Mary Ehrmantraut

Pulmonary Nontuberculous Mycobacterial Disease: Prospective Study of a Distinct Preexisting Syndrome

RATIONALE Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

Relationship of Cortical Atrophy to Fatigue in Patients With Multiple Sclerosis

BACKGROUND Fatigue is a common and disabling symptom of multiple sclerosis (MS). Previous studies reported that damage of the corticostriatothalamocortical circuit is critical in its occurrence. OBJECTIVE To investigate the relationship between fatigue in MS and regional cortical and subcortical gray matter atrophy. DESIGN Case-control study. SETTING National Institutes of Health. PARTICIPANTS Twenty-four patients with MS and 24 matched healthy volunteers who underwent 3.0-T magnetic resonance imaging and evaluations of fatigue (Modified Fatigue Impact Scale) and depression (Center for Epidemiologic Studies Depression Scale). MAIN OUTCOME MEASURES Relationship between thalamic and basal ganglia volume, cortical thickness of frontal and parietal lobes, and, in patients, T2 lesion volume and normal-appearing white matter volume and the extent of fatigue. RESULTS Patients were more fatigued than healthy volunteers (P = .04), while controlling for the effect of depression. Modified Fatigue Impact Scale score correlated with cortical thickness of the parietal lobe (r = -0.50, P = .01), explaining 25% of its variance. The posterior parietal cortex was the only parietal area significantly associated with the Modified Fatigue Impact Scale scores. CONCLUSIONS Cortical atrophy of the parietal lobe had the strongest relationship with fatigue. Given the implications of the posterior parietal cortex in motor planning and integration of information from different sources, our preliminary results suggest that dysfunctions in higher-order aspects of motor control may have a role in determining fatigue in MS.

Thalamic Involvement and Its Impact on Clinical Disability in Patients with Multiple Sclerosis: A Diffusion Tensor Imaging Study at 3T

BACKGROUND AND PURPOSE: Several studies suggest that grey matter involvement may play a role in multiple sclerosis (MS) pathology. Diffusion tensor imaging (DTI) at 3T was used to investigate the presence of damage to the normal-appearing thalamus in MS and its relationship with disability. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting (RR, n = 13, age = 41.7 ± 6.1, Expanded Disability Status Scale [EDSS] score = 2.2 ± 1.2) and secondary-progressive (n = 11, age = 46.9 ± 9.6, EDSS = 5.9 ± 1.0) MS and 24 age- and sex-matched healthy volunteers were studied. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in regions of interest of normal-appearing thalamus. We examined group differences in MD and FA and correlations between DTI-derived metrics and clinical or imaging measures of disease. RESULTS: Patients with MS had higher thalamic FA (P < .0001) and MD (P = .035) than volunteers. MD values correlated with the Paced Auditory Serial Addition Task (r = −0.43, P = .034) and motor EDSS (r = 0.47, P = .021) scores. In patients with RRMS, MD values correlated with global EDSS (r = 0.75, P = .003) and motor EDSS (r = 0.68, P = .010). Correlations were found between MD values and T1 and T2 lesion load (r = 0.58, P < .05) and brain parenchymal fraction (r = −0.46, P < .05). CONCLUSIONS: DTI was able to detect abnormalities in normal-appearing thalamus of patients with MS. The strength of association between thalamic DTI measures and functional impairment was in the same range as those seen with standard MR imaging disease measures. The assessment of the integrity of the thalamus with DTI is a promising metric as a marker of disease for future studies.

Auto-ADP-ribosylation of Pseudomonas aeruginosa ExoS

Pseudomonas aeruginosa Exoenzyme S (ExoS) is a bifunctional type-III cytotoxin. The N terminus possesses a Rho GTPase-activating protein (GAP) activity, whereas the C terminus comprises an ADP-ribosyltransferase domain. We investigated whether the ADP-ribosyltransferase activity of ExoS influences its GAP activity. Although the ADP-ribosyltransferase activity of ExoS is dependent upon FAS, a 14-3-3 family protein, factor-activating ExoS (FAS) had no influence on the activity of the GAP domain of ExoS (ExoS-GAP). In the presence of NAD and FAS, the GAP activity of full-length ExoS was reduced about 10-fold, whereas NAD and FAS did not affect the activity of the ExoS-GAP fragment. Using [32P]NAD, ExoS-GAP was identified as a substrate of the ADP-ribosyltransferase activity of ExoS. Site-directed mutagenesis revealed that auto-ADP-ribosylation of Arg-146 of ExoS was crucial for inhibition of GAP activityin vitro. To reveal the auto-ADP-ribosylation of ExoS in intact cells, tetanolysin was used to produce pores in the plasma membrane of Chinese hamster ovary (CHO) cells to allow the intracellular entry of [32P]NAD, the substrate for ADP-ribosylation. After a 3-h infection of CHO cells withPseudomonas aeruginosa, proteins of 50 and 25 kDa were preferentially ADP-ribosylated. The 50-kDa protein was determined to be auto-ADP-ribosylated ExoS, whereas the 25-kDa protein appeared to represent a group of proteins that included Ras.

