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Biomedical subjects

N Sato

Publications and source records attributed to N Sato.

At least 397 records · Page 22Linked to original sources
PubMed1999

Do plastid envelope membranes play a role in the expression of the plastid genome?

A unique biochemical machinery is present within the two envelope membranes surrounding plastids (Joyard et al., Plant Physiol. 118 (1998) 715-723) that reflects the stage of development of the plastid and the specific metabolic requirements of the various tissues. Envelope membranes are the site for the synthesis and metabolism of specific lipids. They are also the site of transport of metabolites, proteins and information between plastids and surrounding cellular compartments. For instance, a complex machinery for the import of nuclear-encoded plastid proteins is rapidly being elucidated. The functional studies of plastid envelope membranes result in the characterization of an increasing number of envelope proteins with unexpected functions. For instance, recent experiments have demonstrated that envelope membranes bind specifically to plastid genetic systems, the nucleoids surrounded by plastid ribosomes. At early stages of plastid differentiation, the inner envelope membrane contains a unique protein (named PEND protein) that binds specifically to plastid DNA. This tight connection suggests that the PEND protein is at least involved in partitioning the plastid DNA to daughter plastids during division. The PEND protein can also provide a physical support for replication and transcription. In addition, factors involved in the control of plastid protein synthesis can become associated to envelope membranes. This was shown for a protein homologous to the E. coli ribosome recycling factor and for the stabilizing factors of some specific chloroplast mRNAs encoding thylakoid membrane proteins. In fact, the envelope membranes together with the plastid DNA are the two essential constituents of plastids that confer identity to plastids and their interactions are becoming uncovered through molecular as well as cytological studies. In this review, we will focus on these recent observations (which are consistent with the endosymbiotic origin of plastids) and we discuss possible roles for the plastid envelope in the expression of plastid genome.

Animals↗
PubMed1999

Structural requirements of Syk kinase for Fcgamma receptor-mediated phagocytosis.

The tyrosine kinase Syk plays a critical role in the phagocytic pathway mediated by Fcgamma receptors (FcgammaR). In transfected COS1 cells co-expression of Syk enhances FcgammaR mediated phagocytosis. The other member of the Syk kinase family, the highly homologous tyrosine kinase Zap70, also plays a role in signaling by immunoglobulin gene family receptors, but does not increase the phagocytic efficiency of FcgammaRs. The homologous tandem SH2 and kinase domains of Syk and Zap70 are separated by a nonhomologous region referred to as the unique domain. Zap70's inability to enhance phagocytosis was not due to unique domain tyrosine 292, previously implicated in negative regulation of Zap70 function. We determined the regions of Syk important for its interaction with the phagocytic pathway. An intact kinase domain was required for Syk's effect on phagocytosis. Furthermore, the Syk variant SykB, lacking 23 amino acids in the unique region, signaled for phagocytosis as efficiently as did Syk. We then constructed exchange chimeras between Syk and Zap70 and determined the contributions of the SH2, unique and kinase domains to phagocytic signaling. Our data suggest that the Syk kinase domain, which has high intrinsic kinase activity, is important for facilitating phagocytic signaling by FcgammaRI and FcgammaRIIIA.

Animals↗
PubMed1999

Regulation of a novel pathway for cell death by lysosomal aspartic and cysteine proteinases.

