PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD.

BACKGROUND: Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described. METHODS: Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen-glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury. RESULTS: We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen-glucose deprivation, while STAT3 inhibition reduced the protective effect. CONCLUSIONS: We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.

Examining if the relationship between BMI and incident type 2 diabetes among middle-older aged adults varies by race/ethnicity: evidence from the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: Disparities persist on the prevalence of undiagnosed type 2 diabetes in racial/ethnic minorities in the USA. This study evaluated the association between BMI and incident type 2 diabetes risk by racial/ethnic group, to determine whether BMI and presence of type 2 diabetes risk factors may help clinicians better target type 2 diabetes screening. METHODS: This prospective cohort analysis included 5659 adults free of type 2 diabetes at baseline from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort (2000-2011). BMI was measured at baseline and time-updated at subsequent visits. Incident type 2 diabetes was defined as fasting glucose ≥ 7.0 mmol/l, or use of any diabetes medications. RESULTS: The mean (sd) age was 62 (10) years and 42% of participants were white, 26% African American, 20% Hispanic and 12% Chinese American. During follow-up, 696 (12%) new type 2 diabetes cases were observed. In age- and sex-adjusted models, in the presence of one or more type 2 diabetes risk factors (the most common scenario), a 10% risk of incident type 2 diabetes was observed at a BMI of 21.7 kg/m2 [95% confidence interval (CI) 20.1 to 22.8] in Chinese Americans, 23.8 kg/m2 (22.7 to 24.9) in Hispanics, 24.7 kg/m2 (23.7 to 25.6) in African Americans and 26.2 kg/m2 (25.1 to 26.9) in white participants. CONCLUSIONS: This study supports including BMI and presence of type 2 diabetes risk factors as action points for clinicians to prioritize which adults aged ≥ 45 years should be screened. The application of race/ethnicity-specific BMI thresholds may reduce the disparity of undiagnosed type 2 diabetes observed in minority groups.

Incidence of components of metabolic syndrome in the metabolically healthy obese over 9 years follow-up: the Atherosclerosis Risk In Communities study.

BACKGROUND: Some obese adults are not afflicted by the metabolic abnormalities often associated with obesity (the 'metabolically healthy obese' (MHO)); however, they may be at increased risk of developing cardiometabolic abnormalities in the future. Little is known about the relative incidence of individual components of metabolic syndrome (MetSyn). METHODS: We used data from a multicenter, community-based cohort aged 45-64 years at recruitment (the Atherosclerosis Risk In Communities study) to examine the first appearance of any MetSyn component, excluding waist circumference. Body mass index (BMI, kg m-2) and cardiometabolic data were collected at four triennial visits. Our analysis included 3969 adults who were not underweight and free of the components of MetSyn at the initial visit. Participants were classified as metabolically healthy normal weight (MHNW), overweight (MHOW) and MHO at each visit. Adjusted hazard ratios (HR) and 95% confidence intervals were estimated with proportional hazards regression models. RESULTS: The relative rate of developing each risk factor was higher among MHO than MHNW, with the strongest association noted for elevated fasting glucose (MHO vs MHNW, HR: 2.33 (1.77, 3.06)). MHO was also positively associated with elevated triglycerides (HR: 1.63 (1.27, 2.09)), low high-density lipoprotein-cholesterol (HR: 1.68 (1.32, 2.13)) and elevated blood pressure (HR: 1.54 (1.26, 1.88)). A similar, but less pronounced pattern was noted among the MHOW vs MHNW. CONCLUSIONS: We conclude that even among apparently healthy individuals, obesity and overweight are related to more rapid development of at least one cardiometabolic risk factor, and that elevations in blood glucose develop most rapidly.

Measurement of the Target-Normal Single-Spin Asymmetry in Quasielastic Scattering from the Reaction (3)He(↑)(e,e').

We report the first measurement of the target single-spin asymmetry, A(y), in quasielastic scattering from the inclusive reaction (3)He(↑)(e,e') on a (3)He gas target polarized normal to the lepton scattering plane. Assuming time-reversal invariance, this asymmetry is strictly zero for one-photon exchange. A nonzero A(y) can arise from the interference between the one- and two-photon exchange processes which is sensitive to the details of the substructure of the nucleon. An experiment recently completed at Jefferson Lab yielded asymmetries with high statistical precision at Q(2)=0.13, 0.46, and 0.97 GeV(2). These measurements demonstrate, for the first time, that the (3)He asymmetry is clearly nonzero and negative at the 4σ-9σ level. Using measured proton-to-(3)He cross-section ratios and the effective polarization approximation, neutron asymmetries of -(1-3)% were obtained. The neutron asymmetry at high Q(2) is related to moments of the generalized parton distributions (GPDs). Our measured neutron asymmetry at Q(2)=0.97 GeV(2) agrees well with a prediction based on two-photon exchange using a GPD model and thus provides a new, independent constraint on these distributions.

Successful Example of How to Implement and Develop a Deceased Organ Donation System in the Caribbean Region: Five-Year Experience of the SEUSA Program in Trinidad and Tobago.

BACKGROUND: The SEUSA program, the Donation and Transplantation Institute foundation consultancy program, was implemented in Trinidad and Tobago (T&T) in 2010 with the support of the National Organ Transplant Unit (NOTU) and the Ministry of Health of T&T. METHODS: The SEUSA program included (1) diagnosis of the current situation using the ODDS (Organ Donation Diagnostic Surveys); (2) creation of a human resources structure through Transplant Procurement Management (TPM); (3) detection of all brain and cardiac deaths in the hospitals implementing the DAS (Decease Alert System); (4) in-hospital awareness based on the EODS (Essentials in Organ Donation); and (5) external hospital audits. Additionally continued monitoring is performed. RESULTS: Thus far, thanks to implementation of the SEUSA program in Trinidad and Tobago 175, healthcare professionals have been exposed to training programs in the organ donation field. The Living Kidney Program was reinforced and the structure of the Deceased Donation (DD) network was defined. Since 2010, 485 potential organ donors have been detected, and 9 have become actual organ donors; 74 patients have received a kidney transplant (59 from living and 15 from deceased donors). CONCLUSIONS: This project results demonstrate that the application of the SEUSA program is an efficient methodology to develop DD programs that increase and consolidate transplant programs in the Caribbean region.

Prophylactic melatonin significantly reduces Alzheimer's neuropathology and associated cognitive deficits independent of antioxidant pathways in AßPP(swe)/PS1 mice.

BACKGROUND: Alzheimer's disease (AD) underlies dementia for millions of people worldwide, and its occurrence is set to double in the next 20 years. Currently, approved drugs for treating AD only marginally ameliorate cognitive deficits, and provide limited symptomatic relief, while newer substances under therapeutic development are potentially years away from benefiting patients. Melatonin (MEL) for insomnia has been proven safe with >15 years of over-the-counter access in the US. MEL exerts multiple complementary mechanisms of action against AD in animal models; thus it may be an excellent disease-modifying therapeutic. While presumed to provide neuroprotection via activation of known G-protein-coupled melatonin receptors (MTNRs), some data indicate MEL acts intracellularly to protect mitochondria and neurons by scavenging reactive oxygen species and reducing free radical formation. We examined whether genetic deletion of MTNRs abolishes MEL's neuroprotective actions in the AßPP(swe)/PSEN1dE9 mouse model of AD (2xAD). Beginning at 4 months of age, both AD and control mice either with or without both MTNRs were administered either MEL or vehicle in drinking water for 12 months. RESULTS: Behavioral and cognitive assessments of 15-month-old AD mice revealed receptor-dependent effects of MEL on spatial learning and memory (Barnes maze, Morris Water Maze), but receptor-independent neuroprotective actions of MEL on non-spatial cognitive performance (Novel Object Recognition Test). Similarly, amyloid plaque loads in hippocampus and frontal cortex, as well as plasma Aß1-42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL's efficacy in reducing cortical antioxidant gene expression (Catalase, SOD1, Glutathione Peroxidase-1, Nrf2) only when receptors were present. Increased cytochrome c oxidase activity was seen in 16 mo AD mice as compared to non-AD control mice. This increase was completely prevented by MEL treatment of 2xAD/MTNR+ mice, but only partially prevented in 2xAD/MTNR- mice, consistent with mixed receptor-dependent and independent effects of MEL on this measure of mitochondrial function. CONCLUSIONS: These findings demonstrate that prophylactic MEL significantly reduces AD neuropathology and associated cognitive deficits in a manner that is independent of antioxidant pathways. Future identification of direct molecular targets for MEL action in the brain should open new vistas for development of better AD therapeutics.

Using quality indicators to compare outcomes of permanent cardiac pacemaker implantation among publicly and privately funded patients.

BACKGROUND: Funding source/insurance status has been associated with disparity in the management and outcomes of cardiovascular disease, with poorer outcomes among disadvantaged groups. AIM: Using proposed quality indicators for permanent pacemaker (PPM) implantation and administrative data, this study aimed to determine whether quality indicator-based outcomes of PPM implantation were comparable for publicly and privately funded patients within Australia's two-tier health system. METHODS: A population-based cohort study of adults implanted with a PPM between 1995 and 2009 in Western Australia. The association of funding outcomes derived from linked administrative data was tested in multivariate logistic regression models. RESULTS: There were 9748 PPMs implanted, 48% being among privately funded patients. The mean age was 75 years for both public and private patients. Private patients had better health status (fewer with cardiac conditions and lower non-cardiac comorbidity scores), were less likely to be an emergency admission (33% vs 60%, P < 0.001) and more likely to have dual- or triple-chamber pacing. Mean length of stay was significantly greater for private patients (4.3 (standard deviation 6.3) vs 5.1 (6.8) days <0.001), related to longer elective admissions. Crude mortality was lower for private patients in-hospital (0.7 vs 1.3%), 30-day post-procedure (1.3 vs 2.1%) and at 1 year (7.3 vs 9.5%). Emergency admission, comorbidity and other demographic and clinical factors, not funding source, were significant predictors of these outcomes. CONCLUSIONS: There was no difference between publicly and privately funded patients in study outcomes, after adjustment for demographic and clinical factors. The exception was longer hospital stay for elective PPM among privately funded patients.

Three-year weight change and cardiometabolic risk factors in obese and normal weight adults who are metabolically healthy: the atherosclerosis risk in communities study.

BACKGROUND/OBJECTIVES: Approximately 17% of obese Americans are free of the cardiometabolic risk factors, but few studies have compared responses to weight change in metabolically healthy obese (MHO) and metabolically healthy normal weight (MHNW) adults. We compared the impact of weight loss, weight maintenance and weight gain on cardiometabolic risk factors in the MHO and the MHNW. SUBJECTS/METHODS: Data were from the Atherosclerosis Risk in Communities (ARIC) study. Multiple observations on 2710 participants were included, yielding 4541 observations of sequential 3-year intervals. Metabolically healthy was defined as absence of all components of metabolic syndrome excluding waist circumference. Mixed effects models were used to compare changes in each of five cardiometabolic risk factors within weight change categories (<-3% for weight loss, ±3% for weight maintenance and >3% for weight gain). RESULTS: Weight loss was associated with comparable small changes or no changes in cardiometabolic risk factors in MHO and MHNW individuals. Weight gain was associated with larger increases in systolic (8.6 vs 6.2 mm Hg) and diastolic (3.9 vs 2.5 mm Hg) blood pressure, triglycerides (21.9 vs 15.8 mg/dl) and glucose (4.9 vs 1.9 mg/dl) in MHO individuals compared with MHNW individuals. Weight maintenance was associated with larger increases in triglycerides (10.0 vs 6.4 mg/dl) and glucose (1.7 vs 0.9 mg/dl) in MHO compared with MHNW individuals. MHO weight losers had more favorable changes in the five cardiometabolic risk factors compared to MHO weight maintainers (P<0.02) or gainers (P<0.0001). CONCLUSIONS: This work showed differences between MHNW and MHO adults and supports recommendations for weight loss in the MHO in order to avoid increases in risk factors associated with weight maintenance and weight gain.

Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA).

BACKGROUND: Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival. METHODS: In this USA multicentre population-based study, case participants (diagnosed during 1993-1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively. RESULTS: Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29-0.66) and OES (OR=0.43, 95% CI=0.26-0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42-0.95) and modestly for OEA (HR=0.87, 95% CI=0.60-1.26), but CIs were wide. CONCLUSIONS: Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.

Obesity Paradox should not interfere with public health efforts.

The Obesity Paradox could result in confusing messages that derail beneficial environmental changes and lead to reduced efforts by physicians to provide healthy lifestyle treatment plans to their obese patients. The Obesity Paradox applies in the main to individuals who have a disease, and therefore observed associations with mortality illustrating the Paradox may be more susceptible to certain types of bias than would be found in healthy individuals. Although individualization of weight loss advice for patients with serious disease is appropriate in medical settings, this does not supplant the need for general efforts to prevent and treat obesity.

Measurement of double-polarization asymmetries in the quasielastic (3)He[→](e[→],e(')d) process.

We present a precise measurement of double-polarization asymmetries in the ^{3}He[over →](e[over →],e^{'}d) reaction. This particular process is a uniquely sensitive probe of hadron dynamics in ^{3}He and the structure of the underlying electromagnetic currents. The measurements have been performed in and around quasielastic kinematics at Q^{2}=0.25(GeV/c)^{2} for missing momenta up to 270 MeV/c. The asymmetries are in fair agreement with the state-of-the-art calculations in terms of their functional dependencies on p_{m} and ω, but are systematically offset. Beyond the region of the quasielastic peak, the discrepancies become even more pronounced. Thus, our measurements have been able to reveal deficiencies in the most sophisticated calculations of the three-body nuclear system, and indicate that further refinement in the treatment of their two-and/or three-body dynamics is required.

Measurement of the target-normal single-spin asymmetry in deep-inelastic scattering from the reaction (3)He(↑)(e,e')X.

We report the first measurement of the target-normal single-spin asymmetry in deep-inelastic scattering from the inclusive reaction 3)He(↑)(e,e')X on a polarized (3)He gas target. Assuming time-reversal invariance, this asymmetry is strictly zero in the Born approximation but can be nonzero if two-photon-exchange contributions are included. The experiment, conducted at Jefferson Lab using a 5.89 GeV electron beam, covers a range of 1.72 GeV, which is nonzero at the 2.89σ level. Our measured asymmetry agrees both in sign and magnitude with a two-photon-exchange model prediction that uses input from the Sivers transverse momentum distribution obtained from semi-inclusive deep-inelastic scattering.

K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair.

DNA repair is essential for maintaining genomic stability, and defects in this process significantly increase the risk of cancer. Clear-cell renal cell carcinoma (CCRCC) caused by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is characterized by high genomic instability. However, the molecular mechanism underlying the association between the loss of VHL and genomic instability remains unclear. Here, we show that suppressor of cytokine signaling 1 (SOCS1) promotes nuclear redistribution and K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs). Loss of VHL or VHL mutations that compromise its K63-ubiquitylation attenuates the DNA-damage response (DDR), resulting in decreased homologous recombination repair and persistence of DSBs. These results identify VHL as a component of the DDR network, inactivation of which contributes to the genomic instability associated with CCRCC.

Beam-target double-spin asymmetry A{LT} in charged pion production from deep inelastic scattering on a transversely polarized {3}He target at 1.4

We report the first measurement of the double-spin asymmetry A{LT} for charged pion electroproduction in semi-inclusive deep-inelastic electron scattering on a transversely polarized {3}He target. The kinematics focused on the valence quark region, 0.16

Single spin asymmetries in charged pion production from semi-inclusive deep inelastic scattering on a transversely polarized 3He Target at Q2 = 1.4-2.7 GeV2.

We report the first measurement of target single spin asymmetries in the semi-inclusive (3)He(e,e'π(±))X reaction on a transversely polarized target. The experiment, conducted at Jefferson Lab using a 5.9 GeV electron beam, covers a range of 0.16 < x < 0.35 with 1.4 < Q(2) < 2.7 GeV(2). The Collins and Sivers moments were extracted from the azimuthal angular dependence of the measured asymmetries. The π(±) Collins moments for (3)He are consistent with zero, except for the π(+) moment at x = 0.35, which deviates from zero by 2.3σ. While the π(-) Sivers moments are consistent with zero, the π(+) Sivers moments favor negative values. The neutron results were extracted using the nucleon effective polarization and measured cross section ratios of proton to (3)He, and are largely consistent with the predictions of phenomenological fits and quark model calculations.

Long-term electromagnetic field treatment enhances brain mitochondrial function of both Alzheimer's transgenic mice and normal mice: a mechanism for electromagnetic field-induced cognitive benefit?

We have recently reported that long-term exposure to high frequency electromagnetic field (EMF) treatment not only prevents or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, but also improves memory in normal mice. To elucidate the possible mechanism(s) for these EMF-induced cognitive benefits, brain mitochondrial function was evaluated in aged Tg mice and non-transgenic (NT) littermates following 1 month of daily EMF exposure. In Tg mice, EMF treatment enhanced brain mitochondrial function by 50-150% across six established measures, being greatest in cognitively-important brain areas (e.g. cerebral cortex and hippocampus). EMF treatment also increased brain mitochondrial function in normal aged mice, although the enhancement was not as robust and less widespread compared to that of Tg mice. The EMF-induced enhancement of brain mitochondrial function in Tg mice was accompanied by 5-10 fold increases in soluble Aß1-40 within the same mitochondrial preparations. These increases in mitochondrial soluble amyloid-ß peptide (Aß) were apparently due to the ability of EMF treatment to disaggregate Aß oligomers, which are believed to be the form of Aß causative to mitochondrial dysfunction in Alzheimer's disease (AD). Finally, the EMF-induced mitochondrial enhancement in both Tg and normal mice occurred through non-thermal effects because brain temperatures were either stable or decreased during/after EMF treatment. These results collectively suggest that brain mitochondrial enhancement may be a primary mechanism through which EMF treatment provides cognitive benefit to both Tg and NT mice. Especially in the context that mitochondrial dysfunction is an early and prominent characteristic of Alzheimer's pathogenesis, EMF treatment could have profound value in the disease's prevention and treatment through intervention at the mitochondrial level.

Alcohol misuse in the general hospital: some hard facts.

AIMS: To examine (1) the prevalence of alcohol use disorders in adult general hospital inpatients; (2) the accuracy of documentation in relation to alcohol use. METHODS: A total of 210 random patients were interviewed out of 1,448 consecutive new admissions to CUH over 7 days. Case notes were reviewed for 206 (98%). Alcohol consumption was assessed using the Fast Alcohol Screening Test (FAST) and weekly drinking diary. FAST-positive (and a random sample of FAST-negative) patients then had a standardized interview. RESULTS: A total of 82% admitted for drinking alcohol. Among them 22% were drinking in excess of guidelines, 9% had DSM-IV Alcohol Abuse and 7% dependence. The sensitivity and specificity of the FAST for detecting those drinking above guidelines were 89 and 94% and for detecting a DSM-IV diagnosis was 100 and 73%. The majority of case notes contained inadequate information about alcohol intake. CONCLUSION: Alcohol use disorders are common and often undetected in the general hospital setting.

Validity of the GRACE (Global Registry of Acute Coronary Events) acute coronary syndrome prediction model for six month post-discharge death in an independent data set.

OBJECTIVE: To determine the validity of the GRACE (Global Registry of Acute Coronary Events) prediction model for death six months after discharge in all forms of acute coronary syndrome in an independent dataset of a community based cohort of patients with acute myocardial infarction (AMI). DESIGN: Independent validation study based on clinical data collected retrospectively for a clinical trial in a community based population and record linkage to administrative databases. SETTING: Study conducted among patients from the EFFECT (enhanced feedback for effective cardiac treatment) study from Ontario, Canada. PATIENTS: Randomly selected men and women hospitalised for AMI between 1999 and 2001. MAIN OUTCOME MEASURE: Discriminatory capacity and calibration of the GRACE prediction model for death within six months of hospital discharge in the contemporaneous EFFECT AMI study population. RESULTS: Post-discharge crude mortality at six months for the EFFECT study patients with AMI was 7.0%. The discriminatory capacity of the GRACE model was good overall (C statistic 0.80) and for patients with ST segment elevation AMI (STEMI) (0.81) and non-STEMI (0.78). Observed and predicted deaths corresponded well in each stratum of risk at six months, although the risk was underestimated by up to 30% in the higher range of scores among patients with non-STEMI. CONCLUSIONS: In an independent validation the GRACE risk model had good discriminatory capacity for predicting post-discharge death at six months and was generally well calibrated, suggesting that it is suitable for clinical use in general populations.

Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma.

Diarrhea is a major cause of morbidity and discomfort for patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). There are multiple causes of diarrhea in patients undergoing transplantation including antineoplastic chemotherapy, antimicrobials and infection, including Clostridium difficile as the most common pathogen involved. The purpose of this study was to determine the incidence of C. difficile-associated diarrhea (CDAD) 1 week before and 30 days after APBSCT, and to identify risk factors for the development of CDAD including diagnosis. Two hundred and forty-two patients underwent APBSCT for multiple myeloma and lymphoma between October 1996 and October 2001 in two teaching hospitals. Diarrhea was reported in 157 (64.9%) subjects. One hundred and thirty-five out of the 157 subjects were tested for the presence of C. difficile toxin A. These subjects constitute the study group. The incidence of CDAD was 15%. Two thirds of the patients who developed CDAD had multiple myeloma and one third had lymphoma; this difference did not attain statistical significance. The use of cephalosporins (P = 0.03) and the use of intravenous vancomycin (P = 0.02) were the only identified risk factors associated with the development of CDAD. Patients treated with paclitaxel as part of the mobilization regimen had a lower incidence of CDAD than patients who received hematopoietic growth factor only (P = 0.01).