Biomedical subjects

A H Taylor

Publications and source records attributed to A H Taylor.

At least 19 recordsLinked to original sources

PubMed2006

Norepinephrine increases the pathogenic potential of Campylobacter jejuni.

BACKGROUND: Campylobacter jejuni can cause a spectrum of diseases in humans, ranging from enteritis and diarrhoea to severe inflammation, profuse bloody diarrhoea and chronic relapsing infection. Norepinephrine (NE) levels in the intestine increase under conditions of stress and trauma, and are thought to result in spill over of NE into the intestinal lumen. NE is known to stimulate the growth of a range of bacterial species, and to increase the pathogenicity of Escherichia coli. AIM: To determine the effects of NE on the pathogenic potential of C jejuni in a model system. METHODS: C jejuni was grown in iron-replete and iron-limited media in the presence and absence of 100 microM NE. Several virulence-associated characteristics, including motility and cell invasion, were measured. RESULTS: When C jejuni was grown in iron-limited media in the presence of NE, growth rate, motility and invasion of cultured epithelial cells were increased compared with cultures grown in the absence of NE. Bacteria exposed to NE during growth also caused greater subsequent disruption of cultured epithelial cell monolayers, inducing widespread breakdown of tight junctions. CONCLUSION: Exposure to NE causes an increase in the virulence-associated properties of Campylobacter. Stress and concomitant infection could therefore be contributory factors to the variable presentation of this disease.

Caco-2 Cells↗

PubMed2006

Trimegestone differentially modulates the expression of matrix metalloproteinases in the endometrial stromal cell.

Matrix metalloproteinases (MMP) are considered to be of critical importance in the initiation of menstruation where MMP protein levels are reciprocally modulated by the actions of the gonadal steroid hormones, estradiol (E(2)) and progesterone (P4), with P4 being considered the principal suppressor of endometrial MMP expression. Trimegestone (T) is a novel progestagen that tightly controls menstruation timing and duration through mechanisms that might involve MMP suppression. Endometrial stromal cells treated with 10(-6) M E(2), P4 or T in the presence and absence of 10(-6)M RU486 showed that both T and P4 suppressed the expression of MMP-1 and MMP-3 transcripts and secreted protein, whereas MMP-9 was not produced in culture. The suppressive effect of T or P4 on MMP-1 and MMP-3 transcript levels was enhanced in the presence of E(2) and attenuated in the presence of RU486, although MMP-1 proteins were unaffected by the presence of RU486, which alone acted as a partial progesterone agonist in these cultures. Immunohistochemistry with MMP-1, MMP-3 and MMP-9-specific antibodies performed on endometrial biopsies obtained from non-treated, LH-dated, normally cycling women and endometrial biopsies obtained from postmenopausal women treated with T-based HRT showed that immunoreactive MMP-1 and MMP-3 was higher in the menstrual phase, whilst MMP-9 expression was higher in the late luteal phase (P = 0.03) and T significantly inhibited the presence of MMP-9(+) cells. These data suggest that T acts in a similar manner to P4, but causes subtle differences in expression patterns of MMPs that may explain the different clinical effect that this progestagen has on endometrial behaviour compared to P4.

Adult↗

PubMed2004

Guest, a transposable element belonging to the Tc1/mariner superfamily is an ancient invader of Neurospora genomes.

Guest is a transposable element of the Tc1/mariner superfamily with 30-40bp terminal inverted repeats and a TA dinucleotide target site duplication. Guest was originally discovered in the St. Lawrence 74A laboratory strain of the filamentous fungus Neurospora crassa. In this report, Guest iterations subcloned from a cosmid library of the Oakridge 74A strain were used to design PCR primers that permitted the detection of Guest in wild isolates of N. crassa. Guest is present in N. crassa as multiple copies ranging between 100bp and 2.4kb and is present in the mating type locus of several Neurospora species. Bioinformatic analysis of the entire N. crassa genome (Oakridge 74A strain) detected 48 Guest iterations. All iterations appeared to have been inactivated either by repeat-induced point mutation or sequence deletion, with the majority being remnants less than 400bp in length. The possible involvement of Guest in the evolution of the variable region that flanks the mating type idiomorphs in several Neurospora species is discussed.

Amino Acid Sequence↗

PubMed2004

Physical activity and older adults: a review of health benefits and the effectiveness of interventions.

The purpose of this multidisciplinary review paper is to critically review evidence from descriptive, efficacy and effectiveness studies concerned with physical activity and older people. Both levels of fitness (aerobic power, strength, flexibility and functional capability) and measures of physical activity involvement decline with age, and the extent to which this is due to a biological ageing processes or disuse (physical inactivity) is critically examined. The review will consider the evidence for a causal relationship between sedentary behaviour/physical activity programmes and cardiovascular, musculoskeletal and psycho-social health, independent living and health-related quality of life into old age. The review also considers the effectiveness of different physical activity interventions for older people and issues relating to cost-effectiveness. The implications for future policy in terms of research, health care services, and education and training are briefly discussed.

Aged↗

PubMed2004

Infection after total knee arthroplasty.

The aim of our study was to determine the current incidence and outcome of infected total knee arthroplasty (TKA) in our unit comparing them with our earlier audit in 1986, which had revealed infection rates of 4.4% after 471 primary TKAs and 15% after 23 revision TKAs at a mean follow-up of 2.8 years. In the interim we introduced stringent antibiotic prophylaxis, and the routine use of occlusive clothing within vertical laminar flow theatres and 0.05% chlorhexidine lavage during arthroplasty surgery. We followed up 931 primary TKAs and 69 revision TKAs for a mean of 6.5 years (5 to 8). Patients were traced by postal questionnaire, telephone interview or examination of case notes of the deceased. Nine (1%) of the patients who underwent primary TKA, and four (5.8%) of those who underwent revision TKA developed deep infection. Two of nine patients (22.2%) who developed infection after primary TKA were successfully treated without further surgery. All four of the patients who had infection after revision TKA had a poor outcome with one amputation, one chronic discharging sinus and two arthrodeses. Patients who underwent an arthrodesis had comparable Oxford knee scores to those who underwent a two-stage revision. Although infection rates have declined with the introduction of prophylactic measures, and more patients are undergoing TKA, the outcome of infected TKA has improved very little.

Adult↗

PubMed2003

Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin.

Oestrogens play a major role in non-classic target tissues in both sexes, yet there have been few studies on estrogens and skin. Recently a second oestrogen receptor (ERbeta) has been discovered. Therefore, we have compared the expression of oestrogen receptor alpha (ERalpha), beta (ERbeta), the androgen receptor (AR) and a cell proliferation marker in male and female non-balding scalp skin. ERbeta was the major steroid receptor expressed in human skin. It was highly expressed in epidermis, blood vessels and dermal fibroblasts, in contrast to ERalpha and AR. In the hair follicle, ERbeta expression was localized to nuclei of outer root sheath, epithelial matrix and dermal papilla cells, in contrast to ERalpha, and the AR, which was only expressed in dermal papilla cells. Serial sections also showed strong nuclear expression of ERbeta in the cells of the bulge, while neither ERalpha nor AR was expressed. In the sebaceous gland, ERbeta was expressed in both basal and partially differentiated sebocytes. ERalpha exhibited a similar pattern of expression, while the AR was expressed in the basal and very early differentiated sebocytes. There was no obvious difference in the expression of either oestrogen receptor in male or female skin. The wide distribution of ERbeta in human skin suggests that oestrogens may play an important role in the maintenance of skin and in the regulation of the pilosebaceous unit, and provides further evidence for oestrogen action in non-classic target tissues. The differential expression of ERalpha, ERbeta and AR in human skin suggests that the mechanisms by which steroid hormones mediate their effects may be more complex than previously thought.

Aged↗

PubMed2003

Cementless acetabular replacement in patients with rheumatoid arthritis: a 6- to 14-year prospective study.

Sixty-three consecutive patients who had 82 Harris-Galante porous acetabular cups (HGP1) (Zimmer Inc, Warsaw, IN) implanted for the treatment of rheumatoid arthritis were prospectively assessed since 1986. At last examination, 12 patients (16 hips) had died, and 1 patient (1 hip) was lost to follow-up. A total of 65 hips in 50 patients were available for the latest review. The follow-up period was 6.8 years to 14 years (mean, 9.1 years). There had been 6 revisions: 1 for deep infection and 5 for polyethylene cup wear. Survivorship analysis for all failures estimated that 75% of hips would still be revision-free after 4558 days (12.5 years). Polyethylene wear has been identified in a further 7 cases at last examination. The average linear cup wear per year was 0.05 mm(range, 0.00-0.66 mm). There were no cases of acetabular loosening or acetabular migration. These results demonstrate the excellent durability of fixation of the HGP1 cups in patients with rheumatoid arthritis. However, a 32-mm head should probably not be used with this cup given the high associated incidence of polyethylene wear.

