Bone mineral density in feline mucopolysaccharidosis VI measured using dual-energy X-ray absorptiometry

Dual-energy X-ray absorptiometry (DXA) was used to determine the in vivo bone mineral density (BMD) and bone mineral content (BMC) of lumbar vertebrae in six cats affected with the inherited lysosomal storage disease mucopolysaccharidosis VI (MPS VI). DXA was also performed on MPS cats that had a bone marrow transplant (BMT) and total body irradiation (TBI) (MPS+BMT;n=7), normal cats that had a bone marrow transplant, and TBI (control+BMT; n=8) and normal cats (control; n=14). Following euthanasia, one of the lumbar vertebrae that had been scanned (L5) was harvested and bone volume (BV/TV%) was determined by histomorphometry. The in vivo BMD and BMD measurements were compared with the BV/TV%. There was a greater BMD and BMC in the MPS+BMT cats compared with the MPS cats but the difference was not statistically significant. However, there was a greater BV/TV% in the MPS+BMT cats compared with the MPS cats and the difference was significant (P=0.0152). Correlation between the noninvasive in vivo DXA measurements of BMD and BMC and the BV/TV% was significant (r ²=0.767, P<0.0001; r ²=0.504, P<0.0001). Noninvasive in vivo DXA was a rapid and precise method for measuring the lumbar BMD and BMC in cats and it correlated well with histomorphometric determination of bone mass. Further, the response of inherited storage diseases such as MPS VI to therapy, such as BMT, could be monitored in a longitudinal fashion using DXA.     

Anesthesia for an adult with mucopolysaccharidosis I

We describe the anesthetic management difficulties of a man with mucopolysaccharidosis I. We also briefly review the anesthesia literature related to this disease.     

黏多糖贮积症患儿麻醉研究进展

黏多糖贮积症（mucopolysaccharidosis, MPS）是一种先天性遗传病,临床上此类患儿常需通过手术改善症状、提高生存质量。MPS患儿全身状况的改变尤其是困难气道和心脏的受累,对麻醉管理提出了挑战。文章概述了MPS的分型、病理生理改变及临床表现,并围绕术前评估、麻醉诱导与维持、临床麻醉管理要点等方面对相关...     

Growth plate physiology and pathology

The growth plate is made of cartilaginous, bony, and fibrous components, which act together to achieve longitudinal bone growth. The unique metabolism of the growth plate is a result of its unique microcirculation and extracellular microenvironment. The growth plate chondrocytes are responsive to both mechanical and hormonal stimuli, which can alter their normal function. Pathologic states result from environmental, hormonal, nutritional, and genetic factors.     

Stand-alone craniocervical decompression is feasible in children with mucopolysaccharidosis type I,IVA, and VI

Background Context

In patients with mucopolysaccharidosis (MPS), glycosaminoglycan deposits in the dura mater and supporting ligaments cause spinal cord compression and consecutive myelopathy, predominantly at the craniocervical junction. Disease characteristics of craniocervical stenosis (CCS) in patients with MPS differ profoundly from other hereditary and degenerative forms. Because of high periprocedural morbidity and mortality, patients with MPS pose a substantial challenge to the inexperienced medical care provider. As literature remains scarce, we present our experience with a large cohort of patients with MPS treated for CCS without atlanto-occipital instrumentation.

Morphological alterations in dental and periodontal tissues in murine mucopolysaccharidosis type VII

Mucopolysaccharidoses (MPSs) in humans are frequently associated with tooth and periodontal aberrations. Although the cause is known, namely, enzyme deficiency, the pathophysiology of these alterations is not well defined. A murine MPS VII (-glucuronidase deficiency) model has earlier been identified with morphological, genetic, and biochemical characteristics that closely mimic those of human MPS VII. The present investigation describes the histopathological alterations in dental and periodontal tissues from such mutant mice. Homozygous animals were identified by external phenotypical features and as being -glucuronidase deficient by a fluorometric assay of liver samples. In the incisor and the periodontium, abnormalities were evident in both cells and the extracellular matrices. Mesenchyme-derived cells were more aberrant than epithelial cells. Moreover, undifferentiated cells appeared unaffected, whereas actively synthesizing and resorbing cells were distended by virtually empty or granular material-containing vacuoles, the content presumably being glycosaminoglycans. The cells most affected were those in which macromolecular turnover is normally the highest, namely, odontoblasts, postsecretory ameloblasts, and periodontal ligament fibroblasts. Extracellularly, predentin displayed abnormal collagen fibrils, whereas mineralization defects occurred in both dentin and enamel. This murine model of MPS VII provides a good tool for understanding the pathophysiology of this disease in bone, periodontium, and teeth.     

