Protein C Sapporo (protein C Glu 25 --> Lys): a heterozygous missense mutation in the Gla domain provides new insight into the interaction between protein C and endothelial protein C receptor

Interaction of the gamma-carboxyglutamic acid (Gla) domain of protein C with endothelial protein C receptor (EPCR) is a critical step for efficient activation of protein C, though interactions by mutants in the Gla domain of protein C with EPCR have been rarely evaluated. We identified a 44-year-old Japanese woman with a history of recurrent thromboembolism as an inherited missense mutation, the first such case reported in Japan, which involved a protein C Gla 25 mutation. Total protein C antigen and Gla protein C antigen levels in the proband were normal. Protein C activity measured with an anticoagulant assay was reduced, whereas that measured with an amidolytic assay was normal. She was therefore phenotypically diagnosed as type IIb protein C deficiency. Direct sequencing of the PCR fragments revealed a heterozygous G to A transition at nucleotide position 1462 in exon 3, which predicted an amino acid substitution of Glu 25 by Lys. Her mother and one son were also heterozygous for this mutation. A molecular dynamics simulation of Gla 25-->Lys/EPCR complex in water suggested that the affinity between the molecules was decreased compared to the wild type Gla domain/EPCR complex. Since Gla 25 has been shown to play an important role in protein C function, not only in membrane phospholipid binding but also in binding to EPCR, our findings provide new insight into the mechanism by which the Glu 25-->Lys mutation induces type IIb protein C deficiency in individuals.     

Adenovirus-mediated overexpression of the activin betaC subunit accelerates liver regeneration in partially hepatectomized rats

BACKGROUND/AIMS: The expression level of the activin betaC subunit is high in normal liver and reduces after partial hepatectomy, but its function is controversial. METHODS: To determine the role of the betaC subunit during liver regeneration, we overexpressed the betaC subunit gene in the liver by infusing adenovirus vector encoding the flag-tagged betaC subunit into the portal vein. Adenovirus vector encoding the beta-galactosidase was also infused as a control. Seventy percent hepatectomy was performed 4 days after the infection. RESULTS: Approximately 20% of hepatocytes expressed the flag-tagged betaC subunit at the time of hepatectomy and approximately 50% of hepatocytes expressed the betaC subunit 3 days after hepatectomy. In betaC-infected liver, bromodeoxyuridine labeling was significantly greater at 24 and 48 h after partial hepatectomy compared with the control liver. Consistent with this observation, the liver regeneration rate was significantly greater in betaC-transfected liver at 72 and 96 h after hepatectomy. Many of the bromodeoxyuridine-positive nuclei were observed in or by the betaC-transfected hepatocytes. CONCLUSIONS: These results indicate that liver regeneration is accelerated in betaC-overexpressing liver. The betaC subunit may function to promote replication of hepatocytes during liver regeneration.     

Morphologic characteristics of the dentition and palate in cases of skeletal asymmetry

The purpose of this study was to clarify the three-dimensional morphological characteristics of the dentition and palate in skeletal asymmetry in patients with skeletal Class III malocclusion using a newly defined palatal reference plane in a dental cast. Twenty patients (5 males and 15 females) who had skeletal Class III malocclusion with facial asymmetry were selected. Pretreatment posteroanterior cephalometric radiographs and maxillary dental casts were used. The lateral deviation of Me was measured as the distance from a line perpendicular to Lo-Lo' that passed through CG. The angle between the Lo-Lo' plane and the J-J' plane was measured. Each maxillary dental cast was measured using a three-dimensional surface-scanning system, and the newly defined palatal reference plane was calculated. The right/left difference in the radius of curvature of the palate and right/left differences in the vertical and mesiodistal positions of the first molars were analyzed. Linear correlation and regression techniques were used. Our findings demonstrate that the lateral deviation of the mandible is closely related to the morphology of the alveolar process and to the vertical height of the dentition. In this study, the three-dimensional application of a new palatal reference plane is very useful in morphological research, and the results provide detailed information on the characteristics of facial asymmetry.     

