The dopamine D1 receptor agonist, but not the D2 receptor agonist, induces gene expression of Homer 1a in rat striatum and nucleus accumbens

Stimulation of dopamine receptors may induce striatal Homer 1a, an immediate-early gene (IEG) that is involved in the molecular mechanism for the signaling pathway of the group I metabotropic glutamate receptors. This study examined the effects of the agonists for dopamine D(1)-like and D(2)-like receptors on gene expression of Homer 1a, in comparison with the IEG c-fos expression, in the discrete brain regions of rats. The D(1)-like agonist SKF38393 (20 mg/kg, s.c.) significantly increased the mRNA levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or hippocampus, 2 h after injection, whereas the D(2)-like agonist quinpirole (1 mg/kg, s.c.) had no significant effect on Homer 1a mRNA levels in any brain region examined. Co-administration of SKF38393 and quinpirole significantly increased Homer 1a mRNA levels in the striatum, nucleus accumbens and hippocampus, while this effect was not significantly greater than that of SKF38393 alone. Any treatment did not affect the mRNA levels of other splicing variants, Homer 1b or 1c. In contrast, combination of both dopamine agonists produced a greater increase than SKF38393 did in the mRNA levels of c-fos in the nucleus accumbens, striatum and substantia nigra. These results suggest that stimulation of D(1)-like receptors, but not D(2)-like receptors, may induce gene expression of Homer 1a in the striatum and nucleus accumbens. However, in contrast to c-fos expression, it is unlikely that co-activation of both D(1)-like and D(2)-like receptors exerts a synergic action on Homer 1a expression in these regions.     

Annexin 2 and hemorrhagic disorder in vascular intimal carcinomatosis

Vascular intimal carcinomatosis refers to a characteristic tumor proliferation on vascular intima that replaces normal endothelium. This pathological event of unknown cause is quite different from tumor thrombotic microangiopathy due to the absence of thrombi on the tumor cell surfaces. We analyzed renal transitional cell carcinoma cases with metastasis to the main pulmonary arteries and marked hyperfibrino(geno)lysis. The fibrinogen-derived products from patients' plasma were identified as D1A/gamma, D1/gamma, and D1/beta by immunoblotting with the NH2-terminus of the fragment D specific antibody JIF-23. In all cases, the neoplastic cells with vascular intimal carcinomatosis were stained positive for anti-human annexin 2, which is a unique cell surface co-receptor for plasminogen and tissue-type plasminogen activator. In contrast, normal renal pelvic mucosa or renal transitional cell carcinoma without vascular intimal carcinomatosis did not express any annexin 2. The isolated transitional cell carcinoma cells contained annexin 2 mRNA and expressed its protein. Anti-annexin 2 antibody and transfection of annexin 2 small interfering RNA into these carcinoma cells significantly inhibited tissue-type plasminogen activator dependent plasmin generation. These findings suggest that annexin 2 mediated fibrinolysis on the transitional cell carcinoma cells may play a role in inducing hemorrhagic disorder in vascular intimal carcinomatosis.     

Evaluation of brain perfusion SPECT using an easy Z-score imaging system (eZIS) as an adjunct to early-diagnosis of neurodegenerative diseases

The eZIS allows computer-assisted statistical analysis of brain perfusion SPECT images. We evaluated the diagnostic value of brain perfusion SPECT using eZIS in patients with various neurodegenerative diseases at a very early stage, within one year from onset.

Methods

SPECT using eZIS was performed for patients with Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD,), idiopathic Parkinson disease (PD) and vascular Parkinsonism (VP), multiple systemic atrophy of the cerebellar type (MSA-C), cortical cerebellar atrophy (CCA) and amyotrophic lateral sclerosis (ALS).

Results

Decreased rCBF was observed in the posterior cingulate cortex, precuneus and parietal cortex in AD; in the frontal gyrus and insula in FTD; in the occipital lobe, precuneus gyrus and posterior cingulate cortex in DLB; in the striatum and the thalamus in VP; in the cerebellum in CCA; in the cerebellum and pons in MSA-C and in the frontal cortex including the central sulcus in ALS. Increased rCBF in the striatum, thalamus and cerebellar dentate nuclei were observed in PD.

Conclusions

A specific rCBF pattern was observed for each disease using eZIS analysis, consistent with previous reports. Our results showed eZIS can be easily used as an adjunct to early-diagnosis of neurodegenerative diseases in any hospital.     

Tau binding to microtubules does not directly affect microtubule-based vesicle motility

Tau protein is a major microtubule (MT)-associated brain protein enriched in axons. Multiple functional roles are proposed for tau protein, including MT stabilization, generation of cell processes, and targeting of phosphotransferases to MTs. Recently, experiments involving exogenous tau expression in cultured cells suggested a role for tau as a regulator of kinesin-1-based motility. Tau was proposed to inhibit attachment of kinesin-1 to MTs by competing for the kinesin-1 binding site. In this work, we evaluated effects of tau on fast axonal transport (FAT) by using vesicle motility assays in isolated squid axoplasm. Effects of recombinant tau constructs on both kinesin-1 and cytoplasmic dynein-dependent FAT rates were evaluated by video microscopy. Exogenous tau binding to endogenous squid MTs was evidenced by a dramatic change in individual MT morphologies. However, perfusion of tau at concentrations approximately 20-fold higher than physiological levels showed no effect on FAT. In contrast, perfusion of a cytoplasmic dynein-derived peptide that competes with kinesin-1 and cytoplasmic dynein binding to MTs in vitro rapidly inhibited FAT in both directions. Taken together, our results indicate that binding of tau to MTs does not directly affect kinesin-1- or cytoplasmic dynein-based motilities. In contrast, our results provide further evidence indicating that the functional binding sites for kinesin-1 and cytoplasmic dynein on MTs overlap.     

Reliability and validity of the Japanese version of the Dysexecutive Questionnaire (DEX) in Alzheimer's disease: validation of a behavioral rating scale to assess dysexecutive symptoms in Japanese patients with Alzheimer's disease

BACKGROUND: Both executive cognitive dysfunction and behavioral problems contribute to dysexecutive symptoms in daily life. The aim of the present study was to develop a behavior rating scale for assessing dysexecutive symptoms in Japanese patients with AD. METHOD: The Dysexecutive Questionnaire (DEX), devised by Burgess et al. (1998), was used to evaluate 122 Japanese patients with AD. The factor structure, internal consistency, test-retest reliability, and construct validity of the Japanese version of the DEX were then examined. RESULTS: The Japanese version of the DEX demonstrated a good internal reliability and a good test-retest reliability. Factor analysis revealed three factors that were named 'apathy', 'hyperactivity' and 'planning and monitoring process of the purposive action'. The 'apathy' factor of the DEX was significantly correlated with the 'apathy' score of the Neuropsychiatric Inventory (NPI), while 'planning and monitoring process' factor of the DEX was significantly correlated with the total score of the Frontal Assessment Battery (FAB) and the 'hyperactivity' factor of the DEX was significantly correlated with the 'aggression', 'euphoria' and 'disinhibition' scores of the NPI. CONCLUSIONS: The Japanese DEX is a reliable and valid instrument for assessing executive dysfunction conveniently in real life situations of AD patients. While two factors, 'apathy' and 'hyperactivity', were associated with emotional and behavioral changes, the 'planning and monitoring process' was associated with the cognitive executive function in the patients with AD. These findings suggest that both a neuropsychiatric syndrome and cognitive function contribute to the dysexecutive symptoms experienced by AD patients in daily life.     

In vivo observation of the ileal microadenoma in familial adenomatous polyposis

Microadenomas or aberrant crypt foci (ACFs) are regarded as early neoplastic lesions that precede the development of macroscopic adenomas. The aim of this study was to characterize surface features of ileal microadenomas in patients with familial adenomatous polyposis (FAP). Magnifying ileoscopy was performed in 19 patients with FAP. A histologically verified adenomatous tubule, the existence of which was suggested by magnified observation, was regarded as a microadenoma. Magnifying ileoscopy detected microadenoma in five patients. In four of the five cases, the ileal microadenomas were identified as areas with tiny crypt openings or serrated surfaces, which were distinctive of nonneoplastic, diminutive protrusions. Magnifying ileoscopy seems to be useful in the detection of ileal microadenomas.     

Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population

To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore. Genotyping was conducted in 448 Parkinson disease patients and 457 healthy controls. The frequency of A allele in Parkinson disease was significantly higher than in the control (P=1.24x10(-4), odds ratio 2.63, 95% confidence interval 1.56-4.35). Our results suggest that the G2385R variant is a risk factor for sporadic Parkinson disease in the Asian population.