A three-part, mixed-effects model to estimate the habitual total vitamin D intake distribution from food and dietary supplements in Dutch young children

Statistical modeling of habitual micronutrient intake from food and dietary supplements using short-term measurements is hampered by heterogeneous variances and multimodality. Summing short-term intakes from food and dietary supplements prior to simple correction for within-person variation (first add then shrink) may produce estimates of habitual total micronutrient intake so badly biased as to be smaller than estimates of habitual intake from food sources only. A 3-part model using a first shrink then add approach is proposed to estimate the habitual micronutrient intake from food among nonsupplement users, food among supplement users, and supplements. The population distribution of habitual total micronutrient intake is estimated by combining these 3 habitual intake distributions, accounting for possible interdependence between Eq. 2 and 3. The new model is an extension of a model developed by the USA National Cancer Institute. Habitual total vitamin D intake among young children was estimated using the proposed model and data from the Dutch food consumption survey (n = 1279). The model always produced habitual total intakes similar to or higher than habitual intakes from food sources only and also preserved the multimodal shape of the observed total vitamin D intake distribution. This proposed method incorporates several sources of covariate information that should provide more precise estimates of the habitual total intake distribution and the proportion of the population with intakes below/above cutpoint values. The proposed methodology could be useful for other complex situations, e.g. where high concentrations of micronutrients appear in episodically consumed foods.     

Levels of prolactin in relation to coagulation factors and risk of venous thrombosis. Results of a large population-based case-control study (MEGA-study)

The pituitary hormone prolactin is thought to influence coagulation. We aimed to study the relation between prolactin levels, coagulation factors and risk of venous thrombosis (VT). We used data from a large population based case-control study into aetiology of first VT (MEGA-study). Prolactin levels were determined in 2,068 patients with VT and 2,785 age- and sex matched control subjects. The relation between levels of coagulation factors and prolactin was studied among the controls. In addition, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated for the risk of VT for different cut-off points of prolactin levels based on percentiles determined in the controls. Restricted analysis was performed among cases in whom blood was sampled within six months after VT. We found a rise in factor VIII and von Willebrand factor with increasing levels of prolactin in the controls. An increased risk of VT was observed when blood was sampled within six months after thrombosis (OR 2.9, 95%CI 1.1-8.1) for prolactin levels above the 99th percentile (42.6 μg/l) relative to levels between the 20th to 80th percentile. When blood was sampled more than six months after VT no clear association could be observed (OR 1.3, 95%CI 0.7-2.3). In conclusion, we found a modest association between prolactin and symptomatic venous thromboembolism, particularly when blood was sampled close to the event. This may be explained by a causal relation or by prolactin being a marker of stress due to the thrombotic event.     

Effectiveness of functional progressive resistance exercise training on walking ability in children with cerebral palsy: a randomized controlled trial

The objective of the study was to evaluate the effectiveness of functional progressive resistance exercise (PRE) training on walking ability in children with cerebral palsy (CP).Fifty-one ambulant children with spastic CP (mean age 10 years 5 months, 29 boys) were randomized to an intervention (n = 26) or control group (n = 25, receiving usual care). The intervention consisted of 12 weeks functional PRE circuit training, for 3 times a week. Main outcome measures were walking ability and participation. Secondary outcomes were muscle strength and anaerobic muscle power. Possible adverse outcomes were spasticity and passive range of motion (ROM). Muscle strength increased significantly in the training group compared to the control group, but walking ability, participation and anaerobic muscle power did not change. Spasticity and ROM remained unchanged, except for a significant decrease in rectus femoris length in the intervention group. It is concluded that twelve weeks of functional PRE-training does not improve walking ability, despite improved muscle strength.     

The effect of a metalloproteinase inhibitor (GI5402) on tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors during human endotoxemia.

Tumor necrosis factor-alpha (TNF-alpha) is released from the cell surface by cleavage of pro-TNF-alpha by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-alpha, but also to enhance the surface expression of TNF-alpha and TNF-alpha receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (-20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF-alpha release (P <.001), but did not influence the increase in monocyte-bound TNF-alpha. In addition, GI5402 attenuated the rise in plasma-soluble TNF-alpha receptors types I and II after LPS injection (both P <.001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF-alpha receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF-alpha is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF-alpha and TNF-alpha receptor number.     

Quantitative competitive NASBA for measuring mRNA expression levels of the immediate early 1, late pp67, and immune evasion genes US3, US6 and US11 in cells infected with human cytomegalovirus.

