原发性甲状旁腺机能亢进症的术前诊断与临床并发症分型(附60例分析)

本文报告60例原发性甲旁亢(1963～1990)并给以临床分型。男25例,女35例。平均年龄34.2岁,平均病程5.6年。54例接受手术治疗,其中47例为腺瘤,5例增生与2例癌。另6例接受甲腈眯胍治疗。甲旁亢诊断主要依靠高血钙,低血磷,低血镁,AKP 升高,血 Cl/P 比值升高,PTH、BGP 升高,TRP 降低,以及尿钙、磷、镁、HOP 及 cAMP 升高。甲旁亢临床可并发多种疾病,41例骨病变,17例骨肾病变,2例肾结石,7例溃疡病,3例急性胰腺炎,4例危象,6例高血压和6例心脏病等十余种临床并发症。死亡4例(6.6%),术后预后较好。     

Comparison of dried plum supplementation and intermittent PTH in restoring bone in osteopenic orchidectomized rats

Summary Bone loss was confirmed after 90 days in 50 6-month-old male Sprague Dawley rats that were sham-operated or orchidectomized (ORX). In this study, we have shown that dried plum (DP) has potent effects on bone in terms of bone mass, microarchitecture, and strength in osteopenic male rats. Although these changes may be mediated through the suppression of bone resorption, the fact that the restoration in some of the bone structural and biomechanical parameter shares some similarities with parathyroid hormone (PTH) should not be overlooked. Further investigation is needed on a mechanistic level to clarify the influence of DP on bone metabolism. Introduction This study was designed to investigate the extent to which DP reverses bone loss in osteopenic ORX rats and to compare its effects to PTH. Materials and methods Fifty, 6-month-old male Sprague Dawley rats were sham-operated or ORX, and bone loss was confirmed after 90 days. The ORX groups were assigned to control (AIN-93M) diet, 25% DP diet, or PTH (80 μg/kg) for 90 days. Results DP induced an 11% increase in vertebral and femoral BMD compared to ORX-controls. BMD in the PTH-treated group was increased by 20.7% (vertebra) and 17.9% (femur). Vertebral trabecular bone volume (BV/TV) and number were increased by DP and trabecular separation was decreased compared to controls, which were similar to PTH. Alterations in trabecular bone of the femur were similar to those in the vertebra, but DP did not restore BV/TV to the same extent. Cortical thickness was improved by DP and further enhanced by PTH. DP tended to decrease urinary deoxypyridinoline and calcium, but did not alter alkaline phosphatase or osteocalcin. Conclusion We conclude that though the degree of improvement was not equivalent to PTH with regard to all parameters, DP reverses bone loss due to ORX and the mechanisms should be further investigated.     

The effect of 1,25 dihydroxycholecalciferol on parathyroid hormone secretion by monolayer cultures of bovine parathyroid cells

Summary Controversy exists over a direct effect of 1,25(OH)₂D₃ on PTH secretion. To investigate the possibility that the suppressive effect of 1,25(OH)₂D₃ on PTH secretion may be demonstrable in 1,25(OH)₂D₃-depleted tissue and/or after prolonged periods of exposure to 1,25(OH)₂D₃, primary monolayer cultures of bovine parathyroid cells were established in 1∶1 DMEM/Ham's F-12 media supplemented with 2% calf serum but not 1,25(OH)₂D₃. Ionized calcium was maintained at 1.0 mM. Experiments were performed on 4-day-old culture cells. PTH concentration was measured using both a mid-region/carboxyl and an amino-terminal PTH antisera. 1,25(OH)₂D₃ at a concentration of 0.1 ng/ml suppressed PTH secretion by 32±7% after 48 hours. High calcium concentration (2.0 mM) suppressed PTH secretion by 37±10% and this effect was not additive over that of 1,25(OH)₂D₃. PTH secretion rate recovered fully 48 hours after normalization of the external calcium concentration but not after the removal of 1,25(OH)₂D₃. It is concluded that 1,25(OH)₂D₃ directly suppresses PTH secretion by monolayer culture of bovine parathyroid cells.     

Thapsigargin shifts the CA set point of parathyroid cells to lower extracellular [CA]

The hypothesis that cytosolic calcium concentration ([Ca²⁺ _cyt]) is the primary regulator of parathyroid hormone (PTH) secretion is supported by a number of studies that show an inverse relationship between them. One agent shown to inhibit PTH secretion is thapsigargin, a sesquiterpene lactone that raises [Ca²⁺ _cyt] by inhibiting the Ca-ATPase that pumps Ca²⁺ from the cytosol into the lumen of the endoplasmic reticulum. Thapsigargin may act on the parathyroid cell other than to inhibit the Ca-ATPase, however, in ways that might also affect PTH secretion. We have tested its effects on functional parameters, such as protein synthesis, the exocytic machinery, and the ability of parathyroid cells to respond to different concentrations of extracellular Ca²⁺ ([Ca²⁺ _ex]). In particular, we have determined whether the inhibition of PTH secretion by thapsigargin is independent of or is modulated by changes in [Ca²⁺ _ex]. The results revealed no effects of thapsigargin on protein synthesis or the exocytic mechanisms within 2 h of treatment, and showed that [Ca²⁺ _ex] can modulate PTH secretion in the presence of thapsigargin. Its inhibition of PTH secretion, therefore, appears to rest on its ability to shift [Ca²⁺ _cyt] to higher levels, but the possibility that it interacts with the Ca receptor has not been eliminated. The results support the hypothesis that the primary regulator of steady-state PTH secretion is [Ca²⁺ _cyt].     

甲状旁腺素通过磷脂酶C非依赖途径激活蛋白激酶C

目的利用基于荧光共振能量转移(Fluorescence resonance energy transfer,FRET)技术的检测PKC激活或PKC-delta激活的报告分子来确定PTH是否可以通过PLC非依赖途径激活PKC和PKC-delta。方法将表达PKC激活报告分子(CKAR)的质粒和表达PKC-delta激活报告分子的质粒转染HEK293细胞,培养72h后通过共聚焦显微镜检测FRET的改变,并以此判断佛波酯(TPA)是否激活PKC和PKC-delta。将表达甲状旁腺素1型受体(PTHR1)的质粒与CKAR质粒或PKC-delta质粒共转染HEK293细胞,培养72h后通过共聚焦显微镜检测FRET的改变,并判断PTH(1-34)、G1R19(1-34)和0.1%的三氟乙酸(TFA)对PKC和PKC-delta的作用。结果在转染CKAR质粒或PKC-delta质粒的HEK293细胞,TPA均使青色荧光与黄色荧光的强度之比(C/Y)增加。在共转染PTH1R质粒与CKAR质粒或PKC-delta质粒的HEK293细胞,PTH(1-34)和G1R19(1-34)均增加了C/Y的值,而0.1%TFA未引起C/Y的改变。结论 PTH与PTHR1结合后通过PLC非依赖途径激活PKC/PKC-delta。     

On the lipolytic action of parathyroid hormone in man.

An investigation was carried out to determine whether bovine PTH stimulates lipolysis in human fat tissue, whether this action is mediated by cyclic adenosine 3', 5'-monophosphate and whether the N-terminal 1-34 peptide of bovine PTH is responsible for the lipolytic effect. Studies were also performed to determine if parathyroid extract (PTE) produces lipolysis in normal subjects and in patients with pseudohypoparathyroidism in whom there is a defect in the adenylate system in response to PTH in the renal cortex and presumably in the skeletal system as well. It was found that highly purified bovine PTH in the concentration range between 10(-9) M and 10(-5) M stimulated lipolysis in vitro by human fat in a dose-dependent manner. Significant increases in glycerol production were observed at concentrations of PTH as low as 10(-9) M and maximal increases were seen at 10(-6) M. The hormone significantly increased the concentration of cyclic adenosine 3' ,5'-monophosphate in fat tissue. The synthetic N-terminal 1-34 peptide of bovine PTH was as effective as the native hormone in stimulating glycerol production at a concentration of 10(-9) M-10(-6) M. PTE, 100 mU per kg per min for 30 min given intravenously, produced transient increases in the concentration of plasma free fatty acid in each of eight normal subjects, three patients with hypoparathyroidism and eight patients with pseudohypoparathyroidism. Purified bovine PTH also increased plasma free fatty acid in each of two normal subjects. It is concluded that PTH stimulates lipolysis in human subcutaneous fat, that this action of the hormone is mediated through cyclic adenosine 3', 5'-monophosphate and that the N-terminal 1-34 peptide portion of the hormone is responsible for this lipolytic action. Further, PTE stimulates lipolysis in vivo in man. There appears to be no defect in the adenylate cyclase system in the fat cell in response to PTH in patients with pseudohypoparathyroidism.     

