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Interrogating the ecological and geographic factors that influence population divergence dynamics can reveal why some groups of organisms diversify more prolifically than others. One such group is the heathers (Erica, Ericaceae), the largest plant genus in the Cape Floristic Region. We study Erica abietina, a highly variable species complex with four subspecies differing in geographic range, habitat and pollination syndrome. We test for population differentiation, hybridisation, introgression and pollinator‐driven divergence using genotyping‐by‐sequencing on samples across the entire distribution. We find five variably distinct genetic groups, with one subspecies comprising two independent lineages that are geographically isolated and occur on different soil types. Phylogenetic analysis suggests two independent shifts between bird and insect pollination, with accompanying genetic divergence. However, for one pair of populations with different pollinators, we uncover several individuals of hybrid origin at a site of sympatry. These results suggest that floral differentiation driven by divergent selection acts in concert with geographic isolation to maintain reproductive isolation and promote speciation. Our investigations reveal a highly dynamic system whose diversity has been shaped by a variety of interacting forces. We suggest that such a system could be a model for much of the diversification of the Cape flora. [ABSTRACT FROM AUTHOR]

Estimates of the number of vascular plant species currently under threat of extinction are shockingly high, with the highest extinction rates reported for narrow-range, woody plants, especially in biodiversity hotspots with Mediterranean and tropical climates. The large genus Erica is a prime example, as a large proportion of its 851 species, all shrubs or small trees, are endemic to the Cape Floristic Region (CFR) of South Africa. Almost two hundred are known to be threatened and a further hundred are 'Data Deficient'. We need to target conservation efforts and research to fill the most problematic knowledge gaps. This can be especially challenging in large genera, such as Erica, with numerous threatened species that are closely related. One approach involves combining knowledge of phylogenetic diversity with that of IUCN threat status to identify the most Evolutionarily Distinct and Globally Endangered (EDGE) species. We present an expanded and improved phylogenetic hypothesis for Erica (representing 65% of described species diversity) and combine this with available threat and distribution data to identify species and geographic areas that could be targeted for conservation effort to maximise preservation of phylogenetic diversity (PD). The resulting 39 EDGE taxa include 35 from the CFR. A further 32 high PD , data deficient taxa are mostly from outside the CFR , reflecting the low proportion of assessed taxa outside South Africa. The most taxon-rich areas are found in the south-western CFR. They are not the most phylogenetically diverse, but do include the most threatened PD. These results can be cross-referenced to existing living and seed-banked ex situ collections and used to target new and updated threat assessments and conservation action. [ABSTRACT FROM AUTHOR]

Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example, insulin as a marker of b-cells. A major limitation of thesemethods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here, we demonstrate the use of cell type-specific DNAmethylationmarkers for determining the fraction of specific cell types in human islet and pancreas specimens. We identified genomic loci that are uniquely demethylated in specific pancreatic cell types and applied targeted PCR to assess the methylation status of these loci in tissue samples, enabling inference of cell type composition. In islet preparations, normalization of insulin secretion to b-cell DNA revealed similar b-cell function in pre-type 1 diabetes (T1D), T1D, and type 2 diabetes (T2D), which was significantly lower than in donors without diabetes. In histological pancreas specimens from recent-onset T1D, this assay showed b-cell fraction within the normal range, suggesting a significant contribution of b-cell dysfunction. In T2D pancreata, we observed increased a-cell fraction and normal b-cell fraction. Methylation-based analysis provides an accurate molecular alternative to immune detection of cell types in the human pancreas, with utility in the interpretation of insulin secretion assays and the assessment of pancreas cell composition in health and disease. [ABSTRACT FROM AUTHOR]

Species identification is fundamental to all aspects of biology and conservation. The process can be challenging, particularly in groups including many closely related or similar species. The problem is confounded by the absence of an up-to-date taxonomic revision, but even with such a resource all but professional botanists may struggle to recognise key species, presenting a substantial barrier to vital work such as surveys, threat assessments, and seed collection for ex situ conservation. Genus Erica: An Identification Aid is a tool to help both amateurs and professionals identify (using a limited number of accessible characteristics) and find information about the 851 species and many subspecific taxa of the genus Erica. We present an updated version 4.00, with new features including integrating distribution data from GBIF and iNaturalist, links to taxonomic resources through World Flora Online, and a probability function for identifications, that is freely available for PCs. It remains a work in progress: We discuss routes forward for collaboratively improving this resource. [ABSTRACT FROM AUTHOR]

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. Article Highlights: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis. [ABSTRACT FROM AUTHOR]

In the tropical Americas, the Orthosiinae (Apocynaceae) comprises plant species with small but intricate flowers and harbours a tremendous, still understudied diversity currently classified in four genera, Jobinia, Monsanima, Orthosia and Scyphostelma. In this study, we describe and illustrate four new species of Scyphostelma: S. bolivianum, S. gracile, S. rotorum and S. solomonii, based on specimens collected in Bolivia and Peru. Phylogenetic analysis places S. bolivianum and S. gracile in a clade with S. harlingii, a species from southern Ecuador and central Peru, together as sister clade to the rest of Scyphostelma. Due to the size of flowers and the long-filiform peduncles and pedicels, we consider the two new species S. rotorum and S. solomonii and the new combination S. erikseniae a part of the S. harlingii group, for which an identification key is presented. Furthermore, four species names are lectotypified and six new combinations in Scyphostelma are made: S. fasciculiflorum, S. jaramilloi, S. purpurascens, S. quitense, S. stenospira and S. unguiculatum. Citation: Pineda Y. M., Keller H. A., Balderrama-Torrico J. A., Meve U., Nürk N. M. & Liede-Schumann S. 2023: Phylogenetics in Scyphostelma (Apocynaceae: Orthosiinae) and description of new species. – Willdenowia 53: 83–112. Version of record first published online on 5 September 2023 ahead of inclusion in August 2023 issue. En las Américas tropicales, Orthosiinae (Apocynaceae) comprende especies de plantas con flores pequeñas pero complejas y alberga una alta diversidad, aún poco estudiada, actualmente clasificada en cuatro géneros: Jobinia, Monsanima, Orthosia y Scyphostelma. En este estudio, describimos e ilustramos cuatro especies nuevas de Scyphostelma: S. bolivianum, S. gracile, S. rotorum y S. solomonii, con base en especímenes recolectados en Bolivia y Perú. El análisis filogenético ubica a S. bolivianum y S. gracile en un clado con S. harlingii, una especie del sur de Ecuador y el centro de Perú, juntas como clado hermano del resto de Scyphostelma. Debido al tamaño de las flores y a los pedúnculos y pedicelos filiformes largos, consideramos a las dos nuevas especies S. roturum y S. solomonii y la nueva combinación S. erikseniae una parte del grupo S. harlingii, para el cual se presenta una clave de identificación. Además, se lectotipifican cuatro nombres de especies y se realizan seis nuevas combinaciones en Scyphostelma: S. fasciculiflorum, S. jaramilloi, S. purpurascens, S. quitense, S. stenospira y S. unguiculatum. [ABSTRACT FROM AUTHOR]

