Efectividad del ejercicio más suplementación con vitamina D3 sobre la masa y fuerza muscular de pacientes con artritis reumatoidea / Effectiveness of exercise and vitamin D3 on muscle mass and strength in rheumatoid arthritis

Introducción. La artritis reumatoidea es una enfermedad autoinmune con un proceso inflamatorio crónico de las articulaciones y con una respuesta catabólica incrementada que predispone a una elevada pérdida de la masa muscular. Objetivo. Evaluar la efectividad de un programa de ejercicios de resistencia más suplementación con vitamina D3 en la movilidad, la masa y la fuerza muscular de pacientes con artritis reumatoidea que acuden a la consulta de medicina física y rehabilitación. Métodos. Ensayo clínico controlado y aleatorizado realizado en 30 pacientes distribuidos equitativamente en tres grupos: grupo control, grupo con ejercicios durante 10 semanas y un grupo con ejercicios durante 10 semanas más suplementación con 2.000 UI de vitamina D3. Las variables fueron evaluadas al inicio del estudio y a las 10 semanas de iniciada la intervención. Resultados. La edad media de los participantes fue 57,73 años y la gran mayoría (93.3%) eran mujeres. En el primer ítem de la evaluación de la escala SPPB (test de equilibrio) se observó un promedio inicial de 3,5 y final de 3,7, en el segundo ítem (test de velocidad de marcha) el promedio inicial fue de 2,8 y el final, de 3,3, y en el tercer ítem (test de levantarse de la silla) el promedio inicial fue de 1,1 y el final, de 1,6, con un resultado significativo final entre ellos (p<0,001). La medición de la masa mediante ultrasonido evidenció un valor significativo en el grupo de ejercicios más suplementación con vitamina D3. Conclusión. La intervención durante 10 semanas de ejercicios de fuerza más suplementación con vitamina D3 (2.000 UI) produce una mejoría sobre los ítems de la escala SPPB y sobre la masa muscular de los músculos bíceps braquial y recto anterior femoral, lo cual podría incidir sobre la disminución del riesgo de caídas en pacientes con artritis reumatoidea.

Introduction. Rheumatoid arthritis is an autoimmune disease with a chronic inflammatory process of the joints and an increased catabolic response that predisposes to a high loss of muscle mass. Objective. To evaluate the effectiveness of a resistance exercise program plus supplementation with vitamin D3 on the mobility, and the muscle mass and strength of patients with rheumatoid arthritis who attend the consultation of physical medicine and rehabilitation. Methods. Randomized controlled clinical trial conducted in 30 patients equitably distributed into three groups: control group, group with exercises for 10 weeks and a group with exercises for 10 weeks plus supplementation with 2,000 IU of vitamin D3. The variables were evaluated at the beginning of the study and 10 weeks after the start of the intervention. Results. The mean age of the participants was 57.73 years and the vast majority of them (93.3%) were women. In the first item of the evaluation in the SPPB scale (balance test) an initial average of 3.5 and a final average of 3.7 was observed, in the second item (gait speed test) the initial average was 2.8 and the second was 3.3, and in the third item (standing up from a chair) the initial average was 1.1, and the final was 1.6, with a significant final result between them (p<0.001). The measurement of the mass using ultrasound evidenced a significant value in the group of exercises plus supplementation with vitamin D3. Conclusion. The intervention during 10 weeks of strength exercises plus supplementation with vitamin D3 (2,000 IU) produces an improvement in the items of the SPPB scale and in the muscle mass of the biceps brachii and rectus femoris, which might have an impact on the reduction of the risk of falls in patients with rheumatoid arthritis.

Association of circulating 25-hydroxyvitamin D levels with hypertension and blood pressure values in Korean adults: A Mendelian randomization study on a subset of the Korea National Health and Nutrition Survey 2011–2012 population

