Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of ...event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.
Aims To compare obstetric and perinatal outcomes in women with Type1 and Type2 diabetes and relate these to maternal risk factors. Methods Prospective cohort study of 682 consecutive diabetic ...pregnancies in East Anglia during 2006-2009. Relationships between congenital malformation, perinatal mortality and perinatal morbidity (large for gestational age, preterm delivery, neonatal care) with maternal age, parity, ethnicity, glycaemic control, obesity and social disadvantage were examined using bivariable and multivariate models. Results There were 408 (59.8%) Type1 and 274 (40.2%) Type2 diabetes pregnancies. Women with Type2 diabetes were older (P<0.001), heavier (P<0.0001), more frequently multiparous (P<0.001), more ethnically diverse (p<0.0001) and more socially disadvantaged (P=0.0004). Although women with Type2 diabetes had shorter duration of diabetes (P<0.0001) and better pre-conception glycaemic control HbA1c 52mmol/mol (6.9%) Type2 diabetes vs. 63mmol/l (7.9%) Type1 diabetes; p<0.0001), rates of congenital malformation and perinatal mortality were comparable. Women with Type2 diabetes had fewer large-for-gestational-age infants (37.6 vs. 52.9%, P<0.0008), fewer preterm deliveries (17.5 vs. 37.1%, P<0.0001) and their offspring had fewer neonatal care admissions (29.8 vs. 43.2%, P=0.001). Third trimester HbA1c (OR1.35, 95%CI 1.09-1.67, P=0.006) and social disadvantage (OR0.80, 95%CI 0.67-0.98; P=0.03) were risk factors for large for gestational age. Conclusions Despite increased age, parity, obesity and social disadvantage, women with Type2 diabetes had better glycaemic control, fewer large-for-gestational-age infants, fewer preterm deliveries and fewer neonatal care admissions. Better tools are needed to improve glycaemic control and reduce the rates of large for gestational age, particularly in Type1 diabetes.Original Abstract: Diabet. Med. 28, 1060-1067 (2011)
Neurons rely on their metabolic coupling with astrocytes to combat oxidative stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) appears important for ...astrocyte-dependent neuroprotection from oxidative insults. Indeed, Nrf2 activators are effective in stroke, Parkinson disease, and Huntington disease models. However, key endogenous signals that initiate adaptive neuroprotective cascades in astrocytes, including activation of Nrf2-mediated gene expression, remain unclear. Hydrogen peroxide (H₂O₂) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (i) the significance of H₂O₂ in promoting astrocyte-dependent neuroprotection from oxidative stress, and (ii) the relevance of H₂O₂ in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H₂O₂ production in astrocytes cocultured with neurons, we heterologously expressed the H₂O₂-producing enzyme Rhodotorula gracilis D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H₂O₂. Seven hours of low-level H₂O₂ production (∼3.7 nmol·min·mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (∼130 nmol·min·mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H₂O₂, suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H₂O₂ yet H₂O₂-induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H₂O₂-induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H₂O₂ concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms.
Aim
Little is known about the challenges of transitioning from school to university for young people with Type 1 diabetes. In a national survey, we investigated the impact of entering and attending ...university on diabetes self‐care in students with Type 1 diabetes in all UK universities.
Methods
Some 1865 current UK university students aged 18–24 years with Type 1 diabetes, were invited to complete a structured questionnaire. The association between demographic variables and diabetes variables was assessed using logistic regression models.
Results
In total, 584 (31%) students from 64 hospitals and 37 university medical practices completed the questionnaire. Some 62% had maintained routine diabetes care with their home team, whereas 32% moved to the university provider. Since starting university, 63% reported harder diabetes management and 44% reported higher HbA1c levels than before university. At university, 52% had frequent hypoglycaemia, 9.6% reported one or more episodes of severe hypoglycaemia and 26% experienced diabetes‐related hospital admissions. Female students and those who changed healthcare provider were approximately twice as likely to report poor glycaemic control, emergency hospital admissions and frequent hypoglycaemia. Females were more likely than males to report stress odds ratio (OR) 4.78, 95% confidence interval (CI) 3.19–7.16, illness (OR 3.48, 95% CI 2.06–5.87) and weight management issues (OR 3.19, 95% CI 1.99–5.11) as barriers to self‐care. Despite these difficulties, 91% of respondents never or rarely contacted university support services about their diabetes.
