Biomedical subjects

M Kato

Publications and source records attributed to M Kato.

At least 325 records · Page 18Linked to original sources

PubMed2000

Peroral infection of nuclear polyhedrosis virus budded particles in the host, Bombyx mori l., enabled by an optical brightener, Tinopal UNPA-GX.

Perorally inoculated budded particles of a nuclear polyhedrosis virus was used to infect Bombyx mori (BmNPV) (Lepidoptera; Bombycidae), aided by an optical brightener, Tinopal UNPA-GX (Tinopal). BmNPV budded particles not occluded in the occlusion body do not infect successfully the host, B. mori, when administered perorally. It was found that feeding the host Tinopal enabled perorally delivered BmNPV budded particles to infect the host. B. mori larvae ingesting BmNPV budded particles (1.3 x 10(6) TCID(50) units per larva) after they consumed an artificial diet containing 0. 3% Tinopal died of the viral infection. Peroral administration of these particles to host larvae with 1% Tinopal also resulted in virus infection. Tinopal is a candidate for viral activity enhancing agent promoting viral insecticide infection in hosts. The results suggest that B. mori-BmNPV budded particles are convenient for detecting viral infection enhancement activity of a chemical of interest. Since recombinant baculovirus vectors are constructed by replacing the polyhedrin gene with the foreign gene of interest, they do not produce occlusion bodies, i.e. polyhedra. Budded particles of a baculovirus vector not occluded in polyhedra cannot infect their hosts when administered perorally. The peroral inoculation of BmNPV budded particles by Tinopal leads to industrial pharmaceutics production using a baculovirus vector for a huge number of insect hosts, i.e. an 'insect factory'.

Administration, Oral↗

PubMed2000

Delayed clearance of zymosan-induced granuloma and depressed phagocytosis of macrophages with concomitant up-regulated kinase activities of Src-family in a human monocyte chemoattractant protein-1 transgenic mouse.

A human monocyte chemoattractant protein-1 (hMCP-1) transgenic mouse (Tgm) line which constitutively produces a large amount of hMCP-1 (7-13 ng/ml in the serum) was established. Although expression of the transgene was detected in various tissues, an accumulation of macrophages (Mphi) was seen in only lymphoid organs which might be attributed to the high concentration of hMCP-1 in these organs. A reduced phagocytosis by peritoneal Mphi in vivo and a delayed clearance of granulomas in the liver following zymosan administration were observed in these Tgm. However, peritoneal exudate cells (PEC) from Tgm exhibited normal in vitro phagocytic activity and nitric oxide (NO) production upon stimulation with IFN-gamma as compared with those from non-Tgm. In addition, high activities of src-family protein tyrosine kinases (PTK), Fgr and Hck, were also noted in the peritoneal resident cells from Tgm, whereas the level of mitogen-activated protein kinase (MAPK) activity was almost the same as that of non-Tgm. It was suggested that the low functional activities of Tgm Mphi seen in vivo were attributed to down-regulation of the unique transducing system of hMCP-1 signals under the influence of a high concentration of the hMCP-1. It seemed that the depressed functions were recovered when the peritoneal cells were released ex vivo from such a high hMCP-1 environment.

Animals↗

PubMed2000

End-tidal CO2 pressure decreases during exercise in cardiac patients: association with severity of heart failure and cardiac output reserve.

OBJECTIVES: We measured end-tidal CO2 pressure (PETCO2) during exercise and investigated the relationship between PETCO2 and exercise capacity, ventilatory parameters and cardiac output to determine the mechanism(s) of changes in this parameter. BACKGROUND: It is unclear whether PETCO2 is abnormal at rest and during exercise in cardiac patients. METHODS: Cardiac patients (n = 112) and normal individuals (n = 29) performed exercise tests with breath-by-breath gas analysis, and measurement of cardiac output and arterial blood gases. RESULTS: PETCO2 was lower in patients than in normal subjects at rest and decreased as the New York Heart Association class increased, whereas the partial pressure of arterial CO2 did not differ among groups. Although PETCO2 increased during exercise in patients, it remained lower than in normal subjects. PETCO2 in relation to cardiac output was similar in patients and normal subjects. PETCO2 at the respiratory compensation point was positively correlated with the O2 uptake (r = 0.583, p < 0.0001) and the cardiac index at peak exercise (r = 0.582, p < 0.0001), and was negatively correlated with the ratio of physiological dead space to the tidal volume. The sensitivity and specificity of PETCO2 to predict an inadequate cardiac output were 76.6% and 75%, respectively, when PETCO2 at respiratory compensation point and a cardiac index at peak exercise that were less than the respective control mean-2 SD values were considered to be abnormal. CONCLUSIONS: PETCO2 was below normal in cardiac patients at rest and during exercise. PETCO2 was correlated with exercise capacity and cardiac output during exercise, and the sensitivity and specificity of PETCO2 regarding decreased cardiac output were good. PETCO2 may be a new ventilatory abnormality marker that reflects impaired cardiac output response to exercise in cardiac patients diagnosed with heart failure.

