New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways.

Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial-host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen-host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles hampering the development of new therapies that require further research and resolution.

TRPV1 mediates capsaicin-stimulated metabolic activity but not cell death or inhibition of interleukin-1ß release in human THP-1 monocytes.

Human monocytes and dendritic cells express transient receptor potential vanilloid 1 (TRPV1) which may play a role in mediating the inflammatory, immune and cancer surveillance responses of these cells. The aim of the present study was to investigate TRPV1 expression and function in THP-1 monocytic cells. RT-PCR and Western blot were used to detect TRPV1. The metabolic activity and viability of THP-1 cells following exposure to vanilloids was assessed using resorufin production from rezazurin. Cytokine release was measured using ELISA. TRPV1 was expressed in cultured THP-1 monocytic cells and naïve monocytes. Lower concentrations (<250 µM) of capsaicin, but not other putative TRPV1 agonists, were shown to stimulate cell metabolic activity, whereas at concentrations >250 µM, all agonists decreased metabolic activity. Capsaicin-stimulated THP-1 metabolic activity was blocked by the TRPV1 antagonist, 5-iodo-resiniferatoxin (5'-IRTX), whereas the decline in resorufin production by THP-1 cells at higher capsaicin concentrations (due to cell death), was not affected by 5'-IRTX. Finally, capsaicin (≤125 µM) significantly increased lipopolysaccharide-stimulated IL-6 and TNF-α release from THP-1 cells, whereas phytohaemagglutinin-stimulated IL-1ß, TNF-α, MCP-1 and IL-6 release were concentration-dependently inhibited by capsaicin. Modulation of IL-1ß release was not TRPV1 mediated. Overall, these results show that functional TRPV1 channels are present in naïve monocytes and THP-1 cells, and when activated, increase cell metabolic activity. In addition, capsaicin modifies cytokine release from THP-1 cells and induces cell death, most likely by a mechanism that is independent of TRPV1 activation.

Capsaicin-Induced Death of Human Haematological Malignant Cell Lines Is Independent of TRPV1 Activation.

The effect of the plant-derived vanilloid, capsaicin (CAP), on the metabolic activity of THP-1, U266B1 and U937 hematological malignancy cells was determined. CAP reduced metabolic activity in a concentration-dependent manner in the three cell lines. A biphasic effect was observed on THP-1 cells (EC50: IC50 (95% CI) 32.9 (19.9-54.3)/219 (144-246) µmol/l). U266B1 cells were more resistant to CAP than THP-1 and U937. Metabolic activity was significantly inhibited by CAP in U937 compared to U266B1 cells (IC50: 197 versus 431 µmol/l, respectively, p < 0.008). Transient receptor potential vanilloid-1 (TRPV1) and CB1 antagonists (SB452533 and AM251, respectively) suppressed the CAP-induced increase in THP-1 cell metabolic activity (p < 0.001). AM251 and SB452533 appeared to act as partial agonists and displayed a synergistic effect with CAP in U937 cells. CAP inhibits the metabolic activity of malignant hematological cells through non-TRPV1-dependent mechanisms.

Effects of atorvastatin on oxidative stress in chronic kidney disease.

AIM: Statins have pleiotropic effects that include attenuation of oxidative stress that may be relevant for chronic kidney disease (CKD) patients. We investigated the effect of long-term atorvastatin therapy on oxidative stress biomarkers in CKD patients. METHODS: This was a pre-specified secondary analysis of data from a randomized, double-blind, placebo-controlled trial (Lipid lowering and Onset of Renal Disease, LORD) in CKD patients. Participants received 10 mg/day atorvastatin (n = 47) or placebo (n = 39) for 3 years. Plasma measures (total F2-isoprostanes, malondialdehyde. protein carbonyls, uric acid, glutathione peroxidase (GPx) activity and total antioxidant capacity (TAC) ) were performed at baseline and at 3 years. Age and sex matched participants (n = 34) with normal kidney function were controls. RESULTS: CKD patients had significantly (P < 0.05) increased F2-isoprostanes and uric acid and decreased GPx activity compared with controls. When comparing the treatment (atorvastatin (A) vs placebo (P) ) change from baseline to 3 years, there were no significant differences (P > 0.05) in the group difference of the change values: (mean (95% CI), F2-isoprostanes = 5.3 (-29.2 to 39.8) pg/mL, protein carbonyls = 0.03 (-0.13 to 0.19) nmol/mg, GPx activity = -0.10 (-4.73 to 4.52) (U/L), uric acid = 8.8 (-33.9 to 51.6) µmol/L or TAC = -0.03 (-0.10 to 0.04) mmol/L. A significant difference (P = 0.04) in the change in malondialdehyde between groups, 1.52(0.09 to 2.96) µmol/L, was due to a large decrease in the placebo group. CONCLUSION: CKD patients had elevated oxidative stress that was not attenuated by atorvastatin 10 mg/day for 3 years.

Effects of atorvastatin on biomarkers of inflammation in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with inflammation. The effects of atorvastatin on biomarkers of inflammation were assessed in CKD patients in the LORD trial. METHODS: 117 patients with serum creatinine >120 µmol/L were randomized to receive atorvastatin 10 mg/day (56) or placebo (61) and followed for a mean of 2.5 years. 33 individuals with normal kidney function were controls. Outcomes included comparison of changes in pentraxin-3 (PTX3), TNF-α, CRP, IL-6, IL-8, and IL-10 between atorvastatin and placebo-treated patients. RESULTS: At baseline, compared with controls, CKD patients had increased PTX3 (mean, 1.08 vs. 0.58 ng/mL; p < 0.001), CRP (4.9 vs. 1.5 mg/L; p < 0.001), IL-8 (6.00 vs. 4.58 pg/mL; p = 0.001), IL-10 (59.0 vs. 17.6 pg/mL; p = 0.007), and TNF-α (18.0 vs. 5.6 ng/mL; p < 0.001). In patients with raised baseline plasma IL-6/8/10 and/or PTX3 the eGFR decline during the trial was significantly less in those treated with atorvastatin compared to placebo (mean change, -3.36; vs. + 1.25 mL/min/1.73 m2/year; difference, 4.61 95% CI 0.98 - 8.25; p = 0.002), whilst those without raised inflammatory biomarkers showed no difference. Placebo treated patients with raised TNF-α levels had no eGFR decline (p > 0.90), whereas in atorvastatin-treated patients eGFR declined (p = 0.05). CONCLUSIONS: CKD patients with inflammation treated with atorvastatin had significantly less eGFR decline. Larger studies using statin therapy, specifically enrolling CKD patients with inflammation, may be worthwhile exploring.

Effects of atorvastatin on NGAL and cystatin C in chronic kidney disease: a post hoc analysis of the LORD trial.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C are biomarkers of kidney injury and function, respectively. This study assessed whether plasma NGAL and/or serum cystatin C predicted baseline estimated glomerular filtration rate (eGFR) and urinary protein excretion, rate of change of eGFR and urinary protein excretion and whether atorvastatin influenced changes in these biomarkers in patients with chronic kidney disease (CKD). METHODS: This is a post hoc analysis of the Lipid Lowering and Onset of Renal Disease trial, a randomized double-blind, placebo-controlled trial where 88 patients with Stages 2-4 CKD received atorvastatin 10 mg/day (48) or placebo (40). Stored blood samples were analysed for NGAL and cystatin C at baseline and a mean of 1.5 and 2.9 years later. Serum creatinine and Modification of Diet in Renal Disease (MDRD) eGFR were obtained three monthly. RESULTS: There were negative associations between NGAL and cystatin C and eGFR (P = 0.025 and P < 0.001, respectively) at all time points. There were no associations between baseline NGAL and cystatin C and rate of change of eGFR (P = 0.44 and P = 0.49, respectively). Baseline NGAL but not cystatin C (P = 0.043 and P = 0.35, respectively) predicted rate of change of urinary protein excretion. In atorvastatin-treated patients, NGAL decreased (mean, -7.4 ng/mL/year; SD 128.4), whereas it increased in the placebo group [mean, 4.6 ng/mL/year; SD 56.6), the difference being statistically significant (P = 0.049). CONCLUSIONS: NGAL is a biomarker of existing CKD but did not predict CKD progression. Atorvastatin reduced plasma NGAL but the significance and mechanisms require further investigation. Atorvastatin had no significant effect on cystatin C.

