Search PubMed⌕ Search

Biomedical subjects

P Dumas

Publications and source records attributed to P Dumas.

At least 37 records · Page 2Linked to original sources

Stenting of bifurcation lesions: a rational approach.

The occurrence of stenosis in or next to coronary bifurcations is relatively frequent and generally underestimated. In our experience, such lesions account for 15%-18% of all percutaneous coronary intervention > (PCI). The main reasons for this are (1) the coronary arteries are like the branches of a tree with many ramifications and (2) because of axial plaque redistribution, especially after stent implantation, PCI of lesions located next to a coronary bifurcation almost inevitably cause plaque shifting in the side branches. PCI treatment of coronary bifurcation lesions remains challenging. Balloon dilatation treatment used to be associated with less than satisfactory immediate results, a high complication rate, and an unacceptable restenosis rate. The kissing balloon technique resulted in improved, though suboptimal, outcomes. Several approaches were then suggested, like rotative or directional atherectomy, but these techniques did not translate into significantly enhanced results. With the advent of second generation stents, in 1996, the authors decided to set up an observational study on coronary bifurcation stenting combined with a bench test of the various stents available. Over the last 5 years, techniques, strategies, and stent design have improved. As a result, the authors have been able to define a rational approach to coronary bifurcation stenting. This bench study analyzed the behavior of stents and allowed stents to be discarded that are not compatible with the treatment of coronary bifurcations. Most importantly, this study revealed that stent deformation due to the opening of a strut is a constant phenomenon that must be corrected by kissing balloon inflation. Moreover, it was observed that the opening of a stent strut into a side branch could permit the stenting, at least partly, of the side branch ostium. This resulted in the provocative concept of "stenting both branches with a single stent." Therefore, a simple approach is currently implemented in the majority of cases: stenting of the main branch with provisional stenting of the side branch. The technique consists of inserting a guidewire in each coronary branch. A stent is then positioned in the main branch with a wire being "jailed" in the side branch. The wires are then exchanged, starting with the main branch wire that is passed through the stent struts into the side branch. After opening the stent struts in the side branch, kissing balloon inflation is performed. A second stent is deployed in the side branch in the presence of suboptimal results only. Over the last 2 years, this technique has been associated with a 98% angiographic success rate in both branches. Two stents are used in 30%-35% of cases and final kissing balloon inflation is performed in > 95% of cases. The in-hospital major adverse cardiac events (MACE) rate is around 5% and 7-month target vessel revascularization (TVR) is 13%. Several stents specifically designed for coronary bifurcation lesions are currently being investigated. The objective is to simplify the approach for all users. In the near future, the use of drug-eluting stents should reduce the risk of restenosis.

Blood Vessel Prosthesis Implantation↗

Brown Norway chromosome 13 confers protection from high salt to consomic Dahl S rat.

Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170+/-3.3 mm Hg in SS/Mcw rats, 119+/-2.1 mm Hg in SS.BN13 rats, and 103+/-1.3 mm Hg in BN/Mcw rats. After salt depletion, MAP fell an average of 27+/-4.5 mm Hg in SS/Mcw rats, 9+/-2.6 mm Hg in SS.BN13 rats, and 11+/-3.0 mm Hg in BN/Mcw rats. Protein excretion of SS/Mcw rats on a high salt diet averaged 189+/-30 mg/24 h, 63+/-18 mg/24 h in SS.BN13 rats, and 40+/-6.4 mg/24 h in BN/Mcw rats. Compared with SS.BN13 and BN/Mcw rats, SS/Mcw rats exhibited significantly greater increases of renal vascular resistance in response to intravenous norepinephrine and angiotensin II. Severe medullary interstitial fibrosis and tubular necrosis after a high salt diet were found consistently in SS/Mcw rat kidneys but were largely absent in the SS.BN13 and BN/Mcw rat kidneys. A similar degree of glomerular sclerosis was found in both SS/Mcw and SS.BN13 rats. In rats fed a 0.4% salt diet, the glomerular filtration rate of SS/Mcw rats was significantly less than that of BN/Mcw and SS.BN13 rats. These results reveal a powerful gene, or set of genes, within chromosome 13 of BN/Mcw rats that confers protection from the detrimental effects of high salt to the SS/Mcw rats.

