Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function.

As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.

Peroxisome proliferator-activated receptor alpha is essential factor in enhanced macrophage immune function induced by angiotensin converting enzyme.

An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.

Formulation of Functional Liquid Diets Under IDDSI Levels 0 to 2 for Dysphagia Patients: Physico-Chemical, Sensory, Antioxidant and Electromyographic Oral Processing Analyses.

Dysphagia is a significant health concern especially amongst the old age population. It is an ailment brought on by the weakening of the swallowing muscles. To reduce the risk of choking in dysphagia patients, the food is usually diluted to suit their swallowing ability. But dilution results in reducing the nutritional density of the foods thus causing undernutrition and malnutrition in patients. In this study, functional liquid diets were formulated under International Dysphagia Diet Standardization Initiative (IDDSI) levels 0-2. The developed diets were analysed for their proximate composition, colour, antioxidant and sensory properties. Antioxidant activities were determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and total phenolic content (TPC) methods. The highest ABTS+ value was observed in pumpkin puree (level-2) i.e. 98.59%. Black carrot juice (level-1) showed the highest DPPH free radical scavenging activity and FRAP value viz. 88.43% and 689.33 µM TE/g, respectively. Electromyography (EMG) is an upcoming technique of food texture evaluation which provides real-time information about food oral processing. In this study, an EMG was conducted to measure the myoelectrical activity of human suprahyoid and masseter muscles by placing electrodes on the skin's surface during the oral processing of liquid. The EMG parameters correlated significantly with viscosity, ease of swallowing and IDDSI levels of the formulated diets. Hence EMG can be used as a tool for design and development of textured-modified diets for dysphagia patients. The sensory scores of formulated diets in this study were high indicating that these liquid diets may be incorporated into the diet plans of dysphagia patients.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.

The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.

Cervical cell's nucleus segmentation through an improved UNet architecture.

Precise segmentation of the nucleus is vital for computer-aided diagnosis (CAD) in cervical cytology. Automated delineation of the cervical nucleus has notorious challenges due to clumped cells, color variation, noise, and fuzzy boundaries. Due to its standout performance in medical image analysis, deep learning has gained attention from other techniques. We have proposed a deep learning model, namely C-UNet (Cervical-UNet), to segment cervical nuclei from overlapped, fuzzy, and blurred cervical cell smear images. Cross-scale features integration based on a bi-directional feature pyramid network (BiFPN) and wide context unit are used in the encoder of classic UNet architecture to learn spatial and local features. The decoder of the improved network has two inter-connected decoders that mutually optimize and integrate these features to produce segmentation masks. Each component of the proposed C-UNet is extensively evaluated to judge its effectiveness on a complex cervical cell dataset. Different data augmentation techniques were employed to enhance the proposed model's training. Experimental results have shown that the proposed model outperformed extant models, i.e., CGAN (Conditional Generative Adversarial Network), DeepLabv3, Mask-RCNN (Region-Based Convolutional Neural Network), and FCN (Fully Connected Network), on the employed dataset used in this study and ISBI-2014 (International Symposium on Biomedical Imaging 2014), ISBI-2015 datasets. The C-UNet achieved an object-level accuracy of 93%, pixel-level accuracy of 92.56%, object-level recall of 95.32%, pixel-level recall of 92.27%, Dice coefficient of 93.12%, and F1-score of 94.96% on complex cervical images dataset.

Macrophage angiotensin-converting enzyme reduces atherosclerosis by increasing peroxisome proliferator-activated receptor α and fundamentally changing lipid metabolism.

AIMS: The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis. METHODS AND RESULTS: Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of lipid, increased capacity to transport long chain fatty acids into mitochondria, higher oxidative metabolism and lipid ß-oxidation as determined using 13C isotope tracing, increased cell ATP, increased capacity for efferocytosis, increased concentrations of the lipid transporters ABCA1 and ABCG1, and increased cholesterol efflux. These effects are mostly independent of angiotensin II. Human THP-1 cells, when modified to express more ACE, increase expression of PPARα, increase cell ATP and acetyl-CoA, and increase cell efferocytosis. CONCLUSION: Increased macrophage ACE expression enhances macrophage lipid metabolism, cholesterol efflux, efferocytosis, and it reduces atherosclerosis. This has implications for the treatment of cardiovascular disease with angiotensin II receptor antagonists vs. ACE inhibitors.

The Diagnostic Dilemma of Splenic Non-Hodgkin's Lymphoma and Splenic Abscess: A Narrative Review.

Non-Hodgkin's lymphoma (NHL) is a lymphoproliferative disorder that principally displays lymph node involvement but can also spread to extranodal sites such as the spleen. Primary splenic NHL arises in the spleen and, due to its atypical presentation, can sometimes present similarly to other splenic conditions. This review aims to highlight how primary splenic NHL can be effectively differentiated from other splenic conditions, such as splenic abscesses. PubMed, MEDLINE, Scopus, Google, and Google Scholar were used to identify articles mainly focused on splenic non-Hodgkin's lymphoma and splenic abscess. The search was limited to articles published from January 2005 to November 2022. Of the 229 total articles amassed, only 34 were selected and narratively reviewed. From a thorough review of the current literature, it is evident that splenic NHL displays a similar clinical picture to other splenic conditions, namely splenic abscesses. One cannot easily differentiate between the two conditions, both clinically and via diagnostic imaging. Lymphadenopathy, a hallmark sign of nodal NHL, may or may not be present in splenic NHL. Ultimately, splenectomy with biopsy and immunohistochemical staining (IHC) may be required to confirm the diagnosis. In cases of suspected splenic NHL or splenic abscess with little-to-no symptomatic improvement after medication administration, splenectomy followed by histopathological examination may be required for a definitive diagnosis and proper treatment.

miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and ß-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC.

Self-medication practices with conventional and herbal drugs among ear, nose, and throat patients

SUMMARY OBJECTIVE: This study evaluates the self-practices with conventional and herbal drug use among ear, nose, and throat outpatients. METHODS: A cross-sectional survey-based study was carried out among all ear, nose, and throat outpatients on their first visit to the otorhinolaryngology department at a tertiary care hospital. The survey comprised a total of 14 questions with 4 different sections, including demographic characteristics, self-medication of conventional medicines, herbal medication usage, and perception regarding herbal medicines. RESULTS: Overall, 255 questionnaires were distributed among patients, of which 183 completed the questionnaire (response rate=71.7%). Respondents reported self-medication (44.8%) with conventional drugs before visiting a hospital. The most commonly used medicine was analgesics (31.7%) and antibiotics (21.9%). Nearly half of the patients (49.2%) used at least one herbal drug. The most commonly used herbal medications were Tilia cordata (78.8%), Zingiber officinale (62.2%), and Camellia sinensis (45.5%). According to the International Union for Conservation of Nature Red List, most of the medicinal herbs were considered as data deficient/least concern. About 36.6% of the participants perceived that herbal drugs are effective for ear, nose, and throat problems. Moreover, 22.9% of the patients did not know about herbal-drug interaction with other medications. CONCLUSIONS: This study observed a considerable prevalence of self-based practices with conventional and herbal medications. Strict national regulations on conventional and herbal medication access and long-term actions should be implemented to discourage inappropriate drug use.

Tubular IL-1ß Induces Salt Sensitivity in Diabetes by Activating Renal Macrophages.

