GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Suppression of food restriction-evoked hyperactivity in activity-based anorexia animal model through glutamate transporters GLT-1 at excitatory synapses in the hippocampus.

Severe voluntary food restriction is the defining symptom of anorexia nervosa (AN), but anxiety and excessive exercise are maladaptive symptoms that contribute significantly to the severity of AN and which individuals with AN have difficulty suppressing. We hypothesized that the excitability of hippocampal pyramidal neurons, known to contribute to anxiety, leads to the maladaptive behavior of excessive exercise. Conversely, since glutamate transporter GLT-1 dampens the excitability of hippocampal pyramidal neurons through the uptake of ambient glutamate and suppression of the GluN2B-subunit containing NMDA receptors (GluN2B-NMDARs), GLT-1 may contribute toward dampening excessive exercise. This hypothesis was tested using the mouse model of AN, called activity-based anorexia (ABA), whereby food restriction evokes the maladaptive behavior of excessive wheel running (food restriction-evoked running, FRER). We tested whether individual differences in ABA vulnerability of mice, quantified based on FRER, correlated with individual differences in the levels of GLT-1 at excitatory synapses of the hippocampus. Electron microscopic immunocytochemistry (EM-ICC) was used to quantify GLT-1 levels at the excitatory synapses of the hippocampus. The FRER seen in individual mice varied more than 10-fold, and Pearson correlation analyses revealed a strong negative correlation (p = .02) between FRER and GLT-1 levels at the axon terminals of excitatory synapses and at the surrounding astrocytic plasma membranes. Moreover, synaptic levels of GluN2B-NMDARs correlated strongly with GLT-1 levels at perisynaptic astrocytic plasma membranes. There is at present no accepted pharmacotherapy for AN, and little is known about the etiology of this deadly illness. Current findings suggest that drugs increasing GLT-1 expression may reduce AN severity through the reduction of GluN2B-NMDAR activity.

Integrity of White Matter is Compromised in Mice with Hyaluronan Deficiency.

Brain white matter is the means of efficient signal propagation in brain and its dysfunction is associated with many neurological disorders. We studied the effect of hyaluronan deficiency on the integrity of myelin in murine corpus callosum. Conditional knockout mice lacking the hyaluronan synthase 2 were compared with control mice. Ultrastructural analysis by electron microscopy revealed a higher proportion of myelin lamellae intruding into axons of knockout mice, along with significantly slimmer axons (excluding myelin sheath thickness), lower g-ratios, and frequent loosening of the myelin wrappings, even though the myelin thickness was similar across the genotypes. Analysis of extracellular diffusion of a small marker molecule tetramethylammonium (74 MW) in brain slices prepared from corpus callosum showed that the extracellular space volume increased significantly in the knockout animals. Despite this vastly enlarged volume, extracellular diffusion rates were significantly reduced, indicating that the compromised myelin wrappings expose more complex geometric structure than the healthy ones. This finding was confirmed in vivo by diffusion-weighted magnetic resonance imaging. Magnetic resonance spectroscopy suggested that water was released from within the myelin sheaths. Our results indicate that hyaluronan is essential for the correct formation of tight myelin wrappings around the axons in white matter.

Ninety-day and one-year healthcare utilization and costs after knee arthroplasty.