Angiotensin II↗

Workshop: excess growth and apoptosis: is hypertension a case of accelerated aging of cardiovascular cells?

Several groups including ours have demonstrated cardiac hyperplasia in neonates from genetically hypertensive rat strains. We have shown that similar problems exist in the kidney as well. More recently, we found that excessive heart and kidney weight is neonatally related to inhibition of apoptosis. Using recombinant inbred strains derived from a reciprocal cross between Brown Norway and spontaneously hypertensive rat progenitor strains, we mapped the inhibition of neonatal apoptosis to 2 distinct loci on chromosomes 1 (Myl 2) and 18 (Abrb 2). Positional candidate genes at these loci are being explored. These studies have also demonstrated that the loci determining kidney and heart weights in neonates are distinct from those determining increased organ weight in adults. The impact of blood pressure per se is also divergent because adult kidney weight is negatively correlated whereas heart weight is positively correlated with it. Analyses by extremes of low and high percentiles from fetal life to adulthood identified a single locus determining heart weight at Acaa on chromosome 8 in newborn (P=0.0003) and adult (P=0.016) rats. The Acaa region contains a DNA mismatch repair gene (hMLH1). The kinetics of neonatal growth through adulthood by prelabeling DNA with [(3)H]thymidine in pregnant mares showed that although the growth process is complex and nonlinear in the kidney of hypertensive rats, there is an increased turnover of cells, that is, reduced half-life of DNA. This observation is supported by the presence of shorter telomere fragments in kidneys of spontaneously hypertensive rats. These studies suggest that cardiovascular cells from hypertensive animals are subject to accelerated turnover, potentially leading to their accelerated aging.

Animals↗

Coronary angiography using 4 or 6 French diagnostic catheters: a prospective, randomized study.

Diagnostic catheter size has been progressively decreased in order to reduce complications (particularly access-site complications) and permit early ambulation after coronary angiography. However, excessive down-sizing can result in poor catheter conformation and poor imaging quality of coronary angiograms (CA). This study randomly compared the accuracy and angiographic quality (QUAL) of CA performed with 4 French (Fr) vs. 6 Fr diagnostic catheters. Injections were done manually using a low-viscosity, non-heated, low-osmolality contrast media (Iomeprol). CAs were performed via the femoral approach using Judkins catheters. Handling, torque, selectively and stability were graded from 1 (excellent) to 4 (unacceptable) by the operator. QUAL was also graded from 1 (unacceptable) to 10 (excellent) by the operator in all patients and by an independent Core laboratory in 50 patients matched for gender and weight. Between January and April 1997, a total of 405 consecutive patients were randomized. Mean age was 63.4 +/- 11.1 years and 79% were male. Clinical characteristics of patients, quality of left coronary catheter and cross-over rates (1.5% with 6 Fr vs. 3.9% with 4 Fr catheters) were similar in both groups. Using the right coronary catheters, the only difference was handling, which was found to be easier with 6 Fr catheters (1.16 +/- 0.55 vs. 1.34 +/- 0.77, respectively; p = 0.007). Similarly, handling difficulty using the pigtail catheter was the only significant difference between the two groups (1.16 +/- 0.50 vs. 1.33 +/- 0.77, respectively; p = 0.009), but no cross-over was necessary in either group. The QUAL of CA was slightly but significantly better with 6 Fr than with 4 Fr catheters but considered non-diagnostic (< 7/10) in 1.4% vs. 6.8% of left CAs (p = NS). Procedural time (21.0 +/- 7.2 minutes vs. 19.0 +/- 8.1 minutes; p = 0.007) was shorter with 4 Fr catheters, but x-ray exposure, compression times and amount of contrast media used were similar. Ambulation was obtained at 2 hours in 15.1% vs. 34.0% of patients (p < 0.001) and at 4 hours in 43.8% vs. 52.4% (p < 0.05), respectively. The incidence of the worst access-site complication (moderate hematoma) was similar (1%) in both groups. CA can be performed using 4 Fr catheters and manual injections of low-viscosity contrast media with acceptable angiographic results in the majority of cases. This is associated with a shorter procedural time and earlier ambulation, and a decreased but acceptable angiographic quality.

Age Factors↗

The crystal structure of UUCG tetraloop.

All large structured RNAs contain hairpin motifs made of a stem closed by several looped nucleotides. The most frequent loop motif is the UUCG one. This motif belongs to the tetraloop family and has the peculiarity of being highly thermodynamically stable. Here, we report the first crystal structure of two UUCG tetraloops embedded in a larger RNA-protein complex solved at 2.8 A resolution. The two loops present in the asymmetric unit are in a different crystal packing environment but, nevertheless, have an identical conformation. The observed structure is globally close to that obtained in solution by nuclear magnetic resonance. However, subtle differences point to a more detailed picture of the role played by 2'-hydroxyl groups in stabilising this tetraloop.

Base Sequence↗

Genetically defined risk of salt sensitivity in an intercross of Brown Norway and Dahl S rats.

A genetic segregation analysis was performed to identify genes that cosegregate with arterial blood pressure traits reflective of salt sensitivity. A population of 113 F2 male rats was derived from an intercross of inbred SS/JrHsd/Mcw (Dahl salt-sensitive) and BN/SsN/Mcw (Brown Norway) rats. Rats were maintained on an 8% salt diet from the age of 9 to 13 wk, and arterial pressure was measured for 3 h daily during the 4th wk of high salt intake in unanesthetized rats using implanted arterial catheters. At the end of the 3rd day of high-salt pressure recordings, the arterial pressure response to salt depletion was determined 1.5 days following treatment with Lasix and a low-sodium (0. 4%) diet. A genome-wide scan using 265 polymorphic simple sequence length polymorphism (SSLP) markers found that seven arterial pressure phenotypes determined at different times and circumstances, and representing two distinct indexes of salt sensitivity, mapped to the same region of rat chromosome 18. The trait of salt sensitivity was strongly influenced by the presence of SS alleles in this region of chromosome 18, and those rats which were homozygote SS/SS exhibited a significantly greater reduction of mean arterial pressure following sodium depletion (29 +/- 2 mmHg) than homozygote BN/BN (17 +/- 3 mmHg) or heterozygotic (22 +/- 2 mmHg) rats. This region of rat chromosome 18 corresponds to the long arm of human chromosome 5 and a region of human chromosome 18 that has been linked to hypertension in humans. Given the unlikely chance of these different blood pressure traits mapping to the same region, we believe these data provide evidence that this region of rat chromosome 18 plays an important role in salt-induced hypertension.

Alleles↗

Stenting of bifurcation lesions: classification, treatments, and results.

Percutaneous transluminal balloon coronary angioplasty (PTCA) of coronary bifurcations is associated with a low success rate, high rate of complications, and high incidence of target vessel revascularization (TVR). The strategy of systematic coronary stenting in bifurcation lesions involving a side branch >/= 2.2 mm in diameter was prospectively evaluated in a single-center observational study during a 35-month inclusion period. All patients meeting these criteria were consecutively included. Bifurcation lesions and treatment were predefined in the study. The study included 366 patients (12.1% of PTCA) with 373 bifurcation lesions, mean age 63.7 +/- 11.6 years, 79.2% male, 46.7% with unstable angina, and 8.3% acute MI. The left anterior descending/diagonal bifurcation was involved in 55.2% of cases, circumflex/marginal 22. 2%, PDA/PLA 10.4%, left main bifurcation in 6.8%, and others 5.4%. The main branch (2.78 +/- 0.42 mm reference diameter) was stented in 96.3% of cases and the side branch (2.44 +/- 0.43 mm) in 63.2% (the two branches were stented in 59.5% of cases). Procedural success was obtained in 96.3% in both branches and 99.4% in the main branch. At1-month follow-up, The major cardiac event rate (MACE) was 4.8% (death 1.1%, emergency CABG 0.6%, Q-wave MI 0.9%, acute or subacute closure 1.4%, repeat PTCA 1.1%, and non-Q-wave MI 2.3%). At 7-month follow-up, the total MACCE rate was 21.6%, including a TVR rate of 17.2%. Analysis of the 7-month outcome according to two study periods (period I, 1 January 1996 to 31 August 1997, 182 patients; period II, 1 September 1997 to 30 June 1998, 127 patients) showed that the TVR rate decreased from 20.6% to 13.8% (P = 0.04) and the MACE rate from 29.2% to 17.1% (P < 0.01) in period I and II, respectively. This was associated by univariate analysis with an increasing use of tubular stents deployed in the main branch (94.2% vs. 59.1%, P < 0.001) and kissing balloon inflation after coronary stenting (75.4% vs. 18.1%, P < 0.001). Bifurcation lesions are frequent. Procedural success of coronary stenting is high with a low rate of in-hospital MACE. TVR rate at follow-up is relatively low. In-hospital and follow-up results are influenced not only by the learning curve but also by the use of tubular stents in the main branch and final kissing balloon inflation.

Aged↗

Systematic use of transradial approach or suture of the femoral artery after angioplasty: attempt at achieving zero access site complications.

Access site complications occur in 5-15% of cases according to the various series. The predictive factors most often reported in the literature are the size of the puncture site and the intensity of the antiplatelet or anticoagulant treatment associated with the angioplasty procedure. Six senior cardiologists in a high volume Cardiology center (>1,500 procedures a year) with an individual experience >500 procedures in either the radial approach or the percutaneous suture of the femoral artery with the Techstar/Prostar system, conducted a prospective study from January 1 to December 31, 1999. The aim of this study was to eliminate the occurrence of access site complications by using either one of two techniques that were at the operator's discretion, i.e., systematic radial approach, or percutaneous suture of the femoral artery. A total of 956 patients were included over the study period; 60.7% of these patients had percutaneous arterial closure of the femoral artery and the remaining 39.3% were treated via the radial approach; 88.7% were stented. The patients were administered a mean 9,000 IU of heparin during the procedure; 1.9% had been fibrinolyzed and Reopro was used in 5.9%. No complications were documented in the radial group. Of the 580 patients in the femoral suture group, 96.9% had femoral suture, immediately effective in 508 cases (90.4%). Only 3 patients required additional prolonged compression. One significant hematoma (0.2%) necessitating blood transfusion was reported in the femoral group. Infection at the puncture site with subsequent antibiotic treatment was reported in 2 patients (0.3%). No further access site complications were observed at one-month follow-up. After completion of the learning curve, the two techniques (radial approach and percutaneous arterial suture) permit the almost total elimination of access site complications.

Aged↗

The crystal structure of HIV reverse-transcription primer tRNA(Lys,3) shows a canonical anticodon loop.

We have solved to 3.3 A resolution the crystal structure of the HIV reverse-transcription primer tRNA(Lys,3). The overall structure is exactly comparable to the well-known L-shape structure first revealed by yeast tRNA(Phe). In particular, it unambiguously shows a canonical anticodon loop. This contradicts previous results in short RNA fragment studies and leads us to conclude that neither frameshifting specificities of tRNA(Lys) nor tRNA(Lys,3) primer selection by HIV are due to a specific three-dimensional anticodon structure. Comparison of our structure with the results of an NMR study on a hairpin representing a nonmodified anticodon stem-loop makes plausible the conclusion that chemical modifications of the wobble base U34 to 5-methoxycarbonyl-methyl-2-thiouridine and of A37 to 2-methylthio-N-6-threonylcarbamoyl-adenosine would be responsible for a canonical 7-nt anticodon-loop structure, whereas the unmodified form would result in a noncanonical UUU short triloop. The hexagonal crystal packing is remarkable and shows tight dimers of tRNAs forming a right-handed double superhelix. Within the dimers, the tRNAs are associated head-to-tail such that the CCA end of one tRNA interacts with the anticodon of the symmetry-related tRNA. This provides us with a partial view of a codon-anticodon interaction and gives insights into the positioning of residue 37, and of its posttranscriptional modifications, relative to the first base of the codon.

Animals↗

Crystal structure of the S15-rRNA complex.

In bacterial ribosomes, the small (30S) ribosomal subunit is composed of 16S rRNA and 21 distinct proteins. Ribosomal protein S15 is of particular interest because it binds primarily to 16S rRNA and is required for assembly of the small subunit and for intersubunit association, thus representing a key element in the assembly of a whole ribosome. Here we report the 2.8 ¿ resolution crystal structure of the highly conserved S15-rRNA complex. Protein S15 interacts in the minor groove with a G-U/G-C motif and a three-way junction. The latter is constrained by a conserved base triple and stacking interactions, and locked into place by magnesium ions and protein side chains, mainly through interactions with the unique three-dimensional geometry of the backbone. The present structure gives insights into the dual role of S15 in ribosome assembly and translational regulation.

Amino Acid Sequence↗

Mapping of quantitative trait loci (QTL) of differential stress gene expression in rat recombinant inbred strains.

OBJECTIVE: Stress has been shown to be a major environmental contributor to cardiovascular diseases through its effects on blood pressure variability and cardiac function. The cellular stress response is characterized by the expression of specific heat stress genes (hsps), under the transcriptional control of heat shock transcription factors (HSTFs). The levels of hsp mRNA depend on the severity of the stress, with hstf1 acting as a stress sensor. The aim of this work was to evaluate the genetic contribution of the variability in hsp expression, and to identify its putative quantitative trait loci (QTL). METHODS: Twenty recombinant inbred rat strains (RIS) were studied. The animals underwent a standardized, identical 1 h immobilization stress in restraint cages, followed by 1 h of rest before sacrifice. Total RNA was extracted from the heart kidneys and adrenals, and the mRNA levels of hsp27, hsp70, hsp84, hsp86 and hsp105 were measured. The strain distribution pattern (SDP) of hsp expression was correlated with that of 475 polymorphic markers distributed throughout the RIS genome. A polymorphism of rat hstf1 in RIS was used for its mapping in RIS. RESULTS: Despite an identical stress being applied to all strains, hsp expression showed up to a 1 2-fold gradient with little intra-strain variability, indicative of a strong genetic contribution to the trait Heritability ranged from 50 to 77% for most hsp genes in the three target organs. The continuous SDP of stress gene expression indicated the polygenic nature of the trait A common locus on chromosome 7 (at D7Cebrp187s3 marker) was consistently associated with all hsp expression in most of the organs [with a likelihood of odds (LOD) score of 3.0 for hsp27 expression]. We have mapped rat hstf1 on chromosome 7 at the same locus. Finally, the D4Mit19 marker was significantly associated with hsp84 expression in the heart (LOD score of 3.1). CONCLUSION: Two loci were linked with the differential expression of HSPs in response to immobilization stress in target organs of RIS. The chromosome 7 locus unveiled for all HSPs could explain up to 42% of the observed inter-strain variability of hsp levels in response to stress. We propose hstf1 as a positional candidate at this locus.

Adrenal Glands↗

Contribution of autosomal loci and the Y chromosome to the stress response in rats.

Stress is a critical contributor to cardiovascular diseases through its impact on blood pressure variability and cardiac function. Familial clustering of reactivity to stress has been demonstrated in human subjects, and some rodent models of hypertension are hyperresponsive to stress. Therefore, the present study was designed to uncover the genetic determinants of the stress response. We performed a total genome linkage search to identify the loci of the body temperature response to immobilization stress in a set of recombinant inbred strains (RIS) originating from reciprocal crosses of spontaneously hypertensive rats (SHR) with a normotensive Brown Norway Lx strain. Two quantitative trait loci (QTLs) were revealed on chromosomes (Chrs) 10 and 12 (logarithm of odds scores, 2.2 and 1. 3, respectively). The effects of these QTLs were enhanced by a high sodium diet (logarithm of odds scores, 4.0 and 3.3 for Chrs 10 and 12, respectively), which is suggestive of a salt-sensitive component for the phenotype. Congenics for Chr 10 confirmed both the QTL and the salt effect in RIS. Negatively associated loci were also identified on Chrs 8 and 11. Interaction between the loci of Chrs 10 and 12 was demonstrated, with the rat strains bearing SHR alleles at both loci having the highest thermal response to stress. Furthermore, the Y Chr of SHR origin enhanced the response to immobilization stress, as demonstrated in 2 independent models, RIS and Y Chr consomics. However, its full effect requires autosomes of the SHR strain. These findings provide the first evidence for the genetic determination of reactivity to stress with interactions between autosomal loci and between the Y and autosomal Chrs that contribute to the explanation of the 46% of variance in the stress response.

Animals↗

Exploring a biological tissue from atomic to macroscopic scale using synchrotron radiation: example of hair.

A combined approach, using synchrotron radiation-based diffraction and infrared microspectrometry, has been used to study the structure and molecular composition of hair samples. These methods allowed us to get an insight at different structural scales into the composition and structure of hair. Firstly, information about the configuration of amino-acid residues was obtained at atomic scale, secondly, a model was presented for the geometry and the packing of the microfibrils at medium scale and finally different structural zones were evidenced by microdiffraction at macroscopic scale. We also showed that the two main components of hair--proteins and lipids--are not evenly distributed within the fiber. In addition, these two components exhibit different structure, depending upon their location. Moreover, diffraction and microdiffraction data indicate that the cuticle zone is mainly composed of lipid granules, whereas the cortex and the medulla zones are composed primarily of alpha-keratin. Infrared microspectroscopy, using an enhanced lateral resolution thanks to synchrotron radiation, indicates, on one hand, that the protein structure between the cuticle and cortex are different, and on the other hand, that the concentration of lipids, inside the medulla, is much higher than everywhere else. This work emphasizes the complementarity between both techniques, and highlights the potentialities they can offer in the case of various other studies in biology.

Hair↗

[Immediate revascularization by angioplasty and coronary stents in patients over age 80 with myocardial infarction].

The aim of this study was to assess the results of revascularisation by angioplasty and stenting in octogenarians in the acute phase of myocardial infarction. One hundred and four patients over 80 years of age were identified between January 1995 and April 1995 out of 906 patients admitted within 24 hours of the onset of myocardial infarction. The average age was 85 +/- 4 years with a female predominance (63.4%) and a high incidence of cardiogenic shock (28.8%). Ninety eight patients underwent angioplasty with coronary stenting in 81 patients (82.6%) within 39 +/- 35 min of hospital admission. A primary success was obtained in 96% of cases with restitution of TIMI 3 flow in 83.6% of cases. Hospital mortality was 26.5%, highly influenced by the presence of cardiogenic shock (60.7% versus 12.8% without shock). Univariate analysis showed cardiogenic shock (p < 0.0001) and ejection fraction (p = 0.009) to be predictive of mortality, and a tendency in favour of TIMI 3 flow (p = 0.07) and stent implantation (p = 0.09). Complications were rare: 1% of minor cerebrovascular accidents and 4% of vascular complications. There were no cases of emergency bypass surgery and only one patient had a recurrence of ischaemia at 30 days. The authors conclude that the results at 1 month in a high risk group of octogenarians seem to be in favour of an invasive management with coronary stenting in the acute phase of myocardial infarction.

Aged↗

The crystal structure of the dimerization initiation site of genomic HIV-1 RNA reveals an extended duplex with two adenine bulges.

BACKGROUND: An important step in retroviral replication is dimerization of the genomic RNA prior to encapsidation. Dimerization is initiated by the formation of a transient 'kissing-loop complex' that is thought to be subsequently matured into an extended duplex by the nucleocapsid protein (NCp). Although chemical probing and nuclear magnetic resonance spectroscopy have provided insight into the structure of the kissing-loop structure, no structural information concerning the extended-duplex state is available so far. RESULTS: The structure of a minimal HIV-1 RNA dimerization initiation site has been solved at 2.3 A resolution in two different space groups. It reveals a 22 base pair extended duplex with two noncanonical Watson-Crick-like G-A mismatches, each adjacent to a bulged-out adenine. The structure shows significant asymmetry in deep groove width and G-A base-pair conformations. A network of eight magnesium cations was clearly identified, one being unusually chelated by the 3' phosphate of each bulge across an extremely narrowed deep major groove. CONCLUSIONS: These crystal structures represent the putative matured form of the initial kissing-loop complex. They show the ability of this self-complementary RNA hairpin loop to acquire a more stable extended duplex structure. Both bulged adenines form a striking 'base grip' that could be a recognition signal, either in cis for another viral RNA sequence, or in trans for a protein, possibly the NCp. Magnesium binding might be important to promote and stabilize the observed extrahelical conformation of these bulges.

Adenine↗