Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76

Aims/hypothesis Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes.Methods We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors.Results rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54–0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11–1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27–0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus.Conclusions/interpretation We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.     

Should single-stage PEG buttons become the procedure of choice for PEG placement in children?

BACKGROUND: Single-stage PEG buttons (PEG-B) allow initial placement of a skin-level gastrostomy device for children who require enteral access. They offer significant advantages over traditionally placed PEG tubes (PEG-T) but have not been widely accepted into practice. OBJECTIVE: To review our experience with PEG-Bs compared with PEG-Ts. HYPOTHESIS: PEG-B shares a similar safety profile with PEG-T but delays the need for an initial device change well beyond the change that usually occurs at 6 to 8 weeks after PEG-T placement. DESIGN: Retrospective chart review. SETTING: Nemours Children's Clinic, Jacksonville, Florida. PATIENTS: All children undergoing both PEG procedures and attending our clinic from 1997 to 2002. MAIN OUTCOME MEASUREMENTS: Age, sex, weight, indications, postoperative complications, interval until first tube change and first tube change complications. RESULTS: Totals of 145 and 93 patients were identified in the PEG-B and PEG-T groups, respectively. Patient characteristics were similar in the 2 groups with respect to age, weight, indications, and postoperative complications. The interval until first tube change, however, was significantly longer in the PEG-B group (314 days) than in the PEG-T (78 days) (P < .0001). In addition, the PEG-B was found to be as safe as the PEG-T for small infants who weighed less than 5 kg. CONCLUSIONS: PEG-B placement should be considered as the procedure of choice over PEG-T placement for children. It offers similar safety profiles, even for small patients and a significantly longer interval until first device change.     

Modulation of hippocampal norepinephrine release by cholinergic agonists is altered by AF64A lesion

The effect of lesioning hippocampal cholinergic neurons with the neurotoxin AF64A on the ability of cholinergic agonists to modulate stimulation-induced release of ³H-norepinephrine (NE) from rat hippocampal slices was studied. Rats received intracerebroventricular injections of either AF64A (ethylcholine mustard aziridinium, 2 nmol) or vehicle (sham operated). Six weeks after treatment, release of ³H-NE evoked by electrical stimulation (2 Hz, 2 min) in the presence or absence of cholinergic agonists and/or antagonists was measured. Activation of M₂ receptors with oxotremorine (in the presence of the M₁ antagonist pirenzepine) caused a small inhibition of NE release, which was abolished in hippocampi from AF64A-treated rats. The K_d for high-affinity binding of the selective M₂ ligand [³H] AF-DX 384 was increased 10-fold in lesioned tissues. The M₁ selective agonist McN-A-343 produced a significant enhancement of NE release, which was unchanged by AF64A lesion. Binding studies with [³H] pirenzepine showed no change in the affinity or number of M₁ receptors. Nicotine also caused a significant enhancement of evoked NE release, but this effect was markedly reduced in tissues from AF64A-treated rats. AF64A treatment caused a twofold decrease in the number of [³H] nicotine binding sites. This study suggests that long-term lesion of hippocampal cholinergic neurons with AF64A alters the function of postsynaptic muscarinic M₂ and nicotinic cholinergic receptors that modulate the release of NE in the hippocampus.     

Cost-effectiveness modeling of abatacept versus other biologic agents in DMARDS and anti-TNF inadequate responders for the management of moderate to severe rheumatoid arthritis

To assess the cost-effectiveness of abatacept compared to different biologic treatment strategies for moderate to severe rheumatoid arthritis based on current medical practices in Canada. A model was constructed to assess the cost-effectiveness of various biologic treatments over a 2-year time horizon, using two effectiveness endpoints: “low disease activity state” (LDAS) and “remission”. Abatacept, as first biologic agent after an inadequate response to DMARDs, provides greater treatment success rate for achieving LDAS (29.4% versus 15.6%) and remission (14.8% versus 5.2%), and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p < 0.001). Abatacept, as second biologic agent after an inadequate response to one anti-TNF agent, provides greater treatment success rate for achieving LDAS (17.1% versus 10.2%) and remission (7.4% versus 3.9%) and appears significantly more cost-effective compared to the sequential use of anti-TNF agents (p < 0.001). Abatacept is a cost-effective strategy in patients with an inadequate response to DMARDs or to one anti-TNF agent.     

Disease-specific influences on meaning and significance in self-care decision-making in chronic illness.

The purpose of this study was to investigate the everyday self-care decision-making of individuals with chronic illness for the purpose of developing a comparison of decision-making processes between chronic diseases and to identify criteria by which persons with various chronic conditions evaluate the quality of self-care decisions. A sample of 21 individuals with either Type II diabetes, HIV/AIDS, or multiple sclerosis, who were nominated as expert self-care managers by their clinicians, recorded the decisions they made in their daily self-care over a 1-week period and were interviewed in depth to elaborate on the decisions, the processes by which they made them, and the factors that influenced them. This process was repeated to obtain depth and detail in relation to decisions and decision-making processes. The findings revealed that although participants shared similar elements in their self-care decision-making, they differed in the perceived meaning and significance of their decisions, depending on disease-specific attributes relating to timeliness, biomarkers, interaction within a social context, the construction of healthy practices, and available relevant information. Findings were analyzed and compared to suggest future directions for research and educational interventions to enhance the quality of self-care decision-making in chronic illness by considering the influence of disease-specific attributes in self-care management.     

In Italy, a medical degree often means unemployment or underemployment.

Italy's per capita concentration of physicians is the highest in the Western World, and many of them have to struggle to earn a living as they compete for a decreasing number of prestigious hospital positions. Many Italian doctors have more than one job, and some never find work in medicine.     

CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract.

Since unmethylated CpG motifs are more frequent in DNA from bacteria than vertebrates, and the unmethylated CpG motif has recently been reported to have stimulatory effects on lymphocytes, we speculated that bacterial DNA may induce inflammation in the lower respiratory tract through its content of unmethylated CpG motifs. To determine the role of bacterial DNA in lower airway inflammation, we intratracheally instilled prokaryotic and eukaryotic DNA in C3H/HeBFEJ mice and performed whole lung lavage 4 h after the exposure. Heat denatured, single stranded Escherichia coli genomic DNA (0.06 ng endotoxin/microg DNA) was compared to heat denatured, single stranded calf thymus DNA (0.007 endotoxin/microg DNA). 10 microg of bacterial DNA, in comparison to 10 microg of calf thymus DNA, resulted in a fourfold increase in the concentration of cells (P = 0.0002), a fivefold increase in the concentration of neutrophils (P = 0.0002), a 50-fold increase in the concentration of TNF-alpha (P = 0.001), and a fourfold increase in the concentration of both IL-6 (P = 0.0003) and macrophage inflammatory protein-2 (P = 0.0001) in the lavage fluid. Importantly, instillation of 0.60 ng of E. coli LPS resulted in a negligible inflammatory response. To test whether the stimulatory effects of bacterial DNA are due to its unmethylated CpG dinucleotides, we methylated the bacterial DNA and also prepared 20 base pair oligonucleotides with and without CpG motifs. In comparison to instillation of untreated bacterial DNA, methylation of the bacterial DNA resulted in a significant reduction in the concentration of cells and cytokines in the lower respiratory tract. Moreover, oligonucleotides containing embedded unmethylated CpG motifs resulted in inflammation in the lower respiratory tract that was indistinguishable from that observed with untreated bacterial DNA. In contrast, oligonucleotides without the embedded CpG motifs or with embedded but methylated CpG motifs resulted in significantly less inflammation in the lower respiratory tract. The possible relevance of these data to human disease was shown by extracting and analyzing DNA in sputum from patients with cystic fibrosis (CF). Approximately 0.1 to 1% of this sputum DNA was bacterial. Intratracheal instillation of highly purified CF sputum DNA caused acute inflammation similar to that induced by bacterial DNA. These findings suggest that bacterial DNA, and unmethylated CpG motifs in particular, may play an important pathogenic role in inflammatory lung disease.     

Infected thrombus compression of the right ventricular outflow tract in transposition of the great arteries

We describe the first reported case of infected thrombus compressionof the right ventricular outflow tract in a Rastelli patientas a complication of pregnancy. This case emphasizes the importanceof cardiac magnetic resonance imaging and echocardiography inthe assessment of patients with adult congenital heart diseaseprior to and during pregnancy.