The T‐13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intake

The C‐variant of a T‐13910C polymorphism (rs4988235; NT_022135.15:g.25316568G > A) upstream of the lactase phlorizin hydrolase (LPH) gene causes lactose intolerance. Association studies with differences in bone parameters and fracture risk have been inconclusive. The objective of this study was to examine the association of LPH rs4988235 with body height and bone parameters and calcium homeostasis in two elderly populations of Dutch Caucasians and assess interaction with vitamin D receptor (VDR) polymorphisms. Genotyping of LPH and VDR polymorphisms was performed in 6367 individuals from the Rotterdam Study and 844 from the Longitudinal Aging Study Amsterdam (LASA). Associations with age, height, weight, bone mineral density (BMD), skeletal morphometric parameters and serum vitamin D and calcium levels, and dietary calcium intake were assessed using ANOVA or analysis of covariance, and allele dose effect was assessed using linear regression analysis. Fracture risk was analyzed using Cox's proportional hazard regression analysis. Associations with body height (p = 2.7 × 10^?8) and vertebral area (p = .048) found in the Rotterdam Study were explained by population stratification, as assessed by principal‐component analyses, and disappeared after additional adjustments. No associations with femoral neck or lumbar spine BMD or with fracture risk were detected. Calcium intake and serum ionized serum calcium were significantly lower in C‐homozygotes (p = 9.2 × 10^?7, p = .02, respectively). For none of the parameters studied was interaction between the T‐13910C polymorphism and VDR block 5 haplotype 1 observed. We show that the C allele of the T‐13910C polymorphism causing lactose intolerance is associated with lower dietary calcium intake and serum calcium levels but not with BMD or fractures. The associations observed with height and vertebral area were the result of population stratification. This demonstrates the impact of population stratification and urges researchers to carefully take this into account in genetic associations, in particular, in dietary intake–related phenotypes, of which LPH and lactose intolerance are a strong example. © 2010 American Society for Bone and Mineral Research     

Predictors of growth and body composition in HIV‐infected children beginning or changing antiretroviral therapy

Objectives

The aim of the study was to describe growth and body composition changes in HIV‐positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters.

Methods

Ninety‐seven prepubertal HIV‐positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999–2002 (NHANES) to generate z‐scores and with results for HIV‐exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters.

Results

All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height²) z‐scores increased over time (P=0.004, 0.037 and 0.027, respectively) and the waist:height ratio z‐score decreased (P=0.045), but body mass index and per cent body fat z‐scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid‐thigh circumference and FFM z‐scores related to CD4 percentage (P=0.029, P=0.008 and 0.020, respectively) and change in FFM and FFM index z‐scores to CD4 percentage increase (P=0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid‐thigh muscle circumference were also associated with CD4 percentage. Case–control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time.

Conclusions

In these HIV‐positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.     

Deployment-related severe fatigue with depressive symptoms is associated with increased glucocorticoid binding to peripheral blood mononuclear cells

Severe fatigue and co-morbid depressive symptoms are frequently reported by recently deployed military personnel. Stress can induce lasting changes in the negative feedback regulation of the hypothalamic–pituitary–adrenal axis (HPA-axis) and the regulation of the immune system by cortisol. Since these actions of cortisol are modulated via glucocorticoid receptors (GR), we investigated the effect of deployment and of deployment-related fatigue on glucocorticoid binding to peripheral blood mononuclear cells (PBMCs) in a prospective design. Psychological assessments and blood sample collection took place before and one and six months after deployment. Participants were selected from a larger group and assigned to three groups based on their level of fatigue and depressive symptoms six months after deployment. We compared fatigued participants without depressive symptoms (n = 21), fatigued participants with depressive symptoms (n = 14) and non-fatigued participants without depressive symptoms (n = 21). Fatigued participants with depressive symptoms at six months after deployment had higher glucocorticoid binding to PMBCs than the other two groups at all three time points. Notably, this difference was already present before deployment. There was no effect of deployment on glucocorticoid binding to PBMCs. The observed differences in glucocorticoid binding were not related to pre-existing group differences in psychological symptoms. No group differences were observed in the composition of the PBMC population and plasma cortisol levels. These results indicate that high glucocorticoid binding to PBMCs might represent a vulnerability factor for the development of severe fatigue with depressive symptoms after a sustained period of stress, such as deployment.     

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder

BACKGROUND: While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS: Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS: Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS: These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.     

Neuroendocrine and blood pressure responses to rectal distensions in individuals with high and low visceral pain sensitivity

BACKGROUND: The mechanisms of interindividual variations in visceral pain sensitivity remain poorly understood. We characterized the neuroendocrine responses to rectal distensions in healthy individuals with high vs. low rectal pain sensitivity. METHODS: Rectal sensory and pain thresholds were determined, and a series of random painful distensions was carried out. Eighteen subjects were stratified into groups with a low rectal pain threshold ("High Sensitivity" group) vs. a high rectal pain threshold ("Low Sensitivity" group) by median split, and were compared with regard to adrenocorticotropic hormone (ACTH) and cortisol, cardiovascular, and emotional responses. RESULTS: Distensions led to an anticipatory stress response, reflected by elevated baseline anxiety, and increased baseline ACTH and cortisol in both groups. In response to distensions, the "Low Sensitivity" group showed significantly greater ACTH and cortisol concentrations analysis of variance (ANOVA time x group for ACTH: p<.05; for cortisol: p<.01), and elevated diastolic blood pressures (BP) (ANOVA group: p<.01) when compared to the "High Sensitivity" group. CONCLUSIONS: Painful rectal distensions are associated with a pronounced anticipatory stress response, reflected by elevated anxiety and elevated stress hormones. Individuals with high rectal pain sensitivity differ from those with low pain sensitivity in distension-induced hormonal and blood pressure responses, suggesting that neuroendocrine responses may be relevant to the pathophysiology of visceral hyperalgesia.     

Heterogeneous medically unexplained symptoms and immune function

It has been suggested that dysregulation of immune-to-brain communication plays a role in the biopsychological process underlying medically unexplained symptoms (MUS). Immune and non-immune stressors can both be involved in the activation of the central sickness-behavioural-system leading to complaints like malaise, pain and fatigue. We hypothesized increased pro-inflammatory and/or reduced anti-inflammatory cytokine activity to exist in MUS patients. Twenty-seven participants (4 male; 23 female) with heterogeneous MUS were compared with 27 healthy controls (6 male; 21 females). Blood samples were analysed for leukocyte subset cell counts, in vitro T-cell mitogen-stimulated cytokine production (IL-2, IL-4, IL-5, IL-6, IL-10, TNF-alpha and IFN-gamma) and in vitro monocyte cytokine release (IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha) in response to increasing concentrations of LPS. No significant group differences were found for any of the cytokines measured. One unexpected exception was an elevation in the number of circulating B and NK-cells in participants high on MUS. Nonetheless, no support was found for the hypothesized immunological dysregulation in peripheral blood leukocyte function of MUS patients.