,17 as well as a polysaccharide click here component in Chlorella vulgaris.18 The α-glucan and rhamnomannans were obtained from P. boydii by extraction with hot 2% aqueous potassium hydroxide at 100 °C followed by fractionation on a Superdex 200 column (Fig. 4).11,13,14 The chemical structure of the glucan P. boydii was determined, using a combination of techniques including gas chromatography, 1H TOCSY, 1H and 13C NMR spectroscopy and methylation analysis.11 Its structure resembles

glycogen, since it consisted of (14)-linked α-D-Glcp substituted at O-6 with α-D-Glcp units (Fig. 5a and b). Identification of rhamnomannan was by mono-dimensional NMR (1H and 13C) and bi-dimensional COSY, TOCSY and HSQC analyses. The NMR data of the rhamnomannan showed anomeric signals with δ 97.9/4.981, 101.0/4.967,

102.2/5.228 and 103.9/5.060, typical of non-reducing terminal α-Rhap, and 3,6-di-O-substituted 2-O- and 3-O-substituted α-Manp units, respectively. That at δ 79.9/4.127 confirmed the presence of 3-O-substituted α-Manp units.13,14 Polysaccharides and peptidopolysaccharides are especially relevant for the architecture of the Scedosporium/P. boydii cell wall, but selleck chemical several of them are immunologically active with great potential as regulators of pathogenesis and the immune response of the host. In addition, some of these molecules can be specifically recognised by antibodies from the sera of patients, suggesting that they could also be useful in the diagnosis of fungal infections. The structures of PRM-Sp of S. prolificans, as already mentioned, differed from those present in the PRM of P. boydii, which contained a higher proportion of (13)-, but no (12)-linked α-Rhap units. These structural differences in the carbohydrate portion suggest that related infections caused by P. boydii and S. prolificans

would be distinguishable by ELISA using hyperimmune sera against their component PRMs (Fig. 6a and b). Rhamnose-containing structures appear to Digestive enzyme be the immunodominant epitopes in the rhamnomannans of P. boydii,7,8S. prolificans, S. schenckii and Ceratocystis stenoceras,15 particularly if they are present as (13)-linked α-Rhap side-chain units.19 Antibodies recognising this structure may, therefore, recognise both the N-linked high molecular weight polysaccharides and the O-linked oligosaccharides in the glycocomplexes. The O-glycosidically terminated oligosaccharides may account for a significant part of the PRM antigenicity, since de-O-glycosylation decreased its activity by 70–80%.8 Similar results were obtained with the peptidogalactomannan from Aspergillus fumigatus20 and PRM from S. schenckii.15 The immunodominance of the O-linked oligosaccharide chains was evaluated testing their ability to inhibit reactivity between the PRM and anti-P. boydii rabbit antiserum in an enzyme-linked immunosorbent assay (ELISA) hapten system.

There are several chapters that deal with the preparation of reports, education of staff

and regulatory authorities. Parts 3 and 4 are a valuable and practical resource, not only for neurotoxicologists, but also for neuropathologists dealing the pharmaceutical industry and faced with unravelling toxic lesions in human material. At the end of the book, the editors look to the future Alisertib cost with a vision of super specialization in neurotoxicology that will make the current book even more valuable as it will help those in specialist areas to remain in touch with the whole field of neurotoxicology. Finally, there are eight appendices containing supplementary data on techniques and the structure of the nervous system. I do have some criticisms of the book, mainly related to the illustrations. Throughout the chapters, the illustrations are in black-and-white, but in the centre of the book, there are 16 pages of colour illustrations

that duplicate black-and-white pictures in the chapters. Although a little inconvenient, it is possible to see all the important illustrations in colour in MK-2206 chemical structure the central batch of colour illustrations. One important advantage of the use of black-and-white illustrations is that the price of the book is very competitive. Some seven major text books on neurotoxicology have been published since the year 2000. They range from clinical books to those concentrating on the biochemistry of the toxins. The present book is the only one that concentrates almost exclusively on neuropathology. In summary, I enjoyed reading this book for its attitude to practical neuropathology and neurotoxicology and also for the wisdom and empathy of its authors. It will be of great value

