Melatonin Inhibits AGS Cell Proliferation by Binding to the ATP Binding Site of CDK2 Under Hyperglycemic Conditions.

Cancer cells utilize glucose as their primary energy source. The aggressive nature of cancer cells is therefore enhanced in hyperglycemic conditions. This study has been adopted to investigate the therapeutic potential of melatonin against such aggressive proliferation of AGS cells-a human gastric cancer cell line, under hyperglycemic conditions. AGS cells were incubated with high glucose-containing media, and the effects of melatonin have been evaluated, therein. Cell proliferation, ROS generation, flow-cytometric analysis for cell cycle and apoptosis, wound healing, immunoblotting, zymography, reverse zymography assays, in-silico analysis, and kinase activity assays were performed to evaluate the effects of melatonin. We observed that melatonin inhibited the hyperglycemia-induced cell proliferation in a dose-dependent manner. It further altered the expression and activity of MMP-9 and TIMP-1. Moreover, melatonin inhibited AGS cell proliferation by arresting AGS cells in the G0/G1 phase after binding in the ATP binding site of CDK-2, thereby inhibiting its kinase activity. In association, a significant decrease in the expression of cyclin D1, cyclin E, CDK-4, and CDK-2 were observed. In conclusion, these findings suggest that melatonin has anti-gastric cancer potential. Melatonin could therefore be included in future drug designs for gastric cancer-hyperglycemia co-morbidity treatment.

Green chemistry routed sugar press mud for (2D) ZnO nanostructure fabrication, mineral fortification, and climate-resilient wheat crop productivity.

Nanotechnology appears to be a promising tool to redefine crop nutrition in the coming decades. However, the crucial interactions of nanomaterials with abiotic components of the environment like soil organic matter (SOM) and carbon‒sequestration may hold the key to sustainable crop nutrition, fortification, and climate change. Here, we investigated the use of sugar press mud (PM) mediated ZnO nanosynthesis for soil amendment and nutrient mobilisation under moderately alkaline conditions. The positively charged (+ 7.61 mv) ZnO sheet-like nanoparticles (~ 17 nm) from zinc sulphate at the optimum dose of (75 mg/kg blended with PM (1.4% w/w) were used in reinforcing the soil matrix for wheat growth. The results demonstrated improved agronomic parameters with (~ 24%) and (~ 19%) relative increases in yield and plant Zn content. Also, the soil solution phase interactions of the ZnO nanoparticles with the PM-induced soil colloidal carbon (- 27.9 mv and diameter 0.4864 µm) along with its other components have influenced the soil nutrient dynamics and mineral ecology at large. Interestingly, one such interaction seems to have reversed the known Zn-P interaction from negative to positive. Thus, the study offers a fresh insight into the possible correlations between nutrient interactions and soil carbon sequestration for climate-resilient crop productivity.

Preventing severe hypoglycemia in adults with type 2 diabetes (PHT2): Design, delivery and evaluation framework for a randomized controlled trial.

BACKGROUND: Severe hypoglycemia is a common and feared complication of medications used to lower blood glucose levels in individuals with diabetes. Psychoeducational interventions can prevent severe hypoglycemia in individuals with type 1 diabetes (T1D). We aim to determine the effectiveness of this approach among adults with type 2 diabetes (T2D) at elevated risk for severe hypoglycemia. METHODS: Preventing Hypoglycemia in Type 2 diabetes (PHT2) is a two-arm, parallel, randomized controlled trial. Participants are eligible if they are adults with T2D receiving care at an integrated group practice in Washington state and have experienced one or more episodes of severe hypoglycemia in the prior 12 months or have impaired awareness of hypoglycemia (Gold score ≥ 4). Participants are randomized to proactive nurse care management with or without my hypo compass, an evidence-based, psychoeducational intervention combining group and individual self-management training. For this study, my hypo compass was adapted to be suitable for adults with T2D and from an in-person to a virtual intervention over videoconference and telephone. The primary outcome is any self-reported severe hypoglycemia in the 12 months following the start of the intervention. Secondary outcomes include biochemical measures of hypoglycemia, self-reported hypoglycemia awareness, fear of hypoglycemia, and emergency department visits and hospitalizations for severe hypoglycemia. The study includes a process evaluation to assess implementation fidelity and clarify the causal pathway. CONCLUSION: The PHT2 trial will compare the effectiveness of two approaches for reducing severe hypoglycemia in adults with T2D. TRIAL REGISTRATION: clinicaltrials.gov, # NCT04863872.

Genome-wide mining of diversity and evolutionary signatures revealed selective hotspots in Indian Sahiwal cattle.

The Sahiwal cattle breed is the best indigenous dairy cattle breed, and it plays a pivotal role in the Indian dairy industry. This is due to its exceptional milk-producing potential, adaptability to local tropical conditions, and its resilience to ticks and diseases. The study aimed to identify selective sweeps and estimate intrapopulation genetic diversity parameters in Sahiwal cattle using ddRAD sequencing-based genotyping data from 82 individuals. After applying filtering criteria, 78,193 high-quality SNPs remained for further analysis. The population exhibited an average minor allele frequency of 0.221 ± 0.119. Genetic diversity metrics, including observed (0.597 ± 0.196) and expected heterozygosity (0.433 ± 0.096), nucleotide diversity (0.327 ± 0.114), the proportion of polymorphic SNPs (0.726), and allelic richness (1.323 ± 0.134), indicated ample genomic diversity within the breed. Furthermore, an effective population size of 74 was observed in the most recent generation. The overall mean linkage disequilibrium (r2) for pairwise SNPs was 0.269 ± 0.057. Moreover, a greater proportion of short Runs of Homozygosity (ROH) segments were observed suggesting that there may be low levels of recent inbreeding in this population. The genomic inbreeding coefficients, computed using different inbreeding estimates (FHOM, FUNI, FROH, and FGROM), ranged from -0.0289 to 0.0725. Subsequently, we found 146 regions undergoing selective sweeps using five distinct statistical tests: Tajima's D, CLR, |iHS|, |iHH12|, and ROH. These regions, located in non-overlapping 500 kb windows, were mapped and revealed various protein-coding genes associated with enhanced immune systems and disease resistance (IFNL3, IRF8, BLK), as well as production traits (NRXN1, PLCE1, GHR). Notably, we identified interleukin 2 (IL2) on Chr17: 35217075-35223276 as a gene linked to tick resistance and uncovered a cluster of genes (HSPA8, UBASH3B, ADAMTS18, CRTAM) associated with heat stress. These findings indicate the evolutionary impact of natural and artificial selection on the environmental adaptation of the Sahiwal cattle population.

The electronic health record Risk of Alzheimer's and Dementia Assessment Rule (eRADAR) Brain Health Trial: Protocol for an embedded, pragmatic clinical trial of a low-cost dementia detection algorithm.

BACKGROUND: About half of people living with dementia have not received a diagnosis, delaying access to treatment, education, and support. We previously developed a tool, eRADAR, which uses information in the electronic health record (EHR) to identify patients who may have undiagnosed dementia. This paper provides the protocol for an embedded, pragmatic clinical trial (ePCT) implementing eRADAR in two healthcare systems to determine whether an intervention using eRADAR increases dementia diagnosis rates and to examine the benefits and harms experienced by patients and other stakeholders. METHODS: We will conduct an ePCT within an integrated healthcare system and replicate it in an urban academic medical center. At primary care clinics serving about 27,000 patients age 65 and above, we will randomize primary care providers (PCPs) to have their patients with high eRADAR scores receive targeted outreach (intervention) or usual care. Intervention patients will be offered a "brain health" assessment visit with a clinical research interventionist mirroring existing roles within the healthcare systems. The interventionist will make follow-up recommendations to PCPs and offer support to newly-diagnosed patients. Patients with high eRADAR scores in both study arms will be followed to identify new diagnoses of dementia in the EHR (primary outcome). Secondary outcomes include healthcare utilization from the EHR and patient, family member and clinician satisfaction assessed through surveys and interviews. CONCLUSION: If this pragmatic trial is successful, the eRADAR tool and intervention could be adopted by other healthcare systems, potentially improving dementia detection, patient care and quality of life.

Genome-wide identification and annotation of SNPs for economically important traits in Frieswal™, newly evolved crossbred cattle of India.

The Frieswal™ is a crossbred cattle evolved by ICAR-Central Institute for Research on Cattle utilizing more than 15,000 cattle maintained at more than 37 military farms spread all over the agro-climatic regions of the country. The ddRAD sequencing method was used to identify and annotate the SNPs and INDELs. The results of variant calling revealed 1,487,851 SNPs and 128,175 INDELs at a read depth of 10. A total of 3,775,079 effects were identified, and majority (66.41%) of the effects were in the intron region of the genome followed by intergenic (21.87%). Majority (99.18%) of the variants had the modifier effect. The results revealed a higher magnitude of transitions as compared to the transversion. The classification of SNPs by functional class revealed a majority of missense (43%) and silent (56%) effects. Out of 26,278 genes identified, 1841 SNPs were annotated in 207 candidate genes responsible for various milk production and reproduction traits. The observed heterozygosity was 0.2804 against the expected heterozygosity value of 0.2978. The overall average inbreeding coefficient (FIS) was 0.0604. The pathway analysis revealed that the prolactin signaling pathway (GO:0038161) was significant biological process complete for both milk production and reproduction traits. The SNP variations can be effectively used as markers for early and accurate identification of the QTLs and for formulating an efficient and effective breed improvement program in Frieswal™ cattle. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03701-0.

Swietenolide isolated from Swietenia macrophylla King in Hook seeds shows in vitro anti-colorectal cancer activity through inhibition of mouse double minute 2 (MDM2) homolog.

Swietenia macrophylla King in Hook (SM) is known to have several medicinal properties. Chloroform extracts of SM seeds (SMCE) as well as two isolated limonoids swietenine (1) and swietenolide (2) showed significant in vitro anti-CRC activity in human colon carcinoma (HCT116) cell line. 2 (IC50 = 5.6 µM) was found to be two times more potent than 1 (IC50 = 10 µM). Both compounds showed anti-CRC activity through inhibition of the Mouse Double Minute 2 homolog (MDM2) of the MDM2-p53 pathway. The Selectivity Index (S.I.) of isolated compounds 1 and 2 for cancer cells were about 6.6 and 12.8 fold respectively which was significantly better than the S.I. of the extract (S.I. ∼1.5).

Targeting DPP4-RBD interactions by sitagliptin and linagliptin delivers a potential host-directed therapy against pan-SARS-CoV-2 infections.

Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with α/ß-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication.

Young apheresis platelet donors show significant and sustained growth over the last decade in the US, 2010-2019: A favorable sign of the resiliency of the platelet supply.

BACKGROUND: Platelet demand continues to rise and US hospitals frequently face shortages. The peak median age of apheresis platelet donors (APD) is believed to have increased over the last decade, raising concerns that the APD base is not being adequately replenished with young donors. STUDY DESIGN/METHODS: American Red Cross (ARC) apheresis platelet collections were evaluated from calendar years 2010 through 2019. APD, products per procedure/split rate (PPP) and donation frequencies were stratified into age groups. RESULTS/FINDINGS: The number of unique APD from calendar year 2010 through 2019 in the ARC donor pool increased from 87,573 to 115,372 donors, representing a 31.7% overall growth. Donors in the 16-40 year-old (y) age group increased by 78.8% overall, with the largest absolute increases seen in the 26-30 y (4852 donors, 99.9% growth), followed by the 31-35 y (3991, 94.1%) group. Donors aged 56+ increased by 50.4% overall, with the largest increase seen in the 66-70 y (5988 donors, 108.1% growth) group. Middle-aged donors, aged 41-55 y, demonstrated a decrease of 16.5%. Over the last decade, the youngest age groups (16-40 y) comprised 61.3% of first-time donors (FTD). Annual donation frequency increased with increasing age and PPP. The highest donation frequencies were seen in the oldest age groups. CONCLUSION: Although the peak median age of APD increased over the study period, relative contribution of the 16-40 y APD base also increased. Older donors exhibited the highest donation frequencies and thus contributed the largest volume of apheresis platelet units. Platelet donor activity declined in the middle age (41-55 y) group.

Isolation of Food Grade Dye from Flower Petals of Butea monosperma and Determination of Marker Compounds for Its Quantitative Analysis.

