先天性佝偻病与纳米细菌关系研究的现状与展望

先天性佝偻病是胎儿出生后就发生的特殊阶段的佝偻病,病因并不十分清楚,迁延不愈会影响小儿骨骼发育和免疫功能。纳米细菌导致的胎盘钙化与小儿佝偻病有关,推测纳米细菌与先天性佝偻病有关。因此诊断和防治纳米细菌感染可能对于先天性佝偻病的预防有一定临床意义。     

Prevention of rickets in Asian children: assessment of the Glasgow campaign.

In March 1979 the Greater Glasgow Health Board launched a campaign to reduce the high prevalence of rickets in Asian children in the city. A precampaign survey had shown that voluntary low dose vitamin D supplementation would reduce the prevalence of rickets in Asian children. A survey carried out two and three years after the launch of the official campaign also showed a reduction in the prevalence of rickets in children taking low dose supplements equivalent to about 2.5 micrograms (100 IU) vitamin D daily. There was a considerable reduction in the total prevalence of rickets in this survey compared with the precampaign survey. Hospital discharges of Asian children with rickets declined rapidly after the start of the campaign.     

Skeletal manifestations of rickets in infants and young children in a historic population from England

Gross and radiographic changes characteristic of inadequate bone mineralization due to rickets are described in 21 immature skeletons from a 19th century urban population from Birmingham, England. The aims of the study are as follows: to evaluate and if possible augment existing dry-bone criteria for the recognition of rickets in immature skeletal remains; to investigate the value of radiography for the paleopathological diagnosis of rickets; and to compare and contrast the expression of rickets in this group with that previously documented for a rural agrarian population from Wharram Percy, England. Some gross skeletal signs of rickets which were not previously well-documented in paleopathological studies are noted. The worth of radiography for evaluating structural changes to both cortical and trabecular bone in the disease is demonstrated, and features useful for the interpretation of vitamin D deficiency are discussed. The pattern of skeletal elements affected and the severity of changes differs in the Birmingham group from that seen in the comparative rural population. It is emphasized that a variety of factors may influence the expression of rickets in paleopathological material, including rate of skeletal growth, age cohort affected, and intensity of vitamin D deficiency. Nevertheless, careful analysis, not only of the frequency of rickets but also of the degree of severity of lesions and the patterning with respect to skeletal elements affected, may enable more nuanced understanding of the biocultural context of the disease in earlier populations.     

骨密度检测对婴幼儿佝偻病早期诊断的临床意义

目的:探讨骨密度检测在佝偻病早期诊断中的应用价值。方法:收集衡水市哈励逊国际和平医院门诊诊治的600例婴幼儿,以血清维生素D327.5 nmol/L为判定标准分为非佝偻病组和佝偻病组,比较两组婴幼儿维生素D3、骨碱性磷酸酶和骨密度,绘制维生素D3、骨碱性磷酸酶、骨密度诊断结果的ROC曲线图,对骨密度检测结果进行评价。结果:佝偻病组婴幼儿维生素D3和骨密度Z值明显低于非佝偻病组,骨碱性磷酸酶显著高于非佝偻病组(P0.05)。维生素D3诊断佝偻病的ROC曲线下面积为0.951,灵敏度为0.973,特异度为0.840;骨碱性磷酸酶诊断佝偻病的ROC曲线下面积为0.866,灵敏度为0.824,特异度为0.747;骨密度Z值诊断佝偻病的ROC曲线下面积为0.923,灵敏度为0.826,特异度为0.875,骨密度指标诊断佝偻病的曲线下面积和维生素D3比较无统计学意义(P0.05),但骨密度指标诊断佝偻病的曲线下面积大于骨碱性磷酸酶(P0.05)。结论:超声骨密度检测在婴幼儿佝偻病早期诊断中具有一定价值,其诊断敏感性、特异性、准确率与维生素D3诊断基本相当,且骨密度检测存在无创、可重复性高等优点。     

Rickets and Osteomalacia in the Glasgow Pakistani Community, 1961-71

The prevalence of vitamin D deficiency was reassessed in April and May 1971, 10 years after the discovery of widespread late rickets and osteomalacia in the Glasgow Pakistani community. Evidence of vitamin D deficiency was found in 28 out of 115 adults and children examined (24%). Children at the age of puberty were most severely affected by rickets, whereas most infants and younger children in the survey were protected by vitamin D supplements. Mild biochemical osteomalacia was common in Pakistani women.A total of 21 Pakistani and Indian children with rickets were admitted to Glasgow hospitals during 1968-70. These comprised 10 children with infantile rickets and 11 with late rickets. Four of the latter group required osteotomy for severe rachitic deformity.Late rickets and osteomalacia in Pakistani and Indian immigrants are not primarily due to nutritional deficiency of vitamin D, though the high phytate content of their diet may be of aetiological importance. A combination of environmental, social, and endogenous factors, the relative importance of which is not at present clear, may also be involved. Advice on the prophylaxis of vitamin D deficiency should be given to all Pakistani and Indian communities in the United Kingdom.     

