Time and dose dependency of bone-sarcomas in patients injected with radium-224

The time course and dose dependency of the incidence of bone-sarcomas among 900 German patients treated with high doses of radium-224 is analysed in terms of a proportional hazards model with a log-normal dependency of time to tumor and a linear-quadratic dose relation. The deduced dose dependency agrees well with a previous analysis in terms of a non-parametric proportional hazards model, and confirms the temporal distribution which has been used in the Radioepidemiological Tables of NIH. However, the linear-quadratic dose-response model gives a risk estimate for low doses which is somewhat less than half that obtained under the assumption of linearity. Dedicated to Prof. W. Jacobi on the occasion of his 60th birthday Work performed under Euratom contracts BI6-D-083-D, BI6-F-111-D, U.S. Department of Energy contract DE-AC 02-76 EV-00119, the U.S. National Cancer Institut

Highly Efficient Protein Misfolding Cyclic Amplification

Protein misfolding cyclic amplification (PMCA) provides faithful replication of mammalian prions in vitro and has numerous applications in prion research. However, the low efficiency of conversion of PrPC into PrPSc in PMCA limits the applicability of PMCA for many uses including structural studies of infectious prions. It also implies that only a small sub-fraction of PrPC may be available for conversion. Here we show that the yield, rate, and robustness of prion conversion and the sensitivity of prion detection are significantly improved by a simple modification of the PMCA format. Conducting PMCA reactions in the presence of Teflon beads (PMCAb) increased the conversion of PrPC into PrPSc from ∼10% to up to 100%. In PMCAb, a single 24-hour round consistently amplified PrPSc by 600-700-fold. Furthermore, the sensitivity of prion detection in one round (24 hours) increased by 2-3 orders of magnitude. Using serial PMCAb, a 1012-fold dilution of scrapie brain material could be amplified to the level detectible by Western blotting in 3 rounds (72 hours). The improvements in amplification efficiency were observed for the commonly used hamster 263K strain and for the synthetic strain SSLOW that otherwise amplifies poorly in PMCA. The increase in the amplification efficiency did not come at the expense of prion replication specificity. The current study demonstrates that poor conversion efficiencies observed previously have not been due to the scarcity of a sub-fraction of PrPC susceptible to conversion nor due to limited concentrations of essential cellular cofactors required for conversion. The new PMCAb format offers immediate practical benefits and opens new avenues for developing fast ultrasensitive assays and for producing abundant quantities of PrPSc in vitro

In Vitro Amplification of Misfolded Prion Protein Using Lysate of Cultured Cells

Protein misfolding cyclic amplification (PMCA) recapitulates the prion protein (PrP) conversion process under cell-free conditions. PMCA was initially established with brain material and then with further simplified constituents such as partially purified and recombinant PrP. However, availability of brain material from some species or brain material from animals with certain mutations or polymorphisms within the PrP gene is often limited. Moreover, preparation of native PrP from mammalian cells and tissues, as well as recombinant PrP from bacterial cells, involves time-consuming purification steps. To establish a convenient and versatile PMCA procedure unrestricted to the availability of substrate sources, we attempted to conduct PMCA with the lysate of cells that express cellular PrP (PrPC). PrPSc was efficiently amplified with lysate of rabbit kidney epithelial RK13 cells stably transfected with the mouse or Syrian hamster PrP gene. Furthermore, PMCA was also successful with lysate of other established cell lines of neuronal or non-neuronal origins. Together with the data showing that the abundance of PrPC in cell lysate was a critical factor to drive efficient PrPSc amplification, our results demonstrate that cell lysate in which PrPC is present abundantly serves as an excellent substrate source for PMCA

Explanation and relations. How do general practitioners deal with patients with persistent medically unexplained symptoms: a focus group study

