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Current therapy in the management of heterotopic ossification of the elbow: a review with case studies.

Heterotopic ossification, or the appearance of ectopic bone in para-articular soft tissues after surgery, immobilization, or trauma, complicates the surgical and physiatric management of injured joints. The chief symptoms of heterotopic ossification are joint and muscle pain and a compromised range of motion. Current therapies for prevention or treatment of heterotopic ossification include surgery, physical therapy, radiation therapy, and medical management. Unlike heterotopic ossification of the hip, heterotopic ossification of the elbow has not been extensively investigated, leaving its optimal management ill-defined. To remedy this deficiency, we review risk factors, clinical anatomy, physical findings, proposed mechanisms, and current practice for treatment and prevention of heterotopic ossification. We then consider and draw conclusions from four cases of elbow injury treated at our institutions (three complicated by heterotopic ossification) in which treatment included surgery, radiation therapy, physical therapy, and medical therapy. We summarize our institutional practices and conclude with a call for a randomized clinical trial to better define optimal management of heterotopic ossification of the elbow.

Adult↗

The Frank Stinchfield Award. Inhibition of heterotopic ossification with radiation therapy in an animal model.

An animal model for the study of heterotopic ossification was developed and the effects of perioperative radiation were analyzed. In Phase I, New Zealand White rabbits (n = 18) underwent surgery either with or without muscle injury on each hip to establish the most reliable model in which to study heterotopic ossification. In Phase II, rabbits (n = 36) underwent either 400, 800, or 1200 cGy radiation to one hip 24 hours after bilateral hip surgery to establish a dose response relationship for postoperative radiation therapy. In Phase III, rabbits (n = 24) underwent preoperative radiation therapy (800 cGy) at 4, 16, or 24 hours preoperatively to investigate the mechanism of action and efficacy of preoperative radiation therapy. Monthly radiographs were graded by blinded observers for severity of heterotopic ossification. Mean grade, intraobserver and interobserver variability, and statistical significance were evaluated. In Phase II, 17 of 18 rabbits generated heterotopic ossification in both hips, and the mean grade of heterotopic ossification was always greater on the operative side with intentional muscle injury. Variability in the grading was considered excellent. Phase II revealed that 800 cGy was the minimal effective dose. Contrary to hypothesis, Phase III revealed an increasing grade of heterotopic ossification coinciding with a decreasing preoperative time interval, with the difference in heterotopic ossification grade with 24-hour versus 4-hour preoperative radiation being significant. The rabbit model is reliable and reproducible and closely resembles the human clinical situation after hip surgery. Preoperative and postoperative radiation effectively prevented heterotopic ossification formation. The results support the use of preoperative radiation and establish a need for additional investigation regarding the mechanism of action and timing of preoperative radiation therapy.

Animals↗

Morphologic evaluation and surgical simulation of ossification of the posterior longitudinal ligament using helical computed tomography with three-dimensional and multiplanar reconstruction.

STUDY DESIGN: Using helical computed tomography with three-dimensional and multiplanar reconstruction, ossification of the posterior longitudinal ligament in the cervical and thoracic region was observed. Preoperative simulation also was performed, and the availability of these methods was evaluated. OBJECTIVE: To use preoperative evaluation and simulation with helical computed tomography to enhance the accuracy of excision of ossification of the posterior longitudinal ligament lesion. SUMMARY OF BACKGROUND DATA: Ossification of the posterior longitudinal ligament lesion is sometimes so complicated that preoperative morphologic evaluation and excision of the lesion are difficult when using only conventional imaging techniques. METHODS: Seven cases of cervical and two cases of thoracic ossification of the posterior longitudinal ligament were scanned using helical computed tomography at 2-mm or 5-mm slice thickness. Three-dimensional and multiplanar reconstruction were performed at 0.7-mm or 2-mm intervals in the bone window. Surgical simulation of the anterior approach for cervical lesion and posterior approaches for thoracic lesion was performed. RESULTS: Preoperative direct observation of the ossification of the posterior longitudinal ligament lesion was possible, and the complicated structures could be understood more easily than with other conventional methods. When surgical simulation was performed in the workstation, the ossification of the posterior longitudinal ligament lesion was removed sufficiently on arbitrarily reconstructed view in the spinal canal. When the viewpoint then was changed to the approaching side, the location and dimension of the removed area were determined. In all cases, surgical approach and excision of the ossification of the posterior longitudinal ligament lesion were performed more easily and more precisely than in the surgery with no three-dimensional images. CONCLUSION: Helical computed tomography with three-dimensional, multiplanar reconstruction would be a valuable tool for evaluation and surgical simulation of ossification of the posterior longitudinal ligament lesion by enhancing the accuracy of the surgical procedure.

Adult↗

Ossification of the ligamenta flava with severe myelopathy in a black patient. A case report.

STUDY DESIGN: A case of symptomatic ossification of ligamenta flava in a black man from Martinique (French West Indies) is reported. OBJECTIVES: To show that ossification of ligamenta flava may be observed in racial groups other than Japanese people and that the postoperative prognosis of symptomatic ossification of ligamenta flava is not always excellent. SUMMARY OF BACKGROUND DATA: Ossification of ligamenta flava causing slowly progressive myelopathy or radiculopathy is rare. It usually occurs in the lower thoracic spine. Ossification of ligamenta flava has mainly been described as occurring in Japanese people and very rarely in Caucasians. Diagnosis is based on a computed tomographic scan or magnetic resonance imaging, and postoperative prognosis is usually good. METHODS: Low thoracic ossification of ligamenta flava was diagnosed in a black man from Martinique, based on the computed tomographic scan data and on the histopathologic examination of the removed tissue. The patient was clinically evaluated before and 1 year after the operation. A postoperative computed tomographic scan was performed. A magnetic resonance image was not available in this case. RESULTS: The patient exhibited severe subacute myelopathy. After decompression, the neurologic recovery was incomplete. A postoperative computed tomographic scan showed complete excision of ossification of ligamenta flava and decompression of the spinal cord. CONCLUSIONS: Ossification of ligamenta flava may occur in black people. An incomplete postoperative recovery may be observed in such cases of unusual subacute compressive myelopathy.

Aged↗

Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity.

STUDY DESIGN: A case-control association study and a stratified study investigating the genetic etiology for ossification of the posterior longitudinal ligament of the spine. OBJECTIVE: To determine the association of restriction fragment length polymorphisms of estrogen receptor, vitamin D receptor, parathyroid hormone, and interleukin-1alpha and -1beta with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity. SUMMARY OF BACKGROUND DATA: Contribution of genetic backgrounds to the etiology for ossification of the posterior longitudinal ligament of the spine has been suggested by epidemiologic studies. METHODS: Genomic deoxyribonucleic acid samples obtained from 120 patients (77 men and 43 women) with ossification of the posterior longitudinal ligament of the spine and 306 control subjects without the disorder (166 men and 140 women) were amplified by polymerase chain reaction, and polymorphism genotypes were determined by restriction endonuclease digestion. The distribution of genotypes was compared between patients with the disorder and control subjects. In addition, the severity of ossification was determined by the number of ossified vertebrae in patients with the disorder, and associations of the severity with age, gender, and genotypes were examined. RESULTS: Estrogen receptor (P = 0.007) and interleukin-1beta (P = 0.001) polymorphisms exhibited different distributions between patients with ossification of the posterior longitudinal ligament of the spine and control subjects in women, but not in men. In patients with the disorder, the severity of ossification was negatively correlated with age in women (P = 0.013), but not in men. Estrogen receptor polymorphism was associated with the severity only in women (P = 0.001). CONCLUSIONS: The contribution of genetic backgrounds is likely to be stronger in women than in men with ossification of the posterior longitudinal ligament of the spine. Estrogen receptor polymorphism was associated with both initiation and promotion of the disorder, but interleukin-1beta polymorphism was associated only with its initiation in women.

Adult↗

Radiographic appearance of the navicular bone and distal interphalangeal joint and their relationship with ossification of the collateral cartilages of the distal phalanx in Finnhorse cadaver forefeet.