Anaerobic Threshold↗

PubMed2000

Cortical somatosensory evoked potentials of seizure-sensitive and seizure-resistant gerbils.

The Mongolian gerbil is known as an animal model that often exhibits spontaneous seizures that are characteristic of human epilepsy. Whereas there is much more information available relating this phenomenon to anatomical and electrophysiological characteristics of the hippocampal formation, the somatosensory cortex has rarely been the focus of attention. Given the existence of the fine grain cortical barrels developed in an orderly matrix, the vibrissa ascending system was thought the best sensory channel in which the gerbil neocortical excitability was to be tested. In the present study, we compared cortical evoked potentials to electric stimulation of vibrissa (whisker) follicle between the seizure-sensitive (SS) and seizure-resistant (SR) gerbils. Whereas our standard stimulation of the whisker follicle elicited a positive-negative biphasic somatosensory cortical potential in SR animals, it evoked only a positive monophasic potential in SS animals. Although the amplitude of positivity was generally larger in SR animals, the latency to reach this peak was significantly smaller than in the SS animals. Apparently there was no group difference in the laminar profile or the size of barrels that represent, in one-to-one fashion, the array of whisker follicles. It was suggested that an altered level of excitability in the absence of gross anatomy differentiates the seizure-sensitive gerbils from the seizure-resistant counterparts. Possible functional differences between the cortices of the two groups were discussed in light of the known synaptic electrophysiology.

Animals↗

PubMed2000

Propofol dosage achieving spontaneous breathing during balanced regional anesthesia with the laryngeal mask airway.

STUDY OBJECTIVE: To assess an anesthetic technique achieving spontaneous breathing through the laryngeal mask airway (LMA) during combined epidural block and propofol anesthesia. DESIGN: Prospective, consecutive case series study. SETTING: Operating room at a general hospital. PATIENTS: 112 ASA physical status I and II adult surgery patients; 32 patients for lower extremity surgery are enrolled into study 1, and 30 patients for lower extremity surgery and 50 patients for lower abdominal gynecology surgery are enrolled into study 2. INTERVENTIONS: In study 1, patients were given 1.5 to 2.0 mg/kg followed by a 3 mg/kg/h of infusion of propofol, after epidural block, and they were fitted with the LMA. Thirty minutes after induction, the dose of propofol was increased to 4, 5, 6, and 7 mg/kg/h every 15 minutes. In study 2, the patients were given 1.5 to 2.0 mg/kg and 5 mg/kg/h of propofol and the LMA insertion, after epidural block. MEASUREMENTS AND MAIN RESULTS: PaO(2)/FIO(2), PaCO(2), tidal volume or respiratory rate, blood pressure, heart rate, and eye opening and motor response scales in conformity with Glasgow coma scale were recorded. Study 1 suggested an induction dose of 1.5 to 2.0 mg/kg and an infusion of 5 mg/kg/h as an appropriate dose to preserve spontaneous breathing with the LMA and to maintain reasonable depth of anesthesia. Study 2 showed that respiratory and circulatory conditions, depth of anesthesia, and other data related to anesthesia were clinically acceptable. CONCLUSIONS: The best infusion dose of propofol to achieve spontaneous breathing with the LMA seems to be 5 mg/kg/h, and the present balanced regional anesthesia with the LMA, using propofol infusion at 1.5 to 2.0 mg/kg and 5 mg/kg/h combined with epidural block, may be useful in clinical practice for lower extremity and lower abdominal gynecologic operations.