Acetabulum↗

PubMed2003

Infection after total hip arthroplasty. The Avon experience.

Our aim in this study was to determine the outcome of hip arthroplasty with regard to infection at our unit. Infection after total joint arthroplasty is a devastating complication. The MRC study in 1984 recommended using vertical laminar flow and prophylactic antibiotics to reduce infection rates. These measures are now routinely used. Between 1993 and 1996, 1727 primary total hip arthroplasties and 305 revision hip arthroplasties were performed and 1567 of the primary and 284 of the revision arthroplasties were reviewed between five and eight years after surgery by means of a postal questionnaire, telephone interview or examination of the medical records of those who had died. Seventeen (1.08%) of the patients who underwent primary and six (2.1%) of those who underwent revision arthroplasty had a post-operative infection. Only 0.45% of patients who underwent primary arthroplasty required revision for infection. To our knowledge this is the largest multi-surgeon audit of infection after total hip replacement in the UK. The follow-up of between five and eight years is longer than that of most comparable studies. Our study has shown that a large cohort of surgeons of varying seniority can achieve infection rates of 1% and revision rates for infection of less than 0.5%.

Aged↗

PubMed2001

Specific inhibition of estrogen receptor alpha function by antisense oligodeoxyribonucleotides.

We have tested the effect of a range of antisense oligodeoxyribonucleotides (ODN) directed against the human estrogen receptor alpha (ERalpha) on ERalpha protein expression and function. Antisense ERalpha ODN transfected into the ERalpha-positive human breast carcinoma cell line MCF7-K2 showed variable responses dependent on the oligo used. The most active antisense ODN (oligo 7) decreased the levels of ERa protein by 61% as measured by Western blot analysis. Exogenous 17beta-estradiol (17beta-E2), but not 17alpha-E2, augmented this effect, with a threshold effect at 10(-8) M 17beta-E2. The inhibitory effect of antisense ERa oligo 7 was confirmed by measurement of functional ERalpha protein. 3H-17beta-E2 binding to MCF7 cell extracts was inhibited to approximately 40% of control values in the presence of oligo 7. Antisense-transfected MCF7-K2 cell cultures produced a further 30% binding reduction in the presence of exogenous 17beta-E2. An inhibitory effect on 17beta-E2-dependent cell function was confirmed by the demonstration that ERalpha oligo 7-transfected MCF7-K2 cells failed to exhibit 17beta-E2-stimulated cell proliferation. Exogenous 17beta-E2 enhanced the inhibitory effect of the antisense ODN by increasing ODN transfection efficiency but without ERalpha catabolism via the proteosomal pathway, suggesting an effect of 17beta-E2 on the plasma membrane and the existence of different ERalpha degradation pathways in the MCF7-K2 cell subclone. As 17beta-E2 had no effect on ERalpha protein degradation, we conclude that the observed reduction of ERalpha protein levels is due solely to the presence of the antisense ERalpha ODN. Antisense ERalpha ODN molecules, therefore, may form the basis of effective therapies against ERalpha-dependent malignancies.

Adenocarcinoma↗

PubMed2001

Harris Galante cementless acetabular replacement in avascular necrosis.

We describe the results of 76 total arthroplasties of the hip for stage-III or stage-IV avascular necrosis of the femoral head. Harris Galante Porous cups were used in 63 patients between 1986 and 1994 and followed prospectively. We reviewed 70 hips with a follow-up of more than five years (mean 7.6). At the latest review the mean Harris Hip Score had improved from a preoperative value of 29 +/- 14.7 to 94 +/- 6.8. Radiologically, there was no evidence of acetabular migration. The rate of revision for the femoral component was 8.6%, three being undertaken for loosening and three to allow downsizing of the femoral head. The rate of revision for the acetabular component was 7.1% (five cups). At the time of revision none of the cups was clinically loose, and only required the liner to be changed. The rate of complications was low with no case of deep infection or dislocation, but nine of the 76 hips (11.8%) showed grade-III heterotopic ossification. Previous studies of patients undergoing cemented total hip arthroplasty for the treatment of advanced avascular necrosis have indicated a high incidence of loosening of the acetabular component. Our findings show good medium-term results using the Harris Galante Porous cup for acetabular reconstruction, together with a variety of cemented femoral components, for the treatment of this difficult problem.

