An adaptive drug delivery design using neural networks for effective treatment of infectious diseases: A simulation study

An adaptive drug delivery design is presented in this paper using neural networks for effective treatment of infectious diseases. The generic mathematical model used describes the coupled evolution of concentration of pathogens, plasma cells, antibodies and a numerical value that indicates the relative characteristic of a damaged organ due to the disease under the influence of external drugs. From a system theoretic point of view, the external drugs can be interpreted as control inputs, which can be designed based on control theoretic concepts. In this study, assuming a set of nominal parameters in the mathematical model, first a nonlinear controller (drug administration) is designed based on the principle of dynamic inversion. This nominal drug administration plan was found to be effective in curing "nominal model patients" (patients whose immunological dynamics conform to the mathematical model used for the control design exactly. However, it was found to be ineffective in curing "realistic model patients" (patients whose immunological dynamics may have off-nominal parameter values and possibly unwanted inputs) in general. Hence, to make the drug delivery dosage design more effective for realistic model patients, a model-following adaptive control design is carried out next by taking the help of neural networks, that are trained online. Simulation studies indicate that the adaptive controller proposed in this paper holds promise in killing the invading pathogens and healing the damaged organ even in the presence of parameter uncertainties and continued pathogen attack. Note that the computational requirements for computing the control are very minimal and all associated computations (including the training of neural networks) can be carried out online. However it assumes that the required diagnosis process can be carried out at a sufficient faster rate so that all the states are available for control computation.

Effective treatment of infectious diseases: A nonlinear adaptive control theoretic approach

A nonlinear adaptive system theoretic approach is presented in this paper for effective treatment of infectious diseases that affect various organs of the human body. The generic model used does not represent any specific disease. However, it mimics the generic immunological dynamics of the human body under pathological attack, including the response to external drugs. From a system theoretic point of view, drugs can be interpreted as control inputs. Assuming a set of nominal parameters in the mathematical model, first a nonlinear controller is designed based on the principle of dynamic inversion. This treatment strategy was found to be effective in completely curing "nominal patients". However, in some cases it is ineffective in curing "realistic patients". This leads to serious (sometimes fatal) damage to the affected organ. To make the drug dosage design more effective, a model-following neuro-adaptive control design is carried out using neural networks, which are trained (adapted) online. From simulation studies, this adaptive controller is found to be effective in killing the invading microbes and healing the damaged organ even in the presence of parameter uncertainties and continuing pathogen attack.

Effective drug dosage design for treatment of infectious diseases using dynamic inversion

A generic nonlinear mathematical model describing the human immunological dynamics is used to design an effective automatic drug administration scheme. Even though the model describes the effects of various drugs on the dynamic system, this work is confined to the drugs that kill the invading pathogen and heal the affected organ. From a system theoretic point of view, the drug inputs can be interpreted as control inputs, which can be designed based on control theoretic concepts. The controller is designed based on the principle of dynamic inversion and is found to be effective in curing the �nominal model patient� by killing the invading microbes and healing the damaged organ. A major advantage of this technique is that it leads to a closed-form state feedback form of control. It is also proved from a rigorous mathematical analysis that the internal dynamics of the system remains stable when the proposed controller is applied. A robustness study is also carried out for testing the effectiveness of the drug administration scheme for parameter uncertainties. It is observed from simulation studies that the technique has adequate robustness for many �realistic model patients� having off-nominal parameter values as well.

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

Background: Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation. Results: We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed. Conclusion: The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.

Immunointervention for patients with HIV and tuberculosis

Therapeutic options aimed at confronting the HIV pandemic face many obstacles. Current opinion on HIV-induced pathogenic immune activation and strategies aimed at eliminating HIV, including a potential role for non-neutralising antibodies as part of a therapeutic vaccine option, was elegantly reviewed by Martin Cadogan and Angus Dalgleish. 1 It is important to note that, for eliciting such antibody responses in patients, functionally fit antigen presenting cells and effector T and B cells are cruc.

A delphi study on health in future India

PIP: A delphi study was conducted to identify or envision health scenarios in India by the year 2000. Questionnaires consisting of 48 questions on 5 areas (diagnosis and therapy; family planning; pharmaceuticals and drugs; biochemical and biomedical research; health services) were mailed to 250 experts in India. 36 responded. Results were compiled and mailed back to the respondents for changes and comments. 17 people responded. Results of the delphi study shows that policy decisions with respect to compulsory family planning as well as health education at secondary school level will precede further breakthroughs in birth control technology. Non operation reversible sterilization procedures, immunological birth control, Ayurvedic medicines for contraception and abortion, and selection of baby's sex are all possible by 2000 thereafter. Complete eradication of infectious diseases, malnutrition and associated diseases is considered unlikely before 2000, as are advances in biomedical research. Changes in health services (e.g., significant increases in hospital beds and doctors, cheap bulk drugs), particularly in rural areas, are imminent, leading to prolonging of life expectancy to 70 years. Genetic engineering may provide significant breakthroughs in the prevention of malignancies and cardiac disorders. The India delphi study is patterned after a similar delphi study conducted in the U.S. by Smith, Kline and French (SKF) Laboratories in 1968. The SKF study was able to predict some breakthroughs with basic research which have been realized.

Molecular markers for discriminating Streptococcus pyogenes and S.dysgalactiae subspecies equisimilis

Given the increasing aetiological importance of Streptococcus dysgalactiae subspecies equisimilis in diseases which are primarily attributed to S. pyogenes, molecular markers are essential to distinguish these species and delineate their epidemiology more precisely. Many clinical microbiology laboratories rely on agglutination reactivity and biochemical tests to distinguish them. These methods have limitations which are particularly exacerbated when isolates with mixed properties are encountered. In order to provide additional distinguishing parameters that could be used to unequivocally discriminate these two common pathogens, we assess here three molecular targets: the speB gene, intergenic region upstream of the scpG gene (IRSG) and virPCR. Of these, the former two respectively gave positive and negative results for S. pyogenes, and negative and positive results for S. dysgalactiae subsp. equisimilis. Thus,a concerted use of these nucleic acid-based methods is particularly helpful in epidemiological surveillance to accurately assess the relative contribution of these species to streptococcal infections and diseases.

Detection of IgG, IgA, IgM and IgE Antibodies in Invasive Amoebiasis in Endemic Areas

Entamoeba histolytica-specific serum IgG, IgA, IgM and IgE antibodies were assayed in cases of amoebiasis in an endemic area. Patient groups consisted of amoebic liver abscess (n=18), pre-abscess hepatic amoebiasis (n=22) and amoebic colitis (n=30). Control subjects comprised 26 asymptomatic cyst passers, 13 giardiasis cases, 20 typhoid patients and 24 non-amoebic individuals. Serum IgG was assayed by ELISA, using a monoclonal anti IgG β- galactosidase (IgG β-gal) conjugate, a polyclonal avidin biotin horse radish peroxidase (AB-HRP), and a polyclonal anti IgG horse radish peroxidase (IgG HRP) conjugate. IgA and IgM were assayed by the β-gal ELISA and IgE by AB-HRP. Diagnostically significant IgG and IgA while lower IgM and IgE antibody levels were seen in extraintestinal cases. About 40% of suspected pre-abscess hepatic amoebiasis cases were confirmed by antibody estimation. All isotype levels in most dysentery cases were in the range of the controls.

