Definite familial multiple system atrophy with unknown genetics

Multiple system atrophy (MSA) is an oligodendrogliopathy of presumably sporadic origin, characterized by prominent α‐synuclein inclusions with neuronal multisystem degeneration, although a few Mendelian pedigrees have been reported. Here we report two familial cases of MSA of unknown genetic background. One patient was diagnosed as a possible MSA‐C (cerebellar dysfuntion) case, and the other as clinically possible MSA‐P (parkinsonism), which turned out to be definite MSA, based on a detailed autopsy. The neuropathology showed extensive deposition of α‐synuclein in the glia as well as in the neurons located in the cerebral cortices and hippocampal systems, although neither multiplication of the SNCA gene or mutations in COQ2 gene were identified in the family concerned.     

Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats

The anticonvulsant activity of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, was studied in animal models of generalized seizure. YM928 exerted significant anticonvulsant effects in the maximal electroshock (MES) seizure test (ED50 = 7.4 mg/kg p.o.), pentylenetetrazol (PTZ)-induced seizure test (ED50 = 9.6 mg/kg p.o.), AMPA-induced seizure test (ED50 = 5.5 mg/kg p.o.), and strychnine-induced seizure test (ED50 = 14.0 mg/kg p.o.) in mice. Effects in rats were detected in the MES seizure test (ED50 = 4.0 mg/kg p.o.) and PTZ-induced seizure test (ED50 = 6.2 mg/kg p.o.). The profile of YM928 was compared with that of established antiepileptics. Valproate showed beneficial effects in all tests used. In contrast, carbamazepine, phenytoin, lamotrigine, phenobarbital, diazepam, ethosuximide, and gabapentin were not active against seizures induced by at least one stimulant. In the rotarod test, YM928 impaired motor coordination (TD50 = 22.5 mg/kg p.o.). The protective index (TD50 value of the rotarod test/ED50 value of MES seizure) was 3.0, suggesting that YM928 can exert antiepileptic effects with only minor motor disturbances. YM928 at doses of 2, 4, and 8 mg/kg p.o. did not significantly affect the threshold of electroshock seizure in rats after 16 days of repeated administration. These data indicate that YM928 does not induce tolerance after subchronic administration. These results indicate that YM928 is a broad-spectrum anticonvulsant that would prove useful for the treatment of generalized seizure in human epileptic patients.     

TRIM29 as a novel prostate basal cell marker for diagnosis of prostate cancer

Tripartite motif protein 29 (TRIM29) is one of the TRIM family proteins, some of which function as E3 ubiquitin ligases. In this study, we investigated the usefulness of TRIM29 for diagnosis of prostate cancer. Prostate tissues including carcinoma and non-carcinoma tissues obtained by needle biopsy and radical prostatectomy were used. Immunohistochemistry was performed according to standard procedures using an antibody against TRIM29. Immunohistochemical staining with an antibody against 34βE12, which recognizes cytokeratins 1, 5, 10 and 14, was performed as a control. Basal cells of normal prostatic glands were stained with anti-TRIM29 antibody in all cases, whereas prostate cancer tissues had no or little staining with anti-TRIM29 antibody. TRIM29 is selectively expressed in basal cells of the normal prostate gland, and immunohistochemical staining with anti-TRIM29 antibody showed the same expression pattern as that with 34βE12 in prostate cancer and its benign mimics. Our data indicate that TRIM29 may be useful for distinguishing prostate cancers from benign tissues.     

Metabolic changes induced by TGF-β1 via reduced expression of phosphatidylserine decarboxylase during myofibroblast transition

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-β1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-β1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-β1. Knockdown of PISD alone without TGF-β1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.     

Examining the effects of initial smoking abstinence on response to smoking-related stimuli and response inhibition in a human laboratory model

Rationale

Research is needed on initial smoking abstinence and relapse risk.

Objective

This study aims to investigate the effects of different durations of initial abstinence on sensitivity to smoking-related stimuli and response inhibition in the context of a larger battery of outcome measures.

Methods

Smokers were randomly assigned to receive payment contingent on smoking abstinence across all 15 study days (15C) or just the final 2 days (2C). Smoking status and subject ratings were assessed daily. Participants completed fMRI sessions at baseline and day 14 during which they completed craving ratings after exposure to smoking-related and neutral stimuli and performed a response inhibition task. On day 15, participants completed a smoking preference session involving 20 exclusive choices between smoking and money.

Results

The payment contingencies were effective in producing greater smoking abstinence in the 15C vs. 2C conditions. Ratings of withdrawal decreased, while ratings of ease and confidence in abstaining increased in the 15C vs. 2C conditions across the 15-day study. 15C participants were less likely to choose the smoking option in the preference session. 15C participants reported greater reductions in craving compared to the 2C participants in the presence of smoking-related and neutral stimuli (i.e., decreases in generalized craving), but no differences were noted in cue reactivity per se or in response inhibition.

Conclusions

Results systematically replicate prior observations that a period 2 weeks of initial abstinence decreases the relative reinforcing effects of smoking and improves other outcomes associated with relapse risk compared to the initial day or two of a cessation effort, and extends them by underscoring the importance of generalized rather than cue-induced craving in relation to relapse risk during the initial weeks of smoking cessation.     

Exposure time reduction of secondary radiographs used in digital subtraction radiography in detecting intrabony change

Objectives

Digital subtraction radiography (DSR) is a suitable technique for detecting incipient bone changes. However, in DSR, one or more follow-up radiographs must be taken. The aim of this study was to assess the possibility of reducing the exposure time for the radiographs that follow the initial one.

Methods

Maxillary premolar and molar radiographic images of a dry skull were taken with a digital radiography system. The initial radiographs, without bone chips, were taken at 0.32 and 0.16 s. Then, five bone chips (weight range 7–15 mg) were placed on the maxillary molar buccal side of the dry skull. Secondary radiographs were taken at 0.32-, 0.16-, 0.08-, 0.04-, and 0.02-s exposure times. For each bone chip, radiographs were taken three times. The secondary and initial images were subtracted to yield subtraction images. Four observers were asked to evaluate bone change visibility in the subtraction images. The Friedman test was used for statistical analysis.

Results

Significant differences were seen at each of the settings for the 0.32-s group (p = 1.24e?030) and 0.16-s group (p = 7.52e?009). By comparing the different groups, observer evaluations indicated that visibility changed when the secondary radiograph was taken at 1/8 of the exposure time of the initial radiograph. In both groups, the visibility of the 0.02-s subtraction image was significantly lower than that of the other subtraction images.

Conclusion

In DSR, the exposure time of the secondary radiograph can be reduced to 1/4 of the exposure time of the initial radiograph.