An autopsy case of granulocyte-colony-stimulating-factor-producing extrahepatic bile duct carcinoma

A 79-year-old man was referred to this department due to the presence of extrahepatic bile duct carcinoma with a tumor at the left chest wall. The lesion was suspected to be a metastasis of bile duct carcinoma to the left wall, however, computed tomography （CT） revealed no regional lymph node or liver metastases. In addition, cytological and pathological examinations did not show malignancy. At the time of admission, the white blood cell count was 21 460 cells/μL （neutrophils, 18 240 cells/μL） and this elevated to 106 040 before death. In addition, serum granulocyte colony-stimulating factor （G-CSF） was elevated. At 28 d after admission, the patient died. An autopsy showed a poorly differentiated adenocarcinoma with sarcomatous change, which had slightly invaded into the pancreas around the bile duct, and was found in the distal bile duct with multiple metastases to the chest wall, lung, kidney, adrenal body, liver, mesentery, vertebra and mediastinal and para-aortic lymph nodes, without locoregional lymph node and liver metastasis. The cancer cells showed positive immunohistochemical staining for anti-G-CSF antibody. This is believed to be the first report of an extrahepatic bile duct carcinoma that produces G-CSF. Since G-CSF-producing carcinoma and sarcomatous change of the biliary tract leads to poor prognosis, early diagnosis and treatment are needed. When infection is ruled out, the G-CSF in serum should be examined. In addition, examinations such as bonescintigraphy and chest CT should also be considered for distant metastasis.     

Preload-adjusted 2 wave-intensity peaks reflect simultaneous assessment of left ventricular contractility and relaxation.

BACKGROUND: The magnitudes of the first (WI1) and the second wave-intensity peak (WI2) during the ejection period can be used as indices of left ventricular (LV) contractility and relaxation, respectively. However, use of WI to characterize LV dp/dt and the end-diastolic volume (V ed) relationship may be more problematic, as WI may be affected by changes in preload. METHODS AND RESULTS: The LV pressure-volume data sets, consisting of 23 recordings obtained by the conductance method from 12 heart disease patients, were studied. End-systolic elastance (E es) and volume-axis-intercept (V0) were calculated with varying preload. Time constant of LV relaxation (tau), V ed, and WI were calculated from steady-state averaged data. The E es showed a weak correlation with WI1 (r = 0.46, p < 0.05) but a better correlation with preload-adjusted WI1 [WI1/V ed; r=0.86, WI1/V(ed)2; r = 0.92, WI1/(V ed - V0)2; r = 0.89, all p < 0.01]. Similarly, tau did not correlate with WI2 but did correlate with preload-adjusted WI2 [WI2/V ed; r = -0.73, WI2/V(ed) 2; r = -0.63, WI2/(V ed - V0)2; r = -0.78, all p < 0.01]. CONCLUSIONS: These data demonstrate the importance of preload-adjustment when using the WI index for simultaneous assessment of LV contractility and relaxation.     

Improvement of endothelial dysfunction by angiotensin II blockade accompanied by induction of vascular hepatocyte growth factor system in diabetic spontaneously hypertensive rats

 Hepatocyte growth factor (HGF) is a unique growth factor with many protective functions. Previously, we demonstrated that HGF stimulated growth of endothelial cells without replication of vascular smooth muscle cells (VSMC) and that angiotensin (Ang) II significantly decreased local HGF production in VSMC. Moreover, we also reported that high glucose significantly decreased local vascular HGF production. Therefore, we examined effects of Ang II blockade on vascular HGF expression and endothelial injury in diabetic hypertensive rats. An angiotensin-converting enzyme inhibitor (quinapril) and an Ang II type 1 receptor antagonist (GA-0113) or vehicle was administrated to diabetic spontaneously hypertensive rats (SHR-DM), in whom diabetes was induced by streptozotocin. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF and its receptor, c-met, was examined by immunohistochemistry. Both quinapril and GA-0113 significantly improved the vasodilator response to acetylcholine (P < 0.01), while vehicle did not as compared to untreated normotensive Wistar-Kyoto rats (WKY). We next examined the effects of Ang II blockade on vascular HGF expression in SHR-DM. Importantly, the vascular HGF level was markedly decreased in SHR-DM as compared to WKY, while Ang II blockade by quinapril or GA-0113 significantly increased positive staining for HGF in SHR-DM. Similarly, staining of its specific receptor, c-met, was less in the blood vessels of SHR-DM as compared to WKY. In contrast, Ang II blockade also significantly increased c-met production in SHR-DM. The present data demonstrated the improvement of endothelial dysfunction by Ang II blockade in SHR-SM, accompanied by an increase in vascular HGF and c-met. Received: June 7, 2002 / Accepted: September 21, 2002 Acknowledgments We wish to thank Rie Kosai and Keiko Yamaguchi for their excellent technical assistance. This work was partially supported by grants from the Japan Health Sciences Foundation, a Grant-in-Aid from The Ministry of Public Health and Welfare, a Grant-in-Aid for the Development of Innovative Technology, a Grant-in-Aid from Japan Promotion of Science, and through Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government. Correspondence to N. Tomita     

