Search PubMed⌕ Search

Biomedical subjects

S Sawamura

Publications and source records attributed to S Sawamura.

At least 37 records · Page 2Linked to original sources

Inducible nitric oxide synthase knockout mouse macrophages disclose prooxidant effect of interferon-gamma on low-density lipoprotein oxidation.

To test our hypothesis that interferon-gamma (IFN-gamma) has a direct prooxidant effect on macrophage-mediated LDL oxidation behind its antioxidant effect via induction of inducible nitric oxide synthase (iNOS), we incubated LDL with wild-type (iNOS(+/+)) or iNOS knockout mouse (iNOS(-/-)) macrophages preincubated with IFN-gamma or IFN-gamma plus lipopolysaccharide (IFN-gamma/LPS) for 24 h. LDL oxidation was measured in terms of formation of thiobarbituric acid reactive substances (TBARS) and electrophoretic mobility. Thiol production, nitrite production, and superoxide production from macrophages were measured by using Ellman's assay, the Griess reagent, and the SOD-inhibitable cytochrome c reduction method, respectively. IFN-gamma alone or combined with LPS induced iNOS expression and increased nitrite production in iNOS(+/+) macrophages, but not in iNOS(-/-) macrophages. TBARS formation from LDL was suppressed in IFN-gamma- and IFN-gamma/LPS-treated iNOS(+/+) macrophages but was increased in IFN-gamma-treated iNOS(-/-) macrophages. In the presence of N(G)-monomethyl-l-arginine (l-NMMA), a NOS inhibitor, the suppressive effect of IFN-gamma and IFN-gamma/LPS was abolished and TBARS formation was even increased to a level above that of untreated iNOS(+/+) macrophage. NOC 18, an NO donor, dose dependently inhibited macrophage-mediated LDL oxidation. IFN-gamma increased superoxide and thiol productions in both types of macrophages. We conclude that IFN-gamma promotes macrophage-mediated LDL oxidation by stimulating superoxide and thiol production under conditions where iNOS-catalyzed NO release is restricted.

Animals↗

Opioidergic and adrenergic modulation of formalin-evoked spinal c-fos mRNA expression and nocifensive behavior in the rat.

Fos protein expression has been used to reflect neuronal activation in pain processing pathways although analgesics may uncouple behavioral and Fos responses. We determine whether formalin-induced spinal c-fos mRNA expression (Northern blotting) correlates with nocifensive behavior following pretreatment with morphine, the alpha2-adrenoceptor agonist dexmedetomidine, or their respective antagonists naloxone and atipamezole. Both opiate and alpha2-adrenoceptor agonists reduced formalin-induced c-fos gene transcription and nocifensive behavior via their cognate receptors. Unexpectedly, blockade of either the opiate or alpha2-adrenergic receptors, alone, caused an increase in formalin-evoked c-fos mRNA; while blocking the opiate receptor had no effect on formalin-induced behavior, alpha2-adrenoceptor block had an analgesic effect, indicating discordance between c-fos message transcription and nocifensive behavior. We concluded that the formalin-induced spinal c-fos signal was a poor predictor of the behavioral response to pharmacological manipulation of pain processing pathways.

Adrenergic alpha-2 Receptor Antagonists↗

[Therapeutic effects of antibiotics against enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) infection: in vivo analysis using germfree mice].

Though O157 can cause a life-threatening diseases, the therapeutic protocol using antibiotics for the infection is still controversial. Main reasons for hesitating the uses of antibiotics for the infection is their possibility to enhance the release of verotoxins (VT). We have recently established the mouse model of O157 infection using germfree mice. Using this animal model of O157 infection, we examined therapeutic efficacy of antibiotics. Fosfomycin (FOM) and norfloxacin (NFLX) were selected for in vivo examination, because of their lower MIC under anaerobic condition (MIC:FOM = 0.78; NFLX = 0.10 microgram/ml) than those of the other antibiotics including kanamycin, doxycycline, minocycline, choramphenicol, cefaclor and ampicilin. When germfree BALB/c mice were orally infected with 1 x 10(5)CFU of O157 (clinically-isolated strain, TI001) at day 0, all mice died at 8 to 9 d after the infection. Oral treatment of the mice with FOM (500 mg/kg/d, twice a day) or NFLX (50 mg/kg/d, twice a day) everyday for 5 days starting at 3 hr after the infection significantly improved the survival rate from 0% to 83.3%, and 100%, respectively. VT could not be detected in the feces of the mice in either groups, suggesting that neither of these antibiotics enhanced the release of VT. Interestingly, when FOM treatment was started at 3, 6, 12 or 24 hr after the infection, the survival rate was 100%, 100%, 0% and 0%, respectively. Thus, in conclusion, FOM and NFLX are both useful as the therapeutic agents for O157 infection. However, the treatment should be started in the early phase after the infection.

Animals↗

The efficacy of physiological cost index (PCI) measurement of a subject walking with an Intelligent Prosthesis.

The Intelligent Prosthesis may enable lower limb amputees to walk faster than with conventionally damped prostheses and as a result the physical burden involved in walking could be expected to be considerably higher. The aim of this study was to investigate whether or not physiological cost index (PCI) is applicable as an indicator for monitoring the amount of exercise load involved in walking with an Intelligent Prosthesis. The method used a treadmill and monitored gas exchange, ventilation and heart rate (HR) in 6 unilateral trans-femoral amputees, ages were between 17 and 34 with an average age of 23.1. The exercise protocol was as follows: for each person speeds at 0.8 times the subject's free level walking speed, 1.0 times, 1.2 times, 1.4 times and for some 1.6 times were applied. In each case the index of correlation between PCI and oxygen uptake in response to walking speed was calculated. A significant correlation was observed between PCI and oxygen uptake in each case, which indicated a close relationship between cardiopulmonary factor and energy consumption while walking. These results suggest that PCI is of use as an indicator for ascertaining the amount of exercise load in walking with an Intelligent Prosthesis.

Adolescent↗

Improvement of control cable system of trans-humeral body-powered prostheses.

For the purpose of improving the efficiency of a body-powered prosthesis, a control cable system was developed which uses a pulley and a cable housing which includes a highly slippery plastic liner. Improvements were also made to the harness. In this paper, the mechanism of these systems is firstly described and then, the results of a clinical evaluation test of a practical model is presented along with an efficiency evaluation by a testing instrument. For the design of each system, the material and size suitable for the conditions of cosmetic and general versatility were considered. The clinical test was performed on 12 subjects to prove the effectiveness of the system. This test procedure was repeated. These tests proved the effectiveness of the systems.

Humans↗

A case of cervical myelopathy with developmental canal stenosis at the level of the atlas. A case report.

The craniocervical junction is one of the most common sites of malformations. Only three cases of myelopathy due to hypoplasia of atlas have been reported previously. Among these malformations, the hypoplasia of atlas was first described by Wackenheim in 1974. Although developmental canal stenosis due to the hypoplasia of atlas seems to have a tendency of causing the cervical myelopathy, only three cases of cervical myelopathy due to this condition have been reported previously. A 77-year-old man with severe canal stenosis at the level of the atlas is reported. The clinical manifestations were 20-year history of progressive gait disturbance and paresis of both upper and lower extremities. The spinal cord was markedly compressed at the level of the atlas. The clinical manifestations improved after a resection of posterior arch of the atlas.

Aged↗

[Does mixed venous desaturation during a bed bath indicate cardiopulmonary decompensation in postoperative cardiac patients?].

The bed bath procedure consists of cleansing patients' body, passive position change, changing gown and making a bed. During the procedure, mixed venous desaturation was observed consistently in postoperative cardiac patients. We investigated the cause of the phenomenon in 22 patients undergoing cardiac surgery in their first postoperative day. The patients were breathing oxygen-enriched air via a Venturi mask. Cardiac index (CI), transluminal SvO2, arterial blood gas, Hb, DO2, VO2, FIO2, A-aDO2 and Qp/Qs were measured before and during the bed bath, while the patients were in the supine and left lateral position, respectively. Mean 8.5 +/- 1.5 minutes were required to complete the bed bath. During the bed bath, SvO2 decreased from 71 +/- 7% to 59 +/- 9% (P < 0.001), and returned to the baseline 6.5 +/- 7.4 minutes after the completion of the bed bath. VO2 increased markedly from 128 +/- 27 to 194 +/- 47 ml.min-1.m-2 (P < 0.001), while DO2 increased slightly from 480 +/- 91 to 513 +/- 110 ml.min-1.m-2 (P < 0.05). Among the determinants of DO2, CI increased slightly from 3.3 +/- 0.6 to 3.6 +/- 0.8 l.min-1.m-2, Hb remained unchanged and SaO2 decreased from 98.5 +/- 0.8 to 98.0 +/- 1.1%. FIO2 also decreased, while A-aDO2 and Qp/Qs remained unchanged. There was a negative correlation between VO2 change and SvO2 change, but no correlation between DO2 change and SvO2 change. There was a positive correlation between SaO2 change and SvO2 change, as well as between FIO2 change and SaO2 change. Therefore, the major cause of mixed venous desaturation was not the decreased DO2 or cardiopulmonary decompensation but the increased VO2 due to increased activity of the skeletal muscles. However, the decrease in SaO2 due to markedly increased O2 demand and the limited increase in CI might partially contribute to the marked decline in SvO2 through the limited increase in DO2.

Aged↗

The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction.

The role of intestinal bacterial flora in oral tolerance induction to the IgE response was investigated using germfree (GF) mice. When GF mice were orally administered 20 mg of OVA as tolerogen before a systemic challenge with OVA, the Th1-mediated responses, such as the production of IgG2a and IFN-gamma, were abrogated, while the Th2-mediated immune responses, such as the production of IgE, IgG1, and IL-4, were maintained. Moreover, the basal level of IL-4 production in vitro was significantly higher in the GF mice than that of IL-4 in specific pathogen-free mice when challenged systemically with OVA. On the other hand, both Th1 and Th2 responses were fully sensitive to such tolerance induction in specific pathogen-free mice. The reconstitution of intestinal flora of GF mice with Bifidobacterium infantis, one of the predominant bacteria in the intestinal flora, restored the susceptibility of these Th2 responses to oral tolerance induction; however, this was only effective when such reconstitution was performed in neonates, but not in mice at an older age. These results thus suggested that intestinal bacterial flora play a crucial role in generating a Th2 cell population whose size and response are adequately regulated and, consequently, fully susceptible to oral tolerance induction, probably by affecting the development of gut-associated lymphoid tissue at the neonatal stage.

Administration, Oral↗

Atlantoaxial dislocation. A follow-up study of surgical results.

STUDY DESIGN: The cases of 47 patients with atlantoaxial dislocation exclusive of rheumatoid arthritis, cerebral palsy, and tumors as causative pathologies were reviewed after surgical treatment, which was performed between 1979 and 1993. OBJECTIVES: To investigate the surgical results of atlantoaxial dislocation itself without any systemic factors affected by rheumatoid arthritis, cerebral palsy, and tumors. METHODS: Neck pain (or occipitalgia) and extent of myelopathy at follow-up evaluation were compared with that present before surgery. The results were classified into four groups: excellent (no pain or recovery rate in myelopathy of more than 50%), good (decreased pain or recovery rate of 25% to 50%), fair (no improvement of pain or recovery rate of zero to 25%), and poor (aggravation of pain or recovery rate less than zero). The average follow-up period was 4 years and 2 months. RESULTS: Of the patients evaluated, 51% were assessed as excellent, 23% as good, 7% as fair, and 19% as poor. Pain relief was achieved in 95% of patients with non myelopathy. Extent of myelopathy, pathology of atlantoaxial dislocation (ligamentous or osseous instability), loss of reduction after surgery, and surgical procedures were recognized as the major factors affecting surgical results. Better surgical results were obtained in mild myelopathy cases (> 10 points in Japan Orthopaedic Association scoring), ligamentous instability, and cases without loss of reduction. The incidence of pseudarthrosis and loss of reduction was low in Brooks' method for atlantoaxial fusion and in Luque's segmental sublaminal wiring method for occipitocervical fusion. CONCLUSION: The best results occurred in patients with no myelopathy, and the worst results occurred in patients with severe myelopathy; therefore, surgery is best indicated for atlantoaxial dislocation with intractable pain or with mild myelopathy. To avoid pseudarthrosis and loss of reduction, a strong fixation method, such as Brooks' or Luque's segmental sublaminal wiring method, should be selected.

Adult↗

Proteolytic fragments of insulin-like growth factor binding protein-3: N-terminal sequences and relationships between structure and biological activity.

Insulin-like growth factors (IGF-I and IGF-II) in biological fluids bind to high-affinity binding proteins (IGFBP-1 to -6), which transport them and regulate their activities. Limited proteolysis of certain IGFBPs plays a major role in this regulation. IGFBP-3 is proteolysed in vivo and in several cell lines by serine proteases, including plasmin. In earlier studies we reproduced this proteolysis in vitro using recombinant human non-glycosylated IGFBP-3. Two major fragments were obtained, the larger retaining weak affinity for IGF-I and weakly inhibiting IGF I mitogenic effects. The smaller fragment, though lacking affinity for IGFs, is a potent growth inhibitor. These proteolytic fragments were isolated by HPLC and their N-terminal amino acids sequenced. Both major fragments contain the N-terminal region of the intact protein, the larger form corresponding to residues 1-160, and the smaller form, to residues 1-95. Kinetics experiments using the MG-63 osteoblast-like cell line showed that the larger peptide is generated before the smaller peptide, the latter probably being a product of secondary proteolysis of the former. Our data suggest that proteolysis of IGFBP-3 is intimately linked to its biological function. We propose a model for its action at cellular level.

Amino Acid Sequence↗

Beneficial effects of the prone position on the incidence of barotrauma in oleic acid-induced lung injury under continuous positive pressure ventilation.

BACKGROUND: Factors that contribute to ventilator-induced barotrauma are not well defined. This study investigates the effects of posture on ventilator-induced barotrauma, as well as arterial oxygenation. METHODS: Twelve dogs with oleic acid lung injury, lying in the prone position (n = 6) and right lateral position (n = 6), were mechanically ventilated with continuous positive pressure ventilation for 24 hours. The incidence of pneumothorax and arterial oxygenation were investigated in each position. RESULTS: All animals lying in the lateral position developed pneumothorax in the nondependent thorax, while only one animal in the prone position developed pneumothorax in the left thorax (P < 0.05). Postmortem examination revealed that in the lateral group, the nondependent lung consisted of large areas of emphysematous regions and neutrophil infiltration regions, while the dependent lung was composed of extensive atelectasis and neutrophil infiltration. Lung ruptures occurred in the nondependent lung at the regions of either emphysematous change or severe neutrophil infiltration. In the prone group, in contrast, both lungs were inflated fairly homogeneously with only small areas of atelectatic and emphysematous changes. In the dog in whom pneumothorax developed, lung ruptures were limited to the regions of severe neutrophil infiltration in the left lung. No animal in either group had a peak airway pressure more than 20 cmH2O. The peak airway pressures were 17.5 +/- 1.3 cmH2O in the lateral group and 16.6 +/- 2.1 cmH2O in the prone group (P > 0.05). Tidal volume was comparable between the lateral group (13 +/- 2 ml/kg) and the prone group (12 +/- 1 ml/kg) before pneumothorax occurred (P > 0.05). Arterial oxygenation was much better in the prone group than in the lateral group during the experiment (P < 0.05). CONCLUSION: It was concluded that in lung injury dogs, the prone position has beneficial effects on the incidence of ventilator-induced barotrauma and arterial oxygenation when compared with the lateral position. Ventilator-induced barotrauma may occur at lower airway pressure.

Animals↗

A novel component different from endotoxin extracted from Prevotella intermedia ATCC 25611 activates lymphoid cells from C3H/HeJ mice and gingival fibroblasts from humans.