Radiographic findings in the navicular bone and distal interphalangeal joint as well as the ossification status of the collateral cartilages of the distal phalanx were evaluated in 100 Finnhorse cadaver forefeet. The most common shapes of the proximal articular margin of the navicular bone were convex and straight. Remodeling of the navicular bone was common, especially on the lateral extremity. No bony fragments were identified at the distal flexor margin even though this area appeared irregular in several feet. Several large, rounded or lollipop-shaped synovial invaginations were identified in only six feet. The thickness of the flexor cortex varied considerably, and the corticomedullary junction was uni- or bilaterally indistinct in nine feet. The shape of the sagittal ridge of the flexor cortex was commonly flat but varied. It appeared locally irregular or indistinct in 17 feet, but changes elsewhere along the flexor cortex were rare. Osteophytosis on the dorsal and palmar margins of the distal interphalangeal joint and entheseophytosis on the dorsal aspect of the middle phalanx and on the extensor process of the distal phalanx were common. "Possibly significant" ossification of the collateral cartilages (high sidebones or separate centers of ossification) was present in 36 feet; all grades of ossification in the proximal/palmaroproximal direction as well as palmar ossification were seen. A statistically significant relationship was found between entheseophytosis on the proximal flexor margin of the navicular bone and "possibly significant" ossification. Osteophytosis on the palmarodistal margin of the middle phalanx was more common in feet with a relatively long distal phalanx, suggestive of palmar ossification. Radiographic changes in the navicular bone or in the distal interphalangeal joint did not otherwise appear to be associated with ossification of the collateral cartilages of the distal phalanx in Finnhorses.

Animals↗

In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification.

BACKGROUND: The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions. METHODS: BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer. RESULTS: A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification. CONCLUSIONS: BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome. CLINICAL RELEVANCE: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists.

Adenoviridae↗

Prevention of heterotopic ossification with irradiation after total hip arthroplasty. Radiation therapy with a single dose of eight hundred centigray administered to a limited field.

Sixty-two hips in fifty-five patients who were considered to be at risk for postoperative heterotopic ossification were randomly divided into two groups: one received a single 800-centigray dose of limited-field radiation and the other, 1000 centigray of limited-field radiation in divided doses. The risk for heterotopic-bone formation was identified on the basis of previously described criteria, which included previous heterotopic ossification after an operation about the hip, hypertrophic osteoarthritis or post-traumatic osteoarthrosis characterized by formation of extensive osteophytes, radiographic evidence of diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and male sex. The treatment portals excluded prosthetic surfaces that were intended for biological fixation by ingrowth of bone. At a minimum six-month follow-up, progression of heterotopic ossification had occurred in seven (21 per cent) of thirty-four hips in the first group and in six (21 per cent) of twenty-eight hips in the second group. The ossification had advanced more than one grade in only one hip. Extra-field ossification occurred in fifteen (43 per cent) of thirty-five hips that had not had previous heterotopic ossification. Since the time of the study, the treatment portal has been modified to include the lateral aspect of the greater trochanter, so that the risk of bursitis associated with ossification in this area is minimized. Single-dose limited-field radiation is effective for the prevention of heterotopic ossification, without compromise of early fixation of an uncemented implant.

Adult↗

Heterotopic ossification. Incidence and relation to trochanteric osteotomy in 100 total hip arthroplasties.

Heterotopic ossification can impair the functional results of total hip arthroplasty. The causative role of trochanteric osteotomy in heterotopic ossification is uncertain. Postoperative radiographs of 100 total hip arthroplasties were analyzed for incidence of heterotopic ossification. Forty procedures were performed with trochanteric osteotomy and 60 without. There was a 17% overall incidence of clinically significant heterotopic ossification, 22% with osteotomy and 13% without. High- and low-risk categories revealed clinically significant heterotopic ossification in 25% of the high-risk group and in 8% of the low-risk group. In the high-risk group there was a 32% incidence with trochanteric osteotomy and 22% without osteotomy. In the low-risk group there was a 16% incidence without trochanteric osteotomy and a 3% incidence with trochanteric osteotomy. The increase in clinically significant heterotopic ossification in the high-risk group over that of the low-risk group was statistically significant. The present study showed that trochanteric osteotomy tended to increase the incidence and severity of clinically significant heterotopic ossification. These data suggest that trochanteric osteotomy should be avoided, if possible, during total hip arthroplasty to decrease the risk of heterotopic ossification.

Femur↗

Heterotopic ossification in spinal cord-injured patients.

