Role of robot-assisted laparoscopy in deep infiltrating endometriosis with bowel involvement: a systematic review and application of the IDEAL framework.

AIMS: This review aims to evaluate the feasibility of robot-assisted laparoscopic surgery (RALS) as an alternative to standard laparoscopic surgery (SLS) for the treatment of bowel deep-infiltrative endometriosis. Additionally, it aims to provide guidance for future study design, by gaining insight into the current state of research, in accordance with the IDEAL framework. METHOD: A systematic review was conducted to identify relevant studies on RALS for bowel deep infiltrating endometriosis in Medline, Embase, Cochrane Library and PubMed databases up to August 2023 and reported in keeping with PRISMA guidelines. The study was registered with PROSPERO Registration: CRD42022308611 RESULTS: Eleven primary studies were identified, encompassing 364 RALS patients and 83 SLS patients, from which surgical details, operative and postoperative outcomes were extracted. In the RALS group, mean operating time was longer (235 ± 112 min) than in the standard laparoscopy group (171 ± 76 min) (p < 0.01). Patients in the RALS group experienced a shorter hospital stay (5.3 ± 3.5 days vs. 7.3 ± 4.1 days) (p < 0.01), and appeared to have fewer postoperative complications compared to standard laparoscopy. Research evidence for RALS in bowel DE is at an IDEAL Stage 2B of development. CONCLUSION: RALS is a safe and feasible alternative to standard laparoscopy for bowel endometriosis treatment, with a shorter overall length of stay despite longer operating times. Further robust randomized trials recommended to delineate other potential advantages of RALS.

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes.

AIM: To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. METHODS: A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. RESULTS: A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. CONCLUSION: The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer's disease.

A combined 3D-QSAR and molecular docking strategy to understand the binding mechanism of (V600E)B-RAF inhibitors.

B-RAF is a member of the RAF protein kinase family involved in the regulation of cell growth, differentiation, and proliferation. It forms a part of conserved apoptosis signals through the RAS-RAF-MAPK pathway. (V600E)B-RAF protein has much potential for scientific research as therapeutic target due to its involvement in human melanoma cancer. In this work, a molecular modeling study was carried out for the first time with 3D-QSAR studies by following the docking protocol on three different data sets of (V600E)B-RAF inhibitors. Based on the co-crystallized compound (PDB ID: 1UWJ), a receptor-guided alignment method was utilized to derive reliable CoMFA and CoMSIA models. The selected CoMFA model gives the best statistical values (q(2) = 0.753, r(2) = 0.962). With the same alignment protocol, a statistically reliable CoMSIA model out of fourteen different combinations was also derived (q(2) = 0.807, r(2) = 0.961). The actual predictive powers of both models were rigorously validated with an external test set, which gave satisfactory predictive r(2) values for CoMFA and CoMSIA models, 0.89 and 0.88, respectively. In addition, y-randomization test was also performed to validate our 3D-QSAR models. Contour maps from CoMFA and CoMSIA models supported statistical results, revealed important structural features responsible for biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. Based on the developed models few new structures were designed. The newly predicted structure (IIIa) showed higher inhibitory potency (pIC(50) 6.826) than that of the most active compound of the series.

3D-QSPR method of computational technique applied on red reactive dyes by using CoMFA strategy.

Cellulose fiber is a tremendous natural resource that has broad application in various productions including the textile industry. The dyes, which are commonly used for cellulose printing, are "reactive dyes" because of their high wet fastness and brilliant colors. The interaction of various dyes with the cellulose fiber depends upon the physiochemical properties that are governed by specific features of the dye molecule. The binding pattern of the reactive dye with cellulose fiber is called the ligand-receptor concept. In the current study, the three dimensional quantitative structure property relationship (3D-QSPR) technique was applied to understand the red reactive dyes interactions with the cellulose by the Comparative Molecular Field Analysis (CoMFA) method. This method was successfully utilized to predict a reliable model. The predicted model gives satisfactory statistical results and in the light of these, it was further analyzed. Additionally, the graphical outcomes (contour maps) help us to understand the modification pattern and to correlate the structural changes with respect to the absorptivity. Furthermore, the final selected model has potential to assist in understanding the characteristics of the external test set. The study could be helpful to design new reactive dyes with better affinity and selectivity for the cellulose fiber.

