Vaginal yeasts in the era of "over the counter" antifungals

OBJECTIVE: To establish whether there has been any rise in the prevalence of non-albicans Candida species isolated from vaginal swabs since the introduction of “over the counter” antifungal treatments. METHOD: A retrospective review looking at all positive vaginal yeast isolates collected from women attending one genitourinary medicine clinic during the 6 year period from 1993 to 1998 inclusive. All positive vaginal yeast isolates were included, regardless of whether or not the patients were symptomatic. Isolates from HIV positive women were excluded from the analysis. RESULT: No increase in non-albicans vaginal yeast isolates was shown during the period studied. The proportion of non-albicans yeasts remained constant at approximately 5% of the total yeasts isolated. The most common non-albicans yeast isolated was C glabrata. CONCLUSION: There is no evidence from this study to suggest that the increasing use of “over the counter” antifungal treatment has selected for atypical, possibly inherently azole resistant, strains of vaginal yeasts in HIV seronegative women

An investigation into the pathogenesis of vulvo-vaginal candidosis

OBJECTIVE: To monitor yeasts isolated from women during and between episodes of recurrent vulvo-vaginal candidosis (VVC) to determine whether vaginal relapse or re-infection occurred. METHODS:Women presenting at the genitourinary medicine clinic with signs and symptoms of VVC were recruited to the study (n = 121). A vaginal washing, high vaginal swab (HVS) and rectal swab were taken and the women treated with a single 500 mg clotrimazole pessary.Women were asked to re-attend after 1, 4, and 12 weeks, or when the VVC recurred, when vaginal washings and HVS were repeated. Candida isolates recovered were strain typed using the Ca3 probe and their similarity assessed. Antifungal susceptibility to fluconazole and clotrimazole were determined. RESULTS: Of the women recruited, 47 completed the study, either returning for four visits or suffering a recurrence during the study period. Of the 22 women who experienced recurrence, the same strain was responsible for the initial and recurrent episode in 17 women. For the remaining five women, four had strain replacement and one had a change of species. None of the isolates recovered from the women demonstrated resistance to either clotrimazole or fluconazole. CONCLUSIONS: Our findings support the theory of vaginal relapse and thus may support the use of more prolonged courses of antifungal therapy initially to increase the chances of eradication of the yeast

ARQ-197, a small-molecule inhibitor of c-Met, reduces tumour burden and prevents myeloma-induced bone disease in vivo

The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma. Patients with elevated levels of HGF have a poor prognosis, therefore, targeting these entities in such patients may be of substantial benefit. We hypothesized that ARQ-197 (Tivantinib), a small molecule c-Met inhibitor, would reduce myeloma cell growth and prevent myeloma-associated bone disease in a murine model. In vitro we assessed the effects of ARQ-197 on myeloma cell proliferation, cytotoxicity and c-Met protein expression in human myeloma cell lines. In vivo we injected NOD/SCID-γ mice with PBS (non-tumour bearing) or JJN3 cells and treated them with either ARQ-197 or vehicle. In vitro exposure of JJN3, U266 or NCI-H929 cells to ARQ-197 resulted in a significant inhibition of cell proliferation and an induction of cell death by necrosis, probably caused by significantly reduced levels of phosphorylated c-Met. In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group. However, no significant differences on bone parameters were observed in non-tumour mice treated with ARQ-197 compared to vehicle, implying that in tumour-bearing mice the effects of ARQ-197 on bone cells was indirect. In summary, these res ults suggest that ARQ-197 could be a promising therapeutic in myeloma patients, leading to both a reduction in tumour burden and an inhibition of myeloma-induced bone disease

NOD/SCID-GAMMA Mice Are an Ideal Strain to Assess the Efficacy of Therapeutic Agents Used in the Treatment of Myeloma Bone Disease

Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7–8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease

Numerical simulation of the stochastic dynamics of inclusions in biomembranes in presence of surface tension

