Biomedical subjects

G Caffarri

Publications and source records attributed to G Caffarri.

At least 37 records · Page 2Linked to original sources

PubMed1996

Age-dependent decrease in the growth hormone response to growth hormone-releasing hormone in normally cycling women.

OBJECTIVE: To establish possible changes in GH secretion in normally cycling women with increasing age. DESIGN: Controlled clinical study. PATIENTS: Nine younger (18 to 33 years) and nine older (41 to 46 years) healthy women. SETTING: Tests were performed on the 22d day of regular cycles. INTERVENTION: All subjects were tested with GH-releasing hormone (GH-RH) (1 mg/kg body weight), the acetylcholinesterase inhibitor pyridostigmine (120 mg by mouth), the somatostatin inhibitor arginine (30 g infused IV over a 30-minute period) alone, and the combination of GH-RH plus arginine or GH-RH plus pyridostigmine. MAIN OUTCOME MEASURES: Glucose, cortisol, androgens, estrogens, thyroid hormones, and insulin growth-like factor (IGF-I) were measured in basal samples. Serum GH levels were measured in samples taken before and over a 2-hour period after drug administration. RESULTS: All basal hormonal values were similar in younger and older women. Insulin growth like factor-I levels were lower in older women. The GH responses to GH-RH alone, pyridostigmine alone, or the combination were lower in the older than in the younger group and were correlated negatively with age. In contrast, either arginine alone or GH-RH plus arginine produced similar GH responses in the two groups. CONCLUSION: These data indicate that the cholinergic stimulatory regulation of GH release is reduced in the older cycling women. Because acetylcholine inhibits hypothalamic somatostatin release, the reduced cholinergic tone in other subjects may result in an increased somatostatinergic tone. Normalization in older women of the reduced GH response to GH-RH by arginine supports this hypothesis.

Adolescent↗

PubMed1996

Influence of nitric oxide on hypoglycemia--or angiotensin II-stimulated ACTH and GH secretion in normal men.

In order to establish whether nitric oxide (NO) is involved in the regulation of ACTH and/or GH secretion, normal male subjects were treated i.v. with the NO-synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (40 micrograms/kg injected plus 50 micrograms/kg infused over 60 min) in basal conditions and/or during stimulation with insulin (0.15 IU/kg body weight in an i.v. bolus) to induce hypoglycemia (ITT) or ASP 1 ILE-5 angiotensin II (ANG II) (increasing doses of 4, 8 and 16 ng/kg/min, each dose for 20 min). The administration of L-NAME neither changed the basal secretion of ACTH and GH nor modified the hormonal responses to ANG II stimulation. Also the GH response during ITT remained unchanged in the presence of L-NAME. In contrast, the ACTH response to hypoglycemia was significantly higher when L-NAME was administered. These data suggest that in normal men NO has a negative effect on ACTH secretion, but not GH secretion, in response to hypoglycemia. Furthermore, our results argue against a role of NO in the control of basal and ANG II-stimulated ACTH and GH secretions.

Adrenocorticotropic Hormone↗

PubMed1996

Different effects of the serotonergic agonists buspirone and sumatriptan on the posterior pituitary hormonal responses to hypoglycemia in humans.

The responses of serum oxytocin (OT) and vasopressin (AVP) to the serotonergic HT1A agonist buspirone (15 mg p.o.) or the HTD1 agonist sumatriptan (6 mg injected subcutaneously) were evaluated in 7 normal men either in basal conditions or during an insulin (0.15 iu/kg as an i.v. bolus) tolerance test (ITT). Neither buspirone nor sumatriptan administration modified the basal secretion of AVP and OT. Stimulation of 5HT-1D receptors with sumatriptan was unable to change neither AVP nor OT response to insulin-induced hypoglycemia. On the other hand, the pretreatment with the 5HT1A agonist buspirone significantly enhanced the OT response during hypoglycemia, without modifying the AVP rise. The results of this study suggest that serotonergic 5HT1A receptors may interact with hypoglycemia in the stimulation of OT, but not AVP secretion.

Adult↗

PubMed1996

Effects of intravenously infused pituitary adenylate cyclase-activating polypeptide on adenohypophyseal Hormone secretion in normal men.

The possible stimulatory effects of an intravenous infusion of increasing amounts of pituitary adenylate cyclase-activating polypeptide (PACAP) on anterior pituitary hormone secretions were evaluated in humans. Successively increasing doses of PACAP-38 (2, 4 and 8 pmol.kg-1.min-1; each dose for 20 min) were infused i.v. in 7 normal male subjects. On a different occasion, the same subjects were tested with vasoactive intestinal peptide (VIP; 4 pmol.kg-1.min-1 for 60 min). Circulating GH, ACTH, PRL, TSH and gonadotropin concentrations were measured before PACAP infusion and every 20 min, just before increasing the infusion dose of PACAP. Blood samples were taken before and every 15 min after the beginning of VIP administration. Serum levels of GH, TSH and gonadotropins did not change during PACAP or VIP infusion. Circulating ACTH and PRL concentrations were not modified by the infusion of the lowest dose of PACAP, whereas they were significantly increased in a dose-response fashion when higher amounts of PACAP were given. PRL, but not ACTH levels were significantly increased by VIP infusion. These data show for the first time in humans that ACTH and PRL secretions from the anterior pituitary gland are stimulated by the systemic administration of PACAP. In addition, since VIP stimulated only PRL secretion, PACAP-induced ACTH release appears to be mediated by specific receptors.

Adult↗

PubMed1996

Inhibition by somatostatin of the growth hormone, but not corticotropin response to angiotensin II in normal men.

The effect of an i.v. infusion of somatostatin (SRIH) (4.1 micrograms/min/180 min) on angiotensin II (ANG II infusion for 60 min of successively increasing doses of 4, 8 and 16 ng/kg/min; each dose for 20 min)-stimulated growth hormone (GH) and corticotropin (ACTH) release was studied in 7 normal men. In addition, 7 additional normal subjects were tested with ANG II alone (as described above), GH-RH (0.1 microgram/kg body weight as an i.v. bolus) alone or the combination of GH-RH and ANG II. The ACTH response to ANG II was not modified by SRIH infusion; in contrast, the GH response to ANG II was significantly reduced by the concomitant treatment with SRIH. On the other hand, the administration of GH-RH together with ANG II produced peak GH levels comparable to the sum of the individual responses to ANG II and GH-RH, given alone. These findings provide evidence that the stimulatory effect of ANG II on GH, but not ACTH secretion, is under the inhibitory control of somatostatin, suggesting an interaction between ANG II and SRIH in regulation of GH secretion.

Adrenocorticotropic Hormone↗

PubMed1995

Influence of age on the GH response to sumatriptan administration in man.

The present study was undertaken in order to assess the influence of aging on the serotonergic control of GH secretion in humans. For this purpose, 6 mg 5-HT1D-serotonergic receptor agonist sumatriptan (or placebo during control tests) was injected subcutaneously in a group of 9 young (26-40 yr old) and a group of 9 elderly male subjects (64-80 yr old). Sumatriptan-induced plasma GH rise was recorded during the next 2 hours. Plasma ACTH levels were also measured. The administration of the placebo was without effects in all subjects. Sumatriptan induced a striking increase in plasma GH levels in the younger group, whereas it slightly increased GH secretion in the older group (f = 9.59, p < 0.02). Plasma ACTH levels showed a similar physiological decline in all subjects during tests, regardless of sumatriptan treatment. These data show impaired serotonergic stimulatory regulation of GH secretion in elderly subjects.

Adrenocorticotropic Hormone↗

PubMed1995

Effect of substance P on basal and thyrotropin-releasing hormone-stimulated thyrotropin release in humans.

