Increased circulating CC chemokine levels in the metabolic syndrome are reduced by low-dose atorvastatin treatment: evidence from a randomized controlled trial.

OBJECTIVE: Central obesity and insulin resistance are key components of the metabolic syndrome, which is associated with an increased risk of cardiovascular disease. In obesity, CC chemokines, such as monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein-1ß (MIP-1ß) and eotaxin-1 and their respective receptors, are critically involved in peripheral monocyte activation and adipose tissue infiltration. The aim of the current study was to examine whether low-dose atorvastatin (10 mg/d) treatment modulated serum levels of CC chemokines in metabolic syndrome subjects. MATERIALS AND METHODS: Serum levels of MCP-1, eotaxin-1, MIP-1ß, C reactive protein (CRP) and interleukin-6 (IL-6) were measured in lean control and metabolic syndrome subjects at baseline, and following a 6-week randomized placebo-controlled clinical trial of atorvastatin (10 mg/d). Peripheral CD14(+) monocytes were isolated and mRNA levels of MCP-1, MIP-1 ß and CCR5 determined. RESULTS: Serum MCP-1 (P = 0·02), eotaxin-1 (P = 0·02) and MIP-1ß (P = 0·03), CRP (P < 0·001) and IL-6 (P = 0·006) were significantly increased in metabolic syndrome in comparison with lean controls. Furthermore, CD14(+) peripheral monocyte mRNA expression of the chemokine receptor, CCR5, of which MIP-1ß and eotaxin-1 are ligands, was increased two-fold in the metabolic syndrome group (P = 0·03). In addition to the expected improvements in lipid profile, atorvastatin treatment significantly reduced circulating eotaxin-1 (P < 0·05), MIP-1ß (P < 0·05) levels and CD14(+) peripheral monocyte CCR5 mRNA expression (P = 0·02). CONCLUSION: These results support a model whereby atorvastatin treatment, by inhibiting CD14(+) monocyte CCR5 expression, may inhibit monocyte trafficking, reduce chronic inflammation and, thus, lower circulating levels of CC chemokines.

Restoration of adipose function in obese glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein ß up-regulation.

Obese AT (adipose tissue) exhibits increased macrophage number. Pro-inflammatory CD16+ peripheral monocyte numbers are also reported to increase with obesity. The present study was undertaken to simultaneously investigate obesity-associated changes in CD16+ monocytes and ATMs (AT macrophages). In addition, a pilot randomized placebo controlled trial using the PPAR (peroxisome-proliferator-activated receptor) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16+ monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men (n=28) were randomized to placebo, pioglitazone (30 mg/day) and fenofibrate (160 mg/day) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16+ monocyte levels via flow cytometry. A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number, the latter was determined via assessment of CD68 expression by IHC (immunohistochemistry) and real-time PCR. Subcutaneous AT mRNA expression of CEBPß (CCAAT enhancer-binding protein ß), SREBP1c (sterol-regulatory-element-binding protein 1c), PPARγ2, IRS-1 (insulin receptor substrate-1), GLUT4 (glucose transporter type 4) and TNFα (tumour necrosis factor α) were also assessed. Comparisons were made between obese and lean controls (n=16) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, percentage CD14+/CD16+ monocyte numbers and ATM number (all P=0.0001). Additionally, serum TNF-α levels were significantly elevated (P=0.017) and adiponectin levels reduced (total: P=0.0001; high: P=0.022) with obesity. ATM number and percentage of CD14+/CD16+ monocytes correlated significantly (P=0.05). Pioglitazone improved adiponectin levels significantly (P=0.0001), and resulted in the further significant enlargement of adipocytes (P=0.05), without effect on the percentage CD14+/CD16+ or ATM number. Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPß mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the centrality of AT to the cardiometabolic derangement underlying the development of T2D (Type 2 diabetes) and CVD (cardiovascular disease).

Upregulation of oxidative stress markers in human microvascular endothelial cells by complexes of serum albumin and digestion products of glycated casein.

The extent of absorption of dietary advanced glycation end products (AGEs) is not fully known. The possible physiological impact of these absorbed components on inflammatory processes has been studied little and was the aim of this investigation. Aqueous solutions of bovine casein and glucose were heated at 95 degrees C for 5 h to give AGE-casein (AGE-Cas). Simulated stomach and small intestine digestion of AGE-Cas and dialysis (molecular mass cutoff of membrane = 1 kDa) resulted in a low molecular mass (LMM) fraction of digestion products, which was used to prepare bovine serum albumin (BSA)-LMM-AGE-Cas complexes. Stimulation of human microvascular endothelial cells with BSA-LMM-AGE-Cas complexes significantly increased mRNA expression of the receptor of AGE (RAGE), galectin-3 (AGE-R3), tumor necrosis factor alpha, and a marker of the mitogen-activated protein kinase pathway (MAPK-1), as well as p65NF-kappaB activation. Cells treated with LMM digestion products of AGE-Cas significantly increased AGE-R3 mRNA expression. Intracellular reactive oxygen species production increased significantly in cells challenged with BSA-LMM-AGE-Cas and LMM-AGE-Cas. In conclusion, in an in vitro cell system, digested dietary AGEs complexed with serum albumin play a role in the regulation of RAGE and downstream inflammatory pathways. AGE-R3 may protect against these effects.