Adult↗

PubMed2000

The role of dendritic cells in the innate immune system.

Dendritic cells (DCs) are bone-marrow-derived leucocytes that are specialised antigen-presenting cells capable of stimulating a primary T-lymphocyte response to specific antigen. In this chapter we discuss the role DCs play in the innate response acting as a critical link with the adaptive response and the influence of the innate response on dendritic cells.

Animals↗

PubMed2000

Raman study on conformational equilibria of fluoroacetone in aqueous solutions.

The effects of water and heavy water on conformational equilibria of fluoroacetone have been investigated via Raman spectroscopy. Additional Raman bands have been observed in the C-F stretching and the C-C-C symmetric stretching regions for the aqueous solutions. Based on enthalpy and volume differences between the conformers, these bands are assigned to the syn conformer which has hydrogen bonds between the fluorine atom and water molecules (syn' conformer). The number of H2O molecules binding to the syn' conformer is estimated to be 2.4 from the concentration dependence of the spectrum. The enthalpy and the volume differences between the cis and syn conformers in the aqueous solutions show anomalous values in comparison with those in organic solvents. We discuss these thermodynamic behaviors from the viewpoint of the hydration structures of fluoroacetone.

Acetone↗

PubMed2000

Both insulin sensitivity and glucose sensitivity are impaired in patients with non-diabetic liver cirrhosis.

Background: Careful nutritional support is required in patients with liver cirrhosis due to their glucose intolerance. To elucidate the mechanism of glucose intolerance in cirrhotics, we measured insulin secretion, whole body insulin sensitivity (SI), and glucose sensitivity (SG) in non-diabetic cirrhotics.Methods: Eight patients with compensated cirrhosis who showed normal fasting blood glucose levels and non-diabetic curves on a 75 g oral glucose tolerance test participated in this study. Four normal volunteers were selected as controls. After an overnight fast, glucose was injected intravenously at 300 mg kg(-1) in 2 min followed 20 min later by intravenous insulin at 0.02 U kg(-1) in 5 min. Sequential blood samples were drawn from 20 min before the glucose injection to 3 h post-injection, and plasma glucose and insulin levels were determined. Plasma glucose and insulin disappearance curves were analyzed using the minimal compartment model, and kinetic parameters, including glucose clearance (KG), insulin secretion, SI and SG, were estimated.Results: KG was slower in cirrhosis than in controls, although not significant (P=0.051). Insulin secretion was not different between the two groups. However, SI was significantly lower in cirrhotics (0.814x10(-4) min(-1) pM(-1); 0.572-1.403x10(-4) min(-1) pM(-1)) as compared to controls (1.643x10(-4) min(-1) pM(-1); 0.678-2.085x10(-4) min(-1) pM(-1)) (P=0.029). SG was also lower in the cirrhosis (0.0154 min(-1); 0.0071-0.0208 min(-1)) than in the control group (0.0211 min(-1); 0.0184-0.0260 min(-1)) (P=0.026).Conclusion: Both SI and SG are already impaired in non-diabetic cirrhotic patients even when KG is minimally delayed and insulin secretion has not yet been affected.

Journal Article↗

PubMed2000

Improvement of fuel metabolism by nocturnal energy supplementation in patients with liver cirrhosis.

Aims: patients with liver cirrhosis exhibit abnormal fuel metabolism, including increased fat and decreased glucose oxidation. Such altered energy metabolism is similar to that observed after starvation and could lead to malnutrition. We therefore studied whether nocturnal energy supplementation might improve the fuel metabolism in cirrhotic patients. Methods: 12 cirrhotic patients and 14 healthy controls participated in this study. Subjects in the two groups ate isonitrogenous (1.2 g/kg/day) and isocaloric (35 kcal/day) diets for 1 week before and during the study. On day 1 of the study, indirect calorimetry was carried out in the morning after an overnight fast. The next morning, the same measurement was performed after the patients took a liquid nutrient (Ensure Liquid(R), 250 kcal) at 23:00 on day 1. Respiratory quotient (RQ), resting energy expenditure (REE), and substrate oxidation rates of glucose (% CHO), fat (% FAT) and protein were estimated from measured VO(2), VCO(2) and urinary nitrogen. Results: Significant decreases in RQ, and % CHO and a significant increase in % FAT were observed at baseline in cirrhotic patients as compared with controls. After the nocturnal energy supplementation, RQ, % CHO and % FAT in cirrhotic patients were significantly recovered, ending at levels close to normal. Conclusions: These results suggest that nocturnal energy supplementation could be useful to correct abnormal fuel metabolism and to prevent malnutrition in cirrhosis.