Health concerns associated with synthetic dyes/colorants have fostered the use of natural coloring materials for food applications. This study has been carried out to extract a natural dye from the flower petals of Butea monosperma (family Fabaceae) under an eco-friendly and organic solvent-free approach. Hot aqueous extraction of dry B. monosperma flowers followed by lyophilization of the resulting extract furnished an orange-colored dye in ∼35% yield. Silica gel column chromatography of dye powder resulted in the isolation of three marker compounds, viz. iso-coreopsin (1), butrin (2), iso-butrin (3) which were characterized by spectral methods, e.g., ultra violet, Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and high-resolution mass spectrometry. The XRD analysis of isolated compounds established an amorphous nature for compounds 1 and 2 while compound 3 showed good crystallinity. The stability of dye powder and the isolated compounds 1-3 was determined by thermogravimetric analysis which showed excellent stability up to 200 °C. In trace metal analysis, the product B. monosperma dye powder exhibited low relative abundance <4% for Hg along with negligible concentrations of Pb, As, Cd, and Na. The detection and quantification of marker compounds 1-3 in the B. monosperma flower extracted dye powder were carried out by a highly selective UPLC/PDA method of analysis.

Genome wide mining of SNPs and INDELs through ddRAD sequencing in Sahiwal cattle.

The study was conducted in Sahiwal cattle for genome wide identification and annotation of single nucleotide polymorphisms (SNPs) and insertions and deletions (INDELs) in Sahiwal cattle. The double digest restriction-site associated DNA (ddRAD) sequencing, a reduced representation method was used for the identification of variants at nucleotide level. A total of 1,615,211 variants were identified at RD10 and Q30 consisting of 1,480,930 SNPs and 134,281 INDELs with respect to the Bos taurus reference genome. The SNPs were annotated for their location, impact and functional class. The SNPs identified in Sahiwal cattle were found to be associated with a total of 26,229 genes. A total of 1819 SNPs were annotated for 209 candidate genes associated with different production and reproduction traits. The variants identified in the present study may be useful to strengthen the existing bovine SNP chips for reducing the biasness over the taurine cattle breeds. The diversity analysis provides the insight of the genetic architecture of the Sahiwal population Studied. The large genetic variations identified at the nucleotide level provide ample scope for implementing an effective and efficient breed improvement programme for increasing the productivity of Sahiwal cattle.

Can clinical characteristics differentiate patients with unexplained chronic cough from patients with asthma and COPD?

Background: Chronic cough is reported in up to 20% of the adult population and often persists despite medical treatment with currently available therapies. Many clinical conditions, including asthma and chronic obstructive pulmonary disease (COPD), must be excluded before making a Unexplained chronic cough diagnosis. Methods: The primary objective was to use a large hospital dataset to compare clinical features of patients with a primary diagnosis of UCC with those with asthma or COPD without a primary diagnosis of UCC to help clinicians differentiate between these conditions more readily. Data were collected for all hospitalization and outpatient medical encounters for each patient between November 2013 and December 2018. Information included demographics, encounter dates, medications prescribed at every encounter for chronic cough, lung function testing, and hematologic parameters. Asthma and COPD were combined into one group to ensure there was no overlap with UCC and due to limitations of International Classification of Diseases coding to confirm an asthma(A)/COPD diagnosis. Results: Female gender represented 70% of encounters for UCC versus 61.8% for asthma/COPD (p < 0.0001); the mean age was 56.9 years for UCC versus 50.1 years for A/COPD (p < 0.0001). The number of patients on cough medications and the cough medication frequency were significantly higher in the UCC versus A/COPD group (p < 0.0001). UCC versus A/COPD patients had a total of eight versus three cough-related encounters over the study duration (i.e., 5 years) (<0.0001). The average interval between successive encounters was less for UCC (114 days) versus the A/COPD (288 days) group. Gender-adjusted Forced expiratory volume in the first second of exhalation/Forced vital capacity (FEV1/FVC) ratios, residual volume%, and Diffusion capacity for carbon monoxide (DLCO%) were significantly higher in UCC versus A/COPD, whereas the response to bronchodilators of FEV1, FVC and residual volumes were significantly greater in A/COPD patients. Conclusions: Clinical characteristics differentiating UCC from A/COPD could accelerate recognition of UCC diagnosis especially in the subspecialty setting where patients with these disorders are referred.

Differentially expressed microRNAs in biochemically characterized FrieswalTM crossbred bull semen.