not only to neurotoxicologists, but also to neuropathologists and neuroscientists at all stages of their careers, especially to those involved in investigative and experimental neuropathology. “
“This chapter contains sections titled: Introduction What Makes a Report a Good Report? Structure of the Neuropathology Report Methocarbamol The Neuropathologypeer Review Report References “
“Edited by Dennis W. Dickson and Roy O. Weller . Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders (2nd edition) . Blackwell Publishing Ltd , Chichester , 2011 . 477 Pages. Price £170 (hardback). (http://www.wiley.com). ISBN 978-1-4051-9693-2 I remember the first edition of this book well. I was surprised, therefore, when the new second edition of this book, from the International Society of Neuropathology, arrived in a much larger box. Whereas the previous edition seemed to work on the thin margins, thin space between columns, text-dense philosophy, this edition is more elegantly laid out and has a less busy, clearer approach. The book is hard bound, and stands up well to a reasonable amount of unavoidable (wo)man-handling. The paper is as good in quality as its contents.

The γ-PGA-induced FoxP3+ cells expressed CD25, GITR and cytotoxic T lymphocyte antigen 4 (CTLA-4) Selleck MK-2206 at levels equivalent to those in nTreg cells and higher than those in TGF-β-induced aTreg cells (Fig. 2d). Taken together, these results demonstrate that the presence of γ-PGA during priming converts naive non-Treg cells to FoxP3+ aTreg cells with phenotypes equivalent to those of nTreg cells. Because TGF-β is a well-known and potent inducer of FoxP3 [7,8], it seemed possible that γ-PGA induced FoxP3 expression by first stimulating CD4+ T cells to produce

TGF-β. Because the culture medium supplemented with 10% fetal bovine serum (FBS) contained a substantial amount of TGF-β and the cells did not survive under

the serum-free condition, we failed to quantitate the level of TGF-β secreted in the culture supernatant. Instead, we found that CD4+ T cells stimulated in the presence of γ-PGA produced approximately 3·5-fold more TGF-β transcripts than in the absence of γ-PGA (Fig. 3a). This TGF-β seemed to contribute to the induction of FoxP3 because neutralizing antibody to TGF-β reduced significantly the number of γ-PGA-induced FoxP3+ cells (Fig. 3b). Therefore, we conclude that the mechanism by which γ-PGA induces FoxP3 expression is at least partially dependent on the TGF-β produced in response to γ-PGA. Previously selleck chemicals we found that γ-PGA activated dendritic cells via TLR-4 [24]. Therefore, we needed to confirm that the ability of γ-PGA to suppress the development of Th17 cells (Fig. 1) was due solely to its action on naive CD4+ T cells rather than on dendritic cells. To this end, we completely eliminated CD4+CD11c+ dendritic cells from a CD4+ population. γ-PGA still rendered these cells refractory to Th17-polarizing conditions, indicating that γ-PGA acts directly on naive CD4+ T cells (Fig. 4a). Furthermore, in addition to the master Forskolin regulator RORγt, γ-PGA significantly inhibited the induction of other Th17-related factors, such as STAT-3, IRF-4 and Ahr, while increasing the

expression of FoxP3 and SOCS3 (Fig. 4b). Under Th17-polarizing conditions, γ-PGA inhibited TGF-β expression – the opposite outcome to that obtained in neutral conditions. However, the reduced expression of TGF-β may not interfere with the action of γ-PGA, because we found that reducing the concentration of exogenous TGF-β from 5 ng/ml to 2 ng/ml in the Th17-polarizing conditions did not affect the development of Th17 cells (data not shown). Because of the importance of RORγt as a Th17 lineage-determining factor, we tested whether γ-PGA affects the expression of RORγt at the transcriptional level. Mouse thymoma EL4 cells were transfected with a luciferase reporter spanning 2 kb upstream of exon 1 of the Rorc gene encoding RORγt and cultured under Th17 conditions in the presence and absence of γ-PGA. The presence of γ-PGA significantly reduced luciferase activity (Fig. 4c).

Moreover, obesity, which is a phenotypic risk factor for T2D development, has been demonstrated to predispose patients to several autoimmune disorders, including inflammatory bowel disease (IBD) and psoriasis [40,41]. Proinflammatory CD4+ T cells in adipose tissue have been demonstrated to stimulate the development of CD8+ T cells [17,22]. These observations are important, as the CD8+ T cells are generally considered to be the cells capable of lysing cells, both foreign and self, in the development of inflammation and autoreactive responses [42–46]. Until recently, the development of autoinflammatory and autoimmune diseases

was believed to rely on the stimulation of a subset of CD4+ proinflammatory cells designated as T helper type 1 (Th1). However, with the discovery of IL-23 it has now become apparent MDV3100 cost that other immune

system players are implicated in autoimmune disease development. One of the immune system culprits is the cytokine IL-17. IL-17 has been demonstrated to be produced by a new T cell subset designated Th17. The Th17 T cells have been implicated directly in the pathogenesis of both inflammatory and autoimmune diseases [47–49]. Moreover, obesity and chronic inflammation have been demonstrated to promote selectively an expansion of the Th17 T cell subset [50]. The increased Th17 bias, the increases in CD8+ T cell subsets and establishment of an inflammatory milieu may represent the link between inflammation, T2D and subsequent development of islet autoimmune disease selleck kinase inhibitor in T2D patients.

Another component of diabetes disease development is the resulting pancreatic lesion. The pancreatic lesion in patients with diabetes encompasses a spectrum of diminished or destroyed capability of the pancreatic islets to produce insulin. In the pancreas of T1D patients the β cells are destroyed selectively by the immune system in an autoimmune attack, whereas the pancreatic lesion of phenotypic T2D patients has been believed historically to be a metabolic defect, resulting in diminished secretory capability. However, recently the pancreas Demeclocycline of T2D patients have been demonstrated to be infiltrated by immune cells [17–19]. These studies suggest that immune-mediated islet damage may be a component of more than just classic T1D. β cell destruction and damage caused by soluble immune mediators occurs most probably in the pathogenesis of both T1D and T2D. In T1D, the invading immune cells produce cytokines such as IL-1β, TNF-α and interferon (IFN)-γ. These cytokines have been demonstrated to directly induce β cell apoptosis [51]. In T2D, the circulating IL-6 and IL-1β have also been associated with β cell apoptosis [52]. Moreover, elevated levels of IL-1β, IL-6 and C-reactive protein (CRP) are predictive of T2D development [28–31]. Treatment of T2D patients with IL-1ra to block the effects of IL-1β improves β cell function and diabetes control [32].

Nevertheless we have continued to perform annual Al levels on all our dialysis patients. Methods: We retrospectively analysed serum Al from Jan 2010-Dec 2013 using our database (Nephworks 6) as well as RO and water feed levels. Results: 2058 Al tests in 755 patients (62% male, mean age 64 years) were

reviewed showing mean (SD) of 0.41 (0.30) μmol/L. 57 (2.8%) tests from 35 patients had Al levels >1.0 μmol/L and 27 (77%) of these patients were or had been prescribed aluminium hydroxide (AlOH). 7 patients had Al >2.2 μmol/L. In 3 of these patients, no source of Al was identified, at least one patient was dialyzing at home before being transplanted. 182 patients taking AlOH (87% of all patients on AlOH)

had levels ≤ 1.0 μmol/L, but the OR of serum Al >1.0 μmol/L on AlOH selleck chemicals was 9.98. The cost of Deforolimus serum Al assay is $30.60, thus costs were $62,974.80 over the study period or over $1300/month. Despite RO feed water Al levels as high as 48 μmol/L (1300 ng/mL), Al output from the RO was almost always undetectable (<0.1 μmol/L). We have detected dialysate Al levels >2.2 μmo/L only 5 times since 2009, and never in last 3 years. Conclusion: Unselected testing of serum Al appears unnecessary and expensive and we will look to more selective testing of dialysis patients. 236 SURVIVAL TRENDS IN ELDERLY DIALYSIS PATIENTS AND THE GENERAL POPULATION AG RITCHIE1,2, PA CLAYTON2,3 1Concord Hospital, Sydney, NSW; 2Sydney Medical School, Sydney,

NSW; 3ANZDATA Registry, Adelaide, South Australia, Australia Aim: To identify survival trends in elderly dialysis patients compared with the general population. Background: Elderly dialysis patients are the most rapidly growing segment in Australia and survival appears to be improving, but the trends and relationship to general population survival have not been recently assessed. Methods: Observed survival of Australian patients commencing dialysis at 60y or older from 1980–2012 extracted from ANZDATA Registry without censoring for transplantation. Exponential parametric survival analysis used to model dialysis patient survival. Matching age-, sex- and era-specific survival data extracted from the Tolmetin Australian Bureau of Statistics Life Tables. Results: The total number of patients 60y or older commencing dialysis increased from 293 during 1980–82 to 4069 during 2010–2012, and the proportion of patients in this cohort aged 60–64y fell from 60.1 to 21.0%. Over that period the modelled median survival for those commencing dialysis at age 60 improved from 3.5–7.5y (114% increase) in men and women, compared with general population improvements of 17.2–23.3y (35%) in men and 22.0–26.4y (20%) in women. Similar relative survival gains were seen in dialysis cohorts commencing up to 80 years of age however absolute gains were smaller and the life expectancy gap is also increasing.

The indicated size must be used with caution, as the estimate may be affected by glycosylations and rely further

on the relative selleck chemicals shapes of the protein under study compared with the standard proteins used for calibration. The finding of all of MASP-1 in large complexes is still in line with the earlier suggestion, at a time when ficolin-MASP interactions were not known by us [27] and others [30], that much of the MASPs and MAps in serum are not associated with MBL. From birth at term and during the following 3 months there was an increase in MASP-1, but in general a level quite similar to the level after 12 months, and indeed adult levels, were seen (Fig. 5). None were below 3 µg/ml at delivery. This indicates that whatever the function of MASP-1, one may regard the newborn as probably having sufficient quantities. An issue when comparing samples between different groups of patients is the possible variation of the parameters over time. In general, measurements on samples obtained sequentially from four apparently healthy volunteers through a 50-day period showed only minor variations (Fig. 4). This stable level makes it possible

to compare MASP-1 concentrations in samples taken at various time-points, although the situation may be different in some patient populations. Conversely, measurements on samples retrieved during Olopatadine an acute-phase response, induced by a major operation, showed that MASP-1 was rapidly down-regulated and subsequently up-regulated for some time following click here the operation (Fig. 6). The increase happened slowly, roughly 3 days after the peak of the

CRP response, and reached levels only approximately twice that of the pre-operation sample. We do not know if the colon cancer by itself has an influence on the pre-operation MASP-1 levels, and it is possible that a greater response may be induced by infections. A possible acute-phase response must thus be taken into account when studying data sets from patients. A puzzling early finding was that the levels of MASP-1 determined in heparin plasma were higher than in the corresponding serum, citrate plasma or EDTA plasma (Fig. 2). We can offer no explanation for this observation, but it may have to do with interference by the interaction of enzyme inhibitors in serum because, e.g. anti-thrombin-III in complex with heparin is known to bind and inhibit MASP-1 much better than without heparin [13]. For comparison of samples in routine analyses it is thus important to not compare heparin plasma values directly with serum values. A much smaller, but significant, difference between serum and EDTA plasma levels was also indicated. We did not see a strong correlation between serum levels of MASP-1, MASP-3 and MAp44 (Fig. 7).

In malaria endemic settings, adults develop ABT-263 solubility dmso protective immunity after repeated exposures (2), but women are more

susceptible to malarial infection when they become pregnant (1). Severe clinical manifestations associated with this infection include premature delivery and intrauterine growth restriction, contributing to low birth weight (LBW), stillbirth, abortion and maternal mortality (3–5). Increased synthesis of inflammatory cytokines like tumour necrosis factor (TNF), interleukin (IL)-2 and interferon (IFN)-γ (6–8) has been shown in malaria during pregnancy, and levels of TNF in particular have been associated with maternal anaemia and LBW (6,9). Interestingly, such pathogenic immune responses to malaria appear to be influenced by host genetic factors. For example, infants homozygous for TNF2, a polymorphism in the TNF promoter region that is associated with increased TNF production (10), are at increased risk of preterm birth and mortality, suggesting that poor birth outcomes in malaria endemic areas are precipitated by a genetically determined maternal tendency to produce high levels of this inflammatory cytokine (11). In mice, the immune response to malaria is complex and varies as a function

of mouse genetic background (12) and anatomical sites analysed. Moreover, it is dependent on parasite species and strain as well as on route of infection. In B6 mice, early production of TNF, IFN-γ, IL-12 (13) and granulocyte–macrophage colony-stimulating factor (14) is required for resistance to Molecular motor blood-stage CDK inhibitor P. chabaudi AS infection. In contrast, susceptible A/J mice mount early, predominantly Th2-biased cytokine responses (15) and succumb to infection (16). Treatment of these mice with recombinant IL-12 early in infection results in increased production of IFN-γ and TNF and facilitates elimination of parasites and survival (17). Interestingly, A/J mice overcome their Th2-cytokine bias later in infection, exhibiting increased TNF expression in the liver and high serum TNF levels coincident with the time that they begin to succumb to infection (18). Recently, we initiated studies of malaria

during pregnancy using P. chabaudi AS infection in B6 mice as a model platform (19–21). This model recapitulates the severe pregnancy outcomes, namely foetal loss, seen in low endemic areas and in some heavily exposed primigravidae (1). Importantly, similar to human malaria during pregnancy (6,9), TNF plays a critical role in embryo loss in this model; antibody-mediated neutralization of this cytokine rescues mid-gestational pregnancy (21). Because TNF is well known to have a negative impact on pregnancy outcomes even in the absence of infection (22,23), the tendency to produce this factor in response to malarial infection may represent a common pathogenic factor that relative to other host elements is central to disease pathogenesis.

Objective:  We examined the Y-27632 impact of estradiol and progesterone on skin LH and RH in 25 healthy women. Methods: 

Subjects were studied three times over 10–12 days. Endogenous sex hormones were suppressed with a GnRHa. Subjects were studied on day 4 of suppression (study day 1), three to four days later following treatment with either 17β-estradiol or progesterone (study day 2), and another three to four days later, following treatment with both estradiol and progesterone (study day 3). Subjects underwent identical LH and RH protocols on all study days. LH is characterized by an initial peak in blood flow, followed by a prolonged plateau. A brief nadir is seen between the phases. Results:  Blood flow values are expressed as percent maximum CVC. Estradiol alone increased initial peak CVC from 71 ± 2% to 79 ± 2% (p = 0.001). Progesterone alone increased initial peak CVC from 72 ± 2% to 78 ± 2% (p = 0.046). Neither estradiol nor progesterone increased plateau CVC. No significant changes were seen between study days 2 and 3 for either group. No differences were observed in RH. Conclusions:  Both estradiol and progesterone increased initial peak CVC during LH, without altering plateau CVC. There was no additive effect of estradiol and progesterone. “
“Astrocytes are thought to play an important role in neurovascular coupling, a process that allows the brain

to locally control blood flow in response find more to changes in activity. However there is ongoing debate as to when, and under what conditions astrocyte activity is required. In the following review we set forth the hypotheses that astrocytes: 1) act to modulate but not initiate functional hyperemia, and 2) help set the basal tone state of the brain microvasculature by the tonic release of vaso-active messengers. Through these actions astrocytes could help match metabolic demand with supply over a spectrum of activity timescales. This article is protected by copyright. All rights reserved. “
“We studied the effects of S1P on the

diameter and spontaneous contraction of murine iliac collecting lymph vessels. The isolated lymph vessel was cannulated with two glass micropipettes and then pressurized to 4 cmH2O at the intraluminal Bacterial neuraminidase pressure. The changes in lymph vessel diameter were measured using a custom-made diameter-detection device. Immunohistochemical studies were also performed to confirm S1P receptors on the lymph vessels. S1P (10−7 M) had no significant effect on the frequency or amplitude of the lymph vessels’ spontaneous contractions. In contrast, S1P (10−8–10−6 M) produced a concentration-related reduction in lymph vessel diameter (tonic contraction). Pretreatment with 10−4 M l–NAME or 10−5 M aspirin had no significant effect on the S1P-induced tonic contraction of the lymph vessels.

Although ubiquitously expressed, the major focus of IL-17RA biology has concentrated on stromal cells, which are the critical targets for IL-17A and

IL-17F (Table 2). The regulation of IL-17RA expression is not well studied but elevated IL-17RA expression has been detected in human inflammatory diseases such as arthritic joints from patients with RA, suggesting BGJ398 mw a role in autoimmunity.94,95 In accord with these reports, risk haplotypes within the IL-17RA gene that increase susceptibility to Crohn’s disease have been identified by genetic studies.96 As discussed above, IL-17A and IL-17F require the IL-17RA–IL-17RC complex for function. The absence of either chain prevents cytokine-mediated pro-inflammatory cytokine secretion.95 Biochemical measurements revealed that the affinity between IL-17A and IL-17RA was higher than that between IL-17RA and IL-17F, which may explain the discrepancy between the potency of IL-17A and IL-17F dimers.6,11,97 Structural analyses suggest that IL-17RA is a common chain for a number of IL-17 family members. Whereas the loss of IL-17RA inhibits IL-17E function, this website a requirement for this chain in IL-17B, IL-17C and IL-17D responses has not been demonstrated.66,71,74,98 A critical

