The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture.

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects.

BACKGROUND: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. METHODS: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. RESULTS: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 µmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). CONCLUSIONS: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.

Ranges of phenotypic flexibility in healthy subjects.

BACKGROUND: A key feature of metabolic health is the ability to adapt upon dietary perturbations. A systemic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). Recently, it has been shown that the PFT enables the quantification of all relevant metabolic processes involved in maintaining or regaining homeostasis of metabolic health. Furthermore, it was demonstrated that quantification of PFT response was more sensitive as compared to fasting markers in demonstrating reduced phenotypic flexibility in metabolically impaired type 2 diabetes subjects. METHODS: This study aims to demonstrate that quantification of PFT response can discriminate between different states of health within the healthy range of the population. Therefore, 100 healthy subjects were enrolled (50 males, 50 females) ranging in age (young, middle, old) and body fat percentage (low, medium, high), assuming variation in phenotypic flexibility. Biomarkers were selected to quantify main processes which characterize phenotypic flexibility in response to PFT: flexibility in glucose, lipid, amino acid and vitamin metabolism, and metabolic stress. Individual phenotypic flexibility was visualized using the "health space" by representing the four processes on the health space axes. By quantifying and presenting the study subjects in this space, individual phenotypic flexibility was visualized. RESULTS: Using the "health space" visualization, differences between groups as well as within groups from the healthy range of the population can be easily and intuitively assessed. The health space showed a different adaptation to the metabolic PhenFlex test in the extremes of the recruited population; persons of young age with low to normal fat percentage had a markedly different position in the health space as compared to persons from old age with normal to high fat percentage. CONCLUSION: The results of the metabolic PhenFlex test in conjunction with the health space reliably assessed health on an individual basis. This quantification can be used in the future for personalized health quantification and advice.

Distinct white-matter aberrations in 22q11.2 deletion syndrome and patients at ultra-high risk for psychosis.

BACKGROUND: Patients with a deletion at chromosome 22q11.2 (22q11DS) have 30% lifetime risk of developing a psychosis. People fulfilling clinical criteria for ultra-high risk (UHR) for psychosis have 30% risk of developing a psychosis within 2 years. Both high-risk groups show white-matter (WM) abnormalities in microstructure and volume compared to healthy controls (HC), which have been related to psychotic symptoms. Comparisons of WM pathology between these two groups may specify WM markers related to genetic and clinical risk factors. METHOD: Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) were assessed using diffusion tensor magnetic resonance imaging (MRI), and WM volume with structural MRI, in 23 UHR patients, 21 22q11DS patients, and 33 HC. RESULTS: Compared to UHR patients 22q11DS patients had (1) lower AD and RD in corpus callosum (CC), cortical fasciculi, and anterior thalamic radiation (ATR), (2) higher FA in CC and ATR, and (3) lower occipital and superior temporal gyrus WM volume. Compared to HC, 22q11DS patients had (1) lower AD and RD throughout cortical fasciculi and (2) higher FA in ATR, CC and inferior fronto-occipital fasciculus. Compared to HC, UHR patients had (1) higher mean MD, RD, and AD in CC, ATR and cortical fasciculi, (2) no differences in FA. CONCLUSIONS: UHR and 22q11DS patients share a susceptibility for developing psychosis yet were characterized by distinct patterns of WM alterations relative to HC. While UHR patients were typified by signs suggestive of aberrant myelination, 22q11DS subjects showed signs suggestive of lower axonal integrity.

Pyrosequencing reveals bacterial communities in unchlorinated drinking water distribution system: an integral study of bulk water, suspended solids, loose deposits, and pipe wall biofilm.

