A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.

Cryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies, in vitro toxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound against Cryptosporidium parvum Iowa and field isolates was comparable to that against Cryptosporidium hominis Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic for C. parvum, we developed a novel in vitro parasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stage Cryptosporidium drug leads and may aid in planning in vivo efficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis.

Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRß) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRß+ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRß+ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFß activation in primary human skeletal muscle and cardiac PDGFRß+ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Properties of the DASS-21 in an Australian Community Adolescent Population.

BACKGROUND: Although developed for adults, the Depression Anxiety Stress Scales-Short Version (DASS-21) has been used in many research studies with adolescent samples. Evidence as to the applicability of the DASS subscale scores to represent the distinct states of depression, anxiety, and stress as experienced by adolescents is mixed, and the age at which it may be possible to differentiate these 3 states using the DASS-21 has not yet been determined. OBJECTIVE: This study evaluated evidence for a multifactor structure in the DASS-21 in adolescents and the specificity of the 3 subscales for adolescents in general and at different ages. METHOD: Data were from a large cross-sectional survey of 2,873 school students in Grades 6-12 (aged 12-18 years) in Australia. We conducted confirmatory bifactor analyses testing a general mental health distress factor and 3 domain-specific factors for anxiety, depression, and stress for the whole sample and across gender by age groups. The internal consistency reliability of the DASS total and subscale scores was determined using omega coefficients. RESULTS: Analyses identified that most of the variation in the items was explained by the dominance of a single, general factor and the subscales lacked specificity across all age groups. CONCLUSION: The DASS-21 can be reliably used to measure general distress in adolescents, but the subscales fail to discriminate between the 3 states. Our results indicate that this lack of discrimination does not reduce with increasing age. These findings caution against the use of adult theoretical models and measures within adolescent populations.

Kick the habit: a social marketing campaign by Aboriginal communities in NSW.

Tackling smoking is an integral component of efforts to improve health outcomes in Aboriginal communities. Social marketing is an effective strategy for promoting healthy attitudes and influencing behaviours; however, there is little evidence for its success in reducing smoking rates in Aboriginal communities. This paper outlines the development, implementation and evaluation of Kick the Habit Phase 2, an innovative tobacco control social marketing campaign in Aboriginal communities in New South Wales (NSW). The Aboriginal Health & Medical Research Council worked with three Aboriginal communities and a creative agency to develop locally tailored, culturally relevant social marketing campaigns. Each community determined the target audience and main messages, and identified appropriate local champions and marketing tools. Mixed methods were used to evaluate the campaign, including surveys and interviews with community members and Aboriginal Community Controlled Health Service staff. Community survey participants demonstrated high recall of smoking cessation messages, particularly for messages and images specific to the Kick the Habit campaign. Staff participating in interviews reported an increased level of interest from community members in smoking cessation programs, as well as increased confidence and skills in developing further social marketing campaigns. Aboriginal community-driven social marketing campaigns in tobacco control can build capacity, are culturally relevant and lead to high rates of recall in Aboriginal communities.

Mitochondrial phylogeography of a Beringian relict: the endemic freshwater genus of blackfish Dallia (Esociformes).

Mitochondrial genetic variability among populations of the blackfish genus Dallia (Esociformes) across Beringia was examined. Levels of divergence and patterns of geographic distribution of mitochondrial DNA lineages were characterized using phylogenetic inference, median-joining haplotype networks, Bayesian skyline plots, mismatch analysis and spatial analysis of molecular variance (SAMOVA) to infer genealogical relationships and to assess patterns of phylogeography among extant mitochondrial lineages in populations of species of Dallia. The observed variation includes extensive standing mitochondrial genetic diversity and patterns of distinct spatial segregation corresponding to historical and contemporary barriers with minimal or no mixing of mitochondrial haplotypes between geographic areas. Mitochondrial diversity is highest in the common delta formed by the Yukon and Kuskokwim Rivers where they meet the Bering Sea. Other regions sampled in this study host comparatively low levels of mitochondrial diversity. The observed levels of mitochondrial diversity and the spatial distribution of that diversity are consistent with persistence of mitochondrial lineages in multiple refugia through the last glacial maximum.