Therapy programs during the development of heterotopic ossification in spinal cord injury range widely from complete rest to aggressive exercise programs. The literature is confusing by its multiplicity of recommendations because the basic etiology and pathophysiology are unknown and because some basic differences exist between traumatic myositis ossificans and heterotopic ossification associated with severe neurological impairments. Prospective heterotopic ossification roentgenographic (x-ray) surveys of the hips, knees, shoulders, and elbows were made on 250 consecutive spinal cord-injured patients. Those who had x-ray evidence of early or immature heterotopic ossification or who developed early clinical signs of possible heterotopic ossification were treated with an aggressive program of passive progressive range of motion exercises. Several patients who developed bilateral heterotopic ossification had one side used as their own control. Follow-up x-ray studies and range of motion evaluation suggest that an aggressive range of motion exercise program is indicated for patients who are developing or have heterotopic ossification. There is no evidence that exercise increases inflammation with subsequent ossification, and it frequently causes a pseudarthrosis, permitting adequate functional range of motion.

Adolescent↗

Animal models of heterotopic ossification.

Heterotopic ossification is often a severe clinical complication of joint arthroplasty, neurologic trauma, and muscle injury. In rare genetic disorders, such as fibrodysplasia ossificans progressiva, heterotopic ossification can be crippling and often leads to premature death. Reliable animal models of heterotopic ossifications that mimic pathologies seen in man would be invaluable for the development of new treatments to combat heterotopic ossification. Various methods used to induce heterotopic ossification in animals including the use of bone morphogenetic proteins, urinary tract epithelia, and transformed cell lines are described. Genetic animal models of heterotopic ossification and various miscellaneous examples of heterotopic ossification in animals are described. Finally, the use of transgenic mice to manipulate bone morphogenetic protein expression is discussed as a possible future animal model of heterotopic ossification.

Animals↗

Heterotopic ossification after total hip arthroplasty: risk factors and prevention.

A retrospective review of 168 consecutive total hip arthroplasty procedures done in 1983 at the Cochin Teaching Hospital, Paris, France, was conducted to determine the rate of occurrence of heterotopic paraarticular ossification and to look for risk factors for this complication. None of the patients received preventive therapy for heterotopic ossification. Mean age was 66.2 years. The reason for arthroplasty was hip osteoarthritis in every case. The index operation was the first arthroplasty procedure. Heterotopic ossification was noted in 61.3% of patients and was high-grade in 8.3%. The rate of occurrence of heterotopic ossification was not influenced by age, gender, joint destruction, preoperative osteophytosis, duration of the arthroplasty or the occurrence of complications during or after the arthroplasty. However, severe ossification was more common in men that in women (12.7% men versus 5.7% women had grade III ossification) and in patients operated on by relatively inexperienced surgeons (28/8% grade II and III ossifications, versus 14.7% in patients operated on by experienced surgeons). The rate of occurrence of heterotopic ossification in the patients who had no risk factors (60.9%) was not significantly different from that in the overall study population. These data suggest that preventive strategies targeted to specific patient subgroups would probably be ineffective, and that routine preventive therapy of all total hip arthroplasty patients is warranted.

Adult↗

Fetal spine ossification: the gender and individual differences illustrated by ultrasonography.

The spatial and temporal pattern of manifestation of ossification nuclei of the spinal column in fetal life have been well established by histologic and radiologic studies. Sonographic evaluation of the fetal spine depends on visualization of the ossification centers, but the sequence of development of ossification centers in the vertebral column obtained by embryologists and sonographers and radiology are conflicting. We carried out a longitudinal study to establish the ultrasonographic appearance and timing of development of primary ossification centers of the fetal spine in the first and second trimesters of pregnancy. A total of 80 mothers were evaluated during their pregnancy with two echographic controls; in the first trimester, the spine length was measured and, in the second trimester of pregnancy, the timing of ossification of the bodies and neural arches of sacral vertebrae and the difference in appearance between the female and male genders were evaluated. Spinal length measurements obtained in the first trimester and percentage of detection of sacral vertebral structures increased progressively with a regular pattern in relation to gestational age. Spinal length at first ultrasound examination was slightly correlated with time of appearance of sacral bodies and arches. Ossification timing was significantly earlier in females than in males. The study has attempted to improve our understanding of the sonographic detection of the spinal ossification. Data presented give some further information on the stages of appearance of sacral vertebrae body centers during intrauterine development. Differences between genders and interindividual variations in ossification timing were observed at a very early stage of development. This could be of value when fetal growth is evaluated. Moreover, further knowledge of spinal development may be useful for early diagnosis of spinal abnormalities and for fetal biometrics.

