Lines of Descent: Kuhn and Beyond

yesThomas S. Kuhn is famous both for his work on the Copernican Revolution and his ‘paradigm’ view of scientific revolutions. But Kuhn later abandoned the notion of paradigm (and related notions) in favour of a more ‘evolutionary’ view of the history of science. Kuhn’s position therefore moved closer to ‘continuity’ models of scientific progress, for instance ‘chain-of-reasoning’ models, originally championed by D. Shapere. The purpose of this paper is to contribute to the debate around Kuhn’s new ‘developmental’ view and to evaluate these competing models with reference to some major innovations in the history of cosmology, from Copernicanism to modern cosmology. This evaluation is made possible through some unexpected overlap between Kuhn’s earlier discontinuity model and various versions of the later continuity models. It is the thesis of this paper that the ‘chain-of-reasoning’ model accounts better for the cosmological evidence than both Kuhn’s early paradigm model and his later developmental view of the history of science

Prevalence and correlates of alcohol dependence disorder among TB and HIV infected patients in Zambia.

OBJECTIVES: To determine the prevalence and correlates of alcohol dependence disorders in persons receiving treatment for HIV and Tuberculosis (TB) at 16 Primary Health Care centres (PHC) across Zambia. METHODS: 649 adult patients receiving treatment for HIV and/or TB at PHCs in Zambia (363 males, 286 females) were recruited between 1st December 2009 and 31st January 2010. Data on socio-demographic variables, clinical disease features (TB and HIV), and psychopathological status were collected. The Mini International Neuropsychiatric Interview (MINI) was used to diagnose alcohol dependence disorder. Correlates of alcohol dependence were analyzed for men only, due to low prevalence in women. Univariable and multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI), using general estimating equations to allow for within-PHC clustering. RESULTS: The prevalence of alcohol dependence was 27.2% (95%CI: 17.7-39.5%) for men and 3.9% (95%CI: 1.4-0.1%) for women. Factors associated with alcohol dependence disorder in men included being single, divorced or widowed compared with married (adjusted OR = 1.47, 95%CI: 1.00-2.14) and being unemployed (adjusted OR=1.30, 95%CI: 1.01-1.67). The highest prevalence of alcohol dependence was among HIV-test unknown TB patients (34.7%), and lowest was among HIV positive patients on treatment but without TB (14.1%), although the difference was not statistically significant (p=0.38). CONCLUSIONS: Male TB/HIV patients in this population have high prevalence of alcohol dependence disorder, and prevalence differs by HIV/TB status. Further work is needed to explore interventions to reduce harmful drinking in this population

Results of combined treatment of anaplastic thyroid carcinoma (ATC)

<p>Abstract</p> <p>Background</p> <p>Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis.</p> <p>Methods</p> <p>We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin.</p> <p>Results</p> <p>Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months.</p> <p>Conclusion</p> <p>Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.</p

Origin and differentiation of breast nipple syringoma

Similarities in morphology and in glandular and squamous differentiation patterns amongst syringomas of the breast nipple and of the skin suggest a common nature, but the origin of nipple syringoma remains undefined. Using triple immunofluorescence analysis, we found that cells immunopositive for basal keratins K5 and 14 undergo differentiation into glandular and squamous cell lineages. Both tumour types expressed K10, indicative of squamous lineage, but there were specific differences in their glandular lineage. In contrast to the breast nipple syringoma, which expressed glandular keratins K8/18/19, syringoma of the skin only expressed the glandular keratin K19. Therefore, syringomas of the breast nipple and of the skin resemble glandular lineages of the breast nipple duct or eccrine duct epithelium, respectively. From these results we conclude that K5/14-positive cells of the breast nipple ducts are the putative cells of origin for syringomas of the nipple, which highlights the organotypic glandular differentiation potential

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Intimate partner violence among women with HIV infection in rural Uganda: critical implications for policy and practice

<p>Abstract</p> <p>Background</p> <p>Intimate partner violence (IPV) is a major public health problem in Africa and worldwide. HIV infected women face increased IPV risk. We assessed the prevalence and factors associated with IPV among HIV infected women attending HIV care in Kabale hospital, Uganda.</p> <p>Methods</p> <p>This cross-sectional study was conducted among 317 HIV infected women attending Kabale regional hospital HIV treatment centre, from March to December 2010. Participants were interviewed using an interviewer-administered questionnaire. Data was collected on socio-demographic variables, social habits, and IPV (using the abuse assessment screen and the Severity of Violence against Women Scale to identify physical, sexual and psychological violence). Characteristics of the participants who reported IPV were compared with those who did not. Multivariate logistic-regression analysis was conducted to analyze factors that were independently associated with IPV.</p> <p>Results</p> <p>The mean age of 317 respondents was 29.7 years. Twenty two (6.9%) were adolescents and 233 (73.5%) were married or cohabiting. The mean age of the spouse was 33.0 years.</p> <p>One hundred and eleven (35.0%) were currently on antiretroviral therapy. Lifetime prevalence of IPV (physical or sexual) was 36.6%. In the preceding 12 months, IPV (any type) was reported by 93 respondents (29.3%). This was physical for 55 (17.6%), and sexual /psychological for 38 (12.1%). On multivariate multinomial logistic regression analysis, there was a significant but inverse association between education level and physical partner violence (adjusted relative risk (ARR) 0.50, confidence limits (95% CI) 0.31-0.82, p-value = 0.007). There was a significant but inverse association between education level of respondent and sexual/psychological violence (ARR 0.47 95%CI (0.25-0.87), p-value = 0.017) Likewise, there was a significant inverse association between the education level of the spouse and psychological/sexual violence (ARR 0.57, 95% CI 0.25-0.90, p-value = 0.018). Use of antiretroviral therapy was associated with increased prevalence of any type of violence (physical, sexual or psychological) with ARR 3.04 (95%CI 1.15-8.45, p-value = 0.032).</p> <p>Conclusion</p> <p>Almost one in three women living with HIV had suffered intimate partner violence in the preceding 12 months. Nearly one in five HIV patients reported physical violence, and about one in every seven HIV patients reported sexual/psychological violence. Likewise, women who were taking antiretroviral drugs for HIV treatment were more likely to report any type of intimate partner violence (physical, sexual or psychological). The implication of these findings is that women living with HIV especially those on antiretroviral drugs should be routinely screened for intimate partner violence.</p

Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling

Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy.A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt.These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin

Drug-Selected Human Lung Cancer Stem Cells: Cytokine Network, Tumorigenic and Metastatic Properties

Background: Cancer stem cells (CSCs) are thought to be responsible for tumor regeneration after chemotherapy, although direct confirmation of this remains forthcoming. We therefore investigated whether drug treatment could enrich and maintain CSCs and whether the high tumorogenic and metastatic abilities of CSCs were based on their marked ability to produce growth and angiogenic factors and express their cognate receptors to stimulate tumor cell proliferation and stroma formation. Methodology/Findings: Treatment of lung tumor cells with doxorubicin, cisplatin, or etoposide resulted in the selection of drug surviving cells (DSCs). These cells expressed CD133, CD117, SSEA-3, TRA1-81, Oct-4, and nuclear β-catenin and lost expression of the differentiation markers cytokeratins 8/18 (CK 8/18). DSCs were able to grow as tumor spheres, maintain self-renewal capacity, and differentiate. Differentiated progenitors lost expression of CD133, gained CK 8/18 and acquired drug sensitivity. In the presence of drugs, differentiation of DSCs was abrogated allowing propagation of cells with CSC-like characteristics. Lung DSCs demonstrated high tumorogenic and metastatic potential following inoculation into SCID mice, which supported their classification as CSCs. Luminex analysis of human and murine cytokines in sonicated lysates of parental- and CSC-derived tumors revealed that CSC-derived tumors contained two- to three-fold higher levels of human angiogenic and growth factors (VEGF, bFGF, IL-6, IL-8, HGF, PDGF-BB, G-CSF, and SCGF-β). CSCs also showed elevated levels of expression of human VEGFR2, FGFR2, CXCR1, 2 and 4 receptors. Moreover, human CSCs growing in SCID mice stimulated murine stroma to produce elevated levels of angiogenic and growth factors. Conlusions/Significance: These findings suggest that chemotherapy can lead to propagation of CSCs and prevention of their differentiation. The high tumorigenic and metastatic potentials of CSCs are associated with efficient cytokine network production that may represent a target for increased efficacy of cancer therapy. © 2008 Levina et al