Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA).
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Chorea↗
Biomedical subjects
M W Becher
Publications and source records attributed to M W Becher.
Huntington's disease and dentatorubral-pallidoluysian atrophy: proteins, pathogenesis and pathology.
Each of the glutamine repeat neurodegenerative diseases has a particular pattern of pathology largely restricted to the CNS. However, there is considerable overlap among the regions affected, suggesting that the diseases share pathogenic mechanisms, presumably involving the glutamine repeats. We focus on Huntington's disease (HD) and Dentatorubral-pallidoluysian atrophy (DRPLA) as models for this family of diseases, since they have striking similarities and also notable differences in their clinical features and pathology. We review the pattern of pathology in adult and juvenile onset cases. Despite selective pathology, the disease genes and their protein products (huntingtin and atrophin-1) are widely expressed. This presents a central problem for all the glutamine repeat diseases-how do widely expressed gene products give rise to restricted pathology? The pathogenic effects are believed to occur via a "gain of function" mechanism at the protein level. Mechanisms of cell death may include excitotoxicity, metabolic toxicity, apoptosis, and free radical stress. Emerging data indicate that huntingtin and atrophin-1 may have distinct protein interactions. The specific interaction partners may help explain the selective pathology of these diseases.
Adult↗
Brain capillary telangiectasia: MR imaging appearance and clinicohistopathologic findings.
PURPOSE: To demonstrate the clinical and magnetic resonance (MR) imaging findings of brain capillary telangiectasia and compare them with postmortem specimens. MATERIALS AND METHODS: MR images obtained in and clinical histories of 18 adult patients with a presumed diagnosis of capillary telangiectasia examined within 3 years were retrospectively reviewed. All patients had undergone MR imaging with conventional T1- and T2-weighted spin-echo sequences and gadolinium-enhanced T1-weighted and susceptibility-sensitive gradient-echo (GRE) sequences. No biopsies had been performed. Fourteen patients had undergone clinical and MR imaging follow-up (median, 11 months). Postmortem tissues from three cases of histopathologically confirmed capillary telangiectasia were imaged. RESULTS: All lesions were small, homogeneously enhancing, and hypo- to isointense on T1-weighted images and iso- to slightly hyperintense on proton-density- and T2-weighted images. None was hypointense on proton-density- or T2-weighted images. All lesions showed marked GRE signal loss. None had changed at follow-up. Two patients had multiple classic cerebral cavernous angiomas. The three specimens showed no abnormal susceptibility and contained no hemosiderin at tissue analysis. CONCLUSION: Capillary telangiectasia has mild contrast material enhancement but is otherwise undetectable on conventional MR images. It lacks the "hemosiderin rim" of cavernous angioma and demonstrates increased susceptibility only on GRE images, likely owing to blood oxygen-level-dependent contrast. GRE is essential in diagnosing brain capillary telangiectasia, which could otherwise be misdiagnosed as neoplasia, subacute infarction, or demyelination.
Brain↗
Neurofilament subunit NF-H modulates axonal diameter by selectively slowing neurofilament transport.
To examine the mechanism through which neurofilaments regulate the caliber of myelinated axons and to test how aberrant accumulations of neurofilaments cause motor neuron disease, mice have been constructed that express wild-type mouse NF-H up to 4.5 times the normal level. Small increases in NF-H expression lead to increased total neurofilament content and larger myelinated axons, whereas larger increases in NF-H decrease total neurofilament content and strongly inhibit radial growth. Increasing NF-H expression selectively slow neurofilament transport into and along axons, resulting in severe perikaryal accumulation of neurofilaments and proximal axonal swellings in motor neurons. Unlike the situation in transgenic mice expressing modest levels of human NF-H (Cote, F., J.F. Collard, and J.P. Julien. 1993. Cell. 73:35-46), even 4.5 times the normal level of wild-type mouse NF-H does not result in any overt phenotype or enhanced motor neuron degeneration or loss. Rather, motor neurons are extraordinarily tolerant of wild-type murine NF-H, whereas wild-type human NF-H, which differs from the mouse homolog at > 160 residue positions, mediates motor neuron disease in mice by acting as an aberrant, mutant subunit.
