The infant-doctor relationship: an examination of infants' distress reactions in the presence of a doctor.

Fear of doctors is a common source of distress among infants; however, the underlying sources of this distress are unknown. To investigate the doctor-infant relationship, the behaviors of 61 healthy infants (176-617 days old) were observed in a simulated examination room. Their behaviors and electrocardiograms were recorded. Two groups of infants were analyzed: those who cried and those who did not. When an experimenter dressed in the doctor's attire entered the room, all 9 infants who were crying (14.8% of all infants) stopped crying, all infants gazed at the experimenter, and their mean heart rate (HR) decreased. After the auscultation started, 29.5% of all infants cried, and the HRs of infants who cried were higher than those of infants who did not cry. During the auscultation, 80.0% of infants who cried averted from the experimenter, while 34.4% of infants who did not cry. Within 5 s of gazing at the stethoscope, the number of infants who cried increased from 3 to 12, and their mean HR also increased. Our findings suggest that the fear of doctors is not due to the appearance of doctors but rather to specific actions performed by doctors, such as auscultation. Infants may regard a doctor's appearance as a source of interest. Furthermore, a stethoscope is a possible trigger for infants' crying. These behavioral observations suggest the potential for patient-centered care for infants.

Association between vitamin D deficiency and allergic symptom in pregnant women.

BACKGROUND: Vitamin D has been reported to affect both innate, and acquired immunity with immune cells such as dendritic cells having the vitamin D receptors. The co-occurrence of the high prevalence of allergic diseases and vitamin D deficiency globally documented in recent decades, has prompted a hypothesis on whether there is a reasonable association between them. OBJECTIVE: To investigate the association between serum vitamin D deficiency and allergic symptoms. METHODS: Historical cohort. On a cohort study for the association between desert dust exposure and allergic symptoms in 3,327 pregnant women during spring and fall in 2011-2013 in Japan conducted as an adjunct study to the Japan Environment and Children's Study, we promptly acquired subjects' daily allergic symptom scores by sending a web-based questionnaire to each participant on some days. Of the 29,434 answers provided by 3,327 participating pregnant women, we extracted 13,356 answers from 1,475 pregnant women that were answered within a 3-month period after blood samplings. And we measured 25(OH)D levels on those samples to investigate the association between their vitamin D deficiency (serum 25(OH)D < 20ng/mL) and the occurrence of any allergic symptom (allergic symptom score> 0) within 3 months. RESULTS: Serum 25(OH)D was less than 20ng/mL in 1,233 of 1,745 samples (70.7%). The adjusted odds ratio (aOR) for occurrence of any allergic symptom in deficient cases compared with non-deficient cases was 1.33 (95% CI: 1.07-1.64, p = 0.01). Further, vitamin D deficiency significantly enhanced the risk increase at desert dust events and at pollen exposure (p-values for interaction <0.1). CONCLUSION: We confirmed the association between serum vitamin D deficiency and allergic symptoms in Japanese pregnant women.

Papillotubular carcinoma with an invasive micropapillary carcinoma component of the breast, characterized by a rapid increase in size due to intra-tumoral hemorrhage: A case report.

INTRODUCTION: Rapidly enlarging mammary tumors, including invasive breast tumors, are clinically rare. Invasive micropapillary carcinoma (IMPC) of the breast is known to have aggressive behavior and poor clinical course compared to invasive ductal carcinoma. CASE PRESENTATION: An 87-year-old woman presented with a rapidly enlarging tumor of the right breast over the course of 3 weeks. Ultrasonography and computed tomography of the chest revealed a giant tumor located on the right chest wall, with heterogeneous parenchymal components and several cystic lesions. Emergency mastectomy was performed because of rapid tumor enlargement complicated by hemorrhage. Histopathological diagnosis confirmed a papillotubular invasive ductal carcinoma with an IMPC component. Tumor cells were negative for estrogen and progesterone receptors, and the human epidermal growth factor receptor 2 score was 2+. DISCUSSION: There has been only one report of breast carcinoma with rapid enlargement caused by spontaneous intratumoral hemorrhage to date. IMPC is associated with a high incidence of axillary lymph node metastases, frequent local recurrence, and a poor clinical outcome. In the present case, the specific breast cancer type can be considered as potential factors responsible for hemorrhage induction within the tumor that further enhanced rapid tumor growth. CONCLUSION: IMPC is a rare, clinically aggressive variant of invasive ductal carcinoma. Owing to its aggressive clinical behaviors, surgeons should readily recognize the morphology of IMPC.

