Fragment-based QSAR study to explore the structural requirements of DPP-4 inhibitors: a stepping stone towards better type 2 diabetes mellitus management.

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition.

Exploring different classification-dependent QSAR modelling strategies for HDAC3 inhibitors in search of meaningful structural contributors.

Histone deacetylase 3 (HDAC3), a Zn2+-dependent class I HDACs, contributes to numerous disorders such as neurodegenerative disorders, diabetes, cardiovascular disease, kidney disease and several types of cancers. Therefore, the development of novel and selective HDAC3 inhibitors might be promising to combat such diseases. Here, different classification-based molecular modelling studies such as Bayesian classification, recursive partitioning (RP), SARpy and linear discriminant analysis (LDA) were conducted on a set of HDAC3 inhibitors to pinpoint essential structural requirements contributing to HDAC3 inhibition followed by molecular docking study and molecular dynamics (MD) simulation analyses. The current study revealed the importance of hydroxamate function for Zn2+ chelation as well as hydrogen bonding interaction with Tyr298 residue. The importance of hydroxamate function for higher HDAC3 inhibition was noticed in the case of Bayesian classification, recursive partitioning and SARpy models. Also, the importance of substituted thiazole ring was revealed, whereas the presence of linear alkyl groups with carboxylic acid function, any type of ester function, benzodiazepine moiety and methoxy group in the molecular structure can be detrimental to HDAC3 inhibition. Therefore, this study can aid in the design and discovery of effective novel HDAC3 inhibitors in the future.

Insight into the structural requirements of gelatinases (MMP-2 and MMP-9) inhibitors by multiple validated molecular modelling approaches: Part II.

Inhibition of the matrix metalloproteinases (MMPs) is effective against metastasis of secondary tumours. Previous MMP inhibitors have failed in clinical trials due to their off-target toxicity in solid tumours. Thus, newer MMP inhibitors now have paramount importance. Here, different molecular modelling techniques were applied on a dataset of 110 gelatinase (MMP-2 and MMP-9) inhibitors. The objectives of the present study were to identify structural fingerprints for gelatinase inhibition and also to develop statistically validated QSAR models for the screening and prediction of different derivatives as MMP-2 (gelatinase A) and MMP-9 (gelatinase B) inhibitors. The Bayesian classification study provided the ROC values for the training set of 0.837 and 0.815 for MMP-2 and MMP-9, respectively. The linear model also produced the leave-one-out cross-validated Q2 of 0.805 (eq. 1, MMP-2) and 0.724 (eq. 2, MMP-9), an r2 of 0.845 (eq. 1, MMP-2) and 0.782 (eq. 2, MMP-9), an r2Pred of 0.806 (eq. 1, MMP-2) and 0.732 (eq. 2, MMP-9). Similarly, non-linear learning models were also statistically significant and reliable. Overall, this study may help in the rational design of newer compounds with higher gelatinase inhibition to fight against both primary and secondary cancers in future.

First molecular modelling report on tri-substituted pyrazolines as phosphodiesterase 5 (PDE5) inhibitors through classical and machine learning based multi-QSAR analysis.

Phosphodiesterase 5 (PDE5) falls under a broad category of metallohydrolase enzymes responsible for the catalysis of the phosphodiesterase bond, and thus it can terminate the action of cyclic guanosine monophosphate (cGMP). Overexpression of this enzyme leads to development of a number of pathological conditions. Thus, targeting the enzyme to develop inhibitors could be useful for the treatment of erectile dysfunction as well as pulmonary hypertension. In the current study, several molecular modelling techniques were utilized including Bayesian classification, single tree and forest tree recursive partitioning, and genetic function approximation to identify crucial structural fingerprints important for optimization of tri-substituted pyrazoline derivatives as PDE5 inhibitors. Later, various machine learning models were also developed that could be utilized to predict and screen PDE5 inhibitors in the future.

Insight into the structural requirement of aryl sulphonamide based gelatinases (MMP-2 and MMP-9) inhibitors - Part I: 2D-QSAR, 3D-QSAR topomer CoMFA and Naïve Bayes studies - First report of 3D-QSAR Topomer CoMFA analysis for MMP-9 inhibitors and jointly inhibitors of gelatinases together.

Gelatinases [gelatinase A - matrix metalloproteinase-2 (MMP-2), gelatinase B - matrix metalloproteinase-9 (MMP-9)] play key roles in many disease conditions including cancer. Despite some research work on gelatinases inhibitors both jointly and individually had been reported, challenges still exist in achieving potency as well as selectivity. Here in part I of a series of work, we have reported the structural requirement of some arylsulfonamides. In particular, regression-based 2D-QSARs, topomer CoMFA (comparative molecular field analysis) and Bayesian classification models were constructed to refine structural features for attaining better gelatinase inhibitory activity. The 2D-QSAR models exhibited good statistical significance. The descriptors nsssN, SHBint6, SHBint7, PubchemFP629 were directly correlated with the MMP-2 binding affinities whereas nsssN, SHBint10 and AATS2i were directly proportional to MMP-9 binding affinities. The topomer CoMFA results indicated that the steric and electrostatic fields play key roles in gelatinase inhibition. The established Naïve Bayes prediction models were evaluated by fivefold cross validation and an external test set. Furthermore, important molecular descriptors related to MMP-2 and MMP-9 binding affinities and some active/inactive fragments were identified. Thus, these observations may be helpful for further work of aryl sulphonamide based gelatinase inhibitors in future.

Identification of structural fingerprints for ABCG2 inhibition by using Monte Carlo optimization, Bayesian classification, and structural and physicochemical interpretation (SPCI) analysis.

The human breast cancer resistance protein (BCRP), one of the members of the large ATP binding cassette (ABC) transporter superfamily, is crucial for resistance against chemotherapeutic agents. Currently, it has been emerged as one of the best biological targets for the designing of small molecule drugs capable of eliminating multidrug resistance in breast cancer. In order to gain insights into the relationship between the molecular structure of compounds and the ABCG2 inhibition, a multi-QSAR approach using different methods was performed on a dataset of 294 ABCG2 inhibitors with diverse scaffolds. The best models obtained by different chemometric methods have the following statistical characteristics: Monte Carlo Optimization-based QSAR (sensitivity = 0.905, specificity = 0.6255, accuracy = 0.756, and MCC = 0.545), Bayesian classification model (sensitivity = 0.735, specificity = 0.775, and concordance = 0.757); structural and physicochemical interpretation analysis-random forest method (balance accuracy = 0.750, sensitivity = 0.810, and specificity = 0.700). Additionally, structural fingerprints modulating the ABCG2 inhibitory properties were identified from the best models of each method and also validated with each other. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints modulating ABCG2 inhibition.

Post-treatment endodontic pain following occlusal reduction in mandibular posterior teeth with symptomatic irreversible pulpitis and sensitivity to percussion: a single-centre randomized controlled trial.

AIM: This randomized, prospective, controlled trial assessed the effect of occlusal reduction on post-treatment endodontic pain and medication intake following root canal treatment of mandibular posterior teeth with symptomatic irreversible pulpitis with sensitivity to percussion treated in two visits. METHODOLOGY: Three hundred and eight patients were randomly assigned into two equal groups according to whether occlusal reduction was done or not (n = 154). For all patients, root canal treatment was carried out in two visits without intracanal medication. Patients assessed their pain using the 0-10 numerical rating scale (NRS) 6, 12, 24 and 48 h after the first visit (post-instrumentation) and 6 and 12 h following root canal filling (post-obturation). Patients, also, recorded their medication intake (sham or analgesic), post-instrumentation and post-obturation; patients initially received a sham capsule, but, if pain persisted, an analgesic was prescribed. Data were analysed using Mann-Whitney U-test, Friedman's test, Wilcoxon's rank test and chi-square (χ2 ) test. The relative risk (RR) and its 95% confidence interval (CI) were calculated for binary data. RESULTS: Occlusal reduction was associated with lower pain intensity than no occlusal reduction at 12 and 24 h post-instrumentation (P < 0.05). Pain intensity significantly and gradually decreased with both groups at all post-instrumentation and post-obturation time-points compared to preoperative pain (P < 0.05). The RR of moderate-to-severe pain was 0.61 (95% CI: 0.41, 0.91) 12 h post-instrumentation, and the RR of pain incidence, regardless of its level, was 0.75 (95% CI: 0.61, 0.92) 24 h post-instrumentation. There was no significant difference in medication intake (sham or analgesic) between groups (P > 0.05). CONCLUSIONS: Occlusal reduction was effective in reducing the intensity of postoperative pain 12 h and 24 h after root canal instrumentation in the first visit in patients with symptomatic irreversible pulpitis with sensitivity to percussion. Occlusal reduction lowered the risk of moderate-to-severe pain by about 40% 12 h post-instrumentation and the overall risk of pain by 25% 24 h post-instrumentation; yet, it did not affect medication intake.

