Biomedical subjects

H Ichikawa

Publications and source records attributed to H Ichikawa.

At least 163 records · Page 9Linked to original sources

PubMed1998

Early detection of cardiac damage with heart fatty acid-binding protein after cardiac operations.

BACKGROUND: It is still difficult to evaluate myocardial damage in the acute phase of reperfusion in cardiac operations. We investigated the clinical significance of human heart fatty acid-binding protein (HH-FABP) for detecting myocardial damage after cardiac operations earlier than creatine kinase MB isoform or troponin-T. METHODS: Blood samples from 20 patients who underwent coronary artery bypass grafting were collected serially after reperfusion to measure serum levels of creatine kinase-MB, troponin-T, and HH-FABP. RESULTS: Serum HH-FABP levels peaked earliest after reperfusion. In addition, the maximum serum HH-FABP level was predictable immediately after reperfusion. The maximum serum HH-FABP level correlated with the maximum serum creatine kinase-MB or troponin-T level, as well as with the aortic cross-clamp time or the maximum dose of catecholamines administered after reperfusion. CONCLUSIONS: Measurements of HH-FABP allow for earlier evaluation of myocardial damage in the acute phase of reperfusion. Human heart fatty acid-binding protein may be a useful indicator of myocardial damage after cardiac operations.

Adult↗

PubMed1998

NADPH-diaphorase activity in nerves and Schwann cells in the periodontal ligament of rat incisor teeth.

The lingual portion of the incisor periodontal ligament demonstrated activity for nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase. Schwann cells surrounding Ruffini-like endings coexpressed NADPH-diaphorase activity and immunoreactivity for inducible nitric oxide synthase. NADPH-diaphorase-positive nerve fibres which coexpressed immunoreactivity for neuronal nitric oxide synthase were in contact with Schwann cells surrounding Ruffini-like endings or terminated as free nerve endings. Neural NADPH-diaphorase activity could not be found in the tissues covering the labial portion of incisor tooth root. It is possible that nitric oxide in Schwann cells and nerves has functions specific to the incisor periodontal ligament.

Animals↗

PubMed1998

Interleukin-6 derived from hypoxic myocytes promotes neutrophil-mediated reperfusion injury in myocardium.

BACKGROUND: Reperfusion injury in the myocardium has recently been considered to be a type of inflammation, and close attention has been paid to the possible involvement of neutrophils, complement, and cytokines in the onset of this injury. Recently, it has been reported that serum levels of interleukin-6 are elevated significantly after myocardial infarction. The major site of interleukin-6 production and its exact roles are still unknown. In this study, we hypothesized that myocytes may produce interleukin-6 during hypoxia and this may play a role in neutrophil-mediated reperfusion injury. METHODS AND RESULTS: In the clinical study, 20 patients who underwent coronary artery bypass grafting were divided into 2 groups: group F, in which patients were treated with a serine protease inhibitor (FUT-175, 2 mg/kg per hour) during cardiopulmonary bypass, and group C (untreated patients). In group C, myocardial interleukin-6 production, as determined by the difference between the interleukin-6 level in the cardiopulmonary bypass circuit and its level in coronary venous blood, increased significantly after reperfusion (12+/-4 pg/mL) as compared with that before aortic crossclamping (2+/-2 pg/mL). In group F, the increase in the interleukin-6 level was suppressed significantly (before aortic crossclamping, 3+/-2 pg/mL; after reperfusion, 4+/-3 pg/mL). The interleukin-6 production differed significantly between group C and group F. In the in vitro experimental study, the supernatant from myocytes exposed to 2 hours of hypoxia (group 2H) showed significantly higher levels of interleukin-6 (455+/-260 pg/mL) than that from normoxic myocytes (group N) (47+/-15 pg/mL). This interleukin-6 production was suppressed by the addition of FUT-175 (123+/-24 pg/mL). The interleukin-6 production by endothelial cells of coronary vessels did not differ between group 2H (283+/-151 pg/mL) and group N (151+/-86 pg/mL). In a coincubation system with a monolayer of endothelial cells on collagen membrane and myocytes under collagen membrane in a modified Boyden chamber, 2 hours of coincubation showed a significantly higher percent of neutrophil transendothelial migration (group 2H vs N, 78%+/-13% vs 26%+/-11%), value of chemiluminescence (22+/-8 vs 5+/-2 x 10(3) counts/3 minutes), and percent of irreversibly damaged myocytes (48%+/-17% vs 12%+/-8%) than normoxic coincubation. In contrast, anti-interleukin-6 monoclonal antibody significantly attenuated neutrophil transendothelial migration (42%+/-19%) and irreversible damage of myocytes (26%+/-15%) in 2 hours of coincubation. CONCLUSIONS: Interleukin-6 is produced from myocardium during ischemia and reperfusion in patients undergoing coronary bypass grafting. This interleukin-6 may be derived from hypoxic myocytes and play a role in neutrophil-mediated reperfusion injury in myocardium.

