A Common Embryonic Origin of Stem Cells Drives Developmental and Adult Neurogenesis.

New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx+ precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx+ neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx+ quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx+ embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a "continuous" model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.

Co-designing strategies to improve advance care planning among people from culturally and linguistically diverse backgrounds with cancer: iCanCarePlan study protocol.

BACKGROUND: Advance care planning (ACP) describes the process of supporting individuals at any age or stage of health to consider and share their personal values, life goals, and preferences regarding future health care. Engaging in ACP is associated with better-quality of care in which people receive care in lines with their wishes, values and preferences. Direct translations of ACP guides and resources do not attend to the considerable inter- and intra-ethnic variations in cultural and religious or spiritual beliefs that shape preferences among people from culturally and linguistically diverse (CALD) backgrounds. ICanCarePlan is a three-year project that aims to determine the prevalence of ACP documentation among people from CALD backgrounds with cancer, identify resources available and their use to support ACP among CALD communities, identify barriers and facilitators of person-centred ACP, and to develop, through co-design with consumers and clinicians, approaches that enhance the process ACP for people from CALD backgrounds. METHOD: A mixed-method sequential approach will be used comprising of four studies. Study one is retrospective medical record review of approximately 1500 medical records to establish the prevalence of ACP documentation among CALD patient records in cancer services. Study two is a document analysis synthesising the resources available in the Australian health system to support ACP. Study three is a qualitative study with healthcare staff and consumers to explore barriers and enablers of person-centred ACP. Evidence generated from studies one to three will inform the conduct of co-design with stakeholders to develop approaches to improve ACP processes among CALD communities. Language, technical and financial support for meaningful involvement with consumers from CALD backgrounds throughout this project is outlined. A plan for distress management is also made due to sensitive nature of the topic. The research project has also established a project steering group consisting of three consumer members who are from CALD backgrounds. DISCUSSION: The project will address a national priority issue for a growing population of CALD communities in Australia. The project will provide novel evidence of ACP among CALD communities and novel strategies developed with stakeholders to enhance uptake and experiences of ACP.

Outcomes of telephone-delivered low-intensity cognitive behaviour therapy (LiCBT) to community dwelling Australians with a recent hospital admission due to depression or anxiety: MindStep™.

BACKGROUND: In 2006, the British government launched 'Improving Access to Psychological Therapies' (IAPT), a low intensity cognitive behaviour therapy intervention (LiCBT) designed to manage people with symptoms of anxiety and depression in the community. The evidence of the effectiveness of IAPT has been demonstrated in multiple studies from the UK, USA, Australia and other countries. MindStep™ is the first adaptation of IAPT in Australia, delivered completely by telephone, targeting people with a recent history of a hospital admission for mental illnesses within the private health system. This paper reports on the outcome of the first 17 months of MindStep™ implemented across Australia from March 2016. METHODS: This prospective observational study investigated the MindStep™ program in a cohort of clients with a recent hospitalisation for mental illnesses. The study used quantitative methods to compare pre-post treatment clinical measures (N = 680) using Patient Health Questionnaire (PHQ-9) and the Generalised Anxiety Disorder (GAD-7). This study also included in-depth interviews with participants (N = 14) and coaches (N = 4) to determine the feasibility and acceptability of the program. RESULTS: Of the 867 clients referred to MindStep™, 757 had initial assessments by phone making an enrolment rate of 87.3%. Following assessment, 680 commenced treatment and of them, 427 (62.7%) completed treatment. According to 'per-protocol' analysis (N = 427), there was a large effect size for post-treatment PHQ-9 (d = 1.03) and GAD-7 (d = 0.99) scores; reliable recovery rate was 62% (95% CI: 57-68%). For intent-to-treat analysis using multiple imputation (N = 680), effect sizes were also large for pre-post treatment change: PHQ-9 (d = 0.78) and GAD-7 (d = 0.76). The reliable recovery rate was 49% (95% CI: 45-54%). Qualitative findings supported these claims where participants were positive about MindStep™ and found the telephone delivery and use of mental health coaches highly acceptable. CONCLUSIONS: MindStep™ has demonstrated encouraging outcomes that suggest LiCBT can be successfully delivered to people with a history of hospital admissions for anxiety and depressive disorders and achieve target recovery rates of > 50%. Other promising evaluation findings indicate the MindStep™ option is acceptable, feasible and safe within the stepped models of mental health care delivery in Australia.