A novel immunobiologically active fraction was prepared from a phenol-water extract of Prevotella intermedia ATCC 25611 by Sephadex G-100 column chromatography. The fraction consisted mainly of carbohydrate and protein and was devoid of fatty acid. The fraction showed high-molecular-weight bands (10,000 to 12,000) on deoxycholate polyacrylamide gel electrophoresis (DOC-PAGE) and was scarcely active in a Limulus test. We designated the fraction Prevotella glycoprotein (PGP). The PGP fraction showed strong mitogenicity on splenocytes and cytokine-inducing activities on peritoneal macrophages from both C3H/HeJ and C3H/HeN mice, and it stimulated human gingival fibroblasts to produce cytokines. The activities of the PGP fraction were resistant to heat inactivation (100 degrees C for 1 h) and protease treatments and were scarcely inhibited by polymyxin B. In contrast, the purified lipopolysaccharide fraction (LPS-PCP) extracted from the same bacterium with a phenol-chloroform-petroleum ether mixture, which showed strong Limulus activity and a single low-molecular-weight band (approximately 3,000) on DOC-PAGE, lacked the activities on splenocytes and macrophages from C3H/HeJ mice and human gingival fibroblasts. The activities of the LPS-PCP fraction on cells from C3H/HeN mice were completely inhibited by polymyxin B. The LPS extracted from the same bacterium with hot phenol-water (LPS-PW) exhibited the properties of both the PGP fraction and the LPS-PCP fraction. These findings suggest that the unique bioactivities of the LPS-PW fraction of oral black-pigmented bacteria reported to date, which differed from those of the classical endotoxin, were derived from the PGP fraction and not from the LPS itself.

Adjuvants, Immunologic↗

Reactions between hydroxyl-radical-induced 7,8-dihydro-8-oxo-2'-deoxyguanosine precursor and the spin trap alpha-phenyl-N-tert-butylnitrone.

An N2O-saturated aqueous solution containing 2'-dG and the spin trap agent PBN was examined by ESR and HPLC-ECD methods after X irradiation. ESR examination showed that the ESR spectrum obtained consisted of signals due to the PBN-OH and PBN-H adducts. The signal intensity of PBN-H adducts was larger in the presence of 2'-dG than in the absence of 2'dG, while that of PBN-OH adducts was smaller in the presence of 2'-dG than in the absence of 2'-dG. When the OH-radical-induced 8-oxodG was measured by HPLC-ECD, the yield of 8-oxodG was found to be enhanced about twofold in the presence of PBN. By contrast, usual OH-radical scavengers (DMSO, sodium formate and mannitol) inhibited the formation of 8-oxodG beyond expectation. The enhancement of the yield of PBN-H adducts by 2'-dG and the enhancement of the 8-oxodG formation by PBN were explained by the electron transfer and subsequent proton transfer reactions from OH-radical-induced guanine-N7 radicals to PBN to form 8-oxodG and PBN-H. The present study led us to conclude that PBN reacted with the precursor radical of 8-oxodG to accelerate the formation of 8-oxodG, while OH-radical scavengers reacted with it to diminish the formation of 8-oxodG.

8-Hydroxy-2'-Deoxyguanosine↗

The efficacy of the one-leg cycling test for determining the anaerobic threshold (AT) of lower limb amputees.

The aim of this study was to investigate whether or not the one-leg cycling test driven by the subject's sound leg as the exercise load method is an applicable method for determining the anaerobic threshold (AT) of lower limb amputees. To evaluate physical fitness, a graded exercise test that monitored gas exchange, ventilation and heart rate (HR) was performed in 51 unilateral lower limb amputees. AT was successfully measured for 42 out of 51 subjects, an 82.3% success rate. The average AT was 12.7 +/- 2.2 ml/kg/min, and the average HR at AT points was 117.7 +/- 16.2 beats/min. The average peak oxygen uptake was 20.1 +/- 5.6 ml/kg/min, and the average peak HR was 145.1 +/- 22.4 beats/min. The peak HR exceeded the HR at AT by an average 27.4 beats/min, which indicates that a comparatively intense exercise load above the AT level is possible. The average AT was 40.9% of the predicted maximum oxygen uptake, which seems reasonable when compared to the reports of other researchers. These results suggested that the one-leg cycling test driven by the sound limb is of use as a method for determining the AT of lower limb amputees.

Adolescent↗

[Successful treatment of intraoperative myocardial ischemia with nicorandil].

We report five patients who developed intraoperative myocardial ischemia but were treated successfully with nicorandil. Case 1; An 84 year-old male underwent emergent laparotomy and ileolysis under inhalational plus thoracic epidural anesthesia. During his emergence from anesthesia, arterial pressure and heart rate increased abruptly due to excitement, leading to ST-T depression on V5 lead. Bradycardia and hypotension developed subsequently. Immediately after i.v. injections of nicorandil 4 mg and atropine 0.3 mg, ST-T change and hemodynamics improved dramatically. Case 2; A 67 year-old male underwent esophagectomy under inhalational plus thoracic epidural anesthesia. Following the completion of surgery, elevation of ST-T developed suddenly on lead II, though hemodynamics were not compromised. ST-T elevation disappeared immediately after nicorandil 6 mg and continuous infusion of nitroglycerin (TNG) was initiated. Case 3; A 71 year-old female underwent aortic valve replacement under high-dose fentanyl anesthesia. Shortly after starting cardiopulmonary bypass (CPB), ST-T segment on leads II and V5 was elevated suddenly. This was accompanied by severe pulmonary hypertension suggestive of severe left ventricular failure. Shortly after nicorandil 4 mg via a pulmonary artery (PA) catheter, ST-T segment returned to the baseline and pulmonary arterial pressure was normalized. Case 4; A 61 year-old male underwent coronary revascularization under high-dose fentanyl anesthesia. During weaning from CPB, elevation of ST-T segment occurred on leads II and V5. ST change improved, responding to nicorandil 6 mg en bolus via a PA catheter. Case 5; A 67 year-old male underwent coronary revascularization under high-dose fentanyl anesthesia. He was unable to be weaned from CPB for several hours because of frequent and repeated attacks of ventricular tachycardia and ventricular fibrillation. The arrhythmia did not respond to various kinds of treatments including intra-aortic balloon pumping and continuous infusions of inotropes, anti-arrhythmic drugs and anti-anginal drugs. In spite of repeated intracoronary injections of TNG, graft flow to the left anterior descending branch remained low at 40 ml.min-1. After an intracoronary injection of nicorandil 1 mg, however, blood flow increased to 100 ml.min-1, resulting in a marked reduction in frequency of ventricular arrhythmia. The patient came off bypass successfully. In each case, intraoperative myocardial ischemia was treated successfully with nicorandil. Neither hypotension nor arrhythmia resulted from its bolus injection. Nicorandil might be a useful therapeutic tool for myocardial ischemia during anesthesia.

Aged↗

Use of metronidazole gel to control malodor in advanced and recurrent breast cancer.

Intolerable malodor emanating from ulcerated tumors as a result of anaerobic infection is a serious problem in the management of advanced and recurrent breast cancer. Metronidazole can control this malodor, but its oral use may cause adverse reactions. We therefore formulated a metronidazole gel, since no equivalent preparation is commercially available in Japan, and used it in five female patients (four with advanced cancer and one with recurrent cancer) admitted to our hospital between March 1994 and July 1995. The patients were aged between 47 and 71 (median: 59) years, and the duration of morbidity in the four patients with advanced cancer ranged from 10 months to four years. In three patients, the tumors were larger than 10 cm x 10 cm. Metronidazole gel was applied to the surface of ulcerated tumors once or twice daily. Independent assessments by the patient, doctor and nurse were unanimous, and revealed that the malodor was alleviated in one patient after three days, and removed in four patients after two to five (median: four) days of metronidazole gel treatment. Culture of swabs showed a decrease or disappearance of anaerobic colonies. Adverse reactions characteristic of metronidazole did not occur. The topical use of metronidazole in a gel form will improve the quality of life for patients with malodorous ulcerated tumors and facilitate intensive treatment of the underlying disease.

Administration, Topical↗

Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis.

The plasma levels of phenol, p-cresol, and indican are markedly increased in uremic patients, and cannot be efficiently reduced by hemodialysis. Such uremic toxins, which are produced in the intestine as bacterial putrefactive metabolites, accumulate to a great degree in the feces of hemodialysis patients. Oral administration of Lebenin, a preparation consisting of antibiotic-resistant lactic acid bacteria, reduced the levels of fecal putrefactive metabolites to levels comparable with those of healthy subjects. Moreover, the plasma level of indican also significantly decreased in these Lebenin-treated patients. An analysis of the fecal microflora revealed that a disturbed composition of the microflora characterized by an overgrowth of aerobic bacteria is restored to normal by oral administration of Lebenin in hemodialysis patients. These results thus demonstrate that oral administration of lactic acid bacteria in uremic patients is effective in reducing the levels of uremic toxins, especially that of indican, in the blood by inhibiting bacterial production by means of correcting the intestinal microflora.

Administration, Oral↗