Intermittent intravenous followed by intermittent oral 1α(OH)D3 treatment of secondary hyperparathyroidism in uraemia

Brandi L, Daugaard H, Egsmose C, Tvedegaard E, Kjærulff Nielsen P, Olgaard K (Medical Department P, Division of Nephrology, Rigshospitalet, University of Copenhagen, Denmark). Intermittent intravenous followed by intermittent oral 1α(OH)D₃ treatment of secondary hyperparathyroidism in uraemia. J Intern Med 1996; 239: 353–60. Objectives . To examine whether intermittent oral 1α(OH)D₃ treatment of patients on haemodialysis with secondary hyperparathyroidism (HPT) was able to maintain the marked suppression of PTH, which previously had been induced by an intermittent intravenous administration of 1α(OH)D₃. Simultaneously, the effect of the different routes of administration of 1α(OH)D₃ on the circulating levels of N-and C-terminal PTH fragments was measured. Design . An open study of patients on chronic haemodialysis. Setting . Renal division, Rigshospitalet, Copenhagen, Denmark. Subjects . A total of 26 patients started and five patients completed the total protocol. Interventions . The treatment protocol was divided into three parts: (i) 1α(OH)D₃ administered intravenously for >300 days; then (ii) 1α(OH)D₃ administered orally for 100 days, followed by (iii) 1α(OH)D₃ administered intravenously again for another 100 days. 1α(OH)D₃ was given three times a week at the end of each dialysis. Main outcome measures . Intact PTH, N- and C-terminal PTH. Results . Intact PTH levels were significantly (P<0.0001) suppressed by 90.4±3.3% after 56 days of intermittent intravenous 1α(OH)D₃ treatment. This degree of suppression remained stable during the following period of oral treatment and did not change further when intravenous treatment was reinstituted. The circulating levels of intact PTH and N- and C-terminal iPTH were not influenced by the administered route of 1α(OH)D₃. Conclusions . Intravenous 1α(OH)D₃ treatment of the secondary HPT in dialysis patients can safely be changed to oral treatment at the time when optimal suppression of PTH has been achieved.     

小剂量1，25（OH）_2D_3口服冲击治疗尿毒症患者继发性甲状旁腺功能亢进

目的：对２０例尿毒症继发性甲状旁腺功能亢进患者使用小剂量１，２５（ＯＨ）２Ｄ３口服冲击治疗，以比较其与常规治疗的疗效。方法：４０例尿毒症透析患者，随机分为常规治疗组（ｎ＝２０），口服罗钙全０．２５μｇ／ｄ；冲击治疗组（ｎ＝２０），口服罗钙全２μｇ／次，每周２次，８周后改为０．２５μｇ／ｄ维持１个月。结果：冲击治疗组血ＰＴＨ、ＡＫＰ、Ｐ３＋较常规治疗组下降明显，血钙上升，症状改善，无高血钙发生。结论：应用小剂量１，２５（ＯＨ）２Ｄ３，无发生高血钙的危险，是一种经济合理安全有效的治疗方法     

乙肝后肝硬化患者血清1,25(OH)2D3检测及其临床意义

采用竞争性放射受体法测定３２例乙肝后肝硬化患者血清１Ｍ２５（ＯＨ）２Ｄ３水平,并与３２例性乙型肝炎、３１例健康者对照。发现：肝硬化组血清１,２５（ＯＨ）２Ｄ３水平较肝炎组和对照组明显下降（Ｐ〈０．０１,Ｐ〈０．００１）,且与血清骨钙素、尺桡密度呈正相关（Ｐ〈０．０１,Ｐ〈０．０５）。提示：测定乙肝后肝硬化患者血清１,２５（ＯＨ）２Ｄ３水平有利于肝性骨病的早期发现。     

Levels of 1,25(OH)2D3 for patients with pulmonary tuberculosis and correlations of 1,25(OH)2D3 with the clinical features of TB

Background

To determine the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentrations to patients with tuberculosis (TB) and whether it influenced the patient’s clinical features.