PC12 cells undergo apoptosis when cultured under conditions of serum deprivation. In this situation, the activity of caspase-3-like proteinases was elevated, and the survival rate could be maintained by treatment with acetyl-DEVD-cho, a specific inhibitor of caspase-3. In a culture of PC12 cells treated with acetyl-DEVD-cho, where caspase-3-like proteinases are not activated, CA074, a specific inhibitor of cathepsin B induced active death of the cells. Cathepsin B antisense oligonucleotides showed a similar effect to CA074 on the induction of active cell death. By double staining of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and activated caspase-3, the dying cells treated with CA074 were positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining but negative for activated caspase-3. Ultrastructurally, the cells were relatively large and had nuclei with chromatin condensation. The initiation of cell death by CA074 or the cathepsin B antisense were inhibited by the addition of pepstatin A, a lysosomal aspartic proteinase inhibitor, or by cathepsin D antisense. To examine whether this cell death pathway was present in cell types other than PC12 cells, we analysed dorsal root ganglion neurons obtained from rat embryos on the 15th gestational day, a time when they require nerve growth factor for survival and differentiation in culture. When cultured in the absence of nerve growth factor, the neurons survived in the presence of acetyl-DEVD-cho or acetyl-YVAD-cho. Under these conditions, CA074 reduced the survival rate of the neurons, which was subsequently restored by the further addition of pepstain A. These results suggest that a novel pathway for initiating cell death exists which is regulated by lysosomal cathepsins, and in which cathepsin D acts as a death factor. We speculate that this death-inducing activity is normally suppressed by cathepsin B.

Animals↗
PubMed1999

Case report of lymphoepithelioma-like carcinoma of the lung--lymphoid population consisting of cytotoxic T cells in resting state.

The present report describes a case of lymphoepithelioma-like carcinoma (LELC) of the lung and presents immunohistochemical and in situ hybridization (ISH) studies of the tumor. A 39-year-old Chinese woman, who was born in China and emigrated to Japan at the age of 29, suffered from a cough for 2 years and received a middle and lower lobectomy with mediastinal lymph node dissection after induction chemotherapy. The tumor consisted of undifferentiated carcinoma and areas of more differentiated squamous cell carcinoma with an intense lymphoid infiltrate. Serological studies and ISH studies showed EBV infection of the tumor. The immunophenotype of tumor-infiltrating T-lymphocytes (TITL) of the present case was examined immunohistochemically and was compared with that of an LELC case reported previously. Most CD3-positive T cells of TITL in both cases were labeled with both CD8 and TIA-1 but not with granzyme-B, indicating the TITL to be cytotoxic T lymphocytes (CTL) in the resting state. The lack of CTL activation at the tumor site might have been due to local inhibition of EBV-specific CTL responses such as T-cell anergy. Because the EBV-specific CTL derived from peripheral blood lymphocytes, in contrast to the TITL, may not be influenced by either tumor-produced suppressor factors or negative regulatory T cells, they may inhibit the hematogenous metastasis of EBV-positive LELC, possibly resulting in a better prognosis. Because LELC of the lung responded to preoperative chemotherapy in the present study, it may be useful for reducing the local tumor burden and facilitate subsequent local therapy, although the mechanism of chemosensitivity of LELC remains unknown.

Adult↗
PubMed1999

Effect of serial extraction alone on crowding: relationships between tooth width, arch length, and crowding.

In this study, we examined the effect of serial extraction alone on crowding. We also investigated the relationships between tooth width, arch length, and irregularity index. Maxillary dental casts from 32 subjects who had undergone only serial extraction were analyzed at 3 stages: before deciduous canines extraction, after first premolars extraction, and at the end of the observation period. The mean of the irregularity index decreased significantly as serial extraction proceeded and further decreased during the observation period. In cases where the width of the incisor was more than 2 standard deviations above the means for the control subjects, there was a significant correlation between tooth width of the lateral incisors and irregularity index before extraction as well as a significant correlation between the summation of tooth widths of the central and lateral incisors and irregularity index at that time. There was a significant negative correlation between arch length discrepancy and irregularity index before extraction and also a significant correlation between arch length discrepancy and correction of the irregularity index from before deciduous canines extraction to after first premolars extraction. These results suggest that tooth width and arch length discrepancy might preferentially affect the degree of anterior crowding in cases of severe crowding. There was no aggravation of the average crowding level during the observation period in the present study. The present study quantitatively suggested that serial extraction was useful for the purpose of correcting crowding in most cases.

Analysis of Variance↗
PubMed1999

Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum (II).

The thioredoxin (TRX) system, composed of nicotinamide adenine dinucleotide phosphate (reduced form), TRX, and TRX reductase (TRXR), has multiple biologic functions via thiol-mediated redox control. In this study, we investigated the relationship between intracellular TRXR levels and cellular sensitivity to cis-diamminedichloroplatinum (II) (CDDP). HeLa, a human cervical carcinoma cell line, cultured with CDDP showed a time- and dose-dependent reduction of intracellular TRXR activity, which was well correlated with the decrease in cell viability after exposure to CDDP. In a cell-free system, CDDP was found to directly inactivate the reduced form of purified human TRXR. The CDDP-resistant variants of HeLa cells, established by continuous exposure to CDDP, exhibited an increased expression and activity of TRXR as well as TRX compared with the parental cells. In addition, sodium selenate, an inhibitor of TRXR, was found to increase the susceptibility to CDDP in the CDDP-resistant cells. Moreover, the HeLa cells transfected with an antisense TRXR RNA expression vector to reduce the intracellular enzyme activity displayed an enhanced sensitivity to CDDP. Taken together with previous reports on TRX, these results indicate the possible involvement of TRXR as well as TRX in the cellular sensitivity and resistance to CDDP.

Antineoplastic Agents↗
PubMed1999

Radioimmunotherapy of human glioma xenografts in nude mice by indium-111 labelled internalising monoclonal antibody.

The potential of 111Indium (111In)-labelled internalising anti-integrin alpha 3 antibody GA17 in the radioimmunotherapy of human glioblastoma xenografts in nude mice was investigated. A radioisotope retention assay showed a rapid release of radioiodine from the glioblastoma cells after the binding of 125I-GA17, whilst 111In-GA17 was retained in the cells for a longer time period. The glioblastoma xenografts showed a high and prolonged uptake of 111In-GA17, and tumour uptake of 125I-GA17 was lower and decreased with time. In the mice which received two injections of 18.5 MBq of 111In-GA17, the growth of the subcutaneous tumour was significantly suppressed compared with the untreated group and mice injected with an 111In-labelled control antibody. These results indicate that GA17 was internalized into the glioblastoma cells and that 111In was retained within the cancer cells. The injection of a high-dose of 111In-GA17 can suppress the growth of tumour xenografts in nude mice.

Animals↗
PubMed1999

Characterization of Ribes rubrum callus cultured under low temperature.

Ribes rubrum callus was cultured at the temperature of 15 degrees C for 28 d. The contents of proteins and lipids in the callus cultured at 15 degrees C in a 28 d culture was significantly increased, being 1.1- and 1.2-fold, respectively, of those in callus cultured at 25 degrees C. Comparisons of the contents of monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), sulfoquinovosyldiacylglycerol (SQDG) and phosphatidyldiacylglycerol (PG) revealed that in the callus cultured at 25 degrees C, the content of MGDG was significantly decreased and those of the others significantly increased compared to those in callus cultured at 15 degrees C, in a 7 d culture. But, in a 28 d culture, the contents of these lipids in callus at 15 degrees C became the same as those in callus cultured at 25 degrees C. In regard to the protein composition, the contents of proteins 30 KDa or less in callus cultured at 15 degrees C in a 28 d culture were significantly higher than those in callus cultured at 25 degrees C. These consequences reflect that not only increase in the polyunsaturated fatty acid (PUFA) ratio of total fatty acid (TFA) with cold treatment reported by us previously [Hirano, M., J. Ferment. Bioeng., 83, 608-611 (1997)], but also an increase in low-molecular-weight protein content might be responsible for the cold-tolerance of R. rubrum callus.

Journal Article↗
PubMed1999

Ammonia, hydrogen peroxide, and monochloramine retard gastric epithelial restoration in rabbit cultured cell model.

