Abdominal lymphatic pathway in Fontan circulation using non-invasive magnetic resonance lymphangiography.

Lymphatic congestion is known to play an important role in the development of late Fontan complications. This study aimed to (1) develop a gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast three-dimensional heavily T2-weighed MR technique that can detect abnormal lymphatic pathway in the abdomen while simultaneously evaluating hepatocellular carcinoma (HCC) and to (2) propose a new classification of abnormal abdominal lymphatic pathway using a non-invasive method in adults with Fontan circulation. Twenty-seven adults with Fontan circulation who underwent Gd-EOB-DTPA abdominal MR imaging were prospectively enrolled in this study. We proposed MR lymphangiography that suppresses the vascular signal on heavily T2-weighted imaging after EOB contrast. The patients were classified as follows: grade 1 with almost no lymphatic pathway, grade 2 with a lymphatic pathway mainly around the bile duct and liver surface, and grade 3 with a lymphatic pathway mainly around the vertebral body and inferior vena cava. The grade 3 group showed the lowest oxygen saturation level, highest central venous pressure, highest incidence of massive ascites, HCC, and focal nodular hyperplasia. This group also tended to have patients with the oldest age and highest cardiac index; however, the difference was not statistically significant. As for the blood test, the grade 3 group showed the lowest platelet count and serum albumin level and the highest fibrosis-4 index. A novel technique, Gd-EOB-DTPA MR lymphangiography, can detect abnormal abdominal lymphatic pathways in Fontan circulation, which can reflect the severity of failing Fontan.

Relation of quantitative visual and neurologic outcomes to fatigue in multiple sclerosis.

BACKGROUND: The relation of fatigue in multiple sclerosis (MS) to the visual system, an emerging structural and functional surrogate in MS, has not been well established. OBJECTIVE: We examined how physical and cognitive fatigue could be associated with visual dysfunction and neurologic impairment. METHODS: At a single time-point, we assessed 143 patients with: Low-contrast letter acuity (LCLA) and high-contrast visual acuity (VA) testing, the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Neuro-Ophthalmic Supplement, the Modified Fatigue Impact Scale (MFIS), the MS Functional Composite (MSFC), and the Expanded Disability Status Scale (EDSS). RESULTS: Worse binocular LCLA scores were associated with increased levels of total and physical fatigue (p≤0.026). Greater levels of fatigue were also associated with reduced vision-specific QOL (p<0.001). Patients with more physical, but not cognitive, fatigue had greater levels of impairment by the Timed 25-Foot Walk (T25W, r=0.39, p<0.001), 9-Hole Peg Test (9HP r=0.22, p=0.011) and EDSS (r=0.45, p<0.001). CONCLUSIONS: Reduced vision in MS is highly associated with physical fatigue and could be used to capture more global, difficult to describe, symptoms. The potential differences in physical vs. cognitive fatigue and their correlates may begin to provide insight into their underlying mechanisms.

Analysis of the visual system in Friedreich ataxia.

To use optical coherence tomography (OCT) and contrast letter acuity to characterize vision loss in Friedreich ataxia (FRDA). High- and low-contrast letter acuity and neurological measures were assessed in 507 patients with FRDA. In addition, OCT was performed on 63 FRDA patients to evaluate retinal nerve fiber layer (RNFL) and macular thickness. Both OCT and acuity measures were analyzed in relation to genetic severity, neurologic function, and other disease features. High- and low-contrast letter acuity was significantly predicted by age and GAA repeat length, and highly correlated with neurological outcomes. When tested by OCT, 52.7% of eyes (n = 110) had RNFL thickness values below the fifth percentile for age-matched controls. RNFL thickness was significantly lowest for those with worse scores on the Friedreich ataxia rating scale (FARS), worse performance measure composite Z2 scores, and lower scores for high- and low-contrast acuity. In linear regression analysis, GAA repeat length and age independently predicted RNFL thickness. In a subcohort of participants, 21% of eyes from adult subjects (n = 29 eyes) had macular thickness values below the first percentile for age-matched controls, suggesting that macular abnormalities can also be present in FRDA. Low-contrast acuity and RNFL thickness capture visual and neurologic function in FRDA, and reflect genetic severity and disease progression independently. This suggests that such measures are useful markers of neurologic progression in FRDA.

Ganglion cell loss in relation to visual disability in multiple sclerosis.

PURPOSE: We used high-resolution spectral-domain optical coherence tomography (SD-OCT) with retinal segmentation to determine how ganglion cell loss relates to history of acute optic neuritis (ON), retinal nerve fiber layer (RNFL) thinning, visual function, and vision-related quality of life (QOL) in multiple sclerosis (MS). DESIGN: Cross-sectional study. PARTICIPANTS: A convenience sample of patients with MS (n = 122; 239 eyes) and disease-free controls (n = 31; 61 eyes). Among MS eyes, 87 had a history of ON before enrollment. METHODS: The SD-OCT images were captured using Macular Cube (200×200 or 512×128) and ONH Cube 200×200 protocols. Retinal layer segmentation was performed using algorithms established for glaucoma studies. Thicknesses of the ganglion cell layer/inner plexiform layer (GCL+IPL), RNFL, outer plexiform/inner nuclear layers (OPL+INL), and outer nuclear/photoreceptor layers (ONL+PRL) were measured and compared in MS versus control eyes and MS ON versus non-ON eyes. The relation between changes in macular thickness and visual disability was also examined. MAIN OUTCOME MEASURES: The OCT measurements of GCL+IPL and RNFL thickness; high contrast visual acuity (VA); low-contrast letter acuity (LCLA) at 2.5% and 1.25% contrast; on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement composite score. RESULTS: Macular RNFL and GCL+IPL were significantly decreased in MS versus control eyes (P<0.001 and P = 0.001) and in MS ON versus non-ON eyes (P<0.001 for both measures). Peripapillary RNFL, macular RNFL, GCL+IPL, and the combination of macular RNFL+GCL+IPL were significantly correlated with VA (P≤0.001), 2.5% LCLA (P<0.001), and 1.25% LCLA (P≤0.001). Among OCT measurements, reductions in GCL+IPL (P<0.001), macular RNFL (P = 0.006), and the combination (macular RNFL+GCL+IPL; P<0.001) were most strongly associated with lower (worse) NEI-VFQ-25 and 10-Item Supplement QOL scores; GCL+IPL thinning was significant even accounting for macular RNFL thickness (P = 0.03 for GCL+IPL, P = 0.39 for macular RNFL). CONCLUSIONS: We demonstrated that GCL+IPL thinning is most significantly correlated with both visual function and vision-specific QOL in MS, and may serve as a useful structural marker of disease. Our findings parallel those of magnetic resonance imaging studies that show gray matter disease is a marker of neurologic disability in MS. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Vision in multiple sclerosis: the story, structure-function correlations, and models for neuroprotection.

Visual dysfunction is one of the most common clinical manifestations of multiple sclerosis (MS). Just over a decade ago, MS clinical trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function. Low-contrast letter acuity emerged as the leading candidate to measure visual disability in MS, and subsequent studies found low-contrast acuity testing to correlate well with brain MRI lesion burden, visual-evoked potentials, quality of life (QOL), and retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography (OCT). OCT in MS has allowed for assessment of structure-function correlations that make the anterior visual pathway and acute optic neuritis (ON) ideal models for testing novel agents for neuroprotection and repair. New therapies that reduce axonal loss by neuroprotective or myelin repair mechanisms can now be assessed noninvasively by OCT and coupled with visual function data. Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 µm) vs controls (105 µm) and is particularly reduced in MS eyes with a history of ON (85 µm). Worsening of visual function by a clinically significant ≥ 7 letters or approximately 1.5 lines for low-contrast acuity is associated with approximately 4.5 µm reductions in RNFL thickness in MS eyes. Longitudinal studies of OCT have also shown RNFL axonal loss over time that occurs even in the absence of acute ON and that correlates with clinically meaningful worsening of vision and QOL, even in patients with benign MS. The latest OCT investigations involve high-resolution spectral-domain (SD) OCT with segmentation and measurement of specific retinal layers using computerized algorithms. These methods allow quantitation of ganglion cell (neuronal) layer loss and axonal degeneration in MS in vivo. In this review, we examine the data from these studies and ongoing trials that highlight the entity of ON as a model to investigate neuroprotection and neurorepair. In doing so, we also present representative group data from studies that have examined visual function, OCT measures, and QOL scales in patients with MS and ON and disease-free controls. These data, and those from recent meta-analyses, may be used to provide reference values for the development of clinical trial protocols.

The prevalence of personality disorders in hypochondriasis.

BACKGROUND: Although Axis I hypochondriasis is closely related to certain personality characteristics, the nature and extent of personality dysfunction in these patients still needs clarification. This study assessed the prevalence of personality disorders observed in hypochondriacal patients, described the types and comorbidity of personality disorders, and compared the psychological distress of patients with and without the most common comorbid personality disorder. METHOD: One hundred fifteen patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for hypochondriasis completed self-administered assessments, including the Personality Diagnostic Questionnaire-4+ (PDQ-4+), the Hopkins Symptom Checklist-90-Revised (SCL-90-R), the Whiteley Index, and the Somatic Symptom Inventory. These data were taken from a study conducted between September 1997 and November 2001. RESULTS: Eighty-eight patients (76.5%) had 1 or more personality disorders, whereas 27 patients (23.5%) had no personality disorders. Fifty-one patients (44.3%) had more than 3 personality disorders. The most common personality disorder in the hypochondriacal patients was obsessive-compulsive personality disorder (OCPD; 55.7%), followed by avoidant personality disorder (40.9%). The comorbidity of OCPD and avoidant personality disorder was 53.1% (34 of 64 patients with OCPD). The total PDQ-4+ score of the 64 patients with OCPD was significantly higher than that of the 51 patients without OCPD. On the SCL-90-R, the 64 patients with OCPD showed significantly higher scores on all of 3 global indices and 7 of 10 primary symptom dimensions (paranoid ideation, depression, anxiety, phobic anxiety, obsessive-compulsive, interpersonal sensitivity, and psychoticism) on the SCL-90-R compared to the 51 patients without OCPD. CONCLUSIONS: The high prevalence of personality disorders, particularly OCPD, among patients with hypochondriasis suggests that consideration of personality features is important in assessment and therapeutic interventions for hypochondriasis.

Possible de novo CTG repeat expansion in the DMPK gene of a patient with cardiomyopathy.

CTG triplet repeats of "normal" length in the myotonic dystrophy protein kinase (DMPK) gene have been previously believed to be stable and new pathological expansion was not believed to occur. Here we report possible de novo CTG repeat expansion in the DMPK gene in a patient with cardiomyopathy, who was not diagnosed as having myotonic dystrophy type 1 (DM1) by conventional genetic tests.

Biological roles of anti-GM1 antibodies in patients with Guillain-Barré syndrome for nerve growth factor signaling.

To reveal the biological and pathological roles of anti-GM1 antibody in Guillain-Barré syndrome (GBS), we examined its effects on nerve growth factor (NGF) induced TrkA autophosphorylation (NGF-TrkA signaling) in PC12 cells, a sympathetic nerve cell line. The NGF-TrkA signaling is enhanced by exogenous GM1 ganglioside and this phenomenon is regarded as one of the functional aspects of GM1. The IgGs purified from patients' sera inhibited the NGF-TrkA signaling in GM1 pre-incubated PC12 cells. The degrees of inhibition by IgGs from patients paralleled their immunological reactivity to GM1. In addition, the IgGs also inhibited the neurite outgrowth of NGF-treated PC12 cells. Immunoglobulins in the rabbit sera, which were immunized by GM1, also caused a similar suppressive phenomenon. These results suggested that the anti-GM1 antibody could play roles in pathophysiology in anti-GM1 antibody positive GBS through interfering with the neurotrophic action of NGF and GM1 mediated signal modulation including NGF-TrkA signaling. It is suggested that the modulation of GM1 function is one important action of antibodies and could be one of the important mechanisms in GBS.

[Natural killer cell activity among patients with atopic dermatitis].

We examined natural killer (NK) activity in 128 patients with atopic dermatitis (AD) to investigate the relationships between NK activity and severity of dermatitis, duration of disease, and mental states. The results showed the following: 1) No relationship was shown between severity of dermatitis and NK activity, neither between NK activity nor eosinophilic counts nor serum IgE. 2) Patients with longer duration of AD lesions showed significantly lower NK activity (P=0.036). The significant relationship was recognized between severity of dermatitis and the duration of disease (P=0.014). 3) No relationships were recognized between NK activity and mental states evaluated using the Profile Of Mood States (POMS) questionnaire, as tension-anxiety, depression-dejection, anger-hostility, vigor, fatigue and confusion. From a psychoneuroimmunological viewpoint, chronic stress as having AD might influence the lower NK activity of patients with longer duration of AD.

In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).

We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.