To test the possible effects of intravenous administration of substance P (SP) on basal and thyrotropin-releasing hormone (TRH)-stimulated thyrotropin (TSH) release, SP was infused alone (0.5 or 1.5 pmol/kg-1/min-1 for 60 minutes) or after TRH (20 or 400 micrograms in an intravenous bolus) in 21 normal male subjects (aged 26 to 36 years) and in 18 normal women (aged 25 to 32 years). Women were studied during follicular (day 6 to 8) and luteal (day 21 to 23) phases of following regular menstrual cycles. In addition, plasma cortisol levels during SP infusion were measured. In agreement with previous findings, significant increments in plasma cortisol levels were observed in men and women when the higher (1.5 pmol/kg-1/min-1) but not the lower (0.5 pmol/kg-1/min-1) amount of SP was administered. In contrast, in both men and women basal and TRH (20 or 400 mg)-induced TSH releases were not modified by SP at any tested amount. Results in the follicular and luteal phase were similar. These data suggest that in normal men and women plasma SP is not involved in the control of TSH release, at least not outside the blood-brain barrier.

Adult↗

PubMed1995

Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy.

The function of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated in insulin-dependent diabetics without (group I, n = 10) or with (group II, n = 10) established symptomatic neuropathy and in age- and weight-matched normal controls (n = 11). Since the corticotropin (ACTH)/cortisol response to the minimal-effective dose of corticotropin-releasing hormone ([CRH] 0.03 microgram/kg body weight) represents a useful tool for HPA axis examination, all subjects were tested with the low-dose ovine CRH stimulation test. Experiments started at 8:30 AM, when CRH was injected after two basal blood samples were withdrawn, and lasted 2 hours. Basal serum levels of ACTH were similar in the three groups. Administration of CRH induced a small but significant increase in ACTH levels in all subjects; however, the CRH-induced ACTH increase was significantly higher in normal controls than in diabetic groups I and II. Furthermore, a significantly lower ACTH response was observed in group II than in group I. In contrast, basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal controls. Comparisons between diabetic groups showed that both basal and stimulated cortisol secretion was significantly higher in group II than in group I. When peak ACTH responses to CRH and basal cortisol levels were combined, a significant negative correlation was found (r = .545, P < .02). These data show that even uncomplicated diabetes mellitus is associated with adrenal hyperfunction. Such an alteration is more pronounced in the presence of neuropathy.

Adrenocorticotropic Hormone↗

PubMed1995

Mediation by nitric oxide of LH-RH-stimulated gonadotropin secretions in human subjects.

In order to establish whether nitric-oxide (NO) participates in the regulation of gonadotropin secretion in humans, seven normal men were treated with a placebo (normal saline) or the NO synthase inhibitor L-NAME, given at doses (40 micrograms/kg injected plus 50 micrograms/kg infused i.v.) previously found to be unable to change blood pressure. Experiments were carried out either in basal conditions or during stimulation of gonadotropin secretion with an intravenous injection of 100 micrograms LH-RH. The administration of L-NAME was unable to change the basal secretion of FSH and LH. In contrast, L-NAME significantly reduced both FSH and LH increments induced by LH-RH. These data fail to provide evidence of NO involvement in regulation of basal gonadotropin secretion. In contrast, the inhibitory effect of L-NAME on LH-RH-induced LH and FSH secretion suggests the modulation by NO of the gonadotropin releasing action of LH-RH.

Adult↗

PubMed1995

Dopaminergic and cholinergic control of arginine-vasopressin secretion in type I diabetic men.

Enhanced cholinergic and dopaminergic controls of anterior pituitary function have been described in insulin-dependent diabetes mellitus (IDDM). In order to verify whether similar neurotransmitter alterations also affect the regulation of posterior pituitary hormone secretion, the arginine-vasopressin (AVP) responses to the dopaminergic agonist apomorphine and in a different occasion to physostigmine, an acetylcholinesterase inhibitor, were evaluated in normal (n = 10) and type I diabetics (n = 16). In addition, a control test with normal saline was performed in all subjects. None of the diabetic patients were affected by neuropathy or other diabetic complications. They were divided into two groups according to the duration of their disease (less than 10 years: group 1, n = 8; more than 10 years: group 2, n = 8). Physostigmine (12.5 micrograms kg-1) was infused intravenously over 10 min; apomorphine (60 micrograms kg-1) was injected subcutaneously. Basal AVP concentrations were similar in all groups and remained constant during the control test. In contrast, both drugs induced significant increments in plasma AVP levels in the normal controls and diabetic subjects. However, physostigmine- and apomorphine-induced AVP increments were twofold higher in diabetics than in control subjects. No significant differences were observed between diabetics of groups 1 and 2. No significant correlations between duration of diabetes and peak AVP responses to physostigmine or apomorphine were found within each group or when all diabetic subjects were considered together. These data indicate enhancement of both dopaminergic and cholinergic stimulatory regulations of AVP secretion in patients with uncomplicated IDDM, regardless of the duration of diabetes.

