Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging.

PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.     

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Aims/hypothesis

Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.

Methods

This study evaluated N-acetyl-glucagon, (d-Ser²)glucagon and an analogue of (d-Ser²)glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (d-Ser²)glucagon-exe.

Results

All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (d-Ser²)glucagon and (d-Ser²)glucagon-exe evoked significant (p?d-Ser²)glucagon-exe stimulated cAMP production (p?GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (d-Ser²)glucagon retained glucagon-like effects of increasing (p?d-Ser²)glucagon-exe was devoid of hyperglycaemic actions but substantially (p?d-Ser²)glucagon-exe reduced the glycaemic excursion (p?p?d-Ser²)glucagon-exe. Twice-daily administration of (d-Ser²)glucagon-exe to high-fat-fed mice for 28 days significantly (p?p?p?2 consumption and locomotor activity were (p?p?p?p?p?Conclusions/interpretation This study emphasises the potential of (d-Ser²)glucagon-exe for the treatment of obesity-related diabetes.     

Maternal smoking during pregnancy and offspring psychiatric disorder: a longitudinal birth cohort study

Background

There is evidence that prenatal stress and smoking during pregnancy both independently increase the risk of offspring psychopathology. Here we examine whether increased levels of self-reported stress is associated with increased smoking in a population of pregnant women, and whether prenatal smoking is associated with offspring psychiatric diagnoses independent of prenatal stress exposure.

Method

Using a longitudinal birth cohort, we used ordered logistic regressions to examine associations between maternal stress and smoking during pregnancy. We then used logistic regression analyses to examine associations between prenatal smoking and later offspring psychiatric disorders.

Results

A dose–response relationship was found between maternally reported stress and smoking during pregnancy. Pregnant women reporting severe stress were more likely to smoke compared to both the moderate stress and no stress groups, and those reporting moderate stress were significantly more likely to smoke compared to the no stress group. Smoking more than 5 cigarettes daily during pregnancy increased the risk of offspring personality disorder (OR 3.08, 95% CI 1.60–5.94) as well as developing any Axis 1 psychiatric disorder, inclusive of mood, anxiety and psychotic disorders (OR 1.45, 95% CI 1.04–2.04). After adjusting for parental psychiatric history and maternal self-reported stress during pregnancy, associations between smoking more than 5 cigarettes daily when pregnancy and offspring personality (OR 2.58 95% CI 1.32–5.06) disorder remained.

Conclusion

Exposure to cigarette smoking during gestation could impact a child’s mental health. Smoking during pregnancy is a prime target for preventative interventions as unlike most other environmental risk factors, it is very amenable to change.

     

On the use of the not‐at‐random fully conditional specification (NARFCS) procedure in practice

The not‐at‐random fully conditional specification (NARFCS) procedure provides a flexible means for the imputation of multivariable missing data under missing‐not‐at‐random conditions. Recent work has outlined difficulties with eliciting the sensitivity parameters of the procedure from expert opinion due to their conditional nature. Failure to adequately account for this conditioning will generate imputations that are inconsistent with the assumptions of the user. In this paper, we clarify the importance of correct conditioning of NARFCS sensitivity parameters and develop procedures to calibrate these sensitivity parameters by relating them to more easily elicited quantities, in particular, the sensitivity parameters from simpler pattern mixture models. Additionally, we consider how to include the missingness indicators as part of the imputation models of NARFCS, recommending including all of them in each model as default practice. Algorithms are developed to perform the calibration procedure and demonstrated on data from the Avon Longitudinal Study of Parents and Children, as well as with simulation studies.     

Vitamin C supplementation decreases insulin glycation and improves glucose homeostasis in obese hyperglycemic (ob/ob) mice

The effects of dietary vitamin C supplementation on glucose homeostasis and insulin glycation were examined in adult lean and obese hyperglycemic (ob/ob) mice. In lean mice, supplementation of the drinking water with vitamin C (25 g/L) for 14 days did not affect food intake, fluid intake, glycated hemoglobin, plasma glucose, or plasma insulin concentrations. Total pancreatic insulin content and the percentage of glycated pancreatic insulin were also similar to control lean mice. In ob/ob mice, vitamin C supplementation caused significant reductions by 26% to 48% in food intake and fluid intake, glycated hemoglobin, plasma glucose, and insulin concentrations compared with untreated control ob/ob mice. The total insulin content and the extent of insulin glycation in the pancreas of ob/ob mice were also significantly decreased by 42% to 45% after vitamin C supplementation. This change was accompanied by a significant 80% decrease in the percentage of glycated insulin in the circulation of vitamin C-supplemented ob/ob mice. These data demonstrate that vitamin C supplementation can decrease insulin glycation and ameliorate aspects of the obesity-diabetes syndrome in ob/ob mice.     

Work satisfaction,stress, quality of care and morale of older people in a nursing home

The aim in the present study, which was carried out in one nursing home for older people, was to determine the feasibility of working with care workers and very frail service users to investigate links between the levels of work satisfaction and stress of the staff, and the quality of care and morale of the residents. Most of the 44 care staff (70%) and 22 cognitively intact residents (82%) participated willingly in completing rating scales through self-completion questionnaire or by interview. Well-validated scales were used to measure job satisfaction, work stress, organisational commitment, perceived quality of care, and morale and mental health. The findings revealed a staff group with a fairly high level of job dissatisfaction and stress, who were, nevertheless, very committed to the nursing home. The morale of the residents was good although the residents rated the home atmosphere lower than the staff did. Significant correlations emerged, in the expected direction, between satisfaction, commitment, stress and quality of care perceived by staff. The correlations between home atmosphere perceived by residents, and their morale and mental health were low; further investigation is needed with a larger sample. This feasibility study supports the need for further research using a case-study approach in a small number of homes because of the labour-intensive nature of the data collection and the importance of triangulating data from many sources.