The vitamin D receptor as well as its ligand have been localized to various immune tissues and cells. These observations have led researchers to hypothesize a role for vitamin D in the immune system. ...However, a specific role for vitamin D in immunity has yet to be clearly delineated. The work in this report was undertaken to determine if mounting an antibody response is altered in the face of vitamin D-deficiency or when the signaling pathway is eliminated by removal of the nuclear receptor. This investigation provides direct evidence vitamin D is not necessary for producing antibodies, a process paramount for optimal attack against many foreign organisms. The idea that vitamin D plays a significant role in immunity has been proposed repeatedly for many years. To address this important idea we have carried out studies in mice to determine if vitamin D plays a significant role in antibody production. Two animal models were utilized: mice depleted of vitamin D and mice devoid of the vitamin D receptor. Further, a possible role of hypocalcemia resulting from vitamin D deficiency in antibody production was determined. Neither the absence of vitamin D or the vitamin D receptor nor hypocalcemia affected the ability of mice to mount an antibody response to an antigen challenge. Thus, we found no evidence that vitamin D or normal serum calcium is required for this major form of immunity.
Epidemiologic studies in humans have shown associations between greater sunlight exposure, higher serum 25-hydroxycholecalciferol 25(OH)D3 concentrations, and reduced colon cancer risk. However, ...results from a limited number of vitamin D supplementation trials in humans have not shown a protective effect.
We sought to determine whether adding to the diet increasing amounts of either 25(OH)D3, the stable metabolite measured in serum and associated with cancer risk, or cholecalciferol (vitamin D3), the compound commonly used for supplementation in humans, could reduce emergent adenomas (chemoprevention) or decrease the growth of existing adenomas (treatment) in the colons of vitamin D-sufficient rats carrying a truncation mutation of adenomatous polyposis coli (Apc), a model of early intestinal cancer.
Apc(Pirc/+) rats were supplemented with either vitamin D3 over a range of 4 doses 6-1500 μg/(kg body weight · d) or with 25(OH)D3 over a range of 6 doses 60-4500 μg/(kg body weight · d) beginning after weaning. Rats underwent colonoscopy every other week to assess effects on adenoma number and size. At termination (140 d of age), the number of tumors in the small intestine and colon and the size of tumors in the colon were determined, and serum calcium and 25(OH)D3 measurements were obtained.
At lower doses (those that did not affect body weight), neither of the vitamin D compounds reduced the number of existing or emergent colonic tumors (P-trend > 0.24). By contrast, supplementation at higher doses (those that caused a suppression in body weight gain) with either 25(OH)D3 or vitamin D3 caused a dose-dependent increase in colonic tumor number in both males and females (P-trend < 0.003).
No evidence for protection against colon tumor development was seen with lower dose supplementation with either cholecalciferol or 25-hydroxycholecalciferol. Thus, the association between sunlight exposure and the incidence of colon cancer may involve factors other than vitamin D concentrations. Alternative hypotheses warrant investigation. Furthermore, this study provides preliminary evidence for the need for caution regarding vitamin D supplementation of humans at higher doses, especially in individuals with sufficient serum 25(OH)D3 concentrations.
Vitamin D analogs and calcimimetics are used to manage secondary hyperparathyroidism (SHPT) in dialysis patients. DP001 is an oral vitamin D analog that suppresses parathyroid hormone (PTH) in uremic ...rats, osteopenic women, and hemodialysis patients. The safety and effectiveness of DP001 suppressing PTH in dialysis patients previously managed with active vitamin D with or without a calcimimetic are presented.
A multicenter, randomized, double-blind study compared DP001 to placebo in hemodialysis patients with serum-intact PTH (iPTH) ≥300 pg/ml. The primary efficacy endpoint was the proportion of patients achieving 2 consecutive ≥30% decreases in iPTH levels during the 12 weeks of treatment. Calcium, phosphorus, calcium × phosphorus product and safety were also evaluated. The responses to DP001 were compared in patients previously treated with both active vitamin D and a calcimimetic to those previously on active vitamin D alone.
Sixty-two patients were randomized (n = 34 DP001; n = 28 placebo). At week 12, 78% of all DP001-treated patients and 7% of all placebo-treated patients achieved the primary endpoint (p < 0.0001); iPTH fell 45% in the DP001 group and increased 37% in the placebo group. No patient exceeded the safety threshold of 2 consecutively corrected serum calcium levels ≥11.0 mg/dl. Patients previously on cinacalcet plus active vitamin D also responded to DP001 (n = 10) resulting in a 55% decrease in iPTH, while those on placebo (n = 9) increased by 70%.
DP001 safely and effectively suppressed iPTH in hemodialysis patients with SHPT that were previously managed with active vitamin D alone or with a calcimimetic (www.clinicaltrials.gov, NCT01922843).
2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D
(DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis ...and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis.
DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose.
After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus.
In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.
Background
2-Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D
3
(DP001 or 2MD) is a novel, potent 1α-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid ...hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis.
Methods
DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose.
Results
After the first and final dose, the half-life of DP001 was similar (55.8 ± 13.0 and 50.8 ± 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 ± 0.8 h, with a concentration maximum of 3.4 ± 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 ± 23.9 pg h/mL, and apparent volume of distribution was 2.03 ± 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 ± 52 vs 462 ± 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus.
Conclusions
In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2–3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism.
The primary purpose of this study was to determine the rate of peak power (PP) loss during the countermovement jump (CMJ) and split-squat jump (SSJ) across various loads within a set of high ...repetitions. Eleven collegiate track and field athletes who had several years of resistance training experience and were trained in the two types of jumps completed the study. The participants completed a familiarization session and 2 data collection sessions. The CMJ and SSJ were completed in random order during session 1 and 2 separated by a minimum of 72 hours. Three loads using dumbbells took place in random order with each session including body weight only (BW0), body weight plus 15% (BW15) and body weight plus 30% BW(30) for the SSJ and BW(0), BW(25), and BW(50) for the CMJ. PP was determined using the PUSH 2.0 3D accelerometer worn at the waist, which was connected to an ipad app using Bluetooth. The participants completed 14 repetitions each set with 8 min rest between sets. Repetition 3 demonstrated the highest mean PP (PPmax) within the set. No significant decrease in PP was observed until repetition 6 (3.6% below PPmax) during the SSJ and repetition 8 (5.2% below PPmax) during the CMJ. These data indicate that 5 or less repetitions should be completed during the CMJ and 7 or less for the SSJ when training for PP. Using 10% reduction in PP as an effective level to train for power endurance, we recommend completing a minimum of 12 repetitions during the CMJ and a minimum of 10 repetitions for the SSJ.
Background: Epidemiologic studies in humans have shown associations between greater sunlight exposure, higher serum 25-hydroxycholecalciferol 25(OH)D3 concentrations, and reduced colon cancer risk. ...However, results from a limited number of vitamin D supplementation trials in humans have not shown a protective effect.
Objective: We sought to determine whether adding to the diet increasing amounts of either 25(OH)D3, the stable metabolite measured in serum and associated with cancer risk, or cholecalciferol (vitamin D3), the compound commonly used for supplementation in humans, could reduce emergent adenomas (chemoprevention) or decrease the growth of existing adenomas (treatment) in the colons of vitamin D–sufficient rats carrying a truncation mutation of adenomatous polyposis coli (Apc), a model of early intestinal cancer.
Methods:ApcPirc/+ rats were supplemented with either vitamin D3 over a range of 4 doses 6–1500 μg/(kg body weight · d) or with 25(OH)D3 over a range of 6 doses 60–4500 μg/(kg body weight · d) beginning after weaning. Rats underwent colonoscopy every other week to assess effects on adenoma number and size. At termination (140 d of age), the number of tumors in the small intestine and colon and the size of tumors in the colon were determined, and serum calcium and 25(OH)D3 measurements were obtained.
Results: At lower doses (those that did not affect body weight), neither of the vitamin D compounds reduced the number of existing or emergent colonic tumors (P-trend > 0.24). By contrast, supplementation at higher doses (those that caused a suppression in body weight gain) with either 25(OH)D3 or vitamin D3 caused a dose-dependent increase in colonic tumor number in both males and females (P-trend < 0.003).
Conclusions: No evidence for protection against colon tumor development was seen with lower dose supplementation with either cholecalciferol or 25-hydroxycholecalciferol. Thus, the association between sunlight exposure and the incidence of colon cancer may involve factors other than vitamin D concentrations. Alternative hypotheses warrant investigation. Furthermore, this study provides preliminary evidence for the need for caution regarding vitamin D supplementation of humans at higher doses, especially in individuals with sufficient serum 25(OH)D3 concentrations.
Background:
Epidemiologic studies in humans have shown associations between greater sunlight exposure, higher serum 25-hydroxycholecalciferol 25(OH)D
3
concentrations, and reduced colon cancer risk. ...However, results from a limited number of vitamin D supplementation trials in humans have not shown a protective effect.
Objective:
We sought to determine whether adding to the diet increasing amounts of either 25(OH)D
3
, the stable metabolite measured in serum and associated with cancer risk, or cholecalciferol (vitamin D
3
), the compound commonly used for supplementation in humans, could reduce emergent adenomas (chemoprevention) or decrease the growth of existing adenomas (treatment) in the colons of vitamin D–sufficient rats carrying a truncation mutation of adenomatous polyposis coli (
Apc
), a model of early intestinal cancer.
Methods:
Apc
Pirc/+
rats were supplemented with either vitamin D
3
over a range of 4 doses 6–1500 μg/(kg body weight · d) or with 25(OH)D
3
over a range of 6 doses 60–4500 μg/(kg body weight · d) beginning after weaning. Rats underwent colonoscopy every other week to assess effects on adenoma number and size. At termination (140 d of age), the number of tumors in the small intestine and colon and the size of tumors in the colon were determined, and serum calcium and 25(OH)D
3
measurements were obtained.
Results:
At lower doses (those that did not affect body weight), neither of the vitamin D compounds reduced the number of existing or emergent colonic tumors (
P
-trend > 0.24). By contrast, supplementation at higher doses (those that caused a suppression in body weight gain) with either 25(OH)D
3
or vitamin D
3
caused a dose-dependent increase in colonic tumor number in both males and females (
P
-trend < 0.003).
Conclusions:
No evidence for protection against colon tumor development was seen with lower dose supplementation with either cholecalciferol or 25-hydroxycholecalciferol. Thus, the association between sunlight exposure and the incidence of colon cancer may involve factors other than vitamin D concentrations. Alternative hypotheses warrant investigation. Furthermore, this study provides preliminary evidence for the need for caution regarding vitamin D supplementation of humans at higher doses, especially in individuals with sufficient serum 25(OH)D
3
concentrations.
Early childhood is a critical stage for the foundation and development of both the microbiome and host. Early-life antibiotic exposures, cesarean section, and formula feeding could disrupt microbiome ...establishment and adversely affect health later in life. We profiled microbial development during the first 2 years of life in a cohort of 43 U.S. infants and identified multiple disturbances associated with antibiotic exposures, cesarean section, and formula feeding. These exposures contributed to altered establishment of maternal bacteria, delayed microbiome development, and altered α-diversity. These findings illustrate the complexity of early-life microbiome development and its sensitivity to perturbation.
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