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P Koskinen

Publications and source records attributed to P Koskinen.

At least 19 recordsLinked to original sources
PubMed2005

Quantitative PCR in the diagnosis of CMV infection and in the monitoring of viral load during the antiviral treatment in renal transplant patients.

Cytomegalovirus (CMV) infection is a significant problem in transplantation. In this study, a quantitative PCR test was compared with the CMVpp65 antigenemia assay not only in the diagnosis CMV infections but especially in the monitoring of viral loads during ganciclovir treatment of CMV disease in individual renal transplant patients. Altogether 342 blood specimens were obtained from 116 patients. Blood specimens were used for Cobas Amplicor Monitor plasma PCR and for the pp65 assay. Also shell vial culture was performed. The patients with a positive pp65 finding were monitored for CMV weekly during ganciclovir treatment and/or until the antigenemia subsided. CMV was detected in 31/116 (27%) patients, of whom 14 (12%) developed CMV disease and were treated with ganciclovir. CMV was found by shell vial culture in 13/14 cases, but by PCR and pp65 test in all 14 patients. CMV was detected in 156 (45%) samples; by PCR in 121/156 (range 344-103,000 copies/ml) and by pp65 test in 138/156 (range 1-1,000 positive cells/50,000 leukocytes) and by culture in 59/156 (38%) only. The peak viral loads were significantly (P<0.0001) higher in CMV disease than in untreated infections (19,650 vs. 379 copies/ml, and 100 vs. 5pp65 positive cells). In the monitoring of individual patients, the time-related CMV-DNAemia and pp65 antigenemia correlated well during the treatment of CMV disease. In conclusion, Cobas Amplicor Monitor plasma PCR and CMVpp65 antigen assays can be equally used in the diagnosis CMV infection and in the monitoring of viral load during antiviral treatment.

Antigens, Viral↗
PubMed2005

Pre-analytical factors and measurement uncertainty.

Pre-analytical factors are an important source of variation or errors in clinical laboratory measurements. Based on the new accreditation standards, medical and laboratory professions now seek to develop tools to deal systematically with these diverse factors. Several obvious pre-analytical uncertainty components were estimated in pragmatic experiments and combined with data on analytical variation and literature knowledge on biological variation, to estimate the measurement uncertainty of most common chemical and haematological examinations in clinical laboratories. The main aim was to assess quality specifications for regional laboratory services. The expanded measurement uncertainties (level of confidence 95%) of serum cholesterol, albumin and potassium remained within 13-16%. The major uncertainty component for cholesterol was biological variation, whereas those for albumin and potassium were sample collection and pretreatment. The measurement uncertainties for serum free thyroxin, thyrotropin and C-reactive protein, 20%, 42% and 125% respectively, were largely due to their biological variation. The measurement uncertainties of basic erythrocyte parameters (erythrocyte count and mean corpuscular volume, blood haemoglobin concentration) were less than 10%. Larger measurement uncertainties were obtained for thrombocyte and leukocyte counts, 24 and 31%, respectively, and for the reticulocyte fraction, 41%.

Adult↗
PubMed2004

Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes.

OBJECTIVE: To examine the role of the sympathetic nervous system in regulating insulin's action on coronary perfusion in uncomplicated type 1 diabetes by blocking centrally mediated sympathetic activity with dexamethasone. METHODS: Positron emission tomography and oxygen 15 labelled water were used to quantify myocardial blood flow basally and during adenosine infusion with or without simultaneous euglycaemic physiological hyperinsulinaemia in nine non-smoking men with type 1 diabetes and 12 healthy non-diabetic men. Each patient was studied both with and without previous dexamethasone treatment for two days (2 mg/day). RESULTS: Insulin increased coronary flow reserve in diabetic (from 4.3 (0.7) to 5.1 (0.6), p < 0.05) and non-diabetic (from 4.3 (0.3) to 5.4 (0.4), p < 0.05) patients. In contrast to non-diabetic patients dexamethasone pretreatment abolished the insulin induced increase in coronary flow reserve in diabetic patients (p < 0.05) leading to lower coronary flow reserve in diabetic than in non-diabetic patients (3.9 (0.6) v 7.1 (0.9), p < 0.05). CONCLUSIONS: These results show that insulin's ability to modulate coronary perfusion is sustained in young patients with type 1 diabetes without microvascular complications or autonomic neuropathy. Dexamethasone treatment abolished the insulin induced increase in coronary flow reserve in diabetic patients but not in healthy study participants, suggesting that sympathetic activation plays an important part in regulating insulin's effects on myocardial perfusion in patients with type 1 diabetes.

Adenosine↗
PubMed2003

Maternal midtrimester free beta-HCG and AFP serum levels in spontaneous singleton pregnancies complicated by gestational diabetes mellitus, pregnancy-induced hypertension or obstetric cholestasis.

OBJECTIVES: The present study aims at finding out whether a connection exists between altered serum free beta-hCG and/or alpha-fetoprotein (AFP) levels and the manifestation of specific pregnancy complications [i.e. gestational diabetes mellitus (GDM), pregnancy induced hypertension (PIH) or intrahepatic cholestasis of pregnancy (ICP)]. METHODS: We compared free beta-hCG and AFP multiples of median (MoM) values in singleton pregnancies. The study population consisted of 117 pregnancies with GDM, 107 with PIH and 24 with ICP. The control group consisted of 1148 singleton pregnancies without any pregnancy complications. All were spontaneously conceived. RESULTS: In the group with GDM, both the free beta-hCG (0.72 MoM) and AFP MoM values (0.93) were significantly lower than in controls (beta-hCG 0.97 MoM, p = 0.0063 and AFP 1.01 MoM, p = 0.01). No statistically significant differences in the marker levels were observed between the ICP pregnancies and the control group. CONCLUSIONS: GDM has an impact on maternal midtrimester free beta-hCG and AFP levels and may change the DS screening result.

Adult↗
PubMed2002

Serum free beta-HCG and alpha-fetoprotein levels in IVF, ICSI and frozen embryo transfer pregnancies in maternal mid-trimester serum screening for Down's syndrome.

BACKGROUND: The aim of this study was to compare the maternal mid-trimester free beta-HCG and alpha-fetoprotein (AFP) levels in pregnancies conceived by assisted reproduction technology and spontaneous pregnancies in Down's syndrome screening. The influence of the number of embryos transferred and the amount of gonadotrophins used on the marker levels was also evaluated. METHODS: The study population consisted of 58 IVF, 32 ICSI and 26 frozen embryo transfer (FET) singleton pregnancies. The levels of beta-HCG and AFP were compared with the control group of 6548 singleton spontaneous pregnancies. RESULTS: The false positive rate (FPR) in the Down's syndrome screening was 19% overall in assisted reproductive technology pregnancies, being highest (30.8%) in the FET group. The free beta-HCG multiples of the median (MoM) values were statistically significantly elevated only in the FET group (1.33 MoM; P = 0.012). A positive correlation between the number of embryos transferred and the marker levels was observed in the IVF group. No correlation was found between the amount of gonadotrophin medication used and the marker levels. CONCLUSIONS: The present data confirm that the overall FPR in the serum screening for Down's syndrome in assisted reproduction pregnancies is high, resulting in unnecessary invasive procedures.

Adult↗
PubMed2001

Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.

BACKGROUND: Reversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in western societies. In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life. Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora. We assessed the effect on atopic disease of Lactobacillus GG (which is safe at an early age and effective in treatment of allergic inflammation and food allergy). METHODS: In a double-blind, randomised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for 6 months to their infants. Chronic recurring atopic eczema, which is the main sign of atopic disease in the first years of life, was the primary endpoint. FINDINGS: Atopic eczema was diagnosed in 46 of 132 (35%) children aged 2 years. Asthma was diagnosed in six of these children and allergic rhinitis in one. The frequency of atopic eczema in the probiotic group was half that of the placebo group (15/64 [23%] vs 31/68 [46%]; relative risk 0.51 [95% CI 0.32-0.84]). The number needed to treat was 4.5 (95% CI 2.6-15.6). INTERPRETATIONS: Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. Thus, gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics, for prevention of atopic disease.

Child, Preschool↗
PubMed2001

Cytological monitoring of peripheral blood, bronchoalveolar lavage fluid, and transbronchial biopsy specimens during acute rejection and cytomegalovirus infection in lung and heart--lung allograft recipients.