Journal Article↗

PubMed2000

Asymmetric interhemispheric delta waves during all-night sleep in humans.

OBJECTIVE: In order to better understand the asymmetry of brain function during sleep, period-amplitude analysis of delta EEG activity was performed on polysomnograms (PSGs) in normal humans. Twenty healthy, right-handed male volunteers aged 22-35 years (mean age 27.2 years) served as subjects in this study. METHODS: EEGs were recorded from disc electrodes placed at bilateral frontal, central, parietal, occipital, anterotemporal and posterotemporal (10-20 electrode system) sites using A1+A2 for reference. Period-amplitude analysis was performed by the zero-crossing method using the Medilog Sleep Analyzing Computer. RESULTS: Delta counts in the right frontal and central regions during all-night sleep were significantly greater than in those of the left; total delta counts of the right frontal region were greater than those of the left in 18 of the 20 subjects. There were no significant differences in delta counts between the left and right hemispheres in parietal, occipital, anterotemporal, and postero-temporal regions. CONCLUSIONS: These results suggest distinct laterality in the number of delta waves in the frontal and central regions, reflecting functional asymmetry of the brain during sleep.

Adult↗

PubMed2000

Differential temporal coding of the vibratory sense in the hand and foot in man.

OBJECTIVE: We studied the difference in the temporal tuning function of the vibratory senses between the hand and foot in man by using steady-state somatosensory evoked potentials (S-SEPs) to vibratory stimulation. METHODS: Vibratory stimuli were applied to the palm and sole, and the S-SEPs were then recorded in 8 normal subjects. A total of 200 responses were recorded from 4 electrodes including the ipsi-and contralateral somatosensory areas of the hand and foot. The amplitude of the first harmonic component (1F) was obtained by a Fourier analysis. The effect of modulation frequency (17-30 Hz) on the 1F at a stimulus intensity of 0.05 N was studied. RESULTS: The amplitudes of the S-SEPs were the greatest in the contralateral hand and foot areas. The mean 1F amplitudes of the palm S-SEPs as a function of the modulation frequency showed a narrow tuning curve with a peak near 21 Hz while those of the sole demonstrated a broad tuning curve. CONCLUSION: Our results suggest the differential temporal coding of the vibratory sense in the hand and foot areas of the somatosensory cortex in man. This is probably caused by the different characteristics in the receptors situated in the hand and foot.

Adolescent↗

PubMed2000

Outcome of schizophrenia in a non-industrialized society: comparative study between Bali and Tokyo.

OBJECTIVE: The aim of the present study was to contrast the outcome of schizophrenic patients between Bali and Tokyo, the former being a non-industrialized society and the latter an industrialized society in Asia. METHOD: A total of 51 Balinese schizophrenics and 40 schizophrenics in Tokyo were evaluated by five outcome measures at a 5-year follow-up. RESULTS: No significant difference was found in the mean scores of the Positive and Negative Syndrome Scale, Eguma's Social Adjustment Scale and the re-admission rates between the subjects in the two sites. The cumulative length of stay in hospital during the 5-year period was significantly shorter in Bali. The percentage of subjects on psychiatric medication at the follow-up was significantly lower in Bali than that in Tokyo. CONCLUSION: Although the clinical outcome of schizophrenics in Bali was not superior to that in Tokyo, the subjects in Bali tended to be able to live in society without neuroleptic medication.

Adult↗

PubMed2000

Increased midkine expression in intrahepatic cholangiocarcinoma: immunohistochemical and in situ hybridization analyses.

