Follow-Up Mental Health Care in Youth and Young Adults With Type 1 Diabetes After Positive Depression Screen and/or Suicidal Ideation.

Individuals with type 1 diabetes have higher rates of depression and suicidal ideation than the general population, and symptoms of depression are often associated with higher A1C levels and complications. This study evaluated mental health follow-up rates in youth and young adults with type 1 diabetes who screened positive for depressive symptoms or suicidal ideation and identified differences between those who obtained follow-up mental health care and those who did not. Specifically, males were less likely to obtain follow-up, and those who had mental health follow-up had decreasing A1C over the following year. These findings suggest increased assistance and monitoring are needed to ensure follow-up mental health care is obtained.

Gene editing in the context of an increasingly complex genome.

The reporting of the first draft of the human genome in 2000 brought with it much hope for the future in what was felt as a paradigm shift toward improved health outcomes. Indeed, we have now mapped the majority of variation across human populations with landmark projects such as 1000 Genomes; in cancer, we have catalogued mutations across the primary carcinomas; whilst, for other diseases, we have identified the genetic variants with strongest association. Despite this, we are still awaiting the genetic revolution in healthcare to materialise and translate itself into the health benefits for which we had hoped. A major problem we face relates to our underestimation of the complexity of the genome, and that of biological mechanisms, generally. Fixation on DNA sequence alone and a 'rigid' mode of thinking about the genome has meant that the folding and structure of the DNA molecule -and how these relate to regulation- have been underappreciated. Projects like ENCODE have additionally taught us that regulation at the level of RNA is just as important as that at the spatiotemporal level of chromatin.In this review, we chart the course of the major advances in the biomedical sciences in the era pre- and post the release of the first draft sequence of the human genome, taking a focus on technology and how its development has influenced these. We additionally focus on gene editing via CRISPR/Cas9 as a key technique, in particular its use in the context of complex biological mechanisms. Our aim is to shift the mode of thinking about the genome to that which encompasses a greater appreciation of the folding of the DNA molecule, DNA- RNA/protein interactions, and how these regulate expression and elaborate disease mechanisms.Through the composition of our work, we recognise that technological improvement is conducive to a greater understanding of biological processes and life within the cell. We believe we now have the technology at our disposal that permits a better understanding of disease mechanisms, achievable through integrative data analyses. Finally, only with greater understanding of disease mechanisms can techniques such as gene editing be faithfully conducted.

Plasma metabolite profiles in children with current asthma.

BACKGROUND: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. OBJECTIVE: To identify differences in plasma metabolites between children with and without current asthma at mid-childhood. METHODS: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid-childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case-control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. RESULTS: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1-Methyl-2-pyridone-5-carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1-8.0)), a pyrimidine metabolite (5,6-dihydrothymine (OR = 0.4 (95% CI 0.2-0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1-0.9), taurocholate (OR = 2.0 (95% CI 1.2-3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p-cresol sulphate OR = 0.5 (95% CI 0.2-0.9)). The associations for N1-Methyl-2-pyridone-5-carboxamide and p-cresol sulphate replicated in the independent VDAART population (one-sided P values = .03-.04). CONCLUSIONS AND CLINICAL RELEVANCE: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome.

Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis.

BACKGROUND: B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms. METHODS: We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts. RESULTS: Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection. CONCLUSIONS: This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Incidence of cervical intraepithelial neoplasia grade 2 or worse in colposcopy-negative/human papillomavirus-positive women with low-grade cytological abnormalities.

OBJECTIVE: To determine the risk of incident high-grade cervical intraepithelial neoplasia (CIN) in human papillomavirus (HPV) -positive women with low-grade cytological abnormalities who had a satisfactory normal colposcopy. DESIGN: A retrospective follow-up study within the NHS HPV/LBC pilot studies. SETTING: The NHS Cervical Screening Programme in England. POPULATION: A total of 1063 HPV-positive women with borderline or mild dyskaryosis who were negative at colposcopy from three sites within the NHS HPV/liquid-based cytology (LBC) pilot studies. METHODS: HPV triage took place in 2001/02. In 2009 all information on additional management on HPV-positive/colposcopy-negative women was requested. The rate of disease following a negative colposcopy was calculated, and survival analysis was used to determine whether the grade of referral cytology impacted on risk of subsequent disease. Results were compared with those in women from the same population who had not been HPV triaged. MAIN OUTCOME MEASURES: Incident CIN2 or worse during follow up. RESULTS: Of 1063 eligible women 965 had documented follow up. The cumulative rate of CIN2+ at 3 years in these women was 4.4% (95% CI 4.0-7.0%); the median time from normal colposcopy to final result was 27 months. There was no significant increase in the risk of future disease associated with age or initial cytology result. CONCLUSIONS: The rate of subsequent high-grade CIN among colposcopically negative triaged women was sufficiently low to justify return to routine recall.

Knowledge and use of folic acid in women of reproductive age.