BACKGROUND/OBJECTIVES: Lower circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with a higher risk of hypertension (HTN); however, it remains unclear whether the relationship is causal. We aimed to evaluate the causal effects of circulating 25(OH)D levels on the prevalence of HTN in the Korean population using the Mendelian randomization (MR) approach. SUBJECTS/METHODS: Epidemiological data, serum 25(OH)D data, and genomic DNA biospecimens were obtained from 2,591 participants, a subset of the study population in the Korea National Health and Nutrition Survey 2011-2012. Five 25(OH)D-related single nucleotide polymorphisms (SNPs; DHCR7 rs12785878, CYP2R1 rs10741657, CYP2R1 rs12794714, CYP24A1 rs6013897, and GC rs2282679), identified a priori from genome-wide association studies, were used as instrument variables (IVs) for serum 25(OH)D levels. In the MR analysis, we performed IV analyses using the two-stage least squares method. RESULTS: In the observational analysis, circulating 25(OH)D levels were found to be inversely associated with the HTN prevalence in ordinary least squares models (odds ratio: 0.97, 95% confidence interval: 0.96, 0.99) after adjusting for the potential confounders. There were differences in the circulating 25(OH)D levels across genotypes of individual SNPs. In the MR analysis, using individual SNPs as IVs, 25(OH)D levels were not associated with the HTN prevalence. CONCLUSIONS: We found no association between genetically determined circulating 25(OH)D levels and HTN in Korean adults. Our results are listed owing to the relatively small sample size and possible weak instrument bias; therefore, further studies are needed to confirm these results.

Infantile hypercalcemia with novel compound heterozygous mutation in SLC34A1 encoding renal sodium-phosphate cotransporter 2a: a case report

Idiopathic infantile hypercalcemia is characterized by hypercalcemia, dehydration, vomiting, and failure to thrive, and it is due to mutations in 24-hydroxylase (CYP24A1). Recently, mutations in sodium-phosphate cotransporter (SLC34A1) expressed in the kidney were discovered as an additional cause of idiopathic infantile hypercalcemia. This report describes a female infant admitted for evaluation of nephrocalcinosis. She presented with hypercalcemia, hypercalciuria, low intact parathyroid hormone level, and high 1,25-dihydroxyvitamin D3 level. Exome sequencing identified novel compound heterozygous mutations in SLC34A1 (c.1337G>A, c.1483C>T). The patient was treated with fluids for hydration, furosemide, a corticosteroid, and restriction of calcium/vitamin D intake. At the age of 7 months, the patient's calcium level was within the normal range, and hypercalciuria waxed and waned. Renal echogenicity improved on the follow-up ultrasonogram, and developmental delay was not noted. In cases of hypercalcemia with subsequent hypercalciuria, DNA analysis for SLC34A1 gene mutations and CYP24A1 gene mutations should be performed. Further studies are required to obtain long-term data on hypercalciuria and nephrocalcinosis.

Normal physiological functions in two animal species with highly different vitamin d status compared to that of humans / Funciones fisiológicas normales en dos especies animales con estatus de vitamina d muy diferentes del actual en seres humanos

Mole rats live in permanent darkness, in networks of underground tunnels (which extend up to 1 km in the subsoil), excavated with their incisors, in warm and semi-arid areas of South Africa. Mole rats have an unusually impoverished vitamin D3 status with undetectable and low plasma concentrations of 25- hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3, respectively. They express 25-hydroxylase in the liver and 1-hydroxylase and 24-hydroxylase in their kidneys. The presence of specific receptors (VDR) was confirmed in the intestine, kidney, Harderʼs glands and skin. In spite of their poor vitamin D3 status, the apparent fractional intestinal absorption of calcium, magnesium and phosphate was high, always greater than 90%. Oral supplementation with cholecalciferol to mole rats did not improve the efficiency of gastrointestinal absorption of these minerals. Mole ratsdo not display the typical lesion of rickets: hypertrophic and radiolucent growth cartilages. Histological studies reported normal parameters of trabecular and cortical bone quality. Marmosets (monkeys of the New World) are not hypercalcaemic, eventhough they exhibit much higher levels of 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3 and parathyroid hormonethan that of rhesus monkeys and humans. Fed a high vitamin D3 intake (110 IU/day/100 g of body weight), a fraction of the experimental group was found to display osteomalacic changes in their bones: distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption. These findings suggest that some marmosets appears to suffer vitamin D-dependent rickets, type II. The maximum binding capacity of the VDR or the dissociation constant of VDR1α,25(OH)2D3 complex of mole rats and New World monkeys are distinctly different of VDR isolated from human cells. Health status of those species appears to be adaptations to the mutations of their VDR. Though rare, as mutations may occur at any time in any patient, the overall message of this review to clinicians may be: recent clinical studies strongly suggests that the normality of physiological functions might be a better indicator of the health status than the serum levels of vitamin D metabolites. (AU)

Las ratas topo viven en la oscuridad permanente, en redes de túneles subterráneos excavadas con sus incisivos (que se extienden hasta 1 km en el subsuelo), en áreas cálidas y semiáridas de Sudáfrica. Las ratas topo tienen un estatus de vitamina D3 inusualmente empobrecido con concentraciones plasmáticas indetectables de 25-hidroxivitamina D3 y bajas de 1α, 25-dihidroxivitamina D3. Poseen 25-hidroxilasa en el hígado y 1-hidroxilasa y 24-hidroxilasa en sus riñones. La presencia de receptores específicos (VDR) ha sido confirmada en el intestino, el riñón, las glándulas de Harder y la piel. A pesar de su pobre estatus de vitamina D3,la absorción fraccional intestinal aparente de calcio, magnesio y fosfato fue alta, siempre superior al 90%. La suplementación oral con colecalciferol a las ratas topo no mejoró la eficacia de la absorción gastrointestinal de estos minerales. No muestran la lesión típica del raquitismo: cartílagos de crecimiento hipertróficos y radiolúcidos. Varios estudios histológicos confirman los hallazgos radiológicos y se informan parámetros normales de la calidad ósea trabecular y cortical. Los titíes (monos del Nuevo Mundo) exhiben calcemias normales con niveles más elevados de 25-hidroxivitamina D3, 1α,25-dihidroxivitamina D3 y hormona paratiroidea que los monos rhesus y los seres humanos. Un tercio de un grupo de titíes alimentados con una alta ingesta de vitamina D3 (110 I/día/100 g de peso corporal) exhibió cambios osteomalácicos en sus huesos: aumento en la superficie osteoide, volumen osteoide y activa reabsorción osteoclástica. Estos hallazgos sugieren que una fracción de la población de titíes padece raquitismo dependiente de vitamina D, tipo II. Debido a mutaciones ocurridas hace millones de años, las máximas capacidades de ligamiento del VDR o los valores de la constante de disociación del complejo VDR-1α,25(OH)2D3 de las ratas topo o monos del Nuevo Mundo son muy diferentes de los verificables en receptores aislados de células humanas actuales. El mensaje de esta revisión a los médicos clínicos podría ser: varios estudios clínicos recientes indican que la normalidad de las funciones fisiológicas de un paciente es un mejor indicador de su salud que los niveles séricos de los metabolitos de la vitamina D. (AU)

Influence of vitamin D receptor FokI polymorphism on expression of CYP24A1 in periodontal cells / 北京大学学报(医学版)

OBJECTIVE@#There is asingle nucleotide polymorphism (SNP) in the exon 2 of the vitamin D receptor (VDR) gene that can be distinguished using the restriction endonuclease FokI, and accordingly divided into three genotypes: FF, Ff and ff. VDR-FokI polymorphism was the only known SNP that could alter the protein structure of VDR. CYP24A1 is the gene encoding vitamin D 24 hydroxylase and is a vitamin D responsive gene. The influence of rs2228570 on transcriptional activation by VDR in human gingival fibroblasts (hGF) and periodontal ligament cells (hPDLC) was investigated in this study.@*METHODS@#hGF and hPDLC of 12 donors' were primarily cultured and genomic DNA was extracted. A part of genomic DNA with the length of 267 bp was obtained using PCR, which contained the SNP. VDR-Fok I genotypes were determined according to the results of restriction fragment length polymorphism. hGF and hPDLC were stimulated with 10 nmol/L 1α,25 dihydroxy vitamin D3 (1,25OH2D3) or 1 000 nmol/L 25 hydroxy vitamin D3 (25OHD3) for 48 h before RNA was extracted. Then VDR antagonist ZK159222 was used or not used during 1,25OH2D3 or 25OHD3 stimulation with hGF and hPDLC. After 1,25OH2D3 stimulation for 48 h, the proteins in hGF and hPDLC were also collected. The protein expressions of CYP24A1 and VDR were detected using Western blot.@*RESULTS@#Among the 12 donors' cell cultures, the number of FF, ff and Ff genotypes was 4, 3 and 5, respectively.After stimulation with 1,25OH2D3 or 25OHD3 for 48 h,CYP24A1 mRNA levels in FF-hGF were significantly higher than those in other hGF genotypes(1,25OH2D3: F=31.147, P<0.01; 25OHD3: F= 32.061,P <0.01), as was in FF-hPDLC (1,25OH2D3: F=23.347, P<0.01; 25OHD3: F=32.569,P<0.01). When ZK159222 was used before 1,25OH2D3 stimulation, this statistically significant difference disappeared (hGF: F=0.246, P=0.787; hPDLC: F=0.574, P=0.583). When ZK159222 was used before 25OHD3 stimulation, the trend was similar (hGF: F=1.636, P=0.248; hPDLC: F=0.582, P=0.578).After stimulation with 1,25OH2D3 for 48 h, CYP24A1 protein levels in FF-hGF were significantly higher than those in the other hGF genotypes (F=12.368, P <0.01), as was in FF-hPDLC (F=15.749, P <0.01). In hGF and hPDLC, the mRNA or protein expression of VDR of different genotypes was not significantly different under different stimulation conditions.The paired comparison showed that there was no statistically significant difference between the expression of CYP24A1 in hGF and that in hPDLC under all the stimulation conditions, as was the expression of VDR.@*CONCLUSION@#In hGF and hPDLC, the FF-VDR genotype is associated with the more remarkable up-regulation of CYP24A1than the other genotypes, indicating that transcriptional activation of FF-VDR might be higher than those of other vitamin D receptors.

