The clinical application of optimized AT(N) classification in Alzheimer's clinical syndrome (ACS) and non-ACS conditions.

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.

[Trace elements maintaining the vital functions].

In a healthy condition, trace elements constituting the living body are regulated and maintained their balance of each other and their range of physiological optimum concentration in order to maintain the normal vital functions. When the optimum conditions of their balance and their homeostasis, however, are broken down by deficiency or excess of certain trace element, an excess accumulation or deficiency of specified element is induced and it follows that peculiar disease is caused according to function of each specified element. Generally, the disturbance of major elements such as O, C, H, N, Ca, P will induce a nutrition lesion and electrolytic abnormality, and the disturbance of 10 trace elements such as Fe, F, Si, Zn, Sr, Rb, Br, Pb, Mn, Cu being at ppm order and 14 ultra-trace elements such as Al, Cd, Sn, Ba, Hg, Se, I, Mo, Ni, B, Cr, As, Co, V being at ppb order will give rise to functional disorder of enzyme and physiological active substance in living body.

[Zinc- and tin-induced apoptotic mechanisms in immune system and cranial nerve system].

This review explains the mechanisms of apoptosis related to the impacts of zinc deficiency and organotin exposure on the immune and central nervous systems. In the immune systems, both zinc deficiency and trialkyltin exposure lead to severe thymic atrophy and affect T-lymphocyte development through apoptosis of double positive stage pre-T-cells(CD4+/CD8+) in the cortex region. Their apoptosis are caused mainly through decrease in Bcl-2 expression, activation of ROS production/release, oxidative stress, mitochondrial cytochrome c release and activation of caspase cascade, with increases in glucocorticoids in zinc deficiency, without the involvement of glucocorticoid in organotin exposure In the central nervous system, both zinc deficiency and trialkyltin exposure reduce learning, memory and sensory functions through neuronal apoptosis caused by activation of ROS production/release, release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor(AIF), with Fe excessive accumulation leading to ROS production and with depletion of hippocampus Zn (mossy fiber Zn) causing various Ca2+ channel disorder of synapse in the hippocampus, and with excessive accumulation of Ca through cAMP-dependent Ca(2+)-channel disorder by excessive PTH and cAMP excessive production in the olfactory systems such as olfactory epithelium and olfactory bulb.

[Biological functions of tin and disease].

Tin generates a wide variety of biological functions due to its chemical character. In this article, the modes of the biological functions of tin(especially organotin compounds) are reviewed, with special emphasis on the connection with the immune system, brain nervous system and endocrine system, on the basis of our data. To sum up this article, the biological functions of organotin compounds appear to be due to the following several processes: (1) their incorporation into the cells in vesicle form through fusion or in a similar manner to their incorporation in cationic form; (2) transport to and accumulation in the regions of the Golgi apparatus and endoplasmic reticulum (ER), but not to or in the plasma membrane or nucleus because of their hydrophobicity; (3) inhibition of intracellular phospholipid transport between organelles due to impairment of the structures and functions of the Golgi apparatus and ER; (4) inhibition of the membrane-mediated signal transduction system leading to DNA synthesis via phospholipid turnover and Ca2+ mobilization, as in cell proliferation systems; (5) disturbance of the trace element balance and the localization of certain elements; (6) disorders of membrane-mediated Ca2+ homeostasis via various channel functions including Zn modulation on the plasma and organelle membranes, and protein phosphorylation, as in the signal transduction systems of memory and olfaction; (7) necrosis or apoptosis in vivo or toxic cell death in vitro.

Prognostic paradox: brain damage around the glioblastoma resection cavity.

