Kristen Kasza

Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery

There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.

Outcome of Treatment for Congenital Toxoplasmosis, 1981–2004: The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study

Background Without treatment, congenital toxoplasmosis has recurrent, recrudescent, adverse outcomes. Long-term follow-up of infants with congenital toxoplasmosis treated throughout their first year of life with pyrimethamine and sulfadiazine has not been reported. Methods Between 1981 and 2004, one hundred twenty infants (current mean age +/- standard deviation, 10.5 +/- 4.8 years) with congenital toxoplasmosis were treated with 1 of 2 doses of pyrimethamine plus sulfadiazine; therapy was initiated shortly after birth and continued for 12 months. Children who received treatment were evaluated at birth and at predetermined intervals; the focus of the evaluations was on prespecified end points: motor abnormalities, cognitive outcome, vision impairment, formation of new eye lesions, and hearing loss. Results Treatment of infants without substantial neurologic disease at birth with pyrimethamine and sulfadiazine for 1 year resulted in normal cognitive, neurologic, and auditory outcomes for all patients. Treatment of infants who had moderate or severe neurologic disease (as defined in this article in the Treatments subsection of Methods) at birth resulted in normal neurologic and/or cognitive outcomes for >72% of the patients, and none had sensorineural hearing loss. Ninety-one percent of children without substantial neurologic disease and 64% of those with moderate or severe neurologic disease at birth did not develop new eye lesions. Almost all of these outcomes are markedly better than outcomes reported for children who were untreated or treated for 1 month in earlier decades (P .05). Conclusions Although not all children did well with treatment, the favorable outcomes we noted indicate the importance of diagnosis and treatment of infants with congenital toxoplasmosis.

Long-term Functional Results After Ileal Pouch Anal Restorative Proctocolectomy for Ulcerative Colitis: A Prospective Observational Study

Objective To document functional results in patients treated with an ileal pouch anal anastomosis (IPAA). Summary Background Data The restorative proctocolectomy with IPAA has become the procedure of choice for patients with ulcerative colitis, yet the long-term functional results are not well known. Methods We performed this prospective observational study in 391 consecutive patients (56% male; mean age, 33.7 ± 10.8 years; range, 12–66 years) who underwent an IPAA between 1987 and 2002 (mean follow-up, 33.6 months; range, 0 to 180 months). Results The majority of patients underwent the procedure under elective circumstances with a hand-sewn ileal pouch anal anastomosis and a protective ileostomy. In 25 patients (6.4%), the procedure was performed under urgent conditions; in 137 patients (35%), the temporary ileostomy was omitted; in 117 patients (29.9%), the ileal pouch anal anastomosis was stapled. There was 1 hospital mortality (0.25%) and 1 30-day mortality. Mean length of stay was 9.2 ± 5.6 days (3–68 days; median, 8 days) and was increased by the occurrence of septic complications (8.9 versus 13.6 days; P < 0.02) and by the omission of a temporary ileostomy (8.3 versus 10.4 days; P = 0.005). Complications included pelvic abscess (1.3%), anastomotic dehiscence (6.4%), bowel obstruction (11.7%), and anastomotic stenosis in need of mechanical dilatation (10.7%). Patients were asked to record their functional results on a questionnaire for 1 week at 3, 6, 9, 12, 18, and 24 months after the IPAA and yearly thereafter. Our data to 10 years show that median number of bowel movements (bms) was 6 bm/24 hours at all time intervals. The average number of bms increased by 0.3 bm/decade of life (P < 0.001). Throughout the entire follow-up, more than 75% of patients had at least 1 bm most nights, although fewer than 40% found it necessary to alter the time of their meals to avoid bms at inappropriate times. Depending on the time interval, between 57% and 78% of patients were always able to postpone a bm until convenient, and this ability was similar in patients with a stapled or hand-sewn ileoanal anastomosis; only up to 18% were able to always distinguish between flatus and stools, and this ability was similar in patients with a stapled or hand-sewn ileoanal anastomosis. Complete daytime and nighttime continence was achieved by 53–76% of patients depending on the time interval. The percentage of fully continent patients was higher following the stapled rather than the hand-sewn technique (P < 0.001), and this difference persisted over time. When patients experienced incontinence, its occurrence ameliorated over time (P < 0.001), and the occurrence of perianal rash and itching as well as the use of protective pads decreased over time (P < 0.008). At 5 years, patients judged quality of life as much better or better in 81.4% and overall satisfaction and overall adjustment as excellent or good in 96.3% and 97.5%, respectively. Conclusions We conclude that the IPAA confers a good quality of life. The majority of patients are fully continent, have 6 bms/d on average, and can defer a bm until convenient. When present, incontinence improves over time.

Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled Trial.

Context Consuming ginseng, a commonly used herbal dietary supplement, has been associated with a decrease in warfarins anticoagulant effect in at least 1 case report. Contribution Healthy volunteers took warfarin with and without concurrently taking ginseng. Ginseng consumption lowered the international normalized ratio and decreased plasma warfarin levels. Cautions Patients and physicians should be aware that ginseng is among many substances that can interfere with warfarins anticoagulant effect. The Editors The beneficial effects of several commonly used botanicals have been documented (1), but data on the safety of these herbs are limited. At least 16% of people using prescription medication concurrently take herbal supplements. An estimated 15 million Americans are at risk for herbdrug interactions (2). Advocated for almost every purpose, including maintaining general health, combating fatigue, and improving immune function (3), ginseng is one of the best-selling herbs in the United States (4). Herbs such as ginseng may interact with medications that have a narrow therapeutic index, such as warfarin, a commonly used oral anticoagulant (5, 6). A widely cited case report showed a substantial decrease in the anticoagulant effect of warfarin after ginseng consumption in a patient who was previously maintained with stable warfarin therapy (7). We conducted a randomized, double-blind, placebo-controlled trial to evaluate the potential interactions between American ginseng and warfarin. Methods Patients Nine men and 11 nonpregnant women (who were paid

Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: A trial of the Chicago, PMH, and California Phase II consortia

250 after trial completion) were enrolled in this study. Patients were screened with a medical history, physical examination, 12-lead resting electrocardiography, complete blood and platelet counts, international normalized ratio (INR) (the prothrombin time testcontrol ratio) (8), blood chemistry tests, and urinalysis. Patients agreed to abstain from tobacco products for at least 2 weeks before and during the study, abstain from alcohol and other medications during the study, and limit caffeine-containing products for 48 hours before and during the study. Protocol The institutional review board approved this 4-week study conducted at the University of Chicago Medical Center, Chicago, Illinois. All patients provided written, informed consent. Patients received oral warfarin, 5 mg daily, for the first 3 consecutive days during week 1. Beginning in week 2, patients were randomly assigned to receive either oral American ginseng, 1.0 g, or placebo, twice daily, for 3 consecutive weeks. During week 4, all patients again received oral warfarin, 5 mg daily, for the first 3 consecutive days (Appendix Figure). Ginseng or placebo assignment was determined by a table of random numbers with blocks of 8 (4 ginseng and 4 placebo assignments per block), from which sealed, opaque envelopes were prepared and opened sequentially as patients were enrolled in the study. A biostatistician who did not acquire data prepared the assignments. Patients and investigators were blinded to the treatment groups. Patients were instructed to eat a balanced diet to maintain a consistent amount of vitamin K and to avoid drastic changes in dietary habits. The daily intake of vitamin Kcontaining foods was recorded 1 week before the study to obtain the baseline value and to adjust the diet if vitamin K intake was high. Patients recorded their daily diet throughout the study period, completed a written weekly questionnaire, and were asked to report any adverse events. Blood samples were obtained at the same time (0.5 hour) on days 1, 3, 4, 5, and 7 of weeks 1 and 4 to measure INR and plasma warfarin levels (detection limit, 0.1 g/mL). Study Drugs Warfarin (3-(-acetonylbenzyl)-4-hydroxycoumarin or Coumadin, DuPont Pharmaceuticals, Wilmington, Delaware) is a racemic mixture composed of equal amounts of 2 optical isomers. In our laboratory, we ground the root of American ginseng (Panax quinquefolius, Wisconsin Ginseng Board, Wausau, Wisconsin) from 1 lot into a fine powder and placed 0.5 g in nontransparent capsules. Using a high-performance liquid chromatography method, we found that the total ginsenoside content was 5.19%. The constituent split was as follows: ginsenoside Rb1, 1.93%; Rb2, 0.20%; Rc, 0.61%; Rd, 0.42%; Re, 1.68%; and Rg1, 0.35%. We prepared identical placebo capsules that contained cornstarch powder. Statistical Analysis The primary end point of this study was the change in peak INR (week 4 week 1). Additional analysis end points were change in INR area under the curve (AUC) (week 4 week 1), defined as the area under the INR versus time curve; change in peak plasma warfarin level; change in warfarin AUC (week 4 week 1), defined as the area under the plasma warfarin level versus time curve; and weekly vitamin K intake. The AUC was calculated on the basis of the trapezoidal rule by using measurements for days 1 through 7. We compared changes in peak INR, INR AUC, peak plasma warfarin level, and warfarin AUC between the ginseng and placebo groups by using the Wilcoxon rank-sum test. We calculated the difference in median changes between the 2 groups and corresponding 95% CIs according to the method described by Hollander and Wolfe (9), which is based on consideration of all pairwise differences between the 2 sets of observations. We calculated the Spearman rank correlation coefficients to examine the correlation between the change in peak INR and change in peak plasma warfarin levels. Repeated-measures analysis of variance (ANOVA) models were used to test differences in vitamin K intake between the groups and over time. A P value less than 0.05 was considered statistically significant. Stata, version 8 (Stata Corp., College Station, Texas), and Minitab, version 13 (Minitab, Inc., State College, Pennsylvania), were used for statistical analysis. Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Data from all 20 patients (12 patients in the ginseng group and 8 patients in the placebo group) were used in the analysis. For the 6 men and 6 women in the ginseng group (7 patients were white, 3 patients were black, 1 patient was Hispanic, and 1 patient was Asian), the mean age and body weight (SD) were 30.2 7.2 years and 69.220.6 kg, respectively. For the 3 men and 5 women in the placebo group (3 patients were white, 2 patients were black, 2 patients were Hispanic, and 1 patient was Asian), the mean age and body weight (SD) were 24.3 4.0 years and 62.09.1 kg, respectively (Appendix Table). In both groups, INR generally reached peak levels on day 4 after 3 consecutive days of warfarin administration. The Figure shows changes in individual peak INR, INR AUC, peak plasma warfarin level, and warfarin AUC from weeks 1 to 4. The modest reduction in INR magnitude in the ginseng group was statistically significant compared with the change in the placebo group (P= 0.0012). Changes in INR AUC, peak plasma warfarin level, and warfarin AUC were also statistically significantly greater in the ginseng group. The Table summarizes results for the primary and secondary end points. Figure. Changes in individual peak international normalized ratio ( INR ), INR area under the curve ( AUC ), peak plasma warfarin level, and warfarin AUC in weeks 1 and 4 in American ginseng or placebo groups. A. P B. P C. P D. P Appendix Figure. Study flow chart showing American ginseng and placebo dosing and blood sample collection. Table. Changes in Peak International Normalized Ratio, International Normalized Ratio Area under the Curve, Peak Plasma Warfarin Level, and Warfarin Area under the Curve between Weeks 1 and 4 in American Ginseng and Placebo Groups Appendix Table. Patient Information For both peak warfarin level and AUC, the changes in the placebo group were not statistically significant and therefore probably reflected random variation in the small sample size. The Spearman rank correlation coefficient between changes in peak INR values and changes in peak warfarin levels was 0.72 (P< 0.001). One patient (patient 18) in the ginseng group had a high baseline INR (1.32) on day 1 compared with that in the other patients (mean INR [SD], 0.94 0.04). For this patient, peak INR after warfarin administration on day 4 was 5.16. After ginseng administration, the peak INR was 2.75 and the corresponding AUC decreased from 17.46 to 11.1. The patients peak plasma warfarin level also decreased from 1.6 g/mL during week 1 to 0.9 g/mL in week 4. If this patient is excluded from the analysis, the results remain statistically significant. No unusual medical or drug history or diet was noted for this patient. For weeks 1, 2, 3, and 4, average daily vitamin K intake (SD) for the ginseng group was 32.3 5.2 g/d, 42.6 7.6 g/d, 41.9 8.6 g/d, and 34.0 5.5 g/d, respectively. The average daily vitamin K intake (SD) for the placebo group for weeks 1, 2, 3, and 4 was 36.4 11.2 g/d, 32.0 8.4 g/d, 39.5 8.7 g/d, and 38.6 11.4 g/d, respectively. Vitamin K intake did not statistically significantly differ between the 2 groups (P> 0.2) or over time (P> 0.2). No adverse effects of clinical importance occurred in this study. Discussion Among the several different species of ginseng, the major active components are ginsenosides, which are a diverse group of steroidal saponins (3). Ginseng may promote bleeding in surgical patients (6). Ginsenosides prolonged both thrombin time and activated partial thromboplastin time in rats (10) and inhibited platelet aggregation in vitro in human platelets (11). In our healthy patients, however, ginseng reduced the anticoagulant effect of warfarin. We selected the commonly consumed American ginseng and a dose at the high end of the recommended range (12). Warfarin indirectly interferes with blood clotting by depressing the hepatic synthesis of vitamin Kdependent coagulation factors. The atte

Ambulatory Monitoring Detects Sorafenib-Induced Blood Pressure Elevations on the First Day of Treatment

OBJECTIVES The objectives of this phase II trial were to assess the activity and tolerability of the combination of bevacizumab and erlotinib in patients with recurrent ovarian, primary peritoneal or fallopian tube cancer. METHODS This was a single arm, multicenter phase II trial with overall objective response as the primary endpoint. Eligible patients had two or fewer prior chemotherapy regimens for recurrent or refractory disease and no prior anti-VEGF or anti-EGFR agents. Bevacizumab, 15 mg/kg, was administered intravenously every 21 days and erlotinib, 150 mg orally, was given daily. RESULTS Between July and October 2005, 13 patients were enrolled. There were two major objective responses, one complete response of 16+ month duration and one partial response of 11 month duration, for a response rate of 15% (95% CI 1.9% to 45.4%). Seven patients had a best response of stable disease. The most common grade 3 or 4 toxicities included anemia (n=1), nausea (n=2), vomiting (n=1), hypertension (n=1), and diarrhea (n=2). One patient with an ileostomy was removed from the study secondary to grade 3 diarrhea. Two patients had fatal gastrointestinal perforations. CONCLUSION There was no strong suggestion that this combination was superior to single agent bevacizumab, and the rate of gastrointestinal perforation was of concern. The study was therefore stopped. Identification of risk factors for gastrointestinal perforation will be of importance for the use of bevacizumab in the treatment of ovarian cancer.

Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection

Purpose: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. Experimental Design: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. Results: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, −5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, −4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). Conclusions: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy. (Clin Cancer Res 2009;15(19):6250–7)

Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior

BackgroundWorldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.MethodsTo better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5–12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or αPD1 ligand were studied.ResultsTwelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimers disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation.ConclusionIn outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.

Longitudinal Study of New Eye Lesions in Children with Toxoplasmosis Who Were Not Treated During the First Year of Life

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene × exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene × exposure interaction was detected. Exposed boys with the low-activity MAOA 5′ uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene–environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene × exposure interactions may shape behavior through associated changes in brain function.

Women who remember, women who do not: a methodological study of maternal recall of smoking in pregnancy.

PURPOSE To determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year. DESIGN Prospective longitudinal cohort study. METHODS Thirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii. RESULTS Twenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age. CONCLUSIONS More than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.