Parental recovered acute kidney injury causes prenatal renal dysfunction and fetal growth restriction with sexually dimorphic implications for adult offspring.

Introduction: Acute kidney injury (AKI) is rapidly increasing in global incidence and a healthcare burden. Prior maternal AKI diagnosis correlates with later pregnancy complications. As pregnancy influences developmental programming, we hypothesized that recovered parental AKI results in poor pregnancy outcomes, impaired fetal growth, and adult offspring disease. Methods: Using a well-characterized model of rhabdomyolysis-induced acute kidney injury (RIAKI), a form of AKI commonly observed in young people, we confirmed functional renal recovery by assessing glomerular filtration rate (GFR) 2 weeks following RIAKI. We bred sham and recovered RIAKI sires and dams in timed, matched matings for gestational day (GD) 16.5 and offspring (birth-12 weeks, 6 months) study. Results: Despite a normal GFR pre-pregnancy, recovered RIAKI dams at GD16.5 had impaired renal function, resulting in reduced fetoplacental ratios and offspring survival. Pregnant RIAKI dams also had albuminuria and less renal megalin in the proximal tubule brush border than shams, with renal subcapsular fibrosis and higher diastolic blood pressure. Growth-restricted offspring had a reduced GFR as older adults, with evidence of metabolic inefficiency in male offspring; this correlated with reduced renal AngII levels in female offspring from recovered RIAKI pairings. However, the blood pressures of 6-month-old offspring were unaffected by parental RIAKI. Conclusions: Our mouse model demonstrated a causal relationship among RIAKI, gestational risk, and developmental programming of the adult-onset offspring GFR and metabolic dysregulation despite parental recovery.

Legal Performance-enhancing Drugs Alter Course and Treatment of Rhabdomyolysis-induced Acute Kidney Injury.

INTRODUCTION: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment. MATERIALS AND METHODS: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours. RESULTS: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI. CONCLUSIONS: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.

Metformin Impacts Human Syncytiotrophoblast Mitochondrial Function from Pregnancies Complicated by Obesity and Gestational Diabetes Mellitus in a Sexually Dimorphic Manner.

Maternal obesity and gestational diabetes mellitus (GDM) are associated with placental dysfunction, small for gestational age (SGA) offspring, and programming of adult-onset disease. We examine how metformin, commonly used to treat type A2 GDM, affects placental metabolism as well as mitochondrial content and function. Syncytiotrophoblasts (STBs) were prepared from placentas of male and female fetuses collected at term cesarean section from lean (pre-pregnancy BMI < 25), obese (BMI > 30), and obese A2GDM women. Metformin treatment (0.001-10 mM) of STB caused no change in non-mitochondrial respiration but significant concentration-dependent (1 and 10 mM) decreases in basal, maximal, and ATP-linked respiration and spare capacity. Respiration linked to proton leak was significantly increased in STB of male A2GDM placentas at low metformin concentrations. Metformin concentrations ≥1 mM increased glycolysis in STB from placentas from lean women, but only improved glycolytic capacity in female STB. Whereas metformin had little effect on superoxide generation from male STB of any group, it gave a concentration-dependent decrease in superoxide generation from female STB of lean and obese women. Fewer mitochondria were observed in STB from obese women and male STB from lean women with increasing metformin concentration. Metformin affects STB mitochondrial function in a sexually dimorphic manner but at concentrations above those reported in maternal circulation (approximately 0.01 mM) in women treated with metformin for GDM.

Harm! foul! How acute kidney injury SHReDDs patient futures.

PURPOSE OF REVIEW: Transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is increasingly accepted. Less well recognized, but supported by very similar data, is development of disease of other organ systems after AKI. Awareness of other-organ sequelae of AKI may inform efforts to improve the care of patients after AKI. RECENT FINDINGS: Stroke, hypertension, reproductive risk, dementia, and death (SHReDD) are sequelae, which occur with increased risk relative to that of non-AKI within 6 months-3 years after AKI diagnosis, and which are supported by preclinical/mechanistic study. Adjusted hazard ratios for these sequelae are strikingly similar to that of AKI-CKD, ranging from 1.2 to 3.0. Mechanistic studies suggest kidney-centric mechanisms including sodium regulation, volume status regulation, and the renin-angiotensin system are drivers of long-term, extra-renal, change. SUMMARY: Further clinical characterization and mechanistic insight is necessary, and may have considerable translational impact. Programs which screen or follow post-AKI patients may increase clinical utility if focus is expanded to include the SHReDD complications.

Molecular Mechanisms of Rhabdomyolysis-Induced Kidney Injury: From Bench to Bedside.

Rhabdomyolysis-induced acute kidney injury (RIAKI) occurs following damage to the muscular sarcolemma sheath, resulting in the leakage of myoglobin and other metabolites that cause kidney damage. Currently, the sole recommended clinical treatment for RIAKI is aggressive fluid resuscitation, but other potential therapies, including pretreatments for those at risk for developing RIAKI, are under investigation. This review outlines the mechanisms and clinical significance of RIAKI, investigational treatments and their specific targets, and the status of ongoing research trials.

Nano-Theranostic Modality for Visualization of the Placenta and Photo-Hyperthermia for Potential Management of Ectopic Pregnancy.

Ectopic pregnancy (EP) is the leading cause of maternity-related death in the first trimester of pregnancy. Approximately 98% of ectopic implantations occur in the fallopian tube, and expedient management is crucial for preventing hemorrhage and maternal death in the event of tubal rupture. Current ultrasound strategies misdiagnose EP in up to 40% of cases, and the failure rate of methotrexate treatment for confirmed EP exceeds 10%. Here the first theranostic strategy for potential management of EP is reported using a near-infrared naphthalocyanine dye encapsulated within polymeric nanoparticles. These nanoparticles preferentially accumulate in the developing murine placenta within 24 h following systemic administration, and enable visualization of implantation sites at various gestational stages via fluorescence and photoacoustic imaging. These nanoparticles do not traverse the placental barrier to the fetus or impact fetal development. However, excitation of nanoparticles localized in specific placentas with focused NIR light generates heat (>43 °C) sufficient for disruption of placental function, resulting in the demise of targeted fetuses with no effect on adjacent fetuses. This novel approach would enable diagnostic confirmation of EP when current imaging strategies are unsuccessful, and elimination of EP could subsequently be achieved using the same nano-agent to generate localized hyperthermia resulting in targeted placental impairment.

Delineation of blacktip shark (Carcharhinus limbatus) nursery habitats in the north-western Gulf of Mexico.

Coevolution with predators leads to the use of low-risk habitats by many prey species, which promotes survival during early developmental phases. These nurseries are valued by conservation and management agencies because of their contributions to adult populations. However, the physical and geographic characteristics, like shallow depths and isolation from other marine habitats, that restrict access to predators and thereby reduce risk to juvenile animals can also limit scientific research. Consequently, many nursery habitats are still unidentified and understudied. Here we used gillnet monitoring from 1982 to 2018 to delineate blacktip shark (Carcharhinus limbatus) nurseries in the north-western Gulf of Mexico and elucidated their physical, environmental and biological characteristics. Nursery habitats within estuaries (<2% of spatial area) were proximate to the Gulf of Mexico and exhibited significantly lower variability in salinity than non-nurseries. However, relative abundances of predators and prey were not significant delineators of nursery habitats. As such, food and risk may not influence juvenile blacktip habitat use as expected. Alternatively, reduced osmoregulatory stress attributed to predictable environments likely provides advantageous conditions for blacktips to develop foraging and antipredator tactics, which is vital prior to the winter migration of juvenile sharks into the Gulf of Mexico.

Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice.

BACKGROUND: Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate CKD. Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells. METHODS: To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14-32 weeks old) with proximal tubule-specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation. RESULTS: Inducible proximal tubule-specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved GFR, reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion. CONCLUSIONS: We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.

Male fetal sex affects uteroplacental angiogenesis in growth restriction mouse model†.

Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[-6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer (uNK) cell phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional microcomputed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.

Placental mitochondrial dysfunction with metabolic diseases: Therapeutic approaches.

Both obesity and gestational diabetes mellitus (GDM) lead to poor maternal and fetal outcomes, including pregnancy complications, fetal growth issues, stillbirth, and developmental programming of adult-onset disease in the offspring. Increased placental oxidative/nitrative stress and reduced placental (trophoblast) mitochondrial respiration occur in association with the altered maternal metabolic milieu of obesity and GDM. The effect is particularly evident when the fetus is male, suggesting a sexually dimorphic influence on the placenta. In addition, obesity and GDM are associated with inflexibility in trophoblast, limiting the ability to switch between usage of glucose, fatty acids, and glutamine as substrates for oxidative phosphorylation, again in a sexually dimorphic manner. Here we review mechanisms underlying placental mitochondrial dysfunction: its relationship to maternal and fetal outcomes and the influence of fetal sex. Prevention of placental oxidative stress and mitochondrial dysfunction may improve pregnancy outcomes. We outline pathways to ameliorate deficient mitochondrial respiration, particularly the benefits and pitfalls of mitochondria-targeted antioxidants.

Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice.