BACKGROUND: Chronic renal inflammation has been widely recognized as a major promoter of several forms of high blood pressure including salt-sensitive hypertension. In diabetes, IL (interleukin)-6 induces salt sensitivity through a dysregulation of the epithelial sodium channel. However, the origin of this inflammatory process and the molecular events that culminates with an abnormal regulation of epithelial sodium channel and salt sensitivity in diabetes are largely unknown. METHODS: Both in vitro and in vivo approaches were used to investigate the molecular and cellular contributors to the renal inflammation associated with diabetic kidney disease and how these inflammatory components interact to develop salt sensitivity in db/db mice. RESULTS: Thirty-four-week-old db/db mice display significantly higher levels of IL-1ß in renal tubules compared with nondiabetic db/+ mice. Specific suppression of IL-1ß in renal tubules prevented salt sensitivity in db/db mice. A primary culture of renal tubular epithelial cells from wild-type mice releases significant levels of IL-1ß when exposed to a high glucose environment. Coculture of tubular epithelial cells and bone marrow-derived macrophages revealed that tubular epithelial cell-derived IL-1ß promotes the polarization of macrophages towards a proinflammatory phenotype resulting in IL-6 secretion. To evaluate whether macrophages are the cellular target of IL-1ß in vivo, diabetic db/db mice were transplanted with the bone marrow of IL-1R1 (IL-1 receptor type 1) knockout mice. db/db mice harboring an IL-1 receptor type 1 knockout bone marrow remained salt resistant, display lower renal inflammation and lower expression and activity of epithelial sodium channel compared with db/db transplanted with a wild-type bone marrow. CONCLUSIONS: Renal tubular epithelial cell-derived IL-1ß polarizes renal macrophages towards a proinflammatory phenotype that promotes salt sensitivity through the accumulation of renal IL-6. When tubular IL-1ß synthesis is suppressed or in db/db mice in which immune cells lack the IL-1R1, macrophage polarization is blunted resulting in no salt-sensitive hypertension.

The non-cardiovascular actions of ACE.

Angiotensin converting enzyme (ACE) is well known for its role producing the vasoconstrictor angiotensin II and ACE inhibitors are commonly used for treating hypertension and cardiovascular disease. However, ACE has many different substrates besides angiotensin I and plays a role in many different physiologic processes. Here, we discuss the role of ACE in the immune response. Several studies in mice indicate that increased expression of ACE by macrophages or neutrophils enhances the ability of these cells to respond to immune challenges such as infection, neoplasm, Alzheimer's disease, and atherosclerosis. Increased expression of ACE induces increased oxidative metabolism with an increase in cell content of ATP. In contrast, ACE inhibitors have the opposite effect, and in both humans and mice, administration of ACE inhibitors reduces the ability of neutrophils to kill bacteria. Understanding how ACE affects the immune response may provide a means to increase immunity in a variety of chronic conditions now not treated through immune manipulation.

Comparison of mean operative time in patients undergoing Ho: YAG laser lithotripsy and pneumatic lithotripsy in ureterorenoscopy for ureteric calculus.

OBJECTIVE: To compare the mean operative time (MOT) in patients undergoing Ho: YAG laser lithotripsy (LL) and pneumatic lithotripsy (PL) for ureteric stones. METHODS: This randomized study was conducted at Armed Forces Institute of Urology (AFIU) Rawalpindi, Pakistan from July 2016 to November 2018. Non probability consecutive sampling technique utilized to enroll 60 patients of both gender aged 18-60 years, having ureteric calculus ≤1.5cm. Randomization was done into group I (LL) and II (PL) via computer generated number tables. Six Consultant Urologists performed surgeries under spinal anesthesia utilizing Swiss Lithoclast® Master (EMS+ S.A. Switzerland) in group II and holmium laser fiber (365µm, 8-10Hz, 9.6-16W, 2100nm wavelength) in group I respectively. MOT was noted from insertion of cystoscope till removal out of meatus. Data obtained was analyzed through IBM SPSS 24.0. RESULTS: Analysis involved 60 patients (30 each group) having similar baseline characteristics (age, gender, laterality, location). There was statistically significant different MOT between LL & PL (25.48±6.99 vs 34.83± 7.47 minutes, p < 0.001). Data stratification with respect to age, gender, laterality and stone location revealed similar trend. Lithotripsy technique significantly affected MOT (p < 0.001) on Multiple Linear Regression Analysis. CONCLUSIONS: Ho: YAG LL is an efficient technique when compared with PL in terms of MOT for ureteric stones.