Folic acid reduces the risk of neural tube defects. As approximately 50% of pregnancies are unintended, women of reproductive age should be aware of the importance of folic acid. We reviewed the existing literature on these women's knowledge of folic acid and neural tube defects. Databases searched were PubMed, CINAHL, and Health Reference Center Academic. We used terms such as "folic acid knowledge" and "folic acid awareness" to search articles published from 1998 to 2010. Awareness of the benefits of folic acid before conception and during pregnancy was low, although knowledge levels were associated with education and household income. Women who were already knowledgeable about folic acid cited health care professionals, magazines and newspapers, and radio and television as common sources of information. Effective knowledge translation is needed to ensure that women are informed about the benefits of folic acid during the reproductive years. This knowledge will allow them to make informed decisions about folic acid consumption. Health care professionals play an influential role in promoting folic acid knowledge among women of childbearing age. Lower levels of knowledge among women with lower levels of education and/or household income must be addressed.

HPV testing as a triage for borderline or mild dyskaryosis on cervical cytology: results from the Sentinel Sites study.

BACKGROUND: Earlier pilot studies of human papillomavirus (HPV) triage concluded that HPV triage was feasible and cost-effective. The aim of the present study was to study the impact of wider rollout of HPV triage for women with low-grade cytology on colposcopy referral and outcomes. METHODS: Human papillomavirus testing of liquid-based cytology (LBC) samples showing low-grade abnormalities was used to select women for colposcopy referral at six sites in England. Samples from 10,051 women aged 25-64 years with routine call or recall cytology reported as borderline or mild dyskaryosis were included. RESULTS: Human papillomavirus-positive rates were 53.7% in women with borderline cytology and 83.9% in those with mild dyskaryosis. The range between sites was 34.8-73.3% for borderline cytology, and 73.4-91.6% for mild dyskaryosis. In the single site using both LBC technologies there was no difference in rates between the two technologies. The positive predictive value of an HPV test was 16.3% for CIN2 or worse and 6.1% for CIN3 or worse, although there was considerable variation between sites. CONCLUSION: Triaging women with borderline cytological abnormalities and mild dyskaryosis with HPV testing would allow approximately a third of these women to be returned immediately to routine recall, and for a substantial proportion to be referred for colposcopy without repeat cytology. Variation in HPV-positive rates results in differing colposcopy workload.

Comparison of cytology and histology results in English cervical screening laboratories before and after liquid-based cytology conversion: do the data provide evidence for a single category of high-grade dyskaryosis?

OBJECTIVE: To determine whether the difference between the positive predictive value (PPV) for cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+) of referral from moderate dyskaryosis and from severe dyskaryosis was reduced after laboratories converted from conventional to liquid-based cytology (LBC). Furthermore, to explore the cytology/histology agreement after LBC conversion, and to determine post-LBC whether there was increased support for the use of one single category of high-grade dyskaryosis (equivalent to high-grade squamous intraepithelial lesion). METHODS: The association between cytology and histology has been examined using annual Korner return data (KC61 returns) collected by laboratories from the English National Health Service cervical screening programme. The study compares return data before and after LBC conversion. RESULTS: The study examined data from 102 laboratories that converted from conventional cytology to LBC. Before conversion the PPV for CIN2+ of severe dyskaryosis was 88% and after increased to 90% (P = 0.003). For moderate dyskaryosis the PPV for CIN2+ increased from 70% to 72% (P = 0.06). The absolute difference of 18% between severe and moderate dyskaryosis was therefore the same pre- and post-LBC conversion. The PPV of mild dyskaryosis for CIN2+ before and after conversion reduced from 23% to 19% (P < 0.001). The agreement between cytology and histology measured using a weighted Kappa statistic increased from 0.52 to 0.60 after conversion to LBC because of small increases in the proportions of severe dyskaryosis or worse with CIN3+ outcomes and mild dyskaryosis with CIN1 or less outcomes. CONCLUSIONS: Following LBC conversion there was evidence of a modest increase in the agreement between cytology and histology but no evidence of a change in the absolute difference in PPV for CIN2+ between moderate and severe dyskaryosis. The data support the conclusion that women referred with moderate dyskaryosis will on average have a lower risk of progression to invasive cancer than women referred with severe dyskaryosis. If the data were considered to support the categories of high-grade dyskaryosis (moderate) and high-grade dyskaryosis (severe) before LBC conversion then it can be strongly argued that they also support these categories after conversion.

Benzo[a]pyrene cytotoxicity in right whale (Eubalaena glacialis) skin, testis and lung cell lines.

The North Atlantic right whale (NARW) is one of the most endangered great whales. The NARW population consists of only about 300 individuals and is reproducing at an insufficient rate. There is growing concern about the potential effects of environmental contaminants on the reproductive and overall health of NARW. High contaminant burdens can accumulate in tissues of great whales but toxicological studies of their effects are limited due to legal, logistical and ethical restrictions and specific in vitro models are critically needed. Cell lines from NARW skin and internal organs were previously created in our laboratory. In this study, skin, testis and lung primary fibroblast cell lines were exposed to benzo[a]pyrene (BP) as part of a multi-chemical toxicity testing project in NARW. Cells were exposed for 24-72 h to 10 nM-10 microM BP dissolved in dimethylsulfoxide. Cytotoxicity was measured with a clonogenic assay using standard methods. Some cytotoxicity was observed after 24 h, the highest concentration (10 microM BP) resulting in 77, 74 and 51 percent relative survival in testis, skin and lung cells, respectively, and indicating a higher cytotoxicity in the lung (p < 0.05). After 48 and 72-h exposure, 10 microM BP resulted in 24 and 3, 74 and 27, and 42 and 23 percent relative survival in testis, skin and lung cells, respectively. Cytotoxicity significantly increased with exposure time in all three tissues (p < 0.05 for skin and p < 0.01 for lung and testis), suggesting metabolic activation of BP in the three organs. Fibroblast cytotoxicity observed in the testis was higher than that observed either in the skin or lung after 48 h (p < 0.01) and was close to 100% after 72 h, warranting further investigation of the potential effects of PAHs on reproductive health.

Computer simulation of charge-selective electrochemistry of catechols at high-surface-area carbon fibers.

The shape and size of cyclic voltammetric (CV) waves at the ultrahigh surface area carbon fiber are dependent on the pH and the charge of the electroactive species. The high surface area resulted from the fiber being fractured by application of a high anodic potential or current. The CV waves have been computer simulated with a model that assumes the entry of positively charged and, in some cases, neutral ones, but rejection of negatively charged species from the interior of the fractured fibers. Best fit between the computer-calculated and experimental CV waves is obtained for a model containing three components as the source of the current: (a) background capacitive charge, (b) diffusion to the outer cylindrical-shaped fiber, and (c) interior thin-layer volume. Simulation results indicate that the values for the inner void volume are in the nanoliter range when electroactive species penetrate the interior.

Fractured carbon fiber-based biosensor for glucose.

A microsensor for glucose was constructed using DuPont E120 fibers, which exhibit extensive fracturing upon severe anodic pretreatment. The fracturing is accompanied by an increase in the electrochemical surface area of several orders of magnitude, which is exploited here in the design of a microsensor. Following fracture, the fibers were platinized to enhance their ability to detect enzymatically produced hydrogen peroxide, and glucose oxidase was immobilized at the surface of the fiber in polypyrrole. When operated amperometrically in flow injection analysis, the treated electrodes showed a linear response to injected glucose concentration up to 10 mM, with an observed Km' near 20 mM. The sensors were found to be stable for up to 2 months when stored dry at 4 degrees C.

Detection of dopamine overflow and diffusion with voltammetry in slices of rat brain.

Voltammetric electrodes have been used to monitor extracellular dopamine in rat brain slices. The electrode tips are small enough to be immersed inside the slice. Specificity for dopamine is increased through the use of voltammetry and a cation exchange membrane at the electrode tip. Dopamine overflow is observed in the caudate nucleus following electrical stimulation (60 Hz, 1 s, 3 V) with an adjacent bipolar electrode. The amount of overflow observed is increased when the tissue is perfused with 10 microM cocaine or nomifensine, both recognized inhibitors of dopamine uptake. The ability of dopamine in the perfusion buffer to permeate the slice was monitored with two voltammetric electrodes, one in the cerebral cortex and the other in the caudate nucleus. At a high concentration (100 microM), dopamine rapidly appeared (2.7 +/- 0.4 min) in the interior of the cortex, but dopamine was not observed in the caudate until a significantly later time (8.9 +/- 1.0 min). To examine whether this difference is a reflection of the presence of different uptake systems in the two regions, pressure ejection was employed. In this experiment a double-barrelled pipette was used to eject dopamine or DOPAC at a fixed distance (approximately 70 micron) from the voltammetric electrode. Ejection of small amounts of both substances could be detected in the cortex. When the ejector-detector assembly was moved to the caudate, dopamine could only be observed following pressure ejection after perfusion of the slice with 10 microM nomifensine. Detection of DOPAC was unaffected. All of these experiments indicate that uptake systems in the caudate keep dopamine concentrations very low in the extracellular fluid of the slice.

Studies on osteoporosis I. Experimental models. Effect of age, sex, genetic background, diet, steroid and heparin treatment on calcium metabolism of mice.

C3H/St(Ha) and C57Bl/6(J) mice of both sexes and various ages were exposed to whole body neutron irradiation. The 49Ca generated (half life 8.8 minutes) was immediately determined in a whole body counter. Total body calcium content was calculated. It was assumed that 99% of this represented skeletal calcium. In females, significant decrease in calcium content occurred after 23 months of age. In C3H/St(Ha) mice, low calcium diet, heparin (500 i.u./Kg. b.i.d.) and prednisolone (50 mg/Kg) treatment accelerated calcium loss and produced significant decrease in 3 months. C57Bl/6(J) mice were less susceptible to the latter drugs.