[Analysis of long-term survivors with cardiac AL amyloidosis].

Cardiac AL amyloidosis (CA) is generally known as a severe disease with very poor prognosis. Here we retrospectively examined seven patients with CA in our cohort who achieved long-term survival. All six patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT) survived for >3 years, whereas four patients survived for >5 years. Patients who underwent ASCT had prompt hematological responses, and five patients showed organ responses. ASCT helps to achieve a quick and deep hematological response required for long-term survival in patients with CA. New agents have been implemented for the treatment of CA. However, the risks and benefits of each treatment modality should be considered according to patient condition, thus making the best use of ASCT in combination with new agents for the treatment of CA.

Positional relationships of abdominal aorta landmarks for angiography: observations from the intravascular space.

PURPOSE: To clarify the positional relationships of abdominal aorta (Ao) landmarks by way of observations from the intravascular space to facilitate angiography. METHODS: A total of 95 donated Japanese cadavers were observed. We excluded 32 cadavers with anatomical variation at the celiac trunk (CT) or superior mesenteric artery (SMA), with flexure exceeding 5° in the aorta located cranially to the renal artery (RA), and with flexure exceeding 60° in the aorta located caudal to the RA. The maximum longitudinal diameter of the left (Lt.) RA was measured and the Ao was incised by frontal section to acquire photographs of the intravascular space. The inner diameter of the Ao at the Lt. RA level was investigated. The distances between the inferior borders of the CT, SMA, and Lt. RA were also used as the hypotenuse of a right-angled triangle. Lines parallel to the longitudinal diameter of the Ao and those parallel to the transverse diameter of the right-angled triangle were measured by a computer, and expressed as relative distance indexes using the transverse diameter of the aorta at the Lt. RA level as a reference point. The angle between the transverse axis of the Ao and the line connecting the CT to the SMA was also investigated. RESULTS: The mean diameter of the aorta was 20.6 ± 2.0 mm. The indexes between each blood vessel (longitudinal/transverse) were as follows: Lt. RA to CT 1.69/0.41, Lt. RA to SMA 0.86/0.51, and CT to SMA 0.82/0.13. The mean angle between the transverse axis of the Ao and CT to SMA was 81.9° ± 9.5°. CONCLUSION: These indexes should contribute to improving skills for workers new to angiography, and may reduce patient risk.

Positional relationships among the celiac trunk, superior mesenteric artery, and renal artery observed from the intravascular space.

PURPOSE: To clarify the positional relationships among the celiac trunk (CT), the superior mesenteric artery (SMA), and the renal artery (RA) observed from the intravascular space to facilitate angiography. METHODS: After excluding six cadavers in which anatomic variation was found in the CT or SMA and four cadavers in which a curvature of 5° or more was observed in the aorta from 30 Japanese donor cadavers, we used the abdominal aortas of the remaining 20 cadavers as specimens. We made an incision in the maximum longitudinal diameter of the left RA (Lt. RA) and acquired an image of the intravascular space using a digital camera. The distance between the inferior borders of each vessel was used as the hypotenuse of a right-angled triangle. Lines parallel to the longitudinal diameter of the aorta and those parallel to the transverse diameter of the right-angled triangle were measured by a computer and expressed as relative distance indexes using the transverse diameter of the aorta at the Lt. RA level as a reference point. RESULTS: The transverse diameter of the aorta was 20.1 ± 2.9 mm, and the relative distance indexes for longitudinal/transverse lines between each vessel were 1.61/0.35 between Lt. RA and CT, 0.84/0.48 between Lt. RA and SMA, and 0.78/0.13 between CT and SMA. The angle between the transverse axis of the abdominal aorta and the linear line connecting CT and SMA was 80.2° ± 9.4°. The branching point of CT in relation to SMA was located at the upper left in 80 % (n = 16), on the same line in 15 % (n = 3), and at the upper right in 5 % (n = 1) of the subjects. CONCLUSIONS: The relative distance indexes determined in this study will facilitate navigation during catheter insertion, particularly for those with little angiography experience, and thus reduce patient risk.

Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate.

Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been well studied in hematopoietic malignant cells including multiple myeloma (MM) cells.We demonstrate herein that HKII is constitutively over-expressed in MM cells. 3-bromopyruvate (3BrPA), an inhibitor of HKII, promptly and substantially suppresses ATP production and induces cell death in MM cells. Interestingly, cocultures with osteoclasts (OCs) but not bone marrow stromal cells (BMSCs) enhanced the phosphorylation of Akt along with an increase in HKII levels and lactate production in MM cells. The enhancement of HKII levels and lactate production in MM cells by OCs were mostly abrogated by the PI3K inhibitor LY294002, suggesting activation of glycolysis in MM cells by OCs via the PI3K-Akt-HKII pathway. Although BMSCs and OCs stimulate MM cell growth and survival, 3BrPA induces cell death in MM cells even in cocultures with OCs as well as BMSCs. Furthermore, 3BrPA was able to diminish ATP-dependent ABC transporter activity to restore drug retention in MM cells in the presence of OCs. These results may underpin possible clinical application of 3BrPA in patients with MM.

KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts.

The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.

GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-alpha converting enzyme (TACE).

Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). Macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB (RANK) ligand induce OC differentiation from monocytes, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) trigger monocytic differentiation into DCs. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocytic differentiation into OCs while inducing DC differentiation even in the presence of M-CSF and RANK ligand. GM-CSF and IL-4 in combination potently up-regulate tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) and activity in monocytes, causing ectodomain shedding of M-CSF receptor, resulting in the disruption of its phosphorylation by M-CSF as well as the induction of osteoclastogenesis from monocytes by M-CSF and RANK ligand. Interestingly, TACE inhibition robustly causes the resumption of the surface expression of M-CSF receptor on monocytes, facilitating M-CSF-mediated phosphorylation of M-CSF receptor and macrophage/OC differentiation while impairing GM-CSF- and IL-4-mediated DC differentiation from monocytes. These results reveal a novel proteolytic regulation of M-CSF receptor expression in monocytes to control M-CSF signaling and monocytic differentiation into macrophage/OC-lineage cells or DCs.

[Multiple myeloma complicated with disseminated zygomycosis after bortezomib therapy].

A 67-year-old man was diagnosed with multiple myeloma IgA-lambda type, Durie-Salmon classification stage IIIA in October 2001. He received five courses of induction chemotherapy consisting of vincristine, doxorubicin and dexamethasone and then underwent high dose chemotherapy followed by autologous stem cell transplantation in March 2003. He achieved partial response, but then relapsed after treatment with thalidomide and was admitted to our hospital in June 2007. The patient was complicated by tumor lysis syndrome (TLS) after receiving bortezomib therapy twice. Computed tomography after bortezomib therapy showed the rapid appearance of tumors in the right upper lobe of the lung, tail of the pancreas and the spleen. Though he was treated with antifungal agents, micafungin and voriconazole, he died eighty-five days after admission. Autopsy specimen showed fungal clumps and hemorrhagic infarction in the lung and spleen, and vegetation at the mitral valve was the same fungus as found in the lung. We diagnosed disseminated zygomycosis based on the pathological fungal morphology. This case suggested that metabolic acidosis was caused by TLS, while poorly controlled diabetes, secondary hemochromatosis due to transfusion, and breakthrough zygomycosis during antifungal therapy were thought to be factors contributing to the development of zygomycosis.

Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation.

Dramatic changes in morphology and myelin protein expression take place during the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes. Fyn tyrosine kinase was reported to play a central role in the differentiation process. Molecules that could induce Fyn signaling have not been studied. Such molecules are promising therapeutic targets in demyelinating diseases. We provide evidence that the common gamma chain of immunoglobulin Fc receptors (FcRgamma) is expressed in OPCs and has a role in triggering Fyn signaling. FcRgamma cross-linking by immunoglobulin G on OPCs promotes the activation of Fyn signaling and induces rapid morphological differentiation with upregulation of myelin basic protein (MBP) expression levels. Mice deficient in FcRgamma are hypomyelinated, and a significant reduction in MBP content is evident. Our findings indicate that the FcRgamma-Fyn-MBP cascade is pivotal during the differentiation of OPCs into myelinating oligodendrocytes, revealing an unexpected involvement of immunological molecules.

Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth factor and osteopontin.

PURPOSE: Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in myeloma in parallel with tumor progression. We showed previously that myeloma cells and osteoclasts are mutually stimulated to form a vicious cycle to lead to enhance both osteoclastogenesis and tumor growth. The present study was undertaken to clarify whether myeloma cell-osteoclast interaction enhances angiogenesis and whether there is any mutual stimulation between osteoclastogenesis and angiogenesis. EXPERIMENTAL DESIGN: Myeloma cells and monocyte-derived osteoclasts were cocultured, and angiogenic activity produced by the cocultures was assessed with in vitro vascular tubule formation assays and human umbilical vascular endothelial cell (HUVEC) migration and survival. Osteoclastogenic activity was determined with rabbit bone cell cultures on dentine slices. RESULTS: Myeloma cells and osteoclasts constitutively secrete proangiogenic factors, vascular endothelial growth factor (VEGF) and osteopontin, respectively. A cell-to-cell interaction between myeloma cells and osteoclasts potently enhanced vascular tubule formation. Blockade of both VEGF and osteopontin actions almost completely abrogated such vascular tubule formation as well as migration and survival of HUVECs enhanced by conditioned medium from cocultures of myeloma cells and osteoclasts. Furthermore, these factors in combination triggered the production of osteoclastogenic activity by HUVEC. CONCLUSIONS: Osteoclast-derived osteopontin and VEGF from myeloma cells cooperatively enhance angiogenesis and also induce osteoclastogenic activity by vascular endothelial cells. These observations suggest the presence of a close link between myeloma cells, osteoclasts, and vascular endothelial cells to form a vicious cycle between bone destruction, angiogenesis, and myeloma expansion.

Increased pentosidine, an advanced glycation end-product, in urine and tissue reflects disease activity in inflammatory bowel diseases.

BACKGROUND: Under inflammatory conditions with strong oxidative stresses, advanced glycation end-products (AGE), carbonyl compounds, are produced. The concentration of pentosidine, an AGE, reportedly correlates with complications of diabetes mellitus and worsening of rheumatoid arthritis, but its role in the pathogenesis of inflammatory bowel diseases (IBD) is unclear. METHODS: Immunohistochemistry was performed with antibodies against pentosidine, and 8-OH-2-deoxyguanosine. The urinary concentration of pentosidine was also quantified by enzyme-linked immunosorbent assay method. RESULTS: Pentosidine expression was up-regulated in the inflamed tissue of IBD. The expression of both pentosidine and 8-OH-2-deoxyguanosine was similar and increased in the inflamed epithelium and infiltrating cells (neutrophils and lymphocytes). The urinary concentration of pentosidine in active ulcerative colitis was significantly greater than that in inactive ulcerative colitis (0.12+/-0.15 vs 0.021+/-0.011 microg/mg of Cr, P<0.05), and was greater in active Crohn's disease than in inactive Crohn's disease (0.071+/-0.086 vs 0.039+/-0.023 microg/mg of Cr). CONCLUSIONS: The urinary pentosidine level correlated with the activity of ulcerative colitis and may be a marker for disease activity in ulcerative colitis.

Morphological Classification of the Sagittal Tendon Plate in the Soleus Muscle in Japanese Cadavers / Clasificación Morfológica de la Lámina Tendinosa Sagital del Músculo Sóleo en Cadáveres Japoneses

SUMMARY: The human soleus muscle has attracted attention in the fields of sport science, rehabilitation medicine, etc. for improving exercise performance in training, preventing injuries, and rehabilitation. The sagittal tendon plate of the soleus muscle is particularly important in rehabilitation. Few studies, however, have evaluated the shape of the sagittal tendon plate in the human soleus muscle in detail and attempted to classify its variations based on its morphology. In this study, we conducted a detailed analysis of the morphology of the sagittal tendon plates in soleus muscle specimens from Japanese cadavers and constructed a morphology-based classification system and evaluated their frequencies of occurrence. First, the specimens were divided into those with a sagittal tendon plate that was visible on the anterior surface (pennate muscle group) and those without (non-pennate muscle group). Next, based on the "number" and "breadth" of the sagittal tendon plates, the pennate muscle group specimens were further classified into four classes: Class I (one tendon, thin), Class II (one tendon, slightly broad), Class III (one tendon, very broad), and Class IV (two tendons, thin). Subsequently, the specimens were further divided into three types based on the position where the sagittal tendon plate joined the Achilles tendon: median tendon type, lateral tendon type, and medial tendon type (a total 13 divisions). When 458 Japanese soleus muscle specimens were classified into these divisions, the occurrence frequencies of Class I-IV were 80.57 %, 4.59 %, 5.46 %, and 1.09 %, respectively. In Class I, the median tendon type was more frequent than the lateral and medial tendon types, accounting for 48.47 % overall. The classification types of the sagittal tendon plate and their respective occurrence frequencies shown in this study are expected to serve as fundamental data in implementing rehabilitation of soleus muscle.