Cancer diagnosis and treatment may influence reproductive planning and impact fertility in patients of reproductive age. Although guidelines have been established in the past decade, education, practice, and attitudes of medical oncologists regarding fertility preservation remain undecided. A nationwide survey was performed among members of the Dutch Society for Medical Oncology. Demographics, practice, knowledge, and barriers were measured regarding information provision of fertility preservation towards cancer patients of childbearing age. From 392 members, 120 oncologists completed the questionnaire (30.6%). Majority of oncologists was convinced it is their responsibility to discuss impact of cancer treatment to fertility (93.2%), yet 68.3% discussed the subject often or always (n = 82). Oncologists employed in district general hospitals were less likely to discuss fertility (p = 0.033). On average, 44.6% of reproductive men and 28.9% of reproductive women is referred to fertility specialists. Half of the respondents declared to possess sufficient knowledge regarding fertility preservation (n = 57, 47.5%). Poor prognosis (53%), unlikely survival (43.1%), and high chances on fertility recovery (28.7%) were identified as barriers to discussing fertility preservation. Among oncologists, impact of cancer treatment on fertility is a well-accepted responsibility to counsel. Despite, self-reported knowledge regarding fertility preservation is strongly varying. In practice, fertility is discussed to some extent, influenced by several barriers and depending on prognosis and type of hospital. Patients benefit from knowledge improvement among oncology care providers concerning fertility effects of cancer treatment. Education during medical school, residency, and among practicing oncologists may raise awareness, together with enhancement of referral possibilities. [ABSTRACT FROM AUTHOR]

In this work, the first proof of the principal of an in situ diagnostics of the heavy-ion beam intensity distribution in irradiation of solid targets is proposed. In this scheme, x-ray fluorescence that occurs in the interaction of heavy-ions with target atoms is used for imaging purposes. The x-ray conversion to optical radiation and a transport-system was developed, and its first test was performed in experiments at the Universal Linear Accelerator in Darmstadt, Germany. The Au-beam intensity distribution on thin foils and Cu-mesh targets was imaged using multiple x-ray pinholes (polychromatic imaging) and 2D monochromatic imaging of Cu Kα radiation by using a toroidally bent silicon crystal. The presented results are of importance for application in experiments on the investigation of the equation of states of high energy density matter using high intensity GeV/u heavy-ion beams of ≥1010 particles/100 ns. [ABSTRACT FROM AUTHOR]

Societal Impact Statement: Human‐caused habitat destruction and transformation is resulting in a cascade of impacts to biological diversity, of which arguably the most fundamental is species extinctions. The Global Conservation Consortia (GCC) are a means to pool efforts and expertise across national boundaries and between disciplines in the attempt to prevent such losses in focal plant groups. GCC Erica coordinates an international response to extinction threats in one such group, the heaths, or heathers, of which hundreds of species are found only in South Africa's spectacularly diverse Cape Floristic Region. Summary: Effectively combating the biodiversity crisis requires coordinated conservation efforts. Botanic Gardens Conservation International (BGCI) and numerous partners have established Global Conservation Consortia (GCC) to collaboratively develop and implement comprehensive conservation strategies for priority threatened plant groups. Through these networks, institutions with specialised collections and staff can leverage ongoing work to optimise impact for threatened plant species. The genus Erica poses a challenge similar in scale to that of the largest other GCC group, Rhododendron, but almost 700 of the around 800 known species of Erica are concentrated in a single biodiversity hotspot, the Cape Floristic Region (CFR) of South Africa. Many species are known to be threatened, suffering the immediate impacts of habitat destruction, invasive species, changes in natural fire regimes and climate change. Efforts to counter these threats face general challenges: disproportionate burden of in situ conservation falling on a minority of the community, limited knowledge of species‐rich groups, shortfalls in assessing and monitoring threat, lack of resources for in situ and limitations of knowledge for ex situ conservation efforts and in communicating the value of biological diversity to a public who may never encounter it in the wild. GCC Erica brings together the world's Erica experts, conservationists and the botanical community, including botanic gardens, seed banks and organisations in Africa, Madagascar, Europe, the United States, Australia and beyond. We are collaboratively pooling our unique sets of skills and resources to address these challenges in working groups for conservation prioritisation, conservation in situ, horticulture, seed banking, systematic research and outreach. [ABSTRACT FROM AUTHOR]