In-vitro evaluation and in-silico studies applied on newly synthesized amide derivatives of N-phthaloylglycine as Butyrylcholinesterase (BChE) inhibitors.

Amide derivatives of N-phthaloylglycine were synthesized under Schotten Baumann reaction condition. The structures of synthesized compounds (4a-d) were characterized by using FTIR, 1HNMR and EI-MS. The compounds were evaluated for their in-vitro Butyrylcholinesterase inhibition and all of them exhibited good activity against this enzyme. Compound 4a (IC50 = 6.5 ±â€¯0.1) was found to be most potent compared with the reference compound Galantamine (IC50 = 6.6 ±â€¯0.00038) and the other compounds (4b,4c,4d) were also possess that activity and hence can be employed for the discovery of lead compounds against Alzheimer's disease. The depth analysis of the binding mechanism of these newly synthesized compounds inside the binding gorge of BChE, an in silico technique, molecular docking was performed. All the compounds were found to be well accommodated within the binding pocket of BChE. Compounds 4a, 4b and 4c showed hydrogen bonding interaction with binding site residue TYR332. Moreover, hydrophobic and π-π interaction assisted the compounds to attain their enzyme inhibitory activity. These theoretical studies showed significant correlation with experimental results.

Fetal scalp stimulation (FSS) versus fetal blood sampling (FBS) for women with abnormal fetal heart rate monitoring in labor: a prospective cohort study.

OBJECTIVE: To evaluate the performance of fetal scalp stimulation (FSS) compared to fetal blood sampling (FBS) as a second line test of fetal wellbeing in labor. STUDY DESIGN: A prospective cohort study was conducted including 298 fetal blood sampling procedures performed due to abnormal fetal cardiotocography (CTG). Two independent observers interpreted the CTG following stimulation. The FSS test was classified as normal when an elicited acceleration and/or provoked fetal heart rate variability was recorded. The FBS was classified as normal (pH ≥7.25), borderline (pH 7.21-7.24), and abnormal (pH ≤7.20). RESULTS: Of the 298 procedures, 249 (84%) had a normal scalp pH result, 199 (67%) had an acceleration in response to FSS and 255 (86%) had an acceleration or normal variability in response to FSS. All 11 of the neonates classified as normal by FSS, but abnormal by FBS were born with normal Apgar scores and cord pH results. The consistency between FSS and FBS was "fair" (kappa 0.28) while the consistency between either test and cord arterial pH was "poor". CONCLUSIONS: This study suggests that FSS has the potential to be a reliable alternative to FBS. The findings require evaluation in a well-designed randomized controlled trial.

Microchimeric fetal cells play a role in maternal wound healing after pregnancy.

Fetal cells persist in mothers for decades after delivery: in a phenomenon called fetal microchimerism. While persistent fetal cells were first implicated in autoimmune disease, parallel studies in animal and human pregnancy now suggest that microchimeric fetal cells play a role in the response to tissue injury. The aim of this study was to investigate the impact of fetal microchimeric cells in the adult wound, using caesarean section (CS) as a model of wound healing in pregnancy. XY-FISH (fluorescence in situ hybridization) and immunostaining was used in multiple tissue sections from CS skin biopsies from 70 women, to locate, quantitate and characterize microchimeric male presumed-fetal cells. Y-FISH and Nested PCR was used to confirm XY-FISH results. XY-FISH demonstrated the presence of isolated 0-9 male fetal cells per section in the epidermis of the healed CS scars from only those women who had their first male child by CS. Both Y-FISH and Y-PCR confirmed the presence of fetal cells in CS scars. Combined FISH and immunostaining showed all male fetal cells present were keratinocytes, as they expressed cytokeratin, and were almost exclusively located in epidermis. Microchimeric fetal cells also expressed Collagen I, III, and TGF-ß3 in healed maternal scars. Identification of male-presumed fetal cells in healed maternal CS scars after pregnancy suggests that, possibly in response to signals produced by maternal skin injury at CS, fetal cells migrate to the site of damage to become involved in maternal tissue repair, or proliferate locally.

