Facial anatomy applied to live models / Anatomia facial aplicada em modelos vivos

Introduction: Anatomy is one of the foundations in medicine, and choosing a practical and dynamic teaching method is essential for better retention of your learning. The objective is to use facial anatomy applied to live models as an innovative teaching strategy and to evaluate the experience of the learning experience of students assigned to the method. Method: The work analyzes the experience with body painting of 51 students from Instituto Boggio assigned this method (or instructed to use this method) during their classes. Different planes and anatomical structures were represented on live models' faces to simulate and teach the main injectable cosmetic procedures; syringes, needles, cannulas, and ultrasound gel stained with food inks were used. Overlapping latex layers were used for the anatomical study of the temple, middle third of the face, and nose, allowing the reproduction of fillers and biostimulators in these regions. The main muscle groups were represented for the discussion of high-precision botulinum toxin. After the entire demonstration, the students answered a questionnaire via "Google Forms" evaluating the methodology used. Results: According to the answers to the questionnaires, most students considered body painting an innovative methodology that contributed to learning anatomical content and satisfactorily illustrating the demonstrated cosmetic procedures. Conclusion: Practical learning through live models makes this new teaching method something innovative and unique that, in an enjoyable way, enables the study of anatomy and appropriately trains clinical skills.

Introdução: A anatomia é um dos principais alicerces no exercício da medicina e a escolha de um método de ensino prático e dinâmico é fundamental para melhor retenção do seu aprendizado. O objetivo é utilizar a anatomia facial aplicada em modelos vivos como estratégia inovadora de ensino e avaliar a experiência do processo de aprendizagem dos alunos submetidos ao método. Método: O trabalho analisa a experiência vivida com a pintura corporal por 51 alunos do Instituto Boggio submetidos ao método durante as aulas ministradas. Diferentes planos e estruturas anatômicas foram representados nas faces de modelos vivos. Para simulação e ensino dos principais procedimentos cosmiátricos injetáveis, seringas, agulhas, cânulas e gel de ultrassom corado com tintas alimentícias foram utilizados. Camadas de látex sobrepostas foram utilizadas para estudo anatômico da têmpora, terço médio da face e nariz, possibilitando a reprodução do uso de preenchedores e bioestimuladores nestas regiões. Os principais grupamentos musculares foram representados para discussão sobre toxina botulínica de alta precisão. Após toda a demonstração, os alunos responderam a um questionário via "Formulários Google" avaliando a metodologia utilizada. Resultados: De acordo com as respostas dos questionários, a maioria dos alunos considerou a pintura corporal como uma metodologia inovadora e que contribui no aprendizado do conteúdo anatômico, bem como ilustra satisfatoriamente os procedimentos cosmiátricos demonstrados. Conclusão: A aprendizagem prática por meio dos modelos vivos faz deste novo método de ensino algo inovador e único que, de maneira lúdica, possibilita o estudo da anatomia e o treinamento de habilidades clínicas adequadamente.

Comparison of the Physical Characteristics and Behavior in ABC Transporter A1, A7 or Apolipoprotein E Knockout Mice with Lipid Transport Dysfunction.

The physical characteristics and behavior of the ATP-binding cassette (ABC) A1, A7, and apolipoprotein (apo) E knockout (KO) mice with lipid transport dysfunction were investigated. These KO mice exhibited adequate growth, and their body masses increased steadily. No remarkable changes were observed in their blood pressure and heart rate. However, there was a slight increase in the heart rate of the ABCA7 KO mice compared with that of the wild-type (WT) mice. ABCA1 and apoE KO mice showed hypo- and hyper-cholesterol concentrations in the plasma, respectively. With regard to the cerebrum, however, the weight of the ABCA1 KO mice was lighter than those of the other genotypes. Furthermore, the cholesterol, triglyceride and phospholipid concentrations, and fatty acid composition were generally similar. Compared with the WT mice, ABCA1 KO mice stayed for a shorter time in the closed arm of the elevated plus maze, and performed worse in the initial stage of the Morris water maze. To thermal stimuli, the ABCA1 and apoE KO mice showed hyper- and hypo-sensitivities, respectively. Only the response of the ABCA1 KO mice was significantly inhibited by pretreatment with indomethacin. A low concentration of the prostaglandin E metabolites was detected in the plasma of the ABCA1 KO mice. Thus, ABCA1 is thought to play a specific role in the neural function.

The Development of the Arm Fixation Method to Prevent Ipsilateral Shoulder Pain in Patients Undergoing Lung Resection.