El músculo sóleo humano ha atraído la atención de la ciencia del deporte, la medicina de rehabilitación, etc. para mejorar el rendimiento del ejercicio en el entrenamiento, prevenir las lesiones y rehabilitación. La lámina tendinosa sagital del músculo sóleo es particularmente importante en la rehabilitación. Sin embargo, pocos estudios han evaluado en detalle la forma de la placa lámina sagital en el músculo sóleo humano y han intentado clasificar sus variaciones en función de su morfología. Realizamos un análisis detallado de la morfología de las láminas de los tendones sagitales en muestras de músculo sóleo de cadáveres japoneses y construimos un sistema de clasificación basado en la morfología y, además, evaluamos su frecuencia de aparición. Los especímenes se dividieron en aquellos con una lámina de tendón sagital que era visible en la superficie anterior (grupo muscular pennado) y aquellos sin (grupo muscular no pennado). A continuación, según el "número" y el "ancho" de las láminas de los tendones sagitales, las muestras del grupo de músculos pennados se clasificaron en cuatro clases: Clase I (un tendón, delgado), Clase II (un tendón, ligeramente ancho), Clase III (un tendón, muy ancho) y Clase IV (dos tendones delgados). Posteriormente, las muestras se dividieron en tres tipos, según la posición donde la lámina del tendón sagital se unía al tendón calcáneo: tipo de tendón mediano, tipo de tendón lateral y tipo de tendón medial (un total de 13 divisiones). En estas divisiones se clasificaron 458 especímenes de músculo sóleo de indiviuos japoneses, las frecuencias de ocurrencia de Clase I-IV fueron 80,57 %, 4,59 %, 5,46 % y 1,09 %, respectivamente. En la Clase I, el tipo de tendón mediano era más frecuente que los tipos de tendón lateral y medial, representando el 48,47 % del total. Se espera que los tipos de clasificación de la lámina del tendón sagital y sus respectivas frecuencias de aparición, que se reportan en este estudio, sirvan como datos fundamentales para implementar la rehabilitación del músculo sóleo.

Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12(-/-)) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12(-/-) bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12(-/-) mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma.

Bortezomib is a novel proteasome inhibitor that has shown marked antitumor effects in patients with multiple myeloma (MM). We evaluated the feasibility and efficacy of bortezomib plus dexamethasone (BD) therapy and assessed bone metabolism in relapsed or refractory MM. Fourteen patients received 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 along with 20 mg/dose of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 in a 21-day cycle. After 1 to 3 cycles of BD therapy, 9 patients (64%) achieved an objective response (5 very good partial responses and 4 partial responses). Notably, a rapid increase in the serum concentration of alkaline phosphatase (ALP) was observed in 6 of the treatment-responsive patients. Moreover, serum levels of bone-formation markers (bone-specific ALP and osteocalcin) significantly increased in 5 and 2 responsive patients, respectively. Radiographic examination showed improvement in bone lesions, suggesting that BD therapy induces osteoblast activation in responders. Adverse events included thrombocytopenia of grades 1 to 3, peripheral neuropathy of grades 1 to 2, and grade 3 ileus and were transient and manageable. Although severe lung injury has been reported among Japanese patients treated with bortezomib, no pulmonary complications were observed during BD therapy. Our results suggest that BD therapy is a safe and promising therapeutic approach for Japanese patients with MM.

Positional relationships of abdominal aortic branches for contrast radiography of the inferior mesenteric artery using the coeliac trunk and superior mesenteric artery as landmarks.

PURPOSE: To establish a method by which angiography of the inferior mesenteric artery (IMA) can be performed smoothly, we investigated the relative locations of the coeliac trunk (CT), superior mesenteric artery (SMA), IMA, and left renal artery (LtRA). METHODS: From a total of 60 cadavers, 32 cadavers with few arteriosclerotic lesions and little vascular tortuosity were selected for the study. The abdominal aorta (Ao) were removed and incised on both lateral side, along the vertical axis and transected into the ventral and dorsal sides. The intravascular lumen on the ventral side of the Ao was photographed using a digital camera, and the horizontal and vertical diameters of the sites of confluence of the CT, SMA, and IMA, were measured on the computer screen. We also calculated the distances between the branches, including the CT, SMA, IMA, LtRA, and the common iliac artery (CoI). RESULTS: Although the SMA-IMA distance did not correlate with the CT-SMA distance, the ratio of the SMA-IMA to CT-CoI distance was four times greater than the ratio of the CT-SMA to CT-CoI distance. CONCLUSIONS: The site of branching of the IMA can be inferred to some extent from the CT and SMA distance.

