Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

Fusion of fundus images and MRI data of the human eye

Purpose Ophthalmologists are confronted with a set of different image modalities to diagnose eye tumors e.g., fundus photography, CT and MRI. However, these images are often complementary and represent pathologies differently. Some aspects of tumors can only be seen in a particular modality. A fusion of modalities would improve the contextual information for diagnosis. The presented work attempts to register color fundus photography with MRI volumes. This would complement the low resolution 3D information in the MRI with high resolution 2D fundus images. Methods MRI volumes were acquired from 12 infants under the age of 5 with unilateral retinoblastoma. The contrast-enhanced T1-FLAIR sequence was performed with an isotropic resolution of less than 0.5mm. Fundus images were acquired with a RetCam camera. For healthy eyes, two landmarks were used: the optic disk and the fovea. The eyes were detected and extracted from the MRI volume using a 3D adaption of the Fast Radial Symmetry Transform (FRST). The cropped volume was automatically segmented using the Split Bregman algorithm. The optic nerve was enhanced by a Frangi vessel filter. By intersection the nerve with the retina the optic disk was found. The fovea position was estimated by constraining the position with the angle between the optic and the visual axis as well as the distance from the optic disk. The optical axis was detected automatically by fitting a parable on to the lens surface. On the fundus, the optic disk and the fovea were detected by using the method of Budai et al. Finally, the image was projected on to the segmented surface using the lens position as the camera center. In tumor affected eyes, the manually segmented tumors were used instead of the optic disk and macula for the registration. Results In all of the 12 MRI volumes that were tested the 24 eyes were found correctly, including healthy and pathological cases. In healthy eyes the optic nerve head was found in all of the tested eyes with an error of 1.08 +/- 0.37mm. A successful registration can be seen in figure 1. Conclusions The presented method is a step toward automatic fusion of modalities in ophthalmology. The combination enhances the MRI volume with higher resolution from the color fundus on the retina. Tumor treatment planning is improved by avoiding critical structures and disease progression monitoring is made easier.

Comparison of homeopathic globules prepared from high and ultra-high dilutions of various starting materials by ultraviolet light spectroscopy

Objective Homeopathic globules are commonly used in clinical practice, while research focuses on liquid potencies. Sequential dilution and succussion in their production process has been proposed to change the physico-chemical properties of the solvent(s). It has been reported that aqueous potencies of various starting materials showed significant differences in ultraviolet light transmission compared to controls and between different dilution levels. The aim of the present study was to repeat and expand these experiments to homeopathic globules. Methods Globules were specially produced for this study by Spagyros AG (Gümligen, Switzerland) from 6 starting materials (Aconitum napellus, Atropa belladonna, phosphorus, sulfur, Apis mellifica, quartz) and for 6 dilution levels (6x, 12x, 30c, 200c, 200CF (centesimal discontinuous fluxion), 10,000CF). Native globules and globules impregnated with solvents were used as controls. Globules were dissolved in ultrapure water, and absorbance in the ultraviolet range was measured. The average absorbance from 200 to 340 nm was calculated and corrected for differences between measurement days and instrumental drift. Results Statistically significant differences were found for A. napellus, sulfur, and A. mellifica when normalized average absorbance of the various dilution levels from the same starting material (including control and solvent control globules) was compared. Additionally, absorbance within dilution levels was compared among the various starting materials. Statistically significant differences were found among 30c, 200c and 200CF dilutions. Conclusion This study has expanded previous findings from aqueous potencies to globules and may indicate that characteristics of aqueous high dilutions may be preserved and detectable in dissolved globules.

A systematic review of the evidence for use of herbal medicine for the treatment of acute diarrhea

Background. Acute diarrhea (AD) is an important cause of morbidity and mortality among both children and adults. An ideal antidiarrheal treatment should be safe, effective, compatible with Oral Rehydration Solution, and inexpensive. Herbal medicines, if effective, should fit these criteria as well or better than standard treatment. ^ Objective. The objective of the present study was to assess the effectiveness of plant preparations in patients with AD in reports of randomized and non-randomized controlled trials. ^ Aims. The aims of the present study were to identify effective antidiarrheal herbs and to identify potential antidiarrheal herbs for future studies of efficacy through well designed clinical trials in human populations. ^ Methods. Nineteen published studies of herbal management of AD were examined to identify effective plant preparations. Ten plant preparations including Berberine (Berberis aristata), tormentil root ( Potentialla tormentilla), baohauhau (from the baobaosan plant), carob (Ceratonia siliqua), pectin (Malus domestica), wood creosote (Creosote bush), guava (Psidium guajava L.), belladonna (Atropa belladonna), white bean (Phaseolis vulgaris), and wheat (Triticum aestivum) were identified. ^ Results. Qualitative data analysis of nineteen clinical trials indicated berberine’s potentially valuable antisecretory effects against diarrhea caused by Vibrio cholerae and enterotoxigenic Escherichia coli. Tormentil root showed significant efficacy against rotavirus-induced diarrhea; carob exhibited antidiarrheal properties not only by acting to detoxify and constipate but by providing a rich source of calories; guava and belladonna are antispasmodics and have been shown to relieve the symptoms of AD. Finally, white bean and wheat yielded favorable clinical and dietary outcomes in children with diarrhea. ^ Conclusion. The present study is the first to review the evidence for use of herbal compounds for treatment of AD. Future randomized controlled trials are needed to evaluate their efficacy and safety.^