Adult↗

Endochondral ossification is dependent on the mechanical properties of cartilage tissue and on intracellular signals in chondrocytes.

Skeletal elements are formed either by replacing a performed cartilagenous matrix template in a process called endochondral ossification or directly from mesenchyme by a process known as membranous ossification. Longitudinal growth of bones is achieved by growth plates where calcified cartilage is converted into bone. To investigate the role of extracellular matrix as well as intracellular signaling pathways in the formation and growth of bone, the genes coding for type II collagen and cyclic guanosine 3',5'-monophosphate (cGMP)-dependent protein kinase (cGK) II, were disrupted. It is demonstrated that loss of Col2a1 or cGKII led to abnormal endochondral ossification and skeletal development. In cGKII -/- mice, bones derived by membranous ossification developed normally while bones derived by endochondral ossification were shortened. This growth defect was not associated with a general metabolic disturbance. In Col2a1 knockout mice, endochondral ossification was completely absent, whereas membraneous ossification was not affected. Despite the defects in bone formation, invasion of blood vessels into bone cavities and formation of bone marrow occurred in Col2a1-null mice. Taken together, the phenotypes of these two knockout mice show that chondrocytes need a well-functioning extracellular matrix scaffold and a normal cGMP-signaling system for endochondral ossification to form a normal skeleton.

Animals↗

Ossification patterns of the tympanic facial canal in the human fetus and neonate.

Dehiscences in the bony facial canal are comparatively common in the human adult. The highest incidence occurs in the tympanic segment of the facial nerve near the region of the oval window. Thirty-three fetal temporal bones, ranging from 16 to 40 weeks' gestation, and four from 1, 2, 4 and 12 weeks' postpartum neonates, were studied to evaluate the normal patterns of ossification of the fallopian canal of the tympanic facial nerve segment in the human. The tympanic facial nerve segment elongates three-fold during this period (from 1 mm to 3 mm). The ossification starts at 21 weeks' gestation anteriorly from apical otic ossification centers and at 26 weeks from canalicular ossification centers near the stapedius muscle. The ossification proceeds in an anterior-to-posterior direction as two periosteal shelves of bone surround the facial nerve. The superior periosteal bony ledge contributes 75% of the circumference of the fallopian canal. The anterior ossification center forms over 83% of the fallopian canal length. The two centers fuse post partum near the region of the oval window. The anatomic location of the facial nerve, nerve branching, and neural vasculature precede ossification. In 80% of the paired temporal bones, this ossification pattern appears to be symmetrical. The patterns and incidence of bony dehiscences within the tympanic fallopian canal segment can be explained by these observations. This study demonstrates that fallopian canal dehiscences are not congenital anomalies, but variations of normal developmental anatomic processes.

Cartilage↗

Positional changes of the frontoparietal ossification centers in perinatal craniosynostotic rabbits.

It has been suggested that craniosynostosis is caused by abnormally located ossification centers (i.e., bony tubers) in the developing skull prior to suture formation [Mathijssen et al., 1996, 1997]. The present study was designed to test this hypothesis in a rabbit model of human familial, nonsyndromic coronal suture (CS) synostosis. Calvariae were taken from 99 New Zealand White rabbit perinates (55 normal controls, 15 with delayed-onset CS synostosis, and 29 with bilateral or unilateral CS synostosis), ranging in age from 23 to 34 days postconception (synostosis occurs at approximately 23 days in this model). Frontoparietal, interfrontal, and interparietal ossification center distances were obtained using a Wild microscope with camera lucida attachment and a 2-D computer digitization technique. Linear regression analysis was used to compare age-related changes in the perinatal ossification centers among groups. Results revealed that frontoparietal ossification center regression line slopes had similar start points (24-day intercepts) with significantly (P < 0.05) diverging slopes over time. Normal and delayed-onset ossification center distance increased more rapidly than in synostosed perinates. No significant (P > 0.05) differences were noted in regression line slopes among groups for interparietal or interfrontal ossification center distances. Results demonstrated that, in synostosed perinates, frontoparietal ossification center location was similar to normals around the time of synostosis and became displaced later. These findings suggest that ossification center (i.e., bony tuber) displacement seen in infants with craniosynostosis is probably a secondary and compensatory, postsynostotic change and not a primary causal factor of synostosis in this rabbit model.

Animals↗

[Multi-channel cochlear implant in cochlear ossification].

