Impaired perfusion after myocardial infarction is due to reperfusion-induced deltaPKC-mediated myocardial damage

OBJECTIVE: To improve myocardial flow during reperfusion after acute myocardial infarction and to elucidate the molecular and cellular basis that impedes it. According to the AHA/ACC recommendation, an ideal reperfusion treatment in patients with acute myocardial infarction (AMI) should not only focus on restoring flow in the occluded artery, but should aim to reduce microvascular damage to improve blood flow in the infarcted myocardium. METHODS: Transgenic mouse hearts expressing the deltaPKC (protein kinase C) inhibitor, deltaV1-1, in their myocytes only were treated with or without the deltaPKC inhibitor after ischemia in an ex vivo AMI model. deltaV1-1 or vehicle was also delivered at reperfusion in an in vivo porcine model of AMI. Microvascular dysfunction was assessed by physiological and histological measurements. RESULTS: deltaPKC inhibition in the endothelial cells improved myocardial perfusion in the transgenic mice. In the porcine in vivo AMI model, coronary flow reserve (CFR), which is impaired for 6 days following infarction, was improved immediately following a one-minute treatment at the end of the ischemic period with the deltaPKC-selective inhibitor, deltaV1-1 ( approximately 250 ng/kg), and was completely corrected by 24 h. Myocardial contrast echocardiography, electron microscopy studies, and TUNEL staining demonstrated deltaPKC-mediated microvascular damage. epsilonPKC-induced preconditioning, which also reduces infarct size by >60%, did not improve microvascular function. CONCLUSIONS: These data suggest that deltaPKC activation in the microvasculature impairs blood flow in the infarcted tissue after restoring flow in the occluded artery and that AMI patients with no-reflow may therefore benefit from treatment with a deltaPKC inhibitor given in conjunction with removal of the coronary occlusion.     

Hydrophilic polymer microemboli in a patient with a chronic cutaneous ulcer: a case report

Hydrophilic polymer coatings were designed to reduce friction between the catheter and vessel wall and facilitate intravascular manipulations during catheterization and placement of drug‐eluting stents. One newly reported complication of such hydrophilic coatings is the fragmentation and embolization of the polymer, which can lead to ischemia and infarct by blocking the small vasculature. In this report, we present a patient with a non‐healing ulcer on the leg. Biopsy from the ulcer revealed the presence of hydrophilic polymer emboli within the dermal vessels. This is one of the few reports of such a complication involving the skin. Our objective is to emphasize the histopathologic features of this uncommon iatrogenic phenomenon.     

Thymoquinone Attenuates Astrogliosis, Neurodegeneration, Mossy Fiber Sprouting, and Oxidative Stress in a Model of Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is a rather common and difficult-to-treat variant of epilepsy. Nearly one third of people with epilepsy do not respond effectively to currently available anticonvulsants. In this study, we evaluated the protective effect of thymoquinone (TQ), the main constituent of black seed with antioxidant and anti-inflammatory effects, in the intrahippocampal kainate model of TLE in rat. Following kainate injection, seizure activity was observed that was significantly diminished by TQ pretreatment at a dose of 10 mg/kg, p.o. Intrahippocampal kainate also increased malondialdehyde (MDA), nitrite, and nitrate levels and decreased activity of superoxide dismutase and TQ only significantly attenuated MDA. In addition, intrahippocampal kainate caused a significant reduction of neurons in CA1, CA3 and the hilar regions, and TQ significantly attenuated these changes. Timm histochemistry showed a marked mossy fiber sprouting (MFS) in the dentate gyrus of kainate-lesioned rats, and TQ significantly lowered MFS intensity. Meanwhile, a number of reactive astrocytes (astrogliosis) increased significantly in the kainate group, and TQ pretreatment significantly decreased it. These data suggest that TQ pretreatment could attenuate seizure activity and lipid peroxidation, lower hippocampal neuronal loss and MFS, and mitigate astrogliosis in kainate model of TLE.     

Effect of statins on lipoprotein receptor expression in cell lines from human mast cells and basophils

Objective Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and widely used to treat hyperlipidaemia. Apart from their direct lipid-lowering effects, statins may also influence lipid metabolism through modulation of low-density lipoprotein (LDL) receptors. Basophils and mast cells have been reported to express LDL receptors and have been implicated in atherogenesis. The aim of this study was to investigate the effects of statins on the interactions of ¹²⁵I-LDL with purified primary human blood basophils, a human basophil cell line, KU812, and a human mast cell line, HMC-1.Methods Direct binding experiments were carried out with the primary basophils and KU812 as well as HMC-1 cells before and after pretreatment of the cells with atorvastatin, simvastatin, or cerivastatin. The effects of these three statins on the LDL-uptake and degradation as well as on thymidine incorporation in the cells were also studied.Results Primary basophils, HMC-1 and KU812 cells expressed two classes of LDL binding sites. Exposure to atorvastatin, simvastatin or cerivastatin increased significantly (P<0.05) the number of ¹²⁵I-LDL binding sites on primary basophils and HMC-1 as well as KU812 cells. The effects of the statins were dose dependent. The statins also enhanced the uptake and degradation of LDL in primary basophils, HMC-1 and KU812 cells. The increase in the number of LDL binding sites induced by statins was abolished by mevalonic acid (200 mol/l). Statins had no effect on the thymidine incorporation into the cells in an unstimulated condition.Conclusion Our results provide evidence for the upregulation of LDL binding sites on human basophils and mast cells by statins. We hypothesise that effects of statins on the lipid metabolism might also involve basophils and mast cells.     

Hyperkalemia and Hypertension Post Organ Transplantation – A Management Challenge

Potassium is the most important intracellular cation and the kidneys play a pivotal role in potassium homeostasis. Potassium disorder is a common electrolyte abnormality and it increases the risk of death from any cause, particularly cardiovascular events. Hyperkalemia is a common electrolyte abnormality encountered post organ transplantation. The etiology is multifactorial, and includes drugs such as calcineurin inhibitors. In certain regards, the clinical picture of post-transplantation hyperkalemia and hypertension resembles that of Gordon syndrome or familial hyperkalemic hypertension, a disorder characterized by over activity of thiazide-sensitive sodium chloride cotransporter. Effective and safe management of chronic hyperkalemia can be challenging in this special patient population. Despite the significant short-term and long-term side effects, fludrocortisone (a potent synthetic oral mineralocorticoid receptor agonist) has emerged as the default drug of choice for treatment of refractory hyperkalemia in many organ transplant recipients. However, the long-term efficacy and safety of fludrocortisone for management of hyperkalemia in organ transplant recipients remains unknown. This review discusses potassium homeostasis, including the role of the kidneys, and focuses on calcineurin inhibitor-induced hyperkalemia and on the under-appreciated role of thiazide-type diuretic use in management of hyperkalemia and hypertension. We present an illustrative case of post-transplantation hyperkalemia and hypertension with relevant literature.     

The quinazoline-2,4(1H,3H)-diones skeleton: A key intermediate in drug synthesis

Quinazoline-2,4(1H,3H)-dione is a major class of N-fused heterocyclic with a wide range of biological functions, including anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities, and other activities, has attracted high attention in organic and medicinal chemistry. As a consequence, all chemists and pharmaceutical chemists should be familiar with the various procedures for producing quinazoline-2,4(1H,3H)-dione. The main purpose of this paper is to provide an overview of the many manufacturing methods for various biological compounds based on the quinazoline-2,4(1H,3H)-dione and 2,4-dichloroquinazoline cores.     

Resuming Breast Imaging Services in the Aftermath of the COVID-19 Pandemic: Safety and Beyond

As the Coronavirus disease 2019 (COVID-19) epidemic begins to stabilize, different medical imaging facilities not directly involved in the COVID-19 epidemic face the dilemma of how to return to regular operation. We hereby discuss various fields of concern in resuming breast imaging services. We examine the concerns for resuming functions of breast imaging services in 2 broad categories, including safety aspects of operating a breast clinic and addressing potential modifications needed in managing common clinical scenarios in the COVID-19 aftermath. Using a stepwise approach in harmony with the relative states of the epidemic, health care system capacity, and the current state of performing breast surgeries (and in compliance with the recommended surgical guidelines) can ensure avoiding pointless procedures and ensure a smooth transition to a fully operational breast imaging facility.     

Evaluation of corneal topographic, tomographic and biomechanical indices for detecting clinical and subclinical keratoconus: a comprehensive three-device study

AIM:To evaluate the diagnostic ability of topographic and tomographic indices with Pentacam and Sirius as well as biomechanical parameters with Corvis ST for the detection of clinical and subclinical forms of keratoconus(KCN).METHODS:In this prospective diagnostic test study,70 patients with clinical KCN,79 patients with abnormal findings in topography and tomography maps with no evidence on clinical examination(subclinical KCN),and 68 normal control subjects were enrolled.The accuracy of topographic,tomographic,and biomechanical parameters was evaluated using the area under the receiver operating characteristic curve(AUC)and cross-validation analysis.The Delong method was used for comparing AUCs.RESULTS:In distinguishing KCN from normal,all parameters showed statistically significant differences between the two groups(P<0.001).Indices with the perfect diagnostic ability(AUC≥0.999)were Sirius KCN vertex of back(KVb),Pentacam random forest index(PRFI),Pentacam index of height decentration(IHD),and Corvis integrated tomographic/biomechanical index(TBI).In distinguishing subclinical KCN from normal,Sirius symmetry index of back(SIb;AUC=0.908),Pentacam inferior-superior difference(IS)value(AUC=0.862),PRFI(AUC=0.847),and Corvis TBI(AUC=0.820)performed best.There were no significant differences between the highest AUCs within keratoconic groups(De Long,P>0.05).CONCLUSION:In clinical KCN,all topographic,tomographic,and biomechanical indices have acceptable outcomes in terms of sensitivity and specificity.However,in differentiating subclinical forms of KCN from normal corneas,curvature-based parameters(SIb and IS value)followed by integrated indices(PRFI and TBI)are the most powerful tools for early detection of KCN.