Animals↗

PubMed1998

Subcutaneous phaeohyphomycosis caused by Geniculosporium species; a new fungal pathogen.

A 70-year-old Japanese timberworker dealing with imported timber from the U.S.A. and Russia had an asymptomatic subcutaneous nodule with a small fistula on his left knee. Histopathological examination of the nodule revealed brownish hyphal elements in encapsulated pyogranuloma. The fungus isolated from a discharge of the fistula and an excised specimen of the lesion was identified as Geniculosporium sp., which represents a conidial state (anamorph) of several genera such as Anthostomella, Biscogniauxia, Euepixylon, Leprieuria, Nemania, Phylacia and Rosellina in the Xylariaceae. Whereas this dematiaceous hyphomycete is commonly found on decaying wood and bark of various trees, to our knowledge, this is the first case of a phaeomycotic cyst caused by fungi belonging to the genus Geniculosporium.

Aged↗

PubMed1998

Circadian rhythm sleep disorders in adolescents: clinical trials of combined treatments based on chronobiology.

Delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake rhythm are circadian rhythm sleep disorders that are common in adolescents. Most patients have difficulty adjusting to school life, poor class attendance or refuse to go to school. Since a treatment has not been established, the present paper is presented to propose a strategy for treating circadian rhythm sleep disorders in adolescents, based on our clinical studies. Twenty subjects (12 males and eight females, mean age 16.2+/-1.7 years) participated in the study. The onset of sleep disorder occurred between the ages of 11 and 17. The most common factors affecting the onset of disorders were changes in social environment. The subjects kept a sleep-log for the periods before and during treatments. The treatments were based on chronobiology: resetting the daily life schedule, chronotherapy, regulation of the lighting environment, methylcobalamin, and/or melatonin. Bright light exposure was successful in 10 patients, of whom four were treated with methylcobalamin. Melatonin treatment was successful in two patients (one with and one without chronotherapy). Thirteen of the 20 patients were successfully, treated with therapies based on chronobiology. After consideration of these results, a step-by-step procedure of combined treatments for the circadian rhythm sleep disorders is proposed.

Absenteeism↗

PubMed1998

A novel technique for cardiopulmonary bypass using vacuum system for venous drainage with pressure relief valve: an experimental study.

To decrease the circuit priming volume, develop safety, and simplify the equipment, a cardiopulmonary bypass (CPB) circuit using a vacuum suction venous drainage system with a pressure relief valve was developed. The efficacy of this vacuum system was compared to that of a conventional siphon system. The system contains a powerful vacuum generator and a pressure relief valve to keep the negative pressure constant when blood suction is used. Using 8 mongrel dogs, the feasibility and the efficacy of this CPB system was tested. The changes in the negative pressure in the reservoir were within 5 mm Hg whether the suction lines were switched on or off. In all animals the amount of blood in the venous reservoir was stable throughout bypass. The decrease of priming volume was from 725 ml (siphon system) to 250 ml (vacuum system). At the end of CPB, the levels of hemoglobin in the vacuum system were significantly higher than those in the siphon system. These results demonstrated that this vacuum drainage system can provide simplification and a miniaturization of the cardiopulmonary bypass circuit resulting in low hemodilution during CPB.

Animals↗

PubMed1998

The expulsion of Echinostoma trivolvis caused by goblet cell hyperplasia in severe combined immunodeficient (SCID) mice.