Erythropoietin-induced proliferation of gastric mucosal cells.

AIM: To analyze the localization of erythropoietin receptor on gastric specimens and characterize the effects of erythropoietin on the normal gastric epithelial proliferation using a porcine gastric epithelial cell culture model. METHODS: Erythropoietin receptor was detected by RT-PCR, Western blotting and immunohistochermistry. Growth stimulation effects of erythropoietin on cultured gastric mucosal cells were determined by ELISA using bromodeoxyuridine (BrdU). RESULTS: Erythropoietin receptor was detected on cultured porcine gastric mucosal epithelial cells. Erythropoietin receptor was also detected histochemically at the base of gastric mucosal epithelium. BrdU assay demonstrated a dose-dependent increase in growth potential of cultured porcine gastric mucosal epithelial cells by administration of erythropoietin, as well as these effects were inhibited by administration of anti- erythropoietin antibody (P<0.01). CONCLUSION: These findings indicate that erythropoietin has a potential to proliferate gastric mucosal epithelium via erythropoietin receptor.

Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain.

Cyclin-dependent kinase 5 (Cdk5)/p35 is a serine/threonine kinase, and its activity is detected primarily in postmitotic neurons. Mice lacking Cdk5/p35 display migration defects of the cortical neurons in the cerebrum and cerebellum. In this study, we demonstrate that although most brainstem nuclei are found in their proper positions, the motor nucleus of the facial nerve is ectopically located and neurons of the inferior olive fail to position correctly, resulting in the lack of their characteristic structures in the hindbrain of Cdk5-/- mice. Despite the defective migration of these neurons, axonal exits of the facial nerve from brainstem and projections of the inferior cerebellar axons appear unchanged in Cdk5-/- mice. Defective neuronal migration in Cdk5-/- hindbrain was rescued by the neuron-specific expression of Cdk5 transgene. Because developmental defects of these structures have been reported in reeler and Dab1 mutant mice, we analyzed the double-null mutants of p35 and Dab1 and found more extensive ectopia of VII motor nuclei in these mice. These results indicate that Cdk5/p35 and Reelin signaling regulates the selective mode of neuronal migration in the developing mouse hindbrain.

Involvement of CD45 in central nervous system myelination.

Myelin is a multi-layered membranous lipid insulator surrounding axons that allows the rapid conduction of neuronal impulses. In the central nervous system (CNS), myelin is produced by oligodendrocytes. During development, morphologically immature oligodendrocyte precursor cells (OPCs) arise from neural stem cells before differentiating into myelinating oligodendrocytes shortly after birth. Fyn tyrosine kinase (Fyn) has been shown to play a central role during OPC differentiation, including inducing morphological changes in the cells and initiating the expression of myelin basic protein (MBP), a major structural protein required for the compaction of myelin sheaths. Recently, we have shown that signaling via the gamma chain of immunoglobulin Fc receptors (FcRgamma) induces the Fyn-MBP cascade and promotes the morphological differentiation of OPCs. The protein tyrosine phosphatases that are responsible for the positive regulation of Fyn tyrosine kinase activity during this cascade, however, remained unknown. Here we report that a protein tyrosine phosphatase, CD45, is involved in this process. Fyn co-immunoprecipitated with CD45 from differentiating wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate. Additionally, dysmyelination was observed in CD45-deficient mice in vivo. Our findings suggest that CD45 is a key phosphatase involved in OPC differentiation and provide a preliminary explanation for the previously reported CD45 mutations observed in some multiple sclerosis (MS) patients.

Anatomical structure of the subcutaneous tissue on the anterior surface of human thigh.

