Transgenic expression of the protein-L-isoaspartyl methyltransferase (PIMT) gene in the brain rescues mice from the fatal epilepsy of PIMT deficiency

Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues. In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. The mutant mice also showed a neurodegenerative pathology in hippocampi and impaired spatial memory. Still undefined, however, is how the accumulation of isoaspartates leads to the death of PIMT-deficient mice. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT deficiency. Rescue experiments showed that Tg expression of PIMT driven by a prion promoter effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially rescued line, the mice survived. Interestingly, synapsin I, which was extensively modified posttranslationally in PIMT-deficient mice, was specifically repaired in a partially rescued, but symptom-improved, Tg line. Our results suggest that an overall accumulation of damaged proteins does not necessarily lead to a fatal epileptic seizure, whereas certain modifications, such as changes in synapsin I, may play a pivotal pathological role in epilepsy.     

Determination of medullasin levels for the diagnosis of multiple sclerosis

Medullasin levels in granulocytes of patients with neurological diseases and healthy volunteers were determined by the enzyme immunoassay using mouse monoclonal antibodies against human medullasin and o-phenylenediamine-H2O2 as the detection system of the enzyme activity. One hundred twenty-one out of 159 patients with multiple sclerosis (76.1%) showed positive results (above means of normals + 2SD) in this test, while only 16.9% (24/142) of patients with non-inflammatory neurological diseases had positive results. This enzyme immunoassay method for medullasin is considered to be an useful paraclinical test for the diagnosis of multiple sclerosis.     

Fine needle aspiration cytology of nodular fasciitis of the breast

We report a case of nodular fasciitis (NF) of the breast, which was cytologically diagnosed as a spindle cell proliferation with undetermined malignant potential. Owing to small size of the lesion (5.9 × 3.7 × 4.1 mm), only fine needle aspiration (FNA) cytology was performed under ultrasound guidance. The FNA smears were cellular, rich in single/clustered spindle cells but mammary ductal epithelial/myoepithelial cells were absent. These cytologic findings suggested spindle cell growth of mesenchymal origin. Pattern‐less arrangement of spindle cells, heterogeneous composition of the stromal matrix, lack of nuclear/cellular atypia, occasional mitosis but no aberrant mitotic figures, and lymphocyte infiltration indicated reactive rather than neoplastic nature of the lesion. Nonetheless, lumpectomy was conducted because the possibility of neoplasm was not completely ruled out. The histologic diagnosis of the resected nodule was NF. FNA specimens were reviewed thoroughly in an attempt to define the key cytomorphologic features of NF that are important for the correct diagnosis. Differential diagnoses from the lesions that show similar cytologic pictures are discussed in detail. Although NF arising from the breast is rare, cytopathologists should be aware of its clinical and cytopathologic characteristics. Knowledge of the possibility of NF in the breast and its cytologic findings may help cytopathologists to discern its reactive, not neoplastic, characteristics of the lesion. If the referring surgeon is alerted NF as a possibility along with other differential diagnoses, close observation would become a management option. In‐depth discussion of cytologic features and a review of the pertinent literature are also included. Diagn. Cytopathol. 2015;43:222–229. © 2014 Wiley Periodicals, Inc.     

Tumor necrosis factor alpha-induced interleukin-8 production via NF-kappaB and phosphatidylinositol 3-kinase/Akt pathways inhibits cell apoptosis in human hepatocytes

Tumor necrosis factor alpha (TNF-alpha) not only induces apoptotic signals but also causes antiapoptotic and regenerative responses in the liver. However, the molecular mechanism(s) of the latter events remains unclear. In the present study, we examined TNF-alpha-induced genes in Hc human normal (unsensitized) hepatocytes by cDNA microarray analysis. Interleukin-8 (IL-8) induction was the most pronounced of the upregulated genes. The IL-8 protein level was also increased. IL-8 belongs to the ELR-CXC chemokine family and appears to exert mitogenic and antiapoptotic functions in other cell systems. IL-8 expression by TNF-alpha was inhibited when two survival signals, nuclear factor kappaB (NF-kappaB) and phosphatidylinositol 3-kinase (PI3K)/Akt, were inhibited by a mutant form of inhibitor of NF-kappaB (IkappaB); by dominant negative (kinase-dead) Akt; or by treatment with LY 294002, an inhibitor of PI3K. TNF-alpha induced apoptosis in Hc cells that were sensitized by inhibition of NF-kappaB and PI3K activation. IL-8 administration protected mice against concanavalin A-induced hepatitis in vivo. IL-8 also rescued the sensitized Hc cells, at least in part, from TNF-alpha-induced apoptosis in vitro. TNF-alpha inhibited DNA synthesis in unsensitized Hc cells in the absence of serum. Exogenous IL-8 reversed, though anti-IL-8 neutralization antibody enhanced, growth inhibition by TNF-alpha. These results indicate that IL-8, the production of which is stimulated by TNF-alpha, inhibits apoptosis of sensitized hepatocytes and releases normal (unsensitized) hepatocytes from growth inhibition induced by TNF-alpha.     

A case report: verrucous carcinoma of the endometrium--the difficulty of diagnosis, and a review of the literature

A verrucous carcinoma is a subtype of well-differentiated squamous-cell carcinomas, arising in the vagina, vulva, and uterine cervix. But a verrucous carcinoma very rarely arises in the uterine endometrium. The present paper presents a case of a verrucous carcinoma of the endometrium that is described in association with the tumor marker SCC; this paper also includes a review of the relevant literature.     

Diagnosis of Atlantoaxial Subluxation in Morquio's Syndrome and Spondyloepiphyseal Dysplasia Congenita

Compression of the spinal cord due to atlantoaxial subluxation was diagnosed in a patient with Morquio's syndrome and in another with spondyloepiphyseal dysplasia (SED) congenita by cervical radiography and magnetic resonance imaging (MRI). The patient with Morquio's syndrome, a 15 year old boy, had no neurologic symptoms and his somatosensory evoked potential (SSEP) was normal. However, MRI demonstrated spinal cord compression at C1-C2. In contrast, the patient with SED congenita, an 11 year old girl, had neck pain, hyperreflexia and loss of vibration sense in both legs. These findings were explained by the absence of P3 and later waves in SSEP and by compression of the spinal cord observed on MRI. Both SSEP and MRI should be used for evaluating disorders in which atlantoaxial subluxation might be present.     

Influence of Paternal 252Cf Neutron Exposure on Abnormal Sperm, Embryonal Lethality, and Liver Tumorigenesis in the F1 Offspring of Mice

Experiments were conducted to determine whether neutron-induced genetic damage in parental germline cells can lead to the development of cancer in the offspring. Seven-week-old C3H male mice were irradiated with ²⁵²Cf neutrons at a dose of 0, 50, 100, or 200 cGy. Two weeks or 3 months after irradiation, the male mice were mated with virgin 9-week-old C57BL females. Two weeks after irradiation, the irradiated male mice showed an increased incidence of sperm abnormalities, which led to embryo lethalities in a dose-dependent manner when they were mated with unirradiated female mice. Furthermore, liver tumors in male offspring of male mice in the 50 cGy group were significantly increased in 19 of 44 (43.2%) animals, in clear contrast to the unirradiated group (1 of 31; 3.2%) ( P < 0.01). In the 100 cGy group, 6 of 39 (15%) mice had lesions. At 3 months after irradiation abnormal sperm and embryonal lethality were not significantly increased. The incidences of liver tumors in male offspring from the 50 cGy, 100 cGy and 200 cGy groups were 6 of 20 (30%), 5 of 22 (23%) and 1 of 19 (5%), respectively, which are not significantly increased compared with the control. It is concluded that increased hepatic tumor risk in the F₁ generation may be caused by genetic transmission of hepatoma-associated trait(s) induced by ²⁵²Cf neutron irradiation.