Neuropilin-1 on hematopoietic cells as a source of vascular development

Neuropilin-1 (NP-1) is a receptor for vascular endothelial growth factor-165 (VEGF165) and acts as a coreceptor that enhances the function of VEGF165 through VEGF receptor-2 (VEGFR-2). Studies using transgenic and knock-out mice of NP-1 indicated that this molecule is important for vascular development as well as neuronal development. We recently reported that clustered soluble NP-1 phosphorylates VEGFR-2 on endothelial cells with a low dose of VEGF165 and rescues the defective vascularity of the NP-1-/- embryo in vitro and in vivo. Here we show that NP-1 is expressed by CD45+ hematopoietic cells in the fetal liver, can bind VEGF165, and phosphorylates VEGFR-2 on endothelial cells. CD45+NP-1+ cells rescued the defective vasculogenesis and angiogenesis in the NP-1-/- P-Sp (para-aortic splanchnopleural mesodermal region) culture, although CD45+NP-1- cells did not. Moreover, CD45+NP-1+ cells together with VEGF165 induced angiogenesis in an in vivo Matrigel assay and cornea neovascularization assay. The extracellular domain of NP-1 consists of "a," "b," and "c" domains, and it is known that the "a" and "c" domains are necessary for dimerization of NP-1. We found that both the "a" and "c" domains are essential for such rescue of defective vascularities in the NP-1 mutant. These results suggest that NP-1 enhances vasculogenesis and angiogenesis exogenously and that dimerization of NP-1 is important for enhancing vascular development. In NP-1-/- embryos, vascular sprouting is impaired at the central nervous system (CNS) and pericardium where VEGF is not abundant, indicating that NP-1-expressing cells are required for normal vascular development.     

An autopsy case of pulmonary and central nervous system metastatic osteosarcoma treated with thirty-six courses of chemotherapy over four years]

A 32-year-old man presented with cough, dyspnea and orthopnea ten years after amputation of the right humerus because of osteosarcoma. Chest radiographs and chest computed tomographs showed left pleural effusion, pericardial effusion and a giant intrathoracic mass, which was histologically diagnosed as a recurrence of the osteosarcoma. After 4 courses of chemotherapy combined with CDDP, the mass in the left upper lobe of the lung decreased in size, and it was then resected. Three months later, new metastatic lesions were detected in the thoracic area. Therefore, 29 additional courses of chemotherapy were administered (36 courses in total over 4 years; including regimens combined with CDDP, carboplatin, high-dose methotrexate, ifosfamide, dacarbazine, vindesine, etoposide, vincristine, taxotere and gemcitabine). In spite of the several courses of chemotherapy, brain and spinal cord metastases appeared, and the patient eventually died of cerebral hemorrhage. During the four years after the first recurrence he had good quality of life as a result of the chemotherapy.     

Alteration of lipid metabolism associated with the activation of mouse alveolar macrophages induced by 1 alpha, 25-dihydroxyvitamin D3

We have reported that 1 alpha, 25-dihydroxyvitamin D3 [1 alpha, 25-(OH)2D3] directly induces fusion and tumoricidal activity (activation) in murine alveolar macrophages. In this study we examined lipid metabolism associated with the fusion and activation of alveolar macrophages induced by 1 alpha, 25-(OH)2D3. Treatment of alveolar macrophages with 12 nM 1 alpha, 25-(OH)2D3 for 48 h caused a marked increase in incorporation of [14C]acetic acid and [14C]oleic acid into triacylglycerol. The macrophages treated with the vitamin began to fuse and show cytotoxicity at 48 h, whereas incorporation of the radioactive compounds into triacylglycerol started as early as 12 h after 1 alpha, 25-(OH)2D3 was added. The triacylglycerol synthesis induced by 1 alpha, 25-(OH)2D3 was greatly increased when 14C-labeled unsaturated fatty acids were used as tracers compared with 14C-labeled saturated fatty acids. The activity of diacylglycerol acyltransferase, which catalyzes the last step of the three acylations in triacylglycerol synthesis, was significantly higher in the macrophages treated with 1 alpha, 25-(OH)2D3 than in the control macrophages. Like 1 alpha, 25-(OH)2D3, retinoic acid and lypopolysaccharides also activated alveolar macrophages, but not induce any fusion. The activated macrophages cultured with retinoic acid or lypopolysaccharides also induced synthesis of triacylglycerol. These results indicate that 1 alpha, 25-(OH)2D3 induces the synthesis of triacylglycerol by preferentially incorporating unsaturated fatty acids into diacylglycerol, and that the alteration of lipid metabolism is related to the activation, rather than the fusion, of alveolar macrophages.     

Impaired 3,5,3'-triiodothyronine (T3) production in diabetic patients.

Serum concentrations of thyroxine (T₄), 3,5,3′-triiodothyronine (T₃), and 3,3′,5′-triiodothyronine (RT₃) were measured in 50 patients with diabetes mellitus. The mean concentrations of serum T₄, T₃, and RT₃ were 8.5 ± 3.7 (SD) μg/dl, 134 ± 41 ng/dl, and 30 ± 13 ng/dl, respectively, which were not significantly different from values of 33 normal control subjects. The serum $\text{T}{}_3\text{T}{}_4$ ratio showed a significant inverse correlation with the level of fasting blood sugar (FBS) (p < 0.01). Turnover studies were carried out in seven normal control subjects and in 5 insulin-independent diabetic patients on T₄ replacement. T₄ turnover was similar in both groups. The T₃ metabolic clearance rate of the diabetic patients was also normal (20.7 ± 4.0 liter/day/70 kg), but the T₃ disposal rate was reduced when compared to that of normal control subjects (17.0 ± 5.6 vs. 40.6 ± 4.8 μg/day). The RT₃ metabolic clearance rate (80.6 ± 20.2 vs. 105.0 ± 14.0 liter/day/70 kg) and the RT₃ disposal rate (29.4 ± 10.8 vs. 49.4 ± 11.6 μg/day) were both reduced in the diabetic patients. In five other diabetic patients on 3 wk of oral T₄ replacement, the serum $\text{T}{}_3\text{T}{}_4$ ratio was below the normal range (0.0059 ± 0.0041 vs. 0.0152 ± 0.0011) and remained unchanged during insulin infusion during 10 hr. The $\text{T}{}_3\text{T}{}_4$ ratio increased but remained below the normal range after 10 days of dietary and insulin treatment (0.0083 ± 0.0032; p < 0.05). Our results suggest that T₃ production from peripheral T₄ monodeiodination is impaired in uncontrolled diabetic patients. This impairment in T₃ production is correlated with the impairment of glucose utilization.     

Early stage pulmonary alveolar proteinosis detected by chest CT scan in a medical examination]

We report a case of pulmonary proteinosis detected at an early stage and followed up on chest CT. A 49-year-old man underwent detailed examinations because of abnormal shadows on chest CT taken on a routine medical examination. The chest CT revealed almost symmetrical ground glass opacities (GGOs) in both lungs with thickened alveolar septa. We could not make a definitive diagnosis even with bronchoalveolar lavage and transbronchial lung biopsy, but after about half a year, the GGOs increased. VATS-biopsy demonstrated alveoli filled with PAS-positive granular materials, and we made a diagnosis of pulmonary alveolar proteinosis. This case was found at an early stage and we were then able to follow up the disease.     

Pulmonary pressure-flow relation as a determinant factor of exercise capacity and symptoms in patients with regurgitant valvular heart disease

BACKGROUND: Exertional dyspnea is a frequent limiting symptom in patients with chronic heart failure. Furthermore, dyspnea and a plateau in VO(2) (oxygen consumption) at peak exercise often co-exist in chronic heart failure, especially in patients with severe regurgitant valvular heart disease (RVHD), their relevance to hemodynamics and subjective symptoms during exercise have not been fully understood. OBJECTIVES: The purpose of this study was to examine the determinant factor of exercise capacity in patients with RVHD. METHODS: We performed a symptom-limited cardiopulmonary exercise test using a sitting cycle ergometer with right heart catheterization in 20 patients with severe RVHD. VO(2) and hemodynamics were measured at rest and during exercise, and symptomatic end-point at peak exercise was evaluated by using Borg's score. RESULTS: Of the 20 patients, 11 attained a plateau in VO(2) at peak exercise (Group 1). At peak exercise, pulmonary arterial pressure (PAP) was higher, and cardiac output (CO) and VO(2) were lower in Group 1 than in patients without a plateau in VO(2) (Group 2) (mean PAP: 60+/-10 vs. 48+/-9 mm Hg, P=0.05; CO: 8.3+/-2.6 vs. 11.2+/-2.6 l/min, P=0.01; VO(2): 1059+/-259 vs. 1359+/-328 ml/min, P=0.01). In Group 1, 6 patients complaining of dyspnea rather than leg fatigue at peak exercise had lower CO (7.1+/-1.8 vs. 9.7+/-3.0 l/min, P=0.05) and higher slope of mean PAP-CO relation (P-Q slope) (10.6+/-3.6 vs. 5.4+/-1.7, P=0.01), compared with the other 5 patients with leg fatigue. CONCLUSIONS: Development of pulmonary hypertension during exercise is the important limiting factor for exercise capacity in patients with RVHD. The limitation of increase in CO concomitant with pulmonary hypertension could be an important factor in the appearance of dyspnea.     

Multiple early esophageal cancers arising from Barrett's esophagus, and a review of cases of early adenocarcinoma in Barrett's esophagus in Japan

A case of early esophageal adenocarcinoma arising in Barrett's esophagus is reported. Many cases of Barrett's esophagus, which is considered a premalignant condition, have been reported in Western countries, but few cases have been reported in Japan. The patient, a 53-year-old man with nausea and vomiting, was a drinker (four glasses wine/day for about 30 years), but did not smoke. He had had a hiatal hernia of the esophagus. Since endoscopic biopsies demonstrated an early adenocarcinoma in Barrett's esophagus, subtotal esophagectomy was performed. In the resected esophageal material, Barrett's esophagus was seen to extend for 12 cm. In addition to the cancer detected preoperatively as a 0-IIc lesion (1.5 cm in diameter), a 0-IIb lesion (1.5 cm in diameter) was also detected in the post-operative survey. Both lesions were well differentiated adenocarcinoma that had invaded only into the lamina propria mucosa. The 23 cases of early adenocarcinoma in Barrett's esophagus that have been reported in Japan were reviewed, and it was learned that the present case is the second of multiple early cancer arising in Barrett's esophagus so far reported in Japan.     

Volume reduction surgery for advanced hepatocellular carcinoma

Purpose The aim of this study was to evaluate the prognostic impact of reductive surgery on the survival of patients with advanced hepatocellular carcinoma (HCC).Methods Eligible patients had a main tumor greater than 10 cm in diameter with multiple intrahepatic metastases (>5 nodules), and good liver function (Child-Pugh class A), but no tumor thrombus in the main portal vein. The main tumor was surgically removed but the metastases were not removed and were treated with repeated transcatheter hepatic arterial chemo-embolization (TAE).Results From Jun 1997 to May 2003, 13 patients (median age 61 years, range: 48–74) were prospectively enrolled. The median diameter of the main tumor was 14 cm (range 11.5–18.0). No major surgical complications were observed and the median hospital stay was 12 days (range 7–20). The first TAE was performed 1 month after hepatectomy in all patients and was repeated for median of 5 (range: 1 to 16) times. Complete remission was observed in two patients. One patient had recurrence afterwards but another patient survived 41 months without recurrence. Three patients survived more than 3 years. The overall 1-, 3-, and 4-year survival rates of the 13 patients were 67.7%, 40.6%, and 40.6%, respectively.Conclusions Volume reduction surgery followed by TAE might prolong the survival of patients with a large HCC and intrahepatic metastases, especially those with a main tumor on the right side.Source of support: this study was supported by grants-in-aid for cancer research from the Ministry of Health, Labour and Welfare of Japan.     

Two cases of immunoglobulin G4-related sclerosing cholangitis in which transabdominal ultrasonography was useful in diagnosis and follow-up observation

Immunoglobulin G4-related disease (IgG4-RD) represents a group of disorders that share features of inflammation, plasma cell infiltrates, and fibrosis. Sclerosing cholangitis is a disorder involving inflammation, scarring, and destruction of the bile ducts. IgG4-related sclerosing cholangitis (IgG4-SC) has been proposed as a bile duct lesion associated with IgG4-RD. This disease entity can be distinguished from other types of sclerosing cholangitis and classified into four types based upon the region of strictures revealed by cholangiography. Here, we present two cases in which the finding of bile duct wall thickening visualized with transabdominal ultrasonography was useful in the diagnosis of patients with IgG4-SC. At present, transabdominal ultrasonography is not included in the diagnostic algorithm for IgG4-SC. We are certain that detailed observation of the bile duct wall with transabdominal ultrasonography can make a significant contribution to the diagnosis of IgG4-SC. Furthermore, we propose that transabdominal ultrasonography may be useful in following clinical improvement in cases where a steroid trial is the best option for treatment. Both cases emphasize the practicality of transabdominal ultrasonography in the diagnosis and follow-up observation of IgG4-SC.     

Norepinephrine evoked by potassium depolarization increases interstitial adenosine concentration via activation of ecto-5'-nucleotidase in rat hearts

We examined whether the increase of the extracellular potassium ion concentration, [K(+)](o), can increase the production of interstitial adenosine in the ventricular myocardium, with the use of microdialysis techniques in in situ rat hearts. A microdialysis probe was implanted in the left ventricular myocardium of anesthetized rat hearts, and the tissue in the vicinity of the dialysis was perfused with Tyrode's solution containing AMP through the dialysis probe at a rate of 1.0 microl/min to assess the activity of ecto-5'-nucleotidase. When the K(+) concentration of the perfusate ([K(+)](o)) was increased stepwise from 5.4 mM (control) to up to 140.4 mM, the level of dialysate adenosine significantly increased, in a [K(+)](o)-dependent manner. The presence of CsCl or BaCl(2) (20 mM), which markedly depolarized the resting potential, significantly increased the level of adenosine in the dialysate. Equivalent increases in the osmotic concentration of the perfusate, made by adding sucrose (270 mM), did not change the dialysate adenosine concentration. Introduction of high [K(+)](o) (140.4 mM) significantly increased the level of norepinephrine (NE) in the dialysate, and this increase was abolished in the reserpinized rats hearts. In the presence of an antagonist of alpha(1)-adrenoceptor (prazosin, 50 microM) or protein kinase C (PKC) (chelerythrine, 10 microM) and in reserpinized rats, an introduction of high [K(+)](o) failed to increase the AMP-primed dialysate adenosine concentration. We conclude that high [K(+)](o)-induced NE release from sympathetic nerve terminals increases adenosine by stimulating the PKC-ecto-5'-nucleotidase cascade through alpha(1)-adrenoceptors.