Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy

Objective: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? Methods: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Results: Testing of VKORC1 (-1639G\u3eA), CYP2C92, and CYP2C93 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C95, 6, 8, or 11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. Significance: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event

Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline-inducible mouse model of AML, in which the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous, as ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10-induced overexpression. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. Interestingly, high levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia after removal of the primary event. This suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia

Transmission electron microscopy characterization of fluorescently labelled amyloid β 1-40 and α-synuclein aggregates

<p>Abstract</p> <p>Background</p> <p>Fluorescent tags, including small organic molecules and fluorescent proteins, enable the localization of protein molecules in biomedical research experiments. However, the use of these labels may interfere with the formation of larger-scale protein structures such as amyloid aggregates. Therefore, we investigate the effects of some commonly used fluorescent tags on the morphologies of fibrils grown from the Alzheimer's disease-associated peptide Amyloid β 1-40 (Aβ40) and the Parkinson's disease-associated protein α-synuclein (αS).</p> <p>Results</p> <p>Using transmission electron microscopy (TEM), we verify that N-terminal labeling of Aβ40 with AMCA, TAMRA, and Hilyte-Fluor 488 tags does not prevent the formation of protofibrils and amyloid fibrils of various widths. We also measure the two-photon action cross-section of Aβ40 labelled with Hilyte Fluor 488 and demonstrate that this tag is suitable for use with two-photon fluorescence techniques. Similarly, we find that Alexa Fluor 488 labelling of αS variant proteins near either the N or C terminus (position 9 or 130) does not interfere with the formation of amyloid and other types of αS fibrils. We also present TEM images of fibrils grown from αS C-terminally labelled with enhanced green fluorescent protein (EGFP). Near neutral pH, two types of αS-EGFP fibrils are observed via TEM, while denaturation of the EGFP tag leads to the formation of additional species.</p> <p>Conclusions</p> <p>We demonstrate that several small extrinsic fluorescent tags are compatible with studies of amyloid protein aggregation. However, although fibrils can be grown from αS labelled with EGFP, the conformation of the fluorescent protein tag affects the observed aggregate morphologies. Thus, our results should assist researchers with label selection and optimization of solution conditions for aggregation studies involving fluorescence techniques.</p

Patient-provider interaction from the perspectives of type 2 diabetes patients in Muscat, Oman: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Patients' expectations and perceptions of the medical encounter and interactions are important tools in diabetes management. Some problems regarding the interaction during encounters may be related to a lack of communication skills on the part of either the physician or the patient.</p> <p>This study aimed at exploring the perceptions of type 2 diabetes patients regarding the medical encounters and quality of interactions with their primary health-care providers.</p> <p>Methods</p> <p>Four focus group discussions (two women and two men groups) were conducted among 27 purposively selected patients (13 men and 14 women) from six primary health-care centres in Muscat, Oman. Qualitative content analysis was applied.</p> <p>Results</p> <p>The patients identified some weaknesses regarding the patient-provider communication like: unfriendly welcoming; interrupted consultation privacy; poor attention and eye contact; lack of encouraging the patients to ask questions on the providers' side; and inability to participate in medical dialogue or express concerns on the patients' side. Other barriers and difficulties related to issues of patient-centeredness, organization of diabetes clinics, health education and professional competency regarding diabetes care were also identified.</p> <p>Conclusion</p> <p>The diabetes patients' experiences with the primary health-care providers showed dissatisfaction with the services. We suggest appropriate training for health-care providers with regard to diabetes care and developing of communication skills with emphasis on a patient-centred approach. An efficient use of available resources in diabetes clinics and distributing responsibilities between team members in close collaboration with patients and their families seems necessary. Further exploration of the providers' work situation and barriers to good interaction is needed. Our findings can help the policy makers in Oman, and countries with similar health systems, to improve the quality and organizational efficiency of diabetes care services.</p

Greenland ice sheet surface mass loss: recent developments in observation and modeling

Surface processes currently dominate Greenland ice sheet (GrIS) mass loss. We review recent developments in the observation and modelling of GrIS surface mass balance (SMB), published after the July 2012 deadline for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). Since IPCC AR5 our understanding of GrIS SMB has further improved, but new observational and model studies have also revealed that temporal and spatial variability of many processes are still poorly quantified and understood, e.g. bio-albedo, the formation of ice lenses and their impact on lateral meltwater transport, heterogeneous vertical meltwater transport (‘piping’), the impact of atmospheric circulation changes and mixed-phase clouds on the surface energy balance and the magnitude of turbulent heat exchange over rough ice surfaces. As a result, these processes are only schematically or not at all included in models that are currently used to assess and predict future GrIS surface mass loss