Exploring the structural aspects of ureido-amino acid-based APN inhibitors: a validated comparative multi-QSAR modelling study.

The zinc-dependent enzyme aminopeptidase N (APN) is a member of the M1 metalloenzyme family. The multi-functionality of APN as a peptidase, a receptor and a signalling molecule has provided it the access to influence a number of disease conditions namely viral diseases, angiogenesis, cellular metastasis and invasion including different cancer conditions. Hence, the development of potent APN inhibitors is a possible route for the treatment of diseases related to the activity of APN. In this study, different QSAR approaches have been adopted to identify the structural features of a group of hydroxamate-based ureido-amino acid derivative APN inhibitors. This study was able to identify different constitutional aspects of these APN inhibitors which are important for their inhibitory potency. Additionally, some of these observations were also aligned with the observations of previously performed QSAR studies conducted on different APN inhibitors. Therefore, the results of this study may help to design potent and effective APN inhibitors in the future.

Discriminations of active from inactive HDAC8 inhibitors Part II: Bayesian classification study to find molecular fingerprints.

In continuation of our earlier work (Doi: 10.1080/07391102.2019.1661876), a statistically validated and robust Bayesian model was developed on a large diverse set of HDAC8 inhibitors. The training set comprised of 676 small molecules and 293 compounds were considered as test set molecules. The findings of this analysis will help to explore some major directions regarding the HDAC8 inhibitor designing approach. Acrylamide (G1-G3, G9), N-substituted 2-phenylimidazole (G4-G8, G9, G12-G13, G16-G19), benzimidazole (G10-G11), piperidine substituted pyrrole (G13-G14) groups, alkyl/aryl amide (G15) and aryloxy carboxamide (G20) fingerprints were found to play a crucial role in HDAC8 inhibitory activity whereas -CH-N=CH- (B1, B4-B6, B14) motif, benzamide (B2-B3, B9-B13, B16-B17) groups and heptazepine (B7-B8, B15, B18-B20) group were found to influence negatively the HDAC8 inhibitory activity. The importance of such fingerprints was further validated by the HDAC8 enzyme and related inhibitor interactions at the receptor level. These results are in close agreement with those of our previous work that validate each other. Moreover, this comparative learning may enrich future endeavours regarding the designing strategy of HDAC8 inhibitors.

Postoperative pain following endodontic irrigation using 1.3% versus 5.25% sodium hypochlorite in mandibular molars with necrotic pulps: a randomized double-blind clinical trial.

AIM: This randomized, prospective, double-blind, clinical trial assessed the effect of 1.3% and 5.25% sodium hypochlorite (NaOCl) as irrigants on post-endodontic pain and medication intake following root canal treatment of mandibular molars with nonvital pulps. METHODOLOGY: Three hundred and eight patients, each with one symptomatic or asymptomatic molar, were randomly assigned, using the permuted-block method, into two equal groups according to NaOCl concentration: 1.3% or 5.25% (n = 154). For both groups, syringe irrigation was performed using a 27-gauge needle advanced into the canal to a depth of 3 mm from the working length; 3 mL were used between every two consecutive instruments. All root canal treatments were carried out in two visits, with no intracanal medication, by trained postgraduate students. The canals were prepared using the ProTaper Universal rotary system during the first visit. In the second visit 7 days later, the same irrigant per group was used and the canal walls were reprepared with the final instrument before filling the canal using the modified single-cone technique with an epoxy resin-based sealer. Patients assessed their postoperative pain using a 0-10 numerical rating scale immediately after instrumentation, 3, 24, 48 h and 7 days after the first visit and immediately following root canal filling. The incidence of rescue medication intake (Sham or analgesic) was also recorded; patients received a sham capsule to be used first, but, if pain persisted, an analgesic was prescribed. Outcome data were analysed using Mann-Whitney U-test, Friedman's test, Wilcoxon's rank test and chi-square (χ2 ) test. Relative risk reduction (RRR) and its 95% confidence interval (CI) were calculated for binary data. RESULTS: The incidence and intensity of postoperative pain were significantly lower with 1.3% NaOCl than 5.25% NaOCl at all time-points (P < 0.05). Postoperative pain intensity exceeded preoperative pain at 3 and 24 h with 5.25% NaOCl only (P < 0.05). The RRR in pain incidence was 38% (95% CI: 17%, 54%) immediately after instrumentation, 41% (95% CI: 31%, 49%) at 3 h, 42% (95% CI: 32%, 51%) at 24 h, 59% (95% CI: 45%, 69%) at 48 h, 62% (95% CI: 27%, 80%) at 7 days and 81% (95% CI: 68%, 89%) after root filling. RRR was 38% (95% CI: 1%, 61%) for sham intake and 69% (95% CI: 37%, 85%) for analgesic intake. CONCLUSIONS: Using 1.3% NaOCl was associated with less intense and less frequent post-endodontic pain than 5.25% NaOCl in mandibular molars with nonvital pulps treated in two visits. The incidence of pain was reduced by up to 60% within the week post-instrumentation and 80% after root canal filling and the rescue analgesic intake by about 70% on using 1.3% NaOCl compared to 5.25% NaOCl.

Insight into structural features of phenyltetrazole derivatives as ABCG2 inhibitors for the treatment of multidrug resistance in cancer.

ABCG2 is the principal ABC transporter involved in the multidrug resistance of breast cancer. Looking at the current demand in the development of ABCG2 inhibitors for the treatment of multidrug-resistant cancer, we have explored structural requirements of phenyltetrazole derivatives for ABCG2 inhibition by combining classical QSAR, Bayesian classification modelling and molecular docking studies. For classical QSAR, structural descriptors were calculated from the free software tool PaDEL-descriptor. Stepwise multiple linear regression (SMLR) was used for model generation. A statistically significant model was generated and validated with different parameters (For training set: r = 0.825; Q2 = 0.570 and for test set: r = 0.894, r2pred = 0.783). The predicted model was found to satisfy the Golbraikh and Trospha criteria for model acceptability. Bayesian classification modelling was also performed (ROC scores were 0.722 and 0.767 for the training and test sets, respectively). Finally, the binding interactions of phenyltetrazole type inhibitor with the ABCG2 receptor were mapped with the help of molecular docking study. The result of the docking analysis is aligned with the classical QSAR and Bayesian classification studies. The combined modelling study will guide the medicinal chemists to act faster in the drug discovery of ABCG2 inhibitors for the management of resistant breast cancer.

QSAR modelling on a series of arylsulfonamide-based hydroxamates as potent MMP-2 inhibitors.

Matrix metalloproteinase-2 (MMP-2) is a lucrative therapeutic target as far as anticancer drug discovery is concerned. Overexpression of MMP-2 is found to facilitate tumour propagation through the involvement of vascular endothelial growth factor (VEGF). However, even after different techniques, finding a target-specific MMP-2 inhibitor with respectable pharmacodynamic properties is still a challenging task. Regression-dependent quantitative structure-activity relationship (QSAR) strategies might be among the possible drug design methods to explore the essential structural features that would be valuable to find a suitable MMP-2 inhibitor. In this paper, 72 molecules were explored using the PaDEL descriptors and stepwise multiple linear regression (S-MLR). The partial least squares (PLS) method was also used to create a viable statistical model with an acceptable metric related to these models. The final statistical models were formed with statistical parameters within acceptable range (r2 = 0.797, Q2 = 0.725 and r2pred = 0.643 for the MLR model, and r2 = 0.780, Q2 = 0.685 and r2pred = 0.666 for the PLS model). The models were analysed and compared with those already published on the same endpoint.

Tramadol (opioid) abuse is associated with a dose- and time-dependent poor sperm quality and hyperprolactinaemia in young men.

Tramadol, one of the most commonly abused drugs in Middle East, impacts spermatogenesis and disturbs reproductive hormones in animal studies. We aimed to investigate tramadol impact on sperm quality and on levels of testosterone, prolactin and gonadotropins, in tramadol abusers (n = 30) to age-matched control (n = 30). Abusers had significantly low percentages of sperm motility, normal forms and vitality compared with control (95% CI -40.7 to -19.3, -13.5 to -9.3 and -31.9 to -9.7 respectively). Hypoandrogenism (95% CI -4.5 to -2.8), hyperprolactinaemia (CI (95%) 4.9 to 9.4) and hypergonadotropinaemia (95% CI 2.9 to 7.2 for FSH and 2.0 to 7.8 for LH) were observed in tramadol abusers vs controls. Smokers (26 of 30), concurrently abusing other drugs (11 of 30) and asymptomatic leucocytospermic (15 of 30) patients subgroups significantly abused tramadol beyond 3 years (p = .02, <.001, = .03 respectively) and in excess >450 mg/day (p = .02, = .01, = .005 respectively). Progressive motility (a + b%) was significantly low in young men <25 years old (p = .03) subgroup. Tramadol abuse is associated with poor sperm quality, hyperprolactinaemia and hypergonadotropic hypogonadism. We recommend semen analysis for tramadol long-intakes, question sperm donors and follow-up studies to prevent and reverse tramadol-induced testicular damage.

Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified.

The current study deals with chemometric modelling strategies (Naïve Bayes classification, hologram-based quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)) to explore the important features of hydroxylamine derivatives for exerting potent human immunodeficiency virus-1 (HIV-1) protease inhibition. Depending on the statistically validated reliable and robust quantitative structure-activity relationship (QSAR) models, important and crucial structural features have been identified that may be responsible for enhancing the activity profile of these hydroxylamine compounds. Arylsulfonamide function along with methoxy or fluoro substitution is important for enhancing activity. Bulky steric substitution at the sulfonamide nitrogen disfavours activity whereas smaller hydrophobic substitution at the same position is found to be favourable. Apart from the crucial oxazolidinone moiety, pyrrolidine, cyclic urea and methyl ester functions are also responsible for increasing the HIV-1 protease inhibitory profile. Observations derived from these modelling studies may be utilized further in designing promising HIV-1 protease inhibitors of this class.

Multiple molecular modelling studies on some derivatives and analogues of glutamic acid as matrix metalloproteinase-2 inhibitors.

Matrix metalloproteinase-2 (MMP-2) is a potential target in anticancer drug discovery due to its association with angiogenesis, metastasis and tumour progression. In this study, 67 glutamic acid derivatives, synthesized and evaluated as MMP-2 inhibitors, were taken into account for multi-QSAR modelling study (regression-based 2D-QSAR, classification-based LDA-QSAR, Bayesian classification QSAR, HQSAR, 3D-QSAR CoMFA and CoMSIA as well as Open3DQSAR). All these QSAR studies were statistically validated individually. Regarding the 3D-QSAR analysis, the Open3DQSAR results were better than CoMFA and CoMSIA, although all these 3D-QSAR models supported each other. The importance of biphenylsulphonyl moiety over phenylacetyl/naphthylacetyl moieties was established due to its association with favourable steric and hydrophobic characters. HQSAR, LDA-QSAR and Bayesian classification QSAR studies also suggested that the biphenylsulphonamido group was better than the phenylacetylcarboxamido function. Additionally, glutamines were proven to be far better inhibitors than isoglutamines. Observations obtained from the current study were revalidated and supported by the earlier reported molecular modelling studies. Depending on these observations, newer glutamic acid-based compounds may be designed further in future for potent MMP-2 inhibitory activity.

Hydroxyethylamine derivatives as HIV-1 protease inhibitors: a predictive QSAR modelling study based on Monte Carlo optimization.

Application of HIV-1 protease inhibitors (as an anti-HIV regimen) may serve as an attractive strategy for anti-HIV drug development. Several investigations suggest that there is a crucial need to develop a novel protease inhibitor with higher potency and reduced toxicity. Monte Carlo optimized QSAR study was performed on 200 hydroxyethylamine derivatives with antiprotease activity. Twenty-one QSAR models with good statistical qualities were developed from three different splits with various combinations of SMILES and GRAPH based descriptors. The best models from different splits were selected on the basis of statistically validated characteristics of the test set and have the following statistical parameters: r2 = 0.806, Q2 = 0.788 (split 1); r2 = 0.842, Q2 = 0.826 (split 2); r2 = 0.774, Q2 = 0.755 (split 3). The structural attributes obtained from the best models were analysed to understand the structural requirements of the selected series for HIV-1 protease inhibitory activity. On the basis of obtained structural attributes, 11 new compounds were designed, out of which five compounds were found to have better activity than the best active compound in the series.

Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D QSAR approaches.

Schizophrenia is a complex disorder of thinking and behaviour (0.3-0.7% of the population is affected). The over-expression of phosphodiesterase 10A (PDE10A) enzyme may be a potential target for schizophrenia and Huntington's disease. Because 3D QSAR analysis is one of the most frequently used modelling techniques, in the present study, five different 3D QSAR tools, namely CoMFA, CoMSIA, kNN-MFA, Open3DQSAR and topomer CoMFA methods, were used on a dataset of pyrimidine-based PDE10A inhibitors. All developed models were validated internally and externally. The non-commercial Open3DQSAR produced the best statistical results amongst 3D QSAR tools. The structural interpretations obtained from different methods were thoroughly analysed and were justified on the basis of information obtained from the crystal structure. Information from one method was mostly validated by the results of other methods and vice versa. In the current work, the use of multiple tools in the same analysis revealed more complete information about the structural requirements of these compounds. On the basis of the observations of the 3D QSAR studies, 12 new compounds were designed for better PDE10A inhibitory activity. The current investigation may help in further designing new PDE10A inhibitors with promising activity.