STUDY OBJECTIVES: Acute rejection and cytomegalovirus (CMV) infection are important complications after lung and heart--lung transplantation. We sought to investigate whether acute rejection and CMV infection demonstrated as CMV antigenemia had an effect on the cell profiles of peripheral blood (PB), bronchoalveolar lavage fluid (BAL-F), or TBB histology. PATIENTS AND DESIGN: In this prospective study, composition of cells in PB, BAL-F, and TBB samples from 20 lung or heart-lung transplantation patients were analyzed during episodes of acute rejection or CMV antigenemia. Rejection was graded according to the International Society for Heart and Lung Transplantation criteria. As controls, samples with no evidence of rejection or infection were used. To evaluate the effect of time on cellular findings, samples were divided into three groups according to time after transplantation: 1--30, 31--180, and more than 180 d after transplantation. RESULTS: Acute rejection was associated with mild blood basophilia (p<0.05; specificity 94%, sensitivity 42%). In BAL-F during rejection, the number of basophils (p<0.05), eosinophils (p<0.05), and lymphocytes (p<0.05; specificity 77%, sensitivity 64%) was increased compared to controls during the post-operative month 1. Later-occurring rejections were associated with increased amounts of neutrophils in BAL-F (p<0.05; specificity 82%, sensitivity 74%). In TBB histology, acute rejections were associated with perivascular and/or peribronchial infiltration of lymphocytes (p<0.001) and plasma cells (p<0.05) compared to controls. In our patients receiving gancyclovir prophylaxis, CMV antigenemia did not significantly alter the cell profiles in PB and BAL-F nor the inflammatory cell picture in TBB histology. CONCLUSION: TBB histology remains the 'gold standard' for diagnosing rejection in lung and heart-lung transplantation patients, as the inflammatory cell findings in TBB specimens are highly specific for rejection. The cellular changes associated with rejection, mild PB basophilia and increased proportions of lymphocytes in early- and neutrophils in later-occurring rejection, observed in BAL-F cannot be considered specific for rejection, but may warrant clinical suspicion of rejection.

Acute Disease↗
PubMed2000

Angiotensin I-converting enzyme inhibitory properties of whey protein digests: concentration and characterization of active peptides.

The aim of this study was to identify whey-derived peptides with angiotensin I-converting enzyme (ACE) inhibitory activity. The bovine whey proteins alpha-lactalbumin and beta-lactoglobulin were hydrolysed with pepsin, trypsin, chymotrypsin, pancreatin, elastase or carboxypeptidase alone and in combination. The total hydrolysates were fractionated in a two step ultrafiltration process, first with a 30 kDa membrane and then with a 1 kDa membrane. Inhibition of ACE was analysed spectrophotometrically. The peptides were isolated by chromatography and identified by mass and sequencing analysis. The most potent inhibitory peptides were synthesized by the 9-fluorenylmethoxycarbonyl solid phase method. Inhibition of ACE was observed after hydrolysis with trypsin alone, and with an enzyme combination containing pepsin, trypsin and chymotrypsin. Whey protein digests gave a 50% inhibition (IC50) of ACE activity at concentration ranges within 345-1733 micrograms/ml. The IC50 values for the 1-30 kDa fractions ranged from 485 to 1134 micrograms/ml and for the < 1 kDa fraction from 109 to 837 mg/ml. Several ACE-inhibitory peptides were isolated from the hydrolysates by reversed-phase chromatography, and the potencies of the purified peptide fractions had IC50 values of 77-1062 microM. The ACE-inhibitory peptides identified were alpha-lactalbumin fractions (50-52), (99-108) and (104-108) and beta-lactoglobulin fractions (22-25), (32-40), (81-83), (94-100), (106-111) and (142-146).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Interferon-alpha treatment decreases serum cross-linked C-terminal telopeptide of type I collagen in haematological diseases.

Interferon-alpha (IFN-alpha) is used in the treatment of many haematological diseases and it is known that IFN-alpha may affect bone turnover. The effect of IFN-alpha on bone metabolism was studied in 10 haematological patients. The mean duration of the treatment was 4 (range: 2.8-7.2) months. Besides the usual markers of bone metabolism, levels of the cross-linked C-terminal telopeptide of type I collagen (ICTP), the N-terminal propeptide of type I procollagen (PINP) and the bone-specific alkaline phosphatase were measured. The bone mineral density was measured by computed tomography. During IFN-alpha treatment, serum ICTP decreased from a mean of 5.4 (range: 1.8-12.4) to 3.6 (range: 1.4-8.8) microg/l (P = 0.017). All other variables reflecting bone metabolism remained unaltered during IFN-alpha treatment. The bone mineral density remained unchanged. It was concluded that the observed decrease in ICTP may be an indicator of a beneficial therapeutic effect of IFN-alpha on bone turnover, resulting in decreased bone resorption. However, it is possible that elevated pretreatment ICTP values reflected disease of the bone marrow.

Adult↗
PubMed2000

Insulin-induced increment of coronary flow reserve is not abolished by dexamethasone in healthy young men.

Hyperinsulinemia is a risk factor for coronary artery disease. Previous studies have reported that hyperinsulinemia increases cardiac and skeletal muscle sympathetic nerve activity and skeletal muscle blood flow in normal subjects. However, little is known about insulin's effects on myocardial blood flow in humans. The purpose of this study was to investigate whether physiological hyperinsulinemia affects myocardial blood flow and flow reserve in healthy subjects. Additionally, the role of the sympathetic nervous system in regulating insulin's effects on coronary perfusion was tested. We used positron emission tomography and oxygen-15-labeled water to measure myocardial blood flow and coronary flow reserve in 16 healthy nonobese men (age, 34 +/- 4 yr; maximal aerobic capacity, 32 +/- 3 mL x g(-1) x min(-1); blood pressure, 118 +/- 10/65 +/- 8 mm Hg) at fasting and during euglycemic hyperinsulinemic clamp (1 mU x kg(-1) x min(-1) for 80 min). To study the role of the sympathetic nervous system, each subject was studied twice: once after administration of dexamethasone (dexa+) for 2 days (2 mg per day) and once without previous medication (dexa-). All studied subjects had normal left ventricular mass, function, and findings in stress echocardiography. Resting myocardial blood flow was 0.76 +/- 0.19 mL x g(-1) x min(-1), and a significant increase in flow was detected after adenosine infusion (140 microg/kg x min for 5 min i.v.), both in the basal fasting state (P < 0.001) and during hyperinsulinemia (P < 0.001). However, the flow response to adenosine was significantly higher during hyperinsulinemia, thus leading to a higher hyperemic flow (3.38 +/- 0.97 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), basal vs. hyperinsulinemic, P < 0.01) and higher coronary flow reserve (4.6 +/- 1.2 vs. 5.8 +/- 1.9, respectively, P < 0.05). Pretreatment with dexamethasone did not significantly change the resting blood flow [0.72 +/- 0.22 vs. 0.76 +/- 0.19 mL x g(-1) x min(-1), dexa+ vs. dexa-, not significant (NS)], the adenosine stimulated flow (3.56 +/- 1.49 vs. 3.38 +/- 0.97 mL x g(-1) x min(-1), respectively, NS), or the hyperinsulinemic adenosine-stimulated blood flow (4.68 +/- 1.74 vs. 4.28 +/- 1.57 mL x g(-1) x min(-1), respectively, NS). Coronary flow reserves in the basal state (5.3 +/- 2.7 vs. 4.6 +/- 1.2 mL x g(-1) x min(-1), dexa+ vs. dexa-, NS) and during hyperinsulinemia (6.8 +/- 2.9 vs. 5.8 +/- 1.9 mL x g(-1) x min(-1), respectively, NS) tended to be (but were not) significantly higher after dexamethasone treatment. These results demonstrate that insulin acts as a vasodilatory hormone also in the coronary vasculature. Because the insulin-induced increment of myocardial flow reserve remained unchanged by dexamethasone pretreatment, centrally mediated sympathetic activation seems not to play a major role in regulating insulin action on myocardial perfusion in healthy subjects.

Adenosine↗
PubMed2000

Hypothyroidism among infertile women in Finland.

The main aim of this retrospective study was to evaluate the occurrence of hypothyroidism among Finnish women with infertility. For this purpose, the records of 335 women presenting for the first time with infertility at the outpatient clinic of reproductive endocrinology at Turku University Central Hospital during a 3-year period (January 1992 to December 1994) were reviewed. Due to missing data, 36 women were excluded from the analysis. Thyroid function was screened by measuring serum thyroid stimulating hormone (TSH) levels in conjunction with serum prolactin using immunoradiometric assays. Prior to enrolment in the infertility examinations, ten out of 299 women had used thyroxine substitution for primary hypothyroidism. In the TSH screening test, 12 women (4%) exhibited elevated serum TSH levels ranging from 5.7 to 32 mU/l. Three of these cases were previously diagnosed with hypothyroidism and were using an inadequate dose of thyroxine. The prevalence of abnormal TSH levels was highest in the ovulatory dysfunction (6.3%) and unknown infertility (4.8%) groups and lowest in the tubal infertility (2.6%) and male infertility (1.5%) groups, although no statistically significant differences between the groups were observed. Oligo/amenorrhea was present in 101 (34%) women in the whole study population and in eight (67%, p < 0.5) women with elevated serum TSH at screening. The relatively high occurrence of abnormal TSH levels in infertile women with ovulatory dysfunctions or unknown infertility, as well as with oligo/amenorrhea, emphasizes the importance of TSH screening in these patient groups.

Adult↗
PubMed2000

Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies.

We aimed to compare the levels of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (beta-hCG) levels as multiples of the median (MoM) values between spontaneous and in vitro fertilized (IVF) twin pregnancies. The control group of spontaneous singleton pregnancies was used for calculating the gestational age specific median levels of the values. Within a cohort of 19 310 pregnancies, 145 twin pregnancies were identified. The data were collected from Down syndrome (DS) screening programmes in four University catchment areas in Finland between 1994-98. Maternal midtrimester serum marker levels were measured across gestational weeks 14-18. There were no fetal chromosome anomalies in either of the twin groups or the singleton group. Serum AFP of 145 and beta-hCG values of 39 spontaneous twin pregnancies were compared to the values of 6548 singleton pregnancies. In IVF twins 30 AFP and 29 beta-hCG values were compared to the levels of the control group. Both AFP and beta-hCG values were twice as high in the spontaneous twin pregnancies (medians 2.18 and 1.83 MoM respectively) as in the singleton group (medians 1.00 and 1.00 MoM respectively). In IVF twin pregnancies beta-hCG levels were higher (median 2.20 MoM) than in spontaneous twins (p=0.08), whereas no significant difference was found in AFP levels (2.30 MoM). In conclusion, the higher levels of beta-hCG levels in IVF twin pregnancies should be considered in DS screening to avoid high false positive rates.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed1999

Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.

BACKGROUND: Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. METHODS AND RESULTS: The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells. CONCLUSIONS: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.

Animals↗
PubMed1999

Prediction of pre-eclampsia with maternal mid-trimester total renin, inhibin A, AFP and free beta-hCG levels.

We wanted to study if maternal serum mid-trimester total renin, inhibin A, AFP or free beta-hCG levels predict the development of pre-eclampsia. Maternal serum alpha-fetoprotein (AFP) and human chorion gonadotrophin (beta-hCG) were evaluated in the screening programme for Down syndrome in 4356 patients prospectively. Data on pregnancy outcome were available in 1242 women. Pregnancy-induced hypertension (PIH) developed in 69 women, 282 women with uneventful pregnancy outcome were selected for controls. Serum total renin and inhibin A levels were measured retrospectively in the trisomy screening samples of 69 and 30 patients who later developed PIH, and in 282 and 7 patients, respectively, who had an uneventful pregnancy outcome. No significant differences were found in the levels of maternal mid-trimester serum total renin, inhibin A or free beta-hCG levels between PIH and healthy women. The multiples of the median (MoM) of AFP values were significantly higher in the subgroup of patients who later developed severe pre-eclampsia than in patients with mild pre-eclampsia or gestational hypertension and healthy pregnant women. Maternal mid-trimester serum levels of total renin, inhibin A and free beta-hCG are not predictive for development of PIH. High mid-trimester serum AFP values may help in the prediction of severe pre-eclampsia.

Adult↗
PubMed1999

Obesity regulates bioavailable testosterone levels in women with or without polycystic ovary syndrome.

OBJECTIVE: To evaluate [1] the effects of levels of sex hormone-binding globulin (SHBG), albumin, and total testosterone on the distribution of testosterone between SHBG-bound and non-SHBG-bound fractions; [2] the independent effects of polycystic ovary syndrome (PCOS) and body mass index on serum levels of total testosterone, non-SHBG-bound testosterone, SHBG, and albumin; and [3] the usefulness of levels of total testosterone and non-SHBG-bound testosterone and of the free androgen index in the diagnosis of PCOS. DESIGN: Retrospective clinical study. SETTING: An academic research environment. PATIENT(S): Forty-three women with oligomenorrhea and PCOS. Twenty-five women with regular menstrual cycles and without hirsutism served as controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Levels of non-SHBG-bound testosterone, total testosterone, SHBG, and albumin in serum. RESULT(S): Levels of total testosterone and non-SHBG-bound testosterone, and the free androgen index were higher in patients with PCOS than in healthy controls. PCOS did not have an effect on the levels of SHBG or albumin, or on the percentage of non-SHBG-bound testosterone. Levels of SHBG and albumin were inversely related to body mass index. The percentage and concentration of non-SHBG-bound testosterone and the free androgen index were directly related to body mass index. Hirsutism did not have an effect on any outcome measure. CONCLUSION(S): The distribution of total testosterone into SHBG-bound and non-SHBG-bound fractions is associated with body mass index, not with PCOS. The high levels of non-SHBG-bound testosterone and the high free androgen index in patients with PCOS reflect mainly high levels of total testosterone. Thus, the measurement of levels of non-SHBG-bound testosterone and the calculation of the free androgen index provide no further information in the diagnosis of PCOS beyond that provided by the measurement of levels of total testosterone.

Adult↗