Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study

Background

The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson''s disease (PD) remain to be elucidated.

Methods

Fifty-three PD patients without dementia were recruited to participate in a 3-year longitudinal cohort study. The patients were grouped according to the Clinical Dementia Rating (CDR). Group-wise comparisons were made with regard to demographic characteristics, motor symptoms, neuropsychological performances and 18F-fluorodeoxyglucose positron emission tomography.

Results

Patients who had memory-plus cognitive impairment (patients whose CDR was 0 at baseline and 0.5 in memory and other domains at follow-up, and those whose baseline CDR was 0.5 in memory and other domains) exhibited higher age at onset, visuoperceptual impairment, non-tremor-dominant motor disturbance, rapid symptomatic progression and posterior neocortical hypometabolism. In patients who were cognitively unimpaired and those who had memory-dominant cognitive impairment (patients whose CDR was 0 at baseline and 0.5 only in memory domain at follow-up, and those whose baseline CDR was 0.5 only in memory domain), the posterior neocortex was relatively unaffected until a later stage of the disease.

Conclusions

These results suggest that visuoperceptual impairment and the early involvement of the posterior neocortex may be risk factors for rapid symptomatic progression and dementia in PD.     

Isolation of a protein lethal to the endoparasitoid Cotesia kariyai from entomopoxvirus-infected larvae of Mythimna separata

Virion-free plasma from entomopoxvirus (MyseEPV)-infected larvae of the armyworm, Mythimna separata, contains a factor that adversely affects the survival of the gregarious braconid endoparasitoid, Cotesia kariyai. Heating or proteinase K treatment eliminates the toxic effect of virion-free plasma on the parasitoid, suggesting that the lethal factor is a protein. We purified the Protein Lethal to C. kariyai larvae (PLCK) from the virion-free plasma of MyseEPV-infected M. separata larvae by a three-step procedure using gel filtration and cation-exchange chromatography. Toxic activity was measured using an in vitro-cultured parasitoid bioassay. Parasitoid larvae cultured in IPL-41 medium (Weiss et al., In vitro 17 (1981), 495) containing 4.7 microg/ml purified PLCK shrank and died within 3days. The molecular weight of PLCK was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to be about 28,000, under both reducing and non-reducing conditions, indicating that in its native form the protein is a single 28-kDa polypeptide. Western blot analysis indicated that the lethal protein is not present in the hemolymph of uninfected host larvae, but is induced in the hemolymph by infection with MyseEPV. Western blot analysis also indicated that the proteins of virions and occlusion bodies of MyseEPV are not serologically related to PLCK.     

Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease

Background

Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema.

Methods

We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers.

Results

D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p = 0.008; −0.045 vs. −0.01, p = 0.004; 13.9 vs. 1.1, p = 0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes.

Conclusions

Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.     

Enhanced persistency of resting and active periods of locomotor activity in schizophrenia

Patients with schizophrenia frequently exhibit behavioral abnormalities associated with its pathological symptoms. Therefore, a quantitative evaluation of behavioral dynamics could contribute to objective diagnoses of schizophrenia. However, such an approach has not been fully established because of the absence of quantitative biobehavioral measures. Recently, we studied the dynamical properties of locomotor activity, specifically how resting and active periods are interwoven in daily life. We discovered universal statistical laws ("behavioral organization") and their alterations in patients with major depressive disorder. In this study, we evaluated behavioral organization of schizophrenic patients (n?=?19) and healthy subjects (n?=?11) using locomotor activity data, acquired by actigraphy, to investigate whether the laws could provide objective and quantitative measures for a possible diagnosis and assessment of symptoms. Specifically, we evaluated the cumulative distributions of resting and active periods, defined as the periods with physical activity counts successively below and above a predefined threshold, respectively. Here we report alterations in the laws governing resting and active periods; resting periods obeyed a power-law cumulative distribution with significantly lower parameter values (power-law scaling exponents), whereas active periods followed a stretched exponential distribution with significantly lower parameter values (stretching exponents), in patients. Our findings indicate enhanced persistency of both lower and higher locomotor activity periods in patients with schizophrenia, probably reflecting schizophrenic pathophysiology.     

Targeting anticancer drug delivery to pancreatic cancer cells using a fucose-bound nanoparticle approach

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.     

Increased Expression of Phosphatidylcholine (16:0/18:1) and (16:0/18:2) in Thyroid Papillary Cancer

A good prognosis can be expected for most, but not all, cases of thyroid papillary cancer. Numerous molecular studies have demonstrated beneficial treatment and prognostic factors in various molecular markers. Whereas most previous reports have focused on genomics and proteomics, few have focused on lipidomics. With the advent of mass spectrometry (MS), it has become possible to identify many types of molecules, and this analytical tool has become critical in the field of omics. Recently, imaging mass spectrometry (IMS) was developed. After a simple pretreatment process, IMS can be used to examine tissue sections on glass slides with location information.Here, we conducted an IMS analysis of seven cases of thyroid papillary cancer by comparison of cancerous with normal tissues, focusing on the distribution of phospholipids. We identified that phosphatidylcholine (16:0/18:1) and (16:0/18:2) and sphingomyelin (d18:0/16:1) are significantly higher in thyroid papillary cancer than in normal thyroid tissue as determined by tandem mass (MS/MS) analysis. These distributional differences may be associated with the biological behavior of thyroid papillary cancer.     

The Impact of Scale,Recycling Boundary,and Type of Waste on Symbiosis and Recycling

Innovative waste recycling through industrial processes such as industrial and urban symbiosis has long been practiced and recently received much attention in the field of industrial ecology, with researchers making efforts to identify key contributing factors to successful industrial symbiosis. By analyzing 88 sample recycling projects in 23 eco‐towns in Japan, this article focuses on the factors of project scale, recycling boundary, and types of waste in relationship to environmental benefits and operational performance. The results showed that larger eco‐towns achieved more savings of virgin materials and higher stability in operation. Large‐scale projects tended to locate closer to the users of recycled products than did small‐scale projects. For treating similar types of waste, projects producing recycled products for special users (e.g., feedstock to a blast furnace for iron production) tended to locate closer to the users than those not producing for special users. The type of waste had a strong effect on the savings of virgin materials and recycling boundaries, while local factors had significant impacts on operational performance. The results also showed that agglomeration did not significantly contribute to the environmental benefits or operational performance of eco‐town projects. Another finding was that national agencies were helpful for facilitating cross‐prefecture transportation and long‐distance transaction of wastes. Implications of the findings are also discussed.     

A concise review of geographic variation in adult body size in anadromous masu salmon, Oncorhynchus masou

Adult body size (size at maturity) is one of the key life history traits and is well known to sometimes correlate with latitude in anadromous salmonids. However, it is poorly understood whether geographic size patterns except for latitudinal trends occur or why such patterns have been shaped. The present paper briefly reviewed body size variation between anadromous returns of masu salmon Oncorhynchus masou in the Okhotsk group (10 populations along the Sea of Okhotsk coast), the Pacific group (2 populations along the Pacific Ocean coast) and the Sea of Japan group (24 populations along the Sea of Japan coast). The Okhotsk group was smaller than the Sea of Japan group. Although the statistical analysis detected no differences among the remaining combinations, the Okhotsk group was possibly smaller than the other groups because the size of the Pacific group seemed to be within range of the Sea of Japan group but tended to be larger than that of the Okhotsk group. Future research should first test whether size at maturity genetically differs between the Okhotsk group and the other two groups to explore further evolutionary factors shaping geographic size variation.     

Fine‐scale Spatial Genetic Structure of Ten Dipterocarp Tree Species in a Bornean Rain Forest

Fine‐scale spatial genetic structure is increasingly recognized as an important factor in the studies of tropical forest trees as it influences genetic diversity of local populations. The biologic mechanisms that generate fine‐scale spatial genetic structure are not fully understood. We studied fine‐scale spatial genetic structure in ten coexisting dipterocarp tree species in a Bornean rain forest using microsatellite markers. Six of the ten species showed statistically significant fine‐scale spatial genetic structure. Fine‐scale spatial genetic structure was stronger at smaller spatial scales (≤ 100 m) than at larger spatial scales (> 100 m) for each species. Multiple regression analysis suggested that seed dispersal distance was important at the smaller spatial scale. At the larger scale (> 100 m) and over the entire sample range (0–1000 m), pollinators and spatial distribution of adult trees were more important determinants of fine‐scale spatial genetic structure. Fine‐scale spatial genetic structure was stronger in species pollinated by less mobile small beetles than in species pollinated by the more mobile giant honeybee (Apis dorsata). It was also stronger in species where adult tree distributions were more clumped. The hypothesized mechanisms underlying the negative correlation between clump size and fine‐scale spatial genetic structure were a large overlap among seed shadows and genetic drift within clumped species.     

EPR detection of two protein-associated ubiquinone components (SQNf and SQNs) in the membrane in situ and in proteoliposomes of isolated bovine heart complex I

The success of Sazanov's group in determining the X-ray structure of the whole bacterial complex I is a great contribution to the progress of complex I research. In this mini-review of 35 years' history of my laboratory and collaborators, we characterized the function of protein-associated semiquinone molecules in the proton-pumping mechanism in complex I (NADH-quinone oxidoreductase). We have constructed most of the frame work of our hypothesis, utilizing EPR techniques before the X-ray structures of complex I were reported by Sazanov's and Brandt's groups. One of the semiquinones (SQ_Nf) is extremely sensitive to a proton motive force imposed on the energy-transducing membrane, while the other (SQ_Ns) is insensitive. Their sensitivity to rotenone inhibition also differs. These differences were exploited using tightly coupled bovine heart submitochondrial particles with a high respiratory control ratio (> 8). We determined the distance between SQ_Nf and iron–sulfur cluster N2 on the basis of their direct spin–spin interaction. We are extending this line of work using reconstituted bovine heart complex I proteoliposomes which shows a respiratory control ratio > 5. Two frontier research groups support our view point based on their mutagenesis studies. High frequency (33.9 GHz; Q-band) EPR experiments appear to favor our two-semiquinone model. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).