Background: Anti-cancer drugs commonly adversely affect fertility and sexual function. Despite this, patients report a lack of counselling of these potential adverse effects. The aim was to determine Dutch oncologists' knowledge about the adverse effects of various cancer drugs on fertility and sexual function. Methods: A cross-sectional survey was sent to members of the Dutch Society for Medical Oncology (n = 433). The survey questions included various cancer drugs' adverse effects on fertility, ovulation, spermatogenesis, and sexual function. Results: One hundred and five of 392 oncologists responded (26.8%). Oncologists were more aware of the adverse effects on fertility compared to sexual function. Drugs that were mostly believed to negatively affect fertility were cisplatin (n = 81, 80.2%), epirubicin (n = 78, 78.0%) and cyclophosphamide (n = 80, 77.7%). Regarding sexual function, most mentioned drugs were tamoxifen (n = 67, 65.7%), GnRH-agonists (n = 64, 63.4%) and cisplatin (n = 58, 57.4%). Oncologists with expertise in urology possessed more awareness regarding sexuality-related adverse effects (cisplatin p = 0.038, etoposide p = 0.025, ifosfamide p = 0.06, vinblastine p = 0.000). Conclusion: Results revealed that oncologists have different beliefs about possible sexual and fertility-related adverse effects concerning medication resources and literature. Based on our results, oncologists do not possess sufficient knowledge to inform patients about sexual and fertility-related adverse effects. [ABSTRACT FROM AUTHOR]

In lichen symbioses, fungal secondary metabolites provide UV protection on which lichen algae such as trebouxiophycean green algae—the most prominent group of photobionts in lichen symbioses—sensitively depend. These metabolites differ in their UV absorbance capability and solvability, and thus vary in their propensity of being leached from the lichen body in humid and warm environments, with still unknown implications for the global distribution of lichens. In this study covering more than 10,000 lichenised fungal species, we show that the occurrence of fungal‐derived metabolites in combination with their UV absorbance capability and their probability of being leached in warm and humid environments are important eco‐evolutionary drivers of global lichen distribution. Fungal‐derived UV protection seems to represent an indirect environmental adaptation in which the lichen fungus invests to protect the trebouxiophycean photobiont from high UV radiation in warm and humid climates and, by doing this, secures its carbon source. [ABSTRACT FROM AUTHOR]

The Palaeotropical genus Antirhea (Guettardeae, Rubiaceae) currently comprises 37 dioecious species classified into three subgenera, Antirhea , Mesocarpa and Guettardella. It has a complex taxonomic history with varying generic delineation and variable application of species names. Recent phylogenetic studies have indicated the non-monophyly of Antirhea , but the limited sampling does not allow resolution of its circumscription or nomenclatural changes to be proposed. Here, we reconcile the generic boundaries of Antirhea based on phylogenetic analyses of two nuclear (ETS, ITS) and three plastid loci (atpB-rbcL , rps16 , trnT-F) using Bayesian, maximum likelihood and parsimony methods. Our results show that Antirhea in its current circumscription is highly polyphyletic, whereas its three subgenera are retrieved as well-supported independent clades. A new generic framework is proposed based on phylogenetic results and supported by morphological evidence. We intend to restrict Antirhea to species native to the Mascarene Islands and Madagascar, to reinstate the genus Guettardella with emended diagnostic features and to describe the new genus Achilleanthus to accommodate the species of subgenus Mesocarpa plus Guettarda glabrescens , G. hypoplasia and G. ngoyensis. As a consequence, seven new combinations in Achilleanthus and 17 new combinations in Guettardella are made. [ABSTRACT FROM AUTHOR]

Summary: A flexible use of the crassulacean acid metabolism (CAM) has been hypothesised to represent an intermediate stage along a C3 to full CAM evolutionary continuum, when relative contributions of C3 vs CAM metabolism are co‐determined by evolutionary history and prevailing environmental constraints. However, evidence for such eco‐evolutionary interdependencies is lacking.We studied these interdependencies for the leaf‐succulent genus Drosanthemum (Aizoaceae, Southern African Succulent Karoo) by testing for relationships between leaf δ13C diagnostic for CAM dependence (i.e. contribution of C3 and CAM to net carbon gain), and climatic variables related to temperature and precipitation and their temporal variation. We further quantified the effects of shared phylogenetic ancestry on CAM dependence and its relation to climate.CAM dependence is predicted by rainfall and its temporal variation, with high predictive power of rainfall constancy (temporal entropy). The predictive power of rainfall seasonality and temperature‐related variables was negligible. Evolutionary history of the tested clades significantly affected the relationship between rainfall constancy and CAM dependence.We argue that higher CAM dependence might provide an adaptive advantage in increasingly unpredictable rainfall environments when the anatomic exaptation (succulence) is already present. These observations might shed light on the evolution of full CAM. [ABSTRACT FROM AUTHOR]

Sexuality is a significant quality-of-life concern for many cancer patients. Patients may be disadvantaged if they are not informed and not offered sexual health care. We sought to reveal oncologists' current practice and opinions concerning sexual counselling. The aim of this study was to explore the knowledge, attitude and practice patterns of Dutch medical oncologists regarding treatment-related sexual dysfunction. Questionnaires were sent to 433 members of the Dutch Society of Medical Oncology. The majority (81.5%) of the 120 responding medical oncologists (response rate 30.6%) stated they discussed sexual function with fewer than half of their patients. At the same time, 75.8% of the participating oncologists agreed that addressing sexual function is their responsibility. Sexual function was discussed more often with younger patients and patients with a curative treatment intent. Barriers for avoiding discussing sexual function were lack of time (56.1%), training (49.5%) and advanced age of the patient (50.4%). More than half (64.6%) stated they had little knowledge about the subject and the majority (72.9%) wanted to acquire additional training in sexual function counselling. Medical oncologists accept that sexual function counselling falls within their profession, yet they admit to not counselling patients routinely concerning sexual function. Only in a minority of cases do medical oncologists inform their patients about sexual side effects of treatment. Whether they counsel patients is related to how they view patient's prognosis, patient's age, and self-reported knowledge. Findings indicate there is a role for developing education and practical training. [ABSTRACT FROM AUTHOR]

