Sclerotic Patients Research Articles

Real-Time Reflectance Confocal Microscopy of Cutaneous Graft-versus-Host Disease Correlates with Histopathology

Reflectance confocal microscopy (RCM) allows noninvasive, real-time evaluation of the skin at a resolution akin to histopathology (HP), but its application in cutaneous graft-versus-host disease (GVHD) has not been extensively assessed. We describe RCM features of cutaneous GVHD including acute (aGVHD), late acute, chronic (cGVHD; sclerotic and nonsclerotic subtypes), and inactive GVHD and correlate RCM with same-site HP for a subset of patients. Thirty-two adult and pediatric allogeneic hematopoietic cell transplantation (allo-HCT) recipients with cutaneous GVHD received RCM imaging of ≥1 lesions (n = 44), 13 of which necessitated skin biopsy. RCM images were deidentified and assessed by 2 RCM experts blinded to clinical and HP findings to reach a consensus on the features and patterns of the inflammatory dermatoses. Major RCM features (present in ≥65% of lesional sites) and patterns were reported. To determine the correlation between RCM and HP, detection of cellular features and patterns of inflammatory dermatoses were compared using percent agreement and prevalence-adjusted, bias-adjusted kappa estimates. Seven patients with early or late aGVHD (7 lesions) had irregular honeycombing, spongiosis, dermoepidermal junction (DEJ) and dermal inflammation, and melanophages; those with early aGVHD also had hyperkeratosis, dilated vessels, and coarse connective tissue. Both groups had an interface dermatitis pattern. Eighteen patients with nonsclerotic cGVHD (24 lesions) had irregular honeycombing, spongiosis, DEJ and dermal inflammation, dilated vessels, coarse connective tissue, and interface and spongiotic dermatitis patterns. Three sclerotic patients with cGVHD (7 lesions) had irregular honeycombing, DEJ and dermal inflammation with an interface dermatitis pattern. Four patients with inactive GVHD (6 lesions) showed minimal inflammation. RCM and HP had similar detection rates for 6 of 13 features and overall patterns important for diagnosis in 2 patients with late aGVHD (2 lesions; 15%) and 10 with nonsclerotic cGVHD (11 lesions; 85%) necessitating skin biopsy. RCM can detect features commonly reported in cutaneous GVHD and is comparable to HP. Additional characterization of cutaneous GVHD by RCM may enable future use in diagnosing, monitoring, or predicting disease in real time.

The Effect of Telephone Consultation and Follow-up on Pain Reduction in Multiple Sclerotic Patients: a Randomized Clinical Trial

The Effect of Telephone Consultation and Follow-up on Pain Reduction in Multiple Sclerotic Patients: a Randomized Clinical Trial

Prognostic value of markers in associative genetics

The article presents an algorithm for genetic-statistical analysis of a rare chronic disease with a hereditary predisposition. The results of genotyping obtained by one of the authors by the method of associative genetics were used. Multiple sclerosis is a disease with a hereditary predisposition. At present, the association of multiple sclerosis and a large number of genes has already been discovered, but the genetic control is not completely clear. An important step in combating the disease can be preventive measures among groups of people with hereditary predisposition. In this article, using the example of the C677T genetic polymorphism of the MTHFR gene, we show how to determine the effectiveness of identifying individuals at increased risk. Multiple sclerotic patients (n=180) and healthy (n=231) residents of southern Iran were examined by one of the authors previously. Based on these data, population-genetic indicators and statistical characteristics of the test were calculated. The distribution of genotypes in healthy people: CC – 65 %, CT – 29 %, TT – 6 %, in patients with multiple sclerosis CC – 35 %, CT – 46 %, TT – 19 %. The major allele in the population of southern Iran is C (pC = 0.797; qT = 0.203). The frequency of the minor T allele is doubled in the group of patients compared with healthy ones (qT = 0.419). The T allele is considered to be provocative; the allele C is protective. The CC genotype reduces the likelihood of multiple sclerosis by almost half compared with the empirical risk. In heterozygotes of CT, the risk is increased by more than one and half times, in homozygotes of TT more than three times. 95 % CI confidence intervals for the OR odds ratio indicator are: CC (0.19–0.44), CT (1.36–3.10), TT (1.99–7.61), CT + TT (2.29–5.21). The statistical characteristics of the test indicate its low power when used in screening programs. The sensitivity when testing carriers of the T allele (CT + TT genotypes) is 65 %. The very low prognostic value of a positive test makes it inappropriate to use for screening, but this test may be useful in individual genetic counselling for patients with multiple sclerosis, as well as their relatives. The analysis scheme can be used in other studies of traits with a genetic component.

Diagnostic Potential of Five Different Biomechanical Parameters to Detect Sclerotic Cutaneous Graft-Versus-Host Disease

INTRODUCTION Skin sclerosis is a significant cause of morbidity in chronic graft-versus-host disease (cGVHD). The current accepted standard for response assessment is the NIH skin score (0-3 scale) which is based on extent of skin involvement and clinician assessment of degree of sclerosis (superficial vs. deep; movable vs. hidebound). There is an urgent need to develop objective measures of skin sclerosis to enable accurate monitoring of disease. The Myoton device is able in a single rapid measurement to simultaneously measure five biomechanical parameters in soft tissue: dynamic stiffness, mechanical stress relaxation time, tissue oscillation frequency, logarithmic decrement, and creep. Sclerotic cGVHD patients have been shown to have increased skin stiffness, relative to normal individuals, in a small study that lacked post-transplant controls.1 In a cross-sectional study including both cGVHD patients and post-transplant controls, we report the ability to differentiate sclerotic from unaffected post-transplant skin for all five available biomechanical parameters. METHOD Sclerotic cGVHD patients (NIH skin score 2-3) (n=13), post-BMT controls (n=10), and healthy controls (n=14) were measured with the Myoton device modified for skin biomechanical assessment. Each subject was measured on 10 bilateral sites (shin, dorsal forearm, volar forearm, upper arm, shoulder, chest, abdomen, upper back, lower back, calf) for a total of 20 measurement sites. For each of the five biomechanical parameters, the overall value per subject was calculated as the average over all 20 measurement sites. We performed receiver operating characteristic (ROC) and area under the curve (AUC) analyses to compare the diagnostic sensitivity of these parameters. RESULTS Sclerotic cGVHD patients showed significant increases (p<0.05) in stiffness and frequency and decreases (p<0.05) in relaxation time compared to controls. The ROC and AUC analyses revealed that the overall frequency (sensitivity: 91%; specificity: 93%; AUC: 0.92), stiffness (sensitivity: 91%; specificity: 93%; AUC: 0.92), and relaxation time (sensitivity: 100%; specificity: 82%; AUC: 0.85) allow for high accuracy in the differentiation of sclerotic patients from post-BMT controls. Multivariate analysis suggested that stiffness, frequency, and relaxation time provide more value in combination than any parameters alone in the differentiation of sclerotic patients and post-BMT controls. By contrast, decrement and creep likely do not add significant value beyond the other three parameters. The Pearson correlation for each pair of the 3 key parameters (frequency, stiffness, and relaxation time) in post-BMT patients was lowest (R2 = 0.651) for stiffness versus relaxation time, suggesting that this combination provides the highest diagnostic yield. Further, within cGVHD patients, all parameters except decrement were able in univariate analysis to distinguish between a site of affected and unaffected skin on the shin and dorsal forearm (p<0.05). CONCLUSIONS Frequency, stiffness and relaxation time of skin demonstrated high accuracy in the differentiation of sclerotic GVHD patients from post-BMT controls. Larger study is needed to develop a multivariate predictive model based on the combination of stiffness and relaxation time. Prospective longitudinal study is also warranted to assess the ability of the Myoton to monitor progression and treatment response in cGVHD patients as compared to the NIH skin score. ACKNOWLEDGEMENTS This work is partially supported by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service. REFERENCES: Chen F, Dellalana LE, Gandelman JS, et al. Non-invasive measurement of sclerosis in cutaneous cGVHD patients with the handheld device Myoton: a cross-sectional study. Bone marrow transplantation. 2019; 54(4):616 Disclosures Jagasia: Janssen: Research Funding; Kadmon: Consultancy; Incyte: Consultancy. Tkaczyk:Incyte: Consultancy.

