Comparative nephrotoxicity of ribostamycin and gentamicin in rats evaluated by urinalysis

The nephrotoxicity of ribostamycin and gentamicin was compared by urinalysis using 18 parameters. When a dose of 40 mg/kg per day was administered intramuscularly to Fischer rats for 14 days, ribostamycin caused little change of parameters in urine volume, urine osmolality, urine protein, maltase and beta 2-microglobulin. A slight increase with ribostamycin was observed in alpha-fucosidase, beta-N-acetylglucosaminidase, leucine aminopeptidase, lactic dehydrogenase (LDH) and potassium, and a moderate increase was observed in acid phosphatase and alkaline phosphatase. On the other hand, gentamicin caused a large alteration in most parameters. Both antibiotics caused a change of the isoenzyme pattern of LDH1-5, but the pattern with ribostamycin was much closer to the normal pattern than with gentamicin. When a dose of 80 mg/kg of ribostamycin was compared with 10 mg/kg of gentamicin, alteration of urinary parameters was almost comparable. Histopathological observations of the kidney specimens of rats given 40 mg/kg per day showed no histological damage with ribostamycin except for a slight increase and enlargement of lysosomes of the proximal epithelial cells. However, significant histological damage was observed with gentamicin, consistent with the results obtained from urinalysis. Renal accumulation of ribostamycin at a single dose of 20 mg/kg was three times less than that of gentamicin. Ribostamycin caused slightly less nephrotoxicity in rats than kanamycin and far less than dibekacin at an equal dosage of 40 mg/kg per day for 14 days.     

Autopsy case of Lewy body dementia associated with abundant argyrophilic grains]

We report an autopsy case showing neuropathologically abundant Lewy bodies and argyrophilic grains. A Japanese woman without hereditary burden developed parkinsonian gait at the age of 74, following by insomnia, memory disturbance, delirium, resting tremor, rigidity, and retropulsion. About 8 months later, a visual hallucination, concerning small worms, children, and so on, became obvious. About 16 months later, malignant lymphoma was detected. About 17 months later, she died of pneumonia. The total duration of illness was approximately one year and five months. The weight of the brain was 1153 g before fixation. Depigmentation of the substantia nigra and locusceruleus was prominent. Many argyrophilic grains were seen in the temporal lobe (T3, T4), amygdala, and hippocampal CA1. Some ballooned neurons were found in the amygdala. Many Lewy bodies were encountered in the transentorhinal region and cingulated gyrus. A few Lewy bodies were seen in the temporal, frontal, and parietal lobes. In this case, neuropathological examination is compatible for dementia of Lewy bodies and argyrophilic grain dementia, and clinical course is consistent with dementia of Lewy bodies. This report may contribute to the elucidation of the clinicopathological hallmarks of argyrophilic grain dementia and dementia with Lewy bodies.     

Parkinson’s disease mimicking senile dementia of the Alzheimer type: a clinicopathological study of four autopsy cases

This report concerns four Japanese autopsy cases of Parkinson’s disease (PD) mimicking senile dementia of the Alzheimer type. Three patients with a clinical diagnosis of senile dementia of the Alzheimer type developed memory disturbance as the initial sign, and a patient with a clinical diagnosis of atypical senile dementia presented with hallucination and delusion as the initial sign. Dementia was evident in all four patients, and slight parkinsonism appeared in the middle to late stages of the disease in two patients. Macroscopical examination of the brain disclosed slight depigmentation of the substantia nigra and pro‐minent depigmentation of the locus ceruleus in all four cases. Histological examination of the four patients showed neuronal loss with astrocytosis and the appearance of Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. The nucleus basalis of Meynert was involved in three cases, in which this structure was examined. The total Lewy body scores of the four cases were 1 in three cases and 0 in the other, compatible with PD. Massive appearance of senile plaques, consistent with Braak stage C, was found in one case, and the slight appearance of senile plaques, consistent with Braak stage A, was evident in two cases. One case had no evidence of senile plaques. In all four cases, slight neurofibrillary changes were present in the limbic areas, compatible with Braak stages II to III. Based on these clinicopathological findings and a review of the literature, we concluded that PD simulating Alzheimer’s disease without overt parkinsonism rarely exists. Furthermore, we postulate that the clinical features of PD are more widespread than previously believed.     

Toxicological studies of a new cephamycin, MT-141. II. Its subacute toxicity in rats

In this subacute study, male and female rats were administered with 100, 200, 400, 800 and 1,600 mg/kg/day of MT-141 through an intramuscular (i.m.) route or with 50, 100, 200, 400 and 800 mg/kg/day through an intravenous (i.v.) route for 30 days. MT-141 did not cause lethal effect on male and female rats even at the high dosage of 1,600 mg/kg/day i.m. (approx. one-6th of LD50) and 800 mg/kg/day i.v. (approx. one-8th of LD50). Histopathological findings revealed that MT-141 induced slight local irritation at the sites of i.m. and i.v. injection. Only at a high dose of 1,600 mg/kg/day i.m., MT-141 reduced significantly the gain of body weight in male rats, which was closely related to the decrease of food intake. A slight decrease in serum Cr. and Glc. was observed in male rats at the doses more than 200 mg/kg/day i.m. and a slight decrease of liver weight at the doses more than 800 mg/kg/day i.m., while a slight increase of serum CPK, GOT, A1-P and LDH was perceived at the doses more than 800 mg/kg/day i.m. The distention of cecum was induced by the doses more than 400 mg/kg/day i.m. but histopathological findings revealed no abnormality in the cecum. These results suggest that MT-141 at the dosage level of 1,600 mg/kg/day i.m. causes nonspecific slight toxicity based on the disturbance of nourishment in male rats. In female rats given 100 to 1,600 mg/kg/day i.m., MT-141 at the high doses induced a slight increase of serum GOT, LDH and CPK and distention of the cecum. It is assumed from these results that MT-141 at the dosage level of 1,600 mg/kg/day causes nonspecific slight toxicity in female rats. In male rats given 50 to 800 mg/kg/day through an i.v. route, the level of serum Glc. and Cr. and the liver weight slightly decreased at the doses more than 200 mg/kg/day i.v. The cecum distended at the doses more than 100 mg/kg/day i.v. The dose of 800 mg/kg/day i.v. increased the activity of LDH and CPK in the serum. In female rats, MT-141 raised slightly the level of serum GOT, A1-P, LDH and CPK even at the doses more than 400 mg/kg/day i.v., reduced the liver weight at the dose of 800 mg/kg/day i.v. and distended the cecum at the all doses. These results suggest that MT-141 at the dosage level of 800 mg/kg/day i.v. induces nonspecific slight toxicity in male and female rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Toxicological studies on a new cephamycin, MT-141, IV. Its acute toxicity in beagle dogs

The acute toxicity of MT-141 was studied in adult Beagle dogs with intravenous (i.v.) or intramuscular (i.m.) administration to obtain following results. MT-141 at the doses ranging from 2,500 to 7,500 mg/kg i.v. caused no effect on life, bodyweight, food intake, eyeground and ECG in male and female Beagle dogs. MT-141 produced an increase in water intake, urine volume, WBC and LAP and a decrease in Lymph., U-Na, U-K and OP, but any histopathological change was not caused in the organs and tissues. It is suggested that these changes in blood, serum and urine are due to mechanical and transient effects induced by infusing a large volume of hypertonic solution of MT-141 into cephalic vein. When 1,000 or 2,000 mg/kg of MT-141 was injected into the muscles of hind legs, the hind legs had difficulty in walking. It is very probable that this change was due to mechanical effects induced by injecting a hypertonic solution of MT-141 at a rate of 70--130 ml/dog. An injection of 1,000 or 2,000 mg/kg i.m. of MT-141 changed activity of GPT, GOT and CPK in the serum within the limit of physiological variations but did not caused any effect on the other toxicological parameters such as bodyweight, food intake, water intake, urine volume, eyeground examination, ECG and histopathological examination. It is concluded from the above-mentioned results that MT-141 at the dose of 2,500--7,500 mg/kg i.v. or 1,000--2,000 mg/kg i.m. has no significant toxicity in Beagle dogs.     

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.     

An autopsied case of presenile dementia with tangles]

We report an autopsied case of presenile dementia showing neuropathologically abundant neurofibrillary tangles(NFT) without senile plaques(tangle only dementia). A Japanese woman developed memory disturbance when she was 60 years old. At age of 65, her ability to understand deteriorated and euphoria and wandering manifested but neither psychotic symptoms, including hallucination and delusion nor a change in character were observed. The patient was hospitalized at age 66 and a cranial CT scan revealed bilateral moderate atrophy of the cortex and moderate enlargement of the lateral ventricle, especially in the inferior horn. No lobar atrophy was detected. She exhibited an oral tendency and became appallic at her final stage and died at the age of 75. Autopsy showed that her brain weighed 850 g and neuropathological study showed numerous NFT mainly in the entorhinal (trans-entorhinal) region, subiculum, CA1-CA4, dentate gyrus, amygdara, subthalamic nucleus, basal nucleus of Meynert, substantia nigra and locus coeruleus. Severe neuronal loss with gliosis was noted in the temporal lobes including the hippocampal region. No senile plaque was detected in any of the brain regions. There have been some recent reports of patients with abundant NFT with the predominant involvement of the allocortex but no or very little senile plaque. All the patients in the reported cases were very elderly at onset(over 80 years of age). In our case, the onset was presenile and we could exclude any other diseases, that usually present with NFT, and to our knowledge, this is the first report of a presenile dementia with tangles.     

Relative paucity of tau accumulation in the small areas with abundant Aβ42-positive capillary amyloid angiopathy within a given cortical region in the brain of patients with Alzheimer pathology

Cerebral amyloid angiopathy (CAA) is a manifestation of amyloid β-protein (Aβ) accumulation in the elderly as well as in patients with Alzheimer’s disease (AD). Two types of CAA have been noted, based on the type of vasculature in which Aβ is deposited: cerebral capillary amyloid angiopathy (capCAA) and non-capCAA. Non-capCAA is a common form of CAA that consists of Aβ deposited in arteries and arterioles. Recent information on Aβ metabolism in the brain suggests that non-capCAA is associated with Aβ secretion into the cerebrospinal fluid via the perivascular space, whereas capCAA is associated with Aβ removal to blood plasma via the capillary endothelium. Aβ40, a major and relatively soluble Aβ isoform, is deposited predominantly in non-capCAA, and Aβ42, which is insoluble and associated more closely than Aβ40 with AD, is deposited predominantly in capCAA. Studying small areas of microscopic size within a given cortical region, we found an inverse association of capCAA and senile plaques. We also found a relative paucity of tau pathology in the small areas with abundant capCAA compared with the small areas with abundant senile plaques within a cortical region with the same cytoarchitecture. We suppose that both capCAA and senile plaques indicate high Aβ42 in the neuropil but that only Aβ42 in the form of insoluble deposits in senile plaques promotes tau abnormality.     

Clinicopathological study of early progressive multifocal leukoencephalopathy incidentally found in a schizophrenia patient

A 58‐year‐old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti‐JC virus protein, VP‐1 antibody, demonstrated JC virus‐infected cells in not only abnormal glial cells and neurons but also normal‐looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8‐positive lymphocytes were seen, which kill infected cells. PML could be considered a short‐term disease preceding death, as “incidental PML” in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML.     

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.