Histomorphometric Analysis of the Tibial Growth Plate in a Feline Model of Mucopolysaccharidosis Type VI

Mucopolysaccharidosis type VI (MPS VI) is a genetically inherited lysosomal storage disorder. Severely affected children exhibit a range of skeletal abnormalities including short stature, facial dysmorphia, and dysostosis multiplex. Naturally occurring and transgenic animal models of MPS VI are also found which exhibit pathology similar to the human disorder. In this paper we have characterized the formation of trabecular bone from growth plate cartilage in a feline model of MPS VI. Tibial trabecular bone was shown to be osteopenic in MPS VI animals with a bone mineral volume (BV/TV) of 4.51% compared with a BV/TV of 15.64% in normal animals. In addition to osteopenia, a rearrangement of trabecular bone architecture was also observed in MPS VI tibiae, with fewer, thinner trabeculae noted; bone formation rate was also decreased. These observations support those previously made in the L5 vertebrae of MPS VI animals. When the sequential formation of growth plate cartilage structural elements, their transition into primary bone spongiosa, and remodeling into secondary bone spongiosa was characterized, no difference between normal and MPS VI could be detected in the number of cartilage septae and their arrangement in the proliferative and hypertrophic regions of the growth plate or trabecular elements in the primary spongiosa. However, a deviation from normal was observed in the resting zone of the growth plate and in the secondary spongiosa of bone. Thus, the osteopenia observed in MPS VI bone appears to arise primarily from a defect in bone production within the metaphysis and diaphysis rather than the creation of an abnormal template in the preceding growth plate cartilage. Received: 29 March 1998 / Accepted: 21 November 1998     

Glucosaminidase, galactosaminidase, and glucuronidase in the growth plate

The activities of glucosaminidase, galactosaminidase, and glucuronidase were determined in fractions of bovine growth plate cartilage. Glucosaminidase and galactosaminidase activities were lowest in the area corresponding to the reserve cartilage and increased from the upper to the lower portions of the hypertrophic zones of the growth plate, reaching a maximum in the calcifying cartilage. Glucuronidase activity showed a distinct spike of activity in the calcifying cartilage. The spatial distribution of these activities suggests a role in calcification and in the dissolution of the extracellular matrix at the chondro-osseous junction of the growth plate.     

Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome)

INTRODUCTION: The craniovertebral abnormalities found in patients with Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome) are described, and the indications for and outcomes of surgery in this group are assessed. METHODS: The clinical histories and radiological findings in all patients with Type VI mucopolysaccharidosis treated at Royal Manchester Children's Hospital during the past 10 years were reviewed. RESULTS: The typical findings in patients with this disease are of canal stenosis at the level of the foramen magnum and upper cervical spine with or without cord compression. The stenosis is secondary to thickening of the posterior longitudinal ligament. Atlantoaxial instability is rare. Of nine patients under regular clinical review, four underwent decompressive surgery for cervical cord compression. Three of the four showed improvement in their neurological symptoms and signs postoperatively. Of the children reviewed, six had radiological evidence of cord compression, although only those with neurological signs or symptoms were treated surgically. DISCUSSION: Despite the often formidable anesthetic challenge, surgery is indicated in those patients who present with progressive neurological deficit due to cervical myelopathy. Surgery can be undertaken safely if the associated medical problems in these children are recognized and managed appropriately.     

Anesthesia in a patient with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)

We report a case of anesthesia during surgery to enlarge the foramen magnum in a pediatric patient with an extremely rare form of mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome). Airway control was unexpectedly easy, and intraoperative anesthetic management with total intravenous anesthesia went smoothly. However, the disease is progressive, with no guarantee that future anesthetic management of this patient will remain easy. If repeated surgery is required, thorough testing should be conducted over time to assess both airway and systemic complications. Nevertheless, we found that safe anesthetic management of affected patients is possible with anesthetics currently used in a clinical setting.     

Decrease of Trefoil factor 2 in cats with feline idiopathic cystitis

What’s known on the subject? and What does the study add? Feline idiopathic cystitis (FIC) is a common spontaneous disease in domestic cats which resembles painful bladder syndrome/interstitial cystitis in humans in many aspects. For neither of the two diseases a consistent aetiology has yet been established, so that there is no causal therapy and diagnosis is still one of exclusion. The discovery of a deficiency of an important growth factor, the Trefoil Factor 2, in the urine and bladder tissue of cats with FIC gives new insights into possible aetiologic backgrounds of FIC and might serve as future biomarker faciliating diagnosis.

OBJECTIVE

To obtain new insights into aetiological backgrounds, and to search for diagnostic biomarkers by assessing the difference in urinary proteins between cats with spontaneous feline idiopathic cystitis (FIC) and healthy controls.

MATERIALS AND METHODS

Urine supernatants of 18 cats with FIC and 18 healthy control cats, and bladder biopsies of two FIC diseased cats and four healthy controls were included in the study. The Bradford method was used to determine protein quantity in urine supernatants. Urine was separated by two‐dimensional (2‐D) gel electrophoresis. Selected protein spots were excised from two‐dimensional gels and analysed with tandem mass spectrometry. Validation of Trefoil factor 2 expression was realized with Western blot and immunohistochemistry. Western blot signal intensities were quantified with image quant software.

RESULTS

Eleven differentially expressed protein spots were identified between the 2‐D gels of cats with FIC and control cats. Ten spots (only visible in the FIC gel) were identified as albumin and one spot (only visible in the control gel) was identified as Trefoil factor 2.Using quantification of Western blot signal intensities and immunohistochemistry a decrease in Trefoil factor 2 (TFF2) in cats with FIC could be revealed for the first time.

CONCLUSION

Deficiency in TFF2 possibly leads to impaired repairing abilities and immune response of the urothelium. The result could be a greater susceptibility to injury, inflammation and relapse. Therefore TFF2 deficiency might be an important event in FIC pathogenesis. Detection of a decrease in urinary TFF2 could serve as diagnostic biomarker, facilitating diagnosis. As FIC can serve as an animal model for human painful bladder syndrome/interstitial cystitis, the findings of this study might also be valuable for interstitial cystitis research and should be further investigated.     

Growth plate activity in the upper extremity

Roentgenograms of 200 males and females were examined to determine the contribution of each growth center to the total length of the humerus, radius, and ulna. Subjects were healthy, middle-class Americans, mostly of northwest European descent. The nutrient foramen in the cortex provides the site of entry for the nutrient vessel and is a fixed point in the long bone. Growth occurring at each growth plate was measured in relation to the nutrient foramen. The proportion of growth from each upper extremity growth plate is not equal. Also, growth plate activity is not constant or average throughout the growth period. Growth occurs one or two years earlier in females than in males. Overall, approximately 80% of growth in the humerus occurs at the proximal growth plate. Before the age of two years, less than 75% of growth occurs at the proximal growth plate, increasing to 85% at the age of eight and remaining constant at 90% after the age of 11. For the ulna, approximately 85% of overall growth occurs at the distal growth plate, but by the age of five years, 90% of growth occurs distally. After the age of eight years, 95% of growth occurs at the distal growth plate. For the radius, approximately 80% of overall growth occurs distally. At the age of five years, the distal growth plate contributes 85% of total growth, increasing to 90% by the age of eight.     

Intrinsic neuromuscular defects in the neurogenic bladder. VI. Myofiber ultrastructure in the somatically denervated male feline rhabdosphincter

Ordinary somatic striated muscle with purely somatomotor innervation undergoes atrophy with fibrosis when completely denervated. On this basis, it has been suggested that vesical outlet “obstruction” in voiding dysfunction resulting from lower-motor neural lesions is due to fibrosis of a denervated rhabdosphincter. We have shown previously that: (1) this sphincter has natural triple somatomotor/autonomic, cholinergic/autonomic adrenergic innervation of its myofibers; and (2) following its somatomotor denervation by bilateral sacral ventral rhizotomy, its myofibers lose somatomotor innervation and eventually acquires a purely autonomic innervation that includes autonomic re-innervation of their sole plates. The present study was conducted in 16 adult male cats to define the structural changes in myofibers of the somatically denervated rhabdosphincter. Samples of the sphincter, obtained 1, 2, 4, 6, and 10 weeks after bilaterial sacral ventral rhizotomy, were processed and studied by electron microscopy. In all samples, there was a combination of ultrastructurally normal, degenerative, and regenerative myofiber profiles. Degenerative profiles were most frequent in the 1-week, and regenerative profiles in the 6–10 weeks samples. No atrophic myofibers or interstitial fibrosis were observed in any sample. It is concluded that the somatically denervated male feline rhabdosphincter, unlike ordinary somatic striated muscle, maintains its structural integrity through myofiber regeneration and by not undergoing fibrosis. The somatically denervated rhabdosphincter, with its eventual purely autonomic re-innervation, therefore, can play an important role in lowermotor neurogenic dysfunctions that needs further investigation.     

生长板软骨细胞促进骨髓基质干细胞血管内皮生长因子的表达

目的观察骨髓基质干细胞(BMSCs)在生长板软骨细胞旁分泌作用下血管内皮生长因子(VEGF)的表达规律及其与成骨分化的相关性。方法大鼠BMSCs与生长板软骨细胞进行间接共培养,培养终末期做细胞化学染色,定量测定碱性磷酸酶(ALP)活性,用RT-PCR方法半定量检测VEGFmRNA的表达。结果生长板软骨细胞持续高表达VEGF。BMSCs随共培养时间的延长,ALP活性升高,BMSCs的VEGF的表达也逐渐增强。培养液加入两种分泌型VEGF中和抗体后,VEGF表达趋势不变,ALP活性仍为升高趋势,也不影响培养终末期钙化结节的形成。培养终末期BMSCs的CD31和CD34均阴性。结论BMSCs成骨分化过程中VEGF的表达符合成骨细胞分化基因的表达规律,与成骨细胞特征性基因的表达趋势一致,体外条件共培养条件下,中和VEGF后并不能阻碍BMSCs的成骨分化。     

Growth plate behavior after desepiphysiodesis: experimental study in rabbits

The aim of this work was to study the potential healing of the growth plate in the case of a central desepiphysiodesis. A central defect was made in the distal femoral growth plate of thirty 3-week-old rabbits. In group A the growth plate defect was left empty as control. The defects of group B were implanted with a polymeric cylinder fixed in the metaphysis with a pin. In group C the cylinder was fixed in the epiphysis. Two months after implantation, clinical, radiologic, and histologic analyses were carried out. In group A, the mean shortening was 12.63%; it was 4.9% in group B and 1.54% in group C. Histologic analysis showed constant appearance of an epiphysiodesis after migration of the implant in the metaphysis. No regeneration of the growth plate was observed. Prevention of migration of the interpositional material is recommended to avoid recurrence of an epiphysiodesis.     

Structural,compositional, and biomechanical alterations of the lumbar spine in rats with mucopolysaccharidosis type VI (Maroteaux–Lamy syndrome)

Mucopolysaccharidosis (MPS) VI is an inherited lysosomal storage disorder resulting from deficiency of N‐acetylgalactosamine‐4‐sulfatase activity and subsequent accumulation of incompletely degraded dermatan sulfate (DS) containing glycosaminoglycans (GAGs). Painful spinal deformities are commonly found in MPS VI patients. We characterized lumbar spine structure, composition, and biomechanics in a naturally occurring rat MPS VI model and evaluated the role of MMP‐13, ADAMTS‐5 and TNF‐α in modulating the observed changes. MPS VI rats had discs with large vacuolated cells and sizable nuclear defects. MPS spine segments also had structural and functional changes suggestive of spinal instability, including decreased nuclear pressurization, increased joint laxity and increased disc height index. These functional changes were at least partly associated with elevated ADAMTS‐5, MMP‐13, and TNF‐α. Vertebral and endplate biomechanics were also affected by MPS VI with decreased failure load and stiffness. The discal and vertebral dysfunctions observed in MPS VI rats are likely to be associated with pathological spinal conditions, similar to those that afflict MPS patients. Our findings also suggest more broadly that abnormal accumulation of GAGs and the associated chronic pro‐inflammatory and catabolic cascade may also be a source of spinal dysfunction. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 621–631, 2013     

Growth plate explants respond differently to in vitro static and dynamic loadings

This study aimed at investigating the effects of static and dynamic compression applied on growth plate explants using matched compressive strains. Growth plate explants from 4‐week‐old swine ulnae were submitted to in vitro static (10% strain) or dynamic (oscillating between 7% and 13% at 0.1 Hz) unconfined compression for 48 h. The total growth plate height, the combined proliferative and hypertrophic thickness and the resulting ratio between these two thicknesses were evaluated. Standard immunohistochemistry was used to analyze the protein expression of key components of the extracellular matrix: aggrecan, type II collagen, type X collagen, and MMP13. In the statically loaded samples, the columnar organization of the cells was preserved but with slight columns deviation from the growth axis. Decreases in all histomorphological parameters were important and a notable loss of aggrecan, type II and type X collagens expressions was denoted. In the dynamically loaded samples, a severe loss of columnar arrangement was observed in the proliferative and hypertrophic zones. However, dynamic compressive loads preserved the proliferative and hypertrophic zones ratio and contributed to the synthesis of aggrecan and type II collagen in the extracellular matrix. The exact response of the growth plate to mechanical stresses along with optimal loading parameters could help improve the current treatment approaches or develop new treatment approaches for the underlying progressive musculoskeletal deformities. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:473–480, 2011