Prospective analysis of goal-directed fluid therapy vs conventional fluid therapy in perioperative outcome of composite resections of head and neck malignancy with free tissue transfer.

BACKGROUND AND AIM: Head and neck cancer surgeries with free tissue transfer are complex procedures, and fluid management can grossly affect the microvascular anastomosis. We hypothesise that intra-operative goal-directed fluid therapy (GDFT) is the key to administer fluid individualised to a patient's requirement. The aim of this study was to observe the role of GDFT in perioperative flap outcome and length of hospital stay. METHODS: A randomised prospective controlled study was performed in 106 patients undergoing composite resection of head and neck cancer with free tissue transfer. Patients in Group A received GDFT based on stroke volume variation whereas Group B received conventional fluid therapy intra-operatively. The endpoints of this study were total perioperative fluid, fluid boluses, vasopressor requirement, flap outcome and length of intensive care unit and hospital stay. Statistical analysis was done using Chi-square test. RESULTS: The total intra-operative fluid given to both the groups was comparable but patients in Group A received more boluses and vasopressors compared to Group B during intra-operative period. The amount of fluid given in the first 24 hours post-operatively was significantly less in Group A (1807 + 476 ml) compared to Group B (2205 + 382 ml). Incidence of hypotension with tachycardia was observed in three patients in Group B and none in Group A. Poor flap outcome was observed in one patient in Group A versus four in Group B due to thrombosis. CONCLUSION: GDFT helps in early detection of fluid deficit and may avoid complications arising due to inadequate microvascular perfusion during the peri-operative period.

The m6A reader IMP2 directs autoimmune inflammation through an IL-17- and TNFα-dependent C/EBP transcription factor axis.

Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional "epitranscriptomic" mRNA modification [N6-methyladenosine (m6A)] in regulating C/EBPß and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBPß/δ-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase "writer" and suppressed by a demethylase "eraser." The only m6A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17-mediated Cebpd mRNA stabilization and promoted translation of C/EBPß/δ in response to IL-17A, IL-17F, and TNFα. RNA sequencing revealed transcriptome-wide IL-17-induced transcripts that are IMP2 influenced, and RNA immunoprecipitation sequencing identified the subset of mRNAs that are directly occupied by IMP2, which included Cebpb and Cebpd Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPß/δ. Imp2-/- mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Lcn2 Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.

Integrative Omics Analyses Reveal Epigenetic Memory in Diabetic Renal Cells Regulating Genes Associated With Kidney Dysfunction.

Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal failure. Epigenetics has been associated with metabolic memory in which prior periods of hyperglycemia enhance the future risk of developing DKD despite subsequent glycemic control. To understand the mechanistic role of such epigenetic memory in human DKD and to identify new therapeutic targets, we profiled gene expression, DNA methylation, and chromatin accessibility in kidney proximal tubule epithelial cells (PTECs) derived from subjects with and without type 2 diabetes (T2D). T2D-PTECs displayed persistent gene expression and epigenetic changes with and without transforming growth factor-ß1 treatment, even after culturing in vitro under similar conditions as nondiabetic PTECs, signified by deregulation of fibrotic and transport-associated genes (TAGs). Motif analysis of differential DNA methylation and chromatin accessibility regions associated with genes differentially regulated in T2D revealed enrichment for SMAD3, HNF4A, and CTCF transcription factor binding sites. Furthermore, the downregulation of several TAGs in T2D (including CLDN10, CLDN14, CLDN16, SLC16A2, and SLC16A5) was associated with promoter hypermethylation, decreased chromatin accessibility, and reduced enrichment of HNF4A, histone H3-lysine-27-acetylation, and CTCF. Together, these integrative analyses reveal epigenetic memory underlying the deregulation of key target genes in T2D-PTECs that may contribute to sustained renal dysfunction in DKD.

Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells.

Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies.

Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma.

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

Comparative study of effectiveness of Pap smear versus visual inspection with acetic acid and visual inspection with Lugol's iodine for mass screening of premalignant and malignant lesion of cervix.

BACKGROUND AND OBJECTIVE: Cancer of the cervix is a leading cause of morbidity and mortality among women worldwide. Therefore, to curb the disease, there is a need to develop a screening test that has good sensitivity and specificity. The present study is aimed to compare the effectiveness of the Pap smear, visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI) for mass screening of premalignant and malignant lesions of the cervix; to evaluate the usefulness of VIA and VILI as an adjunct to improve sensitivity of cervical cytology; and to evaluate the role of VILI as a parallel screening method with VIA to enhance its test performance. DESIGN AND SETTING: This was a prospective, analytical study in which 210 patients of the reproductive age group attending the gynecology OPD were enrolled. PATIENTS AND METHODS: Patients were first subjected to Pap smear followed by VIA, VILI, colposcopy and biopsy for confirmation of lesion, if needed. Data was obtained and statistically analyzed. RESULTS: Of the 210 patients, 34 (16.27%) had positive Pap test, 29 (13.87%) had positive VIA and 24 (11.43%) had positive VILI and 31 (14.75%) showed features of cervical intraepithelial neoplasia (CIN) on colposcopy. Of the total of 48 patients in whom either of the screening tests was positive and had undergone cervical biopsy, one had CIN-3, three had CIN-2, 12 had CIN-1, three had carcinoma in situ CIS and 29 reported normal. In our study, 40 patients were picked up as positive by combination of these tests, of which 19 (47.50%) had CIN on biopsy. CONCLUSION: Our study showed that VIA and VILI had sensitivity comparable to Pap smear and can thus be a suitable potential alternative/adjunctive screening test not only in a resource-poor setting but in well-equipped centers also. And, use of a combination of tests (Pap+VIA+VILI) had 100% sensitivity but at cost of low specificity and more false-positive results.

Essential oil constituents and biological activities of Peristrophe bicalyculata and Borreria verticillata.

Peristrophe bicalyculata (Retz) Nees (Acanthaceae) or 'The Goddess of Mercy' and Borreria verticillata (L.) G.F.W. Mey., (Rubiaceae), or 'Irawo-Ile' (Yoruba, South-west, Nigeria), are annual herbs, which are poorly exploited. The volatile oils obtained by hydrodistillation in an all glass Clevenger-type apparatus from the plant samples have been investigated by gas chromatography-mass spectrometry (GC-MS). With respect to the oil of P. bicalyculata, beta-caryophyllene (33.9%), alpha-zingiberene (10.4%), germacrene D and globulol (5.0%) were the compounds occurring in abundance. The oil of B. verticillata had an abundance of phytol (56.3%) and 1, 8-cineole (20.4%), with sizeable proportions of alpha-pinene (7.1%) and p-cymene (4.0%). In addition, the volatile oils displayed promising in-vitro antimicrobial activity against the tested micro-organisms, (MIC 12.5-22.3 microg/mL), while only the oil of P. bicalyculata displayed in-vitro cytotoxicity to MCF-7 (human breast tumor) and MDA-MB-468 (human breast tumor) cells. The present investigation may be the first of its kind for the evaluation of the volatile oil constituents of the studied plants.

The impact of perceived child physical and sexual abuse history on Native American women's psychological well-being and AIDS risk.

The impact of perceived child abuse history on 160 adult, Native American women's emotional well-being (i.e., depressive mood and anger) and AIDS risk was examined. How sense of mastery and social support might lead to women's greater resiliency was also investigated. Child physical-emotional abuse was found to have greater impact on depressive mood and anger and AIDS risk than did child sexual abuse. This finding was independent of current stress in women's lives. Women who were physically-emotionally abused as children had 5.14 times greater odds of having a sexually transmitted disease in their lifetimes than did women who experienced only marginal or no physical-emotional abuse. Moreover, consistent with the communal culture of Native Americans, social support was found to contribute more to resilience than sense mastery did. Reasons for the greater predictive power of child physical-emotional abuse compared with child sexual abuse in a growing number of studies are discussed.