Mice with severe combined immunodeficiency (SCID), lacking functional T and B lymphocytes, were each infected with 40 Echinostoma trivolvis metacercarial cysts on day 0. The mice of the test group were given intramuscular injections of dexamethasone (DEX) daily for 2 weeks and necropsied on days 5, 8, 12, 15, 20 and 30 post-infection (p. i.). The control mice, not treated with DEX, were each infected with 40 echinostome cysts on day 0 and necropsied on the same days as the DEX-treated mice. In the control mice, worm rejection began about day 8 p. i. and the worms were completely rejected by day 15 p. i., corresponding to the peak in goblet cell hyperplasia, about day 12 p. i. In the DEX-treated mice, goblet cell hyperplasia was significantly suppressed and the worms were retained until day 15 p. i., and then rejected after the last treatment with DEX. The number of mucosal mast cells, that increased with worm infection and peaked about day 15 p. i., was apparently suppressed by treatment with DEX. The eosinophil number in the controls increased on day 15 p.i. approximately and then decreased. The eosinophil number in the DEX-treated mice increased as in the controls, but was significantly suppressed compared to that of the controls during the period of the experiment. Enzyme-linked immunosorbent assay (ELISA) showed no marked rise in titres of the sera IgM, IgA and IgG throughout the experiment in both groups. These results indicate that DEX-treatment delayed the rejection of E. trivolvis from the small intestine of SCID mice in association with the suppression of goblet cell hyperplasia. It is concluded that the host immune system is not involved in the rejection of E. trivolvis and the effector cells for worm rejection are goblet cells that markedly increase in numbers by infection with E. trivolvis.

Animals↗

PubMed1998

S100 protein-immunoreactive trigeminal neurons innervating the rat molar tooth pulp.

S100-immunoreactivity (ir) was examined in tooth pulp primary neurons of the rat. An immunofluorescence method demonstrated that the molar tooth pulp contained S100-immunoreactive (ir) nerve fibers. In the root pulp, pulp horn and roof of the pulp chamber, S100-ir smooth and varicose fibers ramified and formed subodontoblastic nerve plexuses. All the fibers became varicose at the base of the odontoblastic layer and extended to the odontoblastic layer. Some varicose endings could be traced into the dentin. The trigeminal neurons retrogradely labeled with fluorogold (FG) from the first and second maxillary molar tooth pulps exhibited S100- and parvalbumin-ir. Approximately 60% and 24% of the labeled cells were ir for S100 and parvalbumin, respectively. Virtually all parvalbumin-ir FG-labeled cells showed S100-ir, while 40% of S100-ir ones coexpressed parvalbumin-ir. An immunoelectron microscopic method revealed that all myelinated axons and half of the unmyelinated axons in the root pulp contained S100-ir. In the odontoblastic layer, predentin and dentin, S100-ir neurites lost the Schwann cell ensheathment and made close contact with cell bodies and processes of odontoblasts. The odontoblastic layer also contained parvalbumin-ir neurites. These neurites were devoid of the Schwann cell ensheathment and in close apposition to cell bodies and processes of odontoblasts. S100-ir pulpal axons seemed to be insensitive to repeated neonatal capsaicin treatment. This study suggests that S100-ir tooth pulp primary neurons are mostly myelinated and that S100-ir unmyelinated axons in the root pulp are preterminal segments of myelinated stem axons.

Animals↗

PubMed1998

Stimulation of epithelial cell proliferation of isolated distal colon of rats by continuous colonic infusion of ammonia or short-chain fatty acids is nonadditive.

Dietary fibers accelerate colonic epithelial cell proliferation at least in part by modulating bacterial metabolism in the large intestine. Ammonia and short-chain fatty acids (SCFA) are major metabolites of hindgut bacteria and are believed to affect epithelial cell kinetics of the colon. However, the effect of luminal ammonia itself and the possible interaction of ammonia with SCFA on colonic epithelial cell proliferation have not yet been studied. The colon of rats was surgically isolated and continuously administered infusates with saline, ammonia, SCFA or both into the isolated colon for 7 d in a two-way factorial design. On d 7, vincrystine sulfate was administered intravenously to cause metaphase arrest. The activity of epithelial cell proliferation in the distal colon was estimated by using a stathmokinetic method and by histologic examination. The crypt size was significantly larger in rats given infusates containing SCFA than in rats given infusates without SCFA. Infusion of ammonia or SCFA significantly stimulated colonic epithelial cell proliferation compared with the saline infusion. Infusion of both ammonia and SCFA resulted in accumulated mitoses per crypt that did not differ from the other three infusions although the value tended to be lower than when SCFA alone were infused. Thus, stimulation of epithelial cell proliferation by ammonia and SCFA is not additive, and the interaction between them should be considered when the effects of dietary fibers on gut epithelial proliferation are investigated.

Ammonia↗

PubMed1998

Impairment in biochemical level of arterial dilative capability of a cyclic nucleotides-dependent pathway by induced vasospasm in the canine basilar artery.

The authors investigated the changes and the potential of cyclic nucleotide-dependent signal transduction, which induces smooth muscle relaxation, in the basilar artery with severe vasospasm in dogs with double experimental subarachnoid hemorrhage (SAH) to explore at which biochemical level the arterial dilative capability was impaired. The amount of cyclic adenosine and guanosine monophosphates (cAMP and cGMP) decreased significantly in the basilar artery after SAH. The activities of adenylate and guanylate cyclases also were decreased significantly in the smooth muscle cells of the basilar artery 4 days after SAH. In addition to the failure of the pathways to produce cyclic nucleotides, the activities of cAMP- and cGMP-dependent protein kinases, which are representative actual enzymes that amplify the signal for vascular dilation, also significantly decreased together with the almost total loss of activation by cyclic nucleotides in the same basilar artery after SAH. It was revealed that the system for smooth muscle relaxation was impaired severely in the cerebral arteries with severe vasospasm after SAH, on the biochemical basis of significantly less vasodilative capability and in several of the steps to produce the cyclic nucleotides of intracellular signal transduction.

Adenylyl Cyclases↗

PubMed1998

Efficacy of hypothermic perfusion using University of Wisconsin solution in extended hepatectomy with hepatic inflow occlusion in a canine model.

This study was designed to elucidate the efficacy of University of Wisconsin (UW) solution for preventing liver injury, when used as a hypothermic perfusate infused into the systemic circulation during extended hepatectomy with hepatic inflow occlusion. Adult mongrel dogs (9.5-17.5 kg, n = 14) were subjected to 75% hepatectomy under 60 min hepatic inflow occlusion. The animals were divided into two groups. The UW group (n = 7) underwent hypothermic perfusion using 4 degrees C UW solution (core temperature of the liver: 12.3 +/- 0.2 degrees C). The control group designated as the Ringer's lactate (LR) group (n = 7) underwent hypothermic perfusion using 4 degrees C LR solution. The perfusate was introduced into the systemic circulation via the hepatic vein. Blood from the hepatic vein was sampled, and alanine aminotransferase, purine nucleoside phosphorylase activities and the ammonia concentration were measured. The 7 day survival rate was higher in the UW group than in the LR group. The parameters of liver function were less significantly altered in the UW group than in the LR group. The plasma ammonia concentration was significantly (P < 0.05) lower 6 h after reperfusion in the UW group than in the LR group. A small volume of hypothermic perfusion of the liver using UW solution was safe if it returned to systemic circulation. Hypothermic perfusion of the liver using UW solution may be effective for preventing hepatic tissue injury during extended hepatectomy with hepatic vascular occlusion.

Adenosine↗

PubMed1998

Periodic limb movements and sleep-wake disorder.

The relationship of periodic limb movements (PLM) and sleep-wake disorders in 11 patients was investigated. Two patients complained of insomnia. A patient with cervical spinal canal stenosis had a complaint of difficulty in initiating sleep. Movement index (MI) was 51 and PLM arousal index was 8. A patient with chronic hemodialysis had a complaint of difficulty in initiating and maintaining sleep. MI was 79 and PLM arousal index was 51. One patient with myotonic dystrophy showed 79 in MI and 3 in PLM arousal index. It is suspected that myotonic dystrophy is less sensitive to stimuli during sleep (i.e. PLM). These results suggest that the sleep-wake disorders associated with PLM relate to the threshold of awakening.

Adult↗

PubMed1998

Exogenous NO enhances hydrogen peroxide-mediated neutrophil adherence to cultured endothelial cells.

