From U Cape Town: What is the Cost of Diagnosis and Management of Drug Resistant Tuberculosis in South Africa?

http://www.ncbi.nlm.nih.gov/pubmed/23349933

PLoS One. 2013;8(1):e54587. doi: 10.1371/journal.pone.0054587. Epub 2013 Jan 18.

What is the Cost of Diagnosis and Management of Drug Resistant Tuberculosis in South Africa?

Pooran A, Pieterson E, Davids M, Theron G, Dheda K.

Source

Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Abstract

BACKGROUND:

Drug-resistant tuberculosis (DR-TB) is undermining TB control in South Africa. However, there are hardly any data about the cost of treating DR-TB in high burden settings despite such information being quintessential for the rational planning and allocation of resources by policy-makers, and to inform future cost-effectiveness analyses.

METHODOLOGY:

We analysed the comparative 2011 United States dollar ($) cost of diagnosis and treatment of drug sensitive TB (DS-TB), MDR-TB and XDR-TB, based on National South African TB guidelines, from the perspective of the National TB Program using published clinical outcome data.

PRINCIPAL FINDINGS:

Assuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257). Despite DR-TB comprising only 2.2% of the case burden, it consumed ∼32% of the total estimated 2011 national TB budget of US $218 million. 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively. XDR-TB consumed 28% of the total DR-TB diagnosis and treatment costs. Laboratory testing and anti-TB drugs comprised the majority (71%) of MDR-TB costs while hospitalization and anti-TB drug costs comprised the majority (92%) of XDR-TB costs. A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ∼7%.

CONCLUSION/SIGNIFICANCE:

Although DR-TB forms a very small proportion of the total case burden it consumes a disproportionate and substantial amount of South Africa's total annual TB budget. These data inform rational resource allocation and selection of management strategies for DR-TB in high burden settings.

From the Journal of Medical Ethics: The 'fetus as a patient' in maternal-fetal surgery

http://www.ncbi.nlm.nih.gov/pubmed/23349508

J Med Ethics. 2013 Jan 24. [Epub ahead of print]

Dotting the I's and crossing the T's: autonomy and/or beneficence? The 'fetus as a patient' in maternal-fetal surgery.

Rodrigues HC, van den Berg PP, Düwell M.

Source

Department of Obstetrics and Gynaecology, UMCG, Groningen, Groningen, The Netherlands.

Abstract

Chervenak and McCullough, authors of the most acknowledged ethical framework for maternal-fetal surgery, rely on the 'ethical-obstetrical' concept of the fetus as a patient in order to determine what is morally owed to fetuses by both physicians and the women who gestate them in the context of prenatal surgery. In this article, we reconstruct the argumentative structure of their framework and present an internal criticism. First, we analyse the justificatory arguments put forward by the authors regarding the moral status of the fetus qua patient. Second, we discuss the internal coherence and consistency of the moral obligations those authors derive from that concept. We claim that some of the dilemmas their approach is purported to avoid, such as the debate about the independent moral status of the fetus, and the foundation of the moral obligations of pregnant women (towards the fetuses they gestate) are not, all things considered, avoided. Chervenak and McCullough construct the obligations of physicians as obligations towards entities with equal moral status. But, at the same time, they assume that the woman has an independent moral status while the moral status of the fetus is dependent on the decision of the woman to present it to a physician for care. According to the logic of their own argumentation, Chervenak and McCullough implicitly admit a different moral status of the woman and the fetus, which will lead to different ascription of duties of the physician than those they ascribed.

Financing Medical Care in Underdeveloped Nations

http://www.bullhpl.org/resources/Publications/VanLangendonckOrigArtBHPL-Prod.pdf

Financing Medical Care in Underdeveloped Nations: Reflections from the Past and Context for the FutureJozef Van Langendonck, PhD 

Abstract: Global healthcare financing continues to create challenges for underdeveloped nations at the present time. Yet efforts to address the challenges of providing the necessary resources still continue to focus upon ad hoc solutions rather than a systemically focused, member state, mandatory contributions that build upon extant infrastructures such as WHO, WTO, the Global Fund, and other bodies. Yet it is important to realize these structures continue to need quality assurance, measurement, and evaluation, while a system of global social security oversight still needs creation that can effectively govern such efforts. A funding system based on stable funding and appropriate, governance-based structure can promote more focused, targeted financing, leading to improved global health. 


Published: 10 January 2013
Cite as: Van Langendonck J. Financing Medical Care in Underdeveloped Nations: Reflections from the Past and Context for the Future Bull Health L Policy. 2012;1(2).

http://www.ncbi.nlm.nih.gov/pubmed/23349343

Am J Hosp Palliat Care. 2013 Jan 23. [Epub ahead of print]

Attitude Toward Euthanasia Scale: Psychometric Properties and Relations With Religious Orientation, Personality, and Life Satisfaction.

Aghababaei N, Wasserman JA.

Abstract

End-of-life decisions (ELDs) represent a controversial subject, with ethical dilemmas and empirical ambiguities that stand at the intersection of ethicsand medicine. In a non-Western population, we examined individual differences in perceiving ELDs that end the life of a patient as acceptable and found that an attitude toward euthanasia (ATE) scale consists of 2 factors representing voluntary and nonvoluntary euthanasia. Also, acceptance of ELDs that end the life of a patient negatively correlated with life satisfaction, honesty-humility, conscientiousness, and intrinsic and extrinsic personal motivation toward religion. These findings provided additional construct validity of the ATE scale.

CPRIT: "three grants...were approved without proper review...for a total of approximately $56.3 million"

http://www.texastribune.org/2013/01/28/state-audit-exposes-problems-cancer-institute/

State Audit Exposes More Problems at Cancer Institute

• by Becca Aaronson
• January 28, 2013

State auditors found business and professional relationships between CPRIT’s management, CPRIT’s commercialization review council, and donors who contributed to the CPRIT Foundation, a non-profit association that supplements the salaries of CPRIT’s executive director and chief scientific officer. They also found three grants that were approved without proper review — the executive director recommended the applications receive grants, but the peer review council did not — for a total of approximately $56.3 million. CPRIT also broke a state constitutional requirement by allowing grantees to report matching funds spent on other projects, rather than the CPRIT-funded research project, according to the audit.

Meningitis deathwatch: 44

http://news.yahoo.com/judge-freezes-assets-owners-meningitis-linked-pharmacy-184626153.html

Judge freezes assets of owners of meningitis-linked pharmacy

By Tim McLaughlin | Reuters – 2 hrs 6 mins ago

BOSTON (Reuters) - A bankruptcy judge on Monday froze the assets of the owners of the pharmacy linked to a deadly U.S. meningitis outbreak.

Orders signed by U.S. Bankruptcy Judge Henry Boroff temporarily restrict the owners of New England Compounding Center (NECC) from selling their luxury homes or spending up to $21 million they received last year in salary and shareholder distributions.

NECC filed for bankruptcy protection in December after U.S. authorities shut down its pharmacy operations amid a meningitis outbreak that has killed 44 people and sickened nearly 700 others, according to the U.S. Centers for Disease Control.

http://www.ncbi.nlm.nih.gov/pubmed/23349442

Eur Respir J. 2013 Jan 24. [Epub ahead of print]

3D culture model to distinguish normal from malignant human bronchial epithelial cells.

Fessart D, Begueret H, Delom F.

Source

Centre de recherche Cardio-Thoracique de Bordeaux, U1045, F-33000 Bordeaux, France.

Abstract

In the present study, we have developed an in vitro three-dimensional (3D) model to differentiate normal from lung cancer cells in order to study the mechanisms resulting in lung cancer.Using a reconstituted laminin-rich basement membrane (Matrigel), we were able to culture normal human bronchial epithelial cells (HBEC) and a subset of malignant cells. The two cell types can be readily distinguished by the ability of normal cells to express a structurally and functionally differentiated phenotype within Matrigel. HBEC embedded in Matrigel as single cells were able to form multi-cellular spherical colonies with a final size close to that of true acini in situ. Sections of mature spheres revealed a central lumen surrounded by polarized epithelial cells. In contrast, none of malignant cells tested, cell lines and lung biopsies, responded to basement membrane by lumen formation.These results demonstrated that this in vitro glandular tumour model can be useful for studies of bronchial oncogene. Indeed, these findings may provide basis for a rapid assay to discriminate normal human bronchial epithelial cells from their malignant counterparts.Therefore, the 3D tumour bronchial epithelial acinar-like sphere represents a novel in vitro model to further investigate pathophysiological functions resulting in lung cancer.

Tim Mackey and Bryan Liang: "brain drain continues to destabilise public health systems and their populations globally"

http://www.ncbi.nlm.nih.gov/pubmed/23336617

Glob Health Action. 2013 Jan 15;6(0):1-7. doi: 10.3402/gha.v6i0.19923.

Restructuring brain drain: strengthening governance and financing for health worker migration.

Mackey TK, Liang BA.

Source

Institute of Health Law Studies, California Western School of Law, San Diego, CA; Joint Doctoral Program in Global Health, University of California San Diego-San Diego State University, San Diego, CA; Joint Program on Health Policy & Law, UC San Diego-California Western School of Law, San Diego, CA; tmackey@ucsd.edu.

Abstract

Background: Health worker migration from resource-poor countries to developed countries, also known as ''brain drain'', represents a serious global health crisis and a significant barrier to achieving global health equity. Resource-poor countries are unable to recruit and retain health workers for domestic health systems, resulting in inadequate health infrastructure and millions of dollars in healthcare investment losses. 

Methods: Using acceptable methods of policy analysis, we first assess current strategies aimed at alleviating brain drain and then propose our own global health policy based solution to address current policy limitations. 

Results: Although governments and private organizations have tried to address this policy challenge, brain drain continues to destabilise public health systems and their populations globally. Most importantly, lack of adequate financing and binding governance solutions continue to fail to prevent health worker brain drain. 

Conclusions: In response to these challenges, the establishment of a Global Health Resource Fund in conjunction with an international framework for health worker migration could create global governance for stable funding mechanisms encourage equitable migration pathways, and provide data collection that is desperately needed.

Academic freedoms in the UK: "They are running large businesses."

http://www.guardian.co.uk/education/2013/jan/26/historians-warn-minister-over-academic-freedom

Historians warn minister: hands off our academic freedoms

Proposals by David Willetts are condemned by coalition of academic groups for giving universities a 'stranglehold' over publications

• Daniel Boffey, policy editor
• The Observer, Saturday 26 January 2013 08.57 EST

"Senior managers, even if they were once academics, now seem to be following a completely different agenda very much set by government policy. They are running large businesses."

Tristram Hunt, a fellow of the RHS, presenter of TV history programmes and a Labour MP, added that it was "an attack on the quality and integrity of academic research".

All the concerned groups said they agreed with providing easier access to academic research, but Professor Howard Hotson, a fellow of St Anne's College, Oxford, who sits on the steering council for the Council for the Defence of British Universities, said they all shared grave concerns at the pace of the changes being rolled out.

He said: "One of the things which flabbergasts me is the seemingly insatiable appetite for this government to pursue multiple radical changes simultaneously. It seems extraordinarily naive to suppose that on the basis of a few months of consultation, in a very short space of time, you can radically change the basic way in way academics communicate with each other without having a huge number of unintended knock-on consequences. Open access in principle has a great deal to be said for it, but it has to be handled with care."

http://www.ncbi.nlm.nih.gov/pubmed/23344120

Knee Surg Sports Traumatol Arthrosc. 2013 Jan 24. [Epub ahead of print]

Legitimate division of large data sets, salami slicing and dual publication, where does a fraud begin?

Karlsson J, Beaufils P.

Source

Department of Orthopaedics, Sahlgrenska University Hospital, SE-431 80, Mölndal, Sweden, Jon.karlsson@telia.com.

The number of submitted manuscripts is increasing sharply from year to year in almost all international journals. Among the many reasons for the increased number of manuscripts, salami slicing deserves special attention. Salami slicing consists of splitting data from the same research into small units, each of which is submitted—and in many cases published—separately. Whereas a single study previously led to the submission of a single—large—article, the data may now be divided into several manuscripts, which are subsequently submitted to a single journal or to several journals. The prevalence of salami slicing, although not unappreciable, is difficult to determine. Reported values have ranged from only 1 % [1] or 1.8 % [6] to more than 15 % [2]. Salami slicing is driven by an author’s desire or need to achieve a larger number of publications, in order to gain recognition, move up on the academic career ladder, attract research funds by increasing the institution’s visibility and/or obtain financial gain [3, 7, 9].

http://www.ncbi.nlm.nih.gov/pubmed/23343064

N Engl J Med. 2013 Jan 24;368(4):351-64. doi: 10.1056/NEJMsa1211127.