Ammonia (NH3), hydrogen peroxide (H2O2) and monochloramine (NH2Cl) produced by Helicobacter pylori infection might be responsible for mucosal injury. The aim of this study was to evaluate the role of NH3, H2O2, and NH2Cl in the restoration of rabbit primary cultured gastric mucosal cells with a wound repair model. Artificial wounds were made in confluent monolayer gastric epithelial cell sheets by mechanical denudation, and changes in the size of the cell-free area were analyzed quantitatively. Cell proliferation was assessed by bromodeoxyuridine staining. In controls, the wound healed within 48 hr. However, mucosal cell repair was inhibited by treatment with NH3, H2O2, and NH2Cl in a dose-dependent manner. These results indicate that NH3, H2O2, and NH2Cl retarded the wound healing, which included epithelial cell migration and proliferation of gastric mucosa. Therefore, it is suggested that NH3, H2O2, and NH2Cl delays the healing process of peptic ulcers.

Ammonia↗
PubMed1999

Mouse colitis induced by Escherichia coli producing Yersinia enterocolitica 60-kilodalton heat-shock protein: light and electron microscope study.

In patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), heat-shock protein (Hsp) 60 has been detected in serum and the intestinal tract. Our mouse colitis model was established using Escherichia coli transformed with Yersinia enterocolitica Hsp60 gene as an immunizing antigen, and examined light and electron microscopically as compared with lesions of UC. The large intestine of mice injected with Hsp60 antigen showed swollen goblet cells, glandular dilation, erosion, ulceration, and infiltration of inflammatory cells. The change like crypt abscesses was also found, and various phases of inflammation were observed simultaneously in individual mice. In addition, the reticulum fibers were absent ultrastructurally in the subepithelial reticular layer. Hyperplasia of the thymus was found in antigen-treated mice. These lesions were similar to those of UC. These results suggest that UC-like enteritis in mice was induced by using Hsp60, considered as one of the pathogens for UC.

Animals↗
PubMed1999

Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response.

Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

Alzheimer Disease↗
PubMed1999

A novel immunoscintigraphy technique using metabolizable linker with angiotensin II treatment.

Immunoscintigraphy is a tumour imaging technique that can have specificity, but high background radioactivity makes it difficult to obtain tumour imaging soon after the injection of radioconjugate. The aim of this study is to see whether clear tumour images can be obtained soon after injection of a radiolabelled reagent using a new linker with antibody fragments (Fab), in conditions of induced hypertension in mice. Fab fragments of a murine monoclonal antibody against human osteosarcoma were labelled with radioiodinated 3'-iodohippuryl N-epsilon-maleoyl-L-lysine (HML) and were injected intravenously to tumour-bearing mice. Angiotensin II was administered for 4 h before and for 1 h after the injection of radiolabelled Fab. Kidney uptake of 125I-labelled-HML-Fab was much lower than that of 125I-labelled-Fab radioiodinated by the chloramine-T method, and the radioactivity of tumour was increased approximately two-fold by angiotensin II treatment at 3 h after injection, indicating high tumour-to-normal tissue ratios. A clear tumour image was obtained with 131I-labelled-HML-Fab at 3 h post-injection. The use of HML as a radiolabelling reagent, combined with angiotensin II treatment, efficiently improved tumour targeting and enabled the imaging of tumours. These results suggest the feasibility of PET scan using antibody fragment labelled with 18F-fluorine substitute for radioiodine.

Angiotensin II↗
PubMed1999

Messenger RNA level and protein localization of transforming growth factor-beta1 in experimental tooth movement in rats.

Transforming growth factor-beta1 (TGF-beta1) is known to be associated with local bone remodeling. We hypothesize that TGF-beta1 is induced in bone and regulates adaptive alveolar bone modeling during tooth movement. To test this hypothesis, we examined the steady-state mRNA level of TGF-beta1 and the protein localization of TGF-beta1 and its type II receptor (TbetaR-II) during experimental tooth movement. Maxillary right molars, M1, M2 and M3, of rats were moved palatally for 1, 3 and 7 d by a finger coil spring anchored to the upper incisors. The contralateral side was used as a control. After 3 d of tooth movement, intense immunostaining for TGF-beta1 and TbetaR-II was observed in cuboidally shaped osteoblasts in the tension zone, and in bone-resorbing osteoclasts in the compression zone. On the control side, few active osteoblasts and osteoclasts were observed. Reverse transcriptase-competitive polymerase chain reaction revealed significant increases in TGF-beta1 mRNA in alveolar bone cells on the tooth movement side on day 3 and day 7. Taken together, our data indicate that TGF-beta1 is induced during tooth movement and we propose that this may regulate adaptive alveolar bone modeling.

