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Biomedical subjects

G Romero

Publications and source records attributed to G Romero.

At least 19 recordsLinked to original sources
PubMed2006

Comparative study between nadolol and 5-isosorbide mononitrate vs. endoscopic band ligation plus sclerotherapy in the prevention of variceal rebleeding in cirrhotic patients: a randomized controlled trial.

BACKGROUND: After variceal bleeding, cirrhotic patients should receive secondary prophylaxis. AIM: To compare nadolol plus 5-isosorbide mononitrate (5-ISMN) with endoscopic band ligation. The end points were rebleeding, treatment failure and death. METHODS: One hundred and nine cirrhotic patients with a recent variceal bleeding were randomized: nadolol plus 5-ISMN in 57 patients and endoscopic band ligation in 52 patients. RESULTS: The mean follow-up was 17 and 19 months in nadolol plus 5-ISMN and endoscopic band ligation groups, respectively. No differences were observed between groups in upper rebleeding (47% vs. 46%), variceal rebleeding (40% vs. 36%), failure (32% vs. 22%), major complications (7% vs. 13.5%) and death (19% vs. 20%), respectively. The actuarial probability of remaining free of rebleeding, failure and deaths were similar in both groups. Time to rebleeding shows that endoscopic band ligation patients had an early rebleed, with a median of 0.5 month (95% CI: 0.0-4.2) compared with patients from nadolol plus 5-ISMN, 7.6 months (95% CI: 2.9-12.3, P < 0.013). Multivariate analysis indicated that outcome-specific predictive factor(s) for rebleeding was Child A vs. B + C (P < 0.01); for failure was Child A vs. B + C (P < 0.02); and for death ascites (P < 0.01) and rebleeding (P < 0.02). CONCLUSION: This trial suggests no superiority of endoscopic band ligation over nadolol plus 5-ISMN mononitrate for the prevention of rebleeding in cirrhotic patients.

Endoscopy, Gastrointestinal↗
PubMed2006

[Preliminary results of DERMATEL: prospective randomized study comparing synchronous and asynchronous modalities of teledermatology].

INTRODUCTION: There is considerable variability in the results of studies that evaluate diagnostic reliability in teledermatology. There are only two studies that compare the synchronous and asynchronous modalities of teleconsult in the same sample. We present the results of the pilot project DERMATEL, a study of diagnostic concordance that aims to increase the evidence of these aspects. MATERIAL AND METHODS: One-hundred-fifty.nine patients referred by the general practitioner in the first consult were randomized (algorithm 3:2:1) in three arms: asyncronous teledermatology (store-and-forward or SAF), synchronous teldermatology (real-time or VTC), and conventional consult (CC). We used high-quality, fixed digital images in all cases. The patients on the VTC teledermatology arm were also evaluated by videoconference. Finally all patients attended a face-to-face consult, considered the gold standard of patient care. A second dermatologist evaluated the diagnostic and management concordance between the teleconsults and the face-to-face consults. RESULTS: One-hundred.forty-seven patients completed the study as follows: 74 in the SAF teledermatology arm, 47 in the VTC teledermatology arm and 26 in the conventional consult (control group). The teledermatological (SAF and VTC) and face-to-face evaluations were identical in 100 of 121 patients (82.6%). The errors were mild in 14 cases (11.6%) and severe in 7 (5.8%). The diagnostic concordance was very high (kappa=0,813). The errors grouped by diseases were as follows: 6/54 (11%) for tumors, 10/30 (33.3%) for inflammatory conditions, 1/20 (5%) for infectious diseases, 3/12 (25%) for alopecia/acne and 1/5 (20%) for others. There were 15 errors in the SAF teledermatology arm (20.3%) and 6 in the VTC teledermatology arm (12.8%); these differences were not statistically significant (chi2 1.12; p=0.288). CONCLUSION: The reliability of dermatological teleconsult is very high, especially for tumoral or infectious diseases. The synchronous interaction with audio requires more resources, is difficult to coordinate and its diagnostic efficacy is not superior to SAF teledermatology.

