Evaluation of pulmonary perfusion by SPECT imaging using an endothelial cell tracer in supine humans and dogs.

International audiencePulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the adrenomedullin receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with (99m)Tc-PulmoBind for SPECT imaging. Results were compared with (99m)Tc-PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. PulmoBind uptake in humans was 58 ± 1 % (mean ± SEM) of the injected dose. Dorsal activity was 18.1 ± 2.1 % greater than ventral, and caudal activity was 25.7 ± 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 ± 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 ± 2.5 %, caudal 34.1 ± 5.0 % and lateral 18.1 ± 2.0 %. The perfused pulmonary circulation of supine humans, assessed by an adrenomedullin receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. ClinicalTrial.gov, NCT01539889

Molecular imaging of the human pulmonary vascular endothelium using an adrenomedullin receptor ligand.

Presented at the Sixth Annual Scientific Workshops and Debates of the Pulmonary Vascular Institute, Istanbul, January 24, 2013. An abstract was published in Pulmonary Circulation 2013;3:706.International audienceThis phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N = 20) were included into escalating groups of 5 mCi (n = 5), 10 mCi (n = 5), or 15 mCi (n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension

Scrotal cancer: Incidence, survival and second primary tumours in the Netherlands since 1989

Background: Since the 1970s there have been few epidemiological studies of scrotal cancer. We report on the descriptive epidemiology of scrotal cancer in the Netherlands. Methods: Data on all scrotal cancer patients were obtained from the Netherlands Cancer Registry (NCR) in the period 1989-2006 and age-standardised incidence rates were calculated also according to histology and stage. Relative survival was calculated and multiple primary tumours were studied. Results: The overall incidence rate varied around 1.5 per 1 000 000 person-years, most frequently being squamous cell carcinoma (27%), basal cell carcinoma (19%) and Bowen's disease (15%). Overall 5-year relative survival was 82%, being 77% and 95% for patients with squamous and basal cell carcinoma, respectively. In all, 18% of the patients were diagnosed with a second primary tumour. Conclusion: The incidence rate of scrotal cancer did not decrease, although this was expected; affected patients might benefit from regular checkups for possible new cancers

Therapeutic recreation as a developing profession in South Africa

South Africa experiences socio-economic challenges with a high prevalence of poverty resulting in disability and non-communicable diseases affecting the health and welfare of communities. Health services are not always accessible or available to citizens, especially those of previously disadvantaged or rural communities. The South African National Plan for Development 2030 aims to address these inequality and health issues. One focus area of this plan is the inclusion of recreation, leisure and sport as an important service sector to improve the health and well-being of all individuals. Therapeutic recreation could play an important role in this regard. In South Africa, therapeutic recreation is in its developmental stages. This paper aims to provide the reader with an overview of therapeutic recreation in South Africa as a developing profession. An overview of the current status of the profession is discussed in terms of standard of practice and as it relates to health professions and recreation service providers, programmes with therapeutic value and training needs. The study concludes that there is still groundwork to be done, calling for interested parties to embark on an aggressive advocacy and strategic planning process to develop therapeutic recreation as a profession in South Africa.Scopu

Differential Phagocytosis of White versus Opaque Candida albicans by Drosophila and Mouse Phagocytes

The human fungal pathogen Candida albicans resides asymptomatically in the gut of most healthy people but causes serious invasive diseases in immunocompromised patients. Many C. albicans strains have the ability to stochastically switch between distinct white and opaque cell types, but it is not known with certainty what role this switching plays in the physiology of the organism. Here, we report a previously undescribed difference between white and opaque cells, namely their interaction with host phagocytic cells. We show that both Drosophila hemocyte-derived S2 cells and mouse macrophage-derived RAW264.7 cells preferentially phagocytose white cells over opaque cells. This difference is seen both in the overall percentage of cultured cells that phagocytose white versus opaque C. albicans and in the average number of C. albicans taken up by each phagocytic cell. We conclude that susceptibility to phagocytosis by cells of the innate immune system is an important distinction between white and opaque C. albicans, and propose that one role of switching from the prevalent white form into the rarer opaque form may be to allow C. albicans to escape phagocytosis

Impact of environmental and genetic factors on the scale shape of zebrafish, Danio rerio (Hamilton 1822): A geometric morphometric study

Intraspecific morphological variability may reflect either genetic divergence among groups of individuals or response of individuals to environmental circumstances within the frame of phenotypic plasticity. Several studies were able to discriminate wild fish populations based on their scale shape. Here we examine whether the variations in the scale shape in fish populations could be related to genetic or environmental factors, or to both of them. In the first experiment, two inbred lines of zebrafish Danio rerio (Hamilton 1822) reared under identical environmental conditions were compared. Secondly, to find out what effect environmental factors might have, offsprings were divided into two groups and reared on different diets for 12 weeks. Potential recovery of scales from an environmental effect was also assessed. Experimental groups could successfully be distinguished according to the shape of scales in both experiments, and the results showed that both genetic and environmental factors may notably influence scale shape. It was concluded that scale shape analysis might be used as an explanatory tool to detect potential variability of environmental influences impacting genetically homogeneous groups of fish. However, due to its sensitivity to environmental heterogeneity, the applicability of this technique in identifying intraspecific stock membership of fish could be limited

Potential Risk Factors for Cutaneous Squamous Cell Carcinoma include Oral Contraceptives: Results of a Nested Case-Control Study

Recently, a population-based case-control study observed a 60% increased odds ratio (OR) for cutaneous squamous cell carcinoma (SCC) among women who had ever used oral contraceptives (OCs) compared with non users (95% confidence interval (CI) = 1.0–2.5). To further characterize the putative association between OC use and SCC risk, we conducted a nested case-control study using a large retrospective cohort of 111,521 Kaiser Permanente Northern California members. Multivariable conditional logistic regression was used to estimate ORs and CIs adjusting for known and hypothesized SCC risk factors. Pre-diagnostic OC use was associated with a statistically significant increased OR for SCC in univariate analysis (OR = 2.4, CI = 1.2–4.8), with borderline statistical significance in multivariable analysis (CI = 2.0, CI = 0.91–4.5). Given the high incidence of SCC in the general population and the prevalent use of OCs among women in the United States, there is a need for more large, carefully designed epidemiologic studies to determine whether the observed association between OC use and SCC can be replicated and to better understand the etiologic basis of an association if one exists

Relationship between a Novel Polymorphism of the C5L2 Gene and Coronary Artery Disease

C5L2 has been demonstrated to be a functional receptor of acylation-stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. However, little is known about the variations in the coding region of the C5L2 gene and their association with coronary artery disease (CAD). = 0.047, OR = 2.602, 95% CI: 1.015–6.671).The 698CT genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China

Gymnemic acids inhibit hyphal growth and virulence in Candida albicans

Candida albicans is an opportunistic and polymorphic fungal pathogen that causes mucosal, disseminated and invasive infections in humans. Transition from the yeast form to the hyphal form is one of the key virulence factors in C. albicans contributing to macrophage evasion, tissue invasion and biofilm formation. Nontoxic small molecules that inhibit C. albicans yeast-to-hypha conversion and hyphal growth could represent a valuable source for understanding pathogenic fungal morphogenesis, identifying drug targets and serving as templates for the development of novel antifungal agents. Here, we have identified the triterpenoid saponin family of gymnemic acids (GAs) as inhibitor of C. albicans morphogenesis. GAs were isolated and purified from Gymnema sylvestre leaves, the Ayurvedic traditional medicinal plant used to treat diabetes. Purified GAs had no effect on the growth and viability of C. albicans yeast cells but inhibited its yeast-to-hypha conversion under several hypha-inducing conditions, including the presence of serum. Moreover, GAs promoted the conversion of C. albicans hyphae into yeast cells under hypha inducing conditions. They also inhibited conidial germination and hyphal growth of Aspergillus sp. Finally, GAs inhibited the formation of invasive hyphae from C. albicans-infected Caenorhabditis elegans worms and rescued them from killing by C. albicans. Hence, GAs could be useful for various antifungal applications due to their traditional use in herbal medicine

First Human Model of In Vitro Candida albicans Persistence within Granuloma for the Reliable Study of Host-Fungi Interactions

BACKGROUND: The balance between human innate immune system and Candida albicans virulence signaling mechanisms ultimately dictates the outcome of fungal invasiveness and its pathology. To better understand the pathophysiology and to identify fungal virulence-associated factors in the context of persistence in humans, complex models are indispensable. Although fungal virulence factors have been extensively studied in vitro and in vivo using different immune cell subsets and cell lines, it is unclear how C. albicans survives inside complex tissue granulomas. METHODOLOGY/PRINCIPAL FINDING: We developed an original model of in vitro human granuloma, reproducing the natural granulomatous response to C. albicans. Persistent granulomas were obtained when the ratio of phagocytes to fungi was high. This in vitro fungal granuloma mimics natural granulomas, with infected macrophages surrounded by helper and cytotoxic T lymphocytes. A small proportion of granulomas exhibited C. albicans hyphae. Histological and time-lapse analysis showed that C. albicans blastoconidia were located within the granulomas before hyphae formation. Using staining techniques, fungal load calculations, as well as confocal and scanning electron microscopy, we describe the kinetics of fungal granuloma formation. We provide the first direct evidence that C. albicans are not eliminated by immunocompetent cells inside in vitro human granulomas. In fact, after an initial candicidal period, the remaining yeast proliferate and persist under very complex immune responses. CONCLUSIONS/SIGNIFICANCE: Using an original in vitro model of human fungal granuloma, we herein present the evidence that C. albicans persist and grow into immunocompetent granulomatous structures. These results will guide us towards a better understanding of fungal invasiveness and, henceforth, will also help in the development of better strategies for its control in human physiological conditions