Abatacept: A Promising Repurposed Solution for Myocardial Infarction-Induced Inflammation in Rat Models.

Myocardial infarction (MI) is irreversible damage to the myocardial tissue caused by prolonged ischemia/hypoxia, subsequently leading to loss of contractile function and myocardial damage. However, after a perilous period, ischemia-reperfusion (IR) itself causes the generation of oxygen free radicals, disturbance in cation homeostasis, depletion of cellular energy stores, and activation of innate and adaptive immune responses. The present study employed Abatacept (ABT), which is an anti-inflammatory drug, originally used as an antirheumatic response agent. To investigate the cardioprotective potential of ABT, primarily, the dose was optimized in a chemically induced model of myocardial necrosis. Thereafter, ABT optimized the dose of 5 mg/kg s.c. OD was investigated for its cardioprotective potential in a surgical model of myocardial IR injury, where animals (n = 30) were randomized into five groups: Sham, IR-C, Telmi10 + IR (Telmisartan, 10 mg/kg oral OD), ABT5 + IR, ABT perse. ABT and telmisartan were administered for 21 days. On the 21st day, animals were subjected to LAD coronary artery occlusion for 60 min, followed by reperfusion for 45 min. Further, the cardioprotective potential was assessed through hemodynamic parameters, oxidant-antioxidant biochemical enzymatic parameters, cardiac injury, inflammatory markers, histopathological analysis, TUNEL assay, and immunohistochemical evaluation, followed by immunoblotting to explore signaling pathways. The statistics were performed by one-way analysis of variance, followed by the Tukey comparison post hoc tests. Noteworthy, 21 days of ABT pretreatment amended the hemodynamic and ventricular functions in the rat models of MI. The cardioprotective potential of ABT is accompanied by inhibiting MAP kinase signaling and modulating Nrf-2/HO-1 proteins downstream signaling cascade. Overall, the present work bolsters the previously known anti-inflammatory role of ABT in MI and contributes a mechanistic insight and application of clinically approved drugs in averting the activation of inflammatory response.

Arglabin: A mediator of inflammasome modulated and independent myocardial injury (PARA-AMI study).

BACKGROUND: Arglabin is a plant alkaloid (sesquiterpene lactone) that is used as an anticancer drug. It has potential anti-diabetic and anti-atherogenic effects. PURPOSE: Arglabin has drawn particular attention because of its therapeutic effects as an anti-inflammatory agent in multiple diseases. Since arglabin inhibits Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, concerns for cardiotoxic effects are valid. The present study was designed to investigate the protective effects of arglabin on the myocardium. STUDY DESIGN: This study was designed to evaluate the effect of arglabin on the myocardium in an experimental model of myocardial necrosis in rats. Different doses of arglabin (2.5, 5, and 10 µg/kg) were investigated as pre-treatment for 21 days in the isoproterenol (ISO) model of myocardial necrosis groups and per se groups. METHODS: On the 22nd day, hemodynamic, histopathological, electron microscopy, oxidative stress markers, inflammatory mediators, apoptotic markers, inflammasome mediators, and Western blot analysis were performed to evaluate the effects of arglabin. RESULTS: Arglabin pre-treatment showed improvement in hemodynamic parameters and histopathological findings at low doses in isoproterenol-induced myocardial necrosis model of rats. Arglabin administration altered myocardial structure and modulated myocardial function via activation of NFκB/MAPK pathway that led to myocardial injury with an increase in dose. CONCLUSION: Arglabin imparted partial cardio-protection via an inflammasome-dependent pathway and mediated injury through the inflammasome-independent pathway.

Morin ameliorates myocardial injury in diabetic rats via modulation of inflammatory pathways.

