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Surgery for excision of juvenile nasopharyngeal angiofibroma (JNA) carries the possibility of massive life-threatening haemorrhage. Anaesthetic management aims to maintain haemodynamic stability and reduce blood loss. This case series describes the application of the bundled approach as a multimodal blood loss prevention bundle (MBLPB). Twenty patients underwent 23 surgeries with MBLPB. The blood loss and the number of units of blood transfused were recorded. The surgeon satisfaction score was assessed. The median [interquartile range (IQR)] estimated blood loss was 1300 (650-2350) ml. Patients with tumours in stages I and II had a median (IQR) blood loss of 550 (270-750) ml compared to patients with higher grades of tumours (stages III, IV) with a median (IQR) blood loss of 2100 (1300-2500) ml. Median (IQR) units of packed red cells transfused was 1 (0-3). The surgeon's satisfaction score was high when MBLPB was applied for JNA. However, it does not appear to reduce blood loss markedly. Keywords: Anaesthesia, blood transfusion, dexmedetomidine, juvenile nasopharyngeal angiofibroma, reverse Trendelenburg position, tranexamic acid, Author(s): Ruchi A. Jain (corresponding author) [1]; Devangi A. Parikh [1]; Roshni C. Miranda [2] INTRODUCTION Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular tumour. Surgery is the gold standard [...]

Background and Aims: Neurological complications (NCs) are significantly associated with reduced regional cerebral saturation (rSO[sub.2]) in patients undergoing cardiac surgeries, as assessed with cerebral oximetry (COx). However, limited evidence is available in patients undergoing balloon mitral valvotomy (BMV). Thus, we evaluated the utility of COx in patients undergoing BMV, the incidence of BMV-related NCs and the association of >20 reduction in rSO[sub.2] with NCs. Methods: This pragmatic, prospective, observational study was performed after ethical approval, over November 2018 to August 2020, in the cardiology catherization laboratory of a tertiary care hospital. The study involved 100 adult patients undergoing BMV for symptomatic mitral stenosis. The patients were evaluated at initial presentation, pre-BMV, post-BMV and 3 months after the BMV. Results: The incidence of NCs was 7, including transient ischaemic attack (n = 3), slurred speech (n = 2) and hemiparesis (n = 2). A significantly greater proportion of patients with NCs had a > 20 decrease in the rSO[sub.2] (P value = 0.020). At >20 cut-off, the COx had a sensitivity and specificity of 57.1 and 80, respectively, in the prediction of NCs. Female sex (P value = 0.039), history of cerebrovascular episodes (P value < 0.001) and number of balloon attempts (P value < 0.001) were significantly associated with NCs. Patients with and without NCs had a significantly greater post-BMV mean change in rSO[sub.2] than pre-BMV (both right and left sides), but the magnitude of mean change was greater in those with NCs. Conclusions: COx alone has low sensitivity and specificity in the prediction of NCs and cannot reliably predict the development of post-BMV NCs. Keywords: Brain, cardiac surgery, mitral valve stenosis, oximetry, postoperative cognitive dysfunction, cerebral oximetry, balloon mitral valvotomy, regional cerebral saturation, Author(s): Dhawal R. Wadaskar (corresponding author) [1]; Vidya G. Isal [2]; Ruchi A. Jain [2]; Shakuntala J. Basantwani [2] INTRODUCTION In India, mitral stenosis (MS) of rheumatic origin is a [...]

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.

Extracellular electron transfer by Geobacter species through surface appendages known as microbial nanowires.sup.1 is important in a range of globally important environmental phenomena.sup.2, as well as for applications in bio-remediation, bioenergy, biofuels and bioelectronics. Since 2005, these nanowires have been thought to be type 4 pili composed solely of the PilA-N protein.sup.1. However, previous structural analyses have demonstrated that, during extracellular electron transfer, cells do not produce pili but rather nanowires made up of the cytochromes OmcS.sup.2,3 and OmcZ.sup.4. Here we show that Geobacter sulfurreducens binds PilA-N to PilA-C to assemble heterodimeric pili, which remain periplasmic under nanowire-producing conditions that require extracellular electron transfer.sup.5. Cryo-electron microscopy revealed that C-terminal residues of PilA-N stabilize its copolymerization with PilA-C (to form PilA-N-C) through electrostatic and hydrophobic interactions that position PilA-C along the outer surface of the filament. PilA-N-C filaments lack [pi]-stacking of aromatic side chains and show a conductivity that is 20,000-fold lower than that of OmcZ nanowires. In contrast with surface-displayed type 4 pili, PilA-N-C filaments show structure, function and localization akin to those of type 2 secretion pseudopili.sup.6. The secretion of OmcS and OmcZ nanowires is lost when pilA-N is deleted and restored when PilA-N-C filaments are reconstituted. The substitution of pilA-N with the type 4 pili of other microorganisms also causes a loss of secretion of OmcZ nanowires. As all major phyla of prokaryotes use systems similar to type 4 pili, this nanowire translocation machinery may have a widespread effect in identifying the evolution and prevalence of diverse electron-transferring microorganisms and in determining nanowire assembly architecture for designing synthetic protein nanowires. Structural, functional and localization studies reveal that Geobacter sulfurreducens pili cannot behave as microbial nanowires, instead functioning in a similar way to secretion pseudopili to export cytochrome nanowires that are essential for extracellular electron transfer., Author(s): Yangqi Gu [sup.1] [sup.2] , Vishok Srikanth [sup.1] [sup.3] , Aldo I. Salazar-Morales [sup.1] [sup.3] , Ruchi Jain [sup.1] [sup.3] , J. Patrick O'Brien [sup.1] [sup.3] , Sophia M. [...]

Background/Aim: Glioblastomas (GBM) are infiltrative malignant brain tumors which mostly recur within a year’s time following surgical resection and chemo-radiation therapy. Studies on glioblastoma cells following radiochemotherapy, have been demonstrated to induce transdifferentiation, cellular plasticity, activation of DNA damage response and stemness. As glioblastomas are heterogenous tumors that develop treatment resistance and plasticity, we investigated if there exist genome-wide DNA methylation changes in recurrent tumors. Materials and Methods: Utilizing genome-wide DNA methylation arrays, we compared the DNA methylation profile of 11 primary (first occurrence) tumors with 13 recurrent (relapsed) GBM, to delineate the contribution of epigenetic changes associated with therapy exposure, therapy resistance, and relapse of disease. Results: Our data revealed 1,224 hypermethylated- and 526 hypomethylated-probes in recurrent glioblastomas compared to primary disease. We found differential methylation of solute carrier and ion channel genes, interleukin receptor/ligand genes, tumor-suppressor genes and genes associated with metastasis. We functionally characterized one such hypomethylated-up-regulated gene, namely anthrax toxin receptor 1/tumor endothelial marker 8 (ANTXR1/TEM8), whose expression was validated to be significantly up-regulated in recurrent glioblastomas compared to primary tumors and confirmed by immunohistochemistry. Using overexpression and knockdown approaches, we showed that TEM8 induces proliferation, invasion, migration, and chemo-radioresistance in glioblastoma cells. Additionally, we demonstrated a novel mechanism of β-catenin stabilization and activation of the βcatenin transcriptional program due to TEM8 overexpression via a Src/PI3K/AKT/GSK3β/β-catenin pathway. Conclusion: We report genome-wide DNA methylation changes in recurrent GBM and suggest involvement of the TEM8 gene in GBM recurrence and progression. [ABSTRACT FROM AUTHOR]

The IFIH1 gene, encoding melanoma differentiation‐associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation in weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain‐of‐function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi–Goutieres and Singleton–Merten syndromes, while biallelic loss causes immunodeficiency. In this study, nine patients suffering from recurrent infections, inflammatory diseases, severe COVID‐19 or multisystem inflammatory syndrome in children (MIS‐C) were identified with putative loss‐of‐function IFIH1 variants by whole‐exome sequencing. All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL‐6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID‐19 or MIS‐C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS‐C. There was a significant association between IFIH1 monoallelic loss of function and susceptibility to infections in males. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss‐of‐function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS‐CoV‐2‐related disorders. [ABSTRACT FROM AUTHOR]