RES-macrophage stimulation and liver tumour growth in rats; evaluation with dynamic liver RES scintigraphy

Dynamic liver RES scintigraphy with Nanocoll (99Tcm albumin colloid - 50 nm diameter) assessing RES-macrophage phagocytic function was performed in 40 control, 73 RES-stimulated non-tumour-bearing and 59 tumour-bearing Wistar/FU rats in vivo. Tumour-bearing rats were inoculated with 10(6) x 1.0 cells of a syngeneic nitrosoguanidine-induced colonic carcinoma in the liver. Twenty-eight of these rats had been treated one day previously with Zymosan (3 mg x 100 g-1 i v) as a RES stimulant. The clearance/uptake rate (k) of Nanocoll was calculated from dynamic liver images by the slope in the plot 1n [1 - U(t)/U] versus t where t is time and U liver uptake. k-value in control animals was 0.45 +/- 0.01.10(-2) x s-1 Zymosan injection in non-tumour-bearing rats caused stati-stically significant higher clearance/uptake rate on day 1, through 8 after treatment compared to that of controls. On day 8 k-value was 0.64 +/- 0.04. In tumour-bearing rats the uptake rate (k) was on day 8 0.66 +/- 0.03, while in RES-stimulated tumour-bearing rats it was 0.64 +/- 0.03. Survival was 22 +/- 1 days in tumour bearing rats and 37 +/- 4 days in RES stimulated tumour-bearing rats. The average tumour volume after one week was 132 +/- 24 mm3 in non-stimulated rats and 20 +/- 5 mm3 in RES stimulated rats. There was a negative correlation between uptake rate and tumour volume and a positive correlation between uptake rate and survival on day 8 in non-stimulated tumour-bearing rats. Dynamic liver RES scintigraphy with small size 99Tcm albumin colloid (Nanocoll) can be used to measure RES phagocytic function and the effect of liver tumour growth on RES.     

Energetics of nutrition and polyamine-related tumor growth alterations in experimental cancer.

The aim of this study was to evaluate whether food intake modulates experimental tumour growth by acute alterations in the energy state and blood flow of the tumour, and if so whether such changes are related to alterations in the enzyme ornithinedecarboxylase (ODC) and DNA synthesis. Inbred mice (C57BL/J) bearing a syngeneic undifferentiated and rapidly growing tumour were used. The tumour levels of high energy phosphates were measured in vivo by 31-P-NMR spectroscopy and biochemically following tissue extraction. DNA synthesis was estimated by measuring the incorporation of bromodeoxy-uridine into tumour DNA. Difluoro-methylornithine (DFMO) was used to inhibit ODC-activity. Tumour blood flow was estimated by a 132Xe local clearance technique. Tumour progression was associated with a significant decrease in tumour tissue high energy phosphates. Acute starvation decreased DNA-synthesis and tumour energy charge as well as its PCr/Pi which were rapidly normalised during subsequent refeeding. These changes were related to similar alterations in tumour blood flow. The inorganic phosphate (Pi) resonance and the resonances in the phosphomonoester (PME) region were considerably increased in tumour tissue. Inhibition of ODC-activity by DFMO decreased DNA-synthesis, which was associated with a secondary increase in tumour high energy phosphates probably due to a lowered energy demand for tumour cell division. The results demonstrate that host undernutrition was translated into retarded tumour growth associated with a decrease in the energy state and blood flow of the tumour. The results have bearing for the evaluation and planning of all treatment protocols with potential influence on food intake in experimental tumour-bearing animals.     