[A Case of Gastrointestinal Metastases of Breast Cancer Effectively Treated with Gemcitabine and Paclitaxel Combination Chemotherapy].

A 55-year-old woman was admitted to our hospital complaining of constipation and abdominal distention. She had a history of right breast surgery for cancer at the age of 48 years. An abdominalCT scan revealed tumors at the antrum of the stomach and the ascending colon, and the tumor at the ascending colon caused obstruction of the colon. She was diagnosed with breast cancer recurrence and was administered combination chemotherapy consisting of gemcitabine and paclitaxel. Ileus improved after this treatment, and she was discharged from the hospital and was able to receive outpatient chemotherapy. After 8 months, she experienced symptoms of ileus again, and conservative treatment was considered impossible. Therefore, she underwent distal gastrectomy and right hemicolectomy. Histological and immunohistological analyses confirmed that the tumors were breast cancer metastases. Chemotherapy with gemcitabine and paclitaxel helped our patient to return to daily life and improved her prognosis.

Complicated adult right-sided Bochdalek hernia with Chilaiditi's syndrome: a case report.

An extremely rare adult case that underwent surgery for ileus caused by Bochdalek hernia associated with Chilaiditi's syndrome is presented. A 65-year-old woman complaining of upper abdominal pain presented to our hospital. Abdominal plain radiography showed increased intestinal gas, and computed tomography (CT) showed the transverse colon located above the right lobe of the liver, representing Chilaiditi's sign. She was diagnosed as having ileus and treated with decompression therapy by a nasoenteric tube. After hospitalization, the patient developed dyspnea, and CT showed intestinal herniation into the right thoracic cavity. She was diagnosed as having strangulated ileus caused by Bochdalek hernia. An emergent laparotomy was performed, and it showed a hole of 5 cm in diameter at the right hemi-diaphragm. The transverse colon was incarcerated through the hole, it was pulled back to the abdominal cavity, and a right hemicolectomy was performed because of necrotic changes. A small part of the liver was also herniated into the right thoracic cavity, and it was returned to the abdominal cavity. The defect in the diaphragm was closed by direct suture. Although the patient developed an abscess in the thoracic cavity postoperatively, she improved with antibiotic therapy and was discharged 2 months after the operation.

Platelets prevent acute hepatitis induced by anti-fas antibody.

BACKGROUND AND AIM: Platelets provide many functions in the body, especially to the liver. The purpose of this study is to investigate the effect of thrombocytosis with acute hepatitis induced by anti-Fas antibody and its mechanism. METHODS: Acute hepatitis was induced by administration of anti-Fas antibody in normal and thrombocytotic C57BL6J mice. For thrombocytosis, thrombopoietin; PEG-rHuMGDF was injected 5 days before and just prior to administration of anti-Fas antibody. To investigate the mechanisms, hepatocyte cell line (AML12) and sinusoidal endothelial cell line (M1) were induced apoptosis by staurosporine. They were cultured with platelets or thrombopoietin. Examination items were as follows: platelet number, alanine aminotransferase (ALT), histological findings, TUNEL (TdT-mediated dUTP-biotin Nick End Labeling) staining, and the expression of proteins associated with apoptosis in vivo and in vitro. RESULTS: Platelets were significantly increased in the thrombocytotic group (P < 0.01). Serum ALT levels were significantly reduced by thrombocytosis at 6, 24 and 72 h after the administration (P < 0.05). In histological findings, hemorrhagic necrosis was observed in the normal group, but not observed in the thrombocytotic group. TUNEL-positive hepatocytes were reduced and the expression of cleaved caspase-3 was significantly decreased in the thrombocytotic group. The phosphorylation of Akt, the increment of Bcl-xL and the decrease of cleaved caspase-3 were observed in AML12 cells cultured with platelets, but were not observed cultured with thrombopoietin. Platelets and thrombopoietin had no anti-apoptotic effect on M1 cells. CONCLUSION: Increase of platelets has a preventative effect against acute hepatitis induced by the anti-Fas antibody. It is suggested that platelets have a direct protective effect against apoptosis of hepatocytes.

Mesenchymal mode of migration participates in pulmonary metastasis of mouse osteosarcoma LM8.

The outcomes of osteosarcoma patients still remain poor because of intractable pulmonary metastasis. We previously established a highly metastatic osteosarcoma cell line, LM8 from Dunn mouse osteosarcoma by in vivo selection. We herein aimed to clarify the characteristic biological features related with high metastatic potential and new target molecules to suppress pulmonary metastasis of osteosarcoma, using this syngeneic spontaneous metastatic model. LM8 cells acquired fibroblastic morphology with striking filopodia on the cell surface. Immunostaining showed faint stress fiber formation and peripherally localized integrin ß1, and biochemical analyses showed the activated Cdc42 and autophosphorylation of focal adhesion kinase (FAK) in LM8 cells when compared to Dunn cells. LM8 cells had activated motility in single cell migration mode. LM8 migration was increased by a Rho-associated kinase (ROCK) inhibitor, Y-27632, while decreased by Cdc42 silencing using RNA interference system. We found that a clinically approved camptothecin analog, irinotecan suppressed the migration, Cdc42 activity, and autophosphorylation of FAK, and attenuated integrin ß1 distribution selectively in LM8 cells. Daily oral administration of irinotecan significantly reduced the rate and size of pulmonary metastasis in syngeneic C3H mice. The fibroblastic morphology and activated cell migration with the dependency on Cdc42 but not Rho-ROCK signaling pathway argued that LM8 moved in mesenchymal mode of cell migration. This activated mesenchymal migration was a key component of the pulmonary metastasis of LM8 cells. The inhibition of mesenchymal migration by irinotecan, in addition to its cytotoxic effects, might be effective in preventing pulmonary metastasis of osteosarcoma.

Prognostic significance of the BAALC isoform pattern and CEBPA mutations in pediatric acute myeloid leukemia with normal karyotype: a study by the Japanese Childhood AML Cooperative Study Group.

High BAALC (brain and acute leukemia, cytoplasmic) gene expression may indicate an adverse prognosis for adults who have acute myeloid leukemia (AML) and a normal karyotype, but its prognostic significance for pediatric AML cases is unclear. Whether different BAALC isoform patterns are of prognostic significance is also unclear. Newly diagnosed AML patients with normal karyotype who were treated by the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed in terms of their BAALC expression levels (n = 29), BAALC isoforms (n = 29), and CEBPA mutations (n = 49). Eleven and 18 patients exhibited high and low BAALC expression, respectively, but these groups did not differ significantly in terms of overall survival (54.6 vs. 61.1%, P = 0.55) or event-free survival (61.4 vs. 50.0%, P = 0.82). Three of these 29 patients (10.3%) expressed the exon 1-5-6-8 BAALC isoform along with the expected 1-6-8 isoform and had adverse clinical outcomes. Novel CEBPA mutations were also identified in four of 49 patients (8.2%). All four patients have maintained complete remission for at least 5 years. Thus, 1-5-6-8 isoform expression may be associated with an adverse prognosis in pediatric AML with normal karyotype. CEBPA mutations may indicate a favorable prognosis.

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury.

Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.

Involvement of extracellular signal-regulated kinase activation in human osteosarcoma cell resistance to the histone deacetylase inhibitor FK228 [(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone].

The histone deacetylase inhibitor depsipeptide [(1S,4S,7Z,10S, 16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19, 22-pentone] (FK228) has attracted a great deal of interest because of its antiproliferative and apoptotic properties in various malignancies. Histone deacetylase inhibitors induce the expression of the multidrug resistance transporter P-glycoprotein (P-gp), and FK228 is a known P-gp substrate. Thus, FK228 seems to induce its own mechanism of drug resistance by up-regulating P-gp. The goal of this study was to establish human FK228-resistant osteosarcoma cell lines and to investigate whether there are mechanisms of FK228 resistance in addition to P-gp up-regulation. After 72 h in culture, the 50% inhibitory concentrations (IC(50)) of FK228 were 4.8 and 991 nM in HOS and HOS/FK8 cells, respectively, and 3.6 and 1420 nM in U2OS and U2OS/FK11 cells, respectively. Increased histone H3 acetylation was observed in FK228-resistant cell lines after a 1-h treatment with 10 nM FK228. Unlike in parental cells, significant P-gp overexpression was detected in FK228-resistant cells, and 10 nM FK228 treatment activated the mitogen-activated protein kinase (MAPK) pathway but did not induce Fas ligand (FasL) up-regulation or c-FLIP down-regulation. However, treatment of FK228-resistant cells with a combination of FK228 and mitogen-activated protein kinase kinase (MEK) inhibitors induced apoptosis, up-regulated FasL, and down-regulated c-FLIP. The expression and function of P-gp were unaltered by treatment with MEK inhibitors. These results indicate that the FK228 resistance of osteosarcoma cells is related to P-gp overexpression and MAPK pathway activation by FK228. MEK or P-gp inhibitors may be useful in overcoming this resistance.

Platelets contribute to the reduction of liver fibrosis in mice.

BACKGROUND AND AIM: Several recent studies have reported that liver cirrhosis (LC) can be ameliorated, but few adequate strategies are available against liver fibrosis. Although LC clinically shows thrombocytopenia and hypersplenism, the correlation with liver fibrosis and platelets remains unclear. The aim of the present study was to investigate the effect of platelets on liver fibrosis in mouse models. METHODS: To induce liver fibrosis, C57BL6 female mice were injected i.p. with 1 mL/kg carbon tetrachloride (CCl(4)) twice a week for 8 weeks. Thrombocytosis was achieved by giving thrombopoietin or splenectomy in addition to CCl(4) intoxication. At 8 weeks, whole blood and liver specimens were obtained for studies as follows: peripheral platelet counts, histopathological examination, hydroxyproline assay, immunostaining, quantification of mRNA expression, and microarray analysis. RESULTS: Thrombocytosis significantly reduced liver fibrosis and hydroxyproline content of liver tissues compared to mice with CCl(4) administration alone. Platelets suppressed increments in mRNA expression for transforming growth factor-beta, and increased matrix metalloproteinase-9 expression in the liver. Microarray analysis of the liver revealed that platelets upregulated gene expressions involved in cell proliferation compared to expression in mice with CCl(4) intoxication alone. Platelets also increased liver volume, proliferative cell nuclear antigen labeling index, and mitotic index in fibrotic mice. CONCLUSION: These results clearly show that platelets reduce liver fibrosis and promote liver regeneration, even under cirrhotic conditions. We, therefore, propose that platelets could offer a potent tool in the treatment of liver cirrhosis.

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation.

Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase-independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228-induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells.

Autonomic regulation of liver regeneration after partial hepatectomy in mice.