Understanding how and why rates of evolutionary diversification vary is a key issue in evolutionary biology, ecology, and biogeography. Evolutionary rates are the net result of interacting processes summarized under concepts such as adaptive radiation and evolutionary stasis. Here, we review the central concepts in the evolutionary diversification literature and synthesize these into a simple, general framework for studying rates of diversification and quantifying their underlying dynamics, which can be applied across clades and regions, and across spatial and temporal scales. Our framework describes the diversification rate (d) as a function of the abiotic environment (a), the biotic environment (b), and clade‐specific phenotypes or traits (c); thus, d ~ a,b,c. We refer to the four components (a–d) and their interactions collectively as the "Evolutionary Arena." We outline analytical approaches to this framework and present a case study on conifers, for which we parameterize the general model. We also discuss three conceptual examples: the Lupinus radiation in the Andes in the context of emerging ecological opportunity and fluctuating connectivity due to climatic oscillations; oceanic island radiations in the context of island formation and erosion; and biotically driven radiations of the Mediterranean orchid genus Ophrys. The results of the conifer case study are consistent with the long‐standing scenario that low competition and high rates of niche evolution promote diversification. The conceptual examples illustrate how using the synthetic Evolutionary Arena framework helps to identify and structure future directions for research on evolutionary radiations. In this way, the Evolutionary Arena framework promotes a more general understanding of variation in evolutionary rates by making quantitative results comparable between case studies, thereby allowing new syntheses of evolutionary and ecological processes to emerge. [ABSTRACT FROM AUTHOR]

Background. Drosanthemum, the only genus of the tribe Drosanthemeae, is widespread over the Greater Cape Floristic Region in southern Africa. With 114 recognized species, Drosanthemum, together with the highly succulent and species-rich tribe Ruschieae, constitute the `core ruschioids' in Aizoaceae. Within Drosanthemum, nine subgenera have been described based on flower and fruit morphology. Their phylogenetic relationships, however, have not yet been investigated, hampering understanding of monophyletic entities and patterns of geographic distribution. Methods. Using chloroplast and nuclear DNA sequence data, we performed networkand tree-based phylogenetic analyses of 73 species of Drosanthemum with multiple accessions for widespread species. A well-curated, geo-referenced occurrence dataset comprising the 134 genetically analysed and 863 further accessions was used to describe the distributional ranges of intrageneric lineages and the genus as a whole. Results. Phylogenetic inference supports nine clades within Drosanthemum, seven of which group in two major clades, while the remaining two show ambiguous affinities. The nine clades are generally congruent to previously described subgenera within Drosanthemum, with exceptions such as cryptic species. In-depth analyses of sequence patterns in each gene region were used to reveal phylogenetic affinities inside the retrieved clades in more detail. We observe a complex distribution pattern including widespread, species-rich clades expanding into arid habitats of the interior (subgenera Drosanthemum p.p., Vespertina, Xamera) that are genetically and morphologically diverse. In contrast, less species-rich, genetically less divergent, and morphologically unique lineages are restricted to the central Cape region and more mesic conditions (Decidua, Necopina, Ossicula, Quastea, Quadrata, Speciosa). Our results suggest that the main lineages arose from an initial rapid radiation, with subsequent diversification in some clades. [ABSTRACT FROM AUTHOR]

Random lasers consisting of slab waveguides with two-dimensional disordered wrinkling patterns that act as scattering resonators are reported. As active material 2,2′,7,7′-tetraphenyl-9,9′-spirobifluorene is used which is sandwiched between an oxidized silicon wafer and a cladding with higher glass transition temperature. Wrinkles with tailorable periodicity have been induced by thermal annealing. Photopumping experiments show the transition from amplified spontaneous emission to a multiple peak laser spectrum with linewidths as low as 0.1 nm, demonstrating the applicability of this approach for random laser design. [ABSTRACT FROM AUTHOR]

Three indicators for the determination of the saturation length limiting the validity of the variable stripe length method are presented. Depending on the maximum stripe length being used for the nonlinear fit, the resulting modal gain, its confidence interval, and the spectral full width at half maximum vary and give clear indications on the saturation length. Exemplarily, a blend of organic semiconducting spiro-compounds has been measured to present the importance of this length and demonstrate its determination. Subsequently, the optical modal gain is calculated with consideration of the saturation length. Both the saturation length and modal gain are shown to be dependent on the pump energy but result in a constant gain-length product of 2.2 ± 0.2, independent of the pump energy. Additionally, spectral gain profiles for different pump energies are presented with a maximum net modal gain of (128 ± 4) cm − 1 found at (2.98 ± 0.09) mJ / cm 2 . [ABSTRACT FROM AUTHOR]

Summary: The evolution of secondary (insular) woodiness and the rapid disparification of plant growth forms associated with island radiations show intriguing parallels between oceanic islands and tropical alpine sky islands. However, the evolutionary significance of these phenomena remains poorly understood and the focus of debate.We explore the evolutionary dynamics of species diversification and trait disparification across evolutionary radiations in contrasting island systems compared with their nonisland relatives. We estimate rates of species diversification, growth form evolution and phenotypic space saturation for the classical oceanic island plant radiations – the Hawaiian silverswords and Macaronesian Echium – and the well‐studied sky island radiations of Lupinus and Hypericum in the Andes.We show that secondary woodiness is associated with dispersal to islands and with accelerated rates of species diversification, accelerated disparification of plant growth forms and occupancy of greater phenotypic trait space for island clades than their nonisland relatives, on both oceanic and sky islands.We conclude that secondary woodiness is a prerequisite that could act as a key innovation, manifest as the potential to occupy greater trait space, for plant radiations on island systems in general, further emphasizing the importance of combinations of clade‐specific traits and ecological opportunities in driving adaptive radiations. See also the Commentary on this article by Baldwin, 224: 8–10. [ABSTRACT FROM AUTHOR]

Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents. [ABSTRACT FROM AUTHOR]

These days, the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes, e.g., cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system, have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer's disease (AD), led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert an anti-amyloidogenic effect in mouse models for AD as well as in human patients by stimulating the alpha-secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and evoked increased nest building capability in the 5xFAD mouse model. Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, Interleukin-6 (IL-6) was found to be significantly increased in both—mouse and human neural material. This demonstrates that acitretin exerts an immune stimulatory effect—besides the alpha-secretase induction—which could impact the alleviation of learning and memory disabilities observed in the mouse model. [ABSTRACT FROM AUTHOR]

Purpose: Due to advancing insights, discussing fertility in spinal care is an emerging topic. Studies among neurosurgeons to evaluate clinical practice about discussing fertility are non-existent. The aim of this study is to review knowledge, attitude and practice patterns regarding discussing fertility in spinal care.Methods: Dutch neurosurgeons and residents were sent a mail-based questionnaire addressing attitude, knowledge and practice patterns regarding discussing fertility.Results: Response rate was 62 % (compared to mean of 28 % in similar surveys) with 89 questionnaires suitable for analysis. Mean age was 42 years with 83 % of respondents being male. A quarter of respondents stated neurosurgeons are responsible to discuss fertility, with 12 % indicating to actually do this. Fertility is discussed more often with patients with cauda equina syndrome (70 %) and with men (p = 0.006). Merely 8 % of respondents stated to have adequate knowledge on fertility preservation (FP); this percentage was higher for doctors with spinal surgery as specialty (p = 0.015). In case of cauda equina syndrome, doctors with more knowledge discussed fertility more often (p = 0.002). Fifty-three percent of neurosurgeons wished to enhance their knowledge, in order to feel more comfortable to discuss fertility with their patients. Five percent indicated to have ever referred a patient to a fertility specialist.Conclusion: With the exception of cauda equina syndrome, fertility is not routinely discussed in spinal care. Fertility is discussed more often with men. Recent guidelines state that discussing fertility is an essential part of good practice in spinal care. Education on fertility and FP needs to be integrated in the neurosurgical training program to create more awareness, and to enable clinicians to provide adequate information and care to the patient. [ABSTRACT FROM AUTHOR]

Background: The possible detrimental effects of spinal disease on sexual health are widely recognized; however, it is not known to what extent neurosurgeons discuss this topic with their patients. The aim of this study is to identify knowledge, attitude and practice patterns of neurosurgeons counseling their patients about sexual health.Methods: All members of the Dutch Association of Neurosurgery (neurosurgeons and residents) were sent a questionnaire addressing their attitudes, knowledge and practice patterns regarding discussing sexual health.Results: Response rate was 62% with 89 questionnaires suitable for analysis. The majority of participants (83%) were male; mean age, 42.4 years. The mean experience in neurosurgical practice was 9 years. Respondents assumed that in 34% of their patients, sexual health was affected due to spinal disease. The majority of respondents (64%) stated that responsibility for discussing sexual health lies (partly) with the neurosurgeon; however, 73% indicated to (almost) never do this. The main reasons for not discussing sexual health were patients' old age (42%), lack of knowledge (38%) and lack of patients' initiative to bring up the subject (36%). Twenty-six percent indicated lack of time as a reason. There was no evidence for gender or doctor's age discordance as important barriers. Fifty percent of participants wished to gain more knowledge on discussing sexual health with patients.Conclusion: This study shows that despite high prevalence of sexual dysfunction (SD) in spinal patients, counseling about sexual health is not often done in neurosurgical care. More training on sexual health counseling early in the residency program seems critical. By initiating the discussion, clinicians who deal with spinal patients have the potential to detect sexual dysfunction (SD) and to refer adequately when necessary, thereby improving overall quality of life of their patients. [ABSTRACT FROM AUTHOR]

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Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. The changes in myocardial structure and function associated with diabetes are collectively called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed that could contribute to the development of diabetic cardiomyopathy and have been studied in various animal models of type 1 or type 2 diabetes. The current review focuses on the role of sodium (Na+) in diabetic cardiomyopathy and provides unique data on the linkage between Na+ flux and energy metabolism, studied with non-invasive 23Na, and 31P-NMR spectroscopy, polarography, and mass spectroscopy. 23Na NMR studies allow determination of the intracellular and extracellular Na+ pools by splitting the total Na+ peak into two resonances after the addition of a shift reagent to the perfusate. Using this technology, we found that intracellular Na+ is approximately two times higher in diabetic cardiomyocytes than in control possibly due to combined changes in the activity of Na+–K+ pump, Na+/H+ exchanger 1 (NHE1) and Na+-glucose cotransporter. We hypothesized that the increase in Na+ activates the mitochondrial membrane Na+/Ca2+ exchanger, which leads to a loss of intramitochondrial Ca2+, with a subsequent alteration in mitochondrial bioenergetics and function. Using isolated mitochondria, we showed that the addition of Na+ (1–10 mM) led to a dose-dependent decrease in oxidative phosphorylation and that this effect was reversed by providing extramitochondrial Ca2+ or by inhibiting the mitochondrial Na+/Ca2+ exchanger with diltiazem. Similar experiments with 31P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na+ (3–30 mM) led to significantly decreased ATP levels and that this effect was stronger in diabetic rats. These data suggest that in diabetic cardiomyocytes, increased Na+ leads to abnormalities in oxidative phosphorylation and a subsequent decrease in ATP levels. In support of these data, using 31P-NMR, we showed that the baseline β-ATP and phosphocreatine (PCr) were lower in diabetic cardiomyocytes than in control, suggesting that diabetic cardiomyocytes have depressed bioenergetic function. Thus, both altered intracellular Na+ levels and bioenergetics and their interactions may significantly contribute to the pathology of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

The N-terminally truncated pyroglutamate Aβ3-42 (AαpE3-42) and Aα2-42 peptides are known to be highly Aαundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aα, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AαpE3-42 and Aα2-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aα peptides AαpE3-42 and Aα2-42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AαpE3-42 and Aα2-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AαpE3-42 or Aα2-42. This observation coincides with the robust intraneuronal Aα accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aα accumulation within motor neurons and extracellular Aα deposition. Our observations demonstrate that a combination of AαpE3-42 and Aα2-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AαpE3-42 and Aα2-42 might represent excellent potential therapeutic targets and diagnostic markers for AD. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Tropical mountains around the world harbour an extraordinarily rich pool of plant species and are hotspots of biodiversity. Climatically, they can be zoned into montane climates at mid‐altitudes and tropical alpine climates above the tree line. Around half of the tropical alpine species belong to plant lineages with a temperate ancestry, although these regions are often geographically distant. We test the hypothesis that these temperate lineages are pre‐adapted to the tropical alpine climate. Location: New World, with a focus on tropical alpine Andes. Time period: Miocene to present. Major taxa studied: Flowering plants. Methods: We build multidimensional environmental models representing the full space of New World climates. We quantify the environmental similarity between the tropical alpine ecosystem and those of potential source areas, while correcting for regional differences by kernel density smoothers. Based on spatial observations of the genus Hypericum (St John's Wort), we quantify niche overlap and test for niche conservatism following intercontinental dispersal using density‐weighted nonparametric tests. A dated species tree, biogeographical estimation, multi‐optima Ornstein–Uhlenbeck models and model selection approaches are used to test for niche shifts during establishment in the tropical alpine Andes. Results: The tropical alpine ecosystem is isolated by its climate from adjacent regions and is climatically similar to temperate lowland biomes of both hemispheres. Niche conservatism is evident in the study group, except in the tropical alpine lineage that is characterized by niche expansion and shifts in temperature optima. Main conclusions: Our results reject the pre‐adaptation hypothesis and instead suggest pronounced niche evolution during colonization of tropical alpine ecosystems. Establishment involved substantial niche shifts, mainly in temperature‐related variables, and resulted in a tremendous proliferation of species in the newly invaded tropical alpine ecosystem. [ABSTRACT FROM AUTHOR]

Background and Aims In Central Europe Hypericum perforatum and Hypericum maculatum show significant hybridization and introgression as a consequence of Pleistocene range fluctuations, and their gene pools are merging on higher ploidy levels. This paper discusses whether polyploid hybrid gene pools are trapped in the ecological climatic niche space of their diploid ancestors, and tests the idea of geographical parthenogenesis. Methods DNA sequence information of nuclear ribosomal DNA and plastid loci, ploidy level estimates and ecological niche modelling are used to characterize the various diploid and polyploid gene pools and unravel spatio-temporal patterns of gene flow among them. Key Results On the diploid level, the three gene pools are clearly distinct between and within species of H. perforatum (two gene pools) and H. maculatum, and their divergence dates back to the first half of the Pleistocene. All polyploids in Central Europe show high levels of past and contemporary gene flow between all three gene pools. The correlation of genetic and geographical distances breaks down if the latter is larger than 250 km, indicating recent and ongoing gene flow. The two species are ecologically differentiated, but in particular hybrids among all three gene pools do not show significant niche differences compared to their parental gene pools, except for some combinations with H. maculatum. Conclusions Inter- and intraspecific gene flow between inter- and intra-species gene pools is limited on the diploid level, and the geographical distribution of the diploids largely reflects Pleistocene evolutionary history. Secondary contact promoted hybridization and introgression on the polyploid level, enabling offspring to escape the diploid gene pools. However, the hybrid polyploids do not show significant niche differences compared to their diploid progenitors. It is concluded that the observed absence of niche divergence has precluded further differentiation and geographical partitioning of new polyploid lineages being effectively separated from the parental lines. The predominantly apomictic reproducing polyploids are trapped in the polyploid gene pool and the ecological climatic niche space of their diploid ancestors. [ABSTRACT FROM AUTHOR]

\G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonistinduced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Our aim is to understand the evolution of species-rich plant groups that shifted from tropical into cold/temperate biomes. It is well known that climate affects evolutionary processes, such as how fast species diversify, species range shifts, and species distributions. Many plant lineages may have gone extinct in the Northern Hemisphere due to Late Eocene climate cooling, while some tropical lineages may have adapted to temperate conditions and radiated; the hyper-diverse and geographically widespread genus Hypericum is one of these. Results: To investigate the effect of macroecological niche shifts on evolutionary success we combine historical biogeography with analyses of diversification dynamics and climatic niche shifts in a phylogenetic framework. Hypericum evolved cold tolerance c. 30 million years ago, and successfully colonized all ice-free continents, where today ~500 species exist. The other members of Hypericaceae stayed in their tropical habitats and evolved into ~120 species. We identified a 15--20 million year lag between the initial change in temperature preference in Hypericum and subsequent diversification rate shifts in the Miocene. Conclusions: Contrary to the dramatic niche shift early in the evolution of Hypericum most extant species occur in temperate climates including high elevations in the tropics. These cold/temperate niches are a distinctive characteristic of Hypericum. We conclude that the initial release from an evolutionary constraint (from tropical to temperate climates) is an important novelty in Hypericum. However, the initial shift in the adaptive landscape into colder climates appears to be a precondition, and may not be directly related to increased diversification rates. Instead, subsequent events of mountain formation and further climate cooling may better explain distribution patterns and species-richness in Hypericum. These findings exemplify important macroevolutionary patterns of plant diversification during large-scale global climate change. [ABSTRACT FROM AUTHOR]

Adenylate kinase plays an important role in cellular energy homeostasis by catalysing the interconversion of adenine nucleotides. The goal of present study was to evaluate the contribution of the adenylate kinase reaction to oxidative ATP synthesis by direct measurements of ATP using 31P NMR spectroscopy. Results show that AMP can stimulate ATP synthesis in the presence or absence of ADP. In particular, addition of 1 mM AMP to the 0.6 mM ADP superfusion system of isolated superfused mitochondria (contained and maintained in agarose beads) led to a 25% increase in ATP synthesis as measured by the increase in βATP signal. More importantly, we show that AMP can support ATP synthesis in the absence of ADP, demonstrated as follows. Superfusion of mitochondria without ADP led to the disappearance of ATP γ, α and β signals and the increase of Pi. Addition of AMP to the medium restored the production of ATP, as demonstrated by the reappearance of γ, α and β ATP signals, in conjunction with a decrease in Pi, which is being used for ATP synthesis. Polarographic studies showed Mg2+ dependence of this process, confirming the specificity of the adenylate kinase reaction. Furthermore, data obtained from this study demonstrate, for the first time, that different aspects of the adenylate kinase reaction can be evaluated with 31P NMR spectroscopy. Copyright © 2015 John Wiley & Sons, Ltd. SIGNIFICANCE OF RESEARCH PARAGRAPH The data generated in the present study indicate that 31P NMR spectroscopy can effectively be used to study the adenylate kinase reaction under a variety of conditions. This is important because understanding of adenylate kinase function and/or malfunction is essential to understanding its role in health and disease. The data obtained with 31P NMR were confirmed by polarographic studies, which further strengthens the robustness of the NMR findings. In summary, 31P NMR spectroscopy provides a sensitive tool to study adenylate kinase activity in different physiological and pathophysiological conditions, including but not exclusive of, cancer, ischemic injury, hemolytic anemia and neurological problems such as sensorineural deafness. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations affecting the cholesterol transporter ATP-binding cassette transporter subfamily A member 1 (ABCA1) impair cellular cholesterol efflux and are associated with reduced HDL-cholesterol (HDL-C) levels. ABCA1 may also be important in regulating β-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect β-cell secretory capacity in humans by performing glucose-potentiated arginine tests in three subjects homozygous for ABCA1 mutations (age 25 ± 11 years), eight heterozygous subjects (28 ± 7 years), and eight normal control subjects pair-matched to the heterozygous carriers. To account for any effect of low HDL-C on insulin secretion, we studied nine subjects with isolated low HDL-C with no ABCA1 mutations (age 26 ± 6 years) and nine pair-matched control subjects. Homozygotes for ABCA1 mutations exhibited enhanced oral glucose tolerance and dramatically increased β-cell secretory capacity that was also greater in ABCA1 heterozygous subjects than in control subjects, with no differences in insulin sensitivity. Isolated low HDL-C subjects also demonstrated an increase in β-cell secretory capacity but in contrast to those with ABCA1 mutations, exhibited impaired insulin sensitivity, supporting β-cell compensation for increased insulin demand. These data indicate that loss-of-function mutations in ABCA1 in young adults may be associated with enhanced β-cell secretory capacity and normal insulin sensitivity and support the importance of cellular cholesterol homeostasis in regulating β-cell insulin secretion. [ABSTRACT FROM AUTHOR]

The stability of the Co-Cr-Mo dental alloy immersed in artificial salivas (pH 6.7) was investigated over 24 h. Three artificial salivas have been studied: saline saliva (saliva I); saline saliva buffered with phosphate ions (saliva II) and saliva II plus mucin molecules (saliva III). For all the systems, open circuit potential shift positively over 24 hours of immersion. Data extracted from the steady-state polarization curves demonstrated that the Co-Cr-Mo alloy has higher corrosion potential in saliva III, lower corrosion potential in saliva I and lower initial corrosion resistance in saliva III. After 24 hours of immersion in the artificial salivas, the Co-Cr-Mo alloy presents high corrosion stability, due to the protective action created by the presence of corrosion products. From the analysis of the breakdown potential it was concluded that, the presence of the phosphate ions and mucin promote the oxidation process, inducing the formation of etch pits. Regarding the effect of the mucin concentration in the corrosion behaviour of the Co-Cr-Mo dental alloy, it was observed a negative shift in the corrosion potential, pointing to a cathodic inhibitor role for the mucin molecules. Nevertheless, no correlation between the mucin concentration and corrosion rate was possible to establish. [ABSTRACT FROM AUTHOR]

Advanced, cost-effective and series compatible manufacturing of active structural components demands for short production times and complex multi-material designs. Highest efficiency is achieved when integrating the poling process of the piezoceramic that activates the piezoelectric effect into the manufacturing chain. The present paper reports on first results of the systematic evaluation of parameters governing the poling regime of commercial lead zirconate titanate (PZT) ceramics. It aims to find the conditions for efficient poling of the active material as an integrated technology step in mass production. In the present investigation, the influence of poling field strength and temperature on the obtained remanent polarization is considered by varying the temperature from −175 °C to 150 °C and the electric poling field strength from 1.0 to 2.0 kV/mm. Six commercially available piezoceramic materials, primarily used in actuator applications, were investigated. From the findings, it was possible to deduce technological parameters for an efficient poling process. [ABSTRACT FROM AUTHOR]

The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet. [ABSTRACT FROM AUTHOR]