Hyperintense lesions around the resection cavity on magnetic resonance diffusion-weighted imaging (MR-DWI) frequently appear after brain tumor surgery due to the damage of surrounding brain. The putative connection between the lesion and the prognosis for patients with glioblastoma (GBM) was explored. This retrospective study reviewed consecutive sixty-one patients with newly diagnosed GBM. Postoperative MRI was performed within 2 weeks after the initial surgery. We classified the cases into two groups depending on whether DWI hyperintense lesions were observed or not [DWI(+) group and DWI(-) group]. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. Forty-two patients were identified. The various extents of hyperintense lesions around the resection cavity were observed in 28/42 (66.7%) cases. In the DWI(+) and DWI(-) groups, median PFS was 10.0 [95% confidence interval (CI) 8.4-11.5] and 6.7 (95% CI 4.9-8.5) months, respectively (p = 0.042), and median OS was 18.0 (95% CI 12.2-23.8) and 17.0 (95% CI 15.7-18.3) months, respectively (p = 0.254). On multivariate analysis, the presence of DWI hyperintense lesion was more likely to be an independent predictor for 6-month PFS (p = 0.019; HR, 0.038; 95% CI 0.002-0.582). Tumor recurrence appeared outside the former DWI hyperintense lesion. Hyperintense lesions surrounding the resected GBM on MR-DWI might be a favorable prognostic factor in patients with GBM.

Regression of cerebellar tonsillar descent and hydrocephalus after endoscopic third ventriculostomy in a patient with a quadrigeminal arachnoid cyst.

BACKGROUND: Posterior fossa arachnoid cysts, including quadrigeminal cistern arachnoid cysts, can occasionally cause compression of the quadrigeminal plate, leading to Sylvian aqueduct stenosis and induction of cerebellar tonsillar descent into the foramen magnum. This, in turn, can result in obstructive hydrocephalus. In such cases, the characteristic of hydrocephalus is generally considered to be hypertensive. CASE DESCRIPTION: We present the case of a 28-year-old female complaining of chronic and progressively worsening headaches following the delivery of her first child. Magnetic resonance imaging revealed marked tri-ventriculomegaly, the arachnoid cyst located in the quadrigeminal cistern, and cerebellar tonsillar descent. Ophthalmoscopy revealed bilateral papilledema indicating a long-standing elevation of intracranial pressure. Endoscopic third ventriculostomy (ETV) was performed successfully and resulted in complete recovery from her headaches and papilledema. Postoperative MRI revealed resolution of ventriculomegaly and cerebellar tonsillar descent, suggesting that the fourth ventricle outlet obstruction was associated with the development of the hydrocephalus in this patient. CONCLUSION: Our case is the first report that a quadrigeminal arachnoid cyst associated with both cerebellar tonsillar descent and hydrocephalus was well treated with ETV. It was indicated that the patient's hydrocephalus and cerebellar tonsillar descent were secondary and synergistic events, caused by the arachnoid cyst located in the quadrigeminal cistern.

Ependymoma with "granular cell" features: report of two cases.

We report two cases of ependymoma which showed prominent "granular cell" changes of the cytoplasm. The patients were a 7-year-old boy with a tumor in the cerebellum (case 1) and a 70-year-old man with a tumor in the frontal lobe (case 2). The tumor of case 1 showed a histopathological appearance of ependymoma containing many focal aggregates of large polygonal cells in which the cytoplasm was stuffed with numerous eosinophilic granules. The tumor of case 2 predominantly showed the features of papillary ependymoma, and some tumor cells were swollen and contained similar eosinophilic granules. Intracytoplasmic granules in both tumors were immunoreactive for GFAP and ubiquitin, but not for epithelial membrane antigen, CD68 or mitochondria. Ultrastructurally, they were found as aggregates of membrane-bound, electron-dense, globular structures. Karyotypic analysis of the tumor in case 1 demonstrated 2, 11 and 12 trisomies. Intracytoplasmic eosinophilic granules occasionally occur in astrocytic and oligodendroglial neoplasms, but an appearance of similar granules is very rare in ependymoma. The two cases presented here may represent a new histopathological variant of ependymoma, and the term "granular cell ependymoma" is appropriate for them.

Mechanism underlying the olfactory disturbance induced by an intraperitoneal injection of tributyltin chloride in rats.