The current understanding of drinking water distribution system (DWDS) microbiology is limited to pipe wall biofilm and bulk water; the contributions of particle-associated bacteria (from suspended solids and loose deposits) have long been neglected. Analyzing the composition and correlation of bacterial communities from different phases helped us to locate where most of the bacteria are and understand the interactions among these phases. In the present study, the bacteria from four critical phases of an unchlorinated DWDS, including bulk water, pipe wall biofilm, suspended solids, and loose deposits, were quantified and identified by adenosine triphosphate analysis and pyrosequencing, respectively. The results showed that the bulk water bacteria (including the contribution of suspended solids) contributed less than 2% of the total bacteria. The bacteria associated with loose deposits and pipe wall biofilm that accumulated in the DWDS accounted for over 98% of the total bacteria, and the contributions of bacteria in loose deposits and pipe wall biofilm were comparable. Depending on the amount of loose deposits, its contribution can be 7-fold higher than the pipe wall biofilm. Pyrosequencing revealed relatively stable bacterial communities in bulk water, pipe wall biofilm, and suspended solids throughout the distribution system; however, the communities present in loose deposits were dependent on the amount of loose deposits locally. Bacteria within the phases of suspended solids, loose deposits, and pipe wall biofilm were similar in phylogenetic composition. The bulk water bacteria (dominated by Polaromonas spp.) were clearly different from the bacteria from the other three phases (dominated by Sphingomonas spp.). This study highlighted that the integral DWDS ecology should include contributions from all of the four phases, especially the bacteria harbored by loose deposits. The accumulation of loose deposits and the aging process create variable microenvironments inside loose deposits structures for bacteria to grow. Moreover, loose deposits protect the associated bacteria from disinfectants, and due to their mobility, the associated bacteria reach taps easily.

Sarcoidosis of the liver: to treat or not to treat?

INTRODUCTION: Sarcoidosis is a non-caseating, granulomatous disease of incompletely understood aetiology that can affect nearly all organs including the liver. Hepatic involvement is thought to occur in 50-90% of patients but may remain undiagnosed in many cases. Evidence-based guidelines for the treatment of sarcoidosis of the liver are lacking. Patients usually receive no treatment or are treated pragmatically with corticosteroids. However, treatment with systemic corticosteroids has had mixed results. The use of ursodeoxycholic acid (UDCA) in the treatment of sarcoidosis-associated cholestasis has been reported by several groups, and is empirically prescribed to sarcoidosis patients with hepatic involvement. METHODS: The effect of UDCA on symptoms and serum liver tests was investigated in a retrospective cohort study in which hepatic sarcoidosis patients had received either no treatment, prednisolone treatment or UDCA treatment. For all patients, laboratory results on ASAT, ALAT, AP and GGT were collected. Patients described the severity of their symptoms before and after treatment on a numerical scale. RESULTS: A total of 17 patients participated in the study. Serum liver tests in the group treated with UDCA had improved as compared with the other groups. Also, symptomatic improvement of pruritus and fatigue was reported in the group treated with UDCA. CONCLUSION: This retrospective cohort study supports the empirical first-line use of UDCA in the treatment of sarcoidosis of the liver, especially in symptomatic patients. Prospective randomised trials are needed to adequately support this concept.

Epigallocatechin gallate (EGCG) (TEAVIGO) does not impair nonhaem-iron absorption in man.

A number of studies have shown that tea catechins can inhibit intestinal iron absorption, mostly iron in the nonhaem form. This randomized, double-blind, placebo-controlled, 3-periods cross-over study examined the degree of inhibition of nonhaem iron absorption by pure crystalline epigallocatechin gallate (EGCG). The study was designed to show the maximum inhibitory action of EGCG by selecting 30 healthy women with low iron stores. Treatments were 150 mg, 300 mg EGCG and placebo each for 8 consecutive study days with a wash-out period of 14 days between treatments. Iron incorporation was assessed by supplying 57Fe orally and 58Fe intravenously. Differences in fractional nonhaem iron absorption between the treatments were evaluated by using two-sided ANOVA. Results showed a relative nonhaem iron absorption reduction of 14% with 150mg EGCG and 27% for 300mg EGCG treatment compared to placebo. Differences were statistically significant (p < or = 0.05) between the placebo and the 300mg EGCG treatments and between the 150 and 300 mg EGCG treatments. The inverse relation between EGCG dose and fractional nonhaem iron absorption was linear (p = 0.0002). In this study the magnitude of the inhibitory action of EGCG on nonhaem iron absorption was found to be much lower than that reported in the literature for black tea and similar compounds. The doses of EGCG in supplements, which will be lower than those used in this study, are not expected to have any health relevant effects on iron absorption in subjects with normal iron stores.

