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Abstract??Methanolic extracts of 20 medicinal plants were screened at 1?10?mg/ml for in vitro macrofilaricidal activity by worm motility assay against adultSetaria digitata, the cattle filarial worm. Four plant extracts showed macrofilaricidal activity by worm motility at concentrations below 4?mg/ml and an incubation period of 100?min. Complete inhibition of worm motility and subsequent mortality was observed at 3, 2, 1 and 1?mg/ml, respectively, forCentratherum anthelminticum,Cedrus deodara,Sphaeranthus indicusandRicinus communis. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction assay was carried out at 1?mg ml?1and 4-h incubation period, and the results showed thatC. deodara,R. communis,S. indicusandC. anthelminticumexhibited 86.56, 72.39, 61.20 and 43.15% inhibition respectively in formazan formation compared to the control. [ABSTRACT FROM AUTHOR]

Treatments for Alzheimer's disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration., (© 2024 Stevenson et al.)

Objectives: To investigate factors associated with outcome of second twin during labour., Methods: The study was a retrospective cohort study in a single tertiary centre in Malaysia from 2014 until 2018 involving all twin pregnancies delivered at or more than 24 weeks of gestation., Results: Total of 409 twin pregnancies were included. Dichorionic twin comprises of 54.5 % (n=223) and 45.5 % (n=186) are monochorionic. Women with dichorionic pregnancies are significantly older (p<0.001), have more pre-existing medical disorders (p=0.011) and fetal structural anomalies (p=0.009). Monochorionic pregnancies are significantly more amongst Malay (p=0.01) and conceived spontaneously (p<0.001). There are significantly more fetuses both in cephalic presentation (p=0.026), birthweight discrepancy more than 20 % (p=0.038) and shorter mean inter-twin delivery duration (p=0.048) in monochorionic pregnancies. Second twin delivered with Apgar score <7 is significantly more in dichorionic pregnancies (p=0.006). The second twin is associated with lower birthweight, small for gestational age and arterial cord pH<7.25. Within the group of women who delivered both fetuses vaginally, there was significantly more second twins with intertwin delivery duration less than 30 min who were delivered vaginally without instrumentation (p=0.018). There was significantly more second twin with intertwin delivery duration of 30 min and more with arterial cord pH<7.25 (p=0.045). Those who delivered spontaneously had inter-twin delivery duration within 15-29 min. The outcome of second twin is not influenced by type of twin, gestational age at delivery, inter-twin delivery duration, mode of delivery and presentation at birth., Conclusions: The neonatal outcome for the second twin at birth is not influenced by type of twin, gestational age at delivery, inter-twin delivery duration, mode of delivery and presentation at birth in a cohort managed with non-active management of the second twin in Malaysia., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp 2 )-C(sp 3 ) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing β-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical C sp3 -F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp 3 )-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization., (© 2024. The Author(s).)

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia. They have also been shown to directly bind to CD99 and inhibit ES growth through a distinct mechanism. In the current study, we designed, synthesized and tested new ES specific derivatives of both drugs that would continue to target CD99 but with expected reduction in cellular membrane permeability and rendered unsuitable for inhibiting DNA synthesis. By using commercially available clofarabine and cladribine purine nucleoside analogs, we modified the primary alcohol moiety at the deoxyribose C-5' terminal site to suppress phosphorylation and thus inhibition of subsequent DNA synthesis pathways. In addition, we incorporated a variety of polar groups in the ribose and purine rings to reduce membrane permeability and investigated the effects of configurational changes in the sugar moiety. Among 26 new derivatives, we identified two compounds, BK50164 and BK60106, that cause cell death specifically in ES primarily due to inhibition of CD99 but not via inhibition of DNA synthesis. These findings provide a road map for the future development selective CD99 inhibitors for targeted treatment of ES., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aykut Uren reports financial support was provided by Bone Cancer Research Trust, United Kingdom. Eryn Nelson reports financial support was provided by Henry Luce Foundation. Aykut Uren reports financial support was provided by National Institutes of Health. Christian Wolf reports financial support was provided by Bone Cancer Research Trust, United Kingdom., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Cross-coupling of alkyl fluorides and organocuprates is accomplished via aluminum halide mediated C-F bond activation and subsequent C sp2 -C sp3 and C sp3 -C sp3 bond formation. Relatively mild conditions allow for smooth activation of notoriously challenging primary and secondary alkyl fluorides while competing alkyl chain rearrangement, HF elimination, and homocoupling reactions are effectively controlled. The utility and functional group tolerance are demonstrated with 23 examples and a variety of coupling products obtained in up to 88% yield.

A highly efficient method for C-F bond functionalization of a broad variety of activated and unactivated aliphatic substrates with inexpensive lithium iodide is presented. Primary, secondary, tertiary, benzylic, propargylic and α-functionalized alkyl fluorides react in chlorinated or aromatic solvents at room temperature or upon heating to the corresponding iodides which are isolated in 91-99% yield. The reaction is selective for aliphatic monofluorides and can be coupled with in situ nucleophilic iodide replacements to install carbon-carbon, carbon-nitrogen and carbon-sulfur bonds with high yields. Alkyl difluorides, trifluorides, even in activated benzylic positions, are inert under the same conditions and aryl fluoride bonds are also tolerated., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Background: Anterior cervical spine fixation (ACSF) is a common mode of stabilization of cervical spine injuries. These patients usually need a prolonged mechanical ventilation, so an early tracheostomy is beneficial for them. However, it is often delayed due to the close proximity to the surgical site, due to the concerns of infection, and increased bleeding. Percutaneous dilatational tracheostomy (PDT) is also considered a relative contraindication due to the inability to achieve adequate neck extension., Objectives: The objectives of our study are to assess the:Feasibility of performing a very early percutaneous dilatational tracheostomy in cervical spine injury patients, post-anterior cervical spine fixation.Safety in doing so with regard to surgical-site infection, early, and late complications.Benefits with regard to outcome measures like ventilator days and length of stay (LOS) in the intensive care unit (ICU) and hospital., Materials and Methods: We performed a retrospective review of all patients who underwent anterior cervical spine fixation and bedside percutaneous dilatational tracheostomy in our ICU from 1st January 2015 to 31st March 2021., Results: Out of the 269 patients admitted to our ICU with cervical spine pathology, 84 were included in the study. About 40.4% patients had injury above C5 level ( n -34) and 59.5% had below C5 level. About 86.9% patients had ASIA-A neurology. In our study, percutaneous tracheostomy was done at an average of 2.8 days from the cervical spine fixation. Average length of ventilator days post-tracheostomy was 8.32 days, ICU stay was 10.5 days, and hospital stay was 28.6 days. One patient developed anterior surgical-site infection., Conclusion: We conclude from our study that a very early percutaneous dilatational tracheostomy can be done in post-anterior cervical spine fixation patients as early as within 3 days without significant complications., How to Cite This Article: Paul AL, Varaham R, Balaraman K, Rajasekaran S, Balasubramani VM. Safety and Feasibility of Very Early Bronchoscopy-assisted Percutaneous Dilatational Tracheostomy in Anterior Cervical Spine Fixation Patients. Indian J Crit Care Med 2022;26(10):1086-1090., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; Jaypee Brothers Medical Publishers (P) Ltd.)

Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson's disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13 +/+ mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13 +/- ) or completely (USP13 -/- ) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13 +/+ ), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies.

The widespread use of fluorinated organic compounds in the health, agrochemical, and materials sciences is sustained by a steadily growing pool of commercially available fine chemicals. The synthetic utility of the increasingly ubiquitous Csp 3 ─F bond, however, remains to be fully exploited, which is often a difficult task because of its paramount stability and chemical inertness. Here, we demonstrate chemodivergent activation of monofluoroalkyl compounds toward either nucleophilic or electrophilic intermediates. This is accomplished under conditions that are compatible with several reaction types and many functional groups, which drastically widens the current scope of organofluorine chemistry and sets the stage for carbon-carbon and carbon-heteroatom bond formations, stereoselective construction of bisoxindole alkaloid scaffolds via in situ Umpolung, and cross-electrophilic coupling methodology. The selective generation of either nucleophilic or electrophilic species and the possibility of doing so simultaneously or, alternatively, switching molecular polarity enable previously unidentified synthetic opportunities that recognize alkyl fluorides as chemodivergent building blocks.

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC 50 value of 0.2 µM against Leishmania donovani , and a selectivity index value of 187, together with in vivo activity on the L. donovani /hamster model. Attempts to establish structure-activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.

Suzuki cross-coupling of benzylic and unactivated aliphatic fluorides with aryl- and alkenylboronic acids has been achieved via mechanistically distinct Pd and Ni catalyzed pathways that outperform competing protodeboronation, β-hydride elimination, and homocoupling processes. The utility is demonstrated with more than 20 examples including heterocyclic structures, 1,1-disubstituted and trans -1,2-disubstituted alkenes, and by the incorporation of acetonitrile into functionalized (hetero)arenes.

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.

Aims and Objectives: Diplopia in children is uncommon. However a small group of patients present with diplopia and severe restriction of upward globe movement which requires early diagnosis and prompt intervention. This study aims to evaluate the timing of intervention and functional outcome in the management of white-eyed blowout fractures., Methodology: The study was conducted in a tertiary level trauma center. There were a total of 46 orbital floor injuries over a period of 2 years out of which 4 patients with white-eyed blowout fractures were identified. Details of each case were entered on a standard data base and analysed with respect to age, mode of injury, extent of limitation of gaze, timing of intervention, pre and post-operative diplopia. Minimum follow up period for every case was 1year., Results: All of them had sports related injuries. Three of the four patients had complete recovery from diplopia with full range of eye movements. However one child with delayed presentation didn't recover fully and had persistence of symptoms within the functional range., Conclusion: White-eyed orbital blowout fracture in kids though uncommon need prompt diagnosis and management for complete recovery. The initial clinical presentation mimics that of head injury and hence can be missed, leading to a delay in diagnosis resulting in incomplete recovery., Competing Interests: Conflict of interestAll authors declare that they have no conflict of interest., (© The Association of Oral and Maxillofacial Surgeons of India 2020.)