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D W Kim

Publications and source records attributed to D W Kim.

At least 19 recordsLinked to original sources

Toluene-induced accumulation of trehalose by Pseudomonas sp. BCNU 106 through the expression of otsA and otsB homologues.

AIM: The objective of this study was to investigate toluene-induced accumulation mechanism of trehalose in a toluene-tolerant bacterium Pseudomonas sp. BCNU 106. METHODS AND RESULTS: The accumulation of trehalose by a toluene-tolerant bacterium Pseudomonas sp. BCNU 106 was examined at various cultivation time by measuring the total intracellular trehalose content, trehalase activity and mRNA levels of the trehalose-biosynthetic genes. The pattern of trehalose accumulation corresponded to the mRNA expression pattern of the trehalose-biosynthetic genes with the maximum level at 12 h or 4 h of cultivation with 10% (v/v) toluene, respectively. The trehalose-biosynthetic genes were also cloned and sequenced. Furthermore, the effects of toluene addition on the intracellular osmotic pressure and pH were investigated. It was shown that homeostasis was maintained in the bacterial cells. CONCLUSIONS: In a toluene-tolerant bacterium Pseudomonas sp. BCNU 106, a significant amount of trehalose was accumulated through the toluene-induced expression of the trehalose-biosynthetic genes after the exposure to toluene. SIGNIFICANCE AND IMPACT OF THE STUDY: The accumulation of the high level of intracellular trehalose was preceded by the expression of otsA/B genes in toluene-tolerant bacteria, contributing to the elucidation of the tolerance mechanism.

Gene Expression Regulation, Bacterial↗

Vascular endothelial growth factor (VEGF) is associated with reduced severity of acute graft-versus-host disease and nonrelapse mortality after allogeneic stem cell transplantation.

This study investigated whether or not there is a correlation between the changes in the serum levels of vascular endothelial growth factor (VEGF) and the outcome of allogeneic stem cell transplantation (allo-SCT). Eighty-five patients undergoing allo-SCT were prospectively studied. The serum VEGF levels were measured on days 0, +7 and +14 after transplantation. The VEGF levels decreased significantly on day +7 and recovered on day +14. The highest levels from day +7 through day +14 were categorized by cluster analysis, which were then correlated with the nonrelapse mortality (NRM). There was a significant correlation between a low VEGF level and the occurrence of severe acute graft-versus-host disease (GVHD) including grade III-IV (P=0.029). The 1-year probability of NRM in patients with a low VEGF level was 22.5% compared with 3.5% for those with a high VEGF level (P=0.024). Multivariate analysis revealed clinically defined infections (P=0.011), advanced disease (P=0.014) and a low VEGF cluster (P=0.05) to be significantly associated with the occurrence of NRM in the cohort. In conclusion, low VEGF levels after allo-SCT are associated with NRM with an exacerbated severity of acute GVHD. VEGF monitoring after a transplant might identify those patients at risk of severe transplant-related mortality.

Acute Disease↗

Patterns of C-reactive protein release following allogeneic stem cell transplantation are correlated with leukemic relapse.

The C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes, and is a reliable marker of systemic inflammation, which is relevant to the release of the proinflammatory cytokines. The value of monitoring the CRP levels after stem cell transplantation (SCT) can identify patients at risk of treatment-related complications and mortality. Inflammatory cytokines facilitate donor T-cell activation via antigen presenting cells immediately after SCT. This study examined the relationship between the post-SCT CRP levels and a leukemic relapse. Fifty-four consecutively transplanted patients who relapsed after the allogeneic SCT were compared with nonrelapsing patients. The serum CRP levels were measured on day 0 and every 7 days thereafter until 4 weeks after the SCT. The mean CRP levels throughout the early post-SCT episode were significantly lower in the relapsing patients than in those who did not experience relapse (mean+/-s.e.: 26.8 +/- 6.3 vs 65.3 +/- 9.4 for first week, P = 0.001; 23.9 +/- 3.8 vs 44.6 +/- 6.6 for second week, P = 0.008). Univariate analysis showed that the CRP level on the first and second week, and graft-versus-host disease were significantly associated with a relapse. Multivariate analysis showed that the CRP level on the first week was the strongest independent variable predicting the risk of a relapse after SCT (P = 0.04). These results indicate that the serum CRP levels early after allogeneic SCT might display the graft-versus-leukemia (GvL) effect. CRP is a surrogate of the proinflammatory cytokine release that was not measured in this study. The GvL effect appears to be efficiently strengthened by the high CRP levels that may be reflecting T-cell activation.

