Inhibition of cell proliferation rather than of cell lysis as a measure of immune reactivity in embryo-antigen-challenged mice.

An assay system is described in which effector cells added along with suitable target cells inhibit, in a quantitative fashion, the subsequent uptake of 3H-thymidine by those target cells. Effector cells active in this assay, using embryonic fibroblast cells as targets, develop spontaneously in cultures of mouse lymphoid cells, but are apparently different from those described earlier by investigators of activity in cytotoxic assays. Further evidence is presented to show the development of spleen-derived effector cells with cytostatic activity (for embryonic fibroblast target cells) in mice during the course of normal pregnancy, or growth of spontaneously appearing mammary adenocarcinomas. Indeed, such effector cells can also be found within the growing solid mass itself. Different populations of tumour cells isolated from a solid tumour apparently differ in their susceptibility to growth inhibition by tumour-bearer-derived cytostatic effector cells, a phenomenon which may be related to metastatic spread of tumour cells

Tumour-cell susceptibility to cytotoxic or cytostatic effector cells in vitro and the regulation of tumour-cell growth in vivo.

Tumour-cell growth in lung nodules after i.v. transfer to sublethally irradiated mice has been followed after adoptive transfer of different populations of lymphoid cells. Spleen cells deliberately immunized in vitro and in vivo against stimulator cells bearing embryo-associated antigens and which are cytostatic in vitro for targets bearing such antigens, can diminish the number of lung nodules found after i.v. transfer. In contrast, cytotoxic (in vitro) spleen cells, while capable of diminishing local (s.c.) growth of tumour cells, cannot control systemic tumour growth. Within a given solid tumour mass, the subpopulations resistant to cytostatic effector cells in vitro are the ones most likely to produce lung colonies after adoptive transfer in vivo, though they show no more local (s.c.) growth than to cytostatic-sensitive cells in vivo

Deficiency of the bone mineralization inhibitor NPP1 protects against obesity and diabetes

The emergence of bone as an endocrine regulator has prompted a re-evaluation of the role of bone mineralization factors in the development of metabolic disease. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralization through the generation of pyrophosphate, and levels of NPP1 are elevated both in dermal fibroblast cultures and muscle of individuals with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the gene that encodes NPP1 (Enpp1−/− mice). Enpp1−/− mice exhibited mildly improved glucose homeostasis on a normal diet but showed a pronounced resistance to obesity and insulin resistance in response to chronic high-fat feeding. Enpp1−/− mice had increased levels of the insulin-sensitizing bone-derived hormone osteocalcin but unchanged insulin signalling within osteoblasts. A fuller understanding of the pathways of NPP1 could inform the development of novel therapeutic strategies for treating insulin resistance

Violence, uncertainty, and resilience among refugee women and community workers: An evaluation of gender-based violence case management services in the Dadaab refugee camps.

Reports of gender-based violence (GBV) are common in camps for refugees and displaced populations. In the Dadaab refugee camps in north-eastern Kenya, the International Rescue Committee (IRC) and CARE International (CARE) implement programmes that aim to both respond to and prevent GBV. A cornerstone of this work has been to train refugees, known as refugee community workers, to deliver aspects of GBV prevention and response work in order to develop a broader implementation of traditional GBV outreach, community mobilisation, and case management. To date, there has been limited rigorous research on this broader GBV case management plus task sharing approach in the context of a refugee camp setting. To address this key gap in evidence, the London School of Hygiene and Tropical Medicine (LSHTM) and the African Population and Health Research Centre (APHRC), in collaboration with IRC and CARE, have sought to assess this model to understand its feasibility, acceptability, and influence among female survivors of GBV accessing care. Data for this study, funded by UK aid, were collected in the Dadaab refugee camps between 2014 and 2017, which coincided with a temporary decision to close the camp and repatriate Somali refugees. The research confirms the magnitude and complexity of the violence that women and girls experience in the camps in Dadaab. In the year leading up to this study, 47% of women accessing the GBV centres for case management reported experiencing intimate partner violence and 39% reported experiencing non-partner violence. In addition, the study highlights the specific risks, challenges, opportunities and rewards experienced by refugee community workers in their dual role of community members and GBV activists living side-by-side with survivors and perpetrators of violence. Solely related to their work as GBV caseworkers, one in three refugee community workers reported experiencing non-partner violence in the last 12 months. Despite this, 93% of refugee community workers stated their work was rewarding or extremely rewarding. The majority of women (82%) accessing services reported that their interactions with refugee community workers had a positive effect, and that working with them was useful. However, having refugees deliver services to their own community was not without its challenges, and survivors raised issues on confidentiality, mistranslations, and perceived biases on clan differences. The study also provides an insight into the importance of contextual factors in case management, and the impact of the announcement of the (now-delayed) camp closure in Dadaab. Priorities of both the camp population and service providers (GBV and referral services) shifted greatly during this time of uncertainty and affected when and how women were accessing services

From wormhole to time machine: Comments on Hawking's Chronology Protection Conjecture

The recent interest in ``time machines'' has been largely fueled by the apparent ease with which such systems may be formed in general relativity, given relatively benign initial conditions such as the existence of traversable wormholes or of infinite cosmic strings. This rather disturbing state of affairs has led Hawking to formulate his Chronology Protection Conjecture, whereby the formation of ``time machines'' is forbidden. This paper will use several simple examples to argue that the universe appears to exhibit a ``defense in depth'' strategy in this regard. For appropriate parameter regimes Casimir effects, wormhole disruption effects, and gravitational back reaction effects all contribute to the fight against time travel. Particular attention is paid to the role of the quantum gravity cutoff. For the class of model problems considered it is shown that the gravitational back reaction becomes large before the Planck scale quantum gravity cutoff is reached, thus supporting Hawking's conjecture.Comment: 43 pages,ReV_TeX,major revision

Long-term effectiveness of a digital therapeutic intervention for smoking cessation: a randomized controlled trial

Introduction: The present study evaluated the long-term effectiveness of Quit Genius (QG), an extended digital smoking cessation intervention. Methods: Participants were adult smokers (N=556) recruited between January and November of 2019 via social media and referrals from primary care practices who were given nicotine replacement therapy and randomly assigned to Quit Genius (QG) (n=277), a cognitive behavioral therapy (CBT) based digital intervention or Very Brief Advice (VBA) (n=279), a face-to-face control intervention. Primary analyses (N=530), by intention-to-treat, compared QG and VBA on biochemically verified continuous 7-day abstinence at 4, 26, and 52 weeks post-quit date. Secondary outcomes included sustained abstinence, quit attempts, self-efficacy and mental well-being. Results: Seven-day point prevalence abstinence from weeks 4 through 52 ranged from 27% to nearly 45% among those who received QG, and from 13% to 29% for those in VBA. Continuous 7-day abstinence at 26 and 52 weeks occurred in 27.2% and 22.6% of QG participants, respectively, relative to 16.6% and 13.2% of VBA participants; QG participants were more likely to remain abstinent than those in VBA (Relative Risk [RR]= 1.71, 95% CI 1.17-2.50; p=0.005). Conclusions: This study provides evidence for the long-term effectiveness of an extended digital therapeutic intervention. Implications The long-term effectiveness of digital smoking cessation interventions has not been well-studied. This study established the long-term effectiveness of an extended CBT-based intervention; results may inform implementation of scalable, cost-effective approaches to smoking cessation in the health system

Fecal pollution in water from storm sewers and adjacent seashores in Natal, Rio Grande do Norte, Brazil

A study on the distribution patterns of enteropathogenic bacteria polluting the shoreline in Natal, Rio Grande do Norte, Brazil, was carried out based on 72 samples obtained from three storm sewers and adjoining beach locations, Praia do Meio (PM), Areia Preta (AP) and Ponta Negra (PN). From each location, 12 water samples were taken and analyzed for fecal coliforms (FC) and Escherichia coli. In AP, two (16.7%) of the seawater samples and five (41.7%) of the storm sewer samples yielded values above 1.1 × 107 FC/100 ml, whereas only one (8.3%) of the samples from PM reached this level. There was no correlation (p > 0.05) between rainfall indeces and FC values. A total of 64 E. coli isolates were obtained: 37 from the storm sewer samples and 27 from the seawater samples. Of these isolates, four (O143, two O112ac, and O124) were enteroinvasive and two (O111 and O125) were enteropathogenic. Resistance to antibiotics and to heavy metals was also analyzed. Almost 36% of the E. coli strains isolated were resistant to more than one antibiotic. All strains were resistant to zinc and copper at the highest concentration tested (250 μg/ml), and several (23.4%) were resistant to mercury at 50 μg/ml. Our results agreed with previous reports that antibiotic resistance is commonly associated with heavy-metal resistance in pathogens. [Int Microbiol 2004; 7(3):213–218

Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

Trimethyl­ammonium 2,6-dioxo-5-(2,4,6-trinitro­phen­yl)-1,2,3,6-tetra­hydro­pyrimidin-4-olate

In the title barbiturate salt (trivial name: trimethyl­ammonium 2,4,6-trinitro­phenyl­barbiturate), C3H10N+·C10H4N5O9 −, the asymmetric unit contains two sets of anion–cation moieties. The dihedral angle between the rings in the anions are 44.0 (3) and 45.7 (3)°. Adjacent anions are connected into ribbons along [100] through R 2 2(8) ring motifs formed by N—H⋯O hydrogen bonds involving the barbiturate rings. Attached to both sides of these ribbons via N—H⋯O hydrogen bonds are the trimethyl­ammonium cations. C—H⋯O hydrogen bonds are also observed