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PubMed1999

Calcium metabolism in adolescents and young adults with type 1 diabetes mellitus without and with persistent microalbuminuria.

Alterations in calcium metabolism can be demonstrated in the course of insulin-dependent diabetes mellitus. In order to clarify if the presence of persistent microalbuminuria (MA) can affect the main parameters of calcium metabolism, we studied 22 diabetic adolescents and young adults with persistent MA and compared them with 24 patients without MA and 24 healthy controls. Mean values of serum calcium, phosphorus and magnesium were similar in diabetic children and young adults without persistent MA and in controls. In addition, the mean values of PTH and 25-OHD, 1,25 (OH)2D3 and OC did not differ between these diabetics and controls. Diabetics with persistent MA showed no significant difference from the values of either controls or the group of diabetics without persistent MA for the mean values of serum calcium, phosphorus and magnesium and PTH. In contrast, diabetics with persistent MA had significantly (p<0.01) lower 25-OHD (26.5+/-5.2 ng/ml) and 1,25 (OH)2D3 (24.7+/-5.6 pg/ml) as well as OC levels (9.8+/-2.5 ng/ml; p<0.001) than controls (38.1+/-4.9 ng/ml, 40.7+/-6.4 pg/ml and 16.5+/-5.8 ng/ml, respectively) and subjects with normoalbuminuria (36.0+/-4.5 ng/ml, 38.8+/-8.9 pg/ml and 14.5+/-3.2 ng/ml). In conclusion, our study suggests that abnormalities in 25-OHD, 1,25(OH)2D3 and OC can be present in diabetic adolescents and young adults with incipient nephropathy.

Adolescent↗
PubMed1999

Symptomatic hypercalcemia in the first months of life: calcium-regulating hormones and treatment.

Neonatal hypercalcemia is a rare condition often of unclear pathogenesis. If unrecognized and untreated it may result in central nervous system and renal damage. We studied three infants with symptomatic neonatal hypercalcemia pointing out pathogenetic and therapeutic aspects. One infant was found to have transient hyperparathyroidism with high intact parathyroid hormone (iPTH) levels. One infant had an incomplete form of Williams syndrome with hypercalcemia and an elfin facies. The pathogenesis is unclear in this case. A reduced secretion of calcitonin or an hypersensitivity to vitamin D might be the underlying defect. The third case was found to have subcutaneous fat necrosis and hypercalcemia associated with high 1,25(OH)2D levels and suppressed iPTH levels. These findings suggest an unregulated extrarenal 1,25(OH)2D production. These infants were treated with hydratation, furosemide, corticosteroids and low calcium diet. Symptomatic neonatal hypercalcemia should be treated promptly. However blood has to be taken before starting treatment to study calcium-regulating hormones and clarify pathogenesis.

Adrenal Cortex Hormones↗
PubMed2006

Changes in calcium, 25(OH) vitamin D3 and other biochemical factors during pregnancy.

INTRODUCTION AND AIMS: Calcium and vitamin D play major roles in calcium homeostasis and skeletal development, especially during pregnancy. This study was conducted to determine changes in calcium, 25 hydroxy [25(OH)] vitamin D3 and other biochemical factors (PTH, osteocalcin, alkaline phosphatase, magnesium, phosphorus) related to calcium homeostasis and bone turnover during pregnancy and compare the values to those of non-pregnant women. MATERIALS AND METHODS: In a cohort study, 48 pregnant women, in their first trimester of pregnancy (12+/-2.7 weeks), from 5 prenatal care centers, and 47 non-pregnant women randomly selected from the Tehran Lipid and Glucose Study (TLGS) population were enrolled. These pregnant women were followed in their second (26+/-1.9 weeks) and third trimesters (37+/-3.2 weeks) of pregnancy. Samples were drawn from June 2002 to March 2003. Including criteria were healthy women with no background of disease. Women using photo protection and calcium and vitamin D supplementation were excluded. A questionnaire was used to obtain demographic information for both groups. Venous blood samples were taken after 12-14 h of overnight fasting to measure serum calcium, phosphorus, magnesium, alkaline phosphatase, PTH, 25 (OH) vitamin D3 and serum osteocalcin levels. The repeated measures analysis of variance and t-test were used for statistical analysis. Data were matched for age and weight in both the case (in the first trimester) and control groups. RESULTS: Significant differences were found in the mean serum levels of osteocalcin and alkaline phosphatase between the three trimesters of pregnancy (p< 0.001). Osteocalcin was significantly higher in the first trimester as compared to second and third trimesters of pregnancy. Alkaline phosphatase was significantly lower in the first trimester as compared to the second and third trimesters of pregnancy and their controls. There was also a significant difference in osteocalcin in the second and third trimesters and alkaline phosphatase in the first and third trimesters of pregnancy in comparison to the control group. The mean values of osteocalcin were 12.7+/-8.5, 8.1+/-6.9, 5.6+/-5.0 and 13.9+/-7.9 ng/ml, respectively, and mean values for alkaline phosphatase were 115+/-38, 125+/-37, 174+/-61 and 134+/-35.0 Iu/l, respectively. In the first trimester, alkaline phosphatase was lower and osteocalcin was higher than in the second and third trimesters. In the first trimester of pregnancy, 20 and 40% of women had 25(OH) vitamin D3 < 10 and < 20 ng/ml, respectively, and 19% of women had serum calcium levels < 8.6 mg/dl. CONCLUSION: 60% of women in the first trimester, 48% in the second and 47% in the third trimester had either severe or moderate vitamin D deficiency. It is recommended that the importance of calcium supplements with vitamin D in pregnant women be stressed for these individuals.

Adult↗
PubMed2005

Association between vitamin D receptor FokI. Polymorphism and serum parathyroid hormone level in patients with chronic renal failure.

We investigated the relationship between vitamin D receptor (VDR) start codon polymorphism and serum levels of PTH, calcidiol, and calcium in 64 Spanish patients with chronic renal failure (CRF). An exon 2 fragment of the VDR gene was amplified by PCR, and cleaved with the restriction enzyme FokI. The alleles were identified according to the digestion pattern obtained as F (absence of restriction site) and f (presence of restriction site). Genotype frequencies in the patient population were 54.7% FF, 28.1% Ff and 17.2% ff, vs 46.7% FF, 43.3% Ff and 10% ff in a healthy control population. The difference between the two populations was statistically significant (p<0.01). Within the patient population, mean serum PTH level in the FF group was significantly higher (159.77+/-25.69 pg/ml) than in both the Ff and ff groups (106.67+/-19.07 and 77.55+/-15.85 pg/ml, respectively; p<0.05). However there were no significant differences in serum levels of calcidiol or calcium among genotypes. These results suggest that FokI polymorphisms of the VDR gene may determine parathyroid response in CRF patients.

Calcifediol↗
PubMed1998

Bone turnover is reduced in children with juvenile rheumatoid arthritis.

Juvenile Rheumatoid Arthritis (JRA) is frequently associated with osteoporosis. In order to determine if JRA osteoporosis is related to reduced formation or to increased bone resorption or both, serum levels of calcium (Ca), phosphorus (PO4), magnesium (Mg), alkaline phosphatase (ALP), parathormone (PTHi), 25-hydroxyvitamin D3 (25-OHD) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D), osteocalcin (OT), carboxyterminal propeptide (P-coll-1-c), and carboxyterminal telopeptide of type I collagen (ICTP) were evaluated in 47 JRA children, 33 with active disease and 14 in remission. The therapy consisted of nonsteroidal antiinflammatory (NSAIDs) drugs in pauciarticular subset, NSAIDs and Methotrexate (MTX) in polyarticular, NSAIDs and steroids in systemic onset. OT reflects bone formation, P-coll-1-c reflects collagen production and bone formation, ICTP, marker of collagen degradation in bone, indicates bone destruction. Serum levels of Ca, PO4, Mg, ALP, PTHi 25-OHD and 1,25-(OH)2D were comparable in JRA children and in controls. OT (8.7 +/- 3.7 ng/ml vs 9.6 +/- 5.1), P-coll-1-c (301.2 +/- 118.4 ng/ml vs 264.1 +/- 100.1) and ICTP (15.7 +/- 5.7 ng/ml vs 16.1 +/- 6.1) did not differ statistically in the whole group of JRA children vs controls. OT (8.0 +/- 3.5 vs 10.4 +/- 3.8) and ICTP (14.4 +/- 5.4 vs 18.8 +/- 5.4) were significantly lower in active than inactive group. In polyarticular and systemic onset OT and ICTP were significantly lower than in pauciarticular. No difference was found in active patients treated with steroids vs active patients treated with NSAIDS and NSAIDs plus MTX. The lower serum levels of OT and ICTP in active disease support the hypothesis that both bone formation and resorption are reduced in JRA bone turnover.

Alkaline Phosphatase↗
PubMed1998

Comparative study of the intestinal absorption of three salts of calcium in young and elderly women.

A daily ingestion of 1000 to 1500 mg elemental calcium associated with vitamin D supplement is presently considered to be the adequate and least expensive therapy for senile osteoporosis. There exists only scarce data about calcium absorption with available calcium salts in elderly patients. We have compared the digestive absorption of calcium (Ca) citrate in soluble and solid form and calcium gluconolactate-carbonate in 15 young and 20 elderly, healthy women using the oral calcium loading test. The subjects were divided into two groups. In the first group, the absorption of solid Ca citrate (1000 mg Ca element) was compared to the absorption of Ca gluconolactate-carbonate (1000 mg Ca element) both in young (n = 7) and elderly women (n = 10). In the second group, the absorption of soluble Ca citrate (1000 mg Ca element) was compared to the absorption of Ca gluconolactate-carbonate (1000 mg Ca element) in young (n = 8) and elderly (n = 10) women. In the preload phase, basal calciuria was increased in elderly women (p < 0.01) although basal calcemia was similar in young and elderly women. After oral administration of the calcium salts, an increase in plasma Ca was observed in both groups which was greater for soluble Ca citrate and Ca gluconolactate than for solid Ca citrate. In young women, the increase in plasma calcium was significantly higher with soluble Ca citrate compared to Ca gluconolactate (p < 0.05). In elderly women, the postload calciuria was significantly higher for soluble Ca citrate (p < 0.05) and Ca gluconolactate (p < 0.05) compared to solid Ca citrate. A similar pattern was observed in young women, although it was not significant. In conclusion, an oral load of 1000 mg soluble Ca citrate and Ca gluconolactate-carbonate induces significant biochemical changes suggesting a better digestive absorption compared to Ca citrate in solid form, both in young and elderly women. We did not observe different response, between young and old patients.

Adult↗
PubMedDate not supplied

Seasonal variation of serum 25 hydroxy D3 in residents of Tehran.

BACKGROUND AND AIM: vitamin D is essential for bone health. It has been shown that in many communities serum levels of vitamin D can be subject to seasonal variations but so far no study has been conducted on this variable in natives of Tehran. SUBJECTS AND METHODS: 1172 natives of Tehran, 682 women and 490 men, aged 3-69 yr entered the study. Sampling was performed monthly except during Ramadhan, the holy month of Islamic fasting. Serum 25-hydroxyvitamin D (25-OHD) was measured using protein binding assay and levels below 20 ng/ml were determined as vitamin D deficient. RESULTS: serum 25-OHD concentrations showed monthly variations in both sexes but the magnitude of variations was more pronounced in men. The nadir of serum levels in both sexes were seen in December and February, 12 +/- 13 and 14 +/- 14 ng/ml in women, and 28 +/- 16 and 24 +/- 18 mg/ml in men, respectively with the highest values being seen in October; 29 +/- 29 ng/ml in women and 55 +/- 27 ng/ml in men. During the whole period of study the maximum values for women were either equal or less than the minimum values for men. The values for men during summer and winter (31 +/- 17 and 28 +/- 22 ng/ ml, respectively) were significantly lower than the values for spring and fall (38 +/- 27 and 43 +/- 29 ng/ml respectively). In women there was no significant difference in the values of the first three seasons and only the values pertaining to winter were significantly different from the values of fall. CONCLUSIONS: the absence of expected seasonal variations in women coupled with obvious deficiency of vitamin D can be attributed to patterns of life style and also to the traditional clothing of the women of Tehran. Nationwide strategies to improve the vitamin D status of the community, specially for women and children, are highly recommended.

Adolescent↗
PubMed2005

Limited availability of nutritional vitamin D causing inappropriate treatment of vitamin D deficiency rickets with a response resembling pseudohypoparathyroidism type II in a Japanese patient.

Vitamin D deficiency rickets occasionally resembles pseudohypoparathyroidism type II (PHP type II) with respect to the response to exogenous PTH in the presence of hypocalcemia. We encountered a Japanese patient with stage 2 vitamin D deficiency rickets, who had increased urinary cAMP excretion and no response of urinary phosphate or N-acetyl-beta-D-glucosaminidase excretion to exogenous PTH under normocalcemic and normophosphatemic conditions, after treatment with 1,25(OH)2 vitamin D3. This case shows that it is possible for a response mimicking that of PHP type II to occur when the serum calcidiol level is low due to causes other than hypocalcemia and secondary hyperparathyroidism. When the serum calcidiol level is low, the appropriate treatment should be cholecalciferol or ergocalciferol. However, because neither is commercially available as a useful formulation in Japan, physicians are forced to inappropriately use calcitriol or analogs.

Calcifediol↗
PubMed1984

25-Hydroxycholecalciferol as an antagonist of adverse corticosteroid effects on phosphate and calcium metabolism in man.

The present study was performed in 30 patients who needed steroid therapy: courses of triamcinolone or DTM 8-15 given orally lasted 30 days. In 15 of these patients glucoactive corticosteroids were administered in combination with 5 micrograms/day of 25OH-vitamin D3 (25OHD3). 47Calcium oral test and 99mTc-MDP kinetics, as an index of bone turnover, were performed at the beginning of the therapy and after 30 days. At the end of treatment a significant improvement of intestinal radiocalcium transport together with a decrease in bone turnover in the group of patients treated with 25OHD3 was observed. As it concerns plasma calcium level, inorganic phosphate, the urinary excretion of calcium, phosphate and hydroxyproline no significant difference between the two groups examined were noticed. These results indicate that the adverse effects of glucoactive corticosteroids on intestinal calcium transport and bone turnover may be counteracted by the combined administration of physiological doses of 25OHD3.

Adolescent↗
PubMed1984

Simultaneous measurement of 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D from a single two milliliters serum specimen. Preliminary clinical application.

A simple method for extraction, purification and separation of the principal vitamin D metabolites from a single serum sample is described. The method involved extraction of serum with acetonitrile followed by a first purification employing C-18 Sep-pak cartridges eluted with methanol/water and acetonitrile. Final separation before assay was carried out by high pressure liquid chromatography. 1.25-dihydroxy-vitamin D was measured with radioimmunoassay using an antiserum (S11) with high selectivity for 1 alpha-OH function of the hormone at a final dilution of 1:100,000. 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D were measured employing a competitive binding assay with normal rat serum at a final dilution of 1:10,000 as source of binding protein. The mean (+/- SD) serum 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D concentrations for a group of healthy subjects were 50.4 +/- 17.3 pg/ml, 2.3 +/- 2.6 ng/ml and 20.8 +/- 12.3 ng/ml, respectively. 1.25-dihydroxy-vitamin D concentrations were low or undetectable in patients on dialysis or with mild renal failure. High 1.25-dihydroxy-vitamin D levels were found in 2 out of 17 patients with primary hyperparathyroidism. In 4 normal subjects treated for two weeks with large doses of 25-hydroxy-vitamin D, serum 25-hydroxy-vitamin D rose from 12.5 ng/ml to 119 ng/ml and from 0.89 ng/ml to 15 ng/ml, respectively; no changes in the 1.25-dihydroxy-vitamin D assay were found.

24,25-Dihydroxyvitamin D 3↗
PubMed1988

Serum vitamin D metabolites do not change in response to intravenous injection of thyrotropin releasing hormone (TRH) and growth hormone releasing factor (GHRF 1-44) in children.

Several reports claim that thyroid hormones and growth hormone participate in the regulation of vitamin D synthesis. We investigated whether there was a direct effect of their releasing hormones on vitamin D metabolism. TRH (7 micrograms/kg) was injected iv in 8 children with euthyroid diffuse goiter and GHRF (1 microgram/kg) in 10 short normal children. TRH injection induced significant TSH elevations but no changes in serum vitamin D metabolites, calcium and phosphorus. GHRF administration resulted in marked growth hormone elevations without alterations in the serum vitamin D metabolites, calcium and phosphorus. These results indicate no direct effect of TRH or GHRF itself on vitamin D metabolism, as well as a lack of very short term effect of growth hormone and TSH.

Calcifediol↗
PubMed1990

Effects of vitamin D3 metabolites on thyrotropin secretion from rat pituitary cells in culture.

The effects of several vitamin D3 metabolites on TSH secretion were investigated using rat pituitary cells in culture. After a 24-h incubation in Dulbecco's medium, only 25,26-dihydroxyvitamin D3 [25,26(OH)2D3] at 10(-6) M increased the basal TSH secretion (36% above control). The TRH-induced TSH secretion increased dose-dependently with increasing concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] showing a significant increase at 10(-8) M (41% above control). At 10(-5) M 25,26(OH)2D3 the TRH-stimulated TSH secretion was also increased (63% above control). In medium containing charcoal-treated serum, 1, 24,25-trihydroxyvitamin D3 [1,24,25(OH)3D3] decreased the TRH-induced TSH secretion dose dependently (34% below control at 10(-8) M), while the effects of both 1,25(OH)2D3 and 25,26(OH)2D3 were blunted. Our results indicate that several vitamin D3 metabolites may affect pituitary TSH secretion.

24,25-Dihydroxyvitamin D 3↗
PubMed1990

Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis.

The antifungal drug ketoconazole, a cytochrome P450 inhibitor, has been shown to inhibit renal 1,25-dihydroxyvitamin D production in vitro and to lower serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with primary hyperparathyroidism. To assess the usefulness of this drug in the hypercalcemia of sarcoidosis, a condition thought to result from overproduction of 1,25-dihydroxyvitamin D by sarcoid-involved tissues, two men with sarcoidosis, hypercalcemia, and elevated serum levels of 1,25-dihydroxy-vitamin D were given ketoconazole, 600-800 mg per day, for four to six days. Serum 1,25-dihydroxyvitamin D levels were markedly reduced (by approximately 40%) in both patients during ketoconazole administration, but serum calcium was not affected. In both patients, renal function deteriorated during ketoconazole treatment. We conclude that ketoconazole administration can lower the elevated serum 1,25-dihydroxyvitamin D levels in sarcoidosis. However, deterioration of renal function during ketoconazole administration as well as failure of hypercalcemia to be affected during short-term ketoconazole treatment suggest that this drug might not be appropriate for acute treatment of hypercalcemic sarcoidosis.

Adult↗
PubMed1998

Bone mineral density, collagen type 1 alpha 1 genotypes and bone turnover in premenopausal women with diabetes mellitus.

Osteopenia is a recognised complication of diabetes mellitus which could be due to abnormal bone turnover or disturbances in the calcium/parathyroid hormone/vitamin D axis or both. Genetic factors also play an important part in determining bone mass although this has not been studied in diabetes. Recently a polymorphism of the collagen type 1 alpha 1 (COL1A1) gene has been shown to be associated with low bone mass in British women. To identify subjects with diabetes who may be at risk of developing osteoporosis and fractures, we analysed bone mineral density in relation to the biochemical markers of bone turnover, calcium homeostasis and the COL1A1 genotype in a group of premenopausal women with Type I (insulin-dependent) diabetes mellitus (n = 31), Type II (non-insulin dependent) diabetes mellitus (n = 21) and control subjects (n = 20). Bone mineral density was lower at the femoral neck in the subjects with Type I diabetes (p = 0.08) as were serum 25-hydroxyvitamin D compared with control subjects (p = 0.023) and this was negatively correlated with serum collagen type 1 C-terminal propeptide (r = -0.56, p < 0.001). Bone mineral density in Type II diabetes was not different from control subjects, after correction for body mass index. Bone resorption was, however, raised in the Type II diabetic subjects as reflected by the higher urinary deoxypyridinoline values (p = 0.016) and lower collagen type 1 C-terminal propeptide:deoxypyridinoline ratio (p = 0.04). In the whole group studied, subjects with the COL1A1 's' genotype had lower bone mineral density at the femoral neck (p = 0.01) which was partly attributable to a lower body mass index. Following multiple regression analysis body mass index and collagen type 1 C-terminal propeptide concentrations remained determinants of bone mass at all three sites, whereas genotype appeared to be a predictor of bone mass at the femoral neck only. We conclude that measurement of these variables could prove useful in firstly identifying those diabetic women at risk of osteoporosis and secondly guiding therapeutic intervention.

Adult↗
PubMed2004

Vitamin D insufficiency in adolescent males in Southern Tasmania: prevalence, determinants, and relationship to bone turnover markers.

There are limited data on vitamin D insufficiency in healthy children. The aim of this study was to describe the prevalence and determinants of vitamin D insufficiency and its association with bone turnover in adolescent boys (N = 136, mean age 16 years). Sun exposure and physical activity were assessed by questionnaire. Vitamin D stores were assessed by serum 25-hydroxyvitamin D3 (25[OH]D3). Bone turnover was assessed by bone-specific alkaline phosphatase (BAP) and urinary pyridinoline (PYR) to creatinine (Cr) ratio (mmol PYR/micromol Cr). The mean 25(OH)D3 level was low (44 nmol/l; 68% < 50 nmol/l; range, 16-87) and was associated with self-reported sun exposure on winter weekends (r = 0.23, p = 0.01), school holidays (r = 0.22, p = 0.01), and weekdays (r = 0.17, p = 0.05). It was also associated with number of sports (r = 0.34, p < 0.001) and vigorous activity (r = 0.22, p = 0.01) but not television, computer, and video watching (r = -0.04, p = 0.68). In multivariate analysis, number of sports but not total sun exposure remained significantly associated with 25(OH)D3. Furthermore, 25(OH)D3 was significantly associated with BAP in cutpoint analysis (cutpoint 55 nmol/l, p = 0.03) but not continuous analysis (r = -0.12, p = 0.16) and PYR in both forms (r = -0.23, p = 0.01, cutpoint 43 nmol/l, p = 0.01). In conclusion, vitamin D insufficiency is common in healthy adolescent boys in winter in our setting, is primarily derived from sports-related sun exposure, and is associated with bone turnover markers. These data suggest that a 25(OH)D3 level of at least 43-55 nmol/l is required for optimal bone health in children.

Adolescent↗
PubMed2005

Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women.

Vitamin D supplements have been used to prevent fractures. The effect may be mediated through increased bone mass, but also through reduced falling propensity. The aim of this study was to evaluate the association between 25-hydroxy vitamin D levels (25OHD), fall-associated variables (including tests of functional performance), and fracture in ambulatory women. At baseline 25OHD was measured in 986 women. Fall-associated variables were investigated at baseline. Fractures were recorded during a 3-year follow-up. Four percent of the women had 25OHD levels below 20 ng/ml (50 nmol/l), and 26% had 25OHD levels below 30 ng/ml (75 nmol/l). 25OHD correlated with gait speed (r =0.17, P <0.001), the Romberg balance test (r =0.14, P <0.001), self-estimated activity level (r =0.15, P <0.001), and thigh muscle strength (r =0.08, P =0.02). During the 3-year follow-up, 119 out of the 986 women sustained at least one fracture. The Cox proportional hazard ratio (HR) (95% confidence interval) for sustaining a fracture during the follow-up was 2.04 (1.04-4.04) for the group of women with 25OHD below 20 ng/ml, in which 9 out of 43 women sustained a fracture. Thirty-two of the 256 women with 25OHD levels below 30 ng/ml sustained a fracture during the follow-up, with a non-significant HR of 1.07 (1.07-1.61). This cohort of elderly, ambulatory women had a high mean 25OHD. A low 25OHD was associated with inferior physical activity level, gait speed and balance. A 25OHD level below 30 ng/ml was not associated with an increased risk of fractures in this study. However, a subgroup of women with 25OHD levels below 20 ng/ml had a tendency to an increased risk of fractures, which may be associated with an inferior physical activity and postural stability.

Accidental Falls↗