Search

This study tested the feasibility and initial efficacy of a cognitive-behavioral summer treatment (summerMAXyc) for high-functioning young children, ages 4–6 years, with ASD (HFASD; without intellectual disability). The treatment was conducted 5 days per week, 6 h per day, over 5 weeks in the summer and included skills instruction and therapeutic activities targeting social/social-communication skills, facial-emotion recognition, and interest expansion. Skills instruction sessions and therapeutic activities utilized direct instruction, modeling, role-play, performance feedback, and repeated practice. A behavioral system was also implemented to increase skills development and reduce ASD symptoms and disruptive behaviors, and parents participated in weekly parent training. Feasibility was supported in high levels of treatment fidelity and child, parent, and staff clinician satisfaction, and there was no attrition or adverse events/responses. Results of the primary outcome measure (coding of the children’s social performance by naive raters) indicated that 10 of the 12 children were treatment responders (d = 1.76). Significant post-treatment improvements were also found on secondary measures (parent and staff clinician ratings) of social/social-communication skills and ASD symptoms, as well as a range of adaptive behaviors (effect sizes in the medium and large ranges). Results supported the feasibility of the treatment and suggested that it may yield positive outcomes for 4–6 year olds with HFASD. Recommendations for ongoing testing are provided.

BACKGROUND AND OBJECTIVES Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Screening and treatment reduces this risk, but requires multiple examinations of infants, most of whom will not develop severe disease. Previous work has suggested that artificial intelligence may be able to detect incident severe disease (treatment-requiring retinopathy of prematurity [TR-ROP]) before clinical diagnosis. We aimed to build a risk model that combined artificial intelligence with clinical demographics to reduce the number of examinations without missing cases of TR-ROP. METHODS Infants undergoing routine ROP screening examinations (1579 total eyes, 190 with TR-ROP) were recruited from 8 North American study centers. A vascular severity score (VSS) was derived from retinal fundus images obtained at 32 to 33 weeks’ postmenstrual age. Seven ElasticNet logistic regression models were trained on all combinations of birth weight, gestational age, and VSS. The area under the precision-recall curve was used to identify the highest-performing model. RESULTS The gestational age + VSS model had the highest performance (mean ± SD area under the precision-recall curve: 0.35 ± 0.11). On 2 different test data sets (n = 444 and n = 132), sensitivity was 100% (positive predictive value: 28.1% and 22.6%) and specificity was 48.9% and 80.8% (negative predictive value: 100.0%). CONCLUSIONS Using a single examination, this model identified all infants who developed TR-ROP, on average, >1 month before diagnosis with moderate to high specificity. This approach could lead to earlier identification of incident severe ROP, reducing late diagnosis and treatment while simultaneously reducing the number of ROP examinations and unnecessary physiologic stress for low-risk infants.

Objective: To review efficacy, safety, and place in therapy of solriamfetol for management of excessive daytime sleepiness (EDS) in patients with narcolepsy and obstructive sleep apnea (OSA). Methods: PubMed (1966 to January 2021) was searched using the terms solriamfetol, JZP-110, ADX-N05 and Sunosi. Human studies published in peer-reviewed medical journals in English language were reviewed. Results: The efficacy and safety of solriamfetol has been reported in 2 phase II trials and 4 phase III trials (TONES 2, TONES 3, TONES 4, and TONES 5). Statistically significant improvements in the maintenance of wakefulness test were reported with solriamfetol 150 mg and 300 mg vs placebo in participants with narcolepsy (7.65- to 10.14-minute difference from placebo). In subjects with OSA, statistically significant improvements in maintenance of wakefulness test difference from placebo were also observed in those taking solriamfetol 75 mg, 150 mg, or 300 mg vs placebo (4.5- to 12.8-minute difference from placebo). Statistically significant reductions in Epworth Sleepiness Scale scores were also reported in phase III trials in subjects with narcolepsy or OSA taking solriamfetol vs placebo (ranging from − 4.7 to − 1.9 difference from placebo). Common adverse events in reported in phase III trials were headache, nausea, decreased appetite, anxiety, dry mouth, and diarrhea. Solriamfetol appears to have a reduced risk for drug interactions and fewer adverse effects compared to other agents available for management of EDS in patients with narcolepsy and OSA. Conclusions: Solriamfetol is an effective option for management of EDS in patients with narcolepsy and OSA.

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of long chain fatty acid oxidation with a very high mortality rate due to cardiomyopathy or multiorgan failure. We present the course of a very premature infant with early onset CACT deficiency complicated by multiple episodes of necrotizing enterocolitis, sepsis, and liver insufficiency, followed by eventual demise. The complications of prematurity, potentiated by the overlay of CACT deficiency, contributed to the difficulty of reaching the ultimate diagnosis of CACT deficiency.