Emergence of differentially regulated pathways associated with the development of regional specificity in chicken skin.

BACKGROUND: Regional specificity allows different skin regions to exhibit different characteristics, enabling complementary functions to make effective use of the integumentary surface. Chickens exhibit a high degree of regional specificity in the skin and can serve as a good model for when and how these regional differences begin to emerge. RESULTS: We used developing feather and scale regions in embryonic chickens as a model to gauge the differences in their molecular pathways. We employed cosine similarity analysis to identify the differentially regulated and co-regulated genes. We applied low cell techniques for expression validation and chromatin immunoprecipitation (ChIP)-based enhancer identification to overcome limited cell availabilities from embryonic chicken skin. We identified a specific set of genes demonstrating a high correlation as being differentially expressed during feather and scale development and maturation. Some members of the WNT, TGF-beta/BMP, and Notch family known to be involved in feathering skin differentiation were found to be differentially regulated. Interestingly, we also found genes along calcium channel pathways that are differentially regulated. From the analysis of differentially regulated pathways, we used calcium signaling pathways as an example for further verification. Some voltage-gated calcium channel subunits, particularly CACNA1D, are expressed spatio-temporally in the skin epithelium. These calcium signaling pathway members may be involved in developmental decisions, morphogenesis, or epithelial maturation. We further characterized enhancers associated with histone modifications, including H3K4me1, H3K27ac, and H3K27me3, near calcium channel-related genes and identified signature intensive hotspots that may be correlated with certain voltage-gated calcium channel genes. CONCLUSION: We demonstrated the applicability of cosine similarity analysis for identifying novel regulatory pathways that are differentially regulated during development. Our study concerning the effects of signaling pathways and histone signatures on enhancers suggests that voltage-gated calcium signaling may be involved in early skin development. This work lays the foundation for studying the roles of these gene pathways and their genomic regulation during the establishment of skin regional specificity.

Dataset of process-structure-property feature relationships for AlSi10Mg material fabricated using laser powder bed fusion additive manufacturing.

This dataset reports microstructure and mechanical property features of AlSi10Mg manufactured using laser powder bed fusion over a wide range of processing conditions. Samples were fabricated with different combinations of laser power, scan speed, and hatch spacing to probe dense regimes as well as porous samples resulting from keyholing and lack of fusion. Pore and grain/sub-grain features for each processing set were quantified. Sample porosity was measured using Archimedes density measurements and X-ray computed tomography (XCT). XCT was also used to characterize the surface roughness of samples along with pore size and morphology. Electron backscatter diffraction (EBSD) was used to characterize the grain size and morphology while scanning electron microscope (SEM) imaging and was used to measure solidification cell size. Uniaxial tension tests were performed to ascertain yield and ultimate tensile strengths, elongation, and elastic modulus, and microhardness was measured using Vickers indentation.

Systematic review and meta-analysis of the clinical outcomes of ACEI/ARB in East-Asian patients with COVID-19.

BACKGROUND: SARS-CoV-2 invades human cells and leads to COVID-19 by direct associating with angiotensin converting enzyme 2 (ACE2) receptors, the level of which may be increased by treatment with angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). This meta-analysis aimed to explore the impact of ACEI/ARB treatment on the clinical outcomes of patients with COVID-19 infections among population in the East-Asia region. METHODS: We collected clinical data published from January 2000 to May 2022 in the English databases including PubMed, Embase, and the Cochrane Library. Two reviewers independently screened and identified studies that met the prespecified criteria. Review Manager 5.3 software was used to perform the meta-analysis. RESULTS: A total of 28 articles were included in this analysis. The results showed that patients who were prescribed with ACEI/ARB had a shorter duration of hospital stay [MD = -2.37, 95%CI (-3.59, -1.14), P = 0.000 2] and a lower mortality rate [OR = 0.61, 95% CI (0.52, 0.70), P<0.000 01] than patients who were not on ACEI/ARB. Furthermore, there was no statistically significant difference in disease severity [OR = 0.99, 95% CI (0.83, 1.17), P = 0.90] between individuals receiving ACEI/ARB or not. CONCLUSIONS: This meta-analysis suggested that the use of ACEI/ARB was not associated with adverse clinical outcomes in East-Asian Covid-19 patients and a reduced mortality and shorter duration of hospital stay among East-Asian population (especially for female subjects) was found. Thus, ACEI/ARB should be continued in patients infected by Covid-19.

Basal cell carcinomas in organ transplant recipients versus the general population: clinicopathologic study.

Organ transplant recipients (OTRs) are at greater risk of basal cell carcinomas (BCCs) than non-OTRs, but histopathologic differences between BCCs in OTRs and the general population are largely unknown. We compared clinicopathologic features of BCCs in OTRs vs the general population in Queensland, Australia. Details of BCC tumors (site, size, level of invasion, subtype, biopsy procedure) were collected from histopathology reports in two prospective skin cancer studies, one in OTRs and one general-population-based. We used log-binomial regression models to estimate age- and sex-adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) for BCC features. Overall, there were 702 BCCs in 200 OTRs and 1725 BCCs in 804 population cases. Of these, 327 tumors in 128 OTRs were higher risk BCCs (any head and neck BCC; ≥ 2 cm on trunk/extremities), more per person than 703 higher risk BCCs in 457 cases in the general population (chi-square p = 0.008). Among head/neck BCCs, OTRs were more likely than general population cases to have BCCs on scalp/ear than on face/lip/neck (PR = 1.5, 95%CI 1.2-1.8). Although aggressive subtypes were less common among higher risk BCCs in OTRs, BCCs invading beyond the dermis were almost twice as prevalent in OTRs (PR = 1.8, 95% CI 1.3-2.6) than the general population.

Current Trends in Circulating Biomarkers for Melanoma Detection.

Melanomas have increased in global incidence and are the leading cause of skin cancer deaths. Whilst the majority of early-stage, non-metastatic melanomas can be cured with surgical excision alone, ~5% of patients with early melanomas will experience recurrence following a variable disease-free interval and progression to metastatic melanoma and ultimately death. This is likely because of primary tumor heterogeneity and progressive clonal divergency resulting in the growth of more aggressive tumor populations. Liquid biomarkers have the advantage of real-time, non-invasive longitudinal monitoring of tumor burden and heterogeneity over tissue markers. Currently, the only serological marker used in the staging and monitoring of melanoma is serum lactate dehydrogenase, which is not sufficiently specific or sensitive, and is not used routinely in all centers. An ideal melanoma biomarker would be used to identify patients who are at high-risk of primary melanoma, screen for relapse, detect early-stage melanoma, provide treatment outcomes to personalize systemic treatment, follow tumor heterogeneity, provide prognostic data before, during and after treatment, and monitor response to treatment. This review provides a summary of the current research in this field with a specific focus on circulating tumor cells, circulating tumor DNA, microRNA, and extracellular vesicles which may serve to suit these goals.

Passive Prescription of Secondary Prevention Medical Therapy during Index Hospitalization for Acute Myocardial Infarction Is Prevalent and Associated with Adverse Clinical Outcomes.

Secondary prevention therapy reduces death and reinfarction after acute myocardial infarction (AMI), but it is underutilized in clinical practice. Mechanisms for this therapeutic gap are not well established. In this study, we have explored and evaluated the impact of passive continuation compared to active initiation of secondary prevention therapy for AMI during the index hospitalization. For this purpose, we have analyzed 1083 consecutive patients with AMI to a tertiary referral hospital in Hong Kong and assessed discharge prescription rates of secondary prevention therapies (aspirin, beta-blockers, statins, and ACEI/ARBs). Multivariate analysis was used to identify independent predictors of discharge medication, and Kaplan-Meier survival curve was used to evaluate 12-month survival. Overall, prescription rates of aspirin, beta-blocker, statin, and ACEI/ARBs on discharge were 94.8%, 64.5%, 83.5%, and 61.4%, respectively. Multivariate analysis showed that prior use of each therapy was an independent predictor of prescription of the same therapy on discharge: aspirin (odds ratio (OR) = 4.8, 95% CI = 1.9-12.3, P < 0.01), beta-blocker (OR = 2.5, 95% CI = 1.8-3.4, P < 0.01); statin (OR = 8.3, 95% CI = 0.4-15.7, P < 0.01), and ACEI/ARBs (OR = 2.9, 95% CI = 2.0-4.3, P < 0.01). Passive continuation of prior medication was associated with higher 1-year mortality rates than active initiation in treatment-naïve patients (aspirin (13.7% vs. 5.7%), beta-blockers (12.9% vs. 5.6%), and statins (11.0% vs. 4.6%); all P < 0.01). Overall, the use of secondary prevention medication for AMI was suboptimal. Our findings suggested that the practice of passive continuation of prior medication was prevalent and associated with adverse clinical outcomes compared to active initiation of secondary preventive therapies for acute myocardial infarction during the index hospitalization.

Cervical cancer and human papillomavirus in indigenous Guyanese women.

OBJECTIVE: The purpose of this study was to determine the prevalence of cervical disease, human papillomavirus infection, and human papillomavirus (HPV) genotypes in indigenous villages of Guyana. STUDY DESIGN: This is a retrospective analysis of a clinical cervical cancer screening and treatment program: 2250 women underwent cytologic screening; 1423 women were concomitantly screened for HPV. HPV genotyping was performed in 45 women with high-grade dysplasia and in 9 women with cervical carcinoma. RESULTS: We found invasive cervical carcinoma in 0.80% of the women, cervical intraepithelial neoplasia II and III in 5.07% of the women, and a high-risk HPV infection rate in 19.3% of the women, all of which peaked between the ages of 20-30 years. Sixteen genotypes were detected in women with high-grade dysplasia or cancer: HPV 31, 25.0%; HPV 16, 22.7%; HPV 18, 13.6%. The rate of HPV 16 and 18 in cervical cancer was 55.50%. CONCLUSION: Indigenous Guyanese women have a high rate of cervical cancer and high-grade dysplasia, with an apparent predominance of HPV 16 and 18 in invasive cancer and overrepresentation of HPV 31 in high-grade dysplasia.

Heart health - CHD management gaps in general practice.

BACKGROUND: For many years, the Heart Foundation has been involved in the development of evidence based clinical practice guidelines for the management of cardiovascular diseases and conditions, including coronary heart disease (CHD). However, the production of guidelines does not ensure the uptake of evidence based recommendations in practice. This 'management gap' - or difference between guideline recommendations and actual clinical practice - may contribute significantly to the burden of CHD in Australia. OBJECTIVE: This review aims to identify gaps of clinical significance in the management of CHD in Australian general practice. These identified gaps will then inform future efforts to improve cardiovascular outcomes in this setting. DISCUSSION: A literature and key documents search was undertaken to identify Australian data relating to cardiovascular disease, current practice and treatment gaps in the general practice setting. A number of gaps in the management of CHD exist in Australia. Addressing these gaps will improve patient outcomes. While the reasons for the management gaps are complex and multifaceted, the Heart Foundation will use this information to focus its messages and activities in general practice. The key messages developed present opportunities for improved clinical management of CHD in general practice.

Tailoring consumer resources to enhance self-care in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with high hospitalisation and mortality rates and debilitating symptoms. In an effort to reduce hospitalisations and improve symptoms individuals must be supported in managing their condition. Patients who can effectively self-manage their symptoms through lifestyle modification and adherence to complex medication regimens will experience less hospitalisations and other adverse events. AIM: The purpose of this paper is to explain how providing evidence-based information, using patient education resources, can support self-care. DISCUSSION: Self-care relates to the activities that individuals engage in relation to health seeking behaviours. Supporting self-care practices through tailored and relevant information can provide patients with resources and advice on strategies to manage their condition. Evidence-based approaches to improve adherence to self-care practices in patients with heart failure are not often reported. Low health literacy can result in poor understanding of the information about CHF and is related to adverse health outcomes. Also a lack of knowledge can lead to non-adherence with self-care practices such as following fluid restriction, low sodium diet and daily weighing routines. However these issues need to be addressed to improve self-management skills. OUTCOME: Recently the Heart Foundation CHF consumer resource was updated based on evidence-based national clinical guidelines. The aim of this resource is to help consumers improve understanding of the disease, reduce uncertainty and anxiety about what to do when symptoms appear, encourage discussions with local doctors, and build confidence in self-care management. CONCLUSION: Evidence-based CHF patient education resources promote self-care practices and early detection of symptom change that may reduce hospitalisations and improve the quality of life for people with CHF.

Prognostic Implications of Dual Platelet Reactivity Testing in Acute Coronary Syndrome.

Studies on platelet reactivity (PR) testing commonly test PR only after percutaneous coronary intervention (PCI) has been performed. There are few data on pre- and post-PCI testing. Data on simultaneous testing of aspirin and adenosine diphosphate antagonist response are conflicting. We investigated the prognostic value of combined serial assessments of high on-aspirin PR (HASPR) and high on-adenosine diphosphate receptor antagonist PR (HADPR) in patients with acute coronary syndrome (ACS). HASPR and HADPR were assessed in 928 ACS patients before (initial test) and 24 hours after (final test) coronary angiography, with or without revascularization. Patients with HASPR on the initial test, compared with those without, had significantly higher intraprocedural thrombotic events (IPTE) (8.6 vs. 1.2%, p ≤ 0.001) and higher 30-day major adverse cardiovascular and cerebrovascular events (MACCE; 5.2 vs. 2.3%, p = 0.05), but not 12-month MACCE (13.0 vs. 15.1%, p = 0.50). Patients with initial HADPR, compared with those without, had significantly higher IPTE (4.4 vs. 0.9%, p = 0.004), but not 30-day (3.5 vs. 2.3%, p = 0.32) or 12-month MACCE (14.0 vs. 12.5%, p = 0.54). The c-statistic of the Global Registry of Acute Coronary Events (GRACE) score alone, GRACE score + ASPR test and GRACE score + ADPR test for discriminating 30-day MACCE was 0.649, 0.803 and 0.757, respectively. Final ADPR was associated with 30-day MACCE among patients with intermediate-to-high GRACE score (adjusted odds ratio [OR]: 4.50, 95% confidence interval [CI]: 1.14-17.66), but not low GRACE score (adjusted OR: 1.19, 95% CI: 0.13-10.79). In conclusion, both HASPR and HADPR predict ischaemic events in ACS. This predictive utility is time-dependent and risk-dependent.

A snapshot of the prevalence of physical activity amongst older, community dwelling people in Victoria, Australia: patterns across the 'young-old' and 'old-old'.

BACKGROUND: Physical activity has a range of health benefits for older people. The aim of this study was to determine physical activity prevalence and attitudes amongst respondents to a trial screening survey. METHODS: A cross-sectional survey was conducted. Subjects were community dwelling older people aged > or = 65 years, recruited via general practices in Victoria, Australia. Participants completed a mailed screening tool containing the Geriatric Depression Scale, the Active Australia survey and the Physical Activity Readiness Questionnaire. RESULTS: Of 330 participants, 20% were > or = 80 years. Activity levels were similar to those reported in population studies. The proportion of participants reporting physical activity was greatest for the walking category, but decreased across categories of physical activity intensity. The oldest-old were represented at all physical activity intensity levels. Over half reported exercising at levels that, according to national criteria are, 'sufficient to attain health benefit'. A greater proportion of participants aged 85 years and older were unaware of key physical activity messages, compared to participants aged less than 85 years. CONCLUSION: Most population surveys do not provide details of older people across age categories. This survey provided information on the physical activity of people up to 91 years old. Physical activity promotion strategies should be tailored according to the individual's needs. A better understanding of the determinants of physical activity behaviour amongst older sub-groups is needed to tailor and target physical activity promotion strategies and programs to maximise physical activity related health outcomes for older people.

Exploring the feasibility of a community-based strength training program for older people with depressive symptoms and its impact on depressive symptoms.

BACKGROUND: Depression is a disabling, prevalent condition. Physical activity programs may assist depression management in older people, ameliorate co-morbid conditions and reduce the need for antidepressants. The UPLIFT pilot study assessed the feasibility of older depressed people attending a community-based progressive resistance training (PRT) program. The study also aimed to determine whether PRT improves depressive status in older depressed patients. METHODS: A randomised controlled trial was conducted. People aged > or = 65 years with depressive symptoms were recruited via general practices. Following baseline assessment, subjects were randomly allocated to attend a local PRT program three times per week for 10 weeks or a brief advice control group. Follow-up assessment of depressive status, physical and psychological health, functional and quality of life status occurred post intervention and at six months. RESULTS: Three hundred and forty six people responded to the study invitation, of whom 22% had depressive symptoms (Geriatric Depression Scale, GDS-30 score > or = 11). Thirty two people entered the trial. There were no significant group differences on the GDS at follow-up. At six months there was a trend for the PRT intervention group to have lower GDS scores than the comparison group, but this finding did not reach significance (p = 0.08). More of the PRT group (57%) had a reduction in depressive symptoms post program, compared to 44% of the control group. It was not possible to discern which specific components of the program influenced its impact, but in post hoc analyses, improvement in depressive status appeared to be associated with the number of exercise sessions completed (r = -0.8, p < 0.01). CONCLUSION: The UPLIFT pilot study confirmed that older people with depression can be successfully recruited to a community based PRT program. The program can be offered by existing community-based facilities, enabling its ongoing implementation for the potential benefit of other older people.

Screening for physical activity in family practice: evaluation of two brief assessment tools.

BACKGROUND: Physical activity (PA) is relevant to the prevention and management of many health conditions in family practice. There is a need for an efficient, reliable, and valid assessment tool to identify patients in need of PA interventions. METHODS: Twenty-eight family physicians in three Australian cities assessed the PA of their adult patients during 2004 using either a two- (2Q) or three-question (3Q) assessment. This was administered again approximately 3 days later to evaluate test-retest reliability. Concurrent validity was evaluated by measuring agreement with the Active Australia Questionnaire, and criterion validity by comparison with 7-day Computer Science Applications, Inc. (CSA) accelerometer counts. RESULTS: A total of 509 patients participated, with 428 (84%) completing a repeat assessment, and 415 (82%) accelerometer monitoring. The brief assessments had moderate test-retest reliability (2Q k=58.0%, 95% confidence interval [CI]=47.2-68.8%; 3Q k=55.6%, 95% CI=43.8-67.4%); fair to moderate concurrent validity (2Q k=46.7%, 95% CI=35.6-57.9%; 3Q k=38.7%, 95% CI=26.4-51.1%); and poor to fair criterion validity (2Q k=18.2%, 95% CI=3.9-32.6%; 3Q k=24.3%, 95% CI=11.6-36.9%) for identifying patients as sufficiently active. A four-level scale of PA derived from the PA assessments was significantly correlated with accelerometer minutes (2Q rho=0.39, 95% CI=0.28-0.49; 3Q rho=0.31, 95% CI=0.18-0.43). Physicians reported that the assessments took 1 to 2 minutes to complete. CONCLUSIONS: Both PA assessments were feasible to use in family practice, and were suitable for identifying the least active patients. The 2Q assessment was preferred by clinicians and may be most appropriate for dissemination.

[Asymmetric cortical high signal on diffusion weighted-MRI in a case of Creutzfeldt-Jakob disease].

High signal in the cerebral cortex and/or basal ganglia on diffusion-weighted magnetic resonance imaging (DW-MRI) has been described as a good diagnostic marker for sporadic Creutzfeldt-Jakob disease (sCJD). We report a case of sCJD with atypical clinical evolution and unusual DW-MRI findings. A 53-year-old man was seen with a 2-year history of a rapidly progressive dementia and cerebellar ataxia. Cerebrospinal fluid analysis, including the test for 14-3-3 protein, was normal. EEG did not show periodic activity. However, DW-MRI showed gyriform hyperintensity involving practically the entire cortical ribbon of the left hemisphere, whilst being limited to the posterior cingulate gyrus in the right hemisphere. DNA analysis showed no mutations or insertions in the prion protein gene, and homozigozity for methionine in codon 129. A subsequent brain biopsy confirmed the diagnosis of CJD. Thus, high signal on DW-MRI may be limited to the cerebral cortex and may present a very asymmetric distribution in sCJD.

Motivating patients to move.

BACKGROUND: Numerous studies have demonstrated the benefits of regular physical activity (30 minutes of moderate activity 5 days per week) for a range of chronic diseases including the prevention and management of cardiovascular disease. The challenge remains for general practitioners to incorporate this advice effectively into their routine clinical practice. OBJECTIVE: This article outlines the current physical activity targets for optimal heart health, and approaches GPs can take to facilitate positive behaviour change for their patients in their role as agents of change and leaders of the primary health team. DISCUSSION: Current best practice for GPs incorporates the '5 As' approach: Ask (identify those who can benefit), Assess (current activity level), Advise (individualised), Assist (provide a written 'script' for action and support material) and Arrange (appropriate referral and follow up). Incorporating motivational interviewing techniques, adopting a whole practice approach (including the judicious use of practice nurses) and establishing linkages with community agencies, are additional ways in which GPs can be more effective in this area.

The RNA binding protein MEX-3 retains asymmetric activity in the early Caenorhabditis elegans embryo in the absence of asymmetric protein localization.

The RNA binding protein MEX-3 is required to restrict translation of pal-1, the Caenorhabditis elegans caudal homolog, to the posterior of the early embryo. MEX-3 is present uniformly throughout the newly fertilized embryo, but becomes depleted in the posterior by the 4-cell stage. This MEX-3 patterning requires the CCCH zinc-finger protein MEX-5, the RNA Recognition Motif protein SPN-4, and the kinase PAR-4. Genetic and biochemical evidence suggests that MEX-5 binds to MEX-3 in the anterior of the embryo, protecting MEX-3 from degradation and allowing it to bind the pal-1 3'UTR and repress translation. MEX-3 that is not bound to MEX-5 becomes inactivated by par-4, then targeted for spn-4 dependent degradation. After the 4-cell stage, residual MEX-3 is degraded in somatic cells, and only persists in the germline precursors. To better understand regulation of mex-3, GFP was fused to MEX-3 or regions of MEX-3 and expressed in developing oocytes. GFP::MEX-3 expressed in this manner can replace endogenous MEX-3, but surprisingly is not asymmetrically localized at the 4-cell stage. These results indicate that GFP::MEX-3 retains asymmetric activity even in the absence of asymmetric protein localization. Neither the mex-3 3'UTR nor protein degradation at the 4-cell stage is strictly required. A region of MEX-3 containing a glutamine-rich region and potential ubiquitination and phosphorylation sites is sufficient for soma-germline asymmetry. Results from mex-5/6 and spn-4(RNAi) suggest two pathways for MEX-3 degradation, an early spn-4 dependent pathway and a later spn-4 independent pathway. These results indicate that mex-3 activity is regulated at multiple levels, leading to rapid and robust regulation in the quickly developing early embryo.

sFlt-1 gene therapy of follicular thyroid carcinoma.

Tumor progression largely depends on blood supply and neovessel formation, and angiogenesis is emerging as a promising target for cancer therapy. Vascular endothelial growth factor (VEGF), a major proangiogenic molecule, stimulates angiogenesis via promoting endothelial proliferation, survival and migration. VEGF has been found to be up-regulated in various types of tumors and to be associated with tumor progression and poor prognosis. Inhibition of VEGF or its signaling pathway has been shown to suppress tumor angiogenesis and tumor growth. In the present study, we tested the antiangiogenic and antitumor effects of soluble VEGF receptor-1 [soluble Flt (sFlt)-1] on the growth of follicular thyroid carcinoma (FTC). We constructed a 293 embryonic kidney cell line (293-Flt1-3d) that expresses sFlt-1, which is composed of the first three extracellular domains of Flt-1. The 293-Flt1-3d cells inhibited the in vitro growth of human umbilical vein endothelial cells in a paracrine manner. The in vivo antitumor and antiangiogenic activities of the 293-Flt1-3d cells were tested. When 293-Flt1-3d cells were inoculated at a site remote to the FTC-133 tumor transplant, the growth of FTC-133 tumors were inhibited by 70.37%, as compared with the control treatment with 293 cells expressing control gene LacZ. Immunohistochemical analysis of microvessel densities in treated tumors demonstrated that 293-Flt1-3d cells robustly suppressed intratumoral angiogenesis. Our data suggest that a mammalian cell-mediated approach could effectively deliver sFlt-1 gene therapy and inhibit tumor angiogenesis and tumor growth.