Supramolecular chemistry from small molecules to cavitands: predictive and experimental approaches

Doctor of PhilosophyDepartment of ChemistryChrister B. AakeroyWe used the hydrogen-bond propensity (HBP) protocol for predicting if a co-crystal would form or not for six different target molecules in combination with 25 potential co-formers each. The correct outcome was successfully predicated 92-95% of the time, which indicates that for a series of small molecules, HBP is a very reliable indicator for determining if a co-crystal will form. In order to examine if hydrogen and halogen-bonded systems can mimic each other, we conducted co-crystallization experiments using eight targets in combination with 25 co-formers. Molecular electrostatic potential surface (MEPS) calculations were used to guide the experimental space. The results suggested that in all the cases, hydrogen and halogen-bonds mimic each other. Validation studies of MEPS gave a prediction accuracy range of 64-84%. Three different factors, hydrogen-bond propensity (HBP), hydrogen-bond coordination (HBC), and hydrogen-bond energies (HBE), were evaluated to predict the experimental outcomes of attempted co-crystallizations between two known drug molecules, Nevirapine and Diclofenac, and a series of potential co-formers. HBP gave the correct result in 26 out of 30 cases, whereas the HBC method predicted the correct outcome in 22 out of 30 cases. Finally, HBE gave the correct result in 23 out of 30 experiments. In those cases, where the crystal structure of a co-crystal of either Nevirapine or Diclofenac was known, we also examined how well the three methods predicted which primary hydrogen-bond interactions were present in the crystal structure. HBP correctly predicted 6 out of 6 cases, HBC could not predict any of the synthon formations correctly, and HBE successfully predicted 1 out of 6 cases. Three different factors, hydrogen-bond propensity (HBP), hydrogen-bond energy (HBE), and molecular complementarity (MC), were used for predicting co-crystallization outcomes of seven active pharmaceutical ingredients (APIs) in combination with 42 potential co-formers. Validation studies indicate that individually the methods did not offer high accuracy. Hence, we implemented a combination of methods using Venn diagrams. The results suggested that the combination of MC and HBP method yielded the highest accuracy of 80%. In order to ease the complexity of the predictive approaches, we designed CoForm, an automatic app for predicting co-crystallization outcomes. CoForm was used to predict co-crystallization outcomes for Loratadine and Desloratadine in combination with 42 generally regarded as safe (GRAS) list co-formers. The predictive abilities of CoForm were compared to commercially available tools such as HBP and MC. The results indicate that CoForm delivered a success rate of 80% for both Loratadine and Desloratadine in comparison to HBP 76% and 54%, respectively, and MC 39% and 22%, respectively. Six cavitands were synthesized to explore the guest encapsulation via cavity inclusion, using five solvents (xylene, dichloromethane, ethyl acetate, acetonitrile, and dimethyl sulfoxide) with varying dipole moment as a potential guest. Cavity inclusion studies indicated that the cavitands could encapsulate a guest in five different orientations, with stoichiometries 1:1 to 1:2. A selectivity study showed that the cavitands were more selective towards DMSO, which also had the highest dipole moment. Finally, cavitands were used as molecular containers for fragrant compounds and heterocyclic-N- oxides. In both cases, the host interacted with guests in 1:2 stoichiometry, as indicated by NMR titrations and TGA analysis. The host-guest interaction of cavitands with fragrant compounds lowered the volatility of the fragrant compounds from 5-10 mins to over a month

Abnormalities in semen analysis among male partners of infertile couples: a study in a tertiary care level hospital of West Bengal, India

Background: The prevalence of infertility in the general population is 15%-20%. Of this, the male factor is responsible for 20%-40%.Analysis of semen is the most important diagnostic tool for evaluation of role of males in infertility. The study was conducted to determine the abnormalities in semen among male partners in infertile couples.Methods: A descriptive study with cross-sectional design among male partners of infertile couples was conducted in the laboratory of the Department of Pathology at Burdwan Medical College, Burdwan in West Bengal during August 2011 to July 2012. Analysis of semen was done for semen volume, sperm number, sperm motility and presence of other cells.Results: 7.45% samples were of inadequate quantity. 19.87 % of cases had oligozoospermia, 12.42% had azoospermia and 4.35% of males had asthenozoospermia. Pus cells were found in 12.42% cases.Conclusions: Majority of the cases of infertility in males is due to oligozoospermia followed by azoospermia while less sperm motility or less amount of semen are also responsible in some cases

Cytological profile of Pap smears in a tertiary care hospital of West Bengal, India

Background: Among Indian women cancers of cervix and breast account for a very large proportion of malignancies. Majority of the cancer patients present themselves to the doctor at an advanced and incurable stage. Screening for cervical cancer can be done by Pap test which is a very simple and inexpensive test. Early detection and treatment of pre-cancerous conditions and cancers provide the best possible protection against cancer for the individual and the community.Methods: A descriptive study with cross-sectional design was conducted in the laboratory of the Department of Pathology at Bankura Sammilani Medical College, Bankura in West Bengal during January 2014 to December 2014. Analysis of cervical cytology was done for neoplastic cells.Results: Out of 288 smears 8.3% samples were unsatisfactory, 77.9% were without epithelial cell abnormality while 13.8% were abnormal comprising of atypical squamous cells of undetermined significance (ASCUS) 1.4%, low grade squamous intra-epithelial lesion (LSIL) 8.3%, had high grade squamous intra-epithelial lesion (HSIL) 3.5% and squamous cell carcinoma, and post-radiation effect 0.3% each. Abnormality of smear was significantly associated with age group and religion of the cases (p<0.05).Conclusions: Majority of the cases cervical cytology were reported to be without any epithelial cell abnormality followed by LSIL. Age and religion were significantly associated with the abnormality of smears

