Initial Pathogenic Event Research Articles

Chromosome 9p Duplication Promotes T-Cell Exhaustion and Enhances Stem Cell Clonogenic Potential in JAK2-Mutant Myeloproliferative Neoplasms

Myeloproliferative Neoplasms (MPNs) are a diverse group of clonal hematopoietic disorders originating from a single hematopoietic stem cell, causing an excessive production of mature blood cells. Classic forms of MPNs include polycythemia vera, essential thrombocythemia, and myelofibrosis. The most common mutation is a gain-of-function point mutation in the JAK2 gene, known as JAK2V617F. This mutation leads to constant activation of the JAK-STAT signaling pathway, resulting in the overgrowth of MPN cells. Furthermore, the variant allele frequency (VAF) of JAK2V617F has a significant impact on the severity and phenotype of the disease. Alongside many described genetic mutations, cytogenetic abnormalities are commonly observed in MPNs, particularly involving chromosome 9. As the JAK2 gene is located on the short arm of this chromosome, we hypothesized that chromosome 9 copy number abnormalities might be a disease modifier in JAK2V617F-mutant MPN patients. To characterize the biological effects of chromosome 9 copy number abnormalities on JAK2-mutated MPN cells, we analyzed circulating CD34+ hematopoietic stem and progenitor cells (HSPCs) as well as monocytes and granulocytes from 32 MPN patients. Through Next Generation Sequencing, we categorized the patients into three main groups based on JAK2 mutation and copy number status: patients with two copies of the JAK2 gene with either heterozygous (VAF between 20% and 60%; n=10) or homozygous (VAF > 60% n=10) JAK2V617F mutation, or patients carrying mutant JAK2 and gene amplification (n=12). In-depth analysis of JAK2-amplified patients revealed that the amplification involved the entire chromosome 9p, thus including other gene loci like CD274, which encodes programmed death-ligand 1 (PD-L1). Further investigation of the order-of-events and clonal hierarchies through droplet digital PCR on CD34+ cell-derived colonies showed that most colonies of 9p-duplicated patients had three copies of JAK2, with 2 out of 3 alleles harboring the JAK2 mutation and that point mutations are frequently the initial pathogenic event in clonal evolution, followed by amplification of the JAK2-mutated allele. Functionally, CD34+ cells from +9p patients displayed high clonogenicity and gave rise to a greater number of primitive colonies (Colony Forming Unit-Granulocyte, Erythrocyte, Monocyte, Megakaryocyte, CFU-GEMM). As JAK2 hyperactivation had been previously reported to lead to increased PD-L1 expression, we further explored the functional significance of CD274 amplification in +9p patients. Our analysis showed increased PD-L1 messenger RNA and protein levels in +9p patient CD14+ monocytes compared to those from patients carrying only two copies of chromosome 9. Moreover, immunofluorescence analysis demonstrated significant re-localization of PD-L1 to the cytoplasmic membrane in monocytes from +9p patients, but not in JAK2V617F-homozygous patients (panel A). Increased levels of PD-L1, an immune checkpoint known to curb T cell activation, led us to analyze the T cell compartment, which resulted enriched in CD3+/CD8+/CD57-/PD-1+ exhausted T-cells in +9p patients compared to other MPN patients and healthy donors (panel B). In conclusion, our comprehensive characterization of the molecular interplay between JAK2V617F and chromosome 9 alterations, along with their immunological implications due to PD-L1 hyperactivation, fills a critical knowledge gap and provides valuable insights into the disease progression of 9p-MPNs. Further analysis is ongoing to explore the associations between 9p duplication and hematological parameters in 9p-MPN patients for a better understanding of the clinical implications of this genetic abnormality in MPNs.

