Cardiac Hydatid Cyst: A Rare but Potentially Life-Threatening Presentation of Hydatid Disease.

Cardiac echinococcosis is a rare and severe manifestation of hydatid disease. It is caused by parasitic infestation by the Echinococcus species and can lead to life-threatening complications. Diagnosis is difficult due to nonspecific symptoms, but echocardiography is a highly sensitive diagnostic method. Albendazole treatment is effective in managing these cysts and can be an alternative to surgery. A patient with multiple cardiac hydatid cysts was successfully treated with albendazole, highlighting the importance of prompt diagnosis and treatment to prevent life-threatening complications.

Rare Coronary Anomaly of Posterior Descending Artery Arising from Superdominant Left Anterior Descending Artery.

Coronary artery anomalies are uncommon anatomical variations that are usually detected incidentally during a coronary angiogram or computed tomography angiography. We report a case of a diabetic and hypertensive middle-aged male who presented with chest discomfort. Coronary angiography revealed no signs of coronary artery disease but showed a left anterior descending artery (LAD) looping around the left ventricular apex and running through the posterior interventricular groove as a posterior descending artery (PDA) beyond the crux. The nondominant right coronary artery (RCA) and left circumflex artery (LCX) had no connection with the PDA. The patient's diabetic and hypertensive medications were adjusted, and he remained asymptomatic after 3 months. Interventionalists should be aware of the types of coronary anomalies that may complicate diagnosis and management during percutaneous coronary intervention.

Single Coronary Artery from Right Sinus of Valsalva: A Single Center Experience of Seven Cases.

Background: Single coronary artery (SCA) is a rare anomaly with a prevalence of 0.024-0.066%. Some anomalies are merely benign anatomical variants, whereas some can result in myocardial ischemia or life-threatening arrhythmia. Case Presentation. We described seven cases in which all three major coronaries emerged from the right sinus of Valsalva via a single ostium and supplied the vast majority of the myocardium. A smaller branch arising from the left sinus supplied a modest quantity of myocardium in some of those few cases. These SCA variations do not exactly fit into any existing classification. It is unclear whether we need to modify previous classification systems or newer classification systems. Conclusions: SCA is divided based on its anomalous course and is usually a benign condition but it may present with cardiovascular complications. Clinicians should be aware of this entity along with the role of CT angiogram in its diagnosis and management.

Dabigatran for intracardiac thrombus, yet another promising role of a direct oral anticoagulant: a case report and short review of literature.

A left ventricular (LV) thrombus is a relatively common and well-known condition associated with significant LV systolic dysfunction. However, LV thrombosis is unusual in the absence of kinetic abnormalities. The elderly gentleman presented with subacute onset of bilateral lower limb discomfort and cold extremities, but no gangrene. With normal LV function, an echocardiogram revealed a massive movable LV apical clot. He was treated with dual antiplatelets and heparin at first. He switched to dabigatran 110 mg twice a day in combination with dual antiplatelets. The thrombus had entirely vanished and leg problems had improved after a 2-week follow-up. For the next six months, he was treated with aspirin and dabigatran and was asymptomatic at follow-up. There are no specific guidelines for treating an intracardiac thrombus. Experts agree that a hypermobile and pedunculated LV thrombus with a high embolic risk should be surgically removed as soon as possible. According to ESC/ACC guidelines, all patients with LV thrombus associated with myocardial infarction should be treated with anticoagulation. Warfarin requires regular International Normalized Ratio (INR) monitoring and has a small therapeutic window; hence a direct oral anticoagulant (DOAC) could be a viable therapeutic solution. However, there are no guideline recommendations to date to guide DOAC therapy for this indication.

Brown tumour mimicking skeletal metastasis.

Brown tumours of bone are highly vascular osteolytic lesions that depict a reparative cellular process instead of a neoplastic process in hyperparathyroidism (HPT) patients. These tumours have the potential to be aggressive and destructive. We report a case of a 30-year-old woman who presented with left thigh and lower back pain. The radiological evaluation showed multiple bony lesions in the pelvis and the spine, which mimicked multiple metastatic tumours. However, on biochemistry evaluation, serum calcium, alkaline phosphatase, and parathyroid hormone were all high, while serum phosphate was low, indicating primary HPT (PHPT), which was confirmed by parathyroid scintigraphy showing left parathyroid adenoma. Hence, the bony lesions were diagnosed as brown tumours secondary to PHPT. The patient underwent parathyroidectomy and developed severe hungry bone syndrome requiring parenteral calcium infusion along with oral calcium and active vitamin D supplementation. The clinical symptoms of bone pain improved after surgery.

Redox-dependent condensation of the mycobacterial nucleoid by WhiB4.

Oxidative stress response in bacteria is mediated through coordination between the regulators of oxidant-remediation systems (e.g. OxyR, SoxR) and nucleoid condensation (e.g. Dps, Fis). However, these genetic factors are either absent or rendered non-functional in the human pathogen Mycobacterium tuberculosis (Mtb). Therefore, how Mtb organizes genome architecture and regulates gene expression to counterbalance oxidative imbalance is unknown. Here, we report that an intracellular redox-sensor, WhiB4, dynamically links genome condensation and oxidative stress response in Mtb. Disruption of WhiB4 affects the expression of genes involved in maintaining redox homeostasis, central metabolism, and respiration under oxidative stress. Notably, disulfide-linked oligomerization of WhiB4 in response to oxidative stress activates the protein's ability to condense DNA. Further, overexpression of WhiB4 led to hypercondensation of nucleoids, redox imbalance and increased susceptibility to oxidative stress, whereas WhiB4 disruption reversed this effect. In accordance with the findings in vitro, ChIP-Seq data demonstrated non-specific binding of WhiB4 to GC-rich regions of the Mtb genome. Lastly, data indicate that WhiB4 deletion affected the expression of ~ 30% of genes preferentially bound by the protein, suggesting both direct and indirect effects on gene expression. We propose that WhiB4 structurally couples Mtb's response to oxidative stress with genome organization and transcription.

MUSASHI-Mediated Expression of JMJD3, a H3K27me3 Demethylase, Is Involved in Foamy Macrophage Generation during Mycobacterial Infection.

Foamy macrophages (FM)s harbor lipid bodies that not only assist mycobacterial persistence within the granulomas but also are sites for intracellular signaling and inflammatory mediators which are essential for mycobacterial pathogenesis. However, molecular mechanisms that regulate intracellular lipid accumulation in FMs during mycobacterial infection are not clear. Here, we report for the first time that jumonji domain containing protein (JMJD)3, a demethylase of the repressive H3K27me3 mark, orchestrates the expression of M. tuberculosis H37Rv-, MDR-JAL2287-, H37Ra- and M. bovis BCG-induced genes essential for FM generation in a TLR2-dependent manner. Further, NOTCH1-responsive RNA-binding protein MUSASHI (MSI), targets a transcriptional repressor of JMJD3, Msx2-interacting nuclear target protein, to positively regulate infection-induced JMJD3 expression, FM generation and M2 phenotype. Investigations in in vivo murine models further substantiated these observations. Together, our study has attributed novel roles for JMJD3 and its regulators during mycobacterial infection that assist FM generation and fine-tune associated host immunity.

Reengineering redox sensitive GFP to measure mycothiol redox potential of Mycobacterium tuberculosis during infection.

Mycobacterium tuberculosis (Mtb) survives under oxidatively hostile environments encountered inside host phagocytes. To protect itself from oxidative stress, Mtb produces millimolar concentrations of mycothiol (MSH), which functions as a major cytoplasmic redox buffer. Here, we introduce a novel system for real-time imaging of mycothiol redox potential (EMSH ) within Mtb cells during infection. We demonstrate that coupling of Mtb MSH-dependent oxidoreductase (mycoredoxin-1; Mrx1) to redox-sensitive GFP (roGFP2; Mrx1-roGFP2) allowed measurement of dynamic changes in intramycobacterial EMSH with unprecedented sensitivity and specificity. Using Mrx1-roGFP2, we report the first quantitative measurements of EMSH in diverse mycobacterial species, genetic mutants, and drug-resistant patient isolates. These cellular studies reveal, for the first time, that the environment inside macrophages and sub-vacuolar compartments induces heterogeneity in EMSH of the Mtb population. Further application of this new biosensor demonstrates that treatment of Mtb infected macrophage with anti-tuberculosis (TB) drugs induces oxidative shift in EMSH , suggesting that the intramacrophage milieu and antibiotics cooperatively disrupt the MSH homeostasis to exert efficient Mtb killing. Lastly, we analyze the membrane integrity of Mtb cells with varied EMSH during infection and show that subpopulation with higher EMSH are susceptible to clinically relevant antibiotics, whereas lower EMSH promotes antibiotic tolerance. Together, these data suggest the importance of MSH redox signaling in modulating mycobacterial survival following treatment with anti-TB drugs. We anticipate that Mrx1-roGFP2 will be a major contributor to our understanding of redox biology of Mtb and will lead to novel strategies to target redox metabolism for controlling Mtb persistence.

Swertiamarin: An Active Lead from Enicostemma littorale Regulates Hepatic and Adipose Tissue Gene Expression by Targeting PPAR- γ and Improves Insulin Sensitivity in Experimental NIDDM Rat Model.

Enicostemma littorale (EL) Blume is one of the herbs widely used for treating and alleviating the effects of both type I and type II diabetes. However, lack of understanding of mechanism precludes the use of the herb and its molecules. In this study, we attempt to unravel the molecular mechanism of action of swertiamarin, a compound isolated form EL, by comparing its molecular effects with those of aqueous EL extract in alleviating the insulin resistance in type II diabetes. We further investigated hypolipidemic and insulin sensitizing effect of swertiamarin in experimentally induced noninsulin dependent diabetes mellitus (NIDDM) in rats. Swertiamarin (50 mg/kg) and aqueous extract (15 grams dried plant equivalent extract/kg) were administered to rats orally for 40 days and tight regulation of serum glucose, insulin, and lipid profile was found in both groups. Their mode of action was by restoring G6Pase and HMG-CoA reductase activities to normal levels and restoring normal transcriptional levels of PEPCK, GK, Glut 2, PPAR- γ , leptin, adiponectin, LPL, SREBP-1c, and Glut 4 genes. This suggests that both treatments increased insulin sensitivity and regulated carbohydrate and fat metabolism. This is the first report on the role of SM in regulating the PPAR γ -mediated regulation of candidate genes involved in metabolism in peripheral tissues in vivo.

Mycobacterium tuberculosis WhiB4 regulates oxidative stress response to modulate survival and dissemination in vivo.

Host-generated oxidative stress is considered one of the main mechanisms constraining Mycobacterium tuberculosis (Mtb) growth. The redox-sensing mechanisms in Mtb are not completely understood. Here we show that WhiB4 responds to oxygen (O2) and nitric oxide (NO) via its 4Fe-4S cluster and controls the oxidative stress response in Mtb. The WhiB4 mutant (MtbΔwhiB4) displayed an altered redox balance and a reduced membrane potential. Microarray analysis demonstrated that MtbΔwhiB4 overexpresses the antioxidant systems including alkyl hydroperoxidase (ahpC-ahpD) and rubredoxins (rubA-rubB). DNA binding assays showed that WhiB4 [4Fe-4S] cluster is dispensable for DNA binding. However, oxidation of the apo-WhiB4 Cys thiols induced disulphide-linked oligomerization, DNA binding and transcriptional repression, whereas reduction reversed the effect. Furthermore, WhiB4 binds DNA with a preference for GC-rich sequences. Expression analysis showed that oxidative stress repressed whiB4 and induced antioxidants in Mtb, while their hyper-induction was observed in MtbΔwhiB4. MtbΔwhiB4 showed increased resistance to oxidative stress in vitro and enhanced survival inside the macrophages. Lastly, MtbΔwhiB4 displayed hypervirulence in the lungs of guinea pigs, but showed a defect in dissemination to their spleen. These findings suggest that WhiB4 systematically calibrates the activation of oxidative stress response in Mtb to maintain redox balance, and to modulate virulence.