Painful Subjects, Desiring Relief: Experiencing and Governing Pain in a Medical Cannabis Program.

Cannabis can provide patients benefits for pain and symptom management, improve their functionality, and enhance their well-being. Yet restrictive medical cannabis programs can limit these potential benefits. This article draws on four years of research into Minnesota's medical cannabis program-one of the most restrictive in the United States-including in-depth interviews with patients and a survey of health care professionals.

Flp/-mediated disruption of and in sporozoites inhibits liver-stage development.

causes severe malaria and assembles a protein translocon (PTEX) complex at the parasitophorous vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins are exported to facilitate growth. The preceding liver stage of infection involves growth in a hepatocyte-derived PVM; however, the importance of protein export during liver infection remains unexplored. Here, we use the FlpL/ system to conditionally excise genes in sporozoites for functional liver-stage studies.

Mass Spectrometry Identification of Biomarkers in Extracellular Vesicles From Plasmodium vivax Liver Hypnozoite Infections.

Latent liver stages termed hypnozoites cause relapsing Plasmodium vivax malaria infection and represent a major obstacle in the goal of malaria elimination. Hypnozoites are clinically undetectable, and presently, there are no biomarkers of this persistent parasite reservoir in the human liver. Here, we have identified parasite and human proteins associated with extracellular vesicles (EVs) secreted from in vivo infections exclusively containing hypnozoites.

Medicalising the menace? The symbiotic convergence of medicine and law enforcement in the medicalisation of marijuana in Minnesota.

The medicalisation of marijuana has occurred rapidly, albeit nonuniformly, across the US and around the world over the past 3 decades. This paper centres on the medicalisation of marijuana in Minnesota-which has one of the most restrictive programs in the country-as a case for evaluating the negotiation of institutional boundaries with the shift from criminalisation to medicalisation after nearly a century of criminal prohibition. Drawing upon Foucauldian discourse analyses of the medical and law enforcement associations' position statements and legislative hearings that shaped medical marijuana policy in Minnesota, this paper demonstrates a symbiotic convergence between medicine and law enforcement through the deployment of shared discursive strategies in their opposition to medical marijuana that reinforce marijuana's criminalised status by solidifying the boundaries between proper medicine and dangerous drugs.

Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission.

Tryptophan C-mannosylation stabilizes proteins bearing a thrombospondin repeat (TSR) domain in metazoans. Here we show that Plasmodium falciparum expresses a DPY19 tryptophan C-mannosyltransferase in the endoplasmic reticulum and that DPY19-deficiency abolishes C-glycosylation, destabilizes members of the TRAP adhesin family and inhibits transmission to mosquitoes. Imaging P.

Epitope-coated polymer particles elicit neutralising antibodies against Plasmodium falciparum sporozoites.

The current Malaria RTS,S vaccine is based on virus-like particles (VLPs) comprising the NANP repetitive epitopes from the cicumsporozoite protein (CSP) of Plasmodium falciparum. This vaccine has limited efficacy, only preventing severe disease in about 30% of vaccinated individuals. A more efficacious vaccine is urgently needed to combat malaria.

Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity.

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class.

Platelet derived growth factor receptor β (PDGFRβ) is a host receptor for the human malaria parasite adhesin TRAP.

Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. The thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein that is released from secretory organelles and relocalized on the sporozoite plasma membrane. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors.

Targeting the Extrinsic Pathway of Hepatocyte Apoptosis Promotes Clearance of Plasmodium Liver Infection.

Plasmodium sporozoites infect the liver and develop into exoerythrocytic merozoites that initiate blood-stage disease. The hepatocyte molecular pathways that permit or abrogate parasite replication and merozoite formation have not been thoroughly explored, and a deeper understanding may identify therapeutic strategies to mitigate malaria. Cellular inhibitor of apoptosis (cIAP) proteins regulate cell survival and are co-opted by intracellular pathogens to support development.

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle.

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets.

The Micronemal Proteins P36 and P52 Act in Concert to Establish the Replication-Permissive Compartment Within Infected Hepatocytes.

Within the liver, sporozoites traverse cells searching for a "suitable" hepatocyte, invading these cells through a process that results in the formation of a parasitophorous vacuole (PV), within which the parasite undergoes intracellular replication as a liver stage. It was previously established that two members of the s48/45 protein family, P36 and P52, are essential for productive invasion of host hepatocytes by sporozoites as their simultaneous deletion results in growth-arrested parasites that lack a PV. Recent studies point toward a pathway of entry possibly involving the interaction of P36 with hepatocyte receptors EphA2, CD81, and SR-B1.

A recombinant antibody against Plasmodium vivax UIS4 for distinguishing replicating from dormant liver stages.

Background: Plasmodium vivax is the most geographically widespread of the human malaria parasites, causing 50,000 to 100,000 deaths annually. Plasmodium vivax parasites have the unique feature of forming dormant liver stages (hypnozoites) that can reactivate weeks or months after a parasite-infected mosquito bite, leading to new symptomatic blood stage infections. Efforts to eliminate P.

Immunization of Malaria-Preexposed Volunteers With PfSPZ Vaccine Elicits Long-Lived IgM Invasion-Inhibitory and Complement-Fixing Antibodies.

Background: The assessment of antibody responses after immunization with radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (Sanaria PfSPZ Vaccine) has focused on IgG isotype antibodies. Here, we aimed to investigate if P. falciparum sporozoite binding and invasion-inhibitory IgM antibodies are induced following immunization of malaria-preexposed volunteers with PfSPZ Vaccine.

Humoral protection against mosquito bite-transmitted infection in humanized mice.

A malaria vaccine that prevents infection will be an important new tool in continued efforts of malaria elimination, and such vaccines are under intense development for the major human malaria parasite (). Antibodies elicited by vaccines can block the initial phases of parasite infection when sporozoites are deposited into the skin by mosquito bite and then target the liver for further development. However, there are currently no standardized in vivo preclinical models that can measure the inhibitory activity of antibody specificities against sporozoite infection via mosquito bite.

Plasmodium yoelii S4/CelTOS is important for sporozoite gliding motility and cell traversal.

Gliding motility and cell traversal by the Plasmodium ookinete and sporozoite invasive stages allow penetration of cellular barriers to establish infection of the mosquito vector and mammalian host, respectively. Motility and traversal are not observed in red cell infectious merozoites, and we have previously classified genes that are expressed in sporozoites but not merozoites (S genes) in order to identify proteins involved in these processes. The S4 gene has been described as criticaly involved in Cell Traversal for Ookinetes and Sporozoites (CelTOS), yet knockout parasites (s4/celtos¯) do not generate robust salivary gland sporozoite numbers, precluding a thorough analysis of S4/CelTOS function during host infection.

Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects.

Immunization of humans with whole sporozoites confers complete, sterilizing immunity against malaria infection. However, achieving consistent safety while maintaining immunogenicity of whole parasite vaccines remains a formidable challenge. We generated a genetically attenuated Plasmodium falciparum (Pf) malaria parasite by deleting three genes expressed in the pre-erythrocytic stage (Pf p52/p36/sap1).

An Opsonic Phagocytosis Assay for Plasmodium falciparum Sporozoites.

Plasmodium falciparum malaria remains the deadliest parasitic disease worldwide. Vaccines targeting the preerythrocytic sporozoite and liver stages have the potential to entirely prevent blood-stage infection and disease, as well as onward transmission. Sporozoite surface and secreted proteins are leading candidates for inclusion in a preerythrocytic stage-specific, antibody-based vaccine.

An expanding toolkit for preclinical pre-erythrocytic malaria vaccine development: bridging traditional mouse malaria models and human trials.

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission.

Increased apoptosis and secretion of tryptase by mast cells in infantile haemangioma treated with propranolol.

Propranolol is increasingly used to treat problematic infantile haemangioma (IH), although its molecular mechanisms remain unclear. A key feature of propranolol therapy is the decreased deposition of fibrofatty residuum compared with spontaneously involuting IH. This study investigated the molecular consequences of propranolol treatment for IH in vivo.

Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats.

Cannabis is the most widely used illicit drug, and disruption of learning and memory are commonly reported consequences of cannabis use. We have previously demonstrated a spatial learning impairment by ∆(9)-tetrahydrocannabinol (THC) in adolescent Sprague-Dawley rats (Steel et al., 2011).

Mast cells in infantile haemangioma possess a primitive myeloid phenotype.

Aims: Recent reports on infantile haemangioma (IH) have demonstrated a primitive population of interstitial cells expressing the embryonic transcription factor, Nanog, with decreasing abundance during involution. In this report we investigated the expression of Nanog on mast cells in all three phases of IH progression.

Methods: Paraffin-embedded sections of six proliferating, six involuting and six involuted IH lesions were used to investigate the expression of tryptase, Nanog, CD45, CD34 and GLUT-1 by immunostaining.

Verrucous hemangioma expresses primitive markers.

Background: Verrucous hemangioma (VH) presents clinically as a vascular malformation but has similar histopathologic features to infantile hemangioma. This study characterized the cell population within VH.

Material And Methods: Paraffin-embedded sections from two male patients with VH were processed for immunohistochemistry.

Infantile haemangioma expresses embryonic stem cell markers.

Background: The origin of infantile haemangioma (IH) remains enigmatic. A primitive mesodermal phenotype origin of IH with the ability to differentiate down erythropoietic and terminal mesenchymal lineages has recently been demonstrated.

Aims: To investigate the expression of human embryonic stem cell (hESC) markers in IH and to determine whether IH-derived cells have the functional capacity to form teratoma in vivo.