Acute intoxication by tributyltin compounds has been known to induce olfactory disturbances, although the underlying mechanism remains unclear. This study investigates the acute effect of tributyltin chloride (TBTC) on the olfactory bulb in rats. The time-course characteristics of the intra-olfactory concentration of TBTC, the histopathological changes of the olfactory bulb and the olfactory function were examined for 96 h after a single intraperitoneal injection of 2.5 mg/kg of TBTC. The olfactory function was evaluated by the discriminating ability for a cycloheximide solution which has an unpleasant odor for rats. The concentration of TBTC in the olfactory bulb, which was measured using gas chromatography/mass spectrometry, quickly increased to a peak value within 24 h and then decreased. The viable cell number significantly decreased after the TBTC administration in the mitral cell layer and granule cell layer of the olfactory bulb, while apoptotic cells significantly increased in these areas at the same time. Hyposmia was evident 96 h after the TBTC injection, although olfactory testing could not been performed until that time because of anorexia. These results suggest that intraperitoneally injected TBTC was promptly transferred to the olfactory bulb through the blood-brain barrier, induced apoptosis of the cells in the olfactory bulb and finally elicited the olfactory disturbance.

Ectopic ossification in the cranial dura mater in dialysis patients with secondary hyperparathyroidism.

We report the case of a 69-year-old woman with secondary hyperparathyroidism who underwent maintenance haemodialysis therapy for 17 years and who presented with severe dural calcification and right subdural haematoma. Her dura mater displayed a rock barnacle-like appearance, and cerebral superficial arteries adhered to the sclerotic lesions. On the microscopic observation, calcified tissue with a clear lamellar structure and osteopontin immunoreactivity was observed. Tartrate-resistant acid phosphatase immunoreactive polynucleated giant cells infiltrated around the tissue. Such morphological properties are specific to the calcified tissue formed through a bone formation-like mechanism that is often observed in arterial media in patients with chronic kidney disease.

Analysis of mechanisms of cell death of T-lymphocytes induced by organotin agents.

Organotin compounds are known to cause thymic atrophy and an accompanying deficiency of cell-mediated immunity. The study reported here focused on cell death in the thymus as a contributing factor in the induction of thymic atrophy following exposure to dibutyltin (DBTC) and tributyltin (TBTC). In an in vivo study, a reversible thymic atrophy was induced in rats by a single intraperitoneal administration (2.0 mg/kg) of DBTC or TBTC; the magnitude of this effect over a 4-d post-treatment period differed between the two agents. In in vitro studies, T-lymphocytes were isolated from thymuses of naïve rats and then exposed to 1 microM DBTC or TBTC for varying periods of time. Analysis by flow cytometry showed that DBTC induced primarily necrosis, while TBTC induced apoptosis, of the cells. Activities of caspase-8, -9, and -3 were also measured; TBTC exposure caused marked increases in the activities, while DBTC exposure did not cause any significant change. TBTC exposure also appeared to induce expression of CAD (which fragments DNA), but had minimal effect on levels of the CAD inhibitor, ICAD. In contrast, DBTC exposure resulted in a larger level of ICAD expression. WST-8 and JC-1 assays were used to evaluate mitochondrial function, since a strong activation of caspase-9 by TBTC suggested mitochondrial involvement. The involvement of caspase in the activation was examined using cytochrome c expression; cytochrome expression and the loss of mitochondrial function occurred within 10 min of TBTC exposure. DBTC exposure affected the mitochondria less. These results indicated that effects on mitochondria likely played an important role in the induction of apoptosis by TBTC. The results of this study show that DBTC and TBTC induce necrosis and apoptosis of T-lymphocytes, respectively, by apparently indicating different mechanisms of cell death. It follows that these increases in cell death induced by these organotin compounds likely contributed to the thymic atrophy observed in the rats here.

Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma.

The decoy receptor 3 (DcR3) gene is amplified at high frequency in human lung, colon, and liver cancers. DcR3 has been demonstrated to produce a secreted member of the tumor necrosis factor receptor superfamily that negatively regulates Fas-mediated apoptosis. In this study we examined DcR3 gene amplification, DcR3 mRNA expression, and DcR3 protein expression in 46 human astrocytic brain tumors by quantitative genomic PCR, quantitative reverse transcription-PCR, and immunohistochemistry, respectively. The DcR3 gene amplification was detected in none of 6 (0%) low-grade astrocytomas, 1 of 16 (6%) anaplastic astrocytomas, and 6 of 24 ( 25%) glioblastomas. Six of 7 (86%) cases with gene amplification exhibited both mRNA overexpression and/or protein overexpression, suggesting that DcR3 mRNA and protein were expressed more abundantly in the cases with gene amplification. We thus concluded that high DcR3 mRNA expression and protein expression may be positively related to the gene amplification in astrocytic brain tumors, especially glioblastomas. Further, we speculated that the DcR3 gene amplification with overexpression may be responsible for malignant features in glioblastomas.

Shunt nephritis with positive titers for ANCA specific for proteinase 3.

The authors report a case of shunt nephritis with antineutrophil cytoplasmic autoantibody (ANCA) and review 2 similar cases. A 55-year-old man was admitted to our hospital for continuous fever and foot edema in 2002. A ventriculoperitoneal shunt was implanted because of a brain abscess and subsequent hydrocephalus in 1987; it was changed to a ventriculoatrial (VA) shunt in 1995. Urinary analysis showed proteinuria (5.4 g/d) and microscopic hematuria. Laboratory data showed renal dysfunction and hypocomplementemia. ANCA specific for proteinase 3 (PR3-ANCA) was positive in his serum, and blood culture grew Propionibacterium acnes. Renal biopsy results showed membranoproliferative glomerulonephritis type I. Therefore, the VA shunt was replaced, and antibiotics were administered. Oral prednisolone was initiated at a dose of 50 mg/d. Proteinuria and the serum levels of creatinine were improved concomitant with normalization of the serum complement levels and the decrease in serum PR3-ANCA titer. Similarly, another 2 cases reported in the literature of PR3-ANCA-positive shunt nephritis caused by P acnes and Gemella morbillorum showed good outcomes after removal of the shunt and administration of antibiotics with or without steroid therapy.

Frequent LOH at chromosome 12q22-23 and Apaf-1 inactivation in glioblastoma.

Glioblastoma (GB) often has loss of heterozygosity on the chromosomes, 1p, 10p, 10q, 11p, 17p, 19q, 22q, and several others. In the case of chromosome 12q, however, it remains to be seen whether LOH occurs. Apaf-1, the apoptotic protease activating factor-1, located at chromosome 12q22-23, is a major effecter of the p53 mediated apoptosis pathway, and Apaf-1 inactivation due to chromosome 12q22-23 LOH and hypermethylation may be involved in some of the neoplasms in malignancy. However, little is known about the frequency of the 12q22-23 LOH or the state of Apaf-1 in GB. To elucidate their involvement in GB, we analyzed a series of 33 GBs for chromosome 12q22-23 LOH, Apaf-1 mRNA expression, and Apaf-1 protein expression, using microsatellite analysis, reverse transcription (RT)-PCR analysis, and immunohistochemical (IHC) analysis, respectively. We also evaluated if and how the 12q22-23 LOH correlated with the p53 gene mutation and EGFR gene amplification. Chromosome 12q22-23 LOH was detected in 14 (42%) of 33 cases. Among the examined cases with LOH at 12q22-23, a low expression of Apaf-1 mRNA was detected in 9 (69%) of 13 cases, and a low expression of Apaf-1 protein was detected in 12 (86%) of 14 cases. The 12q22-23 LOH was significantly correlated with low expression of mRNA and protein (p<0.05, p<0.001 respectively). The p53 gene mutation and EGFR gene amplification were found in 13 cases (39%) and 8 cases (24%), respectively, and these gene alterations were inversely correlated. However, 12q22-23 LOH had no correlations with the p53 gene mutation or EGFR gene amplification. Six of 9 GBs (67%) with neither p53 gene mutation nor EGFR gene amplification tested positive for 12q22-23 LOH. These GBs are likely to belong to another subset independent from the 2 common genetic subsets in GB (one with p53 gene mutation and without EGFR gene amplification, and the other with EGFR gene amplification and without p53 gene mutation). Twenty-three (70%) out of the 33 GBs with the 12q22-23 LOH also tested positive for Apaf-1 inactivation or p53 gene mutation. This high frequency of alterations in the apoptosis-associated factors prompts a speculation that abrogation of the Apaf-1 and p53 mediated apoptosis pathway may play an important role in the tumorigenesis of GB.

[Intracerebral pneumocephalus following a head injury: case report].

We report a case of intracerebral pneumocephalus following a head injury. This condition is relatively rare, and only 14 cases, including the present case, have been reported to data. A 40-year-old man fell from a 3rd floor window on June 29, 1999. The patient was admitted to the hospital. Plain skull X-ray films revealed a left basal skull fracture, and CT scan revealed a small contusion at the left frontobasal lobe. The patient was treated conservatively. On July 16, he underwent an MRI, and a small contusion was revealed at the left frontobasal lobe. In addition, the brain appeared to have herniated into the ethmoidal sinus. On July 22, the patient underwent a CT scan, and a intracerebral pneumocephalus was revealed in the left frontal lobe. On August 2, an MRI was performed, and intracerebral pneumocephalus in the left frontal lobe and herniation of the brain into the ethmoidal sinus were noted. In addition, intracerebral pneumocephalus had increased. The patient was admitted to our hospital. Clinotherapy was performed, but intracerebral pneumocephalus increased. On August 9, the patient underwent surgery to repair the skull base. During surgery, it was noted that the left frontal contusion had adhered to the edge of the lacerated dura around the bone defect of the ethmoidal sinus. Following surgery, no recurrence of pneumocephalus was noted. We conclude that once intracerebral air volume increases, early surgical repair should be carried out for intracerebral pneumocephalus. Meticulous MRI investigations of the lesion causing the intracerebral pneumocephalus should be conducted to select an appropriate operative procedure.

[Clinical evaluation of patients with isolated, traumatic, localized subarachnoid hemorrhage].

Three hundred and fifty cases of patients with head injury were admitted to our hospital from 1998 to 2000. Among these cases, 10 cases manifested isolated, localized subarachnoid hemorrhage on the first computed tomographic image after the trauma. Traumatic subarachnoid hemorrhage was found in the ambient, suprasellar, and sylvian fissure, Bleeding was seen in the ambient cistern or suprasellar cistern at the site of the blow on the frontal or occipital area of the head. The bleeding was seen in the sylvian fissure at the site of the temporal head blow. The bleeding was washed out after one day. None of the patients had symptomatic spasms, and all of the patients had a good prognosis. The mechanism of isolated, traumatic, localized subarachnoid hemorrhage was considered as shear strain or coup and contre-coup injury.

Metastasis of breast cancer to intracranial meningioma: case report.

Metastasis of systemic cancer to intracranial tumors is a rare event. The authors report a case of 49-year-old woman with such occurrence, whose breast cancer metastasized to a preexisting parasagittal meningioma at a postoperative interval of 1.5 years. She was admitted to our hospital because of progressive right hemiparesis. Magnetic resonance imaging revealed newly emerged perifocal edema and inhomogeneous contrast enhancement of the meningioma. High choline/creatine ratio and lactate/lipid peak on proton magnetic resonance spectroscopy suggested malignancy. She underwent a tumor resection, and pathologic examination revealed intratumoral metastasis of breast cancer in a transitional meningioma. Immunoreactivity of E-cadherin was detected in both meningioma and breast cancer cells. It is suggested that abrupt appearance of symptoms, inhomogeneous enhancement, and perifocal edema of meningioma is a sign of intratumoral metastasis from systemic cancers.