Lactoferrin and desferrioxamine are ineffective in the treatment of Helicobacter pylori infection and may enhance H. pylori growth and gastric inflammation in mice.

AIMS: To evaluate the efficacy of bovine lactoferrin (BLf), recombinant human lactoferrin (rHLf) and desferrioxamine against Helicobacter pylori in vitro and in mice and also to determine whether BLf or rHLf alter gastric inflammation. METHODS AND RESULTS: In vitro: Broth dilution susceptibility tests were performed using different concentrations of desferrioxamine, BLf and rHLf. Murine trials: In the prevention trial, C57BL/6 female mice were treated with BLf or rHLF, and then infected with the SS1 strain of H. pylori. In the treatment trial, mice were gavaged with either BLf, rHLf or desferrioxamine. In addition, gastric myeloperoxidase activity (MPO) was measured to assess gastric inflammation. Desferoxamine was found to have a direct bactericidal effect, while BLf and rHLf only partially suppressed H. pylori growth in vitro. However, in both prevention and treatment trials all three forms of treatment failed to reduce H. pylori load in mice. Gastric MPO activity and H. pylori load were noted to be higher with lactoferrin treatments. CONCLUSIONS: Our study does not support the use of BLf or rHLF in the treatment of human H. pylori infection. Interestingly, H. pylori growth and gastric inflammation appear to be enhanced by lactoferrin treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: The mouse model is ideal for testing novel H. pylori eradicating agents.

Direct and indirect hydrological controls on E. coli concentration and loading in midwestern streams.

This study investigates hydrological controls on E. coli concentration and loading in two artificially drained agricultural watersheds (58 and 23 km(2)) of the U.S. Midwest. Stream E. coli concentrations are significantly (p < 0.02) lower at base flow than high flow; however, E. coli load is significantly higher at high flow than at low flow (p < 0.001). Although E. coli concentrations are not significantly higher (p = 0.253) in summer/fall (3269 MPN/100 mL) than in the winter/spring (2411 MPN/100 mL), E. coli load is significantly higher (p < 0.05) in winter/spring (346 MPN/day) than in summer/fall season (75 MPN/day). Correlation analysis indicates that discharge and precipitation are the best indicators of E. coli concentration and 7-d antecedent precipitation (7dP), the best indicator of E. coli loading in the watersheds studied regardless of flow conditions and location. However, E. coli concentration and loading best correlate to 7dP and turbidity at base flow. A spatial dependency is also observed at base flow with E. coli concentration and load correlating better to 7dP in the headwaters and to turbidity in the lower reaches of the watersheds studied. For high flow conditions, E. coli concentration and loading are poorly correlated to most variables, except stream water temperature and 7-d antecedent discharge. These results are consistent with those reported in the literature and suggest that, at least during base flow conditions, turbidity and 7dP may be usable in artificially drained landscapes of the Midwest to identify potential hot spots of E. coli contamination.

Short-term zinc supplementation attenuates Helicobacter felis-induced gastritis in the mouse.

BACKGROUND: Mucosal damage by H. pylori infection is mainly caused by neutrophils producing large quantities of reactive oxygen species (ROS). Metallothionein (MT) an intracellular, low-molecular, cysteine-rich protein, which is inducible by dietary zinc (Zn), has been implicated in sequestering ROS. This study examines the effects of Zn supplementation on Helicobacter colonisation and associated gastritis and the relationship with gastric MT levels. METHODS: C57Bl/6 mice were inoculated with either 10(8) H. pylori or H. felis and were infected for 4 weeks or 6 and 12 weeks, respectively. Mice infected with H. pylori (4 weeks) or H. felis (6 weeks) were treated with either Zn acetate (ZnA; 1 mg/ml), or Zn sulphate (ZnSO4; 5 mg/ml) for 2 weeks with 0.1 ml oro-gastric gavage twice daily. H. pylori load and H. felis colonisation density were determined by culture and microscopy, respectively. MT levels and H. felis-induced gastritis were also determined. RESULTS: Zn treatment showed no significant difference in Helicobacter load and gastric MT, however, ZnSO4 treatment showed a significant (p<0.05) increased in gastric MT in H. felis infected mice. Both Zn-treated groups showed a significant (p<0.05) difference in gastritis score in the antrum of the stomach within the basal and submucosal compartments compared to H. felis-infected controls. CONCLUSIONS: We found that H. felis-induced gastritis can be attenuated by short-term treatment of Zn. This observation suggests that Zn alone may be effective for the suppression of gastric mucosal inflammation induced by Helicobacter.

