Furthermore, after 3 days of culture significantly reduced apoptosis rates were observed in CXCL4 or S1P stimulated cells, but no significant differences could be observed between PTX-treated and untreated cells (Fig. 7B). From these data we would INCB024360 datasheet conclude that CXCL4-induced monocyte functions are transduced independently from surface-expressed Gi protein-coupled S1P receptors. In this study, we could show for the first time that CXCL4 regulates genes involved in S1P metabolism in monocytes, and that at the level of

mRNA anti-apoptotic SPHK1 is rapidly up-regulated. In contradiction to other authors who described that SPHK2 is not detectable in monocytes or macrophages 14–16, we could demonstrate that monocytes indeed express SPHK2 although to a much lower degree than SPHK1 (Fig. 1). This discrepancy might be explained by the techniques used for detection

(conventional PCR or northern blot analysis instead of RQ-PCR as used in our approach). For its activation SphK has to be targeted to the plasma membrane 18, 19. In monocytes stimulation with CXCL4 results in a rapid and biphasic translocation of SphK1 into the membrane fractions (Fig. 2A), as well as increase in SphK1 enzymatic activity (Fig. 2B). The role of SphK in the activation of myeloid cells (neutrophils and macrophages) has been documented previously by several authors 15, 20–23. In these reports, the authors either described a rapid activation (within 15 s–2 min) 15, 20, 21, or a more delayed activation Selleckchem Acalabrutinib (after 15–60 min) of Carnitine palmitoyltransferase II SphK 20, 22, 23. Using stimuli which

are known to induce in myeloid cells rapid functions such as ROS formation (fMLP, PAF, or C5a), SphK was seen to become activated within seconds, while stimulation of the cells with TNF or LPS, leading to the induction of long lasting cellular responses like survival or cytokine release, lead to a delayed activation of SphK. To our knowledge, we here report for the first time that SphK can be activated in a biphasic manner in monocytes. This may explain the ability of CXCL4 to induce both, acute and delayed cellular functions in these cells. Using high concentrations of exogenous S1P (50 μM) as well as by the use of SKI or SphK1-specific siRNA we demonstrate here that SphK and its product S1P are involved in CXCL4-stimulated ROS formation, as well as in the rescue from apoptosis (Fig. 3 and 6). S1P is a unique signaling molecule in that it can act both as an extracellular ligand for G protein-coupled receptors and as an intracellular second messenger 11, 24–26. A few studies have suggested that suppression of apoptosis by S1P is mediated via its intracellular action, many others have argued in favor of the involvement of S1P membrane receptors, making this a controversial area (for review, see Hla et al. 27). In 1999 and 2003 Olivera et al.

SHI YIQIN, TSUBOI NAOTAKE, FURUHASHI KAZUHIRO, MARUYAMA SHOICHI, MATSUO SEIICHI Internal Medicine, Nephrology, Nagoya University Graduate School of Medicine Introduction: Mac-1 (CD11b/CD18), a leukocyte adhesion molecule, expressed on neutrophils, eosinophils and macrophages has been shown to mediate several adhesion-dependent processes. Recently, an association of genetic variations in Mac-1

with susceptibility to SLE has been reported in several studies. Methods: To determine the underlying mechanism of how Mac-1 participates in SLE, we introduced pristine (TMPD) to induce pulmonary hemorrhage and experimental lupus nephritis in Mac-1−/− mice on C57BL/6 background. Organ damage was histologically analyzed and flow cytometric analysis and ELISA were performed for the evaluation of leukocyte infiltration and cytokine concentration in inflamed sites including the peritoneal