Assessment of the Serum Ischemia Modified Albumin Level and Its Relation to Total Oxidant Status and Disease Activity in Vitiligo Patients

Abstract Background Vitiligo is an acquired depigmentary skin disorder characterized by loss of functioning epidermal melanocytes. Oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. Total oxidant status (TOS) had been reflect the global status of oxidative stress in serum. While, albumin acts as a buffering agent for toxic molecules within the circulation. It undergoes structural changes when exposed to ischemia or oxidative stress and ischemia modified albumin IMA are produced under these conditions with high levels. Hence it considered as a marker of oxidative stress in different clinical conditions. Aim of the Work The aim of this work was to evaluate the serum level of ischemia modified albumin in vitiligo patients and its relation to total oxidant status and disease activity. Patients and Methods This is a cross sectional study. Forty-eight patients with vitiligo were included in this study. Twenty-four were considered active cases while the other 24 were non-active vitiligo patients. The study also included 48 age-and sex-matched healthy adults as a control group. Five ml of venous blood were withdrawn from each patient and control subjects. The vitiligo activity and tensity were assessed by VIDA and VETI scores respectively. Serum IMA and TOS had been assist by ELISA kits. Results Our study found a significant increase in serum total oxidant status (TOS) and serum ischemia-modified albumin (IMA) levels in vitiligo patients compared to controls. We also found a positive correlation between TOS levels and IMA levels and vitiligo disease activity represented by VIDA score. Conclusion The total oxidant status (TOS) and IMA levels were increased in vitiligo patients' sera and positively correlated to disease activity. To the best of our knowledge, we were the first to detect the significantly positive correlation between serum IMA and vitiligo disease activity.

Quercetin protects endothelial function from inflammation induced by localized disturbed flow by inhibiting NRP2 -VEGFC complex

Atherosclerosis is a focal chronic inflammatory disease, the initial pathogenic event of which is endothelial dysfunction, and disturbed flow (DF) is the primary and vital factor underlying endothelial dysfunction. The present research aims to elucidate the mechanism underlying the regulation of Neuropilin (NRP)2 under DF in endothelial cells (ECs) in an inflammatory state. We observed that NRP2 expression was significantly upregulated in DF-stimulated human umbilical vein endothelial cells (HUVECs). Knockdown of NRP2 in HUVECs significantly ameliorated cell inflammation induced by DF. In addition, quercetin inhibited NRP2 expression as well as endothelial inflammation. Animal experiments suggested that NRP2 knockdown or intraperitoneal injection of quercetin affected the expression of inflammation-related genes. Moreover, the upstream transcription factor GATA2 was found to regulate NRP2 transcription by binding to the −1100 to +100 bp region of the NRP2 promoter. Further studies showed that quercetin inhibited NRP2-VEGFC complex formation induced by disturbed flow, although did not inhibit GATA2 expression. These findings suggest that NRP2 plays an important role in promoting inflammation. Quercetin antagonizes atherosclerosis by inhibiting NRP2 and the formation of NRP2-VEGFC complex by inhibiting the inflammatory effects induced by disordered flow.

Characteristics of MGUS and Multiple Myeloma According to the Target of Monoclonal Immunoglobulins, Glucosylsphingosine, or Epstein-Barr Virus EBNA-1.

Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient’s monoclonal Ig for only 37 patients (15.9%); for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.

Determination of oxidative stress in vitiligo by measuring superoxide dismutase levels in vitiliginous skin

Objective This study was conducted to determine the association between oxidative stress and vitiligo by measuring antioxidant enzyme superoxide dismutase (SOD) in vitiliginous skin. Background Vitiligo is an acquired depigmenting disease characterized by milky white patches of skin due to local destruction and loss of the epidermal melanocytes. Complex genetic, immunological, neural and self-destructive mechanisms interplay in its pathogenesis. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. Oxidative stress is defined as a disruption of the delicate balance between the formation of reactive oxygen species and the antioxidant defense system, The dismutation of superoxide (O2-) by SOD to hydrogen peroxide (H2O2) is generally considered to be the primary antioxidant defense of the body, because this enzyme prevents the further generation of free radicals. SOD exists in virtually every oxygen-respiring organism, and its major function is to catalyze dismutative reaction. Patients and methods We determined the activity of SOD in lesional skin only of 20 female patients with vitiligo. The ages of the patients ranged from 18 to 53 years. A total of 17 patients had nonsegmental vitiligo and three had segmental vitiligo, and 10 age-matched and gender-matched apparently healthy volunteers with no past, present or family history of vitiligo, served as a control group. Every case and control was subjected to skin biopsy, and SOD assay of the obtained biopsy was carried out by spectrophotometry. Results A significant difference was found between cases and controls with regard to tissue SOD (P = 0.01, Conclusion There was a significant association between oxidative stress and vitiligo.

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

Serum Homocysteine and Total Antioxidant Status in Vitiligo: A Case Control Study in Indian Population.