The Denver school-based adolescent hepatitis B vaccination program: a cost analysis with risk simulation.

OBJECTIVES: This study sought to compare the cost-effectiveness of a school-based hepatitis B vaccine delivery program with that of a vaccine delivery program associated with a network health maintenance organization (HMO). METHODS: The vaccination program enrolled 3359 sixth-grade students from 18 middle schools in Denver, Colo. Immunization status and direct and indirect program costs were compiled. The sensitivity of the outcomes was assessed by simulation methods. RESULTS: The per-dose cost-effectiveness ratio for the school-based delivery system was $31. This cost-effectiveness ratio remained stable when the model was simulated with costs that were underestimated or overestimated by 20%. In the network HMO, the direct cost per dose was $68 and the societal cost was $118 when the child's father worked full-time and the mother worked part-time. There is less than a 5% chance that the network HMO-based vaccination program could be more cost-effective than the school-based program. CONCLUSIONS: The cost per dose of the school-based program was significantly less than that of the network HMO-based program, because in the school program government-purchased vaccine was available at a lower cost and parents did not incur work-loss costs.

Changes in energy metabolism in relation to physical activity due to fermentable carbohydrates in group-housed growing pigs.

Fermentable nonstarch polysaccharides (dietary fiber) affect energy retention in group-housed growing pigs by reducing physical activity. This study assessed the effects of fermentation and bulkiness of dietary carbohydrates on physical activity in relation to energy metabolism. Eight clusters of 14 pigs were fed one of four diets in a 2x2 factorial arrangement. Factors included 1) gastrointestinal fermentation and 2) dietary bulkiness. Contrasts in fermentation were created by exchanging gelatinized maize starch with raw potato starch on a volume basis. Bulkiness was altered by adding 15% milled wheat straw to the diets. Apart from these differences, amounts of other dietary ingredients fed to the pigs were similar. Pigs were housed in groups. Nitrogen and energy balances were measured per cluster during a 14-d period. Dietary bulkiness did not affect ME intake, heat production, or energy retention. Metabolizability decreased when maize starch was replaced with raw potato starch (P< .01), resulting in a lower energy retention on the potato starch diets (P<.01). However, the lower ME intake on the potato diets was partially compensated by a reduced energy expenditure on physical activity (P< .01), which was 17.6% lower than that of pigs fed the maize starch diets. Dietary bulkiness did not affect physical activity. The effect of fiber-rich diets (nonstarch polysaccharides) on activity in growing group-housed pigs seems to be related to fermentation in the gastrointestinal tract, and not to bulkiness (volume).

Non-starch polysaccharides in pig feeding.

In pigs and humans, the nutrients starch, protein, fat and some minerals need to be digested prior to the terminal ileum for optimal use of these nutrients. In contrast, the non-starch polysaccharides (NSP) are mainly fermented by microbes in the hindgut. Results of experiments in pigs showed that NSP negatively affected apparent digestion of protein, fat and some minerals. In addition, large amounts of fermented NSP increased the empty weight of the hindgut. Because tissue of organs like the intestinal tract are metabolically very active, it may have required more energy for maintenance, hence leaving less energy for growth. Despite all the negative effects as mentioned above, including NSP-rich ingredients in pig diets also has quite a lot of advantages. Their energy supply can cover the energy requirements for maintenance. In addition, positive effects on the well-being and health of pigs, and on the excretion of ammonia are claimed. In conclusion, in future pig diet formulation not only the nutritional aspects of NSP-rich ingredients should be taken into account, but also their non-nutritional aspects. This might be realized by developing nutrient based feed evaluation systems, rather than the energy based systems which are presently used.

Dietary carbohydrates alter the fecal composition and pH and the ammonia emission from slurry of growing pigs.