OBJECTIVES: This study examined ninety-day and one-year postoperative healthcare utilization and costs following total knee arthroplasty (TKA) from the health sector and patient perspectives. DESIGN: This study relied on: 1) patient-reported medical resource utilization data from diaries in the Knee Arthroplasty Pain Coping Skills Training (KASTPain) trial; and 2) Medicare fee schedules. Medicare payments, patient cost-sharing, and patient time costs were estimated. Generalized linear mixed models were used to identify baseline predictors of costs. RESULTS: In the first ninety days following TKA, patients had an average of 29.7 outpatient visits and 6% were hospitalized. Mean total costs during this period summed to $3,720, the majority attributed to outpatient visit costs (84%). Over the year following TKA, patients had an average of 48.9 outpatient visits, including 33.2 for physical therapy. About a quarter (24%) of patients were hospitalized. Medical costs were incurred at a decreasing rate, from $2,428 in the first six weeks to $648 in the last six weeks. Mean total medical costs across all patients over the year were $8,930, including $5,328 in outpatient costs. Total costs were positively associated with baseline Charlson comorbidity score (P < 0.01). Outpatient costs were positively associated with baseline Charlson comorbidity score (P = 0.03) and a bodily pain burden summary score (P < 0.01). Mean patient cost-sharing summed to $1,342 and time costs summed to $1,346. CONCLUSIONS: Costs in the ninety days and year after TKA can be substantial for both healthcare payers and patients. These costs should be considered as payers continue to explore alternative payment models.

Model-based pain and function outcome trajectory types for patients undergoing knee arthroplasty: a secondary analysis from a randomized clinical trial.

OBJECTIVE: Knee arthroplasty (KA) is an effective surgical procedure. However, clinical studies suggest that a considerable number of patients continue to experience substantial pain and functional loss following surgical recovery. We aimed to estimate pain and function outcome trajectory types for persons undergoing KA, and to determine the relationship between pain and function trajectory types, and pre-surgery predictors of trajectory types. DESIGN: Participants were 384 patients who took part in the KA Skills Training randomized clinical trial. Pain and function were assessed at 2-week pre- and 2-, 6-, and 12-months post-surgery. Piecewise latent class growth models were used to estimate pain and function trajectories. Pre-surgery variables were used to predict trajectory types. RESULTS: There was strong evidence for two trajectory types, labeled as good and poor, for both Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function scores. Model estimated rates of the poor trajectory type were 18% for pain and function. Dumenci's latent kappa between pain and function trajectory types was 0.71 (95% CI: 0.61-0.80). Pain catastrophizing and number of painful body regions were significant predictors of poor pain and function outcomes. Outcome-specific predictors included low income for poor pain and baseline pain and younger age for poor function. CONCLUSIONS: Among adults undergoing KA, approximately one-fifth continue to have persistent pain, poor function, or both. Although the poor pain and function trajectory types tend to go together within persons, a significant number experience either poor pain or function but not both, suggesting heterogeneity among persons who do not fully benefit from KA.

A single-center audit of the indications and clinical impact of prolonged ambulatory small intestinal manometry.

BACKGROUND: Small bowel manometry is a diagnostic test available only in a few specialized referral centers. Its exact place in the management of refractory symptoms is controversial. METHODS: The records of all patients who underwent 24-hour ambulatory duodenojejunal manometry over a 6-year period were retrospectively reviewed. We studied the clinical indications for small bowel manometry, and reviewed the impact of manometric findings on the clinical outcome. One hundred and forty-six studies were performed in 137 patients (46M, 91F) with a mean age of 44.9 ± 15.7 years. Mean follow-up duration was 15.1 ± 22.6 months. Appropriate endoscopic, radiological and gastric scintigraphy studies were performed in all patients prior to small bowel manometry. Criteria for abnormal motor activity were based on Bharucha's classification. KEY RESULTS: The indications for small bowel manometry were chronic abdominal pain (n = 43), slow-transit constipation (n = 17), refractory gastroparesis (n = 16), chronic diarrhea (n = 7), recurrent episodes of subocclusion (n = 16), postsurgical evaluation (n = 36), suspicion of gut involvement in systemic disease (n = 9), and unexplained nausea (n = 2). The most common finding was a normal 24-hour ambulatory small bowel manometry (n = 113). Thirty-three studies yielded abnormal findings which included extrinsic neuropathy (n = 6), intrinsic neuropathy (n = 18), intestinal myopathy (n = 2), and subocclusion (n = 7). Ambulatory small bowel manometry excluded a generalized motility disorder in 77% and had a significant impact on the subsequent clinical course in 23%. CONCLUSIONS & INFERENCES: Ambulatory small bowel manometry is a useful and safe diagnostic tool to complement traditional investigative modalities in patients with severe unexplained abdominal symptoms.

Making of a Synapse: Recurrent Roles of Drebrin A at Excitatory Synapses Throughout Life.

Mature excitatory synapses are composed of more than 1500 proteins postsynaptically and hundreds more that operate presynaptically. Among them, drebrin is an F-actin-binding protein that increases noticeably during juvenile synaptogenesis. Electron microscopic analysis reveals that drebrin is highly enriched specifically on the postsynaptic side of excitatory synapses. Since dendritic spines are structures specialized for excitatory synaptic transmission, the function of drebrin was probed by analyzing the ultrastructural characteristics of dendritic spines of animals with genetic deletion of drebrin A (DAKO), the adult isoform of drebrin. Electron microscopic analyses revealed that these brains are surprisingly intact, in that axo-spinous synaptic junctions are well-formed and not significantly altered in number. This normal ultrastructure may be because drebrin E, the alternate embryonic isoform, compensates for the genetic deletion of drebrin A. However, DAKO results in the loss of homeostatic plasticity of N-methyl-D-aspartate receptors (NMDARs). The NMDAR activation-dependent trafficking of the NR2A subunit-containing NMDARs from dendritic shafts into spine head cytoplasm is greatly diminished within brains of DAKO. Conversely, within brains of wild-type rodents, spines respond to NMDAR blockade with influx of F-actin, drebrin A, and NR2A subunits of NMDARs. These observations indicate that drebrin A facilitates the trafficking of NMDAR cargos in an F-actin-dependent manner to mediate homeostatic plasticity. Analysis of the brains of transgenic mice used as models of Alzheimer's disease (AD) reveals that the loss of drebrin from dendritic spines predates the emergence of synaptic dysfunction and cognitive impairment, suggesting that this form of homeostatic plasticity contributes toward cognition. Two studies suggest that the nature of drebrin's interaction with NMDARs is dependent on the receptor's subunit composition. Drebrin A can be found co-clustering with NR2B-containing NMDARs at the plasma membrane, while NR2A-containing NMDARs co-traffic into the spine cytoplasm but do not co-cluster at the plasma membrane. Most recently, we encountered a physiological condition that supports this idea. When adolescent female rats are reared under a condition of restricted food access and ad libitum wheel access, they paradoxically become excessive runners, choosing to run, even during the limited hours of food availability. This behavioral pattern is termed activity-based anorexia (ABA) and has served as an animal model for anorexia nervosa. Those animals that exhibit the greatest ABA vulnerability, in that they lose the most amount of body weight and run with greatest exuberance to the point of risking their lives, exhibit the highest levels of NR2B-NMDARs and drebrin at the postsynaptic membrane of hippocampal pyramidal neurons. Those animals that exhibit the greatest resilience to ABA, in that they run minimally under such condition, thereby losing minimal amount of weight, exhibit the highest level of NR2A-NMDARs in the spine cytoplasm and lowest levels of drebrin at the postsynaptic membrane. This pattern suggests that drebrin has dual roles: retention of NR2A-NMDARs in the reserve pool and trafficking of NR2B-NMDARs to the postsynaptic membrane, ultimately contributing to an individual's reactivity to stress. Altogether, these observations indicate that drebrin is a protein that is important for synaptic plasticity and deserves the attention of neuroscientists studying the neurobiological basis of cognition and stress reactivity.

Rapid Drink Challenge in high-resolution manometry: an adjunctive test for detection of esophageal motility disorders.

BACKGROUND/AIMS: The Chicago Classification for diagnosis of esophageal motility disorders by high-resolution manometry (HRM) is based on single water swallows (SWS). Emerging data suggest that a "Rapid Drink Challenge" (RDC) increases sensitivity for motility disorders. This study establishes normal values and diagnostic thresholds for RDC in clinical practice. METHODS: Two cohort studies were performed in patients with dysphagia or reflux symptoms (development and validation sets). Healthy subjects and patient controls provided reference values. Ten SWS and two 200-mL RDC were performed. Primary diagnosis for SWS was established by the Chicago Classification. Abnormal RDC was defined by impaired esophagogastric junction (EGJ) function (elevated integrated relaxation pressure during RDC [IRP-RDC]); incomplete inhibition of contractility during and ineffective contraction after RDC. Diagnostic thresholds identified in the development set were prospectively tested in the validation set. RESULTS: Normal values were determined in healthy (n=95; age 37.8 ± 12) and patient controls (n=44; age 46.4 ± 15). Development and validation sets included 178 (54 ± 17 years) and 226 (53 ± 16 years) patients, respectively. Integrated relaxation pressure during RDC was higher for SWS than RDC in all groups (overall P<.001), except achalasia. Rapid Drink Challenge suppressed contractility, except in achalasia type III, spasm, and hypercontractile motility disorders (P<.001). An effective after-contraction was present more often in health than disease (P<.001). Optimal diagnostic thresholds identified in the development set (IRP-RDC ≥12 mmHg achalasia, IRP-RDC ≥ 8mmHg "all cause" EGJ dysfunction), were confirmed in the validation set (both, sensitivity ~85%, specificity >95%). CONCLUSIONS: Rapid Drink Challenge contributes clinically relevant information to routine HRM studies, especially in patients with EGJ dysfunction.

Motilin-induced gastric contractions signal hunger in man.

RATIONALE: Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. OBJECTIVES: To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. FINDINGS: In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (ß=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. CONCLUSIONS: Motilin-induced gastric phase III is a hunger signal from GIT in man.

T-type calcium channels contribute to calcium disturbances in brain during hyponatremia.

Disturbance of calcium homeostasis is implicated in the normal process of aging and brain pathology prevalent in the elderly such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Previous studies demonstrated that applying a hyponatremic iso-osmotic (low-NaCl) artificial cerebrospinal fluid (ACSF) to rodent hippocampus causes extracellular calcium to rapidly decrease. Restoring normonatremia after low-NaCl treatment causes a rapid increase in extracellular calcium that overshoots baseline. This study examined the amplitude, timing, and mechanism of these surprising calcium changes. We also tested whether hyponatremia increased calcium entry into brain cells or calcium binding to chondroitin sulfate (CS), a negatively charged constituent of the extracellular matrix (ECM) that may be occupied by sodium during normonatremia. We report three major findings. First we show that CS does not contribute to extracellular calcium changes during low-NaCl treatments. Second, we show that the time to minimum extracellular calcium during low-NaCl treatment is significantly shorter than the time to maximum extracellular calcium in recovery from low-NaCl treatment. Third, we show that the decrease in extracellular calcium observed during hyponatremia is attenuated by ML 218, a highly selective T-type calcium channel blocker. Together these data suggest that calcium rapidly enters cells at the onset of low-NaCl treatment and is extruded from cells when normonatremia is restored. Calcium binding to CS does not significantly contribute to calcium changes in brain during hyponatremia. Differences in timing suggest that extracellular calcium changes during and in recovery from hyponatremia occur by distinct mechanisms or by a multistep process. Finally, partial block of extracellular calcium influx by ML 218 suggests that T-type channels are involved in calcium entering cells during hyponatremia. Given the high prevalence of hyponatremia among elderly patients and the growing understanding of calcium's role in multiple neurologic pathologies, this study promotes a novel approach for studying and potentially preventing the effects of hyponatremia on calcium dysregulation in brain tissue.

Using geoelectrons to search for velocity-dependent spin-spin interactions.