Interaction and signalling between a cosmopolitan phytoplankton and associated bacteria.

Interactions between primary producers and bacteria impact the physiology of both partners, alter the chemistry of their environment, and shape ecosystem diversity. In marine ecosystems, these interactions are difficult to study partly because the major photosynthetic organisms are microscopic, unicellular phytoplankton. Coastal phytoplankton communities are dominated by diatoms, which generate approximately 40% of marine primary production and form the base of many marine food webs. Diatoms co-occur with specific bacterial taxa, but the mechanisms of potential interactions are mostly unknown. Here we tease apart a bacterial consortium associated with a globally distributed diatom and find that a Sulfitobacter species promotes diatom cell division via secretion of the hormone indole-3-acetic acid, synthesized by the bacterium using both diatom-secreted and endogenous tryptophan. Indole-3-acetic acid and tryptophan serve as signalling molecules that are part of a complex exchange of nutrients, including diatom-excreted organosulfur molecules and bacterial-excreted ammonia. The potential prevalence of this mode of signalling in the oceans is corroborated by metabolite and metatranscriptome analyses that show widespread indole-3-acetic acid production by Sulfitobacter-related bacteria, particularly in coastal environments. Our study expands on the emerging recognition that marine microbial communities are part of tightly connected networks by providing evidence that these interactions are mediated through production and exchange of infochemicals.

Outcome of pregnancy in patients with congenital heart diseases.

This prospective study was conducted to evaluate the outcome of pregnancies in women with congenital heart diseases. In this study 50 pregnant women age between 20-45 years with congenital heart diseases were included. Twenty two (44%) were presented with atrial septal defect, 12(24%) with ventricular septal defect, 5(10%) were with patent ductus arteriosus, 6(12%) with Fallot's tetralogy, 2(4%) with pulmonary stenosis, 2(4%) with Eisenmenger syndrome, 1(2%) with dextrocardia. Shortness of breath (60%) was the main presenting complaint. Normal vaginal delivery (52%) was done in majority of cases. Spontaneous abortion occurred in 16% of pregnancies. Major complications were heart failure 16%, arrhythmias 21%, cardiovascular mortality 4%, preeclampsia 4%, and eclampsia 2%. Premature birth 16%, fetal demise 4%, neonatal death 2% and cardiac anomaly at birth 2% were also observed. The outcome of pregnancy in women with congenital heart diseases is favourable with considerable maternal and neonatal complications.

Tubercular lymphadenitis - diagnostic evaluation.

Tuberculosis is one the commonest disease affecting peripheral lymph node and cervical tubercular lymphadenitis are frequently encountered in Otolaryngological practice. Three hundred fifty six (356) cases of Fine Needle Aspiration for Cytology (FNAC) positive tubercular lymphadenitis were studied from January 2006 to December 2008. FNAC positive but histopathologically negative cases were excluded from the study. Among 356 cases of FNAC positive cervical lymphadenopathy 300 cases (84.27%) were confirmed tuberculosis on histopathological examination. Remaining 50 cases (15.73%) were diagnosed as nontubercular lymphadenitis where nonspecific lymphadenitis was the commonest finding 34(9.55%) followed by metastatic carcinoma 7(1.97%), lymphoma 6(1.08%), Kikuchiz's disease 6(1.08%), Kala-Azar 2(0.56%) & Leukemia 1(0.28%). Most of the patients presented with only multiple lymph node swelling with other symptoms, such as fever 18(5.06%), pain (15.7%), tenderness 53(14.88%), weight loss 29(8.14%), anorexia 33(9.26%). Following observations are evident from this study: i) Disease is comparatively common between 12-35 years ii) Multiple matted/discrete lymph nodes are the earliest presentation iii) Multiple lymph node is the most consistent finding for clinical diagnosis. iv) Very few patients have constitutional symptoms v) Suppuration with or without abscess formation although confirms the diagnosis even then certainty is very essential. Though the evidence of cervical tuberculosis was thought to be decreasing in developing countries the real picture seems to be different. Random survey among the whole population was not done in any country rather hospital based laboratory research was made.