Interobserver Reproducibility of the Myoton and Durometer Devices to Measure Skin Stiffness and Hardness in Chronic Cutaneous Graft-Versus-Host Disease Patients

INTRODUCTION There is an unmet need for quantitatively measuring skin sclerosis to track the progression of sclerosis in chronic cutaneous graft-versus-host disease (cGVHD). Two candidate technologies are the Myoton, a noninvasive device to assess soft tissue biomechanics, and the durometer, an industrial device measuring surface hardness. Both devices have been shown to have high reproducibility in the context of healthy skin,1 but the reproducibility of these devices in sclerotic cGVHD is critical missing information in designing longitudinal studies measuring sclerosis in cGVHD patients. We directly compared the interobserver reproducibility of these devices to measure skin stiffness and hardness in sclerotic cGVHD patients. METHODS The skin stiffness and hardness were measured in seven patients with sclerotic cutaneous cGVHD by three blinded observers with Myoton and durometer on 20 body sites. To estimate the clinical repeatability to differentiate amongst patients, the intraclass correlation coefficients (ICC) was calculated from a single measure, absolute agreement, linear mixed model on log scale. Mean coefficient of variation across the three observers and minimal detectable change (MDC95) were calculated to estimate device ability to track change within patients. RESULTS Patient overall hardness/stiffness interobserver ICCs were 0.92 [0.82 - 1.00] for Myoton and 0.82 [95% confidence interval 0.61 - 1.00] for durometry. The Myoton had superior reproducibility to durometry in calves and upper arms, but was inferior in the dorsal forearms. Coefficients of variation across observers were under 10% and the overall normalized MDC95 was 22 to 23% for both devices. CONCLUSIONS Both the Myoton and durometer devices exhibit high reproducibility to measure skin stiffness/hardness in sclerotic cutaneous cGVHD, and the Myoton trended towards higher reproducibility when compared to the durometer. The interobserver ICCs of both devices to measure sclerotic cGVHD patients is significantly higher than the typical range of ICCs (0.21-0.60)2 associated with clinical exam-based measurement of moveable sclerosis. Prospective longitudinal study following patients over time is warranted to validate the use of skin stiffness measurements to monitor disease progression and treatment response in cGVHD patients. ACKNOWLEDGEMENTS This work is partially supported by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service. REFERENCES Dellalana LE, Chen F, Vain A, Gandelman JS, Poldemaa M, Chen H, Tkaczyk ER. Reproducibility of the durometer and myoton devices for skin stiffness measurement in healthy subjects. Skin Research and Technology. 2019; 25(3): 289-293Mitchell SA, Jacobsohn D, Thormann Powers KE, et al. A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change. Biol Blood Marrow Transplant. 2011;17(11):1619-1629. Disclosures Jagasia: Kadmon: Consultancy; Janssen: Research Funding; Incyte: Consultancy. Tkaczyk:Incyte: Consultancy.

Interleukin-32 plays an essential role in human calcified aortic valve cells.

Interleukin-32 (IL-32) is an inflammatory cytokine produced mainly by T, natural killer, and epithelial cells. Previous studies on IL-32 have primarily investigated its proinflammatory properties. The IL-32 also has been described as an activator of the p38 mitogen-activated protein kinase (MAPK) and NF-κB, and induces several cytokines. In this study, we hypothesized that the inflammatory regulators NF-κB, MAP kinase, STAT1, and STAT3 are associated with the expression of the IL-32 protein in human calcified aortic valve cells. This study comprised aortic valve sclerotic patients and control group patients without calcified aortic valve. Increased IL-32 expression in calcified aortic valvular tissue was shown by immunohistochemical staining and western blotting. There was an increase in NF-κB p65 level, p-ERK, p-JNK, and p-p38 MAPK activation underlying IL-32 expression in the study. The level of p-STAT3 but not p-STAT1 was found to be increased in calcified aortic valve tissue. In cultured primary human aortic valve interstitial cells, inhibition of NF-κB or MAPK kinase pathways results in a decrease of IL-32 expression. Treatment of recombinant IL-32 induced the levels of TNF-α, IL-6, IL-1β, and IL-8. Our findings demonstrate that IL-32 may be an important pro-inflammatory molecule involved in calcific aortic valve disease.

Long-term renal outcome in pediatric glomerulonephritis associated with crescent formation.

Information on long-term renal outcome of pediatric glomerulonephritis associated with crescent formation is limited. A single center retrospective study was conducted to assess long-term renal survival and to determine whether the 2010 classification for antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis can predict renal outcome in pediatric glomerulonephritis associated with crescent formation. Biopsy and clinical data of children, aged≤18years with≥10 glomeruli and≥10% crescentic glomeruli during January 1998 to December 2015, were reviewed. Biopsies were classified according to the 2010 classification into focal, crescentic, mixed, and sclerotic classes. The clinical endpoint was end-stage renal disease (ESRD). Of 72 children, 14 patients (19.4%) had positive ANCA. The biopsy indication was rapidly progressive glomerulonephritis in 38 patients (52.8%) and 22 patients (30.6%) required dialysis at onset. Lupus nephritis was the most common diagnosis (43.1%), followed by IgA nephropathy/Henoch-Schoenlein purpura (HSP) (22.2%). ESRD occurred in 18 patients (25%) and the risk of ESRD differed among the histological classifications (p<0.001). Dialysis at onset and sclerotic class was independent predictors of ESRD in an adjusted model. The risk of ESRD was four-fold higher in patients requiring dialysis at onset and 7.7-fold higher in sclerotic patients than in crescentic patients. The probability of ESRD was substantial in pediatric glomerulonephritis associated with crescent formation. The 2010 classification is useful for establishing long-term renal prognosis. Future research is required to validate whether histological classification could be a determinant in therapeutic guideline modification, since long-term renal prognosis is different in each class.

Age Distribution of Aortic Sclerosis among Bangladeshi Population

Aortic sclerosis (ASc) is defined as thickening or calcification of the aortic valve without significant obstruction of blood flow. Aortic sclerosis is diagnosed when in echocardiography, thickening and calcification of one or more cusps of a tricuspid aortic valve is manifested, whereas in aortic stenosis, cusp separation is restricted and the velocity through the aortic valve is &gt; 2.5 m/s. Its prevalence increases with age. Aortic valve stenosis is associated with systemic endothelial dysfunction, and it carries a 50% increase in risk of cardiac death or myocardial infarction. As aortic sclerosis has proved to be more and more relevant in recent days, it has been important to identify epidemiological data and demographic information of aortic sclerosis in Bangladeshi population. This study tried to determine age distribution of aortic sclerosis in Bangladehsi population. Median age of aortic sclerosis patients was 65 years (mean 67 ± 12 years), most of the patients (17.2%) were in 56-60 years of age group. The same statement holds correct for females, where highest number of patients (7.7% of total patients) were in the same age group. For the males, the highest number of patients (11% of total patients) were in 61-65 years of age group. The minimum age was 45 years for both males and females. Although the minimum age is same for both sex, females are affected a bit earlier than males, and statistically significant difference was found between mean ages of two sexes. Most of the aortic sclerotic patients are below the usually used age cut off of 65 years. There is significant difference between mean age of presentation of aortic sclerosis between males and females. Further study should be undertaken to understand these effects more clearly.Bangladesh Heart Journal 2017; 32(1) : 50-54

Synaptic Reorganization of the Perisomatic Inhibitory Network in Hippocampi of Temporal Lobe Epileptic Patients

GABAergic inhibition and particularly perisomatic inhibition play a crucial role in controlling the firing properties of large principal cell populations. Furthermore, GABAergic network is a key element in the therapy attempting to reduce epileptic activity. Here, we present a review showing the synaptic changes of perisomatic inhibitory neuronal subtypes in the hippocampus of temporal lobe epileptic patients, including parvalbumin- (PV-) containing and cannabinoid Type 1 (CB1) receptor-expressing (and mainly cholecystokinin-positive) perisomatic inhibitory cells, known to control hippocampal synchronies. We have examined the synaptic input of principal cells in the dentate gyrus and Cornu Ammonis region in human control and epileptic hippocampi. Perisomatic inhibitory terminals establishing symmetric synapses were found to be sprouted in the dentate gyrus. Preservation of perisomatic input was found in the Cornu Ammonis 1 and Cornu Ammonis 2 regions, as long as pyramidal cells are present. Higher density of CB1-immunostained terminals was found in the epileptic hippocampus of sclerotic patients, especially in the dentate gyrus. We concluded that both types of (PV- and GABAergic CB1-containing) perisomatic inhibitory cells are mainly preserved or showed sprouting in epileptic samples. The enhanced perisomatic inhibitory signaling may increase principal cell synchronization and contribute to generation of epileptic seizures and interictal spikes.

Types of tremor in patients with cerebrovascular diseases and cardiovascular events

Introduction: Tremor can occur as a part of the clinical picture of cerebrovascular diseases. Many patients with cerebral stroke have cardiovascu- lar diseases as a comorbidity or complication of stroke; sometimes cardiovascular events can lead to embolic stroke. Aim: To present types of tremor in patients with cerebrovascular diseases and cardiovascular events and diabetes mellitus type 2, clinical characteristics of tremor and investigations used. Material and methods: In our study we included 36 patients, 24 men and 12 women, that were exami- ned and followed for 3 years, from 2012-2015. All pa- tients were subjected to the following investigations: neurological examination, laboratory analysis, compu- terized tomography of brain, magnetic resonance ima- ging and electroencephalography. In cardiovascular patients we also performed Doppler sonography of ca- rotid arteries, electrocardiography, cardiac ultrasound. The patients were examined and treated by cardiolo- gists. Results: Of all patients 22% had cerebral infarc- tion, 41% atherosclerosis, 36% multiple lacunar in- farctions and 28% diabetes mellitus type 2. Three pati- ents with cerebral infarction had chorea, hemiballi- smus, dystonia and dystonic tremor, three had postural tremor and two cerebellar intention tremor. Athero- sclerotic patients had atherosclerotic action tremor, while diabetic patients predominantly had with ac- tion-type tremor. Electroencephalography showed irri- tative basic brain activity with slow waves, while caro- tid arteries stenosis was diagnosed by Doppler sono- graphy. Computerized tomography of the brain and magnetic resonance imaging revealed cerebrovascular diseases in certain areas. Patients with cardiomyo- pathy, rhythm disorders, high blood pressure, hyperli- pidemia was investigated and medically treated by a cardiologist. Conclusion: In cerebrovascular diseases different types of tremor can occur as a result of damage of the extrapyramidal system.

腎代替療法へ移行した結節性硬化症の5 例

腎代替療法へ移行した結節性硬化症の5 例

Upregulation of Interferon-Inducible and Damage Response Receptors in Chronic Graft-Versus-Host Disease

Chronic Graft Versus Host Disease (CGVHD) remains the main source of non-relapse mortality and morbidity among recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although our lab and others have identified infiltrates of Th1/Tc1 and Th17 effectors in skin and oral mucosa, CGVHD targets multiple organs and no common factor or pathway has been demonstrated to reflect the broad range of CGVHD inflammatory and fibrotic manifestations. To identify the systemic cytokine pathways supporting the development and persistence of CGVHD, we chose to profile gene expression in circulating monocytes; monocytes up-regulate distinct patterns of gene expression in response to different cytokines, acting as in situ reporters.The NIH Natural History Study of CGVHD (NCT00092235) has primarily enrolled moderate to severely affected patients. Microarray analysis was performed on sorted monocytes from 10 normal controls (ND) and 26 patients selected from this cohort based on severe cutaneous involvement. Two interrelated pathways, each containing multiple genes, were consistently up-regulated across a cutaneous CGHVD spectrum ranging from lichenoid infiltrates to extensive sclerosis: (1) Interferon (IFN)-inducible genes including those involved in signaling, lymphocyte homeostasis and trafficking, apoptosis and antigen uptake and presentation (STAT1, CXCL10, TNFSF13B, TNFSF10, TAP1), and (2) innate immune receptors for pathogens and cellular damage that can trigger IFN production and inflammasome assembly (TLR2, TLR4, TLR7, AIM2, DDX58, CLEC4E). Using multiplex RNA gene expression assays (Nanostring) to verify these pathways, we found significant up-regulation of IFN-inducible and damage-response genes in 69 CGVHD patients with a broad range of organ involvement, as compared with 14 allo-HSCT patients never developing CGVHD, or with 19 normal controls (Figure 1A, B). These pathways were further substantiated in plasma ELISA assays showing elevated levels of IFN-induced chemokines (CXCL9, CXCL10) in both lichenoid and severe sclerotic patients. Immunohistochemistry substantiated expression of Type I IFN-induced factors (MxA) in inflammatory infiltrates in CGVHD-targeted organs: lichenoid and sclerotic skin, oral mucosa and salivary gland. Consistent with induction of Type I IFN by activation of TLR and RIG-I receptors, levels of expression of DDX58 and TLR7 correlated with up-regulation of Type I IFN inducible genes (OAS1, IFIT1, XAF1). Finally, multiplex RNA assessments on monocytes collected from 18 patients over serial time courses following NCI allo-HSCT protocols (NCT00520130 and NCT00074490) substantiated a pattern of parallel up-regulation of multiple IFN-inducible and damage responsive genes at CGVHD onset, and of decline upon therapy and resolution (Figure 1C). A key point is that comparable up-regulation of these pathways was found in patients with extensive lichenoid or sclerotic CGVHD, both in the established CGVHD patients in the initial microarray and in the serial time courses of CGVHD development. These results support a model that IFN and inflammasome activation induced by the innate immune systemÕs response to damage initiates an inflammatory process in CGVHD; IFN then can induce damage receptors, chemokines, cytokines and enhanced antigen presentation that sustain CGVHD. These interlocking analyses of gene expression patterns, plasma analytes and tissue are the first to support a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Effect of Vitamin A Supplementation on Retinoic Acid-Related Orphan Receptor γt (RORγt) and Interleukin-17 (IL-17) Gene Expression in Avonex-Treated Multiple Sclerotic Patients

The aim of this study was to investigate the role of vitamin A on RORγt and IL-17 gene expression in multiple sclerotic patients. Patients in the vitamin A group received 25,000 IU retinyl palmitate per day, while patients in the placebo group took one capsule of placebo per day for 6 months. Gene expression was measured by real-time PCR at the first and end of the study. The results of this study show that vitamin A downregulates IL-17 and RORγt gene expression. No changes in gene expression occurred in the placebo group.

In Vitro Effect of Human Serum and Fetal Calf Serum on CD4+ T Cells Proliferation in Response to Myelin Oligodendrocyte Glycoprotein (MOG) in Correlation with RBP/TTR Ratio in Multiple Sclerotic Patients

Myelin oligodendrocyte glycoprotein (MOG) is one of the autoantigens used in evaluation of the CD4(+) T cells proliferation response in multiple sclerotic patients. In cell culture, human serum (HS) is one of the promising substitutions for fetal calf serum (FCS) that can induce different autoreactivity of T cells and fluctuation of autoantibody production from B cells. Because of immunomodulatory function of vitamin A, we examined the effect of HS and FCS on CD4(+) T cells proliferation in response to MOG in correlation with serum retinol-binding protein (RBP)/transthyretin (TTR) ratio, as an indirect way to assess vitamin A status in multiple sclerotic patients. Patients' peripheral blood mononuclear cells were isolated and cultured in the presence of MOG as well as FCS and HS both separately and together. Cell proliferation was evaluated using BrdU kit. Serum RBP and TTR levels were measured by ELISA kit. FCS and HS increase CD4(+) T cell proliferation. RBP/TTR ratio has significant negative correlation with cell proliferation in the presence of MOG, HS, and FCS. HS with FCS provides an appropriate medium for autoreactivity and proliferation of CD4(+) T cells. Vitamin A has a crucial role in regulation of this pathway.

The Impact of Glucocorticoids for Cirrhosis Patients Performed Major Liver Resection: A Retrospective Control Study

Research on the influence of pre-operation usage of steroids for liver cirrhosis patients performed major liver resection (=3 segments). In total, 741 cirrhosis patients who underwent major hepatectomy (>3 segments) in our medical center were selected for the study. One hundred and five out of 741 patients used 500 mg methylprednisolone between half an hour and one hour before operation and were enrolled in the steroids group. The other 636 patients without steroid injection were assigned in the control group. Our analysis compared the data of bilirubin, ALT, AST, postoperative PT, complications, mortality, IL-6, average length of hospitalization and the like. Blood sample test showed level of bilirubin and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and prothrombin time (PT), IL-6 were significantly lower in the steroids group than the control group in the postoperative days. There were no differences of mortality, morbidity and length of stay between the two groups. Methylprednisolone used in preoperative period could degrade the bilirubin and IL-6 level safely and effectively after operation but does not reduce the mortality and the average hospital stay for liver sclerotic patients with normal liver function with slight side effects; it may have positive clinical effects for marginal liver patients.

Inflammatory Profile, Age of Onset, and the MTHFR Polymorphism in Patients with Multiple Sclerosis

Both genetic and inflammatory factors are suspected in the etiology of multiple sclerosis (MS). Of genetic factors, the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been associated with increased levels of plasma homocysteine, a neuronal excitotoxic amino acid. Sclerotic patients also have elevated levels of plasma and CSF homocysteine. In this study, the association between C677T polymorphism and MS was tested by recruiting 230 healthy and 194 multiple sclerotic age- and gender-matched patients. The MTHFR C677T polymorphism and the serum levels of inflammatory mediators IL-1β, TNFα, and CRP were measured. TNFα, CRP, and IL-1β levels were significantly higher in sclerotic patients. T allele was 1.7 times more present in this group. In patient's group, the levels of all inflammatory mediators were higher in T/T compared to two other genotypes. Evaluation of the age of onset of disease revealed that subjects with T allele developed the MS disease, almost 4years sooner than other genotype. We concluded that having T allele of C677T in MS might be accompanied with higher levels of serum inflammatory mediators and a vulnerability to earlier age of onset of disease. Further studies are needed to elucidate the underlying mechanisms.

Clinical Investigation of a High Level of Arterial Stiffness Index (ASI) in Elderly Sclerotic Patients

Clinical Investigation of a High Level of Arterial Stiffness Index (ASI) in Elderly Sclerotic Patients

Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus

Hippocampal sclerosis is the most frequent pathology encountered in mesial temporal structures resected from patients with intractable temporal lobe epilepsy and it mainly involves hippocampal neuronal loss and gliosis. These alterations are accompanied by changes in the expression of a variety of molecules in the surviving neurons, as well as axonal reorganization in both excitatory and inhibitory circuits. The alteration of a subpopulation of GABAergic interneurons that expresses the calcium binding protein parvalbumin (PV) is thought to be a key factor in the epileptogenic process. We investigated the distribution and density of parvalbumin-immunoreactive (PV-ir) neurons in surgically resected hippocampal tissue from epileptic patients with and without sclerosis. Using quantitative stereological methods, we show for the first time that there is no correlation between total neuronal loss and PV-ir neuronal loss in any of the hippocampal fields. We also observed higher values of the total neuronal density in the sclerotic subiculum, which is accompanied by a lower density of PV-ir when compared with non-sclerotic epileptic and autopsy hippocampi. These findings suggest that, the apparently normal subiculum from sclerotic patients also shows unexpected changes in the density and proportion of PV-ir neurons.

Specific characteristics of prefrontal cortex functions in multiple sclerotic patients

Cognitive dysfunction is common in MS and can cause poor quality of life. Physical examination and EDSS can not reliably predict cognitive impairments. Frontal cortex atrophy predicts cognitive impairment in MS. Dorsolateral prefrontal cortex (DLPFC) processes logical thinking, working memory, attention and executive functions and ventro-medial pre-frontal cortex (VMPFC) processes emotional evaluations, social cognition and response inhibition. We assessed DLPFC and VMPFC dysfunctions in MS patients with neuropsychological assessment tasks.Material and methods:40 patients (27 female) and 40 healthy, age, sex and IQ matched controls were included. The MS clinical manifestations were evaluated according to EDSS by a qualified neurologist. Beck depression inventory II was used for depression. We used Wisconsin Card Sorting Task (WCST) and Time Perception Task (TPT) for DLPFC and Iowa Gambling Task (IGT), Delayed Discounting Task (DDT) and Balloon Analogue Risk Task (BART) for assessment of VMPFC functions.Results:MS patients had more perseveration errors (15.49 VS 8.77) (P=0.007) in WCST. In TPT patients tend to over-estimate and over-reproduce time intervals. MS patients have more delay in selection of risky choices cards on IGT, (3.39 seconds vs 2.48 seconds). In DDT patients have lower discounting amounts over delays. In Bart patients have lower levels of risky behavior tendency.Conclusion:Decision making is being processed logically in dorsolateral and emotionally in ventromedial parts of prefrontal cortex. According to our study, MS patients follow a conservative strategy in their decision makings both logically and emotionally. This may be explained by “multiple disconnection syndrome” seen in MS particularly in frontal lobes or because of the specific effects of disease-stigma burden on patients' behavior.slowing of information processing speed as a primary causative factor must be mentioned.

Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains.

Delivery of iron to the brain traditionally has been considered the responsibility of transferrin. However, transferrin receptors in brain are located primarily within gray matter areas rather than in the iron rich white matter tracts. In this report we present the first demonstration of ferritin binding sites in human brain and provide evidence that these binding sites are primarily in white matter tracts. This distribution of ferritin binding is opposite of that seen for the distribution of the transferrin receptor in normal adult human brain. Ferritin binds to human brain tissue in a competitive and saturable manner with a dissociation constant of 0.35 nM and a binding site density of 116.7 fmol/mg protein. In brain tissue from multiple sclerotic (MS) patients the normal pattern of transferrin and ferritin binding distributions is disrupted. Ferritin binding is absent in the lesion itself and in the immediate periplaque region within the white matter but returns to normal as the distance from the lesion becomes greater. In direct contrast to ferritin binding, transferrin binding in the MS tissue is present in the white matter tracts, but only in the periplaque region. The periplaque region also contains transferrin receptor positive cells (as determined by immunocytochemistry) morphologically consistent with oligodendrocytes. Gray matter binding of transferrin in MS patients appears normal. These data provide the initial evidence of ferritin binding in human brain, address the enigma of the apparent absence of an iron delivery system to the iron-rich white matter, and suggest loss of ferritin binding is involved in or is a consequence of demyelination associated with MS.