AIMS/BACKGROUND: Midkine (MK) is a novel heparin-binding growth factor whose gene was identified in embryonal carcinoma cells in the early stages of retinoic acid-induced differentiation. This study investigates the overexpression of MK in intrahepatic cholangiocarcinoma (CC). METHODS: Forty-five primary CC specimens from patients (aged 19-81 years, 24 males and 21 females) were examined. Histologically, 17 cases of CC were classified as the well-differentiated type, 19 as moderately-differentiated and 9 as poorly-differentiated. Immunohistochemical analysis was performed using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK. RESULTS: We successfully applied this monoclonal antibody against MK to analyze archival paraffin sections. The cancer tissues showed a positive reaction to this antibody, and there was an intense reaction in their cytoplasm. Approximately 40% of individuals with CC (17/45) had tumor cells that expressed MK, and these were classified into the following types: moderately-differentiated type (9/19), well-differentiated type (8/17) and poorly-differentiated type (0/ 9). In situ hybridization analysis revealed that signals of MK transcripts were found in the cytoplasm of the cancer cells; the distribution and localization of the MK-transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. CONCLUSIONS: These findings revealed that CC express increased MK at the messenger RNA and protein levels.

Adult↗

PubMed2000

Divergent expression of midkine in the human fetal liver and kidney: immunohistochemical analysis of developmental changes in hilar primitive bile ducts and hepatocytes.

BACKGROUND/AIMS: Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. In this study, we investigated the developmental expression of MK protein in the human fetal liver and kidney. METHODS: Twenty-one specimens each of the liver and kidney from fetuses (gestational weeks from 9 to 40) and neonates less than 4 weeks old were examined. Immunohistochemical and Western blot analyses were performed using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK. RESULTS: Immunohistochemical analysis revealed MK expression in the human fetal liver and kidney. The MK expression in the fetal liver showed a strong reaction from 9 to 16 gestational weeks. MK was expressed in the ductal plate, migrating biliary cells and newly formed bile ducts, and in hepatocytes of the hilar region in all specimens in the first and second trimesters. By contrast, the MK expression decreased gradually and was weak or not detected in the third trimester and neonatal period. However, MK expression in the kidney was found at 16 gestational weeks, as well as during both gestation and the neonatal period. CONCLUSIONS: Divergent MK-expression was detected in the human fetal liver and kidney, and its expression may be related to fetal development, maturation, and functions of the liver and kidney.

Bile Ducts, Intrahepatic↗

PubMed2000

Telomerase activity significantly correlates with chromosome alterations, cell differentiation, and proliferation in lung adenocarcinomas.

Telomerase activity was examined by the telomeric repeat amplification protocol assay in 25 cases of lung adenocarcinoma, in relation to cancer cell differentiation, proliferation, and chromosome alterations. Telomerase activity, chromosome alterations, and cell proliferation assessed by Ki-67 labeling were significantly lower (P < .001 to .05) in well-differentiated (10 cases) than in moderately differentiated (8 cases) or poorly differentiated (7 cases) lesions. Telomerase activity by semiquantitative analysis with scoring of 0 to 3 was significantly correlated with similarly graded chromosome alterations (P < .05) and Ki-67 labeling indices (P < .002). Telomerase activity and chromosome alteration (T-C) indices generated by multiplication of telomerase activity and chromosome alteration scores also showed a significant correlation with cell differentiation. The Clara cell subtype, confirmed by electron microscopic analysis, significantly predominated in the well-differentiated group, showing a low grade of telomerase activity and chromosome alterations and low Ki-67 labeling indices, suggesting clinical relevance. No significant association of telomerase activity was found with p53 protein accumulation or Bcl-2 protein expression. The good correlation of telomerase activity with chromosome alterations, cell differentiation, and Ki-67 labeling indices suggests that this parameter might have potential application in estimation of prognosis.

Adenocarcinoma↗

PubMed2000

Immunohistochemical and in situ hybridization analyses of midkine expression in thyroid papillary carcinoma.

Midkine (MK) is a novel heparin-binding growth factor whose gene has been identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. We immunohistochemically examined 90 thyroid papillary carcinomas (85 invasive type and five encapsulated type), using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK in archival paraffin sections. The thyroid tumors exhibited an intense reaction in the cytoplasm. Most of the papillary carcinomas (77/90), had tumor cells that expressed MK. These were classified into the following two types: invasive type (76/85) and encapsulated type (1/5). Notably, the intensity of MK was stronger at the invading border area of the tumors than in the center. In tissues adjacent to the cancer tissues, normal follicular epithelial cells expressed MK very faintly or not at all. The in situ hybridization analysis revealed that the signals of MK transcripts were found in the cytoplasm of the cancer cells. In the noncancerous follicular epithelial cells adjacent to neoplasm the signals of MK transcripts were detected very weakly or not at all. The distribution and localization of the MK-transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. We conclude that thyroid papillary carcinoma strongly expresses MK protein and messenger RNA, and that this overexpression may relate to the development and invasion of these carcinomas.

Adult↗

PubMed2000

MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies.

MUM1/IRF4 is a myeloma-associated oncogene transcriptionally activated as a result of t(6;14)(p25,q32) chromosomal translocation and by virtue of its juxtaposition to the immunoglobulin heavy chain gene (IgH) locus. When this oncogene becomes non-functional, no activated B/T lymphocytes and Ig secreting plasma cells are observed, suggesting that MUM1/IRF4 is crucial for lymphoid development. Its expression was analyzed in both reactive lymphoid and lymphoma tissues by means of an immunohistochemical technique using specific goat antiserum against MUM1/IRF4. This analysis detected a 50 kDa MUM1 product whose localization was restricted to the nuclei of the lymphocytes. The MUM1+ cells in reactive lymph nodes were found to consist of plasma cells and a small fraction (approximately 7.9%) of B cells harboring CD20+CD38+, which were located in the light zone of the germinal center. MUM1 expression in peripheral blood B/T lymphocytes was upregulated by mitogenic stimuli, suggesting that MUM1 positivity represents the activated state of the B/T cells. In B cell non-Hodgkin's lymphoma (NHL), MUM1 expression was observed in 73.2% (30/41) of diffuse large B cell lymphoma (DLBCL), 20% (1/5) of marginal zone lymphoma (MZL) and 43% (3/7) of small lymphocytic lymphoma (SLL) cases, whereas it was not seen in any cases of mantle cell lymphoma (MCL) or follicle center lymphoma (FCL). Also, MUM1 was stained at high intensity in various types of T cell lymphomas including adult T cell leukemia/lymphoma (ATL/L) and anaplastic large cell lymphoma (ALCL) and in the majority of Hodgkin's diseases. Our results suggest that a major proportion of lymphomas comprise either physiologically or aberrantly activated neoplastic lymphocytes expressing the MUM1 protein.

B-Lymphocytes↗

PubMed2000

High-dose ecabet sodium improves the eradication rate of helicobacter pylori in dual therapy with lansoprazole and amoxicillin.

AIM: The additive effect of ecabet sodium in combination with dual therapy on Helicobacter pylori eradication was evaluated. METHODS: H. pylori-positive chronic gastritis patients were randomly assigned to one of the following three groups and medicated for 2 weeks. Group LA: dual therapy (lansoprazole 30 mg o.d. plus amoxicillin 750 mg b.d.). Group LA1E: dual therapy plus ecabet sodium (1 g b.d.). Group LA2E: dual therapy plus ecabet sodium (2 g b.d.). Patients were evaluated 4 weeks after the cessation of treatment by culture and 13C-urea breath test. RESULTS: Seventy-one patients (mean age, 56.6 years; range, 26-79 years; 40 males, 31 females) were enrolled in this prospective, single-blind study, and 68 completed the protocol. The eradication rates per protocol patient were 43% in group LA, 62% in group LA1E, and 79% in group LA2E, and those on the intention-to-treat basis were 42% in group LA, 57% in group LA1E and 79% in group LA2E. The eradication rate in group LA2E was significantly higher than group LA (P=0.032 in per protocol, P=0.022 in intention-to-treat). Adverse effects were observed in 10 patients in this study. There were no severe adverse effects caused by ecabet sodium. CONCLUSION: High-dose ecabet sodium increases eradication rates of H. pylori in dual therapy with lansoprazole and amoxicillin.

2-Pyridinylmethylsulfinylbenzimidazoles↗