Fetal growth restriction (FGR) is associated with developmental programming of adult onset hypertension, which may be related to differences in nephron development. Prior studies showed that maternal nutrient restriction is associated with reduced nephrogenesis in rodents, especially in male progeny. We hypothesized that maternal genetic risk for FGR may similarly affect fetal kidney development, leading to adult onset hypertension. We employed an angiotensinogen (AGT) gene titration transgenic (TG) construct with 3 copies of the mouse AGT gene that mimics a common human genotype (AGT A[-6]G) associated with FGR. We investigated whether FGR in 2-copy (wild type, [WT]) progeny from 3-copy TG dams leads to developmental programming differences in kidney development and adult blood pressure compared with age- and sex-matched controls. Progeny were tested in the late fetal period (e17.5), neonatal period (2 weeks of age), and as young adults (12 weeks). We measured weights, tested for renal oxidative stress, compared renal DNA methylation profiles, counted the number of glomeruli, and measured adult blood pressure ± stress. Progeny from TG dams were growth restricted with evidence of renal oxidative stress, males showed fetal renal DNA hypermethylation, they had fewer glomeruli, and they developed stress-induced hypertension as adults. Their female siblings did not share this pathology and instead resembled progeny from WT dams. Surprisingly, glomerular counts in the neonatal period were not different between sexes or maternal genotypes. In turn, we suspect that differences in fetal renal DNA methylation may affect the long-term viability of glomeruli, rather than reducing nephrogenesis.

The role of coagulation and platelets in colon cancer-associated thrombosis.

Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.

Online Dissemination Strategies of a Canada Research Chair: Overview and Lessons Learned.

BACKGROUND: Little is known about the use of online dissemination strategies, such as websites and social media, to increase the visibility and uptake of research. OBJECTIVE: To describe two online dissemination strategies of the Canada Research Chair in Implementation of Shared Decision Making in Primary Care over an eight-year period. METHODS: Our two sources of online dissemination data were the website of the Canada Research Chair in Implementation of Shared Decision Making in Primary Care and the Chair's Twitter account. We conducted a content analysis of the news section of the website. We extracted website usage statistics using Google Analytics and analyzed indicators such as total number of visits, new and returning visitors, page views per visit, time spent onsite per visit, visitors' country of origin, and most popular pages. From the Chair's Twitter account, we collected the number of tweets, followers, and follows. We consulted Google Scholar to chart the trend in citations of the Chair's articles over the same period. RESULTS: From the website's inception in January 2008 to December 2015, we recorded an average of 7906 visits per year (3809 in 2008; 8874 in 2015), 65.85% of which involved new visitors (5206/7906). The average number of pages viewed per visit was 3.2 and average bounce rate was 57.87% (4575/7906). Visitors spent an average of two minutes and 12 seconds per visit. We computed visits from 162 countries, with the majority from Canada (5910/7906, 74.75%). In order of frequency, the seven most visited pages were: (1) home page with news of publications and grants (24,787 visits), (2) profile of Chairholder (8041 visits), (3) profiles of research team members (6272 visits), (4) list of research team members (4593 visits), (5) inventory of shared decision making (SDM) programs (1856 visits), (6) interprofessional approaches to SDM (1689 visits), and (7) description of Chair activities (1350 visits). From the inception of the Twitter account in April 2011 to November 30, 2016 we recorded 5831 tweets in French and English, 1679 followers, and 1112 follows. The total number of visits and visitors to the website increased during the first three years, stabilized, and then dropped slightly, while the number of returning visitors rose slightly. In comparison, citations of the Chair's articles increased steadily over the same period, rising more sharply as visits to the website declined. CONCLUSIONS: Over an eight-year period, visitors to the website increased in the first three years before levelling off. Meanwhile, the Chair's citations rose continuously. There was no observable association between website visits or Twitter activity and rising citations. Our results suggest that online dissemination may not yet be a major determinant of research uptake or visibility in the scientific community.

Do choosing wisely tools meet criteria for patient decision aids? A descriptive analysis of patient materials.

OBJECTIVES: Choosing Wisely is a remarkable physician-led campaign to reduce unnecessary or harmful health services. Some of the literature identifies Choosing Wisely as a shared decision-making approach. We evaluated the patient materials developed by Choosing Wisely Canada to determine whether they meet the criteria for shared decision-making tools known as patient decision aids. DESIGN: Descriptive analysis of all Choosing Wisely Canada patient materials. DATA SOURCE: In May 2015, we selected all Choosing Wisely Canada patient materials from its official website. MAIN OUTCOMES AND MEASURES: Four team members independently extracted characteristics of the English materials using the International Patient Decision Aid Standards (IPDAS) modified 16-item minimum criteria for qualifying and certifying patient decision aids. The research team discussed discrepancies between data extractors and reached a consensus. Descriptive analysis was conducted. RESULTS: Of the 24 patient materials assessed, 12 were about treatments, 11 were about screening and 1 was about prevention. The median score for patient materials using IPDAS criteria was 10/16 (range: 8-11) for screening topics and 6/12 (range: 6-9) for prevention and treatment topics. Commonly missed criteria were stating the decision (21/24 did not), providing balanced information on option benefits/harms (24/24 did not), citing evidence (24/24 did not) and updating policy (24/24 did not). Out of 24 patient materials, only 2 met the 6 IPDAS criteria to qualify as patient decision aids, and neither of these 2 met the 6 certifying criteria. CONCLUSIONS: Patient materials developed by Choosing Wisely Canada do not meet the IPDAS minimal qualifying or certifying criteria for patient decision aids. Modifications to the Choosing Wisely Canada patient materials would help to ensure that they qualify as patient decision aids and thus as more effective shared decision-making tools.

