Children’s Futures: Lessons From a Second-Generation Community Change Initiative

· This article describes Children’s Futures, a 10-year initiative in Trenton, N.J., that seeks to improve the health and well-being of children from 0 to 3 years old and ensure that they are ready for school. · During the first five years, the initiative was successful in implementing a number of evidence-based practices to improve children’s health, such as providing home visits to pregnant women, measuring and improving the quality of day care centers, and improving the use of information systems to track childhood immunizations. · Efforts to provide services for fathers and improve home-based child care were not successful; these are areas in which there are not any evidence-based practices. · Leveraging public and private money beyond the Robert Wood Johnson Foundation’s substantial $20 million commitment proved challenging because the foundation’s commitment was so large. The authors recommend obtaining agreements for matching funds prior to finalizing commitments. · A lack of attention to initiative-wide communications hindered integration across programs. · A need for a citywide data system was identified; this is being implemented in the second five-year funding cycle

Calcium-sensing receptor antagonism or lithium treatment ameliorates aminoglycoside-induced cell death in renal epithelial cells

AbstractThe aminoglycoside antibiotic gentamicin elicits proximal tubular toxicity and cell death. In calcium-sensing receptor (CaR)-transfected HEK-293 (CaR-HEK) cells and CaR-expressing proximal tubule-derived opossum kidney (OK) cells, chronic gentamicin treatment elicits dose-dependent, caspase-mediated apoptotic cell death. Here we investigated whether the renal cell toxicity of the CaR agonist gentamicin could be prevented by CaR antagonism or by lithium cotreatment which may interfere with receptor-mediated signalling. Chronic treatment of OK and CaR-HEK cells with low concentrations of gentamicin elicited cell death, an effect that was ameliorated by cotreatment with the CaR negative allosteric modulator (calcilytic) NPS-89636. This calcilytic also attenuated CaR agonist-induced ERK activation in these cells. In addition, 1 mM LiCl, equivalent to its therapeutic plasma concentration, also inhibited gentamicin-induced toxicity in both cell types. This protective effect of lithium was not due to the disruption of phosphatidylinositol-mediated gentamicin uptake as the cellular entry of Texas red-conjugated gentamicin into OK and CaR-HEK cells was unchanged by lithium treatment. However, the protective effect of lithium was mimicked by glycogen synthase 3β inhibition. Together, these data implicate CaR activation and a lithium-inhibitable signalling pathway in the induction of cell death by gentamicin in renal epithelial cells in culture

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice

Female mice lacking ATRX in the pancreas have increased sensitivity to pancreatic cancer, whereas male mice without ATRX are protected. This study identifies such susceptibility in pancreatic cancer and highlights the need for sex-specific approaches in cancer treatment. BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for \u3e30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler.-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS\u27s ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic METHODS: Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRASG12D). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion. RESULTS: Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients. CONCLUSIONS: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS\u27s ability to promote pancreatic intraepithelial lesion formation

In-vitro viability of bone scaffolds fabricated using the adaptive foam reticulation technique

The adaptive foam reticulation technique combines the foam reticulation and freeze casting methodologies of fabricating bone reparative scaffolds to offer a potential alternative to autografts. For the first time this paper studies the effect of processing on the mechanical properties and in-vitro cell growth of controllably generating a hierarchical structure of macro- (94 ± 6 to 514 ± 36 μm) and microporosity (2–30 μm) by the inclusion of camphene as a porogen during processing. Scaffolds were produced with porogen additions of 0–25 wt%. Porosity values of the structures of 85–96% were determined using the Archimedes technique and verified using X-ray Computed Tomography. The strength of the hydroxyapatite scaffolds, 5.70 ± 1.0 to 159 ± 61 kPa, correlated to theoretically determined values, 3.71 ± 0.8 to 134 ± 12 kPa, calculated by the novel incorporation of a shape factor into a standard equation. Fibroblast (3T3) and pre-osteoblast (MC3T3) cell growth was found to be significantly (P < 0.005) improved using 25 wt% porogen. This was supported by increased levels of alkaline phosphatase and was thought to result from greater dissolution as quantified by increased calcium levels in incubating media. The combination of these properties renders adaptive foam reticulation-fabricated scaffolds suitable for non-structural bone regenerative applications in non-load bearing bone defects

Ultra-high resolution X-ray structures of two forms of human recombinant insulin at 100 K

The crystal structure of a commercially available form of human recombinant (HR) insulin, Insugen (I), used in the treatment of diabetes has been determined to 0.92 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16,000 keV (λ = 0.77 Å). Refinement carried out with anisotropic displacement parameters, removal of main-chain stereochemical restraints, inclusion of H atoms in calculated positions, and 220 water molecules, converged to a final value of R = 0.1112 and Rfree = 0.1466. The structure includes what is thought to be an ordered propanol molecule (POL) only in chain D(4) and a solvated acetate molecule (ACT) coordinated to the Zn atom only in chain B(2). Possible origins and consequences of the propanol and acetate molecules are discussed. Three types of amino acid representation in the electron density are examined in detail: (i) sharp with very clearly resolved features; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry; (iii) poor density and difficult or impossible to model. An example of type (ii) is observed for the intra-chain disulphide bridge in chain C(3) between Sγ6–Sγ11 which has two clear conformations with relative refined occupancies of 0.8 and 0.2, respectively. In contrast the corresponding S–S bridge in chain A(1) shows one clearly defined conformation. A molecular dynamics study has provided a rational explanation of this difference between chains A and C. More generally, differences in the electron density features between corresponding residues in chains A and C and chains B and D is a common observation in the Insugen (I) structure and these effects are discussed in detail. The crystal structure, also at 0.92 Å and 100 K, of a second commercially available form of human recombinant insulin, Intergen (II), deposited in the Protein Data Bank as 3W7Y which remains otherwise unpublished is compared here with the Insugen (I) structure. In the Intergen (II) structure there is no solvated propanol or acetate molecule. The electron density of Intergen (II), however, does also exhibit the three types of amino acid representations as in Insugen (I). These effects do not necessarily correspond between chains A and C or chains B and D in Intergen (II), or between corresponding residues in Insugen (I). The results of this comparison are reported

Social comparison processes in organizations

We systematically analyze the role of social comparison processes in organizations. Specifically, we describe how social comparison processes have been used to explain six key areas of organizational inquiry: (1) organizational justice, (2) performance appraisal, (3) virtual work environments, (4) affective behavior in the workplace, (5) stress, and (6) leadership. Additionally, we describe how unique contextual factors in organizations offer new insight into two widely studied sub-processes of social comparison, acquiring social information and thinking about that information. Our analyses underscore the merit of integrating organizational phenomena and social comparison processes in future research and theory

What Stimulates Researchers to Make Their Research Usable? Towards an Openness Approach

Ambiguity surrounding the effect of external engagement on academic research has raised questions about what motivates researchers to collaborate with third parties. We argue that what matters for society is research that can be absorbed by users. We define openness as a willingness by researchers to make research more usable by external partners by responding to external influences in their own research practices. We ask what kinds of characteristics define those researchers who are more open to creating usable knowledge. Our empirical study analyses a sample of 1583 researchers working at the Spanish Council for Scientific Research (CSIC). Results demonstrate that it is personal factors (academic identity and past experience) that determine which researchers have open behaviours. The paper concludes that policies to encourage external engagement should focus on experiences which legitimate and validate knowledge produced through user encounters, both at the academic formation career stage as well as through providing ongoing opportunities to engage with third parties.The data used for this study comes from the IMPACTO project funded by the Spanish Council for Scientific Research - CSIC (Ref. 200410E639). The work also benefited from a mobility grant awarded by Eu-Spri Forum to Julia Olmos Penuela & Paul Benneworth for her visiting research to the Center of Higher Education Policy Studies. Finally, Julia Olmos Penuela also benefited from a post-doctoral grant funded by the Generalitat Valenciana (APOSTD-2014-A-006).Olmos-Peñuela, J.; Benneworth, P.; Castro-Martínez, E. (2015). What Stimulates Researchers to Make Their Research Usable? Towards an Openness Approach. 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Profiling Movement and Gait Quality Characteristics in Pre-School Children

There is a dearth of suitable metrics capable of objectively quantifying motor competence. Further, objective movement quality characteristics during free play have not been investigated in pre-school children. The aims of this study were to characterize children's free play physical activity and investigate how gait quality characteristics cluster with free play in pre-school children (3–5 years old). Sixty-one children (39 boys; 4.3 ± 0.7 years, 1.04 ± 0.05 m, 17.8 ± 3.2 kg) completed the movement assessment battery for children and took part in free play while wearing an ankle- and hip-mounted accelerometer. Characteristics of movement quality were profiled using a clustering algorithm. Spearman's rho and the Mann-Whitney U tests were used to assess relationships between movement quality characteristics and motor competence classification differences in integrated acceleration and spectral purity, respectively. Significant differences were found between motor competency classifications for spectral purity and integrated acceleration (p < .001). Spectral purity was hierarchically clustered with motor competence and integrated acceleration. Significant positive correlations were found between spectral purity, integrated acceleration and motor competence (p < .001). This is the first study to report spectral purity in pre-school children and the results suggest that the underlying frequency component of movement is clustered with motor competence

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes