A painful journey to antivenom: The therapeutic itinerary of snakebite patients in the Brazilian Amazon (The QUALISnake Study)

Access to antivenoms is not guarranteed for vulnerable populations that inhabit remote areas in the Amazon. The study of therapeutic itineraries (TI) for treatment of snakebites would support strategies to provide timely access to users. A TI is the set of processes by which individuals adhere to certain forms of treatment, and includes the path traveled in the search for healthcare, and practices to solve their health problems. This study aims to describe TIs of snakebite patients in the Brazilian Amazon. This study was carried out at the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, in Manaus, state of Amazonas, Brazil. The itinerary from the moment of the bite to the patient’s admission to the reference unit was analyzed. Sample size was defined by saturation. After an exploratory survey to collect epidemiological variables, in-depth interviews were conducted following a semi-structured guide. Patients originated from rural areas of 11 different municipalities, including ones located >500 kilometers from Manaus. A great fragmentation was observed in the itineraries, marked by several changes of means of transport along the route. Four themes emerged from the analysis: exposure to snakebite during day-to-day activities, use of traditional therapeutic practices, and personal perception of the severity, as well as the route taken and its contingencies. Access to healthcare requires considerable effort on the part of snakebite patients. Major barriers were identified, such as the low number of hospitals that offer antivenom treatment, poor access to healthcare due to long distances and geographic barriers, low acceptability of healthcare offered in countryside, lack of use of personal protective equipment, common use of ineffective or deleterious self-care practices, late recognition of serious clinical signs and resistance to seeking medical assistance. Health education, promotion of immediate transport to health centers and decentralization of antivenom from reference hospitals to community healthcare centers in the Brazilian Amazon are more effective strategies that would to maximize access to antivenom treatment.     

Advances in hPSC expansion towards therapeutic entities: A review

For use in regenerative medicine, large‐scale manufacturing of human pluripotent stem cells (hPSCs) under current good manufacturing practice (cGMPs) is required. Much progress has been made since culturing under static two‐dimensional (2D) conditions on feeders, including feeder‐free cultures, conditioned and xeno‐free media, and three‐dimensional (3D) dynamic suspension expansion. With the advent of horizontal‐blade and vertical‐wheel bioreactors, scale‐out for large‐scale production of differentiated hPSCs became possible; control of aggregate size, shear stress, fluid hydrodynamics, batch‐feeding strategies, and other process parameters became a reality. Moving from substantially manipulated processes (i.e., 2D) to more automated ones allows easer compliance to current good manufacturing practices (cGMPs), and thus easier regulatory approval. Here, we review the current advances in the field of hPSC culturing, advantages, and challenges in bioreactor use, and regulatory areas of concern with respect to these advances. Manufacturing trends to reduce risk and streamline large‐scale manufacturing will bring about easier, faster regulatory approval for clinical applications.

Dynamic suspension culture systems in the form of bioreactors, unlike static ones, can overcome unfavourable environmental culture conditions, assisting hPSCs to remain pluripotent and undifferentiated, or promoting their differentiation and expansion to desired cell types. They reduce medium consumption and workload, have high scalability, and allow easy online sampling for quality control analysis or other needed testing. Depending on the type of bioreactor chosen, their use permit robust expansion of large‐scale hPSCs with high‐quality, relatively homogeneous cultures, and controlled production to meet manufacturing needs for clinical trials. Closed, single‐use, well‐monitored, minimally manipulated systems will easier meet regulatory standards in bringing hPSC therapies to the clinics.     

Honokiol: A review of its pharmacological potential and therapeutic insights

BackgroundHonokiol is a pleiotropic compound which been isolated from Magnolia species such as Magnolia grandiflora and Magnolia dealbata. Magnolia species Magnolia grandiflora is used in traditional medicine for the treatment of various diseases.PurposeThe objective of this review is to summarize the pharmacological potential and therapeutic insights of honokiol.Study designHonokiol has been specified as a novel alternative to treat various disorders such as liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties and others. Therefore, this study designed to represent the in-depth therapeutic potential of honokiol.MethodsLiterature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using the keywords ‘Honokiol’, ‘Health Benefits’ and ‘Therapeutic Insights’ as the keywords for primary searches and secondary search terms were used as follows: ‘Anticancer’, ‘Oxidative Stress’, ‘Neuroprotective’, ‘Antimicrobial’, ‘Cardioprotection’, ‘Hepatoprotective’, ‘Anti-inflammatory’, ‘Arthritis’, ‘Reproductive Disorders’.ResultsThis promising bioactive compound presented an wide range of therapeutic and biological activities which include liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties, and others. Its pharmacokinetics has been established in experimental animals, while in humans, this is still speculative. Some of its mechanism for exhibiting its pharmacological effects includes apoptosis of diseased cells, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6), amelioration of impaired hepatic enzymes and reversal of morphological alterations, among others.ConclusionAll these actions displayed by this novel compound could make it serve as a lead in the formulation of drugs with higher efficacy and negligible side effects utilized in the treatment of several human diseases.     

Plan evaluation indices: A journey of evolution

AimA systemic review and analysis of evolution journey of indices, such as conformity index (CI), homogeneity index (HI) and gradient index (GI), described in the literature.BackgroundModern radiotherapy techniques like VMAT, SRS and SBRT produce highly conformal plans and provide better critical structure and normal tissue sparing. These treatment techniques can generate a number of competitive plans for the same patients with different dose distributions. Therefore, indices like CI, HI and GI serve as complementary tools in addition to visual slice by slice isodose verification while plan evaluation. Reliability and accuracy of these indices have been tested in the past and found shortcomings and benefits when compared to one another.Material and methodsPotentially relevant studies published after 1993 were identified through a pubmed and web of science search using words “conformity index”, “Homogeneity index”, “Gradient index”,” Stereotactic radiosurgery”,” stereotactic Body radiotherapy” “complexity metrics” and “plan evaluation index”. Combinations of words “plan evaluation index conformity index” were also searched as were bibliographies of downloaded papers.Results and conclusionsMathematical definitions of plan evaluation indices modified with time. CI definitions presented by various authors tested at their own and could not be generalized. Those mathematical definitions of CI which take into account OAR sparing grant more confidence in plan evaluation. Gradient index emerged as a significant plan evaluation index in addition to CI whereas homogeneity index losing its credibility. Biological index base plan evaluation is becoming popular and may replace or alter the role of dosimetrical indices.     