输血后肝炎患者HCV感染及其病毒血症的研究

利用血清学ＥＬＩＳＡ方法和ＰＣＲ技术对１６９例输血后肝炎（ＰＴＨ）患者病因学进行了研究。结果表明，ＰＴＨ的主要致病原为ＨＣＶ（９８．２２％），其中部分患者（２４／１６９），同时合并有ＨＢＶ感染，３例ＰＴＨ患者病因仍不明确，ＨＣＶ感染所致ＰＴＨ患者抗ＨＣＶ检出时间为ＰＴＨ症状出现后７ｄ～１年，平均为５４．６２ｄ，ＨＣＶＲＮＡ在感染早期（６～２０ｄ）即可检出，对８４例ＰＴＨ患者１．５年～３年的随访观察     

Changes in 3-dimensional bone structure indices in hypoparathyroid patients treated with PTH(1-84): a randomized controlled study

Hypoparathyroidism (hypoPT) is characterized by a state of low bone turnover and high bone mineral density (BMD) despite conventional treatment with calcium supplements and active vitamin D analogues. To assess effects of PTH substitution therapy on 3‐dimensional bone structure, we randomized 62 patients with hypoPT into 24 weeks of treatment with either PTH(1‐84) 100 µg/day subcutaneously or similar placebo as an add‐on therapy. Micro‐computed tomography was performed on 44 iliac crest bone biopsies (23 on PTH treatment) obtained after 24 weeks of treatment. Compared with placebo, PTH caused a 27% lower trabecular thickness (p < 0.01) and 4% lower trabecular bone tissue density (p < 0.01), whereas connectivity density was 34% higher (p < 0.05). Trabecular tunneling was evident in 11 (48%) of the biopsies from the PTH group. Patients with tunneling had significantly higher levels of biochemical markers of bone resorption and formation. At cortical bone, number of Haversian canals per area was 139% higher (p = 0.01) in the PTH group, causing a tendency toward an increased cortical porosity (p = 0.09). At different subregions of the hip, areal BMD (aBMD) and volumetric BMD (vBMD), as assessed by dual‐energy X‐ray absorptiometry (DXA) and quantitative computed tomography (QCT), decreased significantly by 1% to 4% in the PTH group. However, at the lumbar spine, aBMD decreased by 1.8% (p < 0.05), whereas vBMD increased by 12.8% (p = 0.02) in the PTH compared with the placebo group. © 2012 American Society for Bone and Mineral Research.     

Proteoglycan 4: A dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism

Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH‐responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild‐type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild‐type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild‐type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH‐mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild‐type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF‐2) mRNA and reduced serum FGF‐2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF‐2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone‐ and liver‐derived FGF‐2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure. © 2012 American Society for Bone and Mineral Research     

Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading

Sclerostin, the Wnt signaling antagonist encoded by the Sost gene, is secreted by osteocytes and inhibits bone formation by osteoblasts. Mechanical stimulation reduces sclerostin expression, suggesting that osteocytes might coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. To investigate whether sclerostin downregulation is a pre-requisite for load-induced bone formation, we conducted experiments in transgenic mice (TG) engineered to maintain high levels of SOST expression during mechanical loading. This was accomplished by introducing a human SOST transgene driven by the 8 kb fragment of the DMP1 promoter that also provided osteocyte specificity of the transgene. Right ulnae were subjected to in vivo cyclic axial loading at equivalent strains for 1 min/day at 2 Hz; left ulnae served as internal controls. Endogenous murine Sost mRNA expression measured 24 h after 1 loading bout was decreased by about 50% in TG and wild type (WT) littermates. In contrast, human SOST, only expressed in TG mice, remained high after loading. Mice were loaded on 3 consecutive days and bone formation was quantified 16 days after initiation of loading. Periosteal bone formation in control ulnae was similar in WT and TG mice. Loading induced the expected strain-dependent increase in bone formation in WT mice, resulting from increases in both mineralizing surface (MS/BS) and mineral apposition rate (MAR). In contrast, load-induced bone formation was reduced by 70-85% in TG mice, due to lower MS/BS and complete inhibition of MAR. Moreover, Wnt target gene expression induced by loading in WT mice was absent in TG mice. Thus, downregulation of Sost/sclerostin in osteocytes is an obligatory step in the mechanotransduction cascade that activates Wnt signaling and directs osteogenesis to where bone is structurally needed.