Computational Methods for Structure-Activity Relationship Analysis and Activity Prediction

Structure-activity relationship (SAR) analysis of small bioactive compounds is a key task in medicinal chemistry. Traditionally, SARs were established on a case-by-case basis. However, with the arrival of high-throughput screening (HTS) and synthesis techniques, a surge in the size and structural heterogeneity of compound data is seen and the use of computational methods to analyse SARs has become imperative and valuable. In recent years, graphical methods have gained prominence for analysing SARs. The choice of molecular representation and the method of assessing similarities affects the outcome of the SAR analysis. Thus, alternative methods providing distinct points of view of SARs are required. In this thesis, a novel graphical representation utilizing the canonical scaffold-skeleton definition to explore meaningful global and local SAR patterns in compound data is introduced. Furthermore, efforts have been made to go beyond descriptive SAR analysis offered by the graphical methods. SAR features inferred from descriptive methods are utilized for compound activity predictions. In this context, a data structure called SAR matrix (SARM), which is reminiscent of conventional R-group tables, is utilized. SARMs suggest many virtual compounds that represent as of yet unexplored chemical space. These virtual compounds are candidates for further exploration but are too many to prioritize simply on the basis of visual inspection. Conceptually different approaches to enable systematic compound prediction and prioritization are introduced. Much emphasis is put on evolving the predictive ability for prospective compound design. Going beyond SAR analysis, the SARM method has also been adapted to navigate multi-target spaces primarily for analysing compound promiscuity patterns. Thus, the original SARM methodology has been further developed for a variety of medicinal chemistry and chemogenomics applications

The ‘SAR Matrix’ method and its extensions for applications in medicinal chemistry and chemogenomics

We describe the ‘Structure-Activity Relationship (SAR) Matrix’ (SARM) methodology that is based upon a special two-step application of the matched molecular pair (MMP) formalism. The SARM method has originally been designed for the extraction, organization, and visualization of compound series and associated SAR information from compound data sets. It has been further developed and adapted for other applications including compound design, activity prediction, library extension, and the navigation of multi-target activity spaces. The SARM approach and its extensions are presented here in context to introduce different types of applications and provide an example for the evolution of a computational methodology in pharmaceutical research

Thanatophoric dysplasia: a rare entity

Thanatophoric dysplasia (TD), a rare and lethal skeletal dysplasia of neonatal period. Two clinical forms of Thanatophoric dysplasia have been described. TD is caused by specific autosomal dominant mutations in the gene that codifies for the Fibroblast Growth Factor Receptor 3 (FGFR3). The mutations constitutively activate the tyrosine kinase activity of the receptor. The estimated birth incidence is approximately 1/20,000 to 1/50,000. TD I being more frequent than TD II. Most individuals with TD die within the first few hours or days of life. Currently, specific therapeutic regiments do not exist. Prenatal diagnosis is available, both by ultrasonography and by molecular studies. This case report describes fetus with one of this rare disorder

Comparative Evaluation of Clinical Efficacy of Diode LASER and Cryosurgery for Gingival Pigmentation: A Split-Mouth Randomized Clinical Study

Objective: To compare and evaluate the clinical efficacy of diode laser and cryosurgery for treating melanin pigmentation of gingiva. Material and Methods: A total of twenty-five subjects with physiological gingival pigmentation on the facial aspect of both maxillary and mandibular anterior arches (50 sites), both male and female, with an average age ranging from 18-35 years, participated in the study. The sites were randomly divided into Group I: depigmentation by Laser and Group II: depigmentation by Cryosurgery. The following parameters were assessed for the evaluation of treatment results: Melanin Oral Pigmentation Index (PI), Visual Analogue Scale (VAS) for pain evaluation and Healing index (HI). The data collected was statistically evaluated. Results: On intergroup comparison, there was no statistical difference in the score from baseline (p>0.05); however, a statistically significant difference was seen at the end of 1 year (p<0.05). Moreover, 57-60% of arches showed recurrence of pigmentation in the laser group whereas; only 12.7-17% recurrence was seen in the cryosurgery group at the end of the first year. Conclusion: Treatment of gingival hyperpigmentation with laser and cryosurgery shows a marked improvement of gingival pigmentation in both groups, but the cryosurgery depigmentation sites showed more sustainability.&nbsp

Role of intrauterine tubo-peritoneal insemination and intrauterine insemination in the treatment of infertility

Background: Infertility management has become more substantial and relevant with an increase in the number of infertile patients as well as advances in the science of reproduction. The objective of our study was to assess the role of intrauterine tuboperitoneal insemination (IUTPI) and intrauterine insemination (IUI) in the treatment of infertile patients.Methods: 236 infertile patients, 118 in each group attending the infertility clinic, after applying both inclusion and exclusion criteria were enrolled in the present study. Patients in each study group were given clomiphene citrate for ovarian stimulation followed by injection hCG for triggering ovulation. Insemination with washed husband’s sperm was performed about 36-40 hours after hCG administration, using 10ml of  inseminate in IUTPI and 0.5ml inseminate in IUI. The patient was then called after 2 weeks for urine pregnancy test (UPT) which, if positive was considered as clinical pregnancy.Results: Out of the total 236 cases, 42 cases had a positive outcome. Out of these 42 positive cases, 27 were from IUTPI group whereas 15 from IUI group. The pregnancy rate was 22.88% in IUTPI and 12.71% in IUI (p=0.039), which was a statistically significant difference. Endometrial thickness, preovulatory follicle number and prewash sperm motility significantly affected positive outcome in IUTPI. Factors like patient’s age, BMI<25, bilateral patent tubes and decreased duration of infertility also positively affected the treatment outcome.Conclusions: Our study found IUTPI to have better pregnancy rate compared to IUI. IUTPI may become a first line option for treatment of infertile patients