Contains fulltext : 80758.pdf (publisher's version ) (Open Access)BACKGROUND: Persistent presentation of medically unexplained symptoms (MUS) is troublesome for general practitioners (GPs) and causes pressure on the doctor-patient relationship. As a consequence, GPs face the problem of establishing an ongoing, preferably effective relationship with these patients. This study aims at exploring GPs' perceptions about explaining MUS to patients and about how relationships with these patients evolve over time in daily practice. METHODS: A qualitative approach, interviewing a purposive sample of twenty-two Dutch GPs within five focus groups. Data were analyzed according to the principles of constant comparative analysis. RESULTS: GPs recognise the importance of an adequate explanation of the diagnosis of MUS but often feel incapable of being able to explain it clearly to their patients. GPs therefore indicate that they try to reassure patients in non-specific ways, for example by telling patients that there is no disease, by using metaphors and by normalizing the symptoms. When patients keep returning with MUS, GPs report the importance of maintaining the doctor-patient relationship. GPs describe three different models to do this; mutual alliance characterized by ritual care (e.g. regular physical examination, regular doctor visits) with approval of the patient and the doctor, ambivalent alliance characterized by ritual care without approval of the doctor and non-alliance characterized by cutting off all reasons for encounter in which symptoms are not of somatic origin. CONCLUSION: GPs feel difficulties in explaining the symptoms. GPs report that, when patients keep presenting with MUS, they focus on maintaining the doctor-patient relationship by using ritual care. In this care they meticulously balance between maintaining a good doctor-patient relationship and the prevention of unintended consequences of unnecessary interventions

A Model for Interprofessional Health Disparities Education: Student-Led Curriculum on Chronic Hepatitis B Infection

Although health disparities are commonly addressed in preclinical didactic curricula, direct patient care activities with affected communities are more limited. To address this problem, health professional students designed a preclinical service-learning curriculum on hepatitis B viral (HBV) infection, a major health disparity affecting the Asian/Pacific Islander (API) population, integrating lectures, skills training, and direct patient care at student-run clinics. An urban health professions campus. Medical and other health professional students at University of California, San Francisco, organized a preclinical didactic and experiential elective, and established two monthly clinics offering HBV screening, vaccination, and education to the community. Between 2004 and 2009, 477 students enrolled in the student-led HBV curriculum. Since the clinics’ inception in 2007, 804 patients have been screened for chronic HBV; 87% were API immigrants, 63% had limited English proficiency, and 46% were uninsured. Serologically, 10% were found to be chronic HBV carriers, 44% were susceptible to HBV, and 46% were immune. Our student-led didactic and experiential elective can serve as an interprofessional curricular model for learning about specific health disparities while providing important services to the local community

Syphilis at the Crossroad of Phylogenetics and Paleopathology

The origin of syphilis is still controversial. Different research avenues explore its fascinating history. Here we employed a new integrative approach, where paleopathology and molecular analyses are combined. As an exercise to test the validity of this approach we examined different hypotheses on the origin of syphilis and other human diseases caused by treponemes (treponematoses). Initially, we constructed a worldwide map containing all accessible reports on palaeopathological evidences of treponematoses before Columbus's return to Europe. Then, we selected the oldest ones to calibrate the time of the most recent common ancestor of Treponema pallidum subsp. pallidum, T. pallidum subsp. endemicum and T. pallidum subsp. pertenue in phylogenetic analyses with 21 genetic regions of different T. pallidum strains previously reported. Finally, we estimated the treponemes' evolutionary rate to test three scenarios: A) if treponematoses accompanied human evolution since Homo erectus; B) if venereal syphilis arose very recently from less virulent strains caught in the New World about 500 years ago, and C) if it emerged in the Americas between 16,500 and 5,000 years ago. Two of the resulting evolutionary rates were unlikely and do not explain the existent osseous evidence. Thus, treponematoses, as we know them today, did not emerge with H. erectus, nor did venereal syphilis appear only five centuries ago. However, considering 16,500 years before present (yBP) as the time of the first colonization of the Americas, and approximately 5,000 yBP as the oldest probable evidence of venereal syphilis in the world, we could not entirely reject hypothesis C. We confirm that syphilis seems to have emerged in this time span, since the resulting evolutionary rate is compatible with those observed in other bacteria. In contrast, if the claims of precolumbian venereal syphilis outside the Americas are taken into account, the place of origin remains unsolved. Finally, the endeavor of joining paleopathology and phylogenetics proved to be a fruitful and promising approach for the study of infectious diseases

The use of evidence in public governmental reports on health policy: an analysis of 17 Norwegian official reports (NOU)

<p>Abstract</p> <p>Background</p> <p>Governments increasingly require policy documents to be evidence-based. This paper analyses the use of scientific evidence in such documents by reviewing reports from government-appointed committees in Norway to assess the committees' handling of questions of effect.</p> <p>Methods</p> <p>This study uses the 'Index of Scientific Quality' (ISQ) to analyse all Norwegian official reports (NOUs) that were: (1) published by the Norwegian Ministry of Health and Care Services during 1994-1998 (N = 20); and (2) concerned with questions of effect either because these were included in the mandate or as a result of the committee's interpretation of the mandate. The ISQ is based on scientific criteria common in all research concerning questions of effect. The primary outcome measure is an ISQ score on a five-point scale.</p> <p>Results</p> <p>Three reports were excluded because their mandates, or the committees' interpretations of them, did not address questions of effect. For the remaining 17 NOUs in our study, overall ISQ scores were low for systematic literature search and for explicit validation of research. Two reports had an average score of three or higher, while scores for five other reports were not far behind. How committees assessed the relevant factors was often unclear.</p> <p>Conclusion</p> <p>The reports' evaluations of health evidence in relation to questions of effect lacked transparency and, overall, showed little use of systematic processes. A systematic, explicit and transparent approach, following the standards laid down in the ISQ, may help generate the evidence-based decision-making that Norway, the UK, the EU and the WHO desire and seek. However, policy-makers may find the ISQ criteria for assessing the scientific quality of a report too narrow to adequately inform policy-making.</p

Systematic Neighborhood Observations at High Spatial Resolution: Methodology and Assessment of Potential Benefits

There is a growing body of public health research documenting how characteristics of neighborhoods are associated with differences in the health status of residents. However, little is known about how the spatial resolution of neighborhood observational data or community audits affects the identification of neighborhood differences in health. We developed a systematic neighborhood observation instrument for collecting data at very high spatial resolution (we observe each parcel independently) and used it to collect data in a low-income minority neighborhood in Dallas, TX. In addition, we collected data on the health status of individuals residing in this neighborhood. We then assessed the inter-rater reliability of the instrument and compared the costs and benefits of using data at this high spatial resolution. Our instrument provides a reliable and cost-effect method for collecting neighborhood observational data at high spatial resolution, which then allows researchers to explore the impact of varying geographic aggregations. Furthermore, these data facilitate a demonstration of the predictive accuracy of self-reported health status. We find that ordered logit models of health status using observational data at different spatial resolution produce different results. This implies a need to analyze the variation in correlative relationships at different geographic resolutions when there is no solid theoretical rational for choosing a particular resolution. We argue that neighborhood data at high spatial resolution greatly facilitates the evaluation of alternative geographic specifications in studies of neighborhood and health

Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Activator protein 2 gamma (AP-2γ) is a member of the transcription factor activator protein-2 (AP-2) family, which is developmentally regulated and plays a role in human neoplasia. AP-2γ has been found to be overexpressed in most breast cancers, and have a dual role to inhibit tumor initiation and promote tumor progression afterwards during mammary tumorigensis.</p> <p>Methods</p> <p>To identify the gene targets that mediate its effects, we performed chromatin immunoprecipitation (ChIP) to isolate AP-2γ binding sites on genomic DNA from human breast cancer cell line MDA-MB-453.</p> <p>Results</p> <p>20 novel DNA fragments proximal to potential AP-2γ targets were obtained. They are categorized into functional groups of carcinogenesis, metabolism and others. A combination of sequence analysis, reporter gene assays, quantitative real-time PCR, electrophoretic gel mobility shift assays and immunoblot analysis further confirmed the four AP-2γ target genes in carcinogenesis group: ErbB2, CDH2, HPSE and IGSF11. Our results were consistent with the previous reports that ErbB2 was the target gene of AP-2γ. Decreased expression and overexpression of AP-2γ in human breast cancer cells significantly altered the expression of these four genes, indicating that AP-2γ directly regulates them.</p> <p>Conclusion</p> <p>This suggested that AP-2γ can coordinate the expression of a network of genes, involving in carcinogenesis, especially in breast cancer. They could serve as therapeutic targets against breast cancers in the future.</p