Animals↗
Inherited neurodegenerative diseases and transgenic models.
In recent years, the identification of mutations in specific genes in several inherited neurodegenerative disorders, combined with advances in the field of transgenic methods, has provided neuroscientists and neuropathologists with information and strategies to develop transgenic (Tg) models to study human diseases. These approaches have proved to be extraordinarily useful in modeling familial forms of amyotrophic lateral sclerosis (FALS) and Alzheimer's disease (FAD) and the spectrum of triplet-repeat disorders. Investigations of these models have begun to provide new insights into the roles of disease-specific mutant proteins and the pathogenic mechanisms of disease as well as opportunities to test therapeutic interventions.
Aged↗
Total anomalous pulmonary venous connection: persistence and atresia of the common pulmonary vein.
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Female↗
Anomalous right coronary artery associated with sudden death: an example of a neural crest migration defect.
A unique right coronary artery anomaly of hemodynamic significance was discovered in a young adult who suddenly died. In addition, abnormally migrated, or supernumerary, thymic tissue with embedded parathyroid glands was present. This combination of congenital malformations suggests that the pathogenesis of this rare cardiac anomaly may be explained by a cranial neural crest defect.
Adult↗
Hypospadias repair using laser welding of ventral skin flap in rabbits: comparison with sutured repair.
We tested the feasibility of laser welding in hypospadias repair. A total of 30 New Zealand white rabbits (2 groups of 15) underwent creation of distal hypospadias. In the control group ventrally placed skin flaps were created and sutured to the urethra. In the experimental group the ventrally placed skin flaps were welded to the urethra using a continuous wave diode laser (808 plus or minus 1 nm., 6.25 watts per cm.2). The welded anastomoses were strengthened by applying a solder of fibrinogen combined with a laser energy-absorbing dye. No stents were left indwelling. Operative time using laser welding was considerably less than that with sutured repair. No fistulas were seen in the welded urethras, and no significant foreign body reaction was identified in the laser welded repairs. Hypospadias repair in the rabbit using the laser welding technique seems to be a feasible alternative to suture repair. Topical energy-absorbing dyes that enhance thermosetting solders further increase weld strength while reducing collateral thermal damage to target tissues.
Animals↗
Evidence for cholinergic neurites in senile plaques.
In the neocortices and amygdalae of young and aged macaques, cholinergic axons were identified by means of a monoclonal antibody to bovine choline acetyltransferase. Many fine, linear, immunoreactive profiles were seen in these animals. In the older animals, some cholinergic axons showed multifocal enlargements along their course. In some instances, neurites with choline acetyltransferase immunoreactivity were associated with deposits of amyloid (visualized with thioflavin T fluorescence). The appearance of these amyloid-associated abnormal cholinergic processes was similar to that of neurites in senile plaques, as shown by conventional silver impregnation techniques. Cholinergic systems thus give rise to some of the neurites within senile plaques.
Aging↗
Intrinsic laryngeal muscle regeneration following endotracheal intubation.
The larynges of 33 premature and term neonates who were intubated for the management of respiratory difficulties were studied. In addition to the changes commonly associated with endotracheal intubation (epithelial erosion, ulceration, squamous metaplasia, edema, inflammation, and perichondritis), the intrinsic laryngeal muscles were damaged in 26 of the 33 cases and, in 4 cases, oriented striated skeletal muscle regeneration was found. The active synthetic nature of the myotube formations in the latter cases was confirmed by the demonstration of concentrated vimentin intermediate-filament immunoreactivity. In view of the frequency of neonatal intubation, the probability of muscle damage, and the generally infrequent critical sequelae of this procedure, regeneration of the intrinsic muscles may help to explain the excellent functional recovery of the neonatal larynx. This phenomenon also occurs in the postintubated adult larynx and is therefore not limited to the neonatal period. In addition, these findings support the fact that skeletal muscle regeneration occurs in nonmyopathic human skeletal muscles following injury, as has been shown in experimental animal models.
Adult↗