Efficacy of intravenous immune globulin therapy combined with dexamethasone for the initial treatment of acute Kawasaki disease

We studied the effects of a new regimen consisting of intravenous immune globulin (IVIG) combined with dexamethasone (DEX) on clinical outcome and serum levels of vascular endothelial growth factor (VEGF) in the initial treatment of Kawasaki disease (KD). A total of 46 KD patients received 0.3 mg/kg per day DEX plus heparin i.v. for 3 consecutive days, together with 2 g/kg IVIG over 4 to 5 days (DEX group). Low-dose acetylsalicylic acid was started after completion of DEX therapy. The control group consisted of 46 KD patients retrospectively treated earlier with 2 g/kg IVIG over 4 to 5 days plus higher dose acetylsalicylic acid (CONTROL group). No serious adverse effect was noted in either group. There were no differences in baseline and post-treatment laboratory data except for C-reactive protein between the groups. Post-treatment C-reactive protein in the DEX group (median 0.9 mg/dl, range 0.0 to 24.7 mg/dl) was lower than that (1.2 mg/dl, range 0.2 to 19.5 mg/dl) in the CONTROL group ( P =0.033 by Mann-Whitney U test). In addition, the mean duration of fever after the first IVIG infusion was 2.2 days (median 1 day, range 1 to 12 days) in the DEX group and 2.8 days (2 days, 1 to 16 days) in the CONTROL group ( P =0.015 by Mann-Whitney U test). The new regimen did not reduce VEGF levels. Two patients in each group developed small- or medium-sized coronary artery aneurysms. Conclusion:although this regimen did not affect coronary outcome, intravenous immune globulin therapy combined with dexamethasone for the initial treatment of Kawasaki disease was safe and may accelerate the resolution of systemic inflammation.Abbreviations CAA coronary artery aneurysms - DEX dexamethasone - IVIG intravenous immune globulin - KD Kawasaki disease - VEGF vascular endothelial growth factor     

Family experience with palliative sedation therapy for terminally ill cancer patients

Symptomatic sedation is often required in terminally ill cancer patients, and could cause significant distress to their family. The aims of this study were to clarify the family experience during palliative sedation therapy, including their satisfaction and distress levels, and the determinants of family dissatisfaction and high-level distress. A multicenter questionnaire survey assessed 280 bereaved families of cancer patients who received sedation in 7 palliative care units in Japan. A total of 185 responses were analyzed (response rate, 73%). The families reported that 69% of the patients were considerably or very distressed before sedation. Fifty-five percent of the patients expressed an explicit wish for sedation, and 89% of families were clearly informed. Overall, 78% of the families were satisfied with the treatment, whereas 25% expressed a high level of emotional distress. The independent determinants of low levels of family satisfaction were: poor symptom palliation after sedation, insufficient information-giving, concerns that sedation might shorten the patient's life, and feelings that there might be other ways to achieve symptom relief. The independent determinants of high levels of family distress were: poor symptom palliation after sedation, feeling the burden of responsibility for the decision, feeling unprepared for changes in the patient's condition, feeling that the physicians and nurses were not sufficiently compassionate, and shorter interval to patient death. Palliative sedation therapy was principally performed to relieve severe suffering based on family and patient consent. Although the majority of families were comfortable with this practice, clinicians should minimize family distress by regular monitoring of patient distress and timely modification of sedation protocols, providing sufficient information, sharing the responsibility of the decision, facilitating grief, and providing emotional support.     

Procedures of Choice for Resection of Primary and Recurrent Liver Metastases from Colorectal Cancer

Although liver resection offers the only realistic chance of cure for patients with liver metastases from colorectal cancer, no consensus exists as to the procedure of choice for managing these tumors. Data from 193 patients who underwent hepatectomy for liver metastases from colorectal cancer and 26 of 193 patients who underwent repeat hepatectomy for recurrent metastases were collected. The suitability of resection was evaluated retrospectively based on known risk factors for recurrence and patterns of recurrence. On multivariate analysis, a positive surgical margin (SM+) was the only risk factor for recurrence after the initial resection (p < 0.01). SM+ (p < 0.01) and nonanatomic resection (p < 0·05) that was less than a sectionectomy (p < 0.05) were risk factors for recurrence after repeat hepatectomy. Multiple tumors (four or more) was the most common pattern of recurrence after initial hepatectomy, and recurrence close to the line of resection was most common after repeat hepatectomy. Based on tumor doubling times, recurrence after initial hepatectomy seemed to originate from the primary colorectal lesion, whereas recurrence after repeat hepatectomy was derived from a hepatic metastasis. Retrospective analysis suggests that hepatectomy with clear surgical margins is more important than anatomic resection for initial hepatectomy, and at least sectionectomy is necessary for repeat hepatectomy.     

Outcome after simultaneous colorectal and hepatic resection for colorectal cancer with synchronous metastases

BACKGROUND: Consensus has not been reached concerning the timing of hepatectomy in patients with synchronous colorectal liver metastases, specifically with respect to patient selection criteria for simultaneous resection of the colorectal primary and the liver metastasis. METHODS: Retrospectively obtained clinicopathologic data for 39 consecutive patients with synchronous colorectal cancer metastases to the liver, who underwent curative simultaneous "1-stage" hepatectomy and resection of the colorectal primary at 1 institution, were subjected to univariate and multivariate analysis concerning the safety and success of the combined procedure. RESULTS: Only the volume of the resected liver was selected as a risk factor for postoperative complications (350 g mean resected liver volume in patients with postoperative complications vs 150 g in those without complications; P <.05). Patient age of 70 years or older (P <.05) and poorly differentiated or mucinous adenocarcinoma as the primary lesion (P <.01) predicted decreased overall survival by univariate analysis. Multivariate analysis retained histologic differentiation of the colorectal primary as an independent survival predictor (P <.05). CONCLUSIONS: A 1-stage procedure appears desirable for synchronous colorectal hepatic metastases except for patients requiring resection of more than 1 hepatic section, patients aged 70 years or older, and those with poorly differentiated or mucinous adenocarcinomas as primary lesions.     

Promotion of beta-cell differentiation by conophylline in fetal and neonatal rat pancreas

Conophylline is a vinca alkaloid extracted from the tropical plant Ervatamia microphylla and has been shown to induce differentiation of pancreatic AR42J cells. In the present study, we investigated the effect of conophylline on the differentiation of pancreatic precursor cells. In the rat pancreatic rudiment in organ culture, conophylline inhibited the formation of cystic structure and increased the number of insulin-positive cells. Conophylline also markedly increased the expression of mRNA for insulin and the number of pancreatic duodenal homeobox-1-positive cells. These effects of conophylline were similar to those of activin A. We also examined the effect of conophylline on neonatal rats treated with streptozotocin, a model of type 2 diabetes. Treatment with conophylline significantly reduced the plasma glucose concentration and improved glucose tolerance in response to glucose loading. The insulin content and the beta-cell mass at 2 months were significantly increased by conophylline. The number of islet-like cell clusters and pancreatic duodenal homeobox-1-positive ductal cells was greater in conophylline-treated rats. These results suggest that conophylline induces differentiation of pancreatic precursor cells and increases the formation of beta-cells.     

A case of pharyngolaryngeal edema after posterior occipito-cervical operation

A 70-year-old female developed respiratory failure due to pharyngolaryngeal edema after posterior occipito-cervical fusion. She had a history of total thyroidectomy with bilateral neck dissection for advanced thyroid cancer associated with multiple lung metastases. However, her general condition was good, and she was not in cachexia. Her pulmonary function test revealed %VC of 54% and %FEV1.0 of 79%. This posterior occipito-cervical fusion was necessary for pain relief. Twenty-four hours after surgery she suddenly showed dyspnea, requiring tracheal intubation, and was supported by mechanical ventilation. The pharyngolaryngeal edema was recognized with bronchoscopy from the lower larynx with arytenoid region to nasal choana. In several days she recovered from pharyngolaryngeal edema and was extubated. She was discharged from ICU after close observation for 24 hours after extubation. She developed respiratory distress again due to difficulty in sputum expectoration, resulting in emergency tracheostomy an the floor at midnight. In this case, pharyngolaryngeal edema may have been caused by disturbance of lymphatic flow due to posterior occipito-cervical fusion in a patient with a past history of bilateral neck dissection. We also reviewed the literature in this report.     

Unanticipated endotracheal tube displacement in a short-neck patient with a history of chronic rheumatoid arthritis: a comparison of three kinds of endotracheal tubes

Endotracheal tubes are known to have a risk of being displaced at neck extension or flexion or rotation. However, the displacement seldom causes clinical problems. An 74-year-old patient suffering from chronic rheumatoid arthritis underwent debridement in the infected knee under general anesthesia. Mechanical ventilation had to be continued because of poor oxygenation after the operation. She had been intubated with Hi Lo Evac endotracheal tube (HLE) for 3 days, then extubated. However, she again needed mechanical ventilation because of aggravated oxygenation. At that time, Profile cuff siliconised endotracheal tube (PCS) was placed for 3 days. We encountered dangerous displacement of HLE during the first mechanical ventilation, but did not have any clinically dangerous displacement of PCS during the second mechanical ventilation. Therefore, we compared the hardness of the three popular endotracheal tubes. We found the hardness of HLE was higher than the others. This might be one of the reasons for dangerous displacement of the endotracheal tube in our case.