Methods

For the first part, a total of 153 healthy adults and 74 patients with pulmonary TB (PTB) were enrolled. Serum concentrations of 1,25(OH)2D3 were determined by liquid chromatography-tandem mass spectroscopy to examine the 1,25(OH)2D3 concentrations of the two groups from the peripheral blood. If there are differences between the two groups, what follow will increase the experimental group numbers to examine the relationship among the 1,25(OH)2D3 concentrations with the numbers of the lesion area, the tubercule bacilli in sputum and the CD4/CD8 ratio of T lymphocytes in the peripheral blood.

Results

In the first part, the 1,25(OH)2D3 concentrations was lower in patients with TB than in those healthy adults [365.9 (SD 235.7) vs. 464.3 (SD 335.6), P<0.05]. In the second part, we increased the sample size to 134 (male 91 cases, female 43 cases). we found that the plasma levels of 1,25(OH)2D3 are not correlated with the numbers of the lesion area and the tubercule bacilli in sputum, but the 1,25(OH)2D3 levels can interact the ratio of CD4/CD8 T lymphocytes, it shows a positive correlation with the ratio of CD4/CD8 T lymphocytes.

Conclusions

The 1,25(OH)2D3 concentrations in TB patients lower than the healthy adults, it might exist as a risk factor during the development of TB or TB might affect the levels of 1,25(OH)2D3. But the different status vitamin D concentration might not affect the numbers of the lesion area, the tubercule bacilli in sputum. It shows a positive correlation with the ratio of CD4/CD8 T lymphocytes. The study will have a significance value to clinical medicine, but further study will need to study the levels of 1,25(OH)2D3 with the TB.     

腹膜透析患者1,25二羟基D3冲击治疗的疗效观察

为了探讨口服１，２５（ＯＨ）２Ｄ３冲击治疗对腹膜透析患者钙磷代谢及甲状旁腺功能的影响，我们给予３２例ＣＡＰＤ患者口服１．２５（ＯＨ）２Ｄ３大剂量冲击治疗（２－４μｇ／次，每周２次）．另２９例为常规治疗组（０．２５－０．５ｕｇ／ｄ）作为对照组。结果显示，两组患者血钙均明显升主，血磷及血ＡＫＰ均明显降低；ＰＴＨ和ＣＴ在常规治疗组有轻度降低，但无统计学差异；而口服冲击治疗组，ＰＴＨ和ＣＴ则明显降低，且临床症状明显改善，用药过程中未发现明显副作用。上述结果表明，１，２５（ＯＨ）２Ｄ３口服冲击治疗是纠正钙磷代谢紊乱和甲状旁腺功能亢进的较佳疗法，值得推荐。     

肝硬化患者血清1,25(OH)_2D_3变化对骨代谢的影响

分别采用竞争性放射受体法及放免法测定32例肝硬化患者血清1,25(OH)2D3、PTH水平,并与32例慢性乙型活动性肝炎、31例健康者对照。发现:肝硬化组血清1 ,25(OH)2D3较肝炎组和对照组明显下降(P<0.01,P<0.001),并与血钙、尺桡骨密度呈正相关(P<0.01,P<0.05);肝硬化组血清 PTH较肝炎组和对照组明显升高(P<0.05,P<0.05),但与血钙、尺桡骨密度无相关性。提示:肝硬化患者血清 1,25(OH)2D3降低与肝性骨病的发生关系密切,检测其水平,有利于该病的早期发现。     

Gene expression analysis of 1,25(OH)2D3-dependent differentiation of HL-60 cells: a cDNA array study

The alterations in gene expression associated with 1,25(OH)2D3-induced differentiation of HL-60 cells were studied in order to identify potential targets for further investigation of the genetic basis of acute myeloid leukaemia. Atlas human haematology filters, including 406 genes (Clontech), were used to study gene expression in response to 1,25(OH)2D3 (concentration, 5 x 10-8 mol/l) for 24 and 72 h. Compared with untreated cells, expression differences were found in 43 genes. Downregulated genes at both time-points were: IL2RA, CMYC, NPM, DEK, AF4, FLI1, htlf, MNDA, BCR, IKAROS, BPI and NFAT4. Upregulated genes at both time-points were IL1B, CD14 and MCL1. CD55, CD58, IRF2, CREB1, ATF4, RAC1, TIAR, KIAA0053, BAT2, BTK, RCK, EV12B and EDN were downregulated at 24 h, while SPI1, MKK3, BTG1 and IL8 were upregulated. At 72 h the upregulated genes were IL1RA, IL2RG, CXCR4, SCYA1, SCYA3, SCYA4, SCYA5, SCYA22, ANX2, CD83 and UPAR. cDNA array results were confirmed on randomly selected genes using quantitative real-time polymerase chain reaction for three upregulated (CXCR4, IL1B and CD14) and three downregulated (DEK, AF4 and FLI1) genes. Gene expression analysis after differentiation induction may provide a tool to study the roles of DEK, AF4 and FLI1 in cell proliferation and differentiation. To demonstrate the genes that initiate differentiation, sequential gene expression analysis has to be performed during the first 24 h of the differentiation process.     

Demonstration of a high affinity receptor for 1,25-dihydroxyvitamin D3 in rat pancreas

The existence of a high affinity receptor for 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) in rat pancreas was biochemically demonstrated in this study. In order to study the properties of this putative receptor, we took advantage of the analysis of low ionic strength chromatin-localized 1,25(OH)₂D₃ receptor. Using this method, the susceptibility of receptor protein to enzymatic degradation was so decreased, and the contamination by plasma vitamin D binding protein (DBP) component was so efficiently eliminated that a specific, saturable binding for 1,25(OH)₂D₃ could be demonstrated in the saturation analysis and the peak for the receptor was consistently apparent in the sucrose density gradient analysis. The equilibrium dissociation constant (Scatchard K_d) was found to be 3.7 ± 1.5 × 10^-10 (M), and the concentration of specific binding sites was calculated to be 1.22 ± 0.40 (fmol/mg protein). The number of specific binding sites in the rat pancreas was only 0.44% of that present in rat intestine (277 ± 19 (fmol/mg protein)) and 6.7% of that in rat kidney (18.1 ± 1.0 (fmol/mg)). However, when a correction is made for the 1,25(OH)₂D₃ receptor distribution in the tissues and expressed as the receptor concentration per receptor-containing cells, the rat pancreatic receptor level was calculated to be about 30% of the rat intestine. Sucrose density gradient sedimentation of this receptor yielded a value of 3.2 ± 0.1 (S) for the sedimentation coefficient and this peak was displaceable by a 100-fold excess of nonradioactive 1,25(OH)₂D₃. These data provide evidence for the presence of a specific 1,25(OH)₂D₃ receptor in mammalian pancreas, and we suggest, in conjunction with the facts that vitamin D₃ and its active metabolites play a physiological role on insulin secretion from rat pancreatic β-cells, that this receptor might be involved in the mechanisms of action of vitamin D₃ on insulin secretion from rat pancreas via a genomic effect.     

大剂量1,25(OH)_2D_3口服冲击治疗血透患者甲状旁腺素和血小板胞内游离钙异常

目的：了解大剂量１，２５（ＯＨ）２Ｄ３口服冲击对血透患者血清甲状旁腺素［ＰＴＨ（１～８４）］和血小板胞内游离钙浓度（Ｐｔ［Ｃａ２＋］ｉ）的影响和相互关系。方法：用Ｆｕｒａ２荧光测定法和免疫放射法对１２例血透患者测定Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４）。结果：静息Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４），治疗前是升高的，治疗后则降低；且两者密切相关，其Ｐ值治疗前＜０００１，治疗后＜００２５。多因素逐步回归显示：ＰＴＨ（１～８４）在Ｐｔ［Ｃａ２＋］ｉ的影响中起显著作用。结论：大剂量１，２５（ＯＨ）２Ｄ３冲击治疗能降低Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４），其降低Ｐｔ［Ｃａ２＋］ｉ的作用可能是通过抑制ＰＴＨ合成与分泌     

慢性肾脏病229例25羟基维生素D浓度及影响因素分析

目的了解慢性肾脏病(CKD)患者维生素D不足与缺乏情况及其相关因素。方法测定2009年1月至2010年9月北京大学人民医院229例非肾病综合征、非血液净化的CKD 1～5期患者血清25羟基维生素D[25(OH)D]及其他临床指标,分析维生素D不足及缺乏的发生率,应用Logistic回归分析维生素D缺乏的独立预测因子。结果 229例CKD患者25(OH)D浓度(30.23±13.95)nmol/L。维生素D浓度随CKD分期进展而呈现逐渐下降趋势。维生素D缺乏者169例(73.80%)。CKD各期间维生素D缺乏发生率差异有统计学意义,且随CKD分期的进展,维生素D缺乏的发生率有升高的趋势(χ2=18.289,P=0.001)。在除外糖尿病患者并对年龄进行校正后,维生素D缺乏的发生率在CKD各期间的差异仍具有统计学意义(P=0.025)。Logistic回归分析显示,血清白蛋白、磷及糖尿病是CKD患者25(OH)D缺乏的独立预测因子。结论非肾病综合征、非血液净化CKD患者维生素D不足及缺乏发生率高,且在CKD早期就已存在。血清白蛋白、磷及糖尿病是CKD非血液净化、非肾病综合征患者25(OH)D缺乏的独立预测因子。     

血清25(OH)D_3水平在哮喘发作期、治疗后的变化及与肺功能的相关性分析

目的探讨哮喘患者急性期及治疗后血清25(OH)D_3水平与肺功能及病情的相关性。方法选取来我院诊治的急性发作期哮喘患者60例为研究组,分为成年亚组及未成年亚组各30例,于治疗前及治疗后7d(缓解期),治疗后3个月测定其血清25(OH)D_3水平、第1秒用力呼气容积占预计值百分比(FEV1%pred)、呼气峰流速(PEF),于治疗前及治疗3个月后进行哮喘控制评分(ACT);于上述时间点选择健康人群为对照组测量相应指标,比较健康与患病人群两亚组间各项指标差异,并分析治疗前及3个月后研究组两亚组血清25-(OH)D_3水平与其他指标间的相关性。结果治疗前发作期、开始治疗后7d及3个月,对照组与研究组各亚组之间,各指标均有显著差异;而研究组治疗7d后血清25(OH)D_3水平也远高于治疗前。治疗前两亚组血清25(OH)D_3与FEV1%pred、PEF间无明显相关性;而开始治疗3个月后,两亚组血清25(OH)D_3与FEV1%pred、PEF及ACT评分均有显著正相关(未成年r=0.81,0.79,0.82;P均0.05;成年组r=0.61,0.54,0.70;P均0.05)。结论哮喘患者发作、缓解及稳定期血清25(OH)D_3水平在病情的诊断与预后评估中能发挥重要作用,值得进一步大样本深入研究。     

Refractoriness to alpha-interferon (Intron A) in previously chemotherapy-treated patients with chronic myelocytic leukaemia

8 patients with chronic myeloid leukaemia in the chronic phase who had previously received chemotherapy were given alpha-interferon (Intron A). The Intron A was administered subcutaneously at a dose of 2 x 10(6) I.U./m2 three times a week and this was increased to 4-5 million I.U./m2 daily if no response was obtained after 6-8 months. 1 patient was Philadelphia chromosome-negative and was the only one who showed a major response to treatment. The other 7 patients never achieved haematologic remissions, or even a significant reduction in the immature blood leucocyte count or spleen size.     

Role of beta1- and alpha2c-adrenergic receptor polymorphisms and their combination in heart failure: a case-control study

BACKGROUND: Adrenergic activation has a central role in the development of HF. The function of the beta1- and the alpha2C-adrenergic receptors is influenced by gene polymorphisms: the beta1Arg389 variant is associated with increased beta1-receptor sensitivity and the alpha2C-receptor Del322-325 variant is associated with decreased alpha2C receptor function and increased norepinephrine release. We hypothesised that these polymorphisms could influence the prevalence of heart failure. METHODS: The role of the beta1- and alpha2C-adrenergic receptor gene polymorphisms as risk factors for heart failure (HF) was assessed in an Italian white Caucasian population using a case-control study design. Genomic DNA was analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP). RESULTS: We compared 260 Caucasian patients with HF and 230 normal subjects. The beta1Arg389 allele was frequent both in the patients with HF (69%) and in the normal subjects (73%). The alpha2CDel322-325 variant was rare in both groups (9% and 8%, respectively). Patients homozygotes for either the beta1Arg389 or the alpha(2C)Del322-325 alleles had no increased risk of HF (odds ratio [OR], 0.8; 95%CI: 0.5-1.2 and OR, 0.8; 95% CI: 0.4-1.8, respectively). Patients homozygotes for both the beta1Arg389 and the alpha(2C)Del322-325 alleles had no increased risk of HF as well (OR: 0.6; 95% CI: 0.2-2.1). CONCLUSIONS: Beta1-ARs and alpha2C-ARs polymorphisms are not associated with an increased risk of HF in an Italian white Caucasian population.     

1,25(OH)2D3对应用糖皮质激素治疗的肾病患者骨代谢的影响

目的观察1,25(OH)2D3对应用糖皮质激素治疗的原发性肾脏病患者骨代谢的影响。方法将16例原发性肾脏病患者随机分为治疗组和对照组。治疗组在应用糖皮质激素治疗的同时给予0.25μg的1,25(OH)2D3,每日1次口服,碳酸钙0.75,每日3次口服。对照组单纯给予碳酸钙0.75,每日3次口服。所有患者在治疗前及治疗12周时应用双能X线吸收法骨密度仪测定腰椎和股骨颈的骨密度,同时测定有关骨代谢指标,包括血全段甲状旁腺素,骨钙素,尿脱氧吡啶啉,血钙、磷以及血清白蛋白,24小时尿蛋白定量、尿钙和尿磷。结果治疗12周时两组患者的腰椎和股骨颈骨密度均下降,两组间比较无显著性差异(P>0.05);治疗12周时对照组患者的骨钙素较治疗前明显下降(P<0.05),而治疗组无明显差异;尿脱氧吡啶啉在两组中均下降,但治疗组下降明显(P<0.05);两组患者血全段甲状旁腺素、24小时尿钙和尿磷治疗前后及组间比较均无显著性差异(P>0.05);应用1,25(OH)2D3治疗者无1例出现高钙血症。结论应用糖皮质激素治疗12周的原发性肾脏病患者其腰椎及股骨颈骨密度下降明显。1,25(OH)2D3可促进骨形成,抑制骨的吸收。     

Effect of 1,25-Dihydroxyvitamin D3 on Biochemical Indices of Bone Turnover in Postmenopausal Women

ABSTRACT Bone metabolism was estimated by serum alkaline phosphatase (index of bone formation) and fasting urinary excretions of calcium and hydroxyproline (indices of bone resorption) in a group of early postmenopausal women and a group of 70-year-old women, during 12 months' treatment with 1,25-dihydroxycholecalciferol (1,25(OH)₂D₃), and compared to oestrogen/gestagen treatment or placebo treatment. The groups treated with 1,25(OH)₂D₃ did not show any change in bone metabolism, neither in bone resorption nor in bone formation, during the treatment period when compared to the placebo group, whereas treatment with female hormones decreased both bone resorption and bone formation.     

1,25-Dihydroxy-vitamin D3 (calcitriol)-dependent protein phosphorylation in rat duodenum: effects of ageing

