diets containing 10% (w/w) of either safflower oil, hydrogenated coconut oil/safflower oil, cod liver oil/safflower oil or cod liver oil/linseed oil for a period of four weeks. All diets, with the exception of the safflower oil feed, contained similar levels of linoleic acid. Two further groups of rats placed on the cod liver oil diets were injected with indomethacin (4 mg/kg, i.p.) every three days to establish the completeness of dietary prostaglandin (PG) inhibition. In spite of a 20 fold difference in dietary linoleic acid content, the safflower oil group had similar PG generating capacities to the saturated fat control group, suggesting tight metabolic control of PGs and their precursors. Although there were prostanoid variations in tissue responses, both of the cod liver oil diets substantially reduced generation of aortic, whole blood and renal prostanoids, and decreased urinary PG excretion. The degree of inhibition of renal PGs was substantially greater in the cod liver oil/linseed oil group, with prostaglandin levels being 35% lower than those observed in the cod liver oil/safflower oil fed animals suggesting that linolenic acid and the marine oil fatty acids act synergistically to inhibit formation of 2-series prostaglandins. Concurrent administration of omega-3 fatty acids and indomethacin reduced PG levels further than those obtainable by diet alone, demonstrating that the diets did not result in maximal inhibition. Awareness of these various effects is important for both physiological or clinical studies in which dietary manipulations are used as a means of modifying prostanoid synthesis.

The effect of dietary alteration of prostaglandin synthesis on blood pressure and the reversal of hypertension in the one-kidney, one-clip rat.

This study examined the effect of diet-induced changes in prostaglandin synthesis on systolic blood pressure in one-kidney, one clip (1k, 1C) hypertensive rats and on the fall in blood pressure after unclipping. It tested the hypothesis that inhibition of prostaglandin synthesis exacerbates hypertension in this model and prevents complete reversal after unclipping. Rats with sustained hypertension within 8 weeks of renal artery clipping were fed synthetic diets supplemented to 20% of total energy with either safflower oil (linoleic acid) or a mixture of cod liver oil (90%) (containing eicosapentaenoic acid) and linseed oil (10%) (containing linolenic acid) for 4 weeks. The latter oil mixture resulted in a predictable reduction in kidney PGE2 and 6-keto PGF1 alpha (hydrolysis product of PGI2), aortic 6-keto PGF1 alpha and serum TXB2. However, at the end of 4 weeks dietary treatment there were no differences in systolic blood pressure between the two diet groups, and the blood pressure fall 24 hours after unclipping was similar. These findings therefore do not support a role for prostanoids in the maintenance or reversal of 1K, 1C hypertension.

Onset of changes in phospholipid fatty acid composition and prostaglandin synthesis following dietary manipulation with n-6 and n-3 fatty acids in the rat.

A synthetic diet preparation supplemented with 10% by weight of either safflower oil, hydrogenated coconut oil containing 3% safflower oil, or 'max EPA' fish oil was fed to rats over a 8-week period. Serial measurements of serum fatty acids, serum thromboxane B2 and urinary prostaglandin excretion were taken during the treatment period to assess the rate of change in fatty acid composition and prostaglandin synthesis following dietary manipulation. There was no significant change in weight gain between the dietary groups during the treatment period. Significant changes in serum fatty acids occurred within 48 h of treatment, with the 'max EPA' oil group having arachidonic acid levels reduced by 23% (P less than 0.01) compared to the coconut oil group. Conversely, rats fed safflower oil had an 18% enhancement of arachidonic acid during the same time period. Whole blood synthesis of thromboxane B2 was significantly depressed (P less than 0.01) after 48 h in rats fed 'max EPA' oil compared to the safflower oil or coconut oil groups. This suppression reached a maximum of 65% (P less than 0.001) after 7 days of dietary 'max EPA' oil treatment. The safflower oil and coconut oil-fed groups showed the same levels of serum thromboxane B2 production over the treatment period. Urinary excretion of both 6-ketoprostaglandin F1 alpha and prostaglandin E2 varied significantly (P less than 0.01) between the groups after 7 days of dietary treatment. Rats fed 'max EPA' oil had depressed urinary prostanoid excretion compared to the safflower and coconut oil groups which remained very similar to each other. After the 8-week treatment period rats were killed and the phospholipid fatty acid composition and prostaglandin-generating capacity of platelets, aorta and renal tissue was examined. Prostanoid production by kidney cortex and medulla and segments of aorta was consistently suppressed in rats fed 'max EPA' oil. These observations correlated well with changes in the phospholipid fatty acid profiles in these tissues. This study shows rapid changes in serum fatty acids and thromboxane B2 generation following dietary manipulation, while changes in urinary excretion or prostanoid metabolites occur only after a longer time period.

Dietary modification of platelet and renal prostaglandins.

The effects of specific types of dietary fats on prostanoid biosynthesis, platelet function and the cardiovascular system are reviewed. Studies examining the influence of dietary modification of prostanoid synthesis on blood pressure regulation in normotensive and Goldblatt hypertensive rats showed that while dietary supplementation with either sunflower or linseed oil at 40% of energy respectively stimulated and inhibited tissue prostanoids in vitro and urinary PGE2 excretion in vivo, the development of 1 kidney, 1 clip hypertension was not altered in parallel. Rats on both oil rich diets did however, show an average lower blood pressure than animals on a standard diet. In order to minimise possible non-specific effects of large amounts of dietary fats, the effects on prostanoid metabolism of different oils at 5, 20 and 40% of energy in the diet were studied. While as little as 5% dietary supplements alter fatty acid and prostanoid synthesis in platelets, it appears that higher levels (at least 20%) are required to alter significantly renal prostaglandin metabolism.

An inhibitory effect of dietary polyunsaturated fatty acids on renin secretion in the isolated perfused rat kidney.

The influence of dietary modification of polyunsaturated fatty acids (PUFA) on renin secretion, renal vascular tone and prostanoid excretion was studied in isolated perfused rat kidneys under basal conditions and in response to angiotensin II. After a four-week regimen of diets enriched with safflower oil, linseed oil or saturated fat, providing 20% of total energy intake (20 energy %), the animals which were fed linseed oil showed a significant fall in the proportion of arachidonic acid in renal phospholipids and a reduction in urinary prostaglandin excretion. In comparison with the other dietary groups, linseed oil feeding also resulted in a consistently lower renal vascular tone with increasing doses of angiotensin II. Under basal conditions both the PUFA-fed groups had significantly lower renal venous renin secretion rates relative to the saturated fat-fed control group. Infusion of angiotensin II (10 ng/min) suppressed renin secretion and abolished significant differences between the groups. As both the control group and the safflower oil group excreted similar levels of urinary prostaglandins, these results suggest that dietary enrichment with 20 energy % PUFA alters renin secretion by a prostaglandin-independent mechanism and that this may contribute to the lower blood pressures observed in these animals compared with the saturated fat-fed control group.

Dissociation of effects of dietary fatty acids on blood pressure and prostanoid metabolism in Goldblatt hypertensive rats.

To study the influence of dietary modification of prostaglandin synthesis on blood pressure regulation, the effects of dietary enrichment with linoleic acid were compared with standard rat chow in three groups of 24 rats before and after renal artery constriction and contralateral nephrectomy. Dietary supplementation with 40 energy% sunflower seed oil or linseed oil respectively caused incorporation of linoleic or linolenic acids into tissue phospholipids. Relative to the sunflower seed oil, the linseed oil diet led to inhibition of prostanoid synthesis in kidney, serum or aorta in vitro and urine in vivo. Rats on both oil-rich diets had lower blood pressures than rats on a standard diet. Thus, partial suppression of prostaglandin synthesis did not accelerate one-kidney, one clip Goldblatt hypertension, nor did sunflower oil protect against hypertension in a way that could be specifically ascribed to changes in prostaglandin synthesis.