Tissue specific regulation of glucocorticoids in severe obesity and the response to significant weight loss following bariatric surgery (BARICORT).

CONTEXT: Tissue cortisol exposure is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). 11ß-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11ß-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues. METHODS: We recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies. RESULTS: Gene expression showed a positive correlation with 11ß-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11ß-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = -0.37, P = .04). 11ß-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 µg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss. CONCLUSIONS: This study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11ß-HSD1 activity increases, sc adipose tissue 11ß-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11ß-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11ß-HSD1 expression is reduced in sc adipose tissue after weight loss.

Changes in human dendritic cell number and function in severe obesity may contribute to increased susceptibility to viral infection.

Dendritic cells (DCs) are key immune sentinels linking the innate and adaptive immune systems. DCs recognise danger signals and initiate T-cell tolerance, memory and polarisation. They are critical cells in responding to a viral illness. Obese individuals have been shown to have an impaired response to vaccinations against virally mediated conditions and to have an increased susceptibility to multi-organ failure in response to viral illness. We investigated if DCs are altered in an obese cohort (mean body mass index 51.7±7.3 kg m(-2)), ultimately resulting in differential T-cell responses. Circulating DCs were found to be significantly decreased in the obese compared with the lean cohort (0.82% vs 2.53%). Following Toll-like receptor stimulation, compared with lean controls, DCs generated from the obese cohort upregulated significantly less CD83 (40% vs 17% mean fluorescence intensity), a molecule implicated in the elicitation of T-cell responses, particularly viral responses. Obese DCs produced twofold more of the immunosuppressive cytokine interleukin (IL)-10 than lean controls, and in turn stimulated fourfold more IL-4-production from allogenic naive T cells. We conclude that obesity negatively impacts the ability of DCs to mature and elicit appropriate T-cell responses to a general stimulus. This may contribute to the increased susceptibility to viral infection observed in severe obesity.

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

AIMS/HYPOTHESIS: The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells. METHODS: We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. RESULTS: The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. CONCLUSIONS/INTERPRETATION: The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis.

The role of bacterial antigen detection tests in the diagnosis of bacterial meningitis.

We sought to determine the circumstances under which cerebrospinal fluid (CSF) bacterial antigen detection tests. (BADT) are indicated. The medical records of 146 consecutive patients with bacterial meningitis seen from 1986 to 1991 were reviewed retrospectively (mean age 16 months; median eight months). Bacterial meningitis was defined as a positive CSF culture or a positive CSF BADT, in association with the clinical presentation and response to antibiotic treatment consistent with bacterial meningitis. Before lumbar puncture, 61/146 (42%) of meningitis patients had received treatment with antibiotics. CSF BADT was performed on 56/61 (92%) of pretreated patients; of these, 48 (87%) were positive, and 8 (13%) were negative. In this group, 15/61 (25%) of pretreated patients had a negative CSF culture but a positive CSF BADT. All 85 patients who did not receive antibiotics before lumbar puncture had positive CSF cultures and 52/75 (69%) had positive CSF BADT. Because prior antibiotic therapy may impair bacterial growth from the CSF, a CSF BADT should be performed whenever the patient has received prior antibiotic treatment.

Transcutaneous oxygen tension in preterm neonates during neonatal behavioral assessments and heelsticks.

This study evaluates the effects of neonatal behavioral assessments and heelsticks on transcutaneous oxygen tension (TcPO2) in 37 preterm neonates from a neonatal intensive care unit. Two behavioral assessments were evaluated, the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) and the Neurobehavioral Assessment for Preterm Infants (NAPI). TcPO2 during heelsticks was used as a comparison because reliable decreases have typically been noted during heelsticks. Although the heelsticks resulted in significant declines in TcPO2, the behavioral assessments led to only negligible changes in TcPO2. Observed changes during the behavioral assessments occurred in a small number of infants, primarily during the few test procedures administered to the infants outside of their isolettes. Accordingly, it is suggested that time outside the isolette and associated temperature changes may be more critical variables than the assessments per se.

Early assessment of sensorimotor and cognitive development in high-risk infants.

Assessed 88 infants at risk for mental retardation on the Bayley Scales of Infant Development and a measure of visual recognition memory at 3 months corrected age. Bayley scales were administered again when the infants were 1-year-old. At 3 months of age the Bayley scales and the measure of visual recognition memory were not significantly correlated. Both measures, however, showed significant correlation to the Bayley scales administered at 1 year of age. Results from regression analyses indicated that each measure at 3 months of age was related to a different source of variance in the 1-year measure. These results are consistent with the hypothesis that at 3 months of age the visual recognition memory measure is a better early window into later cognitive development than the Bayley scales.

A comparison of urinary specific gravity and osmolality in sheep.

Urinary specific gravity and osmolality were determined on urine samples collected from three categories of sheep -- animals that were normal, in diuresis or had nephron numbers reduced surgically. Values for specific gravity and osmolality were compared and regression coefficients calculated for each category of sheep. In this study, specific gravity was found to be a relatively reliable indicator of osmolality, the correlation being highest in the urine from the sheep with reduced nephron numbers.