Search

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal–lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done. [ABSTRACT FROM AUTHOR]

Summary: The effects of milk intake on bone health are not clear in elderly Asian men with low dietary calcium intake. This study showed that greater milk intake is associated with lower bone turnover, higher bone density, and higher bone microarchitecture index in community-dwelling elderly Japanese men. Introduction: The consumption of milk or dairy products is widely recommended for maintaining bone health regardless of gender or age. However, little evidence exists on the beneficial effects of milk intake on bone health in elderly Japanese men characterized with relatively low dietary calcium intake. Here we examined whether or not greater milk intake was associated with lower bone turnover, higher bone density, and stronger bone microarchitecture in community-dwelling elderly Japanese men. Methods: Interviews were conducted to obtain information on medical history and lifestyle, including the amount of habitual milk intake, nutrient intake calculations based on a 1-week food diary, and measurements of areal bone mineral density (aBMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) by dual-energy x-ray absorptiometry (DXA), trabecular bone score (TBS) using DXA images at LS, and biochemical markers of bone turnover in sera. Participants with a history of diseases or medications that affect bone metabolism, or with missing data, were excluded from the analysis. Results: The median intake of milk in the 1479 participants (mean age, 73.0 ± 5.1 years) was one glass of milk per day. Bone turnover markers showed a decreasing trend ( p < 0.05) and aBMD at TH ( p = 0.0019) and FN ( p = 0.0057) and TBS ( p = 0.0017) showed increasing trends with greater milk intake after adjusting for demographic and behavioral confounding factors. This association was attenuated after further adjusting for nutrient intake, in particular, calcium intake. Conclusions: Greater milk intake was associated with lower bone turnover, higher aBMD, and higher TBS in community-dwelling elderly Japanese men. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00401-021-02309-z [ABSTRACT FROM AUTHOR]

Navigation systems have been developed to achieve more reliable prosthetic alignment in TKAs. However, the component alignment in the sagittal plane is reportedly less reliable than in the coronal plane even with navigation systems. We measured and compared sagittal prosthetic alignments for TKAs with the conventional technique and three navigation approaches to establish reference frames, using radiographs of the entire lower extremity while standing. The sagittal alignments simulated on the radiographs with the conventional technique and navigation systems differed by a mean of 2 degrees to 4 degrees . Use of navigation systems resulted in a mean of 1 degrees to 4 degrees hyperextension between the femoral and tibial components and use of the conventional technique resulted in a mean of 1 degrees flexion. Use of different reference points on the distal femoral condyle for the navigation systems resulted in differences of as much as 3 degrees alignment in the sagittal plane. Although optimal prosthetic alignment for TKA in the sagittal plane is unknown, surgeons and technicians using navigation systems should be aware of this difference in the sagittal plane and the risk of hyperextension between the femoral and tibial components, which might be associated with osteolysis and anterior post-cam impingement. [ABSTRACT FROM AUTHOR]

Alumina-on-alumina bearings for THA have markedly improved in mechanical properties through advances in technology; however, alumina fracture is still a concern. We retrospectively reviewed 77 patients (82 hips) with cemented alumina-on-alumina THAs to identify factors relating to alumina failure. The mean age of the patients at surgery was 63 years. The prostheses had a cemented polyethylene-backed acetabular component with an alumina inlay and a 28-mm alumina head. Revision surgery was performed because of alumina inlay failure in four hips (three fractures and one dissociation; 5.6%), deep infection in two, and recurrent dislocation in one. The 8-year survival rate was 90.7% with revision for any reason and 94.4% with revision for alumina failure as the end point. There were no differences in age, body mass index, gender, mobility, function, abduction angle, or size of component among the four hips with alumina failure and the remaining 68 hips without it; however, radiolucent lines in the sockets were more apparent in four cases with alumina inlay failure. This alumina-on-alumina THA thus yielded unsatisfactory medium-term results because we observed a high rate of catastrophic alumina inlay failure. [ABSTRACT FROM AUTHOR]

Background. Lip carcinomas are rare oral tumors, and there have been few reports of lip carcinoma in Japan. Methods. Of 914 patients with oral carcinomas treated between January 1980 and December 1998, 12 (1.3%) had lip carcinoma and 5 (0.5%) had lip mucosal carcinoma. We investigated the clinicopathological features of these 17 patients. Results. Of the 12 patients with carcinoma of the lip, 10 had squamous cell carcinomas (9, external lower lip; 1 commissures) and 2 had mucoepidermoid carcinomas (external upper lip). Of the 5 patients with lip mucosal carcinoma, 3 had squamous cell carcinomas (2, mucosa of the lower lip; 1, mucosa of the upper lip), 1 had mucoepidermoid carcinoma (mucosa of the lower lip), and 1 had acinic cell carcinoma (mucosa of the lower lip). Of the 12 patients with lip carcinoma, 9 were classified as stage I, 2 as stage II, and 1 as stage III; all 5 of the patients with lip mucosal carcinoma were stage I. Five patients with lip carcinoma were treated by resection, 5 by a combination of resection and reconstruction, and 2 by radiotherapy alone. All patients with lip mucosal carcinoma were treated by resection. After the initial therapy, 3 patients without neck dissection had regional recurrences and received delayed neck dissection, and 2 died with neck regional recurrence after dissection. The 5-year cumulative survival rates of the patients with lip carcinoma and those with lip mucosal carcinoma were 82.5% and 80.0%, respectively. Conclusion. We suggest that early-stage carcinomas of the lip and of the mucosa of the upper and lower lips are frequent, and we found that the outcome of these patients was excellent. However, an aggressive therapeutic approach to the lip carcinoma patient with cervical metastasis appears warranted, in an attempt to improve locoregional control and ultimate survival. [ABSTRACT FROM AUTHOR]

Interposed fibrous tissue at bone–implant interfaces was quantitatively measured in the presence or absence of polyethylene (PE) or alumina particles. Three different conditions of the interface were designed by implanting a pre-polymerized polymethylmethacrylate (PMMA) plug (plug group), a doughy PMMA (injection group) and a hydroxyapatite (HA) plug (HA group) in the hole drilled at the intercondylar notch of rabbit knees. PE (170±18 μm) or alumina particles (88±26 μm) were repeatedly administered into the knee joints at one month intervals (six times). All animals were sacrificed seven months after the implantation. The bone–implant interface was histomorphometrically examined using undecalcified ground sections. In the plug group, the PE particles significantly increased the extent of the interposed fibrous tissue ( p < 0.05), while the alumina particles showed no effect. In contrast, both particles showed no significant effects in the injection and the HA groups. These results indicate that both particle characteristics and conditions of the bone–implant interface affected particle-induced fibrous tissue interposition. The loose PMMA plug with PE particles induced the greatest amount of fibrous tissue interposition. ©2000 Kluwer Academic Publishers [ABSTRACT FROM AUTHOR]

Recently, evolutionary robotics (ER) has been attracting a lot of attention in the field of robotics artificial life and so on. ER approaches are expected to provide feasible methods to design controllers for autonomous mobile robots with less human intervention. However, most of the conventional studies in ER have been aiming at obtaining very simple (trivial) behaviors such as obstacle avoiding, wall following, and target approaching. To make the ER approach more fruitful, we should pay close attention to obtaining nontrivial behaviors. Based on these considerations, in this paper we propose a method for obtaining nontrivial behaviors using a developmental process with a carefully arranged grafting method. To verify the validity, we apply our idea to the construction of neural controllers that can cope with rough terrain. [ABSTRACT FROM AUTHOR]

IL-4 is a mast cell and T cell produced immune cytokine that is important in the regulation of macrophage function. IL-4 has also been implicated in the induction of foreign body giant cell formation. In patients with long-term joint prostheses, a localized granulomatous inflammation develops in periarticular tissues and other organs where phagocytosis of particulate material from various prosthetic components takes place. In this study we used the inflammatory lesions of the bone–implant interface as a model to investigate the possible production, the frequency and the cellular source of IL-4. 40 samples of the interface membrane obtained from 25 patients undergoing revision of clinically failed implants were analyzed by immunohistochemistry. Cryostat sections were labeled with specific monoclonal antibodies to mast cell products: IL-4, tryptase and the receptor c-kit (CD117). The study has identified a significant level of production of IL-4 by mast cells in all the cases analyzed. There was an apparent difference in the number of mast cells in relation to the histological variants of the interface. The increase in the number of mast cells and IL-4 production was more pronounced in cases with heavy macrophage infiltrate than those exhibiting a predominance of giant cells. The findings imply that the recruitment of mast cell and IL-4 expression precede the granulomatous reaction and may have a role in the induction of a number of immunopathological changes related to mast cell activation by biomaterial particles. © 1998 Kluwer Academic Publishers [ABSTRACT FROM AUTHOR]

src homology 2 (SH2)-containing protein-tyrosine phosphatase SHP2 is known to transduce positive signals from activated receptor protein-tyrosine kinases such as platelet-derived growth factor receptor (PDGFR) beta and insulin receptor. Here, we demonstrate the physiological expression of SHP2 in rats. In northern and western blot analyses, SHP2 expressions were recognized in all tissues, but their expression levels varied significantly among tissues: it is lowest in the liver and kidney. Immunohistochemical staining and in situ hybridization showed SHP2 was expressed ubiquitously but predominantly in vascular smooth muscle cells (SMC). During the development of granulations. SHP2 was expressed predominantly in vascular SMC and also highly expressed in capillary cells. The functional associations of SHP2 with PDGFR beta, which transduces major growth signals in vascular SMC, identify a crucial function of SHP2 in blood vessels in consert with PDGFR beta. [ABSTRACT FROM AUTHOR]

Two distinct novel antigen systems preferentially expressed in rat granulocytes and macrophages were detected using two different monoclonal antibodies (R2-1A6 and R2-2B1). These two antibodies reacted with approximately 50% of rat bone marrow cells, most granulocytes, blood monocytes, alveolar macrophages and peptone-elicited peritoneal macrophages, but not with red blood cells, platelets, thymocytes and T lymphocytes. In addition, R2-2B1 but not R2-1A6 antibody cross-reacted weakly with rat B cells. These two monoclonals also reacted with some reticular elements in rat lymphoid organs including epithelial reticular cells in the thymic medulla and follicular dendritic cells in the lymphoid germinal centre, as well as with the specialized endothelium in the marginal sinuses of the spleen and the post-capillary venules of the lymph node, where lymphocyte recirculation takes place. These antibodies, however, did not label so-called 'dendritic cells' bearing 1a antigens on their cell surfaces, which were found to be located in the thymic medulla, thymus-dependent areas of rat lymphoid tissues and the interstitium of various non-lymphoid organs, suggesting that these dendritic cells, presumably ascribed to those associated with accessory cell function, are separable from the mononuclear phagocyte system in rats by their different reactivities with R2-1A6 and R2-2B1 antibodies. [ABSTRACT FROM AUTHOR]

The wear rate of the ultrahigh molecular weight polyethylene cups in combination with a 28 mm alumina femoral head was measured on the radiographs of patients without any complications, and on cups retrieved due to slight loosening of the prosthesis or due to late infection between bone and components. The wear rate on the radiographs did not include the initial wear, but the wear rate on the retrieved cups did include the initial wear. The wear rate on the retrieved cups was higher, by 50%, than that measured on the radiographs. In both cases, the thicker the polyethylene cups, the lower was the wear rate measured. The average wear rate of the 7 and 8 mm thick cups was about twice that of cups 10 and 11 mm thick. From these results, we conclude that polyethylene cups more than 11 mm thick should be used. [ABSTRACT FROM AUTHOR]

We have studied the shape of the bones and the way in which they move in the normal cadaveric knee using MRI as a first step to developing an MRI protocol for establishing the kinematic behaviour of the knee in the clinical setting. Our results have been confirmed in normal volunteers using Open Access and Interventional MRI. The latter enables the knee to be imaged whilst the subject is weight-bearing. [ABSTRACT FROM AUTHOR]

Bredinin has been found to have an inhibitory effect upon the secondary lesions occurring from adjuvant injection in rats. [ABSTRACT FROM AUTHOR]