Biomedical subjects

T Noda

Publications and source records attributed to T Noda.

At least 91 records · Page 5Linked to original sources

PubMed2000

Increased plasma levels of tissue factor pathway inhibitor-activated factor X complex in patients with disseminated intravascular coagulation.

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.

Anticoagulants↗

PubMed2000

Juvenile-onset generalized neuroaxonal dystrophy (Hallervorden-Spatz disease) with diffuse neurofibrillary and lewy body pathology.

We describe an unusual case of Hallervorden-Spatz disease (HSD). After presenting with limb rigidospasticity at the age of 9 years, our patient developed progressive dementia, spastic tetraparesis and myoclonic movements, leading to akinetic mutism. He died of pneumonia at the age of 39 years. Autopsy revealed a severely atrophic brain, weighing 510 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids throughout the brain and spinal cord. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which were immunolabeled by anti-alpha-synuclein, were found in the brain stem, cerebral cortex and spinal gray matter. Sarkosyl-insoluble tau extracted from the temporal cortex resolved on immunoblots into three major bands of 60, 64 and 68 kDa and a minor band of 72 kDa, as reported for Alzheimer's disease. The present case, together with a few similar cases reported previously, may represent a particular subset of neuroaxonal dystrophy, i.e., HSD associated with extensive accumulation of both tau and alpha-synuclein.

Adolescent↗

PubMed2000

Cytochemical and ultrastructural examination of apoptotic odontoclasts induced by bisphosphonate administration.

Since odontoclasts share similar characteristics with osteoclasts, this study has examined whether odontoclasts exhibit cytological alteration after treatment with bisphosphonate, which induces apoptosis of osteoclasts. After the administration of bisphosphonate to 6-day-old rabbits, many odontoclasts detached from the dentine surface of the deciduous teeth, resulting in the reduction of tartrate-resistant acid phosphatase (TRAP-ase) and immunoreactivity for cathepsin K. Transmission electron microscopy revealed a number of odontoclasts showing poorly developed or a lack of ruffled borders, a Golgi apparatus markedly reduced in size, and numerous cytoplasmic vesicles. The bisphosphonate-treated odontoclasts displayed fragmented DNA in the pyknotic nuclei evidenced by terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick-end labeling, indicating that bisphosphonate can induce apoptosis of the odontoclasts. Ultrastructural observations of the apoptotic odontoclasts revealed condensed heterochromatin at the margin of the nuclear envelope, assembled arrays of rough endoplasmic reticulum, and many vacuoles and vesicles. Some apoptotic odontoclasts showed ladder-like structures between the adjacent nuclear envelopes, enlargement of the nuclear envelopes, and the formation of a ribosome-like granular structure in the nuclei. Thus, odontoclasts are able to undergo apoptosis after bisphosphonate treatment; this results in cytological alterations, including reduced resorption activity and the inhibition of protein synthesis/transport as indicated by the diminished TRAPase and cathepsin K and the poorly developed Golgi apparatus, respectively. Nuclear alteration as evidenced by the appearance of ladder-like and ribosome-like structures was characteristic of apoptotic odontoclasts.

Acid Phosphatase↗

PubMed2000

Responses of immunocompetent cells in the dental pulp to replantation during the regeneration process in rat molars.

Responses of immunocompetent cells to tooth replantation during the regeneration process of the dental pulp in rat molars were investigated by immunocytochemistry using antibodies to class II major histocompatibility complex (MHC) molecules (OX6 antibody), monocyte/macrophage lineage cells (ED1 antibody) and protein gene product 9.5 (PGP 9.5), as well as by histochemical reaction for periodic acid-Schiff (PAS). Tooth replantation caused an increase in both the number of OX6- and ED1-positive cells and their immunointensity in the replanted pulp, but almost all PGP 9.5-immunoreactive nerves diminished in the initial stages. By postoperative day 3, many OX6- and ED -immunopositive cells had accumulated along the pulp-dentin border to extend their cytoplasmic processes into the dentinal tubules in successful cases. Once reparative dentin formation had begun after postoperative day 7, OX6- and ED1-immmunopositive cells became scattered in the odontoblast layer, while reinnervation was found in the coronal pulp. The temporal appearance of these immunocompetent cells at the pulp-dentin border suggests their participation in odontoblast differentiation as well as in initial defense reactions during the pulpal regeneration process. On postoperative day 14, the replanted pulp showed three regeneration patterns: (1) reparative dentin, (2) bone-like tissue formation, and (3) an intermediate form between these. In all cases, PAS-reactive cells such as polymorphonuclear leukocytes (PML) and mesenchymal cells occurred in the pulp space. However, the prolonged stagnation of inflammatory cells was also discernible in the latter two cases. Thus, the findings on PAS reaction suggest that the migration of the dental follicle-derived cells into the pulp space and the subsequent total death of the proper pulpal cells are decisive factors for eliciting bone-like tissue formation in the replanted pulp.

Animals↗

PubMed2000

Loss of diurnal variation in ornithine decarboxylase and apoptosis in small intestine of Mongolian gerbils.

The aim of this study was to examine the diurnal variations in ornithine decarboxylase (ODC) activity and apoptosis in the small intestinal mucosa of Mongolian gerbils. First, the feeding, drinking, and ambulatory patterns of the gerbils were recorded. The results indicated that Mongolian gerbils lost diurnal cyclicity in feeding, drinking, and ambulatory patterns. Second, ODC activity and apoptosis in the intestinal mucosa of gerbils were characterized by measurements at four time points (11:00, 17:00, 23:00, and 05:00 h; light period, 08:00-20:00 h). Apoptosis was evaluated in terms of percent fragmented DNA (fragmented DNA/total DNA). Neither ODC activity nor apoptosis showed diurnal variation in the jejunal mucosa of the Mongolian gerbils. In 48-h fasted gerbils, ODC activity in the intestinal mucosa decreased, but this activity increased significantly 2 h after refeeding; percent fragmented DNA increased in the intestinal mucosa, and returned to the control level 2 h after refeeding. These results indicate that postprandial local nutrients are an important factor in regulating diurnal variation in ODC activity and apoptosis in the small intestine of gerbils.

Animals↗

PubMed2000

Clinico-radiological study of total knee arthroplasty after high tibial osteotomy.

The results of total knee arthroplasty (TKA) after high tibial osteotomy (HTO) and problems encountered during the operation were investigated in 23 patients (28 knees). HTO was performed by Coventry's method in 18 knees and by Maquet's method in 10 knees. The mean interval from HTO to TKA was 86 months (range, 3 to 288 months) and the mean follow-up period after TKA was 25 months (range, 6 to 116 months). Radiological evaluation showed that the proximal part of the tibia was shifted and tilted lateroinferiorly after HTO. Thus, a tendency to patella infera was observed. Lateral shift of the proximal part of the tibia was more marked with Maquet's method than with Coventry's method (P < 0.01). Posterior inclination of the tibial articular surface before TKA was smaller in the patients who gained a range of motion of 90 degrees or more after TKA than in those with less than 90 degrees (P < 0.05). In patients with 70 points or more on the three-university score after TKA, there was no change in the joint line level between before and after TKA, while the joint line was significantly lower after TKA in those with less than 70 points (P < 0.01). When TKA is done after HTO, various technical problems may influence the outcome, such as correction of the soft tissue imbalance, in addition to difficulties with patellar eversion and exposure of the proximal part of the tibia. The clinical results of TKA after HTO tend to be slightly inferior to those of primary TKA, probably because of such technical problems.

Aged↗

PubMed2000

Identification of the dimethylbenzyl mercapturic acid in urine of rats administered with 1,2,4-trimethylbenzene.

A study was undertaken of the mercapturic acid metabolism of 1,2,4-trimethylbenzene in the rat. Of three regioisomeric dimethylbenzyl mercapturic acids, i.e. 2,4-, 2,5- and 3,4-dimethylbenzyl isomers, the third isomer was not found in the urinary mercapturic acid isolated by preparative HPLC, from the comparison of NMR spectrum of the isolate with those of authentic specimens. The urinary mercapturate was then assigned to 2,4- and/or 2,5-dimethylbenzyl isomers. The excretion rate of the mercapturic acid was 14-20% of dose as 2,4-dimethylbenzyl isomer.

Acetylcysteine↗

PubMed2000

Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease.

OBJECTIVES: This study focused on 1) the determination of the optimal preconditioning (PC) duration, and 2) the protective effect of nicorandil (NC), a hybrid nitrate with a KATP channel opening effect, during a percutaneous transluminal coronary angioplasty (PTCA) model in humans. BACKGROUND: The ischemic PC effect is induced in 180 s ischemia, but not in 120 s ischemia in rabbit hearts. However, the duration of ischemia that induces PC effect and the role of the KATP channel in the PC effect in humans are still unclear. METHODS: Forty-six patients with stable angina were randomly allocated to four groups: the duration of the first inflation as PC ischemia was 60 s in the PC60 group (n = 12), and 180 s in the PC180 group (n = 12). In the other groups, NC (80 microg/kg) was intravenously given for 1 min in the NC group (n = 12), and isosorbide dinitrate (ISDN) (40 microg/kg) was given in the ISDN group (n = 10). Five minutes after first inflation or drug administration, a second inflation was conducted for 120 s in each group. In the ECG, the lead with the largest shift in ST segment (deltaST max), and the sum of elevated ST levels in all leads (sigmaST) were determined. RESULTS: In the PC60 group, no significant difference was observed in either deltaST max or sigmaST between the first and second inflation. However, the second inflation in the PC180 group showed significantly lower levels of deltaST max and sigmaST compared with those of the first inflation. In the NC group, both deltaST max and sigmaST measured at 30 s and 60 s after balloon inflation were significantly lower than those of the first inflation in the PC60 and PC180 control groups. In the ISDN group, no significant difference was observed in deltaST max or sigmaST. CONCLUSION: In human PTCA models, a PC effect is observed in 180 s ischemia, but not in 60 s ischemia. A pharmacological PC effect is induced by NC, a KATP channel opener with a nitrate-like effect but not ISDN. This suggests that the opening of KATP channels plays an important role in the protecting effect of NC.

Angina Pectoris↗

PubMed2000

Histaminergic effect on apoptosis of rat small intestinal mucosa after ischemia-reperfusion.

This study aimed to examine the relationship between a harmful effect of histamine and apoptosis following ischemia-reperfusion in the rat intestine. The superior mesenteric artery was occluded for 60 min followed by reperfusion for 60 min. Rats were infused with H1-receptor antagonist (chlorpheniramine maleate) or H2-receptor antagonist (cimetidine). Additional rats were pretreated with aminoguanidine (100 mg/kg). Percent apoptosis in the intestinal mucosa increased after reperfusion, but neither H1 nor H2 antagonists had any effect on apoptosis. Aminoguanidine pretreatment inhibited activity of diamine oxidase and increased the plasma histamine concentration. Aminoguanidine attenuated the increase in mucosal apoptosis following reperfusion. Apoptosis induced by an ischemic insult to the intestinal mucosa was not related to an undesirable effect of histamine. Attenuation of increased intestinal apoptosis might be due to increased plasma histamine level and/or other pharmacological action of aminoguanidine, including inhibition of inducible nitric oxide synthase.

Animals↗

PubMed2000

Prognosis of replanted primary incisors after injuries.

Between 1979 and 1997, 58 avulsed primary teeth were treated at the Pedodontic Clinic of Niigata University Dental Hospital. Among these, we replanted six avulsed incisors of four patients and treated two teeth of two patients replanted at other dental clinics. Referring to the clinical records, oral photographs and radiographs, we examined the injury age, cause of injury, condition of tooth storage, length of time until replantation, and also the prognosis after replantation. Three teeth of two cases remained until eruption of their permanent successors, and one tooth of one case remained under observation without extraction. Although the other four teeth of three cases resulted in extraction, no secondary infection was detected due to replantation. The following reasons were suspected for the poor prognosis of the four teeth. One avulsed tooth was not fixed immediately after replantation. One replanted tooth might not have been compatible with the alveolar socket. In the other two teeth, the periodontal vital tissues might have been removed before replantation. It is generally suggested that replantation of primary teeth is not a good option. However, from the present results, it was considered that replantation can be an effectual method when the condition of the avulsed primary tooth is suitable.

Age Factors↗

PubMed2000

Determination of mercapturic acids in urine by solid-phase extraction followed by liquid chromatography-electrospray ionization mass spectrometry.

A novel method for the determination of five kinds of mercapturic acids, found in urine as metabolites of alkylbenzenes, based on liquid chromatography-electrospray ionization mass spectrometry is described. A solid-phase extraction procedure was used for the extraction of the mercapturic acids from urine and the separation was performed on a reversed-phase C30 column. The detection limits were in the range 2.4-3.2 ng ml-1.

Acetylcysteine↗

PubMed2000

Natural disasters and alcohol consumption in a cultural context: the Great Hanshin Earthquake in Japan.

