For a better understanding of the mechanisms involved in vertical transmission of HIV

Maternal-infant transmission of human immunodeficiency virus-1 (HIV) is the primary cause of this retrovirus infection in neonates. The mechanisms of vertical transmission of HIV, in particular in utero transmission, remain poorly defined. Trophoblastic cells from the placenta are thought to be a target of HIV infection and/or may be utilized by the virus to be transported across the placental barrier by a process known as transcytosis. The vertical transmission of HIV (via infection or transcytosis) may be either favoured or inhibited by factors related to both the viral phenotype and the cellular environment.     

Estimating treatment effects in studies of perinatal transmission of HIV

Fetal loss often precludes the ascertainment of infection status in studies of perinatal transmission of HIV. The standard analysis based on liveborn babies can result in biased estimation and invalid inference in the presence of fetal death. This paper focuses on the problem of estimating treatment effects for mother-to-child transmission when infection status is unknown for some babies. Minimal data structures for identifiability of parameters are given. Methods using full likelihood and the inverse probability of selection-weighted estimators are suggested. Simulation studies are used to show that these estimators perform well in finite samples. Methods are applied to the data from a clinical trial in Dar es Salaam, Tanzania. To validly estimate the treatment effect using likelihood methods, investigators should make sure that the design includes a mini-study among uninfected mothers and that efforts are made to ascertain the infection status of as many babies lost as possible. The inverse probability weighting methods need precise estimation of the probability of observing infection status. We can further apply our methodology to the study of other vertically transmissible infections which are potentially fatal pre- and perinatally.     

Spatial and temporal modelling for parasite transmission studies and risk assessment

Spatial and temporal modelling of parasite transmission and risk assessment require relevant spatial information at appropriate spatial and temporal scales. There is now a large literature that demonstrates the utility of satellite remote sensing and spatial modelling within geographical information systems (GIS) and firmly establishes these technologies as the key tools for spatial epidemiology. This review outlines the strength of satellite remotely sensed data for spatial mapping of landscape characteristics in relation to disease reservoirs, host distributions and human disease. It is suggested that current satellite technology can fulfill the spatial mapping needs of disease transmission and risk modelling, but that temporal resolution, which is a function of the satellite data acquisition characteristics, may be a limitating factor for applications requiring information about landscape or ecosystem dynamics. The potential of the Modis sensor for spatial epidemiology is illustrated with reference to mapping spatial and temporal vegetation dynamics and small mammal parasite hosts on the Tibetan plateau. Future research directions and priorities for landscape epidemiology are considered.     

Mathematical models of HIV pathogenesis and treatment

We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long-term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long-term non-progression.     

Mathematical theory of chemical synaptic transmission

Mathematical theory of chemical synaptic transmission is suggested in which the modes of operation of chemical synapses are given as consequencies of some fundamental theoretical principles presented in the form of systems of quantum and macroscopic postulates. These postulates establish transmitter transfer rules between 3 component parts — cytoplasmic, vesicular and external pools of neurotransmitter. The main features of the transfers are determined by special properties of the dividing membranes (synaptic and vesicle) which show high selectivity towards the direction of the transmitter quantum transfer. The formulation of a previously unknown effect of transmitter quantum transfer from the vesicular pool into the cytoplasmic one is introduced: it is postulated that each arriving presynaptic impulse not only releases a constant fraction of the current contents of the cytoplasmic pool into the synaptic cleft (external pool), but also realizes practically simultaneous transmitter transfer from the vesicular pool into the cytoplasmic one. Zone structure of the vesicular pool is postulated. In accordance with basic equations of the theory a nonlinear control system (dynamic synaptic modulator — DYSYM) of transmitter release from the terminal is constructed.Depending on the parameters relation two types of synapses are classified — those with rapid and slow demobilization. Analytical dependencies of the transmitter pools sizes on the stimulation frequency are introduced. By fitting the frequency dependencies to the empirical data model parameters are determined corresponding to a set of experimentally studied synaptic junctions. Different aspects of the chemical synapse behaviour under the influence of presynaptic stimulation are simulated.     

Mathematical formulation of cardiovascular dynamics by use of the laplace transform

By means of the Laplace transform, the behavior of a simplified model of the cardiovascular system is mathematically formulated. This formulation allows mathematical expression of the periodicity of the cardiac output and the systemic response. With the cardiac output represented as half of a sine function cycle, the systolic aortic pressure becomes the sum of a sine term and exponential terms, while the sum of the exponential terms alone represents the diastolic pressure. The characteristics of the mathematical expressions for systole and diastole are analyzed, and some relationships of potentially practical value are derived. Variation in the parameters of the system yields mathematical results consistent with the expected physical ones.     

Mathematical studies in animal populations

Zusammenfassung Die vorliegende Arbeit ist eine Fortsetzung derThompson'schen Analysen des Parasitenzyklus bei Insekten, die mit der irrealen Folgerung endeten, dass unter gewissen Voraussetzungen — die wir in der gegenwärtigen Analyse akzeptiert haben —jeder Parasit in relativ kurzer Generationenfolge seinen Wirt, und damit sich selbst, zur Ausrottung bringen muss. Der Einfluss von wiederkehrenden Umwelt-katastrophen wie sie z.B. durch ungünstiges Wetter sehr häufig bedingt sind, wurde untersucht mit dem Ergebnis, dass solche Katastrophen, wenn sie in nicht allzugrossen Intervallen auftreten, völlig genügen, um die Unterbrechung der akkumulativen Parasitierung im Zyklus zu erklären.Die grössere Empfindlichkeit der Parasiten, welche aus allen Beobachtungen und Analysen sich ergibt, ist nicht physiologisch, sondern ökologisch bedingt. Methodisch hat sich gezeigt, dass die Analyse tierischer Populationen weitgehend ohne Anwendung von Integralen möglich ist.Die Ergebnisse, welche die hohe Bedeutung der Feinde bei grosser Wirtsdichte, und ihre minimale Wirksamkeit, wenn letztere niedrig ist, zeigen, sind unabhängig von einem besonderen Dichtefaktor der Feindvermehrung — wie er im allgemeinen besteht und die aufgezeigten Tendenzen noch verstärkt — gewonnen. Der Einfluss des Superparasiten wird unter dem Einfluss wiederkehrender Umwelt-katastrophen minimal. Am Modell einiger beobachteter Gradationen wird die Übereinstimmung mit unserer Analvse demonstriert.

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Résumé Le travail ci-dessus est la continuation des analyses deThompson des cycles parasitaires chez les insectes, qui l'ont à la conclusion absurde qu'en acceptant certaines suppositions — que nous avons acceptées dans la présente analyse — chaque parasite exterminerait son hôte et par conséquent soi-même. Nous avons étudié l'influence de certains phénomènes catastrophiques récurrents provenant du milieu comme par exemple celle d'un temps défavorable. Ces phénomènes, pourvu qu'ils ne se présentent pas à des intervalles trop grands, suffisent amplement pour expliquer l'interruption de la parasitation accumulative dans les cycles.La sensibilité plus grande des parasites qui est démontrée dans toutes les observations et analyses ne provient pas de causes physiologiques, mais écologiques.La méthodologie a donné comme résultat intéressant le fait que l'analyse des populations animales peut se faire sans l'application des intégrales.Les résultats démontrant la grande importance des ennemis quand les hôtes sont nombreux, mais par contre une activité minimale des ennemis quand les hôtes sont rares, ont été obtenus indépendamment d'une augmentation spéciale des ennemis qui, en général, constitue un facteur important, ce qui renforce encore les tendances que nous avons trouvées. L'influence des superparasites devient minime sous l'action des catastrophes récurrentes dus au milieu. Finalement, au moyen de quelques gradations bien observées, nous avons démontré que notre analyse est conforme aux faits.

     

The role of HIV replicative fitness in perinatal transmission of HIV

Perinatal transmission of Human immunodeficiency virus(HIV),also called mother-to-child transmission(MTCT),accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers.Among HIV-1 infected mothers,some viruses are transmitted from mothers to their infants while others are not.The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear.Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies.Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted,when those two viruses are grown together.Furthermore,the higher fitness is determined by the gp120 protein of the virus envelope.This suggests that the selective transmission of viruses with higher fitness occurred exclusively,regardless of transmission routes.There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected.This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT.     

Target cells in vaginal HIV transmission

Understanding the mechanisms of HIV transmission to women will be crucial to the development of effective strategies to curb this epidemic. Current data suggest that HIV has at least two routes to penetrate the vaginal epithelium and reach lymphoid tissues, trans-epithelial migration of infected Langerhans cells or virus penetration into the lamina propria through loss of epithelial integrity resulting in direct infection of lymphocytes, dendritic cells and macrophages.     

Network-based analysis of comorbidities risk during an infection: SARS and HIV case studies

Background

Infections are often associated to comorbidity that increases the risk of medical conditions which can lead to further morbidity and mortality. SARS is a threat which is similar to MERS virus, but the comorbidity is the key aspect to underline their different impacts. One UK doctor says "I’d rather have HIV than diabetes" as life expectancy among diabetes patients is lower than that of HIV. However, HIV has a comorbidity impact on the diabetes.

Results

We present a quantitative framework to compare and explore comorbidity between diseases. By using neighbourhood based benchmark and topological methods, we have built comorbidity relationships network based on the OMIM and our identified significant genes. Then based on the gene expression, PPI and signalling pathways data, we investigate the comorbidity association of these 2 infective pathologies with other 7 diseases (heart failure, kidney disorder, breast cancer, neurodegenerative disorders, bone diseases, Type 1 and Type 2 diabetes). Phenotypic association is measured by calculating both the Relative Risk as the quantified measures of comorbidity tendency of two disease pairs and the ϕ-correlation to measure the robustness of the comorbidity associations. The differential gene expression profiling strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response and statistically dysregulates a large number of genes, pathways and PPIs subnetworks in different pathologies such as chronic heart failure (21 genes), breast cancer (16 genes) and bone diseases (11 genes). HIV-1 induces comorbidities relationship with many other diseases, particularly strong correlation with the neurological, cancer, metabolic and immunological diseases. Similar comorbidities risk is observed from the clinical information. Moreover, SARS and HIV infections dysregulate 4 genes (ANXA3, GNS, HIST1H1C, RASA3) and 3 genes (HBA1, TFRC, GHITM) respectively that affect the ageing process. It is notable that HIV and SARS similarly dysregulated 11 genes and 3 pathways. Only 4 significantly dysregulated genes are common between SARS-CoV and MERS-CoV, including NFKBIA that is a key regulator of immune responsiveness implicated in susceptibility to infectious and inflammatory diseases.

Conclusions

Our method presents a ripe opportunity to use data-driven approaches for advancing our current knowledge on disease mechanism and predicting disease comorbidities in a quantitative way.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-333) contains supplementary material, which is available to authorized users.     

Extrasynaptic transmission and the diffusion parameters of the extracellular space

Extrasynaptic volume transmission, mediated by the diffusion of neuroactive substances in the extracellular space (ECS), plays an important role in short- and long-distance communication between nerve cells. The ability of a substance to reach extrasynaptic high-affinity receptors via diffusion depends on the ECS diffusion parameters, ECS volume fraction alpha (alpha=ECS volume/total tissue volume) and tortuosity lambda (lambda2=free/apparent diffusion coefficient), which reflects the presence of diffusion barriers represented by, e.g., fine astrocytic processes or extracellular matrix molecules. These barriers channel the migration of molecules in the ECS, so that diffusion may be facilitated in a certain direction, i.e. anisotropic. The diffusion parameters alpha and lambda differ in various brain regions, and diffusion in the CNS is therefore inhomogeneous. Changes in diffusion parameters have been found in many physiological and pathological states, such as development and aging, neuronal activity, lactation, ischemia, brain injury, degenerative diseases, tumor growth and others, in which cell swelling, glial remodeling and extracellular matrix changes are key factors influencing diffusion. Changes in ECS volume, tortuosity and anisotropy significantly affect the accumulation and diffusion of neuroactive substances and thus extrasynaptic transmission, neuron-glia communication, mediator "spillover" and synaptic crosstalk as well as, cell migration. The various changes occurring during pathological states can be important for diagnosis, drug delivery and treatment.     

Predicting the unpredictable: transmission of drug-resistant HIV

We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.     

Immunostimulatory action of AC II--an ayurvedic formulation useful in HIV

Immunostimulatory activity of AC II, a registered ayurvedic preparation prepared at Amala Ayurvedic Research Centre for treating HIV and AIDS is reported. AC II administration could significantly enhance the mitogen-induced proliferation of lymphocytes of spleen cells. It was also found to increase cell-mediated immune responses in normal and tumor-bearing control animals. Oral administration of AC II significantly enhanced Natural Killer cell activity in normal and tumor-bearing animals on the 7th day, which was observed earlier than the tumor-bearing control animals and normal animals. Antibody dependent cellular cytotoxicity (ADCC) was also increased in AC II treated normal and tumor-bearing animals. An early enhancement of antibody-dependent complement-mediated cytotoxicity was also observed by the administration of AC II in normal as well as tumor-bearing animals. Treatment with AC II elevated the levels of IL-2, TNF-alpha and IFN-gamma in normal mice. Administration of AC II was also found to increase the cytotoxic T lymphocyte production in EL4 treated mice. These studies support the use of this immune stimulatory preparation in HIV patients.