Fearless: Ally Siegel

Encouraging and mentoring young minds, consistently finding new ways to use her love of climbing and adventure to promote character and leadership development, and always ready for the next big challenge, Ally Siegel ’16 fearlessly pushes herself to achieve more, inspiring others to do the same. [excerpt

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children

Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis.

Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects.Supported by NIH grants R01 DK43051, P30 DK57521 (B.B.K.), and R01 DK106210 (B.B.K. and A. Saghatelian); a grant from the JPB Foundation (B.B.K.); and T32DK07516 (B.B.K. and J.L.)

Neurocognitive functioning in acute or early HIV infection

We examined neurocognitive functioning among persons with acute or early HIV infection (AEH) and hypothesized that the neurocognitive performance of AEH individuals would be intermediate between HIV seronegatives (HIV−) and those with chronic HIV infection. Comprehensive neurocognitive testing was accomplished with 39 AEH, 63 chronically HIV infected, and 38 HIV− participants. All AEH participants were HIV infected for less than 1 year. Average domain deficit scores were calculated in seven neurocognitive domains. HIV−, AEH, and chronically HIV infected groups were ranked from best (rank of 1) to worst (rank of 3) in each domain. All participants received detailed substance use, neuromedical, and psychiatric evaluations and HIV infected persons provided information on antiretroviral treatment and completed laboratory evaluations including plasma and CSF viral loads. A nonparametric test of ordered alternatives (Page test), and the appropriate nonparametric follow-up test, was used to evaluate level of neuropsychological (NP) functioning across and between groups. The median duration of infection for the AEH group was 16 weeks [interquartile range, IQR: 10.3–40.7] as compared to 4.9 years [2.8–11.1] in the chronic HIV group. A Page test using ranks of average scores in the seven neurocognitive domains showed a significant monotonic trend with the best neurocognitive functioning in the HIV− group (mean rank = 1.43), intermediate neurocognitive functioning in the AEH group (mean rank = 1.71), and the worst in the chronically HIV infected (mean rank = 2.86; L statistic = 94, p < 0.01); however, post-hoc testing comparing neurocognitive impairment of each group against each of the other groups showed that the chronically infected group was significantly different from both the HIV− and AEH groups on neurocognitive performance; the AEH group was statistically indistinguishable from the HIV− group. Regression models among HIV infected participants were unable to identify significant predictors of neurocognitive performance. Neurocognitive functioning was worst among persons with chronic HIV infection. Although a significant monotonic trend existed and patterns of the data suggest the AEH individuals may fall intermediate to HIV− and chronic participants, we were not able to statistically confirm this hypothesis

Detection of methylated septin 9 in tissue and plasma of colorectal patients with neoplasia and the relationship to the amount of circulating cell-free DNA

BACKGROUND: Determination of methylated Septin 9 (mSEPT9) in plasma has been shown to be a sensitive and specific biomarker for colorectal cancer (CRC). However, the relationship between methylated DNA in plasma and colon tissue of the same subjects has not been reported. METHODS: Plasma and matching biopsy samples were collected from 24 patients with no evidence of disease (NED), 26 patients with adenoma and 34 patients with CRC. Following bisulfite conversion of DNA a commercial RT-PCR assay was used to determine the total amount of DNA in each sample and the fraction of mSEPT9 DNA. The Septin-9 protein was assessed using immunohistochemistry. RESULTS: The percent of methylated reference (PMR) values for SEPT9 above a PMR threshold of 1% were detected in 4.2% (1/24) of NED, 100% (26/26) of adenoma and 97.1% (33/34) of CRC tissues. PMR differences between NED vs. adenoma and NED vs. CRC comparisons were significant (p<0.001). In matching plasma samples using a PMR cut-off level of 0.01%, SEPT9 methylation was 8.3% (2/24) of NED, 30.8% (8/26) of adenoma and 88.2% (30/34) of CRC. Significant PMR differences were observed between NED vs. CRC (p<0.01) and adenoma vs. CRC (p<0.01). Significant differences (p<0.01) were found in the amount of cfDNA (circulating cell-free DNA) between NED and CRC, and a modest correlation was observed between mSEPT9 concentration and cfDNA of cancer (R2 = 0.48). The level of Septin-9 protein in tissues was inversely correlated to mSEPT9 levels with abundant expression in normals, and diminished expression in adenomas and tumors. CONCLUSIONS: Methylated SEPT9 was detected in all tissue samples. In plasma samples, elevated mSEPT9 values were detected in CRC, but not in adenomas. Tissue levels of mSEPT9 alone are not sufficient to predict mSEPT9 levels in plasma. Additional parameters including the amount of cfDNA in plasma appear to also play a role

Probing the Interstellar Medium in Early type galaxies with ISO observations

Four IRAS-detected early type galaxies were observed with ISO. With the exception of the 15 micron image of NGC1052, the mid-IR emission from NGC1052, NGC1155, NGC5866 and NGC6958 at 4.5, 7 and 15 microns show extended emission. Mid-IR emission from NGC1052, NGC1155, and NGC6958 follows a de Vaucouleurs profile. The ratio of 15/7 micron flux decreases with radius in these galaxies, approaching the values empirically observed for purely stellar systems. In NGC5866, the 7 and 15 micron emission is concentrated in the edge-on dust lane. All the galaxies are detected in the [CII] line, and the S0s NGC1155 and NGC5866 are detected in the [OI] line as well. The ISO-LWS observations of the [CII] line are more sensitive measures of cool, neutral ISM than HI and CO by about a factor of 10-100. Three of four early type galaxies, namely NGC1052, NGC6958 and NGC5866, have low ratio FIR/Blue and show a lower [CII]/FIR, which is due to a softer radiation field from old stellar populations. The low [CII]/CO ratio in NGC5866 ([CII]/CO(1-0) < 570) confirms this scenario. We estimate the UV radiation expected from the old stellar populations in these galaxies and compare it to that needed to heat the gas to account for the cooling observed [CII] and [OI] lines. In three out of four galaxies, NGC1052, NGC5866 and NGC6958, the predicted UV radiation falls short by a factor of 2-3. In view of the observed intrinsic scatter in the "UV-upturn" in elliptical galaxies and its great sensitivity to age and metallicity effects, this is not significant. However, the much larger difference (about a factor of 20) between the UV radiation from old stars and that needed to produce the FIR lines for NGC 1155 is strong evidence for the presence of young stars, in NGC1155.Comment: To appear in the Astrophysical Journal. Figure 1 appears as a separate jpg figur

Parents' views on care of their very premature babies in neonatal intensive care units: a qualitative study

Background The admission of a very premature infant to the neonatal intensive care unit (NICU) is often a difficult time for parents. This paper explores parents’ views and experiences of the care for their very premature baby on NICU. Methods Parents were eligible if they had a baby born before 32 weeks gestation and cared for in a NICU, and spoke English well. 32 mothers and 7 fathers were interviewed to explore their experiences of preterm birth. Although parents’ evaluation of care in the NICU was not the aim of these interviews, all parents spoke spontaneously and at length on this topic. Results were analysed using thematic analysis. Results Overall, parents were satisfied with the care on the neonatal unit. Three major themes determining satisfaction with neonatal care emerged: 1) parents’ involvement; including looking after their own baby, the challenges of expressing breast milk, and easy access to their baby; 2) staff competence and efficiency; including communication, experience and confidence, information and explanation; and 3) interpersonal relationships with staff; including sensitive and emotional support, reassurance and encouragement, feeling like an individual. Conclusions Determinants of positive experiences of care were generally consistent with previous research. Specifically, provision of information, support for parents and increasing their involvement in the care of their baby were highlighted by parents as important in their experience of care

Promoter Hypermethylation-Related Reduced Somatostatin Production Promotes Uncontrolled Cell Proliferation in Colorectal Cancer.

BACKGROUND: Somatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line. METHODS: Colonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion. RESULTS: In case of normal aging SST mRNA expression did not alter, but decreased in cancer (p<0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70%+/-0.79%) compared to CRC (0%+/-0%) (p<0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2%+/-11.6%) compared to healthy young individuals (3.5%+/-1.9%) (p<0.05). CONCLUSIONS: In cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity