Thymosins, lymphokines, and the immunology of aging

Recent data point to a significant role for thymosins, lymphokines, and other soluble mediators in the senescence of the immune response that occurs with aging. In recent years, considerable progress has been made in the isolation and physiochemical characterization of several of these soluble mediators. We are now beginning to define the mechanisms by which these molecules regulate and mediate immune responses. In this paper we review the properties of the best characterized thymic hormones and lymphokines and focus on the role of the endocrine thymus in modulating immune responses. Of particular interest is the recent observation that thymosin fraction 5 can enhance production of interleukin-2 (IL-2) and colony-stimulating factor (CSF), and that IL-2 production, but not CSF production, is selectively diminished in aging mice. Several of the products of the immune system also can act as neuroactive immunotransmitters and modulate a number of neuroendocrine responses. Current studies point to an important role for these molecules in modulating neuroendocrine function, suggesting a broader role for the endocrine thymus in the aging process.     

Natriuretic peptides, respiratory disease, and the right heart

It is well-recognized that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are raised in conditions with ventricular volume and pressure overload. In addition to this established role in left ventricular congestive cardiac failure, there is good evidence that BNP has a diagnostic role in right ventricular (RV) dysfunction and pulmonary arterial hypertension (PAH). For example, BNP levels can be used to differentiate between dyspneic patients with pure respiratory defects and those with RV dysfunction. Studies in patients with PAH have demonstrated significant correlations between BNP levels and mean pulmonary arterial pressure as well as pulmonary vascular resistance. Additionally, BNP has a prognostic role in patients with RV pressure overload and pulmonary hypertension, and it offers a noninvasive test that can be used to guide therapy in patients with PAH. However, although measured plasma proBNP levels are raised in conditions with RV overload, its biological significance is still not well-understood. In this article, we review the general physiologic and potential therapeutic role of natriuretic peptides in respiratory disease, RV dysfunction, and PAH. Furthermore, we assess the various clues toward natriuretic peptide action coming from laboratory studies. ANP and BNP knockout mice develop cardiac fibrosis and hypertrophy. Potentiation of the natriuretic pathway has been shown to reduce cardiac hypertrophy and PAH. This is likely to take place as a result of increased intracellular cyclic guanosine monophosphate levels and subsequent pulmonary vasorelaxant activity. In view of this evidence, there may be a rationale for the therapeutic use of recombinant BNP or neutral endopeptidase inhibitors under conditions of RV dysfunction and PAH.     

Targeting of the UmuD, UmuD'', and MucA'' mutagenesis proteins to DNA by RecA protein.

In addition to its critical role in genetic recombination, the Escherichia coli RecA protein plays a pivotal role in SOS-induced mutagenesis. This role can be separated genetically into three steps: (i) depression of the SOS regulon by mediating the posttranslational cleavage of the LexA repressor, (ii) activation of UmuD'-like proteins by mediating cleavage of the UmuD-like proteins, and (iii) a direct step, possibly to interact with and to target the Umu-like mutagenesis proteins to lesions in DNA. We have analyzed RecA's third role biochemically using protein affinity chromatography and an agarose-based DNA mobility-shift assay. RecA730 protein from a crude cell extract was specifically retained on UmuD and UmuD' protein affinity columns, suggesting that these proteins physically interact. Normally, neither UmuD nor UmuD' shows any affinity for DNA. In the presence of RecA protein, however, UmuD and UmuD' were targeted to DNA. RecA1730 protein, which is defective for UmuD' but proficient for MucA'-promoted mutagenesis, showed a dramatically reduced capacity to target UmuD' to DNA but was able to target a significant portion of MucA' to DNA. These data support the suggestion that the direct role of RecA protein in SOS-induced mutagenesis is to interact with and target the Umu-like mutagenesis proteins to DNA.     

Neglected diseases, civil conflicts, and the right to health

Neglected diseases remain one of the largest causes of disease and mortality. In addition to the difficulties in provision of appropriate drugs for specific diseases, many other factors contribute to the prevalence of such diseases and the difficulties in reducing their burden. We address the role that poor governance and politically motivated oppression have on the epidemiology of neglected diseases. We give case examples including filariasis in eastern Burma and vector-borne diseases (Chagas' disease, leishmaniasis, and yellow fever) in Colombia, we show the links between systematic human rights violations and the effects of infectious disease on health. We also discuss the role of researchers in advocating for and researching within oppressed populations.     

Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.     

The left spectrum, the Levitzki radical, and noncommutative schemes

This note contains a brief exposition of the basics of a noncommutative version of affine, quasi-affine, and projective algebraic geometry. In this version, to any associative ring (with unity) a quasi-affine (resp. affine) left scheme is assigned. The notion of the left spectrum of a ring plays the key role.     

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.     

In hypertension,the kidney rules

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Components of the RAS, including renin, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT1) receptors, are expressed throughout the body in tissues that may impact blood pressure control. Blocking actions of individual components of the RAS lowers blood pressure. Although it has been suggested that control of sodium excretion by the kidney is the dominant mechanism for blood pressure regulation by the RAS, pharmacologic antagonists or conventional gene targeting experiments globally interrupt the RAS and cannot discriminate its actions in the kidney from other tissue compartments. Recent experiments using kidney cross-transplantation and genetically engineered mice have confirmed a major role for angiotensin II acting via AT1 receptors in the kidney in hypertension. These actions of renal AT1 receptors are required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy. These findings, with previous experiments, clearly establish the critical role of the kidney in the pathogenesis of hypertension and its cardiovascular complications.     

Estrogen, astrocytes and the neuroendocrine control of metabolism

Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERβ), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.     

Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase

CD36 plays a critical role in the inhibition of angiogenesis through binding to the type 1 repeats of thrombospondin-1 (TSP-1) and activating Fyn tyrosine kinase and MAPK pathways. Here, we reveal a novel association of CD36 with VEGFR-2 and spleen tyrosine kinase (Syk). We also address the correlation between the expression of CD36 and Syk by demonstrating that overexpression of CD36 in HUVECs up-regulates endogenous Syk expression. We also define a new role for TSP-1 and CD36 in the activation of the VEGFR-2 signaling pathway that requires Syk. Our findings also identify a role for Syk as a stimulator of VEGF-A-induced angiogenesis by increasing phosphorylation of Y1175 in VEGFR-2, which is a major tyrosine for promoting VEGF-A-induced endothelial cell migration. Together, these studies introduce a new signaling pathway for TSP-1, CD36, and Syk, and address the role of these proteins in regulating the angiogenic switch.     

Cholesterol,Statins, and Dementia: What the Cardiologist Should Know

Alzheimer dementia (AD) is an important clinical problem that appears to be closely tied to comorbid cardiovascular disease, making it a relevant topic for the clinical cardiologist. Determinants of cardiovascular health, especially midlife dyslipidemia, are associated with an increased risk of dementia based on molecular and epidemiologic data. Given the potential role of dyslipidemia in the development of dementia, statins have been investigated as potential therapeutic options to slow or prevent disease. This review discusses the role of dyslipidemia and other cardiovascular risk factors in the pathogenesis of AD, with a focus on the existing evidence for the use of statin medications in the treatment and prevention of AD from observational studies and randomized clinical trials. Clinical questions for the practicing cardiologist are addressed.     

Disruption of operant oral self-administration of ethanol, sucrose, and saccharin by the AMPA/kainate antagonist, NBQX, but not the AMPA antagonist, GYKI 52466