BACKGROUND: High blood glucose levels in diabetes lead to vascular inflammation which accelerates atherosclerosis. Herein, Morin was orally administered in male Wistar rats, at the dose of 40 mg/kg for 28 days, and on the 27th and 28th day, ISO was administered to designate groups at the dose of 85 mg/kg s.c., to induce myocardial infarction. RESULTS: Free radical generation, including ROS, in diabetes following ISO administration, leads to the activation of both intrinsic and extrinsic pathways of apoptosis. Morin significantly (p ≤ 0.05) reduced oxidative stress (GSH, MDA, SOD), cardiac injury markers (CK-MB, LDH), inflammation (TNF, IL-6), and apoptosis (Bax, BCl2, Caspase-3). In addition, it also reduced insulin and blood glucose levels. Akt/eNOS, Nrf2/HO-1, MAPK signaling pathways, and Insulin signal transduction pathways were positively modulated by morin pre-treatment. CONCLUSIONS: Morin attenuated oxidative stress and inflammation and also modified the activity of various molecular pathways to mitigate cardiomyocyte damage during ISO-induced MI in diabetic rats.

Gut microbiome supplementation as therapy for metabolic syndrome.

The gut microbiome is defined as an ecological community of commensal symbiotic and pathogenic microorganisms that exist in our body. Gut microbiome dysbiosis is a condition of dysregulated and disrupted intestinal bacterial homeostasis, and recent evidence has shown that dysbiosis is related to chronic inflammation, insulin resistance, cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), and obesity. It is well known that obesity, T2DM and CVD are caused or worsened by multiple factors like genetic predisposition, environmental factors, unhealthy high calorie diets, and sedentary lifestyle. However, recent evidence from human and mouse models suggest that the gut microbiome is also an active player in the modulation of metabolic syndrome, a set of risk factors including obesity, hyperglycemia, and dyslipidemia that increase the risk for CVD, T2DM, and other diseases. Current research aims to identify treatments to increase the number of beneficial microbiota in the gut microbiome in order to modulate metabolic syndrome by reducing chronic inflammation and insulin resistance. There is increasing interest in supplements, classified as prebiotics, probiotics, synbiotics, or postbiotics, and their effect on the gut microbiome and metabolic syndrome. In this review article, we have summarized current research on these supplements that are available to improve the abundance of beneficial gut microbiota and to reduce the harmful ones in patients with metabolic syndrome.

The Role of Gut Microbiome Supplementation in COVID-19 Management.

COVID-19, which is caused by the RNA virus, SARS-CoV-2, mainly affects the respiratory system and has a varied clinical presentation. However, several studies have shown that COVID-19 can also affect the gastrointestinal (GI) system. Patients can experience various GI symptoms, such as vomiting and diarrhea, and the virus has been detected in the stool samples of patients hospitalized with COVID-19. There have also been rare reports of COVID-19 presenting with isolated GI symptoms and lack of respiratory symptoms, and the virus has also been detected for prolonged periods in the fecal samples of COVID-19 patients. Major alterations in the gut microbiome in the form of depletion of beneficial organisms and an abundance of pathogenic organisms have been reported in the fecal samples of hospitalized COVID-19 patients. Although the US FDA has approved several drugs to manage COVID-19, their efficacy remains modest. So, there is a constant ongoing effort to investigate novel treatment options for COVID-19. Health supplements like probiotics, prebiotics, postbiotics, and synbiotics have been popularly known for their various health benefits. In this review, we have summarized the current literature, which shows the potential benefit of these health supplements to mitigate and/or prevent the clinical presentation of COVID-19.

In-silico Assessment of Polyherbal Oils as Anti-diabetic Therapeutics.

BACKGROUND: Diabetes mellitus (DM) is characterized by elevated blood glucose levels either due to insufficient insulin production, defective insulin action, or both. It affects nearly 537 million individuals worldwide. Pharmacological treatment involves the use of oral antidiabetic agents as mono or combination therapy that effectively aids in controlling hyperglycemia. Despite providing therapeutic benefits, these medications limit their use owing to adverse side effects. Certain natural products, including essential oils, have promising anti-diabetic properties. OBJECTIVE: The present study explores the effectiveness of two polyherbal oils and their compound towards the treatment of DM based on an In-silico approach to drug investigations. METHODS: Compounds present in the polyherbal oil formulation were identified using GCMS/MS analysis. Selected compounds undergo molecular docking with the receptor, and proteins play an important role in DM. The potential compounds showing higher interactions than the known inhibitors or inducers were evaluated using molecular dynamic simulations RMSD values. RESULTS: The compounds identified through GC-MS analysis possess anti-diabetic and antiinflammatory properties. With the aid of in silico prediction methods, compounds such as geraniol, cinnamaldehyde, anethole, caryophyllene, terpinyl acetate, cymene, linalool, menthol, Phenol,2-methoxy-3-(2-propenyl), and 2,6- octadienal,3,7-dimethyl were identified as strong binders of GLUT4 and insulin receptor proteins. Geraniol and Phenol,2-methoxy-3-(2-propenyl) interaction with GLUT4 were of particular importance owing to their conformational stability. CONCLUSION: Our data suggest an agonistic effect of compounds on target proteins aiding in enhanced insulin activity and could serve as a potential anti-diabetic agent.