Acetabulum↗

PubMed2000

Antibodies against the first Ig-like domain of human platelet endothelial cell adhesion molecule-1 (PECAM-1) that inhibit PECAM-1-dependent homophilic adhesion block in vivo neutrophil recruitment.

Platelet endothelial cell adhesion molecule (PECAM-1), a member of the Ig superfamily, is found on endothelial cells and neutrophils and has been shown to be involved in the migration of leukocytes across the endothelium. Adhesion is mediated, at least in part, through binding interactions involving its first N-terminal Ig-like domain, but it is still unclear which sequences in this domain are required for in vivo function. Therefore, to identify functionally important regions of the first Ig-like domain of PECAM-1 that are required for the participation of PECAM-1 in in vivo neutrophil recruitment, a panel of mAbs against this region of PECAM-1 was generated and characterized in in vitro adhesion assays and in an in vivo model of cutaneous inflammation. It was observed that mAbs that disrupted PECAM-1-dependent homophilic adhesion in an L cell aggregation assay also blocked TNF-alpha-induced intradermal accumulation of neutrophils in a transmigration model using human skin transplanted onto SCID mice. Localization of the epitopes of these Abs indicated that these function-blocking Abs mapped to specific regions on either face of domain 1. This suggests that these regions of the first Ig-like domain may contain or be close to binding sites involved in PECAM-1-dependent homophilic adhesion, and thus may represent potential targets for the development of antiinflammatory reagents.

Amino Acid Sequence↗

PubMed2000

Exercise interventions for smoking cessation.

BACKGROUND: Taking exercise may help people give up smoking by moderating the effects of nicotine withdrawal. OBJECTIVES: To determine whether exercise-based interventions combined with a smoking cessation programme are more effective than a smoking cessation intervention alone. SEARCH STRATEGY: We searched The Cochrane Tobacco Addiction group specialised register for studies including the terms 'exercise' or 'physical activity' in February 2000. SELECTION CRITERIA: We included randomised trials comparing an exercise programme as an adjunct to a cessation programme with a cessation programme alone, recruiting smokers or recent quitters, and with a follow-up of 6 months or more. DATA COLLECTION AND ANALYSIS: We extracted data on study characteristics and smoking outcomes. Because of differences in studies we summarised the results narratively, making no attempt at meta-analysis. MAIN RESULTS: We identified eight trials, six of which had fewer than 25 people in each treatment arm. They varied in the timing and intensity of the smoking cessation and exercise programmes. Only one trial showed a significant benefit from the exercise programme at long term follow-up. REVIEWER'S CONCLUSIONS: Only one of the eight trials offered evidence for exercise aiding smoking cessation but the other trials were too small to exclude reliably an effect of intervention. Trials are needed with larger sample sizes, equal contact control conditions, tailored and lifestyle exercise programmes and measures of exercise adherence.

Exercise↗

PubMed2000

Does exercise aid smoking cessation? A systematic review.

AIMS: To assess the effectiveness of exercise-based interventions in smoking cessation. DESIGN: A systematic review was conducted of articles published between 1980 and 1999. The review focused on randomized controlled trials (RCTs) in which the specific effects of exercise on smoking abstinence were examined. The primary dependent variable was smoking abstinence. Other studies which had both exercise programming as an independent variable and smoking behaviour as a dependent variable are briefly discussed. PARTICIPANTS: The review included interventions targeting both healthy individuals and those with specific medical conditions. SETTINGS: The interventions were delivered in both community and inpatient settings. MEASUREMENTS: Information extracted from each article included details of the participants, exercise and smoking cessation programmes, control conditions, exercise adherence rates, length of follow-up and outcomes. FINDINGS: Of the eight trials satisfying our inclusion criteria, only two trials found a positive effect for exercise on smoking abstinence. The others showed no effect. CONCLUSIONS: There is some evidence for exercise aiding smoking cessation. Of the two trials finding a positive effect one was rigorously designed, the other was found to have numerous methodological limitations. Trials showing no effect lacked sensitivity. This was principally because of small sample sizes and inadequate measurement and control of exercise adherence. There is a need for more rigorously designed studies in this area.