Adolescent↗

Isolation and characterization of outer root sheath melanocytes of human hair follicles.

BACKGROUND: Outer root sheath melanocytes (ORSM) are not yet routinely cultured and their biology is not known in detail because of their relatively low numbers in the hair follicle and their limited proliferative capacity in in vitro culture in routine media. OBJECTIVES: To develop a method for culturing ORSM more easily and to investigate the length of telomeres and antigenic characteristics of ORSM compared with epidermal melanocytes (EM). METHODS: Hair follicles were obtained from three Korean individuals during hair transplantation surgery. Single-cell suspensions of the outer root sheath were made and cultured in melanocyte growth medium with stem cell factor. After 21 days, second-passage outer root sheath keratinocytes (ORSK) (2 x 10(4) mL(-1) MGM) were added into the culture plates. We studied the proliferation pattern, morphological and antigenic characteristics of ORSM for each passage of cultured cells, and observed ORSM telomere length. RESULTS: We established an ORSM culture method using ORSK. Two morphologically different ORSM types were obtained in the primary cultures. At the end of primary culture, ORSM appeared as whitish-cream pellets. The proliferation pattern of ORSM showed a sigmoidal shape, the accumulated numbers of population doublings showed a plateau after approximately 5 months, and senescence occurred at approximately 33 +/- 5 accumulated population doublings. The length of ORSM telomeres continued to shorten as the cells proliferated. In contrast, EM showed a marked proliferation from the early proliferation period which formed a plateau pattern towards the later period, and the number of accumulated population doublings was estimated to be 18 +/- 5 after 2 months. ORSM in the primary culture reacted variably with l-dihydroxyphenylalanine (DOPA): some cells were DOPA negative, some DOPA positive. There were some different antigenic expressions of microphthalmia-associated transcription factor (MITF) showing cytoplasmic expression in ORSM and nuclear expression in EM. By nuclear extraction and Western blotting, we showed that MITF expression of ORSM was marked in the cytoplasm and minimal in the nucleus. Antigenic expression of MITF and Bcl-2 gradually decreased with increasing passage number, whereas tyrosinase-related protein-1 expression did not change. CONCLUSIONS: Culture of ORSM requires ORSK or ORSK-related factors; ORSM have greater proliferation potential and show different MITF antigenic expression compared with EM; and the length of ORSM telomeres shortens with repeated proliferation.

Adult↗

Antibiotic use during the last days of life in cancer patients.

The purpose of this study is to document infection and to better understand current practice relating to antibiotic use and its effect in terminal cancer patients. We retrospectively reviewed patients with terminal stage cancer who were admitted to Seoul National University Boramae Hospital for symptom control only, and who finally died between March 2003 and April 2004. A total of 141 patients were enrolled. Mean duration from admission to death was 31.2 days. A total of 104 patients (75.2%) experienced a febrile episode, and physicians considered 113 patients (80.1%) developed a clinical infection. Total 119 patients (84.4%) received antibiotics. For 90 patients (63.8%), antibiotics were used until the day of death. After using antibiotics, 48% of fevers were controlled, and 31% of organism-proven cases were resolved. Symptomatic improvement of infection was achieved in 18 patients (15.1%), but 66 patients (55.4%) showed no improvement. Improved leucocytosis was achieved by 17% and C Reactive Protein elevation by 29%. In conclusion, our study reveals a high rate of infection and a high rate of antibiotic prescription during the last month of life in cancer patients. But symptomatic improvement was not achieved in more than half of the patients. Further study should be undertaken to clarify the benefit of antibiotics in terminal stage cancer patients.

Adult↗

An extract of Polygonum multiflorum protects against free radical damage induced by ultraviolet B irradiation of the skin.

