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Biomedical subjects

S Ohta

Publications and source records attributed to S Ohta.

At least 253 records · Page 14Linked to original sources

Cytokine patterns and the effects of a preoperative steroid treatment in the patients with abdominal aortic aneurysms.

BACKGROUND: The aim of this study was to investigate the cytokine patterns of patients with abdominal aortic aneurysms and the effects of preoperative steroid administration on surgical stress. METHODS: From January 1996 to August 1996, 20 consecutive patients underwent an elective reconstruction of infrarenal abdominal aortic aneurysms. The patients were randomly divided into two groups consisting of a control group (n=10) and a steroid group (n=10), in whom 1 g of methylprednisolone was intravenously administered two hours before the operation. MEASURES: Interleukin-6 was serially measured and the perioperative parameters including C-reactive protein were compared between both the control and the steroid groups. RESULTS: The interleukin-6 values in the steroid group immediately after declamping, as well as at one and three postoperative days were significantly lower than those in the control group. C-reactive protein values at one postoperative day in the steroid group were also significantly lower than those in the control group. In one patient with a ruptured abdominal aortic aneurysm, the interleukin-6 values were higher than those in the patients undergoing elective surgery throughout the study. CONCLUSIONS: These results thus suggest that preoperative steroid administration using methylprednisolone in patients with abdominal aortic aneurysms appears to reduce surgical stress by decreasing cytokine release.

Aged↗

[A case of Sweet's syndrome (acute febrile neutrophilic dermatosis) showing transient jargon aphasia].

A 54-year-old woman visited our emergency service complaining of a severe language disturbance. She was fluently speaking something but most of the words were merely meaningless syllables. This jargon state lasted only four hours, then her abnormal speech rapidly and completely recovered within 24 hours. She had also suffered from painful oral ulcers, fever and erythema-like eruptions on her face for about three weeks. Skin biopsy of a facial lesion revealed a dense infiltrate of neutrophils in the dermis and minimal features of vasculitis, which, with other typical clinical findings, led us to the diagnosis of Sweet's syndrome. Although head CT scans, MRIs, MRA or SPECT could not detect any brain lesions, a cerebrospinal fluid examination showed a mild pleocytosis of 38/mm3 with 47% polymorphonuclear cells. There have been a few case reports on Sweet's syndrome accompanying neurologic symptoms, most of which are mild meningitis. We speculate that the transient aphasia was due to a focal lesion in the central nervous system attributable to Sweet's syndrome. Sweet's syndrome might bring inflammatory or ischemic lesions to the cerebrum as Behçet's disease.

Acute Disease↗

Involvement of hepatic aldehyde oxidase in conversion of 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) to 1-methyl-4-phenyl-5,6-dihydro-2-pyridone.

To obtain direct evidence of the involvement of aldehyde oxidase (AO), a cytosolic molybdoflavoenzyme, in the metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we investigated the in vitro metabolism of MPTP and the two-electron-oxidized 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+) by using mouse liver enzyme preparations. Incubation of MPTP with mitochondrial fraction gave exclusively 1-methyl-4-phenylpyridinium (MPP+); this reaction was inhibited by deprenyl, a monoamine oxidase (MAO)-B inhibitor, and KCN. When the mitochondrial fraction was combined with the cytosolic fraction, MPP+ formation was markedly decreased, while a large amount of 1-methyl-4-phenyl-5, 6-dihydro-2-pyridone (MPTP lactam) was newly formed. Incubation of MPDP+ with the cytosolic fraction led to rapid formation of MPTP lactam with concomitant disappearance of the substrate. The cytosol-dependent formation of MPTP lactam was inhibited by known AO inhibitors, such as menadione, norharman, and KCN. The activity of cytosol in MPTP lactam formation was completely duplicated by purified mouse liver AO. These results indicate that AO catalyzes the metabolic conversion of MPDP+, produced from MPTP by MAO-B, to MPTP lactam. This metabolic pathway might be an important detoxification route, averting the formation of toxic MPP+.

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

Marginal benefit/disadvantage of granulocyte colony-stimulating factor therapy after autologous blood stem cell transplantation in children: results of a prospective randomized trial. The Japanese Cooperative Study Group of PBSCT.

In this prospective trial, a total of 74 children who were scheduled to undergo high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) were prospectively randomized at diagnosis to evaluate the effectiveness of exogenous granulocyte colony-stimulating factor (G-CSF) treatment in accelerating hematopoietic recovery after PBSCT. The diagnosis included acute lymphoblastic leukemia (ALL) (n = 27), neuroblastoma (n = 29), and miscellaneous solid tumors (n = 18). Eligibility criteria included (1) primary PBSCT, (2) chemotherapy-responsive disease, and (3) collected cell number >1 x 10(5) colony-forming unit-granulocyte-macrophage (CFU-GM)/kg and >1 x 10(6) CD34(+) cells/kg patient's body weight. After applying the above criteria, 11 patients were excluded due to disease progression before PBSCT (n = 6) or a low number of harvested cells (n = 5), leaving 63 patients for analysis; 32 patients in the treatment group (300 microg/m2 of G-CSF intravenously over 1 hour from day 1 of PBSCT) and 31 in the control group without treatment. Two distinct disease-oriented high-dose regimens without total body irradiation consisted of the MCVAC regimen using ranimustine (MCNU, 450 mg/m2), cytosine arabinoside (16 g/m2), etoposide (1.6 g/m2), and cyclophosphamide (100 mg/kg) for patients with ALL, and the Hi-MEC regimen using melphalan (180 mg/m2), etoposide (1.6 g/m2), and carboplatinum (1.6 g/m2) for those with solid tumors. Five patients (two in the treatment group and three in the control group) were subsequently removed due to protocol violations. All patients survived PBSCT. The median numbers of transfused mononuclear cells (MNC), CD34(+) cells, and CFU-GM were, respectively, 4.5 (range, 1 to 19) x 10(8)/kg, 8.0 (1.1 to 25) x 10(6)/kg, and 3.7 (1.2 to 23) x 10(5)/kg in the treatment group (n = 30) and 2.9 (0.8 to 21) x 10(8)/kg, 6.3 (1.1 to 34) x 10(6)/kg, and 5.5 (1.3 to 37) x 10(5)/kg, respectively, in the control group (n = 28), with no significant difference. After PBSCT, the time to achieve an absolute neutrophil count (ANC) of >0.5 x 10(9)/L in the treatment group was less than that in the control group (median, 11 v 12 days; the log-rank test, P =.046), although the last day of red blood cell (RBC) transfusion (day 11 v day 10) and the duration of febrile days (>38 degrees C) after PBSCT (4 v 4 days) were identical in both groups. However, platelet recovery to >20 x 10(9)/L was significantly longer in treatment group than control group (26 v 16 days; P =.009) and >50 x 10(9)/L tended to take longer in the treatment group (29 v 26 days; P =.126), with significantly more platelet transfusion-dependent days (27 v 13 days; t-test, P =.037). When patients were divided into two different disease cohorts, ALL patients showed no difference in engraftment kinetics between the G-CSF treatment and control groups, while differences were seen in those with solid tumors. We concluded that the marginal clinical benefit of 1 day earlier recovery of granulocytes could be offset by the delayed recovery of platelets. We recommend that the routine application of costly G-CSF therapy in children undergoing PBSCT should be seriously reconsidered.

Adolescent↗

Determination of adenosine and deoxyadenosine in urine by high-performance liquid chromatography with column switching.

The means of measurement of adenosine and deoxyadenosine in urine was developed by separating adenosine and deoxyadenosine from other compounds using high-performance liquid chromatography with column switchings. This method is simple and convenient since no pretreatment of the urine is needed. Using this method, it could be demonstrated that urinary adenosine was higher in an adenosine deaminase (ADA) deficient patient who had a bone marrow transplant treatment (1.97 micromol/mmol creatinine) and in a heterozygote who had a markedly low erythrocyte ADA activity (1% of control ADA activity) (1.33 micromol/mmol creatinine) as compared to normal subjects (0.22+/-0.09 micromol/mmol creatinine, n=11). It was also noted that urinary deoxyadenosine was below the detection limits in the ADA-deficient bone marrow transplant patient, but it was detected in the heterozygote (3.7 micromol/mmol creatinine). Furthermore, it was also demonstrated that a fructose infusion increased the urinary concentration of adenosine from 0.21+/-0.03 to 2.66+/-1.21 micromol/mmol creatinine in five normal subjects.

Adenosine↗

Frequent aberration of FHIT gene expression in acute leukemias.

We analyzed the mRNA expression of the FHIT gene by reverse transcription-PCR (RT-PCR) in 54 cases of acute lymphoblastic leukemia (ALL; 11 cases of T-cell ALL [T-ALL] and 43 cases of non-T-ALL) and 40 cases of acute myeloid leukemia (AML). In 46% of the ALL cases and 55% of the AML cases, FHIT expression was absent or markedly decreased. Only abnormal short bands were detected in 30% of the ALL cases and 5% of the AML cases. Eighteen of 19 abnormal transcripts had the same fusion of exons 2-7, and all lacked the starting codon in exon 5. No obvious normal-sized PCR products were detected in cases exhibiting abnormal transcripts. These findings suggest that the expression of functional FHIT protein was lost in the majority of ALL (76%) and AML (60%) cases. Differential quantitative PCR of exons 3-9 of the FHIT gene and RT-PCR of the PTPRG gene, which is centromeric to the FHIT gene, showed the presence of the target sequences. Fluorescence in situ hybridization analysis using probes covering exons 5 and 8 revealed no difference in the signal patterns between leukemia and normal cells, showing one or two signal doublets in more than 90% of nuclei, and indicated that gross segments of the FHIT gene were not homozygously deleted in these cases. A small number of transcripts with an aberrant fusion between exons 2 and 7 were detected by RT-PCR in the bone marrow cells from four healthy individuals. Granulocytes, lymphocytes, and monocytes in the bone marrow cells of a healthy individual contained transcripts with the same fusion. This unique fusion of exons 2 and 7 might be preferentially seen in either neoplastic or normal hematopoietic cells, regardless of their lineage. The finding that FHIT expression was abolished in the majority of leukemia cases might support the hypothesis that the FHIT gene acts as a tumor suppressor, at least in leukemia.

Acid Anhydride Hydrolases↗

Purification and characterization of a glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins from rat brain.

The glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins was purified to an apparent homogeneity from the Nonidet P-40 extract of 2-week postnatal rat forebrain by sequential chromatographies on CM-Sepharose CL-6B, UDP-GlcA-Sepharose 4B, asialo-orosomucoid-Sepharose 4B, Matrex gel Blue A, Mono Q, HiTrap chelating, and HiTrap heparin columns. The purified enzyme migrated as a 45-kDa protein upon SDS-polyacrylamide gel electrophoresis under reducing conditions, but eluted as a 90-kDa protein upon Superose gel filtration in the presence of Nonidet P-40, suggesting that the enzyme forms homodimers under non-denatured conditions. The enzyme transferred glucuronic acid to various glycoprotein acceptors bearing terminal N-acetyllactosamine structure such as asialo-orosomucoid, asialo-fetuin, and asialo-neural cell adhesion molecule, whereas little activity was detected to paragloboside, a precursor glycolipid of the HNK-1 epitope on glycolipids. These results suggested that the enzyme is specifically associated with the biosynthesis of the HNK-1 epitope on glycoproteins. Sphingomyelin was specifically required for expression of the enzyme activity. Stearoyl-sphingomyelin (18:0) was the most effective, followed by palmitoyl-sphingomyelin (16:0) and lignoceroyl-sphingomyelin (24:0). Interestingly, activity was demonstrated only for sphingomyelin with a saturated fatty acid, i.e. not for that with an unsaturated fatty acid, regardless of the length of the acyl group.

Animals↗

Structural significance of azaheterocyclic amines related to Parkinson's disease for dopamine transporter.

We have evaluated the neuronal uptake of 12 neutral and quaternary azaheterocyclic amines that are possible candidates for idiopathic Parkinson's disease via dopamine transporter of striatal synaptosomes. The double-reciprocal plots for dopamine transporter obtained from Wistar rat and C57BL/6 mouse synaptosomes with N-methyl-4-phenylpyridinium cation (MPP+) as a substrate were identical to each other. Neutral beta-carbolines and tetrahydroisoquinolines were unfavorable substrates for dopamine transporter. The quarternization of these compounds strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Although catechol tetrahydroisoquinolines were weak substrates, their quarternization reduced their original properties as substrates for dopamine transporter. These results provide both topographic and electrogenic information of azaheterocyclic amines for the dopamine transporter-mediated influx. The intramolecular distance between the N-atom and the centroid of the benzene ring could be an important factor for the recognition of binding site of dopamine transporter, and an adequate net charge similar to dopamine would be further required for translocation into the cells.

1-Methyl-4-phenylpyridinium↗

A trace amount of the human pro-apoptotic factor Bax induces bacterial death accompanied by damage of DNA.

An amount of human pro-apoptotic Bax as low as 0.01% of total protein was sufficient to cause cell death in Escherichia coli. The bacterial cell death was examined using a viable bacteria-specific fluorescence indicator system and loss of colony formation ability. Co-expression of anti-apoptotic Bcl-xL showed a modest inhibitory effect on the cell death caused by Bax. The trace amount of Bax elongated E. coli and accumulated monounsaturated fatty acids, suggesting an unusual metabolism of redox in the host. In fact, an increase of KCN-dependent O2 consumption accompanied the expression of Bax. At the same time, a fluorescent pH indicator showed the apparent accumulation of protons outside the cell, suggesting that the membrane is intact. Bax increased the level of superoxide anion as measured by the expression of superoxide-dependent promoter. Nicked DNA was significantly generated, and the frequency of mutations resistant to rifampicin was increased by 30-fold, depending upon the expression of Bax. It is proposed that trace amounts of Bax increase oxygen consumption, triggering generation of superoxide, which affects DNA, leading to bacterial death.

Apoptosis↗

Deprenyl decreases an endogenous parkinsonism-inducing compound, 1-benzyl-1,2,3,4-tetrahydroisoquinoline in mice: in vivo and in vitro studies.

We examined the effect of deprenyl, a promising drug for the therapy of Parkinson's disease on the formation of a parkinsonism-inducing compound, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ). The 1BnTIQ content was significantly decreased in the brain of deprenyl-treated mouse in vivo, and deprenyl also inhibited 1BnTIQ formation from phenethylamine by a mouse brain homogenate supernatant in vitro. In vivo, the content of a parkinsonism-preventing compound, 1-methyl-1,2,3, 4-tetrahydroisoquinoline (1MeTIQ) was slightly increased in mice injected with deprenyl. The marked decrease of the ratio of 1BnTIQ to 1MeTIQ might play a role in the clinical effect of deprenyl.

Animals↗

Mucosa-adhesive water-soluble polymer film for treatment of acute radiation-induced oral mucositis.

PURPOSE: To examine the usefulness and safety of a mucosa-adhesive water-soluble polymer film (AD film) containing anesthetics and antibiotics for the treatment of acute radiation-induced oral mucositis. MATERIALS AND METHODS: To prepare AD films, 600 mg of hydroxy-propyl-cellulose was dissolved in ethyl alcohol, and mixed with a solution containing tetracaine, ofloxacine, miconazole, guaiazulene, and triacetin. The gel obtained was dried to form 30 translucent round sheets (20 mg per sheet) of 7.5 cm in diameter and 0.2 mm in thickness. The AD film showed excellent adhesive and coating properties when placed on wet oral mucosa. From 1993 to 1994, we used the AD film in 25 patients with acute radiation-induced oral mucositis, in an attempt to alleviate their pain and prevent secondary oral infection. All patients had received definitive radiotherapy for oral carcinoma. Intensity and duration of oral pain from mucositis, relief rates at rest and while eating, and presence of bacterial and/or fungal infection were compared with those of 27 patients treated with topical anesthetics (viscous lidocaine, Xylocaine and/or general systemic analgesics from 1990 to 1992 (NonAD Group). RESULTS: The intensity of oral pain was the same in the two groups. The mean duration of pain of the AD film Group (10 days) was significantly shortened compared with the NonAD Group (15 days). The rates of complete pain relief at rest and while eating of the AD film Group were statistically higher than those of the NonAD Group: 82% vs. 44%, and 68% vs. 22%, respectively. No secondary bacterial or fungal infections were observed in the AD film Group, whereas 4 cases of documented infections were found in the NonAD Group. No acute or chronic adverse effects of AD film were observed during the 3-year follow-up period. The rates for local control of oral carcinoma and overall survival, at the end of the follow-up period, were 96% and 87% for the AD film Group vs. 92% and 85% for the NonAD Group, respectively. CONCLUSION: The AD film, containing topical anesthetics and antibiotics, proved useful to alleviate pain due to acute radiation-induced oral mucositis, maintain good peroral feeding, and prevent secondary oral infections, without inducing adverse reactions.

Administration, Buccal↗

Pore formation domain of human pro-apoptotic Bax induces mammalian apoptosis as well as bacterial death without antagonizing anti-apoptotic factors.

A trace amount of the pro-apoptotic factor human Bax was sufficient to kill host Escherichia coli (Asoh, S., Nishimaki, K., Nanbu-Wakao, R., and Ohta, S., submitted). The region of Bax lethal to E. coli cells was determined by introducing truncated human bax mutant genes. A peptide corresponding to amino acid residues 115 to 144 of Bax was the smallest peptide capable of inducing cell death of E. coli. A truncated bax gene (Bax112-192) containing the region lethal to E. coli was then introduced into a murine promyeloid cell line, FDC-P1. Constitutively expressed Bax112-192 induced apoptosis as judged by decrease of transfectants surviving and DNA fragmentation. These results indicate that Bax112-192 contains the region directly responsible for mammalian apoptosis as well as bacterial death. Flow cytometric analysis by FITC-Annexin V showed that the transfectant cells expressing Bax112-192 or native Bax became apoptotic even without external stimuli. The apoptotic population in the cells expressing Bax112-192 was not decreased by co-expression of Bcl-2 or Bcl-XL, while Bcl-2 or Bcl-XL suppressed apoptosis in the cells expressing native Bax. Therefore, Bax induces apoptosis by its own activity without blocking the anti-apoptotic activity involved in Bcl-2 or Bcl-XL.

Apoptosis↗

Overexpressed mitochondrial hinge protein, a cytochrome c-binding protein, accelerates apoptosis by enhancing the release of cytochrome c from mitochondria.

Holocytochrome c released from mitochondria has been revealed to be one of the contributors of apoptosis. To investigate how the cytochrome c protein is released from mitochondria, we examined the effects of overexpression of the hinge protein, a cytochrome c-binding protein, or cytochrome c on apoptosis by introducing their cDNAs under a constitutive promoter. Overexpression of the cytochrome c and hinge protein mRNAs was confirmed by Northern blotting, although marked accumulation of the cytochrome c protein was not observed. In transfectants of the hinge protein gene as well as cytochrome c gene, apoptosis was accelerated as judged by FITC-conjugated Annexin V binding to the cell surface and DNA fragmentation. In addition, enhancement of the release of cytochrome c into cytosol was demonstrated in these transfectants by a subcellular fractionation experiment, followed by Western blotting. These findings suggest that the release of the cytochrome c protein from mitochondria is regulated by the hinge protein involved in the respiratory chain in the apoptotic process.

Animals↗

Isolation and characterization of a novel bioactive peptide, Carassius RFamide (C-RFa), from the brain of the Japanese crucian carp.

A novel bioactive peptide with the C-terminal RFamide was isolated from the brain of the Japanese crucian carp, Carassius auratus langsdorfii, by using the intestine of the fish as the bioassay system. The primary structure of the peptide was determined to be SPEIDPFWYVGRGVRPIGRFamide and it was designated Carassius RFamide (C-RFa). The sequence of C-RFa was found to be significantly homologous to the molluscan neuropeptide termed Achatina cardioexcitatory peptide 1 (ACEP-1). Both peptides have RPXGRFamide structure in their C-terminal moieties. C-RFa was found to have an excitatory effect on visceral muscle tissues of fish, newt, quail, and rat. In the stomach of the fish, Zacco temminckii, IGRFamide (C-RFa 17-20) was shown to be the minimal structure required for the excitatory effect and PIGRFamide (C-RFa 16-20) to be almost equipotent with the parent peptide C-RFa.

Amino Acid Sequence↗

Adenoma with clear cell change of the large intestine.

BACKGROUND AND OBJECTIVES: Clear cell change of the large intestinal neoplasm is rare, and its character remains unclear. We report a case of the large intestinal adenoma with clear cell change with immunohistochemical and molecular studies to investigate whether the clear cell change is associated with a malignant progression of the adenoma. METHODS: We studied the histochemical and immunohistochemical staining characteristics of the tumor by staining with hematoxylin-eosin, periodic acid-Schiff, alcian blue, and by immunostaining using antibodies against carcinoembryonic antigen, epithelial membrane antigen, p53, and Ki-67. The c-K-ras codon 12 point mutations were analyzed using a nonradioactive restriction fragment length polymorphism technique. RESULTS: The tumor was composed of a typical tubular adenoma and a tubular adenoma with clear cytoplasm. The clear cytoplasm was negative by mucin stains. Immunohistochemically p53 was negative in both the components. Labeling index of Ki-67 showed no significant difference between the two components. No codon 12 mutation of c-K-ras gene was observed in both the components. CONCLUSION: These findings suggest that the clear cell change of the tubular adenoma is not associated with a malignant progression in adenoma-carcinoma sequence involving c-K-ras and p53.

Adenoma↗

Oral mucosal adhesive film containing local anesthetics: in vitro and clinical evaluation.

In vitro and in vivo studies were conducted to gauge the effectiveness of a novel oral mucosa adhesive, moderately water-soluble, pliant polymer artificial dentifrice (AD) film containing dibucaine (DC) for relief of pain due to oral erosion. The film was prepared from a hydroxypropyl cellulose-M (HPC-M) ethanol solution containing varying amounts of DC, as well as polyethylene glycol. In the in vitro experiments, the disintegration of HPC-M showed a lag time of about 50 min, a much lower rate than that of drug release, which more or less leveled off after 50 min. Twenty-five percent of the DC was released from the film (0.113 and 0.225 mg/cm2) after the initial 5 min, which then reached about 80% after 50 min, the time at which the polymer began to break up. In the in vivo study, the local anesthetic effect of the film was evaluated in 23 patients (10 males, 13 females) suffering from the adverse effects of chemotherapy. When applied to the wet surface of the mucosa, the AD film absorbed moisture and showed excellent adhesion. Pain relief in patients lasted 2.2 +/- 0.21 and 4.3 +/- 0.25 h at DC doses of 0.113 and 0.225 mg/cm2, respectively. These results suggest that the AD film may cover mucositis sites of oral mucosa long enough to allow DC release and bring relief from pain arising from chemotherapy and/or radiotherapy.

Adhesives↗

Two cases of endometrial adenocarcinoma arising from atypical polypoid adenomyoma.

Atypical polypoid adenomyoma (APA) most frequently presents as an endometrial polyp in premenopausal women and is believed to follow a benign course. In hysterectomy specimens from postmenopausal Japanease women, the endometrium contained an APA with an area of endometrial adenocarcinoma. A convincing transition zone between the APA and the adenocarcinoma was seen in our cases, suggesting that APA may develop into endometrial adenocarcinoma in postmenopausal women.

Adenocarcinoma↗

Video-enhanced microscopic visualization of apoptotic cell death caused by anti-Fas antibody in living human glioma cells.

To study the morphological changes of anti-Fas antibody-mediated apoptosis in living U251-SP human glioma cells, we employed video-enhanced contrast differential interference contrast (VEC-DIC) microscopy. In our previous study, we investigated the susceptibility of human glioma cell lines to anti-Fas Immunoglobulin M (IgM) antibody. U251-SP cells express Fas antigen on their surface. The cells exposed to anti-Fas antibody underwent apoptotic cell death, as reported previously. In this study, morphological changes of apoptosis characterized by bleb formation, shrinkage of cells, and nuclear condensation were observed under VEC-DIC microscopy in U251-SP human glioma cells treated with anti-Fas antibody. These results demonstrate the usefulness of VEC-DIC microscopy to study the process of apoptotic cell death.

Antibodies↗