Conformational Disorder of the Most Immature Cu, Zn-Superoxide Dismutase Leading to Amyotrophic Lateral Sclerosis.

Misfolding of Cu,Zn-superoxide dismutase (SOD1) is a pathological change in the familial form of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene. SOD1 is an enzyme that matures through the binding of copper and zinc ions and the formation of an intramolecular disulfide bond. Pathogenic mutations are proposed to retard the post-translational maturation, decrease the structural stability, and hence trigger the misfolding of SOD1 proteins. Despite this, a misfolded and potentially pathogenic conformation of immature SOD1 remains obscure. Here, we show significant and distinct conformational changes of apoSOD1 that occur only upon reduction of the intramolecular disulfide bond in solution. In particular, loop regions in SOD1 lose their restraint and become significantly disordered upon dissociation of metal ions and reduction of the disulfide bond. Such drastic changes in the solution structure of SOD1 may trigger misfolding and fibrillar aggregation observed as pathological changes in the familial form of amyotrophic lateral sclerosis.

Visualization of normal pulmonary fissures on sagittal multiplanar reconstruction MDCT.

OBJECTIVE: Delineation of the interlobar fissures on multiplanar reconstruction (MPR) images is useful to assess masses at the fissures for invasion into adjacent lobes. We performed this study to determine the appropriate MDCT protocol to visualize the interlobar fissures on sagittal MPR images. MATERIALS AND METHODS: For the phantom studies, radiographic film was used to replicate the interlobar fissures. For the clinical studies, we obtained MDCT scans of 130 patients with normal interlobar fissures. Visualization of the interlobar fissures on sagittal MPR was assessed using the following scanning parameters: scan collimations of 0.5, 1, 2, and 3 mm with helical pitches of 1 and 1.5 for the phantom studies; and scan collimations of 0.5, 1, 2, and 3 mm with a helical pitch of 1.5 and a scan collimation of 2 mm with a helical pitch of 1 for the clinical studies. RESULTS: To visualize fissures as a sharp line, a 0.5- or 1-mm collimation was required for the major fissure and 0.5 mm for the minor fissure in the phantom studies. In the clinical studies, 0.5-mm-collimation MPR images depicted interlobar fissures as a sharp line in all cases. Fissures on MPR images using 1-, 2-, and 3-mm collimations appeared as a sharp line in 77.5-95.0%, 0-43.3%, and 0% of cases, respectively. CONCLUSION: Volume data obtained using a 1-mm collimation are required to visualize all the interlobar fissures as a sharp line on sagittal MPR images except the minor fissure and superior portion of the right major fissure, for which a 0.5-mm collimation is required.

A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43.

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein containing two consecutive RNA recognition motifs (RRM1 and RRM2) in tandem. Functional abnormality of TDP-43 has been proposed to cause neurodegeneration, but it remains obscure how the physiological functions of this protein are regulated. Here, we show distinct roles of RRM1 and RRM2 in the sequence-specific substrate recognition of TDP-43. RRM1 was found to bind a wide spectrum of ssDNA sequences, while no binding was observed between RRM2 and ssDNA. When two RRMs are fused in tandem as in native TDP-43, the fused construct almost exclusively binds ssDNA with a TG-repeat sequence. In contrast, such sequence-specificity was not observed in a simple mixture of RRM1 and RRM2. We thus propose that the spatial arrangement of multiple RRMs in DNA/RNA binding proteins provides steric effects on the substrate-binding site and thereby controls the specificity of its substrate nucleotide sequences.

Absent skeletal uptake of (99m)Tc-hydroxymethylene diphosphonate in the presence of AL-type amyloidosis associated with multiple myeloma.

A 66-year-old woman with congestive heart failure suspected to have multiple myeloma underwent bone scintigraphy. The bone scintigraphy using technetium-99m hydroxymethylene-diphosphonate showed the following interesting findings: absent skeletal uptake; increased gastrointestinal, myocardial, and soft tissue uptake; migration of radionuclide to bilateral pleural effusions. Histopathological examination revealed that the patient suffered from AL-type amyloidosis associated with multiple myeloma. Extraosseous uptake is often observed on bone scintigraphy in amyloidosis patients, but in many cases skeletal uptake is preserved. The simultaneous presentation of these findings is rare.

Thymic hyperplasia and thymus gland tumors: differentiation with chemical shift MR imaging.

