Synthesis of poly(vinyl alcohol) having a thiol group at one end and new block copolymers containing poly(vinyl alchohol) as one constitent

Poly(vinyl alcohol) (PVA) and poly(vinyl acetate) having a thiol group at one end were synthesized by free-radical polymerization of vinyl acetate in presence of thioacetic acid as a chain transfer agent followed by treating with sodium hydroxide/methanol and ammonia, respectively. It was found that block copolymers containing the PVA sequence as one constituent were obtained by the redox-initiated polymerization of some vinyl monomers, for example, acrylic acid (AA) and acrylamide (AAm), using PVA having a thiol end group as reductant and an oxidant such as potassium bromate and potassium persulfate.     

Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study

Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor–α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n?=?7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4?weeks for 24?weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P?<?0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.     

Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology

Regional progression of neurofibrillary tangles (NFTs) around the hippocampus was traced on thick sections double immunofluorolabeled with RD3 and RD4 antibodies, specific for three- and four-repeat tau, respectively. As reported, the cubic density of all tau-positive neurons was predominant in the entorhinal cortex and cornu ammonis (CA)1, and decreased progressively to the CA2–4 subregions. Among the three isoform profiles (RD3+/4?, RD3+/4+, and RD3?/4+), this regional gradient was replicated with RD3+/4? and RD3+/4+ neurons, while RD3?/4+ neurons exhibited the reverse gradient. Comparison of the subregion pairs confirmed a consistent profile shift along this gradient in every case regardless of the abundance of NFTs. To clarify the underlying mechanism of this regional profile shift, intraneuronal intensity of RD3 and RD4 immunoreactivity (IR) was quantified. Although their intensities were both lower in dendrites than in the soma, this gradient was steeper with RD4, leaving RD3 IR in dendrites. Dendritic arborization was abundant in RD3?/4+ pretangles, attenuated in RD3+/4+ neurons, and further attenuated in RD3+/4? ghost tangles. These findings suggest that dendritic RD4 IR retracts first, leaving RD3 IR in the dendrites. Taken together, this dendrite-oriented retraction initiates the gradual shift from RD3?/4+ pretangle neurons to RD3+/4? ghost tangles by way of RD3+/4+ NFTs. This intraneuronal profile shift may be a basis for the regional gradation featured by the similar profile shift during progression of NFT pathology.     

Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution

Pretangles are cytoplasmic tau immunoreactivity in neurons without apparent formation of fibrillary structures. In Alzheimer disease, such tau deposition is considered to represent a premature state prior to fibril formation (AD‐pretangles), later to form neurofibrillary tangles and finally ghost tangles. This morphological evolution from pretangles to ghost tangles is in parallel with their profile shift from four repeat (4R) tau‐positive pretangles to three repeat (3R) tau‐positive ghost tangles with both positive neurofibrillary tangles in between. This complementary shift of tau profile from 4R to 3R suggests that these tau epitopes are represented interchangeably along tangle evolution. Similar tau immunoreactivity without fibril formation is also observed in corticobasal degeneration (CBD‐pretangles). CBD‐pretangles and AD‐pretangles share: (i) selective 4R tau immunoreactivity without involvement of 3R tau; and (ii) argyrophilia with Gallyas silver impregnation. However, CBD‐pretangles neither evolve into ghost tangles nor exhibit 3R tau immunoreactivity even at the advanced stage. Because electron microscopic studies on these pretangles are quite limited, it remains to be clarified whether such differences in later evolution are related to their primary ultrastructures, potentially distinct between AD and CBD. As double staining for 3R and 4R tau clarified complementary shift from 4R to 3R tau along evolution from pretangles to ghost tangles, double immunoelectron microscopy, if possible, may clarify similar profile shifts in relation to each tau fibril at the ultrastructural dimension. This will provide a unique viewpoint on how molecular (epitope) representations are related to pathogenesis of fibrillary components.     

Effectiveness of Clipping for Definitive Colonic Diverticular Bleeding in Preventing Early Recurrent Bleeding

Objective Clipping is a common technique for managing colonic diverticular bleeding (CDB), despite the lack of published evidence regarding its effectiveness. We aimed to evaluate the effectiveness of clipping for CDB in preventing early recurrent bleeding. Methods This dual-center retrospective study included 93 patients who underwent emergency hospitalization for bloody stool, diagnosed with definitive CDB, and treated with clipping or conservative treatment. The primary outcome was early recurrent bleeding. A logistic regression analysis was performed to assess the association between the occurrence of early recurrent bleeding and clipping with adjustment for propensity scores. Secondary outcomes included death, transfusion, length of hospitalization, need for transcatheter arterial embolization or surgery, and adverse events. Results The patient characteristics were similar between the clipping (n=85) and conservative treatment (n=8) groups. The rate of early recurrent bleeding was significantly lower in the clipping group than in the conservative treatment group [23.5% (20 cases) vs. 75% (6 cases), p=0.005]. In the propensity score-adjusted logistic regression analysis, the odds ratio for early recurrent bleeding in the clipping group was 0.094 (95% confidence interval, 0.008-0.633, p=0.026). Secondary outcomes were not significantly different between the two groups. Stigmata of recent hemorrhage (SRH) at the time of recurrent bleeding was identified in 79.2% of patients (19/24). In the clipping group, recurrent bleeding was observed in 62.5% of cases (10/16) from the same diverticulum. However, early recurrent bleeding tended to be less likely with direct clipping (p=0.072). Conclusion Clipping for definite CDB was more effective in preventing early recurrent bleeding than conservative treatment.     

Biochemical and metabolic abnormalities in normal and osteoarthritic human articular cartilage

Incorporation of radioactive precursors into macromolecules was studied with human normal and osteoarthritic articular cartilage organ culture. Analysis of the salt extracted matrix components separated by cesium chloride buoyant density gradient centrifugation showed an increase in the specific activities of all gradient fractions prepared from the osteoarthritic cartilage. Further analysis of these fractions showed the osteoarthritic cartilage contained 5 times as much sulfate incorporated into proteoglycans, and an even greater amount of ³H-glucosamine incorporated into material sedimenting to the middle of the gradient. Greater than half of this radioactive middle fraction appears to be hyaluronate, as judged by the position it elutes from a DEAE column and its susceptibility to hyaluronidase digestion. This study supports earlier findings showing increased rates of macromolecular synthesis in osteoarthritis, and in addition, an even greater synthetic rate for hyaluronic acid is demonstrated.     

Effect of depression on progression to end‐stage renal disease or pre‐end‐stage renal disease death in advanced diabetic nephropathy: A prospective cohort study of the Diabetes Study from the Center of Tokyo Women’s Medical University

Aims/IntroductionThis study aimed to determine the effect of depression on the progression to end‐stage renal disease (ESRD) and pre‐ESRD death in patients with advanced diabetic nephropathy.Materials and MethodsThis single‐center prospective cohort study enrolled Japanese patients with type 2 diabetes and advanced diabetic nephropathy. The total Patient Health Questionnaire‐9 score was used to evaluate depression at baseline and classified patients into: no, mild and severe depression groups. The outcomes were ESRD, defined as initiation of renal replacement therapy, and pre‐ESRD death. The relationship between the severity of depression and these outcomes was analyzed using a competing risks model, defining each outcome as the competing risk of the other outcome.ResultsOf the 486 patients with a mean estimated glomerular filtration rate of 37.1 ± 21.1 mL/min/1.73 m², 345 were men. During the median follow up of 4.4 years, 164 patients progressed to ESRD and 50 died. The cumulative incidence function of ESRD was significantly higher in the severe depression group (Gray’s test, P = 0.003). The ESRD risk increased by 12.4% and 45.1% in patients with mild and severe depression, respectively, compared with those without depression, although these differences did not reach statistical significance in the multivariate subdistribution hazard model (P = 0.450 and 0.161, respectively). The cumulative incidence of death was similar for the study groups.ConclusionDepression potentially has a weak impact on progression to ESRD, however, the presence of comorbidities might have the possibility to reduce the effect of depression on the renal outcome in patients with advanced diabetic nephropathy.     

Parallel enlargement of Marinesco bodies and nuclei and progressive deposition of p62 in pigmented neurons of the substantia nigra

Marinesco bodies (MBs) are spherical nuclear inclusions found in pigmented neurons of the substantia nigra. Although MBs are abundant in senescent brains, how they are related to aging processes remains unclear. Here, we performed a morphometric analysis of midbrain pigmented neurons to identify the possible influence of MBs on nuclear size. The transected area of the nucleus (nuclear area) was larger in the presence of MBs and was correlated with the area of MB (MB area) in all tested brains. The MB-associated nuclear enlargement was significant even after MB areas were subtracted from nuclear areas. Moreover, higher MB immunoreactivity of p62 was detected in the nucleoplasm of the enlarged MB-associated nuclei. This study on human brains is the first quantitative approach demonstrating MB-associated nuclear enlargement and progressive accumulation of small nucleoplasmic materials. Although cellular hypertrophy is usually considered to be an indication of the upregulation of cellular function, this might not always be the case. These findings suggest that an age-related decline of ubiquitin-proteasome and autophagy system activity and stagnation of undegradable materials are one of the candidate mechanisms to explain the age-related decline of neural activity in the substantia nigra.     

Specific Detection of Pathological Three‐repeat Tau after Pretreatment with Potassium Permanganate and Oxalic Acid in PSP/CBD Brains

Immunohistochemisty with RD3, a monoclonal antibody specific for three‐repeat (3R) tau, is sometimes hampered by diffuse neuronal staining on formalin‐fixed, paraffin‐embedded sections pretreated with formic acid and heating. Additional pretreatment with potassium permanganate followed by oxalic acid completely eliminated this diffuse RD3‐immunoreactivity (IR) in neurons. Furthermore, this additional pretreatment uniformly enhanced RD3‐IR, as well as RD4‐IR, a monoclonal antibody specific for four‐repeat (4R) tau, on pathological deposits with tau IR. This enhanced sensitivity and specificity may allow more reliable identification of 3R and 4R tau in pathological deposits, which may be variable dependent on disease and regions. Cerebral cortex and midbrain from 8 patients [5 progressive supranuclear palsy (PSP) and 3 corticobasal degeneration (CBD)] were screened for RD3‐ and RD4‐IR with this improved procedure. In addition to RD4‐positive structures found both in cerebral cortex and brainstem, RD3‐positive neurofibrillary tangles (NFTs) were also found in midbrain in 7 of these 8 cases but not in the cortex. Multi‐labeling study demonstrated that most of RD3‐negative neurons were positive for RD4. This reliable demonstration of pathological 3R tau deposits in the brainstem of PSP/CBD, so far presumably characterized by deposition of 4R tau, is useful to map tau‐positive lesions according to their biochemical composition.