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PubMed2006

Inflammatory changes parallel the early stages of Alzheimer disease.

Alzheimer disease (AD) is the most prominent cause of dementia in the elderly. To determine changes in the AD brain that may mediate the transition into dementia, the gene expression of approximately 10,000 full-length genes was compared in mild/moderate dementia cases to non-demented controls that exhibited high AD pathology. Including this latter group distinguishes this work from previous studies in that it allows analysis of early cognitive loss. Compared to non-demented high-pathology controls, the hippocampus of AD cases with mild/moderate dementia had increased gene expression of the inflammatory molecule major histocompatibility complex (MHC) II, as assessed with microarray analysis. MHC II protein levels were also increased and inversely correlated with cognitive ability. Interestingly, the mild/moderate AD dementia cases also exhibited decreased number of T cells in the hippocampus and the cortex compared to controls. In conclusion, transition into AD dementia correlates with increased MHC II(+) microglia-mediated immunity and is paradoxically paralleled by a decrease in T cell number, suggesting immune dysfunction.

Aged↗
PubMed2005

An updated review of the long-term neurological effects of galactosemia.

Classical galactosemia is an autosomal recessive condition in which there is near total absence of the activity of galactose-1-phosphate uridyltransferase. Patients with this condition have substantial motor, cognitive, and psychiatric impairments despite dietary treatment. A characteristic pattern of biochemical abnormalities is observed in patients with this disorder. Galactose-1-phosphate, the substrate of galactose-1-phosphate uridyltransferase, accumulates within cells, and surplus galactose is reduced to galactitol or oxidized to galactonate. Using sophisticated mass spectrometry, these compounds as well as free galactose can be measured in plasma and in urine. It is clear that initiation of dietary restriction of galactose in the newborn period produces reversal of hepatic, renal, brain, and immune dysfunction, along with reduction of the accumulated galactose metabolites. However, the neurologist should be aware that chronic and progressive neurologic impairments occur even in patients spared these neonatal symptoms. The purpose of this review is to summarize current information about neurologic complications of galactosemia and what is known, and still unknown, about its pathophysiology.

Cognition Disorders↗
PubMedDate not supplied

Second-generation beta-oxidation resistant 3-oxa-lipoxin A4 analogs.

Lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 are structurally and functionally distinct eicosanoids, with potent anti-inflammatory and immunomodulatory actions. Therapeutic use of LXA4 is greatly limited by its rapid metabolism in vivo and chemical instability. First-generation synthetic LXA4 analogs such as methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), were designed to minimize metabolism from the omega-end of the molecule. Pharmacokinetic analysis of ATLa revealed beta-oxidation as a novel route for LXA4 metabolism, prompting the development of second-generation 3-oxa-LXA4 analogs with improved pharmacokinetic disposition. Second-generation 3-oxa-LXA4 analogs such as (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoic acid (3), have shown potency and efficacy comparable to ATLa in diverse animal models after topical, intravenous or oral delivery. These include several acute (2-24 h) inflammatory reactions: calcium ionophore-induced skin edema and inflammation (topical), LTB4/PGE2-induced skin inflammation and vascular leak (topical), zymosan A-induced peritonitis (i.v. and oral) and ischemia-reperfusion-induced secondary organ injury (i.v.). Remarkably, 3-oxa-LXA4 analogs have potent once daily oral efficacy in preventing and promoting the resolution of established colitis induced by the hapten trinitrobenzene sulphonic acid (TNBS), an acute/chronic 7-14-day model of Crohn's disease. The second-generation 3-oxa-LXA4 analogs thus provide new stable pharmacophores with which to explore the emerging role of lipoxins as a new therapeutic principle for regulating inflammation, allergy and immune dysfunction in preclinical and clinical research.

Administration, Oral↗
PubMed2005

Psychosomatics and psychopathology: looking up and down from the brain.

The autonomic nervous system (ANS) plays a role in a wide range of somatic and mental diseases. Using a model of neurovisceral integration, this article describes how autonomic imbalance and decreased parasympathetic tone in particular may be the final common pathway linking negative affective states and conditions to ill health. The central nervous system (CNS) network that regulates autonomic balance (central autonomic network, CAN) is closely related and partially overlaps with networks serving executive, social, affective, attentional, and motivated behavior (anterior executive region, AER; and Damasio's [Damasio, A.R., 1998. Emotion in the perspective of an integrated nervous system. Brain Res. Rev. 26, 83-86.] 'emotion circuit'). A common reciprocal inhibitory cortico-subcortical neural circuit serves to regulate defensive behavior, including autonomic, emotional and cognitive features. This inhibitory cortico-subcortical circuit may structurally, as well as functionally, link psychological processes with health-related physiology. When the prefrontal cortex is taken 'offline' for whatever reason, parasympathetic inhibitory action is withdrawn and a relative sympathetic dominance associated with disinhibited defensive circuits is released, which can be pathogenic when sustained for long periods. This state is indicated by low heart rate variability (HRV), which is a marker for low parasympathetic activation and prefrontal hypoactivity. Consistent with this, HRV is associated with a range of psychological and somatic pathological conditions, including immune dysfunction. Finally, we discuss supportive evidence from recent studies of the reflexive startle blink, attention and working memory, which shows that low HRV predicts hypervigilance and inefficient allocation of attentional and cognitive resources.

Animals↗
PubMed2006

[Cutaneous leishmaniasis in polymyositis].

INTRODUCTION: The prevalence of cutaneous leishmaniasis is increasing, especially in immunocompromized subjects. CASE RECORD: We report a case of particular interest, where a patient with steroid refractory polymyositis developed cutaneous leishmaniasis. Clinical outcome was favorable after institution of intralesional antimony therapy. DISCUSSION: Cutaneous leishmaniasis is still recognized to be an opportunistic infection. Its frequency is indeed higher in immunocompromized subjects, mainly HIV-infected patients. In our patient, both polymyositis and steroid therapy were predisposing factors of cutaneous leishmaniasis onset; prednisone therapy has been postulated to be associated with immune dysfunction leading to: reduced blood T cells' levels (CD4 et CD8) as well as decreased cytokine synthesis (e.g. interferon gamma).

Adult↗
PubMed2006

Association study of IL10, IL1beta, and IL1RN and schizophrenia using tag SNPs from a comprehensive database: suggestive association with rs16944 at IL1beta.

Genetic association studies of several candidate cytokine genes have been motivated by evidence of immune dysfunction among patients with schizophrenia. Intriguing but inconsistent associations have been reported with polymorphisms of three positional candidate genes, namely IL1beta, IL1RN, and IL10. We used comprehensive sequencing data from the Seattle SNPs database to select tag SNPs that represent all common polymorphisms in the Caucasian population at these loci. Associations with 28 tag SNPs were evaluated in 478 cases and 501 unscreened control individuals, while accounting for population sub-structure using the genomic control method. The samples were also stratified by gender, diagnostic category, and exposure to infectious agents. Significant association was not detected after correcting for multiple comparisons. However, meta-analysis of our data combined with previously published association studies of rs16944 (IL1beta -511) suggests that the C allele confers modest risk for schizophrenia among individuals reporting Caucasian ancestry, but not Asians (Caucasians, n=819 cases, 1292 controls; p=0.0013, OR=1.24, 95% CI 1.09, 1.41).

Adult↗
PubMed2025

Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.

Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.

Humans↗
PubMed2006

Genistein protects methylglyoxal-induced oxidative DNA damage and cell injury in human mononuclear cells.

Methylglyoxal (MG) is a reactive dicarbonyl compound produced mainly from glycolytic intermediates in the cell and often found at high level in the blood from the diabetic patients. Glycation reactions of MG with amino acids can induce oxidative stress and free radical generation, leading to subsequent cytotoxicity and apoptosis. Recently, studies have demonstrated that high level MG may be the main cause of immune dysfunction in diabetic patients. Here, we examined the effects of genistein, an antioxidant isoflavone compound, on MG-induced effects in vitro and in human mononuclear cells. We first monitored DNA strand breakage to examine the effect of 12.5-100 microM genistein on the ROS generation and oxidative DNA damage induced in vitro by a 50 microM MG/lysine glycation reaction (3h). Our results revealed that genistein concentrations higher than 25 microM decreased the oxidative stress and DNA damage induced by 50 microM MG/lysine. In mononuclear cells, pretreatment with 8-16 microM genistein for 1h followed by co-incubation with genistein and 50 microM MG for an additional 36 h inhibited MG-induced reactive oxygen species (ROS) generation and apoptosis. Finally, animal model experiments showed that dietary genistein effectively blocks MG-induced apoptosis in mononuclear cells. These results collectively suggest that oxidative stress plays a role in MG-induced cell injury, and that genistein blocks these effects by virtue of its antioxidant properties, consequently preventing cell apoptosis.

Adult↗
PubMed2006

Matrix metalloproteinase mRNA expression in canine anal furunculosis lesions.

Although the aetiology of anal furunculosis (AF) in dogs is poorly understood, there is evidence for an underlying immune dysfunction. This is illustrated by the presence of a T helper type 1 cytokine mRNA profile in AF lesions and the clinical response to ciclosporin therapy. Expression of MMPs 2, 9 and 13 were evaluated in AF lesional biopsies by real-time quantitative RT-PCR. There was significantly increased expression of both MMP-9 and MMP-13 mRNA in AF biopsies compared to controls (p<0.001) but no significant difference in MMP-2 mRNA expression. Since MMP-9 and MMP-13 are primarily produced by macrophages, these data suggest that ulceration could be the result of aberrant activation of this cell type in the tissues. It is feasible that such pathological macrophage activity occurs in response to interferon-gamma secreted by T helper type 1 cells. This could explain why the lesions resolve following treatment with the immunosuppressive drug ciclosporin.

Animals↗
PubMed2004

Cyclospora cayetanensis, a food- and waterborne coccidian parasite.

Food- and waterborne coccidia including Cryptosporidium parvum, Cyclospora cayetanensis, Sarcocystis hominis and Sarcocystis suihominis, and Isospora belli are cyst-forming apicomplexan protozoa that cause intracellular infections, predominantly in the epithelial cells of the intestine. They are transmitted by oocysts from person-to-person by the fecal-oral route or via contaminated water or food. The most common symptom of infection is diarrhea, however, asymptomatic infections occur. Infections are associated with intestinal inflammation, with pathological lesions such as villus blunting, and abnormal function such as malabsorption. Mild-to-moderate, self-limiting diarrhea is common in healthy individuals ingesting infective stages of these organisms. However, patients with immune dysfunction can have severe intestinal injury and prolonged diarrhea. Diagnosis in many cases is made by a microscopic examination of the stool, and the use of appropriate staining techniques, but more recently molecular methods for detection are used increasingly. Effective antimicrobial treatment for prolonged infection in immunocompromised patients is available for most of these infections. These gastrointestinal coccidial pathogens have important similarities in epidemiology, disease pathogenesis, clinical manifestations, diagnosis, and treatment. Although there are many other cyst-forming coccidia of public health, veterinary and/or economic importance, discussion in this chapter will be limited to C. cayetanensis, as an important example of the group. Aspects of the biology, epidemiology, diagnosis, disease, treatment and control are considered. This parasite is considered to be an emerging pathogen. From 1990 to 2000, there were 11 foodborne outbreaks of cyclosporosis in North America that affected at least 3600 people. There are many outstanding questions regarding this parasite and under-reporting is common because general diagnostic methods for intestinal parasites are inadequate for detection of Cyclospora.

Animals↗
PubMed2004

Smad2 and Smad3 coordinately regulate craniofacial and endodermal development.

Ligands of the transforming growth factor-beta (TGF-beta) superfamily are involved in numerous developmental and disease processes. TGF-beta, activins, and nodal ligands operate through the highly homologous Smad2 and Smad3 intracellular mediators. Smad2 mutants exhibit early embryonic lethality, while Smad3 mutants are viable, but show a plethora of postnatal phenotypes, including immune dysfunction and skeletal abnormalities. Previously, we have shown that the Smad2 and Smad3 genes function cooperatively during liver morphogenesis. Here we show that Smad2 and Smad3 are required at a full dosage for normal embryonic development. Animals lacking one allele of each gene exhibit a variably penetrant phenotype in which structures in the anterior and ventral midline are reduced or lost; additionally, we demonstrate that this craniofacial defect and the previously reported hepatic phenotypes are both due to defects in the definitive endoderm. A reduction of endodermal gene expression as well as a failure to displace the visceral endoderm occurs despite the formation of a normal foregut pocket. This precedes any defects in anterior patterning and likely causes the abnormalities observed in craniofacial and midline development, as well as hepatogenesis.

Animals↗
PubMed2005

High levels of endogenous nitric oxide produced after burn injury in rats arrest activated T lymphocytes in the first G1 phase of the cell cycle and then induce their apoptosis.

