The relationship between three eGFR formulas and hospitalization for heart failure in 54 486 individuals with type 2 diabetes.

OBJECTIVE: This study aims to study the association between renal function and hospitalization for heart failure (HF) in individuals with type 2 diabetes. METHODS: Renal function was determined according to three formulas used to estimate glomerular filtration rate (eGFR): Cockcroft-Gault, modified diet in renal disease (MDRD) and chronic kidney disease epidemiology (CKD-EPI). Proportional hazards regression models adjusted for age, sex, HbA1c , blood pressure, smoking and cardiovascular comorbidities were constructed for each eGFR formula to estimate risk of hospitalization for heart failure. Systematic pairwise likelihood ratio tests of nested models were used to compare the predictive power of each eGFR formula. RESULTS: In 54 486 patients, evaluated over a median follow-up of 7.0 years, a total of 5936 (10.9%) developed heart failure, with an excess risk in all eGFR categories below 60 mL/min/1.73 m2 (reference: eGFR >90 mL/min/1.73 m2 ). Hazard ratios ranged from 1.25 to 1.35 for eGFR 45-60 mL/min/1.73 m2 , 1.62 to 1.66 for eGFR 30-45 mL/min/1.73 m2 and 2.18 to 2.52 for eGFR <30 mL/min/1.73 m2 in the three eGFR formulas. In pairwise comparisons, the model with the MDRD variable added significantly more information than the Cockcroft-Gault variable. For the model with the CKD-EPI variable, no clear differences in predictive power for HF hospitalization existed in relation to the other eGFR formulas. CONCLUSION: Patients with type 2 diabetes, with eGFR 45 to 60 mL/min/1.73 m2 , have approximately 25-35% increased risk of hospitalization for HF, increasing with lower eGFR, to 2-2.5 times in those with eGFR <30 mL/min/1.73 m2 . The MDRD formula for calculating eGFR is more predictive of hospitalization for heart failure than the Cockcroft-Gault formula. Copyright © 2016 John Wiley & Sons, Ltd.

The incidence of albuminuria after bariatric surgery and usual care in Swedish Obese Subjects (SOS): a prospective controlled intervention trial.

BACKGROUND: Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria. SUBJECTS: The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI ⩾ 34 in men and BMI ⩾ 38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years. RESULTS: During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P < 0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine. CONCLUSIONS: Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.

High glucose causes dysfunction of the human glomerular endothelial glycocalyx.

The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.

Corticosteroid administration alters the mechanical properties of isolated collagen fascicles in rat-tail tendon.

Overload tendon injuries are frequent in recreational and elite sports. The optimal treatment strategy remains unknown, but local administration of corticosteroids is one common treatment option. The direct effects of the corticosteroid administration on the tissue are not fully understood. The present study examined the biomechanical effects of intratendinous corticosteroid injections on healthy rat-tail tendon collagen fascicles. A total of 24 Wistar male rats were divided into (A) a corticosteroid group where the animals were injected in the tail tendon with methylprednisolone acetate, 1.0 mL of 40 mg/mL mixed with 1.0 mL 9% saline (n=12), and (B) a control group that was injected with 9% saline (n=12). Three days after the injections, the animals were sacrificed and single individual collagen fascicles were collected and underwent displacement to failure. Corticosteroid administration significantly reduced tensile fascicle yield strength by 16% and Young's modulus by 14% compared with sham treatment (10.5+/-0.8 vs 12.4+/-0.5 MPa, P< or =0.05, and 537+/-27 vs 641+/-30 MPa, P<0.05, respectively), while the strain properties were unaffected. Peak stress was similar between the two groups. There was no difference in fascicle diameter between the two groups.

Novel methods for tendon investigations.

PURPOSE: Tendon structures have been studied for decades, but over the last decade, methodological development and renewed interest for metabolic, circulatory and tissue protein turnover in tendon tissue has resulted in a rising amount of investigations. METHOD: This paper will detail the various modern investigative techniques available to study tendons. RESULTS: There are a variety of investigative methods available to study the correlations between mechanics and biology in tendons. CONCLUSION: The available methodologies not only allow for potential insight into physiological and pathophysiological mechanisms in tendon tissue, but also, to some extent, allow for more elaborate studies of the intact human tendon.

Changes in muscarinic receptors in the toad urothelial cell line TBM-54 following acrolein treatment.

1. In cyclophosphamide-induced cystitis in the rat, cholinergic function of the bladder and muscarinic receptor expression are altered. In the present study, we investigated whether the toad urothelial cell line TBM-54 expresses functional muscarinic receptors and whether changes in muscarinic receptors can be induced in vitro by treating cells with acrolein, a metabolite of cyclophosphamide causing cystitis. 2. The occurrence of muscarinic receptors on cells was assessed by microphysiometry, a method analysing receptor function by measuring changes in the extracellular acidity rate (ECAR) in response to receptor stimulation. 3. Challenging untreated cells with the muscarinic receptor agonist carbachol gave rise to a concentration-dependent increase in changes in ECAR, with a maximal response at 1 mmol/L carbachol of 51 +/- 6%. Pre-incubating cells with different muscarinic receptor antagonists (i.e. pirenzepine (M(1) receptor selective), methoctramine (M(2)/M(4) receptor selective) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M(3)/M(1)/M(5) receptor selective)), gave rise to a concentration-dependent decrease in the effects of carbachol (0.5 mmol/L) on changes in ECAR. 4. Western blot analysis was used to determine the expression of all muscarinic receptor subtypes (M(1)-M(5)) by the cell line. Following acrolein treatment, cells were markedly less sensitive to carbachol and the expression of muscarinic M(2) receptors was decreased, whereas the expression of muscarinic M(3) receptors was increased. 5. In conclusion, the urothelial cell line TBM-54 expresses functional muscarinic receptors and exposure to acrolein leads to a modulation in the expression of muscarinic receptors. Consequently, acrolein may have direct effects on muscarinic receptor function and expression that contribute to the pathogenesis of cyclophosphamide-induced cystitis.

Massage for mechanical neck disorders.

BACKGROUND: Mechanical neck disorders (MND) are common, disabling and costly. Massage is a commonly used modality for the treatment of neck pain. OBJECTIVES: To assess the effects of massage on pain, function, patient satisfaction and cost of care in adults with neck pain. To document adverse effects of treatment. SEARCH STRATEGY: Cochrane CENTRAL, MEDLINE, EMBASE, MANTIS, CINAHL, and ICL databases were electronically searched, without language restriction, from their inception to September 2004 SELECTION CRITERIA: Studies using random or quasi-random assignment were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently conducted citation identification, study selection, data abstraction and methodological quality assessment. Using a random-effects model, we calculated the relative risk and standardized mean difference. MAIN RESULTS: Nineteen trials met the inclusion criteria. Overall, the methodological quality was low, with 12/19 assessed as low-quality studies. Trials could not be statistically pooled because of heterogeneity in treatment and control groups. Therefore, a levels-of-evidence approach was used to synthesize results. Assessment of the clinical applicability of the trials showed that the participant characteristics were well reported, but neither the descriptions of the massage intervention nor the credentials or experience of the massage professionals were well reported. Six trials examined massage as a stand-alone treatment. The results were inconsistent. Of the 14 trials that used massage as part of a multimodal intervention, none were designed such that the relative contribution of massage could be ascertained. Therefore, the role of massage in multimodal treatments remains unclear. AUTHORS' CONCLUSIONS: No recommendations for practice can be made at this time because the effectiveness of massage for neck pain remains uncertain. Pilot studies are needed to characterize massage treatment (frequency, duration, number of sessions, and massage technique) and establish the optimal treatment to be used in subsequent larger trials that examine the effect of massage as either a stand-alone treatment or part of a multimodal intervention. For multimodal interventions, factorial designs are needed to determine the relative contribution of massage. Future reports of trials should improve reporting of the concealment of allocation, blinding of outcome assessor, adverse events and massage characteristics. Standards of reporting for massage interventions, similar to CONSORT, are needed. Both short- and long-term follow-up are needed.

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice.

AIMS/HYPOTHESIS: Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size- or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks. MATERIALS AND METHODS: During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8 degrees C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications. RESULTS: At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 A with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes. CONCLUSIONS/INTERPRETATION: We conclude that glomerular charge- but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome.

Proteoglycans (PGs) are important for the glomerular barrier, for cell signaling, and for the anchorage of cells to the glomerular basement membrane. They are, however, complex macromolecules, and their production has not yet been thoroughly investigated in podocytes. In the present study, we studied the biosynthesis of PGs by highly differentiated human podocytes and in rats. The cells were treated with puromycin aminonucleoside (PAN; a nephrosis-inducing agent), steroids (used as primary treatment for nephrotic syndrome), or both. Analysis was made by TaqMan real-time PCR, Western blotting, and by metabolic labeling with (35)S and (3)H. We found that podocytes produce versican, syndecan-1, decorin, and biglycan together with the previously known PG syndecan-4, glypican, and perlecan. PAN treatment downregulated the mRNA and the protein expression of both versican (by 24 +/- 6%, P < 0.01, for mRNA and by 50% for protein) and perlecan (by 14 +/- 5%, P < 0.05, for mRNA and by 50% for protein). The decreased expression was confirmed by studying the glomerular gene expression in rats treated with PAN during a time course study. In addition, puromycin decreased the expression of enzymes involved in the glycosaminoglycan biosynthesis. Steroid treatment decreased perlecan (by 24 +/- 3%, P < 0.01) and syndecan-1 expression (by 30 +/- 4%, P < 0.01) but increased the expression of decorin 2.5-fold. The observed alterations of PG synthesis induced by PAN may lead to decreased glomerular anionic charge and disturbed podocyte morphology, factors that are important for the development of a nephrotic syndrome.

Peritoneal dialysis in children: consider the membrane for optimal prescription.

The peritoneal dialysis prescription was, for a long time, based on clinical experience and very empirical, especially for patients on continuous ambulatory peritoneal dialysis (CAPD). Better comprehension of the peritoneal membrane as a dynamic dialysis surface allows an individualized prescription, especially for children on automated peritoneal dialysis (APD). Fill volume prescription should be scaled for body surface area (mL/m(2)) and not in a too low amount to avoid a hyperpermeable exchange. Fill volume enhancement should be done under clinical control and is best secured by intraperitoneal pressure measurement (IPP; cm H2O). A peak fill volume of 1400-1500 mL/m(2) could be prescribed both in terms of tolerance and of efficiency. The dwell times should be determined individually with respect to two opposite parameters namely: short dwell times which provide adequate small solute clearance and maintain ultrafiltration capacity and long dwell times which enhance phosphate clearance but can contribute to dialysate reabsorption. The new peritoneal dialysis fluids which are free of GPD's, have neutral pH and are not exclusively lactate buffered, appear as the best choice in the context of peritoneal exchange membrane recruitment and of peritoneal vascular hyperperfusion preservation.

Region-specific mechanical properties of the human patella tendon.

The present study investigated the mechanical properties of tendon fascicles from the anterior and posterior human patellar tendon. Collagen fascicles from the anterior and posterior human patellar tendon in healthy young men (mean +/- SD, 29.0 +/- 4.6 yr, n = 6) were tested in a mechanical rig. A stereoscopic microscope equipped with a digital camera recorded elongation. The fascicles were preconditioned five cycles before the failure test based on pilot data on rat tendon fascicle. Human fascicle length increased with repeated cycles (P < 0.05); cycle 5 differed from cycle 1 (P < 0.05), but not cycles 2-4. Peak stress and yield stress were greater for anterior (76.0 +/- 9.5 and 56.6 +/- 10.4 MPa, respectively) than posterior fascicles (38.5 +/- 3.9 and 31.6 +/- 2.9 MPa, respectively), P < 0.05, while yield strain was similar (anterior 6.8 +/- 1.0%, posterior 8.7 +/- 1.4%). Tangent modulus was greater for the anterior (1,231 +/- 188 MPa) than the posterior (583 +/- 122 MPa) fascicles, P < 0.05. In conclusion, tendon fascicles from the anterior portion of the human patellar tendon in young men displayed considerably greater peak and yield stress and tangent modulus compared with the posterior portion of the tendon, indicating region-specific material properties.

Puromycin aminonucleoside damages the glomerular size barrier with minimal effects on charge density.

Puromycin aminonucleoside (PAN) has been suggested to reduce glomerular charge density, to create large glomerular "leaks," or not to affect the glomerular barrier. Therefore, we analyzed glomerular charge and size selectivity in vivo and in isolated kidneys perfused at 8 degrees C (cIPK) in control and PAN-treated rats. The fractional clearances (theta) for albumin and Ficoll of similar hydrodynamic size were 0.0017 +/- 0.0004 and 0.15 +/- 0.02, respectively, in control cIPKs. Two-pore analysis gave similar results in vivo and in vitro, with small- and large-pore radii of 47-52 and 85-105 A, respectively, in controls. Puromycin increased the number of large pores 40-50 times, the total pore area over diffusion distance decreased by a factor of 25-30, and the small-pore radius increased by 33% (P < 0.001 for all comparisons of size selectivity and theta). The effect of PAN was less dramatic on the estimated wall charge density, which was 73% of that of controls. We conclude that puromycin effectively destroys the glomerular size barrier with minimal effects on charge density.

Effects of filtration rate on the glomerular barrier and clearance of four differently shaped molecules.

The effect of shape on the transglomerular passage of solutes has not been hitherto systematically studied. We perfused isolated rat kidneys to determine the fractional clearances (theta) at various filtration rates for four molecules of different shapes but with similar Stokes-Einstein radii (aSE = 34-36 A). The theta for hyaluronan, bikunin, and Ficoll36 A were 66, 16, and 11%, respectively, at a glomerular filtration rate (GFR) of 0.07 ml x min(-1) x g wet wt(-1) and decreased to 46, 14, and 7%, respectively, on a fivefold increase in GFR. Under the same conditions, theta for albumin increased from 0.15 to 0.74%, and similar behavior was observed for larger Ficolls (aSE >45 A). Pore analysis showed that the "apparent neutral" solute radii of Ficoll, albumin, bikunin, and hyaluronan were 35, 64, 33, and 24 A, respectively, despite similar aSE. In addition, the properties of the glomerular filter changed with increasing GFR and hydrostatic pressure. We conclude that elongated shape, irrespective of size and charge, drastically increases the transglomerular passage of a solute, an effect that is related to its frictional ratio.

A quantitative analysis of the glomerular charge barrier in the rat.

Modifying the ionic strength (I) is a gentle way to alter charge interactions, but it cannot be done for studies of the glomerular sieving of proteins in vivo. We therefore perfused 18 isolated rat kidneys with albumin solutions of different ionic strengths at a low temperature (cIPK) to inhibit tubular uptake and protease activity. Four anionic proteins were studied, namely albumin (Alb), orosomucoid (Oro), ovalbumin (Ova), and anionic horseradish peroxidase (aHRP), together with the neutral polymer Ficoll. With normal ionic strength of the perfusate (152 mM), the fractional clearance (theta) was 0.0018 +/- 0.0003 for Alb, 0.0033 +/- 0.0003 for Oro, 0.090 +/- 0.008 for Ova, and 0.062 +/- 0.002 for aHRP. These theta values were all lower than for Ficoll of similar hydrodynamic size; e.g., theta(Ficoll 36 A) was >20 times higher than theta for albumin. Low ionic strength (34 mM) increased size selectivity as theta for anionic proteins and Ficoll fell, suggesting a reduction in small-pore radius from 44 +/- 0.4 to 41 +/- 0.5 A, P < 0.01. In contrast, low I reduced the charge density of the membrane, omega, to one-quarter of the 20--50 meq/l estimated at normal I. These dynamic changes in omega seem to be due to volume alterations of the charged gel, fluid shifts that easily are accounted for by the changes in electroosmotic pressures. The finding that low ionic strength induces inverse effects on size selectivity and charge density strongly suggests that separate structures of the glomerular wall are responsible for the two properties.

A gel-membrane model of glomerular charge and size selectivity in series.

We have analyzed glomerular sieving data from humans, rats in vivo, and from isolated perfused rat kidneys (IPK) and present a unifying hypothesis that seems to resolve most of the conflicting results that exist in the literature. Particularly important are the data obtained in the cooled IPK, because they allow a variety of experimental conditions for careful analysis of the glomerular barrier; conditions that never can be obtained in vivo. The data strongly support the classic concept of a negative charge barrier, but separate components seem to be responsible for charge and size selectivity. The new model is composed of a dynamic gel and a more static membrane layer. First, the charged gel structure close to the blood compartment has a charge density of 35-45 meq/l, reducing the concentration of albumin to 5-10% of that in plasma, due to ion-ion interactions. Second, the size-selective structure has numerous functional small pores (radius 45-50 A) and far less frequent large pores (radius 75-115 A), the latter accounting for 1% of the total hydraulic conductance. Both structures are required for the maintenance of an intact glomerular barrier.

Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products.

BACKGROUND: Glucose degradation products (GDPs) are cytotoxic in vitro and potentially toxic in vivo during peritoneal dialysis (PD). We are presenting the results of a two-year randomized clinical trial of a new PD fluid, produced in a two-compartment bag and designed to minimize heat-induced glucose degradation while producing a near neutral pH. The effects of the new fluid over two years of treatment on membrane transport characteristics, ultrafiltration (UF) capacity, and effluent markers of peritoneal membrane integrity were investigated and compared with those obtained during treatment with a standard solution. DESIGN: A two-group parallel design with 80 continuous ambulatory peritoneal dialysis patients was used. The patients were randomly assigned to either the new fluid (N = 40) or to a conventional one (N = 40), and were stratified with respect to age, diabetes, and time on PD. Peritoneal transport characteristics were assessed by the Personal Dialysis Capacity (PDCtrade mark) test at 1, 6, 12, 18, and 24 months after inclusion and by weighing the overnight bag daily. Infusion pain and handling were evaluated using a questionnaire. Peritoneal mesothelial and interstitial integrity were evaluated by analyzing overnight effluent dialysate concentrations of CA 125, hyaluronan (HA), procollagen-1-C-terminal peptide (PICP), and procollagen-3-N-terminal peptide (PIIINP) at 1, 6, 12, 18, and 24 months. RESULTS: The handling of the new two-compartment bag was considered easy, and there were no indications of increased discomfort with the new system. Furthermore, no changes in peritoneal fluid or solute transport characteristics were observed during the study period for either fluid, and neither were there any differences with regard to peritonitis incidence. However, significantly higher dialysate CA 125 (73 +/- 41 vs. 25 +/- 18 U/mL), PICP (387 +/- 163 vs. 244 +/- 81 ng/mL), and PIIINP (50 +/- 24 vs. 29 +/- 13 ng/mL) and significantly lower concentrations of HA (395 +/- 185 vs. 530 +/- 298 ng/mL) were observed in the overnight effluent during treatment with the new fluid. CONCLUSIONS: We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.

Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice.

Huntington's disease is an autosomal dominant disease which presents with striatal and cortical degeneration causing involuntary movements, dementia and emotional changes. We employed 16-week-old transgenic Huntington mice (R6/1 line developed by Bates and coworkers) that express exon 1 of the mutant human Huntington gene with 115 CAG triplet repeats. At this age, R6/1 mice do not exhibit an overt neurological phenotype nor any striatal neuronal loss. Using microdialysis, we monitored basal and intrastriatal N-methyl D-aspartate (NMDA, 100 microM, 15 min)- and KCl (100 mM, 15 min)-induced increases in local aspartate, glutamate and GABA release in halothane-anaesthetized transgenic mice and wild-type controls. Basal striatal dialysate glutamate levels were reduced by 42% in R6/1 mice whilst aspartate and GABA levels did not differ from those observed in control mice. Intrastriatal NMDA was associated with significantly greater aspartate (at 15 min) and GABA (at 30 min) levels in the R6/1 mice compared to controls, whilst glutamate release rapidly increased to the same extent in both groups. Intrastriatal KCl was associated with enhanced increases (30 min) in local aspartate and glutamate release in the R6/1 mice above those observed in controls whilst the rapid increase (15 min) in GABA release was similar in both groups. The results provide compelling evidence for specific alterations in both basal, as well as NMDA- and KCl-induced, release of striatal amino acid neurotransmitters in this transgenic model of Huntington's disease, even in the absence of manifest neurodegeneration.

Optimization of peritoneal dialysis prescription using computer models of peritoneal transport.

Computer models are valuable clinical tools in the effort to improve quality of life for dialysis patients. At present, two software programs have been validated clinically in adult and pediatric populations. They are the Personal Dialysis Capacity (PDC: Gambro Lundia AB, Lund, Sweden) and PD Adequest (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.). Both programs seem to give accurate predictions of small-solute clearance, but the PDC seems to be superior in predicting ultrafiltration volumes. Indeed, the software programs have several important differences that affect their accuracy and, hence, their clinical value. The PDC software introduces the concepts of capillary physiology to the field of peritoneal dialysis. It gives a functional description of the peritoneal membrane of the individual patient. Recently, its "new" area parameter (A0/delta x) was shown to be superior to the peritoneal equilibration test (PET) in predicting transperitoneal exchange.

Impact of fill volume changes on peritoneal dialysis tolerance and effectiveness in children.

In the last decade, it has became apparent that the prescribed fill volume (IPV) in children on peritoneal dialysis (PD) should be expressed per body surface area (BSA in square meters) to avoid a false perception of peritoneal hyperpermeability as determined during a peritoneal equilibration test [PET, dialysate-to-plasma (D/P) ratio]. Nevertheless, the optimal IPV in terms of both tolerance and effectiveness remains under discussion. An individual approach to IPV prescription might balance the measurement of the intraperitoneal pressure, the use of the mass transfer coefficient despite the D/P ratio, and a determination of the effective peritoneal area available for exchanges. Considering these parameters, we usually found the individual optimal fill volume to be less than 1400 mL/m2.

Unrestricted pore area (A0/Deltax) is a better indicator of peritoneal membrane function than PET.

BACKGROUND: How to measure the peritoneal exchange in uremic patients treated with peritoneal dialysis (PD) is still a matter of controversy. Most clinics use the peritoneal equilibration test (PET), but from a theoretical point of view, it would be more appropriate to determine the "area" parameter, A0/Deltax. The latter reflects the total unrestricted pore area per centimeter diffusion distance and can be obtained by three-pore analysis using, for example, the PD capacity test (PDC). To evaluate the different estimates of peritoneal function, PET data and the A0/Deltax parameters were compared with the independently determined uptake of a small diffusible tracer, iohexol (molecular weight of 821 D), from the abdominal cavity to blood. METHODS: Fourteen patients on routine PD underwent determinations of PET and A0/Deltax using PDC. Within a month, the two-hour uptake of iohexol (6 mg/mL) was also determined from the plasma iohexol concentration following abdominal filling. RESULTS: A strong correlation was found between the rate of iohexol plasma concentration increase (k30-120) and A0/Deltax (A0/Deltax = 76,300. k30-120 - 1.56; r2 = 0.799; N = 14) for the 2 L dwell, while the PET data were far less related to iohexol uptake (D/DPurea, r2 = 0.409; D/Pcreatinine, r2 = 0.436; and D/D0glucose, r2 = 0.015, respectively). CONCLUSION: The "area" parameter, A0/Deltax, is superior to the more widely used routine PET as an indicator of peritoneal membrane function. In addition, the concept of A0/Deltax has the virtue of supplying quantitative information about the peritoneal pathophysiology and physiology.