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PubMed1989

Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication.

We examined the sequence of nervous system abnormalities that resulted when rats were given excess amounts of vitamin B6 (pyridoxine). High doses of pyridoxine (1,200 or 600 mg/kg/d) for 6 to 10 days caused a neuronopathy with necrosis of dorsal root ganglion (DRG) sensory neurons, accompanied by centrifugal axonal atrophy and breakdown of peripheral and central sensory axons. Large diameter neurons with long processes and large cytoplasmic volumes were especially affected. Smaller doses (300 to 150 mg/kg/d) for up to 12 weeks had minor effects on DRG neurons, but produced a neuropathy with axonal atrophy and degeneration. Guinea pigs given 1,800 mg/kg/d developed sensory neuronopathy, whereas mice given similar or higher doses did not have neuropathologic abnormalities. Multiple factors including rate of administration, differential neuronal vulnerability, and species susceptibility have bearing on the final expression of pyridoxine neurotoxicity.

Animals↗
PubMed1983

Combined reconstruction of the vertebral and carotid artery in one single procedure.

Patients suffering from vertebrobasilar insufficiency frequently have multiple areas of involvement in the extracranial circulation. Eight patients admitted to Henry Ford Hospital had symptoms suggestive of vertebrobasilar insufficiency and angiograms showing multiple abnormalities. A combined operation that reconstructed the carotid and vertebral circulations in one single procedure was completed in all patients with minimal morbidity and no mortality. The surgical procedure is described in detail.

Aged↗
PubMed2005

Mice deficient in Ext2 lack heparan sulfate and develop exostoses.

Hereditary multiple exostoses (HME) is a genetically heterogeneous human disease characterized by the development of bony outgrowths near the ends of long bones. HME results from mutations in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize heparan sulfate chains. To study the relationship of the disease to mutations in these genes, we generated Ext2-null mice by gene targeting. Homozygous mutant embryos developed normally until embryonic day 6.0, when they became growth arrested and failed to gastrulate, pointing to the early essential role for heparan sulfate in developing embryos. Heterozygotes had a normal lifespan and were fertile; however, analysis of their skeletons showed that about one-third of the animals formed one or more ectopic bone growths (exostoses). Significantly, all of the mice showed multiple abnormalities in cartilage differentiation, including disorganization of chondrocytes in long bones and premature hypertrophy in costochondral cartilage. These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise from deficiencies in other heparan sulfate-dependent pathways. The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the complex molecular mechanisms underlying the development of exostoses.

Amino Acid Sequence↗
PubMed2006

Bone morphogenetic protein receptor 1A signaling is dispensable for hematopoietic development but essential for vessel and atrioventricular endocardial cushion formation.

Bone morphogenetic protein 4 (BMP4) is crucial for the formation of FLK1-expressing (FLK1(+)) mesodermal cells. To further define the requirement for BMP signaling in the differentiation of blood, endothelial and smooth muscle cells from FLK1(+) mesoderm, we inactivated Alk3 (Bmpr1a) in FLK1(+) cells by crossing Alk3(floxed/floxed) and Flk1(+/Cre)Alk3(+/floxed) mice. Alk3 conditional knockout (CKO) mice died between E10.5 and E11.5. Unexpectedly, Alk3 CKO embryos did not show any hematopoietic defects. However, Alk3 CKO embryos displayed multiple abnormalities in vascular development, including vessel remodeling and maturation, which contributed to severe abdominal hemorrhage. Alk3 CKO embryos also displayed defects in atrioventricular canal (AVC) endocardial cushion formation in the heart. Collectively, our studies indicate a crucial role for ALK3 in vessel remodeling, vessel integrity and endocardial cushion formation during the development of the circulation system.

Animals↗
PubMed1997

Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.

Correct development of the limb is dependent on coordination between three distinct signaling centers. Recently, fibroblast growth factor-4 has been identified as a crucial determinant of AER function, which directs limb bud outgrowth, and Sonic hedgehog has been identified as a signaling molecule that mediates ZPA function, which specifies anterior-posterior patterning in the developing limb bud. In addition, Shh and FGF-4 reciprocally reinforce each other's expression via a positive feedback loop, providing a molecular basis for the coordination of limb bud outgrowth and anterior-posterior patterning. The mechanisms by which these signaling centers come to occupy their normal positions in the posterior limb bud during development are not understood. Here we identify and characterize Alx-4, a gene that encodes a paired-type homeodomain protein. Alx-4 is expressed in several populations of mesenchymal cells, including mesenchymal cells in the anterior limb bud, and mice homozygous for targeted disruption of the Alx-4 gene have multiple abnormalities, including preaxial polydactyly. The polydactyly is associated with the formation of an ectopic anterior ZPA, as indicated by anterior expression of Sonic hedgehog, HoxD13 and fibroblast growth factor-4. The expression of other candidate regulators of anterior-posterior positional information in the limb bud, including HoxB8 and Gli3, is not altered in Alx-4 mutant embryos. By chromosomal mapping experiments, Alx-4 is tightly linked to Strong's luxoid, a polydactylous mouse mutant. The results identify Alx-4 as a determinant of anterior-posterior positional identity in the limb and a component of a regulatory program that restricts ZPA formation to the posterior limb bud mesenchyme.

Amino Acid Sequence↗
PubMed1999

Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes.

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, show a limited amino acid sequence divergence. Their embryonic expression patterns overlap in spatial and temporal profiles with two major exceptions: until 8 days post coitum (d.p.c. ) only Otx2 is expressed in gastrulating embryos, and from 11 d.p.c. onwards only Otx1 is transcribed within the dorsal telencephalon. Otx1 null mice exhibit spontaneous epileptic seizures and multiple abnormalities affecting primarily the dorsal telencephalic cortex and components of the acoustic and visual sense organs. Otx2 null mice show heavy gastrulation abnormalities and lack the rostral neuroectoderm corresponding to the forebrain, midbrain and rostral hindbrain. In order to define whether these contrasting phenotypes reflect differences in expression pattern or coding sequence of Otx1 and Otx2 genes, we replaced Otx1 with a human Otx2 (hOtx2) full-coding cDNA. Interestingly, homozygous mutant mice (hOtx2(1)/hOtx2(1)) fully rescued epilepsy and corticogenesis abnormalities and showed a significant improvement of mesencephalon, cerebellum, eye and lachrymal gland defects. In contrast, the lateral semicircular canal of the inner ear was never recovered, strongly supporting an Otx1-specific requirement for the specification of this structure. These data indicate an extended functional homology between OTX1 and OTX2 proteins and provide evidence that, with the exception of the inner ear, in Otx1 and Otx2 null mice contrasting phenotypes stem from differences in expression patterns rather than in amino acid sequences.

Animals↗
PubMed1986

Tracheotomy in infants and young children: the changing perspective 1970-1985.

One hundred fifty-three children 3 years of age or younger who had tracheotomies performed during the past 15 years are reviewed. During this time, short-term endotracheal intubation for airway obstruction from acute infections and long-term intubation for patients on ventilators have replaced early tracheotomy for these conditions. The number of tracheotomies decreased during each of three 5-year periods, from 73 to 55 to 25, respectively. Improvements in medical management resulted in prolonged survival of children with multiple abnormalities and resulted in more prolonged tracheotomies. Early complications occurred in 12% of patients and late complications occurred in 26%. In spite of changes in the indications, basic fundamentals of pediatric tracheotomy management remain unchanged.

Airway Obstruction↗
PubMed2002

Complex vertebral malformation in a stillborn Holstein calf in Japan.

A female stillborn Holstein calf with shortened cervical and thoracic regions, protrusion of the tongue, and bilateral symmetric flexural contraction of the anterior limbs was delivered on gestation day 281. Multiple hemivertebrae, fused and misshaped vertebrae, synostosis and scoliosis of cervical, thoracic and lumbar vertebral column were found in the affected calf by radiographic and computed tomographic (CT) analysis. Ten pairs of ribs were present and the sternum consisted of 9 sternebrae. Multiple morphologic abnormalities including fusion, malformation, and displacement, were found in the ribs and sternum. Cardiac anomalies, including atrial septal defect and hypertrophy of right ventricle, were observed. DNA-polymerase chain reaction (PCR) analysis demonstrated that amplified product from the liver DNA of the affected calf had identical pattern to that associated with complex vertebral malformation (CVM) of Holstein calves and that her dam was a heterozygous carrier of CVM. The affected calf was diagnosed as having CVM based on the DNA-PCR results and the characteristic findings, and was recorded as a first documentation of CVM confirmed in a Holstein calf in Japan.

Abnormalities, Multiple↗
PubMed1998

Cardiomyopathic lentiginosis/LEOPARD syndrome presenting as sudden cardiac arrest.

A 26-year-old apparently healthy man with numerous pigmented skin lesions collapsed during an evening party and was resuscitated from ventricular fibrillation. Hypertrophic cardiomyopathy and subaortic tunnel were disclosed by angiocardiography. A diagnosis of cardiomyopathic lentiginosis/lentigines (multiple), electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth, and deafness (sensorineural) syndrome was made. The patient then underwent treatment with an implantable pacer-cardioverter-defibrillator device. Further evaluation revealed several well-established features of the disorder. This is the first reported case of survival from ventricular fibrillation associated with this rare and little known multifaceted syndrome. Disseminated lentiginosis must prompt clinicians to evaluate such cases further since underlying disorders may be associated with considerable morbidity and, apparently, sudden death.

Abnormalities, Multiple↗
PubMed2006

The structural and functional integrity of peripheral nerves depends on the glial-derived signal desert hedgehog.

We show that desert hedgehog (dhh), a signaling molecule expressed by Schwann cells, is essential for the structural and functional integrity of the peripheral nerve. Dhh-null nerves display multiple abnormalities that affect myelinating and nonmyelinating Schwann cells, axons, and vasculature and immune cells. Myelinated fibers of these mice have a significantly increased (more than two times) number of Schmidt-Lanterman incisures (SLIs), and connexin 29, a molecular component of SLIs, is strongly upregulated. Crossing Dhh-null mice with myelin basic protein (MBP)-deficient shiverer mice, which also have increased SLI numbers, results in further increased SLIs, suggesting that Dhh and MBP control SLIs by different mechanisms. Unmyelinated fibers are also affected, containing many fewer axons per Schwann cell in transverse profiles, whereas the total number of unmyelinated axons is reduced by approximately one-third. In Dhh-null mice, the blood-nerve barrier is permeable and neutrophils and macrophage numbers are elevated, even in uninjured nerves. Dhh-null nerves also lack the largest-diameter myelinated fibers, have elevated numbers of degenerating myelinated axons, and contain regenerating fibers. Transected dhh nerves degenerate faster than wild-type controls. This demonstrates that a single identified glial signal, Dhh, plays a critical role in controlling the integrity of peripheral nervous tissue, in line with its critical role in nerve sheath development (Parmantier et al., 1999). The complexity of the defects raises a number of important questions about the Dhh-dependent cell-cell signaling network in peripheral nerves.

Aging↗
PubMed2005

Dyskeratosis congenita: a disorder of defective telomere maintenance?

Dyskeratosis congenita (DC) is a rare multisystem bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. The gene that is mutated in the X-linked form of the disease is DKC1. The DKC1-encoded protein, dyskerin, is a component of small nucleolar ribonucleoprotein particles, which are important in ribosomal RNA processing, and of the telomerase complex. The autosomal dominant form of DC is due to mutations in the gene for the RNA component of telomerase (TERC). Because both dyskerin and TERC are components of the telomerase complex and all patients with DC have short telomeres, the principal pathology of DC appears to relate to telomerase dysfunction, although defects in ribosomal processing via dyskerin's involvement in pseudouridylation cannot be completely ruled out. The gene or genes involved in autosomal recessive DC remain elusive, although genes whose products are required for telomere maintenance remain strong candidates. The study of DC highlights the importance of telomerase in humans and how its deficiency results in multiple abnormalities, including premature aging, bone marrow failure, and cancer.

Cell Cycle Proteins↗
PubMed1997

[Evoked potentials in neurocysticercosis].

In 25 patients with cysticercosis of central nervous system, classified in two clinical forms, benign and malign, evoked potentials were obtained. Normal exam was found in 9 cases with the benign form. From 4 patients with malign clinical presentations, 2 had multiple abnormalities of the evoked potentials, and F wave alterations (mixed pattern). The authors suggest that this mixed pattern may be indicative of severe prognosis.

Adolescent↗
PubMedDate not supplied

A case of Rendu-Osler-Weber disease with cerebral hemangioma, multiple pulmonary arteriovenous fistulas and hepatic arteriovenous fistula.

A 46-year-old woman was admitted to the hospital because of dyspnea and palpitation. Physical examination showed severe anemia and cardiac distress. Telangiectases were found in the conjunctivas, lips and oral mucosa. Chest roentogenogram showed an enlarged cardiac silhoutte and multiple coin lesions in both lower lung fields. We diagnosed her as Rendu-Osler-Weber disease (ROW). The angiographic studies showed hemangioma in the foramen of Monro, bilateral multiple pulmonary arteriovenous fistulas, and hepatic arteriovenous fistula with a large distortion of the proper hepatic artery. Although associated vascular dysplasias have been described in patients with ROW, there is no reports on ROW in which multiple vascular abnormalities concomitantly existed such as the present case. In 163 detailed cases of ROW in Japan, the frequency of vascular lesions was summarized, and this result showed that the vascular lesions of the lung were more frequent than that of the liver or brain, in comparison with countries in Europe and America. It is very important for diagnosis and its prognosis to perform a detailed angiographic examinations and to demonstrate the precise sites of the vascular dysplasias in patients with ROW.

Abnormalities, Multiple↗
PubMed2004

Heritable anomalies among the inhabitants of regions of normal and high background radiation in Kerala: results of a cohort study, 1988-1994.

In a genetic epidemiological and fertility survey among 70,000 inhabitants in a high-background radiation region (HBRR) and normal radiation region (NRR) in Kerala, India, 985 persons were found to have heritable anomalies. Suggested etiologies for the anomalies were chromosomal and Mendelian, 15 percent; multifactorial, 60 percent; and congenital, 25 percent. There was a statistically significant increase of Down syndrome, autosomal dominant anomalies, and multifactorial diseases and an insignificant increase of autosomal recessive and X-linked recessive anomalies in the HBRR. The total fertility rate was 3.85 per couple; 9 percent of live-born children were reported dead. The rate of untoward pregnancy outcome--death of the offspring or presence of an anomaly in a living child--was 6.4 percent among the unrelated couples in the NRR, with one spouse born outside the area of current residence ("migrant"). Considering this as the base, the excess relative risks in the other groups are: "NRR-nonmigrant," 35 percent; "HBRR-nonmigrant," 69 percent; "NRR-consanguineous," 76 percent; and "NBRR-consanguineous," 157 percent. Ionizing radiation, consanguinity, and nearness of birthplace of the spouse are risk factors for the death of offspring and for anomalies. The higher risk among the "nonmigrant" couples may be due to geographic inbreeding. The findings are suggestive of an autosomal recessive etiology for the majority of the multifactorial anomalies.

Abnormalities, Multiple↗
PubMed2006

Therapeutic efficacy of facet joint blocks.

OBJECTIVE: The objective of our study was to investigate outcome predictors of short- and medium-term therapeutic efficacy of facet joint blocks. MATERIALS AND METHODS: Forty-two patients with chronic lower back pain who were undergoing facet joint blocks at one (n = 29) or two (n = 13) levels were analyzed. All patients underwent MRI or CT of the lumbar spine within 5 months before the facet joint blocks. The facet joint blocks were performed under fluoroscopic guidance. A small amount (< 0.3 mL) of iodinated contrast agent, 0.5 mL of local anesthetics and 0.5 mL of steroids, were injected. The initial pain response was prospectively assessed using a visual analogue scale. Additional data, including short-term effect (> 1 week) and medium-term effect (> 3 months), were collected by a structured telephone interview. CT and MRI were reviewed with regard to the extent of facet joint abnormalities. Multiple logistic regression analyses were conducted to identify outcome predictor for efficacy of facet joint blocks. RESULTS: A positive immediate effect was seen in 31 patients (74%). A positive medium-term effect was found in 14 patients (33%). Pain alleviated by motion (p = 0.035) and the absence of joint-blocking sensation (p = 0.042) predicted pain relief. However, the extent of facet joint osteoarthritis on MRI and CT was not a significant predictor for outcome (p = 0.57-0.95). CONCLUSION: Facet joint blocks appear to have a beneficial medium-term effect in one third of patients with chronic lower back pain and may therefore be a reasonable adjunct to nonoperative treatment. However, outcome appears to depend on clinical, not on morphologic, imaging findings.

Adult↗
PubMed1978

Significant new observations on cervical spine trauma.

The results of a computer analysis of 399 patients with documented fractures and/or dislocations of the cervical spine are summarized. Vertebral arch fractures were present in half of all patients with radiographic evidence of cervical spine trauma. Two-thirds of the patients had two or more injuries. Isolated disk injuries were rare and, when present, were characterized by a vacuum sign. The dens fracture, with or without atlantoaxial dislocation, was rarely associated with injury elsewhere in the cervical spine. The study suggests that the routine five-film cervical spine examination is inadequate to detect the most common traumatic lesions. Thus vertebral arch views (pillar views) should be obtained if there is evidence to suggest hyperextension as the mechanism of injury. In addition, the study underscores the importance of aggressively searching for multiple abnormalities.

Axis, Cervical Vertebra↗