Integrating in silico and in vivo approach for investigating the role of polyherbal oil in prevention and treatment of COVID-19 infection.

Currently, there are no FDA approved antiviral drugs available to treat COVID-19 patients. Also, due to emergence of new SARS-CoV-2 variants, the protective efficacy of vaccines could be reduced, hence it is urgent to have alternative treatments for combating the SARS-CoV-2 infection. Since, there is a long-standing history of herbal medicine in the treatment of respiratory diseases. In the present study, we investigated two polyherbal oil blend viz. Sudarshan AV and Elixir AV (SAV and EAV) in inhibiting SARS-COV-2. From GC-MS analysis of polyherbal oils (SAV and EAV) a total of 11 active compounds were selected, on the basis of their abundance and activity. Further, from the molecular docking studies, we found an inhibitory effect of these compounds on viral envelope and membrane, spike proteins whilst an agonistic effect with human host receptor angiotensin-converting enzyme 2 (ACE2) implicating the crucial role of the individual compound in resistance of SARS-CoV-2. Since, the in-silico results suggest that polyherbal oil (SAV and EAV) contributes in preventing the entry of SARS-CoV-2 into the human body, we further investigated the efficacy of polyherbal formulated essential oil (FEO; SAV & EAV) in prevention and treatment of COVID-19 in hamster model. The male golden Syrian hamsters (n = 23) were divided into 5 groups i.e., Group 1: Control (n = 3); Group 2: Infected (n = 5); Group 3: Infected + Remdesivir (n = 5); Group 4: Infected + FEO (n = 5) and Group 5: Prophylactic FEO + Infected (n = 5). In both treatment and prophylactic groups, the FEO's significantly reduced the lung injury investigated histo-pathologically and viral load expression measured by real time PCR in comparison to infected hamsters. Furthermore, cytokines expression analysis clearly highlighted the efficacy of FEO's due to its anti-inflammatory activity and overall protection in treatment groups. In conclusion, the FEO (SAV & EAV) seem to be potent in both prevention and treatment of COVID-19 and related lung injury.

Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus.

Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.

Real-time continuous glucose monitoring improves glycemic control and reduces hypoglycemia: Real-world data.

AIM: To study the effect of real time continuous glucose monitor (RT-CGM) use on glycemic parameters in patients with diabetes mellitus (DM) in real world practice. METHODS: We retrospectively studied 91 adult subjects with DM who had been using Dexcom™ RT-CGM. Two consecutive hemoglobin A1c (HbA1c), both prior to and after at least 3 months of RT-CGM initiation, were collected. A total of 31 subjects completed a 5-14 day user blinded CGM using a Freestyle Libre™ prior to RT-CGM initiation. The first two week period following at least 3 months use of RT-CGM was analyzed for CGM metrics. RESULTS: A total of 51.6 % of subjects had T1DM, 34.1 % used continuous subcutaneous insulin infusion (CSII), and 62.6 % had DM for > 10 years. Both HbA1c obtained following RT-CGM initiation decreased significantly compared to baseline (8.11 + 1.47% vs 7.69 + 1.25 %; P = 0.002 & 8.16 + 1.51 % vs 7.62 + 1.06 %; P = 0.001). Subjects with baseline HbA1c > 7.0 % showed even more robust reduction in both HbA1c after RT-CGM initiation (8.74 + 1.24 % vs 7.99 + 1.22 %; P = 0.000 & 8.74 + 1.32 % vs 7.85 + 1.07 %; P = 0.001). On comparison of CGM metrics, there was a significant reduction in time spent in hypoglycemia (sugars < 70 mg/dl) including severe hypoglycemia (sugars < 54 mg/dl) after initiation of the RT-CGM (9.16 + 8.68 % vs 1.29 + 2.21 %; P = <0.001 & 4.58 + 5.43 % vs 0.28 + 0.58 %; P = <0.001). CoV of glucose was also decreased significantly (39.61 + 9.36 % vs 31.06 + 6.74 %; P = <0.001) with RT- CGM use. CONCLUSION: RT-CGM use for at least 3 months in patients with DM results in meaningful HbA1c reductions with stable glycemic control without increasing the risk of hypoglycemia.

Correlation of serum amyloid A1 and interleukin-1beta in response to anti-tubercular therapy.

BACKGROUND: Host biomarkers are needed to monitor the response to anti-tubercular therapy (ATT) for ensuring effective therapy and preventing drug-resistant tuberculosis. We sought to find the correlation between the serum levels of SAA1 and IL-1beta in response to ATT in adult patients with pulmonary TB (PTB) or extra-pulmonary TB (EPTB). METHODS: Blood samples of 32 patients with PTB and 28 patients with EPTB were analyzed. The blood samples were collected at baseline, two months and six months following treatment initiation. SAA1 and IL-1beta levels were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: In the PTB group, the mean levels of SAA1 decreased significantly (p <0.001) after the intensive phase (two months) and continuous phase (six months) of ATT in comparison with the baseline value. IL-1beta values also decreased significantly (p = 0.005) after the intensive phase (two months) compared with the baseline values. In the EPTB group, there was a significant reduction in the mean serum level of SAA1 (p <0.001) and IL-1beta (p = 0.001) after the intensive phase (two months) in comparison with the baseline value, whereas the reduction at six months was not significant. CONCLUSIONS: SAA1 and IL-1beta may be useful potential treatment-monitoring biomarkers, especially in the intensive phase of therapy for both PTB and EPTB.

Predictors of colorectal carcinoma and inflammatory bowel disease in patients with colonic wall thickening.

Background and Aim: Colonic wall thickening (CWT) is commonly associated with clinically significant pathologies, but predictive factors of such pathologies are not well known. This study aims to identify the predictors of clinically significant pathologies, such as colorectal carcinoma (CRC) and inflammatory bowel disease (IBD), in patients with CWT. Methods: Subjects with an abnormal abdominal computed tomography (CT) and a follow-up colonoscopy between 2010 and 2020 were retrospectively reviewed. Patients with CWT in the CT were included and examined in this study. A multivariable logistic regression analysis was performed to assess for factors independently associated with CRC or IBD in these subjects. Receiver operating characteristic (ROC) curve analysis was used to further examine significant parameters in multivariable logistic regression analysis. Results: Among 403 patients with CWT on CT scans who underwent a colonoscopy, 269 subjects who met the inclusion criteria were identified and studied. On multivariable logistic regression models, elevated platelet count, low hematocrit, and localized CWT were found to be independently associated with CRC, while elevated platelet count and younger age were independently associated with IBD. On ROC curve analysis for CRC, area under the curve (AUC) for hematocrit, platelets, and localized CWT was 0.76, 0.75, and 0.61, respectively. On ROC curve analysis for IBD, AUC for age and platelets was 0.90 and 0.69, respectively. Conclusion: Elevated platelet count, low hematocrit, and localized CWT can be potentially used as predictors of CRC in patients with CWT. Elevated platelet count and young age can be used to predict IBD in these patients.

Evidence-based mechanistic role of chrysin towards protection of cardiac hypertrophy and fibrosis in rats.