Tumors exploit CXCR4hiCD62Llo aged neutrophils to facilitate metastatic spread.

Granulocytes are key players in cancer metastasis. While tumor-induced de novo expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs) is well-described, the fate and contribution of terminally differentiated mature neutrophils to the metastatic process remain poorly understood. Here, we show that in experimental metastatic cancer models, CXCR4hiCD62Llo aged neutrophils accumulate via disruption of neutrophil circadian homeostasis and direct stimulation of neutrophil aging mediated by angiotensin II. Compared to CXCR4loCD62Lhi naive neutrophils, aged neutrophils more robustly promote tumor migration and support metastasis through the increased release of several metastasis-promoting factors, including neutrophil extracellular traps (NETs), reactive oxygen species, vascular endothelial growth factors, and metalloproteinases (MMP-9). Adoptive transfer of aged neutrophils significantly enhanced metastasis of breast (4T1) and melanoma (B16LS9) cancer cells to the liver, and these effects were predominantly mediated by NETs. Our results highlight that in addition to modulating MDSC production, targeting aged neutrophil clearance and homeostasis may be effective in reducing cancer metastasis.

Bacterial nucleomodulins and cancer: An unresolved enigma.

Recent studies in microbial pathogenesis have identified several bacterial proteins with the potential to influence host cell nuclei. This field of research is in its infancy, however it is rapidly growing. In particular, the role of bacterial nucleomodulins in animal oncogenesis is an area that requires attention. Earlier research has suggested the role of nucleomodulins in plant tumor development and these findings may provide us with a better understanding of the role of these proteins in human cancer development. This proposition is further supported by previous identification of nucleomodulins present in bacteria that have been associated with cancer development, but their role in human cancer is unclear. In this article, we provide an update on the status of these nucleomodulins and their role in cancer etiology. We collected information about known bacterial nucleomodulins and tried to relate their mechanistic implication with already known plant tumor development model. The present research indicates that bacterial nucleomodulins may be an important target in cancer etiology and knowledge of their role in human oncogenesis may help us to create suitable alternative cancer management strategies.

Current status of probiotics for prevention and management of gastrointestinal cancers.

INTRODUCTION: Gastrointestinal cancers contribute to a significant number of cancer- associated mortality. The gastrointestinal tract harbors a multitude of microorganisms, known as the microbiota. Recently, the microbiota is considered to be an accessory organ resulting in several health benefits. The microbiota is involved in almost all aspects of an individual ranging from managing behavior to controlling metabolism, immune status and the response to a disease. Researchers are observing the modulation of microbiota in almost every disease, including cancer. Probiotics are microorganisms that can help to alter the host microbiota toward a healthy state thus providing benefits from many diseases including cancer. AREAS COVERED: We explored the current status of the use of probiotics in cancer patients. Although probiotic bacteria can provide significant benefits to individuals suffering from cancer, the number of cancer-specific clinical products containing probiotics is not comparable to research studies showing their benefits. The lack of available products is due to several factors including a lack of risk assessment data of beneficial probiotics in cancer patients. EXPERT OPINION: Laboratory investigations indicate a huge potential of probiotics for the prevention and management of gastrointestinal cancer, but more clinical studies are required to support their application in clinical settings.

System biological investigations of hydroxychloroquine and azithromycin targets and their implications in QT interval prolongation.

