Developing models of DiGeorge syndrome.

DiGeorge syndrome is a common congenital disorder characterized by neural-crest-related developmental defects. Mouse models of DiGeorge syndrome have been created that recapitulate defects seen in human patients. Here, the genetic pathways regulating cardiac neural crest development are reviewed and the evidence implicating TBX1 and other genes on chromosome 22q11 in the pathogenesis of DiGeorge syndrome is summarized.

Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.

Hirschsprung disease and Waardenburg syndrome are human genetic diseases characterized by distinct neural crest defects. Patients with Hirschsprung disease suffer from gastrointestinal motility disorders, whereas Waardenburg syndrome consists of defective melanocyte function, deafness, and craniofacial abnormalities. Mutations responsible for Hirschsprung disease and Waardenburg syndrome have been identified, and some patients have been described with characteristics of both disorders. Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation. Pax3 can bind to and activate expression of the c-RET gene, which is often mutated in Hirschsprung disease. Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome. Thus, Pax3, Sox10, and c-Ret are components of a neural crest development pathway, and interruption of this pathway at various stages results in neural crest-related human genetic syndromes.

Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor.

The t(2;13) chromosomal translocation occurs at a high frequency in alveolar rhabdomyosarcoma, a common pediatric tumor of muscle. This translocation results in the production of a chimeric fusion protein derived from two developmentally regulated transcription factors, PAX3 and FKHR. The two DNA binding modules, the paired domain and the homeodomain, of PAX3 are fused in frame to the transactivation domain of FKHR. Previously, tumor-specific PAX3-FKHR has been shown to bind to DNA sequences normally recognized by wild-type PAX3 and to exhibit relatively enhanced transcriptional activity. The DNA binding sites used to demonstrate that PAX3-FKHR is a more potent transcriptional activator than PAX3 have included recognition sequences for the paired domain of PAX3. In this report, we demonstrate the ability of PAX3-FKHR to activate the product of a growth control gene, platelet-derived growth factor alpha receptor (PDGFalphaR), by recognizing a paired-type homeodomain binding site located in the PDGFalphaR promoter. PAX3 alone cannot mediate transcriptional activation of this promoter under the conditions tested. This provides the first evidence that chromosomal translocation results in altered target gene specificity of PAX3-FKHR and suggests a transcriptional target that may play a significant role in oncogenic activity and rhabdomyosarcoma development.

Lbx2, a novel murine homeobox gene related to the Drosophila ladybird genes is expressed in the developing urogenital system, eye and brain.

We describe the cloning, expression pattern, and genomic organization of Lbx2, a murine homologue of the Drosophila and mammalian ladybird genes. Lbx2 includes a homeodomain motif most closely related to those of Lbx1 and the Drosophila ladybird proteins. Lbx2 transcripts are first detected at E10.5 when they are located in the gonadal component of the urogenital ridge. Expression of Lbx2 dramatically increases by E11.5 in the urogenital ridges, and in the cranial surface ectoderm. At later stages, Lbx2 transcripts are expressed in the brain and organs derived from the urogenital ridge, including the gonadal tubercle, kidneys, and adrenal glands. From E14.5 to birth, Lbx2 expression is evident in the developing retinal neuroepithelium and the vibrissa.

Pax3, neural crest and cardiovascular development.

The understanding of cardiovascular development has begun a transformation from the descriptive science of anatomy and embryology to a molecular understanding of the cellular and subcellular events leading to proper cardiac morphogenesis. Powerful tools available to molecular geneticists have identified numerous examples of specific gene defects that result in predictable cardiovascular abnormalities. Not only have certain genes been "knocked out" (mutated by homologous recombination in embryonic stem cells), but also single gene defects have been found to underlie the cardiovascular derangements observed in certain inbred mouse lines. Such is the case for the mouse mutant Splotch, which was first described in 1954 as a spontaneously occurring mutation resulting in a white belly spot. More recently, the genetic defect of all of the various Splotch alleles has been found to be due to mutations or deletions of a gene called Pax-3. In the homozygous state, these mutations result in embryonic lethality at about day 13.5 of mouse embryogenesis (E13.5). These embryos display abnormalities strikingly reminiscent of human DiGeorge syndrome. These include outflow tract abnormalities of the heart, such as double-outlet right ventricle (DORV) and persistent truncus arteriosus (PTA), as well as abnormalities of the great vessels and the thyroid and parathyroid glands. These defects suggest an underlying abnormality of neural crest, including its contribution to the cardiovascular system. © 1996, Elsevier Science Inc. (Trends Cardiovasc Med 1996;6:255-261).

Etiology of alcohol use among Hispanic adolescents: sex-specific effects of social influences to drink and problem behaviors.

BACKGROUND: Hispanic adolescents seem to be at greater risk for alcohol use; a greater understanding of the factors that predict alcohol use among Hispanic youth is needed. Social influences to drink and other problem behaviors often predict adolescent alcohol use. However, most past research has concentrated on samples of predominantly white adolescents residing in suburban areas. OBJECTIVES: To determine which demographic factors, social influences, and problem behaviors are associated with alcohol use among Hispanic adolescents and to eludicate the difference in the origins of alcohol use depending on sex. DESIGN: Cross-sectional study. SETTING: Middle schools in New York City. PARTICIPANTS: This study focuses on 1410 adolescents in grade 7 from inner-city schools who identified themselves as Hispanic at the baseline assessment of an investigation of alcohol and other drug use. MAIN OUTCOME MEASURES: Alcohol initiation, alcohol consumption, and future drinking. RESULTS: The findings showed that social influences to drink and reported problem behaviors were associated with alcohol use across and within sex groups. In particular, friends' drinking was related to alcohol initiation, consumption, and plans to drink in the future across sexes and within both sex groups. Other predictors (mother's drinking, siblings' drinking, ease of obtaining alcohol, deviance, cigarette smoking, and marijuana use) exhibited sex-specific effects. CONCLUSION: These findings lend support to teaching social resistance skills to improve Hispanic adolescents' ability to resist social influences to drink and use other drugs.

Clomiphene treatment in oligospermic infertile males.

This study of the effects of long-term clomiphene administration on semen analyses of oligospermic infertile males once again points to the potential therapeutic efficacy of clomiphene in certain subjects. Although the group of 16 subjects was small, all were men with long-standing infertility that had been refractory to previous treatments such as exogenous injections of human chorionic gonadotropin and varicocelectomy; 10 of the 16 men (62.5%) showed improvement in sperm counts within 2 to 5 months of starting clomiphene. Sperm motility improved moderately when counts improved; no effects on sperm morphology were noted. Of the 10 men classified as semen responders to clomiphene, 5 (50%) were successful in impregnating their wives within 2 to 8 months of starting treatment. These results approach the therapeutic efficacy seen with clomiphene in appropriately selected females with ovulatory disturbances. We have been unable to predict or characterize the patient who might be expected to show a semen response to clomiphene by history, physical examination response to previous treatment, or changes in blood testosterone levels while taking clomiphene.

Variations in seminal plasma constituents from fertile, subfertile, and vasectomized azoospermic men.

PIP: Freshly ejaculated semen specimens from 20 normal fertile, 11 subfertile, and 20 vasectomized men whose semen analyses had reached complete azoospermia were compared. The mean levels of seminal acid phosphatase were significantly higher in the vasectomized men. The mean values of sialic acid in normal and postvasectomy seminal plasmas were similar, in contrast to the lower values in oligospermic men. No significant differences were observed in seminal plasma proteins, alkaline phosphatase, and fructose levels. No correlation was found between seminal alkaline phosphatase and fructose levels and sperm concentration. Azoospermia occurring after vas ligation was attributed to high phosphatase values.^ieng

Sperm-agglutinating antibodies in 236 infertile couples.

PIP: 19 wives of 236 couples had positive sperm agglutination tests. (SPAT) 6 of the 19 belonged to the 70 couples (9.4%) with no no known cause for infertility; 11 belonged to the group of 154 couples (7.1%) with a known cause; and 2 to the 12 couples inadequately investigated (15.7%). 6 of these 19 women (31.6%) became pregnant without condon therapy; of these 6, 3 had no known cause for infertility and 3 had a known cause. 11 husbands had positive sperm aggluatination tests. 4 of these 11 were among the 70 couples (5.6%) with no known cause for infertility, while the other 7 were among the 154 couples (4.5%) with a known cause. 5 of their wives (45.5%) became pregnant without any treatment. Outcomes of 8 of 11 pregnancies were normal deliveries and no abortioons, which showed that positive SPAT had no apparent effect on the pregnancies. There was no relationship between postitive SPAT and history of venereal disease, allergy, autoimmune disease, abortioon, postcoital tests, or ABO imcompatability.^ieng

Cervical spinal stenosis.