In addition to the transmission of paternal genome, spermatozoa also carry coding as well as noncoding microRNAs (miRNAs) into the female oocyte during the process of biological fertilization. Based on RNA deep sequencing, a total 28 number of differentially expressed miRNAs were cataloged in categorized FrieswalTM crossbred (Holstein Friesian X Sahiwal) bull semen on the basis of conception rate (CR) in field progeny testing program. Validation of selected miRNAs viz. bta-mir-182, bta-let-7b, bta-mir-34c and bta-mir-20a revealed that, superior bull semen having comparatively (p < .05) lower level of all the miRNAs in contrast to inferior bull semen. Additionally, it was illustrated that, bta-mir-20a and bta-mir-34c miRNAs are negatively (p < .01) correlated with seminal plasma catalase (CAT) activity and glutathione peroxidase (GPx) level. Interactome studies identified that bta-mir-140, bta-mir-342, bta-mir-1306 and bta-mir-217 can target few of the important solute carrier (SLC) proteins viz. SLC30A3, SLC39A9, SLC31A1 and SLC38A2, respectively. Interestingly, it was noticed that all the SLCs were significantly (p < .05) expressed at higher level in superior quality bull semen and they are negatively correlated (p < .01) with their corresponding miRNAs as mentioned. This study may reflect the role of miRNAs in regulating few of the candidate genes and thus may influence the bull semen quality traits.

Genetic variants in 5'UTR and exonic region of NPY gene alter the reproduction performance in Indian cattle breeds.

Neuropeptide Y (NPY) is one of the most potent orexigenic factors which can produce diverse effects on behaviour and other physiological functions and is highly conserved in evolution. The present study was aimed to identify and associate SNPs in the 5' UTR and exon2 region of the NPY gene with reproduction and production traits in Kankrej cattle of Indian origin. Three mutations in the 5'-UTR region and one mutation in the exon2 region of the NPY gene were identified by PCR-SSCP and PCR-RFLP, respectively, followed by sequencing. Further, association studies were conducted with reproduction and production traits in Kankrej cattle. The GACCGA genotyped animals based on the 5'UTR variants indicated better dry period and calving interval, whereas with GGCCGG genotypes showed higher total lactation milk yield and 305-day milk yield in comparison to other genotypes. Also, service period and inter calving period varied significantly among the genotypes of exon2, as the GG genotyped animals had significantly longer calving interval. Other traits like age at first heat, age at first service and age at first calving were not affected by the mutations. So, the present study outlined that the bovine NPY gene may be considered to be one of the candidate gene for improvement of reproductive performance of cattle, after validation on large sample size.

Inferences for multiple interval type-I censoring scheme.

In this paper, we have introduced a new type of censoring scheme named the multiple interval type-I censoring scheme. Further, We have assumed that the test units are drawn from the Weibull population. We have also proposed the maximum product of spacing estimators for unknown parameters under the multiple interval type-I censoring scheme and compare them with the existing maximum likelihood estimators. In addition to this, the Bayes estimators for shape and scale parameters are also obtained under the squared error loss function. Their corresponding asymptotic confidence/credible intervals are also discussed. A real data set containing the breakdown time of insulating fluids are used to demonstrate the appropriateness of the proposed methodology.

Klippel-Feil Syndrome Associated with Renal and Cardiac Anomalies in an Infant: A Case Report.

Klippel-Feil syndrome is a rare congenital bone disorder characterised by a triad of short neck, low posterior hairline and limited lateral bending of the neck with an annual incidence of 1 in 40,000 live births. It has remained an obscure term in the medical literature because of its variability in presentation and wide spectrum of anomalies involving multiple organ systems. It is unusual to find a case that has all three classical triad features. Here, we present a case of a 9-month-old infant who manifests not only all three classical triad features associated with Klippel-Feil syndrome but also demonstrates the presence of congenital heart disease, scoliosis, and renal ectopia. An early comprehensive evaluation of a suspected case is essential for diagnosis and counselling which impacts its prognosis, helps minimize social stigma and affords parents the opportunity to consider cosmetic surgery as an option, should they choose to pursue it. Keywords: case reports; congenital; heart diseases; Klippel-Feil syndrome; scoliosis.

A case report on anesthetic challenges in the post-Covid complication of active mucormycosis: Patient preparedness for family physicians.

Mucormycosis is a well-known yet complicated illness that seems benign but behaves malignantly. This article discusses the anesthesia challenges in providing care for a 49-year-old male who presented with post-Covid pneumonia and uncontrolled diabetes along with active mucormycosis and scheduled for functional endoscope sinus surgery (FESS) and debridement of necrotic tissue. We want to illustrate the importance of anticipated difficult airway, while highlighting the toxicity of intravenous amphotericin-B and its combination against anesthesia drugs.