Phospholipids bound with plasma proteins in children with vitamin D-deficient rickets

Composition of phospholipids bound with plasma proteins in the healthy children and in those with vitamin-D-deficient rickets are studied. It is found that the quantitative and qualitative content of phospholipids in the low- and high-density lipoproteins increases considerably with the rickets. At the same time the content of phospholipids which form complexes wit fibrinogen gets two times lower. The character of changes in the phospholipid composition in protein fractions and in the whole plasma in case of rickets is different.     

Intestinal calcium-binding protein in animals fed normal and rachitogenic diets: I. Rat studies.

Measurements were made of duodenal calcium-binding protein (CaBP) on rats during development of rickets and, subsequently, following vitamin-D2 treatment. Results showed a poor inverse correlation between duodenal CaBP and rickets. In rats fed a phosphate-deficient rachitogenic diet, duodenal CaBP concentration finally fell below detectable limits, but CaBP was still readily measurable 2 weeks after rickets was clearly established. Following a massive dose of vitamin D2 (50 000 I.U.) to rachitic animals, CaBP was formed. However, a small dose of vitamin D2 (500 I.U. daily for 4 days) was insufficient to demonstrate CaBP synthesis than vitamin-D treatment alone. The rachitogenic diet supplemented with phosphate, which caused osteoporosis but not rickets, inhibited CaBP synthesis. The results suggest that nutritional deficiencies from the rachitogenic diet, in addition to vitamin-D deficiency, inhibited CaBP synthesis.     

Idiopathic Fanconi syndrome with progressive renal failure: a case report and discussion

Fanconi syndrome is a complex of renal tubular dysfunctions defined by glycosuria without diabetes, aminoaciduria, phosphaturia, and renal tubular acidosis. It is often associated with hypokalemia, hypophosphatemia, and rickets or osteomalacia. Although it is usually found in the setting of other well-established non-renal diseases, Fanconi syndrome may present without identifiable etiology or association. Very infrequently a patient with idiopathic Fanconi syndrome will progress to chronic renal failure. This case report details the course of such a patient over the 20 years since his diagnosis and discusses the syndrome's genetic background, clinical features, putative pathophysiology, and therapeutic options, including transplantation.     

Comparative studies of type X collagen expression in normal and rachitic chicken epiphyseal cartilage

The levels of type X collagen in mineralizing normal chicken epiphyses and nonmineralizing rachitic chicken tibial epiphyses were measured and compared. Qualitative immunoperoxidase studies with anti-chick type X collagen monoclonal antibodies on sections from normal and rachitic cartilage demonstrated that the type X collagen levels in rachitic growth plates are reduced. Northern hybridization of mRNA and biosynthetic studies have confirmed that type X collagen synthesis in rickets is also decreased. In hypocalcemic rickets, the level of type X collagen mRNA is reduced by 80% whereas the level of type X collagen mRNA is only reduced by 50% in normocalcemic rickets. These observations provide additional evidence that type X collagen is involved in the process of cartilage mineralization and also suggest that the partial recovery of type X collagen synthesis in normocalcemic rickets may be related to the elevated plasma concentration of calcium. Calcium concentration may therefore play an important role in the control of type X collagen synthesis.     

Assessing diagnostic certainty for scurvy and rickets in human skeletal remains

Objectives

Identifying scurvy and rickets has important implications for understanding adaptations and variability among past communities, and bioarchaeologists now regularly evaluate these conditions. Due to the increased number of studies, cases with less clear-cut lesions and variable preservation are now frequently reported. Despite an improved understanding of the biological mechanisms for disease expression, there is a lack of consensus on the language used to express diagnostic certainty, limiting comparability. This article aims to address these issues and provide recommendations on more consistent diagnostic terminology using widely accepted diagnostic methodology based on biological mechanisms.

Materials and Methods

We review diagnostic terms used in bioarchaeology by considering published cases of rickets, scurvy and co-occurrence alongside M.B.B.'s past project notes. We also consider differences in the diagnosis of rickets and scurvy in living and archeological individuals.

