The ASAS-OMERACT core domain set for axial spondyloarthritis.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

Electron microscope autoradiographic study of intestinal absorption of decanoic and octanoic acids in the rat.

Intestinal absorption of [3H]octanoic acid and [3H]decanoic acid was investigated in the rat by electron microscope autoradiography. The common duct (bile and pancreatic common duct) of the rats was diverted and a loop of the duodenum was cannulated 24 h later. The lipid mixture to be investigated was introduced into each experimental loop, and after 15 min or less the loop was removed. One part of each loop was used to determine the distribution of radioactivity in different lipid fractions, and an autoradiographic study was performed on the other part of the loop. Radioactivity distribution studies confirmed that medium chain fatty acids are absorbed in their nonesterified form and established that these fatty acids are absorbed much more rapidly than oleic acid. Autoradiographic studies indicated that the medium chain fatty acids are taken up in a molecular or aggregate molecular form, leave the epithelial cells by way of the lateral plasma membrane, and are next found in the blood capillaries. Our results suggest that the Golgi complex does not play an important role in the absorption of unesterified fatty acids.

Expression of fatty acid binding protein in the liver during pregnancy and lactation in the rat.

Expression of the liver fatty acid binding protein (L-FABP) has been studied in the liver of pregnant and lactating rats. The L-FABP concentration found in the cytosol by immuno-enzymatic assay (ELISA) was consistently higher in the dams during the pregnancy and the lactation than in the age-matched virgin females. Paradoxically, a decrease in the L-FABP mRNA level occurred in the maternal liver during the last days of the gestation. This level remained low on days 7 and 14 of the lactation. Since the transcription rate of the L-FABP gene was unchanged in the maternal liver, these data suggest a post-transcriptional regulation of the L-FABP during pregnancy and lactation in the rat. The nutritional adaptations occurring during pregnancy and lactation are not involved in this regulation since a chronic maternal food-restriction failed to correct these modifications. The mechanism of this regulation is presently unknown, but possibilities include hormonally mediated effects.

Prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine.

OBJECTIVES: To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR). METHODS: Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR. RESULTS: Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51). CONCLUSIONS: The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

Transcriptional induction of the fatty acid binding protein gene in mouse liver by bezafibrate.

The mechanism by which hypolipidemic peroxisome proliferators of the fibrate family induce the liver fatty acid binding protein in liver of rodents is unknown. In order to delineate the level at which this protein is induced, the transcriptional activity of the specific gene encoding for liver fatty acid binding protein was measured in isolated hepatocyte nuclei obtained from male Swiss mice daily force-fed during 7 days with 400 mg/kg body weight bezafibrate. This treatment induced a 4-fold increase in the liver fatty acid binding protein transcription rate. Liver fatty acid binding protein mRNA level, measured by Northern blot analysis and cytosolic content of this protein, analyzed by immunoblotting, increased concurrently. From these results we conclude that the increase in the cytosolic liver fatty acid binding protein level by bezafibrate is due to an enhancement of the transcription rate of the liver fatty acid binding protein gene. Whether the transcriptional effect is mediated by peroxisome proliferator-receptor remains to be elucidated.

Traumatic rupture of the diaphragm. Review of 62 successive cases.

From 1970 to 1987, 62 patients, suffering from traumatic rupture of the diaphragm, have been treated. In more than 75% of the cases, other severe post-traumatic associated lesions were noticed. In 54 cases these concerned blunt trauma, most of which were due to road accidents. There were 53 lesions of the left hemidiaphragm. Early diagnostics were made 40 times (i.e. within 24 hours after the accident). This is why it is all-important to correctly interpret the simple X-ray of thorax and abdomen, possibly after inserting a nasogastric tube. In general, exploration by laparotomy was preferred. Thoracolaparotomy or sternolaparotomy was only used in cases of thoracic or thoraco-abdominal injuries associated with important lesions at the lungs or the mediastinal organs; or in the case of long-standing ruptures accompanied by herniation of different organs. The total mortality rate was 21%. Death was due to hypovolemia, serious brain injuries or multiple organ failure (MOF) due to sepsis.