Incidental retained intrauterine Lippe’s loop in 65 years old woman: a rare case report

Intrauterine contraceptive devices are a widely used method of contraception. It is cheap, easy and an effective method. The first intrauterine device was Lippe’s loop which was double S shaped trapezoid loop introduced in 1962. Nowadays, third generation intrauterine devices are used which are effective for 5 and as well as 10 years. Here we presented a rare case of first generation of intrauterine device, that was, Lippe’s loop in a 65 year old lady which was found as an incidental finding. Intrauterine device insertion without the knowledge of women can lead to the forgotten device which can adversely affect the health of women

Localizing ECoG electrodes on the cortical anatomy without post-implantation imaging

AbstractIntroductionElectrocorticographic (ECoG) grids are placed subdurally on the cortex in people undergoing cortical resection to delineate eloquent cortex. ECoG signals have high spatial and temporal resolution and thus can be valuable for neuroscientific research. The value of these data is highest when they can be related to the cortical anatomy. Existing methods that establish this relationship rely either on post-implantation imaging using computed tomography (CT), magnetic resonance imaging (MRI) or X-Rays, or on intra-operative photographs. For research purposes, it is desirable to localize ECoG electrodes on the brain anatomy even when post-operative imaging is not available or when intra-operative photographs do not readily identify anatomical landmarks.MethodsWe developed a method to co-register ECoG electrodes to the underlying cortical anatomy using only a pre-operative MRI, a clinical neuronavigation device (such as BrainLab VectorVision), and fiducial markers. To validate our technique, we compared our results to data collected from six subjects who also had post-grid implantation imaging available. We compared the electrode coordinates obtained by our fiducial-based method to those obtained using existing methods, which are based on co-registering pre- and post-grid implantation images.ResultsOur fiducial-based method agreed with the MRI–CT method to within an average of 8.24mm (mean, median=7.10mm) across 6 subjects in 3 dimensions. It showed an average discrepancy of 2.7mm when compared to the results of the intra-operative photograph method in a 2D coordinate system. As this method does not require post-operative imaging such as CTs, our technique should prove useful for research in intra-operative single-stage surgery scenarios.To demonstrate the use of our method, we applied our method during real-time mapping of eloquent cortex during a single-stage surgery. The results demonstrated that our method can be applied intra-operatively in the absence of post-operative imaging to acquire ECoG signals that can be valuable for neuroscientific investigations

Comparative Evaluation of Clinical Efficacy of Diode LASER and Cryosurgery for Gingival Pigmentation: A Split-Mouth Randomized Clinical Study

Objective: To compare and evaluate the clinical efficacy of diode laser and cryosurgery for treating melanin pigmentation of gingiva. Material and Methods: A total of twenty-five subjects with physiological gingival pigmentation on the facial aspect of both maxillary and mandibular anterior arches (50 sites), both male and female, with an average age ranging from 18-35 years, participated in the study. The sites were randomly divided into Group I: depigmentation by Laser and Group II: depigmentation by Cryosurgery. The following parameters were assessed for the evaluation of treatment results: Melanin Oral Pigmentation Index (PI), Visual Analogue Scale (VAS) for pain evaluation and Healing index (HI). The data collected was statistically evaluated. Results: On intergroup comparison, there was no statistical difference in the score from baseline (p>0.05); however, a statistically significant difference was seen at the end of 1 year (p<0.05). Moreover, 57-60% of arches showed recurrence of pigmentation in the laser group whereas; only 12.7-17% recurrence was seen in the cryosurgery group at the end of the first year. Conclusion: Treatment of gingival hyperpigmentation with laser and cryosurgery shows a marked improvement of gingival pigmentation in both groups, but the cryosurgery depigmentation sites showed more sustainability.

IgG4-related disease: a review with an Indian perspective

IgG4-related disease (IgG4-RD) is a recently discovered (2003) complex disease, manifesting in various organs with symptoms mimicking other diseases. Progression of the disease leads to organ failure and hence early diagnosis is an urgent requirement in these patients. There is scarcity in reporting of IgG4-RD globally and in India. The aim of the study was to generate awareness on the epidemiology, diagnosis, and practice trends for IgG4-RD in India and globally, and to aid Indian physicians in early diagnosis of IgG4-RD in patients. Additionally, the evidence currently available in the Indian subpopulation has been evaluated. A preliminary literature search was performed using the PubMed database with the keywords including ‘IgG4-related disease’ in the title and abstract to obtain the relevant data. In total, PubMed identified 2071 publications comprising world-wide studies published in the English language before 30 April 2021. Studies were filtered region-wise by adding ‘India’ to the search strategy and total 60 publications were identified. The relative newness of IgG4-RD and the ensuing paucity in literature limits diagnosis by clinicians. Awareness of the disease among Indian clinicians would improve understanding of the disease and development of a country-specific consensus-based management guideline might lead to better prognosis in Indian patients with IgG4-RD