Relationship between antioxidant enzyme genotype and activity and kidney function: a case-control study.

BACKGROUND: Oxidative stress is associated with the progression of chronic kidney disease (CKD). Links between antioxidant enzyme SNPs such as superoxide dismutase (SOD) Ala16Val, glutathione peroxidase (GPx) Pro197Leu and catalase C- 262T and CKD have not been investigated. This study compared antioxidant genotypes and activities of CKD patients with population controls, and determined their relationship to kidney function. METHODS: CKD patients (n = 230) and controls (n = 224) were screened for the GPx, SOD and catalase SNPs. Plasma and red blood cell (RBC) GPx, RBC SOD and RBC catalase activities, and estimated glomerular filtration rate (eGFR) were measured. RESULTS: Significantly more CKD patients (n = 5) had the GPx Leu/Leu genotype compared to controls (n = 0), and had lower eGFR (p = 0.054). CKD patients had significantly lower plasma GPx and RBC catalase activities compared to controls, whereas RBC GPx and RBC SOD activities were significantly higher in CKD patients (p < 0.001). CONCLUSIONS: CKD is associated with reduced plasma GPx and catalase activities and enhanced RBC GPx and SOD activities. Although, genotype frequencies were similar for both groups, lower eGFR was associated with the GPx Leu/ Leu genotype.

Optimized flow cytometric detection of transient receptor potential vanilloid-1 (TRPV1) in human hematological malignancies.

The ectopic overexpression of transient receptor potential vanilloid-1 (TRPV1) has been detected in numerous solid cancers, including breast, prostate, pancreatic, and tongue epithelium cancer. However, the expression of TRPV1 in hematological malignancies remains unknown. Here we show through in silico analysis that elevated TRPV1 mRNA expression occurs in a range of hematological malignancies and presents an optimized flow cytometry method to rapidly assess TRPV1 protein expression for both cell lines and primary patient samples. Three anti-TRPV1 antibodies were evaluated for intracellular TRPV1 detection using flow cytometry resulting in an optimized protocol for the evaluation of TRPV1 in hematological malignant cell lines and patients' peripheral blood mononuclear cells (PBMC). Overexpression of TRPV1 was observed in THP-1 (acute monocytic leukemia) and U266B1 (multiple myeloma, MM), but not U937 (histiocytic lymphoma) compared to healthy PBMC. TRPV1 was also detected in all 49 patients including B-cell non-Hodgkin's lymphoma (B-NHL), MM, and others and 20 healthy controls. TRPV1 expression was increased in 8% of patients (MM = 2, B-NHL = 2). In conclusion, we provide an optimized flow cytometry method for routine expression analysis of clinical samples and show that TRPV1 is increased in a subset of patients with hematological malignancies.

Glutathione peroxidase, superoxide dismutase and catalase genotypes and activities and the progression of chronic kidney disease.

