Inequality in Care and Differences in Outcome Following Stroke in People With ESRD

Acknowledgments: MF is funded by a Kidney Research UK Training Fellowship and is supported by a grant from Darlinda’s Charity for Renal Research.Peer reviewedPublisher PD

The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Overexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5) promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas. CK5 is known to be expressed in myoepithelial cells of the mammary gland, suggesting the possibility that transgenic BK5.ATF3 mice may exhibit mammary gland phenotypes.</p> <p>Methods</p> <p>Mammary glands from nulliparous mice in our BK5.ATF3 colony, both non-transgenic and transgenic, were examined for anomalies by histopathology and immunohistochemistry. Nulliparous and biparous female mice were observed for possible mammary tumor development, and suspicious masses were analyzed by histopathology and immunohistochemistry. Human breast tumor samples, as well as normal breast tissue, were similarly analyzed for ATF3 expression.</p> <p>Results</p> <p>Transgenic BK5.ATF3 mice expressed nuclear ATF3 in the basal layer of the mammary ductal epithelium, and often developed squamous metaplastic lesions in one or more mammary glands by 25 weeks of age. No progression to malignancy was seen in nulliparous BK5.ATF3 or non-transgenic mice held for 16 months. However, biparous BK5.ATF3 mice developed mammary carcinomas with squamous metaplasia between 6 months and one year of age, reaching an incidence of 67%. Cytokeratin expression in the tumors was profoundly disturbed, including expression of CK5 and CK8 (characteristic of basal and luminal cells, respectively) throughout the epithelial component of the tumors, CK6 (potentially a stem cell marker), CK10 (a marker of interfollicular epidermal differentiation), and mIRSa2 and mIRSa3.1 (markers of the inner root sheath of hair follicles). Immunohistochemical studies indicated that a subset of human breast tumors exhibit high levels of nuclear ATF3 expression.</p> <p>Conclusion</p> <p>Overexpression of ATF3 in CK5-expressing cells of the murine mammary gland results in the development of squamous metaplastic lesions in nulliparous females, and in mammary tumors in biparous mice, suggesting that ATF3 acts as a mammary oncogene. A subset of human breast tumors expresses high levels of ATF3, suggesting that ATF3 may play an oncogenic role in human breast tumorigenesis, and therefore may be useful as either a biomarker or therapeutic target.</p

Effectiveness of attentional bias modification training as add-on to regular treatment in alcohol and cannabis use disorder:A multicenter randomized control trial

BACKGROUND: Attentional bias for substance-relevant cues has been found to contribute to the persistence of addiction. Attentional bias modification (ABM) interventions might, therefore, increase positive treatment outcome and reduce relapse rates. The current study investigated the effectiveness of a newly developed home-delivered, multi-session, internet-based ABM intervention, the Bouncing Image Training Task (BITT), as an add-on to treatment as usual (TAU). METHODS: Participants (N = 169), diagnosed with alcohol or cannabis use disorder, were randomly assigned to one of two conditions: the experimental ABM group (50%; TAU+ABM); or the control group (50%; split in two subgroups the TAU+placebo group and TAU-only group, 25% each). Participants completed baseline, post-test, and 6 and 12 months follow-up measures of substance use and craving allowing to assess long-term treatment success and relapse rates. In addition, attentional bias (both engagement and disengagement), as well as secondary physical and psychological complaints (depression, anxiety, and stress) were assessed. RESULTS: No significant differences were found between conditions with regard to substance use, craving, relapse rates, attentional bias, or physical and psychological complaints. CONCLUSIONS: The findings may reflect unsuccessful modification of attentional bias, the BITT not targeting the relevant process (engagement vs. disengagement bias), or may relate to the diverse treatment goals of the current sample (i.e., moderation or abstinence). The current findings provide no support for the efficacy of this ABM approach as an add-on to TAU in alcohol or cannabis use disorder. Future studies need to delineate the role of engagement and disengagement bias in the persistence of addiction, and the role of treatment goal in the effectiveness of ABM interventions

Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance

Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR functio

“Everything You Always Wanted to Know about Sex (but Were Afraid to Ask)” in Leishmania after Two Decades of Laboratory and Field Analyses

Leishmaniases remain a major public health problem today (350 million people at risk, 12 million infected, and 2 million new infections per year). Despite the considerable progress in cellular and molecular biology and in evolutionary genetics since 1990, the debate on the population structure and reproductive mode of Leishmania is far from being settled and therefore deserves further investigation. Two major hypotheses coexist: clonality versus sexuality. However, because of the lack of clear evidence (experimental or biological confirmation) of sexuality in Leishmania parasites, until today it has been suggested and even accepted that Leishmania species were mainly clonal with infrequent genetic recombination (see [1] for review). Two recent publications, one on Leishmania major (an in vitro experimental study) and one on Leishmania braziliensis (a population genetics analysis), once again have challenged the hypothesis of clonal reproduction. Indeed, the first study experimentally evidenced genetic recombination and proposed that Leishmania parasites are capable of having a sexual cycle consistent with meiotic processes inside the insect vector. The second investigation, based on population genetics studies, showed strong homozygosities, an observation that is incompatible with a predominantly clonal mode of reproduction at an ecological time scale (∼20–500 generations). These studies highlight the need to advance the knowledge of Leishmania biology. In this paper, we first review the reasons stimulating the continued debate and then detail the next essential steps to be taken to clarify the Leishmania reproduction model. Finally, we widen the discussion to other Trypanosomatidae and show that the progress in Leishmania biology can improve our knowledge of the evolutionary genetics of American and African trypanosomes

Miniaturised SH EMATs for fast robotic screening of wall thinning in steel plates

Electromagnetic acoustic transducers (EMATs) are well suited to generating and detecting a variety of different ultrasonic wavemodes, without the need for couplant, and they can be operated through some coatings. EMATs can be used to generate shear horizontal (SH) waves, which show promise for fast screening of wall thinning and other defects. However, commercial SH-wave EMATs are not suitable for robotic implementation on ferritic steel due to the large magnetic drag force from the magnets. This article describes the design and characterisation of miniaturised SH guided wave EMATs, which significantly reduce the magnetic drag and enable mounting onto a small crawler robot for sample scanning. The performance of the miniaturised EMATs is characterised and compared to a commercial EMAT. It is shown that signal to noise ratio is reduced, but remains within an acceptable range to use on steel. The bandwidth and directivity are increased, depending on the exact design used. Their ability to detect flat bottomed holes mimicking wall thinning is also tested

Towards guided wave robotic NDT inspection : EMAT size matters

The first steps towards fast robotic screening of wall thinning in the industrially relevant example of 10mm thick steel plates are reported. Electromagnetic acoustic transducers (EMATs) are used to generate and detect guided shear horizontal wavemodes, as these show promise for this type of inspection. EMATs are miniaturised to reduce magnetic drag on ferritic steels, and are designed to produce SH0 and SH1wavemodes with 22mm wavelength, which is suitable for testing wall thinning in these samples. Miniaturisation and the resulting reduction of magnetic drag force allows the EMATs to be mounted on a small crawler robot which can then be used to scan the sample/structure

From ‘sugar daddies’ to ‘sugar babies’: exploring a pathway among age-disparate sexual relationships, condom use and adolescent pregnancy in South Africa

Background: Adolescent pregnancy has been linked to adverse outcomes. Most studies proposing risk pathways for adolescent pregnancy in South Africa are qualitative, hypothesising links among age-disparate relationships, reduced condom use and higher pregnancy rates. No known South African studies have quantitatively explored pathways to adolescent pregnancy. Objectives: This study aimed to: (i) identify the factors associated with adolescent pregnancy and (ii) explore a pathway of risk by assessing whether condom use mediated the relationship between age-disparate sexual relationships and adolescent pregnancy. Methods: A cross-sectional survey of 447 sexually active girls aged 10–19 years was undertaken in six health districts of South Africa. Multivariate logistic regressions controlled for confounders. Mediation tests used bootstrapping. Results: Consistent condom use (ß = –2.148, odds ratio (OR) = 8.566, P = 0.001) and school enrolment (ß = –1.600, OR = 0.202, P = 0.001) were associated with lower pregnancy rates. Age-disparate sex (ß = 1.093, OR = 2.982, P = 0.001) and long-term school absences (ß = 1.402, OR = 4.061, P = 0.001) were associated with higher pregnancy rates. The indirect effect of age-disparate sex on adolescent pregnancy through condom use was significant, irrespective of age, age at sexual initiation, poverty and residential environment (B = 0.4466, s.d. = 0.1303, confidence interval: 0.2323–0.7428). Conclusion: This survey supports hypotheses that inability to negotiate condom use in age-disparate sexual relationships may drive adolescent pregnancy. Interventions addressing these relationships, facilitating condom use and increasing access to sexual health services among adolescents might avert unwanted pregnancies