Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid

Within the developing mammalian cortex, neural progenitors first generate deep-layer neurons and subsequently more superficial-layer neurons, in an inside-out manner. It has been reported recently that mouse embryonic stem cells (mESCs) can, to some extent, recapitulate cortical development in vitro, with the sequential appearance of neurogenesis markers resembling that in the developing cortex. However, mESCs can only recapitulate early corticogenesis; superficial-layer neurons, which are normally produced in later developmental periods in vivo, are under-represented. This failure of mESCs to reproduce later corticogenesis in vitro implies the existence of crucial factor(s) that are absent or uninduced in existing culture systems. Here we show that mESCs can give rise to superficial-layer neurons efficiently when treated with valproic acid (VPA), a histone deacetylase inhibitor. VPA treatment increased the production of Cux1-positive superficial-layer neurons, and decreased that of Ctip2-positive deep-layer neurons. These results shed new light on the mechanisms of later corticogenesis.     

A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors

In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.     

Hepatoid carcinoma of the pancreas penetrating into the gastric cavity: a case report and literature review

A 79-year-old Japanese woman was admitted to our hospital for treatment of a pancreatic tumor measuring approximately 7 × 5 cm. The tumor had invaded the left adrenal gland and gastric wall and had penetrated into the gastric cavity. Surgical resection was performed. The tumor was composed of a brown to whitish solid area and a zone of hemorrhage, necrosis, and cystic degeneration resembling the gross features of solid pseudopapillary tumor (SPT). Histologically, the tumor showed a heterogeneous growth pattern with a combination of seat-like, trabecular, papillary and hemorrhagic-necrotic areas in various proportions. The differential diagnoses first considered were acinar cell carcinoma, neuroendocrine carcinoma and SPT with malignant transformation. Immunohistochemistry showed tumor cells were negative for pancreatic exocrine enzymes and endocrine markers. Tumor cells diffusely expressed cytokeratin 19, alpha-fetoprotein, carcinoembryonic antigen and glypican-3, but lacked vimentin or β-catenin expression. Small proportions of tumor cells expressed hepatocyte paraffin-1. Although typical morphological features of well-differentiated hepatocellular carcinoma (HCC) were not distinctly apparent, the tumor morphology partly resembled poorly differentiated HCC. Given these findings and considerations, the tumor was finally diagnosed as poorly differentiated hepatoid carcinoma of the pancreas.     

Role of dynamin,synaptojanin, and endophilin in podocyte foot processes

Podocytes are specialized cells that play an integral role in the renal glomerular filtration barrier via their foot processes. The foot processes form a highly organized structure, the disruption of which causes nephrotic syndrome. Interestingly, several similarities have been observed between mechanisms that govern podocyte organization and mechanisms that mediate neuronal synapse development. Dynamin, synaptojanin, and endophilin are functional partners in synaptic vesicle recycling via interconnected actions in clathrin-mediated endocytosis and actin dynamics in neurons. A role of dynamin in the maintenance of the kidney filtration barrier via an action on the actin cytoskeleton of podocytes was suggested. Here we used a conditional double-KO of dynamin 1 (Dnm1) and Dnm2 in mouse podocytes to confirm dynamin’s role in podocyte foot process maintenance. In addition, we demonstrated that while synaptojanin 1 (Synj1) KO mice and endophilin 1 (Sh3gl2), endophilin 2 (Sh3gl1), and endophilin 3 (Sh3gl3) triple-KO mice had grossly normal embryonic development, these mutants failed to establish a normal filtration barrier and exhibited severe proteinuria due to abnormal podocyte foot process formation. These results strongly implicate a protein network that functions at the interface between endocytosis and actin at neuronal synapses in the formation and maintenance of the kidney glomerular filtration barrier.     

Elevated S100B level in cerebrospinal fluid could predict poor outcome of carbon monoxide poisoning

Objective

S100B is a calcium-binding protein produced by astroglia in the brain and has been used as a marker of neuronal damage after brain trauma. We investigated the utility of S100B in cerebrospinal fluid (CSF) measured during the early phase of carbon monoxide (CO) poisoning in predicting the subsequent clinical course.

Methods

The study included 31 patients who were admitted to the hospital with loss of consciousness following CO poisoning. S100B levels were measured by enzyme-linked immunosorbent assay in CSF, and serum samples collected simultaneously within 24 hours and on the fourth day after CO exposure. All patients were followed for at least 3 months and divided into 3 groups based on the clinical course: persistent vegetative state (PVS), delayed encephalopathy (DE), and complete recovery with no complications (NC).

Results

During the 3-month period, 3 patients developed PVS, 5 developed DE, and 23 were classified as NC. The mean S100B levels in the CSF within 24 hours after CO exposure were higher in the PVS group (9.25 ng/mL) than in the DE (2.03 ng/mL) and NC groups (1.86 ng/mL). However, the mean serum S100B levels were not elevated in the 3 groups (0.21, 0.59, and 0.16 ng/mL, respectively).

Conclusion

Early elevation of S100B in CSF after CO poisoning could be a suitable predictor of subsequent development of PVS.     

Phase 2 Study of Modified Irinotecan and Bolus 5-Fluorouracil/<Emphasis Type="Italic">l</Emphasis>-Leucovorin in Japanese Metastatic Colorectal Cancer Patients

Introduction  

Using the recommended doses obtained from our previous phase 1 trial of a modified Saltz chemotherapy regimen for metastatic colorectal cancer (weekly irinotecan and bolus 5-fluorouracil/l-leucovorin for 3 weeks every 28 days), we performed the present phase 2 trial to evaluate efficacy and toxicity.     

Merkel cell carcinoma with bone metastasis: a case report

 A case of Merkel cell carcinoma with bone metastasis is described. The patient, who had a history of Merkel cell carcinoma of the skin in the right cheek, had spontaneous pain in the right thigh. At the initial visit, the right hip range of motion was slightly limited, but there was no gait disturbance or abnormality in the radiographs of the right hip. However, the pain gradually increased and caused gait disturbance. The patient underwent surgical treatment. A bipolar type of femoral prosthesis was implanted into the femur, and sampling of cancellous bone was performed at the time of osteotomy. Pathological examination showed the findings of Merkel cell carcinoma. Merkel cell carcinoma is a rare malignant tumor of the skin, which usually occurs on the head, neck, or extremities and metastasizes to the lymph nodes. Although osseous involvement often occurs in the adjacent facial bones through direct invasion, distant osseous metastasis appears to be extremely rare. Received: November 12, 2001 / Accepted: April 18, 2002     

Relationship between the maximum flexion-internal rotation test and the torn acetabular labrum of a dysplastic hip

To determine the relationship between pain at flexion-rotation and the status of a labral tear in patients with dysplastic hips, physical examination maneuvers and hip arthroscopy were carried out in 59 patients with dysplastic osteoarthritis (5 men and 54 women; mean age, 41 years; range, 16 to 64 years). Between January 1998 and June 2000, these patients underwent 60 hip arthroscopies at Kyushu University Hospital. All hip joints arthroscoped demonstrated incomplete or complete detaching tears of the acetabular labrum in one portion of the weight-bearing area. Twenty-three patients (39%) experienced pain during the maximum flexion-internal rotation test; 16 patients (27%) showed a positive result for the maximum flexion-external rotation test. There was no statistically significant relationship between the results of the maximum flexion-external rotation test and the arthroscopic findings of labral tears. A positive maximum flexion-internal rotation test result, however, correlated well with incomplete detaching tears in the posterosuperior portion of the acetabular labrum. In contrast, a complete detaching tear of the posterosuperior labrum was associated with a negative maximum flexion-internal rotation test result. The maximum flexion-internal rotation test is useful for assessing the magnitude of a labral tear in the posterosuperior portion of the acetabular labrum in dysplastic hips. Received: April 19, 2001 / Accepted: September 4, 2001     

Long-term follow-up of ulcerative colitis patients treated on the basis of their cytomegalovirus antigen status

AIM:To clarify the impact of cytomegalovirus(CMV)activation and antiviral therapy based on CMV antigen status on the long-term clinical course of ulcerative colitis(UC)patients.METHODS:UC patients with flare-up were divided into CMV-positive and-negative groups according to the CMV antigenemia assay.The main treatment strategy provided for the patients in the CMV-positive group comprised a dose reduction of corticosteroids and administration of ganciclovir.RESULTS:The median number of days to initial remission was significantly greater for the patients in the CMV-positive group(21 d vs 16 d,P=0.009).However,the relapse rate after remission and colectomy rate during more than 30 mo of observation did not differ between the two groups.Multivariate analysis revealed that administration of ganciclovir was the only independent factor for avoiding colectomy in patients of the CMV-positive group.CONCLUSION:CMV antigen status did not significantly affect the long-term prognosis in UC patients under treatment with appropriate antiviral therapy.