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Ceramic BiFe1−xZnxO3 multiferroic samples were prepared by the solid combustion method for x = 0.1, 0.15, and 0.2. Structural, magnetic, and magnetocaloric properties of the multiferroics have been studied. For all samples, an antiferromagnetic phase transition is observed in the region of 630 K. With increase in x, the reduction in magnitude of magnetization and Neel temperature is observed. The magnetocaloric properties, entropy, relative cooling power, and heat capacity have been calculated within the framework of thermodynamic theory. It has been established that the maximum changes of magnetocaloric properties of multiferroics are observed in the region of magnetic phase transition. [ABSTRACT FROM AUTHOR]

Reports on the influence of 60 keV N[sub2][sup+] ion implantation on aqueous degradation of a YBaCuO high-T[subc] superconductor. Capability of the ion implantation technique; Significance of surface nitridation; Irradiation of the superconducting samples.

Presents an abstract of the study 'Current Transport in Y[sub1]Ba[sub2]Cu[sub3-x]M[subx]O[sub7-sigma] (M≡Fe, Zn) Epitaxial Thin Films,' by S.B. Ogale and S.T. Bendre.

Allergic rhinitis and asthma are commonly coexisting conditions, significantly impacting patient health and quality of life. Despite their interrelation, diagnosing allergic rhinitis in patients with asthma remains challenging, leading to underdiagnosis and suboptimal management. The expert consensus engaged a modified Delphi method involving 29 experts including pulmonologists, ear, nose, and throat surgeons, and allergologists. Through group discussions, consensus statements were developed regarding the epidemiology, diagnosis, and management of allergic rhinitis and asthma. Final consensus statements were formulated based on the experts' collective clinical judgment and experience. This expert consensus provides updated recommendations tailored to the Indian context, addressing the gaps in existing research and clinical practice. By promoting a systematic and evidence-based approach to diagnosis and management, this consensus aims to support clinicians in effectively identifying and treating allergic rhinitis in patients with asthma, thereby improving overall disease management and patient well-being., (© 2024. The Author(s).)

Fibroblast activation protein-α (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with ≥90% radiochemical purities and 22-76% decay-corrected radiochemical yields. nat Ga-labeled complexes displayed dose-dependent FAP inhibition, with binding potency of nat Ga-SB03178 being ∼17 times higher than nat Ga-SB04033. To evaluate their pharmacokinetic profiles, PET imaging and ex vivo biodistribution analyses were executed in FAP-overexpressing HEK293T:hFAP tumor-bearing mice. While both tracers displayed clear tumor visualization that was primarily FAP-arbitrated, with negligible uptake in most peripheral tissues, [ 68 Ga]Ga-SB03178 demonstrated higher tumor uptake and superior tumor-to-background contrast ratios than [ 68 Ga]Ga-SB04033. 177 Lu-labeled SB03178 was subjected to tumor retention studies, mouse dosimetry profiling and mouse-to-human dose extrapolations also using the HEK293T:hFAP tumor model. [ 177 Lu]Lu-SB03178 exhibited a combination of high and sustained tumor uptake, with excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. Our preliminary findings are considerably encouraging to support clinical development of [ 68 Ga]Ga-/[ 177 Lu]Lu-SB03178 theranostic pair for use in a vast majority of FAP-overexpressing neoplasms, particularly carcinomas., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kuo-Shyan Lin reports a relationship with Alpha-9 Oncology Inc that includes: consulting or advisory, equity or stocks, and funding grants. Helen Merkens reports a relationship with Alpha-9 Oncology Inc that includes: equity or stocks. Francois Benard reports a relationship with Alpha-9 Oncology Inc that includes: board membership, consulting or advisory, equity or stocks, and funding grants. Hsiou-Ting Kuo reports a relationship with Alpha-9 Oncology Inc that includes: employment and equity or stocks. Zhengxing Zhang reports a relationship with Alpha-9 Oncology Inc that includes: equity or stocks. Kuo-Shyan Lin has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Francois Benard has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Zhengxing Zhang has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. Shreya Bendre has patent #PCT/CA2023/050040 pending to Provincial Health Services Authority. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Some bispecific radiotracers have been developed to overcome the limitations of monospecific tracers and improve detection sensitivity for heterogeneous tumor lesions. Here, we aim to synthesize two bispecific tracers targeting prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are key markers expressed in prostate cancer. A pyridine-based FAP-targeted ligand was synthesized through multi-step organic synthesis and then connected to the 2-Nal-containing PSMA-targeted motif. The K i (PSMA) values of Ga-complexed bispecific ligands, Ga-AV01084 and Ga-AV01088, were 11.6 ± 3.25 and 28.7 ± 6.05 nM, respectively, and the IC 50 (FAP) values of Ga-AV01084 and Ga-AV01088 were 10.9 ± 0.67 and 16.7 ± 1.53 nM, respectively. Both [ 68 Ga]Ga-AV01084 and [ 68 Ga]Ga-AV01088 enabled the visualization of PSMA-expressing LNCaP tumor xenografts and FAP-expressing HEK293T:hFAP tumor xenografts in PET images acquired at 1 h post-injection. However, the tumor uptake values from the bispecific tracers were still lower than those obtained from the monospecific tracers, PSMA-targeted [ 68 Ga]Ga-PSMA-617 and FAP-targeted [ 68 Ga]Ga-AV02070. Further investigations are needed to optimize the selection of linkers and targeted pharmacophores to improve the tumor uptake of bispecific PSMA/FAP tracers for prostate cancer imaging.