[Early mortality following multiple trauma: a retrospective study]. / Vroegtijdige mortaliteit na polytrauma: een retrospective studie.

Early mortality after polytrauma: a retrospective study. The medical charts of all patients, who died in 1986 in the reanimation phase after an accident, were reviewed. Twenty-five patients (86%) were victim of a traffic accident, 2 of an accident at work and 2 of an accident at home. The average ISS of the 29 patients was 40.7. The patients, who received the first aid at the place of accident from an emergency doctor, had an average ISS of 44.2. The patients, who received the first aid from a team without doctor had an average ISS of 33.8. The first aid was given after an average time of 10 minutes. Ten patients were transported during the reanimation phase from the first hospital to our trauma center. Eighteen patients died due to a severe craniocerebral trauma, eight of them were transported secondarily. Six patients died due to hemorrhagic shock, only in two patients an emergency doctor was at the place of accident. Five patients died due to asphyxia after a thoracic trauma. This retrospective study clearly demonstrates that the first aid of a polytraumatized patient must be given at the place of accident by an emergency doctor, that a quick and direct transport to a regional trauma center is desirable, that a more aggressive shock therapy is necessary and that the first aid-team must be able to evacuate a tension-pneumothorax at the preclinical scene.

Biochemical and electron microscope radioautographic study of intestinal absorption of tritiated palmitic and oleic acids in control and actidione-cycloheximide-treated rats.

Intestinal absorption of tritiated palmitic and oleic acids was investigated in control and actidione-cycloheximide-treated rats. Pancreatic juice was collected and 24 hr later an intestinal loop was cannulated in situ. A 90 mumole-lipid emulsion composed of an equimolar mixture of monopalmitin, palmitic and oleic acids with bile was infused with either 3H-labeled palmitic or oleic acid. After 15 or 30 min biochemical analysis was carried out to follow the uptake and the transfer of the labeled fatty acids. Mucosa was removed for both biochemical analysis of lipid classes and the ultrastructural or radioautographic electron microscope study depending on the radioactive activity. Following actidione-cycloheximide treatment, the uptake of both fatty acids decreased, but the amount of lipids in the mucosa greatly increased, while amount of the reesterification of fatty acids in the mucosa diminished. Consequently the amount of infused palmitic acid which was transferred in 15 min decreased from 36% in the absence of treatment to 4.6% when treatment was used. The corresponding figures for oleic acid are 70% and 20.9%. Unstructured lipids were in the intercellular spaces, indicating that a cytotoxic effect had occurred which produced a defect in the lipoprotein particle organization. The Golgi complex, in the final step of the chylomicron synthesis before exocytosis, showed low level of radioautographic reaction indicating less participation by the complex in lipid transfer. The various processes which were inhibited during long-chain fatty acid absorption from the luminal area to the Golgi complex included fatty acid binding by proteins, enzymatic acylation and esterification, apoprotein participation. This inhibition explains why long-chain fatty acid absorption was greatly impaired. Moreover, our observations compared with those obtained during decanoic acid absorption, particularly our radioautography based observations, emphasize the important role of the Golgi complex which requires intense membrane turnover during lipid absorption.

[Intraenterocytic metabolism and blood uptake of caproic and oleic acids in control and actidione-cycloheximide-treated rats]. / Métabolisme intraentérocytaire et absorption par la voie sanguine des acides caprique et oléique chez le rat témoin et traité par l'actidione-cycloheximide.

Intestinal absorption of capric and oleic acids from the intestinal lumen into mesenteric portal vein blood was investigated in control and actidione-cycloheximide-treated rats using the ex vivo vascular perfusion technique. The measurement of 14C-labeled lipids, 14CO2 and 14C-labeled acid-soluble products was simultaneously carried out with blood collected at 5-min intervals for 60 min. The enterocyte catabolism of capric and oleic acids, one of which was preferentially absorbed via the blood, has been interpreted by the different processes of absorption. The greater enterocyte catabolic activity with capric acid, compared to oleic acid, could be related to the slight affinity of FABP Z for this medium-chain fatty acid and also to lack of capric acid esterification; a non-negligible fraction of this fatty acid actually disappeared from the lumen and was catabolized into the enterocyte at an early stage of its absorption. The actidione-cycloheximide treatment affected oleic acid absorption via the blood to a greater degree than that of capric acid. But it modified both intestinal blood absorption and the catabolism of the two fatty acids in the same manner.