BACKGROUND: AMPAergic transmission has been suggested to be important in mediating the rewarding effects of drugs. We therefore examined the role of non-NMDA glutamate-receptors in mediating the reinforcing properties of ethanol in an oral self-administration paradigm. METHODS: The competitive antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline) and the non-competitive antagonist, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H2,3- be nzodiazepine), were administered to animals previously trained to self-administer ethanol, sucrose, or saccharin, on a progressive ratio schedule. RESULTS: GYKI 52466 (5 & 10 mg/kg) had no effect on operant responding for ethanol, but increased spontaneous locomotor activity, whereas the highest doses of NBQX (3 & 6 mg/kg) significantly decreased operant responding and correspondingly decreased the breaking point in responding for ethanol on a progressive ratio schedule. NBQX (but not GYKI 52466) also significantly decreased operant responding for a food reinforcer (sucrose) as well as for a sweet tasting reinforcer (saccharin). Doses of NBQX that disrupted operant performance caused a significant reduction in locomotor activity, indicating that NBQX decreased ethanol self-administration only at doses which disrupt motor activity. CONCLUSIONS: These results suggest non-NMDA glutamate-receptors may not have a specific role in the maintenance of responding for an ethanol reinforcer, but may generally disrupt operant performance. Because, unlike GYKI 52466, NBQX possesses an action at central kainate receptors, these results suggest that kainate, but not AMPA (alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionate) receptors may be important in mediating the reinforcing effects of ethanol.     

Correlation between the CAMCOG, the MMSE, and three clock drawing tests in a specialized outpatient psychogeriatric service

Our objective was to assess the correlation between (1) the Cambridge Cognitive Examination (CAMCOG) (including the Mini-Mental State Examination [MMSE]) score and three clock drawing tests (CDT) and (2) the three CDTs independently, in a specialized outpatient psychogeriatric service. One hundred and fourteen subjects completed a comprehensive evaluation and were allocated to one of the following groups: dementia of the Alzheimer's type (DAT) in 52; vascular dementia (VD) in 36; non-dementia (ND; Mood or Anxiety Disorders) in 26. When the entire sample of patients is considered, all three CDTs used were highly and significantly correlated to the MMSE score, the CAMCOG score, and to each other. In this patient population, these cognitive tests may be interchangeable for providing an initial objective measure of cognitive function. However, when the same correlations were studied in the separate diagnostic groups, in the dementia group (DAT and VD) even though the high correlations between the various CDTs themselves did not change, the correlations between the MMSE score, the CAMCOG score and the CDTs decreased, more evidently in the VD group. This trend became even more conspicuous in the ND group, where some of the above mentioned correlations became non-significant. We hypothesize that in a real clinical situation the clinician initially assumes the role of cognitive "evaluator" (in terms of the total sample) followed by the role of cognitive "monitor" (in relation to specific diagnostic groups). In the first instance, CDTs, the MMSE, and the CAMCOG might be considered interchangeable as an initial objective measure of cognitive dysfunction, while in the second role, different CDTs might be diversely used, presumably supplemented by other cognitive tests and clinical methods.     

炎症因子与糖尿病心肌病关系的实验研究

目的探讨核因子-κB(NF-κB)、诱导型一氧化氮合酶(iNOS)、环氧化酶(COX-2)在糖尿病心肌病发病中的作用。方法将60只SD大鼠随机分成对照组(30例),糖尿病组(30例)。分别于1、3、6个月末留取心肌标本,观察心肌的病理改变并用免疫组织化学法分析NF-κBi、NOS、COX-2的表达,NF-κB做凝胶电迁移(EMSA)电泳条带灰度分析。结果糖尿病大鼠较正常大鼠心肌组织中NF-κBi、NOS、COX-2的表达明显增加(P<0.01)。心肌病理结果显示:与对照组相比,糖尿病组心肌间质纤维化、凝固性坏死等病变明显加重。结论NF-κBi、NOS、COX-2伴随着心脏病理学改变而持续活化,可能在糖尿病心肌病中发挥重要作用。     

Interferon-gamma, the activated macrophage, and host defense against microbial challenge

Recent research on human macrophage activation has reemphasized the critical role of the lymphokine-secreting T cell in converting quiescent macrophages to efficient microbicidal phagocytes. Interferon-gamma, a key lymphokine secreted by antigen-triggered T4+ helper cells, is capable of inducing the macrophage to act against a diverse group of microbial targets, in particular, intracellular pathogens. In animal models, treatment with recombinant interferon-gamma is beneficial in systemic intracellular infections, and inhibition of endogenous interferon-gamma activity impairs host resistance. Trials in patients with cancer, leprosy, and the acquired immunodeficiency syndrome (AIDS) have shown that interferon-gamma can activate the mononuclear phagocyte in humans. This research and the identification of patients whose T cells fail to produce interferon-gamma properly has set the stage for evaluating the role of macrophage-activating immunotherapy using interferon-gamma in various human infectious diseases.     

Dopamine,the Kidney,and Hypertension

There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.     

CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract

CD74 is a protein whose initial role in antigen presentation was recognized two decades ago. Recent studies have revealed that it has additional functions as a receptor for macrophage migration inhibitory factor and as a receptor for an important human pathogen, Helicobacter pylori （H pylon）. The role of CD74 as a receptor is important because after binding of migration inhibitory factor or H pylori, NF-κB and Erkl/2 activation occurs, along with the induction of proinflammatory cytokine secretion. This review provides an up-to-date account of the functions of CD74 and how it might be involved in inflammation and cancer within the gastrointestinal tract.     

Hypoxia regulates the adenosine transporter, mENT1, in the murine cardiomyocyte cell line, HL-1

OBJECTIVE: Adenosine is an important paracrine hormone in the cardiovascular system. Adenosine flux across cardiomyocyte membranes occurs mainly via equilibrative nucleoside transporters (ENTs). The role of the ENTs in adenosine physiology is poorly understood, particularly in response to metabolic stress such as hypoxia. Therefore, we investigated the effects of chronic hypoxia on ENT1, the predominant ENT isoform in cardiomyocytes. METHODS: HL-1 cells (immortalized murine cardiomyocytes) were exposed to hypoxia (2% O2) for 0-20 h. Cell viability, lactate dehydrogenase (LDH) release, glucose uptake, GLUT1 and GLUT4 protein, adenosine uptake, PKC activity, translocation profiles of PKCdelta and, nitrobenzylthioinosine (NBTI) binding and mENT1 mRNA levels were measured. The role of PKC in regulating mENT1 was further investigated using phorbol ester (100 nM, 18 h) and a dominant negative PKC construct, pSVK3PKC1-401. RESULTS: HL-1 cells have typical cardiomyocyte responses to hypoxia based on cell viability, LDH release, glucose uptake and GLUT protein levels. Hypoxia (8-20 h) down-regulates mENT1-dependent adenosine uptake, NBTI-binding and PKC but not PKCdelta in HL-1 cells. Abrogation of PKC activity using chronic phorbol ester or a dominant negative PKC mimicked the effect of hypoxia on adenosine uptake suggesting that PKC is involved in regulation of mENT1. Hypoxia (4 h) decreases mENT1 mRNA, which returns to basal levels by 20 h. CONCLUSIONS: Chronic hypoxia down-regulates mENT1 activity possibly via PKC. Hypoxia and PKC also regulate mENT1 RNA levels. Cardiomyocytes may regulate mENT1 (via PKC) to modulate release and/or uptake of adenosine. However, the relationship between mENT1 mRNA levels, protein levels and functional transport is complex.     

Role of fleas, the principal and secondary plague vectors, in the circulation of the causative agent in Siberian natural foci

The paper reviews data on the role of fleas as the principal and secondary vectors of infection in the Siberian natural foci of plague. The role of Citellophilus tesquorum as the principal plague vectors in the Transbaikalian and Tuvinian natural foci is shown to be determined by their ecological characteristics (the degree of specificity to the main host, numbers, and natural infection) to a greater extent and by the rate of block formation to a lesser extent. The significance of principal and secondary vectors is estimated in the circulation of the causative agent in the monovectoral (Transbaikalian and Tuvinian) and multivectoral (Gorno-Altai) foci of plagues. It is suggested that the "microfocal" form (phenotype) of the agent's existence is characteristic of the Siberian natural foci where the rate of block formation does not generally show high indices. This phenomenon might be a basis for the long circulation of the plague microbe in the mountain (Tuva and Gorno-Altai) foci where protracted interepizootic periods have not been registered.