PURPOSE: To prospectively evaluate chemical shift magnetic resonance (MR) imaging for differentiating thymic hyperplasia from tumors of the thymus gland. MATERIALS AND METHODS: The institutional review board approved this study; informed consent was obtained and patient confidentiality was protected. The authors assessed 41 patients (17 male, 24 female; age range, 16-78 years) in whom thymic lesions were seen at chest computed tomography. Patients were assigned to a hyperplasia group (n=23) (18 patients with hyperplastic thymus associated with Graves disease and five with rebound thymic hyperplasia) and a tumor group (n=18) (seven patients with thymomas, four with invasive thymomas, five with thymic cancers, and two with malignant lymphomas). T2-weighted fast spin-echo and T1-weighted in-phase and opposed-phase MR images were obtained in all patients and visually assessed. A chemical shift ratio (CSR), determined by comparing the signal intensity of the thymus gland with that of the paraspinal muscle, was calculated for quantitative analysis. Mean CSRs for the patient groups and subgroups were analyzed by using Welch t and Newman-Keuls tests. P<.05 indicated a significant difference. RESULTS: The thymus gland had homogeneous signal intensity in all 23 patients in the hyperplasia group and in 12 of the 18 patients in the tumor group. The mean CSR (+/- standard deviation) was 0.614 +/- 0.130 in the hyperplasia group and 1.026 +/- 0.039 in the tumor group. Mean CSRs in the patients with a hyperplastic thymus and Graves disease, rebound thymic hyperplasia, thymoma, invasive thymoma, thymic cancer, and malignant lymphoma were 0.594 +/- 0.120, 0.688 +/- 0.154, 1.033 +/- 0.043, 1.036 +/- 0.040, 1.020 +/- 0.044, and 0.997 +/- 0.010, respectively. The difference in CSR between the hyperplasia and tumor groups was significant (P<.001). Mean CSRs in the hyperplasia subgroups were lower than those in the tumor subgroups (P<.001). All hyperplasia group patients had an apparent decrease in thymus gland signal intensity at chemical shift MR imaging; no tumor group patients had a decrease in thymus gland signal intensity. CONCLUSION: Chemical shift MR imaging can be used to differentiate thymic hyperplasia from thymic tumors.

Evaluation of normal fatty replacement of the thymus with chemical-shift MR imaging for identification of the normal thymus.

PURPOSE: To clarify the influences of age and gender on normal fatty replacement of the thymus in childhood, adolescence, and early adulthood using chemical-shift MRI. MATERIALS AND METHODS: A total of 95 normal subjects (52 males and 43 females, mean age = 15.6 years, range = 7-25 years) who underwent chemical-shift MRI of the thymus were assessed prospectively. Signal intensity loss (SIL) of the thymus was determined by dividing the thymus/muscle ratio on the opposed-phase image by that on the in-phase image. We evaluated SIL for its correlation with age and gender, and assessed SIL of the thymus with uncommon morphological features. RESULTS: A significant correlation was found between SIL and age (r = 0.750, P < 0.001). There was no significant difference in SIL between the genders. No significant SIL was identified in any of the subjects aged 10 years or less. However, significant SIL was found in 70.8% of those aged 11-20 years, 100% of those aged 21 years or more, and 46.2% of subjects with uncommon morphological features of the thymus. CONCLUSION: Chemical-shift MRI can depict physiologic fatty infiltration within the normal thymus in subjects over 11 years of age. It is crucial to correlate these normal age-related findings with clinical cases in order to avoid misinterpretation.

Characterization of the normal and hyperplastic thymus on chemical-shift MR imaging.

OBJECTIVE: We designed our study to prospectively assess a potential role for chemical-shift MR imaging in identifying a thymus that has not been completely replaced by fat tissue. CONCLUSION: The thymic tissue revealed homogeneous decrease in intensity on opposed-phase MR images relative to that seen on in-phase images in 15 healthy volunteers and two patients with hyperplastic thymus. Chemical-shift MR imaging may be useful in identifying normal thymic tissue and the hyperplastic thymus in early adulthood.

[Imaging findings of pulmonary vascular disorders in portal hypertension].

PURPOSE: The purpose of this study was to demonstrate and compare the imaging findings of hepatopulmonary syndrome and portopulmonary hypertension. MATERIALS AND METHODS: We retrospectively reviewed the imaging findings of five patients with hepatopulmonary syndrome and four patients with portopulmonary hypertension. We evaluated chest radiographs, chest and abdominal computed tomography (CT) scans, 99mTc-macroaggregated albumin (MAA) lung perfusion scans, and pulmonary angiograms. RESULTS: In patients with hepatopulmonary syndrome, the presence of peripheral pulmonary vascular dilatation was detected by chest radiograph, chest CT scan, and pulmonary angiogram, especially the basilar segment. 99mTc-MAA lung perfusion scan showed extrapulmonary tracer distribution (brain, thyroid, and kidney), which revealed pulmonary R-L shunting. In patients with portopulmonary hypertension, chest radiographs and chest CT scans showed the classic findings of primary pulmonary hypertension. In patients with both disorders, extrahepatic features of portal hypertension including ascites, splenomegaly, and portosystemic collateral vessels were seen on abdominal CT. CONCLUSION: In conclusion, chest radiographs and CT in hepatopulmonary syndrome usually showed peripheral pulmonary vascular dilatation, whereas those in portopulmonary hypertension showed central pulmonary artery dilatation. The extrahepatic features of portal hypertension might be helpful for the diagnosis of both disorders.