Background:Oxidative stress is considered as an initial pathogenic event in melanocyte destruction. These free radicals are scavenged by antioxidants, whose sum of activity in serum is measured by total antioxidant status (TAS). In addition, homocysteine (Hcy) may mediate melanocyte destruction via increased oxidative damage. However, previous studies investigating these parameters in vitiligo provide equivocal results.Aims:To study and compare serum Hcy and TAS levels in vitiligo patients with controls and also to correlate these parameters with the various disease characteristics. The present study further looked into any correlation between serum Hcy and TAS in vitiligo.Materials and Methods:A case control study was conducted on 82 vitiligo patients and 83 controls aged 18–45 years after excluding factors which could potentially alter serum Hcy or TAS levels. Disease characteristics were studied and blood samples were obtained for measuring serum Hcy and TAS levels.Results:TAS levels were lower in vitiligo patients than controls (1.79 ± 0.51 vs. 2.16 ± 0.63 mmol/L; P < 0.001) and had a negative correlation with disease activity (r = −0.410, P < 0.001). However, serum Hcy levels were comparable between vitiligo patients (18.68 ± 9.90 μmol/L) and controls (20.21 ± 13.39 μmol/L) (P = 0.406). No significant correlation was found between serum Hcy and serum TAS levels.Conclusions:Serum TAS may be further investigated to establish its role as biomarker for vitiligo since its levels also correlate with disease activity. However, serum Hcy may not be a reliable marker in Indian population probably because of differences in dietary habits.

Comparison of oxidant-antioxidant status in patients with vitiligo and healthy population.

Vitiligo is a well-recognized pigmentary disorder of the skin and /or mucous membrane characterized by circumscribed ivory or chalky white macules devoid of identifiable melanocytes. The pathogenesis of vitiligo is complex and still not well understood. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. The role of free radicals and oxidative damage in the pathophysiology of vitiligo has been documented in recent studies. To evaluate the role of oxidative stress in patients with vitiligo and of healthy controls by measuring levels of the oxidant malondialdehyde (MDA) and antioxidants vitamin C and vitamin E in serum and catalase (CAT) in erythrocytes. A total of 80 clinically diagnosed cases of vitiligo and 80 control subjects were included in the study to assess the activity of MDA, vitamin C and vitamin E in serum and CAT in erythrocytes of patients and controls by using the spectrophotometric assay. There was statistically significant increase in the levels of MDA in patients with vitiligo compared to the control group (p<0.001). No significant difference was found in the levels of vitamin C (p=0.411) and vitamin E (p=0.771) between the patients with vitiligo and control group. The levels of CAT in the vitiligo patients were found to be significantly lower than those of controls (p<0.001). Increased oxidative stress and decreased catalase have been observed in vitiligo patients and the data suggesting that the free radicals may be involved in the destruction of melanocytes or dysregulation of melanogenesis.

Study of oxidative stress in peripheral blood of Indian vitiligo patients

Background:Vitiligo is an acquired skin disease that involves the interplay of complex genetic, immunological, neural and self-destructive mechanisms in its pathogenesis. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration.Objectives:The aim of our investigation was to evaluate the role of oxidative stress by studying the role of catalase (CAT) in the destruction of melanocytes in patients with vitiligo and compare the same in healthy normal controls.Materials and Methods:We determined the serum catalase enzyme by ELISA method. The catalase activity was studied in two groups, Group I—localized vitiligo: (i) active stage, (ii) static or inactive stage and Group II—generalized vitiligo: (i) active stage, (ii) static or inactive stage patients, and the levels were compared with healthy controls.Results:Group I active stage patients showed significant difference in the catalase levels with a P < 0.044 when compared with healthy controls, whereas Group II static stage patients did not show any significant difference (P < 0.095) although the catalase activity was increased.Conclusion:Our study could not explain the cause of melanocyte damage in patients in the active stage of the disease. The increase in the oxidative stress as detected by catalase activity was more significant in Group I active disease than Group II active disease patients although the levels were higher than the healthy normals. This is the first study conducted on active and static stage of vitilgo in India. It is possible that the number of compounds of hydrogen peroxide produced is not balanced by the production of catalase in the body.

Storage problems in lysosomal diseases

Biochemical disorders in lysosomal storage diseases consist of the interruption of metabolic pathways involved in the recycling of the degradation products of one or several types of macromolecules. The progressive accumulation of these primary storage products is the direct consequence of the genetic defect and represents the initial pathogenic event. Downstream consequences for the affected cells include the accumulation of secondary storage products and the formation of histological storage lesions, which appear as intracellular vacuoles that represent the pathological hallmark of lysosomal storage diseases. Relationships between storage products and storage lesions are not simple and are still largely not understood. Primary storage products induce malfunction of the organelles where they accumulate, these being primarily, but not only, lysosomes. Consequences for cell metabolism and intracellular trafficking combine the effects of primary storage product toxicity and the compensatory mechanisms activated to protect the cell. Induced disorders extend far beyond the primarily interrupted metabolic pathway.

Oral minocycline in the treatment of vitiligo - A preliminary study

For effective treatment of vitiligo, it is as important to arrest the progression of the disease, as it is to induce repigmentation. Epidermal oxidative stress has been documented in vitiligo patients, and there is much support for a free-radical-mediated damage as an initial pathogenic event in melanocyte degeneration in vitiligo. Minocycline possesses a wide repertoire of anti-inflammatory, immunomodulatory, and free-radical scavenging actions in addition to their well-characterized antimicrobial effects. Recently, it has been shown that minocycline can rescue melanocytes from oxidative stress in vitro. Minocycline 100 mg was tried in this study to elucidate its role in arresting disease activity. Thirty-two patients with gradually progressive (slow spreading) vitiligo were enrolled in this study. The patients were advised to take minocycline 100 mg once daily. In 29 patients, the progression of the disease was arrested, and only three patients showed development of new lesions and/or enlargement of existing lesions. Ten patients showed arrest of further depigmentation after 4 weeks of treatment. Thus, minocycline offers a unique and potentially powerful approach to the management of arresting the activity of the disease. The present study showed the effectiveness of minocycline in the treatment of vitiligo. Further controlled studies should be undertaken to confirm its efficacy.

Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin

Vitiligo is an acquired disorder characterized by circumscribed depigmented macules devoid of identifiable melanocytes. Complex genetic, immunological, neural and self destructive mechanisms interplay in its pathogenesis. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. The aim of our investigation was to evaluate the role of oxidative stress by measuring levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lesional and normal skin of patients with vitiligo and in the skin of normal controls. We determined the activity of SOD in lesional and non-lesional skin and CAT in lesional skin only of 25 vitiligo patients and 25 controls by using the spectrophotometric assay and Aebi's method, respectively. There was statistically significant increase in the levels of SOD in vitiliginous and non vitiliginous skin of patient group compared to the control group (P < 0.001). No significant difference was found between the levels of SOD in lesional skin and non-lesional skin of vitiligo patients. The levels of CAT in the skin of patients were found to be significantly lower than those of controls (P < 0.001). There is increased oxidative stress in vitiligo as is indicated by high levels of SOD and low levels of CAT in the skin of vitiligo patients.

The susceptibility to vitiligo is associated with NF‐E2‐related factor2 (Nrf2) gene polymorphisms: a study on Chinese Han population

Vitiligo is an acquired pigmentary disorder and its pathogenesis remains unclear. Oxidative stress is considered to be the initial pathogenic event in the melanocyte destruction. NF-E2-related factor2 (Nrf2) is a transcription factor regulating the expression of detoxifying and antioxidant genes. To investigate the association of the Nrf2 gene promoter polymorphisms with vitiligo in Chinese Han population, the genotypes of -686A/G, -684G/A and -650C/A and the genotyping of variable number of tandem repeat were detected. The data were analysed by the chi-square test and the risk was evaluated by calculating OR and 95% CI. There was statistically significant difference in genotypic and allelic frequencies of -650C/A between the two groups (P < 0.05). A(-650) allele was significantly associated with the risk for vitiligo (OR = 1.724, chi(2) = 18.096). Polymorphism of the Nrf2 gene promoter at -650C/A was associated with the development of vitiligo and A(-650) allele may be one of the risk factors.

Basal-like subtype and BRCA1 dysfunction in breast cancers

Basal-like breast cancers are characterized by their unique expression profile, with the frequent loss of BRCA1, caused by such mechanisms as promoter methylation and the overexpression of high-mobility group proteins of the A type 1 or inhibitor of differentiation 4. Clinicopathologically, basal-like cancers are estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor type 2 (HER2)-negative; they are of high grade and have a poor prognosis. The fundamental similarity between BRCA1-mutated and basal-like cancers indicates that disruption of BRCA1 may be an essential common initial pathogenic event. Furthermore, p53 mutation and EGFR overexpression occur similarly in BRCA1-mutated and basal-like cancers; these shared alterations provide very important information for understanding not only the genetic and epigenetic carcinogenic pathways in these tumors but also therapeutic strategies. Despite the limited available clinical data about response to chemotherapy, anthracycline-based chemotherapy seems to be effective in a distinct subset of basal-like cancers. Both disrupted BRCA1 and overexpressed topoisomerase II-alpha possibly found in basal-like cancers are speculated to be associated with their increased sensitivity to anthracyclines. If these tumors respond to this chemotherapy, a favorable prognosis might be expected; however, in patients who do not respond, the prognosis is poor. Currently, the sensitivity of basal-like cancers to taxanes is not clear, but considering that these tumors have disrupted mitotic checkpoint function, a poor response may be suggested. On the basis of in vitro studies, BRCA1-disrupted basal-like cancers may be sensitive to DNA-damaging agents including platinum-based compounds, topoisomerase I and II inhibitors, and alkylating agents. In future, new therapeutic approaches for patients with basal-like cancers that are unlikely to respond to chemotherapy should focus on molecules that are involved in the pathogenic pathways of this disease.

Neuroinflammation and Peripheral Immune Infiltration in Parkinson's Disease: An Autoimmune Hypothesis

Despite decades of research and the development of a large group of animal models, our understanding of the mechanisms responsible for the progressive loss of dopamine neurons in Parkinson's disease (PD) is unknown. So-called neuroprotective studies demonstrate that a vast group of molecules readily attenuate the dopamine (DA) neuron loss produced by DA neurotoxin insult. Despite these successes, these neuroprotective strategies have been surprisingly ineffective in patients. This may reflect the fact that the initial pathogenic event and the subsequent disease progression is a consequence of different mechanisms. As we began to think about this disconnect, we discovered that animals exposed to DA neurotoxins exhibited blood-brain barrier (BBB) dysfunction. If the BBB in PD patients is disrupted, then the barrier that normally segregates peripheral vascular factors from brain parenchyma is no longer present. Immune cells could then enter brain and produce a self-perpetuating (progressive) degenerative process. In this review, we propose that peripheral immunity contributes to the degenerative process of PD and may be responsible for the progressive nature of the disease. This hypothesis is supported by a broad and diverse literature that is just beginning to come together to suggest that PD is, in part, an autoimmune disease. In order to understand this hypothesis, the reader must question the conventional wisdom that the BBB is intact in PD, the brain is an immune privileged area, and that pathogenic insult and disease progression may reflect different mechanisms.

Enfermedad inflamatoria del páncreas por autoagresión enzimática: un modelo excepcional de «crinofagia» glandular

The exocrine pancreas is a functionally dangerous structure since it is exposed to digestion by its most aggressive enzymes (proteases, etc) despite self-protective measures such as the synthesis of some of these enzymes in the form of inactive zymogens (trypsinogen, etc.). We review inflammatory pancreatic disease by separately analyzing its classical forms of onset: acute and chronic pancreatitis (AP and CP). There is general consensus that the initial pathogenic event in AP is intraacinar activation of trypsinogen into trypsin, followed by that of the remaining proenzymes, giving rise to an unusual model of autophagic inflammation. In contrast, consensus is lacking on the initial pathogenic event in CP (toxic-metabolic lesion, oxidative stress, ductal hypertension, etc.?), although in some cases a <<necrosis-fibrosis>> sequence due to recurrent episodes of AP seems evident. The pathogenic features shared by both forms of the disease and which justify some recent attempts to formulate an overall explanation of the pathogenesis of pancreatitis are discussed. Such an explanation would place both forms of pancreatitis within the conceptual framework of an <<inflammatory pancreatic disease due to enzyme autodigestion>>.

Inflammation and Neuroaxonal Injury in Multiple Sclerosis and AIDS Dementia Complex: Implications for Neuroprotective Treatment

Multiple sclerosis (MS) and AIDS dementia complex (ADC), also termed HIV-associated dementia (HAD), are two examples of CNS diseases with a strong inflammatory component. In particular, macrophage/microglia activation in the deep white matter (DWM) is a key feature of both diseases. Activated macrophages/microglia have been shown to produce multiple cellular substances which can cause injury and apoptosis to all cell types in the CNS. This potentially provides a link between the initial pathogenic event and subsequent widespread neuroaxonal injury, which recent studies have found to be an early finding and an important determinant of clinical burden in both diseases. This review summarizes important immunopathological and neurobiological aspects of MS and ADC, with a special focus on the relation between macrophage/microglia activation and neuroaxonal injury, and discusses potential neuroprotective strategies.

The role of oxidants and antioxidants in generalized vitiligo at tissue level.

The role of oxidative stress has not been fully understood in the aetiopathogenesis of vitiligo in different studies. We aimed to investigate the role of the oxidative stress in the pathogenesis of vitiligo. In this study, we examined levels of superoxide dismutase, glutathione peroxidase, malondialdehyde and nitric oxide in tissue of 25 patients with generalized vitiligo and 25 healthy controls. Our results revealed that levels of superoxide dismutase, glutathione peroxidase and malondialdehyde in tissue were significantly increased in patients with generalized vitiligo (P < 0.05). However, there was no statistically significantly difference between two groups at tissue level of nitric oxide (P > 0.05). Our results demonstrate the presence of an imbalance in the oxidant-antioxidant system in vitiligo at tissue level and provide further support for a free radical-mediated damage as an initial pathogenic event in melanocyte degeneration in vitiligo.

Immunotoxin Lesion of the Cholinergic Nucleus Basalis Causes A&amp;#946; Deposition: Towards a Physiologic Animal Model of Alzheimers Disease

Transgenic βAPP mice are valid and useful models of Alzheimers disease (AD) as they effectively recreate Aβ deposition, which is widely regarded as the central pathogenic event in the disease. Transgenic mice do not, however, replicate the initial pathogenic event of the most common form of AD. The majority of AD is not caused by any of the gene mutations employed to create these mice. As cortical Aβ deposition is a common, if not universal, occurrence in many mammalian species, its cause is likely to lie within the physiologic process of aging. We have created an animal model of Aβ deposition by inducing cortical cholinergic deafferentation, a well-known aging change, in the brains of young rabbits. Lesioning the cholinergic nucleus basalis magnocellularis (nbm) results in cortical cholinergic deafferentation and cortical Aβ deposition. The Aβ deposits are primarily vascular, with occasional perivascular plaques. The specificity of this change for cholinergic processes has been demonstrated by the reduction of lesion-induced Aβ deposition by cholinergic therapy with AF267B, an m1-selective muscarinic agonist, and physostigmine, an acetylcholinesterase inhibitor, and by showing that lesioning of the noradrenergic locus ceruleus does not cause Aβ deposition. Significant decreases in cortical synaptic antigen density occur at 6 months post-lesion. Examination of longer survival periods has been complicated by regeneration of cortical cholinergic afferents but repetitive nbm lesions are expected to overcome this obstacle. Agerelated degeneration of the nbm in humans may be a major contributor to Aβ deposition in normal aging and AD. Keywords: immunotoxin lesion, cholinergic nucleus, deposition, cholinergic differentiation

The role of oxidants and antioxidants in generalized vitiligo.

Oxidative stress may be induced by increasing the generation of reactive oxygen species (ROS) and other free radicals. The generation of ROS is known to be associated with a decrease in antioxidant levels. In the present study, the role of oxidative stress was assessed in the pathogenesis of generalized vitiligo. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) levels in erythrocytes and serum malondialdehyde (MDA) and nitric oxide (NO) levels were investigated in 24 patients with generalized vitiligo and 20 healthy controls. Our results indicated that significantly increased levels of erythrocyte SOD, serum MDA, and NO were associated with a marked reduction of erythrocyte GSH-Px and GSH activities in patients with generalized vitiligo (p<0.05). Our observations suggest that the presence of an imbalance in the oxidant-antioxidant system might play a role in the pathogenesis of vitiligo. Our results further support the concept that free radical-mediated damage may be the initial pathogenic event in melanocyte degeneration in generalized vitiligo.