Screening study for genetic polymorphisms affecting pharmacokinetics of talniflumate

Talniflumate is a phthalidyl ester of niflumic acid, which has potent analgesic and anti-inflammatory effects and is widely used to treat inflammatory disorders, such as rheumatoid arthritis. To screen the possible genetic factors affecting the pharmacokinetics (PK) of talniflumate, 23 male Korean volunteers were enrolled from two separate bioequivalence studies. All subjects received 740 mg (two tablets) talniflumate in a standard 2×2 cross-over model in a randomized order. For the genetic study, PK parameters of the reference drug were used. We used Illumina Human610Quad v1.0 DNA Analysis BeadChip for whole genome single nucleotide polymorphism (SNP) analysis and whole genome genotyping data were processed by linear regression analysis for PK parameters. Whole genome analysis revealed 1498 significant SNPs (P < 0.0001) for Cmax, 65 significant SNPs (P < 0.0001) for T(max), and 1491 significant SNPs (P < 0.0001) for AUC(inf). For clinical pharmacological purposes, we selected SNPs from drug metabolizing enzymes and transporters, and analyzed the PK parameters of various genotypes. Two SNPs (rs11165069 from ABCA4 (p=0.00002); rs17847036 from CYP2C9 (p=0.000001)) showed significant associations with talniflumate C(max). In the T(max) group, two SNPs (rs3787555 from CYP24A1 (p=0.00035); rs2275034 from ABCA4 (p=0.000587)) showed significant associations with talniflumate T(max). In the AUC(inf) group, two SNPs (rs11165069 from ABCA4 (p=0.00002); rs12461006 from SLC1A6 (p=0.00008)) exhibited significant associations with talniflumate absorption. These results show that genetic factors could affect the PK parameters, and provide information that may be used in the development of personalized talniflumate therapy.

The effects of serum calcium and 1 alpha hydroxylase on the expression of 24-hydroxylase gene / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effects of 1 alpha hydroxylase and serum calcium on the expression of 24-hydroxylase gene in mice kidney.</p><p><b>METHODS</b>Mice with targeted deletion of the 25-hydroxyvitamin D 1 alpha hydroxylase gene(1alpha (OH)ase-/-), and the vitamin D receptor gene (VDR-/-) were used. The study of each mutant had two groups which were (1) mutant with high calcium diet, which maintained fertility but left mice hypocalcaemia; (2) mutant with high lactose diet, which normalized calcium in two mutant. Mice in same litter were as control. There were six groups in total and each group had five mice. All mice were killed at 10-week-old. Serum calcium was determined by an autoanalyzer. RNA was isolated from mouse kidney and the express of 1 alpha hydroxylase gene and 24-Hydroxylase gene were studied by RT-PCR.</p><p><b>RESULTS</b>On the high calcium intake, all mutant animals were hypocalcaemia (1alpha (OH)ase-/- (78 +/- 10.4) mg/L, P < 0.05; VDR-/- (68 +/- 9.8) mg/L, P < 0.05. WT (111 +/- 16.5 mg/L), but when the high lactose diet was administered, serum calcium levels in two mutant mice rose to wild-type levels. The 1 alpha hydroxylase gene was expressed at very higher levels in the vitamin D receptor mutant mice than in wild-type mice when animals received a high calcium intake; This was reduced by eliminating hypocalcaemia with the high lactose diet. Expression of the 24(OH)ase gene was extremely down-regulated in two mutant mice on the high calcium diet but was restored to wild-type levels on the high lactose diet.</p><p><b>CONCLUSION</b>The express of 24-hydroxylase gene was directly regulated by serum calcium rather than 1 alpha-hydroxylase. These studies indicate that both the serum calcium and 1 alpha-hydroxylase exert effects on the expression of 24-hydroxylase gene, but 1 alpha-hydroxylase take the effects by elevated the concentration of serum calcium. There are no direct interaction between 1 alpha-hydroxylase gene and 24-hydroxylase gene.</p>