CMT4A: identification of a Hispanic GDAP1 founder mutation

Mutations of the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina.     

Tau protein immunoreactivity in dementia of the Alzheimer type: II. Electron microscopy and pathogenetic implications. Effects of fixation on the morphology of the Alzheimer's abnormal filaments

I have used Tau-1 and Tau-2, two monoclonal antibodies against tau protein, to study at the electron microscopic level the tau immunoreactivity in 8 cases with dementia of the Alzheimer type, using the peroxidase-antiperoxidase technique and formalin-fixed autopsy and biopsy brain tissues. In neurons and astrocytes, excessive amounts of tau immunoreactivity were noted in association with ribosomes. The Alzheimer's abnormal filaments in neurofibrillary tangles in neuronal perikarya, in senile plaques, and in a multitude of abnormal neuropil neurites were frequently stained intensely. However, many neurons contained either stained ribosomes only or stained ribosomes and unstained abnormal filaments both scattered and in neurofibrillary tangles. In all locations, the immunostained abnormal filaments were straight without appreciable periodic constrictions and, on cross-section, had a tubular appearance with stained walls, frequently demonstrable unstained lumens and an accentuation of staining intensity at the periphery. In addition, conventional electron microscopy showed that formalin-fixed and glutaraldehyde-fixed neurofibrillary tangles were made of compactly arranged straight filaments and loosely arranged paired helical filaments, whereas osmium tetroxide-fixed neurofibrillary tangles were made almost exclusively of paired helical filaments. These findings suggest that: (a) localization of excessive tau immunoreactivity with ribosomes might be the primary event and association of detectable tau immunoreactivity with already assembled filaments might be an epiphenomenon; and (b) the mode of fixation and subsequent preparatory procedures might alter the morphology of the Alzheimer's abnormal filaments.     

Fibromatosis of the breast.

A case of fibromatosis of the breast occurring in a 37-year-old woman is described. Only 15 cases of this type have been previously reported. In 5 of these cases there was also involvement of the underlying pectoral muscles, raising the possibility that some of these may have been of pectoral musculoaponeurotic origin. Two of the previously reported cases occurred in patients with Gardner's syndrome and 1 in a patient with "familial muticentric fibromatosis." It is anticipated that fibromatosis of the breast will behave in a similar fashion to fibromatosis occurring in other sites; i.e., as a local aggressive lesion which exhibits a high incidence of local recurrence following incomplete excision.     

Primary intracerebral Hodgkin's disease: a case report

The authors report a case of primary intracerebral Hodgkin's disease in an 84-year-old woman who presented with a solitary intraparenchymal parieto-occipital lesion and absence of extracranial disease. The histologic diagnosis of Hodgkin's disease was further confirmed with positive immunohistochemical staining of Hodgkin's mononuclear cells and Reed-Sternberg cells and electron microscopy. Such an initial presentation of a solitary intracerebral tumor is extremely rare in Hodgkin's disease. This case helps establish primary intracerebral Hodgkin's disease as a true entity.     

Actin immunoreactivity localizes with segregated microtubules and membraneous organelles and in the subaxolemmal region in the beta,beta'-iminodipropionitrile axon

Using the peroxidase-antiperoxidase staining technique with monoclonal and polyclonal antibodies against actin, we found that, in beta,beta'-iminodipropionitrile (IDPN)-treated axons, actin immunoreactivity was codistributed with segregated microtubules and membranous organelles in the central region and excluded from the peripheral axoplasm occupied by neurofilaments. Actin immunoreactivity was also present in the subaxolemmal region. Fast axonal transport is localized in the central region of the IDPN axon (Papasozomenos et al., 1982a). As both microtubules and actin are present in the central region of IDPN axons, a possible role of actin in fast axonal transport warrants further investigation.     

Ultrastructural localization of Fras1 in the sublamina densa of embryonic epithelial basement membranes

Fras1 is the first identified member of a protein family comprising Fras1 and the related extracellular matrix proteins Frem1, Frem2 and Frem3. Mutations in Fras1, Frem1 and Frem2 have been associated with the bleb phenotype in mouse, whereas mutations in the human orthologs FRAS1 and FREM2 have been implicated in the pathogenesis of the human Fraser syndrome. Bleb mutant mice are characterized by embryonic sub-epidermal blistering, unilateral or bilateral renal agenesis or dysgenesis, cutaneous syndactyly and fused eyelids. As revealed by immunofluorescence, Fras1 co-localizes with the markers of epithelial basement membranes and is ultrastructurally detected underneath the lamina densa of embryonic mouse epithelia. Since the loss of Fras1 mainly affects the cohesiveness of the embryonic skin basement membrane with its underlying mesenchyme, we compared here the ultrastructural localization of Fras1 in the dermal–epidermal junction and in the basement membrane of other embryonic epithelia that do not show any overt phenotype using preembedding immunocytochemistry. Fras1 immunoreactivity was detected in all epithelia examined, within the sublamina densa adjacent to stromal tissue, as clustered gold/silver enhanced depositions, usually attached to anchoring fibrils. Interestingly, clusters corresponding to Fras1 were frequently detected in close proximity to mesenchymal cells, indicating that Fras1 could serve as a direct link between the sublamina densa and mesenchyme. The localization of Fras1 is consistent with previous results indicating that Fras1 exerts its function below the lamina densa and that Fras1 displays the same localization pattern in all epithelial basement membranes.     

Subependymal giant cell astrocytoma

Summary Twenty-two cases of subependymal giant cell astrocytoma (SGCA), five of which associated with tuberous sclerosis, were reviewed by conventional neurohistological stains and by peroxidase-antiperoxidase (PAP) immunohistochemistry for glial fibrillary acidic (GFA) protein, the 68 Kd neurofilament subunit (68 Kd-NF), and neuron-specific enolase (NSE). Neurohistological stains confirmed the presence of PTAH-positive fibrils and the absence of Nissl bodies and of neurites originating from the tumor cells. GFA protein-positive cells were present in all tumors not associated with tuberous sclerosis. However, the number of positive cells in each tumor was highly variable. GFA protein-positive cells were rare in the two SGCA accompanying tuberous sclerosis and absent in the remaining three. Neurohistological stains showed no differences between GFA protein-positive and negative cells. 68 Kd-NF-positive cells were found in six tumors. In one tumor, associated with tuberous sclerosis, it was present in the large ganglion-like cells only. NSE-positive cells were found in 13 of 18 tumors examined, including four of the five SGCA associated with tuberous sclerosis. The significance of NSE-positivity in central neuroepithelial neoplasms in respect of their possible neuronal origin remains open.This study suggests that the SGCA, especially those associated with tuberous sclerosis, include cells that are apparently unable to express GFA protein. Some of the tumor cells express the 68 Kd-NF, but this expression falls short of the complete expression of neuronal differentiation. The unique morphological appearances of the SGCA and the discrepancies reported in electron-microscopic and immunohistochemical studies suggest that the cell of origin of these tumors is the product of a dysgenetic event in early development. As a result, the potential of that cell for astrocytic or neuronal differentiation may be incompletely or aberrantly expressed, in particular when the stigmata of tuberous sclerosis are also present. No evidence of obvious ganglionic differentiation and no inference of a neuronal origin of the tumor cells in SGCA could be adduced from the present histochemical findings. This study supports the general interpretation of these tumors as a variant of astrocytoma.Supported in part by research grant CA 31271 (LJR) from the National Cancer Institute, US Dept. of Health and Human ServicesDr. Bonnin is supported by Clinical Fellowship no. 5732 of the American Cancer Society and by Neuropathology Research Training grant T32 NS 07236 of the National Institute of Neurological and Communicable Diseases and Stroke, US Dept. of Health and Human Services     

Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting

Summary Didemnin B (NSC 325319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m² was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m². Neuromuscular toxicity was dose-limiting. Neusea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m², following the premedication of patients with antiemetics.This work was supported in part by grant NO1CM57 739 from the National Cancer Institute. The senior author (D. M. S.) is a recipient of the American Cancer Society Clinical Oncology Career Development Award     

Einfluß ionisierender Strahlen auf Gehör-und Gleichgewichtsorgan

Summary Patients, who got a X-ray radiation of the base of skull show a combined disturbance of sound conduction and perception. Histochemical investigation of Guinea pigs which got a X-ray radiation of skull with a tissue dose of the inner ear of 4000, 5000 and 6000 R, may show localisation and cause of radiation induced labyrinth disturbance. Change in activity of non-specific esterase, lipase, ß-galactosidase, ß-glucuronidase, ß-glucosaminidase, acid and alkaline phosphatase, proteinbound sulfhydryles and acid mucopolysaccharides were studied. Ferments at first mostly showed an increase of activity but with higher doses of radiation a decrease of activity was stated. Proteinbound sulfhydryles and hyaluronidase-sensitive acid mucopolysaccharides brought to view a proportionate decrease.

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Einfluß ionisierender Strahlen auf Gehör-und Gleichgewichtsorgan

Zusammenfassung An Patienten, die einer Röntgenbestrahlung der Schädel-basis ausgesetzt waren, ließ sich ein kombinierte Schalleitungs-Schallempfindungsschwerhörigkeit nachweisen. Histochemische Untersuchungen an Meerschweinchen, denen eine Röntgenbestrahlung des Schädels mit einer Herddosis am Innenohr von 4000, 5000 und 6000 R verabfolgt wurde, sollen Lokalisation und Ursache der strahlenbedingten Labyrinthschäden beleuchten. Nachgewiesen wurden Änderungen an unspezifischer Esterase, -Galaktosidase, -Glucuronidase, -Gluco-saminidase, saurer und alkalischer Phosphatase und Lipase sowie proteingebundenen Sulfhydrylen und sauren Mucopolysacchariden. Während die Fermente vorwiegend zunächst eine Aktivitätszunahme und erst unter höheren Strahlendosen eine Aktivitätsabnahme erkennen ließen, wurde unter der Bestrahlung eine gleichmäßige Abnahme proteingebundener Sulfhydryle und Hyaluronidase-sensibler saurer Mucopolysaccharide deutlich.