Conditions of Alzheimer-type dementia in the old-old and oldest-old patients with special reference to extreme conditions of brain aging

A neuropathological study on 1540 consecutive autopsy brains ranging from 60 to 107 years of age revealed the following points. (1) Of the of the demented cases of the plaque-predominant type, 93% were complicated with multiple tiny cortical infarcts. They showed a tendency for dementia to develop before or after the appearance or worsening of a systemic disorder such as cardiovascular disease, respiratory infection and cancer. However, there was no case showing Alzheimer-type dementia (ATD). (2) The plaque-predominant type might be an extreme condition of brain aging in terms of senile plaques (SP). It is likely that although the pathological appearance of SP alone is not responsible for dementia, its coexistence with multiple cortical infarcts could be the cause of dementia. Therefore, this type should be distinguished from ATD. (3) Primary hippocampal degeneration could also be an extreme condition of brain aging in terms of neurofibrillary tangles. This condition was different pathologically from the hippocampal lesion in ATD. (4) Several characteristics of old-old and oldest-old patients were clarified.     

"Cross-talk" in recording evoked potentials.

When two potentials having large amplitude differences are simultaneously recorded, the large amplitude potential contaminates the small amplitude response. The small, early potentials generated by this contamination resemble far-field potentials. Although scalp-recorded SEP was contaminated by waves similar to the peripheral potential, peak latencies and wave form were not identical. Experiments simulating the recording situation verified the presence of "cross-talk." Capacitive coupling would shift peaks and alter the wave forms. Other possible mechanisms for the cross-talk and methods of minimizing it are offered. One should be cautious interpreting the results when potentials of large amplitude differences are simultaneously recorded.     

The influence of interfering input from the peroneal nerve on tibial-nerve somatosensory evoked potential.

Using a conditioning-test paradigm, we studied the recovery function of tibial nerve somatosensory evoked potentials (SEPs) conditioned by preceding peroneal nerve stimulation. The inter-stimulus intervals (ISIs) ranged from 0 to 400 msec, where 0 msec indicated simultaneous arrival of tibial and peroneal nerve volleys at the L1 spine. The recovery curve was W-shaped, showing two peaks of SEP suppression, maximum at 6 msec ISI (1st phase) and 50-75 ISI msec (2nd phase). In the 1st phase suppression, we found distinct differences in wave forms between 0-2 msec ISI and 4-6 msec ISI. At 0-2 msec ISI, P40-N50-P60 amplitude decreased and latencies shortened, while P31 and N35 were unchanged. At 4-6 msec ISI, all peaks, possibly excluding P31, were markedly depressed. We attribute the former change to an "occlusive effect" and the latter to an "inhibitory effect," each mediated via a central synaptic network between the two nerves. The attenuation of the 2nd but not the 1st phase suppression by peroneal nerve block distal to the stimulating electrodes provided evidence that the 2nd phase suppression resulted primarily from interfering afferent signals generated by peroneal nerve peripheral receptors, activated by foot movement.     

Juvenile parkinsonism with marked diurnal fluctuation

We presented a report on four cases of juvenile parkinsonism with a marked diurnal fluctuation of symptoms and dystonia. Among parkinsonian signs, rigidity fluctuated the most and increasing rigidity by passive or active movements or emotional stress was observed. When we analyzed patients previously reported, in addition to our own new patients, apart from the diurnal fluctuation and predominant occurrence in females, many similarities to Yokochi's third group of juvenile parkinsonism were found. In the previous reports, the patients with the marked fluctuation of parkinsonian symptoms have not always shown dystonia. The changes of symptoms in relation to menstruation and pregnancy were other characteristic features in our three female patients. Here we proposed that for the present, it is preferable to call this disorder "juvenile parkinsonism with a marked diurnal fluctuation."     

Thermoelastic effect in chemically skinned frog skeletal muscle in rigor

The thermoelasticity in rigor muscle was investigated using chemically skinned frog sartorius muscles. The use of chemically skinned muscles enabled us to study the thermoelasticity under various intracellular circumstances. Effects on the thermoelasticity of the presence or the absence of Ca and the lowering of pH in the rigor solution were investigated. All values of the thermoelastic heat: tension ratios obtained under various circumstances were within the range reported for active muscles. In rigor state, the cross-bridges are fixed on the thin filaments and head can no longer rotate. Hence the present results indicate that the thermoelasticity in active muscles originates from the thermoelasticity of the myofilaments or the cross-bridges.     

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.     

Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable,epigenetic gene silencing: a mammalian cell culture model of gene variegation

Heterochromatin protein 1 (HP1) is a key component of constitutive heterochromatin in Drosophila and is required for stable epigenetic gene silencing classically observed as position effect variegation. Less is known of the family of mammalian HP1 proteins, which may be euchromatic, targeted to expressed loci by repressor-corepressor complexes, and retained there by Lys 9-methylated histone H3 (H3-MeK9). To characterize the physical properties of euchromatic loci bound by HP1, we developed a strategy for regulated recruitment of HP1 to an expressed transgene in mammalian cells by using a synthetic, hormone-regulated KRAB repression domain. We show that its obligate corepressor, KAP1, can coordinate all the machinery required for stable gene silencing. In the presence of hormone, the transgene is rapidly silenced, spatially recruited to HP1-rich nuclear regions, assumes a compact chromatin structure, and is physically associated with KAP1, HP1, and the H3 Lys 9-specific methyltransferase, SETDB1, over a highly localized region centered around the promoter. Remarkably, silencing established by a short pulse of hormone is stably maintained for >50 population doublings in the absence of hormone in clonal-cell populations, and the silent transgenes in these clones show promoter hypermethylation. Thus, like variegation in Drosophila, recruitment of mammalian HP1 to a euchromatic promoter can establish a silenced state that is epigenetically heritable.     

Ground-glass hepatocytes in fibrinogen storage disease in Japanese Black calves

This paper reports the occurrence of large intracytoplasmic inclusions observed in the hepatocytes of six Japanese Black calves showing clinical illness. These inclusions were round to elongated polyhedral in shape, with a consistently homogeneous glassy appearance. Hepatocytes with the inclusions had a ground-glass appearance. The inclusions were negative for the periodic acid-Schiff reaction and methenamine silver stain. Immunohistochemically, they were strongly positive for fibrinogen. Electron microscopy revealed that the inclusions consisted of granular material, showing moderate electron density and bounded by a unit membrane. On the external surface of the unit membrane, there were direct connections to cellular organelles, including the ribosomes and rough-surfaced endoplasmic reticulum. The results showed these inclusions to be entirely consistent with fibrinogen inclusions described in man. Hepatocellular fibrinogen storage disease, as identified in this study, has not previously been described in animals.     

Seminoma in a postmenopausal woman with a Y;15 translocation in peripheral blood lymphocytes and a t(Y;15)/45,X Turner mosaic pattern in skin fibroblasts.

We report an unusual case of a 55 year old Japanese woman with a seminoma but relatively normal menses. The patient was a phenotypic female with late onset menarche (18 years of age), who was amenorrhoeic for the first year, followed by menses of one to three days' slight flow with dysmenorrhoea, but an otherwise normal menstrual history. A typical seminoma was removed from the left adnexal region and an immature testis was identified separately as an associated right adnexal mass. Repeated karyotypic studies on peripheral blood lymphocyte cultures showed only 46,X,-Y,t(Y;15)(q12;p13). Cytogenetic examination of the patient's younger brother, who had fathered three healthy children, showed an identical karyotype. Mosaicism of 46,X,-Y,t(Y;15)(q12;p13)/45,X cell lines was found in skin samples from the patient's elbow and genital regions, although there were no clinical stigmata of Turner syndrome. An androgen receptor binding assay of cultured genital skin fibroblasts was negative. Molecular analysis using Southern blot hybridisation, PCR, and direct DNA sequencing showed that neither the patient nor her brother had a detectable deletion or other abnormalities of Y chromosome sequences, including the SRY (sex determining region of the Y chromosome) gene sequence. These findings suggest that Turner mosaicism of the 45,X cell line may have contributed to this atypical presentation in an XY female, although we cannot exclude abnormalities of other genes related to sex differentiation.