Sera from Adult Patients with Cystic Fibrosis Contain Antibodies to Pseudomonas aeruginosa Type III Apparatus

ABSTRACT Expression of type III proteins of Pseudomonas aeruginosa in patients with cystic fibrosis (CF) was investigated by measuring the immune response against components of the type III pathway. Twenty-three of the 33 sera contained antibodies against PcrV, a protein involved in translocation of type III cytotoxins into eukaryotic cells, and 11 of 33 had antibodies against ExoS, while most CF sera contained antibodies against PopB and PopD, components of the type III apparatus. These data indicate that P. aeruginosacommonly expresses components of the type III translocation apparatus in adult CF patients.

T1 cortical hypointensities and their association with cognitive disability in multiple sclerosis

Background: Neocortical lesions (NLs) largely contribute to the pathology of multiple sclerosis (MS), although their relevance in patients’ disability remains unknown. Objective: To assess the incidence of T1 hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. Methods: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm3 three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T1- and T2-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. Results: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NLpatients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. Conclusions: Although T 1 hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease.

Heterogeneity in Response to Interferon Beta in Patients With Multiple Sclerosis: A 3-Year Monthly Imaging Study

OBJECTIVES To investigate the heterogeneity in magnetic resonance image (MRI) patterns of response to interferon beta across patients with multiple sclerosis or within an individual patient over time. DESIGN, SETTING, AND PATIENTS Fifteen patients with relapsing-remitting multiple sclerosis underwent monthly MRIs and clinical examinations (6-month pretherapy phase and 36-month therapy phase) and bimonthly neutralizing antibody tests. On each MRI, the total number of contrast-enhancing lesions was noted. Therapy MRI responders were defined as those with a reduction of 60% or more in the total number of contrast-enhancing lesions during each semester of therapy. INTERVENTION Subcutaneous administration of interferon beta-1b, 250 microg, every other day for 3 years. MAIN OUTCOME MEASURE Reduction in the number of contrast-enhancing lesions. RESULTS Eight patients (53.3%) were MRI responders and 7 (46.7%) were nonresponders. Of those 7, 3 (20.0%) had only an initial optimal reduction of the total number of contrast-enhancing lesions, 2 (13.3%) never reached an optimal response, and 2 (13.3%) had a delayed optimal response. No clear association between neutralizing antibody profile and MRI response was evident. CONCLUSIONS Multiple MRI evaluations disclose that approximately only half of the patients treated with interferon beta achieve and maintain a full response to the drug over time, although an additional small number of individuals may still restore an optimal response to the drug after an initial failure.

Quality and Quantity of Diffuse and Focal White Matter Disease and Cognitive Disability of Patients with Multiple Sclerosis

Using high‐field magnetic resonance imaging (MRI), we investigated the relationships between white matter (WM) lesion volume (LV), normal‐appearing WM (NAWM) normalized volume, WM‐lesion and NAWM magnetization transfer ratios (MTRs), brain parenchyma fraction (BPF), and cognitive impairment (CI) in multiple sclerosis (MS).

A case study on the effect of neutralizing antibodies to interferon beta 1b in multiple sclerosis patients followed for 3 years with monthly imaging

Interferon beta (IFN‐β) is among the first‐line treatment options for patients with multiple sclerosis (MS). A potential caveat of therapy, however, is the development of neutralizing antibodies (NAb) and/or neutralizing activity (NA) non‐antibody mediated, although debate is still ongoing as to whether NAb significantly hampers the efficacy of the drug or rather represents an immunologically irrelevant epiphenomenon. In the present study, we describe the effect of NAb on IFN‐β‐1b through clinical and magnetic resonance imaging (MRI) outcome measures of five relapsing–remitting multiple sclerosis (RRMS) patients who were treated with 250 μg of subcutaneously administered IFN‐β‐1b every other day and developed NAb at varying titres and times during the course of therapy. Despite the small number of NAb+ patients, heterogeneity in MRI/clinical response to IFN‐β‐1b was identified. Response to IFN‐β‐1b therapy was observed in the absence or presence of NAb. Also observed was failure to IFN‐β‐1b coincident with high and sustained NAb titres, but also before NAb development or in the presence of low NAb titres. Multiple MRI and NAb measurements performed within the same individual allow for a better description of the complex heterogeneous response to IFN‐β‐1b with respect to NAb occurrence.

Diffuse and Focal Corticospinal Tract Disease and Its Impact on Patient Disability in Multiple Sclerosis

We investigated the impact of focal and diffuse corticospinal tracts damage on sensory‐motor disability in multiple sclerosis (MS) patients.