Results

We provide recommendations on a framework that can be used to show diagnostic certainty in cases of rickets, scurvy, and co-occurrence. Core lesions of rickets and scurvy are used alongside a limited lexicon of diagnostic terminology based on the Istanbul protocol.

Discussion

It is not the number of lesions that determines whether an individual is assigned to a particular diagnosis category, but rather the range and expression of lesions present. Avoiding a “tick-list” approach to core lesions of these diseases will be critical to ensure that identifying rickets and scurvy continues to contribute to understanding adaptations and variability among past communities. The framework allows more consistency in diagnostic certainty, facilitating greater comparability in research.     

Detection of gynecological cancer; use of fluorescence microscopy to show nucleic acids in malignant growth

Vitamin D resistant rickets is not a rare disorder. Increased awareness of this metabolic disorder during the examination of children with bowed legs, even infants receiving normal supplements of vitamin D, may lead to diagnosis oftener. Ten previously unrecorded cases of this disorder are included within this report. Three of the patients had associated congenital anomalies which also required treatment. Treatment of the vitamin D resistant rickets consists of the oral administration of large doses of vitamin D. Careful observation of patients during vitamin D therapy to prevent overdosage and resultant hypercalcemia is of utmost importance. Surgical correction of the bony deformities is rarely necessary. The cause of vitamin D resistant rickets is thought to be a defect of renal tubular mechanisms.     

VITAMIN D RESISTANT RICKETS

Vitamin D resistant rickets is not a rare disorder. Increased awareness of this metabolic disorder during the examination of children with bowed legs, even infants receiving normal supplements of vitamin D, may lead to diagnosis oftener. Ten previously unrecorded cases of this disorder are included within this report. Three of the patients had associated congenital anomalies which also required treatment. Treatment of the vitamin D resistant rickets consists of the oral administration of large doses of vitamin D. Careful observation of patients during vitamin D therapy to prevent overdosage and resultant hypercalcemia is of utmost importance.Surgical correction of the bony deformities is rarely necessary.The cause of vitamin D resistant rickets is thought to be a defect of renal tubular mechanisms.     

Vitamin-D-deficient rickets in Manitoba, 1972-84.

Vitamin-D-deficient rickets still exists in children in Manitoba and adjacent areas. Between 1972 and 1984, 48 cases were documented at Winnipeg Children''s Hospital. The patients ranged in age from 1 to 49 months; 40 were Canadian natives (38 Indians and 2 Inuit), most of whom lived in the Island Lake area of northern Manitoba. Of the 48, 16 had clinical signs of rickets, 12 had tetany due to hypocalcemia and 38 had radiologic evidence of rickets. Hypocalcemia was found in 27, and hypophosphatemia in 19; hyperaminoaciduria was found in 7 of 20. All 48 had elevated serum alkaline phosphatase levels. In addition to rickets, 16 patients aged 12 months or more had evidence of malnutrition. Climate and lifestyle in northern areas of the Canadian midwest result in little or no biosynthesis of vitamin D by solar radiation; therefore, adequate dietary vitamin D intake is essential to prevent deficiency. The diets of pregnant women and infants in these areas are deficient in vitamin D. The authors recommend vitamin D supplements for all pregnant women and infants in areas of risk to eradicate this preventable disease.     

In vivo function of VDR in gene expression-VDR knock-out mice

Vitamin D exerts many biological actions through nuclear vitamin D receptor (VDR)-mediated gene expression. The transactivation function of VDR is activated by binding 1,25-dihydroxyvitamin D₃[1,25(OH)₂D₃], an active form of vitamin D. Conversion from 25(OH)D₃ is finely regulated in kidney by 25(OH)D₃ 1-hydroxylase[25(OH)D 1-hydroxylase], keeping serum levels of 1,25(OH)₂D₃ constant. Deficiency of vitamin D and mutations in the genes like VDR (type II genetic rickets) are known to cause rickets like lowered serum calcium, alopecia and impaired bone formation. However, the molecular basis of vitamin D–VDR system in the vitamin D action in intact animals remained to be established. In addition, the 1-hydroxylase gene from any species had not yet been cloned, irrespective of its biological significance and putative link to the type I genetic rickets. We generated VDR-deficient mice (VDR KO mice). VDR KO mice grew up normally until weaning, but after weaning they developed abnormality like the type II rickets patients. These results demonstrated indispensability of vitamin D–VDR system in mineral and bone metabolism only in post-weaning life. Using a newly developed cloning system, we cloned the cDNA encoding a novel P450 enzyme, mouse and human 1-hydroxylase. The study in VDR KO mice demonstrated the function of liganded VDR in the negative feed-back regulation of 1,25(OH)₂D₃ production. Finally, from the analysis of type I rickets patients, we found missense genetic mutations in 1-hydroxylase, leading to the conclusion that this gene is responsible for the type I rickets.     

Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation.

A girl with autosomal dominant hypophosphatemic rickets, presented with clinical, radiological and laboratory signs of rickets at the age of 11 months. She showed a good response to the treatment with low doses of oral phosphate and calcitriol. Surprisingly, she lost her renal phosphate wasting at the age of 8 years, indicating that the disturbed phosphate metabolism can be compensated by hormonal or other factors.     

Screening Rastafarian children for nutritional rickets.

We examined 42 Rastafarian children under 5 years of age who were registered with a single inner city general practice to determine the prevalence of nutritional rickets. Twenty children were receiving a strict vegan(I-tal) diet and were considered to be at high risk of developing rickets and were referred for biochemical and radiological investigation. Seven of 20 children investigated had rickets, giving an overall prevalence of 7/42. Treatment with oral cholecalciferol was successful in all seven children. Fourteen out of 18 children had evidence of iron deficiency, with low haemoglobin concentrations and hypochromic-microcytic blood films. Before this study Rastafarian children rarely attended the well baby clinic, received no vitamin supplements, and few had been immunised. They now regularly attend the clinic, receive vitamin and iron supplements, and all have completed primary immunisation.     

Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3

Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.     

Policy for prevention of Asian rickets in Britain: a preliminary assessment of the Glasgow rickets campaign.

Evidence of continuing hospital admissions of patients with Asian rickets and osteomalacia led to a further attempt to provide more effective preventive measures for the Glasgow Asian community. Dose-response studies showed that the equivalent of 10 microgram of vitamin D daily would provide effective prophylaxis, and a general practice survey showed that self-administered vitamin D supplements would reduce the prevalence and severity of Asian rickets. A multidisciplinary working group devised a preventive campaign based on the free issue of vitamin D supplements on demand to children who required them. Supported by a health education programme for community health personnel and the Asian community, the first 16 months of the campaign produced an eight-fold rise in the issue of supplements to older Asian children and a 33% increase in their issue to infants of all ethnic groups. Because more children are receiving vitamin D supplementation the campaign seems likely to reduce the prevalence of Asian rickets in Glasgow.     

A novel nonsense mutation in the DMP1 gene identified by a genome-wide association study is responsible for inherited rickets in Corriedale sheep

Inherited rickets of Corriedale sheep is characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Previous outcross and backcross studies implicate inheritance as a simple autosomal recessive disorder. A genome wide association study was conducted using the Illumina OvineSNP50 BeadChip on 20 related sheep comprising 17 affected and 3 carriers. A homozygous region of 125 consecutive single-nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 6 Mb on ovine chromosome 6. Among 35 candidate genes in this region, the dentin matrix protein 1 gene (DMP1) was sequenced to reveal a nonsense mutation 250C/T on exon 6. This mutation introduced a stop codon (R145X) and could truncate C-terminal amino acids. Genotyping by PCR-RFLP for this mutation showed all 17 affected sheep were "T T" genotypes; the 3 carriers were "C T"; 24 phenotypically normal related sheep were either "C T" or "C C"; and 46 unrelated normal control sheep from other breeds were all "C C". The other SNPs in DMP1 were not concordant with the disease and can all be ruled out as candidates. Previous research has shown that mutations in the DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans. Dmp1_knockout mice exhibit rickets phenotypes. We believe the R145X mutation to be responsible for the inherited rickets found in Corriedale sheep. A simple diagnostic test can be designed to identify carriers with the defective "T" allele. Affected sheep could be used as animal models for this form of human rickets, and for further investigation of the role of DMP1 in phosphate homeostasis.     

Intestinal calcium-binding protein in animals fed normal and rachitogenic diets: II. Pig studies.

Experiments were carried out in pigs to investigate the relationship between concentration of intestinal calcium-binding protein (CaBP) and the presence of rickets. Pigs made rachitic by a diet deficient in calcium and in vitamin D had concentrations of intestinal CaBP no less than values obtained on control pigs. These experiments, together with earlier work on rats (Can. J. Physiol. Pharmacol. 1975. 53, 137--143), demonstrate a poor inverse correlation between levels of intestinal CaBP and rickets.