骨碱性磷酸酶检测对早期筛查新生儿佝偻病的临床研究

为了解新生儿佝偻病发病情况，我们检测了107例健康足月新生儿骨碱性磷酸酶（BAlp）活性。BAlp活性正常仅27例，可疑佝偻病与临界佝偻病80例。107例中母孕期有小腿抽筋史的新生儿BAlp活性高于无抽筋史的新生儿。经统计学处理，有差异（P＜0.05），说明早期低钙可影响新生儿BAlp活性，骨代谢改变早期有生化指标的异常，BAlp可以作为早期筛查佝偻病的一项敏感指标。提示佝偻病的防治应从围产期开始。     

Dental Problems in Hypophosphatemic Rickets,a Cross Sectional Study

Objective

Hypophosphatemic rickets is an uncommon metabolic bone disorder which affects all ages and both sexes. It is characterized by low concentration of serum phosphate levels, impairment of mineralization of bone matrix and teeth with variable etiology. Dental problems in this disorder have not been described well in previous studies.

Methods

All hypophosphatemic rickets patients who came to a referral clinic during 2008-2010 enrolled in this study. All patients had low phosphorous and high ALP, normal PTH and 25-hydroxy-vitamin D and normal or low level of serum calcium. After diagnosis all patients were examined by a dentist for enamel hypoplasia, taurodontism, dental abscess, gingivitis, dental caries, and dentition delay.

Findings

Nineteen patients were enrolled in this study. The average age of the patients was 10 (±4.23) years (range 3-17). Seventy-nine percent of patients had regular follow-up after diagnosis of background disease. Dental caries and delay in the dentition were most prevalent (each one 47.7%) followed by enamel hypoplasia in 42.1% of the patients. Other problems were taurodontism in 15.8% patients, dental abscess and gingivitis in 10.9%.

Conclusion

Hypophosphatemic rickets is a disease with different clinical features; one of them is dental problem, dental caries is the most common problem.     

Hereditary vitamin D–resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor

Hereditary vitamin D–resistant rickets (HVDRR) is a rare autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). Patients exhibit severe rickets and hypocalcemia. Heterozygous parents and siblings appear normal and exhibit no symptoms of the disease. We analyzed the VDR gene of a young girl who exhibited the clinical features of HVDRR without alopecia. The patient had clinical and radiographic features of rickets, hypocalcemia, and elevated serum concentrations of 1,25‐dihydroxyvitamin D [1,25(OH)₂D]. A single heterozygous missense mutation was found in the VDR gene that substituted glutamic acid with alanine at amino acid 420 (E420A). Sequencing of the girl's VDR cDNAs showed that the f/M1 allele contained the E420A mutation, whereas the F/M4 allele was completely normal. The girl's father, who was also heterozygous for the E420A mutation on the f/M1 allele, exhibited minor symptoms of vitamin D resistance. In contrast, the mother had no signs of the disease and had no mutations in her VDR gene. Both the girl and the father's skin fibroblasts showed resistance to 1,25(OH)₂D₃ by their severely reduced induction of CYP24A1 gene expression. In transactivation assays, the E420A mutant VDR showed dominant‐negative activity towards the wild‐type VDR. This is the first report that we are aware of describing a patient with HVDRR caused by a single heterozygous missense mutation in the VDR gene. The E420A mutant appears to act in a dominant‐negative fashion, silencing the wild‐type VDR and resulting in an attenuated response to 1,25(OH)₂D₃. © 2011 American Society for Bone and Mineral Research     

Distribution of type X collagen in tibiotarsi of broiler chickens with vitamin D deficiency

Summary Type X collagen is a significant component of the extracellular matrix of the hypertrophic zone of physeal cartilage, but its precise role in endochondral ossification has not been determined. The concentration of type X collagen increases in physeal cartilage in chicks with vitamin D deficiency. The purpose of our study was to determine whether defective endochondral ossification due to vitamin D deficiency was associated with abnormalities in the distribution of type X collagen in the proximal tibiotarsus of chicks. To accomplish this, we induced vitamin D deficiency in broiler chicks and sequentially evaluated the pattern of type X collagen immunoreactivity in the proximal tibiotarsus using a monoclonal antibody specific for chicken type X collagen. Type X collagen immunoreactivity was present in the matrix of the prehypertrophic zone, hypertrophic zone, cartilage cores of the primary spongiosa, and within the chondrocytes of the prehypertrophic and early hypertrophic zones in vitamin D-deficient and D-replete chicks. However, rachitic chicks exhibited two consistent differences in type X collagen immunoreactivity: hypertrophic chondrocytes in the late hypertrophic zone and primary spongiosa contained intracellular type X collagen; and type X collagen was concentrated into laminated aggregates in the pericellular and territorial matrices in the late hypertrophic zone and primary spongiosa. We conclude from these findings that (1) normal serum concentrations of 1,25(OHD)₂D₃ and 25OHD₃ are not required for type X collagen production; (2) type X collagen production does not decrease in the most mature zones of the physes in chicks with vitamin D deficiency; and (3) newly secreted type X collagen accumulates in the pericellular and territorial matrices of the late hypertrophic zone and primary spongiosa of rachitic chicks, perhaps because it is not readily incorporated into the interterritorial matrix.     

Interglobular dentine in first and third molars: Relation to hours of sunshine during growth in two archeological populations from England

Summary Thin ground sections of first molars (M1), third molars (M3), and second premolars (P2) were scanned by light microscopy for relative amounts of interglobular dentine (IGD) in the top half of the crown. Two well-dated cemetery series of English provenance were sampled: the Saint Bride's Church collection (SB) from eighteenth century London, for which the sex, age, and calendar year at death of each individual are known; and the early Anglo-Saxons from Abingdon (A-AS), near Oxford. A lesser number of prehispanic aboriginal Guanche teeth from Tenerife (TG) were also studied. Estimates of insolation in the past were developed indirectly by reference to δ 0¹⁸ mass spectrometer analyses of dated layers of the Greenland ice sheet. In the M1 and M3 of the SB and the A-AS populations, IGD varied as an inverse linear function of average annual hours of bright sunshine below a certain critical level, the insolation deficit threshold being significantly higher and IGD formation faster in the M1 than in the M3. No such dose-response gradient was apparent in the P2 data, presumably because the calcification of this tooth during the fourth year of life coincides with serious pediatric illnesses and weaning of the child onto cereal foods rich in phytate, which together confound and overwhelm the insolation deficit effect. IGD in all three types of teeth of the small TG series was considerably higher than had been predicted on the basis of bright sunshine availability; but the discrepancy is readily explainable in terms of this population's dietary, which relied on barley as the main staple.     

0～6岁儿童佝偻病影响因素的logistic回归分析

目的：探讨绵阳市城区0-6岁儿童佝偻病的影响因素。方法：以分层整群随机抽样的方法选取绵阳城区0-6岁儿童1490例，采用自行设计的调查表进行佝偻病及相关因素的调查。运用logistic回归对资料进行多因素分析。结果：绵阳市城区0-6岁儿童佝偻病患病率为22.6%，该地区儿童佝偻病发生与年龄，维生素D添加，父亲文化程度，家庭经济收入，住院朝向阳光是否充足，户外活动时间，虾皮和豆浆进食情况有关，其OR值分别为1.293,0.742,0.738,0.649,2.226,0.400,3.561和1.449。结论：绵阳市城区儿童佝偻病发生是多种因素综合作用的结果，防治佝偻病时应采用综合防治措施。     

Inhibition of epiphyseal cartilage collagenase by tetracyclines in low phosphate rickets in rats

Drugs in the tetracycline family can inhibit mammalian tissue collagenase both in vitro and in vivo by a mechanism that is independent of antibiotic action. The epiphyseal cartilages of rachitic rats contain extremely high levels of collagenase (CGase), and we have used this model to study further the phenomenon of tetracycline inhibition of tissue CGase. Rickets was induced in rats by phosphate/vitamin D deficiency and parameters of gross bone morphology, bone chemistry, and serum chemistry were evaluated in both rachitic and nonrachitic animals with and without treatment with oral tetracyclines (TETs). Minocycline (or doxycycline) partially suppressed the appearance of many of the expected changes in the rachitic animals, including gross bone hardness, growth plate widening, long bone length, suppression of weight gain, and decreased bone ash content. The effects were dose dependent and were associated with marked suppression of the enhanced CGase activity. Examination of collagen breakdown products by SDS-PAGE documented that the rachitic enzyme behaved like other mammalian collagenases including in vitro inhibition with minocycline 10-20 micrograms/ml and with a nonantibiotic tetracycline. No evidence of TET osseous toxicity was noted, and, in fact, administration of TET to nonrachitic animals had a mildly favorable effect on growth and development. TET suppression of CGase can be demonstrated in a well defined model system and this form of pharmacologic enzyme inhibition can be a useful probe for delineating the role of the enzyme in connective tissue pathology.     

Changes in vitamin D metabolites and bone histology in rats during recovery from rickets

Summary The relative roles of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-(OH)₂D) and 24,25-dihydroxyvitamin D (24,25-(OH)₂D) in bone mineralization are largely unknown. Young vitamin D depleted rats were fed increasing amounts of vitamin D and grouped radiologically in accordance with the rat line test. They ranged from severely rachitic to normal. Radiology was correlated with serum levels of 25-OHD, 1,25-(OH)₂D, 24,25-(OH)₂D, ionized calcium, magnesium, and phosphate, with bone histology, and with the total mineral content of the animals. Serum 1,25-(OH)₂D rose in a linear fashion to supranormal values during bone healing and correlated with the radiological degree of rickets. Serum 25-OHD was below detection limit in the most rachitic and low in the radiologicall normal rats, whereas 24,25-(OH)₂D was low in all groups. These two metabolites showed no correlation with the radiologic, histologic or biochemical parameters. In rachitic rats, 1,25-(OH)₂D appears to play a major role in bone healing and possibly exerts a direct effect on bone cells. It cannot be ruled out, however, that the effect is mediated through a rise in serum levels of calcium and phosphorus, although signs of bone healing were seen in the presence of a subnormal calcium x phosphorus product. Initiation of mineralization can take place with unmeasurable 25-OHD, and 24,25-(OH)₂D seems to be without importance.     

Rickets as a complication of intravenous hyperalimentation in infants

Fifteen newborn infants developed roentgenographic evidence of rickets while on long-term intravenous hyperalimentation. In each instance, the initial diagnosis of rickets was suggested on the chest roentgenogram, where characteristic cupped and frayed upper humeral metaphyses were noted; subsequent knee and wrist roentgenograms substantiated these findings. Factors which may have predisposed to the development of rickets include inadequate doses of vitamin D, prematurity and a rapid change in body weight during hyperalimentation therapy.     

Infantile hypophosphatasia: Enzymatic defect explored with alkaline phosphatase-deficient skin fibroblasts in culture

Summary Evidence that infantile hypophosphatasia may result from defective regulation of an intact structural gene for the tissue nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (TNSALP) was explored by studying physicochemical properties of ALP in sonicates of monolayers of cultured dermal fibroblasts from 7 patients (PT) and 5 age- and sex-matched control (CT) subjects. Both groups had low levels of ALP activity when assayed with 4-methylumbelliferyl phosphate substrate. The mean specific activity of ALP in the PT fibroblasts was markedly subnormal (V_max less than 1% of CT), but apparently not from extracellular loss of enzyme, since defined medium had less ALP activity when conditioned by PT compared to CT cells. Although the mean Km for the sonicate ALP was similar for both groups at pH 10.1, pH optimum, thermal stability and response to several inhibitors appeared to be different. Nevertheless, it seemed that some TNSALP-like enzyme was present in the PT group. Exposure of cells in culture to 5-azacytidine and several putative inducers of ALP failed to increase the enzyme activity in either the PT or CT groups. Had the physicochemical properties of the constitutive (or inducible) ALP been the same in the PT and CT cell groups, the findings would have provided evidence for the generality of our previous observations in one patient which indicated that defective regulation of an intact structural gene for TNSALP could account for hypophosphatasia. Our results do not, however, refute this possibility; e.g., especially minute amounts of typical TNSALP may have been present in our PT fibroblasts but were masked by (1) normal or compensatory expression of trace levels of ALP from a separate gene, (2) heterogeneity of the ALPs in the various PT (or CT) cell lines, or (3) the presence of some additional TNSALP that was different from the constitutive ALP of normal fibroblasts. Indeed, review of the findings for individual cell lines suggested that in one patient with relatively high levels of ALP activity, the physicochemical properties of this ALP was most like the enzyme in CT cells. Although further studies—including use of sensitive immunologic and electrophoretic methods—will be necessary to further characterize the minute amounts of residual ALP(s) in infantile hypophosphatasia tissues, presence of some TNSALP-like ALP in PT fibroblasts indicates that the disorder is not commonly due to a complete gene deletion for TNSALP. Our findings do indicate an especially profound and stable deficiency of typical constitutive TNSALP in fibroblasts in this disorder and suggest, therefore, that these cells might be a valuable model to explore the physiologic role of TNSALP.