Yoshikiyo Akasaka

Histopathological predictors of regional lymph node metastasis at the invasive front in early colorectal cancer

Akishima‐Fukasawa Y, Ishikawa Y, Akasaka Y, Uzuki M, Inomata N, Yokoo T, Ishii R, Shimokawa R, Mukai K, Kiguchi H, Suzuki K, Fujiwara M, Ogata K, Niino H, Sugiura H, Ichinose A, Kuroda Y, Kuroda D & Ishii Tu2028(2011) Histopathology59, 470–481

The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing

While investigating the mechanisms underlying cell death during wound healing processes, we uncovered the pro‐apoptotic effects of basic fibroblast growth factor (bFGF) on granulation tissue fibroblasts following pretreatment with transforming growth factor (TGF)‐β1 in vitro. bFGF induced caspse‐3 activation and apoptosis in TGF‐β1‐pretreated granulation tissue‐derived fibroblasts (GF‐1) following bFGF treatment for 48 and 96 h. In contrast, fibroblasts that had been treated in the same manner and that originated from the uninjured dermis did not display apoptosis, indicating that the mechanisms underlying apoptosis events in fibroblasts that originate from normal dermal and wound tissues differ. In this process, we also found that bFGF inhibited Akt phosphorylation at serine 473 and induced a rapid loss of phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 in pretreated GF‐1 cells, an event that coincided with the dissociation of phosphorylated FAK from the focal adhesions. Therefore, inhibition of survival signals relayed via the disrupted focal adhesion structures and inactivated Akt following bFGF treatment may lead to apoptosis in GF‐1 cells pretreated with TGF‐β1. Pretreatment of GF‐1 with TGF‐β1 followed by the addition of bFGF resulted in significantly greater inhibition of phosphorylation of Akt and FAK compared to treatment with TGF‐β1 or bFGF alone. The combinatorial treatment also led to proteolysis of FAK and inhibition of FAK and Akt protein expression in GF‐1 cells. These findings demonstrated a significant role for the two cytokines in apoptosis of granulation tissue fibroblasts during wound healing. In vivo studies also confirmed a marked decline in phosphorylation and protein expression of Akt and FAK in bFGF‐injected skin wounds. These results led to the hypothesis that temporal activation of TGF‐β1 and bFGF at the injury site promotes apoptosis in granulation tissue fibroblasts, an event that is critical for the termination of proliferative granulation tissue formation. Copyright

Histopathologic profiles of coronary atherosclerosis by myocardial bridge underlying myocardial infarction

OBJECTIVEnAnatomic properties of myocardial bridge (MB) are sometimes responsible for myocardial infarction (MI) through the changes in the atherosclerosis distribution in the left ascending coronary artery (LAD). The purpose of this study was to investigate histopathologic profiles of atherosclerotic lesions resulting from the MB presence in the LAD in the MI cases.nnnMETHODSnIn 150 consecutive autopsied MI hearts either with MBs [MI(+)MB(+); nxa0=xa067] or without MBs [MI(+)MB(-); nxa0=xa083] and 100 normal hearts with MBs [MI(-)MB(+)], LADs were consecutively cross-sectioned at 5-mm intervals. The most advanced intimal lesion and unstable plaque-related lesion characteristics (UPLCs) in each section were histopathologically evaluated in conjunction with the anatomic properties of the MB, such as its thickness, length, location, and MB muscle volume burden (MMV: the total volume of MB thickness multiplied by MB length).nnnRESULTSnThe MB showed a significantly greater thickness (Pxa0=xa00.0090), length (Pxa0=xa00.0300), and MMV (Pxa0=xa00.0019) in MI(+)MB(+) than in MI(-)MB(+). Mean age of acute MI cases was significantly younger (Pxa0=xa00.0227) in MI(+)MB(+) than in MI(+)MB(-). Frequency of plaque fissure/rupture in the proximal LAD was significantly higher in acute MI cases of MI(+)MB(+) than in MI(+)MB(-). UPLCs tended to be located proximally in MI(+)MB(+) and frequent 2.0xa0cm or more proximal to the MB entrance in MI(+)MB(+).nnnCONCLUSIONnIn MI(+)MB(+), UPLCs tend to be located more proximally, and a plaque in the LAD proximal to the MB is prone to rupture, resulting in MI at younger age.

Evidence of intravenous immunoglobulin as a critical supportive therapy against Clostridium difficile toxin-mediated lethality in mice

OBJECTIVESnClostridium difficile produces toxins and is an aetiological organism of pseudomembranous colitis. Immunoglobulin is one of the treatment strategies against fulminant C. difficile infections, but the clinical evidence is still limited. We examined the efficacy of intravenous immunoglobulin (IVIg) in C. difficile toxin (CDT)-mediated lethality and cellular injury in mice.nnnMETHODSnMice were intraperitoneally injected with 0.2 mL of filter-sterilized C. difficile culture supernatant (CDT preparation). The IVIg preparation was intravenously administered at several timepoints. We also examined alteration of intestinal permeability and an apoptosis marker in the gut. In in vitro experiments, HEp-2 cells were incubated with a CDT preparation in the presence or absence of the IVIg preparation, after which cell viability and lactate dehydrogenase release were examined.nnnRESULTSnAll control mice died by day 2 after injection of the CDT preparation. The maximum effects of IVIg (100% survival) were observed when the mice were treated with IVIg at the same time as injection of the CDT preparation. The IVIg effects were closely associated with improvement of intestinal vascular permeability and mucosal damage in the gut. In addition, reduction of an apoptosis marker (histone-associated DNA fragments) was demonstrated in the mice treated with IVIg. Interestingly, a smaller increase in histone-associated DNA fragments was observed in FasL-deficient mice treated with the CDT preparation compared with wild-type.nnnCONCLUSIONSnThese data demonstrated that IVIg may be protective against CDT-mediated lethality, when administered at the appropriate time. The present data also suggest an increase in intestinal permeability, probably through exaggeration of Fas/FasL-mediated apoptosis, as a key mechanism of C. difficile-mediated diseases.

Association of variance in anatomical elements of myocardial bridge with coronary atherosclerosis

OBJECTIVESnThe myocardial bridge (MB) is an anatomical structure consisting of myocardium covering a part of the left anterior descending coronary artery (LAD). The extent and spatial distribution of atherosclerosis in the LAD with an MB is influenced by the anatomical properties of the MB. In this study, the relationship between the overall anatomical framework of the MB including the periarterial adipose tissue as well as fibrosis of the MB itself and coronary atherosclerosis was histomorphometrically examined.nnnMETHODSnFull-length LADs with an MB from 180 autopsied hearts were cross-sectioned at 5-mm intervals. Together with measurements of MB - length, thickness, and location, proportional decrease of the atherosclerosis ratio of LAD segments beneath MB for that of LAD segments proximal to MB was defined as the atherosclerosis suppression ratio. The area ratio of adipose tissue in the periarterial area beneath MB and area ratio of fibrosis in the MB muscle were also measured.nnnRESULTSnThe atherosclerosis suppression ratio was significantly proportional to MB length and thickness. Periarterial adipose tissue beneath MB was detected in all cases (100%), and fibrosis within MB muscle for 136 cases (75.6%). The amount of adipose tissue beneath MB and MB fibrosis did not statistically affect the atherosclerosis suppression ratio. Multivariate analysis revealed MB length and thickness were the independent factors affecting the atherosclerosis suppression ratio.nnnCONCLUSIONSnThe anatomical properties of an MB, especially of its length and thickness, play decisive roles as regulators of atherosclerosis in the LAD regardless of the amount of adipose tissue around LAD and MB fibrosis.

Pathogenesis of lupus-like nephritis through autoimmune antibody produced by CD180-negative B lymphocytes in NZBWF1 mouse.

Toll-like receptors appear to play an important role in the pathogenesis of lupus-like nephritis in mice. In human and mouse, CD180 is a homologue of TLR4. In SLE patients, the number of CD180-negative B cells in peripheral blood changes in parallel with disease activity. In the present study using NZBWF1 mice, the population of splenic CD180-negative B cells increased with progression of renal lesions and aging. These cells produced both anti-dsDNA and histone antibodies; the peripheral blood levels of anti-dsDNA antibody increased markedly with aging. B cells infiltrating into renal lesions were CD180-negative and produced anti-dsDNA antibody. Considered together, these findings indicate that CD180-negative B cells contribute significantly to development of SLE-like morbidity in NZBWF1 mice by autoantibody production.

Malignant Adrenal Rest Tumor of the Retroperitoneum Producing Adrenocortical Steroids

We present a case of a malignant adrenal rest tumor arising from the retroperitoneum with Cushings syndrome in a 31-year-old female. Her serum cortisol and dehydroepiandrosterone sulfate levels were elevated, while adrenocorticotropic hormone levels were low. Computed tomography scans and magnetic resonance imaging revealed a retroperitoneal tumor with no visible lesions in the adrenal glands and ovaries. From those results and the histopathologic findings following biopsy of an enlarged supraclavicular lymph node, the patient was diagnosed as a malignant adrenal rest tumor of the retroperitoneum. Despite chemotherapy, the patient died of rapid development of multiple metastases. Autopsy revealed a large tumor that extended around the abdominal aorta from the levels of the left kidney to the aortic bifurcation with generalized metastases. Tumor cells were characterized by clear and eosinophilic cytoplasm and atypical nuclei that exhibited frequent and atypical mitoses. Immunohistochemistry regarding steroidogenesis was performed and revealed that the tumor cells were immunopositive for adrenal 4 binding protein/steroidogenic factor-1, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase. We thus elucidated the adrenocortical steroid production in the tumor cells causing Cushings syndrome. This case report first demonstrates the steroidogenic capacity in a malignant adrenal rest tumor.

Coronary arterial complications after percutaneous coronary intervention in Behçet's disease

Behcets disease is a multisystemic vascular inflammatory disease, but concurrent cardiac diseases, such as acute myocardial infarction, are rare. Several complications may arise after coronary intervention for coronary lesions that interfere with treatment, and the incidence of coronary arterial complications due to invasive therapy remains unclear. Further, the long- term outcomes in patients with Behcets disease after stenting for acute myocardial infarction have not been described. The present report describes a 35-year-old Japanese man with Behcets disease who developed acute myocardial infarction. A coronary aneurysm developed at the stent- ing site of the left anterior descending coronary artery, along with stenosis in the left anterior descending segment proximal to the site. Although invasive therapy was considered, medication including immunosuppressants was selected because of the high risk of vascular complications after invasive therapy. The coronary artery disease has remained asymptomatic for the 4 years since the patient started medication. This case underscores the importance of considering the