BACKGROUND

One in 7 US children and adolescents is obese, yet little is known about their health-related quality of life (QOL).

OBJECTIVE

To examine the health-related QOL of obese children and adolescents compared with children and adolescents who are healthy or those diagnosed as having cancer.

METHODS

Cross-sectional study of 106 children and adolescents (57 males) between the ages of 5 and 18 years (mean [SD], 12.1 [3] years), who had been referred to an academic children's hospital for evaluation of obesity between January and June 2002. Children and adolescents had a mean (SD) body mass index (BMI) of 34.7 (9.3) and BMI z score of 2.6 (0.5).

METHODS

Child self-report and parent proxy report using a pediatric QOL inventory generic core scale (range, 0-100). The inventory was administered by an interviewer for children aged 5 through 7 years. Scores were compared with previously published scores for healthy children and adolescents and children and adolescents diagnosed as having cancer.

RESULTS

Compared with healthy children and adolescents, obese children and adolescents reported significantly (P<.001) lower health-related QOL in all domains (mean [SD] total score, 67 [16.3] for obese children and adolescents; 83 [14.8] for healthy children and adolescents). Obese children and adolescents were more likely to have impaired health-related QOL than healthy children and adolescents (odds ratio [OR], 5.5; 95% confidence interval [CI], 3.4-8.7) and were similar to children and adolescents diagnosed as having cancer (OR, 1.3; 95% CI, 0.8-2.3). Children and adolescents with obstructive sleep apnea reported a significantly lower health-related QOL total score (mean [SD], 53.8 [13.3]) than obese children and adolescents without obstructive sleep apnea (mean [SD], 67.9 [16.2]). For parent proxy report, the child or adolescent's BMI z score was significantly inversely correlated with total score (r = -0.246; P =.01), physical functioning (r = -0.263; P<.01), social functioning (r = -0.347; P<.001), and psychosocial functioning (r = -0.209; P =.03).

CONCLUSIONS

Severely obese children and adolescents have lower health-related QOL than children and adolescents who are healthy and similar QOL as those diagnosed as having cancer. Physicians, parents, and teachers need to be informed of the risk for impaired health-related QOL among obese children and adolescents to target interventions that could enhance health outcomes.

OBJECTIVE

To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA).

METHODS

One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score.

RESULTS

The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of>>/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of>>/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups.

CONCLUSIONS

Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

OBJECTIVE

Previous investigations have shown that women undergoing chemotherapy for breast cancer experience both disturbed sleep and fatigue. However, most of the previous research examined women either during or after chemotherapy. This study examined sleep, fatigue, and circadian rhythms in women with breast cancer before the start of chemotherapy.

METHODS

Eighty five women with Stages I-IIIA breast cancer who were scheduled to begin adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Each had sleep/wake activity recorded with actigraphy for 72 consecutive hours and filled out questionnaires on sleep, fatigue, depression, and functional outcome.

RESULTS

On average, the women slept for about 6 h a night and napped for over an hour during the day. Sleep was reported to be disturbed and fatigue levels were high. Circadian rhythms were robust, but women who were more phase-delayed reported more daily dysfunction (p<0.01).

CONCLUSIONS

The data from the current study suggest that the women with breast cancer likely experience both disturbed sleep and fatigue before the beginning of chemotherapy. Although their circadian rhythms are robust, breast cancer patients with more delayed rhythms experience more daily dysfunction secondary to fatigue. These data suggest that strategies to improve disturbed sleep and to phase-advance circadian rhythms prior to initiation of chemotherapy may be beneficial in improving daily function in breast cancer patients.

BACKGROUND

Mechanisms involving oxidative stress and inflammation have been proposed to explain associations of ambient air pollution with cardiovascular morbidity and mortality. Experimental evidence suggests that organic components and ultrafine particles (UFP) are important.