We investigated the effects of dietary carbohydrates on the composition and pH of fecal material and on the ammonia emission from the slurry of growing pigs. Thirty-four barrows (BW approximately 40 kg) were randomly allotted to 1 of 10 diets. A basal diet was formulated to meet all requirements for protein, amino acids, minerals, and vitamins. The control diet was composed of the basal diet plus heat-treated cornstarch. In the other diets, the cornstarch in the control diet was replaced with three levels of either coconut expeller, soybean hulls, or dried sugar beet pulp. Feces were collected separately from urine in a balance experiment. Feces were mixed with a standardized urine (ratio of 1:2.5, wt/wt) to form a slurry. A sample of this slurry was placed in an in vitro system to determine the pH and the ammonia emission for 16 d at 20 degrees C. The fecal and slurry DM contents decreased (P < .001) and the total VFA concentrations increased (P < .001) when the level of dietary carbohydrates increased. The pH and the ammonia emission decreased as the level of carbohydrates increased (P < .001). The addition of soybean hulls to the diet had the greatest effect on reducing the pH and ammonia emission (P < .001), and the effects of sugar beet pulp and coconut expeller were approximately the same. A linear relationship was found between the intake of dietary nonstarch polysaccharides (NSP) and the ammonia emission (P < .001). For each 100-g increase in the intake of dietary NSP, the slurry pH decreased by approximately .12 unit and the ammonia emission from slurry decreased by 5.4%. We conclude that replacing cornstarch in the diet with components that have a high concentration of fermentable carbohydrates increases the VFA concentration of feces and slurry and reduces the pH and ammonia emission from the slurry of growing pigs.

Effect of resistant starch on net portal-drained viscera flux of glucose, volatile fatty acids, urea, and ammonia in growing pigs.

Net portal-drained viscera (PDV) flux of glucose, VFA, ammonia, and urea was determined in pigs fed diets with or without resistant starch. Diets consisted of 65% cornstarch (diet CS), 32.5% cornstarch and 32.5% raw potato starch (diet CPS), or 65% raw potato starch (diet PS); the remaining 35% supplied all amino acids, fat, fiber, minerals, and vitamins. The diets contained twice the maintenance requirement for energy and were fed twice daily to four barrows (initial BW 56 kg) in three periods in a crossover design. The pigs were fitted with catheters in a mesenteric vein, a mesenteric-artery, and the portal vein, and net PDV flux was calculated by multiplying portal-arterial concentration differences and corresponding portal vein flow. Net PDV flux of glucose was significantly less after feeding diets CPS and PS, and portal absorption of ileally digested glucose was 89, 66, and 41% for diets CS, CPS, and PS, respectively. Net PDV flux of VFA was lowest after feeding diet CS and three to four times higher after feeding diets CPS and PS. Net PDV flux of ammonia was highest for diet CS and almost halved after feeding diets CPS and PS. There was a small negative net PDV flux of urea for diets CS and CPS, which significantly increased after feeding diet PS. These results suggest that excretion of nitrogen is shifted from urine to feces primarily by reduction of the net PDV flux of ammonia when resistant starch is fed.

Apparent digestibility of nutrients in diets with different energy density, as estimated by direct and marker methods for pigs with or without ileo-cecal cannulas.

The objective of this study were a) to compare the apparent total tract digestibility (TD) between non-cannulated (intact) and cannulated (steered ileo-cecal valve technique, SICV) pigs fed diets differing in energy density (Exp. 1) and b) to compare the direct vs marker (Cr2O3) methods for estimation of the TD and apparent ileal digestibility (ID) in SICV-cannulated pigs (Exp. 2). In Exp. 1, 24 intact and 18 SICV-cannulated castrates of approximately 40 kg initial BW were randomly assigned to six treatments in a 2 x 3 x 2 factorial arrangement (two pig types, three carbohydrate sources, and two fat levels). In Exp. 2, the same SICV-cannulated pigs from Exp. 1 were given those treatments in a 2 x 3 x 2 factorial arrangement (two methods of digestibility estimation, three carbohydrates sources, and two fat levels). In both experiments either cornstarch, soybean hulls, or pure cellulose, without or with fat, were incorporated into a barely-soybean meal based diet to alter energy density. Daily diets were isoenergetic (based on NEf), and water supply was .33 L/MJ of NEf. In Exp. 1, the pig type effect on the TD of DM, OM, CP, and the pig type x carbohydrate interactions for the TD of DM, OM, and crude fiber (CF) were significant (P < .05), merely due to a larger difference found for the diet enriched with cellulose. In Exp. 2, the TD and ID evaluated with the marker method were significantly lower (except for the TD of CF) than with the direct method, mainly because Cr recovery was below 100%. Overall, the marker method seems to be superior because the TD means obtained from Cr ratios were closer to the TD obtained from intact pigs. In general, the SICV technique seems to be suitable for long-term digestibility studies to measure the TD and ID in the same pig fed low-or high-fiber diets.

Biochemical lung maturity, static respiratory compliance, and pulmonary gas transfer in intubated preterm infants with and without respiratory distress syndrome.

We investigated the relationship between tests of biochemical lung maturity [lecithin/sphingomyelin ratio (L/S ratio)], static compliance of the respiratory system (Crs), and estimates of pulmonary gas transfer [venous admixture and arterial/alveolar (a/A) ratio] in a group of intubated preterm infants with and without respiratory distress syndrome (RDS). Thirty infants were studied once (n = 26) or twice (n = 4). The L/S ratio was obtained by means of high-performance thin-layer chromatography and determination of the phosphorus content. Crs was obtained by the multiple occlusion technique. Transcutaneous blood gases and the percentage of oxygen in the inspired gas were recorded and estimates of pulmonary gas transfer were calculated using algorithms. L/S ratio and Crs correlated well (r = 0.73), indicating a higher compliance in biochemically more mature lungs. Both the a/A ratio and venous admixture correlated significantly with the L/S ratio and Crs (P < 0.001). Crs, L/S ratio, and a/A ratio decreased with increasing severity of radiological RDS, and the percentage venous admixture increased (P < 0.001). Sequential measurements in four infants during the acute phase and after RDS resolved indicated that clinical improvement coincided with improvements in biochemical lung maturity, Crs, and estimates of pulmonary gas transfer.

Thermodynamics of the equilibrium unfolding of oxidized and reduced Saccharomyces cerevisiae iso-1-cytochromes c.

We report thermodynamic data for the chemical denaturation of iso-1-cytochromes c from Saccharomyces cerevisiae having amino acid substitutions R38A, N52I, and F82S in all possible combinations. The guanidine hydrochloride denaturation of isolated proteins was monitored by fluorescence measurements. The redox potentials, Eo', for both the folded and unfolded conformations have been measured. Free energy changes of chemical unfolding together with direct electrochemical measurement of the free energy changes of reduction for both the native and unfolded proteins yield a complete thermodynamic cycle, which includes four states of cytochrome c: oxidized folded, oxidized unfolded, reduced folded, and reduced unfolded. Completed cycles illustrate that the stability of cytochrome c to denaturing conditions is different for each amino acid substitution by an amount that depends on the heme oxidation state. Thus, the differential protein stability cannot be interpreted simply in terms of a hydrophobic effect, without also considering coupled Coulombic effects.

[Influenza epidemic in a nursing home caused by a virus not included in the vaccine]. / Influenza-epidemie in een verpleeghuis door een virus dat niet in het vaccin was opgenomen.

In the autumn of 1992 two-thirds of the population of a nursing home in Amsterdam was vaccinated against influenza. However, in March 1993 an outbreak of an influenza like illness occurred with a morbidity rate of 49% and a mortality rate of 10%. There was sufficient serological evidence to show that the vaccine as such had induced adequate immunity. As the causative agent an influenza A/H3N2 virus was identified. The failing activity of the vaccine in this instance was apparently caused by the absence of sufficient antigen similarity between the A/H3N2 vaccine component and the epidemic virus ('vaccine mismatch').

Effects of sandostatin and castration on pancreatic carcinogenesis in rats and hamsters.

The effects of treatment with the somatostatin analogue Sandostatin, separately and in combination with surgical castration, on the development of azaserine-induced lesions in rat pancreas and N-nitrosobis(2-oxopropyl)amine (BOP)-induced lesions in hamster pancreas were investigated. The animals were divided in 4 groups and treated as follows: (a) controls, injected s.c. with saline solution (0.9% NaCl); (b) orchiectomy directly after the last treatment with carcinogen; (c) Sandostatin (SMS 201-995) subcutaneously; (d) orchiectomy followed by treatment with Sandostatin. No significant suppressive effects on plasma EGF or IGF-I concentrations were noted after Sandostatin treatment, but plasma gastrin levels decreased slightly in the rats, not in the hamsters. In rats, Sandostatin treatment enhanced rather than inhibited growth of acidophilic atypical acinar cell nodules. In hamster pancreas, by contrast, Sandostatin inhibited the development of putative pre-neoplastic ductular lesions. There was no interaction between treatment with Sandostatin and surgical castration. It was concluded that Sandostatin, when administered prophylactically, has an inhibitory effect on the growth of putative pre-neoplastic ductular, but not acinar, lesions.

Development of a human lung surfactant, derived from extracted amniotic fluid.

Using a surfactant preparation of human origin for the treatment of the respiratory distress syndrome (RDS) instead of an animal-derived surfactant will minimize immunological problems. Therefore we isolated surfactant material from human amniotic fluid. Protein and phospholipid fractions of extracted human amniotic fluid (HAFS) were separated by Lipidex 5000 or acidulated LH20 liquid chromatography systems. Fractions of HAFS, the phospholipid or the recombined phospholipid-protein fractions, were tested in the 27-day fetal rabbit model. The results were compared with the results of the corresponding fractions of extracted ovine lung lavage (EOS) and of the already clinically tested surfactant Curosurf. The in situ surface activity of HAFS, EOS, and of their combined phospholipid + protein fractions (200 mg/kg body wt.) resulted in a lung compliance which was significantly higher than the control (saline) values. The compliances of HAFS, EOS, their combined fractions, and Curosurf were similar, but the lung stability values (V5) differed significantly among these surfactant extracts. The best V5 values (greater than or equal to 0.020 ml/g body wt.) were found after installing EOS or its LH20 phospholipid + protein fractions. HAFS had a poor stabilizing capacity which increased significantly after Lipidex chromatography and even more after enrichment of the Lipidex material with 10% palmitic acid. The Lipidex HAFS + 10% palmitic acid surfactant is at present the best obtainable human surfactant extract. Further development is in progress for the clinical application of this surfactant in preterm neonates.

Effects of castration, alone and in combination with aminoglutethimide, on growth of (pre)neoplastic lesions in exocrine pancreas of rats and hamsters.

We studied the effects of hormonal manipulation by orchiectomy, alone or in combination with the aromatase inhibitor aminoglutethimide (AGT), and by luteinizing hormone-releasing hormone agonist (LH-RH-A) (goserelin) treatment on the development of early putative (pre)neoplastic lesions induced in the pancreas of rats and hamsters by azaserine and N-nitrosobis(2-oxopropyl)amine respectively. Treatment of the animals started 1 week after the last injection with carcinogen and continued for 4 months. Orchiectomy caused a significant inhibition of growth of acidophilic atypical acinar cell nodules in the rat model, whereas surgical castration did not show an effect in the hamster model. In rats, but not in hamsters, orchiectomy resulted in a significant decrease in body weight and in absolute, but not relative pancreatic weight. Treatment of the animals with AGT or goserelin did not cause a significant effect on the development of either putative preneoplastic acinar lesions in rat pancreas or early ductular lesions in hamster pancreas. Hamsters showed clearly higher plasma epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) concentrations than rats, while plasma testosterone levels were significantly lower. Plasma EGF and IGF-1 levels decreased with increasing age in both control and treatment groups. Compared to controls there were no clear unequivocal effects of treatment on EGF, IGF-1 and gastrin levels. Plasma testosterone levels decreased by orchiectomy and LH-RH-A treatment. In rats hormone-induced effects on food intake and altered nutritional status might be important with respect to the development of carcinogen-induced preneoplastic pancreatic lesions.