FALS with Gly72Ser mutation in SOD1 gene: report of a family including the first autopsy case

Clinical information on familial amyotrophic lateral sclerosis (FALS) with Gly72Ser mutation in the Cu/Zn superoxide dismutase-1 (SOD1) gene has been limited and autopsy findings remain to be clarified. We describe one Japanese family with ALS carrying Gly72Ser mutation in the SOD1 gene, in which autopsy was performed on one affected member. The autopsied female patient developed muscle weakness of the left thigh at age 66 and showed transient upper motor neuron signs. She died of respiratory failure 13 months after onset without artificial respiratory support. There were no symptoms suggesting bladder or rectal dysfunction throughout the clinical course. Her brother with ALS was shown to have Gly72Ser mutation in the SOD1 gene. Histopathologically, motor neurons were markedly decreased throughout the whole spinal cord, whereas corticospinal tract involvement was very mild and was demonstrated only by CD68 immunohistochemistry. Degeneration was evident in the posterior funiculus, Clarke's nucleus, posterior cerebellar tract, and Onuf's nucleus. Neuronal hyaline inclusions were rarely observed in the neurons of the spinal cord anterior horn including Onuf's nucleus, and were immunoreactive for SOD1. To date, neuron loss in Onuf's nucleus has hardly been seen in ALS, except in the patients showing prolonged disease duration with artificial respiratory support. Involvement of Onuf's nucleus may be a characteristic pathological feature in FALS with Gly72Ser mutation in the SOD1 gene.     

Elastic fiber-mediated enthesis in the human middle ear

Adaptation to constant vibration (acoustic oscillation) is likely to confer a specific morphology at the bone-tendon and bone-ligament interfaces at the ear ossicles, which therefore represent an exciting target of enthesis research. We histologically examined (i) the bone attachments of the tensor tympani and stapedius muscles and (ii) the annular ligament of the incudostapedial joint obtained from seven elderly donated cadavers. Notably, both aldehyde-fuchsin and elastic-Masson staining demonstrated that the major fibrous component of the entheses was not collagen fibers but mature elastic fibers. The positive controls for elastic fiber staining were the arterial wall elastic laminae included in the temporal bone materials. The elastic fibers were inserted deeply into the type II collagen-poor fibrocartilage covering the ear ossicles. The muscle tendons were composed of an outer thin layer of collagen fibers and an inner thick core of elastic fibers near the malleus or stapes. In the unique elastic fiber-mediated entheses, hyaluronan, versican and fibronectin were expressed strongly along the elastic fibers. The hyaluronan seemed to act as a friction-reducing lubricant for the elastic fibers. Aggrecan was labeled strongly in a disk- or plica-like fibrous mass on the inner side of the elastic fiber-rich ligament, possibly due to compression stress from the ligament. Tenascin-c was not evident in the entheses. The elastic fiber-mediated entheses appeared resistant to tissue destruction in an environment exposed to constant vibration. The morphology was unlikely to be the result of age-related degeneration.     

Effects of aging on the morphologies of Heschl's gyrus and the superior temporal gyrus in schizophrenia: a postmortem study

The etiology of schizophrenia has been proposed to be neurodevelopmental based on neuroimaging and molecular biological studies. If there is neuronal vulnerability based on neurodevelopment failures in schizophrenic brains, then the impact of aging may have a greater effect on schizophrenic brains than on normal brains. To determine the impact of aging on schizophrenic brains, we investigated the age-related morphological changes of the cross-sectional area of the gray matter (GM) in the left Heschl's gyrus (HG) and the left superior gyrus (STG) in 22 schizophrenic and 24 age- and sex-matched normal control postmortem brains two-dimensionally. The subject groups were divided into younger groups (30-54years of age) and older groups (65-84years of age) on the basis of age at death. Both in schizophrenic and control subjects, the GM area in HG and the STG was significantly smaller in the older group than in the younger group, however, no significant differences were observed between the schizophrenic and control subjects. In the STG, the cross-sectional area of the white matter (WM) was also measured. In the older group, the ratio of the GM area to the WM area in the STG was significantly larger in schizophrenic subjects than controls, although there was no significant difference between the schizophrenic and control subjects in the younger group. These findings indicate that the impact of aging has a greater effect on the WM in the STG in schizophrenic subjects than in normal individuals, although the pathological basis is still unclear.     

Frequency characteristics of contralateral sound suppression of 40-Hz auditory steady-state response

Sound presented to the contralateral ear suppresses the amplitude of the 40-Hz auditory steady-state response (ASSR). The frequency characteristics of this suppression of the 40-Hz ASSR for amplitude modulated (AM) tones at 1,000 Hz (79-dB SPL) were examined in 12 healthy volunteers (10 males and 2 females, mean age 32.3 years) using contralateral AM tones (500, 1,000, 2,000, and 4,000 Hz) and 1/3 octave-band noise (500, 1,000, 2,000, and 4,000 Hz). The 40-Hz ASSR at 1,000 Hz was suppressed by a relatively wide frequency range of contralateral sound than expected from the known characteristics of psychophysical central masking by contralateral sound: the greatest suppression was obtained with 500- and 1,000-Hz sounds, but considerable suppression was also obtained with 2,000- and 4,000-Hz sounds. Substantial differences in the suppression pattern were not observed between two types of contra-suppressors; i.e., AM tones and 1/3 octave-band noise. Therefore, any sound presented to the contralateral ear, regardless of the frequency, can suppress the 40-Hz ASSR. Moreover, the different frequency characteristics of the contralateral sound effects between the psychophysical central masking and the 40-Hz ASSR would support the idea that the 40-Hz ASSR has an additive role in the processing of auditory signals to simple threshold judgment. Investigation of the type of psychophysical measurement using the AM signal showing similar suppression patterns by the presentation of contralateral sound would be helpful to reveal the functional relevance of ASSRs.     

Factors Affecting the Variation of Maximum Speech Intelligibility in Patients With Sensorineural Hearing Loss Other Than Apparent Retrocochlear Lesions

Objectives

To examine the relationship between speech intelligibilities among the similar level of hearing loss and threshold elevation of the auditory brainstem response (ABR).

Methods

The relationship between maximum speech intelligibilities among similar levels of hearing loss and relative threshold elevation of the click-evoked ABR (ABR threshold - pure tone average at 2,000 and 4,000 Hz) was retrospectively reviewed in patients with sensorineural hearing loss (SNHL) other than apparent retrocochlear lesions as auditory neuropathy, vestibular schwannoma and the other brain lesions.

Results

Comparison of the speech intelligibilities in subjects with similar levels of hearing loss found that the variation in maximum speech intelligibility was significantly correlated with the threshold elevation of the ABR.

Conclusion

The present results appear to support the idea that variation in maximum speech intelligibility in patients with similar levels of SNHL may be related to the different degree of dysfunctions of the inner hair cells and/or cochlear nerves in addition to those of outer hair cells.     

The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells

ObjectiveGlucagon-like peptide 1 (GLP-1), one of the incretin hormones, has been reported to increase positive inotropic activity in cardiac myocytes and protect against myocardial injury. However, the effects upon endothelial cells and the mechanisms involved are not fully understood. We assessed the hypothesis that GLP-1 has protective effects against inflammation and oxidative stress on human endothelial cells.Methods and resultsThe effects of the GLP-1 analog liraglutide upon TNF-α-induced injury of the human umbilical vein endothelial cells (HUVECs) were evaluated. First, ROS induced by TNF-α was measured by staining with CM-H₂DCFDA. Intracellular ROS production of HUVECs was significantly decreased in a dose-dependent manner until 30 nM while liraglutide inhibited the induction of gp91^phox and p22^phox, subunit of NADPH oxidase, by TNF-α? In addition, protein levels of SOD-2, catalase and GPx were significantly increased by liraglutide. Second, rapid translocation of PKC-α into the membrane following TNF-α was evident. Liraglutide significantly inhibited this very rapid TNF-α-induced translocation of PKC-α into membrane at 2.5 min. Third, liraglutide significantly inhibited NF-κB activation and upregulated I-κB family while phosphorylation of IKK-α/β, which is upstream of NF-κB signaling, was also downregulated after 15 min of TNF-α treatment. Finally, liraglutide inhibited apoptosis of HUVEC and expression of Pentraxin-3 induced by TNF-α.ConclusionLiraglutide exerts marked anti-oxidative and anti-inflammatory effects on endothelial cells with inhibition of PKC-α, NADPH oxidase, NF-κB signaling and upregulation of protective anti-oxidative enzymes.     

Atypical FTLD‐FUS associated with ALS‐TDP: A case report

A 30‐year‐old Japanese woman without relevant family history presented with a behavioral abnormality followed by motor weakness about 14 years later. The patient died at age 45. Post mortem examination revealed degeneration of the frontal and temporal lobes, as well as lower motor neurons in the brainstem and spinal cord. These features were reported previously as being consistent with a diagnosis of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). In the present study, we show abundant fused in sarcoma (FUS)‐positive dystrophic neurites but only a few neuronal cytoplasmic inclusions in the frontal and temporal cortices. TAR DNA‐binding protein 43 (TDP‐43)‐positive inclusions were absent in the cerebrum. However, TDP‐43‐positive inclusions were present in the lower motor neurons of the brainstem and spinal cord. To our knowledge, this is the first report of a case in which FTLD‐FUS pathology is of a dystrophic neurites‐predominant type and FTLD‐FUS is associated with ALS‐TDP.