Acetylcholine↗

PubMed1995

Influence of residual C-peptide secretion on the arginine vasopressin response to hypoglycaemia and metoclopramide in insulin-dependent diabetes.

Arginine vasopressin (AVP) hypersecretion in response to metoclopramide or to insulin-induced hypoglycaemia has been described in type I diabetes mellitus. In the present study, we examined whether residual endogenous insulin secretion may play a role in the control of this abnormal AVP secretory pattern. For this purpose, 21 insulin-dependent diabetic men and 10 age- and weight-matched normal men were tested with MCP (20 mg in an i.v. bolus). On a different occasion, subjects were tested with insulin (0.15 IU kg-1). The diabetic patients were subdivided into C-peptide negative patients (CpN, 11 patients without detectable endogenous pancreatic beta cell activity) (group I) and C-peptide positive patients (CpP, 10 patients with residual endogenous insulin secretion) (group II). Experiments started after optimization of the metabolic status of the diabetic men by 3 days of treatment with continuous subcutaneous insulin infusion. The basal concentrations of AVP were similar in all groups. The administration of MCP induced a striking elevation in plasma AVP levels in the normal controls and in the diabetic subjects of groups I and II. However, the AVP rise was significantly higher in group I and group II than in normal controls. Furthermore, group I diabetics showed higher AVP increments than group II. Insulin induced a similar hypoglycaemic nadir in all subjects at 30 min, even though the diabetic subjects of groups I and II had a delayed recovery in blood glucose levels. The hypoglycaemic pattern was similar in group I and II. Hypoglycaemia induced a striking AVP increase in the normal controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1994

Lack of seasonal variation in abnormal TSH secretion in patients with seasonal affective disorder.

The circadian variations in thyroid-stimulating hormone (TSH) secretion, with particular attention to the nocturnal serum TSH surge and the TSH response to thyrotropin releasing hormone (TRH), were measured in seven patients with seasonal affective disorder (SAD) and in eight normal controls. Both patients with SAD and normal controls were tested in fall/winter, when patients were suffering depressive symptoms, and in spring/summer, when patients were euthymic. The TRH tests were performed in the morning. In all tests, the mean peak TSH response to TRH was significantly lower in the patients with SAD than in the normal controls. No significant differences were observed in either group between spring/summer and fall/winter tests. At both periods, patients with SAD showed normal TSH levels in the morning, but did not experience a nocturnal TSH surge. In this group, morning and night TSH levels were similar. In contrast, normal controls showed significantly higher TSH levels at night than in the morning. Serum-free thyroid hormone levels were in the normal range in all subjects. Morning and night serum cortisol levels and 24-hour urinary cortisol concentrations were similar in all subjects. These data show that the secretion of TSH is impaired in SAD, regardless of the phase of the psychiatric disease. The low TSH response to TRH in the presence of normal serum thyroid hormone levels and the lack of the TSH nocturnal surge suggest that patients with SAD might be affected by mild central hypothyroidism.

Adult↗

PubMed1994

Endogenous opioid mediation of the inhibitory effect of ethanol on the prolactin response to breast stimulation in normal women.