Improving Decision Making about Genetic Testing in the Clinic: An Overview of Effective Knowledge Translation Interventions.

BACKGROUND: Knowledge translation (KT) interventions are attempts to change behavior in keeping with scientific evidence. While genetic tests are increasingly available to healthcare consumers in the clinic, evidence about their benefits is unclear and decisions about genetic testing are thus difficult for all parties. OBJECTIVE: We sought to identify KT interventions that involved decisions about genetic testing in the clinical context and to assess their effectiveness for improving decision making in terms of behavior change, increased knowledge and wellbeing. METHODS: We searched for trials assessing KT interventions in the context of genetic testing up to March 2014 in all systematic reviews (n = 153) published by two Cochrane review groups: Effective Practice and Organisation of Care (EPOC) and Consumers and Communication. RESULTS: We retrieved 2473 unique trials of which we retained only 28 (1%). Two EPOC reviews yielded two trials of KT interventions: audit and feedback (n = 1) and educational outreach (n = 1). Both targeted health professionals and the KT intervention they assessed was found to be effective. Four Consumers and Communication reviews yielded 26 trials: decision aids (n = 15), communication of DNA-based disease risk estimates (n = 7), personalized risk communication (n = 3) and mobile phone messaging (n = 1). Among these, 25 trials targeted only health consumers or patients and the KT interventions were found to be effective in four trials, partly effective in seven, and ineffective in four. Lastly, only one trial targeted both physicians and patients and was found to be effective. CONCLUSIONS: More research on the effectiveness of KT interventions regarding genetic testing in the clinical context may contribute to patients making informed value-based decisions and drawing the maximum benefit from clinical applications of genetic and genomic innovations.

Hybrid Capture 2 is as effective as PCR testing for high-risk human papillomavirus in head and neck cancers.

High-risk human papillomavirus (HPV) infection is a common cause of oropharyngeal squamous cell carcinoma, especially in young male nonsmokers. Accurately diagnosing HPV-associated oral cancers is important, because they have a better prognosis and may be treated differently than smoking-related oral carcinomas. Various methods have been validated to test for high-risk HPV in cervical tissue samples, and they are in routine clinical use to detect dysplasia before it progresses to invasive disease. Similarly, future screening for HPV-mediated oropharyngeal dysplasia may identify patients before it progresses. Our objective was to compare 4 of these methods in a retrospective series of 87 oral and oropharyngeal squamous cell carcinomas that had archived fresh-frozen and paraffin-embedded tissue for evaluation. Patient age, sex, smoking history, and tumor location were also recorded. DNA prepared from fresh-frozen tissue was tested for HPV genotypes by multiplex polymerase chain reaction analysis, and high-risk HPV screening was carried out using Hybrid Capture 2 and Cervista. Histologic sections were immunostained for p16. HPV-positive outcome was defined as agreement between at least 2 of the 3 genetic tests and used for χ analysis and calculations of diagnostic predictive value. As expected, high-risk HPV-positive oral cancers were most common in the tonsil and base of the tongue (oropharynx) of younger male (55 vs. 65 y) (P=0.0002) nonsmokers (P=0.01). Most positive cases were HPV16 (33/36, 92%). Hybrid Capture 2 and Cervista were as sensitive as polymerase chain reaction and had fewer false positives than p16 immunohistochemical staining.

Investigation of Mn, Fe, and Ni incorporation in CeCo2Al8.

Single crystals of CeCo(2-x)M(x)Al(8) (M = Mn, Fe, Ni; 0 ≤ x < 1) were grown and characterized by X-ray diffraction and magnetic susceptibility. The unit cell volumes of Mn-doped compounds increase and those of Ni-doped compounds decrease with increasing dopant concentration. All samples display a magnetic ordering near 6 K with magnetic moments of the analogues ranging from 2.61 to 2.81 µ(B)/mol Ce and slightly higher than Ce(3+) only magnetic moment. The unit cell volumes of Fe-doped compounds also increase with increasing Fe concentration. However, the cell volume of CeCo(2-x)Fe(x)Al(8) decreases for x = 1.00 and is not Curie-Weiss possibly because of valence fluctuation.