Over the last decades, the incidence of ultraviolet B (UVB)-related skin problems has been increasing. Damages induced by UVB radiation are related to mutations that occur as a result of direct DNA damage and/or the production of reactive oxygen species. We investigated the anti-oxidant effects of a Polygonum multiflorum thumb extract against skin damage induced by UVB irradiation. Female SKH-1 hairless mice were divided into three groups: control (N = 7), distilled water- (N = 10), and P. multiflorum extract-treated (PM, N = 10) groups. The PM (10 g) was extracted with 100 mL distilled water, cryo-dried and 9.8 g was obtained. The animals received a topical application of 500 microL distilled water or PM extract (1, 2, 4, 8, and 16%, w/v, dissolved in distilled water) for 30 min after UVB irradiation (wavelength 280-320 nm, 300 mJ/cm(2); 3 min) of the dorsal kin for 14 days, and skin immunohistochemistry and Cu,Zn-superoxide dismutase (SOD1) activity were determined. SOD1 immunoreactivity, its protein levels and activities in the skin were significantly reduced by 70% in the distilled water-treated group after UVB irradiation compared to control. However, in the PM extract-treated groups, SOD1 immunoreactivity and its protein and activity levels increased in a dose-dependent manner (1-16%, w/v, PM extract) compared to the distilled water-treated group. SOD1 protein levels and activities in the groups treated with 8 and 16%, w/v, PM extract recovered to 80-90% of the control group levels after UVB. These results suggest that PM extract strongly inhibits the destruction of SOD1 by UV radiation and probably contains anti-skin photoaging agents.

Administration, Topical↗

OK-432 sclerotherapy of plunging ranula in 21 patients: it can be a substitute for surgery.

BACKGROUND AND PURPOSE: Although first-choice therapy for the ranula is surgery, this choice presents technical difficulties and frequent recurrences because of insufficient surgery. We evaluated the efficacy of OK-432 sclerosis of the plunging ranula as a substitute for surgery. METHODS: Twenty-one patients with plunging ranula were treated with intralesional injection of OK-432. The liquid content of the ranula was aspirated as much as possible, after which OK-432 solution was injected in the same volumes as that drawn out. Patients were followed on sonography or CT. RESULTS: Seven (33.3%) patients with plunging ranulas showed total shrinkage and resolution, and 4 (19%) patients showed near-total shrinkage (more than 90% of the volume). Four (19%) patients revealed marked shrinkage (more than 70% of the volume), and 3 (14.3%) patients showed partial shrinkage (less than 70% of the volume). Three (14.3%) patients showed recurrence after total shrinkage 1 month after injection. The overall recurrence rate after each injection was 47% (16 of 34 injections in 21 patients), but the recurrence rate after the last sclerotherapy was only 14%. There were no serious side effects except for fever lasting 2-3 days (12 patients) and swelling (10 patients) for 3-5 days. Mild odynophagia for 1-2 days was also noted in 7 patients, and there was 1 severe case of odynophagia. CONCLUSION: OK-432 sclerotherapy of plunging ranula is a safe and potentially curative procedure that may be used as a primary treatment for plunging ranula before considering surgery.

Adolescent↗

Valproic acid reduces enhanced vesicular glutamate transporter immunoreactivities in the dentate gyrus of the seizure prone gerbil.

To elucidate the relationship between glutamatergic current and vesicular glutamate transporter (VGLUT) expressions, we performed the comparative analyses of evoked potentials and VGLUT immunoreactivities in the dentate gyrus, and its response to antiepileptic drug treatments in a gerbil model. The EPSP slope that could be evoked in seizure sensitive (SS) gerbils was significantly greater than in seizure resistant (SR) gerbils. There was also a strong trend towards the larger population spike amplitude in SS gerbils. In addition, VGLUT immunoreactivities were markedly enhanced in the dentate gyrus of SS gerbils, as compared with the SR gerbils. Following valproic acid (VPA, 30 mg/kg), the population spike amplitude and the EPSP slope in response to the stimulus were markedly reduced in the dentate gyri both of SR and of SS gerbils, although this dosage of VPA had no effect in low stimulus currents in SS gerbils. Vigabatrin (VGB) and low dosage of VPA treatment did not affect the evoked responses. Similarly, VPA treatment reduced enhanced VGLUT immunoreactivities in the dentate gyrus of SS gerbils, whilst VGB did not. These findings suggest that up-regulation of VGLUT immunoreactivities may be related to the hyperexcitability of granule cells in SS gerbils, and altered VGLUT immunoreactivity in the dentate gyrus may be independent of GABAergic transmission.

Action Potentials↗

Effect of seizure on hippocampus in mesial temporal lobe epilepsy and neocortical epilepsy: an MRS study.

This study was performed to evaluate the effect of seizures on the bilateral hippocampus in mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy by single voxel proton magnetic resonance spectroscopy (MRS). Forty-one patients with mTLE having unilateral hippocampal sclerosis and 43 patients with a neocortical epilepsy who underwent subsequent epilepsy surgery were recruited. Ninety-five percent confidence intervals of N-acetyl aspartate/choline (NAA/Cho) and NAA/creatine (NAA/Cr) ratios in 20 healthy control subjects were used as threshold values to determine abnormal NAA/Cho and NAA/Cr. NAA/Cho and NAA/Cr were significantly lower in the ipsilateral hippocampus of mTLE and neocortical epilepsy. Using asymmetry indices for patients with bilaterally abnormal ratios of NAA/Cho and NAA/Cr in addition to using unilateral abnormal ratio, the seizure focus was correctly lateralized in 65.9% of patients with mTLE and 48.8% of neocortical epilepsy patients. Bilateral NAA/Cho abnormality was significantly related to a poor surgical outcome in mTLE. No significant relationship was found between the results of NAA/Cho or NAA/Cr and surgical outcome in neocortical epilepsy. The mean contralateral NAA/Cr ratio of the hippocampus in mTLE was significantly lower in patients with a history of secondary generalized tonic-clonic seizure (SGTCS) than in those without. Our results demonstrate effects of seizures on the hippocampi in neocortical epilepsy and the relation between SGTCS and NAA/Cr of the contralateral hippocampus in mTLE. This proves the presence of a seizure effect on the hippocampus in neocortical epilepsy as well as in mTLE.

Adult↗

Automatic stimulus breaker for electric dental pulp tester using pain response.

The pulp test provides a means of examining the vitality of dental pulp using physical or chemical stimulation. During electrical pulp testing, an electrical current stimulates the intradental nerve, which may be painful and stressful to patients. The study involved measurement of the electromyogram (EMG) from the anterior belly of the digastric muscle, finger movement and voice response during electrical pulp testing. The excessive stimulus time from the onset time of response (EMG, voice and finger movement) to the end of the stimulation was obtained. The results indicated that the responses occurred in the order: EMG, finger and voice. Based on these results, an automatic stimulus shut-off circuit was developed using the above-mentioned responses to stimulus during electric pulp testing. Excessive stimulus time was reduced by prompt switching-off of the pulp tester output, 64 ms on average after the first detected response (EMG). Consequently, excessive stimulus times were reduced by 284 and 152 ms on average for the subject and examiner disconnection, respectively, using the developed automatic shut-off circuit. Therefore it was possible to minimise pain and stress by reducing excessive pulp stimulation.

Adult↗

The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons.

The A9 dopaminergic (DA) neuronal group projecting to the dorsal striatum is the most vulnerable in Parkinson's disease (PD). We genetically engineered mouse embryonic stem (ES) cells to express the transcription factors Nurr1 or Pitx3. After in vitro differentiation of Pitx3-expressing ES cells, the proportion of DA neurons expressing aldehyde dehydrogenase 2 (AHD2) increased, while the total number of DA neurons remained the same. The highest levels of AHD2 expression were observed in mouse A9 DA neurons projecting to the dorsal striatum. Furthermore, real-time PCR analyses of in vitro differentiated Pitx3-expressing ES cells revealed that genes highly expressed in A9 DA neurons were up-regulated. When transplanted into the mouse striatum, Pitx3-expressing cells generated an increased proportion of AHD2-expressing DA neurons. Contrastingly, in Nurr1-expressing ES cells, increases of all midbrain DA markers were observed, resulting in a higher total number of DA neurons in vitro and in vivo, whereas the proportion of AHD2-expressing DA neurons was not changed. Our data, using gain-of-function analysis of ES cells, suggest that Pitx3 may be important for specification and/or maintenance of A9-like neuronal properties, while Nurr1 influences overall midbrain DA specification. These findings may be important for modifying ES cells to generate an optimal cell source for transplantation therapy of PD.

Alcohol Dehydrogenase↗

Reduction of excessive electrical stimulus during electric pulp testing.

AIM: To measure excessive electrical stimulus time during pulp testing via electromyography (EMG) in the anterior belly of the digastric muscle, voice and finger movement, and to determine whether excessive stimulus time could be attenuated by a specially designed automatic circuit breaker on the basis of the EMG signal. METHODOLOGY: The signals from three human responses (EMG, finger and voice), induced by the Digitest (Parkell Inc., Farmingdale, NY, USA) electric pulp tester, were captured using a MP100 (Biopac System Inc., Goleta, CA, USA) and recorded into a personal computer. The excessive stimulus time from activation to the end of electrical stimulation was calculated for each of these three responses. The automatic circuit breaker was designed to disconnect the electrical output of the electric pulp testing (EPT) unit immediately after detecting the preset EMG level (100 mV). Each of the right central incisors and first premolars of 23 healthy individuals (16 males and seven females) was tested to see whether there was a difference in tooth type or gender. This was analysed by Wilcoxon signed rank test (nonparametric paired t-test) and Mann-Whitney test (nonparametric independent t-test), respectively. RESULTS: Amongst three human responses, the electrical onset occurred in the order of EMG, finger and voice. Excessive stimulus time was 347.8 +/- 78.3 ms when observed by the EMG, 264.9 +/- 63.9 ms when observed by finger span and 229.4 +/- 41.8 ms when observed by the voice, which were all found to be significantly different (P < 0.05). When the automatic circuit breaker was used, the excessive stimulus time was 61.0 ms, which was 286.8 ms shorter than that measured from EMG onset when using the conventional EPT. CONCLUSIONS: When the automatic circuit breaker was used, excessive stimulus time on the basis of EMG was attenuated on average by 286.8 ms.

Adult↗

Perforating disorder caused by salt-water application and its experimental induction.

BACKGROUND: Perforating disorders are uncommon diseases characterized by transepidermal elimination histopathologically and include reactive perforating collagenosis, elastosis perforans serpiginosa, Kyrle's disease and perforating folliculitis. In addition, perforating disorders can develop in patients with diabetes mellitus, renal failure and even by accidental exposure of calcium salts. METHODS: We report two cases of perforating disorder caused by chemical burn with commercially available salt-water application for self-treatment of chronic dermatitis or pruritus. RESULTS: The commercially used salt water for making bean curd was analyzed and it consisted of calcium and other salts without harmful heavy metals. We induced a similar phenomenon by experimental application of commercial salt water on guinea pigs. CONCLUSION: Bean curd is used as a food commonly in the Far-East, allowing a greater chance of exposure to salt water accidentally or occupationally. Bean curd is becoming more popular even in Western countries. To confirm causation, we induced a similar phenomenon in guinea pigs by experimental application of commercial salt water.

Aged↗

Observation of radiative B-->phi K gamma decays.

The radiative decay B-->phi K gamma is observed for the first time. The branching fraction for the charged B--->phi K- gamma decay mode is measured to be B(B--->phi K- gamma)=(3.4+/-0.9+/-0.4)x10(-6). The photon energy distribution for the B--->phi K- gamma decay is presented. The signal for the neutral B(0)-->phi K(0)gamma decay mode is not statistically significant and an upper limit, B(B(0)-->phi K(0)gamma)<8.3x10(-6) at 90% C.L., is set. The analysis is based on a data set of 90 fb(-1) collected by the Belle experiment at the e(+)e(-) asymmetric collider KEKB.

Journal Article↗

Relationship between circulating cytokine levels and thyroid function following bone marrow transplantation.

The relation between thyroid hormone changes and cytokines in bone marrow transplantation (BMT) patients has not been studied. This prospective study was designed to determine the relation between thyroid hormones and cytokine levels after BMT and their effects on the mortality. We studied 80 patients undergoing allogeneic BMT. Serum thyroid hormone parameters and cytokine levels were measured before and serially during 6 months after BMT. Serum T(3) decreased to a nadir 3 weeks post-BMT and serum T(4) was lowest at 3 months post-BMT. Serum thyroid stimulating hormone (TSH) sharply decreased to a nadir at 1 week and recovered. Serum interleukin-6 increased for 2 weeks after BMT and declined thereafter. Serum tumor necrosis factor-alpha increased for 3 weeks after BMT and declined thereafter. After 3 weeks post-BMT, both cytokine levels were negatively correlated with serum T(3) and T(4) levels. A total of 29 patients died before 1 year post-BMT and 51 patients survived longer than 1 year. Those patients who died before 1 year post-BMT had significantly lower levels of T(4) at 3 weeks, 3 and 6 months than surviving patients. In conclusion, increased levels of serum IL-6 and TNF-alpha were negatively correlated with thyroid hormone concentrations in BMT recipients suggesting the role of these cytokines in euthyroid sick syndrome.

Adult↗

A multicenter trial of the efficacy and safety of 0.03% tacrolimus ointment for atopic dermatitis in Korea.

BACKGROUND: Atopic dermatitis is a chronically relapsing, common inflammatory skin disease, which significantly affects quality of life negatively in many respects. Topical steroids are the mainstay of atopic dermatitis treatment but they carry the risk of local side effects. A topical formulation of tacrolimus, a macrolide calcineurin inhibitor, has recently been developed. OBJECTIVE: To evaluate the efficacy and safety of 0.03% tacrolimus ointment for the treatment of moderate to severe atopic dermatitis in Korea. METHODS: An open, non-comparative, multi-center study with 4 weeks' follow-up was performed. A total of 180 patients (aged 2-57 years old) were enrolled. Tacrolimus ointment (0.03%) was applied to all involved areas twice daily. Efficacy was evaluated by an investigator's global assessment, the eczema area and severity index score, and by the patient's assessment of pruritus and clinical response at baseline, and after weeks 1, 2 and 4. Dermatology life quality index (DLQI), children's DLQI (CDLQI) and toddler's DLQI were assessed at baseline and at week 4. The safety assessment included monitoring all adverse events and clinical laboratory values. RESULTS: All efficacy parameters were improved. The mean EASI (eczema area and severity index) score was 19.7 at baseline and reduced to 8.0 at the end of the study. Moderate improvement was observed by the investigator's global assessment after 4 weeks' treatment. A marked decrease of pruritus was observed, and mild or moderate improvement was observed by patients' global assessments after the treatment period. Significant benefits in terms of quality of life in adults and children with atopic dermatitis were obtained. The most common adverse events associated with tacrolimus treatment were transient skin burning sensation (45.3%) and pruritus (41.6%) at the site of application. CONCLUSION: 0.03% tacrolimus ointment should be considered effective and safe in both Korean children and adults with moderate to severe atopic dermatitis.

Administration, Cutaneous↗

Prevention of postoperative sore throat using capsicum plaster applied at the Korean hand acupuncture point.

In a randomised, double-blind, sham-controlled study, we compared the efficacy of capsicum plaster (PAS) applied at the Korean hand acupuncture point for the prevention of postoperative sore throat in 150 patients scheduled to undergo abdominal hysterectomy. The K group had PAS applied at the K-A20 of both hands and placebo tape at both non-acupoints. The PAS was applied prior to induction of anaesthesia and removed 8 h postoperatively. The sore throat scores of Group K were significantly lower than those of other groups at 24 h following surgery (p = 0.00027). The prevalence of moderate to severe sore throat at 24 h was lower for Group K (0%) than for sham and placebo controls (16%[p = 0.038] and 19%[p = 0.032], respectively). There were no differences in the recovery room of the sore throat scores for all groups. We found that the PAS applied at the K-A20 was an alternative method for reducing postoperative sore throat.

Acupuncture Points↗

Observation of the D(sJ)(2317) and D(sJ)(2457) in B decays.

We report the first observation of the B-->Dmacr;D(sJ)(2317) and B-->Dmacr;D(sJ)(2457) decays based on 123.8x10(6) BBmacr; events collected with the Belle detector at KEKB. We observe the D(sJ)(2317) decay to D(s)pi(0) and the D(sJ)(2457) decay to the D(*)(s)pi(0) and D(s)gamma final states. We also set 90% C.L. upper limits for the decays D(sJ)(2317)-->D(*)(s)gamma, D(sJ)(2457)-->D(*)(s)gamma, D(sJ)(2457)-->D(s)pi(0), and D(sJ)(2457)-->D(s)pi(+)pi(-).

Journal Article↗