We use the recently developed model of the electron spins within Earth to investigate all of the six possible long-range velocity-dependent spin-spin interactions associated with the exchange of an ultralight (mz'<10(-10) eV) or massless intermediate vector boson. Several laboratory experiments have established upper limits on the energy associated with various fermion-spin orientations relative to Earth. We combine the results from three of these experiments with the geoelectron-spin model to obtain bounds on the velocity-dependent interactions that couple electron spin to the spins of electrons, neutrons, and protons. Five of the six possible potentials investigated were previously unbounded. In the long-range limit we have improved the bound on the sixth potential by 30 orders of magnitude.

Influence of a neurokinin-1 receptor antagonist (aprepitant) on gastric sensorimotor function in healthy volunteers.

BACKGROUND: Substance P (SP) is a member of the neurokinin (NK) family and is one of the established neurotransmitters in the mammalian central and enteric nervous system. It is unclear whether NK1 receptors are involved in the control of gastric sensorimotor function in man. METHODS: We studied the effects of aprepitant, an NK1 receptor antagonist used in the treatment of chemotherapy-induced emesis, on gastric sensorimotor function in healthy volunteers. Sixteen healthy volunteers (six males, 32.4 ± 2.7 years) were studied on three separate occasions after placebo, aprepitant 80 or 125 mg in randomized double-blind study to assess gastric compliance, perception to isobaric distensions, and gastric accommodation with a gastric barostat. KEY RESULTS: Compared to placebo, both doses of aprepitant did not influence gastric compliance or sensitivity to gastric distension. Aprepitant 80 and 125 mg did not have any significant effects on gastric accommodation compared with placebo (mean postprandial gastric volume increase, respectively, 83.4 ± 28.4 vs 35.3 ± 16.2 vs 83.9 ± 30.4 mL, NS). Postprandial gastric compliance and sensitivity to distention were also not altered. CONCLUSIONS & INFERENCES: In health, NK1 receptors do not appear to be involved in the control of gastric compliance, accommodation or sensitivity to distention in man.

Measurement of gastric accommodation: a reappraisal of conventional and emerging modalities.

Impaired gastric accommodation is an important cause of functional dyspepsia. Currently available tests that evaluate gastric accommodation provide relevant physiological information, but they pose technical difficulties and their clinical impact remains controversial. Gastric barostat remains the gold standard, but it is an invasive procedure. In recent years, emerging modalities including single photon emission computed tomography (SPECT), three-dimensional ultrasound and magnetic resonance imaging have been developed to measure gastric volumes and hold promise as alternative methods of assessing gastric accommodation non-invasively. Studies are underway to validate these techniques with recent data proving the performance characteristics of SPECT. The non-invasive nutrient drink test measures satiety scores as a surrogate marker of gastric accommodation and remains controversial. More recently, intragastric monitoring has been proposed as yet another non-invasive modality to assess gastric accommodation. Each of these different modalities brings its associated advantages and disadvantages, as is discussed in this review. Ongoing studies to validate these new techniques are in progress and are likely to lead to further progress in neurogastroenterology.

Cost effectiveness of duloxetine in the treatment of fibromyalgia in the United States.

OBJECTIVE: To evaluate the cost effectiveness of duloxetine when considered as an alternative treatment for patients in the United States (US) being treated for fibromyalgia pain. RESEARCH DESIGN AND METHODS: A Markov model was used to evaluate the economic and clinical advantages of duloxetine in controlling fibromyalgia pain symptoms over a 2-year time horizon. A base-case treatment sequence was adopted from clinical guidelines, based on tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, anticonvulsants, and opioids. Treatment response was modeled using changes from baseline in pain severity, and response thresholds: full response (at least a 50% change), response (30-49% change), and no response (less than a 30% change). Clinical efficacy and discontinuation data were taken from placebo- and active-controlled trials identified in a systematic literature review and mixed-treatment comparison. Utility data were based on EQ-5D data. MAIN OUTCOME MEASURES: Additional symptom-control months (SCMs), defined as the amount of time at a response level of 30% or less, and quality-adjusted life-years (QALYs) over a 2-year time horizon. RESULTS: For every 1000 patients, first-line duloxetine resulted in an additional 665 SCMs and 12.3 QALYs, at a cost of $582,911 (equivalent to incremental cost-effectiveness ratios [ICERs] of $877 per SCM and $47,560 per QALY). Second-line duloxetine resulted in an additional 460 SCMs and 8.7 QALYs, at a cost of $143,752 (equivalent to ICERs of $312 per SMC and $16,565 per QALY). LIMITATIONS: Response data for TCAs are limited to 30% improvement levels, reported trials are small, and have low placebo response rates. The model necessarily assumes that response rates are independent of placement in the treatment sequence. CONCLUSIONS: The results suggest that the introduction of duloxetine into the standard treatment sequence for fibromyalgia not only provides additional patient benefits, reflected by time spent in pain control, but also is cost effective when compared with commonly adopted thresholds.