cavity, lung and kidney. Results: Mac-1−/− AUY-922 purchase mice had reduced prevalence of pulmonary hemorrhage compared to wild-type (WT) mice within 1 month after TMPD injection, but after 4 months demonstrated severe proteinuria that was significantly higher than WT mice. In Mac-1−/− mice, lupus nephritis was evident with glomerular hypercellularity and leukocyte infiltration associated with glomerular IC deposition. The analysis of the peritoneal lavage on day 5 and 10 after pristine treatment revealed an Midostaurin datasheet increase in eosinophils and immune regulatory (M2) macrophages but lower numbers of neutrophils and classic (M1) macrophages in Mac-1−/− mice compared to WT. Higher expression of IL-4 and IL-13, both key mediators of macrophage polarization toward M2 macrophages, was observed in the peritoneal cavity of Mac-1−/− mice. Conclusion: Mac-1 promotes acute inflammatory immune responses that lead to pulmonary hemorrhage but downregulates chronic immune responses to protect mice from IC-mediated renal injury in a model of experimental lupus nephritis induced by TMPD. KUO LI-CHUEH1, HWANG JYH-CHANG2, CHENG BEN-CHUNG1, SU many YU-JEN1, CHEN JIN-BOR1 1Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang

Gung University College of Medicine, Kaohsiung; 2Division of Nephrology, Chi-Mei Medical Center, Tainan, Taiwan Introduction: Hyperphosphatemia and residual renal function (RRF) had been demonstrated to linkage with prognosis in continuous ambulatory peritoneal dialysis (CAPD) patients. Present study was conducted to investigate whether hyperphosphatemia is a risk factor to accelerate decline in renal function. Methods: A total of 181 incident CAPD patients were enrolled, mean age 45 ± 15 year-old, male 40%, diabetes 13%. We defined rapid residual renal function downhill (RRFD) rate with a slope of trend equation based on the first three data of renal weekly creatinine clearance rate measured after initiation CAPD therapy. The data of hemogram, biochemistry were collected for comparison.

Regardless of renal function, a positive effect of ASV treatment was observed. HAN IN MEE1,2, RYU HAN JAK1, HAN JAE HYUN1, OH HYUNG JUNG1, PARK JUNG TAK1, HAN SEUNG HYEOK1, YOO TAE-HYUN1, KANG SHIN-WOOK1,2 1Department of Internal Medicine, Yonsei University College of Medicine; 2Severance Biomedical Science Institute, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine Introduction: Diastolic

heart failure (HF), whose prevalence is steadily increasing, is associated with cardiovascular (CV) morbidity and mortality in not only the general population but also patients with end-stage renal disease (ESRD). However, the impact of diastolic dysfunction on the CV outcomes MK-1775 research buy has never been explored in incident dialysis patients with preserved systolic function. Methods: This prospective observational cohort study was undertaken to investigate the clinical consequence

of diastolic dysfunction and the predictive power of diastolic echocardiographic parameters for CV events in 194 incident ESRD patients, who started maintenance dialysis between July 2008 and August 2012 and had normal or near normal systolic function. Results: During a mean follow-up duration of 27.2 months, 57 patients (29.4%) experienced CV events. Compared

to CV Florfenicol EMD 1214063 datasheet event-free group, left ventricular (LV) mass index (LVMI), E/E′, LA volume index (LAVI), deceleration time (DT), and right ventricular systolic pressure (RVSP) were significantly higher, while LV ejection fraction (LVEF) and E′ were significantly lower in patients with CV events. In multivariate Cox proportional hazard analysis, LVEF, E/E′, LAVI, E/E′ > 15, and LAVI > 32 mL/m2 were demonstrated to be significant independent predictors of CV events even after adjusting for clinical and laboratory parameters. Among these, E/E′ > 15 and LAVI > 32 mL/m2 had significant power to predict CV events [E/E′ > 15: hazard ratio (HR) = 5.40, 95% confidence interval (CI) = 2.73–10.70, P < 0.001; LAVI > 32 mL/m2: HR = 5.56, 95% CI = 2.28–13.59, P < 0.001]. In addition, E/E′ and LAVI provided higher predictive values for CV events than other echocardiographic parameters. Kaplan-Meier analysis revealed that patients with both E/E′ > 15 and LAVI > 32 mL/m2 had the worst CV outcomes. Conclusion: Both elevated E/E′ and high LAVI were significant risk factors for CV events in incident dialysis patients with preserved LV systolic function.

However, the generation of effective antiviral or autoreactive adaptive learn more immune responses requires blocking of immunosuppression by Tregs. In this study, we show that TLR7 ligands reduce the number of Tregs generated

de novo from naïve murine T cells in vitro and in vivo. In the presence of TLR7-activated splenic DCs, Foxp3 was transiently induced in naïve T cells by TGF-β but was downregulated at later time points. Neutralization experiments revealed that loss of Foxp3 after initial induction was mostly dependent on IL-6 produced in the DC–T-cell cocultures containing TLR7 ligands. Thus, under the influence of TLR7 ligands fewer Tregs were generated and these expressed lower levels of Foxp3 correlating with a reduced capacity to suppress responder T-cell proliferation. Thus, we provide evidence that TLR7

ligands affect Treg-dependent immune regulation and may thereby contribute to the development of autoimmune diseases such as systemic lupus erythematosus. Viral RNA as well as self-RNA present in nuclear autoantigens of patients with autoimmune diseases such as systemic lupus erythematosus (SLE) activate Toll-like receptor (TLR) 7 1–6. Accordingly, TLR7 has been shown to play an important role in antiviral defense 7 as well as autoimmunity, as was shown in several mouse models of SLE 8–13. DCs and B cells which are directly activated by TLR7 ligands support the activation and expansion of effector T and B lymphocytes directed against viral antigens 7 or autoantigens

Rapamycin datasheet 10. In addition, TLR7 activation could be involved in breaking peripheral tolerance mediated by Tregs, which has to be overcome in order to generate protective antiviral immune responses 14 or pathogenic autoreactive immunity. In several murine models of SLE and in patients with active Olopatadine SLE, reduced frequencies and suppressive functions of Tregs have been observed 15–18, supporting the concept that defects in the Treg compartment are critical factors in the pathogenesis of this autoimmune disease. We propose that in addition to the direct stimulatory effects on APCs, TLR7 activation by exogenous and endogenous TLR7 ligands impairs Treg generation and function. However, the studies investigating the effect of TLR7 ligands on Treg suppressive function have yielded controversial results 19, 20 and the influence of TLR7 activation on the de novo generation of Tregs from naïve T cells has not been examined. We show that TGF-β induces Foxp3 expression in naïve T cells even in the presence of TLR7 ligand and DCs; however, Foxp3 expression is only transient and is downregulated at later time points. Loss of Foxp3 expression is dependent on soluble factors – mainly IL-6 – produced in DC–T-cell cocultures in response to TLR7 ligands. Upon exposure to TLR7 ligands, reduced numbers of Tregs are generated which additionally express lower levels of Foxp3 and have a reduced capacity to inhibit the proliferation of responder T cells.

9 ± 0.5 mm) at the 15-cm site and 0.8 to 2.0 mm (1.2 ± 0.4 mm) for the vein at the 10-cm site and 1.0 to 3.0 mm (1.9 ± 0.5 mm) at the 15-cm site. Under clinical

conditions, the two case flaps survived well without major complications. The clinical follow-up period Selleck AZD2014 was from 12 to 14 months (mean: 13 months). The advantage in using this recipient pedicle lies not only in its superficial aspect but also in the protection offered by the surrounding muscle. Thus the defect could be reconstructed efficiently without stress upon the surgeon; if the ALTP flap of the ipsilateral side was used, the defect could be reconstructed efficiently within the same surgical field. © 2009 Wiley-Liss, Inc. Microsurgery 2010. “
“Replantation of amputated body parts is a highly specialized, cost-intensive procedure and can offer significantly increased quality of life in

selected cases.[1] Continued technical HSP signaling pathway innovation and experience have been reflected in a number of successful personal operative series being reported in the literature.[2] In the absence of custom made devices for storage of the amputated part, prehospital preparation is often determined by the referring practitioner, prior to contact with the referring department. To optimize chances of successful replantation, appropriate preparation and transfer to the replantation center are critical. However, literature regarding perceptions about correct preoperative storage and transfer by referring practitioners is limited. Our intital study reported significant deviations from the advanced trauma life support (ATLS) guidelines in this regard, excluding suitable patients from replantation.[3, 4] In consideration of the increased penetrance of ATLS and equivalent courses in the medical community and the recent nationwide reconfigurations in health service delivery, we performed a 5-year follow-up survey (reaudit) to determine any changes in referring practitioner perceptions of this procedure. The survey was conducted on centers

referring to the Welsh Centre for Burns and Plastic Surgery (n = 16) between November 2012 and February 2013. To facilitate comparisons, the same semi-structured telephonic questionnaire and best practice guidelines (ATLS) as our earlier study[3] were adopted Beta adrenergic receptor kinase (Table 1). A total of 68 healthcare practitioners were invited, of whom 51 responded (78% respondent rate), from 90% of referring units. The respondents included the following grades: consultant (14%), specialist registrar (12%), and core trainee/senior house officer (50%); foundation year/house officer (4%); nurse practitioner (10%); and acute care GP (10%). Of the respondents, only 25% described the entire procedure correctly. Of the remainder, only 4% remarked they would seek advice on storage of the amputated part before preparing for transfer. Labeling of the amputation with any identification details was mentioned by only 10% of respondents.

Important issues covered in this multidisciplinary clinic include CKD complications and cardiovascular risk, informing patients and their families, consideration of living transplantation, exploration of psychosocial issues that may impinge on ESKD care, patient transport, choice and preservation of dialysis access sites and vaccination. Patients are referred early to surgeons to assess dialysis access. Clinical and even Doppler examination

is used to identify and mark for preservation of future sites of vascular access. The success of such pre-dialysis programs can be assessed by the percentage of patients that attend the program, that commence dialysis electively, that have Proteasome structure an arteriovenous (AV) fistula as their first haemodialysis access, that commence PD after a 4 week rest of the catheter and – most importantly

– long-term patient outcomes. Similar pre-dialysis educational programs now exist in most countries, and are adapted to suit local needs. For example, in Hong Kong where such programs are run in all dialysis units, there is a major focus on the advantage of PD, consistent with its policy of PD-first. In some Hong Kong centres professionally-produced videos, involving staff and established patients, are an important tool in pre-dialysis education. One of the main determinants of optimal initiation of dialysis is the time of referral of the patient to a nephrologist or renal unit. Australia BMN 673 concentration and New Zealand have comprehensive data on all dialysis and transplant patients, in the Australian and New Zealand Society Of Nephrology (ANZDATA) registry. According to ANZDATA,15 23–28% of patients annually during the 5 year period from 2003 were referred late (defined Tobramycin as referral within 3 months of commencing dialysis). There has been no improvement in the rates of

late referral and the rates do not differ across all age groups (excluding the very elderly). Amongst Aboriginal and Torres Strait Islanders and Pacific Islanders late referral in Australia is 33–37%. This is important because patient 1, 2 and 3 year survival is worse amongst those referred late. The Dialysis Outcomes and Practice Patterns Study (DOPPS) has collected relevant data.16 In countries surveyed (including several from Asia), between 70% and 90% of patients had a nephrology visit within a month of commencing haemodialysis. Survival of patients with a pre-dialysis visit was significantly better than for those who had no visit prior to dialysis, and survival correlated with the number of visits, being greatest in those with five or more in the year prior to commencement. Other guidelines have been developed in Australia to educate general practitioners about the appropriate time to refer a patient to a nephrologist.

In experiments 1 and 2, infants spontaneously and selectively informed Ibrutinib nmr the adult about the aversive material in the location the adult falsely believed to hold her toy. In contrast, in experiment 3, infants informed the ignorant adult about both locations equally. Results reveal that infants expected the adult to commit a specific action mistake when she held a false belief, but

not when she was ignorant. Further, infants were motivated to intervene proactively. Findings reveal a predictive action-based usage of “theory-of-mind” skills at 18 months of age. “
“This study investigates infants’ discrimination abilities for familiar and unfamiliar regional English accents. Using a variation of the head-turn preference procedure, 5-month-old infants demonstrated that they were

able to distinguish between their own South-West English accent and an unfamiliar Welsh English accent. However, this distinction was not seen when two unfamiliar accents (Welsh English and Scottish English) were presented to the infants, indicating they had not acquired the general ability to distinguish between regional Y-27632 in vitro varieties, but only the distinction between their home accent and unfamiliar regional variations. This ability was also confirmed with 7-month-olds, challenging recent claims that infants lose their sensitivity to dialects at around that age. Taken together, our results argue in favor of an early sensitivity to the intonation system of languages, and to the early learning of accent-specific intonation and potentially segmental patterns. Implications for the development of accent normalization abilities are discussed. “
“Behne, Carpenter, Call, and Tomasello

(2005) showed that 9- to 18-month-olds, but not 6-month-olds, Cyclic nucleotide phosphodiesterase differentiated between people who were unwilling and unable to share toys. As the outcome of the two tasks is the same (i.e., the toy is not shared), the infants must respond to the different goals of the actor. However, visual habituation paradigms have shown an earlier onset of goal awareness. The present study reconciles this disparity by replicating the findings of Behne et al. with both 6- and 9-month-olds, using similar tasks and additional response measures. “
“Infant phonetic perception reorganizes in accordance with the native language by 10 months of age. One mechanism that may underlie this perceptual change is distributional learning, a statistical analysis of the distributional frequency of speech sounds. Previous distributional learning studies have tested infants of 6–8 months, an age at which native phonetic categories have not yet developed. Here, three experiments test infants of 10 months to help illuminate perceptual ability following perceptual reorganization.

1B). As shown in the figure, we co-precipitated pro-IL-16 and MHC class II molecules and confirmed the association between pro-IL-16 and MHC class II molecules. More importantly, the level of pro-IL-16

was increased by LPS treatment of resting B cells for 15 min, and increased JQ1 nmr expression of pro-IL-16 protein was inhibited by anti-I-Ad MHC class II antibody treatment. This inhibitory effect was haplotype-specific and was not detected when we used a monoclonal antibody (10-3.6.2) specific to an unrelated haplotype (I-Ak) (data not shown). To characterize the form of IL-16 present in 38B9 resting B cells, we performed Western blot analysis using a commercial antibody specific to the C-terminal part of mouse IL-16, which can recognize both precursor and mature forms of IL-16 (Fig. 1C). Extracts prepared from 38B9 cells showed a single band at 80 kDa, representing pro-IL-16, but there was no band at 20 kDa (C-terminal mature form of IL-16) or at 60 kDa (remaining N-terminal part of pro-IL-16). In contrast, control EL4 cells, which are mouse CD8+ T cells known to express IL-16, showed only a single band at 20 kDa, indicating the presence of the mature form of IL-16. These results suggest that the precursor form of IL-16, rather than the mature form, is predominantly BIBW2992 mouse expressed in 38B9 resting B cells. We assumed that

cleaved mature IL-16 was rapidly secreted rather than stored in the cytoplasm of B cells because we detected the expression of caspase-3, which is involved in pro-IL-16 cleavage, in 38B9 resting B cell lysates through Western blot analysis (data not shown). Collectively, we confirmed that pro-IL-16 is associated with MHC class II molecules

and that it is involved in MHC class II-mediated inhibitory signalling in resting B cells. It is known that cleavage of the C-terminal portion of pro-IL-16 Selleckchem Gefitinib by caspase-3 yields the mature form of IL-16 [23, 24]. Mature IL-16 is secreted, and the N-terminal fragment of pro-IL-16 or full-length pro-IL-16 translocates into the nucleus where pro-IL-16 or full-length pro-IL-16 induces G0/G1 cell-cycle arrest [18, 19]. Cytoplasmic pro-IL-16 can therefore be considered as a precursor of secreted IL-16, while pro-IL-16 in the nuclear compartment acts as cell-cycle regulator. Those previous reports and our observation of an association between pro-IL-16 and MHC class II-mediated negative signalling in resting B cells prompted us to determine whether pro-IL-16 has an inhibitory effect on B cell proliferation, as shown in T cells. Consequently, we initially examined the intracellular location of pro-IL-16 in resting B cells (Fig. 2). Western blot analysis of nuclear and cytoplasmic fractions prepared from resting B cells demonstrated that pro-IL-16 was present in both the cytoplasmic and nuclear compartments (Fig. 2A).

The volume of CSF sample is very important to achieve good PCR results, and the difficulty in collecting an adequate volume of CSF sample makes diagnosis of TB meningitis a daunting challenge in the paediatric

subjects (Kulkarni et al., 2005; Galimi, 2011). Kulkarni et al. (2005) selleck chemicals documented a sensitive PCR test targeting 38 kDa protein gene using small volume of whole CSF for the diagnosis of TB meningitis in children. Their test could detect 10 femtogram (fg) of DNA and that is equivalent to 2–3 tubercle bacilli. Rafi et al. (2007) used ‘whole’ CSF instead of using the ‘sediment’ for their PCR assay, thus proving that the M. tuberculosis DNA could be present as free DNA molecules in CSF samples. The utility of CSF ‘filtrate’ for detecting M. tuberculosis

DNA by conventional PCR targeting IS6110 and devR genes as well as by real-time PCR targeting devR has been demonstrated by Haldar et al. (2009). Interestingly, it was found that CSF ‘filtrate’ exhibited better sensitivity and specificity than the ‘sediment’ by both assays. Takahashi & Nakayama (2006) designed a quantitative nested real-time PCR (QNRT-PCR) assay targeting MPB-64 protein gene to detect M. tuberculosis DNA in CSF samples, and their method was extremely useful for assessing the clinical course of patients with TB meningitis on ATT (Takahashi et al., 2008). To detect M. tuberculosis DNA in CSF samples with a wide detection range (1–105 Fluorouracil cost copy

numbers) during the clinical course of disease, a novel wide-range quantitative nested real-time PCR (WR-QNRT-PCR) assay targeting MPB-64 protein gene has been meticulously developed (Takahashi et al., 2008). Osteoarticular TB accounts for about 1–3% of all TB cases and is the major cause of osteomyelitis (Yun et al., 2005; Sun et al., 2011). Any bone, joint or bursa can be infected but the spine, hip and knee are the preferred sites of infection, representing 70–80% of the infections (Pandey et al., 2009). TB of the spine which if not diagnosed properly and treated adequately may develop kyphosis and/or neurological complication (paraplegia; Jain et al., 2008). The accurate diagnosis of osteoarticular ALOX15 TB poses difficulty owing to deep inaccessible lesions and initiation of empirical ATT in majority of the cases (Vardhan & Yanamandra, 2011). Mostly, the diagnosis of osteoarticular TB is based on clinical suspicion and imaging findings, particularly in the endemic regions (Agashe et al., 2009; Sun et al., 2011). PCR tests based on IS6110, 16S rRNA gene and 65 kDa protein gene targets have been widely employed to confirm osteoarticular TB with varying sensitivities (Verettas et al., 2003; Negi et al., 2005b; Jain et al., 2008; Agashe et al., 2009; Sun et al., 2011; Table 1).

When activated, they can perform many diverse functions which may be either beneficial or harmful depending on the situation. Although microglial activation may be accompanied by changes in morphology, morphological changes cannot accurately predict the function being undertaken by a microglial

cell. Studies of peripheral macrophages and in vitro and animal studies of microglia have resulted in the definition of specific activation states: M1 Acalabrutinib in vivo (classical activation) and M2 (sometimes subdivided into alternative activation and acquired deactivation). Some authors have suggested that these might be an overlapping continuum of functions rather than discrete categories. In this review, we consider translational GDC-0973 purchase aspects of our knowledge of microglia: specifically, we discuss the question as to what extent different activation states of microglia exist in the human central nervous system, which tools can be used to identify them and emerging evidence for such changes in ageing and in Alzheimer’s disease. “
“M. Höistad, H. Heinsen, B. Wicinski, C. Schmitz and

P. R. Hof (2013) Neuropathology and Applied Neurobiology39, 348–361 Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities Aims: The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data, however, are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. Methods: We investigated Amino acid the dorsal anterior cingulate cortex (dACC) in 13 men with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neurone and glial numbers, and glia/neurone index (GNI) in both layers II–III and V–VI. Results: We

observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neurone numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V–VI than in layers II–III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development. Conclusions: Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology.