In vivo light scattering measurements for detection of precancerous conditions of the cervix

OBJECTIVE: To examine the utility of in vivo elastic light scattering measurements to diagnose high grade squamous interepithelial lesions (HSIL) of the cervix. METHODS: A newly developed fiber optic probe was used to measure light transport in the cervical epithelium of 36 patients undergoing standard colposcopy. Both unpolarized and polarized light transport were measured in the visible and near-infrared. Spectroscopic results of 29 patients were compared with histopathology of the measured sites using ROC curves, MANOVA and logistic regression. RESULTS: Three spectroscopic parameters are statistically different for HSIL compared with low-grade lesions and normal tissue. When these three spectroscopic parameters are combined, retrospective sensitivities and specificities for HSIL versus non-HSIL are 100% and 80%, respectively. CONCLUSIONS: Reflectance measurements of elastically scattered light show promise as a non-invasive, real-time method to discriminate HSIL from other abnormalities and normal tissue. These results compare favorably with those obtained by fluorescence alone and by fluorescence combined with light scattering.     

Evaluating the Impact of Overactive Bladder on Sexual Health in Women: What Is Relevant?

IntroductionTo assess sexual health, relevant, valid, and reliable questionnaires need to be used.AimTo assess the relevance and content validity of three sexual health questionnaires in women with overactive bladder (OAB) and urinary incontinence.Main Outcome MeasuresSexual Quality of Life Questionnaire––Female (SQoL‐F), Sexual Function Questionnaire (SFQ), and Pelvic Organ Prolapse–Incontinence Sexual Function Questionnaire (PISQ).MethodsWomen with OAB and urinary incontinence were recruited from five urology clinics in the United States; those who were interested in participating were mailed questionnaire packets with instructions. Each questionnaire item was followed by three questions regarding the understandability, relevance, and impact of bladder condition when responding to the question. Patients returned the completed questionnaires by mail; clinical information was obtained from chart review.ResultsA total of 129 patients (74% response) returned the questionnaires. The mean age was 56 years; 78% were white; 64% were married. In this sample, 64% had urge incontinence; 32% had mixed incontinence; and 4% had stress incontinence. Participants experienced bladder symptoms for a mean of 12.2 years with the following treatments: surgery (43%), bladder training (26%), exercise/biofeedback (42%), and medications (67%). SQoL‐F items were understood by more than 97% of the respondents, more than 89% for SFQ, and more than 82% for PISQ. There were two SQoL‐F items, one SFQ item, and 11 PISQ items that less than 60% of the respondents deemed relevant to their bladder condition. Correlations among questionnaire items and relevance to bladder condition ranged from 0.04 to 0.64 for the SQoL‐F, 0.04 to 0.47 for the SFQ, and 0.01 to 0.58 for the PISQ.ConclusionWomen with OAB found the majority of items on all three questionnaires to be relevant to their bladder condition. Of these questionnaires, the SQoL‐F had the highest understandability, fewest questions considered irrelevant, and correlated well with OAB symptoms. Coyne KS, Margolis MK, Brewster‐Jordan J, Sutherland SE, Bavendam T, and Rogers RG. Evaluating the impact of overactive bladder on sexual health in women: What is relevant? J Sex Med 2007;4:124–136.     

A predictive microfluidic model of human glioblastoma to assess trafficking of blood–brain barrier-penetrant nanoparticles

The blood–brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood–brain-barrier vasculature. Here, we report a vascularized human glioblastoma multiforme (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood–brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood–brain-barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.

High-grade gliomas are the most common primary malignant brain tumors in adults (1). These include grade IV astrocytomas, commonly known as glioblastoma multiforme (GBM), which account for more than 50% of all primary brain cancers and have dismal prognoses, with a 5-y survival rate of less than 5% (2). Due to their infiltrative growth into the healthy brain tissue, surgery often fails to eradicate all tumor cells (3). While chemotherapy and radiation modestly improve median survival (4), most patients ultimately succumb to their tumors. This is primarily due to the presence of a highly selective and regulated endothelium between blood and brain parenchyma known as the blood–brain barrier (BBB) (5), which limits the entry of therapeutics into the brain tissue where tumors are located. The BBB, characterized by a unique cellular architecture of endothelial cells (ECs), pericytes (PCs), and astrocytes (ACs) (6, 7), displays up-regulated expression of junctional proteins and reduced paracellular and transcellular transports compared to other endothelia (8). While this barrier protects the brain from toxins and pathogens, it also severely restricts the transport of many therapeutics, as evidenced by the low cerebrospinal fluid (CSF)-to-plasma ratio of most chemotherapeutic agents (9). There is thus an important need to develop new delivery strategies to cross the BBB and target tumors, enabling sufficient drug exposure (10).Despite rigorous research efforts to develop effective therapies for high-grade gliomas, the majority of trialed therapeutics have failed to improve outcomes in the clinic, even though the agents in question are effective against tumor cells in preclinical models (11). This highlights the inability of current preclinical models to accurately predict the performance of therapeutics in human patients. To address these limitations, we developed an in vitro microfluidic model of vascularized GBM tumors embedded in a realistic human BBB vasculature. This BBB-GBM platform features brain microvascular networks (MVNs) in close contact with a GBM spheroid, recapitulating the infiltrative properties of gliomas observed in the clinic (12) and those of the brain tumor vasculature, with low permeability, small vessel diameter, and increased expression of relevant junctional and receptor proteins (7). This platform is well suited for quantifying vascular permeability of therapeutics and simultaneously investigating modes of transport across the BBB and into GBM tumor cells.There is strong rationale for developing therapeutic nanoparticles (NPs) for GBM and other brain tumors, as they can be used to deliver a diverse range of therapeutic agents and, with appropriate functionalization, can be designed to exploit active transport mechanisms across the BBB (13, 14). Liposomal NPs have been employed in the oncology clinic to improve drug half-life and decrease systemic toxicity (15), but, to date, no nanomedicines have been approved for therapeutic indications in brain tumors. We hypothesize that a realistic BBB-GBM model composed entirely of human cells can accelerate preclinical development of therapeutic NPs. Using our BBB-GBM model, we investigated the trafficking of layer-by-layer NPs (LbL-NPs) and ultimately designed a GBM-targeted NP. The LbL approach leverages electrostatic assembly to generate modular NP libraries with highly controlled architecture. We have used LbL-NPs to deliver a range of therapeutic cargos in preclinical tumor models (16, 17) and have recently demonstrated that liposomes functionalized with BBB-penetrating ligands improved drug delivery across the BBB to GBM tumors (18). Consistent with clinical data (19), we observed that the low-density lipoprotein receptor-related protein 1 (LRP1) was up-regulated in the vasculature near GBM spheroids in the BBB-GBM model and leveraged this information to design and iteratively test a library of NPs. We show that the incorporation of angiopep-2 (AP2) peptide moieties on the surface of LbL-NPs leads to increased BBB permeability near GBM tumors through LRP1-mediated transcytosis. With intravital imaging, we compared the vascular permeabilities of dextran and LbL-NPs in the BBB-GBM platform to those in mouse brain capillaries and validated the predictive potential of our in vitro model. Finally, we show the capability of the BBB-GBM platform to screen therapeutic NPs and predict in vivo efficacy, demonstrating improved efficacy of cisplatin (CDDP) when encapsulated in GBM-targeting LbL-NPs both in vitro and in vivo.     

Exploring how pregnant women in a remote northern community select a delivery location

ObjectiveTo explore the perspectives and preferences of pregnant women receiving prenatal care in a rural community regarding delivery location.DesignExploratory qualitative research project.SettingThe La Ronge Medical Clinic in northern Saskatchewan.ParticipantsPregnant women of any parity aged 18 years or older who attended the clinic for prenatal care from March 1, 2018, to March 31, 2019, were invited to participate. The closest obstetric and surgical services are 240 km away.MethodsThis project was undertaken using semistructured interviews. The interviews were audiorecorded, transcribed, and analyzed using an inductive thematic analysis, taking into consideration both saturation and analyst triangulation. The investigators and researchers on this project were family medicine residents and faculty in a remote medical clinic.Main findingsThe factors that played a substantial role in influencing the patients’ decisions regarding delivery location included access to medical services, proximity to home community, perceptions of medical care providers, and some unique features of local hospitals. The participants largely believed they maintained their autonomy in selecting their preferred delivery location while seeking input from their prenatal care providers and families.ConclusionPregnant women in this rural community consider many factors when deciding on their delivery location. These findings can be taken into consideration by physicians when discussing with their rural patients the risks and benefits of delivery in both rural and urban centres. Barriers to local delivery should be addressed, while maintaining a woman’s autonomy to choose where she gives birth.     

Wastewater irrigation and environmental health: implications for water governance and public policy

Climate change is a large-scale and emerging environmental risk. It challenges environmental health and the sustainability of global development. Wastewater irrigation can make a sterling contribution to reducing water demand, recycling nutrients, improving soil health and cutting the amount of pollutants discharged into the waterways. However, the resource must be carefully managed to protect the environment and public health. Actions promoting wastewater reuse are every where, yet the frameworks for the protection of human health and the environment are lacking in most developing countries. Global change drivers including climate change, population growth, urbanization, income growth, improvements in living standard, industrialization, and energy intensive lifestyle will all heighten water management challenges. Slowing productivity growth, falling investment in irrigation, loss of biodiversity, risks to public health, environmental health issues such as soil salinity, land degradation, land cover change and water quality issues add an additional layer of complexity. Against this backdrop, the potential for wastewater irrigation and its benefits and risks are examined. These include crop productivity, aquaculture, soil health, groundwater quality, environmental health, public health, infrastructure constraints, social concerns and risks, property values, social equity, and poverty reduction. It is argued that, wastewater reuse and nutrient capture can contribute towards climate change adaptation and mitigation. Benefits such as avoided freshwater pumping and energy savings, fertilizer savings, phosphorous capture and prevention of mineral fertilizer extraction from mines can reduce carbon footprint and earn carbon credits. Wastewater reuse in agriculture reduces the water footprint of food production on the environment; it also entails activities such as higher crop yields and changes in cropping patterns, which also reduce carbon footprint. However, there is a need to better integrate water reuse into core water governance frameworks in order to effectively address the challenges and harness the potential of this vital resource for environmental health protection. The paper also presents a blueprint for future water governance and public policies for the protection of environmental health.     

Transmission of Streptococcus equi Subspecies zooepidemicus Infection from Horses to Humans

Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) is a zoonotic pathogen for persons in contact with horses. In horses, S. zooepidemicus is an opportunistic pathogen, but human infections associated with S. zooepidemicus are often severe. Within 6 months in 2011, 3 unrelated cases of severe, disseminated S. zooepidemicus infection occurred in men working with horses in eastern Finland. To clarify the pathogen’s epidemiology, we describe the clinical features of the infection in 3 patients and compare the S. zooepidemicus isolates from the human cases with S. zooepidemicus isolates from horses. The isolates were analyzed by using pulsed-field gel electrophoresis, multilocus sequence typing, and sequencing of the szP gene. Molecular typing methods showed that human and equine isolates were identical or closely related. These results emphasize that S. zooepidemicus transmitted from horses can lead to severe infections in humans. As leisure and professional equine sports continue to grow, this infection should be recognized as an emerging zoonosis.     

Endocrine Active Compounds: From Biology to Dose Response Assessment

Histone deacetylase (HDAC) inhibitors target key steps of tumor development: They inhibit proliferation, induce differentiation and/or apoptosis, and exhibit potent antimetastatic and antiangiogenic properties in transformed cells in vitro and in vivo. Preliminary studies in animal models have revealed a relatively high tumor selectivity of HDAC inhibitors, strenghtening their promising potential in cancer chemotherapy. Until now, preclinical in vitro research has almost exclusively been performed in cancer cell lines and oncogene-transformed cells. However, as cell proliferation and apoptosis are essential for normal tissue and organ homeostasis, it is important to investigate how HDAC inhibitors influence the regulation of and interplay between proliferation, differentiation, and apoptosis in primary cells as well. This review highlights the discrepancies in molecular events triggered by trichostatin A, the reference compound of hydroxamic acid-containing HDAC inhibitors, in hepatoma cells and primary hepatocytes (which are key targets for drug-induced toxicity). The implications of these differential outcomes in both cell types are discussed with respect to both toxicology and drug development. In view of the future use of HDAC inhibitors as cytostatic drugs, it is highly recommended to include both tumor cells and their healthy counterparts in preclinical developmental studies. Screening the toxicological properties of compounds early in their development process, using a battery of different cell types, will enable researchers to discard those compounds bearing undesirable adverse activity before entering into expensive clinical trials. This will not only reduce the risk for harmful exposure of patients but also save time and money.     

Primary hepatocyte cultures as in vitro tools for toxicity testing: quo vadis?

Cultures of primary hepatocytes are versatile tools that can serve many in vitro toxicity testing purposes. However, they cope with dedifferentiation, a process that is already initiated during the hepatocyte isolation procedure and that is manifested as the progressive loss of functionality upon subsequent cultivation. A number of strategies to prevent dedifferentiation have been introduced over the last decades, all which aim at re-establishing the in vivo hepatocyte micro-environment in vitro, but that are of merely limited success. Recent mechanistic insight into the mechanisms that underlie hepatocyte dedifferentiation has opened new avenues for the development of novel approaches that target the actual causes of this deteriorative process and thus for the generation of a long-term hepatic in vitro tool. Such experimental system is urgently needed, especially in the light of the stringent European legislative modifications that are currently encountered by the pharmaceutical, chemical and, particularly, the cosmetic industry.     

Does Tweeting Improve Citations? One-Year Results From the TSSMN Prospective Randomized Trial

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