Patenting genes and gene sequences: Analysis of public health implications and the law

At issue is whether or not isolated DNA is patent eligible under the U.S. Patent Law and the implications of that determination on public health. The U.S. Patent and Trademark Office has issued patents on DNA since the 1980s, and scientists and researchers have proceeded under that milieu since that time. Today, genetic research and testing related to the human breast cancer genes BRCA1 and BRCA2 is conducted within the framework of seven patents that were issued to Myriad Genetics and the University of Utah Research Foundation between 1997 and 2000. In 2009, suit was filed on behalf of multiple researchers, professional associations and others to invalidate fifteen of the claims underlying those patents. The Court of Appeals for the Federal Circuit, which hears patent cases, has invalidated claims for analyzing and comparing isolated DNA but has upheld claims to isolated DNA. The specific issue of whether isolated DNA is patent eligible is now before the Supreme Court, which is expected to decide the case by year's end. In this work, a systematic review was performed to determine the effects of DNA patents on various stakeholders and, ultimately, on public health; and to provide a legal analysis of the patent eligibility of isolated DNA and the likely outcome of the Supreme Court's decision. ^ A literature review was conducted to: first, identify principle stakeholders with an interest in patent eligibility of the isolated DNA sequences BRCA1 and BRCA2; and second, determine the effect of the case on those stakeholders. Published reports that addressed gene patents, the Myriad litigation, and implications of gene patents on stakeholders were included. Next, an in-depth legal analysis of the patent eligibility of isolated DNA and methods for analyzing it was performed pursuant to accepted methods of legal research and analysis based on legal briefs, federal law and jurisprudence, scholarly works and standard practice legal analysis. ^ Biotechnology, biomedical and clinical research, access to health care, and personalized medicine were identified as the principle stakeholders and interests herein. Many experts believe that the patent eligibility of isolated DNA will not greatly affect the biotechnology industry insofar as genetic testing is concerned; unlike for therapeutics, genetic testing does not require tremendous resources or lead time. The actual impact on biomedical researchers is uncertain, with greater impact expected for researchers whose work is intended for commercial purposes (versus basic science). The impact on access to health care has been surprisingly difficult to assess; while invalidating gene patents might be expected to decrease the cost of genetic testing and improve access to more laboratories and physicians' offices that provide the test, a 2010 study on the actual impact was inconclusive. As for personalized medicine, many experts believe that the availability of personalized medicine is ultimately a public policy issue for Congress, not the courts. ^ Based on the legal analysis performed in this work, this writer believes the Supreme Court is likely to invalidate patents on isolated DNA whose sequences are found in nature, because these gene sequences are a basic tool of scientific and technologic work and patents on isolated DNA would unduly inhibit their future use. Patents on complementary DNA (cDNA) are expected to stand, however, based on the human intervention required to craft cDNA and the product's distinction from the DNA found in nature. ^ In the end, the solution as to how to address gene patents may lie not in jurisprudence but in a fundamental change in business practices to provide expanded licenses to better address the interests of the several stakeholders. ^

Insights from Native American Veterans on Developing a Patient-Centered, Integrative Model for Mental Health Services

Thesis (Master's)--University of Washington, 2016-06

A combined analysis of two randomized controlled trials evaluating the effect of Mindfulness-Based Stress Reduction on self-reported emotional experience and physiological symptoms among Veterans with Posttraumatic Stress Disorder

Thesis (Master's)--University of Washington, 2016-06

Evaluation of the Feasibility of a Yoga and Mindfulness-Based Mental Health Intervention for Latina Immigrant Mothers

Thesis (Master's)--University of Washington, 2016-06

Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-I trials

Objectives: To investigate the effectiveness of valerian for the management of chronic insomnia in general practice. Design: Valerian versus placebo in a series of n-of-1 trials, in Queensland, Australia. Results: Of 42 enrolled patients, 24 (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to valerian was fair for 23 (96%) participants evaluating their 'energy level in the previous day' but poor or modest for all 24 (100%) participants' response to 'total sleep time' and for 23 (96%) participants' response to 'number of night awakenings' and 'morning refreshment'. As a group, the proportion of treatment successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for the six elicited outcome sleep variables. There was no significant difference in the number (P = 0.06), distribution (P = 1.00) or severity (P = 0.46) of side effects between valerian and placebo treatments. Conclusions: Valerian was not shown to be appreciably better than placebo in promoting sleep or sleep-related factors for any individual patient or for all patients as a group. (C) 2003 Elsevier Ltd. All rights reserved.

A profile of middle-aged women who consult a chiropractor or osteopath: Findings from a survey of 11,143 Australian women

Purpose: The aim of this study is to examine the prevalence of chiropractic and osteopathy use and the profile of chiropractor/osteopath users among middle-aged Australian women. Methods: This article reports on research conducted as part of the Australian Longitudinal Study on Women's Health. The focus of this article is the middle-aged women who responded to Survey 3 in 2001 when they were between the ages of 50 and 55 years. The demographic characteristics, health status, and health service use of chiropractic/osteopathy users and nonusers were compared using chi(2) tests for categorical variables and t tests for continuous variables. Results: We estimate that 16% of middle-aged women consult with a chiropractor or osteopath (after adjustment for the oversampling of rural women). Area of residence, education, and employment status were all statistically significantly associated with chiropractic and osteopath use. Specifically, women who live in nonurban areas were more likely to consult a chiropractor or osteopath, compared with women who live in urban areas. Women are significantly more likely to consult with a chiropractor/osteopath if they have had a major personal injury in the previous year, and women who use chiropractic/osteopathy are also high users of 'conventional' health services. Conclusions: Chiropractic/osteopathy use among women in Australia is substantial and cannot be ignored by those providing or managing primary health care services for women. It is essential that the interface and communication between chiropractors/osteopaths and other health care providers be highlighted and maximized to establish and maintain effective overall patient coordination and management.

The effect of St John's wort extracts on CYP3A: a systematic review of prospective clinical trials

Aim The aim of this systematic review was to assess the quality and outcomes of clinical trials investigating the effect of St John's wort extracts on the metabolism of drugs by CYP3A. Methods Prospective clinical trials assessing the effect of St John's wort (SJW) extracts on metabolism by CYP3A were identified through computer-based searches (from their inception to May 2005) of Medline, Cinahl, PsycINFO, AMED, Current Contents and Embase, hand-searches of bibliographies of relevant papers and consultation with manufacturers and researchers in the field. Two reviewers selected trials for inclusion, independently extracted data and recorded details on study design. Results Thirty-one studies met the eligibility criteria. More than two-thirds of the studies employed a before-and-after design, less than one-third of the studies used a crossover design, and only three studies were double-blind and placebo controlled. In 12 studies the SJW extract had been assayed, and 14 studies stated the specific SJW extract used. Results from 26 studies, including all of the 19 studies that used high-dose hyperforin extracts (> 10 mg day(-1)), had outcomes consistent with CYP3A induction. The three studies using low-dose hyperforin extracts (< 4 mg day(-1)) demonstrated no significant effect on CYP3A. Conclusion There is reasonable evidence to suggest that high-dose hyperforin SJW extracts induce CYP3A. More studies are required to determine whether decreased CYP3A induction occurs after low-dose hyperforin extracts. Future studies should adopt study designs with a control phase or control group, identify the specific SJW extract employed and provide quantitative analyses of key constituents.

Deregulation, competition policy and intra-professional contests in medical education

This paper investigates how government policy directions embracing deregulation and market liberalism, together with significant pre-existing tensions within the Australian medical profession, produced ground breaking change in the funding and delivery of medical education for general practitioners. From an initial view between and within the medical profession, and government, about the goal of improving the standards of general practice education and training, segments of the general practice community, particularly those located in rural and remote settings, displayed increasingly vocal concerns about the approach and solutions proffered by the predominantly urban-influenced Royal Australian College of General Practitioners (RACGP). The extent of dissatisfaction culminated in the establishment of the Australian College of Rural and Remote Medicine (ACRRM) in 1997 and the development of an alternative curriculum for general practice. This paper focuses on two decades of changes in general practice training and how competition policy acted as a justificatory mechanism for putting general practice education out to competitive tender against a background of significant intra-professional conflict. The government's interest in increasing efficiency and deregulating the 'closed shop' practices of professions, as expressed through national competition policy, ultimately exposed the existing antagonisms within the profession to public view and allowed the government some influence on the sacred cow of professional training. Government policy has acted as a mechanism of resolution for long standing grievances of the rural GPs and propelled professional training towards an open competition model. The findings have implications for future research looking at the unanticipated outcomes of competition and internal markets.

The early career researcher's toolkit:translating tissue engineering, regenerative medicine and cell therapy products

Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.