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At least 1,423 records · Page 79Linked to original sources
PubMed1994

Second-generation anti-HCV screening in a Saudi Arabian donor population.

The 2nd-generation anti-HCV test system was applied to a Saudi Arabian multi-ethnic donor population. When donors were stratified according to first-time donations versus repeat donations, the latter having been screened previously by a 1st-generation set of tests, it was found that in Saudi Arabian and Middle East nationals, the 2nd-generation tests (EIA and RIBA), identified close to double the number of anti-HCV-positive donors, compared to an earlier study using the 1st-generation tests. Part of this finding was due to a 38% higher rate of RIBA-confirmable repeat-positive EIA results. In groups of donors, previously screened by the 1st-generation system, some additional cases of anti-HCV reactivity were identified, most prominently in Middle East nationals. It is assumed that some of these represented recent seroconversions, while others were cases of serologic subtypes of HCV, not reacting in the 1st-generation tests. The current test system identifies 0.66% of Saudi-Arabian, and 2.87% of other Middle East donors as putative carriers of hepatitis C virus. The study lends support to the opinion that donors who return regularly over the years have a lower prevalence of disease markers, thereby being a safer source of blood than first-time donors.

Blood Donors↗
PubMed1990

Reconstitution of the partially purified membrane component of the superoxide-generating NADPH oxidase of pig neutrophils with phospholipid.

The NADPH-dependent superoxide-generating oxidase of pig neutrophils is activated by sodium dodecyl sulfate in a cell-free system. The activation requires both membrane and cytosolic components. The membrane component was effectively extracted with 0.75% octyl glucoside and the extract was fractionated by wheat-germ-agglutinin-agarose column chromatography. The chromatography resulted in loss of the O2--generating activity in the cell-free system. The activity, however, was restored by the reconstitution with the fraction which passed through the column (fraction A) and the one eluted with N-acetylglucosamine (fraction B) using an octyl glucose dilution procedure: both fractions were pre-mixed in the presence of 0.75% octyl glucoside and diluted by putting the mixture into the detergent-free assay mixture. The latter fraction was copurified with cytochrome b558, the content of which is 2.12 +/- 0.53 nmol/mg protein (mean +/- SD, n = 5). The potency of fraction B in the reconstitution of the O2--generating activity was lost by heat treatment and decreased by protease treatment, whereas that of fraction A was not affected. Fraction A in the reconstitution of the O2--generating activity was replaced by lipid extracted from fraction A, furthermore, by exogenous phospholipid, azolectin. The O2--generating activity reconstituted with azolectin and the partially purified component in fraction B was dependent on SDS, cytosol and the concentrations of azolectin and FAD. The activity was sensitive to p-chloromercuribenzoate but not to azide. The maximal activity was obtained at pH 7.0-7.5. The Km values for NADPH and NADH were 0.024 mM and 0.57 mM, respectively. These properties were consistent with those of the NADPH oxidase responsible for the respiratory burst. The activity in the reconstitution system was 20.5 +/- 3.5 mumol O2-.min-1.mg-1 membrane-derived protein (mean +/- SD, n = 5) which shows that the membrane component was purified about 100-fold. These findings indicate that cytochrome b558 is probably a membrane component of the O2--generating NADPH oxidase and its activation in the cell-free system requires the reconstitution with phospholipids.

Animals↗
PubMed1995

Interferon-alpha potentiates priming-dependent FMLP-induced neutrophil superoxide generation in a patient with chronic myeloid leukemia.

A 13 year old girl diagnosed as having chronic myeloid leukemia (CML) was treated with interferon-alpha (IFN-alpha) alone and 4 months later hematological remission was obtained. In the course of the IFN-alpha treatment there was neither infectious sign nor side effects. In this study we have examined the effect of IFN-alpha on superoxide O2- generation by polymorphonuclear neutrophils (PMN). The PMN of the patient generated less O2- than PMN from normal controls. When patient PMN were cultured in the presence of 1000 U/mL IFN-alpha, enhancement of the formyl-methionyl-leucyl-phenylalanine induced O2- generation following priming with tissue necrosis factor-alpha was observed. Over the course of the IFN-alpha therapy, such O2- generation was gradually restored. It is suggested that CML PMN are in the resting condition in terms of their ability to generate O2- and that IFN-alpha is effective in inducing O2- generation by CML PMN.

Adolescent↗
PubMed1996

An audit of third generation cephalosporin prescribing in a tertiary care hospital.

BACKGROUND: There is increasing resistance to commonly used antibiotics, including third generation cephalosporins, and an increasing cost burden. AIMS: To assess the appropriateness of prescribing of third generation cephalosporin antibiotics in a tertiary teaching hospital. METHODS: Prescriptions of third generation cephalosporins (ceftriaxone, cefotaxime and ceftazidime) to inpatients were identified prospectively by the Hospital Pharmacy Department for a six week period during May-June 1994. Clinical data and indications were obtained from patient records and, when necessary, by interviewing the prescriber and by patient assessment. Criteria for appropriate prescribing were according to nationally accepted criteria outlined in the 1994-95 Antibiotic Guidelines handbook. All inpatients who were prescribed a third generation cephalosporin at Flinders Medical Centre for the duration of the audit period were eligible. This included medical, surgical, paediatric, obstetric and gynaecology inpatients. RESULTS: Sixty-five per cent of prescriptions for third generation cephalosporins were judged appropriate, 31% inappropriate and 4% doubtful. Inappropriate use was found particularly in the treatment of respiratory tract infections and abdominal sepsis, and in surgical prophylactic use. CONCLUSION: Third generation cephalosporin prescribing in a tertiary care teaching hospital is frequently inappropriate, as judged against widely available Australian guidelines.

Adult↗
PubMed2006

Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity.

Oxidative modification of cellular components may contribute to tissue dysfunction during aging. In skeletal muscle, contractile activity increases the generation of reactive oxygen and nitrogen species (ROS). The question of whether contraction-induced ROS generation is further increased in skeletal muscle of the elderly is important since this influences recommendations on their exercise participation. Three different approaches were used to examine whether aging influences contraction-induced ROS generation. Hind limb muscles of adult and old mice underwent a 15-min period of isometric contractions and we examined ROS generation by isolated skeletal muscle mitochondria, ROS release into the muscle extracellular fluid using microdialysis techniques, and the muscle glutathione and protein thiol contents. Resting skeletal muscle of old mice compared with adult mice showed increased ROS release from isolated mitochondria, but no changes in the extracellular levels of superoxide, nitric oxide, hydrogen peroxide, hydroxyl radical activity or muscle glutathione and protein thiol contents. Skeletal muscle mitochondria isolated from both adult and old mice after contractile activity showed significant increases in hydrogen peroxide release compared with pre-contraction values. Contractions increased extracellular hydroxyl radical activity in adult and old mice, but had no significant effect on extracellular hydrogen peroxide or nitric oxide in either group. In adult mice only, contractile activity increased the skeletal muscle release of superoxide. A similar decrease in muscle glutathione and protein thiol contents was seen in adult and old mice following contractions. Thus, contractile activity increased skeletal muscle ROS generation in both adult and old mice with no evidence for an age-related exacerbation of ROS generation.

Aging↗
PubMed1994

Loss of contractile activity of endothelin-1 induced by electrical field stimulation-generated free radicals.