role for IL-17RA in host defence has been demonstrated using genetically deficient mice and blocking reagents. Neutrophil recruitment and granulopoiesis are impaired in il17ra−/− mice rendering them susceptible to microbial infections.36,37,99–101 The inability to mount efficient immune responses protects these mice from developing disease in pre-clinical models of arthritis, IBD and influenza infection.100,102,103 Likewise, soluble versions of IL-17RA confer protection from allograft rejection, joint-damage

in models of arthritis Wilson disease protein and Chlamydia infection.104–106 However, given the emerging data demonstrating the importance of IL-17RA in other cytokines, it is difficult to conclude that the effects of this reagent are solely the result of inhibition of IL-17A and IL-17F.66 Further studies are required to evaluate this molecule in vivo. The IL-17RB chain was identified through screening of expressed sequence tag databases for IL-17RA-like molecules. As described above, both IL-17B and IL-17E bind to IL-17RB in vitro.61,82 Expression of IL-17RB is detected in lung, kidney, bone and fetal liver tissues.82 Interleukin-17RB is detected on multiple cell types and receptor expression is augmented by inflammatory signals (Table 2). Cross-linking the T-cell receptor, addition of the IL-7/15 cytokines, or co-culturing with dendritic cells stimulated with thymic stromal lymphoprotein, augment IL-17RB expression in memory Th2 cells.64 Likewise, the addition of IL-33 and/or IL-17E enhances IL-17RB expression on the ckit+ lin− cells, suggesting that receptor expression is partly regulated by an autocrine feedback loop.

There were no statistically significant differences in demographics between the three Braak stage groups, although the Braak stage 0-I-II (non-AD) group trended toward younger age (P = 0.013 by Kruskal-Wallis,

no differences were detected with Dunn’s multiple comparison test). UBL immunoreactivity had distinct patterns in the three Braak stage groups Palbociclib cell line (described below), and localization was almost exclusively neuronal in all groups, with only in 2/11 cases (one Braak stage VI, one Braak stage IV with family history of AD) exhibiting UBL immunoreactivity in cells with the morphological appearance of microglia and oligodendrocytes, and located throughout the gray and white matter, respectively (not shown). In Braak stage 0-I-II cases (NFT absent or confined to the this website entorhinal cortex), UBL immunoreactivity was observed in the neuropil in the stratum pyramidale

of the Ammon’s horn (CA) and molecular layer of the dentate gyrus (DG). UBL immunoreactivity was also detected in neuronal soma, dendrites and in the nucleoplasm in hippocampal neurons, including pyramidal and multipolar neurons in the CA fields, and DG granular neurons. In the majority of neurons, UBL immunoreactivity intensity was higher in the nucleoplasm compared to the cytoplasm (Fig. 1; Table 2). UBL immunoreactivity in the nucleoplasm appeared punctuate/vesicular (Fig. 1 inset a; Fig. 4A) and was most prominent in the CA2/3 field (Table 2). In Braak stage III-IV cases (NFT involving the entorhinal cortex and hippocampus but not neocortex), UBL immunoreactivity in the neuropil was reduced in the CA1 and CA2/3 regions, and was unchanged in the CA4 and DG, compared to Braak stage 0-I-II cases. The majority of CA1 neurons exhibited reduced cytoplasmic and nucleoplasmic labelling; however, a subset of CA1 pyramidal neurons had prominent UBL immunoreactivity in the nucleoplasm (Fig. 1B). The intensity of UBL immunoreactivity in the nucleoplasm increased markedly in the

majority of CA2/3 pyramidal Niclosamide neurons, CA4 multipolar neurons and DG granular neurons (Figs 1E, 2H,K; Table 2). We also observed UBL immunoreactivity in fibers in the CA2/3 radiatum/moleculare and DG molecular layer in three of the Braak stage III-IV cases (Braak III: 1; Braak IV: 2; not shown). In Braak stage V-VI cases, UBL immunoreactivity was less intense in the CA1 field, both in the neuropil and in pyramidal neurons, except those with the morphological appearance of extracellular NFT (eNFT), where UBL immunoreactivity was prominent (Fig. 1C. inset c). In contrast, UBL immunoreactivity in neuropil and neuronal cytoplasm in CA2/3, CA4 and DG was similar to the pattern observed in Braak stage III–IV cases, albeit with a less prominent increase in nucleoplasmic UBL immunoreactivity (Fig. 1F,I,L; Table 2). Analysis of UBL immunoreactivity optical density confirmed a significant increase (P < 0.