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine–glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

Objective: To review the efficacy, safety, and place in therapy of ixekizumab for the treatment of moderate to severe plaque psoriasis. Data Sources: PubMed (1966 to July 2018) and clinicaltrials.gov were searched using the terms ixekizumab, LY2439821, interleukin-17, and psoriasis. Study Selection and Data Extraction: Human studies published in peer-reviewed medical journals in English were used. Data Synthesis: The efficacy and safety of ixekizumab has been primarily reported by 4 phase III trials (UNCOVER-1, UNCOVER-2, UNCOVER-3, and UNCOVER-J) and multiple post hoc analyses. The average proportions of patients achieving a 75%, 90%, and 100% reduction in their Psoriasis Area and Severity Index (PASI) were 89%, 70%, and 38%, respectively, after 12 weeks of therapy. PASI75 was maintained for up to 3 years in 80.5% of participants. Ixekizumab was statistically significantly more effective than ustekinumab, with 76.5%, compared with 59%, of patients achieving PASI90 in 52 weeks. The most common adverse events include nasopharyngitis (14.1%), upper respiratory tract infections (7.9%), and injection-site reactions (6.8%), which are similar to that for other biological agents. The risk of inflammatory bowel disease may be increased with ixekizumab. Relevance to Patient Care and Clinical Practice: This review summarizes and evaluates clinical data regarding the efficacy and safety of ixekizumab and discusses relevant differences compared with other biological agents used for the management of chronic plaque psoriasis. Conclusions: Ixekizumab is a highly efficacious and well-tolerated treatment option for patients with moderate to severe plaque psoriasis.

Objectives To determine fluorescently labeled aerolysin (FLAER) binding and glycophosphatidylinositol–anchored protein expression in bone marrow (BM) cells of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) detected in peripheral blood (PB); compare PNH clone size in BM and PB; and detect PNH in BM by commonly used antibodies. Methods Flow cytometry analysis of FLAER binding to leukocytes and expression of CD55/CD59 in erythrocytes. Analysis of CD16 in neutrophils and CD14 in monocytes in BM. Results FLAER binds to all normal BM leukocytes, and binding increases with cell maturation. In PNH, lymphocytic clones are consistently smaller than clones of other BM cells. PNH clones are detectable in mature BM leukocytes with high specificity and sensitivity using common antibodies. Conclusions PNH clone sizes measured in mature BM leukocytes and in PB are comparable, making BM suitable for PNH assessment. We further demonstrate that commonly used reagents (not FLAER or CD55/CD59) can reliably identify abnormalities of BM neutrophils and monocytes consistent with PNH cells.

Objective To evaluate if premature infants delivered ≤7 days after rescue antenatal steroid treatment (ideal treatment) have increased passive respiratory compliance compared to those delivered ˃7 days after treatment (remote treatment). Methods Secondary analysis of a randomized trial of rescue antenatal steroids on respiratory compliance. Infants in the treatment group were stratified by the interval between rescue antenatal steroids and delivery. We then compared the respiratory compliance in the ideal versus remote groups. Results 44 women (56 infants) received rescue antenatal steroids. 49 infants had evaluable respiratory compliance measurements, with 27 (GA 30.0 weeks, BW 1362g) “ideally” treated, and 22 (GA 33.8 weeks, BW 2248g) “remotely” treated. Respiratory compliance was significantly higher for the ideal compared to the remote group (1.32 vs 1.06 mL/cm H20/kg; p = 0.037). Conclusion Infants treated with rescue antenatal steroids have a significantly higher respiratory compliance if delivery occurs within 7 days after treatment.

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2(ne/ne) and 1% of Fras1(Q1263*/Q1263*) mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

Objective/Purpose Retinopathy of prematurity (ROP) is a leading cause of childhood blindness related to oxygen exposure to the developing retina in premature infants. Since oxygen monitoring protocols have reduced the incidence of treatment-requiring ROP (TR-ROP), it remains unclear whether oxygen exposure remains a relevant risk factor for incident TR-ROP and aggressive ROP (A-ROP), a severe, rapidly progressing form of ROP. The purpose of this proof-of-concept study was to use electronic health record (EHR) data to evaluate early neonatal oxygen exposure as a predictive variable for developing TR-ROP and A-ROP. Design Retrospective cohort study. Subjects, Participants, and/or Controls 244 infants screened for ROP at a single academic center. Methods Intervention, or Testing: For each infant, oxygen saturations and fraction of inspired oxygen (FiO₂) were manually extracted from the EHR until 31 weeks PMA. Cumulative minimum, maximum, mean oxygen saturation and FiO₂ were calculated on a weekly basis. Random forest models were trained with 5-fold cross-validation using GA and cumulative minimum FiO₂ at 30 weeks PMA to identify infants who developed TR-ROP. Secondary ROC analysis on infants with/without A-ROP was performed without cross-validation due to small numbers. Main Outcomes/Measures For each model, cross-validation performance for incident TR-ROP was assessed using area under the receiver operating curve (AUROC) and precision-recall curve (AURPC) scores. For A-ROP, we calculated AUROC, and evaluated sensitivity and specificity at a high-sensitivity operating point. Results Of the 244 infants included, 33 developed TR-ROP and 5 were diagnosed with A-ROP. For incident TR-ROP, random forest models trained on GA plus cumulative minimum FiO₂ (AUROC=0.93±0.06, AUPRC=0.70±0.08) were not significantly better those trained on GA alone (AUROC=0.92±0.06, p=0.59; AUPRC=0.74±0.12, p=0.32). However, models using oxygen alone had an AUROC of 0.80±0.09. Secondary ROC analysis for A-ROP found an AUROC=0.92 [95% CI 0.87-0.96]. Conclusions Oxygen exposure can be extracted from the EHR and quantified as a risk factor for incident TR-ROP and A-ROP. Extracting quantifiable clinical features from the EHR may be useful in the future for building integrative risk models for multiple diseases, and evaluating the complex relationships between oxygen exposure, ROP, and other sequelae of prematurity.

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.

The goal of the present study was to perform a systematic review of the published data on talar neck fractures for a better understanding of the postoperative clinical outcomes using open reduction and internal fixation stratified by Hawkins type. A PubMed search was performed using the keywords "talar," "neck," and "fracture." This search identified 209 potential studies, which were reviewed to yield 16 studies that met the criteria. The surgical outcomes of talar neck fractures stratified by the Hawkins classification analyzed in the present study were as follows: American Orthopaedic Foot and Ankle Society scale score was 77.00 for type I, 86.10 for type II, 68.30 for type III, 68.30 for type IV, and 76.50 for all talar neck fractures. Avascular necrosis presented in 0.00% of type I fractures, 15.91% of type II fractures, 38.89% of type III fractures, 55.00% of type IV fractures, and 26.47% of all fractures. Osteoarthritis presented in 25.00% of type I fractures, 41.33% of type II fractures, 54.23% of type III fractures, 72.73% of type IV fractures, and 51.69% of all fractures. Subtalar arthritis presented in 0.00% of type I fractures, 54.29% of type II fractures, 46.43% of type III fractures, 45.45% of type IV fractures, and 44.97% of all fractures. The malunion prevalence was 13.29% and the nonunion prevalence was 3.97% for all fractures. Type II fractures were the most common (50.88%) fracture type reported in the reports reviewed in the present study.

Binge eating is present in obesity and clinical eating disorder populations and positively associated with poor health outcomes. Emotional eating may be related to binge eating, but relationships with emotional reactivity remain unexplored. The present study examined the relationships between negative and positive emotional eating and emotional reactivity in predicting binge eating. A cross-sectional study was employed using an online community sample in the United States. Participants (N = 258) completed surveys assessing negative (Emotional Eating Scale-Revised, depression subscale) and positive emotional eating (Emotional Appetite Questionnaire), negative and positive emotional reactivity (Perth Emotional Reactivity Scale), and binge eating (Binge Eating Scale). Six moderation analyses were calculated with negative and positive emotional reactivity (ease of activation, intensity, and duration) as moderators of the relationship between negative and positive emotional eating, respectively, and binge eating. Increased negative emotional eating was associated with increased binge eating when duration of negative emotional reactivity was 1 standard deviation above average (p < .001), but at 1 standard deviation below average (p < .001), increased negative emotional eating was associated with decreased binge eating. Increased positive emotional eating was associated with increased binge eating when intensity (p < .01) of positive emotional reactivity was 1 standard deviation above average and when activation (p < .05) of positive emotional reactivity was slightly above 1 standard deviation above average. Increased positive emotional eating was associated with decreased BE when intensity of positive emotional reactivity was 1 standard deviation below (p < .05) average. Emotional reactivity may uniquely impact the relationship between emotional eating and binge eating. Research and clinical implications for the contribution of negative and positive emotional eating and emotional reactivity on binge eating are discussed.

This study extended the research on correlates of adaptive functioning of high-functioning children with autism spectrum disorder (HFASD) using the Behavior Assessment System for Children-Second Edition (BASC-2). Specifically, this study investigated the relationships between adaptive behavior and age, IQ, and ASD symptomology, in a well-characterized sample of 119 children with HFASD, ages 6-11 years. Results revealed age and IQ were not significantly correlated with adaptive ability. However, total autism symptoms [measured by the Autism Diagnostic Interview-Revised (ADI-R)], as well as ASD-social symptoms were negatively correlated with adaptive ability. Mean comparisons revealed that participants falling into the clinically-significant range of the BASC-2 Adaptive Skills Composite (ASC) displayed significantly greater levels of both overall and social ASD symptoms.

This study compared parent and teacher ratings of ASD-related symptoms of 120 high-functioning children, ages 6-12 years with ASD (HFASD) using the Developmental Social Disorders (DSD) scale of the BASC-2. DSD ratings (parent and teacher) were significantly higher than normative estimates. The cross-informant comparison was significantly higher for parents (vs. teachers), and correlations (ICC and Pearson) between the informant groups were significant (but low in magnitude). Agreement among parents and teachers accurately placed 81 % of cases above the at-risk cutpoint for symptoms of ASD, and agreement was highest in the at-risk range of perceived symptoms. Additional analyses indicated a significant difference in the trend across the parent-teacher discrepancies, and no significant moderators of the discrepancies. Implications for assessment are provided.

This study examined informant discrepancies for parent and teacher adaptive behavior ratings of 103 children, ages 6-12 years, with ASD (without intellectual disability). Scores on the Adaptive Behavior Assessment System, third edition (Harrison and Oakland, Western Psychological Services, Los Angeles, 2015) General Adaptive Composite (GAC) and practical, social, and conceptual domains were examined for mean differences, level of agreement, and moderators of difference scores between informant groups. Teacher scores were significantly higher (indicating better functioning) than parents for the GAC and practical domain. Parent and teacher scores were moderately correlated and Bland-Altman plots and regression analyses revealed no systematic differences in parent-teacher agreement across the range of scores. None of the tested variables moderated the parent-teacher difference scores. Implications for clinical practice are discussed.

Introduction Adherence to positive airway pressure (PAP) therapy continues to be a challenge. The main objective of this study was to determine whether mobile text-message reminders increased PAP adherence in veterans with obstructive sleep apnea. Methods This is a retrospective study of 25 patients with poor adherence to PAP therapy who used the Veterans Affairs ANNIE app to receive nightly mobile text message reminders. PAP adherence was measured at baseline, 1,and 3 months. A one-way repeated measures ANOVA was used to compare the effect of time on PAP adherence, specifically the percentage of overall days used and percentage use >4 hours. A two-way repeated measures ANOVA without replication was used to determine the effects of AHI severity and time on PAP adherence. Results Our sample demographics included a mean age of 59 ±12 years, mean BMI of 33.5% ±5.4, and mean AHI of 26.3 ±25.4. The mean PAP overall percentage use and mean use >4 hours respectively were 32% ± 27 and 18% ± 19 at baseline, 66% ± 27 and 45% ± 30 at 1 month, and 54% ±32 and 37% ± 30 at 3 months. After three months of receiving nightly text-message reminders, there was a statistically significant effect of time on percentage overall PAP use, F (2, 48)=21.54, p=2.10E-07, as well as in the percentage PAP use >4 hours, F (2, 48)=22.05, p=1.61E-07. A two-way repeated measures ANOVA without replication yielded a main effect of the interaction of time with PAP adherence, F (2, 48)=22, p= Conclusion Nightly text message reminders significantly improved PAP adherence from baseline to 3 months. Though PAP adherence was not optimal, it doubled initially in our sample. Further studies are warranted to determine how text-messages can be used long term to improve adherence. Support Nil

HEY2 is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in the developing mammalian heart and brain. In humans, nonsynonymous mutations in HEY2 have been described in patients with atrial ventricular septal defects, and a subset of individuals with chromosomal deletions involving HEY2 have cardiac defects and cognitive impairment. Less is known about the potential effects of HEY2 overexpression. Here, we describe a female child with tetralogy of Fallot who developed severe right ventricular outflow tract obstruction due to a combination of infundibular and valvular pulmonary stenosis. She was also noted to have hypotonia, lower extremity weakness, fine motor delay and speech delay. A copy number variation (CNV) detection analysis followed by real-time quantitative PCR analysis revealed a single gene duplication of HEY2. This is the only duplication involving HEY2 identified in our database of over 70,000 individuals referred for CNV analysis. In the developing heart, overexpression of HEY2 is predicted to cause decreased expression of the cardiac transcription factor GATA4 which, in turn, has been shown to cause tetralogy of Fallot. In mice, misexpression of Hey2 in the developing brain leads to inhibition of neurogenesis and promotion of gliogenesis. Hence, duplication of HEY2 may be a contributing factor to both the congenital heart defects and the neurodevelopmental problems evident in our patient. These results suggest that individuals with HEY2 duplications should be screened for congenital heart defects and monitored closely for evidence of developmental delay and/or cognitive impairment.

Congenital diaphragmatic hernia (CDH) is a relatively common, life-threatening birth defect. We present a family with recurrent CDH—paraesophageal and central—for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p. Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice—FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.

Objective: To describe the current data evaluating the efficacy and safety of memantine for the prevention of primary headache disorders. Data Sources: A literature search using MEDLINE (1966-July 2014) and EMBASE (1973-July 2014) was conducted using the search terms memantine, headache, migraine, glutamate, and NMDA. References of identified articles were reviewed for additional, relevant citations. Study Selection and Data Extraction: All English-language articles dealing with the use of memantine for prevention of primary headache disorders were included. Data Synthesis: Data from several retrospective reports and 2 prospective clinical trials suggest that memantine may be a useful treatment option for the prevention of primary headache disorders. The majority of available literature focuses specifically on chronic migraine prevention in refractory patients who had failed multiple previous prophylactic therapies. In these patients, 10 to 20 mg of memantine daily reduced the frequency and intensity of migraine headaches and was generally well tolerated, with few adverse events. Data regarding the efficacy of memantine for other primary headache disorders such as chronic tension type and cluster headaches are limited. Conclusion: Although further studies evaluating the efficacy of memantine for prevention of primary headache disorders are warranted, memantine may be a reasonable option, used either as monotherapy or adjunctive therapy, in the refractory chronic migraine prophylaxis setting.

Assessment of clinical symptoms requires information from multiple informants. Discrepancies between informants' ratings can have significant implications in school settings (e.g., access to services, treatment planning, progress monitoring). This study examined parent-teacher discrepancies for ratings of internalizing and externalizing symptoms, and adaptive skills of high-functioning children with autism spectrum disorder. A total of 236 Behavior Assessment System for Children-2nd Edition ratings of children with high-functioning children with autism spectrum disorder from 2 informant groups (parents and teachers) were analyzed. Each informant pair (n = 118 parents/caregivers and n = 118 teachers) rated the same child. Scores on the Internalizing Problems, Externalizing Problems, and Adaptive Skills Composites were examined for mean differences, level of agreement, linear relationship, and moderators of discrepancies. There were no significant mean differences between raters for the Internalizing and Externalizing Composites or their constituent scales (except Hyperactivity). Parent-teacher ratings on these composites and scales were significantly correlated (generally moderate), and the discrepancies were not moderated by the included child or parent variables. In contrast, teacher ratings were significantly higher than parents for the Adaptive Skills Composite and several of its constituent scales. Correlations between informants on the Adaptive Skills Composite were significant (low-to-moderate), with notable variability in the correlations among its constituent scales. The degree of parent-teacher discrepancy differed significantly across the Adaptive Skills Composite score range, but it was not moderated by the included child or parent variables. This study suggests a reduced likelihood of informant discrepancies for externalizing and internalizing symptoms, with larger discrepancies expected when assessing adaptive skills. (PsycINFO Database Record

Allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) is challenged by severe adverse events, as cytotoxic effects of the conditioning may result in systemic inflammation, leaky epithelial barriers and organ toxicities, contributing to treatment-related morbidity and mortality. We hypothesised that insulin-like growth factor-1 (IGF-1), a mediator of growth and proliferation of various tissues, may attenuate chemotherapy-induced tissue damage after HSCT. We prospectively measured plasma levels of IGF-1 and its binding protein 3 (IGFBP-3) in 41 patients undergoing myeloablative HSCT. IGF-1 and IGFBP-3 levels were inversely correlated with C-reactive protein and interleukin-6 levels post HSCT. In multivariate analyses, low levels of IGF-1 and IGFBP-3 before conditioning were associated with increased risk of developing sinusoidal obstruction syndrome (SOS; OR=5.00 per 1 SDS decrease in IGF-1 (95% CI: 1.45–16.67), P=0.011 and OR=5.00 (1.37–20.00), P=0.015, respectively). Furthermore, low pre-transplant levels of IGF-1 and IGFBP-3 were associated with increased fluid retention during the first 21 days post transplant (OR=7.69 (95% CI: 1.59–33.33), P=0.012, and OR=2.94 (1.03–8.33), P=0.045). These data suggest that high levels of IGF-1 and IGFBP-3 may have a protective effect against fluid retention and SOS, possibly by attenuating systemic inflammation, and may prove useful as predictive biomarkers of SOS.

Background The non-POU domain containing octamer-binding gene ( NONO ) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects. Methods We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis. Results We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO . We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother. Conclusions We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

Law, R.-J., Breslin, A., Oliver, E., Mawn, L., Markland, D., Maddison, P., Thom, J. (2010). Exercise and rheumatoid arthritis: what's in it for us? Poster 288 in: Abstracts of the Rheumatology BSR and BHPR Conference, 21-23 April 2010, Rheumatology, 49(suppl 1), i139-i143.

PurposeThe patient journey from detection of an eye problem by optometrists to assessment and treatment by ophthalmologists can be streamlined by direct referral from optometrist to hospital eye service (HES). This requires locally agreed guidelines and training and feedback for optometrists to ensure high diagnostic competence. The purpose of this paper is to evaluate the quality of the West Suffolk Direct Referral Scheme, one of the first direct referral schemes in the UK to include all ophthalmic sub‐specialties.Design/methodology/approachTwo‐cycle audit of existing practice, including all new patients referred by optometrists and seen at West Suffolk Hospital during a three‐month period in 2003 and a seven‐week period in 2006. Three interventions: direct referral clinics for urgent patients; introduced in 2003; six‐monthly training sessions for optometrists; and regular, prompt feedback via letter about individual consultation outcome. Prospective data collection via proforma in both cycles; additional retrospective data collection in the second cycle. Diagnostic accuracy, perception of urgency and request of subspecialty clinic were evaluated.FindingsThe direct referral scheme streamlines the patient journey, and patients with acute problems have fast access to HES. In total, 99 per cent of referrals are appropriate. Diagnostic competence is high (87 per cent), and has improved with tighter communication between HES and optometrists. Agreement is less for referral urgency (75 per cent) and choice of subspecialty clinic (74 per cent).Originality/valueThe West Suffolk Direct Referral Scheme provides an efficient service of high quality. Good communications and continued feedback between community‐ and hospital‐based eye care services improve standards and facilitate efficient use of resources.

Atherosclerosis is a chronic inflammatory disease involving plaque buildup in the arteries and can lead to heart attack and stroke. A key step in the pathogenesis of atherosclerosis is oxLDL uptake...

OBJECTIVE: To review the pharmacology, efficacy, and safety of efalizumab for the treatment of moderate to severe plaque psoriasis. DATA SOURCES: A MEDLINE search (1966–May 2005%) using the key words hu1124, anti-CD11a, efalizumab, Raptiva, Xanelim, and psoriasis was conducted. References of identified articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: Clinical trials evaluating the pharmacology, efficacy, and safety of efalizumab for treatment of moderate to severe plaque psoriasis in adults were included in our review. DATA SYNTHESIS: Efalizumab's ability to inhibit the binding of CD11a, a subunit of leukocyte function–associated antigen type 1, to intracellular adhesion molecule 1 results in decreased T-cell activation and migration, 2 key steps in the immunopathogenesis of psoriasis. Results of clinical trials have demonstrated that efalizumab administered subcutaneously is a safe and effective treatment for moderate to severe plaque psoriasis. Efalizumab was well tolerated in trials, with the majority of adverse events arising with the first dose and decreasing with subsequent doses. The high cost of this agent and lack of head-to-head trials with other drugs will likely restrict its use to patients who have failed prior systemic therapy or phototherapy. CONCLUSIONS: Efalizumab is a safe and effective therapy for treatment of moderate to severe plaque psoriasis in patients who have failed prior systemic therapy or phototherapy.

The idea that women, particularly new mothers, are overly concerned with weight and body shape has much currency in our culture. The literature in this area is contradictory, some arguing, for example, that body image is integral to women's narratives of early motherhood, others that it is of peripheral concern. This paper presents the results of research conducted into women's body image after pregnancy. The study used Q methodology to explore the manifold understandings of women who had recently given birth. Research and piloting produced 60 statements identified as relevant to the concerns of new mothers. Twenty participants, who had given birth in the previous 3 years, were asked to sort these statements into quasi‐normal distributions. These sorts were then factor analysed to identify six dominant narratives: ‘family centred’, ‘stressed’, ‘happy mothers’, ‘missing personal space’, ‘supportive family’ and ‘mother/child oriented’. By focusing on the complexity of these narratives, rather than isolating...

To estimate the prevalence of posterior embryotoxon (PE) in the general ophthalmic clinic and to identify any features of PE that suggest that it is pathological rather than physiological. Over 700 consecutive patients of all ages were examined with the slit lamp during their routine eye clinic appointment. Patients with posterior embryotoxon were invited to return for full ocular examination including keratometry, corneal topography, and gonioscopy. In all, 49 out of 723 patients were found to have PE. This gives a prevalence of 6.8% with an age range of 18 months to 95 years. There was a higher prevalence in the younger age group of 22.5% (age range 18 months to 20 years) compared to 5.9% in the older age range (21–95 years). A total of 29 patients with PE returned for further examination. Six patients had glaucoma (two with Axenfeld's syndrome and one with aniridia), and one had ocular hypertension. In all, 20 patients had bilateral PE on slit-lamp examination, which increased to 24 with gonioscopy. The majority of the PE was seen temporally (97.9%) and limited to a few clock hours. Gonioscopy showed that eight patients with PE had associated inferior pigmentation of schwalbes line. This large series found the prevalence of PE the general ophthalmic clinic to be 6.8%. Its presence should prompt careful anterior segment examination, including gonioscopy, to identify any associated abnormalities that may carry a risk of glaucoma. Children should also be assessed for any associated systemic or genetic abnormality.

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease with early lesions characterized by mononuclear cellular infiltrate, edema, demyelination, and axonal loss that contribute to the clinical course of the disease. Experimental autoimmune encephalomyelitis (EAE) in the mouse is a valuable model with a similar disease course to relapsing-remitting MS. The ability to detect the migration of encephalitogenic T cells into the central nervous system in EAE and MS would provide key information on these cells role in the development of lesions observed on magnetic resonance imaging (MRI). T cells were labeled for detection by magnetic resonance imaging using Food and Drug Administration-approved, superparamagnetic iron oxide nanoparticles (Ferumoxides) complexed to poly-L-Lysine (FE-PLL). EAE was induced by adoptive transfer of either labeled or unlabeled T cells. After disease onset, FE-PLL-labeled T cells were detected in the mouse spinal cord using in vivo and ex vivo cellular MRI. Excellent correlation was seen between MRI-visible lesions in the spinal cord and histopathology. The results demonstrate that T cells labeled with FE-PLL can induce EAE disease and can be detected in vivo in the mouse model. The magnetic labeling of cells opens the possibility of monitoring specific cellular phenotypes or pharmacologically or genetically engineered cells by MRI.

Purpose To compare the detection of diabetic retinopathy from digital images with slit-lamp biomicroscopy, and to determine whether British Diabetic Association (BDA) screening criteria are attained (>80% sensitivity, >95% specificity

In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.

A 51-yr-old male presented with an 8-mo history of lower back pain. Computerized axial tomography (CT) and magnetic resonance imaging (MRI) studies showed a 3.5 X 3.0 cm sacral mass within the spinal canal in the region of the left S2 nerve root. A fine-needle aspirate biopsy (FNAB) was performed under CT guidance. The cytologic findings included a spindle-cell population with a fibrillary background arranged in a vaguely streaming pattern, wavy nuclei with mild atypia, wispy cytoplasm, rare intranuclear inclusions, and dilated vascular spaces. Some cells contained a nonrefractile granular brown pigment consistent with melanin. Also identified were calcified concentric laminations typical of psammoma bodies. Immunohistochemically, the neoplastic cells were strongly immunoreactive for S-100 protein and HMB-45. A diagnosis of psammomatous melanotic schwannoma was rendered. No stigmata of Carney's complex were identified on physical examination. The patient has declined the recommendation of surgical excision of the mass. We herein describe a case unequivocally diagnosed as psammomatous melanotic schwannoma by FNAB.