We have examined the ability of 1,25(OH)₂-vitamin D₃ [1,25(OH)₂D₃; calcitriol], the hormonal form of vitamin D₃, to stimulate the phosphorylation of proteins in rat duodenum from young (3 months) and aged (22–24 months) rats. Brief (30 s) exposure of duodenum preincubated with ³²P-orthophosphate to the hormone increased the labeling of whole tissue proteins, an effect that was greatly diminished in aged animals. The response was dose-dependent, with maximal stimulation achieved at 1 nM calcitriol (+113% and +10% for young and aged rats, respectively). Phosphoproteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified by autoradiography. The hormone potentiated the phosphorylation predominantly on serine, threonine, and tyrosine residues of five acidic proteins of relative molecular masses of 66, 48, 45, 28, and 16 kDa. Moreover, the effects of calcitriol were exerted at the membrane level and varied as a function of exposure time. Direct treatment of purified basal lateral membranes for 30 s with the hormone (1 nM) stimulated the incorporation of ³²P of a 66kDa protein by 75% and of a 48 and 45kDa proteins by 60%. The effects of the hormone on basal lateral membrane protein phosphorylation were suppressed by the PKA, PKC, and tyrosine kinase inhibitors, Rp-cAMPS, bisindolylmaleimide, and genistein, respectively. In basal lateral membrane isolated from old animals, only minor changes in calcitriol–induced protein phosphorylation of the 66-kDa protein were observed. Taken together, these results suggest that calcitriol modulates duodenal membrane protein phosphorylation, at least in part through PKA, PKC, and tyrosine kinases, and that this mechanism is severely altered with ageing. The identity of the proteins whose phosphorylation was stimulated by calcitriol and their physiological role is currently under investigation.     

1,25(OH)_2D_3对去卵巢大鼠骨组织成骨细胞、骨细胞凋亡的影响

目的观察1,25(OH)_2D_3对去卵巢大鼠骨组织中成骨细胞、骨细胞凋亡的影响。方法 36只雌性SD大鼠随机分成四组,对尼尔雌醇组和1,25(OH)_2D_3组分别给予尼尔雌醇(0.1mg/kg)和1,25(OH)_2D_3(0.05μg/kg)治疗12周。12周后,以DXA法测定大鼠全身的骨密度;放射免疫法测定各组大鼠血清中骨钙素及雌二醇的水平;处死各组大鼠,采用3′-OH末端DNA原位标记技术和透射电镜检测骨细胞、成骨细胞凋亡。结果 12周后,去卵巢组大鼠的骨密度和血清雌二醇水平明显降低,骨钙素含量升高,与假手术组相比,差异有显著性(P0.05)。1,25(OH)_2D_3可以增加去卵巢大鼠的全身骨密度和血清骨钙素含量(P0.05),但是不增加血清雌二醇的水平(P0.05)。1,25(OH)_2D_3可以抑制骨细胞、成骨细胞凋亡,与去卵巢组相比差异有显著性(P0.05)。结论 1,25(OH)_2D_3对去卵巢大鼠骨质疏松症具有防治作用,其部分机制可能为1,25(0H)_2D_3抑制了骨细胞、成骨细胞凋亡,从而调节骨重建。     

The relationship between balance and vitamin 25(OH)D in fibromyalgia patients

Introduction: Fibromyalgia syndrome (FMS) is a chronic disease characterized by diffuse pain of unknown cause, fatigue, sleep disorders, cognitive dysfunction, and sensitivity. Fibromyalgia was shown to be associated with balance problems and increased incidence of falls. There are many theoretical mechanisms related to the impact of vitamin D on postural control. The aim of the current study was to investigate the relationship between vitamin 25(OH)D levels and pain, balance and daily activities in patients with FMS.

Method: Patients aged 35–65 years who were diagnosed with FMS according to 1990 ACR diagnostic criteria were screened. Seventy patients diagnosed with FMS and 60 healthy controls with comparable age and gender were included in the study. Fibromyalgia impact scale (FIQ), Berg Balance Scale (BBS), the Nottingham Health Profile (NHP), and visual analog scale (VAS) were applied to the subjects. The subjects were divided into two groups by vitamin 25(OH)D level being above or below 30?ng/ml.

Results: A statistically significant difference was established between VAS, BBS value and all NHP subscale and NHP total values of FMS patients and those of healthy control group. The relationship between BBS and the level of vitamin 25(OH)D of all participants was investigated, a positive statistically significant relationship was found with Vit-D at r?=?0.481 level (p?Conclusion:: It was observed that low vitamin D levels affected balance in both FMS group and healthy control group. It should be kept in mind that vitamin D level is likely to negatively affect balance and VAS values in FMS.