Characterization of four rice mutants with alterations in the defence response pathway.

SUMMARY A fast-neutron mutagenized population of rice seedlings was screened with Magnaporthe grisea, the causal agent of rice blast disease, to identify mutants with alterations in the defence response. Three mutant lines, ebr1, ebr2 and ebr3 (enhanced blast resistance) were identified that display enhanced resistance to M. grisea. ebr1 and ebr3 also confer enhanced resistance to the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). ebr3 develops a lesion mimic (LM) phenotype upon inoculation with M. grisea, and the phenotype is also induced by a shift in environmental conditions. The fourth mutant line, ncr1 (necrosis in rice), has an LM phenotype under all conditions tested and lacks enhanced resistance to either M. grisea or Xoo. Complementation testing using the mutant lines ebr3 and ncr1 indicates that the ebr3 and ncr1 loci are nonallelic and recessive. ebr1 and ebr2 display no alterations in expression of the rice pathogenesis-related (PR) genes PBZ1 and PR1, compared to wild-type CO39. ebr3 has an elevated expression of PBZ1 and PR1 only in tissue displaying the LM phenotype. ncr1 strongly expresses PBZ1 in tissue displaying the LM phenotype, whereas PR1 expression in this tissue is similar to wild-type CO39.

Development of Co-Dominant Amplified Polymorphic Sequence Markers in Rice that Flank the Magnaporthe grisea Resistance Gene Pi7(t) in Recombinant Inbred Line 29.

ABSTRACT Pi7(t), a dominant blast resistance gene derived from the rice cultivar Moroberekan, confers complete resistance against the fungal pathogen Magnaporthe grisea. Pi7(t) previously was positioned on chromosome 11 by restriction fragment length polymorphism (RFLP) mapping of a recombinant inbred line population. One derivative of this population, recombinant inbred line (RIL)29, was designated as the representative line for Pi7(t). A segregating F2 population was created from RIL29 in order to determine the location of Pi7(t). The new mapping data indicate a position for Pi7(t) 30 centimorgans distal to the original location. Pi7(t) shares a common position with the previously mapped Pi1 M. grisea resistance gene. RIL29 carries DNA not derived from either parent used to create the RIL population at the newly assigned Pi7(t) locus. RFLP analysis has identified a possible donor source.

Helicobacter-induced gastritis in mice not expressing metallothionein-I and II.

BACKGROUND: Helicobacter pylori a primary cause of gastritis and peptic ulcer disease, is associated with increased production of reactive oxygen species within the gastric mucosa. Metallothionein (MT), a low-molecular-weight, cysteine-rich, metal-binding ligand, has been shown to sequester reactive oxygen species and reduce tissue damage. This study investigates the role of MT in H. pylori-induced gastritis in mice. MATERIALS AND METHODS: Control (MT+/+) and MT-null (MT-/-) mice were inoculated with either 1 x 108H. pylori or H. felis, and were infected for 4, 8 and 16 weeks or 8 weeks, respectively. H. pylori load was determined by culture. Myloperoxidase activity and MT levels were also determined. RESULTS: The stomachs of H. felis-infected mice were more severely inflamed than those of H. pylori-infected mice. H. felis-induced gastritis was more severe (p =.003) in MT-/- than in MT+/+ mice. MT-/- mice also had higher (60%; p <.05) H. pylori loads than MT+/+ mice 4 weeks after infection but not 8 or 16 weeks after infection. Myloperoxidase activity with H. pylori was similar between MT+/+ and MT-/- mice. Thirty-three per cent greater (p <.05) myloperoxidase activity was observed in MT-/- than in MT+/+ mice infected with H. felis. In MT+/+ mice infected with H. pylori, liver MT was increased by 33 and 39% (p <.05) at 8 and 16 weeks, respectively, whereas gastric MT increased by 46% (p <.05) at 4 weeks and declined to baseline levels at 8 and 16 weeks. CONCLUSIONS: Mice lacking MT are more susceptible to H. pylori colonization and gastric inflammation, indicating that MT may be protective against H. pylori-induced gastritis.

Identification of a peptide that protects the human acetylcholine receptor against antigenic modulation.

mAb 192 is a rat monoclonal antibody with very high affinity for the major immunogenic region (MIR) of the human muscle acetylcholine receptor (AChR). An epitope mimic of this antibody was selected from a phage display peptide library screened with mAb 192. The peptide-presenting phage has been shown to specifically bind to solid phase mAb 192 with an equilibrium dissociation constant (K(d)) of 8.45x10(-9) M, as directly measured with surface plasmon resonance. This value represents the avidity of the interaction between selected phage and mAb 192. A synthetic version of this peptide QPSPYNGWRMEI, referred to as MG15, binds to its selecting antibody and blocks the interaction of mAb 192 with human AChR. Peptide MG15 was able to protect acetylcholine receptors on human RD cells from antibody-mediated down-modulation. The negative charge of glutamic acid plays a important role in antibody binding. Replacement of the glutamic acid with an alanine completely abolishes the inhibitory activity.

Bioactive proteinase 3 on the cell surface of human neutrophils: quantification, catalytic activity, and susceptibility to inhibition.

Although proteinase 3 (PR3) is known to have the potential to promote inflammation and injure tissues, the biologic forms and function of PR3 in polymorphonuclear neutrophils (PMN) from healthy donors have received little attention. In this paper, we show that PMN contain 3.24 +/- SD 0.24 pg of PR3 per cell, and that the mean concentration of PR3 in azurophil granules of PMN is 13.4 mM. Low levels of PR3 are detectable on the cell surface of unstimulated PMN. Exposure of PMN to cytokines or chemoattractants alone induces modest (1.5- to 2.5-fold) increases in cell surface-bound PR3. In contrast, brief priming of PMN with cytokines, followed by activation with a chemoattractant, induces rapid and persistent, 5- to 6-fold increases in cell surface expression of PR3, while causing minimal free release of PR3. Membrane-bound PR3 on PMN is catalytically active against Boc-Alanine-Alanine-Norvaline-thiobenzyl ester and fibronectin, but in marked contrast to soluble PR3, membrane-bound PR3 is resistant to inhibition by physiologic proteinase inhibitors. PR3 appears to bind to the cell surface of PMN via a charge-dependent mechanism because exposure of fixed, activated PMN to solutions having increasing ionic strength results in elution of PR3, HLE, and CG, and there is a direct relationship between their order of elution and their isoelectric points. These data indicate that rapidly inducible PR3 expressed on the cell surface of PMN is an important bioactive form of the proteinase. If PR3 expression on the cell surface of PMN is dysregulated, it is well equipped to amplify tissue injury directly, and also indirectly via the generation of autoantibodies.

Catabolism of newly synthesized decorin by explant cultures of bovine ligament.

The catabolism of newly synthesized decorin by explant cultures of bovine collateral ligament was investigated. The tissue was placed in explant culture for 6 days then incubated with radiolabeled sulfate for 6 h and replaced in culture for 5 days to allow for the loss of the radiolabeled large proteoglycan. The metabolic fate of the remaining radiolabeled decorin present in the matrix of the tissue over the next 9-day period was determined. It was shown that this pool of decorin was lost from ligament explant cultures either directly into the culture medium or taken up and degraded within the cells of the tissue. The intracellular degradation of the radiolabeled pool of decorin by ligament explant cultures was shown to result in the generation of [35S]sulfate. This process required metabolically active cells and involved the lysosomal system since sulfate generation was inhibited when cultures were maintained at 4 degrees C or in the presence of either 10 mM ammonium chloride or 0. 05 mM chloroquine. The inhibition of intracellular processing of decorin resulted in an increase in the rate of loss of this proteoglycan into the medium of the cultures. The inhibition of intracellular degradation of decorin was reversible on incubation of the explant cultures at 37 degrees C or removal of ammonium chloride from the culture medium. After removal of the ammonium chloride from the culture medium the rate of intracellular catabolism was greater than that observed in cultures maintained in medium alone, which suggested that there was an intracellular accumulation of native and/or partially degraded material within the cells.

