Lyme Disease Associated with Alzheimer’s Disease

This case report discusses a patient with co-occurring neuroborreliosis and Alzheimer’s disease (AD). Although no claim is made for causality nor is there objective evidence that spirochetes are involved in AD, co-infection may exacerbate the symptoms of either neuroborreliosis or AD. Much is to be learned about the role of spirochetes in degenerative central nervous system disease.     

Intestinal T-cell Responses in Celiac Disease – Impact of Celiac Disease Associated Bacteria

A hallmark of active celiac disease (CD), an inflammatory small-bowel enteropathy caused by permanent intolerance to gluten, is cytokine production by intestinal T lymphocytes. Prerequisites for contracting CD are that the individual carries the MHC class II alleles HLA-DQ2 and/or HLA-DQ8 and is exposed to gluten in the diet. Dysbiosis in the resident microbiota has been suggested to be another risk factor for CD. In fact, rod shaped bacteria adhering to the small intestinal mucosa were frequently seen in patients with CD during the “Swedish CD epidemic” and bacterial candidates could later be isolated from patients born during the epidemic suggesting long-lasting changes in the gut microbiota. Interleukin-17A (IL-17A) plays a role in both inflammation and anti-bacterial responses. In active CD IL-17A was produced by both CD8⁺ T cells (Tc17) and CD4⁺ T cells (Th17), with intraepithelial Tc17 cells being the dominant producers. Gluten peptides as well as CD associated bacteria induced IL-17A responses in ex vivo challenged biopsies from patients with inactive CD. The IL-17A response was suppressed in patients born during the epidemic when a mixture of CD associated bacteria was added to gluten, while the reverse was the case in patients born after the epidemic. Under these conditions Th17 cells were the dominant producers. Thus Tc17 and Th17 responses to gluten and bacteria seem to pave the way for the chronic disease with interferon-γ-production by intraepithelial Tc1 cells and lamina propria Th1 cells. The CD associated bacteria and the dysbiosis they might cause in the resident microbiota may be a risk factor for CD either by directly influencing the immune responses in the mucosa or by enhancing inflammatory responses to gluten.     

Natural Antioxidants Protect Neurons in Alzheimer’s Disease and Parkinson’s Disease

“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models, and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models. Special issue in honor of Dr. Akitane Mori.     

Vascular Occlusions in Grapevines with Pierce’s Disease Make Disease Symptom Development Worse

Vascular occlusions are common structural modifications made by many plant species in response to pathogen infection. However, the functional role(s) of occlusions in host plant disease resistance/susceptibility remains controversial. This study focuses on vascular occlusions that form in stem secondary xylem of grapevines (Vitis vinifera) infected with Pierce’s disease (PD) and the impact of occlusions on the hosts’ water transport and the systemic spread of the causal bacterium Xylella fastidiosa in infected vines. Tyloses are the predominant type of occlusion that forms in grapevine genotypes with differing PD resistances. Tyloses form throughout PD-susceptible grapevines with over 60% of the vessels in transverse sections of all examined internodes becoming fully blocked. By contrast, tylose development was mainly limited to a few internodes close to the point of inoculation in PD-resistant grapevines, impacting only 20% or less of the vessels. The extensive vessel blockage in PD-susceptible grapevines was correlated to a greater than 90% decrease in stem hydraulic conductivity, compared with an approximately 30% reduction in the stems of PD-resistant vines. Despite the systemic spread of X. fastidiosa in PD-susceptible grapevines, the pathogen colonized only 15% or less of the vessels in any internode and occurred in relatively small numbers, amounts much too small to directly block the vessels. Therefore, we concluded that the extensive formation of vascular occlusions in PD-susceptible grapevines does not prevent the pathogen’s systemic spread in them, but may significantly suppress the vines’ water conduction, contributing to PD symptom development and the vines’ eventual death.Pierce’s disease (PD) of grapevines (Vitis vinifera), currently jeopardizing the wine and table grape industries in the southern United States and California, as well as in many other countries, is a vascular disease caused by the xylem-limited bacterium Xylella fastidiosa (Hopkins, 1989; Varela et al., 2001). The pathogen is transmitted mostly via xylem sap-feeding sharpshooters (e.g. Homalodisca vitripennis; Redak et al., 2004) and inhabits, proliferates, and spreads within the vessel system of a host grapevine (Fry and Milholland, 1990a; Hill and Purcell, 1995). PD symptom development in grapevines depends on the interactions between the pathogen and the host vine’s xylem tissue, through which the pathogen may achieve its systemic spread (Purcell and Hopkins, 1996; Krivanek and Walker, 2005; Pérez-Donoso et al., 2010; Sun et al., 2011). Since the path for this spread is the host’s xylem system, xylem tissue and its vessels have become the major focus for studying potential X. fastidiosa-host vine interactions at the cellular or tissue levels (Fry and Milholland, 1990b; Stevenson et al., 2004a; Sun et al., 2006, 2007; Thorne et al., 2006).One major issue related to this host-pathogen interaction is the relationship of a vine’s xylem anatomy to the X. fastidiosa population’s spread. Sun et al. (2006) did a detailed anatomical analysis of the stem secondary xylem, especially the vessel system. Stevenson et al. (2004b) described xylem connection patterns between a stem and the attached leaves. Other studies reported the presence of open continuous vessels connecting stems and leaves, which represent conduits that might facilitate the pathogen’s stem-to-leaf movement (Thorne et al., 2006; Chatelet et al., 2006, 2011). Chatelet et al. (2011) also suggested that vessel size and ray density were the two xylem features that were most relevant to the restriction of X. fastidiosa’s movement. These studies indicate the importance of understanding the grapevine’s xylem anatomy in order to characterize the grapevine host’s susceptibility or resistance to PD.Another focus of PD-related xylem studies is the tylose, a developmental modification that has important impacts on a vessel’s role in water transport and, potentially, its availability as a path for X. fastidiosa’s systemic spread through a vine. Tyloses are outgrowths into a vessel lumen from living parenchyma cells that are adjacent to the vessel and can transfer solutes into the transpiration stream via vessel-parenchyma (V-P) pit pairs (Esau, 1977). Tylose development involves the expansion of the portions of the parenchyma cell’s wall that are shared with the neighboring vessels, specifically the so-called pit membranes (PMs). Intensive tylose development may eventually block the affected vessel (Sun et al., 2006). Since tyloses occur in the vessel system of PD-infected grapevines (Esau, 1948; Mollenhauer and Hopkins, 1976; Stevenson et al., 2004a; Krivanek et al., 2005) that is also the avenue of X. fastidiosa’s spread and water transport, a great deal of effort has been made to understand tyloses and their possible relations to grapevine PD as well as to diseases caused by other vascular system-localized pathogens. One major aspect is to clarify the process of tylose development itself, in which an open vessel may be gradually sealed (Sun et al., 2006, 2008). Our investigations of the initiation of tylose formation in grapevines have identified ethylene as an important factor (Pérez-Donoso et al., 2007; Sun et al., 2007). In terms of the relationship of tyloses to grapevine PD, studies have so far led to several controversial viewpoints that are discussed below (Mollenhauer and Hopkins, 1976; Fry and Milholland, 1990b; Stevenson et al., 2004a; Krivanek et al., 2005). However, more convincing evidence is still needed to support any of them.Another issue potentially relevant to PD symptom development is the possibility that X. fastidiosa cells and/or their secretions contribute to the blockage of water transport in host vines. The bacteria secrete an exopolysaccharide (Roper et al., 2007a) that contributes to the formation of cellular aggregates. Accumulations of X. fastidiosa cells embedded in an exopolysaccharide matrix (occasionally identified as biofilms, gums, or gels) have been reported in PD-infected grapevines (Mollenhauer and Hopkins, 1974; Fry and Milholland, 1990a; Newman et al., 2003; Stevenson et al., 2004b). However, a more detailed investigation is still needed to clarify if and to what extent these aggregates affect water transport in infected grapevines.The xylem tissue in which X. fastidiosa spreads can be classified as primary xylem or secondary xylem, being derived from procambium or vascular cambium, respectively. Primary xylem is located in and responsible for material transport and structural support in young organs (i.e. leaves, young stems, and roots), while secondary xylem is the conductive and supportive tissue in more mature stems and roots (Esau, 1977). It should be noted that most of the earlier experimental results have been based on examinations of leaves (petioles or veins) or young stems of grapevines, which contain mostly primary xylem with little or no secondary xylem. However, X. fastidiosa’s systemic spread generally occurs after introduction during the insect vector’s feeding from an internode of one shoot. The pathogen then moves upward along that shoot and also downward toward the shoot base. The downward movement allows the bacteria to enter the vine’s other shoots via the shared trunk and then move upward (Stevenson et al., 2004a; Sun et al., 2011). These upward and downward bacterial movements occur through stems that contain significant amounts of secondary xylem but relatively dysfunctional primary xylem. Secondary and primary xylem show some major differences in the structure and arrangement of their cell components (Esau, 1977). In terms of the vessel system that is the path of X. fastidiosa’s spread, the secondary xylem has a large number of much bigger vessels with scalariform (ladder-like) PMs (and pit pairs) as the sole intervessel (I-V) PM type, compared with the primary xylem, which contains only a limited number of smaller vessels with multiple types of I-V PMs (Esau, 1948; Sun et al., 2006). Vessels in secondary xylem are also different from those in primary xylem in forming vessel groups and in the number of parenchyma cells associated with a vessel (as seen in transverse sections of xylem tissue). These features of secondary xylem can affect the initial entry and subsequent I-V movement of the pathogen and the formation of vascular occlusions, respectively, in stems containing significant amounts of secondary xylem. Recently, the X. fastidiosa population size only in stems with secondary xylem was found to correlate with the grapevine’s resistance to PD (Baccari and Lindow, 2011), indicating an important role of stem secondary xylem in determining a host vine’s disease resistance. Despite these facts, little is known about the pathogen-grapevine interactions in the stem secondary xylem and their possible impacts on disease development.This study addresses X. fastidiosa-grapevine interactions in stem secondary xylem and examines the resulting impacts on overall vine physiology, with a primary focus on vine water transport. We have made use of grapevine genotypes displaying different PD resistances and explored whether differences in the pathogen’s induction of vascular occlusions occur among the genotypes and, if so, how the differences impact X. fastidiosa’s systemic spread. Our overall, longer-term aim is to elucidate the functional role of vascular occlusions in PD development, an understanding that we view to be essential for identifying effective approaches for controlling this devastating disease.     