Cardiac hypertrophy is the enlargement of cardiomyocytes in response to persistent release of catecholamine which further leads to cardiac fibrosis. Chrysin, flavonoid from honey, is well known for its multifarious properties like antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic. To investigate the cardioprotective potential of chrysin against isoproterenol (ISO), cardiac hypertrophy and fibrosis are induced in rats. Acclimatised male albino Wistar rats were divided into seven groups (n 6): normal (carboxymethyl cellulose at 0·5 % p.o.; as vehicle), hypertrophy control (ISO 3 mg/kg, s.c.), CHY15 + H, CHY30 + H & CHY60 + H (chrysin; p.o.15, 30 and 60 mg/kg respectively + ISO at 3 mg/kg, s.c.), CHY60 (chrysin 60 mg/kg in per se) and LST + H (losartan 10 mg/kg p.o. + ISO 3 mg/kg, s.c.) were treated for 28 d. After the dosing schedule on day 29, haemodynamic parameters were recorded, after that blood and heart were excised for biochemical, histological, ultra-structural and molecular evaluations. ISO administration significantly increases heart weight:body weight ratio, pro-oxidants, inflammatory and cardiac injury markers. Further, histopathological, ultra-structural and molecular studies confirmed deteriorative changes due to ISO administration. Pre-treatment with chrysin of 60 mg/kg reversed the ISO-induced damage to myocardium and prevent cardiac hypertrophy and fibrosis through various anti-inflammatory, anti-apoptotic, antioxidant and anti-fibrotic pathways. Data demonstrated that chrysin attenuated myocardial hypertrophy and prevented fibrosis via activation of transforming growth factor-beta (TGF-ß)/Smad signalling pathway.

Maturity-Onset Diabetes of the Young: Rapid Evidence Review.

Maturity-onset diabetes of the young (MODY) is a non-insulin-dependent form of diabetes mellitus that is usually diagnosed in young adulthood. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on the causative genetic mutation. Subtypes 1 to 3 account for 95% of cases. MODY is often misdiagnosed as type 1 or 2 diabetes and should be suspected in nonobese patients who have diabetes that was diagnosed at a young age (younger than 30 years) and a strong family history of diabetes. Unlike those with type 1 diabetes, patients with MODY have preserved pancreatic beta-cell function three to five years after diagnosis, as evidenced by detectable serum C-peptide levels with a serum glucose level greater than 144 mg per dL and no laboratory evidence of pancreatic beta-cell autoimmunity. Patients with MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to patients with types 1 and 2 diabetes. Lifestyle modification including a low-carbohydrate diet should be the first-line treatment for MODY1 and MODY3. Sulfonylureas are the preferred pharmacologic therapy based on pathophysiologic reasoning, although clinical trials are lacking. Patients with MODY2 have mild stable fasting hyperglycemia with low risk of diabetes-related complications and generally do not require treatment, except in pregnancy. Pregnant patients with MODY may require insulin therapy and additional fetal monitoring for macrosomia.

Amelioration of immune and digestive system through weed supplemented feed against Aeromonas hydrophila in Clarias gariepinus.

Aquaculture is one of the important globally growing industries. It serves as an important food source of protein for human beings. With the expanding demand for the fish and their products it has become extremely important to improve the aquaculture practices. Aquaculture in India has witnessed huge mortalities caused by bacteria, viruses, fungi, nematodes etc. Aquatic weeds plants are harmful for aquaculture in many ways. Present study is aimed to overcome the disease caused by Aeromonas hydrophila (fish pathogenic bacteria) through feed supplementation of two aquatic weed plants (Azolla pinnata and Ceratophyllum demersum). The fish were divided into 6 groups: experimental groups (fish fed on supplementary feed at 5% and 2.5% concentration for individual plant and challenged with bacteria), positive control (fish fed on non-supplemented feed and challenged with bacteria) and negative control (fish fed on non-supplementary feed and not challenged with bacteria). It was observed that supplemented feed enhanced both cell mediated and humoral immunity in fish. Therefore, we advocate that feed formulated with incorporation of Azolla pinnata and Ceratophyllum demersum leaf powder at 5% and 2.5% could be used to prevent disease caused by A. hydrophila or can be used to enhance fish health by boosting its immune system. The results of this study also showed an improved digestibility in fish fed on supplemented feed.

Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart.

It is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

Effect of serum zinc and copper levels on insulin secretion, insulin resistance and pancreatic ß cell dysfunction in US adults: Findings from the National Health and Nutrition Examination Survey (NHANES) 2011-2012.

