Detecting genes for variation in parasite burden and immunological traits in a wild population: testing the candidate gene approach.

Identifying the genes underlying phenotypic variation in natural populations can provide novel insight into the evolutionary process. The candidate gene approach has been applied to studies of a number of traits in various species, in an attempt to elucidate their genetic basis. Here, we test the application of the candidate gene approach to identify the loci involved in variation in gastrointestinal parasite burden, a complex trait likely to be controlled by many loci, in a wild population of Soay sheep. A comprehensive literature review, Gene Ontology databases, and comparative genomics resources between cattle and sheep were used to generate a list of candidate genes. In a pilot study, these candidates, along with 50 random genes, were then sequenced in two pools of Soay sheep; one with low gastrointestinal nematode burden and the other high, using a NimbleGen sequence capture experiment. Further candidates were identified from single nucleotide polymorphisms (SNPs) that were highly differentiated between high- and low-resistance sheep breeds. A panel of 192 candidate and control SNPs were then typed in 960 individual Soay sheep to examine whether they individually explained variation in parasite burden, as measured as faecal egg count, as well as two immune measures (Teladorsagia circumcincta-specific antibodies and antinuclear antibodies). The cumulative effect of the candidate and control SNPs were estimated by fitting genetic relationship matrices (GRMs) as random effects in animal models of the three traits. No more significant SNPs were identified in the pilot sequencing experiment and association study than expected by chance. Furthermore, no significant difference was found between the proportions of candidate or control SNPs that were found to be significantly associated with parasite burden/immune measures. No significant effect of the candidate or control gene GRMs was found. There is thus little support for the candidate gene approach to the identification of loci explaining variation in parasitological and immunological traits in this population. However, a number of SNPs explained significant variation in multiple traits and significant correlations were found between the proportions of variance explained by individual SNPs across multiple traits. The significant SNPs identified in this study may still, therefore, merit further investigation.

Selection and microevolution of coat pattern are cryptic in a wild population of sheep.

Understanding the maintenance of genetic variation in natural populations is a core aim of evolutionary genetics. Insight can be gained by quantifying selection at the level of the genotype, as opposed to the phenotype. Here, we show that in a natural population of Soay sheep which is polymorphic for coat pattern, recessive genetic variants at the causal gene, agouti signalling protein (ASIP) are associated with reduced lifetime fitness. This was due primarily to a reduction in juvenile survival of uniformly coloured (self-type) sheep, which are homozygous recessive, and occurs despite significantly higher reproductive success in surviving self-type adults. Consistent with their relatively low fitness, we show that the frequency of self-type individuals has declined from 1985 to 2008. Remarkably though, the frequency of the underlying self-allele has increased, because the frequency of heterozygous individuals (who harbour the majority of all self-alleles) has increased. Indeed, the ratio of observed/expected heterozygous individuals has increased during the study, such that there is now a significant excess of heterozygotyes. By employing gene-dropping simulations, we show that microevolutionary trends in the frequency and excess of ASIP heterozygotes are too pronounced to be caused by genetic drift. Studying this polymorphism at the level of phenotype rather than underlying genotype would have failed to detect cryptic fitness differences. We would also have been unable to rule out genetic drift as an evolutionary force driving genetic change. This highlights the importance of resolving the underlying genetic basis of phenotypic variation in explaining evolutionary dynamics.

The genetic basis of recessive self-colour pattern in a wild sheep population.

Bridging the genotype-phenotype gap for traits of ecological and evolutionary importance in natural populations can provide a novel insight into the origin and maintenance of variation. Here, we identify the gene and putative causal mutations underlying a recessive colour pattern phenotype ('self' or uniform colour) in a wild population of primitive Soay sheep. We targeted the agouti signalling protein (ASIP) gene, a positional candidate based on previous study that mapped the Coat pattern locus to a presumptive region on chromosome 13. We found evidence for three recessive mutations, including two functional changes in the coding sequence and a putative third cis-regulatory mutation that inactivates the promoter. These mutations define up to five haplotypes in Soays, which collectively explained the coat pattern in all but one member of a complex multi-generational pedigree containing 621 genotyped individuals. The functional mutations are in strong linkage disequilibrium in the study population, and are identical to those known to underlie the self phenotype in domestic sheep. This is indicative of a recent (and simultaneous) origin in Soay sheep, possibly as a consequence of past interbreeding with modern domestic breeds. This is only the second study in which ASIP has been linked to variation in pigmentation in a natural population. Knowledge of the genetic basis of self-colour pattern in Soay sheep, and the recognition that several mutations are segregating in the population, will aid future studies investigating the role of selection in the maintenance of the polymorphism.

Estimated frequency of the canine hyperuricosuria mutation in different dog breeds.

BACKGROUND: Hyperuricosuria is a condition that predisposes dogs to urate urolithiasis. A mutation that causes canine hyperuricosuria was previously identified in 3 unrelated dog breeds. The occurrence of the mutation in additional breeds was not determined. HYPOTHESIS/OBJECTIVES: Identify additional breeds that have the hyperuricosuria mutation and estimate the mutant allele frequency in those breeds. ANIMALS: Three thousand five hundred and thirty dogs from 127 different breeds were screened for the hyperuricosuria mutation. METHODS: DNA samples were genotyped by pyrosequencing and allele-specific polymerase chain reaction methods. RESULTS: Mutant allele frequencies that range from 0.001 to 0.15 were identified in the American Staffordshire Terrier, Australian Shepherd, German Shepherd Dog, Giant Schnauzer, Parson (Jack) Russell Terrier, Labrador Retriever, Large Munsterlander, Pomeranian, South African Boerboel, and Weimaraner breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: The hyperuricosuria mutation has been identified in several unrelated dog breeds. The mutant allele frequencies vary among breeds and can be used to determine an appropriate breeding plan for each breed. A DNA test is available and may be used by breeders to decrease the mutant allele frequency in breeds that carry the mutation. In addition, veterinarians may use the test as a diagnostic tool to identify the cause of urate urolithiasis.

Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles.

Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity.

Changing practice to improve pain control for renal patients.

Pain is a common symptom described by patients with end-stage kidney disease (ESKD) but remains ineffectively managed. The aim of this audit was to determine what proportion of these patients report pain, then introduce the use of an analgesic ladder adapted specifically for ESKD, and finally re-evaluate the prevalence of pain symptoms, looking for an improvement. A cohort of inpatients on the renal wards of a West London teaching hospital was studied. The number of patients reporting pain and the severity of their pain on a scale of 1-10 were recorded. A considerable number of patients were barred from participating because of a language barrier. Interpreters were introduced, and the phase was repeated. The World Health Organization (WHO) three-step analgesic ladder was adapted for patients with ESKD and introduced to medical staff on the renal wards. The number of patients reporting pain and the severity of their pain were re-recorded. There was a significant reduction in the number of patients reporting pain and the severity of their pain. Pain control in patients with ESKD is improved through the use of an adapted version of the WHO analgesic ladder. Strategies must be in place for effective communication with foreign patients.

Development and validity of the Burns-Child Adult Medical Procedure Interaction Scale (B-CAMPIS) for young children.

BACKGROUND: Young children are at increased risk of burn injury and of procedural distress during the subsequent wound care. There are currently few observational measures validated for use with young children during medical procedures. The aim of this research was to adapt the Child-Adult Medical Procedure Interaction Scale-Revised (CAMPIS-R) to assess parent-young child interactions during burn wound care by including nonverbal behavioral coding. METHOD: Eighty-seven families of children (1-6years old) were recruited at their first burn dressing change. Potential behaviors were identified through a literature review, consulting health professionals, and direct observation of parents and children during burn wound care. Nonverbal behaviors were coded live, and verbal behaviors were audio recorded for later assessment. RESULTS: Inter-coder reliability was good to excellent for the Burns-CAMPIS (B-CAMPIS). The additional behaviors were correlated with the hypothesized coping, distress, coping-promoting and distress-promoting categories of the CAMPIS-R. Some behaviors differed in frequency across child age groups, with older children demonstrating more verbal behaviors. Convergent validity was demonstrated through correlations with previously validated observational parent-child behavior measures, and parent- and nurse- reported measures of child pain and anxiety. Univariate regression analyses demonstrated the child categories of the B-CAMPIS accounted for equal or more of the variance of parent- and nurse- reported child pain and anxiety, compared to the CAMPIS-R. CONCLUSIONS: The B-CAMPIS is a reliable and valid measure, for assessing coping and distress relationships in young children and their families. Pending further validation, the B-CAMPIS assists researchers and clinicians to recognize and target important behaviors to improve young child coping during pediatric burn wound care.

Peritoneal dialysis for older people: overcoming the barriers.

The proportion of older dialysis patients on peritoneal dialysis (PD) is considerably lower than that of younger patients. This is despite the fact that clinical outcome studies show that older patients cope at least as well as younger patients with PD, and that many older patients do not cope well with hemodialysis (HD). Barriers to PD include medical and social factors, physician bias, late referral, and education not tailored to the needs of older patients. The development of assisted PD can overcome some of the barriers and enable frail older patients to have home-based dialysis treatment.

Impact of new dialysis solutions on peritonitis rates.

Peritonitis remains a major cause of morbidity among patients on peritoneal dialysis (PD), yet there is little information about the effect of new biocompatible dialysis solutions on peritonitis rates and treatment. In our unit, information on each peritonitis episode is prospectively collected. Since 2003, bicarbonate/lactate dialysate has been gradually introduced for new patients and for patients experiencing abdominal pain with conventional lactate solutions. From 2002 to 2005, data from 121 episodes of peritonitis (71 automated PD and 50 continuous ambulatory PD) were analyzed; 107 episodes occurred in patients using standard lactate dialysate and 14 episodes in patients using bicarbonate/lactate solution. Patients using bicarbonate/lactate had a significantly lower peritonitis rate of 1 per 52.5 patient-months compared to those using standard lactate dialysate (1 per 26.9 patient-months) (P=0.0179). Response to treatment, however, was not affected by the type of dialysate; cure rates (71.4 and 69.1%, respectively) and recurrence rates (21.4 and 15.8%, respectively) were not significantly different. Catheter removal was required in three (21.4%) patients using bicarbonate/lactate and 23 (22.4%) patients using lactate solution. Use of biocompatible dialysate appears to reduce the peritonitis rate by 50%, although this has to be confirmed in a randomized study. The type of dialysate, on the other hand, does not affect response to treatment.

Semi-allogeneic cell hybrids stimulate HIV-1 envelope-specific cytotoxic T lymphocytes.

OBJECTIVE: The present study was designed to determine whether the HLA allogeneic T helper response stimulated by semi-allogeneic cell lines could be used as an in vitro model of immune-based therapy to stimulate HIV-specific cytotoxic T lymphocytes. DESIGN AND METHODS: Semi-allogeneic cell hybrids were obtained by the fusion of peripheral blood mononuclear cells from HIV-infected patients with the allogeneic beta2-microglobulin-deficient FO1-12 melanoma cell line. These hybrids were used as antigen presenting cells for HIV envelope peptide (env)-specific cytotoxic assays. RESULTS: The hybrid cell lines express HLA class I and II antigens from both parental cells, as well as the CD86 costimulatory molecule. HIV-specific cytotoxic T lymphocyte activity was obtained when patients' peripheral blood mononuclear cells were costimulated with env peptides plus semi-allogeneic hybrids, in contrast with stimulation with either env or hybrid cells alone. Thus, the semi-allogeneic hybrids enhanced HIV-specific killing of target cells. CONCLUSIONS: Irradiated, semi-allogeneic cell hybrids engineered for individual AIDS patients provide efficient and simultaneous co-recognition of HLA allogeneic determinants and viral antigenic determinants presented by self-HLA molecules on the same antigen presenting cells and results in the generation of enhanced HIV-specific cytotoxic T lymphocyte activity.

The clinical course of mesangial proliferative glomerulonephritis.

Patients with a pure mesangial proliferative glomerulonephritis may present with either hematuria, asymptomatic proteinuria, or nephrotic syndrome. For patients with hematuria, the clinical course is self-limited, and spontaneous resolution of recurrent episodes of macroscopic hematuria occurred in many of these patients. For patients with asymptomatic proteinuria, a spontaneous decrease in proteinuria occurred and none of these patients developed a progressive course. The clinical course of patients with nephrotic syndrome was similar to that usually observed in children and adults with pure minimal change lesions. A complete remission of the nephrotic syndrome occurred in most of these patients during treatment with prednisone and cyclophosphamide. Overall, the prognosis for the patients reported in this series was quite good.

Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? A nested case control study from the West of Scotland Coronary Prevention Study.

The clinical utility of a new assay for plasma lipoprotein(a)-cholesterol (Lp(a)-C) was assessed in parallel with our routine Lp(a) mass measurements in a nested-case control study of subjects within the placebo arm of the West of Scotland Coronary Prevention Study (WOSCOPS). A total of 238 control patients and 108 patients who had suffered a serious vascular event during the course of the WOSCOPS were examined. Lp(a) mass was assessed within 2 years of sampling by an ELISA method on baseline EDTA plasma samples which had been stored at -70 degrees C. Subsequently, the Lp(a) mass was re-measured by an immunoturbidimetric assay approximately 8 years after sampling. On the same stored aliquot the Lp(a)-C was measured. These analyses allowed us to assess whether the Lp(a)-C assay could provide any additional information over and above that which would be obtained from our Lp(a) mass assays. In addition the apo(a) isoform sizes of these subjects were measured using a high resolution immunoblotting system. The Lp(a)-C and Lp(a) mass measurements provided exactly the same information in the study, as they were equally non-discriminatory between cases and controls. The only difference between the two patient groups was the percentage of 'null' apo(a) alleles (control: 25.6% versus cases: 19.4%). We conclude that these results reinforce the concordance of the two assay systems and confirm that the Lp(a)-C assay provides no added information over and above that gained from traditional Lp(a) mass assays, which may be faster and less expensive.

Predictors of plasma lipoprotein(a) concentration in the West of Scotland Coronary Prevention Study cohort.

An elevated plasma lipoprotein(a) (Lp(a)) concentration is an independent risk factor for coronary heart disease (CHD). Plasma Lp(a) levels are believed to be predominantly controlled by the APO(a) gene, which encodes the apo(a) glycoprotein moiety of the Lp(a) particle. However, other parameters in the lipoprotein profile as well as co-existing disease states or personal traits have been proposed as co-varieties. In order to examine these potential controlling factors in greater detail than previously possible, 1760 unrelated Caucasian subjects were studied, from which were identified 907 with a single expressing APO(a) allele. This strategy was followed to obviate the difficulty in dealing with the co-expression of different apo(a) isoforms and the resulting compound plasma Lp(a) level. After cube-root transformation of the plasma Lp(a) levels to normalise their distribution, a series of correlates were computed. There was no good correlation between Lp(a) concentration and any other measured lipid or lipoprotein in the lipid profile or with any other variable examined, with the important exception of the length of the expressed apo(a) isoform (r = -0.491, P = 0.0001). We conclude that in this population the plasma Lp(a) concentration is not predicted by the plasma lipid profile, alcohol intake, or smoking status but is predicted, albeit incompletely, by the length polymorphism of the APO(a) gene.

An FPGA-based approach to high-speed simulation of conductance-based neuron models.

The constant requirement for greater performance in neural model simulation has created the need for high-speed simulation platforms. We present a generalized, scalable field programmable gate array (FPGA)-based architecture for fast computation of neural models and focus on the steps involved in implementing a single-compartment and a two-compartment neuron model. Based on timing tests, it is shown that FPGAs can outperform traditional desktop computers in simulating these fairly simple models and would most likely provide even larger performance gains over computers in simulating more complex models. The potential of this method for improving neural modeling and dynamic clamping is discussed. In particular, it is believed that this approach could greatly speed up simulations of both highly complex single neuron models and networks of neurons. Additionally, our design is particularly well suited to automated parameter searches for tuning model behavior and to real-time simulation.

Ring D oxygenated Spirolactones. Characterization of human metabolic product of spironolactone.

15alpha-Hydroxycanrenone (1b) was prepared from canrenone (1a) by microbiological oxidation with a penicillium species. The product was identical with one obtained from the metabolism of spironolactone(3) in human. Oxidation of 1b with Jones regent furnished the corresponding 15-oxocanrenone (1d) which underwent base-catalyzed beta elimination to generate an alpha,beta-unsaturated cyclopentenone system. 15alpha-Hydroxycanrenone (1b) failed to show antimineralocorticoid activity at the screening dose of 2.4 mg while the oxo derivative 1d exhibited approximately 15% the activity of 3. Since the activity of canrenone is 38% that of spironolactone, introduction of the carbonyl group at the 15 position of canrenone resulted in a reduction in activity. This effect is opposite to that observed with 6-dehydroprogesterone.

Lysis of human glial cells by major histocompatibility complex-unrestricted CD4+ cytotoxic lymphocytes.

We have investigated lysis of cultured human glial cells by non-major histocompatibility complex (MHC)-restricted or 'promiscuous' CD(4+)-T lymphocytes, activated either under relatively long-term limiting dilution culture conditions in the presence of phytohemagglutinin (PHA) and interleukin (IL)-2, or under short-term PHA-activated bulk culture conditions. Specific effector:target cell ratio-dependent lysis of oligodendrocytes (OGCs) by CD4+ T lymphocytes, generated under both of the above conditions, was observed in an 18-h 51Cr-release assay, but not in a 5-h assay. The extent of CD4 T-cell-mediated OGC lysis was less than for the tumor necrosis factor (TNF)-alpha-sensitive cell line U937, but greater than for TNF-resistant cell lines (K562, EL4). The effect could not be reproduced by T-cell culture supernatants or by high concentrations of recombinant TNF-alpha or beta. Anti-TNF-alpha antibody did not inhibit CD4-mediated lysis of OGC or U937 cells, but did inhibit U937 lysis induced by recombinant TNF-alpha, added in amounts exceeding those secreted by CD4 T cells. Human astrocytes and microglia were also susceptible to CD4+ T-cell-mediated lysis. Our results suggest that non-antigen non-MHC-restricted CD4+ T-cell-mediated injury of human glial cells can occur and may be dependent or enhanced by effector:target cell contact.

Captopril renal scintigraphy in patients with hypertension and chronic renal failure.

UNLABELLED: The aim of this prospective study was to determine the ability of the captopril renogram to reveal the presence of angiotensin II-dependent renovascular disorder in hypertensive patients with chronic renal failure and to assess the possibility of predicting beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on renal function. METHODS: Forty-one patients were evaluated. Baseline renal scintigraphy was performed with 80 MBq of 99mTc-mercaptoacetyltriglycine (MAG3) injected intravenously. Scintigraphy was repeated within a week with 25 mg of oral captopril given 60 min prior to the test. Using the measurements outlined by the Working Party on Diagnostic Criteria of Renovascular Hypertension with Captopril Renography, the patients were categorized into high (7 patients), indeterminate (19 patients) and low (15 patients) probability for renal artery stenosis (RAS). RESULTS: In five of the seven patients with high probability, the presence of RAS was confirmed angiographically and corrective surgical procedure performed in two. In patients with GFR of 10 ml/min/1.73 m2 and/or split renal function of 10% or less, all qualitative and semiquantitative scintigraphic parameters were nonspecific. Mean parenchymal transit time of tracer was a useful parameter to predict the beneficial effect of ACE inhibition therapy in 23 patients (14 low and 9 indeterminate probability of RAS). CONCLUSION: In hypertensive patients with renal failure, captopril renal scintigraphy can be utilized to identify the presence of angiotensin II-dependent renal dysfunction and possibly help to predict the beneficial effect of ACE inhibitor therapy.

Surface-secreted von Willebrand factor mediates aggregation of ADP-activated platelets at moderate shear stress: facilitated by GPIb but controlled by GPIIb-IIIa.

We previously showed that ADP activation of washed human platelets in plasma-free suspensions supports aggregation at moderate shear stress (0.4-1.6 Nm-2) in Poiseuille flow. Although most activated platelets expressed maximal fibrinogen-occupied GPIIb-IIIa receptors, aggregation appeared to be independent of bound fibrinogen, but blocked by the hexapeptide GRGDSP. Here, we tested the hypothesis that von Willebrand factor (vWF) secreted and expressed on activated platelets mediates aggregation at moderate shear rates from 300 to 1000 s-1 corresponding to shear stresses from 0.3 to 1.1 Nm-2. Relatively unactivated platelets (< 15% expressing prebound fibrinogen) were prepared from acidified citrated platelet rich plasma (cPRP) by single centrifugation with 50 nM stable prostacyclin derivative ZK 36374 and resuspended in Tyrodes-albumin at 5 x 10(4) cells microliter-1. Flow cytometric measurements with monoclonal antibody (mAb) 2.2.9 reporting on surface-bound vWF, and with mAb S12 reporting on alpha-granule secreted P-selectin, showed that 65% and 80%, respectively, of all platelets were maximally activated with respect to maximal secretion and surface expression of these proteins. "Resting" washed platelets exhibited both surface-bound vWF and significant P-selectin secretion. We showed that mAbs 6D1 and NMC4, respectively blocking the adhesive domains on the GPIb receptor recognizing vWF, and on the vWF molecule recognizing the GPIb receptor, partially inhibited ADP-induced aggregation under shear in Couette flow, the degree of inhibition increasing with increasing shear stress. In contrast, mAb 10E5, blocking the vWF binding domain on GPIIb-IIIa, essentially blocked all aggregation at the shear rates tested. We conclude that vWF, expressed on ADP-activated platelets, is at least the predominant cross-bridging molecule mediating aggregation at moderate shear stress. There is an absolute requirement for free activated GPIIb-IIIa receptors, postulated to interact with platelet-secreted, surface bound vWF. The GPIb-vWF cross-bridging reaction plays a facilitative role becoming increasingly important with increasing shear stress. Since aurin tricarboxylic acid, which blocks the GPIb binding domain on vWF, was also found to completely block aggregation in Poiseuille flow, we conclude that it too affects the GPIIb-IIIa interaction.

Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist with negligible ability to penetrate the central nervous system.

SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine H1-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. Oral pretreatment with SK&F 93944 in conscious rats and guinea-pigs afforded protection versus the response to intradermal histamine injection. Comparative studies in each of the test systems showed that SK&F 93944 was of comparable or significantly greater potency than the standard compound, mepyramine. SK&F 93944 was found to be a weak, non-competitive antagonist of carbachol on the guinea-pig ileum but was devoid of measurable anticholinergic activity in vivo. Studies on the penetration of [14C]-SK&F 93944, labelled either in the isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady-state blood concentrations. In contrast, brain concentrations of [3H]-mepyramine exceeded blood concentrations by a factor of approximately 3. SK&F 93944 may have an advantage over classical histamine H1-receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.

Initial treatment of peritoneal dialysis peritonitis without vancomycin with a once-daily cefazolin-based regimen.

To reduce the use of vancomycin, the current recommendations of the International Society of Peritoneal Dialysis (PD) for the initial treatment of peritonitis complicating PD are to administer intraperitoneal (IP) cefazolin or cephalothin in every PD fluid bag, together with once-daily gentamicin. In view of the inherent impracticalities of this regimen, we studied the efficacy of once-daily cefazolin (1.5 g) IP with gentamicin IP as initial treatment for primary (nonrecurrent) PD peritonitis. This regimen has been used in all episodes of peritonitis not associated with tunnel or exit-site infections or fluid leaks. Sixty-nine episodes in 61 patients were analyzed (44 patients, continuous ambulatory PD; 22 patients, automated PD; and 3 patients, hospital-based intermittent PD), of which 38 episodes (55%) were gram-positive infections, 6 episodes (9%) were gram-negative infections, and 18 episodes (26%) had negative culture results. Four patients died within 4 weeks of infection (none considered attributable to inadequate treatment of their peritonitis). Ten catheters (14.5%) required removal to clear the infection; 7 catheters were in patients with gram-negative infections. The relapse rate within 4 weeks of ceasing antibiotic therapy was 8.9%. Compared with the results of 40 episodes of peritonitis treated initially with our previous IP vancomycin and gentamicin regimen, successful treatment (no death, catheter removal, or recurrence) was achieved in 52 of 69 episodes in the cefazolin group (75.4%) versus 23 of 40 episodes in the vancomycin group (57.5%; P: = 0.058). In conclusion, once-daily IP cefazolin and gentamicin for the initial treatment of PD peritonitis is at least as effective as a vancomycin-based regimen and is well tolerated.