Influence of zymosan (a non-specific macrophage stimulator) and of indomethacin on liver tumours—an experimental study in rats

Zymosan—a non-specific macrophage-stimulating agent-reduces tumour take in the liver. The mechanism for this effect is not clear, but it may be mediated via the Kupffer cells and prostaglandins. On the other hand, the Prostaglandin-synthesis inhibitor, indomethacin, inhibits tumour growth. Pretreatment with zymosan (3 mg 100 g^–1) for 3 days of two different strains of rats, inoculated in the liver with a hepatoma or an adenocarcinoma cell suspension respectively, reduced tumour take and also initial tumour growth. The effect on tumour take and initial growth was inhibited by concomitant administration of indomethacin (0.2 mg 100 g^–1). When zymosan was administered after tumour cell inoculation the growth rate of the hepatoma was retarded, but this effect was not abrogated by indomethacin. Pretreatment with indomethacin had no significant effect on tumour take or initial growth. When given after the tumour was established in the liver, indomethacin reduced the growth rate of the hepatoma, but not of the adenocarcinoma. These results suggest that there are different mechanisms for the effects of zymosan on tumour take and on growth of an established tumour. In immunoincompetent nude mice the effect on the hepatoma was similar to the effect in the rat. In vitro both tumours were insensitive to zymosan and indomethacin. This study confirms that pretreatment with a non-specific macrophage stimulator (zymosan) diminishes tumour take and growth in the liver, that the effect of zymosan on tumour take in the liver is abrogated by indomethacin and that the zymosan effect on tumour take in the liver is at least partly mediated by the Kupffer cells and prostaglandins.This study was supported by grants from Swedish Medical Research Foundation (grant no. B94-17X-07184-10C), Assar Gabrielsson's Foundation for Cancer Research and the King Gustaf V Jubilee Clinic Cancer Research Foundation in Gothenburg     

Effect of sulphasalazine and sulphapyridine on neutrophil superoxide production: role of cytosolic free calcium.

As the neutrophil granulocyte plays an important part in rheumatoid inflammation the effect of sulphasalazine on neutrophil function was studied. The results show that sulphasalazine, and its metabolite sulphapyridine, inhibit neutrophil superoxide production elicited by the receptor mediated stimulus N-formyl-methionyl-leucyl-phenyl-alanine (fMLP) and by the calcium ionophore A23187. This effect seems to be dependent on inhibition of intracellular Ca++ increase as both substances reduce this increase upon cell activation with fMLP and A23187. Sulphasalazine and sulphapyridine do not inhibit superoxide production after stimulation with the ester phorbol myristate acetate, a stimulus response coupling which is independent of intracellular Ca++ increase. The reported inhibition of superoxide generation may explain, at least partly, the antirheumatic property of sulphasalazine.     

Rheumatoid cachexia,central obesity and malnutrition in patients with low-active rheumatoid arthritis: feasibility of anthropometry,Mini Nutritional Assessment and body composition techniques

Background and aims  The concurrent decrease in fat free mass (FFM) and increase in fat mass (FM), including central obesity, in patients with rheumatoid arthritis (RA) may be related to increased cardiovascular morbidity as well as to functional decline. The objectives of this study were to evaluate body composition and nutritional status in patients with RA and the feasibility of bioelectrical impedance (BIA) to detect rheumatoid cachexia. Methods  Eighty RA outpatients (76% women), mean age 61 (range 22–80) years and with mean disease duration of 6 (range 1–52) years, were assessed by body mass index (BMI), waist circumference (WC), whole-body dual-energy X-ray absorptiometry (DXA), BIA and the Mini Nutritional Assessment (MNA). Results  Fat free mass index (FFMI; kg/m²) was low in 26% of the women and in 21% of the men. About every fifth patient displayed concomitant low FFMI and elevated fat mass index (FMI; kg/m²), i.e. rheumatoid cachexia. BMI and MNA were not able to detect this condition. Sixty-seven percent had increased WC. Reduced FFM was independently related to age (p = 0.022), disease duration (p = 0.027), ESR (p = 0.011) and function trendwise (p = 0.058). There was a good relative agreement between DXA and BIA (FM r ² = 0.94, FFM r ² = 0.92; both p < 0.001), but the limits of agreement were wide for each variable, i.e. for FM −3.3 to 7.8 kg; and for FFM −7.9 to 3.7 kg. Conclusion  Rheumatoid cachexia and central obesity were common in patients with RA. Neither BMI nor MNA could detect this properly. There was a good relative agreement between DXA and BIA, but the limits of agreement were wide, which may restrict the utility of BIA in clinical practice. This work has in part been presented at the Congress of American College of Rheumatology in San Francisco, October 2008.     

Effects of low-dose prednisolone on endothelial function, atherosclerosis, and traditional risk factors for atherosclerosis in patients with rheumatoid arthritis--a randomized study

OBJECTIVE: To determine the influence of low-dose prednisolone on atherosclerosis, endothelial function, and risk factors for atherosclerosis in patients with early rheumatoid arthritis (RA). METHODS: At start of the first disease modifying antirheumatic drug, 67 patients with early, active RA were randomized to either 7.5 mg prednisolone daily (n = 34) or no prednisolone (n = 33). In the prednisolone group, 21 were treated for 2 years and 13 continuously. After a mean of 5 years intima-media thickness (IMT) and calculated intima-media area (cIMa) of the carotid arteries were determined by B-mode ultrasound. Endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery. RESULTS: IMT [median (interquartile range) 0.675 mm (0.58-0.82) vs 0.673 mm (0.0.62-0.80)], cIMa [13.7 mm2 (11.45-20.37) vs 14.1 mm2 (12.34-17.38)], prevalence of atherosclerotic plaques (82.3% vs 81.9%), and endothelial function [FMD% (mean +/- SD) 3.88% +/- 2.8 vs 3.74% +/- 2.9] did not differ between patients treated with and those not treated with prednisolone. There were no differences in lumen diameter of carotid arteries, or levels of lipoproteins, glucose, and blood pressure. Patients treated for at least 4 years (and currently treated) with prednisolone had a trend to higher systolic blood pressure (157 +/- 29 mm Hg) compared with untreated patients (141 +/- 28 mm Hg; p = 0.06) and had higher cholesterol levels (5.6 mmol/L +/- 1.39 vs 4.9 +/- 28; p = 0.03). In the whole cohort, age and HDL were independently associated with IMT; age, HDL, and blood pressure with cIMa; and age and serum creatinine with presence of atherosclerotic plaques. CONCLUSION: Low-dose prednisolone did not influence endothelial function and atherosclerosis in patients with RA. However, total cholesterol was higher in patients treated with prednisolone.     

Randomized withdrawal of long-term prednisolone treatment in rheumatoid arthritis: effects on inflammation and bone mineral density

OBJECTIVE: Short-term, low-dose glucocorticoid (GC) treatment has anti-inflammatory and disease-modifying effects in rheumatoid arthritis (RA). However, scientific support for long-term, low-dose GC treatment, although widespread, is poor, and information on the effects on bone density is scarce. The aim of this study was to investigate how long-term GC treatment in RA affects inflammation as well as bone density, and also to investigate the feasibility of withdrawal of GC. PATIENTS AND METHODS: Fifty-eight patients with RA treated with 5-7.5 mg prednisolone daily for at least 2 years were randomized either to withdraw or to continue GC treatment. The patients were followed prospectively for 2 years with respect to disease activity [using the Disease Activity Score calculated for 28 joints, (DAS28)], functional ability [using the Health Assessment Questionnaire (HAQ) score] and bone mineral density (BMD) of the lumbar spine and hip. RESULTS: Only 11 patients out of 26 randomized to stop GC treatment and available for outcome measures succeeded in stopping the GC medication within 1 year. Fifteen patients failed withdrawal of GC because of increased joint symptoms. A higher mean DAS28 during the study was associated with loss of bone mass in the trochanter. The group that continued with unchanged GC treatment did not deteriorate in BMD during the 2 years but in fact Z-scores improved significantly. CONCLUSION: Our results indicate that low-dose GC treatment after several years has persisting anti-inflammatory effects in RA and no further negative impact on BMD. It thus seems to be more important to control disease activity than withdraw low-dose GC treatment in this population considering bone health.     

Non-nutritive sucking in full-term and preterm infants studied at term conceptional age

Non-nutritive sucking (NNS) patterns in full-term newborn and preterm infants were studied at term conceptional age. The preterm group showed a distinct NNS pattern with a higher frequency and lower amplitude. In the preterm group, gender differences were observed, the girls having higher frequency and larger amplitude. The full-term infants' NNS patterns were also related to pacifier use during early childhood. Experience, gender, maturity and level of tension are suggested as explanatory factors for differences in NNS patterns.