The effectiveness of the Training and Support Program for parents of children with disabilities: a randomized controlled trial.

OBJECTIVE: The Training and Support Program (TSP) was designed to equip parents of children with disabilities with a simple massage skill for use with their children in the home environment. The effectiveness of the TSP was examined in a randomized controlled trial with a wait-list control group. METHODS: Parents were trained in massage by suitably qualified therapists in eight weekly sessions, each lasting 1 h. The sample comprised 188 parents who were randomized to an intervention group (n=95), who attended the TSP with their children immediately, or a control group (n=93), who were offered the TSP after 4 months of follow-up. Data were collected by self-administered questionnaires at baseline and at 4-month follow-up. RESULTS: The majority of participants were mothers (88%), with a partner (88%), and White European (82%); 40% worked full-time or part-time, and 34% had health problems (e.g., chronic fatigue, cancer, and arthritis). The TSP demonstrated statistically significant positive effects on parental self-efficacy (PSE) for managing children's psychosocial well-being and depressed mood (0.004 and 0.007). There were trends toward improvement on parental satisfaction with life (P=.053), global health (P=.065), and parental ratings of children's sleeping (P=.074) and mobility (P=.012). Effect sizes were small (0.11-0.23). Levels of anxiety, depression, and perceived stress were all higher than published norms. CONCLUSION: The TSP is an effective means of improving PSE and depressed mood. Additional means of supporting parents need to be investigated.

Exploring a massage intervention for parents and their children with autism: the implications for bonding and attachment.

This exploratory study aimed to address two questions: (1) What does touch mean between parents and their children with autism on completion of a massage intervention? (2) Do parents feel that their relationship with their children has changed on completion of a massage intervention? Fourteen parents agreed to be interviewed. Data were collected before the massage intervention (baseline), immediately after the massage intervention and 16 weeks from baseline and were analysed using interpretative phenomenological analysis. At baseline, parents felt distressed that they felt unable to get 'close' to their children. After the intervention, parents reported feeling physically and emotionally closer to their children. Children expressed a range of cues to initiate massage at home. These benefits were maintained at follow-up for parents who continued to use massage at home. In conclusion, giving massage to children with autism may help to enhance the emotional bond between parent and child.

High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells.

Diabetes is associated with oxidative stress and increased concentrations of inflammatory cytokines. The aim of the study was to assess the effects of inflammatory cytokines and oxidative stress associated with increased glucose concentrations on inducible nitric oxide synthase (iNOS) promoter activity in intestinal epithelial cells. High-glucose (25 mmol/l) conditions reduced glutathione (GSH) concentrations in the human intestinal epithelial cell line, DLD-1. Addition of the antioxidant, alpha-lipoic acid, resulted in the restoration of GSH concentrations to normal. Upregulation of basal iNOS promoter activity was observed when cells were incubated in high glucose alone. This effect was significantly reduced by the addition of the antioxidant, alpha-lipoic acid, and completely blocked with inhibition of nuclear factor kappa B (NFkappaB) activity. Stimulation of cytokines (interleukin-1 beta, tumour necrosis factor-alpha, interferon-gamma) induced iNOS promoter activity in all conditions and this was accompanied by an increase in nitric oxide (NO) production. Inhibition of NFkappaB activity decreased, but did not completely inhibit, cytokine-induced iNOS promoter activity and subsequent production of NO. In conclusion, iNOS promoter activity induced by high concentrations of glucose is mediated in part through intracellular GSH and NFkappaB.

Differences in mitochondrial and nuclear DNA status of high-density and low-density sperm fractions after density centrifugation preparation.

OBJECTIVE: To determine the mitochondrial DNA and nuclear DNA fragmentation of sperm populations separated by using discontinuous density gradient. DESIGN: Analysis of mitochondrial and nuclear DNA status of sperm from high and low density layers. SETTING: Regional fertility center. PATIENT(S): Twenty-eight men who presented for an initial infertility investigation. MAIN OUTCOME MEASURE(S): Semen was prepared by using discontinuous density gradient (90.0%:45.0%) and subjected to a modified long polymerase chain reaction to assess mitochondrial DNA deletions and to a modified single-cell alkaline gel electrophoresis assay to determine nuclear DNA fragmentation. RESULT(S): The high-density fraction displayed significantly more wild-type mitochondrial DNA (75% of samples) than did the low-density fraction (25% of samples). In the high-density fraction, the incidence of single deletions was higher than that of double or multiple deletions, and the deletions were predominantly small. A strong correlation was observed between nuclear DNA fragmentation and the number and size of mitochondrial DNA deletions. CONCLUSION(S): Density centrifugation isolates a population of sperm with high-quality mitochondrial DNA and nuclear DNA.

Linoleic acid increases monocyte chemotaxis and adhesion to human aortic endothelial cells through protein kinase C- and cyclooxygenase-2-dependent mechanisms.

The effects of polyunsaturated n-6 linoleic acid on monocyte-endothelial interactions were investigated with particular emphasis on the expression of platelet/endothelial cell adhesion molecule (PECAM)-1 and the role of protein kinase C (PKC) and cyclooxygenase-2 (COX-2). As a diet rich in polyunsaturated fatty acids may favour atherosclerosis in hyperglycaemia, this study was performed in both normal and high-glucose media using human aortic endothelial cells (HAEC). The HAEC were preincubated with normal (5 mM) or high (25 mM) D-glucose for 3 days before addition of fatty acids (0.2 mM) for 3 days. Linoleic acid enhanced PECAM-1 expression independently of tumor necrosis factor (TNF)-α and significantly increased TNF-α-induced monocyte adhesion to HAEC in comparison to the monounsaturated n-9 oleic acid. Chronic glucose treatment (25 mM, 6 days) did not modify the TNF-α-induced or fatty acid-induced changes in monocyte binding. The increase in monocyte binding was accompanied by a significant increase in E-selectin and vascular cell adhesion molecule (VCAM)-1 expression and could be abrogated by an interleukin (IL)-8 neutralising antibody and by the PKC and COX inhibitors. Inhibition of PKC-δ reduced VCAM-1 expression regardless of experimental condition and was accompanied by a significant decrease in monocyte binding. Conditioned medium from linoleic acid-treated HAEC grown in normal glucose conditions significantly increased THP-1 chemotaxis. These results suggest that linoleic acid-induced changes in monocyte chemotaxis and subsequent binding are not solely mediated by changes in adhesion molecule expression but may be due to secreted factors such as IL-8, monocyte chemoattractant protein-1 or prostaglandins (PGs) such as PGE(2), as IL-8 neutralisation and COX-2 inhibition reduced monocyte binding without changes in adhesion molecule expression.

The psychosocial well-being of parents of children with cerebral palsy: a comparison study.

PURPOSE: Parents of children with cerebral palsy (CP) may be at risk from poor psychosocial well-being, compared with parents of children without a long-term health condition (LTHC). However, research has produced some conflicting findings on the topic and no comparison studies have been conducted in the UK. Furthermore, studies have only used measures of negative psychosocial well-being. The aim of this study was to conduct a comparative study of parents of children with CP and parents of children without a LTHC in the UK. METHOD: Seventy parents of children with CP and 70 parents of children without a LTHC completed self-administered questionnaires, comprising measures of psychosocial distress and positive psychosocial well-being. RESULTS: This study demonstrated that parents of children with CP have significantly poorer psychosocial well-being compared with parents of children without a LTHC: parents of children with CP had lower satisfaction with life and higher levels of anxious and depressed mood. CONCLUSIONS: These results suggest caring for a child with CP may put parents at risk from poor psychosocial well-being. Interventions to improve parental well-being are urgently needed.

Glucose-induced oxidative stress in mesangial cells.

BACKGROUND: Hyperglycemia is a well-recognized pathogenic factor of long-term complications in diabetes mellitus. Hyperglycemia not only generates reactive oxygen species but also attenuates antioxidant mechanisms creating a state of oxidative stress. METHODS: Porcine mesangial cells were cultured in high glucose (HG) for ten days to investigate the effects on the antioxidant defenses of the cell. RESULTS: Mesangial cells cultured in HG conditions had significantly reduced levels of glutathione (GSH) compared with those grown in normal glucose (NG). The reduced GSH levels were accompanied by decreased gene expression of both subunits of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in de novo synthesis of GSH. Elevated levels of intracellular malondialdehyde (MDA) were found in cells exposed to HG conditions. HG also caused elevated mRNA levels of the antioxidant enzymes CuZn superoxide dismutase (SOD) and MnSOD. These changes were accompanied by increased mRNA levels of extracellular matrix proteins (ECM), fibronectin (FN) and collagen IV (CIV). Addition of antioxidants to high glucose caused a significant reversal of FN and CIV gene expression; alpha-lipoic acid also up-regulated gamma-GCS gene expression and restored intracellular GSH and MDA levels. CONCLUSIONS: The results demonstrate the existence of glucose-induced oxidative stress in mesangial cells as evidenced by elevated MDA and decreased GSH levels. The decreased levels of GSH are as a result of decreased mRNA expression of gamma-GCS within the cell. Antioxidants caused a significant reversal of FN and CIV gene expression, suggesting an etiological link between oxidative stress and increased ECM protein synthesis.