Wnt2 accelerates cardiac myocyte differentiation from ES-cell derived mesodermal cells via non-canonical pathway

The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyocyte differentiation from ES cells. Therefore, we investigated when and how Wnt2 acts in cardiogenesis during ES cell differentiation. Wnt2 was strongly expressed in the early developing murine heart. We applied this embryonic Wnt2 expression pattern to ES cell differentiation, to elucidate Wnt2 function in cardiomyocyte differentiation. Wnt2 knockdown revealed that intrinsic Wnt2 was essential for efficient cardiomyocyte differentiation from ES cells. Moreover, exogenous Wnt2 increased cardiomyocyte differentiation from ES cells. Interestingly, the effects on cardiogenesis of intrinsic Wnt2 knockdown and exogenous Wnt2 addition were temporally restricted. During cardiomyocyte differentiation from ES cells, Wnt2 didn't activate canonical Wnt pathway but utilizes JNK/AP-1 pathway which is required for cardiomyocyte differentiation from ES cells. Therefore we conclude that Wnt2 plays strong positive stage-specific role in cardiogenesis through non-canonical Wnt pathway in murine ES cells.     

Pivot technique combined with mandibular backward distraction osteogenesis for the patient with high risk for relapse

Severe skeletal relapse is one of the most difficult problems after mandibular advancement, and the management to overcome such problems tends to require more compromised methods and longer treatment period. We described that mandibular backward distraction osteogenesis with maxillomandibular fixation at an appropriate occlusion. Furthermore, to avoid inappropriate distraction vector, the distal plates of the distraction device were fixed with 1 screw to work as a pivot after the manipulation of the condyle to the glenoid fossa at the end of distraction activation. This technique was applied to 3 female patients with mandibular deficiency. The intraoral distractors were set on the lateral surface of the mandibular body; the fixation of the distal plate was fixed with 1 monocortical screw to make the proximal segment including the condyle manipulating at the end of the distraction phase by releasing the maxillomandibular fixation. The distraction rate was 1 mm/d, and the latency period was 7 days. The follow-up period after mandibular backward distraction osteogenesis ranged from 26 to 56 months. No specific complication, such as broken device, severe infection, or bony nonunion, occurred. Postoperative relapse was not observed during the follow-up period. This technique might become 1 choice to apply for mandibular deficiency in a patient with high risk for relapse.     

A septic pulmonary embolism associated with right-sided infective endocarditis and a ventricular septal defect in a patient with atopic dermatitis

A 30-year-old woman was admitted to our hospital with high fever and chest pain. She had a ventricular septal defect, but was asymptomatic and had not undergone surgical repair. She also had had atopic dermatitis since childhood that had not been adequately treated. Chest computed tomography showed multiple peripheral nodules and infiltrates in both lungs. A transthoracic echocardiogram detected vegetation on the wall of the right ventricle, and Staphylococcus aureus was cultured from a peripheral blood sample. She was diagnosed as having a septic pulmonary embolism associated with right-sided infective endocarditis caused by S. aureus. She was treated with Cefazolin, resulting in gradual improvement of laboratory and chest radiographic findings. Recent studies have revealed that atopic dermatitis is one of the risk factors for infective endocarditis. In this case, uncontrolled atopic dermatitis might have caused the right-sided infective endocarditis.     

Ventral simultanagnosia and prosopagnosia for unfamiliar faces due to a right posterior superior temporal sulcus and angular gyrus lesion

We report a patient with ventral simultanagnosia, prosopagnosia for “unfamiliar faces” (dorsal prosopagnosia), spatial agraphia, and constructional disorder, particularly on the left spatial side, due to a lesion in the right posterior superior and middle temporal gyri and angular gyrus. The patient showed impairment of fundamental visual and visuospatial recognition, such as in object size, configuration, and horizontal point location, which probably underlay the mechanism of simultanagnosia and prosopagnosia. This case also suggests that the coexistence of simultanagnosia and prosopagnosia results from a right hemispheric insult, and damage to the temporoparietal area interrupts the incorporation of spatial information into object recognition. This disconnection of information flow, together with impaired object recognition per se, may impair the parallel processing of multiple objects, leading to object-by-object or part-by-part recognition.     

Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells

DNA methylation and BLC-2 are potential therapeutic targets in acute myeloid leukemia (AML). We investigated pharmacologic interaction between the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) and the BCL-2 inhibitor ABT-737. Increased BCL-2 expression determined by reverse phase protein analysis was associated with poor survival in AML patients with unfavorable cytogenetics (n?=?195). We found that 5-AZA, which itself has modest apoptotic activity, acts synergistically with ABT-737 to induce apoptosis. The 5-AZA/ABT-737 combination enhanced mitochondrial outer membrane permeabilization, as evidenced by effective conformational activation of BAX and ?ψ_m loss. Although absence of p53 limited apoptotic activities of 5-AZA and ABT-737 as single agents, the combination synergistically induced apoptosis independent of p53 expression. 5-AZA down-regulated MCL-1, known to mediate resistance to ABT-737, in a p53-independent manner. The 5-AZA/ABT-737 combination synergistically induced apoptosis in AML cells in seven of eight patients. 5-AZA significantly reduced MCL-1 levels in two of three samples examined. Our data provide a molecular rationale for this combination strategy in AML therapy.     

Strategy to differentiate autoimmune pancreatitis from pancreas cancer

Autoimmune pancreatitis (AIP) is a newly described entity of pancreatitis in which the pathogenesis appears to involve autoimmune mechanisms. Based on histological and immunohistochemical examinations of various organs of AIP patients, AIP appears to be a pancreatic lesion reflecting a systemic "IgG4-related sclerosing disease". Clinically, AIP patients and patients with pancreatic cancer share many features, such as preponderance of elderly males, frequent initial symptom of painless jaundice, development of new-onset diabetes mellitus, and elevated levels of serum tumor markers. It is of uppermost importance not to misdiagnose AIP as pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, and approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological, and histopathological features. Findings suggesting AIP rather than pancreatic cancer include: fluctuating obstructive jaundice; elevated serum IgG4 levels; diffuse enlargement of the pancreas; delayed enhancement of the enlarged pancreas and presence of a capsule-like rim on dynamic computed tomography; low apparent diffusion coefficient values on diffusion-weighted magnetic resonance image; irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography; less upstream dilatation of the main pancreatic duct on magnetic resonance cholangiopancreatography, presence of other organ involvement such as bilateral salivary gland swelling, retroperitoneal fibrosis and hilar or intrahepatic sclerosing cholangitis; negative work-up for malignancy including endoscopic ultrasound-guided fine needle aspiration; and steroid responsiveness. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection.