Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis.

Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be ß-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs) S. mitis/S. oralis strain and its daptomycin-resistant (DAPr) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAPr variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPs strain following treatment with daptomycin. The parental strain and the DAPr variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPr variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.

Generation and characterisation of monoclonal antibodies specific to avian influenza H7N9 haemagglutinin protein.

INTRODUCTION: Emerging virulent strains of influenza virus pose a serious public health threat with potential pandemic consequences. A novel avian influenza virus, H7N9, breached the species barrier from infected domestic poultry to humans in 2013 in China. Since then, it has caused numerous infections in humans with a close contact to poultry. MATERIALS AND METHODS: In this study, we describe the preliminary characterisation of five murine monoclonal antibodies (MAbs) developed against recombinant haemagglutinin (rHA) protein of avian H7N9 A/Anhui/1/2013 virus by their Western blot and enzyme-linked immunosorbent assay (ELISA) reactivity and binding affinity. RESULTS: Of the five MAbs, four were highly specific to H7N9 HA and did not show any cross-reactivity in ELISA with rHA protein from pandemic as well as seasonal H1N1, H2N2, H3N2, H5N1 and influenza virus B (B/Brisbane/60/2008). However, one of the MAbs, MA-24, in addition to HA protein of H7N9 also reacted strongly with HA protein of H3N2 and weakly with HA of pandemic and seasonal H1N1 and H2N2. All the five MAbs also reacted with H7N9 rHA in Western blot. The MAbs bound H7N9 rHA with an equilibrium dissociation constant (KD) ranging between 0.14 and 25.20 nM, indicating their high affinity to HA. CONCLUSIONS: These antibodies may be useful in developing diagnostic tools for the detection of influenza H7N9 virus infections.

Stratifying empiric risk of schizophrenia among first degree relatives using multiple predictors in two independent Indian samples.

BACKGROUND: Schizophrenia (SZ) has an estimated heritability of 64-88%, with the higher values based on twin studies. Conventionally, family history of psychosis is the best individual-level predictor of risk, but reliable risk estimates are unavailable for Indian populations. Genetic, environmental, and epigenetic factors are equally important and should be considered when predicting risk in 'at risk' individuals. OBJECTIVE: To estimate risk based on an Indian schizophrenia participant's family history combined with selected demographic factors. METHODS: To incorporate variables in addition to family history, and to stratify risk, we constructed a regression equation that included demographic variables in addition to family history. The equation was tested in two independent Indian samples: (i) an initial sample of SZ participants (N=128) with one sibling or offspring; (ii) a second, independent sample consisting of multiply affected families (N=138 families, with two or more sibs/offspring affected with SZ). RESULTS: The overall estimated risk was 4.31±0.27 (mean±standard deviation). There were 19 (14.8%) individuals in the high risk group, 75 (58.6%) in the moderate risk and 34 (26.6%) in the above average risk (in Sample A). In the validation sample, risks were distributed as: high (45%), moderate (38%) and above average (17%). Consistent risk estimates were obtained from both samples using the regression equation. CONCLUSIONS: Familial risk can be combined with demographic factors to estimate risk for SZ in India. If replicated, the proposed stratification of risk may be easier and more realistic for family members.

Knowledge & attitudes of mental health professionals regarding psychiatric research.

BACKGROUND & OBJECTIVES: Mental health professionals have varied attitudes and views regarding informed consent and confidentiality protections in psychiatric research and clinical care. The present study was designed to understand the knowledge and views of mental health professionals (MHPs) regarding informed consent and confidentiality protection practices. METHODS: Mental health professionals (n=121) who were members of the Delhi Psychiatric Society, were invited to participate in this questionnaire-based study of their knowledge and attitudes regarding informed consent and confidentiality. Half of them expressed willingness to discuss participation and gave initial oral consent (n=62); of these, 31 gave written informed consent to participate and completed the questionnaires. The questionnaires included both forced choice (yes / no / do not know) and open-ended questions. Questionnaires content reflected prominent guidelines on informed consent and confidentiality protection. RESULTS: Attitudes of the majority of the participants towards informed consent and confidentiality were in line with ethical principles and guidelines. All expressed the opinion that confidentiality should generally be respected and that if confidentiality was breached, there could be mistrust of the professional by the patient/participant. The mean knowledge scores regarding informed consent and confidentiality were 8.55 ± 1.46 and 8.16 ± 1.29, respectively. INTERPRETATION & CONCLUSIONS: The participating mental health professionals appeared to have adequate knowledge of basic ethical guidelines concerning informed consent and confidentiality. Most respondents were aware of ethical issues in research. Given the small sample size and low response rate, the significance of the quantitative analysis must be regarded with modesty, and qualitative analysis of open-ended questions may be more valuable for development of future research. Increased efforts to involve mental health professionals in research on ethical concerns pertinent to their work must be made, and the actual practices of these professionals with regard to ethical guidelines need to be studied.

Tutorials on basics of bioethics: an experience with post-graduate health professionals.

BACKGROUND: All health professionals are morally bound to recognize and address ethical issues in their daily practice. Understanding basics of bioethics can help professionals promote autonomy and protect the welfare of both patients and research participants. As part of the Fogarty International Center, NIH, USA, funded "Training Program for Psychiatric Genetics in India," NNM was trained in bioethics at University of Pittsburgh under the mentorship of Lisa S Parker, PhD. OBJECTIVES: The overall goal of this Tutorial project was to translate NNM's Ethics training for hospital-based Indian health professionals to sensitize them to the ethical issues arising in psychiatric research and practice. METHODOLOGY: After receiving official permission from the medical superintendent of PGIMER-Dr. R.M.L. Hospital, New Delhi, the program was announced. Candidates with a degree in one of the Health Care Sciences were enrolled. Five two-hour interactive sessions were held weekly on five topics. An evaluation of the effectiveness of the interactive tutorial program was conducted. RESULTS: A total of 16 participants enrolled in these tutorials. The post-program evaluation of satisfaction for all topics of the program by participants indicated high mean score. The main need identified was for continued refreshing of bioethical knowledge and skills through academic activities.

Disability certificates in India: a challenge to health privacy.

A "disability certificate" is necessary to access benefits afforded under the Persons with Disabilities Act (1995) in India. This paper analyses this requirement and concludes that it constitutes a major challenge to maintaining privacy of health information especially for persons with mental health disabilities in India and recommends modifications in the certificate's format and use, to reduce the magnitude of privacy infringement for those using the disability certificate to access benefits to which they are legally entitled.

Clinical and genetic correlates of severity in schizophrenia in India: an ordinal logistic regression approach.

Genetic association studies of schizophrenia typically utilize diagnostic status as the trait of interest. Among Indian schizophrenia (SZ) participants, we evaluated genetic associations (selected single nucleotide polymorphisms (SNPs) associated with SZ) with selected indices of severity and symptom pattern. Ordinal logistic regression enabled us to analyze variables with multiple categories as outcome variables, while incorporating key demographic variables; this form of analysis may be useful in future genetic association studies. No significant associations were detected following corrections for multiple comparisons.

Privacy and the Right to Information Act, 2005.

Privacy is a key component of individual autonomy, and a voluminous literature has established both its practical value in healthcare contexts and its status as a fundamental, but not absolute ethical right. Because the Right to Information Act (2005) permits citizens to gain information under government control, it might be thought to threaten the privacy of patients and research subjects, especially those in government institutions. It is important for clinicians, administrators, information officers, patients, and research subjects to understand that the RTI Act generally does not require or permit disclosure of personal health information to third parties. Only under unusual circumstances when the larger public interest is properly certified to warrant it, would information shared or created within the fiduciary relationships of clinical care or research be required to be disclosed. Against this background concerning the right to privacy and the RTI Act, we consider a 2007 legal case that used the RTI Act to expose patient information of a public official and argue that the "public interest" claimed in this case did not justify disclosure of the official's private health information. We conclude that the provisions of the RTI Act, when properly interpreted, are compatible with the important value of safeguarding patient privacy.

Membrane fluidity and lipid composition in clinical isolates of Candida albicans isolated from AIDS/HIV patients.

In this study, we describe the membrane lipid composition of eight clinical isolates (azole resistant and sensitive strains) of Candida albicans isolated from AIDS/ HIV patients. Interestingly, fluorescence polarization measurements of the clinical isolates displayed enhanced membrane fluidity in fluconazole resistant strains as compared to the sensitive ones. The increase in fluidity was reflected in the change of membrane order, which was considerably decreased (decrease in fluorescence polarization "p" value denotes higher membrane fluidity) in the resistant strains. The ergosterol content in azole susceptible isolates was greater, almost twice as compared to the resistant isolates. However, no significant alteration was observed in phospholipid and fatty acid composition of these isolates. Labeling experiments with fluorescamine dye revealed that the percentage of phosphatidylethanolamine exposed to the membrane's outer leaflet was higher in the resistant strains as compared to the sensitive strains, indicating increased floppase activity of the two major ABC drug efflux pumps, CDR1 and CDR2 possibly due to their overexpression in resistant strains. The results of the present study suggest that changes in the status of membrane lipid phase especially the ergosterol content and increased activity of drug efflux pumps by overexpression ofABC transporters, CDR1 and CDR2 might contribute to fluconazole resistance in C. albicans isolated from AIDS/HIV patients.

Synthesis and in vivo hypoglycemic screening studies on some life essential metal complexes of oral antidiabetic [N-(p-tolylsulphonyl)-N'-n butyl-urea] (tolbutamide).

Present communication deals with the synthesis of complexes of [N-(p-tolylsulphonyl)-N'-n butyl-urea], with certain transition metals viz. Cu(II), Zn(II), Fe(II) and Cd(II). Structures of all the complexes have been established on the basis of their consistent elemental and spectral analysis. Also, it reports their in vivo hypoglycemic screening on albino rats. Out of all the complexes studied, Zn-Tolbutamide complex could be recommended as more potent hypoglycemic agent in lieu of tolbutamide alone.