Deciphering modern glucocorticoid cross-pharmacology using ancestral corticosteroid receptors.

Steroid receptors (SRs) are the largest family of metazoan transcription factors and control genes involved in development, endocrine signaling, reproduction, immunity, and cancer. The entire hormone receptor system is driven by a molecular switch triggered by the binding of small lipophilic ligands. This makes the SRs ideal pharmaceutical targets, yet even the best clinically approved synthetic steroidal agonists are prone to cross-reactivity and off-target pharmacology. The mechanism underlying this promiscuity is derived from the fact that SRs share common structural features derived from their evolutionary relationship. More often than not, rational attempts to probe SR drug selectivity via mutagenesis fail even when high quality structural and functional data are available due to the fact that important mutations often result in nonfunctional receptors. This highlights the fact that SRs suffer from instability, preventing in-depth mutational analysis and hampering crystallization of key receptor-ligand complexes. We have taken a unique approach to address this problem by using a resurrected ancestral protein to determine the structure of a previously intractable complex and identified the structural mechanisms that confer activation and selectivity for a widely used glucocorticoid, mometasone furoate. Moreover, we have identified a single residue located outside of the ligand-binding pocket that controls mometasone furoate antagonism versus agonism in the human mineralocorticoid receptor.

Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor.

Understanding how protein structures and functions have diversified is a central goal in molecular evolution. Surveys of very divergent proteins from model organisms, however, are often insufficient to determine the features of ancestral proteins and to reveal the evolutionary events that yielded extant diversity. Here we combine genomic, biochemical, functional, structural, and phylogenetic analyses to reconstruct the early evolution of nuclear receptors (NRs), a diverse superfamily of transcriptional regulators that play key roles in animal development, physiology, and reproduction. By inferring the structure and functions of the ancestral NR, we show--contrary to current belief--that NRs evolved from a ligand-activated ancestral receptor that existed near the base of the Metazoa, with fatty acids as possible ancestral ligands. Evolutionary tinkering with this ancestral structure generated the extraordinary diversity of modern receptors: sensitivity to different ligands evolved because of subtle modifications of the internal cavity, and ligand-independent activation evolved repeatedly because of various mutations that stabilized the active conformation in the absence of ligand. Our findings illustrate how a mechanistic dissection of protein evolution in a phylogenetic context can reveal the deep homology that links apparently "novel" molecular functions to a common ancestral form.

Conflicting accountabilities: Doctor's dilemma in TB control in rural India.

OBJECTIVE: The aim of this study was to analyse how the implementation strategy of direct observed treatment short course (DOTS) has shaped and influenced patient-provider encounters in a district tuberculosis centre (DTC) in a rural district of India. METHOD: Qualitative methods, combining observations and interviews, were carried out in a DTC focusing on the medical encounters between a TB doctor and his patients. RESULTS: The findings showed that the TB doctor seemed to be working with a dilemma, defined as conflicting accountabilities, in the medical encounters. In an organization perceived as inefficient and resource-constrained, the doctor struggled to find a balance between meeting the obligations of the DOTS programme and meeting the needs and expectations of the patients. Strategies to deal with these conflicting accountabilities were identified as limiting patients' involvement, struggling to maintain authority, and transferring responsibility. CONCLUSION: Professional involvement and patient participation were seen as part of a linked process in this study, and the importance of empowering doctors and health care workers who are implementing DOTS is emphasized. The development of DOTS guidelines needs to be based on the actual process of health care delivery, and staff empowering efforts should also include strengthening of public health care infrastructure.

Power imbalance and consumerism in the doctor-patient relationship: health care providers' experiences of patient encounters in a rural district in India.

The aim of this study is to explore health care providers' experiences and perceptions of their encounters with male and female patients in a rural district in India with special reference to tuberculosis (TB) care. The authors conducted semistructured interviews with 22 health care providers, 17 men and 5 women, from the public and private health care sectors. Findings reveal that doctors adopted an authoritarian as well as a consumerist approach in the medical encounter, indicating that power imbalances in the doctor-patient relationship are negotiable and subject to change. Gender was identified as an influencing factor of the doctor's dominance. A patient-centered approach, acknowledging patients' own experiences and shared decision making, is called for and should be included in TB control activities. This seems to be especially important for female patients, whose voices were not heard in the medical encounter.

Spatial pattern of private health care provision in Ujjain, India: a provider survey processed and analysed with a Geographical Information System.

In developing countries like India, official information on private health care providers is scanty. This is an obstacle for effective health care planning and policy development. In this paper, we present a project aimed to enumerate, characterise and digitally map all private providers (PPs) using Geographical Information System (GIS) in a rural district in India. A team of surveyors carried out a census of private providers in the district. This data was combined with official data on geophysical characteristics and infrastructure, demographic situation and location of settlements and public health care providers. This study highlights the need to consider PPs in health policy making in India. The survey identified about 2000 additional PPs over and above those listed with the health authorities. About half practised modern medicine (Allopathy) while the rest practised other types of formal medical systems (Ayurveda or Homeopathy) or informal therapeutic systems. Individuals with no formal health care training constituted the majority of PPs. Formally trained doctors were highly concentrated in urban areas while trained non-doctors and untrained PPs dominated in the rural areas. The study shows how GIS can be used to create an improved basis for health services research. In the future, the digitised map will be used as a sampling frame and point of reference for studies on quality and utilisation of PPs in Ujjain district. However, the utility for health care planning is less clear. GIS has limitations in countries like India due to lack of valid routine data to enter into GIS as well as to competing demand for health care resources.

Establishment of social club for adolescents living in urban slums: a potential tool to impart HIV/AIDS education.

An interventional study was carried out under a Government of Madhya Pradesh, India supported project with aims to describe establishment of a social club (a youth club), incorporating strategy of life-skill-based education and its potential as a tool for creating HIV/AIDS awareness among adolescents of age 15-19 years living in slums of Ujjain city. The social club activities included AIDS education by combined methods, vocational training and recreational activities for the adolescents. Establishment of social club was feasible with available local resources. Social club activities were need based, thus received good response from adolescents (94% had attendance above 75% in AIDS awareness sessions). Knowledge and attitude improved and misconceptions reduced significantly by AIDS education. Majority (86%) of the participants contributed as AIDS messengers in the community. The social clubs seem to have potential to improve HIV/AIDS awareness and empower adolescents to adopt healthy lifestyle through combination of teen friendly activities and atmosphere.