Cochlear ossification, considered until only a few years ago as a contraindication for cochlear implants (C.I.), may now be managed by means of a wide variety of surgical techniques. In cases with massive ossification, the drill-out circummodiolar technique described by Gantz et al. in 1988 and successively modified by Balkany et al. in 1997 may be adopted. The technique of electrode insertion in the scala vestibuli, perfected by Steenerson et al. in 1990, may be used when cochlear ossification has spread no further than the scala tympani. Other methods call for a groove to be drilled along the proximal tip of the basal turn of the cochlea (Cohen and Waltzman, 1993), the insertion of electrodes through the middle cranial fossa (Colletti et al., 2000), or the utilization of a double electrode array (Bredberg et al., 1997, Lenarz et al., 2001). This study reports the experience conducted at the Cochlear Implants Centre of the Otorhinolaryngoiatrics, Otological and Otoneurological Microsurgery Section of the University of Parma in a group of 15 patients who underwent C.I. in the presence of varying degrees of ossification. In 3 cases the ossification was limited to the region of the round window and a few millimetres of the scala tympani; cochleostomy was performed anteriorly and inferiorly to the anterior niche of the round window. In 11 cases (of which 3 of pediatric age), the ossification had spread to the horizontal portion of the scala tympani; in these cases, the electrodes were inserted in the scala vestibuli. The scala vestibuli was opened by drilling anteriorly to the round window and superiorly to the spiral ligament. In the only case of massively ossified cochlea, it was possible to partially insert the electrodes in a circum-modiolar tunnel. In the 12-month follow-up hearing test, the 3 patients with ossification of the round window region and the first millimetres of the scala tympani respectively averaged 61.6% in recognizing 2-syllable words and 59% in recognizing words embedded in phrases. The averages on the 12-month follow-up hearing test in the 8 adult patients who received the implant in the scala vestibuli were 80.6% in recognizing 2-syllable words and 89.1% in recognizing words in phrases. The 3 pediatric patients were classified on the Geers and Moog scale, which situated 2 of them in the 6th category of perception and 1 of them in the 4th category of perception. As regards the only case of massive cochlear ossification, the patient underwent surgery recently, and the sole follow-up available is the one conducted after only 3 months; the vowel identification average was 55%; the average on the VCV test was 31%; and the 2-syllable word recognition average was 20%.

Acoustic Stimulation↗

The timing of ossification of the limb bones, and growth rates of various long bones of the fore and hind limbs of the prenatal and early postnatal laboratory mouse.

In order to study the pattern of ossification of the skeletal components of the fore and hind limb of the mouse, intact embryos were isolated between days (d) 15 and 19 of pregnancy (the morning of finding a vaginal plug is termed d 1 of pregnancy), and postnatal animals isolated on d 1 (newborns), 7 and 14 after birth. The total number of fore and hind limbs studied for each day of pregnancy or postnatal day for the bone growth study is given in parentheses: d 15 (2), d 16, 17, 18 and 19 of pregnancy (5 specimens for each of these days), d 1 (newborn), wk 1 and 2, postnatal (4 specimens analysed at each of these times), since only the right limbs were studied. For the study involving the time of first appearance of ossification centres, either the right or the left limb of each of these prenatal and postnatal specimens was analysed. All specimens were fixed in 80% ethanol, bulk-stained using alizarin and Alcian blue, in order to stain ossification centres and cartilage, respectively, and cleared. The limbs were then disarticulated from the axial skeleton at the sternoclavicular and sacroiliac joints to facilitate (1) the determination of the sequential pattern of ossification in the various cartilage primordia analysed, and (2) the analysis of the pattern of growth of the humerus, ulna, femur and tibia. The latter values were plotted graphically, and the individual growth rate of each of the long bones studied was then deduced and also plotted graphically. The findings demonstrated that, with the exception of the femur and ulna, all of the long bones studied had significantly different growth patterns. The time of appearance of the various centres of ossification in the skeletal elements studied proceeded in a similar order to that described by previous authors, though there was some discrepancy in the exact time of first appearance of certain ossification centres. Of particular interest was the somewhat unusual pattern of ossification of the first digits of both the fore and hind limb compared with that of the other digits. The data presented here provide useful baseline information on the normal sequential pattern of ossification in the fore and hind limb, and the characteristic growth pattern of the individual long bones of the limbs in this species.

Animals↗