PurposeTo report on the long-term outcomes and risk factors for failure with the EX-PRESS shunt implanted under a scleral flap.SettingsEye Department, University of Ancona, Ancona, Italy and the Oxford Eye Center, University of Witwatersrand, Johannesburg, South Africa.MethodsThe medical records of glaucoma patients who underwent consecutive EX-PRESS implantations under a scleral flap between 2000 and 2009 were reviewed. The operations were performed by two experienced surgeons using an identical surgical technique. The potential risk factors for failure that were analysed included age, sex, race, glaucoma type, previous antiglaucoma medications, previous glaucoma surgeries, diabetes, and smoking. Complete success was defined as postoperative intraocular pressure (IOP) 5 mm Hg>IOP<18 mm Hg without antiglaucoma medications. Qualified success was defined as 5 mm Hg>IOP<18 mm Hg with or without antiglaucoma medications.ResultsTwo hundred and forty-eight eyes of 211 consecutive patients were included. The mean IOP was reduced from 27.63±8.26 mm Hg preoperatively (n=248) to 13.95±2.70 mm Hg at 5 years (n=95). The mean follow-up was 3.46±1.76 years. Complete and qualified success rates decreased gradually from 83% and 85% at 1 year to 57% and 63% at 5 years follow-up, respectively. The risk factors for failure were diabetes, non-Caucasian race, and previous glaucoma surgery. Complete success rates of diabetic patients and non-Caucasian patients decreased from 63% and 75% at 1 year to 42% and 40% at 5 years follow-up, respectively.ConclusionsEX-PRESS success rates decrease over time but compare favourably with trabeculectomy literature data. The main identifiable risk factors for failure are diabetes, non-Caucasian race, and previous glaucoma surgery. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: In patients with cardiovascular disease, sexual dysfunction is frequently encountered. Erectile dysfunction shares the same modifiable risk factors as coronary artery disease and the fear of triggering cardiovascular events can create stress and anxiety impacting the sexual lives of patients and their partners. To optimise healthcare, knowledge of cardiologists' attitude and practice patterns regarding the discussion about sexual function is essential. Methods: A 31-itemed anonymous questionnaire was mailed to 980 members of the Netherlands Society of Cardiology (cardiologists and residents in cardiology training). The questionnaire addressed awareness, knowledge and practice patterns about sexual dysfunction in cardiac patients. Results: Of the cardiologists 53.9 % responded. Sixteen percent stated to discuss sexual function regularly. In the past year, an estimated mean of 2 % of patients was referred for help with a sexual problem. The majority (70 %) of cardiologists advised patients never or seldom about resuming sexual activity after myocardial infarction. PDE5-inhibitor use was assessed by 19.4 % of the cardiologists. Important reasons not to discuss sexual function were lack of initiative of the patient (54 %), time constraints (43 %) and lack of training on dealing with SD (35 %). Sixty-three percent of the cardiologists stated they would be helped with a directory of sexual healthcare professionals where they can refer patients to. Conclusion: Sexuality is not routinely discussed in the cardiology practice. Explanations for the lack of attention toward sexual matters are ambiguities about responsibility and a lack of time, training and experience regarding the communication and treatment of sexual dysfunction. [ABSTRACT FROM AUTHOR]

Objectives To estimate the reduction in maternal mortality associated with the emergency obstetric care provided by Médecins Sans Frontières ( MSF) and to compare this to the fifth Millennium Development Goal of reducing maternal mortality. Methods The impact of MSF's intervention was approximated by estimating how many deaths were averted among women transferred to and treated at MSF's emergency obstetric care facility in Kabezi, Burundi, with a severe acute maternal morbidity. Using this estimate, the resulting theoretical maternal mortality ratio in Kabezi was calculated and compared to the Millennium Development Goal for Burundi. Results In 2011, 1385 women from Kabezi were transferred to the MSF facility, of whom 55% had a severe acute maternal morbidity. We estimated that the MSF intervention averted 74% (range 55-99%) of maternal deaths in Kabezi district, equating to a district maternal mortality rate of 208 (range 8-360) deaths/100 000 live births. This lies very near to the 2015 MDG 5 target for Burundi (285 deaths/100 000 live births). Conclusion Provision of quality emergency obstetric care combined with a functional patient transfer system can be associated with a rapid and substantial reduction in maternal mortality, and may thus be a possible way to achieve Millennium Development Goal 5 in rural Africa. [ABSTRACT FROM AUTHOR]

Glucokinase activators ( GKAs) are being developed and clinically tested for potential antidiabetic therapy. The potential benefits and limitations of this approach continue to be intensively debated. To contribute to the understanding of experimental pharmacology and therapeutics of GKAs, we have tested the efficacy of one of these agents (Piragliatin) in isolated islets from humans with type 2 diabetes mellitus ( T2DM), from mice with glucokinase ( GK) mutations induced by ethyl-nitroso-urea ( ENU) as models of Maturity Onset Diabetes of the Young linked to GK and Permanent Neonatal Diabetes Mellitus linked to GK ( PNDM-GK) and finally of islets rendered glucose insensitive by treatment with the sulphonyl urea compound glyburide in organ culture. We found that the GKA repaired the defect in all three instances as manifest in increased glucose-induced insulin release and elevated intracellular calcium responses. The results show the remarkable fact that acute pharmacological activation of GK reverses secretion defects of β-cells caused by molecular mechanism that differ vastly in nature, including the little understood multifactorial lesion of β-cells in T2DM of man, the complex GK mutations in mice resembling GK disease and acute sulphonylurea failure of mouse β-cells in tissue culture. The implications of these results are to be discussed on the theoretical basis underpinning the strategy of developing these drugs and in light of recent results of clinical trials with GKAs that failed for little understood reasons. [ABSTRACT FROM AUTHOR]

It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (O2), glucose usage and oxidation, intracellular Ca2+, and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a "staircase" glucose stimulus, whereas IR and O2 were measured. O2 of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal VO2 of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min-1·100 islets-1, and the glucose S0.5 was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, Vmax of 0.32 ± 0.01 nmol·min-1·100 islets-1, and the S0.5 shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca(2+) were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective O2, IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for normal human, mouse, and rat islets and the data for all species fitted a single sigmoidal curve. The shared threshold rate for IS was ∼13 pmol·min-1·islet-1. Exendin-4, a GLP-1 analog, shifted the ATP production-IS curve to the left and greatly potentiated IS with an ATP production rate threshold of ∼10 pmol·min-1·islet-1. Our data suggest that impaired β-cell bioenergetics resulting in greatly reduced ATP production is critical in the molecular pathogenesis of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]