Deterministic mechanical model of T-killer cell polarization reproduces the wandering of aim between simultaneously engaged targets

T-killer cells of the immune system eliminate virus-infected and tumorous cells through direct cell-cell interactions. Reorientation of the killing apparatus inside the T cell to the T-cell interface with the target cell ensures specificity of the immune response. The killing apparatus can also oscillate next to the cell-cell interface. When two target cells are engaged by the T cell simultaneously, the killing apparatus can oscillate between the two interface areas. This oscillation is one of the most striking examples of cell movements that give the microscopist an unmechanistic impression of the cell's fidgety indecision. We have constructed a three-dimensional, numerical biomechanical model of the molecular-motor-driven microtubule cytoskeleton that positions the killing apparatus. The model demonstrates that the cortical pulling mechanism is indeed capable of orienting the killing apparatus into the functional position under a range of conditions. The model also predicts experimentally testable limitations of this commonly hypothesized mechanism of T-cell polarization. After the reorientation, the numerical solution exhibits complex, multidirectional, multiperiodic, and sustained oscillations in the absence of any external guidance or stochasticity. These computational results demonstrate that the strikingly animate wandering of aim in T-killer cells has a purely mechanical and deterministic explanation. © 2009 Kim, Maly

Setting Priorities in Child Health Research Investments for South Africa

Nearly 100,000 children under 5 years die annually in South Africa. This paper defines health research priorities to address this unacceptably high mortality rate

Results of a multi-country exploratory survey of approaches and methods for IMCI case management training

<p>Abstract</p> <p>Background</p> <p>The Integrated Management of Childhood Illness Strategy (IMCI) is effective in improving management of sick children, and thus child survival. It is currently recommended that in-service IMCI case management training (ICMT) occur over 11-days; that the participant: facilitator ratio should be ≤4:1 and that at least 30% of ICMT time be spent on clinical practice. In 2006–2007, approximately ten years after IMCI implementation, we conducted a multi-country exploratory questionnaire survey to document country experiences with ICMT, and to determine the acceptability of shortening duration of ICMT.</p> <p>Methods</p> <p>Questionnaires (QA) were sent to national IMCI focal persons in 27 purposively-selected countries. To probe further, questionnaires (QB and QC respectively) were also sent to course-directors or facilitators and IMCI trainees, selected using snowball sampling after applying pre-defined criteria, in these countries. Questionnaires gathered quantitative and qualitative data.</p> <p>Results</p> <p>Thirty-three QA, 163 QB, 272 QC and two summaries were returned from 24 countries. All countries continued to adapt course content to local disease burden. All countries offer shorter ICMT courses, ranging from 3–10 days (commonest being 5–8 days). The shorter ICMT courses offer fewer exercises, more homework, less individual feedback and reduced clinical practice (<30% time). Whereas changes to course content were usually evidence-based, changes to training methodology and course duration evolved as pressure to expand implementation mounted. Participants varied in their self-reported skill and perception about each course. However, the varied methodology and integrated approach to management of illnesses were commonly cited as strengths of ICMT, and the chart booklet and clinical practice sessions were identified as critical components of ICMT. Four themes emerged from the qualitative work, viz. the current 11-day course is too expensive and should be shortened; advocacy around IMCI should increase; content should be regularly updated, new content areas should be introduced cautiously and more attention should be paid to skills-building rather than knowledge accumulation.</p> <p>Conclusion</p> <p>Whilst the 11-day ICMT course is still recommended, as efforts intensify to increase access to quality care and meet MDG4, standardized shorter ICMT courses, that include participatory methodologies and adequate clinical practice, could be acceptable globally.</p

Changes in Personal Networks of Women in Residential and Outpatient Substance Abuse Treatment

Changes in personal network composition, support and structure over 12 months were examined in 377 women from residential (n=119) and intensive outpatient substance abuse treatment (n=258) through face-to-face interviews utilizing computer based data collection. Personal networks of women who entered residential treatment had more substance users, more people with whom they had used alcohol and/or drugs, and fewer people from treatment programs or self-help groups than personal networks of women who entered intensive outpatient treatment. By 12 months post treatment intake, network composition improved for women in residential treatment; however, concrete support was still lower and substance users still more prevalent in their networks. Network composition of women in outpatient treatment remained largely the same over time. Both groups increased cohesiveness within the network over 12 months. Targeting interventions that support positive changes in personal networks may heighten positive long term outcomes for women entering treatment

Inhibition of FOXO3 Tumor Suppressor Function by βTrCP1 through Ubiquitin-Mediated Degradation in a Tumor Mouse Model

The ubiquitin-proteasome system is the primary proteolysis machine for controlling protein stability of the majority of regulatory proteins including those that are critical for cancer development. The forkhead box transcription factor FOXO3 plays a key role in regulating tumor suppression; however, the control of FOXO3 protein stability remains to be established. It is crucial to elucidate the molecular mechanisms underlying the ubiquitin-mediated degradation of FOXO3 tumor suppressor.Here we show that betaTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkappaB kinase-beta phosphorylation dependent manner. Silencing betaTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing betaTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing betaTrCP1 promotes tumorigenesis and tumor growth in vivo.This is a unique demonstration that the betaTrCP1-mediated FOXO3 degradation plays a crucial role in tumorigenesis. These findings significantly contribute to understanding of the control of FOXO3 stability in cancer cells and may provide opportunities for developing innovative anticancer therapeutic modalities

Setting Research Priorities to Reduce Global Mortality from Childhood Pneumonia by 2015

Igor Rudan and colleagues report the results of their consensus building exercise that identified health research priorities to help reduce child mortality from pneumonia

Risk adjustment for inter-hospital comparison of primary cesarean section rates: need, validity and parsimony

BACKGROUND: Cesarean section rates is often used as an indicator of quality of care in maternity hospitals. The assumption is that lower rates reflect in developed countries more appropriate clinical practice and general better performances. Hospitals are thus often ranked on the basis of caesarean section rates. The aim of this study is to assess whether the adjustment for clinical and sociodemographic variables of the mother and the fetus is necessary for inter-hospital comparisons of cesarean section (c-section) rates and to assess whether a risk adjustment model based on a limited number of variables could be identified and used. METHODS: Discharge abstracts of labouring women without prior cesarean were linked with abstracts of newborns discharged from 29 hospitals of the Emilia-Romagna Region (Italy) from 2003 to 2004. Adjusted ORs of cesarean by hospital were estimated by using two logistic regression models: 1) a full model including the potential confounders selected by a backward procedure; 2) a parsimonious model including only actual confounders identified by the "change-in-estimate" procedure. Hospital rankings, based on ORs were examined. RESULTS: 24 risk factors for c-section were included in the full model and 7 (marital status, maternal age, infant weight, fetopelvic disproportion, eclampsia or pre-eclampsia, placenta previa/abruptio placentae, malposition/malpresentation) in the parsimonious model. Hospital ranking using the adjusted ORs from both models was different from that obtained using the crude ORs. The correlation between the rankings of the two models was 0.92. The crude ORs were smaller than ORs adjusted by both models, with the parsimonious ones producing more precise estimates. CONCLUSION: Risk adjustment is necessary to compare hospital c-section rates, it shows differences in rankings and highlights inappropriateness of some hospitals. By adjusting for only actual confounders valid and more precise estimates could be obtained

Setting health research priorities using the CHNRI method: VII. A review of the first 50 applications of the CHNRI method

BACKGROUND: Several recent reviews of the methods used to set research priorities have identified the CHNRI method (acronym derived from the "Child Health and Nutrition Research Initiative") as an approach that clearly became popular and widely used over the past decade. In this paper we review the first 50 examples of application of the CHNRI method, published between 2007 and 2016, and summarize the most important messages that emerged from those experiences. METHODS: We conducted a literature review to identify the first 50 examples of application of the CHNRI method in chronological order. We searched Google Scholar, PubMed and so-called grey literature. RESULTS: Initially, between 2007 and 2011, the CHNRI method was mainly used for setting research priorities to address global child health issues, although the first cases of application outside this field (eg, mental health, disabilities and zoonoses) were also recorded. Since 2012 the CHNRI method was used more widely, expanding into the topics such as adolescent health, dementia, national health policy and education. The majority of the exercises were focused on issues that were only relevant to low- and middle-income countries, and national-level applications are on the rise. The first CHNRI-based articles adhered to the five recommended priority-setting criteria, but by 2016 more than two-thirds of all conducted exercises departed from recommendations, modifying the CHNRI method to suit each particular exercise. This was done not only by changing the number of criteria used, but also by introducing some entirely new criteria (eg, "low cost", "sustainability", "acceptability", "feasibility", "relevance" and others). CONCLUSIONS: The popularity of the CHNRI method in setting health research priorities can be attributed to several key conceptual advances that have addressed common concerns. The method is systematic in nature, offering an acceptable framework for handling many research questions. It is also transparent and replicable, because it clearly defines the context and priority-setting criteria. It is democratic, as it relies on "crowd-sourcing". It is inclusive, fostering "ownership" of the results by ensuring that various groups invest in the process. It is very flexible and adjustable to many different contexts and needs. Finally, it is simple and relatively inexpensive to conduct, which we believe is one of the main reasons for its uptake by many groups globally, particularly those in low- and middle-income countries

Cadmium Induces p53-Dependent Apoptosis in Human Prostate Epithelial Cells

Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis

Galvanizing collective action to accelerate reductions in maternal and newborn mortality and prevention of stillbirths

Every day, there are an estimated 810 maternal and 7,000 newborn deaths, and more than 5,000 stillbirths, most of which are preventable.1-3 While progress has been made in reducing maternal and neonatal morbidity and mortality and preventing stillbirths worldwide, inequities and gaps in quality of care persist4 and are disproportionately most dire in countries affected by conflict.5 In 2020, the coronavirus disease (COVID19) pandemic and response exposed multiple system vulnerabilities, exacerbated inequities to accessing care, and caused widespread disruption in reproductive, maternal, newborn, and child health services.6,7 Emerging evidence and modeling estimates of the indirect effects of the COVID-19 pandemic on maternal and newborn mortality in low- and middle-income countries (LMICs) reflect a sobering picture of what could lay ahead, with additional deaths estimated to be in the tens of thousands for mothers and hundreds of thousands for stillbirths and children aged under 5 years.3, 8-10 A dedicated, focused effort must be made to ensure maternal and newborn health (MNH) and prevention of stillbirths remain a priority