Conclusion
The study quantifies the high level of risk experienced by students with Type 1 diabetes during the transition to university, in particular, female students and those moving to a new university healthcare provider.
What's new?
This national survey is unique and captured data from approximately one‐third of all students with Type 1 diabetes at UK universities.
Current diabetes care systems for university students are not functioning well, resulting in poor glycaemic control (25% higher HbA1c, 63% increased difficulty in diabetes management), diabetes complications that interrupt studies (43% frequent hypoglycaemia) and excess hospital admissions (25%).
Higher risk groups were female students (hypoglycaemia, depression, etc.) and those who had moved healthcare providers (higher HbA1c, hypoglycaemia, ketoacidosis and hospital admissions).
Despite these challenges, 91% never/rarely contacted university support services.
There is scope for a national approach to improving the focus care pathway.
Background
Higher levels of sedentary behaviour (SB) and screen-time are associated with greater symptoms of depression in adolescents, but the effect of the type and context of SB and screen-time ...remains underexplored. As part of a nationally-representative observational study, the current cross-sectional study examined associations between SB, screen-time and depressive symptoms among 422 adolescents (13.5 ± 0.92 years; 125 female) in the Republic of Ireland.
Method
Participants completed the Quick Inventory of Depressive Symptomatology and self-reported weekly SB, categorised into mentally-active screen-time (e.g., computer use for fun), mentally-passive screen-time (e.g., television viewing) and mentally-active non-screen-based SB (e.g., reading). Mann–Whitney
U
tests and Kruskal–Wallis
H
tests examined differences in screen-time and depressive symptoms by relevant covariates. Linear regression quantified crude and adjusted associations between total SB and mentally-active and mentally-passive screen-time and SB, and depressive symptoms.
Results
Crude and adjusted linear regressions showed total SB was significantly, positively associated with depressive symptoms (unadjusted:
β
= 0.27,
p
= 0.002, adjusted:
β
= 0.27,
p
= 0.002). When type and context were examined in the same model, only mentally-active screen-time was positively associated with depressive symptoms (unadjusted:
β
= 0.37,
p
= 0.009, adjusted:
β
= 0.39,
p
= 0.007).
Conclusion
Differential associations between total SB and mentally-active screen-time and SB, versus mentally-passive screen-time, and depressive symptoms among Irish adolescents were observed. Findings highlight the importance of investigating the context and type of SB and screen-time in adolescents.
Objectives: To study the training effects of eight weeks of stair climbing on Vo2max, blood lipids, and homocysteine in sedentary, but otherwise healthy young women. Methods: Fifteen women (mean (SD) ...age 18.8 (0.7) years) were randomly assigned to control (n = 7) or stair climbing (n = 8) groups. Stair climbing was progressively increased from one ascent a day in week 1 to five ascents a day in weeks 7 and 8. Training took place five days a week on a public access staircase (199 steps), at a stepping rate of 90 steps a minute. Each ascent took about two minutes to complete. Subjects agreed not to change their diet or lifestyle over the experimental period. Results: Relative to controls, the stair climbing group displayed a 17.1% increase in Vo2max and a 7.7% reduction in low density lipoprotein cholesterol (p<0.05) over the training period. No change occurred in total cholesterol, high density lipoprotein cholesterol, triglycerides, or homocysteine. Conclusions: The study confirms that accumulating short bouts of stair climbing activity throughout the day can favourably alter important cardiovascular risk factors in previously sedentary young women. Such exercise may be easily incorporated into the working day and therefore should be promoted by public health guidelines.
A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the ...pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a (125)I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.
Fibrotic diseases such as SSc (systemic sclerosis, scleroderma) are characterized by the abnormal presence of the myofibroblast, a specialized type of fibroblast that overexpresses the highly ...contractile protein α-smooth muscle actin. Myofibroblasts display excessive adhesive properties and hence exert a potent mechanical force. We aim to identify the precise contribution of adhesive signalling, which requires integrin-mediated activation of focal adhesion kinase (FAK)/src, to fibrogenic gene expression in normal and fibrotic SSc fibroblasts.
We subject either FAK wild-type and knockout fibroblasts or normal and SSc fibroblasts treated with FAK/src inhibitors to real-time polymerase chain, western blot, cell migration and collagen gel contraction analyses.
FAK operates downstream of both integrin β1 and reactive oxygen species (ROS) to promote the expression of genes involved in matrix production and remodelling, including CCN2, α-smooth muscle actin and type I collagen. Blocking either FAK/src with PP2 or ROS with N-acetyl cysteine alleviates the elevated contractile and migratory capability of lesional SSc dermal fibroblasts.
Excessive adhesive signalling is intimately involved with the fibrotic phenotype of lesional SSc fibroblasts; blocking adhesive signalling or ROS generation may be beneficial in controlling the fibrosis observed in SSc.
Optimal glycaemic control before and during pregnancy improves both maternal and fetal outcomes. This article summarizes the recently published guidelines on the management of glycaemic control in ...pregnant women with diabetes on obstetric wards and delivery units produced by the Joint British Diabetes Societies for Inpatient Care and available in full at www.diabetes.org.uk/joint-british-diabetes-society and https://abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group. Hyperglycaemia following steroid administration can be managed by variable rate intravenous insulin infusion (VRIII) or continuous subcutaneous insulin infusion (CSII) in women who are willing and able to safely self‐manage insulin dose adjustment. All women with diabetes should have capillary blood glucose (CBG) measured hourly once they are in established labour. Those who are found to be higher than 7 mmol/l on two consecutive occasions should be started on VRIII. If general anaesthesia is used, CBG should be monitored every 30 min in the theatre. Both the VRIII and CSII rate should be reduced by at least 50% once the placenta is delivered. The insulin dose needed after delivery in insulin‐treated Type 2 and Type 1 diabetes is usually 25% less than the doses needed at the end of first trimester. Additional snacks may be needed after delivery especially if breastfeeding. Stop all anti‐diabetes medications after delivery in gestational diabetes. Continue to monitor CBG before and 1 h after meals for up to 24 h after delivery to pick up any pre‐existing diabetes or new‐onset diabetes in pregnancy. Women with Type 2 diabetes on oral treatment can continue to take metformin after birth.
What's new?
The benefits of optimal maternal glycaemia are clear but how to achieve it during the gestational challenges of antenatal steroid administration, labour and birth remains unclear.
The current guideline suggests a simple standardized approach to achieve the recommended National Institute for Health and Care Excellence targets of glycaemic control in a safe and effective manner.
Improving maternal glycaemia before and during delivery may help to reduce the burden of neonatal hypoglycaemia and clinic‐to‐clinic variation in neonatal intensive care unit admissions.
Diabet. Med. 29, e249–e254 (2012)
Aims To evaluate the effectiveness of a family‐centred group education programme, in adolescents with Type 1 diabetes.
Methods Three hundred and five adolescents ...with Type 1 diabetes; age 13.1 ± 1.9 years, diabetes duration 5.6 ± 3.3 years, BMI 20.9 ± 3.7 kg/m2, HbA1c 78 ± 6 mmol/mol (9.3 ± 1.9%) were randomly allocated to the Families and Adolescents Communication and Teamwork Study (FACTS) diabetes education programme; (six 90‐min monthly sessions attended by parents and adolescents incorporating skills training and family teamwork) or conventional clinical care. Primary outcome was HbA1c at 18 months (12 months post‐intervention). Secondary outcomes were HbA1c at 9 months, psychosocial outcomes, adolescent quality of life, well‐being, family responsibility and insulin dose adjustment behaviours at 12 months (6 months post‐intervention) and episodes of severe hypoglycaemia and diabetic ketoacidois during the 12 months post‐intervention. All analyses are intention to treat.
Results Session attendance was poor with 48/158 families (30.4%) not attending any sessions and only 75/158 (47.5%) families attending ≥ 4 group education sessions. All biomedical and psychosocial outcomes were comparable between groups. At 18 months there was no significant difference in HbA1c in either group and no between‐group differences over time: intervention group 75 mmol/mol (9.0%) to 78 mmol/mol (9.3%), control group 77 mmol/mol (9.2%) to 80 mmol/mol (9.5%). Adolescents perceived no changes in parental input at 12 months.
Conclusion Poor attendance of group education sessions delivered in routine clinics was a major challenge. More personalized educational approaches may be required to support and motivate families who are struggling to integrate the demands of intensive insulin regimens into their daily lives.
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