Strategic protein target analysis for developing drugs to stop dental caries

Dental caries is the most common disease to cause irreversible damage in humans. Several therapeutic agents are available to treat or prevent dental caries, but none besides fluoride has significantly influenced the disease burden globally. Etiologic mechanisms of the mutans group streptococci and specific Lactobacillus species have been characterized to various degrees of detail, from identification of physiologic processes to specific proteins. Here, we analyze the entire Streptococcus mutans proteome for potential drug targets by investigating their uniqueness with respect to non-cariogenic dental plaque bacteria, quality of protein structure models, and the likelihood of finding a drug for the active site. Our results suggest specific targets for rational drug discovery, including 15 known virulence factors, 16 proteins for which crystallographic structures are available, and 84 previously uncharacterized proteins, with various levels of similarity to homologs in dental plaque bacteria. This analysis provides a map to streamline the process of clinical development of effective multispecies pharmacologic interventions for dental caries.     

Copper mediated one-pot synthesis of quinazolinones and exploration of piperazine linked quinazoline derivatives as anti-mycobacterial agents

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C–N bonds in good to excellent yields. With the optimised method, we synthesized a library of piperazine linked quinazoline derivatives and the synthesized compounds were evaluated for their inhibitory activity against Mycobacterium tuberculosis. The compounds 8b, 8e, 8f, 8m, 8n and 8v showed potent anti-mycobacterial activity with MIC values of 2–16 μg mL⁻¹. All the synthesized compounds follow Lipinski''s rules for drug likeness.

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C–N bonds in good to excellent yields.     

Biomarkers in sarcoidosis

Introduction: Numerous biomarkers have been evaluated for the diagnosis, assessment of disease activity, prognosis, and response to treatment in sarcoidosis. In this report, we discuss the clinical and research utility of several biomarkers used to evaluate sarcoidosis.

Areas covered: The sarcoidosis biomarkers discussed include serologic tests, imaging studies, identification of inflammatory cells and genetic analyses. Literature was obtained from medical databases including PubMed and Web of Science.

Expert commentary: Most of the biomarkers examined in sarcoidosis are not adequately specific or sensitive to be used in isolation to make clinical decisions. However, several sarcoidosis biomarkers have an important role in the clinical management of sarcoidosis when they are coupled with clinical data including the results of other biomarkers.     

Setting priorities in global child health research investments: assessment of principles and practice

This article reviews theoretical and practical approaches for setting priorities in global child health research investments. It also provides an overview of previous attempts to develop appropriate tools and methodologies to define priorities in health research investments. A brief review of the most important theoretical concepts that should govern priority setting processes is undertaken, showing how different perspectives, such as medical, economical, legal, ethical, social, political, rational, philosophical, stakeholder driven, and others will necessarily conflict each other in determining priorities. We specially address present research agenda in global child health today and how it relates to United Nation's (UN) Millennium Development Goal 4, which is to reduce child mortality by two-thirds between 1990 and 2015. The outcomes of these former approaches are evaluated and their benefits and shortcomings presented. The case for a new methodology for setting priorities in health research investments is presented, as proposed by Child Health and Nutrition Research Initiative, and a need for its implementation in global child health is outlined. A transdisciplinary approach is needed to address all the perspectives from which investments into health research can be seen as priorities. This prioritization requires a process that is transparent, systematic, and that would take into account many perspectives and build on advantages of previous approaches.     

Setting priorities in global child health research investments: addressing values of stakeholders

Aim

To identify main groups of stakeholders in the process of health research priority setting and propose strategies for addressing their systems of values.

Methods

In three separate exercises that took place between March and June 2006 we interviewed three different groups of stakeholders: 1) members of the global research priority setting network; 2) a diverse group of national-level stakeholders from South Africa; and 3) participants at the conference related to international child health held in Washington, DC, USA. Each of the groups was administered different version of the questionnaire in which they were asked to set weights to criteria (and also minimum required thresholds, where applicable) that were a priori defined as relevant to health research priority setting by the consultants of the Child Health and Nutrition Research initiative (CHNRI).

Results

At the global level, the wide and diverse group of respondents placed the greatest importance (weight) to the criterion of maximum potential for disease burden reduction, while the most stringent threshold was placed on the criterion of answerability in an ethical way. Among the stakeholders’ representatives attending the international conference, the criterion of deliverability, answerability, and sustainability of health research results was proposed as the most important one. At the national level in South Africa, the greatest weight was placed on the criterion addressing the predicted impact on equity of the proposed health research.

Conclusions

Involving a large group of stakeholders when setting priorities in health research investments is important because the criteria of relevance to scientists and technical experts, whose knowledge and technical expertise is usually central to the process, may not be appropriate to specific contexts and in accordance with the views and values of those who invest in health research, those who benefit from it, or wider society as a whole.When decisions on investments in health research are made, the term “stakeholders” refers to all individuals and/or groups who have interest in prioritization of those investments. The stakeholders will therefore comprise a large and highly heterogeneous group. Some apparent examples may include research funding agencies (eg, governmental agencies, private organizations, public-private partnerships, international and regional organizations, and taxpayers of a certain region), direct recipients of the funding (eg, researchers and research institutions), beneficiaries of the research (eg, policy makers and the general population of a country), and any other group with interest in prioritization process (eg, advocacy groups, journalists and media, lawyers, economists, experts in ethics, and many others).Two fundamental characteristics of any acceptable and successful priority setting process are legitimacy and fairness (1). In order to ensure the legitimacy and fairness of the priority setting decisions in health research investments, involvement of a wide range of stakeholders (and/or eliciting their values) is needed. Unfortunately, health research priorities are presently mainly driven by technical experts (2-5). The results of prioritization are therefore in danger of being mostly influenced by their personal views, with minimal input from representatives from the wider community who also may have interest in the process but lack technical expertise. Since the values and criteria important to scientists and technical experts may vary remarkably from those of other relevant stakeholders (6-8), the relevance of eliciting wider stakeholders’ input is increasingly being acknowledged (9-11). However, the main challenge is to develop a systematic, flexible, and repeatable strategy on how this can be achieved in different contexts.The literature on priority setting for health interventions identifies two main strategies: 1) stakeholders’ values may impact decisions through procedural processes (by having access to the decisions and the rationales behind the decisions, and by having the authority to deliberate on the decisions and influence the final outcome); 2) stakeholders’ values can be directly elicited using quantitative methods (through surveys where respondents rank, weigh, or rate their values) and qualitative methods (involving individual interviews, Delphi technique, complaints procedures or group discussions, concept mapping, citizen’s jury, and public meetings) (12). The main challenges in those attempts have mainly been the lack of capacity for some stakeholders to engage in meaningful deliberations (13) and how to practically incorporate the elicited stakeholders’ values in decision-making (12,14). This paper presents our suggestions and experiences on how the values and interests of large and diverse group of stakeholders could still be incorporated in decisions on health research investment priorities. We specified thresholds and weights needed to address stakeholders’ values within CHNRI methodology using three different versions of a questionnaire. We aimed to assess stakeholders’ values for priority setting in global health research investments. We tested questionnaires that presented different levels of complexity and detail of the questions that stakeholders’ representatives would be asked. We also aimed to evaluate different strategies of turning their responses into numerical thresholds and weights.     

Epithelioid hemangioma of the temporal artery: a case report

Temporal or giant cell arteritis is the most common vasculitis affecting the temporal artery. We encountered an unusual case of involvement of the temporal artery, which showed marked proliferating capillaries admixed with a dense infiltrate of eosinophils affecting all layers of the vessel. It was concluded that these changes were those of an epithelioid hemangioma of the temporal artery.     

Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

For weeks after primary immunization with thymus-dependent antigens the responding lymph nodes contain effector CD4 T cells in T zones and germinal centers as well as recirculating memory T cells. Conversely, remote nodes, not exposed to antigen, only receive recirculating memory cells. We assessed whether lymph nodes with follicular effector CD4 T cells in addition to recirculating memory CD4 T cells mount a more rapid secondary response than nodes that only contain recirculating memory cells. Also, the extent to which T cell frequency governs accelerated CD4 T cell recall responses was tested. For this, secondary antibody responses to a superantigen, where the frequency of responding T cells is not increased at the time of challenge, were compared with those to conventional protein antigens. With both types of antigens similar accelerated responses were elicited in the node draining the site of primary immunization and in the contralateral node, not previously exposed to antigen. Thus recirculating memory cells are fully capable of mounting accelerated secondary responses, without the assistance of CD4 effector T cells, and accelerated memory responses are not solely dependent on higher T cell frequencies. Accelerated memory CD4 T cell responses were also seen in B cell-deficient mice.