Enhancing Topical Pharmacotherapy for Acne and Rosacea: Vehicle Choices and Outcomes

The choice of vehicle is an important consideration in the treatment of acne and rosacea. Agents used to treat these common conditions may be limited by multiple factors, including poor stability during storage, limited residence time in the skin and follicular unit, and high potential for skin irritation. Novel drug delivery systems have been developed to address these problems, including microencapsulation, liposomal encapsulation, and the use of a variety of nanocarriers. New vehicle technologies for acne and rosacea treatments have appeared over the past 20 years and have somewhat improved stability, tolerability, and possibly efficacy. One of the latest vehicle technologies in acne and rosacea to enhance efficacy, stability, and tolerability is microencapsulation of benzoyl peroxide and tretinoin, which resulted in significant efficacy and good tolerability in patients with each of these two diseases. Other new vehicle technologies include a polymeric form of tretinoin and a microsphere product that combines tretinoin plus clindamycin. It is likely that there will be more reports of clinical success as experience with the rapidly evolving delivery technologies increases. This review summarizes drug delivery systems that have been developed with the aim of improving outcomes for patients being treated for either acne or rosacea. It also focuses, where possible, on formulations that have been evaluated in clinical studies

Spectral diversity and photometric behavior of main-belt and near-Earth vestoids and (4) Vesta: A study in preparation for the Dawn encounter

In anticipation of the Dawn Mission to 4 Vesta, we conducted a ground-based campaign of Bessel BVRI filter photometry of five V-type near-Earth asteroids over a wide range of solar phase angles. We also obtained medium-resolution optical spectroscopy (0.38 μm < λ < 0.92 μm; R ∼ 500) of sixteen near-Earth and main-belt V-type asteroids in order to investigate their spectral diversity and to draw connections between spacecraft data of Vesta and V-type asteroids. Our disk-integrated photometry extended the excursion in solar phase angle beyond the maximum of 24° available from Earth for Vesta to 87°, which is more typical of the geometry during the Dawn approach and mapping phases. The majority of our broad-band observations were obtained at the JPL 0.6-m Table Mountain Observatory but multiple nights were also contributed by the Calar Alto 1.2-m and 2.2-m telescopes, as well as by the Purple Mountain 1-m Schmidt. Our results include a determination of rotation periods for 4 asteroids, identification of a binary candidate and four new V-type asteroids, including a confirmation of two main-belt V-type asteroids beyond the Jupiter 1:3 resonance (Cruikshank, D.P., Tholen, D.J., Bell, J.F., Hartmann, W.K., Brown, R.H. [1991]. Icarus 89, 1–13; Lazzaro, D. et al. [2000]. Science 288, 2033–2035; Roig, F., Gil-Hutton, R. [2006]. Icarus 183(2), 411–419; Moskovitz, N.A., Jedicke, R., Gaidos, E., Willman, M., Nesvorný, D., Fevig, R., Ivezić, Ž. [2008]. Icarus 198, 77–90). This latter finding supports the hypothesis that some vestoids may be crustal fragments of a disrupted basaltic parent body compositionally similar to 4 Vesta. We also obtained rotationally resolved medium resolution spectra of Vesta during the Dawn orbit insertion phase, which will be valuable for calibration and comparison of spacecraft data. Modeling of a composite V-type asteroid phase curve yielded a generic photometric model for V asteroids. We also find that a significant amount of the spectral diversity in the V class comes from changes in solar phase angle. A fit of a composite solar phase curve containing our vestoid observations, previously published groundbased observations of Vesta, and early disk-integrated Dawn observations show important differences with other asteroids. The macroscopic surface roughness of V-type asteroids is significantly larger than that of C-type or S-types (Helfenstein, P., Veverka, J. [1989]. Physical characterization of asteroid surfaces from photometric analysis. In: Binzel, R., Gehrels, T., Matthews, M.S. (Eds.), Asteroids II. University of Arizona Press, Tucson, pp. 557–593). This result is consistent with radar studies showing that igneous rocky asteroids – the E and V types – exhibit the largest surface roughness (Benner, L. et al. [2008]. Icarus 198, 294–304). The effects of what appears to be space weathering can be largely explained by phase reddening in our collection of V-type NEOs, but our finding that smaller vestoids, which have shorter lifetimes, are more similar to Vesta suggests that some type of alteration of the surface through time occurs. Our observations confirm that the south polar region of Vesta has a more diogenitic composition than its equatorial regions. The south pole, which is dominated by a large impact feature, thus may offer a view into the interior of Vesta. We derive a visible phase integral of 0.44 ± 0.02 and a corresponding Bond albedo of 0.15 ± 0.03 from our composite V-type asteroid solar phase curve