Need for sustainable approaches in antileishmanial drug discovery

Leishmaniasis is a neglected parasitic disease for which the current antileishmania therapeutics are hampered by drug toxicity, high cost, need for parenteral administration, increasing treatment failure rates, and emergence of drug resistance. The R&D pipeline had run fairly dry for several years, but fortunately some new drug candidates are now under (pre)clinical development. Identification of novel drugs will nevertheless remain essential to adequately sustain and improve effective disease control in the future. In this review, a package of standard and accessible R&D approaches is discussed with expansion to some alternative strategies focusing on parasite–host and vector–host interactions.

     

A unique telomere DNA expansion phenotype in human retinal rod photoreceptors associated with aging and disease

We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non‐neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non‐telomerase‐mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra‐bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus‐positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human‐specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra‐bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus‐positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus‐positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus‐positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.     

Effect of Aryl Substituents and Fluorine Addition on the Optoelectronic Properties and Organic Solar Cell Performance of a High Efficiency Indacenodithienothiophene‐alt‐Quinoxaline π‐Conjugated Polymer

A series of donor‐acceptor (D‐A) π‐conjugated polymers, based on indacenodithienothiophene (IDTT) as an electron‐donating unit and quinoxaline as an electron‐deficient moiety, are synthesized via a Pd‐catalyzed Stille cross‐coupling polymerization. Molecular characteristics, photovoltaic parameters, and optoelectronic properties are examined through structural differences corresponding to thienyl versus phenyl side group substitutions on the IDTT and the non‐fluorinated versus the monofluoro quinoxaline derivatives. One of the most important outcome is that the power conversion efficiency (PCE) in the studied polymers is more device architecture dependent (conventional vs inverted) rather than chemical structure dependent. From single junction solar cells based on bulk heterojunction polymer:[6,6]‐phenyl‐C₇₁‐butyric acid methyl ester (PC₇₁BM) systems as the active layer, a maximum PCE of 5.33% has been achieved from the polymer containing the thienyl substituent on the IDTT and one fluorine atom on the quinoxaline. This demonstrates that finding the optimum molecular weight of ThIDTT‐QF or introducing the monofluoro‐quinoxaline in a regioregular motif in the polymer backbone significantly higher PCE can be expected versus the fully optimized high performance PhIDTT‐Q conjugated polymer.     

Effects of of habitats and pesticides on aerobic capacity and survival of soil fauna

Faunal health is largely dependent on their soil environment and available litter quality. So the effects of different soil habitats and pesticides on citrate synthase (CS) activity of soil fauna and its population were studied. Methods The soil animals were collected from different pedoecosystems for habitat study. Whereas Vigna radiata based system was selected for pesticidal observations. The field was divided into five equal plots for control and treatment of γ-BHC, quinalphos, carbaryl and cypermethrin. Soil fauna was collected by quadrat method and extracted by Tullgren funnel. Individuals of a species having similar sizes were collected for the estimation of CS activity. They were homogenized and fractions were obtained by differential centrifugation. The activity of CS was assayed spectrophotometrically. Results Citrate synthase (CS) activity of beetle (Rasphytus fregi), woodlouse (PorceUio laevis) and centipede (Scolopendra morsitans) varied significantly with respect to changes in different soil habitats. Though the CS activity of R. fregi, P. laevis, and S. morsitans differed among themselves but the highest activity of CS in these animals was in V. radiata and lowest in A. nilotica based pedoecosystem. The aerobic capacity of centipede was maximum followed by woodlouse and beetle. The treatment of γ-BHC, quinalphos, carbaryl and cypermethrin significantly reduced the CS activity of these animals. γ-BHC showed maximum reduction in CS activity indicating highly toxic effect of organochlorine on aerobic metabolism of soil fauna. However, minimum reduction was obseryed in response to carbaryl (in beetle) or cypermethrin (in woodlouse/centipede) leading to impairment of aerobic capacity. The differences in pesticide effects might be assigned to the differences in chemical nature of pesticides and their interactions with below-ground fauna. Treatment ofγ-BHC and quinalphos reduced the population of Acari, Coleoptera, Collembola, other arthropods as well as total soil fauna. Acari was least affected by γ-BHC and maximally affected (72%) in response to quinalphos. The effect of γ-BHC was fairly similar on Coleoptera, Collembola, other arthropod and total soil fauna suggesting almost similar sensitivity to this pesticide. Likewise, quinalphos was similarly effective on Collemobola and other soil arthropods. Application of carbaryl decreased Acari and Coleoptera population but increased Collembola, other arthropods and total faunal populations. However, application of cypermethrin significantly reduced the population of Acari, Coleoptera, Collembola and total soil fauna and increased the population of other soil arthropods. In both the cases, acarine population was least affected. Conclusion The observations show the habitat-specific variation in aerobic capacity of soil fauna. However, pesticide-dependent loss in population might be due to impairment of aerobic capacity of soil inhabiting animals in desert.     

Advanced Electrocardiogram Analysis in the Amitriptyline‐poisoned Pig Treated with Activated Charcoal Haemoperfusion

Coated activated charcoal haemoperfusion (CAC‐HP) does not reduce the plasma concentration in amitriptyline (AT)‐poisoned pigs. The aim of this non‐blinded, randomized, controlled animal trial was to determine if CAC‐HP reduces the pathological ECG changes caused by AT poisoning. Fourteen female Danish Landrace pigs (mean weight 27.7 kg, range 20–35 kg (CAC‐HP) and 24.4 kg, range 18–30 kg (control group, CG), n = 7 in each group) were included. After randomization, the pigs were anaesthetized and intravenously poisoned with AT. The intervention group underwent 4 hr of CAC‐HP plus standard care (oral activated charcoal). Intervention was compared to standard care alone. From each pig, a 12‐lead ECG and haemodynamic variables were obtained at baseline, at full AT loading dose, before and during CAC‐HP. Baseline ECG variables (RR, PR, QRS, QTc, QTp, QTe, TpTe and TpTe/QT) for lead II, v2 and v5 were not significantly different (F = 0.035–0.297, p‐values 0.421–0.919). Differences within groups over time and between groups were tested by anova repeated measures. For all variables, the time‐plus‐group level of significance revealed a p‐value > 0.05. Severe cardiovascular arrhythmias occurred in both groups with 3 in the CAC‐HP group versus 1 incident with premature death in the CG. The attenuating effect of CAC‐HP to orally instilled activated charcoal alone on AT‐induced ECG alterations did not differ significantly. We conclude that the use of modern CAC‐HP as an adjunctive treatment modality in AT‐poisoned pigs is inadequate.     

Moral dilemmas of community pharmacists: a narrative study

International Journal of Clinical Pharmacy - Background Pharmacists are increasingly involved in patient care. This new role in a complex healthcare system with demanding patients may lead to moral...     

Content of First Prenatal Visits

Objective The purpose of this study was to examine the content of the first prenatal visit within an academic medical center clinic and to compare the topics discussed to 2014 American College of Obstetrics and Gynecologists guidelines for the initial prenatal visit. Methods Clinical interactions were audio recorded and transcribed (n?=?30). A content analysis was used to identify topics discussed during the initial prenatal visit. Topics discussed were then compared to the 2014 ACOG guidelines for adherence. Coded data was queried though the qualitative software and reviewed for accuracy and content. Results First prenatal visits included a physician, nurse practitioner, nurse midwife, medical assistant, medical students, or a combination of these providers. In general, topics that were covered in most visits and closely adhered to ACOG guidelines included vitamin supplementation, laboratory testing, flu vaccinations, and cervical cancer screening. Topics discussed less often included many components of the physical examination, education about pregnancy, and screening for an identification of psychosocial risk. Least number of topics covered included prenatal screening. Conclusions for Practice While the ACOG guidelines may include many components that are traditional in addition to those based on evidence, the guidelines were not closely followed in this study. Identifying new ways to disseminate information during the time constrained initial prenatal visit are needed to ensure improved patient outcomes.     

Assessing Lung Cancer Screening Programs under Uncertainty in a Heterogeneous Population

Background

Lung cancer screening can reduce cancer mortality. Most implementation studies focus only on low-dose computed tomography (LDCT) and clinical attributes of screening and do not include preferences of potential participants. In this study we evaluated the perceived value of screening programs based on LDCT, breath analysis (BA), or blood biomarkers (BB) according to the perspective of the target population.