Profiling of key heat shock proteins and their relationship with male sexual behavior and seminal characteristics in Kankrej (Bos indicus) breeding bulls during different seasons.

The goal of this study is to use indirect ELISA to determine the concentration of major heat shock proteins (Hsps) in Kankrej (Bos indicus) breeding bulls and their relationship with certain male phenotypic traits including sexual behavior, sperm quality, and bull fertility in different seasons. The seasonal fluctuation in the concentration of three major Hsps (60, 70, and 90) was determined using an indirect enzyme-linked immunosorbent assay (ELISA). According to the findings, Hsps levels are significantly higher during the summer season and are associated with both fresh and post-thawed semen quality traits in Kankrej breeding bulls. The better sexual behavior of bulls and seminal parameters of fresh or thawed semen was observed in the winter season together with the lower concentrations of HSPs. These could suggest negative association between HSPs with bull sexual behavior and seminal parameters. As a result, the concentration of Hsps in breeding bulls may be a useful indicator for determining fertility traits.

Determining biomarkers for evaluation and diagnosis of hereditary angioedema.

Rationale: Kallikrein-bradykinin-forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell-surface receptors for example, g-C1qR, cytokeratin-1, and plasminogen-activator-urokinase-receptor (PLAUR) were hypothesized as biomarkers of AE attacks. Method: To understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi-RNAseq data of total RNA extracted from skin biopsies of lesional versus non-lesional skin collected during and between attacks in Type-1 HAE patients (n = 11; F:M = 8:3) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor (n = 5, F:M = 5:0), and non-HAE (n = 7; F:M = 3:4) patients were compared. Gene-set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators. Results: PLAUR gene, encoding urokinase-type plasminogen activator (u-PAR), was constitutively over-expressed in HAE-Type-1 versus non-HAE controls suggestive of overactive u-PAR-mediated signaling via binding to Factor-XII. Baseline PLAUR expression was associated with severe AE (p = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1-HAE were enriched in beta1/beta3-integrin cell surface interactions and IL-6-mediated signaling. Regulator effects analysis suggests a role for IL-1b in HAE flares. AKT2, the mRNA regulated by the differentially-expressed miR-184A, was also associated with HAE attacks. Conclusion: Angiopoetin-activated ß1-integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u-PAR are possible novel mechanisms for progression of the endothelial kinin-bradykinin-forming cascade in HAE attacks.

Longitudinal experience with treatment of acquired angioedema using tranexamic acid.

Background: Acquired angioedema (AAE) is a rare form of angioedema (AE) and is often associated with lymphoproliferative conditions and/or anti-C1 esterase inhibitor (C1-INH) antibodies without clear treatment consensus. Current treatments have been reported to have variable effectiveness with different safety concerns. A large Italian cohort of patients with AAE was previously found to respond well to tranexamic acid (TXA). Herein, we report our experience treating AAE with TXA used as prophylaxis. Objective: The objective was to describe clinical characteristics of patients with AAE and to report our experience with treating AAE with TXA. Methods: A retrospective chart review of patients with AAE (N = 13) from a large practice was conducted to assess characteristics and treatment responses. Patient demographics in addition to C1-INH quantitative, C1-INH functional, C4, and C1q levels; the presence of C1-INH antibodies; and a history of lymphoproliferative disease were extracted. The patients were also characterized by their treatment response to TXA. Results: All the patients were white, with a mean age at diagnosis of 67 years, an average body mass index of 31.3 kg/m², and a male-to-female ratio of 7:6. Nine patients had positive C1-INH antibodies. The patients were on various prophylaxis treatments before TXA, including chemotherapy that targeted malignancy, cyclophosphamide, rituximab, and plasmapheresis. Ultimately, 11 of the 13 patients were on TXA for prophylaxis. At 1, 12, and 24 months after TXA treatment, attacks decreased by 97, 86, and 99%, respectively. One patient developed a deep vein thrombosis and TXA was stopped. Conclusion: These findings demonstrated that treatment of AAE with TXA was effective as prophylaxis for AE attacks. However, potential adverse effects remain a concern, which emphasizes the need for additional options.