Clinical Outcomes of Ustekinumab in Inflammatory Bowel Disease.

Inflammatory bowel diseases including Crohn's disease (CD) and ulcerative colitis (UC) are characterized by abdominal pain, diarrhea, blood in stools, weight loss, and fatigue. It presents in patients with varying severity from mild to severe depending on the inflammation. Detailed analysis and guidelines are required for the safe usage of biological therapies in the treatment of inflammatory bowel diseases as surgery is reserved for more complex cases. There is also geographical variation in inflammatory bowel disease (IBD) incidence and prevalence based on environmental and climate changes, and socio-demographics. Studies also show that there is more hospitalization and reduced health-related quality of life in IBD patients when compared to normal people. We conducted an extensive literature database search for articles with keywords within the last 10 years on adults >18 years of age with IBD and its treatment, especially with ustekinumab. Ustekinumab is a human immunoglobulin G1 (IgG1) kappa monoclonal antibody, that blocks IL-12 and IL-23 and was approved by the FDA for the treatment of moderate to severe IBD, especially in patients who are intolerant to immunomodulators or corticosteroids treatment. There are several retrospective studies that show the effectiveness of ustekinumab dosage escalation every four weeks in IBD patients. This escalation of dose not only improved the clinical outcome but also reduced the worsening of the disease. Previous studies also show the importance of considering dosage escalation before switching biological agents in the IBD treatment. Ustekinumab has also demonstrated both efficacy and safety in the induction and maintenance of the treatment of this disease. There are certain challenges and opportunities associated with ustekinumab usage in IBD patients that require further research. Ustekinumab seems to be more cost-effective in the tumor necrosis factor (TNF)-alpha-inhibitor failure population when compared to previously used biological treatment regimes.

The Sensory Abnormalities and Neuropsychopathology of Autism and Anxiety.

Autism spectrum disorder (ASD) is a developmental disorder of interpersonal communications and restricted interest and deficits in sensory and social interactions. It co-occurs with anxiety and mostly in 30% of cases related to specific phobia. This review article summarises the sensory association between anxiety and ASD. The role of emotions and neurobiology discussed and sensory over-reactivity (SOR) was related to ASD and anxiety. PubMed database systematically searched for related articles on ASD and anxiety. The keywords used are autism spectrum disorder, autism spectrum disorder and emotion, anxiety disorder, sensory in autism and anxiety, and psychopathology. The results were most significant and related to the sensory association between ASD and anxiety. Out of 19 studies discussed, there were eight systematic reviews with meta-analysis, seven systematic reviews, three traditional reviews, and one included both systematic reviews with randomized controlled trials (RCTs). However, due to possible limitations and considerations, like small sample size and few clinical trials; hence, further recommendations to randomized clinical trials and cohort studies warranted. This review article helps scientists to plan and focus on necessary studies and possible screening for the disease to improve possible clinical outcomes. People gain awareness of the disease. Early recognition, as well as educational, behavioral, and family therapy, might decrease symptoms and support learning and development in children.

Design, synthesis, and antimicrobial evaluation of 1,4-dihydroindeno[1,2-c]pyrazole tethered carbohydrazide hybrids: exploring their in silico ADMET, ergosterol inhibition and ROS inducing potential.

A series of new 1,4-dihydroindeno[1,2-c]pyrazole tethered carbohydrazide hybrids (5a-u) were designed, synthesized and evaluated for their antimicrobial activity. Compounds 5d, 5g, 5j, 5k and 5q demonstrated significant activity against the entire panel of test pathogens. Further, compounds 5d and 5g exhibited significant anti-Candida activity. These potential hybrids (5d and 5g) also exhibited promising ergosterol biosynthesis inhibition against Candida albicans, which was further validated through molecular docking studies. Furthermore, compounds 5d and 5g caused intracellular ROS accumulation in C. albicans MTCC 3017 and were non-toxic to normal human lung cell line MRC5. In silico studies revealed that they demonstrated drug likeness and an appreciable pharmacokinetic profile. Overall, the findings demonstrate that 5d and 5g may be considered as promising leads for further development of new antifungal drugs.

ARtPM: Article Retrieval for Precision Medicine.

BACKGROUND: Information curation and literature surveillance efforts that synthesize the current knowledge about the impact of genetic variability on disease states and drug responses are vitally important for the practise of evidence-based precision medicine. For these efforts, finding the relevant and comprehensive set of articles from the ever growing scientific literature is a challenge. METHODS: We have designed and developed Article Retrieval for Precision Medicine (ARtPM), an end-to-end article retrieval system that employs multi-stage architecture to retrieve and rank relevant articles for a given medical case summary (genetic variants, disease, demographic, and other medical conditions). We compared ARtPM with five baselines, including PubMed Best Match, the improved search functionality recently introduced by PubMed. RESULTS: The differences in the performance of ARtPM and five baselines were statistically significant for four metrics that quantify different aspects of search effectiveness (P-values for P@10, R-prec, infNDCG, Recall@1000 were <.001, <.001,.003,.009, respectively). Pairwise systems' comparisons show that ARtPM is comparable or better than the best performing baseline on three metrics (R-prec: 0.324 vs 0.299, P-value=.06; infNDCG: 0.556 vs 0.465, P-value=.08; R@1000: 0.665 vs 0.572, P-value=.007), but performance in P@10 (0.603 vs 0.630, P-value:.64) needs to improve. CONCLUSION: The recall-focused phase of the ARtPM is effective at retrieving more relevant articles. The precision-focused ranking phase performs well at deeper ranks but needs further work on early ranks (e.g., richer feature set). Overall, the ARtPM system effectively facilitates evidence-based precision medicine practice, and provides a robust search framework for further work in this direction.

A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies.

A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.

Pd(II)/PhI(OAc)2 promoted direct cross coupling of glucals with aromatic acids.

A highly efficient oxidative C2-aroyloxylation of D-glucal with aromatic carboxylic acids has been achieved for the first time using 5 mol% Pd(OAc)2 and 1 equiv of PhI(OAc)2 to produce C2-aroyloxyglycals in good yields. The use of excess of PhI(OAc)2 (2 equiv) provides C2-acyloxyglycal exclusively.

Potential antimicrobial agents from triazole-functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones.

A series of substituted triazole functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones were synthesized by employing click chemistry and further characterized based on 1H NMR, 13C NMR, IR and mass spectral studies. All the synthesized derivatives were screened for their in vitro antimicrobial activities. Further, molecular docking studies were accomplished to explore the binding interactions between 1,2,3-triazol-4-yl-2H-benzo[b][1,4]oxazin-3(4H)-one and the active site of Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCS). These docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9c, 9d and 9e were identified as promising antimicrobial leads.

Novel Pathogens in Periodontal Microbiology.

Periodontitis is a polymicrobial disease caused by complex interactions between distinct pathogens in a biofilm resulting in the destruction of periodontal tissues. It seems evident that unknown microorganisms might be involved in onset or progression of periodontitis. For many decades, research in the field of oral microbiology failed to identify certain subgingival microbiota due to technical limitations but, over a period of 12 years using molecular approaches and sequencing techniques, it became feasible to reveal the existence of new periodontal pathogens. Therefore, it is evident that in addition to conventional periodontal pathogens, other microbes might be involved in onset and progression of periodontitis. The novel pathogens enlisted under periodontal phylogeny include Cryptobacterium curtum, Dialister pneumosintes, Filifactor alocis, Mitsuokella dentalis, Slackia exigua, Selenomonas sputigena, Solobacterium moorei, Treponema lecithinolyticum, and Synergistes. The polymicrobial etiology of periodontitis has been elucidated by comprehensive techniques, and studies throwing light on the possible virulence mechanisms possessed by these novel periodontal pathogens are enlisted.

Tandem Prins/Wagner/Ritter process for the stereoselective synthesis of (3-oxabicyclo[4.2.0]octanyl)amide and (1-(5-aryltetrahydrofuran-3-yl)cyclobutyl)amide derivatives.

Three-component coupling of aldehydes, vinylcyclopropyl carbinols, and nitriles in the presence of 10 mol% TMSOTf at -40 to 0 °C in dichloromethane affords a novel class of (3-oxabicyclo[4.2.0]octanyl)amides in high yields with excellent selectivity, whereas (1-vinylcyclobutyl)methanol provides the corresponding (1-(5-aryltetrahydrofuran-3-yl)cyclobutyl)amides under similar conditions. This is the first report on the synthesis of oxabicycles through a sequential Prins/Wagner/Ritter process.

Design, Synthesis and Evaluation of New 2, 6-Dihydroimidazo[1, 2-c]Pyrimido[5, 4-e]-Pyrimidine-5(3H)-thiones as Possible Antihistaminic/Antiasthmatic Agents.

