Objective. Gout affects a large fraction of persons with advanced chronic kidney disease, and hyperuricemia may increase the risk of cardiovascular disease. Several hypouricemic agents are contraindicated in patients with end-stage renal disease. Sevelamer is a nonabsorbed hydrogel that binds phosphorus and bile acids in the intestinal tract. Results of short-term and open-label studies suggest that sevelamer might lower the concentration of uric acid, another organic anion. We undertook this study to test our hypothesis that the reduction in serum uric acid concentration induced by sevelamer would be confirmed in a long-term, randomized, clinical trial comparing sevelamer with calciumbased phosphate binders.Methods. Two hundred subjects undergoing maintenance hemodialysis were randomly assigned to receive either sevelamer or calcium-based phosphorus binders in an international, multicenter, clinical trial. Data on baseline and end-of-study uric acid concentrations were available in 169 subjects (85%); the change in uric acid concentration from baseline to the end of the study was the outcome of interest.Results. Baseline clinical characteristics, including mean uric acid concentrations, were similar in subjects randomly assigned to receive sevelamer and calcium-based phosphate binders. The mean change in uric acid concentration (from baseline to the end of the study) was significantly larger in sevelamer-treated subjects (؊0.64 mg/dl versus ؊0.26 mg/dl; P ‫؍‬ 0.03). The adjusted mean change in uric acid concentration was more pronounced when the effects of age, sex, diabetes, vintage (time since initiation of dialysis), dialysis dose, and changes in blood urea nitrogen and bicarbonate concentrations were considered (؊0.72 mg/dl versus ؊0.15 mg/dl; P ‫؍‬ 0.001). Twenty-three percent of sevelamer-treated subjects experienced a study-related reduction in the concentration of uric acid equal to ؊1.5 mg/dl or more, compared with 10% of calcium-treated subjects (P ‫؍‬ 0.02).Conclusion. In a randomized clinical trial comparing sevelamer and calcium-based phosphate binders, treatment with sevelamer was associated with a significant reduction in serum uric acid concentrations.Currently, more than 300,000 persons are undergoing dialysis in the US (1). Persons with chronic kidney disease, including end-stage renal disease (ESRD), experience an increased prevalence of metabolic abnormalities, including hyperphosphatemia, hyperparathyroidism, and hyperuricemia, the last generally defined as a serum uric acid concentration Ͼ6.5 or 7.0 mg/dl in men and Ͼ6.0 mg/dl in women. Hyperuricemia is largely caused by a reduction in glomerular filtration rate

Cognitive deficits are the most enduring and disabling sequelae of human traumatic brain injury (TBI), but quantifying the magnitude, duration, and pattern of cognitive deficits produced by different types of TBI has received little emphasis in preclinical animal models. The objective of the present study was to use a battery of behavioral tests to determine if different impact sites produce different patterns of behavioral deficits and to determine how long behavioral deficits can be detected after TBI. Prior to surgery, rats were trained to criteria on delayed nonmatching to position, radial arm maze, and rotarod tasks. Rats received sham surgery (controls), midline frontal contusions (frontal TBI, 2.25 m/sec impact), or unilateral sensorimotor cortex contusions (lateral TBI, 3.22 m/sec impact) at 12 months of age and were tested throughout the next 12 months. Cognitive deficits were more robust and more enduring than sensorimotor deficits for both lateral TBI and frontal TBI groups. Lateral TBI rats exhibited transient deficits in the forelimb placing and in the rotarod test of motor/ambulatory function, but cognitive deficits were apparent throughout the 12-month postsurgery period on tests of spatial learning and memory including: (1)reacquisition of a working memory version of the radial arm maze 6-7 months post-TBI, (2) performance in water maze probe trials 8 months post-TBI, and (3) repeated acquisition of the Morris water maze 8 and 11 months post-TBI. Frontal TBI rats exhibited a different pattern of deficits, with the most robust deficits in tests of attention/orientation such as: (1) the delayed nonmatching to position task (even with no delays) 1-11 weeks post-TBI, (2) the repeated acquisition version of the water maze--especially on the first "information" trial 8 months post-TBI, (3) a test of sensorimotor neglect or inattention 8.5 months post-TBI, and (4) a DRL20 test of timing and/or sustained attention 11 months after surgery. These results suggest that long-term behavioral deficits can be detected in rodent models of TBI, that cognitive deficits seem to be more robust than sensorimotor deficits, and that different TBI impact sites produce dissociable patterns of cognitive deficits in rats.

No abstract

Background. Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient-friendly alternative to tablet phosphate binders. This study compared the safety and efficacy of sevelamer carbonate powder with sevelamer hydrochloride tablets in CKD patients on haemodialysis.Methods. This was a multi-centre, open-label, randomized, crossover design study. Thirty-one haemodialysis patients were randomly assigned to either sevelamer carbonate powder or sevelamer hydrochloride tablets for 4 weeks followed by a crossover to the other regimen for an additional 4 weeks.Results. The mean serum phosphorus was 1.6 ± 0.5 mmol/L (5.0 ± 1.5 mg/dL) during sevelamer carbonate powder treatment and 1.7 ± 0.4 mmol/L (5.2 ± 1.1 mg/dL) during sevelamer hydrochloride tablet treatment. Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus; the geometric least square mean ratio was 0.95 (90% CI 0.87–1.03). No statistically significant or clinically meaningful differences were observed in calcium × phosphorus product and lipid levels between sevelamer carbonate powder and sevelamer hydrochloride tablets. Serum bicarbonate levels increased 2.7 ± 3.7 mmol/L (2.7 ± 3.7 mEq/L) during sevelamer carbonate treatment. No statistically significant change in bicarbonate was observed during sevelamer hydrochloride treatment. Sevelamer carbonate powder and sevelamer hydrochloride were well tolerated during this study.Conclusions. Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus and well tolerated in CKD patients on haemodialysis. Bicarbonate levels improved only during sevelamer carbonate treatment. Sevelamer carbonate powder should provide a welcomed new option for the treatment of hyperphosphataemia for CKD patients on dialysis.

Hotplate studies rarely match subjects into groups and often use high temperatures that are less sensitive to the effects of mild analgesics. Subjects may not be matched into groups because it has not been clearly demonstrated that there are reliable and robust individual differences in performance on the hotplate, and out of concern that the testing required to match subjects into groups might reduce the sensitivity of the task to mild analgesics by producing 'behavioral tolerance'. Higher hotplate temperatures may be preferred because they reduce variability in response latencies, and it may be assumed that this precludes the need to match subjects into groups. The results of the present study demonstrate that there are reliable and robust differences among individuals tested on the hotplate, regardless of whether the hotplate is 50 degrees C or 55 degrees C (alpha's > 0.90). The present results also confirm that lower hotplate temperatures are much more sensitive to the effects of mild analgesics: increased response latencies following a low dose of morphine (3 mg/kg) could be reliably detected with only 8 rats at 50 degrees C, while the same dose would not be detected reliably at 55 degrees C unless more than 55 rats were tested. Finally, there was no evidence that habituation to the hotplate produced 'behavioral tolerance' or reduced the sensitivity of the test to the effects of morphine. These findings suggest that hotplate studies should match subjects into groups and use lower hotplate temperatures in order to increase the sensitivity of the test, but also out of an ethical obligation to minimize the intensity of the noxious stimulus and the number of animals exposed to it.