Exercise↗

PubMed2000

Oestrogen receptor beta is not present in the pilosebaceous unit of red deer skin during the non-breeding season.

Androgens and oestrogens both have roles in skin physiology. Recently a second oestrogen receptor (ERbeta) has been identified in androgen-dependent tissues. The red deer grows a breeding season, androgen-dependent mane when plasma testosterone rises; this is replaced with small neck hairs during the non-breeding season. In non-breeding season deer skin, ERbeta was localised to the blood vessels and arrector pili muscle, but in contrast to human skin, not in the pilosebaceous unit or epidermis. The androgen receptor was not expressed. Further studies with breeding season skin may help to elucidate whether serum androgens or androgen receptor expression can modulate the expression of ERbeta in skin.

Animals↗

PubMed2000

Immunolocalisation of oestrogen receptor beta in human tissues.

Oestrogens exert their actions via specific nuclear protein receptors that are members of the steroid/thyroid receptor superfamily of transcription factors. Recently, a second oestrogen receptor (ERbeta) has been cloned, and using reverse transcription-PCR and immunohistochemistry it has been shown to have a wide tissue distribution in the rat that is distinct from the classical oestrogen receptor, ERalpha. Using commercial polyclonal antisera against peptides specific to human ERbeta, we have determined the sites of ERbeta expression in archival and formalin-fixed human tissue and compared its expression with that of ERalpha. ERbeta was localised to the cell nuclei of a wide range of normal adult human tissues including ovary, Fallopian tube, uterus, lung, kidney, brain, heart, prostate and testis. In the ovary, ERbeta was present in multiple cell types including granulosa cells in small, medium and large follicles, theca and corpora lutea, whereas ERalpha was weakly expressed in the nuclei of granulosa cells, but not in the theca nor in the copora lutea. In the endometrium, both ERalpha and ERbeta were observed in luminal epithelial cells and in the nuclei of stromal cells but, significantly, ERbeta was weak or absent from endometrial glandular epithelia. Epithelial cells in most male tissues including the prostate, the urothelium and muscle layers of the bladder, and Sertoli cells in the testis, were also immunopositive for ERbeta. Significant ERbeta immunoreactivity was detected in most areas of the brain, with the exception of the hippocampus - a tissue that stained positively for ERalpha. In conclusion, the almost ubiquitous immunohistochemical localisation of ERbeta indicates that ERbeta may play a major role in the mediation of oestrogen action. The differential expression of ERalpha and ERbeta in some of these tissues suggests a more complex control mechanism in oestrogenic potential than originally envisioned.

Adult↗

PubMed2000

Oestradiol decreases rat apolipoprotein AI transcription via promoter site B.

Oestrogens protect against ischaemic heart disease in the post-menopausal female by increasing serum concentrations of apolipoprotein (apo) AI and the abundance of high-density lipoprotein particles. In men and experimental male animals, the administration of oestrogen has variable effects on apo AI expression. As the major mode of oestrogen action on target genes involves regulating promoter activity and hence transcription, oestrogen is expected to alter transcription of the apo AI gene. To test this hypothesis, the effect of 17beta-oestradiol (E(2)), on rat apo AI promoter activity in male hepatoma HuH-7 cells, was tested by co-transfecting a reporter template, pAI.474.CAT containing-474 to-7 of the rat apo AI promoter and an oestrogen receptor (ER) expression vector, pCMV-ER. Transfected cells exposed to E(2) showed a dose-dependent decrease in chloramphenicol acetyltransferase (CAT)-activity, with a maximum 91+/-1.5% reduction at 1 microM E(2). Deletional analysis of the promoter localized the inhibitory effect of ER and E(2) to site B (-170 to-144) with an adjacent 5' contiguous motif, site S (-186 to-171) acting as an amplifier. HuH-7 cell nuclear extracts showed binding activities with both sites S and B, but recombinant human ER did not. Furthermore, nuclear extracts from E(2)-treated HuH-7 cells showed weaker binding activity to site B, but not to site S. In summary, the inhibitory effect of ER and E(2) on rat apo AI gene activity is mediated by a promoter element, site B. This inhibitory effect arises from a mechanism that does not involve direct ER binding to the B-element. The conclusion that E(2) inhibits apo AI transcription was confirmed in vivo. Treatment of male adult Sprague-Dawley rats with up to 200 microg E(2) for 7 days decreased apo AI protein and hepatic mRNA by 72+/-21% and 68+/-1.4% respectively. Results of 'run-on' transcription of the apo AI gene in isolated hepatic nuclei showed a 55% decrease in hormone-treated male rats. These findings suggest that E(2) exerts primarily an inhibitory effect within male hepatic nuclei.