The effect of ethanol on the prolactin (PRL) response to breast stimulation was tested in normal women. The possible role of endogenous opioids in the control of the PRL response to breast stimulation and ethanol action was also examined. Eleven normal women were tested four times on the 22nd day of four consecutive regular menstrual cycles. All women underwent mechanical breast stimulation (for 10 min) with the concomitant administration of normal saline, naloxone (2 mg in an iv bolus plus 10 mg over 75 min. or 4 mg in an iv bolus plus 20 mg over 75 min.), ethanol (50 ml in 110 ml of whiskey p.o.) or the combination of ethanol and naloxone. Serum PRL levels rose significantly after breast stimulation, with a mean peak response (71.4% higher than baseline at 20 min). The PRL response to breast stimulation was not changed by the treatment with the lower (2 plus 10 mg) or the higher (4 plus 20 mg) dose of naloxone, whereas it was strikingly decreased by ethanol (mean peak was 25% higher than baseline). However, when ethanol was given together with naloxone, the peak rise induced by breast stimulation was only partially inhibited by ethanol (the mean PRL peak was 46.2% higher than baseline). At both doses naloxone produced similar effects. These data demonstrate that ethanol inhibits the PRL response to breast stimulation. Naloxone-sensitive endogenous opioids do not appear to be involved in the control of the PRL rise induced by breast stimulation. In contrast, since naloxone partially reversed the inhibiting effects of ethanol, a partial involvement of opioid peptides in ethanol action is supposed.

Adult↗

PubMed1994

Influence of thyroid status on the paradoxical growth hormone response to thyrotropin-releasing hormone in human obesity.

Thyrotropin-releasing hormone (TRH) tests were performed in 38 age- and weight-matched obese but otherwise healthy men. In all subjects, total thyroxine (T4) and triiodothyronine (T3) concentrations were in the normal range. According to basal and TRH-stimulated serum thyrotropin (TSH) levels, subjects were divided into the following three groups: group I (n = 14), euthyroid subjects; group II (n = 11), euthyroid subjects with normal basal but abnormally elevated TSH responses to TRH; group III (n = 13), subjects with elevated basal and TRH-induced TSH levels (subclinical hypothyroidism). Basal TSH levels were 1.8 +/- 0.4 mU/L in group I, 1.7 +/- 0.3 in group II, and 6.0 +/- 0.7 in group III. In both groups II and III, TRH-induced TSH increments were above the normal range (maximal increment > 14 mU/L) and were significantly higher than in group I. The definition of euthyroidism for groups I and II and of subclinical hypothyroidism for group III according to the basal levels of TSH was confirmed by clinical (Billewicz index), hormonal (serum free-T4 levels), and metabolic (serum apoprotein [apo] AI levels) parameters. Basal concentrations of growth hormone (GH) were similar in all groups. When GH levels after TRH stimulation were measured, significant increments (peak minus baseline > 5 micrograms/L) were observed in nine of 13 hypothyroid obese men. The overall mean peak GH increase in group III was 4.5 times higher than baseline and was observed at 45 minutes. None of the euthyroid obese subjects of groups I and II showed any significant change in GH levels in response to TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth Hormone↗

PubMed1994

Different effects of delta-sleep-inducing peptide on arginine-vasopressin and ACTH secretion in normal men.

UNLABELLED: Delta-sleep-inducing peptide (DSIP) is a well-known inhibitor of pituitary ACTH secretion. In order to evaluate the possible influence of DSIP on basal arginine-vasopressin (AVP) secretion and/or on the AVP-response to osmotic and pressure/volumetric stimuli, DSIP (25 nmol/kg) was infused in 10 min to 8 normal men (23-34 years old) just before a 2-hour infusion of normal saline (NaCl 0.9%; DSIP test) or hypertonic saline (0.51 M NaCl; osmotic test) or before an orthostatic test (standing upright and maintaining an orthostatic position for 20 min). In different occasions, a 10-min infusion of normal saline (placebo) was given instead of DSIP. In an additional 7 subjects, DSIP or placebo was given 60 min before hypertonic saline or the orthostatic test. The results obtained after the administration of DSIP at time 0 and at -60 min were similar. RESULTS: The administration of DSIP or normal saline alone did not change the concentrations of circulating AVP. A slight physiological decline in ACTH levels was observed during saline infusion, whereas a significant decrease in ACTH levels was induced by DSIP administration. Osmotic stimulation of AVP secretion by hypertonic NaCl induced a significant increase in plasma AVP concentrations which was not modified by DSIP administration. The ACTH secretory patterns during hypertonic NaCl and hypertonic NaCl plus DSIP were similar to those observed during normal saline and normal saline plus DSIP, respectively. The orthostatic test provided similar plasma AVP increments, regardless of the previous treatment with DSIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1994

Opioid modulation of the gamma-aminobutyric acid-controlled inhibition of exercise-stimulated growth hormone and prolactin secretion in normal men.

The possible involvement of endogenous opioids in the gamma-aminobutyric acid-controlled (GABAergic) inhibition of growth hormone (GH) and prolactin (PRL) during physical exercise was evaluated in normal men. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3-min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an iv bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. During exercise, plasma GH and PRL levels rose 5.5- and 1.9-fold, respectively. The administration of naloxone did not modify, whereas sodium valproate significantly reduced the plasma GH and PRL rise during exercise. In the presence of sodium valproate, GH and PRL levels rose 3- and 1.5-fold, respectively, in response to exercise. When naloxone was given together with sodium valproate, both GH and PRL responses to exercise were abolished completely. These data suggest the involvement of a GABAergic mechanism in the regulation of GH and PRL responses to physical exercise in men. Furthermore, the data argue against a role of naloxone-sensitive endogenous opioids in the control of these hormonal responses to exercise, whereas they suggest a modulation by opioids of the GABAergic inhibitory action.

Adult↗

PubMed1993

Role of GABA and opioids in the regulation of the vasopressin response to physical exercise in normal men.

The present study was undertaken in order to establish the possible involvement of GABAergic and/or opioid pathways in the mechanism underlying the arginine-vasopressin (AVP) response to physical exercise. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3 min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an i.v. bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. Plasma AVP levels rose 4-fold during exercise. The administration of naloxone did not modify, whereas sodium valproate completely abolished the plasma AVP rise during exercise. When naloxone was given together with sodium valproate, AVP rose 3-fold in response to exercise. These data suggest the involvement of a GABAergic mechanism in regulation of the AVP response to physical exercise in men. Furthermore, the data argue against a role of naloxone sensitive endogenous opioids in the control of AVP during exercise, whereas they suggest a partial opioid mediation of the GABAergic inhibitory action.

Adult↗

PubMed1993

Gamma-aminobutyric acid mediation of the inhibitory effect of endogenous opioids on the arginine vasopressin and oxytocin responses to nicotine from cigarette smoking.

Previous studies have demonstrated that naloxone exerts positive effects on the responsiveness of arginine vasopressin (AVP) and oxytocin (OT) to nicotine, suggesting inhibitory actions of endogenous opioids. The present study was designed to determine whether a gamma-aminobutyric acid (GABA)ergic pathway is involved in the regulation of naloxone-sensitive endogenous opioid action. AVP and OT secretory patterns after (two nonfilter) cigarette smoking were examined in seven normal male subjects with (experimental test) and without (control test) concomitant treatment with naloxone (4 mg in an intravenous bolus plus 6 mg infused over 2 hours), the GABAergic agent sodium valproate (600 mg in three divided doses orally), or the combination of naloxone and sodium valproate. Cigarette smoking increased by 2.4-fold (peak v baseline) the plasma concentrations of AVP without modifying OT levels. In the presence of naloxone, plasma AVP and OT levels in response to nicotine were significantly higher than those in the control test. In the naloxone plus nicotine test, AVP levels increased 4.2-fold (peak v baseline) and OT concentrations increased 1.6-fold (peak v baseline). Pretreatment with sodium valproate changed neither AVP nor OT secretory patterns during the cigarette-smoking test. In contrast, sodium valproate abolished the facilitating effect of naloxone on both AVP and OT responses to nicotine. In the sodium valproate plus naloxone plus nicotine test, plasma AVP and OT levels were not significantly higher than those obtained during the nicotine test. These data indicate a GABAergic mediation of the inhibitory modulation by endogenous opioids of the AVP and OT responses to nicotine.

Adult↗