A series of new 10-(alkylamino)-8-methyl-2, 6-dihydroimidazo[1, 2-c]pyrimido[5, 4-e]pyrimidine-5(3H)-thiones (4a-g) were subjected to molecular property prediction (drug-likeness, lipophilicity and solubility parameters) using Osiris Property Explorer, ALOGPS 2.1, Molinspiration and ACD/Chemsketch 12.0 software programmes. The calculated drug-related properties of the designed molecules were similar to those found in most marketed drugs. Amongst the proposed analogues, four promising candidates were chosen (4a-d) for synthesis on the basis of Lipinski's 'Rule of Five' and drug-likeness scores. The significant biological activity of the test compounds in two in vitro modes (isolated guinea pig tracheal chain preparation, isolated guinea pig ileum) supports the promise and accuracy of the prediction. Among them, 4a was the most potent antihistaminic (IC50 value of 30.2 µM; standard, chlorpheniramine maleate showed an IC50 of 14.1 µM).

Effect of ß-cyclodextrin on Rheological Properties of some Viscosity Modifiers.

Cyclodextrins are a group of novel excipients, extensively used in the present pharmaceutical industry. Sometimes they show significant interactions with other conventional additives used in the formulation of dosage forms. The effect of ß-cyclodextrin on the rheological properties of aqueous solutions of some selected viscosity modifiers was studied in the present work. ß-cyclodextrin showed two different types of effects on the rheology of the selected polymers. In case of natural polymers like xanthan gum and guar gum, enhanced apparent viscosity was found and in case of semi-synthetic polymers like sodium carboxymethyl cellulose and methyl cellulose, reduction in apparent viscosity was found. ß-cyclodextrin was included at 0.5, 1 and 2% w/v concentrations into the polymeric solutions. These findings are useful in the adjustment of concentrations of viscosity modifiers during the formulation of physically stable disperse systems.

Cryopreservation of zona-free cloned buffalo (Bubalus Bubalis) embryos: slow freezing vs open-pulled straw vitrification.

This study was carried out to compare the post-thaw cryosurvival rate and the level of apoptosis in vitro produced zona-free cloned buffalo blastocysts subjected to slow freezing or vitrification in open-pulled straws (OPS). Zona-free cloned embryos produced by handmade cloning were divided into two groups and were cryopreserved either by slow freezing or by vitrification in OPS. Cryosurvival of blastocysts was determined by their re-expansion rate following post-thaw culture for 22-24 h. The post-thaw re-expansion rate was significantly (p < 0.05) higher following vitrification in OPS (71.2 ± 2.3%) compared with that after slow freezing (41.6 ± 4.8%). For examining embryo quality, the level of apoptosis in day 8 frozen-thawed blastocysts was determined by TUNEL staining. The total cell number was not significantly different among the control non-cryopreserved cloned embryos (422.6 ± 67.8) and those cryopreserved by slow freezing (376.4 ± 29.3) or vitrification in OPS (422.8 ± 36.2). However, the apoptotic index, which was similar for embryos subjected to slow freezing (14.8 ± 2.0) or OPS vitrification (13.3 ± 1.8), was significantly (p < 0.05) higher than that for the control non-cryopreserved cloned embryos (3.4 ± 0.6). In conclusion, the results of this study demonstrate that vitrification in OPS is better than slow freezing for the cryopreservation of zona-free cloned buffalo blastocysts because it offers a much higher cryosurvival rate.

Choice of diagnostic and therapeutic imaging in periodontics and implantology.

Imaging forms an integral component for diagnosis of dental and in specific periodontal diseases. To date, intra-oral radiographic techniques are the main non-invasive diagnostic aids for the detection and assessment of internal changes in mineralized periodontal tissues like alveolar bone. These analog radiographic techniques suffer from inherent limitations like: Two dimensional projection, magnification, distortion, superimposition and misrepresentation of anatomic structures. The evolution of novel imaging modalities, namely cone beam computed tomography, tuned aperture CT empowered dental researchers to visualize the periodontium three dimensionally. This improves interpretation of structural and biophysical changes, ensures densitometric assessments of dentoalveolar structures including variations in alveolar bone density, and peri-implant bone healing more precisely. This detailed review, highlights current leading edge concepts, envisions a wide range of imaging modalities which pave the way for better understanding and early intervention of periodontal diseases.

Melatonin: a novel indolamine in oral health and disease.

This paper attempts to summarise the findings accumulated within the last few years concerning the hormone of darkness "melatonin." Based on its origin, from the pineal gland until recently it was portrayed exclusively as a hormone. Due to its lipophilic nature, it is accessible to every cell. Thus, in the classic sense it is a cell protector rather than a hormone. Recent studies, by Claustrat et al. (2005), detected few extrapineal sources of melatonin like retina, gastrointestinal tract, and salivary glands. Due to these sources, research by Cutando et al. (2007), is trying to explore the implications of melatonin in the oral cavity, in addition to its physiologic anti-oxidant, immunomodulatory and oncostatic functions at systemic level that may be receptor dependent or independent. Recently, certain in vivo studies by Shimozuma et al. (2011), detected the secretion of melatonin from salivary glands further emphasising its local activity. Thus, within our confines the effects of melatonin in the mouth are reviewed, adding a note on therapeutic potentials of melatonin both systemically and orally.

Green tea extract for periodontal health.

Tea, the commonly consumed beverage, is gaining increased attention in promoting overall health. In specific, green tea is considered a healthful beverage due to the biological activity of its polyphenols namely catechins. Among the polyphenols Epigallo catechin 3 gallate and Epicatechin 3 Gallate are the most predominant catechins. The antioxidant, antimicrobial, anticollagenase, antimutagenic, and c hemopreventive properties of these catechins proved to be helpful in the treatment of chronic diseases like periodontal disease. Studies have demonstrated that the type of processing mainly effects the concentration of catechins. Several epidemiological studies have proved that green tea also has some general health benefitting properties like antihypertensive, reduction of cardiovascular risk, antibacterial, antiviral, and antifungal activity. The present review concentrates on the effects of green tea in periodontal and general health.

Bioslurry phase remediation of chlorpyrifos contaminated soil: process evaluation and optimization by Taguchi design of experimental (DOE) methodology.

Design of experimental (DOE) methodology using Taguchi orthogonal array (OA) was applied to evaluate the influence of eight biotic and abiotic factors (substrate-loading rate, slurry phase pH, slurry phase dissolved oxygen (DO), soil water ratio, temperature, soil microflora load, application of bioaugmentation and humic substance concentration) on the soil bound chlorpyrifos bioremediation in bioslurry phase reactor. The selected eight factors were considered at three levels (18 experiments) in the experimental design. Substrate-loading rate showed significant influence on the bioremediation process among the selected factors. Derived optimum operating conditions obtained by the methodology showed enhanced chlorpyrifos degradation from 1479.99 to 2458.33microg/g (over all 39.82% enhancement). The proposed method facilitated systematic mathematical approach to understand the complex bioremediation process and the optimization of near optimum design parameters, only with a few well-defined experimental sets.

Degradation of chlorpyrifos contaminated soil by bioslurry reactor operated in sequencing batch mode: bioprocess monitoring.

Bioslurry reactor (SS-SBR) was studied for the degradation of chlorpyrifos contaminated soil using native mixed microflora, by adopting sequencing batch mode (anoxic-aerobic-anoxic) operation. Reactor operation was monitored for a total cycle period of 72 h consisting of 3 h of FILL, 64 h REACT, 2 h of SETTLE, and 3 h of DECANT with chlorpyrifos concentrations of 3000 micrpg/g, 6000 microg/g and 12000 microg/g. At 3000 microg/g of chlorpyrifos concentration, 91% was degraded after 72 h of the cycle period, whereas in the case of 6000 microg/g of chlorpyrifos, 82.5% was degraded. However, for 12000 microg/g of chlorpyrifos, only 14.5% degradation was observed. The degradation rate was rapid at lower substrate concentration and 12000 microg/g of substrate concentration was found to be inhibitory. Chlorpyrifos removal rate was slow during the initial phase of the sequence operation. Half-life of chlorpyrifos degradation (t0.5) was estimated to be 6.3 h for 3000 microg/g of substrate, 17.5 h for 6000 microg/g and 732.2 h for 12000 microg/g. Process performance was assessed by monitoring chlorpyrifos concentration and biochemical process parameters viz., pH, oxidation and reduction potential (ORP), dissolved oxygen (DO), oxygen consumption rate (OCR) and microbial count (CFU) during sequence operation. From the experimental data obtained it can be concluded that the rate-limiting step with the bioslurry phase reactor in the process of chlorpyrifos degradation may be attributed to the concentration of substrate present in either soil or liquid phase. Periodic operations (SBR) by varying individual components of substrate with time in each process step place micro-organisms under nutritional changes from feast to famine and maintains a wide distribution in the population of micro-organisms resulting in high uptake of the substrate in the bioslurry reactor.