Plumbagin, a vitamin K3 analogue ameliorate malaria pathogenesis by inhibiting oxidative stress and inflammation

Abstract

Plumbagin, a vitamin K3 analogue is the major active constituent in several plants including root of Plumbago indica Linn. This compound has been shown to exhibit a wide spectrum of pharmacological activities. The present investigation was to evaluate the ameliorative effects of plumbagin (PL) against severe malaria pathogenesis due to involvement of oxidative stress and inflammatory response in Plasmodium berghei infected malaria in mice. Malaria pathogenesis was induced by intra-peritoneal injection of P. berghei infected red blood cells into the Swiss albino mice. PL was administered orally at doses of 3, 10 and 30 mg/kg/day following Peter's 4 day suppression test. Oral administration of PL showed significant reduction of parasitaemia and increase in mean survival time. PL treatment is also attributed to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. Significant inhibition in level of oxidative stress and pro-inflammation related markers were observed in PL treated group. The trend of inhibition in oxidative stress markers level after oral treatment of PL was MPO > LPO > ROS in organ injury in P. berghei infected mice. This study showed that plumbagin is able to ameliorate malaria pathogenesis by augmenting anti-oxidative and anti-inflammatory mechanism apart from its effect on reducing parasitaemia and increasing mean survival time of malaria-induced mice.

Graphical Abstract

Java Tea ( Orthosiphon stamineus ) protected against osteoarthritis by mitigating inflammation and cartilage degradation: a preclinical study

Abstract

The effect of Orthosiphon stamineus aqueous (OSA) extract against osteoarthritis (OA) was investigated in explant cartilage culture and in postmenopausal OA rat model. Female rats were bilaterally ovariectomized (OVX). Osteoarthritis was induced after surgical recovery, by intra-articular injection of monosodium iodoacetate (MIA) into the right knee. Rats were grouped (n = 8) into: healthy sham control; non-treated OA; OA + diclofenac (positive control 5 mg/kg); and two doses OSA (150–300 mg/kg). After 4 weeks' treatment, rats were evaluated for OA-related parameters and biomarkers. The OSA reduced proteoglycan and ROS release from the cartilage explants under inflammatory (IL-1b) conditions. In the OA-induced rats' cartilages, the OSA downregulated the mRNA expressions for IL-1β, IL-6, IL-10, TNF-α, NF-κβ, NOS2, PTGS2, PTGER2, ACAN, COL2A1, MMP1, MMP13, ADAMTS4, ADAMTS5 and TIMP1, mostly dose-dependently. The OSA reduced the OA rats' serum levels for PGE₂, CTX-II, TNF-α, MMP1, MMP13, PIINP, OPG, RANKL, OC and BALP, but not dose-dependently. The OSA contained polyphenols and flavonoids (tetramethoxyflavone). The OSA alleviated articular cartilage degradation, inflammation, collagenase/aggrecanase activities, to improve joint and subchondral bone structure. O. stamineus mitigated osteoarthritis by downregulating inflammation, peptidases and aggrecanases, at a dose equivalent to about 30 mg/kg for humans.

Detectability of residual invasive bladder cancer in delayed 18 F-FDG PET imaging with oral hydration using 500 mL of water and voiding-refilling

Abstract

Objective

2-Fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG PET) imaging is not considered useful for assessing bladder cancer due to the physiological uptake of ¹⁸F-FDG in the bladder. Despite reports of the detection of bladder cancer by washing out ¹⁸F-FDG from the bladder, such methods are invasive and impractical in the routine practice. The purpose of this study was to evaluate prospectively the utility of oral hydration with 500 mL of water and voiding-refilling, a minimally invasive method that we introduced to enable detection of residual invasive bladder cancer on delayed ¹⁸F-FDG PET imaging.

Methods

From January 2015 to December 2017, 267 consecutive patients with bladder cancer underwent ¹⁸F-FDG PET/computed tomography scans. Among these patients, 25 (19 men and 6 women; mean age, 72.0 ± 11.3 years) were newly diagnosed as having muscle-invasive bladder cancer by transurethral resection of bladder tumor and T3b or T4 by magnetic resonance imaging (MRI). All patients were orally hydrated with only 500 mL of water and were then instructed to void frequently for 60 min before early ¹⁸F-FDG PET imaging. After the scans, they were instructed to hold their urine for 60 min. Then, delayed imaging was performed. Two radiologists evaluated the early and delayed ¹⁸F-FDG PET images to determine whether residual invasive bladder cancer could be detected. The maximum standardized uptake values (SUVmax) of the bladder urine and residual tumor site were also measured on early and delayed images. The maximum diameter of the primary bladder tumor was measured on MRI.

Results

The sensitivity for detecting residual invasive bladder cancer on early and delayed imaging were 24.0 and 92.0%, respectively (P < 0.001). The SUVmax of the bladder urine on the early and delayed imaging were 34.7 ± 29.7 and 16.0 ± 10.7 (mean ± SD), respectively. The SUVmax of the residual tumor site on the early and delayed imaging were range 15.65–30.83 and 10.06–45.70, respectively.

Conclusion

Delayed ¹⁸F-FDG PET imaging with oral hydration using only 500 mL of water and voiding-refilling is useful for detecting residual invasive bladder cancer.

Dekubitus erkennen und richtig klassifizieren: ein Positionspapier

Zusammenfassung

Hintergrund

Dekubitalulzera sind schwerwiegende Haut- und Gewebeschäden. Die korrekte Diagnose und Einteilung in verschiedene Kategorien gestaltet sich in der Praxis oft schwierig.

Fragestellung

Welches Vorgehen kann empfohlen werden, um Dekubitalulzera in der Praxis richtig zu diagnostizieren und zu klassifizieren?

Material und Methoden

Die Initiative Chronische Wunden (ICW) e. V. berief eine Expertengruppe ein, die, basierend auf der aktuellen Literatur und eigener Expertise, praktische Empfehlungen für die Diagnostik und Klassifikation von Dekubitalulzera entwickelte.

Ergebnisse

Die Diagnose Dekubitus soll nur dann gestellt werden, wenn Haut- und/oder Gewebeschäden mit hoher Wahrscheinlichkeit infolge von länger andauerndem Druck oder Druck in Verbindung mit Scherkräften entstanden sind. Es muss eine vollständige Anamnese durchgeführt werden, um Phasen von vorhergehender längerer Immobilität zu erfassen. Dekubitalulzera befinden sich in der Regel an typischen Prädilektionsstellen. Bei der Kategorie I und „vermuteter tiefer Gewebeschädigung" liegen Gewebeschäden unter (zunächst) intakter Haut vor. Die Diagnose ist jedoch unsicher, und die Klassifikation soll erst im weiteren Verlauf vorgenommen werden. Ein Kategorie-II-Dekubitus ist in der Regel eine Ausschlussdiagnose. Die Kategorien III und IV sind Dekubitalulzera im eigentlichen Sinn. Solange die Abgrenzung zwischen Kategorie III und IV nicht möglich ist, soll die niedrigere Kategorie kodiert werden.

Schlussfolgerungen

Derzeit soll passend für das jeweilige Setting einheitlich eine relevante Klassifikation verwendet werden. Die am besten dem klinischen Bild entsprechende Diagnose kann dann gestellt werden. Dabei ist es unerheblich, welches Klassifikationssystem verwendet wird. Mithilfe der zukünftig zu erwartenden Version des ICD-11 der WHO können Dekubitalulzera dann besser klassifiziert werden.

Postulational Rhetoric and Presumptive Tautologies: The Genre of the Pedagogical, Negativity, and the Political

Abstract

In the paper I analyze two features of the genre of the pedagogical. First is a particular usage of "should" statements (which I call postulational rhetoric) where one can identify an effect of erasing present normative behavior, while that which is postulated is turned into an unattainable ideal, or a value. Second, I analyze "presumptive tautologies" in the discourse of aims of education. I focus on negative dimensions of these two features and, using theoretical insights from Laclau and Rancière, I connect them to the work of negativity in political ontology so that the relation between the pedagogical and the political can thus be re-articulated.

Autonomous Driving and Perverse Incentives

Abstract

This paper discusses the ethical implications of perverse incentives with regard to autonomous driving. We define perverse incentives as a feature of an action, technology, or social policy that invites behavior which negates the primary goal of the actors initiating the action, introducing a certain technology, or implementing a social policy. As a special form of means-end-irrationality, perverse incentives are to be avoided from a prudential standpoint, as they prove to be directly self-defeating: They are not just a form of unintended side effect that must be balanced against the main goal or value to be realized by an action, technology, or policy. Instead, they directly cause the primary goals of the actors—i.e., the goals that they ultimately pursue with the action, technology, or policy—to be "worse achieved" (Parfit). In this paper, we elaborate on this definition and distinguish three ideal-typical phases of adverse incentives, where only in the last one the threshold for a perverse incentive is crossed. In addition, we discuss different possible relevant actors and their goals in implementing autonomous vehicles. We conclude that even if some actors do not pursue traffic safety as their primary goal, as part of a responsibility network they incur the responsibility to act on the common primary goal of the network, which we argue to be traffic safety.

Penile lymphoedema: approach to investigation and management

Clinical and Experimental Dermatology, EarlyView.

Corrigendum to ``Patient-rated long-term results after complete denervation of the wrist'' [Journal of Plastic, Reconstructive & Aesthetic Surgery Volume 71 Issue 1 (2018) 57–61]

The authors regret that after reevaluation of the paper we unfortunately found an obvious mistake concerning a missing author and the order of appearance. The author was added and a change in the order had to be corrected. The authors would like to apologise for any inconvenience caused.

Sun protection behaviour after diagnosis of high-risk primary melanoma and risk of a subsequent primary

Melanoma survivors are at high risk of further primary melanomas.

The Role of Sunscreen in the Prevention of Cutaneous Melanoma and Non-Melanoma Skin Cancer

Second Primary Melanomas: Increased Risk and Decreased Time to Presentation in Patients exposed to Tanning Beds

Melanoma incidence has increased; the primary modifiable risk factor is ultraviolet radiation (UVR) from the sun or artificial (arUVR) from tanning beds.

Polarized Secretion of Extracellular Vesicles by Mammary Epithelia

Abstract

Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia.

Histology and Transcriptome Profiles of the Mammary Gland across Critical Windows of Development in Sprague Dawley Rats

Abstract

Breast development occurs through well-defined stages representing 'windows of susceptibility' to adverse environmental exposures that potentially modify breast cancer risk. Systematic characterization of morphology and transcriptome during normal breast development lays the foundation of our understanding of cancer etiology. We examined mammary glands in female Sprague Dawley rats across six developmental stages – pre-pubertal, peri-pubertal, pubertal, lactation, adult parous and adult nulliparous. We investigated histology by Hematoxylin and Eosin and Mallory's Trichrome stain, proliferative and apoptotic rate by immunohistochemistry and whole-transcriptome by microarrays. We identified differentially expressed genes between adjacent developmental stages by linear models, underlying pathways by gene ontology analysis and gene networks and hubs active across developmental stages by coexpression network analysis. Mammary gland development was associated with large-scale changes in the transcriptome; particularly from pre-pubertal to peri-pubertal period and the lactation period were characterized by distinct patterns of gene expression with unique biological functions such as immune processes during pre-pubertal development and cholesterol biosynthesis during lactation. These changes were reflective of the shift in mammary gland histology, from a rudimentary organ during early stages to a secretory organ during lactation followed by regression with age. Hub genes within mammary gene networks included metabolic genes such as Pparg during the pre-pubertal stage and tight junction-related genes claudins and occludins in lactating mammary glands. Transcriptome profile paired with histology enhanced our understanding of mammary development, which is fundamental in understanding the etiologic mechanism of breast cancer, especially pertaining to windows of susceptibility to environmental exposures that may alter breast cancer risk.