Adolescent↗
PubMed2002

A randomized, double-blind, parallel-group, duration-finding study of oral terbinafine and open-label, high-dose griseofulvin in children with tinea capitis due to Microsporum species.

BACKGROUND: Tinea capitis, a common clinical pattern of dermatophyte infection in children is becoming a public health hazard in some countries. Several studies have reported terbinafine to be a safe and well-tolerated fungicidal drug for the treatment of this infection. However, the optimal treatment duration for its use in the treatment of tinea capitis caused by Microsporum species has not yet been determined. OBJECTIVE: (i) To establish the optimal duration for terbinafine treatment to bring about complete cure of tinea capitis due to Microsporum infection in a large paediatric population, and (ii) to obtain information on the maximum therapeutic effect of the existing therapy. PATIENTS AND METHODS: This parallel-group, double-blind, multicentre study was conducted in Europe and South America. Patients were randomized to one of four oral terbinafine treatment arms (6, 8, 10 or 12 weeks treatment) or to an open label, 12-week, high-dose griseofulvin (20 mg x kg(-1) x day(-1)) arm at a 1 : 1 : 1 : 1 : 1 ratio. All patients were followed up for 4 weeks after the end of the treatment phase. RESULTS: In this group of 134 intention-to-treat patients, effective treatment was observed at the end of study in 62% of patients treated with terbinafine for 6 weeks and in 63% treated for 8 weeks. Mycological cure was obtained in 59% and 57%, respectively, and clinical cure in 76% and 80%. In the griseofulvin group, effective treatment was 88%, mycological cure was 76% and clinical cure 96%. However, these high rates were believed to be due to the high dosage of this drug and the prolonged course of treatment. Complete cure was observed at the end of study in 62% patients treated with terbinafine for 6 weeks, in 60% treated for 8 weeks and in 84% patients treated with griseofulvin for 12 weeks. CONCLUSIONS: Although there was no statistical trend between the duration of terbinafine treatment within the groups for complete cure at the end of study, there was a positive correlation between the daily dose of terbinafine (mg x kg(-1)) and complete cure. Terbinafine therapy for 6 weeks could represent an alternative to griseofulvin for the treatment of Microsporum tinea capitis. However, further clinical trials are required in order to optimize the dose regimen to allow higher cure rates to be reached.

Adolescent↗
PubMed2002

Severe lung involvement in systemic scleromyxoedema: a highly unusual finding.

Scleromyxoedema is a rare systemic disorder characterized by a lichenoid papular rash. Although scleromyxoedema can involve any organ, very few cases of pulmonary involvement have been reported. Moreover, there are no reports in the literature on treatment of this condition, especially with lung transplantation. The authors report a case of scleromyxoedema in a young man with neurological, skin and respiratory involvement, the latter being mainly characterized by pulmonary emphysema. Due to the serious respiratory compromise, and to the stability of the systemic lesions, a bilateral lung transplantation was performed with successful results at 4.5 yrs. In conclusion, lung transplantation may be required in patients with severe respiratory failure caused by scleromyxoedema.

Adult↗
PubMed2001

Agonist-dependent traffic of raft-associated Ras and Raf-1 is required for activation of the mitogen-activated protein kinase cascade.

Stimulation of HIRcB fibroblasts with insulin leads to accumulation of active components of the mitogen-activated protein kinase cascade in endocytic compartments. However, the factors that regulate the mobilization of these components through the endocytic pathway and the relevance of this event to cellular signaling remain unclear. Here we report that Ras proteins are associated with lipid rafts in resting HIRcB fibroblasts. Ras is rapidly internalized into the endocytic compartment following stimulation with insulin. The redistribution of Ras is independent of its activation. Attachment of the C-terminal 20 amino acids of Ha-Ras to green fluorescent protein was sufficient to target this construct to the same loci as the endogenous Ras protein, indicating that Ras distribution is a consequence of the association of its lipid modified C terminus with membranes. Depletion of plasma membrane cholesterol delocalized Ras and blocked insulin-dependent Ras traffic. Cholesterol depletion also blocked insulin-dependent phosphorylation of MEK and mitogen-activated protein kinase (MAPK) but had no effects on the translocation and activation of Raf-1. A second inhibitor of endocytosis, cytochalasin D, also blocked insulin-dependent MAPK phosphorylation. Taken together, these results suggest that mobilization of active Raf-1 through the endocytic compartment is required for completion of the MAPK cascade.