Factors associated with 2009 pandemic influenza A (H1N1) vaccination acceptance among university students from India during the post-pandemic phase

Background: There was a low adherence to influenza A (H1N1) vaccination program among university students and health care workers during the pandemic influenza in many parts of the world. Vaccination of high risk individuals is one of the recommendations of World Health Organization during the post-pandemic period. It is not documented about the student's knowledge, attitude and willingness to accept H1N1 vaccination during the post-pandemic period. We aimed to analyze the student's knowledge, attitude and willingness to accept H1N1 vaccination during the post-pandemic period in India. Methods: Vaccine against H1N1 was made available to the students of Vellore Institute of Technology, India from September 2010. The data are based on a cross-sectional study conducted during October 2010 to January 2011 using a self-administered questionnaire with a representative sample of the student population (N = 802). Results: Of the 802 respondents, only 102/802 (12.7%) had been vaccinated and 105/802 (13%) planned to do so in the future, while 595/802 (74%) would probably or definitely not get vaccinated in the future. The highest coverage was among the female (65/102, 63.7%) and non-compliance was higher among men in the group (384/595; 64.5%) (p < 0.0001). The representation of students from school of Bio-sciences and Bio-technology among vaccinees is significantly higher than that of other schools. Majority of the study population from the three groups perceived vaccine against H1N1 as the effective preventive measure when compared to other preventive measures. 250/595 (42%) of the responders argued of not being in the risk group. The risk perception was significantly higher among female (p < 0.0001). With in the study group, 453/802 (56.4%) said that they got the information, mostly from media. Conclusions: Our study shows that the vaccination coverage among university students remains very low in the post-pandemic period and doubts about the safety and effectiveness of the vaccine are key elements in their rejection. Our results indicate a need to provide accessible information about the vaccine safety by scientific authorities and fill gaps and confusions in this regard.

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-beta (TGF-beta)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for ``decoding'' these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-beta- or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2- and NOD receptor-mediated surmounting of CTLA-4- and TGF-beta -suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC delta-MAPK-dependent activation of NF-kappa B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

HLA-B*57 and Gender Influence the Occurrence of Tuberculosis in HIV Infected People of South India

Background. Substantial evidence exists for HLA and other host genetic factors being determinants of susceptibility or resistance to infectious diseases. However, very little information is available on the role of host genetic factors in HIV-TB coinfection. Hence, a longitudinal study was undertaken to investigate HLA associations in a cohort of HIV seropositive individuals with and without TB in Bangalore, South India. Methods. A cohort of 238 HIV seropositive subjects were typed for HLA-A, B, and DR by PCR-SSP and followed up for 5 years or till manifestation of Tuberculosis. HLA data of 682 HIV Negative healthy renal donors was used as control. Results. The ratio of males and females in HIV cohort was comparable (50.4% and 49.6%). But the incidence of TB was markedly lower in females (12.6%,) than males (25.6%). Further, HLA-B* 57 frequency in HIV cohort was significantly higher among females without TB (21.6%, 19/88) than males (1.7%, 1/59); P = 0.0046; OR = 38. CD4 counts also were higher among females in this cohort. Conclusion. This study suggests that HIV positive women with HLA-B* 57 have less occurrence of TB as compared to males.

Multifaceted roles of curcumin: two sides of a coin!

Introduction: Curcumin has been a front-line topic of mainstream scientific research for a variety of diseases from cancer to Alzheimer's to infectious diseases. Curcumin suppresses the type 1 immune response, which might lead to alleviation of type 1 immune response disorders. However, the inhibition of type 1 immune response might invite infections with opportunistic pathogens. Considering its low bioavailability, several curcumin derivatives have been designed to improve its functionality. Areas covered: This is a consolidated review which aims to compare and contrast diverse aspects of curcumin in variety of diseases. The intricate underlying mechanisms and the functional determinants of curcumin are discussed. Expert opinion: Curcumin being considered as a spicy panacea, is not a remedy for all diseases. However, its ability to act differentially as an antioxidant or pro-oxidant akin to that of a double-edged sword/friend turning foe can be either beneficial or harmful for the host. It exhibits antioxidant properties at concentrations achievable in the body, making the host vulnerable to infections due to the suppression of innate immune responses. With the increase in knowledge of its functional groups, production of analogues of curcumin is underway to enhance its bioavailability and hence its therapeutic potency.