The stochastic dynamics of inclusions in a randomly fluctuating biomembrane is simulated. These inclusions can represent the embedded proteins and the external particles arriving at a cell membrane. The energetics of the biomembrane is modelled via the Canham-Helfrich Hamiltonian. The contributions of both the bending elastic-curvature energy and the surface tension of the biomembrane are taken into account. The biomembrane is treated as a two-dimensional sheet whose height variations from a reference frame is treated as a stochastic Wiener process. The lateral diffusion parameter associated with this Wiener process coupled with the longitudinal diffusion parameter obtained from the standard Einsteinian diffusion theory completely determine the stochastic motion of the inclusions. It is shown that the presence of surface tension significantly affects the overall dynamics of the inclusions, particularly the rate of capture of the external inclusions, such as drug particles, at the site of the embedded inclusions, such as the embedded proteins.Comment: 17 pages, 4 figures, to appear in physica

Machine learning approaches for cancer bone segmentation from micro computed tomography images

Many types of cancers such as multiple myeloma cause bone destruction, resulting in pain and fractures in patients and increased fatality. To quantify the degree of bone disease caused by cancer and analyse treatment response for bone repairing, accurate knowledge of the volumetry of all lesions is needed. To this end, this study proposes to apply two main approaches to the segmentation of bone lesions in cancer-induced bone disease from Micro Computed Tomography (μCT) images - structured forest-based edge detection approach and deep learning approach. A fast edge detection approach with structured forest, an extension of [1], is applied to identify the volumetry of all lesions in mice tibia, where the obtained results are evaluated against the manually labelled data, demonstrating the efficiency of the compared approaches. The Gaussian processes (Convnet GP) approach has achieved the best performance among the compared approaches, with 99.6% intersection of union and 99.7% precision. Our results demonstrate that the developed approach provides a reasonable delineation of the samples, showing the great potential towards fully automatic bone tumour segmentation

Detection of H2O and evidence for TiO/VO in an ultra hot exoplanet atmosphere

This is the author accepted manuscript. The final version is available from American Astronomical Society via the DOI in this recordWe present a primary transit observation for the ultra hot (Teq 2400 K) gas giant expolanetWASP-121b, made using the Hubble Space Telescope Wide Field Camera 3 in spectroscopic mode across the 1.12{1.64 m wavelength range. The 1.4 m water absorption band is detected at high con dence (5:4 ) in the planetary atmosphere. We also reanalyze ground-based photometric lightcurves taken in the B, r0, and z0 lters. Signi cantly deeper transits are measured in these optical bandpasses relative to the near-infrared wavelengths. We conclude that scattering by high-altitude haze alone is unlikely to account for this di erence, and instead interpret it as evidence for titanium oxide and vanadium oxide absorption. Enhanced opacity is also inferred across the 1:12{1:3 m wavelength range, possibly due to iron hydride absorption. If con rmed, WASP-121b will be the rst exoplanet with titanium oxide, vanadium oxide, and iron hydride detected in transmission. The latter are important species in M/L dwarfs, and their presence is likely to have a signi cant e ect on the overall physics and chemistry of the atmosphere, including the production of a strong thermal inversionThe research leading to these results has received funding from the European Research Council under the European Union Seventh Framework Program (FP7/2007-2013) ERC grant agreement no. 336792

Superficial deep-water sediments of the Eastern Marmara Basin

Superficial sediments (top ∼ Im) of the Eastern Mediterranean Basin, Sea of Marmara, Turkey accumulated rapidly (0.087 ± 0.012 g/cm2 · y) by hemipelagic sedimentation with only limited amounts of gravity flow or bottom current action under low oxygenated but not anoxic conditions. They have restricted faunas, relatively higher organic carbon (1-1.8%) and lower calcium carbonate (14-20%) contents than other Eastern Mediterranean Basin sediments. Sedimentation shows little change over the last millenium except for an increase in Cu, Zn, Pb, Cr, and P over the last few centuries. The increase was most likely caused by increased metallurgical activities since the eighteenth century but are not at sufficient levels for the area to be regarded as polluted. © 1989 Springer-Verlag New York Inc

TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model

Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumour phase murine model mimicking the plateau phase in patients, as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo microCT we show substantial and rapid bone lesion repair (and prevention) driven by SD‐208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266‐GFP‐luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair‐like mechanism and that SD‐208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte‐derived PTHrP, increased osteoblasts, decreased osteoclasts and lower serum TRACP‐5b. SD‐208 also completely prevented bone lesion development mice with aggressive JJN3 tumors, and was more effective than an anti‐TGFβ neutralizing antibody (1D11). We also discovered that SD‐208 promoted osteoblastic differentiation (and overcame the TGFβ‐induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture‐resistance with SD‐208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality