Search

Previous single-center or meta-analysis studies analyzed myocardial I-metaiodobenzylguanidine (I-MIBG) scintigraphy in a single image session and demonstrated low sensitivity and high specificity for discriminating Parkinson disease (PD) from atypical Parkinsonian syndromes (APS). This study aimed to assess diagnostic ability of myocardial I-MIBG scintigraphy at 2 phases to discriminate PD from APS.This hospital-based prospective study enrolled 162 PD and 26 APS patients who underwent 2 sequential I-MIBG scintigraphy evaluations. Patients were stratified into normal and decreased I-MIBG groups according to early and delayed heart-to-mediastinum (H/M) ratios. Patients with PD and normal I-MIBG uptake (initial delayed H/M ratio, ≥1.78) were considered scans without evidence of cardiac norepinephrine deficit (SWEND). Early and delayed H/M ratios on the initial and 2-year follow-up scintigraphs were studied. The diagnostic sensitivity and specificity were calculated from these confusion matrices and were analyzed according to receiver-operating characteristic curve analysis. A repeated-measures general linear model was used to investigate differences among groups over time in H/M ratio changes and washout rates.Follow-up I-MIBG scintigraphy analysis had a higher diagnostic sensitivity (89.5%) than the initial imaging (72.2%). The improved sensitivity was associated with a steeper decrease in H/M ratio in the SWEND group than in the APS group.Follow-up I-MIBG scintigraphy can identify cardiac sympathetic denervation and its progression in patients with PD and may be effective in discriminating PD from APS. A later decrease in myocardial I-MIBG uptake in the group with SWEND meets the Braak staging threshold hypothesis for synucleinopathy.

Background Urinary dysfunction is relatively common, however, is often underestimated and diagnosed by subjective questionnaires in patients with Parkinsonism. Objective To determine the correlation between subjective urinary dysfunction and post-void residual urine volume in patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and to assess the relationship between clinical characteristics and subjective or objective urinary dysfunction. Methods A total of 196 patients with de novo Parkinsonism without urological and gynecological disorders were included. For all subjects, data were collected on sonographic post-void residual urine volume and urinary symptoms. All patients were also assessed on motor symptom severity, cognitive and affective measurements, other nonmotor symptoms, 39-item Parkinson's Disease Questionnaire, and renal functions. Results Seventeen out of 196 parkinsonian patients showed abnormal post-void residual urine volumes, with ≥100 ml. The MSA group showed significantly higher post-void residual urine volume compared to the PD and PSP groups. Symptoms of the sense of incomplete emptying, weak urine stream, and nocturia were strongly correlated with post-void residual urine volume. Post-void residual urine volume was positively related to autonomic symptoms, other non-motor symptoms, patient activities of daily living, and negatively related to renal function. Conclusion Increased post-void residual urine volumes were observed in small portion of early drug-naive Parkinsonian patients, especially in MSA. Post-void residual urine volume was significantly related to subjective urinary and other autonomic dysfunctions. Voiding dysfunction is associated with not only end organ damage, but also other nonmotor dysfunctions and patient activities of daily living.

This study evaluated the effects of alpha-s1 casein hydrolysate (ACH, Lactium&reg, ) on the subjective and objective sleep profiles of a community-based sample of Koreans with poor sleep quality. We performed a double-blind, randomized crossover trial with 48 participants (49.0 &plusmn, 1.7 years old, 65% female) who exhibited a mild to moderate degree of sleep disturbance. Either ACH or placebo was administered for the initial four weeks, and the counterpart was administered in precisely the same manner after a four-week washout period. Sleep disturbance scales, daytime functioning, and psychiatric aspects showed a similar tendency to improve during both ACH and placebo phases without significant group differences. Overall perceived sleep profiles in sleep diaries were significantly improved during the ACH phase, represented by increased total sleep time and sleep efficiency (SE), as well as decreased sleep latency and wake after sleep onset (WASO). Interestingly, actigraphy demonstrated significantly increased SE after continuous use of ACH for four weeks, clearly more improved when compared to two weeks of use. The polysomnography measures showed a similar tendency without statistically significant group differences. Our findings suggest that refined ACH was well tolerated and could improve sleep quality, with possible cumulative beneficial effects with long-term administration.

To compare the diagnostic performances of digital breast tomosynthesis (DBT) and ultrasound for the dense breasts with category 0 at conventional digital mammography.This retrospective study was approved by the institutional review board, and informed consent was waived. Among the 1103 patients who underwent screening digital mammography at our institution, 769 (69.7%) patients had dense breasts. Of the 769 patients, 229 (29.8%) lesions were categorized as 0. DBT, breast ultrasound and digital mammography were performed in 108 (47.2%) patients. BI-RADS final assessments for DBT and ultrasound were recorded. Categories 1-3 were clinically considered as benign, and categories 4 and 5 were clinically considered as malignant. The diagnostic performances of breast ultrasound and DBT were correlated with final pathologic reports or follow-up images.Among 108 lesions, 17 (15.7%) were malignant and 91 (84.3%) were benign. Sensitivity was 100% for both ultrasound (17/17) and DBT (17/17) and negative predictive value was also 100% for both ultrasound (49/49) and DBT (74/74). Specificity and positive predictive value for ultrasound were 53.9% (49/91) and 28.8% (17/59), respectively. Specificity and positive predictive value for DBT were 81.3% (74/91) and 50% (17/34), respectively. DBT showed higher diagnostic accuracy than that of breast ultrasound (DBT: 84.3%, 91/108; ultrasound: 61.1%, 66/108; p0.001). The benign biopsy rate of DBT (50%, 17/34) was lower than that of ultrasound (71.2%, 42/59).DBT showed better diagnostic performance than breast ultrasound for dense breasts with category 0. DBT may reduce the benign biopsy rate and short term follow-up.

Purpose To evaluate the diagnostic performances of preoperative 3-T breast MRI for predicting nipple–areolar complex (NAC) involvement. Materials and methods We analyzed the predictors of NAC involvement in breast cancer, with diagnostic performances. Results Among the 403 patients, 43 cases were surgically confirmed for NAC involvement. For predicting NAC involvement, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 60.5%, 87.5%, 36.6%, 94.9%, and 84.6%, respectively. Continuity to NAC, unilateral enhancement of NAC and thickening of NAC were significant magnetic resonance findings predictive of NAC involvement. Conclusions Preoperative 3-T breast MRI is a useful method to predict NAC involvement in breast cancer patients.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose “fractionated” schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%–40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. Implications for Practice Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

Recent studies have suggested that preserved cardiac sympathetic denervation may be associated with a small motor burden in Parkinson disease (PD) and serve as a good marker, which is not associated with other nonmotor symptoms. We sought to investigate whether cardiac sympathetic denervation increases the risk of the early wearing-off phenomenon in PD. Methods: This hospital-based prospective study enrolled 266 de novo patients with PD who underwent 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy on initial evaluation. The patients visited the outpatient clinic every 2-6 mo and were followed for a minimum of 18 mo from the time they began taking dopaminergic medication. Each patient was assessed for the wearing-off phenomenon on the basis of the clinical assessments and symptom diaries. Clinical events were analyzed from the date of evaluation by 123I-MIBG scintigraphy until the date of the first occurrence of the wearing-off phenomenon, or until the last follow-up date without wearing-off. Results: During a mean follow-up period of 30.4 ± 14.8 mo, 71 patients developed wearing-off. The wearing-off phenomenon occurred more in patients with decreased 123I-MIBG uptake. A Cox regression analysis revealed that both low 123I-MIBG uptake and early onset age significantly predicted the development of wearing-off. Conclusion: Our study suggests that a reduction in myocardial 123I-MIBG uptake in PD patients may be associated with a subsequent increased risk for the wearing-off phenomenon. Findings strongly support that PD patients with normal cardiac sympathetic innervation might have less involvement of the midbrain dopaminergic circuitry and a concomitant reduced risk for motor complications, such as wearing-off.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51–0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53–0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242–6. ©2018 AACR.

The serotonin transporter (SERT) is an integral protein that provides an index of serotonergic innervation. Until recently, few studies have investigated SERT binding in thalamic subregions in schizophrenia. The purpose of this study was to examine SERT availability in thalamic subdivisions (anterior nucleus, mediodorsal nucleus, and pulvinar) using 7.0-T magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) in schizophrenia. Antipsychotic-free patients with schizophrenia (n=12) and healthy controls (n=15) underwent PET and MRI scans. For SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model (SRTM2). The analysis revealed that there were no significant differences in SERT availability between the two groups. In patients with schizophrenia, the severity of negative symptoms had a negative correlation with SERT availability in the anterior nucleus of the left thalamus. The present study did not reveal significant differences in SERT availability in thalamic subdivisions between patients with schizophrenia and control subjects. The association of SERT availability in the anterior nucleus with negative symptoms may suggest a role for the anterior thalamic nucleus in the pathophysiology of symptoms of schizophrenia. The ultra-high resolution imaging system could be an important asset for in vivo psychiatric research by combining structural and molecular information.

Olfactory impairment might be an important clinical marker and predictor of Alzheimer's disease (AD). In the present study, we aimed to compare the degree of olfactory identification impairment in each mild cognitive impairment (MCI) subtype, subjective memory impairment, and early AD dementia and assessed the relationship between olfactory identification and cognitive performance. We consecutively included 50 patients with amnestic MCI, 28 patients with non-amnestic MCI, 20 patients with mild AD, and 17 patients with subjective memory impairment (SMI). All patients underwent clinical and neuropsychological assessments. A multiple choice olfactory identification cross-cultural smell identification test was also utilized. Controlling for age and gender, olfactory impairment was significantly more severe in patients with AD and amnestic MCI compared with the results from the non-amnestic MCI and SMI groups. Higher scores on MMSE, verbal and non-verbal memory, and frontal executive function tests were significantly related to olfactory identification ability. In conclusion, olfactory identification is impaired in amnestic MCI and AD. These findings are consistent with previous studies. In amnestic MCI patients, this dysfunction is considered to be caused by underlying AD pathology.

Mitochondria play key roles in cellular immunity. How mitochondria contribute to organismal immunity remains poorly understood. Here, we show that HSP‐60/HSPD1, a major mitochondrial chaperone, boosts anti‐bacterial immunity through the up‐regulation of p38 MAP kinase signaling. We first identify 16 evolutionarily conserved mitochondrial components that affect the immunity of Caenorhabditis elegans against pathogenic Pseudomonas aeruginosa (PA14). Among them, the mitochondrial chaperone HSP‐60 is necessary and sufficient to increase resistance to PA14. We show that HSP‐60 in the intestine and neurons is crucial for the resistance to PA14. We then find that p38 MAP kinase signaling, an evolutionarily conserved anti‐bacterial immune pathway, is down‐regulated by genetic inhibition of hsp‐60 , and up‐regulated by increased expression of hsp‐60 . Overexpression of HSPD1 , the mammalian ortholog of hsp‐60 , increases p38 MAP kinase activity in human cells, suggesting an evolutionarily conserved mechanism. Further, cytosol‐localized HSP‐60 physically binds and stabilizes SEK‐1/MAP kinase kinase 3, which in turn up‐regulates p38 MAP kinase and increases immunity. Our study suggests that mitochondrial chaperones protect host eukaryotes from pathogenic bacteria by up‐regulating cytosolic p38 MAPK signaling. ![][1] The chaperone HSP‐60 binds and stabilizes SEK‐1/MAP kinase kinase to regulate p38 MAP kinase activity and anti‐bacterial immunity. The EMBO Journal (2017) 36: 1046–1065 [1]: /embed/graphic-1.gif

The brachial-ankle pulse wave velocity (baPWV) is a marker for arterial stiffness, which is associated with cardiovascular diseases. Arterial stiffness is associated with cognitive function in the elderly and patients with Alzheimer’s disease (AD). We aimed to investigate the association between arterial stiffness and cognitive function in patients with Lewy body disorder (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We consecutively included 123 patients with PD, 10 patients with DLB, and 27 AD controls. Patients with PD were divided into three groups of normal cognition (PD-NC, n = 63), mild cognitive impairment (PD-MCI, n = 43), and dementia (PD-D, n = 17). Arterial stiffness, measured as baPWV, was compared between the PD-NC, PD-MCI, PD-D, DLB, and AD patients. In LBD, we analyzed the association between arterial stiffness and each cognitive domain with adjustment for covariates. Higher baPWV was significantly associated with cognitive decline in patients with LBD (baPWV in PD-D > PD-MCI > PD-NC; DLB > PD-NC). There was no significant difference in baPWV between PD-D, DLB, and AD patients. In LBD patients, higher baPWV was associated with lower mini mental state examination score (β ± SE = −0.003 ± 0.001, p = 0.007) and more severe dementia. Higher baPWV was also associated with lower performance in attention, language, visuospatial function, memory, and executive function in LBD patients. This suggests that vascular brain injury is associated with cognitive dysfunction in LBD.

AIM To assess whether multimodal magnetic resonance imaging (MRI) could detect neuroanatomical substrates that are distinctive to hyposmic Parkinson's disease (PD). MATERIALS AND METHODS Among 102 PD patients, 62 were hyposmic and 40 were normosmic. For each patient, a sagittal structural three-dimensional (3D) T1-weighted image was obtained with the magnetisation-prepared rapid acquisition of the gradient-echo sequence to generate subcortical grey matter masking templates and to perform a voxel-based morphometry analysis of the subcortical grey matter volumes. A 3D multi-echo gradient sequence was run to obtain axial magnitude and phase images to produce a quantitative susceptibility map (QSM), and a diffusion-weighted image was acquired to generate an apparent diffusion coefficient (ADC) map. The volumes and average QSM and ADC values of the 15 subcortical grey matter structures were calculated, and the group differences were evaluated using a one-way analysis of covariance with age and gender as covariates. RESULTS The QSM of the left thalamus significantly increased, while that of the right thalamus significantly decreased in hyposmia. No effects on the cortical volume changes were found other than aging. CONCLUSION The present results suggest that accumulation of disease-related substances in the left and right thalamus and the increasing asymmetry between the two sides are associated with hyposmia in PD.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naive human immunodeficiency virus 1-infected pediatric subjects 3 to

Objective To evaluate the diagnostic performance of shear-wave elastography (SWE) for the differential diagnosis of breast papillary lesions. Methods This study was an institutional review board-approved retrospective study, with a waiver of informed consent. A total of 79 breast papillary lesions in 71 consecutive women underwent ultrasound and SWE prior to biopsy. Ultrasound features and quantitative SWE parameters were recorded for each lesion. All lesions were surgically excised or excised using an ultrasound-guided vacuum-assisted method. The diagnostic performances of the quantitative SWE parameters were compared using the area under the receiver operating characteristic curve (AUC). Results Of the 79 lesions, six (7.6%) were malignant and 12 (15.2%) were atypical. Orientation, margin, and the final BI-RADS ultrasound assessments were significantly different for the papillary lesions (p < 0.05). All qualitative SWE parameters were significantly different (p < 0.05). The AUC values for SWE parameters of benign and atypical or malignant papillary lesions ranged from 0.707 to 0.757 (sensitivity, 44.4–94.4%; specificity, 42.6–88.5%). The maximum elasticity and the mean elasticity showed the highest AUC (0.757) to differentiate papillary lesions. Conclusion SWE provides additional information for the differential diagnosis of breast papillary lesions. Quantitative SWE features were helpful to differentiate breast papillary lesions.

Telaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin, ortho -hydroxy atorvastatin, and para -hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum ( C max ) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC 0-∞ ); for atorvastatin, they were 10.6 (8.74, 12.9) for the C max and 7.88 (6.84, 9.07) for the AUC 0-∞ . Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents.

Objective Vilazodone was recently approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). The purpose of this review is to summarize the FDA's approach to its review of the clinical pharmacology and the clinical efficacy and safety data for this new drug application, important issues in its decision-making, and its conclusions. Data sources The data sources for this review were the original raw data sets for all clinical trials included in the development program for vilazodone, as well as the sponsor's original analyses of these data. Study selection Data were available from 24 human trials involving vilazodone, and included a total of 2,898 human subjects exposed to 1 or more doses of this drug. Data extraction The FDA had access to original raw data sets for these trials. Results Vilazodone is effective in treating MDD at a dose of 40 mg/d, but it needs to be incrementally adjusted to this dose to minimize gastrointestinal symptoms. It needs to be taken with food to ensure adequate plasma concentrations. Vilazodone's profile of adverse events is similar to that seen with selective serotonin reuptake inhibitors. No dose adjustment is needed based on age, gender, or renal or hepatic impairment. It is recommended that the vilazodone dose be reduced to 20 mg when it is taken with strong cytochrome P450 (CYP) 3A4 inhibitors, eg, ketoconazole. Vilazodone is not expected to have important effects on the clearance of other drugs that are cytochrome P450 substrates. Conclusions Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC0-∞) by approximately 4.6-fold and increased tacrolimus DN_AUC0-∞ by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t½) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t½ of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained. (HEPATOLOGY 2011;)

Background: Biological measurements that distinguish individuals with autism from typically developing individuals and those with other developmental and neuropsychiatric disorders must demonstrate very high performance to have clinical value as potential imaging biomarkers. We hypothesized that further study of white matter microstructure (WMM) in the superior temporal gyrus (STG) and temporal stem (TS), two brain regions in the temporal lobe containing circuitry central to language, emotion, and social cognition, would identify a useful combination of classification features and further understand autism neuropathology. Methods: WMM measurements from the STG and TS were examined from 30 high-functioning males satisfying full criteria for idiopathic autism aged 7–28 years and 30 matched controls and a replication sample of 12 males with idiopathic autism and 7 matched controls who participated in a previous case–control diffusion tensor imaging (DTI) study. Language functioning, adaptive functioning, and psychotropic medication usage were also examined. Results: In the STG, we find reversed hemispheric asymmetry of two separable measures of directional diffusion coherence, tensor skewness, and fractional anisotropy. In autism, tensor skewness is greater on the right and fractional anisotropy is decreased on the left. We also find increased diffusion parallel to white matter fibers bilaterally. In the right not left TS, we find increased omnidirectional, parallel, and perpendicular diffusion. These six multivariate measurements possess very high ability to discriminate individuals with autism from individuals without autism with 94% sensitivity, 90% specificity, and 92% accuracy in our original and replication samples. We also report a near-significant association between the classifier and a quantitative trait index of autism and significant correlations between two classifier components and measures of language, IQ, and adaptive functioning in autism.

Voxel-based analysis (VBA) is commonly used for statistical analysis of image data, including the detection of significant signal differences between groups. Typically, images are co-registered and then smoothed with an isotropic Gaussian kernel to compensate for image misregistration, to improve the signal-to-noise ratio (SNR), to reduce the number of multiple comparisons, and to apply random field theory. Problems with typical implementations of VBA include poor tissue specificity from image misregistration and smoothing. In this study, we developed a new tissue-specific, smoothing-compensated (T-SPOON) method for the VBA of diffusion tensor imaging (DTI) data with improved tissue specificity and compensation for image misregistration and smoothing. When compared with conventional VBA methods, the T-SPOON method introduced substantially less errors in the normalized and smoothed DTI maps. Another confound of the conventional DTI-VBA is that it is difficult to differentiate between differences in morphometry and DTI measures that describe tissue microstructure. T-SPOON VBA decreased the effects of differential morphometry in the DTI VBA studies. T-SPOON and conventional VBA were applied to a DTI study of white matter in autism. T-SPOON VBA results were found to be more consistent with region of interest (ROI) measurements in the corpus callosum and temporal lobe regions. The T-SPOON method may be also applicable to other quantitative imaging maps such as T1 or T2 relaxometry, magnetization transfer, or PET tracer maps.

Recent MRI studies have indicated that regions of the temporal lobe including the superior temporal gyrus (STG) and the temporal stem (TS) appear to be abnormal in autism. In this study, diffusion tensor imaging (DTI) measurements of white matter in the STG and the TS were compared in 43 autism and 34 control subjects. DTI measures of mean diffusivity, fractional anisotropy, axial diffusivity, and radial diffusivity were compared between groups. In all regions, fractional anisotropy was significantly decreased and both mean diffusivity and radial diffusivity were significantly increased in the autism group. These results suggest that white matter microstructure in autism is abnormal in these temporal lobe regions, which is consistent with theories of aberrant brain connectivity in autism.

The corpus callosum is the largest commissural white matter pathway that connects the hemispheres of the human brain. In this study, diffusion tensor imaging (DTI) was performed on subject groups with high-functioning autism and controls matched for age, handedness, IQ, and head size. DTI and volumetric measurements of the total corpus callosum and subregions (genu, body and splenium) were made and compared between groups. The results showed that there were significant differences in volume, fractional anisotropy, mean diffusivity, and radial diffusivity between groups. These group differences appeared to be driven by a subgroup of the autism group that had small corpus callosum volumes, high mean diffusivity, low anisotropy, and increased radial diffusivity. This subgroup had significantly lower performance IQ measures than either the other individuals with autism or the control subjects. Measurements of radial diffusivity also appeared to be correlated with processing speed measured during the performance IQ tests. The subgroup of autism subjects with high mean diffusivity and low fractional anisotropy appeared to cluster with the highest radial diffusivities and slowest processing speeds. These results suggest that the microstructure of the corpus callosum is affected in autism, which may be related to nonverbal cognitive performance.

Digital implementations of control laws typically involve discretization with respect to both time and space, and a control law that can achieve a task at coarser levels of discretization can be said to require less control attention, and also reduced implementation costs. One means of quantitatively capturing the attention of a control law is to measure the rate of change of the control with respect to changes in state and time. In this paper we present an attention-minimizing control law for ball catching and other target tracking tasks based on Brockett's attention criterion. We first highlight the connections between this attention criterion and some well-known principles from human motor control. Under the assumption that the optimal control law is the sum of a linear time-varying feedback term and a time-varying feedforward term, we derive an LQR-based minimum attention tracking control law that is stable, and obtained efficiently via a finite-dimensional optimization over the symmetric positive-definite matrices. Taking ball catching as our primary task, we perform numerical experiments comparing the performance of the various control strategies examined in the paper. Consistent with prevailing theories about human ball catching, our results exhibit several familiar features, e.g., the transition from open-loop to closed-loop control during the catching movement, and improved robustness to spatiotemporal discretization. The presented control laws are applicable to more general tracking problems that are subject to limited communication resources.

Segmental dilatation of the ileum is one of the uncommon causes of intestinal obstruction. Preoperative diagnosis of segmental dilatation of the ileum is difficult. We report two cases of this condition that were diagnosed preoperatively by contrast studies.

The diffusion properties of biological tissues are independent of magnetic field strength. Field strength, however, does affect the signal-to-noise ratio (SNR) and artifacts of diffusion-weighted (DW) images, which ultimately will influence the quantitative and spatial accuracy of diffusion tensor imaging (DTI). In this article, the effects of field strength on DTI are reviewed. The effects of parallel imaging also are discussed. A small study comparing DTI measurements both as a function of field strength (1.5 T and 3.0 T) and parallel imaging was performed. Overall, the SNR of the DW images roughly doubled going from 1.5 T to 3.0 T, and there was a relatively small decrease in SNR (15% to 30%) when parallel imaging was used. The increased SNR at 3.0 T resulted in smaller variances in the estimated mean diffusivities and fractional anisotropies. As expected, the amount of echo-planar image distortion roughly doubled going from 1.5 T to 3.0 T, but was reduced by 50% when using parallel imaging. In summary, DTI studies at 3.0 T using parallel imaging will provide significantly improved DTI measurements relative to studies at 1.5 T.

Cytomegalovirus (CMV) and Aspergillus fumigatus are opportunistic pathogens that cause fatal infections in graft recipients mainly 1–6 months after transplantation, the period of maximal immunosuppression required for the prevention of acute graft rejection. A CMV infection has been known to increase the risk of fungal infection in an immunocompromised host, and concurrent CMV andAspergillus pneumonias have been reported in bone marrow transplant recipients [1]. Desquamative interstitial pneumonia (DIP), considered to be a non-specific pulmonary reaction to injury, is pathologically characterized by the presence of numerous macrophages within the airspace with minimal fibrosis. We report here on a patient who in his ninth post-transplant year suffered from DIP following concurrent CMV andAspergillus pneumonias, and who was treated successfully with corticosteroids combined with antiviral and antifungal agents.

This study investigated factors that could affect background uptake of 99mTc- methoxyisobutylisonitrile (MIBI) on normal breast by breast-specific gamma imaging (BSGI). In addition, the impact of background 99mTc-MIBI uptake on the diagnostic performance of BSGI was further investigated. One hundred forty-five women with unilateral breast cancer who underwent BSGI, MRI, and mammography were retrospectively enrolled. Background uptake on BSGI was evaluated qualitatively and quantitatively. Patients were classified into non-dense and dense breast groups according to mammographic breast density. Background parenchymal enhancement (BPE) was rated according to BI-RADS classification. The relationship of age, menopausal status, mammographic breast density, and BPE with background 99mTc-MIBI uptake was analyzed. Heterogeneous texture and high background uptake ratio on BSGI were significantly correlated with younger age (p

Background B1 transmission-field inhomogeneity has been reported at 3.0 Tesla (T) breast imaging. Enhancement measurements of breast cancers at 3.0T may be insufficient for some patients and improvements in imaging protocols are needed. Purpose To quantify B1 inhomogeneities in normal tissue and malignant masses at 3.0T breast MR imaging and to evaluate effect of an imaging protocol using an interleaved sagittal sequence in dynamic contrast-enhanced MRI (DCE-MRI). Material and Methods A total of 76 patients were included who underwent DCE-MRI of the breast at 3.0T with an imaging protocol consisting of 1st, 2nd, and 4–6th bilateral axial sequences, and 3rd and 7th unilateral sagittal sequences. Signal intensity (SI) of normal breast tissue was measured at nipple level in four bilateral locations (anterior, posterior, medial, and lateral). Mean whole breast and location specific SI were calculated and compared between right and left breast using a paired t-test. All malignant masses were classified into three groups according to tumor size on MRI (≤2 cm, 2–4 cm, >4 cm). SI of malignant masses was measured independently on axial and sagittal sequences. The axial–sagittal SI gap in each mass was calculated and difference between right and left breast was compared using the t test. Size of each malignant mass was compared with pathologic findings to assess performance of the imaging protocol. Results SI of normal breast tissue were lower for the right breast (R-L difference, −91.9; P < 0.0001) and in all four locations (anterior, P < 0.01; posterior, P < 0.01; medial, P < 0.0001; lateral, P < 0.0001). SI of malignant masses were lower for the right breast among same size of the lesions ( P < 0.0001), particularly < 4 cm ( P < 0.0001). Decreased right to left difference in SI was produced with an interleaved sagittal sequence, as axial–sagittal gap of malignant masses was significant when tumor locates on the right side ( P < 0.001). The concordance rate in predicting size of mass in this imaging protocol was 92.2%. Conclusion The interleaved sagittal sequence is helpful to adjust reduced SI of malignant masses on right breast at 3.0T. This imaging protocol is clinically applicable by adding a single sequence during DCE-MRI of the breast.

Context Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. Objectives To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. Design Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. Setting University magnetic resonance imaging facility. Participants Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. Main Outcome Measures The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. Results Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. Conclusions Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

Despite the fact that mammography has been the golden standard in breast cancer detection for several decades, its sensitivity decreases for women with dense breast tissue, which happens to be common in Korea. As an alternative, breast ultrasonography can be effective diagnostic modalities that complement the defect of mammography. Recently, breast-specific gamma imaging (BSGI) has been introduced as a new diagnostic modality for breast cancer. This study was designed to analyze the effectiveness of BSGI in particular. In a retrospective study, 471 patients underwent BSGI, breast ultrasonography, and mammography simultaneously during the period between February 2009 and March 2010. The indications of BSGI were as follows: (a) patient who was diagnosed with malignancy prior to surgery, (b) patient who is under follow up after cancer surgery, (c) patient with lesions which cannot be evaluated by breast ultrasonography or mammography, (d) patient with multiple benign lesions, and (e) patient with suspicious lesion who refuses biopsy. Among these patients, 121 patients underwent biopsy, whereas others were followed up with imaging studies. We compared the BSGI results with those of mammography, breast ultrasonography, and pathology. The mean age of the patients was 49.63 ± 10.43 years. There were 107 patients with 110 malignant lesions and 364 patients with benign lesions. Total 474 lesions were evaluated. The sensitivities of BSGI, mammography, and breast ultrasonography were 94.45%, 93.64%, and 98.18%, respectively, whereas the specificities of BSGI, mammography, and breast ultrasonography were 90.93%, 90.66%, and 87.09%, respectively. The sensitivity and specificity of BSGI for axillary lymph node (LN) status were 44.7 4% and 87.88%, respectively. BSGI is a good complementary imaging modality with high sensitivity and high specificity for breast cancer detection. However, it has low efficacy for the evaluation for axillary LN status.

We present a novel parametric encoding scheme for efficiently recording white matter fiber bundle information obtained from diffusion tensor imaging. The coordinates of fiber tracts are parameterized using a cosine series expansion. For an arbitrary tract, a 19 degree expansion is found to be sufficient to reconstruct the tract with an average error of about 0.26 mm. Then each tract is fully parameterized with 60 parameters, which results in a substantial data reduction. Unlike traditional splines, the proposed method does not have internal knots and explicitly represents the tract as a linear combination of basis functions. This simplicity in the representation enables us to design statistical models, register tracts and perform subsequent analysis in a more streamlined mathematical framework. As an illustration, we apply the proposed method in characterizing abnormal tracts that pass through the splenium of the corpus callosum in autistic subjects.

The segmentation of diffusion tensor imaging (DTI) data is a challenging problem due to the high variation and overlap of the distributions induced by individual DTI measures (e.g., fractional anisotropy). Accurate tissue segmentation from DTI data is important for characterizing the mi-crostructural properties of white matter (WM) in a subsequent analysis. This step may also be useful for generating a mask to constrain the results of WM tractography. In this study, a graph-cuts segmentation method was applied to the problem of extracting WM, gray matter (GM) and cerebral spinal fluid (CSF) from brain DTI data. A two-phase segmentation method was adopted by first segmenting CSF signal from the DTI data using the third eigenvalue (lambda(3)) maps, and then extracting WM regions from the fractional anisotropy (FA) maps. The algorithm was evaluated on ten real DTI data sets obtained from in vivo human brains and the results were compared against manual segmentation by an expert. Overall, the graph cuts method performed well, giving an average segmentation accuracy of about 0.90, 0.77 and 0.88 for WM, GM and CSF respectively in terms of volume overlap(VO).

Diffusion Tensor Imaging (DTI) provides unique information about the underlying tissue structure of brain white matter in vivo, including both the geometry of fiber bundles as well as quantitative information about tissue properties as characterized by measures such as tensor orientation, anisotropy, and size. Our objective in this paper is to evaluate the utility of shape representations of white matter tracts extracted from DTI data for classification of clinically different population groups (here autistic vs control). As a first step, our algorithm extracts fiber bundles passing through approximately marked regions of interest on affinely aligned brain volumes. The subsequent analysis is entirely based on the geometric modeling of the extracted tracts. A key advantage of using such an abstraction is that it allows us to capture invariant features of brains allowing for efficient large sample size studies. We demonstrate that with the use of an appropriate representation of the tract shapes, classifiers can be built with reasonable prediction accuracies without making heavy use of the spatial normalization machinery needed when using voxel based features.

We report a case of acute severe hepatitis with Mycoplasma pneumoniae (M. pneumoniae) infection and transient depression of multiple coagulation factors. A 5-year-old boy, previously healthy, was admitted with pneumonia. M. pneumoniae infection was confirmed by serology testing. Liver enzymes were elevated on admission without any past medical history. After treatment with azithromycin for 3 days, pneumonia improved, but the hepatitis was acutely aggravated. Partial thromboplastin time (PTT) was prolonged and depression of multiple coagulation factors developed. Liver biopsy revealed features consistent with acute hepatitis. A week later, liver enzymes were nearly normalized spontaneously. Normalization of prolonged PTT and coagulation factors were also observed several months later. This may be the first case of transient depression of multiple coagulation factors associated with M. pneumoniae infection.

The aim of this study was to evaluate the value of use of multidetector CT (MDCT) to predict the need for subsequent surgery in patients with small-bowel obstruction (SBO) due to adhesion. During a 3-year period, 128 patients with an SBO due to adhesion were enrolled in this prospective study. Initially, all patients were treated conservatively. Surgery was performed in patients who developed signs of strangulation or did not improve, despite a conservative treatment for at least 5 days. Of the 128 patients, 37 patients eventually underwent surgery. Two radiologists interpreted MDCT findings regarded as predictive indicators for subsequent surgery in consensus. The findings included degree of SBO, presence of transition zone, and an abnormal vascular course. These findings were statistically compared between the group operated on and the group not operated on. A higher degree of SBO, an abnormal vascular course, and the presence of transition zone were more frequently seen in the group of patients operated on (p0.001). Sensitivities, specificities, positive and negative predictive values, and risks for the use of MDCT to predict the need for surgery were 100%, 46.1%, 43%, 100%, and 1.9 (1.5or = 95% confidence interval (CI)or = 2.2) for a high-grade obstruction; 100%, 23%, 34.5%, 100%, and 1.3 (1.2or = 95% CIor = 1.5) for the presence of a transition zone; and 70.2%, 90.1%, 74.2%, 88.1%, and 7.1 (3.7or = 95% CIor = 13.7) for the presence of an abnormal course of the mesenteric vessels, respectively. The presence of a high degree of SBO and an abnormal vascular course around transition zone are useful indicators on MDCT to predict the need for surgery in patients with an SBO due to adhesion.

BACKGROUND Point-of-care-testing (POCT) kits for tetanus toxoid antibody are used in emergency departments to evaluate the immunization status of patients with tetanus. The objective of this study was to evaluate the analytical performance and the utility of SD BIOLINE tetanus kit (Standard Diagnostic Inc., Yongin, Korea), as a POCT. METHODS A total of 326 peripheral blood specimens (whole blood, 319; serum, 326) from healthy subjects and patients were used. SD BIOLINE tetanus kit was evaluated for precision, accuracy, effect of specimens, operator variance, and the total processing time. The results from SD BIOLINE tetanus kit were compared with those from 2 quantitative ELISA kits. RESULTS Compared with ELISA kits, SD BIOLINE tetanus kit revealed a sensitivity of 88-97%, specificity of 87-92%, positive predictive value of 81-89%, negative predictive value of 90-98%, and kappa agreement of 0.78-0.82. SD BIOLINE tetanus kit also showed an excellent precision and a high accuracy. It showed a high concordance rate between whole blood and serum specimens. The total processing time of SD BIOLINE tetanus kit was 30-40 min. CONCLUSIONS SD BIOLINE tetanus kit showed an excellent analytical performance. With its rapid turnaround time and the ease of handling and interpretation, SD BIOLINE tetanus kit seems appropriate for the evaluation of tetanus immunization status as a POCT device. However, education for operators and standardized guidelines for result interpretation should be emphasized.

Post-transplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of diseases that represent serious complications following immunosuppressive therapy for solid organ or hematopoietic-cell recipients. In contrast to B-cell PTLD, T-cell PTLD is less frequent and is not usually associated with Epstein Barr Virus infection. Moreover, to our knowledge, isolated T-cell PTLD involving the breast is extremely rare and this condition has never been reported previously in the literature. Herein, we report a rare case of isolated T-cell PTLD of the breast that occurred after a patient had been treated for allogeneic peripheral blood stem cell transplantation due to acute myeloblastic leukemia.