Modulatory effects of TGF-ß1 and BMP6 on thecal angiogenesis and steroidogenesis in the bovine ovary.

Angiogenesis plays an integral role in follicular and luteal development and is positively regulated by several intra-ovarian factors including vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 2 (FGF2). Various transforming growth factor-ß (TGF-ß) superfamily members function as intra-ovarian regulators of follicle and luteal function, but their potential roles in modulating ovarian angiogenesis have received little attention. In this study, we used a bovine theca interna culture model (exhibiting characteristics of luteinization) to examine the effects of TGF-ß1 and bone morphogenetic protein 6 (BMP6) on angiogenesis and steroidogenesis. VEGFA/FGF2 treatment promoted endothelial cell network formation but had little or no effect on progesterone and androstenedione secretion or expression of key steroidogenesis-related genes. TGF-ß1 suppressed basal and VEGFA/FGF2-induced endothelial cell network formation and progesterone secretion, effects that were reversed by an activin receptor-like kinase 5 (ALK5) inhibitor (SB-431542). The ALK5 inhibitor alone raised androstenedione secretion and expression of several transcripts including CYP17A1. BMP6 also suppressed endothelial cell network formation under VEGFA/FGF2-stimulated conditions and inhibited progesterone secretion and expression of several steroidogenesis-related genes under basal and VEGFA/FGF2-stimulated conditions. These effects were reversed by an ALK1/2 inhibitor (K02288). Moreover, the ALK1/2 inhibitor alone augmented endothelial network formation, progesterone secretion, androstenedione secretion and expression of several steroidogenesis-related genes. The results indicate dual suppressive actions of both TGF-ß1 and BMP6 on follicular angiogenesis and steroidogenesis. Further experiments are needed to unravel the complex interactions between TGF-ß superfamily signalling and other regulatory factors controlling ovarian angiogenesis and steroidogenesis.

Hepatitis C virus and its cutaneous manifestations: treatment in the direct-acting antiviral era.

New all-oral direct-acting antivirals (DAA) have changed the hepatitis C virus (HCV) treatment landscape. Given that dermatologists frequently encounter HCV-infected patients, knowledge of the current treatment options and their utility in treating HCV-associated dermatologic disorders is important. In addition to highlighting the new treatment options, we review four classically HCV-associated dermatologic disorders - mixed cryoglobulinaemia (MC), lichen planus (LP), porphyria cutanea tarda (PCT) and necrolytic acral erythema (NAE) - and examine the role for all-oral direct-acting antiviral (DAA) regimens in their treatment. A literature search of English-language publications was conducted of the PubMed and EMBASE databases using search terms including 'hepatitis C', 'direct acting antivirals', 'cutaneous', 'mixed cryoglobulinemia', 'necrolytic acral erythema', 'lichen planus', 'porphyria cutanea tarda', 'rash', as well as specific drug names, related terms and abbreviations. Currently, limited data exist on the use of DAAs in HCV-infected patients with cutaneous side-effects, although treatment of the underlying HCV is now recommended for nearly all patients, with the new drugs offering much-improved dosage schedules and side-effect profiles. The most data exist for MC, in which several studies suggest that DAAs and achievement of sustained virologic response (SVR) improve cutaneous symptoms. Studies of both older and newer regimens are limited by their small size, retrospective nature, lack of appropriate controls and wide variability in study protocols. Given the strong association, screening for HCV should be considered in patients with MC, LP, PCT and NAE.

A dynamical calibration of the mass-luminosity relation at very low stellar masses and young ages.

Mass is the most fundamental parameter of a star, yet it is also one of the most difficult to measure directly. In general, astronomers estimate stellar masses by determining the luminosity and using the 'mass-luminosity' relationship, but this relationship has never been accurately calibrated for young, low-mass stars and brown dwarfs. Masses for these low-mass objects are therefore constrained only by theoretical models. A new high-contrast adaptive optics camera enabled the discovery of a young (50 million years) companion only 0.156 arcseconds (2.3 au) from the more luminous (> 120 times brighter) star AB Doradus A. Here we report a dynamical determination of the mass of the newly resolved low-mass companion AB Dor C, whose mass is 0.090 +/- 0.005 solar masses. Given its measured 1-2-micrometre luminosity, we have found that the standard mass-luminosity relations overestimate the near-infrared luminosity of such objects by about a factor of approximately 2.5 at young ages. The young, cool objects hitherto thought to be substellar in mass are therefore about twice as massive, which means that the frequency of brown dwarfs and planetary mass objects in young stellar clusters has been overestimated.

Angiogenesis and vascular function in the ovary.

Ovarian function is dependent on the establishment and continual remodelling of a complex vascular system. This enables the follicle and/or corpus luteum (CL) to receive the required supply of nutrients, oxygen and hormonal support as well as facilitating the release of steroids. Moreover, the inhibition of angiogenesis results in the attenuation of follicular growth, disruption of ovulation and drastic effects on the development and function of the CL. It appears that the production and action of vascular endothelial growth factor A (VEGFA) is necessary at all these stages of development. However, the expression of fibroblast growth factor 2 (FGF2) in the cow is more dynamic than that of VEGFA with a dramatic upregulation during the follicular-luteal transition. This upregulation is then likely to initiate intense angiogenesis in the presence of high VEGFA levels. Recently, we have developed a novel ovarian physiological angiogenesis culture system in which highly organised and intricate endothelial cell networks are formed. This system will enable us to elucidate the complex inter-play between FGF2 and VEGFA as well as other angiogenic factors in the regulation of luteal angiogenesis. Furthermore, recent evidence indicates that pericytes might play an active role in driving angiogenesis and highlights the importance of pericyte-endothelial interactions in this process. Finally, the targeted promotion of angiogenesis may lead to the development of novel strategies to alleviate luteal inadequacy and infertility.

Astronomical demonstration of an optical vortex coronagraph.

Using an optical vortex coronagraph and simple adaptive optics techniques, we have made the first convincing demonstration of an optical vortex coronagraph that is coupled to a star gazing telescope. We suppressed by 97% the primary star of a resolvable binary system, Cor Caroli. The stars had an angular separation of 1.9lambda/D at our imaging camera. The secondary star suffered no suppression from the vortex lens.

Optical calibration and performance of the adaptive secondary mirror at the Magellan telescope.

In this paper we describe the procedure for the optical calibration of large size deformable mirrors, acting as wavefront correctors for adaptive optics systems. Adaptive optics compensate the disturbance due to the atmospheric turbulence to restore the telescope resolution. We will showcase in particular the activities performed for the Adaptive Secondary Mirror (ASM) of the Magellan Adaptive Optics system (MagAO), which is an instrument for the 6.5 m Magellan Clay Telescope, located at Las Campanas Observatory, in Chile. The MagAO ASM calibration is part of the MagAO-2K project, a major MagAO upgrade that started in 2016 with the goal of boosting adaptive optics (AO) correction at visible wavelengths to image exoplanets. For the first time, the optical quality of MagAO mirror is reported. We describe the procedures developed to achieve high SNR interferometric measurements of the ASM modes under the presence of dome convection noise and telescope vibrations. These measurements were required to produce an improved control matrix with up to 500 modes to close the AO loop on sky with enhanced performances. An updated slaving algorithm was developed to improve the control of actuators vignetted by the central obscuration. The calibrations yielded also a new ASM flattening command, updating the one in use since the MagAO commissioning in 2013. With the new flattening command, a 22 nm RMS surface error was achieved. Finally, we present on-sky results showing the MagAO performance achieved with the new calibrations.

Cabozantinib Loaded DSPE-PEG2000 Micelles as Delivery System: Formulation, Characterization and Cytotoxicity Evaluation.

Cabozantinib, a potent pan-tyrosine kinase inhibitor, has been reported to provide enhanced antitumor efficacy by simultaneously inhibiting both MET and VEGF pathways, which are critical to tumor angiogenesis, survival and migration. It's very poor water solubility prevents its administration by the intravenous route, which may be important in patients unable to take the drug orally. In this study, we developed an efficient PEG-lipid-based polymeric micelle formulation with enhanced drug solubility and stability for cabozantinib delivery. DSPE-PEG2000 micelles encapsulating cabozantinib were prepared by a thin-film rehydration method followed by a lyophilization process to generate the dry dosage form. The average hydrodynamic diameter of freshly prepared micelles was 11 nm with a narrow size distribution, and the dry micelle cake could be fully reconstituted by rehydration. Approximately 75% of the drug was encapsulated into the lyophilized cake, and a sustained drug release profile was observed in simulated normal physiological release medium. Compared with the free cabozantinib solution, the drug-loaded micelles displayed significantly enhanced intracellular accumulation and cytotoxicity in human glioblastoma cancer cells and non-small lung cancer cells. These results suggest that the micellar formulation of cabozantinib may serve as a promising nanocarrier in anticancer treatments.

Hypothalamic pituitary adrenal function in the extremely low birth weight infant.

Extremely premature infants manifest clinical features suggestive of adrenal insufficiency. Yet, serum cortisol levels are similar in ill and well preterm infants in a setting where one would expect high stress levels in the ill infants. We investigated the hypothalamic-pituitary-adrenal axis in 17 extremely low birth weight stressed premature infants, mean birth weight 739 g, gestational age, 26.1 weeks, using ovine CRH (oCRH) and ACTH stimulation. oCRH (1 microgram/kg) was administered at 2-7 days of life (mean = 4.1). ACTH rose from a basal value 6.0 +/- 0.8 pmol/L (mean +/- SEM) to 9.6 +/- 1.8 pmol/L (P < 0.01) at 15 min and 9.5 +/- 1.7 pmol/L (P < 0.01) at 60 min. Basal cortisol rose from 349.3 +/- 58.1 nmol/L to 422.3 +/- 57.9 nmol/L (P < 0.01) at 15 min and 568.7 +/- 60.2 nmol/L (P < 0.01) at 60 min. Cortisol values remained significantly (P < 0.05) elevated 24 h after oCRH. An ACTH stimulation test performed 24 h after the oCRH test demonstrated a significant cortisol rise from 603.5 +/- 130.5 nmol/L to 882.7 +/- 136.6 nmol/L (P < 0.05) at 60 min. Plasma CRH immunoactivity was also measured before oCRH testing and was detectable in 10 of 15 infants. The mean CRH immunoactivity was 21.8 +/- 4.4 pmol/L in the infants, significantly higher than 8 adult male controls (P < 0.04). Our results show a normal pituitary response to ovine CRH and a normal adrenal response to ACTH. We hypothesize that cortisol levels are inappropriately low in some ill preterm infants because of the inability of the extremely premature brain to recognize the stress of the illness or because of inadequate hypothalamic secretion of CRH. The significance of the measurable plasma CRH in the first week of life is unknown.

Nitroprusside inhibits neurotransmitter release at the frog neuromuscular junction.

Sodium nitroprusside (SNP), when applied at concentrations ranging from 0.01 microM to 1.0 mM, reduced endplate potentials in sartorius muscle fibers of the frog (Rana pipiens) by a mean of 57% (range 37-79%). Using quantal analysis, this reduction was shown to be predominantly, if not exclusively, due to a reduction in neurotransmitter release rather than a decrease in postsynaptic sensitivity. Inhibition of neuromuscular transmission was not observed if the preparation was pretreated with bovine hemoglobin prior to the addition SNP nor if 'old' SNP solutions, in which the SNP had decomposed for at least 24 h, were applied. These results suggest that nitric oxide inhibits the evoked release of neurotransmitter at the frog neuromuscular junction.

Interrelationships between the renin angiotensin system and uteroplacental blood flow--a recent perspective.

In pregnancy, the maternal circulating renin-angiotensin system (RAS) and uteroplacental tissue RAS has been thought to support maternal placental flow by raising maternal arterial pressure or changing placental vascular resistance. Also, the placenta or uterus may alter maternal circulating RAS. Recent studies in the authors' laboratory using chronically catheterized rabbits are compared with previous studies on interactions between the RAS and uteroplacental flow. When uterine driving pressure was reduced either mechanically or after converting enzyme inhibition, maternal placental flow decreased in proportion to change in driving pressure; myoendometrial flow did not change. Angiotensin II (AII) infusion to increase pressure by 21 +/- 2 mm Hg decreased placental but not myoendometrial flow. Thus, there is no evidence that maternal placental flow is autoregulated or supported by a specific renin-angiotensin mechanism. Normally, there is no net uterine release or uptake of active plasma renin activity, AI, or AII, but there is a small net release of trypsin-activated plasma renin activity (tPRA), presumably prorenin. Distal aortic occluder inflation produced upper-body hypertension, and uterine release of tPRA increased. There was a significant uterine arteriovenous concentration difference for AII during AII infusion. These methods are adaptable for studying interactions between uteroplacental flow and other vasoactive agents.