Alveolar Process↗
PubMed1999

Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection-comparison with omeprazole and lansoprazole.

BACKGROUND: A recent trend in curative therapy for Helicobacter pylori infection is the so-called triple therapy, which consists of a proton pump inhibitor (PPI) and two different antimicrobials. Various regimens employing this triple therapy have been reported. However, little is known about the effectiveness of rabeprazole, a recently developed proton pump inhibitor, when used in the triple therapy. AIM: To validate its usefulness by comparing rabeprazole with omeprazole and lansoprazole, in combination with amoxycillin and clarithromycin. PATIENTS AND METHODS: 221 H. pylori-positive patients with peptic ulcer disease were randomized to receive one of three different proton pump inhibitor/amoxycillin-clarithromycin (PPI/AC) regimens for 7 days. (i) OAC regimen (n = 75): omeprazole 20 mg b.d., amoxycillin (AMOX) 500 mg t.d.s. and clarithromycin (CAM) 200 mg b.d.; (ii) LAC regimen (n = 74): lansoprazole 30 mg b.d. , AMOX 500 mg t.d.s. and CAM 200 mg b.d.; and (iii) RAC regimen (n = 72): rabeprazole 20 mg b.d., AMOX 500 mg t.d.s. and CAM 200 mg b.d. Cure of the infection was determined by the 13C urea breath test 1 month after completion of the treatment. RESULTS: Intention-to-treat based cure rates for OAC, LAC and RAC regimens were 85% (95% CI, 75-92), 84% (95%, CI 73-91) and 88% (95% CI, 78-94), respectively, and per protocol based cure rates of these regimens were 88% (95% CI, 78-94), 91% (95%, CI 82-99) and 93% (95% CI, 84-98), respectively. Adverse effects in the entire study population, which included diarrhoea, glossitis or skin rash, were reported by 15% of the patients, and complete compliance was achieved in 95% of these patients. CONCLUSION: 1-week proton pump inhibitor/AC regimens for H. pylori infection were effective in the Japanese population. Rabeprazole can be considered as equivalent to omeprazole and lansoprazole in the PPI/AC triple therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

A monoclonal antibody, 3G12, reacts with a novel surface molecule, Hal-1, with high expression in CD30-positive anaplastic large cell lymphomas.

We established a monoclonal antibody, 3G12 (IgG1), with antiproliferative effects on a human T-cell leukaemia cell line, SUP-T13. Among haematolymphoid cell lines, 3G12 reacted with most T-cell lines, Epstein-Barr transformed B-cell lines, some myelomonocytic cell lines and, most strongly with an anaplastic large cell lymphoma (ALCL) cell line, Karpas 299. The cell panel reactive with 3G12 was similar, but not identical, to that of the anti-CD30 antibody Ber-H2. 3G12 induced Fas-independent apoptosis in SUP-T13 and it also induced growth-inhibition in a limited number of other cell lines, but not Karpas 299. Immunohistochemical studies on paraffin-embedded tissue specimens demonstrated that 3G12 reacted with most CD30-positive ALCL cases and some T-cell lymphomas and some Hodgkin's lymphomas, but not with B-cell lymphomas or non-haematogeneic tumours. The immunoprecipitation study with 3G12 demonstrated a major band of 200 kD and a minor band of 100 kD, which were different from CD30. Thus 3G12 defines a novel antigen that shares a similarity to CD30 in terms of distribution among haemopoietic cells. The data suggest that the 3G12-defined antigen, designated Hal-1, is important as a marker for ALCL and may play a role in its pathogenesis.