Animals↗
PubMed2001

Decrease of adenylyl cyclase activity and expression by a sigma1 receptor ligand and putative atypical antipsychotic.

We examined whether changes in the adenylyl cyclase system could be induced by the administration of the sigma1 receptor ligand and putative atypical antipsychotic 4-[4-fluorophenyl]-1,2,3,6-tetrahydro-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842). Repeated (21 days) but not acute (2 h) treatment with E-5842 induced a significant decrease in adenylyl cyclase type I immunoreactivity and adenylyl cyclase activity in rat frontal cortex membranes, with less or no effect in other brain regions such as the hippocampus or the striatum. Changes in immunoreactivity were not observed in other adenylyl cyclases (type V/VI). The reported changes, observed only after a chronic treatment, could be related to the mechanism of action of sigma receptor ligands in general or to that of E-5842 in particular and should be taken into account, given the long duration of treatment in psychiatric patients.

Adenylyl Cyclases↗
PubMed2000

Changes in phosphoinositide signalling activity and levels of the alpha subunit of G(q/11) protein in rat brain induced by E-5842, a sigma(1) receptor ligand and potential atypical antipsychotic.

Changes in the phosphoinositide (PPI) signal transduction system induced by E-5842, a new sigma(1) (sigma(1)) receptor ligand and potential atypical antipsychotic, were studied in the rat frontal cortex, hippocampus and striatum. Acute treatment with E-5842 increased phospholipase C (PLC) activity in the striatum and the hippocampus. Chronic treatment with E-5842 induced an increase in the activity of PLC in the frontal cortex and the striatum. Similar up-regulation of the activity of the enzyme was also observed in rat frontal cortex membranes in presence of GTPgammaS. After chronic treatment with E-5842, it was also observed a significant increase of the immunoreactivity levels of G(q/11)alpha in the frontal cortex. Our results suggest that part of the antipsychotic effects of E-5842 could be related to the regulation of the PPI signal transduction pathway, especially after a prolonged treatment.

Animals↗
PubMed2000

The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras.

The serine/threonine kinase Raf-1 is an essential component of the MAPK cascade. Activation of Raf-1 by extracellular signals is initiated by association with intracellular membranes. Recruitment of Raf-1 to membranes has been reported to be mediated by direct association with Ras and by the phospholipase D product phosphatidic acid (PA). Here we report that insulin stimulation of HIRcB fibroblasts leads to accumulation of Ras, Raf-1, phosphorylated MEK, phosphorylated MAPK, and PA on endosomal membranes. Mutations that disrupt Raf-PA interactions prevented recruitment of Raf-1 to membranes, whereas disruption of Ras-Raf interactions did not affect agonist-dependent translocation. Expression of a dominant-negative Ras mutant did not prevent insulin-dependent Raf-1 translocation, but inhibited phosphorylation of MAPK. Finally, the PA-binding region of Raf-1 was sufficient to target green fluorescent protein to membranes, and its overexpression blocked recruitment of Raf-1 to membranes and disrupted insulin-dependent MAPK phosphorylation. These results indicate that agonist-dependent Raf-1 translocation is primarily mediated by a direct interaction with PA and is independent of association with Ras.

Animals↗
PubMed2000

Up-regulation of sigma(1) receptor mRNA in rat brain by a putative atypical antipsychotic and sigma receptor ligand.

Sigma(1) (sigma(1)) receptor mRNA expression was studied in the prefrontal cortex, striatum, hippocampus and cerebellum of rat brain by northern blot and in situ hybridization. The effects of a chronic treatment with antipsychotic drugs (haloperidol and clozapine), and with E-5842, a sigma(1) receptor ligand and putative atypical antipsychotic on sigma(1) receptor expression were examined. A significant increase in the levels of sigma(1) receptor mRNA in the prefrontal cortex and striatum after E-5842 administration was observed, while no apparent changes were seen with either haloperidol or clozapine. Our results suggest a long-term adaptation of the sigma(1) receptor at the level of mRNA expression in specific areas of the brain as a response to a sustained treatment with E-5842.

Animals↗
PubMed2000

Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF.

Granulocyte colony-stimulating factor (G-CSF) is the major hematopoietic factor which controls the production and differentiation of granulocytes. The G-CSF receptor (G-CSFR) belongs to the superfamily of the cytokine receptors, which transduce signals via the activation of cytosolic protein tyrosine kinases (PTK). To determine the role of specific PTK in G-CSF signaling we expressed the human G-CSFR in cell lines derived from DT40 B cells, which lack either the Src-related Lyn or Syk. Wild-type (wt) and syk-deficient cells underwent increased DNA synthesis in response to G-CSF; lyn-deficient cells did not. The purpose of these studies is to identify Lyn's downstream effectors in mediating DNA synthesis. While G-CSF stimulated Ras activity in all cell lines, G-CSF failed to induce the tyrosine phosphorylation of Shc in lyn-deficient cells. G-CSF induced a statistically significant activation of Erk1/Erk2 Kinase or p90Rsk only in the wt cells. G-CSF induced the tyrosine phosphorylation of Cbl and increased activity of PI 3-kinase in wild-type and syk-deficient, but non in lyn-deficient, cells. Inhibition of Shc by over-expression of its SH2 or PTB domains or PI 3-kinase by either treatment with wortmannin or expression of the CblY731F mutant decreased G-CSF-induced DNA synthesis. Thus, the Lyn, Cbl-PI 3-kinase, and Shc/non-Ras-dependent pathways correlate with the ability of cells to respond to G-CSF with increased DNA synthesis.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Variceal band ligation and variceal band ligation plus sclerotherapy in the prevention of recurrent variceal bleeding in cirrhotic patients: a randomized, prospective and controlled trial.

BACKGROUND: The combination treatment of band ligation plus sclerotherapy has been proposed to hasten variceal eradication. The aim of this study was to assess the efficacy of band ligation alone versus band ligation plus sclerotherapy in the prevention of recurrent variceal bleeding. METHODS: Eighty cirrhotic patients were randomized to group I (band ligation) with 41 patients or to group II (band ligation plus sclerotherapy) with 39 patients in whom polidocanol (2%) was injected 1 to 2 cm proximal to each band. RESULTS: At baseline, both groups were similar with regard to clinical, demographic and laboratory data. Mean follow-up time (standard error) for group I was 336.5 +/- 43.4 days and for group II 386.1 +/- 40.1 days (p = 0.4). No statistical differences were observed between group I and group II in relation to recurrence of bleeding (31.7% vs. 23%, p = 0.38), treatment failure (24.4% vs. 12. 8%, p = 0.18), death (39% vs. 30.8%, p = 0.44) and variceal eradication (65.8% vs. 74.4%, p = 0.40). Group II had a significantly higher number of complications than group I, 30.8% versus 7.3%, respectively (p = 0.05). The number of bleeding related deaths was higher in group I than in group II (22% vs. 10.3%, respectively; p = 0.15). CONCLUSIONS: No significant difference was observed between band ligation and band ligation plus sclerotherapy in prevention of recurrent variceal bleeding. Furthermore, there was a higher incidence of complications in the latter group.

Combined Modality Therapy↗
PubMed2000

Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients.

BACKGROUND/AIMS: Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. METHODS: Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. RESULTS: No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. CONCLUSIONS: Our results demonstrate that terlipressin produces significant and prolonged decreases in variceal pressure and variceal wall tension and has intrinsic effects on portal pressure and systemic hemodynamics. Variceal pressure provides a better assessment of the effects of terlipressin administration on esophageal varices than hepatic venous pressure gradient.

Adolescent↗
PubMed2000

Brain-stem auditory evoked potentials in children with perinatal encephalopathies.

OBJECTIVE: We sought to describe if neurological damage, in terms of brain lesions, syndrome and syndrome severity led to abnormalities in the brain-stem auditory evoked potentials (BAEPs) in order to provide a profile of children that could be used as an indicator of subsequent neurological sequelae. We analyzed the BAEPs from a group of children having prior evidence of neurological damage and determined the presence of neurological sequelae when the subjects were 3 years old. METHODS: Brain-stem auditory evoked potentials (BAEPs) were carried out in a group of 154 children with perinatal neurological damage. The children were classified with neurofunctional (clinical and EEG alterations) or organic and neurofunctional brain disease (clinical, EEG and image alteration) and were all followed from the first month of life and serially for 3 years. We used principal component analysis (PCA), clustered analysis and linear correlation to determine association between BAEPs, risk factors and future sequelae. RESULTS: Latencies of BAEPs decreased significantly with age, and the time of conduction was modified by the presence of neurological damage. All statistical analyses suggested positive and significant associations between risk factors (trophism and condition at birth), and the latencies of waves I, III and V as well as with IPL III-V (interpeak latency) and I-V. PCA showed that IPL I-III was also positively associated with condition at birth, severity of the neurological syndrome and encephalopathy. In addition, we found that the presence and type of sequela reflected changes in the latencies of the waves, as well as IPLs, primarily those of IPL I-III. CONCLUSIONS: Our results suggest that statistical methods are often needed to analyze neurological damage. The relation between BAEPs, risk factors and neurological sequelae allowed us to obtain a profile of children, which can be then used as an aid in the prognosis of children having a risk of developing neurological sequelae.

Adolescent↗
PubMed2000

Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicentric, and randomized clinical trial.

BACKGROUND: Sclerotherapy is the most widely used method for treatment of acute variceal bleeding. Previous reports have suggested that octreotide infusion is as effective as sclerotherapy. Our aim was to investigate the efficacy and safety of octreotide in comparison with sclerotherapy in controlling variceal bleeding. METHODS: Seventy-six cirrhotic patients were randomized to receive either sclerotherapy (n = 37) or octreotide (n = 39) infusion of 50 microg/h intravenously for 48 h after a bolus of 100 microg, followed by subcutaneous injection of 100 microg/8 h for an additional 72 h. RESULTS: The two groups were similar in base-line data. A similar initial control of bleeding was obtained in 94.6% for sclerotherapy and 84.6% for octreotide (NS). No difference was observed between sclerotherapy and octreotide in rebleeding (23% versus 33%) and treatment failure (22% versus 36%, respectively). Furthermore, the overall success of treatment was 78% for sclerotherapy and 64% for octreotide. No significant difference in mortality was observed between treatments (eight patients for octreotide and three patients for sclerotherapy, NS). CONCLUSIONS: These results show that both treatments present a very high and similar initial and final control of bleeding. However, there is a trend that could be clinically important towards better results in the patients treated with sclerotherapy.

Acute Disease↗
PubMed2000

Patients with ascites have higher variceal pressure and wall tension than patients without ascites.

OBJECTIVE: It has been suggested that ascites is a risk factor for variceal bleeding. Recently, it has been demonstrated that total paracentesis decreases variceal pressure. However, no data are available showing the basal variceal pressure in patients with and without ascites. METHODS: We studied 76 cirrhotic patients, 49 with and 27 without ascites. Variceal pressure was measured by direct puncture. Variceal size, variceal pressure gradient, and variceal wall tension were also obtained. RESULTS: No demographic differences were observed between the groups. Child score was higher (9.7+/-1.5 vs 7.8+/-2.1, p < 0.001) and serum albumin lower (2.6+/-0.6 vs 3.0+/-0.7 mg %, p < 0.02) in ascitic than in nonascitic patients, respectively. Variceal pressure and variceal pressure gradient were significantly higher in patients with ascites than in those without ascites (25.0+/-6 vs 20.4+/-4.6 mm Hg, p < 0.001 and 18.75+/-4.7 vs 13.70+/-4.1 mm Hg, p < 0.0001, respectively). The variceal wall tension was significantly higher in patients with ascites (71.0+/-25.1 mm Hg/mm) than in those without ascites (55.1+/-22.1 mm Hg/mm, p < 0.03). No relationship was observed between variceal pressure gradient and liver function. Ascites patients included in Child-Pugh grade A+B presented a similar variceal pressure to Child C patients (18.5+/-4.2 vs 19.3+/-5.7 mm Hg, respectively, p = ns). In addition, no relationship was observed between variceal pressure gradient and etiology of cirrhosis. CONCLUSION: Our results demonstrate that patients with ascites have significantly higher variceal pressure and wall tension than patients without ascites. These results suggest that patients with ascites may be at risk for variceal bleeding.

Ascites↗
PubMed2000

The activation of phospholipase D by endothelin-1, angiotensin II, and platelet-derived growth factor in vascular smooth muscle A10 cells is mediated by small G proteins of the ADP-ribosylation factor family.

We show here that A10 cells express the phospholipase D (PLD) isoforms PLD1b and PLD2. The activation of PLD in these cells by angiotensin II (AngII), endothelin-1 (ET-1), and platelet-derived growth factor (PDGF) was found to be sensitive to inhibitors of the activation of ADP-ribosylation factor (ARF) but not to blockers of Rho protein function. PDGF, AngII, and ET-1 induced the binding of ARF proteins to cell membranes in a permeabilized cell assay. Cells permeabilized and depleted of ARF were no longer sensitive to stimulation with AngII, ET-1, or PDGF, but the addition of recombinant myristoylated human ARF1 restored agonist-dependent PLD activity. Expression of dominant negative ARF mutants blocked receptor-dependent activation of PLD. PLD activity was also potently stimulated by treatment with phorbol esters, but this activity was only partially inhibited by brefeldin A or by the overexpression of ARF dominant negative mutants. Transient expression of catalytically inactive mutants of PLD2, but not PLD1, inhibited significantly PDGF- and AngII-dependent PLD activity. We conclude: 1) the activation of PLD by cell surface receptors occurs primarily by an ARF-dependent mechanism in A10 cells, whereas the activation of PLD by protein kinase C-dependent pathways is only partially dependent on the regulation of ARF proteins; and 2) cell surface receptors, such as AngII and PDGF, signal primarily via PLD2 in A10 cells.

ADP Ribose Transferases↗
PubMed1999

The KDEL receptor regulates a GTPase-activating protein for ADP-ribosylation factor 1 by interacting with its non-catalytic domain.

ADP-ribosylation factor 1 (ARF1) is a key regulator of transport in the secretory system. Like all small GTPases, deactivation of ARF1 requires a GTPase-activating protein (GAP) that promotes hydrolysis of GTP to GDP on ARF1. Structure-function analysis of a GAP for ARF1 revealed that its activity in vivo requires not only a domain that catalyzes hydrolysis of GTP on ARF1 but also a non-catalytic domain. In this study, we show that the non-catalytic domain of GAP is required for its recruitment from cytosol to membranes and that this domain mediates the interaction of GAP with the transmembrane KDEL receptor. Blocking its interaction with the KDEL receptor leaves the GAP cytosolic and prevents the deactivation in vivo of Golgi-localized ARF1. Thus, these findings suggest that the KDEL receptor plays a critical role in the function of GAP by regulating its recruitment from cytosol to membranes, where it can then act on its membrane-restricted target, the GTP-bound form of ARF1.

ADP-Ribosylation Factor 1↗