PTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons.

Excitatory transmission in the brain is commonly mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In amyotrophic lateral sclerosis (ALS), AMPA receptors allow cytotoxic levels of calcium into neurons, contributing to motor neuron injury. We have previously shown that oculomotor neurons resistant to the disease process in ALS show reduced AMPA-mediated inward calcium currents compared with vulnerable spinal motor neurons. We have also shown that PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown via siRNA promotes motor neuron survival in models of spinal muscular atrophy (SMA) and ALS. It has been reported that inhibition of PTEN attenuates the death of hippocampal neurons post injury by decreasing the effective translocation of the GluR2 subunit into the membrane. In addition, leptin can regulate AMPA receptor trafficking via PTEN inhibition. Thus, we speculate that manipulation of AMPA receptors by PTEN may represent a potential therapeutic strategy for neuroprotective intervention in ALS and other neurodegenerative disorders. To this end, the first step is to establish a fibroblast-iPS-motor neuron in vitro cell model to study AMPA receptor manipulation. Here we report that iPS-derived motor neurons from human fibroblasts express AMPA receptors. PTEN depletion decreases AMPA receptor expression and AMPA-mediated whole-cell currents, resulting in inhibition of AMPA-induced neuronal death in primary cultured and iPS-derived motor neurons. Taken together, our results imply that PTEN depletion may protect motor neurons by inhibition of excitatory transmission that represents a therapeutic strategy of potential benefit for the amelioration of excitotoxicity in ALS and other neurodegenerative disorders.

Forefoot pain involving the metatarsal region: differential diagnosis with MR imaging.

Many disorders produce discomfort in the metatarsal region of the forefoot. These disorders include traumatic lesions of the soft tissues and bones (eg, turf toe, plantar plate disruption, sesamoiditis, stress fracture, stress response), Freiberg infraction, infection, arthritis, tendon disorders (eg, tendinosis, tenosynovitis, tendon rupture), nonneoplastic soft-tissue masses (eg, ganglia, bursitis, granuloma, Morton neuroma), and, less frequently, soft-tissue and bone neoplasms. Prior to the advent of magnetic resonance (MR) imaging, many of these disorders were not diagnosed noninvasively, and radiologic involvement in the evaluation of affected patients was limited. However, MR imaging has proved useful in detecting the numerous soft-tissue and early bone and joint processes that occur in this portion of the foot but are not depicted or as well characterized with other imaging modalities. Frequently, MR imaging allows a specific diagnosis based on the location, signal intensity characteristics, and morphologic features of the abnormality. Consequently, MR imaging is increasingly being used to evaluate patients with forefoot complaints. Radiologists should be familiar with the differential diagnosis and MR imaging features of disorders that can produce discomfort in this region.

Cystic synovial sarcoma.

A case of synovial sarcoma of the paraspinal region showing massive cystic changes is described. The tumor presented in a 53-year-old white woman who noticed a lump on the upper aspect of her back. Magnetic resonance imaging of the cervical spine showed a heterogeneous paraspinal mass with well-defined margins and a multilocular quality with foci of hemorrhage. Fine needle aspiration of the mass showed clusters of polygonal cells admixed with a scattered spindle cell component. Surgical excision of the mass showed a well-circumscribed but nonencapsulated tumor that showed multiple small cystic structures on cross-section. Histologic examination showed a biphasic neoplasm characterized by bland-appearing glandular elements embedded in a moderately cellular spindle cell stroma. The tumor contained multiple cysts of varying size. Immunohistochemical studies showed the glandular component to be positive for cytokeratin and epithelial membrane antigen. The spindle cell component was immunoreactive for cytokeratin, vimentin, bcl-2, and CD99. Stains for muscle-specific actin, smooth muscle actin, S-100 protein, and CD34 were negative. Cytogenetic analysis showed a balanced reciprocal translocation involving chromosomes X and 18, in addition to other clonal abnormalities. Synovial sarcoma should be considered in the differential diagnosis of cystic lesions involving the soft tissues. Magnetic resonance imaging is considered the procedure of choice for the evaluation of soft tissue tumors because of its superior soft tissue contrast and multiplanar imaging capability. While the imaging features of soft tissue tumors are often nonspecific, magnetic resonance imaging may provide helpful clues, thus narrowing the differential diagnosis. Immunohistochemical studies and cytogenetic analysis may be very helpful for establishing the correct diagnosis in cases with this unusual presentation. Ann Diagn Pathol 5:48-56, 2001.

Satisfaction of search in osteoradiology.

OBJECTIVE: "Satisfaction of search" describes a situation in which the detection of one radiographic abnormality interferes with that of others. This phenomenon has not been investigated for the interpretation of skeletal radiographs. We determined whether satisfaction of search occurs in the interpretation of conventional radiographs of the musculoskeletal system. SUBJECTS AND METHODS: Twelve volunteers from radiology (10 residents and two staff members) and 13 volunteers from orthopedic surgery (all residents) were shown in random order 15 cases in which one abnormality was present and 15 cases in which either two or three abnormalities were present. The cases with multiple findings contained a total of 19 abnormalities. All cases were selected from the emergency department. The volunteers received three scores reflecting their ability to detect abnormalities on a single-finding case, at least one abnormality on a multiple-finding case, and additional findings in cases with multiple abnormalities. The scores were compared using the chi-square test with Yates correction. Analysis of variance and Bonferroni adjustment were also performed. RESULTS: Among the cases with single findings, detection rates averaged 11.25; for the 15 multiple-finding cases, the detection rate for one finding averaged 11.72. The difference was not statistically significant. Detection rates for the second and third abnormalities in the multiple-finding cases were significantly lower, averaging 6.12 (p < 0.01). CONCLUSION: A significant satisfaction of search effect occurred and was operative in the interpretation of radiographs of the musculoskeletal system.

Valve data collection: problems and pitfalls.

Since 1981, the Department of Medical Physics and Clinical Engineering at the University of Sheffield has been responsible for the organization, management and data collection associated with the largest multicentre heart valve implant patient follow-up study in the Western world. At the present time, the database comprises information on over 16,000 valve implants, which have been provided by 57 surgeons working at 22 centres in the UK. All this data is available for in-depth statistical analysis. Over 30 individual valve models presently are included in the Study and these can be categorized into five main types: ball, disc, porcine, pericardial and homograft. Analysis includes descriptive statistics as well as valuable information on the various performances of the different valves. Survival and event-free survival graphs are obtained by actuarial methods and individual valve types can be studied in depth in terms of freedom from thromboembolic complications and valve dysfunction. Whilst this approach provides interesting and valuable survival data, it does not take account of the wide variation in prognostic factors which occur within large groups of patients. This latter problem can be addressed by the use of proportional hazards analysis and this paper provides details of this approach and typical results obtained from the use of this method. These include the comparative performances of the major types of valves currently in use in terms of the event-free survival of the patients.