The anterior thighs of 16 limbs from eight donated cadavers were observed using ultrasonic imaging and gross dissection with a specific focus on the subcutaneous tissue, which is considered an auxiliary element of locomotion. On ultrasonic imaging, the subcutaneous tissue was found to comprise multiple layers. The number of layers gradually decreased on progressing distally in the thigh. On gross dissection, a lot of fatty tissue and loose multiple laminar structures were observed in the medial and proximal areas. However, on progressing distally, these layers thinned out and became less fatty. Cutaneous nerves were apparent among the layers below the dermis. In addition, there were many associated fiber bundles between the dermis and muscle fascia, some of which appeared to be so-called skin ligaments that run through the subcutaneous tissue perpendicularly from the fascia to dermis, accompanying cutaneous nerve fibers and blood vessels. While identifying the peripheral cutaneous nerve fibers, several anastomosing rami and neural networks were recognized. These observations suggest that skin ligaments could be elements regulating motor restriction during muscular movement.

Neural cell adhesion molecule L1 is required for fasciculation and routing of thalamocortical fibres and corticothalamic fibres.

To examine the role of neural cell adhesion molecule L1 in thalamocortical projections, we analysed L1 deficient (L1-/y) mice. Immunohistochemistry of pleiotrophin/HB-GAM, a marker for thalamocortical axons and axonal tracing experiments showed that thalamocortical axons were abnormally and highly fasciculated when they pass through the developing internal capsule. Within the cortex, however, their course was more diffuse. The corticofugal fibres immunoreactive for TAG-1 were also more strongly fasciculated and their number was decreased in L1-/y mice. Furthermore, no TAG-1-positive corticofugal axons reached the dorsal thalamus. These data suggest that L1 plays an important role in the fasciculation and routing of axons connecting between the thalamus and the cortex.

[Unique structure of the esophago-gastric junction of the house musk shrew (Suncus murinus)].

The house musk shrew (Suncus murinus) belongs to the Order Insectivora, and has been used for the research in comparative anatomy as one of the most primitive placental mammals. Another feature of this shrew is its ability to easily vomit which mimics the human emesis or motion sickness response. The house musk shrew has thus been utilized as a rare small experimental animal for studies on the neurophysiological mechanism of vomiting. However, there is no report investigating the morphological background of vomiting in this species. The purpose of this study is to provide detailed morphological and histological features of the house musk shrew stomach as they possibly correlate to vomiting. The stomachs of ten female house musk shrews were used. Six of them were the wild type (Jic: SUN), two were the high-emesis strain (Jic: SUN-Her) and the rest of them were the low-emesis strain (Jic: Sun-Ler). In addition to the macroscopic anatomy, the region of esophago-gastric (EG) junction and the gastric groove were observed using the light and transmission electron microscopy. Although evident differences in structure of stomach were not found among the three strains, some interesting findings in comparative anatomy were noted. The circular valve-like thick fold was seen at the cardiac portion, which protruded into the esophageal lumen forming a deep groove between its frilled edge and the esophagus. The second frilled ridge was often found as inner ridge of this valve-like thick fold. The esophago-gastric junction between the stratified squamous and the simple columnar epithelium was found at the edge of the second frilled ridge. The lamina propria of the frilled edge was occupied by loose connective tissue and many large lumens of lymphatic vessels. The lamina muscularis mucosae, which developed in the esophageal region, was not in the main frilled edge. A well-developed inner muscle layer was found around the base of the fold, which seemed to correspond to the human lower esophageal sphincter. Cardiac glands occupied most of the thick cardiac wall, forming complicated crypts lined by simple columnar epithelium, and ducts of cardiac gland opened to these crypts. Since the house musk shrew has no esophageal gland, these cardiac glands may actively protect the lower part of the esophagus. In the cardiac wall, the inner circular and outer longitudinal muscle layer largely crossed each other obliquely as same as other reports. The transition area from the striated to the smooth muscle was observed in the sphincter surrounding the distal end of the cardiac wall. The gastric groove, lined by simple columnar epithelium in the lesser curvature, which has been reported to play a role as a shortcut from the cardia to the pylorus in other species including rodents, was also confirmed in the house musk shrew. The mucosal fold in the boundary between the esophageal and the gastric epithelium of house musk shrew may correspond to the structure called the limiting ridge (in mouse, rat and hamster), the teeth-like fimbria or Grenzfalten (in vole), and the gastric teeth (in crustacean and mollusk). The valve-like mucosal fold protruding into the esophageal cavity, the well developed huge cardiac glands, and the cardiac sphincter localized distally to the cardiac gland appear to facilitate the regurgitation of the stomach content, that is, vomiting. These findings suggest that this structure might have developed to support the feeding habit of house musk shrew, and that the differences of strains in vomiting may be determined by neurophysiological mechanisms.