Stakeholder perceptions on patient-centered care at primary health care level in rural eastern Uganda: A qualitative inquiry

Background: Patient-centered care (PCC) offers opportunities for African health systems to improve quality of care. Nonetheless, PCC continually faces implementation challenges. In 2015, Uganda introduced PCC as a concept in their national quality improvement guidelines. In order to investigate whether and how this is implemented in practice, this study aims to identify relevant stakeholders’ views on the current quality of primary health care services and their understanding of PCC. This is an important step in understanding how the concept of PCC can be implemented in a resource constrained, sub-Saharan context like Uganda. Methods: This qualitative study was conducted in Uganda at national, district and facility level, with a focus on three public and three private health centres. Data collection consisted of in-depth interviews (n = 49); focus group discussions (n = 7); and feedback meetings (n = 14) across the four main categories of stakeholders identified: patients/communities, health workers, policy makers and academia. Interviews and discussions explored stakeholder perceptions on the interpersonal aspects of quality primary health care and meanings attached to the concept of PCC. A content analysis of Ugandan policy documents mentioning PCC was also conducted. Thematic content analysis was conducted using NVivo 11 to organize and analyze the data. Findings and conclusion: While Ugandan stakeholder groups have varying perceptions of PCC, they agree on the following: the need to involve patients in making decisions about their health, the key role of healthcare workers in that endeavor, and the importance of context in designing and implementing solutions. For that purpose, three avenues are recommended: Firstly, fora that include a wide range of stakeholders may offer a powerful opportunity to gain an inclusive vision on PCC in Uganda. Secondly, efforts need to be made to ensure that improved communication and information sharing–important components of PCC–translate to actual shared decision making. Lastly, the Ugandan health system needs to strengthen its engagement of the transformation from a community health worker system to a more comprehensive community health system. Cross-cutting the entire analysis, is the need to address, in a culturally-sensitive way, the many structural barriers in designing and implementing PCC policies. This is essential in ensuring the sustainable and effective implementation of PCC approaches in low- and middle-income contexts

Religious change, social conflict and legal competition: the emergence of Christian personal law in colonial India

Copyright © Cambridge University Press 2010One of the most contentious political issues in postcolonial India is the unfulfilled project of a ‘uniform civil code’ which would override the existing ‘personal laws’ or religion-based laws of domestic relations, inheritance and religious institutions. If the personal laws are admitted to be preserved (if somewhat distorted) remnants of ‘religious laws’, then the legitimacy of state intervention is called into question, especially since the Indian state claims to be secular. This paper, by discussing the history of the lesser-known Christian personal law, demonstrates that this conundrum is of considerable heritage. From the earliest days of British imperial rule in India, the quest to establish a universal body of law conflicted with other legal principles which upheld difference: that of religion, as well as race. It was the historical role of Indian Christians to occasion legal dilemmas regarding the jurisdictions of British and ‘native’ law, and concurrently about the identity of people subject to those different laws. In trying to discover who the Indian Christians were, and what laws ought to apply to them, British judges had perforce to reflect on who the ‘British’ were, whilst also dealing with conflicting collective claims made by Hindus, Muslims, Parsis, and Christians themselves about their own identity and religious rights. The Indian Christian personal law was an unintended by-product of this process, a finding which throws light both on the dynamics of colonial legislation, and on the essentially modern nature of Indian personal laws

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases

The Social Nature of Perceived Illness Representations of Perinatal Depression in Rural Uganda

While the global health community advocates for greater integration of mental health into maternal health agendas, a more robust understanding of perinatal mental health, and its role in providing integrated maternal health care and service delivery, is required. The present study uses the Illness Representation Model, a theoretical cognitive framework for understanding illness conceptualisations, to qualitatively explore multiple stakeholder perspectives on perinatal depression in rural Uganda. A total of 70 in-depth interviews and 9 focus group discussions were conducted with various local health system stakeholders, followed by an emergent thematic analysis using NVivo 11. Local communities perceived perinatal depression as being both the fault of women, and not. It was perceived as having socio-economic and cultural causal factors, in particular, as being partner-related. In these communities, perinatal depression was thought to be a common occurrence, and its negative consequences for women, infants and the community at large were recognised. Coping and help-seeking behaviours prescribed by the participants were also primarily socio-cultural in nature. Placing the dynamics and mechanisms of these local conceptualisations of perinatal depression alongside existing gaps in social and health care systems highlights both the need of, and the opportunities for, growth and prioritisation of integrated perinatal biomedical, mental, and social health programs in resource-constrained settings