Different cell types were infected with human cytomegalovirus (HCMV) and RNA expression dynamics were analyzed by quantitative NASBA assays for IE1 (UL123), pp67 (UL65) and the immune evasion genes (US3, US6 and US11). The quantitative NASBA assays gave reproducible quantification in the range of 10(3)-10(6) RNA copies for IE1 and pp67 RNA, from 3x10(3) to 1x10(6) RNA copies for US6 and US11 RNA, and from 1x10(4) to 1x10(6) RNA copies for US3 RNA. SMC, HAEC and HUVEC cells infected with an, in endothelial cells, propagated HCMV strain (VHL/E) showed similar RNA expression dynamics for the analyzed genes. Expression of all genes studied was observed within the first 4 h post-infection. The first gene for which expression could be detected was IE1, followed by US3, US11, pp67 and US6. Fibroblasts infected with HCMV strain AD169 showed a different RNA expression pattern for US3. Translation of the mRNA studied was demonstrated by detection of the proteins 48 h post-infection by immunofluorescence.     

cAMP inhibits modulation of airway smooth muscle phenotype via the exchange protein activated by cAMP (Epac) and protein kinase A

BACKGROUND AND PURPOSE

Changes in airway smooth muscle (ASM) phenotype may contribute to the pathogenesis of airway disease. Platelet-derived growth factor (PDGF) switches ASM from a contractile to a proliferative, hypo-contractile phenotype, a process requiring activation of extracellular signal-regulated kinase (ERK) and p70^S6 Kinase (p70^S6K). The effects of cAMP-elevating agents on these processes is unknown. Here, we investigated the effects of cAMP elevation by prostaglandin E₂ (PGE₂) and the activation of the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (Epac) on PDGF-induced phenotype switching in bovine tracheal smooth muscle (BTSM).

EXPERIMENTAL APPROACH

Effects of long-term treatment with the PGE₂ analogue 16,16-dimethyl-PGE₂, the selective Epac activator, 8-pCPT-2′-O-Me-cAMP and the selective PKA activator, 6-Bnz-cAMP were assessed on the induction of a hypo-contractile, proliferative BTSM phenotype and on activation of ERK and p70^S6K, both induced by PDGF.

KEY RESULTS

Treatment with 16,16-dimethyl-PGE₂ inhibited PDGF-induced proliferation of BTSM cells and maintained BTSM strip contractility and contractile protein expression in the presence of PDGF. Activation of both Epac and PKA similarly prevented PDGF-induced phenotype switching and PDGF-induced activation of ERK. Interestingly, only PKA activation resulted in inhibition of PDGF-induced phosphorylation of p70^S6K.

CONCLUSIONS AND IMPLICATIONS

Our data indicate for the first time that both Epac and PKA regulated switching of ASM phenotype via differential inhibition of ERK and p70^S6K pathways. These findings suggest that cAMP elevation may be beneficial in the treatment of long-term changes in airway disease.     

A nation‐wide study comparing sporadic and familial adenomatous polyposis‐related desmoid‐type fibromatoses

Desmoid‐type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP‐associated desmoid‐type fibromatoses, we tried to identify clinical characteristics, which may indicate FAP. Histopathology data of all Dutch patients with desmoid‐type fibromatoses diagnosed between 1999 and 2009 were retrieved from PALGA, the nation‐wide network and registry of histopathology in the Netherlands. For calculation of incidence rates, person‐years from the general matched population were used. Based on polyp counts in pathological records, the cohort was divided into a FAP group and a non‐FAP group. Patient‐ and tumor characteristics were compared between the two groups. A total number of 519 patients older than 10 years with a confirmed diagnosis of desmoid‐type fibromatoses were included. Thirty‐nine (7.5%) desmoid patients were documented of having FAP. The incidences of sporadic and FAP‐related desmoid‐type fibromatoses were 3.42 and 2,784 per million person‐years, respectively. The majority of FAP patients developed desmoid‐type fibromatoses after the diagnosis of FAP. Having FAP was associated with male gender [odds ratio (OR) 2.0, p = 0.034], desmoid diagnosis at an earlier age (mean 36 vs. 42 years, p = 0.031), and desmoid localization intra‐abdominally (OR 18.9, p ≤ 0.001) or in the abdominal wall (OR 4.8, p ≤ 0.001), compared to extra‐abdominal desmoid localization. In conclusion, patients with desmoid‐type fibromatoses are at risk of underlying FAP. Especially cases with desmoid localization intra‐abdominal or in the abdominal wall, and all patients younger than 60 years, have a substantial increased risk and should be referred for colonoscopy.