Reward processing in trichotillomania and skin picking disorder

Brain Imaging and Behavior - Trichotillomania (hair pulling disorder) and skin picking disorder are common and often debilitating mental health conditions, grouped under the umbrella term of body...     

New 6-bromoimidazo[1,2-a]pyridine-2-carbohydrazide derivatives: synthesis and anticonvulsant studies

In the present work, we report the facile synthesis and anticonvulsant study of new imidazo[1,2-a]pyridines carrying biologically active hydrazone functionality (3a–3e) and suitably substituted 1,2,4-triazole moieties (4, 5a–5d, 6, and 7a–7d). The newly synthesized intermediates and final compounds were characterized by various spectral techniques such as FTIR, ¹H NMR, ¹³C NMR, and mass spectral and elemental analysis studies. The in vivo anticonvulsant study of the target compounds were carried out following maximal electroshock seizure and subcutaneous pentylene tetrazole methods, while their toxicity study was performed following rotarod method by taking 20, 40, and 100 mg/kg dose levels. Most of the new compounds displayed remarkable anticonvulsant properties at these doses. Particularly, compounds 3b and 4 carrying hydrogen bond donor groups, viz. hydroxyl and amine moieties respectively, exhibited complete protection against seizure and their results are comparable to that of standard drug diazepam. Further, the motor impairment study revealed that all the compounds are nontoxic upto 100 mg/kg.     

Treatment of Lesch–Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians,including a girl

Background: Lesch–Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment. Aim: For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy. Results: Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy. Discussion: Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies.     

HDL in Children with CKD Promotes Endothelial Dysfunction and an Abnormal Vascular Phenotype

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2–5 (HDL^CKD), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL^CKD strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.Patients with CKD no longer die from renal failure but from cardiovascular disease. There is an independent, graded association between a reduced eGFR and the risk of death and cardiovascular events.¹ Typically, patients with CKD develop calcification in the tunica media of their arteries,² but a concomitant process of endothelial damage leading to atherosclerosis is also³ present beginning in predialysis CKD.^4,5LDL is crucially involved in the pathogenesis of atherosclerotic cardiovascular disease in the general population,⁶ whereas HDL is thought to be antiatherogenic by promoting reverse cholesterol transport and exerting direct protective endothelial effects.⁷ HDL from healthy participants increases the bioavailability of nitric oxide (NO) by activating endothelial NO synthase inducing vasodilation and decreasing arterial BP. Moreover, HDL diminishes the production of reactive oxygen species such as superoxide (SO) radicals, which have been demonstrated to reduce NO bioavailability leading to endothelial dysfunction and promoting atherogenesis. However, recent evidence suggests that HDL may lose its vasoprotective properties in patients with manifest cardiovascular disease (e.g., coronary artery disease), diabetes, or inflammatory disease states (e.g., antiphospholipid syndrome).^8–10 Similarly, in adults on dialysis, HDL has reduced cholesterol efflux capacity and proinflammatory effects on mononuclear cells.^11–13 Observational studies have shown a strong association between high HDL levels and reduced risk of cardiovascular disease in the general population¹⁴ but not in dialysis patients.¹⁵Cardiac and vascular damage has also been documented in children on dialysis,^2,16,17 and cardiovascular disease accounts for the majority of deaths in pediatric dialysis patients.¹⁷ In contrast with adult patients with CKD, in whom cardiovascular risk factors such as diabetes dyslipidemia, hypertension, and smoking are highly prevalent,¹⁸ CKD in children is mainly caused by inherited disorders such as malformations of the kidney or urinary tract.¹⁸ Accordingly, examining HDL function in children who are free of “traditional” cardiovascular risk factors and underlying inflammatory diseases and who are nonsmokers gives us an unique opportunity to study the effects of renal failure on the vascular functions of HDL.We studied the endothelial properties of HDL in a cohort of children at different stages of CKD on dialysis and after transplantation and compared them with healthy children. Furthermore, to determine the clinical relevance of in vitro effects of HDL, we examined its relationship with clinical measures of the vascular phenotype as well as circulating markers of endothelial dysfunction. Finally, to show a causal link between renal function and HDL properties, we examined children on dialysis and 3 months after kidney transplantation. This study allowed us to examine when HDL dysfunction develops during the natural history of renal decline, its effects on vascular function, and the potential for recovery after kidney transplantation.     

Potent Irreversible Inhibitors of LasR Quorum Sensing in Pseudomonas aeruginosa

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Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.Malaria is a global health problem with 214 million new cases of malaria and 438,000 deaths reported in 2015, mostly in sub-Saharan Africa (1). The endoperoxide class of antimalarial drugs, such as artemisinin (ART), is the first line of defense against malaria infection against a backdrop of multidrug-resistant parasites (2) and lack of effective vaccines (3, 4). Given the effectiveness of the ART class, the question arises: how do these drugs kill parasites? A suggested mechanism of action involves the cleavage of the endoperoxide bridge by a source of Fe²⁺ or heme. This cleavage results in the formation of oxyradicals that rearrange into primary or secondary carbon-centered radicals. These radicals have been proposed to alkylate parasite proteins that somehow result in the death of the parasite (5). However, this proposal remains a subject of intense debate (6, 7), while these alkylated proteins are yet to be formally identified. So far, the proposed targets of ART action include a PfATP6 enzyme, the Plasmodium falciparum ortholog of mammalian sarcoendoplasmic reticulum Ca²¹-ATPases (SERCAs) (5), translational controlled tumor protein, and heme (5). Additionally, Haynes et al. (8) proposed that ART may act by impairing parasite redox homeostasis as a consequence of an interaction between the drug and flavin adenine dinucleotide (FADH) and/or other parasite flavoenzymes in the parasite, leading to the generation of reactive oxygen species (ROS). New approaches are required for definitive identification of ART molecular targets. This insight into the drug activation-dependent mechanism of action will be invaluable in the target-led development of more potent drugs with the potential to circumvent the emergence of resistance to current first-line ART-based therapies. The goal of this study was to identify ART-targeted proteins and their interacting partners in P. falciparum. We recently adopted a proteomic approach developed by Speers and Cravatt (9) to synthesize a suite of pyrethroid activity-based protein profiling probes (ABPPs) (10). Using alkyne/azide-coupling partners through “click chemistry,” we identified several cytochrome P450 enzymes that metabolized deltamethrin in rat liver microsomes (10). More recently, a chemical proteomic approach was developed to identify parasite proteins targeted by an albitiazolium antimalarial drug candidate in situ using a photoactivation cross-linking approach (11). However, this generic approach can introduce significant promiscuity in the proteins tagged based on the intracompartmental distribution of drug independent of actual mechanisms.Here, we introduced the design and synthesis of click chemistry-compatible activity-based probes incorporating the endoperoxide scaffold of ART as a warhead to alkylate and identified the ART molecular target(s) in asexual stages of the malaria parasite (Fig. 1). A major advantage of this strategy is that the reporter tags are introduced under “click” reaction conditions performed after the drug has achieved its biological effects, enabling purification, identification, and quantification of alkylated parasite’s proteins and their interacting partners as shown in Fig. 1B. To avoid nonspecific probe-dependent tagging, a common limitation of these approaches, we generated the respective “control” nonperoxide partners to improve the specificity and biological relevance of our resultant tagged protein list.Open in a separate windowFig. 1.Rational design of the ART-ABPPs. (A) Conversion of ART to ART-ABPPs involves the addition of a clickable handle (i.e., an alkyne or azide to the ART drug pharmacophore by the peptide-coupling method illustrated in SI Text). The structures of the alkyne (P1) and azide (P2) probes and respective inactive deoxy controls CP1 and CP2 with in vitro IC₅₀ values are presented. (B) General workflow of copper-catalyzed and copper-free click chemistry approaches used in the identification of alkylated proteins after in situ treatment of P. falciparum parasite with alkyne and azide ART-ABPPs. The azide- and alkyne-modified proteins are tagged with biotin azide and biotin dibenzocyclooctyne (Biotin-DIBO), respectively, via click reactions followed by affinity purification tandem with LC-MS/MS for protein identification.     

Evaluating Direct Medical Expenditures Estimation Methods of Adults Using the Medical Expenditure Panel Survey: An Example Focusing on Head and Neck Cancer

ObjectiveTo inform policymakers of the importance of evaluating various methods for estimating the direct medical expenditures for a low-incidence condition, head and neck cancer (HNC).MethodsFour methods of estimation have been identified: 1) summing all health care expenditures, 2) estimating disease-specific expenditures consistent with an attribution approach, 3) estimating disease-specific expenditures by matching, and 4) estimating disease-specific expenditures by using a regression-based approach. A literature review of studies (2005–2012) that used the Medical Expenditure Panel Survey (MEPS) was undertaken to establish the most popular expenditure estimation methods. These methods were then applied to a sample of 120 respondents with HNC, derived from pooled data (2003-2008).ResultsThe literature review shows that varying expenditure estimation methods have been used with MEPS but no study compared and contrasted all four methods. Our estimates are reflective of the national treated prevalence of HNC. The upper-bound estimate of annual direct medical expenditures of adult respondents with HNC between 2003 and 2008 was $3.18 billion (in 2008 dollars). Comparable estimates arising from methods focusing on disease-specific and incremental expenditures were all lower in magnitude. Attribution yielded annual expenditures of $1.41 billion, matching method of $1.56 billion, and regression method of $1.09 billion.ConclusionsThis research demonstrates that variation exists across and within expenditure estimation methods applied to MEPS data. Despite concerns regarding aspects of reliability and consistency, reporting a combination of the four methods offers a degree of transparency and validity to estimating the likely range of annual direct medical expenditures of a condition.     

The regulation of maturation promoting factor during prophase I arrest and meiotic entry in mammalian oocytes

Mammalian oocytes arrest at prophase of meiosis I at around birth and they remain arrested at this stage until puberty when the preovulatory surge of luteinizing hormone (LH) causes ovulation. Prophase I arrest in the immature oocyte results from the maintenance of low activity of maturation promoting factor (MPF), which consists of a catalytic subunit (CDK1) and regulatory subunit (cyclin B1). Phosphorylation-mediated inactivation of CDK1 and constant degradation of cyclin B1 keep MPF activity low during prophase I arrest. LH-mediated signaling manipulates a vast array of molecules to activate CDK1. Active CDK1 not only phosphorylates different meiotic phosphoproteins during the resumption of meiosis but also inhibits their rapid dephosphorylation by inhibiting the activities of CDK1 antagonizing protein phosphatases (PPs). In this way, CDK1 both phosphorylates its substrates and protects them from being dephosphorylated. Accumulating evidence suggests thatthe net MPF activity that drives the resumption of meiosis in oocytes depends on the activation status of CDK1 antagonizing PPs. This review aims to provide a summary of the current understanding of the signaling pathways involved in regulating MPF activity during prophase I arrest and reentry into meiosis of mammalian oocytes.