Inhibition of protein synthesis and intestinal absorptive cell ultrastructure in cycloheximide or puromycin-treated rats.

Inhibitors of protein synthesis are useful for the investigation of some aspects of intestinal fatty acid absorption. The aim of the present study was to investigate both the biochemical and morphological effects of two inhibitors of protein synthesis on the intestinal mucosa of adult rats. Our results showed that 4 or 4 1/2 h after a single dose of cycloheximide or multiple doses of puromycin, the inhibition of protein synthesis in the jejunal mucosa, measured by the incorporation of 14C-leucine, stabilized at 60% of the controls. At the same time, these two drugs had different effects on absorptive cell morphology: cycloheximide definitely altered the apical surface of these cells, disorganizing their cytoplasm; puromycin did not modify brush border morphology but remodeled the mitochondria and the Golgi complexes.

Absorption and intestinal catabolism of fatty acids in the rat: effect of chain length and unsaturation.

Simultaneous portal blood absorption and intestinal mucosal catabolism of labelled fatty acids were investigated. Anaesthetized adult Wistar rats were infused intraduodenally either with 90 mumol of capric (C10:0), oleic (C18:1), linoleic (C18:2) or arachidonic (C20:4) 1-14C acids or with 30 mumol of each labelled fatty acid in addition to 30 mumol of oleic acid and 30 mumol of monopalmitin. For mixed infusates, experiments were carried out with two additional long-chain fatty acids: palmitic (C16:0) and erucic (C22:1) 1-14C acids. Radioactivity was quantified in the lipids and in the catabolic products in portal blood recovered at 5 min intervals for 1 h after infusion. At the end of the experiment, the disappearance of radioactivity from the mucosa was quantified. When labelled fatty acids were infused alone, 49% of the radiolabelled lipid disappearing from the mucosa was recovered in the blood for C10:0, but only 7.8% for C18:1, 6.4% for C18:2 and 10.6% for C20:4. With mixed infusates, 41% of the radiolabelled lipid disappearing from the mucosa was recovered in the blood for C10:0 compared with 12% for C18:1, 10.2% for C18:2, 10.5% for C20:4 and 2.7% for C16:0 and 2% for C22:1. Labelled catabolites appear with the same profiles as those of the respective fatty acids in blood. These studies confirm a minor absorption into blood of long-chain fatty acids compared to the medium-chain fatty acids and highlight differences in the catabolism of the fatty acids according to their chain length and their degree of unsaturation. The differences might be related to the differences in the fatty acid hydrosolubility and to their different affinities for the I- and L-cytosolic fatty acid binding proteins. These phenomena may be important in nutrition in relation to the availability of essential fatty acids.

[Intestinal lymphatic absorption of labelled oleic acid in the normal rat and rat treated with actidione-cycloheximide or acetoxycycloheximide]. / Absorption intestinale par la voie lymphatique de l'acide oléique marqué chez le rat normal et le rat traité par l'actidione-cyclohéximide ou l'acétoxycyclohéximide.

Actidione-cycloheximide or acetoxycycloheximide treated and control Rats prepared with main mesenteric lymph duct cannulation were infused with a 90 mumol lipid emulsion composed of an equimolar mixture of monopalmitin, palmitic acid and 14C oleic acid and added with bile. In control Rats 75% of 14C oleic was recovered in lymph instead of 4,5% in treated rats. Although a low amount of lipids was concerned in this experiment, actidionecycloheximide and acetoxycycloheximide strongly inhibit intestinal absorption of oleic acid in lymph.

Erucic acid metabolism in rat heart. A combined biochemical and radioautographical study.