METHODS

We conducted a panel study of 60 elderly subjects with coronary artery disease living in retirement communities within the Los Angeles, California, air basin. Weekly biomarkers of inflammation included plasma interleukin-6, tumor necrosis factor-alpha soluble receptor II (sTNF-RII), soluble platelet selectin (sP-selectin), and C-reactive protein (CRP). Biomarkers of erythrocyte antioxidant activity included glutathione peroxidase-1 and superoxide dismutase. Exposures included outdoor home daily particle mass [particulate matter < 0.25, 0.25-2.5, and 2.5-10 microm in aerodynamic diameter (PM(0.25), PM(0.25-2.5), PM(2.5-10))], and hourly elemental and black carbon (EC-BC), estimated primary and secondary organic carbon (OC(pri), SOC), particle number (PN), carbon monoxide (CO), and nitrogen oxides-nitrogen dioxide (NO(x)-NO(2)). We analyzed the relation of biomarkers to exposures with mixed effects models adjusted for potential confounders.

RESULTS

Primary combustion markers (EC-BC, OC(pri), CO, NO(x)-NO(2)), but not SOC, were positively associated with inflammatory biomarkers and inversely associated with erythrocyte anti-oxidant enzymes (n = 578). PN and PM(0.25) were more strongly associated with biomarkers than PM(0.25-2.5). Associations for all exposures were stronger during cooler periods when only OC(pri), PN, and NO(x) were higher. We found weaker associations with statin (sTNF-RII, CRP) and clopidogrel use (sP-selectin).

CONCLUSIONS

Traffic-related air pollutants are associated with increased systemic inflammation, increased platelet activation, and decreased erythrocyte antioxidant enzyme activity, which may be partly behind air pollutant-related increases in systemic inflammation. Differences in association by particle size, OC fraction, and seasonal period suggest components carried by UFP are important.

Delay discounting refers to the fact that an immediate reward is valued more than the same reward if it occurs some time in the future. To examine the neural substrates underlying this process, we studied 13 healthy volunteers who repeatedly had to decide between an immediate and parametrically varied delayed hypothetical reward using a delay discounting task during event-related functional magnetic resonance imaging. Subject's preference judgments resulted in different discounting slopes for shorter (<1 year) and for longer >> or =1 year) delays. Neural activation associated with the shorter delays relative to the longer delays was associated with increased activation in the head of the left caudate nucleus and putamen. When individuals selected the delayed relative to the immediate reward, a strong activation was found in bilateral posterior insular cortex. Several brain areas including the left caudate nucleus showed a correlation between the behaviorally determined discounting and brain activation for the contrast of intervals with delays <1 and>> or =1 year. These results suggest that (1) the posterior insula, which is a critical component of the decision-making neural network, is involved in delaying gratification and (2) the degree of neural activation in the striatum, which plays a fundamental role in reward prediction and in time estimation, may code for the time delay.

BACKGROUND

Biochemical, genetic, and clinical evidence indicates that smooth-muscle proliferation around small pulmonary vessels is an essential part of the pathogenesis of pulmonary hypertension. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been linked to familial cases of pulmonary hypertension, but the molecular basis of the common nonfamilial forms is unknown.

METHODS

We evaluated the pattern of expression of angiopoietin-1, a protein involved in the recruitment of smooth-muscle cells around blood vessels; TIE2, the endothelial-specific receptor for angiopoietin-1; and bone morphogenetic protein receptor type 1A (BMPR1A) and BMPR2 in lung-biopsy specimens from patients with pulmonary hypertension and from normotensive control patients. The effect of angiopoietin-1 on the modulation of BMPR expression was also evaluated in subcultures of human pulmonary arteriolar endothelial cells.

RESULTS

The expression of angiopoietin-1 messenger RNA and the protein itself and the phosphorylation of TIE2 were strongly up-regulated in the lungs of patients with various forms of pulmonary hypertension, correlating directly with the severity of disease. A mechanistic link between familial and acquired pulmonary hypertension was demonstrated by the finding that angiopoietin-1 shuts off the expression of BMPR1A, a transmembrane protein required for BMPR2 signaling, in pulmonary arteriolar endothelial cells. Similarly, we found that the expression of BMPR1A was severely reduced in the lungs of patients with various forms of acquired as well as primary nonfamilial pulmonary hypertension.

CONCLUSIONS

These findings suggest that all forms of pulmonary hypertension are linked by defects in the signaling pathway involving angiopoietin-1, TIE2, BMPR1A, and BMPR2 and consequently identify specific molecular targets for therapeutic intervention.

Motor adaptation to a novel dynamic environment is primarily thought of as a process in which the nervous system learns to anticipate the environmental forces to eliminate kinematic error. Here we show that motor adaptation can more generally be modeled as a process in which the motor system greedily minimizes a cost function that is the weighted sum of kinematic error and effort. The learning dynamics predicted by this minimization process are a linear, auto-regressive equation with only one state, which has been identified previously as providing a good fit to data from force-field-type experiments. Thus we provide a new theoretical result that shows how these previously identified learning dynamics can be viewed as arising from an optimization of error and effort. We also show that the coefficients of the learning dynamics must fall within a specific range for the optimization model to be valid and verify with experimental data from walking in a force field that they indeed fall in this range. Finally, we attempted to falsify the model by performing experiments in two conditions (repeated exposure to a force field, exposure to force fields of different strengths) for which the single-state, auto-regressive equation might be expected to not fit the data well. We found however that the equation adequately captured the pattern of errors and thus conclude that motor adaptation to a force field can be approximated as an optimization of effort and error for a range of experimental conditions.

The objective of this research was to determine the prevalence of retrospectively recalled childhood trauma among depressed patients and to examine the relationship between retrospective recall of childhood maltreatment and the onset, course, and severity of major depression in adulthood. Forty-seven adults with DSM-IV major depression and forty-one healthy comparison subjects were administered the Childhood Trauma Questionnaire (CTQ), a self-report measure of traumatic experiences in childhood. Age at onset of first depressive episode, number of lifetime depressive episodes, current depressive severity, and presence of lifetime anxiety and substance use comorbidity were determined for the depressed patients using the Structured Clinical Interview for DSM-IV. Patients with major depression recalled significantly more severe emotional abuse, emotional neglect, and physical abuse than the healthy comparison subjects. Among the depressed subjects, the severity of childhood trauma (most notably emotional abuse) predicted 25-28% of the variance in age at onset of first depressive episode (earlier onset) and number of lifetime depressive episodes (more episodes). Depressed patients with recall of childhood trauma also experienced a significantly greater number of comorbid mental disorders (2.9 vs. 1.9) than depressed patients without trauma histories. The findings must be tempered by the possibility of a recall bias toward more adverse childhood experiences in the depressed patients. To the extent that these data are valid, they suggest that childhood maltreatment may influence the onset, course, and comorbid character of major depression.

BACKGROUND

Subjective sleep disturbances have been associated with increased risk of coronary artery disease (CAD). We hypothesized that disrupted sleep as verified by polysomnography is associated with increased levels of prothrombotic hemostasis factors previously shown to predict CAD risk.

METHODS

Full-night polysomnography was performed in 135 unmedicated men and women (mean age +/- SD, 36.8 +/- 7.8 years) without a history of sleep disorders. Morning fasting plasma levels of von Willebrand Factor (VWF) antigen, soluble tissue factor (sTF) antigen, d-dimer, and plasminogen activator inhibitor (PAI)-1 antigen were determined. Statistical analyses were adjusted for age, gender, ethnicity, body mass index, BP, and smoking history.

RESULTS

Higher total arousal index (ArI) was associated with higher levels of VWF (beta = 0.25, p = 0.011, DeltaR(2) = 0.045), and longer wake after sleep onset was associated with higher levels of sTF (beta = 0.23, p = 0.023, DeltaR(2) = 0.038). More nighttime spent at mean oxygen saturation < 90% (beta = 0.20, p = 0.020, DeltaR(2) = 0.029) and higher apnea-hypopnea index (AHI) [beta = 0.19, p = 0.034, DeltaR(2) = 0.024] were associated with higher PAI-1. There was a trend for a relationship between mean oxygen desaturation < 90% and PAI-1 (p = 0.053), even after controlling for AHI. Total ArI (beta = 0.28, p = 0.005, DeltaR(2) = 0.056) and WASO (beta = 0.25, p = 0.017, DeltaR(2) = 0.042) continued to predict VWF and sTF, respectively, even after controlling for AHI.