Kinetics of fluid delivery from methylcellulose sponges.

PURPOSE: The authors quantitatively evaluate the kinetics of fluid transfer from microsurgical sponges in a laboratory model to understand the kinetics of mitomycin C (MMC) delivery. METHODS: The amount of fluid transferred from soaked methylcellulose (Weck-cel, Weck Inc., Durham, NC, U.S.A.) sponges to small pieces of hydrated or dry filter paper used to simulate episcleral tissue and Tenon fascia was measured as a function of time, sponge size, hydration status of the filter paper, and technique of sponge application. RESULTS: The time course of fluid delivery from methylcellulose sponges to filter paper was nonlinear and characterized by a rapid delivery phase over the first 15 to 30 seconds, followed by a slow phase extending to at least 5 minutes. Sponge size and baseline hydration of the paper significantly influenced the rate and amount of fluid delivered, as did replacing the sponge every minute with a new sponge. CONCLUSION: The transfer of fluid from a microsurgical sponge displays nonlinear kinetics, with the majority of delivery occurring in the first 15 to 30 seconds. Sponge size, hydration of the recipient tissue, and technique of sponge application are significant variables influencing the amount of fluid, and therefore mitomycin C, delivered.

Screening for middle ear disease in a school for the deaf.

During the 1977-78 academic year, a study was conducted at the Western Pennsylvania School for the Deaf (WPSD) to evaluate, in a population of profoundly deaf students: 1) the incidence of middle ear (ME) effusion; 2) the correlation between high negative ME pressure (HNP) and ME effusion; and 3) the effect of HNP (> -100 mm H2L) on auditory acuity. All 446 students at WPSD were screened three times (fall, winter, and spring) by both otoscopy and tympanometry and were then classified as belonging to one of five categories according to the status of their ME. Otoscopic, tympanometric, and audiometric evaluations were conducted monthly for 41 study-group students with HNP and 41 controls with normal ears. Tabulations of the incidence of ME conditions over the year-long period showed that 8% of the students had effusion, 21% HNP, 1% inactive disease, 26% residual disease, and 44% normal ME. The majority of severe ME problems occurred in children between the ages of two and eight years. HNP proved insufficient to predict the occurrence of an effusion in children aged 6 to 21 years. However, only 21% of the ears in which HNP was identified returned to and remained normal for the entire year, as contrasted with the initially normal or "controls," of which 77% remained normal. In this profoundly deaf population, the correlation between HNP and threshold shifts proved difficult to document. A small but significantly greater fluctuation in threshold during the period of a year was noted, however, when the students with HMP were compared with the controls.

New Zealand's northern mosquito survey, 1988-89.

The latest mosquito survey of the warmer regions of New Zealand (NZ) sampled 2,304 larval mosquito habitats of all major categories. While revealing no evidence of new establishments of exotic mosquitoes, it produced important data revealing the underutilization of types of habitats that could be invaded now or in the future (especially if the "greenhouse effect" eventually causes even quite small rises in average temperatures and sea levels). Although long feared additions of malaria vectors to a fauna still lacking any species of Anopheles, or of essentially tropical arbovirus vectors from neighboring countries to the north and northeast, may not materialize failing climatic amelioration, a new danger appeared at the beginning of the 1988-89 Northern Mosquito Survey when Aedes albopictus was reported for the first time from Fiji. This vector of dengue hemorrhagic fever and Ross River virus has since been spreading widely on the archipelago's main island, Viti Levu, whence much air and sea traffic reaches NZ. Information presented and discussed herein strongly supports the continuance and improvement of international aircraft disinsection and other insect quarantine measures.

Northernmost occurrences of the protistan pathogen, Coelomomyces stegomyiae var. stegomyiae.

Now reported as parasitizing the ovaries of female Aedes albopictus on Kabeshima (33.33N x 129.53E), Coelomomyces stegomyiae var. stegomyiae had been found earlier in larvae of this mosquito on Mikura-jima (33.53N x 139.35E). These findings from 2 widely separated little Japanese islands constitute the parasite's most northerly records to date. Few previous reports of Coelomomyces spp., none concerning C. stegomyiae, have involved adult mosquitoes. Possible reasons for this are advanced.

Japanese Aedes albopictus among four mosquito species reaching New Zealand in used tires.

Since a 1988-89 survey of northern New Zealand revealed no additions to the known mosquito fauna, this country's used tire importations have much increased. Relevant entomological quarantine was thus monitored in a November 1992-January 1993 Auckland project, during which almost 1/3 of 8,549 casings from Japan proved wet on inspection. In this study and at 2 South Island ports afterwards, 5 vessels from Japan and one from Australia were found to have brought in mosquito-infested used tires. Live Aedes albopictus (all larval instars, pupae, and adults) and Aedes japonicus, and dead Tripteroides bambusa were discovered in shipments from Japan (3 interceptions each in the first 2 cases, and one in the 3rd). Live Tripteroides tasmaniensis were recorded from the Australian cargo. One of the Ae. albopictus arrivals was followed by an apprehended introduction at an Auckland importer's premises.

Contraceptives: a look at the future.

PIP: Some future contraceptives promise new reliability and convenience. The Silastic vaginal ring is expected to be available worldwide in the mid-1990s. The ring releases 250 to 280 mcg of levonorgestrel and 180 mcg of estradiol, a combination that virtually eliminates ovulation. A low-dose ring is also being investigated. Contraceptive implants of Silastic polymer-based rods or capsules are inserted under the skin; these slowly release progestogen that suppresses ovulation. These implants are currently available in Scandinavian countries, Indonesia, and South America. The cervical cap has recently returned to the US market. The woman applies a spermicidal cream or jelly in the cap and places it over her cervix. It can be left in place for up to 36 hours. At present, 80 countries use various injectable drugs that inhibit ovulation for 2-3 months, but they are not yet approved in the USA because of their potential side effects. Under investigation in the US and elsewhere are antispermatogenic agents that create temporary infertility by interfering either with spermatogenesis or with the sperm's ability to fertilize ova. The agents can be given by injection or taken orally. Developed in France and undergoing clinical trials in the US, RU-486 is a pill that disrupts gestation by interfering with progesterone receptors in the inner lining of the uterus. RU-486 can be used to induce early nonsurgical abortions or routinely each month just before menstruation is due.^ieng

Predicting and preventing pressure ulcers in adults.

Advanced practice nurses and staff nurse skin-care team members provided the necessary expertise and information to integrate AHCPR recommendations in a protocol for patients at risk for skin impairment. Regular practice monitoring and education regarding skin management have proven to be successful strategies. A skin-impairment management protocol is provided.

[Studying the course of HIV-1 infection in cell culture]. / A HIV-1 fertözés lefolyásának tanulmányozása sejtkultúrákban.

The hallmark of AIDS is the gradual loss of CD4+ T-lymphocytes, in spite of their infection in low ratio. The pathomechanism is hardly known, therefore, the production of HIV-1 and certain aspects of cell death were studied. Infectivity was decreased by the acidification of culture media. C8166 cells transformed by HTLV-I and exhibiting features of both immature T lymphocytes and myeloid cells, produced transient protoplasmic surface extrusions, similar to the hairy cell leukemia. These can have a role in the direct cell-to-cell spread of HIV-1. Polarization of nuclei and cell organelles as well as sites of virus budding during syncytium formation resembled the directed lymphokine secretion. Both cell membrane and intravacuolar buddings were characteristic. Abnormal virus particles also were seen. Certain morphological signs resembled apoptosis. Fibroblast cultures in the presence of HIV-1 infected lymphoid cells were arrested in growth and underwent cell death without syncytium formation. The results draw attention to the faster development of AIDS in the case of HIV-1 infection of precursor immune cells. Double infection by HTLV and HIV-1 can result in atypical leukemias.

[Integrated vector control methods and the threat of dengue hemorrhagic fever in the tropical zone of the Pacific Ocean]. / Integrirovannye metody bor'by s perenoschikami i ugroza gemorragicheskoi likhoradlki Denge v tropicheskoi zone Tikhogo Okeana.

Together with a story of the author's earliest visit to Leningrad and first meeting with the late Academician E. N. Pavlovsky , this contribution outlines subsequent developments concerning innovative approaches to the control of Culicidae of medical importance, with particular attention to a major field trial on the atoll of Funafuti , Tuvalu .