Prescription of potentially inappropriate medications in elderly outpatients: a survey using 2015 Japanese Guidelines

International Journal of Clinical Pharmacy - Background In recent years, rapid increase of elderly population has become a major social problem in developed&nbsp;countries. They tend to...     

Endosonographic features in patients with non-alcoholic early chronic pancreatitis improved with treatment at one year follow up

Since the prevention of early chronic pancreatitis (ECP) into chronic pancreatitis might be critical for the reduction of pancreatic cancer, we tried to clarify the pathophysiology of ECP patients, focusing on ECP patients without alcoholic chronic pancreatitis. 27 ECP patients without alcoholic chronic pancreatitis and 33 patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) were enrolled in this study. Diagnosis of ECP was made when imaging findings showed the presence of more than 2 out of 7 endoscopic ultrasound features. Duodenal degranulated eosinophils and glucagon-like peptide 1 producing cells were estimated by immunostaining. There were no significant differences in characteristics and psychogenic factors between ECP and FD-P patients. Interestingly, endoscopic ultrasound score in ECP patients significantly improved, albeit clinical symptoms in ECP patients showed no improvement at one year follow up. The extent of migration of duodenal degranulated eosinophils in FD-P patients was significantly higher compared to that in ECP patients. The levels of elastase-1 and trypsin in ECP patients with improved endoscopic ultrasound features were significantly reduced by the treatment. Further studies will be needed to clarify whether clinical symptoms and endoscopic ultrasound features in ECP patients without alcoholic chronic pancreatitis were improved in longer follow up study.     

Generation of a large number of functional dendritic cells from human monocytes expanded by forced expression of cMYC plus BMI1

Anticancer vaccination therapies with monocyte-derived dendritic cells (DC) are widely conducted. A large number of primary monocytes (approximately 10⁸ cells) are needed to generate the number of DC required to achieve an effect upon vaccination, and monocytes are usually purified from peripheral blood mononuclear cells obtained by apheresis procedure, which is somehow invasive for cancer patients. As a means to facilitate the generation of DC for therapeutic use, we herein report a method to amplify human monocytes. We found that lentivirus-mediated transduction of cMYC along with BMI1 induced proliferation of CD14⁺ monocytes derived from 9 out of 12 blood donors, and we named the monocyte-derived proliferating cells CD14-ML. Their proliferation continued for 3–5 weeks in the presence of M-CSF and GM-CSF, resulting in 20–1000-fold amplification. Importantly, the expanded CD14-ML differentiated into fully functional DC (CD14-ML-DC) upon the addition of IL-4 to the culture. We successfully stimulated autologous CD8⁺ T cells with CD14-ML-DC pulsed with cytomegalovirus peptide or MART-1 peptide to generate antigen-specific CTL lines. This is the first report describing the method for in vitro expansion of human peripheral blood monocytes.     

Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.     

Low-dose Interferon-α Treatment Improves Survival and Inflammatory Responses in a Mouse Model of Fulminant Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of symptoms, therapeutic strategies for this pathologic condition are still poorly developed. Interferon (IFN)-α is well known as an antiviral cytokine and low-dose IFN-α has been reported to show antiinflammatory effects. Therefore, we investigated how this cytokine affected ARDS in a mouse model. C57BL/6 mice received sequential intratracheal administration of α-galactosylceramide (α-GalCer) and lipopolysaccharide (LPS), which resulted in the development of fulminant ARDS. These mice were then treated intranasally with IFN-α and their survival, lung weight, pathological findings, and cytokine production were evaluated. Administration of low-dose IFN-α prolonged survival of fulminant ARDS mice, but higher doses of IFN-α did not. Histological analysis showed that low-dose IFN-α treatment improved findings of diffuse alveolar damage in fulminant ARDS mice, which was associated with reduction in the wet/dry (W/D) lung weight ratio. Furthermore, IFN-γ production in the lungs was significantly reduced in IFN-α-treated mice, compared with control mice, but tumor necrosis factor (TNF)-α production was almost equivalent for both groups. Low-dose IFN-α shows antiinflammatory and therapeutic effects in a mouse model of fulminant ARDS, and reduced production of IFN-γ in the lung may be involved in the beneficial effect of this treatment.