Decision making in migraine patients taking sumatriptan: an exploratory study.

Until recently, much of the medical and psychological literature has examined and conceptualized the taking of medication from the viewpoint of adherence to or compliance with recommendations from health professionals. However, some authors have argued that medication taking is mostly determined by patient decision making. In order to investigate the factors and processes influencing the patient's decision to take or not take abortive therapy for migraines, 20 migraineurs (according to International Headache Society criteria) were asked, using a semistandardized interview, what factors influenced their decision to take or not take sumatriptan when they had a migraine. Qualitative analysis revealed a 2-stage decision-making process. First, the patient collects information from interoceptive and environmental cues (symptom monitoring) to predict whether the headache that is beginning will become a migraine. Then, if the patient decides it is a migraine, he or she weighs various factors to decide whether to take sumatriptan. These results are consistent with the current cognitive psychology literature on decision-making processes and could lead to significant improvements in understanding the process by which patients make decisions about taking sumatriptan and, ultimately, could lead to better patient education and more effective headache control. They also open a whole new field in the empirical investigation of medication-taking behavior.

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in alpha 1-antitrypsin deficiency.

Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in alpha 1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.

Non-pharmacologic strategies used by adolescents for the management of menstrual discomfort.

BACKGROUND: This study was a retrospective examination of adolescents' use of non-pharmacologic methods to manage menstrual discomfort. METHODS: A convenience sample of 289 female adolescents (mean age = 16.28 years, SD = 1.00) recruited from a public high school completed a questionnaire designed for this study. RESULTS: Ninety-eight percent of these adolescents reported using at least one non-pharmacologic method (e.g., heat, distraction) to manage menstrual discomfort. The mean perceived effectiveness of most of these methods was reported by adolescents to be below 40% (range = 3-74%). CONCLUSION: It is possible that some methods are used because they have a physiologic impact on pain (e.g. heat), whereas others (e.g., distraction) provide a sense of comfort and control. Further research is necessary to examine the determinants of why and when certain management strategies are used by adolescents.

Recent changes in residency requirements for pediatrics: who agrees?

The purposes of this study were to determine the opinion of private and academic pediatricians about changes in pediatric residency requirements proposed by the Residency Review Committee (RRC) in October 1994 and to compare the results with the requirements finalized in February 1996 and implemented in February 1997. Surveys were mailed to all Fellows of the American Academy of Pediatrics in South Carolina. Those surveyed were asked to agree or disagree with 57 proposed changes. The level of agreement among all groups of pediatricians was very high; however there were significant differences between groups of pediatricians. Many controversial items were modified or deleted in the final version.

"U" curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, Inc.

BACKGROUND: Hypertension may play an important role in the pathogenesis of the excess cardiovascular and cerebrovascular (CV) morbidity observed in hemodialysis patients (HD). However, the optimal blood pressure (BP) range for HD patients has not been defined. We postulated that there is a "U" curve relationship between BP and CV mortality. To explore this hypothesis we studied 5,433 HD patients in Dialysis Clinic Inc., a large not-for-profit chain, over a five year period. METHODS: Cox regression, with fixed and time-varying covariates, was used to assess the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP), pre- and post-dialysis, on CV mortality, while adjusting for age, gender, ethnicity, primary cause of end-stage renal disease, Kt/V, serum albumin, and antihypertensive medications. RESULTS: The overall impact of BP on CV mortality was modest. Pre-dialysis, neither systolic nor diastolic hypertension were associated with an increase in CV mortality. Post-dialysis, SBP > or = 180 mm Hg (RR = 1.96, P < 0.015) and DBP > or = 90 mm Hg (RR = 1.73, P < 0.05) were associated with increased CV mortality. Low SBP (SBP < 110 mm Hg) was associated with increased CV mortality, pre- and post-dialysis. CONCLUSIONS: The results suggest the presence of a "U" curve relationship between SBP post-dialysis and CV mortality in HD patients.