PURPOSE: The aim of the present study was to investigate the efficacy of a new upper limb fixation method-body pillow position for preventing postoperative ipsilateral shoulder pain (ISP) in patients undergoing lung resection. DESIGN: An experimental study design was used. METHODS: We conducted two comparisons (group A: the previous position using the arm fixation device; group B: the body pillow position) at random and examined an arm fixation method that is effective for ISP prophylaxis in patients undergoing surgery in the lateral decubitus position. FINDINGS: We approached 87 patients, two were excluded, and, thus, 85 were randomly assigned to group A (n = 43) or group B (n = 42). No significant differences were observed in the frequency of ISP between groups A and B (25.6% vs 26.2%). The intensity of ISP between both groups was analyzed by a repeated-measures analysis of variance and was shown to decrease over time in 22 patients (P = .010). The intensity of ISP on postoperative days 0 to 3 was slightly lower in group B than in group A (P = .158). Risk factors for ISP were the duration of surgery (odds ratio, 1.01; 95% confidence interval, 1.00 to 1.01) and pre-existing shoulder stiffness (odds ratio, 5.15; 95% confidence interval, 1.07 to 24.83). CONCLUSIONS: There was no significance in the frequency of ISP between group A and group B. The intensity of ISP on postoperative days 0 to 3 was lower in group B than in group A, although there was no significant difference. It is important perspective for perioperative care providers to prevent ISP for early postoperative recovery and improvement of postoperative quality of life. These results suggested that we must consider a better position for preventing postoperative ISP in patients undergoing lung resection.

Effects of adipokine administration to the hypothalamic preoptic area on body temperature in rats.

The effects of adipokine administration to the hypothalamic preoptic area (POA), which is one of the body temperature (BT) regulation centers in the central nervous system, on BT were investigated in male Wistar rats. BT was measured in conscious rats using telemetry. Insulin-like growth factor-1 (IGF-1), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 and lipocalin-2 produced hyperthermia, and the effects induced by IL-1ß (25 ng) and IGF-1 (5 µg) were sustainable and remarkable. IL-6 did not show any significant effect. The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK). NVP-induced inhibition was observed only in the early phase of IGF-1-induced hyperthermia. In addition, IGF-1 increased the IL-1ß concentration in the microdialysate of POA perfusion, but did not increase the IL-1ß concentration in the plasma or the PGE2 concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1ß concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA.

Dietary soybean oil, canola oil and partially-hydrogenated soybean oil affect testicular tissue and steroid hormone levels differently in the miniature pig.

The present study was conducted to examine the influence of dietary canola oil (CAN) and partially-hydrogenated soybean oil (HSO) compared to soybean oil (SOY, control) on the morphology and function of testes using miniature pigs as the test subject. Male miniature pigs were fed a diet containing 10%SOY, 9%CAN+1%SOY, or 9%HSO+1%SOY for 18 months. The scheduled autopsies revealed no abnormalities in histopathological examination of the major organs, except the testes. Atrophy of the seminiferous tubules and hyperplasia in the Leydig cells were found in the SOY and CAN groups. DNA microarray analysis indicated downregulation in the CAN and the HSO groups of genes encoding for gonadotropins in the pituitary gland and of enzymes and proteins involved in steroid hormone metabolism in the testes, compared to the SOY group. Plasma levels of sex hormones in the CAN and HSO groups tended to be higher and testosterone and dihydrotestosteorne in the HSO group were significantly higher than in the SOY group. These results demonstrate that testes are morphologically and functionally affected by the dietary oils, while the plasma steroid hormone levels do not necessarily reflect the gene expression, probably owing to feedback regulation via the gonadal hormones in the hypothalamus-pituitary-gonadal axis.

Ipsilateral shoulder pain in patients following lung resection in the decubitus position.