BACKGROUND: Oxidative stress has been linked to the progression of disease, including chronic kidney disease (CKD). The aim of the present study was to determine the association between single-nucleotide polymorphisms (SNPs) of the antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase and their activities and the progression of CKD. METHODS: This is a prospective cohort study of 185 CKD patients (Stages 2-4), followed for up to 12 months. All patients were genotyped for SNPs of SOD (SOD Ala16Val), GPx (GPx Pro197Leu) and catalase (C-262T). The rate of change over the study period of estimated glomerular filtration rate (eGFR), plasma and red blood cell (RBC) GPx, RBC SOD and RBC catalase activities were determined. RESULTS: CKD patients with the SOD Ala/Val and Val/Val genotypes had a significantly greater eGFR decline compared to those with the Ala/Ala genotype (Ala/Val compared with Ala/Ala odds ratio (OR) 0.35, 95% CI 0.19 to 0.64, P = 0.001; Val/Val compared with Ala/Ala OR 0.25, 95% CI 0.10 to 0.65, P = 0.005). The progression of CKD was not associated with SNPs of the GPx or catalase genes studied but there was a direct relationship between the rate of change of plasma GPx activity and the rate of change of eGFR over 12 months (P = 0.025). CONCLUSION: CKD patients with the SOD Ala/Val and Val/Val genotypes have a greater decline in kidney function than those with the Ala/Ala genotype.

Effects of systemic capsaicin treatment on TRPV1 and Tachykinin NK(1) receptor distribution and function in the nucleus of the solitary tract of the adult rat.

Vanilloids including capsaicin and resiniferatoxin (RTX) have been identified as potential novel anti-inflammatory and analgesic compounds. We have previously shown that systemic capsaicin administration to neonatal rats evokes profound long-term alterations in transient receptor potential vanilloid 1 (TRPV1)- and neurokinin 1 (NK(1)) receptor-mediated respiratory responses in the commissural nucleus of the solitary tract (cNTS). Whether this effect of capsaicin is unique to developmentally immature animals is unknown. Therefore, in the present study, we investigated the effects of systemic capsaicin administration to adult rats on NK(1) receptor binding sites, TRPV1 and NK(1) immunoreactivity and function in the cNTS. Microinjection of capsaicin (1 nmol) or RTX (75 pmol) into the cNTS of vehicle-pretreated rats produced a profound bradypnoea (maximum change: -45 breaths·min(-1)) and a small increase in tidal volume (VT). Similarly, microinjection of the selective NK(1) receptor agonists [Sar(9), Met(O(2))(11)]substance P (SP; 66 pmol) and septide (20 pmol) decreased respiratory frequency and increased VT. Thirteen to 18 days after systemic administration of capsaicin (125 mg·kg(-1) s.c.), the bradypnoeic responses to both capsaicin and RTX were absent (p < 0.05), indicative of sensory neuron ablation/desensitisation. Systemic capsaicin pretreatment significantly (p < 0.05) reduced the density of both [(125)I]Bolton-Hunter SP binding sites (NK(1) receptors) and NK(1) receptor immunoreactivity in the cNTS, but did not alter the respiratory responses evoked by microinjection of [Sar(9), Met(O(2))(11)]SP and septide into this region. These studies show that systemic capsaicin administration reduces NK(1) receptor density in the cNTS without adversely affecting NK(1) receptor function at this site. We speculate that adult rats may be more resistant than neonatal rats to the neuroplastic effects of systemic capsaicin administration.

Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death.

Transient receptor potential vanilloid (TRPV) 1 channels function as sensors for a variety of noxious and inflammatory signals, including capsaicin, heat and protons, and are up-regulated under inflammatory conditions. As end-stage kidney disease (ESKD) is associated with chronic inflammation, impaired immunity and depressed lymphocyte numbers, we sought to determine whether altered TRPV1 (and related TRPV2) expression in immune cells might be a contributing factor. TRPV1 and TRPV2 mRNA expression in peripheral blood mononuclear cells (PBMC) was similar in controls and ESKD patients by quantitative real-time RT-PCR. However, using immunocytochemistry, TRPV1-immunoreactivity was significantly higher and TRPV2-immunoreactivity was significantly lower in PBMC from ESKD patients compared to controls. The plant-derived TRPV1 agonists, capsaicin and resiniferatoxin (RTX) and the putative endovanilloid/endocannabinoids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine (OLDA), induced concentration-dependent death of PBMC from healthy donors with a rank order of potency of RTX>NADA>OLDA>>capsaicin. TRPV1 (5'-iodoresiniferatoxin) and cannabinoid (CB2; AM630) receptor antagonists blocked the cytotoxic effect of NADA. In subsequent experiments, PBMC from ESKD patients exhibited significantly increased susceptibility to NADA-induced death compared to PBMC from controls. The apparent up-regulation of TRPV1 may be a response to the inflammatory milieu in which PBMC exist in ESKD and may be responsible for the increased susceptibility of these cells to NADA-induced death, providing a possible explanation as to why ESKD patients have reduced lymphocyte counts and impaired immune function. Thus, TRPV1 (and possibly CB2) antagonists may have potential for the treatment of immune dysfunction in ESKD.

Comparison of markers of oxidative stress, inflammation and arterial stiffness between incident hemodialysis and peritoneal dialysis patients--an observational study.

BACKGROUND: Patients on peritoneal and hemodialysis have accelerated atherosclerosis associated with an increase in cardiovascular morbidity and mortality. The atherosclerosis is associated with increased arterial stiffness, endothelial dysfunction and elevated oxidative stress and inflammation. The aims of this study are to investigate the effects of peritoneal and hemodialysis on arterial stiffness, vascular function, myocardial structure and function, oxidative stress and inflammation in incident patients with end stage kidney disease. METHODS: This is an observational study. Eighty stage five CKD patients will be enrolled and followed for one-year. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity, 2) oxidative stress assessed by plasma F2 isoprostanes and 3) inflammation measured by plasma pentraxin-3. Secondary outcomes will include additional measures of oxidative stress and inflammation, changes in vascular function assessed using the brachial artery reactivity technique, carotid artery intimal medial thickness, augmentation index and trans thoracic echocardiography to assess left ventricular geometry, and systolic and diastolic function. Patients will undergo these measures at baseline (6-8 weeks prior to starting dialysis therapy), then at six and 12 months after starting dialysis. DISCUSSION: The results of this study may guide the choice of dialysis modality in the first year of treatment. It may also lead to a larger study prospectively assessing the effect of dialysis modality on cardiovascular morbidity and mortality. TRIAL REGISTRATION: ACTRN12609000049279.

Astaxanthin vs placebo on arterial stiffness, oxidative stress and inflammation in renal transplant patients (Xanthin): a randomised controlled trial.

BACKGROUND: There is evidence that renal transplant recipients have accelerated atherosclerosis manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress and inflammation associated with immunosuppressive therapy. The dietary supplement astaxanthin has shown promise as an antioxidant and anti-inflammatory therapeutic agent in cardiovascular disease. The aim of this trial is to investigate the effects of astaxanthin supplementation on arterial stiffness, oxidative stress and inflammation in renal transplant patients. METHOD AND DESIGN: This is a randomised, placebo controlled clinical trial. A total of 66 renal transplant recipients will be enrolled and allocated to receive either 12 mg/day of astaxanthin or an identical placebo for one-year. Patients will be stratified into four groups according to the type of immunosuppressant therapy they receive: 1) cyclosporine, 2) sirolimus, 3) tacrolimus or 4) prednisolone+/-azathioprine, mycophenolate mofetil or mycophenolate sodium. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by plasma isoprostanes and 3) inflammation by plasma pentraxin 3. Secondary outcomes will include changes in vascular function assessed using the brachial artery reactivity (BAR) technique, carotid artery intimal medial thickness (CIMT), augmentation index (AIx), left ventricular afterload and additional measures of oxidative stress and inflammation. Patients will undergo these measures at baseline, six and 12 months. DISCUSSION: The results of this study will help determine the efficacy of astaxanthin on vascular structure, oxidative stress and inflammation in renal transplant patients. This may lead to a larger intervention trial assessing cardiovascular morbidity and mortality. TRIAL REGISTRATION: ACTRN12608000159358.

The Lipid lowering and Onset of Renal Disease (LORD) Trial: a randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease.

