Satellite Hyperspectral Imagery to Support Tick-Borne Infectious Diseases Surveillance

This study proposed the use of satellite hyperspectral imagery to support tick-borne infectious diseases surveillance based on monitoring the variation in amplifier hosts food sources. To verify this strategy, we used the data of the human rickettsiosis occurrences in southeastern Brazil, region in which the emergence of this disease is associated with the rising capybara population. Spatio-temporal analysis based on Monte Carlo simulations was used to identify risk areas of human rickettsiosis and hyperspectral moderate-resolution imagery was used to identify the increment and expansion of sugarcane crops, main food source of capybaras. In general, a pixel abundance associated with increment of sugarcane crops was detected in risk areas of human rickettsiosis. Thus, the hypothesis that there is a spatio-temporal relationship between the occurrence of human rickettsiosis and the sugarcane crops increment was verified. Therefore, due to the difficulty of monitoring locally the distribution of infectious agents, vectors and animal host’s, satellite hyperspectral imagery can be used as a complementary tool for the surveillance of tick-borne infectious diseases and potentially of other vector-borne diseases.     

Development of a technical arsenal of the method of fluorescent probes

A brief history of the development of the method of fluorescent probes and examples of its application are presented. Works done at the 2nd Moscow medical institute and institute of physical chemical medicine in collaboration with other institutes on: (1) detection of T- and B-lymphocytes in immune pathology; (2) investigation of the structure and clinical estimation of lipoproteins from blood plasma or serum in relation to the assessment of risk factors for the development of cardiovascular diseases; (3) detection of changes in album molecule in a series of pathological processes improving the prognosis of the development of such diseases as peritonitis, pancreatitis, poisoning with psychotropic preparations etc.; (4) intravital measurement of the potentials in electric fields in leukocytes and changes of these fields in the course of immunological diseases are described. With these approaches it is possible to study molecular events in the course of pathogenesis and also obtain diagnostically significant information on physical chemical aspect of these events. This information is not a conventional method used in the clinical laboratory.     

SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for Immunomodulation

The experimental compound SU5416 went as far as Phase III clinical trials as an anticancer agent, putatively because of its activity as a VEGFR-2 inhibitor, but showed poor results. Here, we show that SU5416 is also an aryl hydrocarbon receptor (AHR) agonist with unique properties. Like TCDD, SU5416 favors induction of indoleamine 2,3 dioxygenase (IDO) in immunologically relevant populations such as dendritic cells in an AHR-dependent manner, leading to generation of regulatory T-cells in vitro. These characteristics lead us to suggest that SU5416 may be an ideal clinical agent for treatment of autoimmune diseases and prevention of transplant rejection, two areas where regulatory ligands of the AHR have shown promise. At the same time, AHR agonism might represent a poor characteristic for an anticancer drug, as regulatory T-cells can inhibit clearance of cancer cells, and activation of the AHR can lead to upregulation of xenobiotic metabolizing enzymes that might influence the half-lives of co-administered chemotherapeutic agents. Not only does SU5416 activate the human AHR with a potency approaching 2,3,7,8-tetrachlorodibenzo-p-dioxin, but it also activates polymorphic murine receptor isoforms (encoded by the Ahr(d) and Ahr(b1) alleles) with similar potency, a finding that has rarely been described and may have implications in identifying true endogenous ligands of this receptor.     

RNA recognition by autoantigens and autoantibodies

The La, Ro, Sm and RNP autoantigens have been intensely studied over the past decade since cDNAs encoding autoantigens have become available. Most of these autoantigens are closely associated with RNA in RNP particles and molecular studies have provided insights into their modes of recognition and binding to RNA. For example, a common RNA Recognition Motif (RRM) was found to be a critical component of the RNA-binding domain of these autoantigens and the three dimensional structure of the RRM has been solved. As described in other articles in this series, the presence of La, Ro, Sm and RNP autoantibodies correlates with disease subsets, such as Sjogren's syndrome, systemic lupus erythematosus and other connective tissue diseases. Immunological analysis of sera from autoimmune patients using recombinant autoantigens has revealed that multiple epitopes reside along the proteins and these represent both continuous and discontinuous (conformational) autotopes. Findings to date support a model of autoantibody induction which involves the direct presentation of proteinaceous autoantigens to the immune system. Circumstantial evidence has suggested that immunological crossreactivity between systemic autoantigens and structural components of infectious agents may play an initial role in the autoimmune response to certain antigens. However, the etiology of autoimmune diseases is probably multifactoral with genetic and other immune features acting on the organismal level. In addition, RNA molecules themselves can be autoantigens with higher order structural conformations which are recognized by RNP-type autoantibodies. Immune crossreactivity and/or direct presentation may generate autoantibodies reactive with conformational RNA epitopes. If crossreactivity with components of cellular or infectious agents give rise to RNA epitopes, they may represent structural or functional mimetics of the primary epitopes that actually drive the response. These ideas are discussed with respect to the role of mimetic processes in molecular recognition during autoimmunity.     

Combined focus of tick-borne encephalitis, tick-borne rickettsiosis and tularemia in the habitat of Haemaphysalis concinna in south central Siberia

For the first time in the Krasnoyarsk region the population Haemaphysalis concinna ticks were found to be infected with the causative agents of three natural focal tick-borne infections--tick-borne encephalitis, tick-borne rickettsiosis and tularemia. The existence of the combined natural focus of these three infections has been confirmed by epidemiological data. Ticks Dermacentor nuttalli also play a similar role in combined foci of tick-borne encephalitis and tick-borne rickettsiosis in these focal territories.     

Recent advances in gene therapy and future prospects

Gene therapy, which is treatment of diseases by introducing normal genes into the body, is becoming feasible as the result of advances in genetic engineering. The hematopoietic stem cells have been considered as the appropriate target for gene transfer in many genetic diseases for which allogeneic bone marrow transplantation has been employed successfully. However, there are still many problems to be solved. In particular, expression from retrovirally transduced genes in bone marrow cells has been transient and unstable. On the other hand, an alternative approach to somatic cell gene therapy using nonhematopoietic cells, including skin fibroblasts, endothelial cells, keratinocytes, and lymphocytes, has been shown to possess several advantages. This kind of approach is usually applied to supplementation therapy in not only hereditary disorders but also various acquired diseases, such as cancer or infectious diseases. Recently, clinical application of gene transfer into lymphocytes to treat cancer and immunodeficiency have been approved at NIH (USA). The trial could represent the start of a new era in molecular medicine.     

Present stage of chemotherapy and chemoprophylaxis of rickettsiosis and Q fever

The analysis of the published experimental and clinical data on chemoprophylaxis and chemotherapy of rickettsiosis and Q fever confirmed the preserved role of doxycycline, the main drug of choice in the treatment of the diseases, then followed chloramphenicol. Macrolides, such as azithromycin and clarithromycin proved to be useful in pediatric practice and the treatment of pregnant women with rickettsiosis. The treatment of acute and chronic Q fever required the use of doxycycline, fluoroquinolobes, co-trimoxazole and hydroxachloroquine in combined therapy. It is concluded that in vivo studies of novel drugs and investigation of prospective macrolides and fluoroquinolones are necessary. Clinical trials of a new glycycline, i.e. tigecycline, which experimentally showed highy strong activity against the Q fever pathogen, should be accelerated.     

Predictive diagnostics and personalized medicine for the prevention of chronic degenerative diseases

Progressive increase of mean age and life expectancy in both industrialized and emerging societies parallels an increment of chronic degenerative diseases (CDD) such as cancer, cardiovascular, autoimmune or neurodegenerative diseases among the elderly. CDD are of complex diagnosis, difficult to treat and absorbing an increasing proportion in the health care budgets worldwide. However, recent development in modern medicine especially in genetics, proteomics, and informatics is leading to the discovery of biomarkers associated with different CDD that can be used as indicator of disease's risk in healthy subjects. Therefore, predictive medicine is merging and medical doctors may for the first time anticipate the deleterious effect of CDD and use markers to identify persons with high risk of developing a given CDD before the clinical manifestation of the diseases. This innovative approach may offer substantial advantages, since the promise of personalized medicine is to preserve individual health in people with high risk by starting early treatment or prevention protocols. The pathway is now open, however the road to an effective personalized medicine is still long, several (diagnostic) predictive instruments for different CDD are under development, some ethical issues have to be solved. Operative proposals for the heath care systems are now needed to verify potential benefits of predictive medicine in the clinical practice. In fact, predictive diagnostics, personalized medicine and personalized therapy have the potential of changing classical approaches of modern medicine to CDD.     

Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways

A close comorbidity between endocrine diseases and psychopathological symptoms has been described in the literature. Until now only a few studies have reported about an increased anxiety and depressive symptoms in patients with primary hyperaldosteronism (PHA). The exact pathways of psychiatric comorbidities have not been totally clarified yet, although the renin-angiotensin-aldosterone-system has gained more attention in research on anxiety and depression. There are several structures and factors, which could mediate anxiety or a depressive symptomatology. Additionally a possible influence of the standardised treatment with a mineralocorticoidreceptor (MR) antagonist or adrenalectomy should be investigated as they have been shown to affect mood. Psychiatric comorbidities are not only an additional burden in these patients, but as depression and anxiety are additional risk factors in patients with cardiovascular diseases. Possible pathomechanisms in the relation between PHA and psychiatric symptoms should be more closely investigated. For the clinical practice a regular screening for psychiatric comorbidities and an adequate treatment are required.     

Nanotechnology in respiratory medicine

Like two sides of the same coin, nanotechnology can be both boon and bane for respiratory medicine. Nanomaterials open new ways in diagnostics and treatment of lung diseases. Nanoparticle based drug delivery systems can help against diseases such as lung cancer, tuberculosis, and pulmonary fibrosis. Moreover, nanoparticles can be loaded with DNA and act as vectors for gene therapy in diseases like cystic fibrosis. Even lung diagnostics with computer tomography (CT) or magnetic resonance imaging (MRI) profits from new nanoparticle based contrast agents. However, the risks of nanotechnology also have to be taken into consideration as engineered nanomaterials resemble natural fine dusts and fibers, which are known to be harmful for the respiratory system in many cases. Recent studies have shown that nanoparticles in the respiratory tract can influence the immune system, can create oxidative stress and even cause genotoxicity. Another important aspect to assess the safety of nanotechnology based products is the absorption of nanoparticles. It was demonstrated that the amount of pulmonary nanoparticle uptake not only depends on physical and chemical nanoparticle characteristics but also on the health status of the organism. The huge diversity in nanotechnology could revolutionize medicine but makes safety assessment a challenging task.     

Neural regeneration therapies for Alzheimer's and Parkinson's disease-related disorders

Neurodegenerative diseases are devastating mental illnesses without a cure. Alzheimer's disease (AD) characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. Although tremendous progress has made in understanding the basic biology in disease processes in AD and PD, we still do not have early detectable biomarkers for these diseases. Just in the United States alone, federal and nonfederal funding agencies have spent billions of dollars on clinical trials aimed at finding drugs, but we still do not have a drug or an agent that can slow the AD or PD disease process. One primary reason for this disappointing result may be that the clinical trials enroll patients with AD or PD at advances stages. Although many drugs and agents are tested preclinical and are promising, in human clinical trials, they are mostly ineffective in slowing disease progression. One therapy that has been promising is ‘stem cell therapy’ based on cell culture and pre-clinical studies. In the few clinical studies that have investigated therapies in clinical trials with AD and PD patients at stage I. The therapies, such as stem cell transplantation – appear to delay the symptoms in AD and PD. The purpose of this article is to describe clinical trials using 1) stem cell transplantation methods in AD and PD mouse models and 2) regenerative medicine in AD and PD mouse models, and 3) the current status of investigating preclinical stem cell transplantation in patients with AD and PD.     

Diseases of echinoderms

Diseases of echinoderms are poorly documented. Most reports concern biotic diseases caused by animal agents. While parasites on echinoderms have been described in increasing numbers of papers for more than one century, the host-parasite relationship and the effects of parasitism on echinoderm life-cycles were rarely considered. The parasitic fauna differs markedly according to the echinoderm group concerned, depending on various factors such as feeding-habits or symbiogenesis. Microorganismic diseases undoubtedly occur in echinoderms but they were not investigated until recently. Microorganisms have frequently been assumed to act as agents causing mass mortalities. As for stress-caused diseases, the only — and very preliminary — data available concern almost exclusively those induced by pollution. Since echinoderms are major components of benthic ecosystems, echinoderm diseases may be expected to exert prominent ecological effects.     

Synthesis and hybridization data of oligonucleotide analogs with triazole internucleotide linkages, potential antiviral and antitumor agents

Triazolyl-functionalized oligonucleotide (ON) analogs have received much attention as potential antitumor and antiviral agents. The most promising of such analogs are those exhibiting high binding affinity toward native DNA/RNA, since they may prove to be efficient antisense or siRNA agents. To date, relatively few ON analogs with triazole internucleotide linkages have been described. In this paper, we report an improved synthesis of a modified dinucleoside phosphoramidite and hybridization data of ON analogs with four-bond triazole internucleotide linkages. We believe these data are essential for comprehensive analysis of the relation between the length of triazole internucleotide linkages and duplex stability.     

Genetic determinants of platelet function in thromboembolic diseases

Within the past decade our understanding of thromboembolic disorders has become even more sophisticated as recent discoveries have suggested the influence of gene variants on the development of atherosclerotic disease and arterial thrombosis. Candidate genes encode proteins involved in processes relevant to atherosclerosis, ranging from cholesterol metabolism to arterial thrombosis. Platelets are key elements in primary hemostasis, but also in arterial thrombosis. Moreover, a number of genetic polymorphisms of platelet proteins may also induce gain or loss of function, supporting a role predisposing some individuals to thrombotic events. However, after thousands of studies, much controversy remains whether individual platelet polymorphisms contribute to an increased likelihood of thromboembolic disorders. Although platelet polymorphisms are a promising addition to more established cardiovascular risk factors, identifying genetic variants as a single cause of cardiovascular disease would be an oversimplification; instead, the contribution of these polymorphisms should also be considered in the context of a multifactorial disease. Gene-gene and gene-environment studies would identify specific combinations associated with a high risk to suffer from these diseases. The platelet's genetic heterogeneity should also be considered in every aspect of clinical medicine, ranging from susceptibility to diseases, pathogenesis, and clinical outcome to diversity in responses to drug treatment (pharmacogenomics), and bleeding.     

Nanoparticles and cancer therapy: Perspectives for application of nanoparticles in the treatment of cancers

Rapid growth in nanotechnology toward the development of nanomedicine agents holds massive promise to improve therapeutic approaches against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multifunctionality. Nowadays, nanoparticles (NPs) have multiple applications in different branches of science. In recent years, NPs have repetitively been reported to play a significant role in modern medicine. They have been analyzed for different clinical applications, such as drug carriers, gene delivery to tumors, and contrast agents in imaging. A wide range of nanomaterials based on organic, inorganic, lipid, or glycan compounds, as well as on synthetic polymers has been utilized for the development and improvement of new cancer therapeutics. In this study, we discuss the role of NPs in treating cancer among different drug delivery methods for cancer therapy.     

Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common. Genetic variants, especially single nucleotide polymorphisms (SNPs), show substantial heterogeneity in frequency among different GPCRs but have not been evaluated for some GPCR. Many therapeutic agonists and antagonists target GPCR and show inter-subject variability in terms of efficacy and toxicity. For most of those agents, it remains an open question whether genetic variation in primary sequence of the GPCR is an important contributor to such inter-subject variability, although this is an active area of investigation.     

Antiresorptive agents and osteoclast apoptosis

Antiresorptive agents have proven to be effective therapies for the treatment of bone diseases associated with excessive osteoclast activity. Decreased osteoclast formation, inhibition of osteoclast actions, and reduced osteoclast survival represent mechanisms by which antiresorptive agents could act. The goals of this article are to present the evidence that antiresorptive agents can decrease osteoclast survival through apoptosis, to review the mechanisms by which they are thought to activate the apoptotic process, and to consider whether the actions on apoptosis fully account for the antiresorptive effects. As background, the apoptotic process will be briefly summarized together with the evidence that factors that promote osteoclast survival affect steps in the process. Following this, therapeutic agents that are both antiresorptive and can stimulate osteoclast apoptosis will be discussed. Other bone therapeutic agents that are either antiresorptive or apoptotic, but not both, will be described. Finally, newer antiresorptive compounds that elicit apoptosis and could represent potential therapeutic agents will be noted.     

Suppression of premature termination codons as a therapeutic approach

In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.     

Suppression of premature termination codons as a therapeutic approach

In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.