COVID-2019 pandemic is affecting people worldwide in the absence of an effective treatment strategy. Several suggestive therapeutic options through drug repurposing are recommended, but a complete consensus is not reached. A combination of Hydroxychloroquine (HCQ) and Azithromycin (AZM) has been widely tried and discussed but its administration has also led to potential adversities in patients. Studies are suggesting that most prominent adverse event with HCQ and AZM combination is QT interval prolongation. We studied interaction of HCQ with AZM and subsequent effect of this drug combination on QT interval prolongation. We performed system biological investigation of HCQ and AZM targets and screened important targets and pathways possibly involved in QT interval prolongation. The best core hub protein drug targets involved in QT interval prolongation were identified as HSP90AA1 exclusively associated with HCQ, while AKT1 exclusively associated with AZM on the basis of node degree value. It was found that PI3K/Akt, VEGF, ERBB2 pathways must be given consideration for understanding the role of HCQ and AZM in QT interval prolongation. Conclusion: Computational methods have certain limitations based on source database coverage and prediction algorithms and therefore this data needs experimental correlation to draw final conclusion, but current findings screen targets for QT interval prolongation associated with HCQ and AZM. These proteins and pathways may provide ways to reduce this major risk associated with this combination.

Audit of antibiotic prophylaxis and adherence of surgeons to standard guidelines in common abdominal surgical procedures.

BACKGROUND: Prophylactic use of antibiotics before surgery is evidence-based practice for prevention of surgical site infections (SSIs). AIMS: To investigate adherence to and surgeons' perception of antibiotic prophylaxis guidelines. METHODS: A two-phase, cross-sectional prospective study conducted in two teaching hospitals. Phase 1: 6-month audit of prescriptions to investigate adherence rate to evidence-based guidelines. The important information was collected from medical charts through a predesigned proforma. Phase 2: self-administration questionnaire was used to investigate the surgeons' perception. Descriptive statistics, independent-sample Kruskal-Wallis test and multivariate linear regression analysis were performed using SPSS version 21.0. RESULTS: A total of 866 eligible surgical cases (acute appendectomy; n = 418; 48.2%), laparoscopic cholecystectomy (n = 278; 32.1%) and inguinal hernia (n = 170; 19.7%) were investigated. Surgical antibiotic prophylaxis was prescribed in 97.5% of procedures. Out of these, 9.5% adhered to guidelines with respect to correct choice, 40% for timing, and 100% for dose and route (optimal value 100%). Most patients received ceftriaxone (n = 503; 59.5%) as prophylactic antibiotic. The questionnaire (good internal consistency; α ≥ 0.7) was filled out by 200 surgeons. More than half (69%) of participants thought that antibiotics were overused. Most surgeons perceive that poor adherence to treatment guidelines is due to poor awareness, underestimation of infection, lack of consensus, and disagreement with guidelines recommendations. CONCLUSIONS: Surgeons have positive perception that antibiotics should be used according to guidelines recommendations. However, we found poor treatment adherence to antibiotic prophylaxis guidelines.

Role of angiotensin-converting enzyme in myeloid cell immune responses.

Angiotensin-converting enzyme (ACE), a dicarboxypeptidase, plays a major role in the regulation of blood pressure by cleaving angiotensin I into angiotensin II (Ang II), a potent vasoconstrictor. Because of its wide substrate specificity and tissue distribution, ACE affects many diverse biological processes. In inflammatory diseases, including granuloma, atherosclerosis, chronic kidney disease and bacterial infection, ACE expression gets upregulated in immune cells, especially in myeloid cells. With increasing evidences connecting ACE functions to the pathogenesis of these acquired diseases, it is suggested that ACE plays a vital role in immune functions. Recent studies with mouse models of bacterial infection and tumor suggest that ACE plays an important role in the immune responses of myeloid cells. Inhibition of ACE suppresses neutrophil immune response to bacterial infection. In contrast, ACE overexpression in myeloid cells strongly induced bacterial and tumor resistance in mice. A detailed biochemical understanding of how ACE activates myeloid cells and which ACE peptide(s) (substrate or product) mediate these effects could lead to the development of novel therapies for boosting immunity against a variety of stimuli, including bacterial infection and tumor.