Neutrophilic urticarial dermatosis as a presenting feature of systemic juvenile idiopathic arthritis

This report describes a case of chronic neutrophilic urticarial dermatosis as a presenting feature of systemic juvenile idiopathic arthritis. When encountered in children, neutrophilic urticarial dermatosis should raise suspicion of autoimmune or autoinflammatory disease.     

Food as Medicine for Secondary Prevention of Cardiovascular Events Following an Acute Coronary Syndrome

Cardiovascular disease is the leading cause of death in men and women in the USA. Once a patient experiences an acute coronary syndrome (ACS), they are at increased risk for hospital readmission within 30 days and 6 months after discharge and more importantly, they have worse survival. Hospital readmissions lead to poor clinical outcomes for the patient and also significantly increase healthcare costs due to repeat diagnostic evaluation, imaging, and coronary interventions. The goal after hospital discharge is to modify cardiovascular (CV) risk factors including hypertension, hyperlipidemia, and diabetes to prevent repeat coronary events; however, drug therapy is only one aspect. Several diets have been shown to decrease weight and reduce these risk factors over short durations; however, most people typically cannot sustain their diet and regain the weight. The Intelligent Quisine (IQ) diet is a prepared meal plan that was designed to meet the American Heart Association and American Diabetes Association nutritional guidelines and simplify the daily consumption of a nutritionally complete, calorie conscious meal. The IQ diet has been shown to significantly reduce blood pressure, cholesterol levels, glucose levels, and weight over a 10-week period. Additional studies have shown that patients are able to remain compliant on the diet for a year and maintain the reduction of their CV risk factors. If patients are consistent with a healthy calorie conscious and nutritionally complete diet modifying CV risk factors long term, then food could be as powerful in reducing CV events as evidence-based drug therapy. There is a need to begin conceptualizing food as medicine. To this end, it is time for a randomized control trial implementing the IQ diet versus current standard dietary recommendations in a large number of patients and measuring hard CV endpoints. Many readmissions can be avoided with proper patient education and support emphasizing lifestyle modifications such as eating healthy and smoking cessation on a foundation of optimal medical therapy.     

Aspirin and clopidogrel treatment impair nitric oxide biosynthesis by platelets

Aspirin and clopidogrel are used therapeutically for their anti-platelet effects. We examined the effects of aspirin and clopidogrel on basal and β-adrenoceptor (β-AR)-mediated platelet nitric oxide (NO) synthesis in healthy subjects and patients with coronary heart disease (CHD). Healthy subjects (n = 19) were randomized in a double-blind cross-over manner to receive aspirin or clopidogrel, each at 75 mg daily, for 14 days. Patients (n = 17) of similar age with CHD, taking aspirin, were randomized double-blind to either continue on aspirin 75 mg daily or to receive clopidogrel 75 mg daily for 14 days. NO synthase (NOS) activity was measured from l-[³H]arginine to l-[³H]citrulline conversion, and cGMP was determined by radioimmunoassay, in platelets basally and following incubation with isoproterenol or albuterol (each at 10⁻⁵ mol/L). In healthy subjects, aspirin did not affect basal NOS activity or cGMP in platelets, but suppressed the normal increase in both by isoproterenol and albuterol. Clopidogrel suppressed platelet NOS activity and cGMP both basally and in response to β-AR agonists. In platelets from CHD patients, clopidogrel suppressed basal and β-AR-stimulated NOS activity and cGMP as compared with aspirin. Platelet NOS activity and cGMP were lower in CHD subjects pre-randomization compared with healthy subjects both pre-randomization and post-aspirin. We conclude that chronic aspirin treatment suppresses β-AR-stimulated but not basal platelet NO synthesis, as previously described, whereas chronic clopidogrel treatment suppresses both, with resultant functional consequences. Moreover, CHD may itself be associated with decreased platelet NO biosynthesis.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.     

Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery

Purpose

The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

Methods

Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (K_p,uu,brain) and cell (K_p,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.

Results

Assessment of K_p,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. K_p,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.

Conclusions

With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.     

Structural and Binding Studies of SAP-1 Protein With Heparin

SAP-1 is a low molecular weight cysteine protease inhibitor (CPI) which belongs to type-2 cystatins family. SAP-1 protein purified from human seminal plasma (HuSP) has been shown to inhibit cysteine and serine proteases and exhibit interesting biological properties, including high temperature and pH stability. Heparin is a naturally occurring glycosaminoglycan (with varied chain length) which interacts with a number of proteins and regulates multiple steps in different biological processes. As an anticoagulant, heparin enhances inhibition of thrombin by the serpin antithrombin III. Therefore, we have employed surface plasmon resonance (SPR) to improve our understanding of the binding interaction between heparin and SAP-1 (protease inhibitor). SPR data suggest that SAP-1 binds to heparin with a significant affinity (K_D = 158 nm ). SPR solution competition studies using heparin oligosaccharides showed that the binding of SAP-1 to heparin is dependent on chain length. Large oligosaccharides show strong binding affinity for SAP-1. Further to get insight into the structural aspect of interactions between SAP-1 and heparin, we used modelled structure of the SAP-1 and docked with heparin and heparin-derived polysaccharides. The results suggest that a positively charged residue lysine plays important role in these interactions. Such information should improve our understanding of how heparin, present in the reproductive tract, regulates cystatins activity.     

Assessing Ethnic Traditional Knowledge,Biology and Chemistry of Lepidium didymum L., Lesser-Known Wild Plants of Western Himalaya

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Tribal communities have a long history of association living in close contact with nature as herdsmen, and...     

Synthesis of high surface area porous carbon from anaerobic digestate and it's electrochemical study as an electrode material for ultracapacitors

The remnants of the anaerobic digestion process, ‘the digestate,’ mainly consist of fibrous lignin and cellulose like molecules, as a significant carbon repository along with some other inorganic impurities. The present work demonstrates the potential use of anaerobically treated fruit and vegetable waste (FVW) as a source of porous carbon for supercapacitor electrode materials. This work suggests that the FVW digestate can inherit silicon (Si) and calcium (Ca) based inorganic impurities, which play an essential role as structure directing agents for digestate derived carbon. These contaminants act as hard templates during carbonization to create hierarchical pores and contribute to an enhancement in surface area. Different batches from an anaerobic biogas digester plant are converted to porous carbon and examined as a potential supercapacitor electrode material. A maximum capacitance of 235 F g⁻¹ is achieved from DDHPC-4kh carbon with a specific surface area of 2502 m² g⁻¹ at a current density of 1 A g⁻¹ in an acidic aqueous electrolyte. The results are significant in comparison to other bio-sourced precursors studied previously.

The remnants of the anaerobic digestion process, ‘the digestate,’ mainly consist of fibrous lignin and cellulose like molecules, as a significant carbon repository along with some other inorganic impurities.