BACKGROUND/AIMS: The autonomic vagus nerve is thought to play an essential role in liver regeneration since hepatic vagotomy delays hepatic DNA synthesis. However, how the parasympathetic vagus nerve is involved in liver regeneration remains obscure. Kupffer cells are located in liver sinusoids adjacent to hepatocytes and might regulate liver regeneration by releasing interleukin-6 (IL-6). The present study examines the role of the vagus nerve and how Kupffer cells are involved in parasympathetic nerve-mediated liver regeneration in mice. METHODS: We performed surgical vagotomy of the hepatic branch and then partial hepatectomy (PH); some mice received acetylcholine (ACh) agonist/antagonist before PH. We then evaluated liver regeneration and signal transducer and activator of transcription-3 (STAT3) activation. We also investigated whether ACh stimulates IL-6 release from Kupffer cells. RESULTS: Surgical vagotomy impaired liver regeneration. STAT3, which is activated by IL-6 after hepatectomy and plays a pivotal role in liver regeneration, was less activated in vagotomized mice after PH. Post-PH STAT3 activation was recovered by administering vagotomized mice with an ACh agonist. Furthermore, ACh stimulated IL-6 release in Kupffer cells in vitro. CONCLUSION: The parasympathetic system (vagus nerve) contributes to liver regeneration after hepatectomy by stimulating IL-6 release from Kupffer cells followed by STAT3 activation in hepatocytes.

Clinically relevant dose of zoledronic acid inhibits spontaneous lung metastasis in a murine osteosarcoma model.

Clinically obtainable concentrations of zoledronic acid (ZOL) inhibited the production of vascular endothelial growth factor and reduced the migration, adhesion, and invasiveness of osteosarcoma (OS) cells in vitro. The in vivo effects of ZOL were investigated by using a murine model of spontaneous lung metastasis. The higher dose of ZOL (80 microg/kg three times/week) inhibited the growth of OS at the primary site, accompanied by inhibition of neovascularization in the tumor. Interestingly, while the lower dose of ZOL (80 microg/kg once a week) could not inhibit the growth of OS at the primary site, it significantly prevented lung metastasis.

Single administration of thrombopoietin prevents progression of liver fibrosis and promotes liver regeneration after partial hepatectomy in cirrhotic rats.

OBJECTIVE: To evaluate the effect of thrombopoietin on liver regeneration after hepatectomy and antifibrosis under conditions of liver cirrhosis in rats. SUMMARY BACKGROUND DATA: We revealed that platelets induced by thrombopoietin administration promote liver regeneration after hepatectomy in the normal liver. METHODS: Seventy percent hepatectomy was carried out in rats, which were subsequently divided into 4 groups: (1) normal group without any treatment, (2) liver cirrhosis (LC) group, (3) combined thrombopoietin and liver cirrhosis (LC+TPO) group, and (4) combined thrombopoietin, antiplatelet serum and liver cirrhosis (LC+TPO+APS) group. Growth kinetics in the liver regeneration and growth factors were analyzed. Liver fibrotic area and activation of hepatic stellate cells were also investigated. RESULTS: In LC group, liver regeneration was significantly delayed compared with normal group 24 hours after hepatectomy. On the other hand, liver regeneration of LC+TPO group increased significantly compared with LC group, to a level that was the same as that recorded in normal group. In LC group, liver fibrotic area before hepatectomy was significantly higher compared with the normal group. Liver fibrosis of LC+TPO group was significantly reduced compared with LC group. The antifibrotic and liver regeneration promoting effects of LC+TPO group were inhibited by antiplatelet serum in LC+TPO+APS group. CONCLUSION: The administration of thrombopoietin reduces liver fibrosis and stimulates regeneration after hepatectomy through increment and accumulation of platelets in the cirrhotic liver. This could be a potentially useful treatment for liver cirrhosis.

Role of platelets on liver regeneration after 90% hepatectomy in mice.

BACKGROUND/AIMS: Mortality after 90% partial hepatectomy in mice was associated with severe acute liver failure. Recently, we revealed that platelets have a strong promotional effect on hepatic regeneration. In the present study, we investigated the effect of thrombocytosis on liver regeneration after 90% hepatectomy in mice. METHODS: For thrombocytosis induction PEG-rHuMGDF was injected 5 days before operation. Hepatectomy, sparing only the caudate lobe, was performed in normal and thrombocytotic BALB/c mice. Survival rate, platelet number, liver weight/body weight ratio, proliferating cell nuclear antigen, serum parameters, signal transduction and overexpressed genes were examined. RESULTS: Platelet number was significantly higher in thrombocytotic group. All mice in normal group died within 30 h after hepatectomy. Survival rate in thrombocytotic group was 6/11 at 30 h and 3/11 one week after hepatectomy. Activation of Akt and STAT3 signaling pathways in thrombocytotic group was observed earlier and recognized to be stronger compared to normal group. Cell cycle, signaling pathways, metabolism and transport genes were significantly overexpressed in thrombocytotic group up to 24h after hepatectomy. CONCLUSIONS: Under the thrombocytotic condition, liver regeneration occurred even in 90% hepatectomized mice. Platelets contribute to cell cycle progression and metabolic pathways in addition to preventing acute liver failure.

Platelet dynamics in the early phase of postischemic liver in vivo.

BACKGROUND: In liver surgery, ischemia/reperfusion injury occasionally leads to liver failure by activating Kupffer cells (KCs) and leukocytes. However, few reports have demonstrated a relationship between KCs and platelets in vivo. This study investigated the relationship between these cells using intravital microscopy. MATERIALS AND METHODS: Male Wistar rats were divided into two groups: (1) KC+ group, receiving 1 mL saline; and (2) KC- group, intravenously injected with liposome-encapsulated dichloromethylene disphosphonate for elimination of KCs. At 48 h after administration, 20 min of total normothermic hepatic ischemia was induced. Rhodamine-6G-labeled platelets and sinusoidal alterations were monitored using intravital microscopy up to 120 min after reperfusion. P-selectin, accumulated leukocytes and morphological damage, and alanine aminotransferase were evaluated. RESULTS: In the KC+ group, numbers of adherent platelets increased significantly within 30 min after reperfusion. Endothelial cells of sinusoids in which KCs were mainly located were destroyed and the sinusoids were significantly constricted after reperfusion. Conversely, in the KC- group, adherent platelets in sinusoids were suppressed, and sinusoidal perfusion, endothelial cell damage and serum alanine aminotransferase levels were significantly improved. P-selectin on sinusoidal endothelial cells was not observed up to 120 min after reperfusion in either group. CONCLUSIONS: Adherent platelets appear to reflect activation of KCs and lead to leukocyte accumulation, resulting in sinusoidal perfusion disturbance and liver failure. Evaluation of adherent platelets in the microcirculation offers an important marker of hepatic injury.

Platelets promote liver regeneration under conditions of Kupffer cell depletion after hepatectomy in mice.

BACKGROUND: Platelets have been proven to promote liver regeneration after hepatectomy. Kupffer cells produce inflammatory cytokines and also promote liver regeneration. In the present study, we examined whether platelets promote liver regeneration after hepatectomy under conditions of Kupffer cell depletion. METHODS: Seventy percent hepatectomy was carried out in mice, which were subsequently divided into four groups: (1) a normal group without any treatment, (2) a Kupffer cell depleted (KD) group, (3) a thrombocytotic group, and (4) a combined thrombocytotic and Kupffer cell depleted (TKD) group. Growth kinetics in the liver regeneration, growth factors, inflammatory cytokines, and signal transduction relating to hepatocyte proliferation were analyzed. RESULTS: In the KD group, liver regeneration was significantly delayed compared to the normal group 48 h after hepatectomy. On the other hand, liver regeneration of the TKD group increased significantly compared to KD group, to a level that was the same as that recorded in the normal group. In the thrombocytotic group, liver regeneration increased significantly compared to the normal group. Tumor necrosis factor alpha (TNF-alpha) expression was lower in the KD and TKD groups than in the normal group after hepatectomy, but, in the TKD group, hepatocyte growth factor and Akt phosphorylation were higher than in the normal and KD groups. CONCLUSIONS: After hepatectomy, liver regeneration in the Kupffer cell depleted group was delayed because of lower TNF-alpha expression. Platelets promote liver regeneration even under condition of Kupffer cell depletion by stimulating hepatocyte growth factor and insulin-like growth factor-1 expression, and they activate Akt.