1. Electrical field stimulation (EFS; 10 V, 10 Hz, 2 ms) of porcine coronary artery strips precontracted with 10 nM endothelin-1 (ET-1) for 5 min caused a biphasic response, consisting of a slight contraction during EFS and a marked and irreversible relaxation just after EFS. This irreversible relaxation after EFS has never been investigated. In the present study, we have investigated the mechanism of the relaxation after EFS. 2. The EFS-induced response was not affected by the presence or absence of endothelium and was insensitive to 10 microM tetrodotoxin (TTX). 3. In the presence of free radical scavengers (40 u ml-1 superoxide dismutase (SOD), 1200 u ml-1 catalase or 80 mM D-mannitol), the relaxation after EFS was significantly inhibited. Moreover, relaxation after EFS was not observed in porcine coronary artery strips precontracted with 20 mM KCl. 4. In a cascade experiment, EFS of Krebs-Ringer solution containing 10 nM ET-1 induced marked suppression of the contractile activity of ET-1 in porcine coronary artery strips, which was in accord with the observed decrease in release of immunoreactive ET-1 (ir-ET-1). This effect of EFS was significantly inhibited by each of the free radical scavengers, 3 mM vitamin C, 40 u ml-1 SOD, 1200 u ml-1 catalase and 80 mM D-mannitol. 5. The exchange of 95% O2/5% CO2 gas for 95% N2/5% CO2 gas significantly inhibited the EFS-induced decrease in release of ir-ET-1. 6. Neither superoxide anions generated by xanthine (10 JM) plus xanthine oxidase (0.1 micro ml-1) nor hydrogen peroxide (10 microM) exogenously added to Krebs-Ringer solution containing 10 nM ET-1 affected the level of ir-ET-1.7. Generation of hydroxyl radicals was detected in the EFS-applied Krebs-Ringer solution. The EFS-induced generation of hydroxyl radicals was dependent on the period of stimulation and 02-bubbling, and significant generation of hydroxyl radicals was detectable with stimulation of over 5 min.Moreover, hydroxyl radicals generated in 50 mM NaCl solution containing 10 nM ET-1 by H202 plus Fe2 , i.e. the Fenton reaction, significantly decreased the level of ir-ET-l.8. These findings suggest that oxygen-derived hydroxyl radicals generated by EFS of porcine coronary artery strips inactivate ET-1, probably by structural modification. Thus, porcine coronary artery strips precontracted with ET-1 are potently relaxed by EFS.

Animals↗
PubMedDate not supplied

Time-series data and the "migraine generator".

OBJECTIVE: To examine circadian and menstrual patterns of migraine frequency in order to identify properties of the putative migraine generator. METHODS: Analysis of circadian and menstrual migraine attack frequency distributions, using between-interval differences as estimates, at each time point, of the derivative of the equation that would, theoretically, model the observed oscillating functions. RESULTS: Circadian and menstrual analyses exhibit many similarities that are consistent with a single migraine generator in the final common pathway for expression of the phenotype. These analyses are inconsistent with a role for cortisol or ACTH to be activators of the putative migraine generator, could be consistent with visual stimulation as a deactivator of the generator, and may also be consistent with a low threshold concentration of estradiol and/or progestagens as inactivators of the migraine generator. CONCLUSIONS: Analysis of time-series data using differentials uncovers some previously unidentified chronobiological properties of migraine, helps select amongst various candidate provocative factors, and suggests some properties of a putative migraine generator.

Adult↗
PubMed1995

Selective effects of ethanol on the generation of cAMP by particular members of the adenylyl cyclase family.

A selective action of ethanol on major signal transduction proteins, such as adenylyl cyclase, has been considered to be important for certain actions of ethanol, and alcoholics have been demonstrated to differ from controls in measures of platelet adenylyl cyclase activity. Recent advances in identification and characterization of isoforms of adenylyl cyclase have demonstrated that there exists at least eight different forms of this enzyme. To examine whether the effect of ethanol on generation of cAMP is modified by the presence of particular isoforms of adenylyl cyclase within a cell, we transiently expressed each of six adenylyl cyclases in human embryonic kidney (HEK293) cells and measured cAMP accumulation in whole cells in the presence and absence of ethanol. The treatment of cells expressing the various adenylyl cyclases with ethanol alone did not enhance cAMP generation. In the presence of prostaglandin E1, cAMP generation by type I and type III adenylyl cyclases was insensitive to ethanol. cAMP accumulation generated by the other adenylyl cyclases was, however, increased by incubation of cells with ethanol in the presence of stimulatory agonists (e.g., prostaglandin E1). Stimulation by ethanol of cAMP generation by type VII adenylyl cyclase was 2- to 3-fold greater than that seen with the other tested adenylyl cyclases. The noted stimulation of cAMP generation by ethanol was dose-dependent and required concurrent activation of adenylyl cyclase through the stimulatory G protein. The effects of ethanol were reversible and mimicked by butanol but not by chloroform.

Adenylyl Cyclases↗
PubMed2005

The plasma hemostatic proteome: thrombin generation in healthy individuals.