Major physical traumas provoke a systemic inflammatory response and immune dysfunction. In a model of thermal injury in rats, we previously showed that an overproduction of nitric oxide (NO) was responsible for the collapse of lymphoproliferative responses. In the present work, we performed a time-course analysis of cell proliferation and cell death parameters in order to establish the sequence of events triggered by the high NO output in Wistar/Han rat splenocytes activated with Con A, 10 days after burn injury. We demonstrate that activated T cells from burned rats never divided whereas normal T cells underwent four division cycles. However, T cells from both burned and normal rat entered the G1 phase as shown by increase of cell size, mitochondria hyperpolarization, and expression of cyclin D1. Burned rat T cells progressed to the late G1 phase as shown by expression of the nuclear Ki-67 antigen, but they never entered the S phase. They underwent apoptosis as shown by morphological parameters, disruption of transmembrane mitochondrial potential, and DNA fragmentation. Persistent accumulation of the p53 protein accompanied these phenomena. NO synthase inhibitors antagonize alterations of cell proliferation and cell death parameters in burned rat T cells and accelerated p53 turnover.

Animals↗
PubMed2002

Host cell invasion by the opportunistic pathogen Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular protozoan that infects an astonishing variety of vertebrate hosts including humans. Classified in the phylum Apicomplexa, T. gondii causes an opportunistic disease, toxoplasmosis, in individuals with immune dysfunction and congenital disease in infected infants. Re-emergence of toxoplasmosis as a life-threatening disease in patients with AIDS is anticipated in the wake of emerging multi-drug resistant strains of HIV. In immunodeficient patients, the available evidence suggests that tissue pathology associated with T. gondii infection is due to parasite-directed lytic destruction of individual host cells. The Toxoplasma lytic cycle begins when the parasite actively invades a target cell. In association with invasion, T. gondii sequentially discharges three sets of secretory organelles beginning with the micronemes, which contain adhesive proteins involved in parasite attachment to a host cell. Deployed as protein complexes, several micronemal proteins possess vertebrate-derived adhesive sequences that function in binding receptors on the surface of a target cell. Each protein in these adhesive complexes fulfills a specific role in movement through the secretory pathway, targeting to the micronemes, or adhesion. It is anticipated that these adhesive complexes recognize a variety of host receptors, including some that are expressed on multiple cell types, and that this diversity in host cell receptors contributes to the remarkably broad tissue- and host-range of T. gondii.

AIDS-Related Opportunistic Infections↗
PubMed1997

The new dietary fats in health and disease.

Lipids are an integral part of the routine diet of patients and the general public. In this article, the physiologic properties of various dietary lipids are reviewed, beginning with those most commonly consumed-the long-chain triglycerides (LCTs) and extending to those with special purposes: the short- and medium-chain triglycerides. The nutritional dietary management of patients typically includes physical mixtures of lipids. Recently, structured triglycerides (STs), which combine advantages from conventional fats with those of special purposes, have become available. STs are currently developed by interesterifying a mixture of conventional fats and oils, usually with medium-chain triglycerides, to achieve a specific fatty acid profile. This results in a triglyceride containing combinations of short-, medium-, and long-chain fatty acids on a single glycerol backbone. They have unique chemical, physical, or physiologic properties that are not observed by simply blending mixtures of the starting fats and oils. A number of STs are under intense laboratory and clinical investigation in models of cancer, burns, and immune dysfunction. Much interest in the fatty acids resides in the sn-2 position on the glycerol molecule. This is because the fatty acid in the sn-2 position of triglycerides is preferentially absorbed as the 2-monoglyceride and serves as the template for reesterification by intestinal cells to re-form triglycerides. The sn-2 fatty acids are also preferentially preserved as components of chylomicrons and very-low-density lipoprotein particles for ultimate incorporation in tissue membranes. Technology is evolving to create STs with a selected fatty acid in this sn-2 position. For instance, incorporating linoleic, arachidonic, or eicosapentaenoic acid at the sn-2 position is being evaluated for the specific objective of modulating serum cholesterol concentrations and essential fatty acid absorption (a review of this work is included).

Absorption↗
PubMed1993

Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus-related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome.

We prospectively studied 132 patients with acquired immunodeficiency syndrome (AIDS) to determine the cross-sectional prevalence of cytomegalovirus retinitis. All patients had serum CD4+ lymphocyte counts to determine the degree of immune dysfunction. Correlations between CD4+ counts, the presence of cytomegalovirus retinitis or human immunodeficiency virus (HIV)-related noninfectious retinal vasculopathy, and ocular symptoms were made. The study disclosed that 26 of 132 patients with AIDS (20%) had cytomegalovirus retinitis. However, subset analysis according to CD4+ count disclosed that in patients with CD4+ counts of 50 cells/mm3 or less, 26 of 87 (30%) had cytomegalovirus retinitis, whereas in patients with CD4+ counts of 50 cells/mm3 or more, none of 45 was noted to have cytomegalovirus retinitis. Similarly, 46 of 132 patients (35%) were noted to have HIV-related noninfectious retinal vasculopathy, with a trend toward increasing prevalence associated with declining CD4+ count. In patients with CD4+ counts of 50 cells/mm3 or less, 39 of 87 (45%) had HIV-related noninfectious retinal vasculopathy, whereas seven of 45 patients (16%) with CD4+ counts of 50 cells/mm3 or more were noted to have these changes. We confirmed the clinical impression that cytomegalovirus retinitis and HIV-related noninfectious retinal vasculopathy are late manifestations of AIDS, demonstrated an increased risk for patients with low CD4+ counts, and suggested a basis for coherent chemoprophylaxis and screening strategies for cytomegalovirus retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1999

ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a human disorder with pleiotropic manifestations that include neoplasms, immune dysfunction and neurodegeneration. The disorder is due to mutations in the gene known as ATM (A-T, mutated), which causes a deficiency in its protein product (Atm in mice) that is necessary for DNA damage surveillance. This nuclear function of Atm explains in principle the propensity to cancer and immunodeficiency in A-T, but not the neurodegeneration which results in the earliest clinical manifestations and causes progressive disability. Here we report ultrastructural evidence of cytoplasmic localization of Atm-like immunoreactivity (ALI) within endosomes in murine cerebellocortical neurons, one of the principal targets of A-T. The ALI was obtained with two separate monoclonal antibodies that recognize Atm specifically. By contrast, electron-dense endosomes that could be confused with ALI occur in negligible amounts in both wild-type mice and in mice deficient in Atm ("knockout" mice). Furthermore, there was a marked preferential distribution of Atm-immunopositive endosomes in the granule cell layer - where they are present in granule neurons - with a much lower density in the Purkinje and molecular layers. These observations suggest that endosome-bound Atm may be more important for the function of certain neurons than others - or that it is processed differently among them - and that this protein may be involved in molecular sorting in the cytoplasm. This is relevant to elucidating the role of Atm deficiency in the pathobiology of neurodegeneration in A-T.

Animals↗
PubMed1996

Impaired antigen presentation to CD4+ T-cells by HIV-infected monocytes is related to down-modulation of CD4 expression on helper T-cells: possible involvement of HIV-induced cellular factors.

Defective antigen presentation by HIV-infected monocytes is related to severe immune dysfunction in patients with AIDS, although the mechanism by which this process occurs is not well defined. Here we report that reduced capacity by HIV-infected monocytes to stimulate or present antigen to CD4+ T-cells was mediated by cellular factors associated with the plasma membranes of HIV-infected monocytes. In contrast, soluble factors secreted by HIV-infected monocytes had little or no effect on T-cell stimulation. Reduced T-cell stimulation by HIV-infected monocytes was related to down-modulation of CD4 expression on helper T-cells and was not affected by the inclusion of anti-HIV-gpl20 Ab, indicating the involvement of soluble or cell-associated viral envelope protein to be less likely. Exposure of CD4+ T-cells, that had been in co-culture with HIV-infected monocytes, to uninfected monocytes partially restored impaired T-cell stimulation. Thus, for the first time we report that altered capacity of HIV-infected monocytes to stimulate and present antigen to CD4+ T-cells is related to down-modulation of CD4 expression on T-cells, and appears to occur via membrane-associated cellular factors on HIV-infected monocytes.

CD4 Antigens↗
PubMed2003

Fighting a virus with a virus: a dynamic model for HIV-1 therapy.

A mathematical model examined a potential therapy for controlling viral infections using genetically modified viruses. The control of the infection is an indirect effect of the selective elimination by an engineered virus of infected cells that are the source of the pathogens. Therefore, this engineered virus could greatly compensate for a dysfunctional immune system compromised by AIDS. In vitro studies using engineered viruses have been shown to decrease the HIV-1 load about 1000-fold. However, the efficacy of this potential treatment for reducing the viral load in AIDS patients is unknown. The present model studied the interactions among the HIV-1 virus, its main host cell (activated CD4+ T cells), and a therapeutic engineered virus in an in vivo context; and it examined the conditions for controlling the pathogen. This model predicted a significant drop in the HIV-1 load, but the treatment does not eradicate HIV. A basic estimation using a currently engineered virus indicated an HIV-1 load reduction of 92% and a recovery of host cells to 17% of their normal level. Greater success (98% HIV reduction, 44% host cells recovery) is expected as more competent engineered viruses are designed. These results suggest that therapy using viruses could be an alternative to extend the survival of AIDS patients.

CD4-Positive T-Lymphocytes↗