Modification of Proteins by Metabolites in Immunity.

Immunometabolism has emerged as a key focus for immunologists, with metabolic change in immune cells becoming as important a determinant for specific immune effector responses as discrete signaling pathways. A key output for these changes involves post-translational modification (PTM) of proteins by metabolites. Products of glycolysis and Krebs cycle pathways can mediate these events, as can lipids, amino acids, and polyamines. A rich and diverse set of PTMs in macrophages and T cells has been uncovered, altering phenotype and modulating immunity and inflammation in different contexts. We review the recent findings in this area and speculate whether they could be of use in the effort to develop therapeutics for immune-related diseases.

SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use?

Since their discovery, SOCS have been characterised as regulatory cornerstones of intracellular signalling. While classically controlling the JAK/STAT pathway, their inhibitory effects are documented across several cascades, underpinning their essential role in homeostatic maintenance and disease. After 20 years of extensive research, SOCS3 has emerged as arguably the most important family member, through its regulation of both cytokine- and pathogen-induced cascades. In fact, low expression of SOCS3 is associated with autoimmunity and oncogenesis, while high expression is linked to diabetes and pathogenic immune evasion. The induction of SOCS3 by both viruses and bacteria and its impact upon inflammatory disorders, underscores this protein's increasing clinical potential. Therefore, with the aim of highlighting SOCS3 as a therapeutic target for future development, this review revisits its multi-faceted immune regulatory functions and summarises its role in a broad ranges of diseases.

The use of new concepts in vascular physiology and pharmacology to improve hemodialysis access outcomes.

Greater insight into vascular pathophysiology and intimal hyperplasia has resulted in observational studies that suggest that interventions which decrease inflammatory mediators, improve endothelial function and inhibit smooth muscle migration and proliferation may be of benefit in improving hemodialysis vascular access survival. Longer dialysis times may also reduce inflammatory mediators and restore vascular sensitivity to endothelium dependent relaxation factor. In contrast, the common procedure of angioplasty is the experimental model to develop intimal hyperplasia and stenosis, while the efficacy of stents to prevent that stenosis in hemodialysis accesses remains controversial. Common drugs that interfere with metalloproteinases may prevent aneurysm formation while avoiding drugs that aid quorum sensing and using drugs that interfere with it may prevent biofilm infection in hemodialysis vascular catheters. Large prospective randomized studies will be needed to determine the true benefit.

Surface tension, proteinuria, and the urine bubbles of Hippocrates.

Hippocrates noted that bubbles in urine were associated with kidney disease. We examined changes in surface tension responsible for bubble formation in urine, to investigate whether surface tension could be a more accurate and continuous linear predictor of 24-h proteinuria than currently available tests on spot urine.

Edema, oncotic pressure, and free entropy: novel considerations for the treatment of edema through attention to thermodynamics.

Over 170 years after Richard Bright and a century after Ernest H. Starling, the development, location, and severity of edema in patients with renal impairment continue to baffle the predictions of most nephrologists. While much of the phenomenon can be explained by levels of serum proteins, or hydrostatic pressures, there are stunning exceptions well known to any practicing nephrologist. Some of the derangement is undoubtedly due to unmeasured but well-known variables, such as membrane permeability; however, other factors such as free entropy of plasma are also clearly involved. The study of other polyelectrolyte colloids, similar to plasma proteins, for industrial purposes has led to the identification of various phenomena such as counterion condensation that can result in loss of entropy and consequently osmotic pressure. Variables known to result in a loss of free entropy, such as pH, oxidation products and ligand binding, are discussed. Older equations developed by van't Hoff and Donnan might require replacement by newer mathematical models such as the nonlinear Poisson-Boltzmann equation or the Monte Carlo simulator. Attempts to restore free entropy to plasma would be a more physiological treatment of edema than diuretic use. Implications are noted for future drug development to treat edema.

The importance of timing of surgery for hemodialysis vascular access thrombectomy.

The effect of delay in thrombectomy of occluded hemodialysis accesses was examined to determine whether a critical period exists during which a salvage procedure was more likely to be successful. A total of 1,126 vascular access surgeries between January 1, 1989, and December 31, 1994, were analyzed. No period of delay in thrombectomy was found when it was possible to say with certainty that an access could not be salvaged, although success was greatest in the first 48 h. Autogenous fistulas were less likely to be salvaged and surgery was unlikely to be successful if performed later than the day of thrombosis. However, grafts were likely to undergo successful thrombectomy even 3 days after thrombosis. Overall when the delay was more than 3 weeks after thrombosis, a new access was more likely to be constructed than the thrombosed access was to be successfully declotted.

Effect of cholestyramine resin on single dose valproate pharmacokinetics.

Cholestyramine, a nonabsorbable anion exchange resin, has been reported to bind concomitantly administered drugs and decrease their bioavailability. The objective of the study was to determine the effect of cholestyramine on the plasma concentrations of valproic acid (VPA) following concurrent and staggered (VPA 3 hours before cholestyramine) dosing. Six healthy volunteers participated in an open-label, 3-way crossover study. In each phase fasting subjects received 250 mg of VPA followed by serial blood sampling for VPA plasma concentrations over a 37-hour period. In the concurrent and staggered phase the subjects received 4 g of cholestyramine (CHOL) twice daily 24 hours prior to and following the VPA dose. During the concurrent phase the coadministration of CHOL resulted in a decrease (p < 0.05) in the area under the curve (AUC) for VPA compared to VPA alone (415.2 +/- 113.2 mg*hr/l vs 489.2 +/- 153.0 mg*hr/l, respectively). When the same dose of each drug was administered 3 hours apart, the AUC for VPA (454.8 +/- 123.1 mg*hr/l) was not significantly decreased when compared to VPA alone (489.2 +/- 153.0 mg*hr/l). Also, the bioavailability relative to VPA alone was 86.2% +/- 7.1 for the concurrent phase and 95.3% +/- 13.6 for the staggered phase. Based on the AUC of VPA concurrent administration of CHOL significantly decreases VPA absorption and separating the doses of the 2 drugs by 3 hours may lessen the interaction.

The periodicity of vascular access thrombosis.

A periodicity has been observed in thrombotic events that occur in a variety of vascular beds. There also has been a recent suggestion that there is an increased failure of hemodialysis vascular accesses due to thrombosis during the summer months. We reviewed the last 949 episodes of vascular access thrombosis and found no seasonal pattern, but a weekly pattern was noted that corresponded to the patients' dialysis schedule. That pattern was apparently due to our technique of observation and not due to any intrinsic periodicity in the thrombosis itself. We find no evidence to support the belief in any intrinsic periodicity in hemodialysis vascular access thrombosis and since the thrombotic event itself is usually asymptomatic, any accurate assessment of a diurnal or circumseptan pattern is not possible under ordinary clinical conditions.

Effects of hand dominance and sleep side preference on hemodialysis vascular access survival.

We examined the effects of hand dominance and the patients' stated preference of the sleeping position on the survival of vascular accesses for hemodialysis in different locations. Analysis was made of vascular access survival times after 1, 126 vascular access surgeries performed between January 1, 1989, and December 31, 1994. We found that hand dominance and access site were not related to any survival differences in patients with autogenous fistulas, but thigh grafts on both sides had greater survival than arm grafts. The preferential side for sleeping similarly did not seem to affect access survival, but patients who stated a sleep preference on the side opposite their vascular graft tended to have longer access survival time.