Animals↗
PubMed1999

Efficacy of 1 week omeprazole or lansoprazole-amoxycillin-clarithromycin therapy for Helicobacter pylori infection in the Japanese population.

BACKGROUND: The effectiveness of curative therapy for Helicobacter pylori may vary according to the geographic region and patient population, thus the efficacy of each treatment regimen should be determined according to the specific patient population. However, there is no literature available concerning the efficacy of 1 week omeprazole-amoxycillin-clarithromycin (OAC) regimens for the cure of H. pylori infection in Japan. METHODS: Helicobacter pylori-positive patients (224) with peptic ulcer disease or non-ulcer dyspepsia were randomized to receive one of three different omeprazole or lansoprazole-amoxycillin-clarithromycin (PPI/AC) regimens for 7 days: (1) OAC 20 regimen (n = 76), omeprazole (OPZ) 20 mg daily, amoxycillin (AMOX) 500 mg t.d.s. and clarithromycin (CAM) 200 mg b.d.; (2) LAC 30 regimen (n = 73), Lansoprazole (LPZ) 30 mg daily, AMOX 500 mg t.d.s. and CAM 200 mg b.d.; and (3) OPZ 40 regimen (n = 75), OPZ 20 b.d., AMOX 500 mg t.d.s. and CAM 200 mg b.d. Cure of the infection was determined by the [13C]-urea breath test, 1 month after completion of the treatment. RESULTS: Intention-to-treat based cure rates for OAC 20, LAC 30 and OAC 40 regimens were 75.0% (95% CI, 64-84%), 82.2% (95%, CI 72-90), and 80.0% (95% CI, 69-88), respectively and per-protocol based cure rates of these regimens were 79.2% (95% CI, 68-88%), 83.3% (95%, CI 73-91), and 83.1% (95% CI, 72-91%), respectively. Adverse effects, which included diarrhoea, glossitis or skin rash, were reported by 26.1% of the patients. However, these were mild and did not affect compliance. CONCLUSION: One week PPI/AC regimens for H. pylori infection with smaller proton pump inhibitors and antimicrobial dosages compared to regimens used in Western countries were revealed to provide sufficient cure rate (more than 80% by ITT analysis) with mild adverse effects in the Japanese population.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Selective high dose gamma-globulin treatment in Kawasaki disease: assessment of clinical aspects and cost effectiveness.

BACKGROUND: High-dose intravenous gamma-globulin (IVGG) plus aspirin (ASA) treatment is effective in preventing coronary artery complications in acute Kawasaki disease (KD). However, gamma-globulin is very expensive, especially in Japan. Furthermore the indication for IVGG treatment and the optimal dose of gamma-globulin remain controversial. OBJECTIVES: To examine these two issues, we used Harada's scoring system to investigate whether a single 2 g/kg dose therapy has any advantage over the 5 day 400 mg/kg per day therapy. METHODS: We studied 203 patients with KD who had no coronary artery complications on admission. Of these, 145 patients scored 4 or more on Harada score within the first 9 days of illness and were treated with IVGG treatment. Using a random number table, 72 patients were selected to receive a single 2 g/kg dose (2 g group), while the remaining 73 patients were treated with 400 mg/kg per day for 5 consecutive days (400 mg group). Those who had a Harada score of three or less received no IVGG (non-IVGG group) treatment (58 patients). RESULTS: The incidence rate of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. The duration of high fever, positive duration of C-reactive protein and the number of hospital days in the 2 g group were each significantly shorter than in the 400 mg group. The total medical expense in the 2 g group was significantly lower than in the 400 mg group. There were no coronary artery complications in the non-IVGG group. CONCLUSIONS: It was found to be clinically more effective and more cost effective to select a patient by Harada's scoring system and, where a score of four or more was obtained, to administer a single 2 g/kg intravenous dose of gamma-globulin for acute KD.

Anti-Inflammatory Agents, Non-Steroidal↗