Cervical spinal stenosis occurs at the craniovertebral junction, usually incident to a congenital malformation, or it appears as a developmental defect with diffuse narrowing of the cervical canal. In its acquired form the lesion may be limited to one or two levels, or it may be more extensive and affect three or more segments.

Lumbar spinal stenosis.

Recognition and management of problems inherent in spinal stenosis require a clear understanding of the diverse anatomic changes, their radiologic representations, and careful correlation with a wide spectrum of fluctuating clinical manifestations. Although a common basis might be postulated for narrowing of the spinal canal, emphasis should be placed on its various forms.

Lumbar spondylolisthesis with isthmic defects.

The importance of spondylolisthesis, aside from the obvious malalignment and malformation of the affected vertebrae, rests mainly on the possibility and the extent of impairment of activity. In this discussion the authors are concerned mainly with the myelographic signs associated with spondylolisthesis in patients with isthmic changes.

Degenerative spondylolisthesis with an intact neural arch.

Whereas the skeletal, anatomic, and clinical aspects of this condition have been scrutinized in detail, the radiologic changes have received less attention. In this discussion the plain film changes are briefly reviewed, and emphasis is directed toward the myelographic manifestations that reflect intraspinal and intraforaminal instrusions and their clinical sequelae.

Treatment of fractures of the vertebral limbus and spinal stenosis in five adolescents and five adults.

Fractures of the vertebral limbus occur between the vertebral ring apophyses and the cartilaginous rim of the superior or inferior margins of the vertebral end plates. These fractures are typically seen in adolescents or young adults, since fusion in this area is not complete until the ages of 18 to 25. Of 85 cases reported, 24 occurred in adolescents. The authors present the clinical, neurodiagnostic, and surgical management of fractures of the vertebral limbus and coincident segmental spinal stenosis in a group of 5 adolescents and 5 adults. An additional category for fractures of the vertebral limbus is proposed, namely, a lesion that is not confined to the superior or inferior margins of the vertebral end plates, but that spans the full length of the vertebral body.

Unilateral S-1 root compression syndrome caused by fracture of the sacrum.

Unilateral S-1 nerve root compression after an S-1 sacral fracture was found in an 18-year-old man after a motor vehicle accident. The positive myelogram, myelogram-computed tomogram, and magnetic resonance studies led to surgical intervention. Marked bony callous formation contiguous with the S-1 alar fracture protruded into the canal and was responsible for tethering the S-1 nerve root. A right L-5 hemilaminectomy, an L-4, L-5 and L-5, S-1 medial facetectomy, and foraminotomy facilitated nerve root decompression. Postoperatively, the patient was markedly improved. The authors suggest a more aggressive attitude in the diagnostic, radiographic, and surgical management of sacral fractures now that more specific technical facilities are available to define the precise character of the lesions involved.

Osteoid osteomas and osteoblastomas of the spine.

Benign osteoblastic lesions are rare bone tumors and they are usually divided into osteoid osteomas and benign osteoblastomas based on their biological behavior. Both lesions are prevalent in the spine, with the lamina and pedicle being involved frequently. Long diagnostic delays are frequent. Pain, the most prominent symptom, is often nocturnal and is relieved by aspirin in 30 to 40% of patients. Radicular pain occurs in 50% of the patients. The most common physical finding is tenderness in the vicinity of the lesion. Neurological abnormalities are more frequent in patients with osteoblastomas, which frequently extend into the neural canal. Tomograms are invaluable in most patients in whom plain films are normal. The bone scan is one of the most important diagnostic studies and provides an excellent means of accurately demonstrates the location and extent of the tumor. Permanent relief of pain and neurological recovery is dependent primarily on total removal of the lesion.

Degenerative spondylolisthesis with an intact neural arch: a review of 60 cases with an analysis of clinical findings and the development of surgical management.

The treatment over the past 12 years of 60 patients with degenerative spondylolisthesis with an intact neural arch is reviewed. The patients averaged 65 years of age, with women outnumbering men by a ratio of 2:1. Symptoms in the lower extremities had been present for 3 months to 10 years, although varying back pain had existed for longer periods. Two-thirds showed signs of motor dysfunction. Sensory alterations and a positive Las ègue's sign could be demonstrated in only one-half of the patients studied. Four of 5 patients developed intermittent neurogenic claudication, with varying evidence of painful radiculopathy. The marked disability caused by claudication contrasted sharply with the lesser neurological changes, and these patients required early surgical decompression. Diagnostic studies included electromyography, plain x-ray films, tomography, computed tomographic scanning, and myelography. The latter outlined a relative stenosis caused by olisthesis as well as arthrotic and spondylotic changes that determined the extent of decompressive operation required. The L-4, L-5 interspace was involved in 56 patients, L-3, L-4 was involved in 2, and L-5, S-1 was involved in 2. The ideal operation with L-4, L-5 olisthesis included complete laminectomy of L-4 and L-5 with unroofing of the lateral recesses and foraminotomy. This more extensive procedure was justified because of the failures encountered in previous patients in whom inadequate decompression had been performed. Among failures, obesity, diabetes, hyperlordosis, and extensive long-standing dysfunction were prominent. The relief of symptoms of intermittent neurogenic claudication was the most gratifying response observed. There was no unusual morbidity.

Coexisting cervical and lumbar spinal stenosis: diagnosis and management.

An attempt has been made to identify and manage patients symptomatic from both cervical and lumbar spinal stenosis. The order of operative intervention was related to the degree of myelopathy and radiculopathy. Patients requiring cervical surgery first had absolute stenosis with a spinal canal equal to or less than 10 mm in anteroposterior diameter. Those requiring lumbar surgery first presented with stenosis and a canal between 11 and 13 mm in depth. In the latter group, patients presented with radiculopathy in their upper and lower extremities. A significant portion (50%) had intermittent neurogenic claudication (INC). Motor and sensory changes were severe in those with absolute as compared to relative stenosis. After cervical laminectomy, myelopathy improved or stabilized, and the subsequent lumbar decompression could be completed with less risk. Cervical cord decompression often resulted in improvement in lumbar symptoms with resolution of pain, spasticity, and sensory deficits of myelopathic origin. However, latent symptoms of INC caused by lumbar stenosis were not affected by cervial decompression and increased in severity. Electrodiagnostic studies were helpful in that somatosensory evoked potentials showed conduction delays in the cervical cord in patients with significant disease. The identification of motor neuron disease and peripheral neuropathies was essential. The surgical management included extensive, multiple level laminectomy, unroofing of the lateral recesses, and foraminotomy. Neurolysis and untethering of the spinal cord was essential. Significant improvement was shown by 90% of these patients.

Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience.

The intraspinal administration of morphine has been employed increasingly in the management of intractable pain of malignant as well as benign origin. We have encountered a previously unreported clinical complication: spinal cord compression by an inflammatory tissue mass surrounding a subarachnoid infusion catheter administering morphine, leading to paraplegia. The patient was referred to our institution after catheter and pump implantation for chronic, intractable pain associated with pre-existing lumbar arachnoid fibrosis, after multiple myelograms and surgeries. The patient may, therefore, have had an underlying propensity to foreign body reactions. We have encountered a similar phenomenon, however, in a canine laboratory model. The pathological features in both our patient and our laboratory preparation, with inflammatory tissue masses around the tip of the catheter but not around proximal subarachnoid segments, suggest an effect related to infusion, as opposed to infection or the presence of the catheter. We review the pathological features in both settings and the pertinent literature.

Complete embolization of artery of Adamkiewicz to obliterate an intramedullary arteriovenous aneurysm. Case report.

A case history of an intramedullary arteriovenous aneurysm of the thoracolumbar junction is presented, and an unusual 14-year follow-up after the original sub-arachnoid bleeding episode is detailed. Embolization of anterior and mixed angiomas involving the artery of Adamkiewicz may be feasible when the artery is large and shunting is present.