Synapses and Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein (“plaques”) and by insoluble filaments composed of hyperphosphorylated tau protein (“tangles”). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.Alzheimer’s disease (AD) is a common neurodegenerative disease of the elderly, first described by the physician-pathologist Alois Alzheimer in 1907 (Maurer and Maurer 2003). Clinically, AD is characterized by progressive impairment of memory (particularly short-term memory in early stages) and other cognitive disabilities, personality changes, and ultimately, complete dependence on others. The most prevalent cause of dementia worldwide, AD afflicts >5 million people in the United States and >25 million globally (Alzheimer’s Association, http://www.alz.org). Age is the most important risk factor, with the prevalence of AD rising exponentially after 65 (Blennow et al. 2006). However, many cases of so-called AD above 80 yr of age may result from a combination of pathological dementia processes (Fotuhi et al. 2009). The apolipoprotein E (ApoE) gene is the most important genetic susceptibility factor for AD, with the relatively common ApoE4 allele (prevalence ∼16%) increasing the risk for AD threefold to fourfold in heterozygous dose (Kim et al. 2009).The histopathological hallmarks of AD are amyloid plaques (extracellular deposits consisting largely of aggregated amyloid beta [Aβ] peptide that are typically surrounded by neurons with dystrophic neurites) and neurofibrillary tangles (NFTs, intracellular filamentous aggregates of hyperphosphorylated tau, a microtubule-binding protein) (Blennow et al. 2006). The development of amyloid plaques typically precedes clinically significant symptoms by at least 10–15 yr. Amyloid plaques are found in a minority of nondemented elderly patients, who may represent a “presymptomatic” AD population. As AD progresses, cognitive function worsens, synapse loss and neuronal cell death become prominent, and there is substantial reduction in brain volume, especially in the entorhinal cortex and hippocampus. The best correlation between dementia and histopathological changes is observed with neurofibrillary tangles, whereas the relationship between the density of amyloid plaques and loss of cognition is weaker (Braak and Braak 1990; Nagy et al. 1995). In addition to amyloid plaques and neurofibrillary tangles, many AD cases exhibit widespread Lewy body pathology. (Lewy bodies are intracellular inclusion bodies that contain aggregates of α-synuclein and other proteins.) Particularly in very old patients, considerable overlap between AD, frontotemporal dementia, Lewy body dementia, and vascular disease is observed, and pure AD may be rare (Fotuhi et al. 2009).     

Autophagy and Alzheimer’s Disease

Autophagy is an essential degradation pathway in clearing abnormal protein aggregates in mammalian cells and is responsible for protein homeostasis and neuronal health. Several studies have shown that autophagy deficits occurred in early stage of Alzheimer’s disease (AD). Autophagy plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its malfunction may lead to the progress of AD. By considering the above evidences, autophagy may be a new target in developing drugs for AD. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD and the potential therapeutic effects of autophagy modulators in AD.     

Tumoral Calcinosis—an Unrecognized Disease

Twenty-six cases of tumoral calcinosis are reported from Kenya. The disease, frequently misdiagnosed, is of unknown origin. It presents as calcified tumours, usually around the hips and buttocks, in muscle and subcutaneous tissue. The tumours are partly solid, partly multiloculated cysts which contain a chalky fluid. They may grow rapidly or very slowly, and are found in children and adults. Both sexes are affected and there is no obvious tribal or geographical localization.     

A New Hope for a Devastating Disease: Hydrogen Sulfide in Parkinson’s Disease

Hydrogen sulfide (H₂S) has been regarded as the third gaseous transmitter alongside nitric oxide (NO) and carbon monoxide (CO). In mammalian brain, H₂S is produced redundantly by four enzymatic pathways, implying its abundance in the organ. In physiological conditions, H₂S has been found to induce the formation of long-term potential in neuronal cells by augmenting the activity of N-methyl-D-aspartate (NMDA) receptor. Likewise, it also actively takes part in the regulation of intracellular Ca²⁺ and pH homeostasis in both neuronal cells and glia cells. Intriguingly, emerging evidence indicates a connection of H₂S with Parkinson’s disease. Specifically, the endogenous H₂S level in the substantia nigra (SN) is significantly reduced along with 6-hydroxydopamine (6-OHDA) treatment in rats, while supplementation of H₂S not only reverses 6-OHDA-induced neuronal loss but also attenuates the following disorders of movement, suggesting a protective effect of H₂S in Parkinson’s disease (PD). Remarkably, the protective effect has been extensively demonstrated with various in vitro and in vivo PD models. These suggest that H₂S may be a new hope for the treatment of PD. Further studies have shown that the protective effects can be ascribed to H₂S-mediated anti-oxidation, anti-inflammation, anti-apoptosis, and pro-survival activity, which are also summarized in the review. Moreover, the progresses on the development of H₂S donors are also conveyed with an emphasis on the treatment of PD. Nevertheless, one should bear in mind that the precise role of H₂S in the pathogenesis of PD remains largely elusive. Therefore, more studies are warranted before turning the hope into a real therapy for PD.     

Aβ Toxicity in Alzheimer's Disease

Alzheimer's Disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive cognitive decline, synaptic loss, the formation of extracellular β-amyloid plaques and intracellular neurofibrillary tangles, and neuronal cell death. Despite the massive neuronal loss in the ‘late stage’ of disease, dendritic spine loss represents the best pathological correlate to the cognitive impairment in AD patients. The ‘amyloid hypothesis’ of AD recognizes the Aβ peptide as the principal player in the pathological process. Many lines of evidence point out to the neurotoxicity of Aβ, highlighting the correlation between soluble Aβ oligomer accumulation, rather than insoluble Aβ fibrils and disease progression. Pathological increase of Aβ in AD brains, resulting from an imbalance between its production, aggregation and clearance, might target mitochondrial function promoting a progressive synaptic impairment. The knowledge of the exact mechanisms by which Aβ peptide impairs neuronal function will help us to design new pharmacological tools for preventing AD neurodegeneration.     

Glia Disease and Repair—Remyelination

The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, although this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granular neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet, remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this review, we will review the biology of remyelination, including the cells and signals involved; describe when remyelination occurs and when and why it fails and the consequences of its failure; and discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain.     

Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn''s disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn''s disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn''s disease, clinical improvement as assessed by the Crohn''s disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment.     

Paraoxonase and Arylesterase Levels in Behcet’s Disease and Their Relations with the Disease Activity

The aim of this study was to determine the paraoxonase (PON) and arylesterase (ARE) enzyme activity levels in Behcet’s disease (BD) and to investigate whether they are associated with the disease activity. Twenty-six patients (study group) with active BD and 28 healthy controls (control group) were included in this study. While the patients who had at least one of the symptoms related to genital ulcer, skin lesions, active uveitis, arthritis, thrombophlebitis, or central nervous system involvement in addition to oral ulcers were considered as the active group, the patients who did not show clinical symptoms in the last one month due to the medical treatment were considered as the inactive group in the clinical evaluation of patients with BD. The PON and ARE levels were found to be significantly lower in the study group than the control group (p < 0.05). The PON levels of the active and inactive groups were 96.23 ± 57.84 and 112.2 ± 65.14, respectively. The ARE levels of the active and inactive groups were 30.49 ± 5.81 and 30.85 ± 6.40, respectively. No significant correlations were found between clinical findings and the activity levels of PON and ARE in the active patient group (p > 0.05). The activities of the antioxidant PON and ARE enzymes are reduced in BD. Therefore, it may be useful to add antioxidant therapy to the conventional treatment of the disease.