PURPOSE: Visual field testing is increasingly being performed by optometrists in order to improve glaucoma detection. The aim of this study was to assess the positive predictive value (PPV) of visual field testing as currently practised by optometrists. METHODS: A retrospective study was performed of referrals for suspected glaucoma to an ophthalmology department during a 3 month period. The PPV for glaucoma was determined according to the reason for referral. RESULTS: There were 86 referrals for suspected glaucoma. Isolated field loss accounted for 12% of these referrals but no cases of glaucoma detection. These subjects were either false positive referrals or had field defects of nonglaucomatous aetiology (tilted optic disc and porencephalic cyst). The PPV for glaucoma among referrals with isolated field loss was significantly less than that among referrals with field loss in association with corroborative abnormalities (0 vs. 60%, p = 0.005). No such difference was found for referrals with raised intraocular pressure (43% vs. 57%, p = 0.38) or suspicious discs (25% vs. 53%, p = 0.60). CONCLUSIONS: Visual field testing is currently leading to unnecessary referrals to the hospital eye service with no detectable improvement in the accuracy of glaucoma suspect referrals. It is important that optometrists perform visual field testing in accordance with validated screening methodology.

Background— The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca 2+ leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca 2+ release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. Methods and Results— CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca 2+ release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca 2+ /calmodulin-dependent protein kinase II–mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca 2+ release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca 2+ -dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. Conclusions— RyR2-mediated SR Ca 2+ leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca 2+ release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

Helicobacter pylori is a common cause of chronic gastritis and has been implicated as the main agent responsible for the development of lymphomas of mucosa associated lymphoid tissue (MALT) in the stomach. An uncommon cause of salivary gland swelling is salivary lymphoepithelial lesion (SLEL), which shows histological features of acquired MALT and is associated with the development of MALT-type lymphomas. Since H. pylori has been identified in the oral cavity, we hypothesised that this organism might act as a potential antigen for the development of MALT in salivary glands. Routinely processed biopsies of 20 SLEL were screened for H. pylori DNA using a sensitive two-stage PCR technique to amplify the 16S ribosomal RNA gene. Immunoglobulin heavy chain gene monoclonality was determined by amplifying the VDJ gene using a nested PCR technique. All SLEL had histological features of organised MALT and 14 cases showed Ig heavy chain gene monoclonality consistent with MALT lymphoma. None of the SLEL contained H. pylori DNA. In contrast to the putative role of H. pylori as an antigenic stimulus in gastric MALT lymphomas, it appears not to play a role locally in the development of MALT or MALT lymphomas of the salivary gland.

We hypothesized that acute kidney injury (AKI) in asphyxiated neonates treated with therapeutic hypothermia would be associated with hypoxic-ischemic lesions on brain magnetic resonance imaging (MRI).Medical records of 88 cooled neonates who had had brain MRI were reviewed. All neonates had serum creatinine assessed before the start of cooling; at 24, 48, and 72 h through cooling; and then on day 5 or 7 of life. A neonatal modification of the Kidney Disease: Improving Global Outcomes guidelines was used to classify AKI. MRI images were evaluated by a neuroradiologist masked to outcomes. Outcome of interest was abnormal brain MRI at 7-10 d of life.AKI was found in 34 (39%) of 88 neonates, with 15, 7, and 12 fulfilling criteria for stages 1, 2, and 3, respectively. Brain MRI abnormalities related to hypoxia-ischemia were present in 50 (59%) newborns. Abnormal MRI was more frequent in infants from the AKI group (AKI: 25 of 34, 73% vs. no AKI: 25 of 54, 46%; P = 0.012; odds ratio (OR) = 3.2; 95% confidence interval (CI) = 1.3-8.2). Multivariate analysis identified AKI (OR = 2.9; 95% CI = 1.1-7.6) to be independently associated with the primary outcome.AKI is independently associated with the presence of hypoxic-ischemic lesions on postcooling brain MRI.

To test the hypothesis that acute kidney injury (AKI) would be independently associated with increased morbidity and mortality.A total of 96 consecutively cooled infants were reviewed retrospectively. Modified Acute Kidney Injury Network criteria were used to classify AKI based on absolute rise in serum creatinine (SCr) level from a previous trough (stage I, rise in SCr of 0.3 mg/dL or SCr 150-200%; stage II, rise in SCr of 200-300%; stage III, rise in SCr of ≥300%, SCr 2.5 mg/dL, or dialysis). Outcomes were mortality, duration of neonatal intensive care unit (NICU) stay, and duration of mechanical ventilation.AKI occurred in 36 of 96 infants (38%). Overall mortality was 7% and was higher for those with AKI, with the difference approaching statistical significance (14% vs 3% in those without AKI; P = .099). Patients with AKI stayed longer in the NICU (mean, 15.4 ± 9.3 days vs 11 ± 5.9 days; P = .014) and required prolonged mechanical ventilation (mean, 9.7 ± 5.9 days vs 4.8 ± 3.7 days; P .001). On multivariate analysis, AKI remained predictive of prolonged duration of mechanical ventilation and prolonged NICU stay.We used the Acute Kidney Injury Network definition for AKI in asphyxiated newborns undergoing therapeutic hypothermia to demonstrate that the incidence of AKI remains high, but lower than rates published before the advent of therapeutic hypothermia. We highlight the importance of recognizing AKI in asphyxiated newborns undergoing therapeutic hypothermia, along with the potential benefits of early recognition.

The amino acid sequence of raccoon islet amyloid polypeptide (IAPP), as predicted by analysis of polymerase chain reaction (PCR)-amplified sequences from genomic DNA, contains the same putative amyloidogenic sequence (GAILS) at residues 24-28 as human and cat IAPP. These findings are consistent with evidence that the occurrence of islet amyloidosis, usually in association with age-associated (type 2) diabetes, is limited to a few unique species (e.g., humans, cats, raccoons) that produce IAPP molecules containing an inherent amyloidogenic structural motif. Although the presence of an intrinsic amyloidogenic structural motif within the IAPP molecule appears to be a prerequisite for the development of this form of amyloidosis, it is increasingly clear that additional factors are importantly involved in the ultimate expression of IAPP fibrillogenesis and deposition as islet amyloid deposits.

To evaluate and compare circulating concentrations of islet amyloid polypeptide (IAPP), insulin, and glucose in nondiabetic cats classified by body condition score (BCS) and in cats with naturally occurring diabetes mellitus.109 (82 nondiabetic, 21 nonketoacidotic diabetic, and 6 ketoacidotic diabetic) cats.Cats were examined and BCSs were assessed on a scale of 1 to 9. After food was withheld for 12 hours, blood was collected and plasma concentrations of IAPP and serum concentrations of insulin and glucose were measured. Differences in these values were evaluated among nondiabetic cats grouped according to BCS and in diabetic cats grouped as ketoacidotic or nonketoacidotic on the basis of clinicopathologic findings. Correlations were determined among variables.In nondiabetic cats, BCS was significantly and positively correlated with circulating IAPP and insulin concentrations. Mean plasma IAPP concentrations were significantly different between cats with BCSs of 5 and 7, and mean serum insulin concentrations were significantly different between cats with BCSs of 5 and 8. Serum glucose concentrations were not significantly different among nondiabetic cats. Mean IAPP concentrations were similar between nonketoacidotic diabetic cats and nondiabetic cats with BCSs of 8 or 9. Mean IAPP concentrations were significantly reduced in ketoacidotic diabetic cats, compared with those of nondiabetic cats with BCSs of 6 through 8 and of nonketoacidotic diabetic cats.Results indicated that increased BCS (a measure of obesity) is associated with increased circulating concentrations of IAPP and insulin in nondiabetic cats.

Background: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. Results: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6—36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. Conclusions: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.

This study uses quantitative T(2)* imaging to track ferumoxides--protamine sulfate (FEPro)-labeled MDA-MB-231BR-Luc (231BRL) human breast cancer cells that metastasize to the nude rat brain. Four cohorts of nude rats were injected intracardially with FEPro-labeled, unlabeled or tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-treated (to induce apoptosis) 231BRL cells, or saline, in order to develop metastatic breast cancer in the brain. The heads of the rats were imaged serially over 3-4 weeks using gradient multi-echo and turbo spin-echo pulse sequences at 3 T with a solenoid receive-only 4-cm-diameter coil. Quantitative T(2)* maps of the whole brain were obtained by the application of single-exponential fitting to the signal intensity of T(2)* images, and the distribution of T(2)* values in brain voxels was calculated. MRI findings were correlated with Prussian blue staining and immunohistochemical staining for iron in breast cancer and macrophages. Quantitative analysis of T(2)* from brain voxels demonstrated a significant shift to lower values following the intracardiac injection of FEPro-labeled 231BRL cells, relative to animals receiving unlabeled cells, apoptotic cells or saline. Quartile analysis based on the T(2)* distribution obtained from brain voxels demonstrated significant differences (p 0.0083) in the number of voxels with T(2)* values in the ranges 10-35 ms (Q1), 36-60 ms (Q2) and 61-86 ms (Q3) from 1 day to 3 weeks post-infusion of labeled 231BRL cells, compared with baseline scans. There were no significant differences in the distribution of T(2)* obtained from serial MRI in rats receiving unlabeled or TRAIL-treated cells or saline. Histologic analysis demonstrated isolated Prussian blue-positive breast cancer cells scattered in the brains of rats receiving labeled cells, relative to animals receiving unlabeled or apoptotic cells. Quantitative T(2)* analysis of FEPro-labeled metastasized cancer cells was possible even after the hypointense voxels were no longer visible on T(2)*-weighted images.