AIMS: To assess changes in alcohol consumption attributable to the Great Hanshin Earthquake to test the assumption that alcohol consumption increases after natural disasters. METHODS: Quarterly alcohol sales figures were compared for three periods: before, immediately after and subsequent to the Great Hanshin Earthquake in three areas of the Hyogo prefecture: the severely affected area, the moderately affected area and the unaffected area. Possible confounding by population movement, damage to retail outlets and normal variation in sales, was assessed. FINDINGS: The quantity of alcoholic beverages consumed in the heavily damaged areas as well as throughout the prefecture decreased from the 1994 pre-disaster level, both immediately after the Great Hanshin Earthquake (January-March 1995) and 2 years after the disaster. This finding remained once possible confounding factors were taken into consideration. CONCLUSIONS: More attention should be placed on drinking in the cultural context where a disaster occurs. It may sometimes deter, rather than encourage, drinking among the affected population.

Alcohol Drinking↗

PubMed2000

Targeted disruption of the homeobox transcription factor Bapx1 results in lethal skeletal dysplasia with asplenia and gastroduodenal malformation.

BACKGROUND: NK homeobox genes have been shown to play important roles in cell-type specification and organogenesis. Murine Bapx1, a member of NK homeobox gene family, is expressed in all the cartilageous tissues that undergo endochondral bone formation, and in gut mesentery during embryogenesis, suggesting that Bapx1 may be a key transcription factor ragulating the development of these organs. RESULTS: We generated Bapx1-deficient mice by gene targeting. Bapx1-/- mice exhibited lethal skeletal dysplasia, with abnormal development of the vertebral column and some craniofacial bones, accompanied with asplenia and gastroduodenal malformation. We showed that the proliferative activity of the sclerotome cells, forming the vertebral column, was significantly reduced in Bapx1-/- embryos. The sclerotome cells of the mutants appeared to migrate and condense normally, but subsequent differentiation into the mature vertebral bodies and intervertebral discs were affected. The sclerotome cells in the vertebral bodies failed to differentiate into hypertrophic chondrocytes, as revealed by the undetected expression of Col10a1 and Osteopontin, and the sclerotome cells in the intervertebral discs failed to express the typical extracellular matrix proteins Col2a1, Col9a2 and aggrecan. Furthermore, we investigated the effect of loss of Bapx1 on the expression of some transcription factors, identified to be expressed in the developing sclerotome and be required for normal development of the vertebral column. Among them, we found that the expression of MFH-1 (mesenchyme forkhead-1), which was reported to regulate the proliferation and differentiation of sclerotome cells, was significantly reduced in ventromedial sclerotome cells in Bapx1-/- mice. CONCLUSION: Our analysis provided evidence that Bapx1 was indispensable for normal development of ventromedial structure of vertebral column and some of craniofacial bones, splenogenesis and morphogenesis of gastroduodenal tract.

Abnormalities, Multiple↗

PubMed2000

Complex phenotype of mice lacking occludin, a component of tight junction strands.

Occludin is an integral membrane protein with four transmembrane domains that is exclusively localized at tight junction (TJ) strands. Here, we describe the generation and analysis of mice carrying a null mutation in the occludin gene. Occludin -/- mice were born with no gross phenotype in the expected Mendelian ratios, but they showed significant postnatal growth retardation. Occludin -/- males produced no litters with wild-type females, whereas occludin -/- females produced litters normally when mated with wild-type males but did not suckle them. In occludin -/- mice, TJs themselves did not appear to be affected morphologically, and the barrier function of intestinal epithelium was normal as far as examined electrophysiologically. However, histological abnormalities were found in several tissues, i.e., chronic inflammation and hyperplasia of the gastric epithelium, calcification in the brain, testicular atrophy, loss of cytoplasmic granules in striated duct cells of the salivary gland, and thinning of the compact bone. These phenotypes suggested that the functions of TJs as well as occludin are more complex than previously supposed.

Animals↗

PubMed2000

A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice.

Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenicity, as a consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1(+/-) mutation, instead of Mlh1(-/-), in these methyltransferase-deficient mice. Mgmt(-/-) Mlh1(+/-) mice, with about half the amount of MLH1 protein as Mgmt(-/-) Mlh1(+/+) mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg body wt. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated Mgmt(-/-) Mlh1(+/-) mice had thymic lymphomas and there were no tumors in those mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways leading to mutation induction or to apototic cell death. Loss of Mlh1 expression was frequently observed in tumors of Mgmt(-/-) Mlh1(+/-) mice and this might be related to progression of the tumors.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG.

UNLABELLED: Autonomic disorder is not infrequent in patients with akinetic-rigid syndromes, including idiopathic Parkinson's disease. In the advanced stage of Parkinson's disease, abnormal blood pressure responses, such as orthostatic hypotension and abnormal circadian blood pressure rhythm, may occur. Few cases of reduced 123I-metaiodobenzylguanidine (MIBG) accumulation in the heart or limbs of Parkinson's disease patients have been reported. However, whether reduced accumulation is caused by damage to the postganglionic sympathetic nervous system or by central autonomic failure corresponding to abnormalities in blood pressure regulation is unknown. METHODS: We evaluated sympathetic denervation in 32 Parkinson's disease patients using 123I-MIBG cardiac scintigraphy and compared the findings with those for autonomic dysfunction detected by orthostatic hypotension and diurnal blood pressure variation. Cardiac 125I-MIBG accumulation was also determined in an experimental model of Parkinson's disease using mice pretreated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Cardiac 123I-MIBG accumulation 15 min after injection and 4 h after injection was markedly reduced in the Parkinson's disease patients (heart-to-mediastinum ratio: 1.58 +/- 0.37 and 1.33 +/- 0.28, respectively) compared with 7 healthy volunteers (2.42 +/- 0.27 and 2.60 +/- 0.15, respectively). This reduction was observed even at the earlier stages of physical activity or disease duration and also in patients with normal blood pressure response and variation, indicating that the marked decrease in cardiac 123I-MIBG accumulation may be a special feature of Parkinson's disease. Pretreatment with a total dose of 100 mg/kg MPTP, which is the standard dose used to destroy the dopaminergic neurons in models of Parkinson's disease, significantly reduced cardiac 125I-MIBG accumulation in C57BL/6 mice. Interestingly, the reduction of 125I-MIBG accumulation was still significant when MPTP was reduced to 5 mg/kg. These findings indicated that the postganglionic sympathetic nerves may be damaged by MPTP or unknown toxic substrates in experimental or human Parkinson's disease during the early stage, because dopaminergic neurons and sympathetic nerves are substantially similar in their plasma membrane transporters. CONCLUSION: Cardiac scintigraphy with 123I-MIBG may be used as a new imaging approach in the diagnosis and characterization of akinetic-rigid syndromes, especially Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

[Efficacy of stress management classes at a health center].

Although interest in mental health promotion has recently been increasing, the most appropriate approaches remain to be determined. Therefore we conducted Stress Management Classes (SMCs) at Higashi Osaka City Naka Health Center in an attempt to help residents to improve their mental health. The purpose of this study was to evaluate the efficacy of SMCs, held four times over 2 months, with an educational program including the concept of stress and instruction in autogenic training as a relaxation technique. Subjects who attended a Health Promotion Class (HPC) at Osaka Prefectural Kaizuka Health Center were used as controls for the study. The aim of the HPC was to prevent chronic physical diseases such as hypertension, diabetes, and hyperlipidemia, with the program consisting mainly of exercise once a week for 3 months. The results were as follows: 1) People who attended SMCs were more likely to have mental health problems than those who attended the HPC. As a result, mentally ill patients could be diagnosed and receive psychiatric treatment at an early stage in the SMC group. 2) Both SMC and HPC attenders reported improvement of their mental health status with the use of POMS (Profile of Mood States). 3) Both SMC and HPC attenders exhibited significant decrease of blood pressure. Although attenders of both classes improved their mental health status, it is important to be able to attract individuals who are in a poor mental condition in case of mental health promotion. In this trial, we found that the term "stress management" was very useful because people who suffered stress were likely to be interested in it. After the Community Health Law was established in 1994, the flow of community health activities has been shifting from the prefectural government to the municipality. However, promoting mental health and welfare is still mainly the role of the prefectural government. In this sense, health centers are appropriate institutions to hold classes as in this trial.

Autogenic Training↗

PubMed2000

Rescue of embryonic lethality in hepatocyte growth factor/scatter factor knockout mice.

While the targeted disruption of a gene is a powerful tool for investigating the physiological functions of that gene, disruption of a gene essential for embryogenesis leads to embryonic death. Rescue of the defect(s) causing embryonic death should promote survival, thus permitting further evaluation of the roles that the gene plays later in the developmental process. Disruption of the gene for mouse hepatocyte growth factor/scatter factor (HGF/SF) leads to middle-stage embryonic lethality because of a defect in placental development. Here we report that a single injection of HGF/SF at embryonic day 9.5 (E9.5) into the amniotic cavity of HGF/SF(-/-) embryos rescued the placental defect and resulted in the survival of the embryos until term. Histological analysis suggested that HGF/SF is also required at the late stage of development for tissue organogenesis. Thus, injection of a secreted factor can be a useful method to rescue the defects causing embryonic lethality.

Amniotic Fluid↗