Metabolism of Erucic Acid was studied in rat heart in comparison with that of oleic acid, particularly in relation with diet lipids. Rats were fed for 3 or 60 days a diet containing 30% of the calories of either Rapessed Oil, rich in erucic acid or sunflower seed oil rich in linoleic acid. They were I.V. injected with tritiated erucic or oleic acid. After 1 or 15 min the radioactivity recovered in heart lipids was very low whatever the diet (1 to 2%). One minute after injection of erucic acid the radioactivity was mainly recovered in the free fatty acid fraction and as untransformed erucic acid. After 15 min the major part of radioactivity was recovered in the triacylglycerol fraction which contained a high proportion of labelled oleic acid formed by shortening of erucic acid. When oleic was injected, the radioactivity was principally recovered in triacylglycerols as untransformed oleic acid whatever the experimental conditions. Electron microscopy showed that a much higher proportion of peroxisomes, was present in heart cells, following sunflower seed oil diet as compared to rapeseed oil diet. In all cases mitochondria supported the greater part of radioactivity, especially when erucic acid was injected in rats fed rapeseed oil. After sunflower seed oil, a noticeable radioactivity was observed in peroxisomes, most of them containing silver grains, especially when oleic acid was injected. According to the data reported, peroxisomes do not seem more implicated than mitochondria in the metabolism of erucic acid in myocardium.

Effect of albumin on oleic acid lymphatic absorption in rats.

1. The aim of this study was to investigate how fatty acid absorption was affected when exogenous fatty acids were complexed with albumin in absence of bile. Experiments were carried out in vivo, in order to study overall absorption processes. 2. An equimolar mixture of 14C oleic acid, palmitic acid and monopalmitin was infused intraduodenally in bile- and pancreatic juice-diverted rats. 3. Lipids were emulsified with either sodium taurocholate or fatty acids complexed with albumin. 4. Lymphatic lipid output was compared during the 6 hr following infusion of 90 mumol of the radioactive lipid mixture. 5. Lymphatic radioactive lipid recovery was significantly decreased by albumin. 6. Only 17% of the infused radioactivity was recovered in lymph when fatty acids were complexed with albumin against 37% when lipids were emulsified with sodium taurocholate. 7. Unrecovered lymph radioactivity was found at the distal part of intestine. Moreover, albumin significantly decreased lymph flow. 8. We conclude that undigested albumin acted at the luminal level of lipid absorption processes and specifically decreased fatty acid uptake.

Influence of the diet on the portal and lymph transport of decanoic acid in rats. Simultaneous study of its mucosal catabolism.

The absorption route of decanoic acid, a medium chain fatty acid, infused in the intestinal lumen in the presence and absence of long chain fatty acids, has been analyzed. Ex vivo perfusion of isolated intestinal loop and intestinal lymph fistula was the technique used. Decanoic acid infused alone was essentially transported through the portal system. If infused in association with monopalmitin, oleic or palmitic acid, up to 3% of decanoic acid could be diluted in the lymph. Moreover, decanoic acid oxidation by the mucosa increased significantly with palmitic acid and in contrast decreased with oleic acid. These data show that both intestinal absorption processes and mucosal oxidation of the medium chain fatty acids are modulated by the lipid components of the diet.

[Quantification of mRNA coding for enterocyte fatty acid binding proteins (FABP) in rats: effect of high lipid diet and starvation]. / Quantification des ARNm codant pour les fatty acid binding proteins (FABP) entérocytaires de rat: effet d'un régime hyperlipidique et du jeûne.

We have tested in adult rat the specificity and the sensitivity of two cDNA probes derived from recombinant plasmids pJG19 and pJG418. The Northern blot analysis of total RNA extracted from small bowel reveals 0.9 and 0.7 kb mRNA corresponding respectively to the I and L-FABPc mRNA. A linear relation occurs between the amounts of input total RNA and the quantities of specific mRNA found by hybridization with cDNA probes (r = 0.991 and r = 0.998 for I and L-FABPc respectively). We have also evaluated the effect of drastic nutritional status: a high fat diet containing 45% of lipids and a starvation of three days. A two fold increase in I and L-FABPc mRNA occurs in starved rats. By contrast, only the I-FABPc mRNA are slightly enhanced after the hyperlipidic diet (50%). These preliminary results, which must be confirmed by further experiments, suggest a differential nutritional regulation of I and L-FABPc gene expression in rat intestine.

Digestion and absorption of polyunsaturated fatty acids.

Polyunsaturated fatty acids play an important part in the structure and function of cellular membranes and are precursors of lipid mediators which play a key role in cardiovascular and inflammatory diseases. Dietary sources of essential fatty acids are vegetable oils for either linoleic or alpha-linolenic acids, and sea fish oils for eicosapentaenoic and docosahexaenoic acids. Because of the specificity of the pancreatic lipid hydrolases, triglyceride fatty acid distribution is an essential parameter in the digestibility of fats. The efficiency of the intestinal uptake depends on the hydrolysis and especially on their micellarization. n-3 polyunsaturated fatty acid ethyl ester digestion is recognized to be impaired, but n-3 polyunsaturated fatty acid triglyceride hydrolysis remains a controversial point, and to some authors explains differences observed between vegetable and fish oil absorption. So additional studies are required to investigate this intestinal step. In enterocytes, morphological and biochemical absorption processes involve reesterification of long-chain fatty acids and lipoprotein formation. At this level, specific affinity of I- and L-FABPc (cytosolic fatty acid binding proteins) to polyunsaturated fatty acids requires further investigation. A better understanding of the role of these FABPc might bring to light the esterification step, particularly the integration of polyunsaturated fatty acids into phospholipids. With reference to differences published between fish and vegetable oil absorption, longer-term absorption studies appear essential to some authors. Polyunsaturated fatty acid absorption is thought to be not very dissimilar to that of long-chain mono-unsaturated fatty acid absorption. However, several digestion and absorption specific steps are worth studying with reference to the crucial role of polyunsaturated fatty acids in the organism, and for example adaptation of possible dietary supplements.

Incorporation of exogenous unsaturated fatty acids in mouse jejunal explants.

Esterification processes of oleic (OA), linoleic (LA) and arachidonic acids (AA) were investigated in mouse jejunal explants with some references to age (2.5, 12 and 21 months) of the animal tissue donors. Explants were incubated either for 15 min in a stirred medium enriched with lipids or cultured for 15 min in Falcon dishes in a culture medium enriched with lipids, then for 6 h in a lipid-free medium. In 2.5-month-old mice, released lipoprotein OA secreted in the medium was especially integrated into the triacylglycerols, while LA was significantly integrated into glycerophospholipids. Triacylglycerol formation from released AA was always significantly lower than from OA. With increasing age of the animals, decreasing amounts of OA appeared in triacylglycerols. The preferential association of OA with triacylglycerols observed in jejunal explants coincided with a preferential esterification of OA observed with the enzymatic assays. The utilization of the arachidonoyl-coenzyme A by the microsomal acyltransferase was low at all ages.

Linoleic acid chyloportal partition and metabolism during its intestinal absorption.

1-14C linoleic acid intestinal absorption and simultaneous biochemical events were followed up on rats under vascular perfusion and on main mesenteric lymphatic duct fistulated rats. 1-14C linoleic acid was introduced in the duodenum alone in doses from 1.2 to 90 mumol or in the presence of oleic acid and monopalmitin (30/30/30 mumol/mumol/mumol). Mesenteric portal venous blood and chyle, respectively, were collected continuously for 1 and 6 h after the infusions. Blood-labeled lipid recovery varied from 4.7 to 2.2% of the 14C linoleic acid infused as the 14C linoleic acid dose infused increased, and dropped to 1.8% with the mixed lipid infusate. Lymph-labeled lipid recovery increased from 25.7 to 31.8% of the 14C linoleic acid infused as the dose infused increased, and rose to 48.1% with the mixed lipid infusate. The oxidation of 1-14C linoleic acid remained low: 0.8-3% of the infused radioactivity. A desaturation and elongation of 14C linoleic acid into 14C arachidonic acid was detected and discussed. We can conclude that the linoleic lymph absorption pathway remained preferential in our experimental conditions, simultaneous to a low rate of oxidation and an eventual ability for the enterocyte to convert this essential fatty acid arachidonic acid.