50-year trends in smoking-related mortality in the United States.

Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, Hartge P, Gapstur SM.

Source

Department of Epidemiology, American Cancer Society, Atlanta, GA 30303-1002, USA. michael.thun@cancer.org

Abstract

BACKGROUND:

The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear.

METHODS:

We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up.

RESULTS:

For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates.

CONCLUSIONS:

The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.

http://www.ncbi.nlm.nih.gov/pubmed/23344557

Psychopharmacology (Berl). 2013 Jan 24. [Epub ahead of print]

Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers.

Dawkins L, Turner J, Crowe E.

Source

School of Psychology, University of East London, Water Lane, Stratford, London, E15 4LZ, UK, l.e.dawkins@uel.ac.uk.

Abstract

RATIONALE:

It is well established that nicotine improves, and deprivation impairs, cognitive performance and mood in smokers. Prospective memory (PM), remembering to execute a delayed intention at a given time point, is under-explored in smokers. Whilst a handful of studies have shown improved PM with nicotine, the effects of nicotine delivered via the electroniccigarette (e-cigarette) have not been investigated.

OBJECTIVE:

This study explores whether, by comparison with placebo, nicotine delivered via the e-cigarette can improve PM,tobacco withdrawal symptoms and desire to smoke in abstinent smokers.

METHODS:

Twenty smokers, abstinent for 8-10 h, each completed two experimental sessions under nicotine (18 mg) and placebo (0 mg) e-cigarette conditions. Participants completed a single-item desire-to-smoke scale and the Mood and Physical Symptoms Scale. PM was measured using the Cambridge Prospective Memory Test.

RESULTS:

Compared with placebo, the nicotine e-cigarette reduced the desire to smoke and tobacco withdrawal symptoms, and improved time-based but not event-based PM. There was a moderate, marginally significant negative correlation between PM performance during abstinence and nicotine dependence.

CONCLUSIONS:

This is the first study to show that nicotine derived via e-cigarette can improve PM in abstinent smokers, suggesting efficient nicotine delivery. The finding that the effect of nicotine was restricted to time-based rather than event-based PM is consistent with the view that nicotine acts to improve performance on strategic (effortful) rather than automatic processing. These findings add to the growing body of evidence that the e-cigarette can replace some of the effects of nicotine derived from tobacco smoking, thus highlighting its potential for smoking cessation.

From Columbia U: Cognitive insight in individuals at clinical high risk for psychosis

http://www.ncbi.nlm.nih.gov/pubmed/23343417

Early Interv Psychiatry. 2013 Jan 24. doi: 10.1111/eip.12023. [Epub ahead of print]

Cognitive insight in individuals at clinical high risk for psychosis.

Kimhy D, Jobson-Ahmed L, Ben-David S, Ramadhar L, Malaspina D, Corcoran CM.

Source

Department of Psychiatry, Columbia University, New York, New York, USA; Center of Prevention and Evaluation, New York State Psychiatric Institute, New York, New York, USA.

Abstract

AIM:

Reduced cognitive insight has been associated with psychotic symptoms, in particular with the presence of delusions; however, there is little information about whether such reductions are present in at-risk individuals prior to the onset of threshold psychotic symptoms.

METHOD:

We conducted a cross-sectional comparison of cognitive insight (as indexed by the Beck Cognitive Insight Scale) in 62 help-seeking individuals at clinical high risk for psychosis, Fifty-nine individuals with schizophrenia-spectrum disorders and 37 healthy controls (HC). In patients, we evaluated associations of insight with positive symptoms, including later transition topsychosis in high-risk patients.

RESULTS:

Individuals with schizophrenia reported significantly higher self-certainty scores than the at-risk patients and HCs, with the at-risk patients scoring intermediate to the individuals with schizophrenia andcontrols. Similarly, individuals with schizophrenia scored significantly higher on self-reflectiveness, with no differences between the at-risk patients and controls. In individuals with schizophrenia, delusions were significantly correlated with self-certainty. In at-risk patients, cognitive insight was not associated with positive symptom severity and did not differentiate those at-risk patients who later developedpsychosis from those who did not. However, post hoc analyses suggested that at-risk patients with marked unusual thought content (approaching threshold psychosis) had lower self-reflectiveness; whereas those with high suspiciousness had significantly higher self-certainty.

CONCLUSIONS:

The findings are discussed in the context of normal developmental processes occurring during adolescence, their putative links to neurobiological functioning, and their implications for treatment and future research.

From U New Mexico: An Evidence-Based Preschool Intervention for Obesity Prevention in Head Start

http://www.ncbi.nlm.nih.gov/pubmed/23343323

J Sch Health. 2013 Mar;83(3):223-9. doi: 10.1111/josh.12018.

CHILE: An Evidence-Based Preschool Intervention for Obesity Prevention in Head Start.

Davis SM, Sanders SG, Fitzgerald CA, Keane PC, Canaca GF, Volker-Rector R.

Source

Director, (SDavis@salud.unm.edu), Prevention Research Center, University of New Mexico, 1 University of New Mexico, MSC 11 6145, Albuquerque, NM 87131.

Abstract

BACKGROUND:

Obesity is a major concern among American Indians and Hispanics. The Child Health Initiative for Lifelong Eating and Exercise (CHILE) is an evidence-based intervention to prevent obesity in children enrolled in 16 Head Start (HS) Centers in rural communities. The design and implementation of CHILE are described.

METHODS:

CHILE uses a socioecological approach to improve dietary intake and increase physical activity. The intervention includes: a classroom curriculum; teacher and food service training; family engagement; grocery store participation; and health care provider support.

RESULTS:

Lessons learned from CHILE include the need to consider availability of recommended foods; the necessity of multiple training sessions for teachers and food service; the need to tailor the family events to local needs; consideration of the profit needs of grocery stores; and sensitivity to the time constraints of health care providers.

CONCLUSIONS:

HS can play an important role in preventing obesity in children. CHILE is an example of a feasible intervention that addresses nutrition and physical activity for preschool children that can be incorporated into HS curricula and aligns with HS national performance standards.

http://www.ncbi.nlm.nih.gov/pubmed/23345086

J Bioeth Inq. 2013 Jan 24. [Epub ahead of print]

Bioethics and Its Gatekeepers: Does Institutional Racism Exist in Leading Bioethics Journals?

Chattopadhyay S, Myser C, De Vries R.

Source

Department of Physiology and Institutional Ethics Committee, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok, Sikkim, 737102, India, linkdrsc@yahoo.com.

Abstract

Who are the gatekeepers in bioethics? Does editorial bias or institutional racism exist in leading bioethics journals? We analyzed the composition of the editorial boards of 14 leading bioethics journals by country. Categorizing these countries according to their Human Development Index (HDI), we discovered that approximately 95 percent of editorial board members are based in (very) high-HDI countries, less than 4 percent are from medium-HDI countries, and fewer than 1.5 percent are from low-HDI countries. Eight out of 14 leading bioethics journals have no editorial board members from a medium- or low-HDI country. Eleven bioethics journals have no board members from low-HDI countries. This severe underrepresentation of bioethics scholars from developing countries on editorial boards suggests that bioethics may be affected by institutional racism, raising significant questions about the ethics of bioethics in a global context.

Should Radiologists Perform Interventional Procedures in the Absence of Clinical Backup?

http://www.ncbi.nlm.nih.gov/pubmed/23345386

AJR Am J Roentgenol. 2013 Feb;200(2):W215. doi: 10.2214/AJR.12.8895.

MEDICOLEGAL: Malpractice and Ethical Issues in Radiology: Should Radiologists Perform Interventional Procedures in the Absence of Clinical Backup?

Berlin L.

Source

NorthShore University HealthSystem, Department of Radiology, Skokie Hospital, Skokie, IL; Professor of Radiology, Rush University and University of Illinois, Chicago, IL (lberlin@live.com).

Unfortunately, no abstract.

From Temple U: Code of ethics: principles for ethical leadership

http://www.ncbi.nlm.nih.gov/pubmed/23346028

Perspect Health Inf Manag. 2013;10:1d. Epub 2013 Jan 1.

Code of ethics: principles for ethical leadership.

Flite CA, Harman LB.

Source

Department of Health Information Management at Temple University in Philadelphia, PA.

Abstract

The code of ethics for a professional association incorporates values, principles, and professional standards. A review and comparative analysis of a 1934 pledge and codes of ethics from 1957, 1977, 1988, 1998, 2004, and 2011 for a health information management association was conducted. Highlights of some changes in the healthcare delivery system are identified as a general context for the codes of ethics. The codes of ethics are examined in terms of professional values and changes in the language used to express the principles of the various codes.

http://www.ncbi.nlm.nih.gov/pubmed/23346043

Ger Med Sci. 2013;11:Doc03. Epub 2013 Jan 21.

Aspects of vulnerable patients and informed consent in clinical trials.

Kuthning M, Hundt F.

Source

University Duisburg-Essen, Germany.

Abstract

Scope: To discuss the rationale behind informed consent in clinical trials focusing on vulnerable patients from a European and German viewpoint. 

Methods: Scientific literature search via PubMed, Medline, Google.

Results: Voluntary informed consent is the cornerstone of policies regulating clinical trials. To enroll a patient into a clinical trial without having obtained written and signed consent is to be considered as a serious issue in the conduct of a clinical trial. Development of ethical guidance for physicians started before Christ Era with the Hippocratic Oath. Main function of consent, as articulated in all guidelines developed for clinical research, is to facilitate an individual's freedom of choice, respect autonomy, and thus to ensure welfare of the participants in clinical trials. Minors are unable to provide legally binding informed consent, this issue is addressed through a combination of parental permission and minor's assent. Illiteracy is a critical problem that affects all corners of our earth; it has no boundaries and exists among every race and ethnicity, age group, and economic class. New strategies to improve communication with patients including the use of videotapes or animated cartoon illustrations could be taught. Finally the time with the potential participant seems to be the best way to improve understanding. 

Conclusion: Discovery of life saving and life enhancing new treatments requires partnership that is based on good communication and trust between patients and researchers, sponsors, ethics committees, authorities, lawyers and politicians so that vulnerable patients can benefit from the results of well controlled clinical trials.

http://www.ncbi.nlm.nih.gov/pubmed/23331027

Curr Pharm Des. 2013 Jan 17. [Epub ahead of print]

Rescuing mutant CFTR: a multi-task approach to a better outcome in treating Cystic Fibrosis.

Amaral MD, Farinha CM.

Source

BioFiG - Center for Biodiversity, Functional and Integrative Genomics Department of Chemistry & Biochemistry, Faculty of Sciences, University of Lisboa Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal. mdamaral@fc.ul.pt.

Abstract

Correcting multiple defects of mutant CFTR with small molecule compounds has been the goal of an increasing number of recent Cystic Fibrosis (CF) drug discovery programmes. However, the mechanism of action (MoA) by which these molecules restore mutant CFTR is still poorly understood, in particular of CFTR correctors, i.e., compounds rescuing to the cells surface the most prevalent mutant in CF patients - F508del-CFTR. However, there is increasing evidence that to fully restore the multiple defects associated with F508del-CFTR, different small molecules with distinct corrective properties may be required. Towards this goal, a better insight into MoA of correctors is needed and several constraints should be addressed. The methodological approaches to achieve this include: 1) testing the combined effect of compounds with that of other (non-pharmacological) rescuing strategies (e.g., revertants or low temperature); 2) assessing effects in multiple cellular models (non-epithelial vs epithelial, non-human vs human, immortalized vs primary cultures, polarized vs non polarized, cells vs tissues); 3) assessing compound effects on isolated CFTR domains (e.g., compound binding by surface plasmon resonance , assessing effects on domain folding and aggregation); and finally 4) assessing compounds specificity in rescuing different CFTR mutants and other mutant proteins. These topics are reviewed and discussed here so as to provide a state-of-the art review on how to combine multiple ways of rescuing mutant CFTR to the ultimate benefit of CF patients.