BACKGROUND AND OBJECTIVES: The range of plasma concentrations of hemostatic analytes in the population is wide. In this study these components of blood coagulation phenotype are integrated in an attempt to predict clinical risk. METHODS: We modeled tissue factor (TF)-induced thrombin generation in the control population (N = 473) from the Leiden Thrombophilia Study utilizing a numerical simulation model. Hypothetical thrombin generation curves were established by modeling pro- and anticoagulant factor levels for each individual. These curves were evaluated using parameters which describe the initiation, propagation and termination phases of thrombin generation, i.e. time to 10 nm thrombin (approximate clot time), total thrombin and the maximum rates and levels of thrombin generated. RESULTS AND CONCLUSIONS: The time to 10 nm thrombin varied over a 3-fold range (2.9-9.5 min), maximum levels varied over a approximately 4-fold range (200-800 nm), maximum rates varied approximately 4.8-fold (90-435 nm min(-1)) and total thrombin varied approximately 4.5-fold (39-177 microm s(-1)) within this control population. Thrombin generation curves, defined by the clotting factor concentrations, were distinguished by sex, age, alcohol consumption, body mass index (BMI) and oral contraceptive (OC) use (OC > sex > BMI > age). Our results show that the capacity for thrombin generation in response to a TF challenge may represent a method to identify an individual's propensity for developing thrombosis.

Adult↗
PubMed2004

Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics.

The hemostatic activity of plasma is determined by platelet activation and coagulation, which processes are mutually stimulatory. We studied this interaction by measuring the cleavage of fluorescent thrombin substrate in platelet-rich plasma (PRP), using the calibrated thrombogram method. In freshly isolated human plasma, thrombin formation triggered by tissue factor was fully dependent on the presence of platelets. It was abolished by annexin A5, indicating dependence on phosphatidylserine (PS) exposure at activated platelets. Comparison of plasmas from various subjects showed considerable interindividual variation in total amount of thrombin generation, regardless of whether platelets or PS-containing phospholipids were present. Integrin alphaIIbbeta3 antagonists and ADP receptor blockage, but not aspirin, decreased the rate of thrombin generation (thrombin peak level) and extended the time of onset. Platelet inhibition with cAMP-elevating agents decreased the thrombin-forming rate, but surprisingly shortened the onset time. Stimulation of platelets with agonists of Gi/q-coupled receptors and, to a larger extent, with collagen or Ca2+-ionophore increased the rate of thrombin generation and shortened its onset. In PRP from donors with low and high generation, platelet inhibitors and activators were similarly effective. Taken together, these results indicate that, in tissue factor-triggered PRP, PS exposure on activated platelets regulates both onset and rate of thrombin generation. However, coagulant activity rather than platelet activation determines the total amount of thrombin formed, i.e. the endogenous thrombin potential. Thus, kinetics of thrombin generation in PRP are controlled by platelet inhibitors and agonists, but the process is restricted in amount by the subject-dependent variation in coagulation.

Blood Platelets↗
PubMed1986

The effects of magnetic resonance imaging on implantable pulse generators.

The effects of magnetic resonance imaging were assessed on four dual chamber and two single chamber pulse generators. The tests were performed with a resistive, water-cooled magnet operating at 0.15 T. The 6.4-MHz radiofrequency (RF) field was operated at a maximum power of 1,000 watts with a period adjusted from 130 to 500 ms. Reed switch closure occurred in all six pulse generators tested when placed near the entrance of the magnetic resonance imaging scanner, and the generators reverted to asynchronous operation unless programmed to the "magnet off" mode. None of the pulse generators exhibited any alterations in programmed parameters or in the ability to be reprogrammed after RF pulsing. When the RF field was turned on, there was no change in the asynchronous paced cycle length in four pulse generators; however, during RF scanning there was rapid cardiac stimulation at the RF pulse period in one single chamber and one dual chamber pulse generator.

Animals↗
PubMed1990

A technique for the prevention of automatic implantable cardioverter defibrillator generator migration.

In order to prevent AICD generator migration in nine patients and correct chronic painful generator migration in three patients, we placed the AICD generator in an absorbable microfibrillar collagen pouch at the time of implant to facilitate fibrous capsule formation. Over a mean follow-up period of 14 +/- 2 months for the new implants, there have been no episodes of generator erosion, migration or infection. The three patients who suffered from generator migration have been symptom free for 12 +/- 2 months. We conclude that use of a microfibrillar collagen pouch at the time of AICD implant is a safe, inexpensive, and effective method for preventing generator migration.

Abdominal Muscles↗
PubMed1995

Determinants of dual chamber pulse generators longevity.

The aim of this study was to investigate the effect of battery capacity, internal current drain, and stimulation energy on pulse generators longevity, and if battery impedance measurements can reliably predict pulse generators end-of-life. For this purpose, the records of 577 patients with a mean age of 65 +/- 14 years who had undergone implantation of two different dual chamber pulse generators (PG1: 409; PG2: 168) were retrospectively reviewed. Battery capacity were 2.3 Ah (PG1) and 3.0 Ah (PG2) while current drain at comparable nominal settings was 20 microA (PG1) and 30 microA (PG2) indicating a higher internal current drain of PG2. After a mean follow-up of 46 +/- 23 months, stimulation energy at reprogrammed output settings was significantly higher in PG1 as compared to PG2 (17.1 +/- 0.14) vs 15.5 +/- 0.24 J). Three PG1 (0.7%) and 12 PG2 (7.1%) (P < 0.01) had to be exchanged after a mean of 77.3 +/- 5.3 months (PG1) and 75 +/- 13.5 months (PG2) (P = NS) due to end-of-life being reached. The difference in battery impedances of PG1 and PG2 gained statistical significance 5 years after implantation (1.0 k omega vs 2.4 +/- 6.7 k omega) preceding the significant difference in PG survival after 6 years (98.7 +/- 1.3% vs 90.7 +/- 4.8%). These results indicate that internal current drain is the most important determinant of the pulse generators longevity and that battery impedance can reliably predict end-of-life. Therefore, the essential information about internal current drain should be available for each pacemaker, since it is required for adequate pulse generator selection. Diagnostic functions of dual chamber pulse generators should include measurements of battery impedance.

Adult↗
PubMed2004

Quality of life in persons with schizophrenia in out-patient treatment with first- or second-generation antipsychotics.

OBJECTIVE: Effects of first in comparison with second-generation antipsychotics on the subjective quality of life (QoL) of patients with schizophrenia under routine treatment conditions were examined. METHOD: In a prospective naturalistic trial the QoL, social, clinical, and treatment-related characteristics and type of antipsychotic medication of 307 patients with schizophrenia (ICD-10 F 20) were assessed five times with 6-month intervals over 2.5 years. Longitudinal and cross-sectional effects of antipsychotic medication were assessed by hierarchical regression models. Selection bias was controlled by propensity scores. RESULTS: While positive effects of first-generation antipsychotics on subjective QoL in comparison with no antipsychotic treatment were found, second-generation antipsychotics caused no better QoL than first-generation antipsychotics. CONCLUSION: The hypothesis that second-generation in comparison with first-generation antipsychotics have a better effect on the improvement of subjective QoL of people with schizophrenia in routine out-patient treatment was not supported.

Adolescent↗
PubMed2005

IFN-gamma decreases CTL generation by limiting IL-2 production: A feedback loop controlling effector cell production.

IFN-gamma is produced by cytotoxic T lymphocytes (CTL) but can also decrease CTL generation. We used IFN-gamma-R1-deficient (GRKO) and IFN-gamma-deficient (GKO) mice to study the effects of IFN-gamma in MLC on the generation of CTL activity and CTL number, IL-2 production and cell proliferation. CTL activity was increased in MLC when GRKO responders or GKO stimulators and responders were used, compared to wild-type (WT) MLC. The number of cells displaying the CTL phenotype (CD3+, CD8+, CD25+) was also increased, accompanied by increased IL-2 production and proliferation. Combinations of WT or GRKO CD4+ T cells with WT or GRKO CD8+ T cells as responders showed that IFN-gamma mostly affects CD4+ T cells to limit CTL generation. Intracellular staining indicated that IL-2 production was largely by CD4+ T cells. Moreover, addition of IL-2 to WT responders mimicked GKO CTL generation and activity, whereas neutralizing IL-2 decreased CTL activity in GRKO and WT responders. Thus IFN-gamma reduces CTL generation in alloimmune responses largely by limiting proliferation of IL-2 producing CD4+ T cells. This creates a feedback loop in which effectors produce IFN-gamma that limits IL-2 production which in turn limits CTL generation.

Animals↗
PubMed1998

Influence of twinline, an elemental diet, on the generation of nitric oxide and reactive-oxygen intermediates from mouse peritoneal macrophages and polymorphonuclear leukocytes.

The influence of Twinline (SNN-6010), an elemental diet containing medium-chain triglycerides, on the generation of nitric oxide (NO) and superoxide (O2.-) has been examined in mouse peritoneal macrophages and polymorphonuclear leukocytes (PMN). When PMN and peritoneal macrophages obtained from untreated mice were cultured in medium containing 0.1% and 1% (v/v) Twinline for 48h and stimulated with phorbol myristate acetate or N-formyl-methionyl-leucyl-phenylalanine, their chemiluminescence and O2.- generation were strongly suppressed, as was NO generation from peritoneal macrophages. PMN and peritoneal macrophages obtained from mice fed Twinline for 30 days generated much smaller amounts of 02.- and NO compared with PMN and peritoneal macrophages from control mice. In conjunction with this suppressed NO generation, inducible NO synthase and its mRNA expression in peritoneal macrophages were suppressed by Twinline both in-vivo and ex-vivo. Although phagocytosis of PMN and peritoneal macrophages was not suppressed by Twinline; their candida-killing activity was markedly suppressed. These results indicate that Twinline suppresses the host-defence function of PMN and peritoneal macrophages by down-regulating their generation of reactive-oxygen intermediates and NO.

Animals↗
PubMed1995

Action potential generation in rat slow- and fast-twitch muscles.

1. In skeletal muscle fibres, voltage-gated sodium channels are concentrated at the neuromuscular junction. The effect of this accumulation of sodium channels on action potential generation was investigated in rat slow- and fast-twitch muscle fibres. 2. Intracellular microelectrodes were used to generate and record action potentials, from an imposed membrane potential of -75 and -90 mV, in junctional and extrajunctional regions of the muscle fibre. To identify junctional regions, preparations were incubated with 5 x 10(-7) M d-tubocurarine (dTC) to block muscle contraction in response to nerve stimulation whilst allowing endplate potentials (EPPs) to be recorded. Injection of rectangular depolarizing current pulses initiated action potentials at the endplate with threshold values several millivolts lower than those generated elsewhere in the fibre. In addition, the maximum rate of rise of the action potential was greater at the endplate than in extrajunctional regions. 3. In other muscles, neuromuscular transmission was partially blocked with dTC (2 x 10(-7) M), such that repetitive nerve stimulation evoked action potentials and EPPs in the same fibre. The threshold of these nerve-evoked action potentials was approximately 50% lower than values derived from action potentials generated by current injection. 4. It is concluded that the threshold for action potential generation is significantly lower at the neuromuscular junction than in extrajunctional regions of skeletal muscle fibres. Furthermore, nerve-evoked current is more effective at generating an action potential than is injected current.

Action Potentials↗
PubMed1995

Rhythm generation in the segmented hindbrain of chick embryos.

1. The embryonic hindbrain of chick is segmented until stage 24, when it starts to generate rhythmic activities in cranial nerves. In order to recognize a possible influence of segmentation on the organization of neuronal systems generating motor rhythms, the activity of trigeminal, facial, glossopharyngeal, vagal and hypoglossal nerves was studied during embryonic stages 24-36, by simultaneous recording of different cranial nerves in an isolated, superfused chick hindbrain preparation. 2. Highly correlated recurrent episodes of cyclical burst discharges occurred in all nerves studied (correlation coefficients, 0.8 +/- 0.1) throughout stages 24-36. 3. Such coactivation is unlikely to be due to monosynaptic connections between widely divergent premotor neurons and motoneurons, or between motoneurons themselves, because no short-term correlation was apparent in the millisecond range between activities of different motor nerves. 4. Complete transverse or midsagittal sectioning of the hindbrain disrupted coactivation of nerves located at distinct rostrocaudal levels or occupying an ipsi- or contralateral position, respectively, while sparing the ability of individual nerves to generate rhythmic activity. Each hindbrain segment thus contains bilaterally the motor nuclei together with their own rhythm generator. Coactivation of motor patterns appears to result from intersegmental and cross-median connections between these rhythm generators. 5. The results are in keeping with the hypothesis of a segmental organization of the primordial hindbrain rhythm generator and give further support to the early determination of both the anatomical and the functional fate of neurons in this region of the vertebrate central nervous system.

Animals↗