Fibroblast activation protein (FAP) is a membrane-tethered serine protease overexpressed in the reactive stromal fibroblasts of >90% human carcinomas, which makes it a promising target for developing radiopharmaceuticals for the imaging and therapy of carcinomas. Here, we synthesized two novel ( R )-pyrrolidin-2-yl-boronic acid-based FAP-targeted ligands: SB02055 (DOTA-conjugated ( R )-(1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)glycyl)pyrrolidin-2-yl)boronic acid) and SB04028 (DOTA-conjugated (( R )-1-((6-(3-(piperazin-1-yl)propoxy)quinoline-4-carbonyl)-D-alanyl)pyrrolidin-2-yl)boronic acid). nat Ga- and 68 Ga-complexes of both ligands were evaluated in preclinical studies and compared to previously reported nat Ga/ 68 Ga-complexed PNT6555. Enzymatic assays showed that FAP binding affinities (IC 50 ) of nat Ga-SB02055, nat Ga-SB04028 and nat Ga-PNT6555 were 0.41 ± 0.06, 13.9 ± 1.29 and 78.1 ± 4.59 nM, respectively. PET imaging and biodistribution studies in HEK293T:hFAP tumor-bearing mice showed that while [ 68 Ga]Ga-SB02055 presented with a nominal tumor uptake (1.08 ± 0.37 %ID/g), [ 68 Ga]Ga-SB04028 demonstrated clear tumor visualization with ~1.5-fold higher tumor uptake (10.1 ± 0.42 %ID/g) compared to [ 68 Ga]Ga-PNT6555 (6.38 ± 0.45 %ID/g). High accumulation in the bladder indicated renal excretion of all three tracers. [ 68 Ga]Ga-SB04028 displayed a low background level uptake in most normal organs, and comparable to [ 68 Ga]Ga-PNT6555. However, since its tumor uptake was considerably higher than [ 68 Ga]Ga-PNT6555, the corresponding tumor-to-organ uptake ratios for [ 68 Ga]Ga-SB04028 were also significantly greater than [ 68 Ga]Ga-PNT6555. Our data demonstrate that ( R )-(((quinoline-4-carbonyl)-d-alanyl)pyrrolidin-2-yl)boronic acid is a promising pharmacophore for the design of FAP-targeted radiopharmaceuticals for cancer imaging and radioligand therapy.

Cortical projection neurons polarize and form an axon while migrating radially. Even though these dynamic processes are closely interwoven, they are regulated separately-the neurons terminate their migration when reaching their destination, the cortical plate, but continue to grow their axons. Here, we show that in rodents, the centrosome distinguishes these processes. Newly developed molecular tools modulating centrosomal microtubule nucleation combined with in vivo imaging uncovered that dysregulation of centrosomal microtubule nucleation abrogated radial migration without affecting axon formation. Tightly regulated centrosomal microtubule nucleation was required for periodic formation of the cytoplasmic dilation at the leading process, which is essential for radial migration. The microtubule nucleating factor γ-tubulin decreased at neuronal centrosomes during the migratory phase. As distinct microtubule networks drive neuronal polarization and radial migration, this provides insight into how neuronal migratory defects occur without largely affecting axonal tracts in human developmental cortical dysgeneses, caused by mutations in γ-tubulin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fibroblast activation protein α (FAP-α) is a cell-surface protein overexpressed on cancer-associated fibroblasts that constitute a substantial component of tumor stroma and drive tumorigenesis. FAP is minimally expressed by most healthy tissues, including normal fibroblasts. This makes it a promising pan-cancer diagnostic and therapeutic target. In the present study, we synthesized two novel tracers, [ 68 Ga]Ga-SB03045 and [ 68 Ga]Ga-SB03058, bearing a (2 S ,4 S )-4-fluoropyrrolidine-2-carbonitrile or a (4 R )-thiazolidine-4-carbonitrile pharmacophore, respectively. [ 68 Ga]Ga-SB03045 and [ 68 Ga]Ga-SB03058 were evaluated for their FAP-targeting capabilities using substrate-based in vitro binding assays, and in PET/CT imaging and ex vivo biodistribution studies in an HEK293T:hFAP tumor xenograft mouse model. The IC 50 values of nat Ga-SB03045 (1.59 ± 0.45 nM) and nat Ga-SB03058 (0.68 ± 0.09 nM) were found to be lower than those of the clinically validated nat Ga-FAPI-04 (4.11 ± 1.42 nM). Contrary to the results obtained in the FAP-binding assay, [ 68 Ga]Ga-SB03058 demonstrated a ~1.5 fold lower tumor uptake than that of [ 68 Ga]Ga-FAPI-04 (7.93 ± 1.33 vs. 11.90 ± 2.17 %ID/g), whereas [ 68 Ga]Ga-SB03045 (11.8 ± 2.35 %ID/g) exhibited a tumor uptake comparable to that of [ 68 Ga]Ga-FAPI-04. Thus, our data suggest that the (2 S ,4 S )-4-fluoropyrrolidine-2-carbonitrile scaffold holds potential as a promising pharmacophore for the design of FAP-targeted radioligands for cancer diagnosis and therapy.

Compared to quinoline-based fibroblast activation protein (FAP)-targeted radiotracers, pyridine-based FAP-targeted tracers are expected to have faster pharmacokinetics due to their smaller molecular size and higher hydrophilicity, which we hypothesize would improve the tumor-to-background image contrast. We aim to develop 68 Ga-labeled pyridine-based FAP-targeted tracers for cancer imaging with positron emission tomography (PET), and compare their imaging potential with the clinically validated [ 68 Ga]Ga-FAPI-04. Two DOTA-conjugated pyridine-based AV02053 and AV02070 were synthesized through multi-step organic synthesis. IC 50 (FAP) values of Ga-AV02053 and Ga-AV02070 were determined by an enzymatic assay to be 187 ± 52.0 and 17.1 ± 4.60 nM, respectively. PET imaging and biodistribution studies were conducted in HEK293T:hFAP tumor-bearing mice at 1 h post-injection. The HEK293T:hFAP tumor xenografts were clearly visualized with good contrast on PET images by [ 68 Ga]Ga-AV02053 and [ 68 Ga]Ga-AV02070, and both tracers were excreted mainly through the renal pathway. The tumor uptake values of [ 68 Ga]Ga-AV02070 (7.93 ± 1.88%ID/g) and [ 68 Ga]Ga-AV02053 (5.6 ± 1.12%ID/g) were lower than that of previously reported [ 68 Ga]Ga-FAPI-04 (12.5 ± 2.00%ID/g). However, both [ 68 Ga]Ga-AV02070 and [ 68 Ga]Ga-AV02053 showed higher tumor-to-background (blood, muscle, and bone) uptake ratios than [ 68 Ga]Ga-FAPI-04. Our data suggests that pyridine-based pharmacophores are promising for the design of FAP-targeted tracers. Future optimization on the selection of a linker will be explored to increase tumor uptake while maintaining or even further improving the high tumor-to-background contrast.

Tumor heterogeneity limits the efficacy and reliability of monospecific radiopharmaceuticals in prostate cancer diagnosis and therapy. To overcome this limitation and improve lesion detection sensitivity, we developed and evaluated three bispecific radiotracers that can target both prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), which are the two key proteins overexpressed in prostate cancer. Three FAP-targeting ligands with various linker lengths were synthesized through multistep organic synthesis, and then connected to the PSMA-targeting motif. IC 50 (PSMA) and IC 50 (FAP) values of Ga-complexed bispecific ligands, Ga-AV01017, Ga-AV01030, and Ga-AV01038 were 25.2-71.6 and 1.25-2.74 nM, respectively. The uptake values in PSMA-expressing LNCaP tumor xenografts were 4.38 ± 0.55, 5.17 ± 0.51, and 4.25 ± 0.86 %ID/g for [ 68 Ga]Ga-AV01017, [ 68 Ga]Ga-AV01030, and [ 68 Ga]Ga-AV01038, respectively, which were lower than the monospecific PSMA-targeting tracer [ 68 Ga]Ga-HTK03041 (23.1 ± 6.11 %ID/g). The uptake values in FAP-expressing HEK293T:hFAP tumor xenografts were 2.99 ± 0.37, 3.69 ± 0.81, 3.64 ± 0.83 %ID/g for [ 68 Ga]Ga-AV01017, [ 68 Ga]Ga-AV01030, and [ 68 Ga]Ga-AV01038, respectively, which were also lower than the monospecific FAP-targeting tracer, [ 68 Ga]Ga-FAPI-04 (12.5 ± 2.00 %ID/g). We observed that the bispecific tracers had prolonged blood retention, in which tracers with a longer linker tend to have a higher blood uptake and lower tumor uptake. Further investigations are needed to optimize the linker selection to generate promising bispecific PSMA/FAP-targeting tracers for prostate cancer imaging.