In-silico analysis of chromone containing sulfonamide derivatives as human carbonic anhydrase inhibitors.

Computational tools of analysis were used on a set of synthetic chromone containing sulfonamide derivatives for evaluation of their enzyme inhibitory activity against Carbonic Anhydrase (CA) isozymes. GOLD docking software was utilized to dock the compounds against two human Carbonic Anhydrase (hCA) proteins; hCAII and hCA-IX. Differences in conformation and orientation of molecules within hCA-II and hCA-IX binding pockets were studied in detail which revealed that compounds with fluorine at R1 position and phenyl sulfonamide substituent at para position served as potent inhibitors against both proteins due to anomalous chemistry of fluorine atom. It was also noticed that the activity was decreased when sulfonamide moiety was shifted from para to meta position since it dragged the interacting specie of compounds away from Zn metal. Similarly, when substituents were replaced by F > Br > C2H5 > H, the activity declined due to the electronegativity effect. Binding interaction results against CA-IX seemed to be better than CA-II due to large binding cavity, predicting the more potent inhibitory activity against hCA-IX.

Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone.

BACKGROUND: Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites. RESULTS: Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3ß,17ß-diol (2), and 5ß-androstan-3α,17ß-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17ß-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12ß-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5-7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities. CONCLUSION: Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5-7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer's disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced.

A combined 3D-QSAR and docking studies for the In-silico prediction of HIV-protease inhibitors.

BACKGROUND: Tremendous research from last twenty years has been pursued to cure human life against HIV virus. A large number of HIV protease inhibitors are in clinical trials but still it is an interesting target for researchers due to the viral ability to get mutated. Mutated viral strains led the drug ineffective but still used to increase the life span of HIV patients. RESULTS: In the present work, 3D-QSAR and docking studies were performed on a series of Danuravir derivatives, the most potent HIV- protease inhibitor known so far. Combined study of 3D-QSAR was applied for Danuravir derivatives using ligand-based and receptor-based protocols and generated models were compared. The results were in good agreement with the experimental results. Additionally, docking analysis of most active 32 and least active 46 compounds into wild type and mutated protein structures further verified our results. The 3D-QSAR and docking results revealed that compound 32 bind efficiently to the wild and mutated protein whereas, sufficient interactions were lost in compound 46. CONCLUSION: The combination of two computational techniques would helped to make a clear decision that compound 32 with well inhibitory activity bind more efficiently within the binding pocket even in case of mutant virus whereas compound 46 lost its interactions on mutation and marked as least active compound of the series. This is all due to the presence or absence of substituents on core structure, evaluated by 3D-QSAR studies. This set of information could be used to design highly potent drug candidates for both wild and mutated form of viruses.

Pregnancy outcomes in a patient with Sjögren's disease with renal involvement.

BACKGROUND: Maternal and fetal outcome in pregnancy with renal failure is unpredictable, where each condition can adversely affect the other. We present a case of steroid sensitive Sjögren's nephritis worsened by pregnancy, demonstrated over the course of multiple pregnancies and investigated the aetiology. CASE: A 28-year-old nullipara with a diagnosis of primary Sjögren's syndrome presented with a deterioration of renal function. A diagnosis of secondary tubulo-interstitial nephritis was made on renal biopsy. Her first pregnancy ended in the second trimester with a decision to deliver a female infant at 27 weeks due to worsening maternal renal function. Renal function improved immediately. A second pregnancy ended in a first trimester miscarriage. The third and fourth pregnancies delivered male infants at 35 and 34 weeks, with worsening renal function in each pregnancy, reaching end stage. Repeat biopsy showed extensive glomerulosclerosis and male cells were identified. CONCLUSIONS: This case of Sjögren's syndrome with renal disease demonstrated the increased risk of fetal and maternal adverse pregnancy outcomes. Renal function worsened in each pregnancy and progressed to end-stage renal disease. Fetal microchimerism offers an interesting mechanism for our patient's renal failure and its apparent relationship to her pregnancies.

Ligand-based 3D-QSAR studies of diaryl acyl-sulfonamide analogues as human umbilical vein endothelial cells inhibitors stimulated by VEGF.

Diaryl acylsulfonamide derivatives were reported as Human Umbilical Vein Endothelial cell (HUVEC) inhibitors, stimulated by Vascular Endothelial Growth Factor (VEGF). VEGF has angiogenic property to cause colorectal cancer. A ligand-based 3D-QSAR technique was carried out on diaryl acylsulfonamide derivatives by using Comparative Molecular Field Analysis (CoMFA) studies to find relations between biological activities of inhibitors and their structures. In absence of binding mechanism for the ligand with VEGF receptor, current study hopes to shed some light on the inhibition mechanism of the ligands with HUVEC. 3D-QSAR technique was applied to a set of fifty ligands in order to facilitate the design of more potent inhibitors. However, the maximum cross-validated correlation coefficient value was found to be 0.417. The value is relatively low when compared to the usual acceptable cross-validated correlation coefficient, but no further improvements were observed by applying different available options. Therefore, the final model was used for further analysis. Additionally, the resulted CoMFA model was validated by an external set of 10 compounds yielding surprisingly, a satisfactory correlation coefficient value (r(2) (pred) ) 0.80. Moreover, the analysis of the individual generated 3D contours helped in understanding the possible structural modifications of molecules to improve the inhibitory potency.

Pregnancy and the risk of autoimmune disease.

Autoimmune diseases (AID) predominantly affect women of reproductive age. While basic molecular studies have implicated persisting fetal cells in the mother in some AID, supportive epidemiological evidence is limited. We investigated the effect of vaginal delivery, caesarean section (CS) and induced abortion on the risk of subsequent maternal AID. Using the Danish Civil Registration System (CRS) we identified women who were born between 1960 and 1992. We performed data linkage between the CRS other Danish national registers to identify women who had a pregnancy and those who developed AID. Women were categorised into 4 groups; nulligravida (control group), women who had 1st child by vaginal delivery, whose 1st delivery was by CS and who had abortions. Log-linear Poisson regression with person-years was used for data analysis adjusting for several potential confounders. There were 1,035,639 women aged >14 years and 25,570 developed AID: 43.4% nulligravida, 44.3% had their first pregnancy delivered vaginally, 7.6% CS and 4.1% abortions. The risk of AID was significantly higher in the 1st year after vaginal delivery (RR = 1.1[1.0, 1.2]) and CS (RR = 1.3[1.1, 1.5]) but significantly lower in the 1st year following abortion (RR = 0.7[0.6, 0.9]). These results suggest an association between pregnancy and the risk of subsequent maternal AID. Increased risks of AID after CS may be explained by amplified fetal cell traffic at delivery, while decreased risks after abortion may be due to the transfer of more primitive fetal stem cells. The increased risk of AID in the first year after delivery may also be related to greater testing during pregnancy.

Ligand-based 3D-QSAR studies of physostigmine analogues as acetylcholinesterase inhibitors.

Natural alkaloid Physostigmine is one of the most potent pseudo-irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long-term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D-QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co-crystallized Ganstigmine as template. The strategy yielded significant 3D-QSAR models with the cross-validated q(2) values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r(2) values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.