Georgia Deretzi

The association between Helicobacter pylori infection and insulin resistance: a systematic review.

Background:  Helicobacter pylori infection has been associated with diverse extradigestive morbidity, including insulin resistance (IR) syndrome. The aim of this systematic review was to summarize the epidemiologic evidence concerning the association between H. pylori infection and IR quantitative indexes.

Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron

In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities. We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls. In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed. MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration. Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages. Lesions developed on the background of inflammation. Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions. Demyelination and neurodegeneration were associated with oxidative injury. Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination. In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration. This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons. Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron. Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients.

Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis

Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Delivery of BMSCs in the cerebrospinal fluid via intracerebroventricular (ICV) transplantation is a useful tool to identify mechanisms underlying the migration and function of these cells. In the current study, BMSCs were ICV administered in severe and mild EAE, as well as naive animals; neural precursor cells (NPCs) served as cellular controls. Our data indicated that ICV-transplanted BMSCs significantly ameliorated mild though not severe EAE. Moreover, BMSCs exerted significant anti-inflammatory effect on spinal cord with concomitant reduced axonopathy only in the mild EAE model. BMSCs migrated into the brain parenchyma and, depending on their cellular density, within brain parenchyma formed cellular masses characterized by focal inflammation, demyelination, axonal loss and increased collagen-fibronectin deposition. These masses were present in 64% of ICV BMASC-transplanted severe EAE animals whereas neither BMSCs transplanted in mild EAE cases nor the NPCs exhibited similar behavior. BMSCs possibly exerted their fibrogenic effect via both paracrine and autocrine manner, at least partly due to up-regulation of connective tissue growth factor (CTGF) under the trigger of TGFb1. Our findings are of substantial relevance for clinical trials in MS, particularly regarding the possibility that ICV transplanted BMSCs entering the inflamed central nervous system may exhibit - under conditions - a local pathology of yet unknown consequences.

Association between Helicobacter pylori infection and acute inflammatory demyelinating polyradiculoneuropathy.

The aim of this study was to investigate a possible association between Helicobacter pylori infection and acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Of 17 consecutive patients with Guillain–Barré syndrome (GBS), 13 patients (six females; mean age 50 ± 24 years) with AIDP were investigated. Clinical status was evaluated according to Hughes’ score, and electrophysiological tests were performed within 2 weeks from disease onset. Helicobacter pylori infection was detected histologically and serum H. pylori‐specific IgG antibodies were analysed by ELISA. Twenty asymptomatic patients (12 females; mean age 63 ± 8 years), undergoing upper gastrointestinal endoscopy for investigation of mild iron deficiency anaemia, served as controls. Helicobacter pylori was found in 12 of 13 AIDP patients (92%), and in 10 of 20 controls (50%), (P = 0.02). Electrophysiological studies showed demyelination in all AIDP patients. High levels of anti‐H. pylori IgG antibodies correlated with advanced clinical status. Five of seven AIDP patients with high levels of anti‐H. pylori IgG antibodies had delayed F‐wave latencies, indicating affection of proximal segments of peripheral nerves. Helicobacter pylori infection seems to be more frequent in AIDP patients. Anti‐H. pylori titre might reflect advanced clinical status. Anti‐H. pylori IgG antibodies are also associated with involvement of the proximal parts of peripheral nerves in AIDP.

Nonalcoholic Fatty Liver Disease: Multimodal Treatment Options for a Pathogenetically Multiple-hit Disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a significant public health problem. Besides the liver, NAFLD is also associated with increased cardiovascular and overall morbidity and mortality. NAFLD warrants intensive research, because no treatment has been established as yet. This may be partly attributed to the fact that the majority of the relative clinical trials have a monotherapeutic direction. However, the multifactorial pathogenesis of NAFLD may probably direct clinical trials to a combined therapeutic approach. The aim of this review is to provide a description of the multifactorial pathogenesis of NAFLD and type II diabetes mellitus-NAFLD interplay, and to summarize the therapeutic trials focusing on the combined NAFLD treatment, providing a link between the multiple-hit pathogenesis and the multimodal treatment of NAFLD patients. A diabetes-like therapeutic approach for NAFLD is finally proposed.

Dynamics of production of MIP-1α, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of the peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. In the present study, the dynamics of the expression of the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) were determined in the sciatic nerves of EAN rats. Additionally, the effect of neutralizing antibodies against MIP-1alpha, MIP-2 and MCP-1 on the clinical course of EAN and the chemokine expression was investigated. The maximum of MIP-1alpha positive cells in the sciatic nerves was seen on day 14 post immunization (p.i.) correlating with the development of severe clinical signs. Administration of an anti-MIP-1alpha antibody suppressed the clinical signs of EAN and inhibited inflammation and demyelination in the sciatic nerve. Peak numbers of MCP-1 positive cells in the sciatic nerves were detected on day 7 p.i. Administration of an anti-MCP-1 antibody caused a delay of onset of EAN. However, 4 of the 6 EAN rats receiving the anti-MCP-antibody showed the same degree of inflammatory cell infiltration and demyelination in the sciatic nerves as sham-treated EAN rats, whereas only 2 EAN rats had less inflammation and demyelination. The numbers of MIP-2 positive cells reached a maximum on day 21 p.i. Anti-MIP-2 antibody failed to suppress the clinical signs of EAN and the inflammation and demyelination in the sciatic nerves. Only administration of the anti-MIP-1alpha antibody resulted in a significant reduction in the number of chemokine (MIP-1alpha)-positive cells and ED1-positive macrophages in the sciatic nerves. The present results demonstrate that MIP-1alpha and MCP-1 may play a role in the immunopathogenesis of EAN, and that MIP-1alpha induced trafficking of inflammatory cells can be inhibited by immunoneutralization. Further elucidation of the regulation and coordination of MIP-1alpha and MCP-1 production may lead to new therapeutic approaches to GBS in humans.

Enhancement of acute phase and inhibition of chronic phase of experimental autoimmune neuritis in Lewis rats by intranasal administration of recombinant mouse interleukin 17: potential immunoregulatory role.

Experimental autoimmune neuritis (EAN) is a CD4(+) T-cell-mediated demyelinating disease of the peripheral nervous system (PNS). We examined the effect of recombinant mouse interleukin 17 (rmIL-17) on chronic EAN induced in Lewis rats by inoculation of P2 57-81 peptide in Freunds complete adjuvant. Animals were treated nasally for 6 days with either 0.1 or 0.9 microg/rat/day rmIL-17 from the onset of neurological signs, i.e., days 9 to 14 postimmunization (p.i.). Prolonged follow-up demonstrated a chronic course in control and rmIL-17-treated rats. Treated rats had more severe disease initially (days 18-36 p.i.) with a stronger enhancing effect observed with the higher rmIL-17 dose. At day 19 rmIL-17-treated rats showed increased infiltration of inflammatory cells into the sciatic nerve, more severe demyelination, augmented proliferation of regional lymph node cells, and increased serum levels of tumor necrosis factor-alpha. After the initial phase of disease enhancement the IL-17-treated EAN rats improved gradually and ultimately recovered completely, whereas the control EAN rats remained affected until the end of the observation (day 120 p.i.). The lower dose of rmIL-17 induced an earlier recovery from clinical deficits than the higher one. The results indicate that IL-17 plays an immunoregulatory role in chronic EAN which could have implications for immunomodulatory treatments of chronic autoimmune disease of the PNS.

The Emerging Role of Endocrine Disruptors in Pathogenesis of Insulin Resistance: A Concept Implicating Nonalcoholic Fatty Liver Disease

Endocrine disruptors or endocrine-disrupting chemicals (EDCs) represent a highly heterogeneous group of molecules found in the environment or in consumer products. Toxicology and epidemiology studies have suggested the involvement of diverse EDCs in an increasing number of metabolic disorders, including insulin resistance (IR) and IR-related co morbidities, such as obesity, type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Nonalcoholic fatty liver disease (NAFLD), another IR related condition, is emerging as a significant public health concern, affecting 30-45% of the general population in the Western world. To evaluate whether EDCs may also play a role in the pathogenesis of NAFLD, we reviewed the literature on well-studied EDCs, such as dioxins, bisphenol A, phthalates and other persistent organic pollutants, in relation to pathways that might contribute to the pathogenesis of fatty liver / NAFDL. Certain EDCs may be responsible for inducing alterations similar to those encountered in NAFLD either directly through a hepatotoxic effect and/or indirectly by triggering hepatic and systematic IR. Considering these effects, which act in concert with the effects of the epidemics of obesity and T2DM, EDCs may play a significant role in the pathogenesis of fatty liver, thereby increasing the prevalence of NAFLD worldwide. Translational studies and clinical trials investigating the association between EDCs and NAFLD are required to confirm and extent these studies.

Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients.

BackgroundAlzheimer disease (AD) is a progressive, fatal neurodegenerative condition. ObjectiveWe tested the hypothesis that eradication of Helicobacter pylori infection (Hp-I) could improve survival in a Greek cohort of AD patients, in a 5-year follow-up. MethodForty-six patients diagnosed with probable AD were enrolled in the analysis. Study population was classified into 3 groups: patients for whom Hp eradication treatment was successful; those for whom eradication of Hp had failed, they refused, and/or were noncompliant with eradication therapy; and those who were Hp negative at baseline. Cox proportional hazards model was built with all-cause mortality as the dichotomous outcome. ResultsDuring the 5-year follow-up [47.19±15.11 mo (range 12 to 60)], overall 21 patients died and 25 patients remained alive. Patients who died were older and exhibited lower mean MMSE score compared with the patients still alive. Successful eradication of Hp-I was associated with a significantly lower mortality risk [HR (95% CI)=0.287 (0.114-0.725), P=0.008]. The results were similar in adjusted and unadjusted models, for age and MMSE at baseline. ConclusionHp eradication regimen in AD patients is associated with a higher 5-year survival rate.

Increased Cerebrospinal Fluid Helicobacter Pylori Antibody in Alzheimer’s Disease

Background: Helicobacter pylori (H. pylori) infection may play a role in Alzheimers disease (AD). Aim: A prospective, nonrandomized, comparative study was car- ried out to examine the levels of anti-H. pylori-specific IgG antibodies in the cerebrospinal fluid (CSF) and serum of AD patients, compared with those of age-matched cognitively normal controls. Patients: CSF was aspirated from 27 AD patients and 27 age-matched cognitively normal patients with prostate hyperplasia or long-bone fractures necessitating surgery after epidural anesthesia. Serum samples were obtained from AD patients and the day before surgery from controls. Methods: CSF and serum anti-H. pylori IgG concentrations were measured by means of an enzyme-linked immunosorbent assay. Results: The mean concentration of anti-H. pylori-specific IgG was significantly greater in (a) the CSF of AD patients (10.53 ± 12.54 U/mL) than in controls (8.63 ± 8.01 U/mL, p = 0.047), and (b) the serum of AD patients (30.44 ± 33.94 U/mL) than in controls (16.24 ± 5.77 U/mL, p = 0.041). CSF anti-H. pylori IgG antibodies correlated with the degree of severity of the disease. Conclusion: H. pylori-specific IgG antibody levels are significantly increased in CSF and serum of AD; its titer in CSF might reflect the AD severity, thereby supporting a role for this common infection in the pathobiology of the disease.