Regulation of the ovarian follicular vasculature

Angiogenesis is associated with follicular development and is regulated independently within each follicle potentially making the functioning of its vasculature critically important in determining its fate. This review examines the various ways in which follicular angiogenesis may be monitored, describes the follicular localisation and changes in pro- and anti-angiogenic factors that may regulate the process and how antagonists may be used to elucidate their physiological role in vivo. Thus, inhibition of vascular endothelial growth factor (VEGF), VEGF receptor-2, vascular endothelial cell cadherin or interference with the angiopoietin system can inhibit follicular development or prevent ovulation

Angiogenesis in the corpus luteum

The corpus luteum (CL) is a site of intense angiogenesis. Within a short period, this is followed either by controlled regression of the microvascular tree in the non-fertile cycle, or maintenance and stabilisation of the new vasculature a conceptual cycle. The molecular regulation of these diverse aspects is examined. The CL provides a unique model system in which to study the cellular and molecular regulation of angiogenesis. Vascular endothelial growth factor (VEGF) has been found to have a major role in the CL. By targeting its action at specific stages of the luteal phase in vivo by antagonists, profound inhibitory effects on luteal angiogenesis and function are observed

Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable. ©2004 British Editorial Society of Bone and Joint Surgery

Contemporary habitat discontinuity and historic glacial ice drive genetic divergence in Chilean kelp

<p>Abstract</p> <p>Background</p> <p>South America's western coastline, extending in a near-straight line across some 35 latitudinal degrees, presents an elegant setting for assessing both contemporary and historic influences on cladogenesis in the marine environment. Southern bull-kelp (<it>Durvillaea antarctica</it>) has a broad distribution along much of the Chilean coast. This species represents an ideal model taxon for studies of coastal marine connectivity and of palaeoclimatic effects, as it grows only on exposed rocky coasts and is absent from beaches and ice-affected shores. We expected that, along the central Chilean coast, <it>D. antarctica </it>would show considerable phylogeographic structure as a consequence of the isolating effects of distance and habitat discontinuities. In contrast, we hypothesised that further south - throughout the region affected by the Patagonian Ice Sheet at the Last Glacial Maximum (LGM) - <it>D. antarctica </it>would show relatively little genetic structure, reflecting postglacial recolonisation.</p> <p>Results</p> <p>Mitochondrial (COI) and chloroplast (<it>rbc</it>L) DNA analyses of <it>D. antarctica </it>from 24 Chilean localities (164 individuals) revealed two deeply divergent (4.5 - 6.1% for COI, 1.4% for <it>rbc</it>L) clades from the centre and south of the country, with contrasting levels and patterns of genetic structure. Among populations from central Chile (32° - 44°S), substantial phylogeographic structure was evident across small spatial scales, and a significant isolation-by-distance effect was observed. Genetic disjunctions in this region appear to correspond to the presence of long beaches. In contrast to the genetic structure found among central Chilean populations, samples from the southern Chilean Patagonian region (49° - 56°S) were genetically homogeneous and identical to a haplotype recently found throughout the subantarctic region.</p> <p>Conclusions</p> <p>Southern (Patagonian) Chile has been recolonised by <it>D. antarctica </it>relatively recently, probably since the LGM. The inferred trans-oceanic ancestry of these Patagonian populations supports the notion that <it>D. antarctica </it>is capable of long-distance dispersal via rafting. In contrast, further north in central Chile, the correspondence of genetic disjunctions in <it>D. antarctica </it>with long beaches indicates that habitat discontinuity drives genetic isolation among established kelp populations. We conclude that rafting facilitates colonisation of unoccupied shores, but has limited potential to enhance gene-flow among established populations. Broadly, this study demonstrates that some taxa may be considered to have either high or low dispersal potential across different temporal and geographic scales.</p

Inhibition of delta-like ligand 4 induces luteal hypervascularization followed by functional and structural luteolysis in the primate ovary

Using specific inhibitors established that angiogenesis in the ovarian follicle and corpus luteum is driven by vascular endothelial growth factor. Recently, it has been demonstrated that the Notch ligand, delta-like ligand 4 (Dll4) negatively regulates vascular endothelial growth factor-mediated vessel sprouting and branching. To investigate the role of Dll4 in regulation of the ovarian vasculature, we administered a neutralizing antibody to Dll4 to marmosets at the periovulatory period. The vasculature was examined on luteal d 3 or d 10: angiogenesis was determined by incorporation of bromodeoxyuridine, staining for CD31 and cell death by staining for activated caspase-3. Ovulatory progesterone rises were monitored to determine effects of treatment on luteal function and time to recover normal cycles in a separate group of animals. Additionally, animals were treated in the follicular or midluteal phase to determine effects of Dll4 inhibition on follicular development and luteal function. Controls were treated with human IgG (Fc). Corpora lutea from marmosets treated during the periovulatory period exhibited increased angiogenesis and increased vascular density on luteal d 3, but plasma progesterone was significantly suppressed. By luteal d 10, corpora lutea in treated ovaries were significantly reduced in size, with involution of luteal cells, increased cell death, and suppressed plasma progesterone concentrations. In contrast, initiation of anti-Dll4 treatment during the midluteal phase produced only a slight suppression of progesterone for the remainder of the cycle. Moreover, Dll4 inhibition had no appreciable effect on follicular development. These results show that Dll4 has a specific and critical role in the development of the normal luteal vasculature

Genetic affinities between trans-oceanic populations of non-buoyant macroalgae in the high latitudes of the Southern Hemisphere

Marine biologists and biogeographers have long been puzzled by apparently non-dispersive coastal taxa that nonetheless have extensive transoceanic distributions. We here carried out a broad-scale phylogeographic study to test whether two widespread Southern Hemisphere species of non-buoyant littoral macroalgae are capable of long-distance dispersal. Samples were collected from along the coasts of southern Chile, New Zealand and several subAntarctic islands, with the focus on high latitude populations in the path of the Antarctic Circumpolar Current or West Wind Drift. We targeted two widespread littoral macroalgal species: the brown alga Adenocystisutricularis (Ectocarpales, Heterokontophyta) and the red alga Bostrychiaintricata (Ceramiales, Rhodophyta). Phylogenetic analyses were performed using partial mitochondrial (COI), chloroplast (rbcL) and ribosomal nuclear (LSU / 28S) DNA sequence data. Numerous deeply-divergent clades were resolved across all markers in each of the target species, but close phylogenetic relationships - even shared haplotypes - were observed among some populations separated by large oceanic distances. Despite not being particularly buoyant, both Adenocystisutricularis and Bostrychiaintricata thus show genetic signatures of recent dispersal across vast oceanic distances, presumably by attachment to floating substrata such as wood or buoyant macroalgae.This work was funded by New Zealand Marsden contract 07-UOO-099, Department of Zoology and University of Otago Research grants to JMW and CIF; a Shackleton Scholarship to CIF; an Allan Wilson Centre for Molecular Ecology and Evolution postdoctoral grant to CIF; Australian Antarctic Division AAS project #2914

Size induced metal insulator transition in nanostructured Niobium thin films: Intragranular and intergranular contributions

With a reduction in the average grain size in nanostructured films of elemental Nb, we observe a systematic crossover from metallic to weakly-insulating behavior. An analysis of the temperature dependence of the resistivity in the insulating phase clearly indicates the existence of two distinct activation energies corresponding to inter-granular and intra-granular mechanisms of transport. While the high temperature behavior is dominated by grain boundary scattering of the conduction electrons, the effect of discretization of energy levels due to quantum confinement shows up at low temperatures. We show that the energy barrier at the grain boundary is proportional to the width of the largely disordered inter-granular region, which increases with a decrease in the grain size. For a metal-insulator transition to occur in nano-Nb due to the opening up of an energy gap at the grain boundary, the critical grain size is ~ 8nm and the corresponding grain boundary width is ~ 1.1nm

Conditional ablation of macrophages disrupts ovarian vasculature

Macrophages are the most abundant immune cell within the ovary. Their dynamic distribution throughout the ovarian cycle and heterogenic array of functions suggest the involvement in various ovarian processes, but their functional role has yet to be fully established. The aim was to induce conditional macrophage ablation to elucidate the putative role of macrophages in maintaining the integrity of ovarian vasculature. Using the CD11b-diphtheria toxin receptor (DTR) mouse, in which expression of human DTR is under the control of the macrophage-specific promoter sequence CD11b, ovarian macrophages were specifically ablated in adult females by injections of diphtheria toxin (DT). CD11b-DTR mice were given DT treatment or vehicle and ovaries collected at 2, 8, 16, 24 and 48 h. Histochemical stains were employed to characterise morphological changes, immunohistochemistry for F4/80 to identify macrophages and the endothelial cell marker CD31 used to quantify vascular changes. In normal ovaries, macrophages were detected in corpora lutea and in the theca layer of healthy and atretic follicles. As macrophage ablation progressed, increasing amounts of ovarian haemorrhage were observed affecting both luteal and thecal tissue associated with significant endothelial cell depletion, increased erythrocyte accumulation and increased follicular atresia by 16 h. These events were followed by necrosis and profound structural damage. Changes were limited to the ovary, as DT treatment does not disrupt the vasculature of other tissues likely reflecting the unique cyclical nature of the ovarian vasculature and heterogeneity between macrophages within different tissues. These results show that macrophages play a critical role in maintaining ovarian vascular integrity

Development and Deployment of the OpenMRS-Ebola Electronic Health Record System for an Ebola Treatment Center in Sierra Leone.

BACKGROUND: Stringent infection control requirements at Ebola treatment centers (ETCs), which are specialized facilities for isolating and treating Ebola patients, create substantial challenges for recording and reviewing patient information. During the 2014-2016 West African Ebola epidemic, paper-based data collection systems at ETCs compromised the quality, quantity, and confidentiality of patient data. Electronic health record (EHR) systems have the potential to address such problems, with benefits for patient care, surveillance, and research. However, no suitable software was available for deployment when large-scale ETCs opened as the epidemic escalated in 2014. OBJECTIVE: We present our work on rapidly developing and deploying OpenMRS-Ebola, an EHR system for the Kerry Town ETC in Sierra Leone. We describe our experience, lessons learned, and recommendations for future health emergencies. METHODS: We used the OpenMRS platform and Agile software development approaches to build OpenMRS-Ebola. Key features of our work included daily communications between the development team and ground-based operations team, iterative processes, and phased development and implementation. We made design decisions based on the restrictions of the ETC environment and regular user feedback. To evaluate the system, we conducted predeployment user questionnaires and compared the EHR records with duplicate paper records. RESULTS: We successfully built OpenMRS-Ebola, a modular stand-alone EHR system with a tablet-based application for infectious patient wards and a desktop-based application for noninfectious areas. OpenMRS-Ebola supports patient tracking (registration, bed allocation, and discharge); recording of vital signs and symptoms; medication and intravenous fluid ordering and monitoring; laboratory results; clinician notes; and data export. It displays relevant patient information to clinicians in infectious and noninfectious zones. We implemented phase 1 (patient tracking; drug ordering and monitoring) after 2.5 months of full-time development. OpenMRS-Ebola was used for 112 patient registrations, 569 prescription orders, and 971 medication administration recordings. We were unable to fully implement phases 2 and 3 as the ETC closed because of a decrease in new Ebola cases. The phase 1 evaluation suggested that OpenMRS-Ebola worked well in the context of the rollout, and the user feedback was positive. CONCLUSIONS: To our knowledge, OpenMRS-Ebola is the most comprehensive adaptable clinical EHR built for a low-resource setting health emergency. It is designed to address the main challenges of data collection in highly infectious environments that require robust infection prevention and control measures and it is interoperable with other electronic health systems. Although we built and deployed OpenMRS-Ebola more rapidly than typical software, our work highlights the challenges of having to develop an appropriate system during an emergency rather than being able to rapidly adapt an existing one. Lessons learned from this and previous emergencies should be used to ensure that a set of well-designed, easy-to-use, pretested health software is ready for quick deployment in future