One important aspect of oxidant injury is the enhancement of neutrophil-endothelial adhesion by oxidants such as hydrogen peroxide. Recent studies suggest that nitric oxide (NO) can limit oxidant-mediated tissue injury, since inhibitors of endogenous NO synthesis often promote neutrophil-endothelial adhesion. However, less is known about the direct role of exogenous NO in modulating proadhesive effects of oxidants. The objective of this study was to examine how an NO donor modifies hydrogen peroxide-mediated adhesion of neutrophils to cultured endothelial cells. Human umbilical vein endothelial cell monolayers were exposed for 30 min to 0-0.1 mM hydrogen peroxide with or without the NO donor spermine-NONOate (SNO; 0-0.5 mM), and the adhesion of 51Cr-labeled polymorphonuclear neutrophils (PMNs) was measured in a static adhesion assay. PMN adherence was not altered by either peroxide (up to 0.1 mM) or SNO (up to 0.5 mM) alone but was significantly increased by over 300% by coadministration of both 0.1 mM peroxide and 0.5 mM SNO. This increase in adhesion with these two agents was correlated with an increase in the presentation of surface P-selectin but not intercellular adhesion molecule-1. Both PMN adhesion and P-selectin presentation were blocked by 0.1 mM desferrioxamine (an iron chelator) and 1 mM methionine (an oxyradical scavenger). WEB-2086, a platelet-activating factor-receptor antagonist (10 microM), also prevented PMN adhesion but not P-selectin expression. An antibody directed against either P-selectin or intercellular adhesion molecule-1 also blocked adhesion. These data indicate that NO may actually exacerbate rather than protect against the inflammatory effects of peroxide in some models of inflammation through the synthesis of platelet-activating factor and the mobilization of P-selectin.

Azepines↗

PubMed1998

Soluble P-selectin is released from activated platelets in vivo during hemodialysis.

During hemodialysis, platelets are activated across a dialyzer. Soluble P-selectin (sP-selectin) is a form of P-selectin which is a glycoprotein relocated from secretory granules to the surfaces of platelets and endothelial cells after these cells have been physiologically activated. To investigate whether sP-selectin is useful as a marker of platelet activation during hemodialysis, we measured the plasma concentration of sP-selectin by enzyme-linked immunosorbent assay in 6 patients hemodialyzed in our institute using regenerated cellulose (RC) membranes and thereafter polysulfone membranes. Concomitantly, we also measured the plasma concentration of platelet factor 4 and beta-thromboglobulin which are released from alpha-granules of activated platelets. During hemodialysis with RC membranes, the beta-thromboglobulin level was significantly increased 15 min (p < 0.05) and the sP-selectin level 15 (p < 0.05) and 180 min (p < 0.05) after initiation of dialysis on the venous side as compared with the arterial side of the hemodialyzer. During hemodialysis with polysulfone membranes, no significant variation in plasma beta-thromboglobulin and sP-selectin levels was detected. The platelet factor 4 level increased more significantly across a dialyzer 180 min after initiation of dialysis with RC than with polysulfone membranes (p < 0.01). The changes in plasma platelet factor 4 and beta-thromboglobulin levels demonstrated that platelets are more activated during hemodialysis with RC than with polysulfone membranes. The changes in plasma sP-selectin levels during hemodialysis with RC confirm that the release of P-selectin purely from activated platelets was detected by enzyme-linked immunosorbent assay. sP-selectin may be a marker of platelet activation during hemodialysis.

Adult↗

PubMed1998

Serum leptin concentrations in patients on hemodialysis.

Serum leptin concentrations in normal humans have been reported to correlate with the body mass index (BMI) as well as with the body fat mass. In this study, we measured serum leptin concentrations in 107 patients on hemodialysis, 30 of whom had diabetes mellitus as the cause, and examined the clinical significance. Furthermore, we evaluated the effects of high-flux dialysis membranes on serum leptin levels. Serum leptin concentrations had a linear correlation with BMI as well as with the percentage of body fat in patients on hemodialysis. The serum leptin concentrations showed a positive correlation with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglyceride, the body weight, the BMI, and the percentage of body fat. The serum leptin levels were not different between the diabetic and the nondiabetic groups. The serum leptin levels in the nondiabetic group were nearly fourfold higher in women than in men. We investigated the differences in the rate of reduction in serum leptin after dialysis with polysulfone membrane dialyzers (PS-N and PS-UW) in comparison with a cellulose membrane dialyzer (AM-SD), and as a result, we found that the polysulfone membrane dialyzers removed serum leptin, while the cellulose membrane dialyzer did not. We conclude that in patients on hemodialysis, the serum leptin concentration is a valuable clinical marker of the body fat content and may also contribute to the evaluation of hyperlipidemia.

Adipose Tissue↗

PubMed1998

Fatal hyperammonemia in a patient with systemic lupus erythematosus.

We treated a 31-year-old woman with systemic lupus erythematosus, renal failure with nephrotic syndrome, and a long-standing seizure disorder, who developed severe hyperammonemia with a fatal outcome. Blood chemistry examination did not indicate liver disease, and amino acid concentrations did not suggest a defect in the urea cycle. Discontinuation of anticonvulsant treatment with valproic acid (VPA) failed to bring about improvement. We speculated that hyperammonemia in this case was induced by VPA, and the existence of other underlying factors, including the administration of aspirin and cimetidine, hypoalbuminemia, and renal failure might elevate the concentration of the serum free fraction of VPA.

Adult↗

PubMed1998

The effects of the hypothermic management of brain dead dogs on preserving graft viability in heart transplantation.

The effect of hypothermic management for brain dead dogs on preserving graft viability was evaluated through preservation and transplantation. After the occurrence of brain death, 43 dogs were divided into two groups; the normothermic group (37.2+/-0.3 degrees C) and the hypothermic group (31.8+/-0.3 degrees C) according to the esophageal temperature. After the 6-hour management of brain dead donors, the heart beat was arrested using a cardioplegic solution followed by coronary vascular bed washout. The donor heart was then harvested and preserved for 12 hours with simple immersion into the University of Wisconsin solution. Following preservation, orthotopic transplantation was performed in six grafts randomly selected from each group. During the 6-hour management of brain dead dogs; 1) heart rates, rate-pressure products, and the total amount of catecholamine were significantly (p<0.05) lower in the hypothermic group than in the normothermic group, and 2) lactate contents collected from the coronary sinus blood and O2-extraction rates of the heart tended to be lower in the hypothermic group than in the normothermic group. During 12 hours of preservation, intracellular pH and creatine phosphate contents were higher in the hypothermic group than in the normothermic group. Following orthotopic transplantation, the animals in the hypothermic group showed a significantly (p<0.05) higher recovery rate of left ventricular (LV) pressure and the maximum rate of the rise of LV pressure compared with normothermic group animals. We conclude that the hypothermic management of brain dead dogs may be effective in preserving graft viability and may provide a clinical application for heart transplantation with acceptable outcomes.

Adenosine↗

PubMed1998

[A case of scleroderma renal crisis with massive pericardial effusion and positivity on antiphospholipid antibody test].

A 47-year-old woman was admitted to our hospital for evaluation of general fatigue and dyspnea. She had been diagnosed with progressive systemic sclerosis (PSS) when she was 39 years of age, on the basis of Raynaud's phenomenon, proximal sclerosis, and pigmentation of the skin. On admission, her blood pressure was 206/128 mmHg. Funduscopy revealed grade III (Keith & Wagener) hypertensive retinopathy. Laboratory data showed positivity for anti-nuclear antibody and anticardiolipin beta 2 glycoprotein I antibody, and the plasma level of renin activity (PRA) was abnormally high. Chest X-ray and UCG revealed massive pericardial effusion. On the second hospital day, she was operated on for pericardiodiaphragmatic fenestration. The volume of pericardial effusion amounted to more than 2000 ml. Post operative malignant hypertension persisted. Laboratory data showed thrombocytopenia, hemolytic anemia, and acute renal failure. We diagnosed scleroderma renal crisis (SRC) associated with antiphospholipid syndrome. Following the initiation of angiotensin converting enzyme inhibitor (ACE-I) combined with calcium antagonist and alpha-one blocker, her blood pressure and PRA decreased. She also had been treated with aspirin 81 mg daily. These therapies were effective in recovering the platelet count and stopped the progression of anemia and renal failure. Although either the finding of large pericardial effusion or SRC is associated with poor prognosis in PSS, this case has had a good clinical course. In this case, the findings suggested that anti-phospholipid antibody may have contributed to the pericarditis and SRC.

Acute Kidney Injury↗