AIMS AND OBJECTIVES: To examine the frequency, influencing factors and clinical course of shoulder pain in patients following lung resection. BACKGROUND: Thoracoscopes have been introduced in the surgical treatment of lung cancer and allow for less invasive surgery with a minimal incision. However, decubitus position-related shoulder pain on the operated side has not yet been investigated. DESIGN: A longitudinal descriptive study. METHODS: Patients who underwent lung resection in the decubitus position. Patients were interviewed 2 days before surgery and once daily for 5 days after surgery. Interview items included background data, the concomitant use of epidural anaesthesia, operative duration, the presence of preoperative shoulder stiffness (excluding shoulder pain), type of surgery and site of operation. The intensity of pain was approximately 5 on an 11-point numerical rating scale. Descriptive statistics on patient backgrounds were obtained using SPSS Statistics 22 for Windows. RESULTS: Of the 74 patients who underwent lung resection in a decubitus position, 30 (40.5%) developed shoulder pain on the operated side. The highest rating occurred 1 day after surgery and decreased over time. The following two factors were found to influence shoulder pain on the operated side: operative duration (Z = -2.63; p = .01) and the presence of preoperative shoulder stiffness (excluding shoulder pain) (χ2  = 4.16; p = .04). CONCLUSIONS: This study demonstrated that approximately 40% of patients who underwent lung resection in the decubitus position developed shoulder pain. RELEVANCE TO CLINICAL PRACTICE: The presence of postoperative shoulder pain was related to both the duration of the operation and to the presence of preoperative shoulder stiffness. Although the shoulder pain resolves within 4 days, it causes the patient additional discomfort and distress. Therefore, further research is needed on positioning for thoracotomy in order to investigate ways to reduce or eliminate this complication of lung surgery.

Long-term high-soybean oil feeding alters regulation of body temperature in rats.

We investigated whether body temperature (BT) regulatory mechanisms are influenced by dietary fatty acids (FA). Male Wistar rats were fed a high-fat diet containing fish oil (HFD), soybean oil (HSD) or lard (HLD). At the 20-week intervention, the BT of the HSD and HLD groups were lower than that of the normal diet (ND) group in the light and dark periods. The intracerebroventricular injections of interleukin-1ß and bombesin in the HSD group induced greater hyperthermia and weaker hypothermia, respectively, than in the ND group. The HSD differentially affected BT under both physiological and pharmacological conditions. In the hypothalamus, the ratio of n-6/n-3 FAs was higher in the HSD group compared with the ND group. DNA microarrays revealed increased expression of thyroid-stimulating hormone ß-subunit, and decreased expression of several genes in the hypothalamus of the HSD group compared with the ND group. The HSD feeding increased several adipokine concentrations in the plasma. However, there were no adipokines or gene expressions that changed in only the HSD and HLD groups showing significant hypothermia under the physiological condition. These findings suggested that long-term HSD intake produces abnormal BT regulation. It is less likely that adipokines or proteins/peptides are involved in abnormal BT regulation under the physiological conditions after HSD feeding.

Three dissimilar high fat diets differentially regulate lipid and glucose metabolism in obesity-resistant Slc:Wistar/ST rats.

Epidemiologic and ecologic studies suggest that dietary fat plays an important role in the development of obesity. Certain Wistar rat strains do not become obese when fed high-fat diets unlike others. In a preliminary study, we confirmed that Slc:Wistar/ST rats did not become obese when fed high-fat diets. The mechanisms governing the response of hepatic lipid-metabolizing enzymes to large quantities of dietary lipids consumed by obesity-resistant animals are unknown. The aim of the present study is to examine how obesity-resistant animals metabolize various types of high-fat diets and why they do not become obese. For this purpose, male Slc:Wistar/ST rats were fed a control low-fat diet (LS) or a high-fat diet containing fish oil (HF), soybean oil (HS), or lard (HL) for 4 weeks. We observed their phenotypes and determined lipid profiles in plasma and liver as well as mRNA expression levels in liver of genes related to lipid and glucose metabolism using DNA microarray and quantitative reverse transcriptase polymerase chain analyses. The body weights of all dietary groups were similar due to isocaloric intakes, whereas the weight of white adipose tissues in the LS group was significantly lower. The HF diet lowered plasma lipid levels by accelerated lipolysis in the peroxisomes and suppressed levels of very-low-density lipoprotein (VLDL) secretion. The HS diet promoted hepatic lipid accumulation by suppressed lipolysis in the peroxisomes and normal levels of VLDL secretion. The lipid profiles of rats fed the LS or HL diet were similar. The HL diet accelerated lipid and glucose metabolism.

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation.

Glial cells missing Drosophila homolog a (GCMa) is a member of the GCM transcription factor family and plays critical roles in trophoblast differentiation and placental functions. It is well established that the cyclic AMP (cAMP)-dependent pathway induces the expression and transcriptional activity of GCMa by regulating post-translational modifications of GCMa, which results in enhancement of trophoblast differentiation. We previously observed that phorbol 12-myristate 13-acetate (PMA) stimulates phosphorylation of GCMa on serines 328, 378 and 383 through the protein kinase C (PKC)- and mitogen-activated protein kinase kinase (MEK)/extracellular signalregulated kinase (ERK)-dependent pathway, which decreases the protein stability of GCMa. Here we report that PMA increases the ubiquitination level of GCMa, dependent on the phosphorylation of GCMa on serines 328, 378 and 383. We found that this phosphorylation also stimulates the transcriptional activity of GCMa. Our data indicate that the PMA-induced PKC- and MEK/ERKdependent pathway enhances the degradation as well as the transcriptional activity of GCMa. We also examined the impact of this signaling pathway on trophoblasts and the results suggest that the PKC- and MEK/ERK-dependent pathway is involved in the regulation of trophoblast differentiation.

PMA induces GCMa phosphorylation and alters its stability via the PKC- and ERK-dependent pathway.

The glial cells missing a (GCMa) transcription factor plays a pivotal role in the placental development by regulating the expression of several genes in the placenta that are responsible for the proper formation of the syncytiotrophoblast. It is well known that the function of GCMa is regulated at both transcriptional and post-translational levels by the cyclic AMP (cAMP)/protein kinase A (PKA)-dependent pathway, the activation of which increases the GCMa protein level and leads to trophoblast differentiation into the syncytiotrophoblast. However, little is known about the regulatory control of GCMa by PKC-dependent signaling mechanism(s). To investigate whether GCMa is regulated by PKC-dependent pathway, we treated the human choriocarcinoma JEG-3 cells with phorbol 12-myristate 13-acetate (PMA) and studied its effect on the GCMa protein using a monoclonal anti-GCMa antibody we prepared. PMA caused a transient decrease in the endogenous GCMa protein level in JEG-3 cells that was accompanied by an increase in GCMa phosphorylation. The phosphorylation and degradation of GCMa by PMA treatment was effectively reduced by pretreatment with protein kinase C (PKC) inhibitors and a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor, indicating a PKC- and MEK-dependent mechanism. Furthermore, we identified the serine residues 328, 378 and 383 to be the phosphorylation sites on GCMa that are involved in the PMA-induced degradation of GCMa. Our data demonstrate for the first time that GCMa is phosphorylated by the PKC- and MEK/extracellular signal-regulated kinase (ERK)-dependent mechanism, and that this phosphorylation is involved in its degradation process.

Biochemical responses to dietary α-linolenic acid restriction proceed differently among brain regions in mice.

Previously, we noted that the dietary restriction of α-linolenic acid (ALA, n-3) for 4 weeks after weaning brought about significant decreases in the BDNF content and p38 MAPK activity in the striatum of mice, but not in the other regions of the brain, compared with an ALA- and linoleic acid (LNA, n-6)-adequate diet. In this study, we examined whether a prolonged dietary manipulation induces biochemical changes in other regions of the brain as well. Mice were fed a safflower oil (SAF) diet (ALA-restricted, LNA-adequate) or a perilla oil (PER) diet (containing adequate amounts of ALA and LNA) for 8 weeks from weaning. The docosahexaenoic acid (DHA, 22:6n-3) contents and p38 MAPK activities in the cerebral cortex, striatum and hippocampus were significantly lower in the SAF group. The BDNF contents and protein kinase C (PKC) activities in the cerebral cortex as well as in the striatum, but not in the hippocampus, were significantly lower in the SAF group. These data indicate that the biochemical changes induced by the dietary restriction of ALA have a time lag in the striatum and cortex, suggesting that the signal is transmitted through decreased p38 MAPK activity and BDNF content and ultimately decreased PKC activity.

Testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat.

Canola and some other types of oil unusually shorten the survival of stroke-prone spontaneously hypertensive rats (SHRSP), compared with soybean oil, perilla oil and animal fats. Since differential effects of canola and soybean oil on steroid hormone metabolism were suggested by a preliminary DNA microarray analysis as a reason for this, the steroid hormone levels in the serum and tissues of SHRSP fed different oils were investigated. The testosterone levels in the serum and the testes were found to be significantly lower in the canola oil group than in the soybean oil group, while no significant differences were detected in the corticosterone and estradiol levels in tissues. In a second experiment, it was found that hydrogenated soybean oil, with a survival-shortening activity comparable to that of canola oil, also decreased the testosterone level in testes to a similar degree. The testosterone-lowering activity of canola and hydrogenated soybean oil observed in SHRSP was considered in relation to other factors possibly affecting the physiology of SHRSP.

Regional differences of the mouse brain in response to an α-linolenic acid-restricted diet: Neurotrophin content and protein kinase activity.

AIMS: The purpose of this study was to determine a relatively short-term effect of feeding an α-linolenic acid (ALA, n-3)-restricted, linoleic acid (LA, n-6)-adequate diet on neurotrophin contents and protein kinase activities in brain regions of the mouse. MAIN METHODS: After feeding mice a safflower oil (SAF) diet (ALA-restricted, LA-adequate) or perilla oil (PER) diet (containing adequate amounts of ALA and LA) for 4 weeks from weaning, the fatty acid compositions of brain regions were analyzed by capillary column gas-liquid chromatography, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents were measured using enzyme-linked immunosorbent assay. KEY FINDINGS: The striatum and hippocampus, but not the cerebral cortex, from the SAF group, contained a smaller amount of docosahexaenoic acid (DHA, 22:6n-3) than those from the PER group. The NGF contents in these brain regions were not different between the two dietary groups. However, the striatal BDNF content of the SAF group was significantly lower than that of the PER group. Protein kinase A, protein kinase C, and p44/42 mitogen-activated protein kinase (p44/42 MAPK) activities in brain regions showed no significant difference between the two dietary groups. However, the striatal p38 MAPK activity was significantly lower in the SAF group than in the PER group. No such differences were observed in the hippocampus or the cerebral cortex. SIGNIFICANCE: A relatively short-term feeding of an α-linolenic acid-restricted, linoleic acid-adequate diet was found to lower the DHA content, BDNF content and p38 MAPK activity in the mouse striatum.

Class II malocclusion treated with miniscrew anchorage: comparison with traditional orthodontic mechanics outcomes.

INTRODUCTION: Anchorage control in patients with severe skeletal Class II malocclusion is a difficult problem in orthodontic treatment. In adults, treatment often requires premolar extractions and maximum anchorage. Recently, incisor retraction with miniscrew anchorage has become a new strategy for treating skeletal Class II patients. METHODS: In this study, we compared treatment outcomes of patients with severe skeletal Class II malocclusion treated using miniscrew anchorage (n = 11) or traditional orthodontic mechanics of headgear and transpalatal arch (n = 11). Pretreatment and posttreatment lateral cephalograms were analyzed. RESULTS: Both treatment methods, miniscrew anchorage or headgear, achieved acceptable results as indicated by the reduction of overjet and the improvement of facial profile. However, incisor retraction with miniscrew anchorage did not require patient cooperation to reinforce the anchorage and provided more significant improvement of the facial profile than traditional anchorage mechanics (headgear combined with transpalatal arch). CONCLUSIONS: Orthodontic treatment with miniscrew anchorage is simpler and more useful than that with traditional anchorage mechanics for patients with Class II malocclusion.

Distal movement of maxillary molars using miniscrew anchorage in the buccal interradicular region.

OBJECTIVE: To quantify the treatment effects of interradicular miniscrew anchorage and to confirm the validity of the clinical usage of interradicular miniscrews in the distal movement of maxillary molars in nonextraction treatment. MATERIALS AND METHODS: Twenty-four maxillary molars were moved to the distal using miniscrews placed in the interradicular space between the second premolar and the first molar at an oblique angle of 20 to 30 degrees to the long axis of the proximal tooth. The teeth were evaluated as to how the molars were moved to the distal with the use of lateral cephalograms and dental casts. RESULTS: Maxillary molars were moved to the distal by 2.8 mm with distal tipping of 4.8 degrees and intruded by 0.6 mm. Maxillary incisors were moved to the distal by 2.7 mm with palatal tipping of 4.3 degrees. Molar extrusion and/or consequent mandibular rotation was not observed in any patient. CONCLUSION: Miniscrews placed in the maxillary interradicular space provide successful molar distal movement of 2.8 mm without patient compliance and with no undesirable side effects such as incisor proclination, clockwise mandibular rotation, or root resorption.

Dietary lipids impacts on healthy ageing.

Healthy ageing is gaining attention in the lipid nutrition field. As in vivo biomarkers of healthy ageing, we have evaluated the survival, learning/memory performance, and physical potencies in rodents fed a diet supplemented with high-linoleic acid (LNA, omega6) safflower oil or high-alpha-linolenic acid (ALA, omega3) perilla oil for long periods. The results suggested that perilla oil with a low omega6/omega3 ratio is beneficial for healthy ageing. In order to address this issue further, we determined the survival of stroke-prone SHR (SHRSP) rats fed a conventional rodent diet supplemented with 10% fat or oil. Survival was longer with omega3-rich oils compared with omega6-rich oils. However, some kinds of vegetable oils and hydrogenated oils shortened the survival of SHRSP rats to an unusual degree (ca. 40% compared with that of omega6-rich oil) that could not be accounted for by the fatty acid and phytosterol composition of the oils. The observed decrease in platelet counts was associated with pathological changes in the kidney and other organs. Dihydro-vitamin K1 is proposed as a likely candidate as a stroke-stimulating factor in hydrogenated oils. Thus, factors other than fatty acids (omega6/omega3 balance) and phytosterols must be taken into account when fats and oils are evaluated in relation to healthy ageing.

Root proximity is a major factor for screw failure in orthodontic anchorage.

INTRODUCTION: The purpose of this study was to evaluate root proximity as a risk factor for the failure of miniscrews used as orthodontic anchorage. METHODS: We used dental radiographs and 3-dimensional computed tomography images to examine 216 titanium screws in 110 patients. Each screw was classified according to its proximity to the adjacent root. Category I, the screw was absolutely separate from the root; category II, the apex of the screw appeared to touch the lamina dura; and category III, the body of the screw was overlaid on the lamina dura. If the orthodontic force could be applied to the screw for 1 year (or until completion of orthodontic treatment), we recorded the screw anchorage as a success. RESULTS: The screws had a high success rate--above 80%. Screws placed in the maxilla had a significantly higher success rate than those in the mandible. There was a significant correlation between success rate and root proximity. There were significant differences in the success rates between categories I and II, I and III, and II and III. Although screws in all 3 categories in the maxilla and categories I and II in the mandible showed high success rates above 75%, screws in category III in the mandible had a low success rate of 35%. CONCLUSIONS: The proximity of a miniscrew to the root is a major risk factor for the failure of screw anchorage. This tendency is more obvious in the mandible.

R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models.

We found that a novel compound, R-130823 {2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole}, had highly selective inhibition against mitogen-activated protein kinase p38alpha (IC50=22 nM). The release of tumor necrosis factor-alpha, interleukin-1beta, -6 and -8 was inhibited in lipopolysaccharide-stimulated human blood pretreated by R-130823, with IC50 values of 0.089, 0.066, 0.95 and 0.16 microM, respectively. R-130823 reduced the established hind paw swelling in rat adjuvant-induced arthritis, while methotrexate showed no suppression. In the same model, R-130823 ameliorated adjuvant-induced hyperalgesia with rapid onset and long duration comparable to a cyclooxygenase-2 inhibitor, celecoxib. In murine collagen-induced arthritis, R-130823 blocked the progress of arthritis when administered just after the onset of the arthritis. Histological analysis of the knee joints showed that proliferation of fibroblasts and synoviocytes and infiltration of neutrophils were ameliorated. In conclusion, R-130823 is expected to be an efficacious treatment for rheumatoid arthritis by blocking the p38 pathway.

Cartilage degradation independent of MMP/aggrecanases.

OBJECTIVE: To identify and characterize a cartilage degradation mechanism that is independent of the proteolytic cleavages by matrix metalloproteinases (MMPs) and aggrecanases. METHODS: The sensitivity of glycosaminoglycan (GAG) release and collagen release to an MMP/aggrecanase inhibitor, AG3340, was compared using a bovine nasal cartilage explant culture. The release of matrix proteins and hyaluronan (HA) from the culture was analyzed by immunoblotting and radioimmunoassay, respectively. Induction of HA-degrading activity by retinoic acid was examined using the cartilage explant culture and a primary culture of chondrocytes. Degradation of the matrix components of cartilage was also characterized in vivo using an acute arthritis model induced by an intra-articular injection of interleukin 1alpha (IL-1alpha). RESULTS: AG3340 did not effectively inhibit GAG release at a concentration of more than 10muM, while 10nM of the inhibitor completely suppressed collagen degradation. Retinoic acid induced the release of the aggrecan G1 domain, link protein and HA into the culture medium, and the release of these molecules was not completely inhibited by 10muM of AG3340. The molecules were released as ternary complexes. Retinoic acid induced HA degradation in the explant culture and hyaluronidase activity in the primary culture of chondrocytes. The release of the G1 domain of aggrecan and link protein into the synovial fluid was also observed in the IL-1alpha-induced acute arthritis model. CONCLUSION: A novel mechanism by chondrocyte-derived hyaluronidase(s) is involved in the release of the matrix components from cartilage, and the hyaluronidase(s) and MMPs/aggrecanases act in a coordinated manner in cartilage degradation.