Review article: endpoints used in functional dyspepsia drug therapy trials.

BACKGROUND: The measurement of patient-reported outcomes (PRO) in treatment trials for functional gastrointestinal disorders is a matter of controversy. AIM: To focus on instruments and endpoints that have been used to evaluate the efficacy of therapeutic agents in functional dyspepsia (FD) trials, also considering the newly defined Rome III FD criteria. METHODS: A Medline search was conducted to identify relevant studies pertaining to FD treatment, with particular emphasis on the studies to date which have used validated outcome measures. RESULTS: Currently available outcome measures are heterogeneous across studies. They include global binary endpoints, analogue or categorical scoring scales, uni- or multi-dimensional disease specific questionnaires, global outcome evaluations and quality of life questionnaires. Across the available outcome measures, substantial heterogeneity is found, not only in the type of endpoint measure, but also in the number and types of symptoms that are considered to be part of the FD symptom complex. Especially based on content validity, none of the existing questionnaires or endpoints can be considered sufficiently validated to be recommended unequivocally as the primary outcome measure for FD trials according to the Rome III criteria. On the other hand, existing well-validated multi-dimensional questionnaires that include many non-FD symptoms can be narrowed down to evaluate only the cardinal symptoms according to Rome III. CONCLUSIONS: There is an urgent need to develop Rome III-based patient-reported outcomes for functional dyspepsia. Well-validated multi-dimensional questionnaires may serve as a guidance for this purpose, and could also be considered for use in ongoing clinical trials.

Insights into the mechanism of magnetic particle assisted gene delivery.

In magnetic particle assisted gene delivery DNA is complexed with polymer-coated aggregated magnetic nanoparticles (AMNPs) to effect transfection. In vitro studies based on COS-7 cells were carried out using pEGFP-N1 and pMIR-REPORT-complexed, polyethylenimine (PEI)-coated iron oxide magnetic nanoparticles (MNPs). PEI-coated AMNPs (PEI-AMNPs) with average individual particle diameters of 8, 16 and 30 nm were synthesized. Normal, reverse and retention magnetic transfection experiments and cell wounding assays were performed. Our results show that the optimum magnetic field yields maximum transfection efficiency with good viability. The results of the normal, reverse and retention magnetic transfection experiments show that the highest transfection efficiency was achieved in normal magnetic transfection mode due to clustering of the PEI-AMNPs on the cells. Cell wounding assay results suggest that the mechanism of magnetic transfection is endocytosis rather than cell wounding.

Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options.

Oxidative stress has been increasingly linked to the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to account for the huge cardiovascular morbidity and mortality in this population group. Oxidative stress is increased in patients with renal impairment as a result of increased oxidant activity and reduced antioxidant capacity, and this is increased in a graded manner with increasing renal dysfunction. Inflammation, which is also present in CKD, further amplifies the oxidant generation process. The two clinical sequelae of oxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adverse cardiovascular consequences. With our new understanding of oxidative stress, it is now important to assess treatment options that reduce it in the hope that they reverse endothelial dysfunction and left ventricular hypertrophy and the clinical sequelae of these abnormalities.