BACKGROUND: There is evidence that dyslipidemia is associated with chronic kidney disease (CKD). Experimental studies have established that lipids are damaging to the kidney and animal intervention studies show statins attenuate this damage. Small clinical trials, meta-analyses, observational studies and post-hoc analyses of cardiovascular intervention studies all support the concept that statins can reduce kidney damage in humans. Based on this background, a double blind randomized placebo controlled trial was designed to assess the effectiveness of atorvastatin 10 mg on slowing the progression of kidney disease in a population of patients with CKD. METHOD/DESIGN: The Lipid lowering and Onset of Renal Disease (LORD) trial is a three-year, single center, multi-site, double blind, randomized, placebo controlled trial. The primary outcome measure is kidney function measured by eGFR calculated by both Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault equations. Secondary outcome measures include kidney function measured by 24-hour urine creatinine clearance and also 24-hour urinary protein excretion, markers of oxidative stress, inflammation and drug safety and tolerability. DISCUSSION: The results of this study will help determine the effectiveness and safety of atorvastatin and establish its effects on oxidative stress and inflammation in patients with CKD. TRIAL REGISTRATION: ANZCTRN012605000693628.

Expression of transient receptor potential vanilloid 1 (TRPV1) and 2 (TRPV2) in human peripheral blood.

The vanilloid receptor family of cation channels includes the capsaicin-sensitive, proton- and heat-activated TRPV1 and noxious heat-activated TRPV2. The present study demonstrates both gene and protein expression of TRPV1 and TRPV2 in human peripheral blood cells (PBCs) using molecular and immunocytochemical techniques. Using reverse-transcription polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR (qRT-PCR), TRPV1 and TRPV2 mRNA was detected in mRNA isolated from human whole peripheral blood. Using qRT-PCR, TRPV2 mRNA was highly expressed in human whole blood isolates (9.33+/-1.19 x 10(4)copies per 10(6)copies of the housekeeping gene GAPDH), whereas TRPV1 message was detected at approximately 150-fold lower levels (638+/-121 copies per 10(6)copies GAPDH). At the protein level, TRPV1 and TRPV2 activity was determined immunocytochemically in a lymphocyte-enriched mononuclear cell preparation (83+/-2% lymphocytes). Cells were labelled with rabbit anti-TRPV1 or goat anti-TRPV2 (1:500) and subsequently labelled with goat Texas red- (TRPV1) or FITC-(TRPV2) conjugated secondary antibodies (1:1000). All cells demonstrated punctate TRPV1-immunoreactivity, which appeared to be on the plasma membrane and in the cytoplasm. In contrast, cells within subjects appeared to express the TRPV1 protein at varying intensities. TRPV2-immunoreactivity appeared diffuse. This is the first study to demonstrate the presence of both TRPV1 and TRPV2 in human peripheral lymphocytes. Further studies need to be undertaken in order to determine the role of TRPV channels in these cells.

Did general practice health assessments of older Australians improve equity?

OBJECTIVE: To examine if claims for general practice health assessments of older persons in Australia over the period 1 November 1999 to 30 September 2002 were equitably distributed. DESIGN: Closed cohort study with data analysis using logistic regression. SETTING: Private general practice in Australia. PARTICIPANTS: All Australians aged 75 or more years at 1 October 1999, who were eligible to claim for a health assessment. MEASURES STUDIED: Medicare and Department of Veterans' Affairs (DVA) medical claims data, and personal characteristics of claimants: age, sex, DVA beneficiary status, rurality and socio-economic status of postcode of residence. Rurality was classified by the Rural Remote and Metropolitan Area Classification (RRMA) and socio-economic status by the Index of Relative Socio-economic Deprivation (IRSD) for the postcode. RESULTS: The cohort initially contained 886 185 subjects. Over the 35 months, 271 939 individuals (31%) claimed at least one health assessment. Those most likely to have claimed for a health assessment were aged 80 to 84 years, female, entitled to treatment under DVA arrangements, lived in postcodes classified as RRMA 1-4 and classified as the most disadvantaged IRSD quartile. CONCLUSION: Over this period, general practice health assessments appear to have been equitably distributed except for those living in postcodes classified as RRMA 5-7.

Cell Stress Signaling Cascades Regulating Cell Fate.

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

Dietary intake of patients with chronic kidney disease entering the LORD trial: adjusting for underreporting.

OBJECTIVE: The study objective was to determine the dietary intake of patients with chronic kidney disease before and after filtering for suspected underreporters and to investigate the impact of underreporting on the interpretation of diet data. DESIGN: This was a cross-sectional study. SETTING: The study included outpatients from hospitals and clinics in Northern Tasmania, Australia. PATIENTS: Data from 113 patients enrolled in the Lipid Lowering and Onset of Renal Disease trial were used in this study. Patients with serum creatinine greater than 120 mmol/L were included, and those taking lipid-lowering medication were excluded. METHODS: Patients completed a 4-day self-report diet diary, and FoodWorks software was used to determine their daily intake of energy, macronutrients, and specific micronutrients. Diet diaries were assessed for likely underreporting using the Goldberg cutoff approach with a ratio of energy intake to estimated resting energy expenditure of 1.27. Nutrient intakes were compared with current National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines, World Health Organization recommendations, recommended daily allowances, and daily values adjusted for energy intake. RESULTS: Demographics of the patients were as follows: male/female, 71/42; age (mean +/- standard deviation), 60 +/- 15 years; body mass index, 28.6 +/- 6.0 kg/m(2), and serum creatinine, 223.4 +/- 110.0 mmol/L. According to the criteria, 80 patients (70.8%) were underreporting their energy intake. Underreporters were more likely to be female and younger, and have a higher body mass index and elevated serum creatinine. In all patients, daily energy intake (89.6 +/- 32.4 kJ/kg) was lower than recommended (125-145 kJ/kg); however, this was not the case for valid reporters (128.3 +/- 23.7 kJ/kg). Protein intake was higher (0.9 +/- 0.3 g/kg) than recommended (0.75 g/kg) in all patients and even higher (1.2 +/- 0.3 g/kg) in valid reporters. Mean calcium, zinc, and dietary fiber intakes were all below recommendations in all patients, but these differences were not apparent in valid reporters. CONCLUSION: Interpreting self-report diet diary data from patients with chronic kidney disease without attempting to exclude underreporters will lead to erroneous conclusions, especially in respect to energy, protein, dietary fiber, calcium, and zinc intakes.

TRPV1 Channels in Immune Cells and Hematological Malignancies.

Transient receptor potential vanilloid-1 (TRPV1) is a member of the TRP family of channels that are responsible for nociceptive, thermal, and mechanical sensations. Originally associated exclusively with sensory neurons, TRPV1 is now known to be present in almost all organs, including cells of the immune system, where TRPV1 has been shown to play a pivotal role in inflammation and immunity. Monocytes, macrophages, and dendritic cells express TRPV1, with both mouse and human studies suggesting that TRPV1 activation protects against endotoxin-induced inflammation. In contrast, TRPV1 (and other TRP channels) appears to be required for T-cell receptor activation by mitogens. Additionally, studies in cell lines derived from hematological and other malignancies suggest altered expression/function of TRPV1 might serve as a target for novel cytotoxic therapies.

Mammalian l-to-d-amino-acid-residue isomerase from platypus venom.

The presence of d-amino-acid-containing polypeptides, defensin-like peptide (DLP)-2 and Ornithorhyncus venom C-type natriuretic peptide (OvCNP)b, in platypus venom suggested the existence of a mammalian d-amino-acid-residue isomerase(s) responsible for the modification of the all-l-amino acid precursors. We show here that this enzyme(s) is present in the venom gland extract and is responsible for the creation of DLP-2 from DLP-4 and OvCNPb from OvCNPa. The isomerisation reaction is freely reversible and under well defined laboratory conditions catalyses the interconversion of the DLPs to full equilibration. The isomerase is approximately 50-60 kDa and is inhibited by methanol and the peptidase inhibitor amastatin. This is the first known l-to-d-amino-acid-residue isomerase in a mammal.