| 151. |
- Tuisku, Fredrik
(författare)
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Nerve fibres in relation to gingiva, tooth germs and teeth in the polyphyodont cichlid Tilapia mariae
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the late 19th century Retzius observed the presence of nerve fibres in goldfish tooth pulps. However, later studies on the relationship between the dentition and its innervation in non-mammalian vertebrates and its use in experimental research are rare. This thesis presents data on how nerve fibres are related to gingiva, tooth germsand teeth in the lower jaw of a polyphyodont teleost- the cichlid Tilapia mariae. It provides some new aspects on the structure and function of gingival and dental axons. Paper I shows that the complexity of the nodal-paranodal organization in trigeminal alveolar branch (TAB) nerve fibres decreases with decreasing fibre size, like in mammalian nerve fibres. The exceptionally thin myelinated TAB fibres of T. mariae (axonal diameters down to 0. 3 µm) exhibit nodes of Ranvier. The internodal lengths of these fibres varies between 35-50 µm. Theoretical calculations suggest that these extremely thin fibres may be capable of saltatory conduction. Paper II shows that the normal turnover time of an individual tooth (i.e. from eruption to shedding)is about 100 days. Following unilateral neurectomy of the TAB, tooth turnover stops on the denervated side of the jaw. The arrest in tooth turnover is due to a cessation of tooth germ formation. Papers III and IV show that gingival and dental domains are extensively innervated by nerve fibres exhibiting neurofllarnent-, calcitonin generelatedpeptide-, substance P-, tyrosine hydroxylase-, neuropeptide Y -,choline acteyl transferase- or vasoactive intestinal polypeptide-like itnmunoreactivity in a pattern similar to the mammalian counterpart. The rich innervation of odontogenic tissue components in T. mariae by sensory as well as autonomic axons is compatible with the results obtttined in paper II that axons may be involved in odontogenesis. Paper V shows that gingiva and tooth pulps in T. mariae are innervated by trigeminal ganglion (TG) neurons. Like in the rat, TG neurons in T. mariae differ in size and neuropeptide content depending on whether they project to gingiva or tooth pulps.While gingival neurons are exclusively small (perikaryal diameter [Pd]< 20 µm), pulpal neurons may be small or large (Pd;o: 20 µm). Hence, this seems to be an evolutionary old pattern. Taken together, the present results show that the lower jaw dentition and its trigeminal branch in T. mariae is a useful experimental system that may be used for future studies on e. g. the functional properties of the exceptionally thin TAB fibres or the molecular mechanisms behind the neuronal influence on tooth germ formation.
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| 152. |
- Valdimarsson, Trausti
(författare)
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Bone in coeliac disease
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with untreated and treated coeliac disease were examined regarding bone mineral density (BMD) and biochemical factors of importance for bone metabolism. The occurrence of disturbances and their correction during treatment with a gluten-free diet were studied. BMD was measured in the forearm using single photon absorptiometry and in the hip and spine using dual-energy X-ray absorptiometry.Among the 288 adult patients with known coeliac disease in our catchment area, 13 patients with persistent villous atrophy of the proximal small bowel mucosa despite dietary recommendation were identified and compared with matched control-patients whose intestinal mucosa had normalised at least 4 years earlier. BMD was reduced in patients with persistent villous atrophy but within normal limits in patients responsive to the diet.In 105 adult patients with untreated coeliac disease, HN.ID was reduced compared to a local healthy control group. During the first year on a gluten-free diet the BMD increased rapidly (by a median of 3 %in the spine) even in patients with minor symptoms and in older patients. Secondary hyperparathyroidism was found in 27% of untreated patients and these patients had more severely reduced BMD compared to those with normal initial parathyroid hormone. Twenty-three % of the untreated patients also had low serum calcidiol (25-hydroxyvitarnin D) levels. BMD continued to increase in the second and third follow-up years, but only became normal within three years in the group of patients without initial secondary hyperparathyroidism.In 29 consecutive adult patients with untreated coeliac disease, serum insulin-like growth factor I and BMD were lower than in matched controls. In 14 untreated patients with normal parathyroid hormone values the increase in insulin-like growth factor I correlated positively to the increase in BMD during the first year after starting a gluten-free diet.In 46 adult patients with coeliac disease trt;atedfor 8-12 years in routine care, median BMD was normal but five patients who did not follow strict gluten-free diet had a lower BMD in the femoral neck than the group of 41 patients who claimed strict adherence.TI1ese studies show that untreated coeliac disease is associated with a low B:MD. BMD inereases rapidly when a gluten-free diet is followed, even in older patients. Circulating insulin-like growth factor I may reflect some changes in hone metabolism but its pathogenetic role behind the low BMD seen in adults with coeliac disease is unclear. Secondary hyperparathyroidism is common and vitamin D deficiency also seems to be an important underlying mechanism. These findings underline the importance of a gluten-free diet for all patients with coeliac disease.
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| 153. |
- Vasar, Marie
(författare)
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Allergic diseases and bronchial hyperreactivity in Estonian children in relation to environmental influences
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on the cross-sectional and prospective study of Estonian children. The aim of this thesis was to assess the prevalence of allergic diseases and respiratory symptoms in Estonian schoolchildren and in young children, to study environmental risk factors for allergic diseases and repiratory symptoms. The cross-sectional study was a part of an epidemiological study in Northeastern part of Europe of the same age group and using standardised methodology in order to allow meaningful comparisons between the countries. The Estonian study was extended to include more extensive assessment of lung function to assess bronchial hyperreactivity (BHR) in Estonian schoolchildren.1580 schoolchildren from Tallinn and Tartu participated in a cross-sectional study which included parental questionnaires, skin-prick tests, serial peak-flow measurements, methacholine provocation and exercise challenge tests.Among 10-12 year-old schoolchildren the prevalence of asthma was lower than in children of similar age in Sweden (2.9% vs 8.1% ). In contrast to the low prevalence of atopic diseases, the frequent respiratory infections were more common among the Estonian schoolchildren than in Sweden. Respiratory symptoms and allergic disorders in Tall inn, compared to Tartu showed a similar tendency as the urban-rural gradient in Sundsvall, Sweden. These findings suggest an influence of air pollutants and other adjuvant factors, as related to urbanisation in both countries. Atopic heredity, current dampness and maternal smoking were significant risk factors for the respiratory symptoms in Estonia. The prevalence of BHR to methacholine was 19% in Tall inn and 32% in Tartu (pIn prospective study 298 healthy, consecutively born newborn babies werefollowed from birth up to 2 years of age. Skin-prick tests with fresh food allergens and inhaled allergens were carried out at 6, 12, and 24 months of age. Symptoms of allergy were searched by employing questionnaires at 3, 6, 9, 12 and 24 months of age.The prevalence of allergic diseases .increased from 8% at 6 months to 17% at 24 months. The cumulative incidence of allergy was 25%, and atopic dermatitis was the main manifestation of atopy with a peak prevalence of 15% at 2 years of life. Asthma was present in 4 children and allergic rhinoconjunctivitis in 2 children at 2 years. The results of our prospective study showed that prevalence of allergy among Estonian young children was not as low as would be expected. This could possibly indicate that 'western lifestyle' has already affected the infant population born in 1993/94.
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| 154. |
- Vavruch, Ludek
(författare)
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DNA content, proliferation markers and histopathology as prognostic factors in Astrocytic tumours
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The DNA index and S-phase fractions obtained from freshly frozen and paraffin-embedded specimens of 49 primary intracranial tumors showed significant correlation. Very similar results were obtained when a subgroup of astrocytomas was analyzed. Thus, the feasibility of DNA-flow cytometry for retrospective studies of archival tumor specimens was confirmed. In a study of 134 astrocytomas a strong correlation between grade of malignancy, S-phase fraction and DNA ploidy type was seen. In multivariate Cox regression analysis of 60 cases with grade II or Ill astrocytomas, age, grade of malignancy, DNA ploidy and S-phase were independent prognostic factors. An age of under 50, grade II, low S-phase and tetraploid DNA pattern correlated with long survival. Twenty-two recurrent astrocytomas were investigated after primary and repeated surgery. The grade of malignancy had significantly increased at the time of re-operation. The S-phase also tended to increase while the DNA-index was essentially unchanged. In recurrent astrocytomas the original_grade of malignancy was the most important prognostic parameter, which significantly correlated with time to recurrence and with survival after reoperation. The recurrence-free interval was significantly shorter in patients over 50 years of age and patients with an aneuploid DNA pattern at the time of the first surgery. However, when DNA ploidy, histopathological grade and age were evaluated simultaneously in a multivariale analysis, DNA ploidy was not an independent prognostic indicator. A strong correlation was found between the cell replication measured as Ki-67 labeling index and grades of malignancy at primary and repealed surgery. When less than 10 percent of cells were stained by Ki-67 after primary surgery, patient survival was prolonged approximately three times compared to survival of patients with a high Ki-67 labeling index.
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| 155. |
- Vergis, Anil, 1961-
(författare)
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Sagittal plane knee translation in healthy and ACL deficient subjects : a methodological study in vivo with clinical implications
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study on human subjects, comprises of four cross sectional and one prospective cohort study. The general purpose of this work was to develop a technique for measuring in vivo, sagittal anterior-posterior translatory motions in the knee joint using a computerized electrogoniometer (CA-4000, OS Inc., Hayward CA, USA). Healthy human subjects served as controls while patients with arthroscopically confirmed unilateral ACL deficiency served as the experimental group.The measurements were repeatable, accurate and valid. In all groups, as a consistent pattern, the tibia maintained an anterior position in relation to the femur during the load bearing phases and a posterior rosition in the non load bearing phases of step ascents and descents. Contraction of the gastro-soleus grour of muscles, before the lift off phase of ascent, resulted in an anterior positiOn of the tibia in relation to femur which was anterior to the posterior limit of static laxity testing. Step heights between 15 to 23 cm did not influence the amount of tibial translation.During step ascent the amount of femoral roll-forward per degree extension was significantly smaller in the ACL deficient knees than the contralateral noninjured or healthy control knees.ACL deficiency resulted in a larger than normal static space (125% to 257%) in the injured knees. It also resulted in an anterior shift of the tibia-femoral resting position of the injured knees.The amount of the static laxity space the ACL deficient knee utilised during stair climbing varied, depending upon the knee flexion angle. Nearer to extension it was 90% and near to mid flexion (50°--{50°) it was 42% of the maximal static laxity space. In the conservatively treated ACL deficient group, the contralateral healthy knees showed 28% increase in the static AP laxity at follow up when compared to the index measurement and the control knees.In the ACL reconstructed group, the increased static AP laxity and anterior shift of the tibia-femoral resting position in the reconstructed knees persisted at a minimum follow up of 21 months. Over the same period of time, the contralateral healthy knee also showed an anterior shift in the tibia-femoral resting position. The force at the anterior inflection point in static laxity testing, which was similar at index examination in both knees, diminished by 20% in the reconstructed knees at follow up.The ACL plays an important role in optimally positioning the tibia-femoral articulation and maintaining the position during quadriceps and gastro-soleus muscle contraction.
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| 156. |
- Vitak, Bedrich
(författare)
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Interval cancers, positive predictive value for malignance and other early quality indicators in mammographic screening for breast cancer
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The study was designed to evaluate early quality indicators in screening for breast cancer. lt comprised, (i) investigations of compliance, recall, referral, cancer detection, and interval cancer rates in the Östergötland screening programme of women aged 40-74 years; (ii) evaluation of the three-stage diagnostic procedure for pre-operative assessment of women with suspicious mammographic findings; (iii) comprehensive analysis of all invasive interval cancers detected; and (iv) investigation into how to reduce the number of interval cancers without a concomitant increase in false positives.The attendance rates were 85.5% at the initial screen and 81.3% at subsequent screens. The referral rates for further examination at subsequent screens were roughly half of th'lt at the initial screen. The cancer detection rates were 6.4/1000 at the initial and 2.6/1000 at subsequent screens. The positive predictive value for malignancy at surgery was 96% for ages 50-74 years. Apart from the tumour grade (not analysed) the diagnostic outcome tallied with the quality targets stipulated by Tabár et al.The study confirmed the less favourable prognosis for interval cancer patients and cancers in non-attenders compared to screen-detected patients, but the mode of detection was not an independent predictor of metastatic capacity (hazard rate ratio [RR] of distant recurrence /adjusted for other variables/ RR=1.39, 95%confidence interval [95%CI] 0.78-2.46 for interval cancers; and RR=1.6, 95%CI 0.76-3.36 for non-attenders). The higher metastatic potential in these tumours could be explained by the differences in tumour characteristics at the time of diagnosis.The incidence risk of interval cancer was 0.46/1000 for tumours detected within 1 year of the latest screen, and 1.2/1000 for tumours detected within 2 years of the latest screen. Despite the lower age-specific breast cancer incidence in women aged 40-49 years, these women ran roughly the same risk of interval cancer after a negative screen as did the other age groups in the screening programme.Patients with potential iatrogenic delay in diagnosis (overlooked or misinterpreted cancers) constituted 25% of all patients with invasive interval cancer, and patients with true interval cancer 49%. The radiological category of interval cancer had no significant influence on the survival (overall comparison, p=0.1202; comparison of true interval with missed interval cancers, p=0.3175). In the present study there was no clear evidence of difference in prognosis between true interval and overlooked or misinterpreted interval cancers.The interval between the latest screen and diagnosis was not an independent prognostic factor in patients with true interval cancers (RR=0.47, 95%CI 0.16-1.35 for tumours detected 21 year after the latest screen), and there was no significant difference in survival according to this interval (comparison of tumours detected <1 year with tumours detected 21 year of the latest screen, p=0.3844).The study confirmed the association of criteria for referral for further examination with number of false positives. Efforts to reduce the number of interval cancers by lowering the mammographic threshold for recall are likely to be counterproductive. The early quality indicators constitute. an excellent means of monitoring of the quality of screening.
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| 157. |
- Wandt, Birger
(författare)
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Mitral Ring Motion in Assessment of Left Ventricular Function
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The motion of the mitral ring was studied with M-mode echocardiography using the apical four- and two-chamber views.With the purpose of obtaining adequate reference materials for mitral ring motion, 70 healthy subjects were studied. Stepwise multiple regression analysis with age, gender, height, weight, body i surface area and heart rate as independent variables, showed that ring motion amplitude (mm) is best i described as 2.2 + 0.078 x height (cm) (SD = 1.0 mm) in subjects under age 18, and as 12.7- 0.060 [ x age (years)+ 0.031 x height (cm) (SD = 1.2 mm) in subjects over age 18, or if only age is taken ! into account as 18.4-0.065 x age (SD = 1.2 mm).Both in children and adults the atrial contribution to the total mitral ring motion was best described as 0.15 + 0.0039 x age (SD = 0.027).Comparison between the four sites of measuring showed that the mitral ring "tilts" slightly during the systolic motion towards the apex. The septal point moved significantly less than the lateral point (pIn 20 healthy subjects changes in mitral ring motion and in short axis contractions with respiration was studied. It was shown that the decrease in left ventricular stroke volume on inspiration is a net effect of decrease in diastolic short axis diameter by 4.8% (p<0.001) and an increase in mitral ring motion by 5.5% (p<0.001).In 40 healthy subjects aged 18 - 70 years changes in long axis and short axis contraction with increasing age was studied. It was shown that from age 18 to age 70 the long axis systolic shortening[ decreases by 20% (p<0.001) and minor axis shortening increases by 18% (p=0.012). These findings have important implications for the calculation of ejection fraction (EF) from M-mode measurements.In 16 patients with left ventricular hypertrophy because of hypertension or hypertrophic cardiomyopathy, ejection fraction calculations were made by Teichholz' formula, by the equation EF 1'[ (%)=mitral ring motion (mm) x 5 and by Simpson .. s rule. Radionuclide angiography was used as , gold standard for ejection fraction. The study showed that in patients with hypertrophy Teichholz .. formula overestimates ejection fraction by 10% (6.7 EF%) (p--Q.002). Calculation by using mitral ring motion x 5 underestimates the ejection fraction by 19.3% ( 12.9 EF%) (p=0.002). Compared to healthy controls the hypertrophy group had 28.9% decreased mitral ring motion (pMaximal longitudinal diastolic relaxation velocity was investigated in 22 patients on day 3-21 after first transmural myocardial infarction. The maximal diastolic slope was measured on the M-mode recording from the mitral ring motion. Compared to healthy controls the patients had significantly decreased relaxation velocity (p
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| 158. |
- Warner, Aina M.
(författare)
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Childhood asthma and indoor environment
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background:During the last decades, the prevalence of asthma in childhood has increased in Sweden as well as in the rest of the western world. Some factor or factors in the indoor environment may be responsible for this. Asthma development and the precipitation of asthma symptoms is dependent on sensitivity to inhalation allergens, of which indoor allergens are of special interest because they are not seasonal. Other factors, such as humidity and inorganic compounds may have a direct effect on the development or the symptoms of asthma. This may be due to an enhancing effect on sensitivity.Aims:To find relevant indoor factors for asthmatic children with perennial symptoms living in three climatic zones in Sweden. One part of the thesis was a study on the importance of known indoor allergens on the sensitivity and asthmatic symptoms, the other part aimed at finding new potential allergens that may explain the symtomatology.Patients and methods:148 children from Helsingborg, Linköping and Umeå, representing three climatic zones in Sweden were enrolled in the project. They answered a questionnaire which recorded their medication and symptoms, computed to an asthma score, their indoor environment, allergic reactions to dust and animal contacts. Skin tests and blood tests were used to assess sensitivity to indoor allergens.House dust samples from three locations in the house were analysed with ELISA for detection of indoor allergens (Der p 1, Der f 1, Der m 1, Fe/ d 1, Canf I, Per a !), and for microscopic identification and counting of mites and insects.In 60 homes a thorough environmental investigation was done by specialised engineers, who judged the house structure, measured ventilation efficiency, humidity, volatile organical compounds and particles. Dust was collected for analysis of moulds, bacteria and endotoxin levels.Results: Serum IgE antibodies to inhalation allergens were found in 80 % of the children. Aoimal dander allergens dominated in terms of frequency of sensitivity (62%), followed by pollen (54%) and mites (35%). Sensitivity to mites was dominating only in the south, animal dander allergens dominated in the north. Sensitivity to animal dander, pollen and mites was associated to an elevated asthma score.Aoimal dander allergens were found in all homes, even in homes without pets. Occasional visits by pets augmented the allergen levels.Current level of exposure at home to house dust mites and storage mites was associated with sensitivity, even at low levels, in contrast to animal allergens at home. Mite allergen levels were usually highest in the bedroom samples, but in 115 of the homes the living-room samples had the highest levels in the home. Humid homes had higher mite allergen levels than dry and well ventilated homes. The use of mite allergens as environmental assays of mite may underestimate exposure levels, if all relevant allergens are not included, for example Der m I.Other mites as well as insects are potential new allergen sources.Discussion and conclusion:The home environment contains allergens from animal dander as well as mites and insects. Insufficient ventilation and excess humidity offers a milieu that enhances growth of mites, and has an effect on asthmatic symptoms in its own right. The outdoor climate has an influence on the indoor climate in the number and species of mites found, but in homes with hi!ih humidity mite allergens may reach very high levels also in regions where mites normally are not founs, such as the northern part. Indoor allergens are important for the sensitivity and symptoms of asthmatic children with perennial symptoms.
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| 159. |
- Wei, Xiaochun
(författare)
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Maturation-dependent normal and injury-induced changes in rabbit knee articular cartilage
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cartilage injuries are common in sports, and may on the long term develop to osteoarthritis. Prosthetic joint replacement is not satisfactory for young active individuals with extended cartilage injuries in large weight-bearing joints. In these cases, a treatment is needed which reestablishes normal joint surfaces by biologic means. Though different cartilage repair enhancing methods have been tried, up till now none of them has achieved regrowth of hyaline cartilage which duplicates the structure and functions of normal articular cartilage. More knowledge is needed to understand the response of articular cartilage to injury. Moreover, a better understanding of how articular cartilage develops may open ways to improve the repair response. The purpose of this work was to investigate maturation-related changes of articular cartilage during postnatal maturation, and to investigate the natural healing response to full-thickness cartilage injury as a function of maturation stage.Physiologically, proteoglycan fragment concentrations in knee joint fluid decreased with maturation, and were inversely correlated with the maturation stage of the rabbits (r =- 0.69). The relatively high proteoglycan fragment concentrations in young animals might be the result of a higher turnover rate of proteoglycans in growing articular cartilage. The stiffness of articular cartilage in the rabbit knee joint decreased with maturation and was associated with an increase of subchondral bone volume fraction, and on the same time a substantial change in subchondral morphology. The results suggest that cartilage mechanics may also depend on the structural characteristics of subchondral bone.Cartilage repair in young rabbits showed a faster filling of an osteochondral defect, and an earlier differentiation to hyaline-like cartilage than repairs in adult ones. The higher repair quality in young animals compared with the adults remained up to 48 weeks. Repairs in initially adolescent and adult animals showed furthermore signs of progressing degeneration between 12 and 48 weeks with decrease of the amount of hyaline-like cartilage in the tissue. However, irrespective of age, surface disruption of the repair was common, and no repair achieved regeneration to normal articular cartilage. The compressive stiffness of the repair tissues was always markedly softer compared with normal cartilage.In preoperative joint fluid samples, TGF-ß1 decreased with maturation, and was moderately correlated with the proteoglycan fragment concentrations. Shortly after trauma, the concentrations of both substances were found increased, which was followed by a decrease up to 3 months, and then again an increase up to one year. However, meanwhile proteoglycan fragment concentrations had similar magnitude irrespective of age, TGF-ß1 concentrations never reached similarly high levels in adulthood as in infancy or adolescence. The cartilage adjacent to the defect had more signs for degeneration in younger rabbits. The similar patterns of TGF-ß1 and proteoglycan fragment concentrations during postnatal maturation may reflect the stimulatory effect of TGF-ß1 on proteoglycan synthesis. The higher TGF-ß1 concentrations in younger animals may be a reason for their better healing capacity, but also for their higher susceptibility to osteoarthritic change compared with the adult animals
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| 160. |
- Wigren, Jane, 1967-
(författare)
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Identification of natural activators of the nuclear receptor peroxisome proliferator-activated receptor : relevance to the pathogenesis of atherosclerosis
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polyunsaturated fatty acids induce peroxisome proliferation. This phenomenon is mediated by the ligand-dependent transcription factor peroxisome proliferator-activated receptor (PPAR). This thesis is an investigation on the role of eicosanoids and oxidized products of linoleic acid for the activation of PPARs. Special emphasis was given to the subtype PPAR/gamma/ in the context of atherosclerosis.It had earlier been shown that arachidonic acid induces peroxisome proliferation in Morris Hepatoma 7800C1 cells. We investigated whether this effect could be attributed to a cytochrome P-450IVA product of arachidonic acid, 20-hydroxy-arachidonic acid. Arachidonic acid, but not 20-hydroxy-arachidonic acid induced lauryl-CoA oxidase activity. The effect of arachidonic acid was potentiated by all-trans retinoic acid, consistent with the notion that PPAR/RXR heterodimers mediate the effect.Several reports in the litterature were suggestive of an important role of peroxisomes in eicosanoid metabolism. However, nobody had isolated pure peroxisomes and investigated their eicosanoid metabolizing ability. We therefore investigated the ability of peroxisomes to metabolize the eicosanoid 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(S)-HETE). Incubation of tritium-labeled 12(S)-HETE with isolated peroxisomes from rat liver or kidney peroxisomes demonstrated that more than 90 % of the diethyl ether extractable radioactivity was due to a single metabolite, identified as 8-hydroxy-6, 8, 12-octadecatrienoic acid (8-OH-16:3). This compound was apparently formed by two rounds of ß-oxidation. The data for the first time provided conclusive evidence for a role of peroxisomes in HETE metabolism.The second half of the thesis deals with the identification of natural PPAR/gamma/ ligands in LDL from atherosclerotic patients and in activated macrophages. Analyses of the endogenous content of selected monohydroxy fatty acids in LDL isolated from a group of patients diagnosed with intermittent claudication, showed the presence of 9- and 13-HODE, 5-, 12-, and 15-HETE. These compounds activated PPAR/gamma/ in macrophages and preferentially recruited the coactivator protein CBP to PPAR/gamma/RXR/alpha/ heterodimers. 15-deoxy-/DELTA/12,14-Prostaglandin J2 (15-deoxy-/DELTA/12,14-PGJ2) was identified as a PGD2 metabolite in macrophage cultures (see below). It induced the interaction of PPAR/gamma/RXR/alpha/ heterodimers with both CBP and SRC-1. This observation suggests that different PPAR/gamma/ ligands may induce different effects through a single kind of receptor by differential recruitment of coactivators.Although PGD2, is not a PPAR/gamma/ ligand, it induces PPAR/gamma/-mediated effects in IFN-/gamma/-stimulated RAW 264.7 macrophages, suggesting that the effects required metabolism. We therefore investigated PGD2 metabolism in macrophage cultures, and determined the capacity of these metabolites to activate PPAR/gamma/. Two novel (/DELTA/12-PGD2, 15-deoxy-/DELTA/12,14-PGD2) and two previously known PPAR/gamma/ activators (/DELTA/12-PGJ2 and 15-deoxy-/DELTA/12,14-PGJ2) were identified by mass spectrometry. The structural difference between the novel products and the previously recognized PPAR/gamma/ agonists , /DELTA/12-PGJ2 and 15-deoxy-/DELTA/12,14-PGJ2, is that they contain a 9/alpha/-hydroxy group and lack a /DELTA/9,10 double bond. Two novel PPAR/gamma/ activators were formed in equal or greater amounts and were more potent activators of PPAR/gamma/ in macrophages.
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