Animals↗

PubMed1998

Effects of glucose and insulin on rat apolipoprotein A-I gene expression.

We have examined the regulation of apolipoprotein A-I (apoA-I) gene expression in response to glucose and insulin. In Hep G2 cells, endogenous apoA-I mRNA was suppressed by one-half or induced 2-fold following 48 h of exposure to high concentrations of glucose (22.4 mM) or insulin (100 microunits/ml), respectively, compared with control. Transcriptional activity of the rat apoA-I promoter (-474 to -7) in Hep G2 cells paralleled endogenous mRNA expression, and this activity was dependent on the dose of glucose or insulin. Deletional analysis showed that a 50-base pair fragment spanning -425 to -376 of the promoter mediated the effects of both insulin and glucose. Within this DNA fragment there is a motif (-411 to -404) that is homologous to a previously identified insulin response core element (IRCE). Mutation of this motif abolished not only the induction of the promoter by insulin but also abrogated its suppression by glucose. Electrophoretic mobility shift assay analysis of nuclear extracts from Hep G2 cells revealed IRCE binding activity that formed a duplex with radiolabeled probe. The IRCE binding activity correlated with insulin induction of apoA-I expression. In summary, our data show that glucose decreases and insulin increases apoA-I promoter activity. This effect appears to be mediated by a single cis-acting element.

Animals↗

PubMed1998

Randomised controlled trial to examine the effects of a GP exercise referral programme in Hailsham, East Sussex, on modifiable coronary heart disease risk factors.

OBJECTIVE: To examine the effects of a GP exercise referral programme on modifiable coronary heart disease risk factors. DESIGN: Randomised controlled trial. A battery of validated measures were carried out at 0, 8, 16, 26, and 37 weeks. SETTING: Two community health centres and a leisure centre in Hailsham, East Sussex. SUBJECTS: 389 patients (smokers, hypertensive or overweight) were selected from medical records, screened for contraindications to exercise and 345 were invited into the study. Of 142 patients randomly allocated, 40 (41%) completed the study in the exercise group and 31 (69%) in the control group. Sixty (35%) invited smokers (48% of non-smokers), 71 (38%) invited hypertensive patients (45% of non-hypertensive patients), and 107 (45%) overweight patients (33% of non-overweight patients) were randomised. Of those randomised, 27 (45%) smokers, 52 (48%) overweight, and 43 (61%) hypertensive patients completed the study. INTERVENTION: The exercise group was offered 20, half price sessions over 10 weeks at a leisure centre. Patients engaged in moderate and vigorous aerobic type activity on various exercise machines, in a semi-supervised, informal environment. RESULTS: 87% of those referred used the prescription and 28% (high adherers)(45% of obese patients) did at least 15 sessions. The exercise group reduced sum of skinfolds by 8.1% (2.9 to 13.3, 95% confidence intervals) more than the control group, up to 16 weeks after baseline. High adherers reduced sum of skinfolds by 9.2% (0.9 to 17.5) more than the control group, up to 26 weeks. High adherers reduced systolic blood pressure by 7.2% (-0.7 to 14.9) (that is, 9 mm Hg) more than low adherers, up to 37 weeks. Non-smokers and obese patients attended more prescribed sessions than smokers and non-overweight patients. CONCLUSIONS: Reduction in sum of skinfolds was maintained up to 26 weeks, among high adherers compared with controls. Reduction in systolic blood pressure was evident up to 37 weeks among high adherers, but only in comparison with low adherers. Selection of appropriate referees and use of other strategies to improve exercise adherence will help to maximise the benefits from GP exercise prescription schemes.

Coronary Disease↗