AIM: To compare zinc (Zn) and copper (Cu) levels in US adults with normoglycemia, prediabetes and diabetes, and study the association of serum Zn and Cu levels with pancreatic ß cell insulin secretion, pancreatic dysfunction and insulin resistance in US adults with normoglycemia and prediabetes. METHOD: Homeostatic Model Assessment (HOMA2) calculator was used to compute estimates of steady state ß cell insulin secretion (HOMA2-B), peripheral insulin sensitivity (HOMA2-S), insulin resistance (HOMA-IR), and disposition index (HOMA-DI) in 804 adult individuals from the National Health and Nutrition Examination Survey (NHANES 2011-2012). RESULTS: There was no significant difference between serum Zn and Cu levels among subjects with normoglycemia, prediabetes, and diabetes. After adjusting for multiple possible confounders, higher serum Zn concentrations were associated with lower ß cell insulin secretion (HOMA2-B; p = 0.01) and lower insulin resistance (HOMA-IR; p = 0.04) in the prediabetic subjects. In normoglycemic group, higher serum Zn levels were associated with improved pancreatic function (HOMA-DI; P = 0.02). On the other hand, higher serum Cu levels were associated with increased ß cell insulin secretion (HOMA2-B, P = 0.03) only in the subjects with prediabetes. CONCLUSION: These findings support the need for further studies to investigate the role of trace elements in diabetes pathogenesis.

Association of Monoamine Oxidase A with Tumor Burden and Castration Resistance in Prostate Cancer.

BACKGROUND: Metastatic burden and aggressive behavior determine severity stratification and guide treatment decisions in prostate cancer (PCa). Monoamine oxidase A (MAOA) may promote tumor burden and drug/castration resistance in PCa. A positive association will pave the way for MAOA inhibitors such as moclobemide for PCa therapy. OBJECTIVE: To analyze MAOA in peripheral blood mononuclear cells qualitatively and p38, c-Jun N-terminal kinases, nuclear factor kappa B, and their phosphorylated forms, vascular endothelial growth factor (angiogenesis), transforming growth factor beta, interleukin 6, and tumor necrosis factor-α (cytokines), Bcl-2 associated X, B-cell lymphoma 2, and P53 (apoptosis), prostate-specific membrane antigen, and epithelial cell adhesion molecules (surface markers) in plasma of patients with PCa. METHODS: This was a 1-year pilot study in which patients with PCa were recruited and stratified into 2 groups and subgroups: treatment-naive with (M1) (n = 23) or without (M0) (n = 23) bone metastasis; hormone-sensitive prostate cancer (n = 26) or hormone/castration-resistant prostate cancer (n = 26). MAOA was detected using ELISA and other proteins were detected using immunoblotting technique. RESULTS: MAOA was detected in 8.6% of M0 compared with 30.4% of M1 patients, and in 7.7% of hormone-sensitive compared with 27% of hormone/castration resistant PCa patients, associating it with bone metastasis and castration resistance. Multivariable regression analysis showed a correlation of MAOA with serum prostate-specific antigen, a marker for progression in PCa (Pearson correlation coefficient r = 0.30; P < 0.01). In patients with positive MAOA, there was overexpression of p38, phosphorylated-p38, c-Jun N-terminal kinases, phosphorylated c-Jun N-terminal kinases, nuclear factor kappa B, phosphorylated nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, interleukin 6, tumor necrosis factor α, Bcl-2 associated X, B-cell lymphoma 2, prostate-specific membrane antigen, and epithelial cell adhesion molecule in M1 compared with M0 group patients, associating these proteins with tumor burden. Overexpression of Bcl-2 associated X, tumor protein 53, c-Jun N-terminal kinases, nuclear factor kappa B, transforming growth factor beta, vascular endothelial growth factor, and prostate-specific membrane antigen and underexpression of B-cell lymphoma 2 and phosphorylated nuclear factor kappa B were observed in hormone-sensitive prostate cancer compared with hormone/castration-resistant prostate cancer, associating these proteins with castration resistance. CONCLUSIONS: Association of key molecules of oncogenesis and metastasis with MAOA suggests that MAOA inhibitors such as moclobemide might be effective in the management of PCa.

Erdosteine salvages cardiac necrosis: Novel effect through modulation of MAPK and Nrf-2/HO-1 pathway.

Isoproterenol (ISO) induced oxidative stress and inflammation is involved in the pathogenesis of myocardial necrosis. To optimize the effect of erdosteine against myocardial necrosis, male albino Wistar rats were divided into eight groups (n = 6), that is, normal, ISO-control, erdosteine pretreatment with ISO. Rats were administered erdosteine orally for 28 days. Two doses of ISO (85 mg/kg), s.c. were given to ISO-C and erdosteine treatment groups on the 27th and 28th day. On the 29th day, hemodynamic parameters were recorded and the heart was excised for further parameters. In ISO-C rats, significantly increased levels of inflammatory markers, pro-oxidants, and structural damage were observed as compared with normal group. Furthermore, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed an increased expression of apoptotic proteins. Erdosteine at 80 mg/kg reversed the deleterious effects of ISO and normalized myocardium. Erdosteine showed anti-inflammatory, antiapoptotic, and antioxidant activities through inhibition of MAPK and Nrf-2/HO-1 pathways. To conclude, erdosteine was found protective in ISO-induced myocardial necrosis through MAPK and Nrf-2/HO-1 pathway.

Thyroid Nodules: Advances in Evaluation and Management.

Thyroid nodules can be detected by ultrasonography in up to 68% of the general population. They are typically benign and are often discovered incidentally. The primary goal of thyroid nodule evaluation is to determine whether it is malignant. After thyroid ultrasonography has been performed, the next step is measurement of serum thyroid-stimulating hormone. If levels are low, a radionuclide thyroid uptake scan is indicated. Hyperfunctioning nodules are rarely malignant and do not require tissue sampling. Nonfunctioning nodules and nodules in a patient with a normal or high thyroid-stimulating hormone level may require fine-needle aspiration based on ultrasound characteristics and size. Nodules with suspicious features and solid hypoechoic nodules 1 cm or larger require aspiration. The Bethesda System (categories 1 through 6) is used to classify samples. Molecular testing can be used to guide treatment when aspiration yields an indeterminate result. Molecular testing detects mutations associated with thyroid cancer and can help inform decisions about surgical excision vs. continued ultrasound monitoring. Treatment of pregnant women with nonfunctioning thyroid nodules and of children with thyroid nodules is similar to that for nonpregnant adults, with the exception of molecular testing, which has not been validated in these populations.

Avascular Necrosis of Both Hips From Iatrogenic Cushing 's Syndrome due to Coadministration of Fluticasone and Ritonavir in an HIV-Infected Patient.

We report a case of avascular necrosis (AVN), hypercalcemia, and iatrogenic Cushing's syndrome in an HIV-positive patient taking inhaled (ICS) and nasal corticosteroids fluticasone and ritonavir. A 45-year-old HIV-infected African-American woman was seen for initial evaluation for multinodular goiter in December 2015. Relevant medications were ritonavir, raltegravir, darunavir, fluticasone propionate HFA, and nasal fluticasone propionate. Physical examination revealed classical cushingoid appearance but laboratory testing showed abnormal adrenocorticotropic hormone (ACTH) stimulation test. A diagnosis of iatrogenic Cushing's syndrome due to inhibition of fluticasone metabolism from protease inhibitor (PI) therapy with secondary adrenal suppression was made. Fluticasone nasal spray and HFA were discontinued and hydrocortisone replacement dose was initiated. The patient's Cushing's related symptoms improved over several months. Follow-up evaluation showed non-parathyroid hormone-mediated hypercalcemia. A detailed laboratory evaluation looking for the etiology for hypercalcemia was unremarkable except for an elevated urine N-telopeptide/creatinine ratio. Meanwhile, the patient developed a new symptom of hip pain. MRI of both hips showed bilateral AVN. Sickle cell screen was negative and a right hip replacement was completed in May 2017. Since this is the fourth case report of AVN from iatrogenic Cushing's syndrome in an HIV-infected patient taking a PI and ICS concomitantly, there is more likely a causal relationship and not simply a coincidental finding. Extreme caution should be used when considering any ICS therapy in combination with PIs in HIV-infected patients.