CONCLUSIONS

Polysomnographically verified sleep disruptions were associated with prothrombotic changes. Measures of sleep fragmentation and sleep efficiency were related to VWF and sTF, respectively. Apnea-related measures were related to PAI-1. Our findings suggest that sleep disruptions, even in a relatively healthy population, are associated with potential markers of prothrombotic cardiovascular risk.

People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT>> 43) and the cut point based on the 95th percentile of healthy subjects (ALT>> 30 for men; ALT>> 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05-0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33-0.79).

CONCLUSIONS

Modest wine consumption is associated with reduced prevalence of suspected NAFLD. The current study supports the safety of one glass of wine per day for cardioprotection in patients at risk for both coronary heart disease and NAFLD.

BACKGROUND

The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a validated patient-reported outcome (PRO) containing both generic scales and scales specific to cystic fibrosis (CF). The minimal clinically important difference (MCID) score for a PRO corresponds to the smallest clinically relevant change a patient can detect. MCID scores for the CFQ-R respiratory symptom (CFQ-R-Respiratory) scale were determined using data from two 28 day, open-label, tobramycin inhalation solution (TIS) studies in patients with CF and chronic Pseudomonas aeruginosa airway infection. At study enrollment, patients in the study 1-exacerbation had symptoms indicative of pulmonary exacerbation (n = 84; < 14 years of age, 31 patients;>> or = 14 years of age, 53 patients); patients in study 2-stable had stable respiratory symptoms (n = 140; < 14 years of age, 14 patients;>> or = 14 years, 126 patients).

METHODS

The anchor-based method utilized a global rating-of-change questionnaire (GRCQ) that assessed patients' perceptions of change in their respiratory symptoms after TIS treatment. The mean change from baseline CFQ-R-Respiratory scores were mapped onto the GRCQ to estimate the MCID. The two distribution-based methods were as follows: (1) 0.5 SD of mean change in CFQ-R-Respiratory scores (baseline to end of TIS treatment); and (2) 1 SEM for baseline CFQ-R-Respiratory scores. Triangulation of these three estimates defined the MCIDs.

RESULTS

MCID scores were larger for patients in study 1-exacerbation (8.5 points) than for those in study 2-stable (4.0 points), likely reflecting differences in patient disease status (exacerbation/stable) between these studies.

CONCLUSIONS

Patient benefit from new and current CF therapies can be evaluated using changes in CFQ-R-Respiratory scores. Using the MCID provides a systematic way to interpret these changes, and facilitates the identification of CF treatments that improve both symptoms and physiologic variables, potentially leading to better treatment adherence and clinical outcomes. Trial registration (study 1-exacerbation): Australian-New Zealand Clinical Trials Registry Identifier: ACTRN 12605000602628 Trial registration (study 2-stable): ClinicalTrials.gov Identifier: NCT00104520.

Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.

Performance of automated methods to isolate brain from nonbrain tissues in magnetic resonance (MR) structural images may be influenced by MR signal inhomogeneities, type of MR image set, regional anatomy, and age and diagnosis of subjects studied. The present study compared the performance of four methods: Brain Extraction Tool (BET; Smith [2002]: Hum Brain Mapp 17:143-155); 3dIntracranial (Ward [1999] Milwaukee: Biophysics Research Institute, Medical College of Wisconsin; in AFNI); a Hybrid Watershed algorithm (HWA, Segonne et al. [2004] Neuroimage 22:1060-1075; in FreeSurfer); and Brain Surface Extractor (BSE, Sandor and Leahy [1997] IEEE Trans Med Imag 16:41-54; Shattuck et al. [2001] Neuroimage 13:856-876) to manually stripped images. The methods were applied to uncorrected and bias-corrected datasets; Legacy and Contemporary T1-weighted image sets; and four diagnostic groups (depressed, Alzheimer's, young and elderly control). To provide a criterion for outcome assessment, two experts manually stripped six sagittal sections for each dataset in locations where brain and nonbrain tissue are difficult to distinguish. Methods were compared on Jaccard similarity coefficients, Hausdorff distances, and an Expectation-Maximization algorithm. Methods tended to perform better on contemporary datasets; bias correction did not significantly improve method performance. Mesial sections were most difficult for all methods. Although AD image sets were most difficult to strip, HWA and BSE were more robust across diagnostic groups compared with 3dIntracranial and BET. With respect to specificity, BSE tended to perform best across all groups, whereas HWA was more sensitive than other methods. The results of this study may direct users towards a method appropriate to their T1-weighted datasets and improve the efficiency of processing for large, multisite neuroimaging studies.

Scanner-to-scanner variability of activation in multicenter fMRI studies is often considered undesirable. The purpose of this investigation was to evaluate the effect of a new procedure, "smoothness equalization", on reducing scanner differences in activation effect size as part of a multicenter fMRI project (FIRST BIRN). Five subjects were sent to 9 centers (10 scanners) and scanned on 2 consecutive days using a sensorimotor fMRI protocol. High-field (4 T and 3 T) and low-field (1.5 T) scanners from three vendors (GE, Siemens, and Picker) were included. The activation effect size of the scanners for the detection of neural activation during a sensorimotor task was evaluated as the percent of temporal variance accounted for by our model (percent of variance accounted for or PVAF). Marked scanner effects were noted for both PVAF as well as the degree of smoothness of the raw and processed images. After smoothness equalization, there was a dramatic (low field) or consistent (high-field) reduction in scanner-to-scanner variation of activation. It was shown that the likely basis of the scanner differences in smoothness was differences in k-space filtering algorithms. This work highlights the need to account for differences in smoothness when comparing scanners on activation effect size in multicenter fMRI studies.

OBJECTIVE

To evaluate magnetic resonance imaging (MRI)-determined proton density fat fraction (PDFF) reproducibility across two MR scanner platforms and, using MR spectroscopy (MRS)-determined PDFF as reference standard, to confirm MRI-determined PDFF estimation accuracy.

METHODS

This prospective, cross-sectional, crossover, observational pilot study was approved by an Institutional Review Board. Twenty-one subjects gave written informed consent and underwent liver MRI and MRS at both 1.5T (Siemens Symphony scanner) and 3T (GE Signa Excite HD scanner). MRI-determined PDFF was estimated using an axial 2D spoiled gradient-recalled echo sequence with low flip-angle to minimize T1 bias and six echo-times to permit correction of T2* and fat-water signal interference effects. MRS-determined PDFF was estimated using a stimulated-echo acquisition mode sequence with long repetition time to minimize T1 bias and five echo times to permit T2 correction. Interscanner reproducibility of MRI determined PDFF was assessed by correlation analysis; accuracy was assessed separately at each field strength by linear regression analysis using MRS-determined PDFF as reference standard.

RESULTS

1.5T and 3T MRI-determined PDFF estimates were highly correlated (r = 0.992). MRI-determined PDFF estimates were accurate at both 1.5T (regression slope/intercept = 0.958/-0.48) and 3T (slope/intercept = 1.020/0.925) against the MRS-determined PDFF reference.

CONCLUSIONS

MRI-determined PDFF estimation is reproducible and, using MRS-determined PDFF as reference standard, accurate across two MR scanner platforms at 1.5T and 3T.

The toxicity and pharmacokinetics of cis-diamminedichloroplatinum (cisplatin) (90 mg/sq m) administered as a single 4-hr peritoneal dialysis, with or without concurrent i.v. infusion of sodium thiosulfate, 0.43 or 2.13 g/sq m/hr for 12 hr, were studied on 20 courses of treatment. When given without thiosulfate, the toxicity of cisplatin was systemic rather than local, and the peritoneal cavity/plasma ratio of the area under the curve was 12. Addition of i.v. thiosulfate significantly reduced the nephrotoxicity. The concentration of cisplatin in the peritoneal cavity was sufficiently greater than that in the plasma to prevent thiosulfate, which equilibrated into the cavity, from interfering with the antitumor activity of cisplatin in the peritoneum. This study demonstrates a pharmacokinetic advantage of i.p. chemotherapy with cisplatin.

To assess the need for a trauma system in San Diego County, a concurrent audit of trauma care was performed by an independent consultant in 1982. During the study period from 15 March through 15 June 1982, 591 consecutive major trauma victims (MTV) were collected by the 30 participating hospitals. All medical records, including autopsy reports, were audited for the timeliness and appropriateness of diagnosis and definitive care. Deaths were classified as being not preventable, potentially salvageable, or preventable. A trauma system subsequently became functional on 1 August 1984, with five adult centers and one pediatric center. A Medical Audit Committee composed of physicians and nurses from designated and nondesignated hospitals was organized to perform a monthly concurrent audit of trauma care. Between 1 August and 31 December 1984, 1,366 MTV were triaged to trauma centers. The care of MTV was considered suboptimal in 32% of patients before regionalization, compared to 4.2% after regionalization (p less than 0.01). Preventable deaths occurred in 13.6% of fatalities occurring before implementation of a trauma system, compared to 2.7% after implementation (p less than 0.01). Regionalization of trauma care significantly reduced delays, inadequate care, and preventable deaths due to trauma.

OBJECTIVE

To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that correlate with differences in MSC effects.

METHODS

A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints.

RESULTS

Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral>> intra-arterial>> IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate>> rat>> mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥ 24 hours poststroke; results were overall very similar.

CONCLUSIONS

In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.

Nonalcoholic fatty liver disease (NAFLD) covers the spectrum of features found in liver laden with macrovesicular fat and variable degrees of inflammation, cell injury, and fibrosis. By definition, NAFLD excludes those with significant ingestion of alcohol or alternative potential cause of steatohepatitis. NAFLD develops with rare exception in children who are obese. Given the rapid rise in prevalence of obesity in children globally, NAFLD is now recognized as the most common cause of liver disease in pediatrics. In obese individuals, Hispanic ethnicity and male gender appear to increase risk. Recent studies suggest that insulin resistance and oxidative stress are important in pathogenesis. Treatment trials are underway to determine if reduction of insulin resistance or oxidative stress will favorably affect outcome. This review summarizes what is known about pediatric nonalcoholic steatohepatitis in terms of prevalence, demographics, clinical presentation, histology,pathogenesis, and treatment. Important differences between pediatric and adult fatty liver disease are highlighted.

BACKGROUND

Patients with chronic kidney disease are at increased risk for cardiovascular (CV) events.

METHODS

We randomly assigned 1,094 African Americans with hypertensive nephrosclerosis (glomerular filtration rate [GFR], 20 to 65 mL/min/1.73 m(2) [0.33 to 1.08 mL/s]) to initial antihypertensive treatment with either: (1) a beta-blocker, metoprolol; (2) an angiotensin-converting enzyme inhibitor, ramipril; or (3) a dihydropyridine calcium channel blocker, amlodipine, and either a usual-blood pressure (BP) or low-BP treatment goal. Using a design powered to detect renal outcome differences, we compared the effect of treatment on the CV event rate (cardiac death, myocardial infarction, stroke, and heart failure) during a mean follow-up period of 4.1 years and determined baseline factors that predict CV outcomes.

RESULTS

Thirty-one patients died of CV disease (0.7%/patient-year), and 149 patients experienced at least 1 CV outcome (3.3%/patient-year). Overall, 202 CV events (4.5%/patient-year) occurred. The CV outcome rate was not related significantly to randomized interventions. In multivariable analyses, 7 baseline risk factors remained independently associated with increased risk for the CV composite outcome after controlling for age, sex, baseline GFR, and baseline proteinuria group: pulse pressure, duration of hypertension, abnormal electrocardiogram result, non-high-density lipoprotein cholesterol level, serum urea nitrogen level, urine protein-creatinine ratio, urine sodium-potassium ratio, and annual income less than 15,000 dollars.

CONCLUSIONS

Neither randomized class of antihypertensive therapy nor BP level had a significant effect on the occurrence of CV events, possibly because of limited power. However, this analysis identifies unique and potentially modifiable CV risk factors in this high-risk cohort.

BACKGROUND

Postpartum depression (PPD) is common and has serious implications for the mother and her newborn infant. A possible link between placental corticotropin-releasing hormone (pCRH) and PPD incidence has been hypothesized, but empirical evidence is lacking.

OBJECTIVE

To determine whether accelerated increases in pCRH throughout pregnancy are associated with PPD symptoms.

METHODS

Pregnant women were recruited into this longitudinal cohort study. Blood samples were obtained at 15, 19, 25, 31, and 37 weeks' gestational age (GA) for assessment of pCRH, cortisol, and adrenocorticotropic hormone (ACTH). Depressive symptoms were assessed with a standardized questionnaire at the last 4 pregnancy visits and post partum.

METHODS

Subjects were recruited from 2 southern California medical centers, and visits were conducted in research laboratories.

METHODS

One hundred adult women with a singleton pregnancy. Main Outcome Measure Symptoms of PPD were assessed at a mean (SD) of 8.7 (2.94) weeks after delivery with the Edinburgh Postnatal Depression Scale.

RESULTS

Sixteen women developed PPD symptoms. At 25 weeks' GA, pCRH was a strong predictor of PPD symptoms (R(2) = 0.21; beta = 0.46 [P < .001]), an effect that remained significant after controlling for prenatal depressive symptoms. No significant associations were found for cortisol and ACTH. Receiver operating characteristic curve analyses revealed that pCRH at 25 weeks' GA is a possible diagnostic tool (area under the curve, 0.78 [P = .001]). Sensitivity (0.75) and specificity (0.74) at the ideal cutoff point (pCRH, 56.86 pg/mL) were moderate. Growth curve analyses indicated that the trajectories of pCRH in women with PPD symptoms are significantly accelerated from 23 to 26 weeks' GA.

CONCLUSIONS

At a critical period in midpregnancy, pCRH is a sensitive and specific early diagnostic test for PPD symptoms. If replicated, these results have implications for the identification and treatment of pregnant women at risk for PPD.

The relationship between insulin action and control of the adipocyte-derived factor adiponectin was studied in age- and weight-matched obese individuals with type 2 diabetes failing sulfonylurea therapy. After initial metabolic characterization, subjects were randomized to troglitazone or metformin treatment groups; all subjects received glyburide (10 mg BID) as well. Treatment was continued for 3 months. The extent of glycemic control after treatment was similar in both groups. However, the increase in maximal insulin-stimulated glucose disposal rate was greater following troglitazone therapy (+44%) compared with metformin treatment (+20%). Troglitazone treatment increased serum adiponectin levels nearly threefold. There was no change in serum adiponectin with metformin treatment. A positive correlation was found between increases in whole-body glucose disposal rates and serum adiponectin levels after troglitazone; no such relationship was seen with metformin. The adiponectin protein content of subcutaneous abdominal adipocytes was increased following troglitazone treatment and unchanged after metformin. Adiponectin release from adipocytes was also augmented with troglitazone treatment. Adiponectin was present in adipocytes and plasma in several multimeric forms; a trimer was the major form secreted from adipocytes. These results indicate that increases in adiponectin content and secretion are associated with improved insulin action but are not directly related to glycemic control. Modulation of adipocyte function, including upregulation of adiponectin synthesis and secretion, may be an important mechanism by which thiazolidinediones influence insulin action.