Cancer stem cells: A review from origin to therapeutic implications

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are elucidated as cells that can perpetuate themselves via autorestoration. These cells are highly resistant to current therapeutic approaches and are the main reason for cancer recurrence. Radiotherapy has made a lot of contributions to cancer treatment. However, despite continuous achievements, therapy resistance and tumor recurrence are still prevalent in most patients. This resistance might be partly related to the existence of CSCs. In the present study, recent advances in the investigation of different biological properties of CSCs, such as their origin, markers, characteristics, and targeting have been reviewed. We have also focused our discussion on radioresistance and adaptive responses of CSCs and their related extrinsic and intrinsic influential factors. In summary, we suggest CSCs as the prime therapeutic target for cancer treatment.     

A journey into space

The fission yeast, Schizosaccharomyces pombe, has been used as a model eukaryote to study processes such as the cell cycle and cell morphology. In this single-celled organism, growing in a straight line and maintaining the nucleus in the centre of the cell depend on intracellular positional information. Microtubules and microtubular transport are important for generating positional information within the fission yeast cell, and these molecular mechanisms are also probably relevant for generating positional information in other eukaryotic cells.     

The therapeutic use of heroin: a review of the pharmacological literature

Heroin is currently being advocated by some as a superior therapeutic agent for use in terminal illness. However, a review of the literature on heroin presently available does not support this contention. Administered orally, heroin is approximately 1.5 times more potent than morphine in controlling chronic pain in terminal cancer patients. Its effects on mood and the incidence and nature of side effects do not differ from those of morphine except in males where poorer pain control probably accounts for the worse effect on mood. Given parenterally for acute pain, heroin is 2-4 times more potent than morphine and faster in onset of action. When the potency difference is accounted for, the pharmacological effects of heroin do not differ appreciably from those of morphine. Heroin is metabolized to 6-acetylmorphine and morphine. After oral administration of heroin, morphine but not heroin or 6-acetylmorphine is detected in blood. In this case, heroin is a prodrug for the delivery of systemic morphine. Following acute i.v. administration, heroin appears transiently in blood with a half-life of about 3 min. The half-life of heroin exposed to blood or serum in vitro is 9-22 min, indicating that organ metabolism is involved in blood clearance as well. Direct renal clearance of heroin is less than 1% of the administered dose. In animal studies, heroin and 6-acetylmorphine are both more potent and faster acting than morphine as analgesics, effects attributed to their greater lipid solubility and subsequent penetration of the blood-brain barrier. Given centrally, morphine is more potent than heroin and 6-acetylmorphine in producing analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistin: A journey from metabolism to cancer

Resistin, a small secretory molecule, has been implicated to play an important role in the development of insulin resistance under obese condition. For the past few decades, it has been linked to various cellular and metabolic functions. It has been associated with diseases like metabolic disorders, cardiovascular diseases and cancers. Numerous clinical studies have indicated an increased serum resistin level in pathological disorders which have been reported to increase mortality rate in comparison to low resistin expressing subjects. Various molecular studies suggest resistin plays a pivotal role in proliferation, metastasis, angiogenesis, inflammation as well as in regulating metabolism in cancer cells. Therefore, understanding the role of resistin and elucidating its’ associated molecular mechanism will give a better insight into the management of these disorders. In this article, we summarize the diverse roles of resistin in pathological disorders based on the available literature, clinicopathological data, and a compiled study from various databases. The article mainly provides comprehensive information of its role as a target in different treatment modalities in pre as well as post-clinical studies.     

The journey of squid sperm

Sperm storage is common in internally fertilizing animals, but is also present in several external fertilizers, such as many cephalopods. Cephalopod males attach sperm packets (spermatangia) to female conspecifics during mating. Females of eight externally fertilizing families comprising 25% of cephalopod biodiversity have sperm-storage organs (seminal receptacles) in their buccal area, which are not in direct physical contact with the deposited spermatangia. The mechanism of sperm transmission between the implantation site and the storage organ has remained a major mystery in cephalopod reproductive biology. Here, jumbo squid females covering almost the entire life cycle, from immature to a laboratory spawned female, were used to describe the internal structure of the seminal receptacles and the process of sperm storage. Seminal fluid was present between the spermatangia and seminal receptacles, but absent in regions devoid of seminal receptacles. The sperm cellular component was formed by spermatozoa and round cells. Although spermatozoa were tracked over the buccal membrane of the females to the inner chambers of the seminal receptacles, round cells were not found inside the seminal receptacles, suggesting that spermatozoa are not sucked up by the muscular action of the seminal receptacles. This finding supports the hypothesis that spermatozoa are able to actively migrate over the female skin. Although further experimental support is needed to fully confirm this hypothesis, our findings shed light on the elusive process of sperm storage in many cephalopods, a process that is fundamental for understanding sexual selection in the sea.     

Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors

Substituted benzimidazoles were profiled as inhibitors of kinesin spindle protein (KSP), an increasingly important target for the development of anticancer drugs. This series demonstrated the monoastral phenotypic response and was found to be active in both enzymatic and cellular-based assays.