Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-6. Toxicity of metabolites of miocamycin: subacute toxicity of Mb2 in rats

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. At previous study, the acute and subacute toxicity of Mb1 and acute toxicity of Mb2 were performed that those metabolites did not exhibit any lethal toxicity even at the maximum physically applicable dose. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb2 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is, therefore, concluded that Mb2 exerted no toxic effects in this subacute toxicity.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-3. Toxicity of metabolites of miocamycin: subacute toxicity of Mb1 in rats

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female rats as Mb1 did not exhibited any lethal toxicity even at the maximum physically applicable dose of 5,000 mg/kg. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb1 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxicity was observed in this subacute toxicity study on Mb1 in rats.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-12. Toxicity of metabolites of miocamycin: subacute toxicity of Mb12 in rats

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous study, LD0 values of Mb12 in male and female rats were estimated more than 5,000 mg/kg. The object of this study was to evaluate subacute toxicity in male and female rats after repeated oral administration of Mb12 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxic effects were caused by Mb12 even at the highest dosage level of 1,000 mg/kg/day for 5 weeks to male and female rats.     

Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases

We investigated five Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), both clinically and pathologically, and examined the degree and distribution of the basal ganglia lesions, especially in the amygdala, striatum, pallidum, and substantia nigra. The lesions in the amygdala, striatum, and pallidum were classified into three categories (mild, moderate, and severe). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. Severe dementia was observed in four cases neuropathologically showing pronounced neuronal loss in the cerebral cortex, but one case without neuronal loss in the cerebral cortex showed mild memory disturbance. Extrapyramidal signs were evident in three cases. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four cases. Basal ganglia lesions in all five cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus moderate to slight lesions, and the putamen and pallidum slight lesions to normal. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group, inconsistent with those in the amygdala of Alzheimer's disease. Moderate lesions were evident in the basolateral group of the amygdala in the case without neuronal loss in the cerebral cortex. In DNTC, the degree and distribution of the basal ganglia lesions, except for nigral lesions, were analogous to those found in Pick's disease with Pick bodies. These clinicopathological findings may contribute to the elucidation of the clinicopathological hallmarks in this disorder.     

Immunohistochemical study of brain-derived neurotrophic factor and its receptor,TrkB, in the hippocampal formation of schizophrenic brains

Recently, the pathogenesis of schizophrenia has been investigated from the perspective of neurodevelopmental dysfunction theory. On the other hand, it has been indicated that neurotrophic factors, such as nerve growth factors, brain-derived neurotrophic factor (BDNF), and neurotrophin-3, are significantly involved in the development and functional differences of central nervous system (CNS). Some reports proposed that the dysfunction of these factors could explain the pathogenesis of schizophrenia possibly. In this study, the authors investigated immunohistochemically the distribution and/or morphology of BDNF and TrkB, its peculiar receptor, in the hippocampal formation of schizophrenic brain. As a result, BDNF-positive pyramidal cells in the CA2 and neurons in the CA3 and the field of the CA4 were intensely stained compared to those of normal control. Staining of TrkB-positive neurons showed a signet-ring like shape in the hippocampus of normal control brains. Such figures were not observed on staining of those neurons from schizophrenic brains. In the control cases, TrkB-immunopositive varicose fibers were frequently seen. Those observed differences between schizophrenic and normal cases may indicate the existence of dysfunction of BDNF and TrkB in schizophrenic brain, and this dysfunction may be one of the factors involved in the pathogenesis of schizophrenia.     

Atypical late-onset dementia characterized by limbic degeneration with coiled bodies and argyrophilic threads

This report concerns an autopsy case of late-onset dementia with atypical neuropathological features. The patient was a Japanese man who was 83 years old at the age of death. At 73 years, he developed behavioral disorders, including emotional changes, and dementia. He died at the age of 83. A neuropathological study revealed largely confined involvement of the limbic regions, characterized by degeneration consisting of neuronal loss with a spongy state and gliosis. Massive tau-positive oligodendroglial coiled bodies and argyrophilic threads were also observed mainly in these regions. Although the clinicopathological findings of the present case showed some similarities to those of a unique subtype of frontotemporal dementia, including mesolimbocortical dementia, argyrophilic grain disease, corticobasal degeneration and dementia with tangles, there seems to be no suitable category of neurodegenerative disease into which our case can be classified. Further study is needed to determine whether the present case could be classified as an atypical case of these diseases or represents a new entity.     

Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies

Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein.     

Examination of the clinical usefulness of TS-1 in locally recurrent breast cancer

This study examined the therapeutic efficacy of TS-1 in the treatment of locally recurrent breast cancer. Between August 2006 and May 2009, 7 patients with local breast cancer recurrences were selected included in the study. The sites of recurrence were the cervical lymph nodes in 4 patients, the axillary lymph nodes in 2 and the thoracic wall in 1. Among the 7 patients, 6 were administered TS-1 as first-line treatment and 1 was administered TS-1 as second-line treatment. Complete response (CR) was achieved in 2 patients, 1 achieved partial response, 2 had stable disease (SD), 1 had long SD and 1 had progressive disease. The overall response rate was 43%, and the clinical benefit rate was 57%. A patient with recurrence of breast cancer in the thoracic wall 28 years after surgery also achieved CR following therapy. The only adverse event observed was a case of hand-foot syndrome in 1 patient. No patients withdrew from treatment, and favorable compliance was achieved in the study. The results indicated that TS-1 has the potential to be one of the drugs for first-line treatment of locally recurrent breast cancer.     

Relationship of calbindin D28K‐immunoreactive cells and neuropathological changes in the hippocampal formation of Alzheimer's disease

Previous studies have reported that calcium binding proteins, which have important functions in regulating the intracellular ion concentration, may influence the vulnerability of neurons in neurodegenerative disease. It has been observed that the neurons containing calbindin D28K (CB) may in certain circumstances be more resistant to excitotoxic and ischemic injury. In the present study the susceptibility of hippocampal neurons containing CB to develop NFT was studied, and the distribution of CB cells was compared with hippocampal plaque density in the Alzheimer's disease (AD) brain. Interestingly CB‐positive hippocampal neurons did not contain tangles and could be seen next to degenerating tau‐positive pyramidal cells. Comparison of the hippocampal plaque distribution with that of CB neurons showed that in general CB‐positive neurons were found in areas with a low plaque burden. Further comparison of cases with differing degrees of severity indicated that CB‐positive neurons were relatively preserved in cases with moderate plaque and tangle content but that in severe cases the CB‐positive pyramidal cells were lost. These findings indicate that CB cells may be protected in the earlier stages of the disease but that this resistance ability is lost in the late stages of AD. The observation that CB‐positive pyramidal cells do not accumulate NFT suggests that proteolysis of tau differs in CB‐negative and CB‐positive cells.