Development of targeted therapies will be a critical step towards reducing the mortality associated with triple-negative breast cancer (TNBC). To achieve this, we searched for targets that met three criteria: (1) pharmacologically targetable, (2) expressed in TNBC, and (3) expression is prognostic in TNBC patients. Since nuclear receptors have a well-defined ligand-binding domain and are thus highly amenable to small-molecule intervention, we focused on this class of protein. Our analysis identified TLX (NR2E1) as a candidate. Specifically, elevated tumoral TLX expression was associated with prolonged recurrence-free survival and overall survival for breast cancer patients with either estrogen receptor alpha (ERα)-negative or basal-like tumors. Using two TNBC cell lines, we found that stable overexpression of TLX impairs in vitro proliferation. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. We identify SERPINB2 as a likely mediator of these effects. Taken together, our work indicates that TLX impedes the progression of TNBC. Several ligands have been shown to regulate the transcriptional activity of TLX, providing a framework for the future development of this receptor for therapeutic intervention., Competing Interests: Declaration of competing interest The authors have no competing interests or conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Among all genetic mutations of LRRK2, the G2019S mutation is the most commonly associated with the late-onset of Parkinson's disease (PD). Hence, one potential therapeutic approach is to block the hyperactivity of mutated LRRK2 induced by kinase inhibition. To date, only a few LRRK2 kinase inhibitors have been tested for in vivo quantification of target engagement by positron emission tomography (PET). In this study, we performed biological evaluations of two radiolabeled kinase inhibitors i.e. [ 18 F]FMN3PA (14) and [ 18 F]FMN3PU for LRRK2 (15)., Procedures: Radiosyntheses of [ 18 F]FMN3PA (14) and [ 18 F]FMN3PU (15) were performed using K[ 18 F]-F-K222 complex in a TRACERlab FXN module and purification was carried out via C18 plus (Sep-Pak) cartridges. In vitro specific binding assays were performed in rat brain striatum and kidney tissues using GNE-0877 as a blocking agent (K i  = 0.7 nM). For in vivo blocking, 3 mg/kg of GNE-0877 was injected 30 min before radiotracer injection via tail vein in wild-type (WT) mice (n = 4). Dynamic scans by PET/CT (Siemens Inveon) were performed in WT mice (n = 3)., Results: Radiofluorinations resulted in radiochemical yields (RCYs) of 25 ± 1.3% (n = 6) ([ 18 F]FMN3PU, 15) and 37 ± 1.6% (n = 6) ([ 18 F]FMN3PA, 14) with ≥96% radiochemical purity (RCP) and a molar activity (MA) of 3.55 ± 1.6 Ci/μmol (131 ± 56 GBq/μmol) for [ 18 F]FMN3PU (15) and 4.57 ± 1.7 Ci/μmol (169 ± 63 GBq/μmol) for [ 18 F]FMN3PA (14), respectively. Saturation assays showed high specific binding for rat brain striatum with K d 20 ± 1.3 nM ([ 18 F]FMN3PA, 14) and 23.6 ± 4.0 nM ([ 18 F]FMN3PU, 15). In vivo blocking data for [ 18 F]FMN3PA (14) was significant for brain (p < 0.0001, 77% blocking) and kidney (p = 0.0041, 65% blocking). PET images showed uptake in mouse brain striatum., Conclusion: In the presence of GNE-0877 as a blocking agent, the specific binding of [ 18 F]FMN3PA (14) and [ 18 F]FMN3PU (15) was significant in vitro. [ 18 F]FMN3PA (14) showed good brain uptake in vivo, though fast clearance from brain was observed (within 10-15 min)., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Temperature-sensitive radiopharmaceutical precursors require lower reaction temperatures (<100 °C) during nucleophilic radiofluorination in order to avoid compound thermolysis, often resulting in sub-optimal radiochemical yields (RCYs). To facilitate nucleophilic aromatic substitution (S N Ar) of nucleofuges commonly used in radiofluorination (e.g., nitro group), we explored the use of Lewis acids as nucleophilic activators to accelerate [ 18 F]fluoride incorporation at lower temperatures, and thereby increasing RCYs for thermolabile activated precursors. Lewis acid-assisted radiofluorination was exemplified on the temperature-sensitive compound 1-(4-(4-morpholino-7-neopentyl-7 H -pyrrolo[2,3-d]pyrimidin-2-yl)phenyl)-3-(6-nitropyridin-3-yl)urea (MN3PU, compound 3) targeting leucine-rich repeat kinase 2 (LRRK2), an important target in the study of Parkinson's disease and various cancers., Methods: To a vessel containing dried K[ 18 F]F-K222 complex, a solution of precursor MN3PU ((3), 1 mg; 1.8 μmol) and Lewis acid (6 μL of 0.2 μmol: chromium II chloride (A), ferric nitrite (B) or titanocene dichloride (C)) in 500 μL of N,N -dimethylformamide (DMF) (with 10% t -BuOH for B) were added. Reactions were stirred for 25 min at 90 °C. In parallel, reactions were conducted without the addition of Lewis acids for baseline comparison. After purification via preconditioned Sep-Pak C18 plus cartridges, aliquots were analyzed by analytical radio-HPLC., Results: Non-decay corrected radiochemical yields (ndc RCYs) for [ 18 F]FMN3PU (7) were improved from 1.7 ± 0.7% (no addition of Lewis acids) to 41 ± 1% using Cr(II) and 37 ± 0.7% using Ti(II)-based Lewis acids, with radiochemical purities of ≥96% and molar activities (A m ) of up to 3.23 ± 1.7 Ci/μmol (120 ± 1.7 GBq/μmol)., Conclusion: RCYs of [ 18 F]FMN3PU (7) improved from ~5% using conventional nucleophilic radiofluorination, up to 41 ± 1% using Lewis-acid supported S N Ar.

High kidney uptake is a common feature of peptide-based radiopharmaceuticals, leading to reduced detection sensitivity for lesions adjacent to kidneys and lower maximum tolerated therapeutic dose. In this study, we evaluated if the Met-Val-Lys (MVK) linker could be used to lower kidney uptake of 68 Ga-labeled DOTA-conjugated peptides and peptidomimetics. A model compound, [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH (AmBz: aminomethylbenzoyl), and its derivative, [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH, coupled with the PSMA (prostate-specific membrane antigen)-targeting motif of the previously reported HTK01166 were synthesized and evaluated to determine if they could be recognized and cleaved by the renal brush border enzymes. Additionally, positron emission tomography (PET) imaging, ex vivo biodistribution and in vivo stability studies were conducted in mice to evaluate their pharmacokinetics. [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH was effectively cleaved specifically by neutral endopeptidase (NEP) of renal brush border enzymes at the Met-Val amide bond, and the radio-metabolite [ 68 Ga]Ga-DOTA-AmBz-Met-OH was rapidly excreted via the renal pathway with minimal kidney retention. [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH retained its PSMA-targeting capability and was also cleaved by NEP, although less effectively when compared to [ 68 Ga]Ga-DOTA-AmBz-MVK(Ac)-OH. The kidney uptake of [ 68 Ga]Ga-DOTA-AmBz-MVK(HTK01166)-OH was 30% less compared to that of [ 68 Ga]Ga-HTK01166. Our data demonstrated that derivatives of [ 68 Ga]Ga-DOTA-AmBz-MVK-OH can be cleaved specifically by NEP, and therefore, MVK can be a promising cleavable linker for use to reduce kidney uptake of radiolabeled DOTA-conjugated peptides and peptidomimetics.

Background: Bronchial asthma remains a clinical enigma with poorly controlled symptoms or exacerbations despite regular use of inhaled corticosteroids. Home nebulization offers a simplified solution for the delivery of rescue and maintenance bronchodilators, which is especially true for patients with frequent exacerbations during management of uncontrolled or difficult-to-treat asthma., Objective: We aimed to assess the clinical impact and outcomes associated with home nebulization-delivered long-acting bronchodilators for uncontrolled or difficult-to-treat asthma., Methods: This observational, concurrent study was conducted with 60 patients at 2 centers during November 2018. Statistical analyses for prebronchodilator forced expiratory volume in one second (FEV1) and Global Initiative for Asthma (GINA) asthma control score in patients on long-acting bronchodilators and corticosteroids were conducted, with two-tailed P values <.05 considered statistically significant., Results: Per protocol analyses (53/60) for consecutive cases receiving home nebulization with long-acting bronchodilators and corticosteroids were conducted. The baseline demographics included a male-to-female ratio of 30:23 and mean values of the following: age, 60.3 years (SD 11.8 years); weight, 64 kg (SD 16.8 kg); FEV1, 43% (SD 16%); GINA asthma control score, 3.0 points (SD 0.8 points); serum eosinophil level, 4% (SD 3%); fractional exhaled nitric oxide (FeNO), 12.1 ppb (SD 6 ppb). Of the patients, 100% (53/53) had uncontrolled symptoms, 69.8% (37/53) had prior exacerbations, 100% (53/53) used formoterol/budesonide, and 75.5% (40/53) used glycopyrronium. The per protocol group (n=53) had significantly improved mean prebronchodilator FEV1 (23.7%, SD 29.8%; 0.46 L, SD 0.58 L; P<.001) and GINA asthma control score (2.1 points, SD 0.8 points, P<.001). At baseline, patients (n=40) receiving glycopyrronium/formoterol/budesonide (25/20/500 mcg) nebulization admixture had the following mean values: prebronchodilator FEV1, 38% (SD 15%); GINA asthma control score, 3.0 points (SD 0.8 points); reversibility, 12% (SD 6%); peripheral eosinophil level, 4% (SD 3%); FeNO, 12 ppb (SD 5.7 ppb). In the post hoc analyses, these patients had significantly improved mean prebronchodilator FEV1 of 27.7% (SD 26.2%; 0.54 L, SD 0.51 L; P<.001) at 8 weeks compared with baseline. At baseline, patients (n=13) receiving formoterol/budesonide (20/500 mcg) nebulization had the following mean values: FEV1, 55% (SD 12%); GINA asthma control score, 3.0 points (SD 1.2 points); reversibility, 14% (SD 7%); serum eosinophil level, 4% (SD 3%); FeNO, 13.3 ppb (SD 6.8 ppb). In the post hoc analyses, these patients showed a significant improvement in prebronchodilator FEV1 of 11.2% (SD 13.1%; 0.22 L, SD 0.25 L; P<.001) from baseline. Breathlessness of mild to moderate intensity was reported by 10 cases (10/53, 18.9%), with no other treatment-emergent adverse events or serious adverse events., Conclusions: Home nebulization remains a viable option for symptomatic difficult-to-treat asthma cases with frequent use of rescue medications. Glycopyrronium as add-on therapy offers a synergistic response in patients on corticosteroids with difficult-to-treat asthma., Trial Registration: Clinical Trial Registry of India CTRI/2018/11/016319; https://tinyurl.com/y78cctm3., (©Deepak Talwar, Salil Bendre. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 29.04.2020.)

Clathrin ensures mitotic spindle stability and efficient chromosome alignment, independently of its vesicle trafficking function. Although clathrin localizes to the mitotic spindle and kinetochore fiber microtubule bundles, the mechanisms by which clathrin stabilizes microtubules are unclear. We show that clathrin adaptor interaction sites on clathrin heavy chain (CHC) are repurposed during mitosis to directly recruit the microtubule-stabilizing protein GTSE1 to the spindle. Structural analyses reveal that these sites interact directly with clathrin-box motifs on GTSE1. Disruption of this interaction releases GTSE1 from spindles, causing defects in chromosome alignment. Surprisingly, this disruption destabilizes astral microtubules, but not kinetochore-microtubule attachments, and chromosome alignment defects are due to a failure of chromosome congression independent of kinetochore-microtubule attachment stability. GTSE1 recruited to the spindle by clathrin stabilizes microtubules by inhibiting the microtubule depolymerase MCAK. This work uncovers a novel role of clathrin adaptor-type interactions to stabilize nonkinetochore fiber microtubules to support chromosome congression, defining for the first time a repurposing of this endocytic interaction mechanism during mitosis., (© 2020 Rondelet et al.)

On March 24 and 25, 2017 researchers and clinicians from around the world met at Temple University in Philadelphia to discuss the current knowledge of Mycobacterium avium ssp. paratuberculosis (MAP) and its relationship to human disease. The conference was held because of shared concern that MAP is a zoonotic bacterium that poses a threat not only to animal health but also human health. In order to further study this problem, the conferees discussed ways to improve MAP diagnostic tests and discussed potential future anti-MAP clinical trials. The conference proceedings may be viewed on the www.Humanpara.org website. A summary of the salient work in this field is followed by recommendations from a majority of the conferees.

Objective: The purpose of this study was to determine the effect of continuous glucose monitoring (CGM) on glycemic control in children, adolescents, and young adults ages 7-21 years with poorly controlled diabetes HbA1c 9.0% or more (74 mmol/mol IFCC)., Materials and Methods: The primary outcome was improvement in HbA1c. The secondary outcome included self-reported hypoglycemia. This 12-week study used a prospective, one-group, pre- and posttest pre-experimental design with a convenience sample. The study used the Medtronic Guardian CGM with Enlite Sensor., Results and Conclusions: Thirty-three subjects enrolled in the study. The mean age of the participants was 15.57 years, range was 11-20 years, 47.6% were male, and 52.4% were female. Twenty-one (63.6%) completed the final study visit. There was a clinically and statistically significant reduction of 1.46 (SD = 1.6711) (p = .001) in HbA1c at 12 weeks. Fifteen of the 21 participants (71.4%) had an HbA1c reduction of greater than 0.5%. The CGM monitor was worn a mean of 4.262 days a week. None of the subjects reported significant hypoglycemia while wearing the monitor. CGM was effective in improving glycemic control in this population with poorly controlled diabetes., (© 2016, Wiley Periodicals, Inc.)

The dynamic regulation of microtubules (MTs) during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore MTs have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The MT depolymerase MCAK (mitotic centromere-associated kinesin) can influence CIN through its impact on MT stability, but how its potent activity is controlled in cells remains unclear. In this study, we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumors, regulates MT stability during mitosis by inhibiting MCAK MT depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning as a result of MT instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, whereas artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus, GTSE1 inhibition of MCAK activity regulates the balance of MT stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability., (© 2016 Bendre et al.)

Since the isolation of HIV in 1983, the TB graph which was on the decline saw a spurt since 1990s. The fall in immunity caused by HIV leads to reactivation as well as new infections. The developing and developed countries showed two specific patterns with TB first and HIV later and vice versa respectively. Clinical presentation of TB in HIV showed a distinctive pattern with fulminant disease in extrapulmonary forms. The correlation between HIV and TB is important. Treatment of TB in HIV and non-HIV patients remains the same. DOTS therapy has shown significant success in HIV-TB co-infection.

Objective: To investigate the etiology and outcome of fulminant hepatic failure (FHF) in children., Setting: Hospital based descriptive., Methods: 36 children (22 males and 14 females) presenting with FHF over a period of one year were investigated. The ages ranged from 1.5 to 9 years. FHF was defined as occurrence of encephalopathy within eight weeks of onset of jaundice with no evidence of pre-existing liver disease. Detailed history, clinical examination, routine biochemical parameters and relevant diagnostic tests were carried out. Viral markers studied were anti HAV-IgM, HBsAg, anti HBc-IgM, anti-HCV and anti HEV-IgM., Results: A viral etiology could be established in 22 children (61.1%). Hepatitis A (n = 12), Hepatitis B (n = 3), Hepatitis A and B (n = 2), and Hepatitis A and E (n = 4). Two children had enteric fever (1 with associated HEV), 2 children had Wilson's disease, 1 child had Indian Childhood Cirrhosis (ICC) and 2 children had drug induced hepatitis. Etiological diagnosis was not possible in 8 children (22%). Fourteen children (39%) died. Poor outcome was associated with spontaneous bleeding, raised prothrombin time, lower transaminases and higher bilirubin on admission., Conclusion: Viral hepatitis is the commonest cause of FHF in children. HAV alone or in combination is responsible for upto 50% of all FHF in children. Chronic liver disease can also present as FHF. Etiological diagnosis is not possible to upto one-fourth of all cases.