The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury.

BACKGROUND: Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. AIM: To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. METHODS: Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. RESULTS: In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. CONCLUSIONS: The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.

Expression of the chemokine CXCL14 and cetuximab-dependent tumour suppression in head and neck squamous cell carcinoma.

Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients. We previously reported that the chemokine CXCL14 exhibits tumour-suppressive effects against xenografted HNSCC cells, which may be classified into two groups, CXCL14-expressing and non-expressing cells under serum-starved culture conditions. Here we employed CXCL14-expressing HSC-3 cells and CXCL14-non-expressing YCU-H891 cells as representatives of the two groups and compared their responses to cetuximab and their CXCL14 expression under various conditions. The growth of xenografted tumours initiated by HSC-3 cells, which expressed CXCL14 in vivo and in vitro, was suppressed by the injection of cetuximab into tumour-bearing mice; however, neither the expression of the chemokine nor the cetuximab-dependent suppression of xenograft tumour growth was observed for YCU-H891 cells. Both types of cells expressed EGFR and neither type harboured mutations in signalling molecules downstream of EGFR that have been reported in cetuximab-resistant colon cancer patients. The inhibition of the extracellular signal-regulated kinase (ERK) signalling increased the levels of CXCL14 messenger RNA (mRNA) in HSC-3 cells, but not in YCU-H891 cells. We also observed that the CXCL14 promoter region in YCU-H891 cells was hypermethylated, and that demethylation of the promoter by treatment with 5-aza-2'-deoxycytidine restored CXCL14 mRNA expression and in vivo cetuximab-mediated tumour growth suppression. Finally, we observed in vivo tumour growth suppression when YCU-H891 cells were engineered to express CXCL14 ectopically in the presence of doxycycline. These results indicate that CXCL14 expression may be a good predictive biomarker for cetuximab-dependent tumour suppression.

Videoendoscopic surgery combined with a minimal sternotomy for removing a thyroid tumor extending into the mediastinum. A case report.

We report the case of a 55-year-old man with a giant goiter descending to the mediastinum. Video-endoscopic surgery combined with a minimal sternotomy was performed to remove a thyroid tumor. In the course of our dissection of the subplatysmal space, an endoscopic approach was applied to avoid incisions of the neck. Three trocars were inserted from the anterior chest wall, and carbon dioxide (CO2) was insufflated at a pressure of 5 mmHg to create a working space. This technique improves the cosmesis of thyroidectomies and cervical operations.

Minimally invasive surgery for lung cancer with coronary artery disease.

We report a 69-year-old woman with lung cancer and severe stenosis in the left anterior descending coronary artery. To perform a curative operation for the lung cancer without myocardial infarction, minimally invasive direct coronary artery bypass and left lower lobectomy with video-endoscopic assistance were performed simultaneously. There was no major complication, and she was discharged at 14 days after the operation. This procedure may be useful and safe for patients with lung cancer and coronary artery disease.

[Hemodynamics of the lower extremities in patients with decubitus ulcers using the ultrasonic Doppler method].

Our clinical experience indicates that decubitus ulcers with tissue loss/necrosis extending beyond the subcutaneous fat in aged patients are liable to become refractory and that most of these patients experience a cold feeling/cyanosis in the lower extremities. In order to determine the relationship between the severity of the decubitus ulcers and the hemodynamics in the lower extremities, we conducted a blood flow test using the ultrasonic Doppler method on the lower extremities in patients. Sixty-eight inpatients (38 men, 30 women, with an average age of 80.5 +/- 7.6 years old) were selected. B-mode tomographs were obtained with an ultrasonic diagnostic apparatus. The power Doppler method was used to measure blood flow rate, vascular lumen diameter, and intravascular blood flow at the dorsalis pedis artery, posterior tibial artery, peroneal artery furcation, and femoral artery. The subjects were divided into three groups: patients without decubitus ulcers; patients with mild to moderate decubitus ulcers of IAET Classification grade I-III; and patients with severe decubitus ulcers (IAET Classification grade IV), and the measurements were compared among the groups. The results revealed a tendency for the vascular lumen to become narrowed and intravascular blood flow to be reduced at all sites as decubitus ulcers increased in severity and showed the hemodynamics in the lower extremities to be particularly poor in the severe group. We measured the hemodynamics in the lower extremity with the ultrasonic Doppler method from the viewpoint of decubitus ulcer prevention and found differences in blood flow in the lower extremities according to the severity of decubitus ulcers. A reduction in blood flow in the lower extremities is considered to indirectly indicate a susceptibility to decubitus ulcers and to serve as a sign of its exacerbation. We consequently considered the test to be useful and concluded that deterioration of hemodynamics due to the progress of arteriosclerosis is one of the causes of decubitus ulcer exacerbation.

[Nutritional status of patients with decubitus ulcers, and changes in the skin blood flow when the sacral region was compressed].

We studied the relationship between decubitus ulcers and changes in skin blood flow with respect to the presence or absence of a decompression medium. We also studied the relationship between decubitus ulcers and the results of biochemical tests that reflect nutritional status. Two groups of inpatients with decubitus ulcers in areas other than the sacral region were studied: One used cloth diapers and the other used paper diapers. Skin blood flow was measured with a laser Doppler blood flowmeter and a sheet of polyurethane (decompression medium) in the sacral region. Data were also obtained from patients with and without decubitus ulcers, and whose levels of albumin, total cholesterol, and triglyceride for three months were known. When the decompression medium was used, skin blood flow changed significantly after body position was changed in the patients who used paper diapers. Nutritional analyses showed significant differences in the levels of albumin and total cholesterol between patients with and without decubitus ulcers. The levels of albumin and total cholesterol were lower in the patients with decubitus ulcers than in those without decubitus ulcers. Because the cloth diapers acted as a compression factor, even an externally applied decompression medium did not suppress the reductions in skin blood flow.

[Serum sodium imbalance in the bedridden elderly. Part One: Realities and problem of management].

Symptoms and other abnormalities associated with serum sodium imbalance were studied in bedridden elderly and healthy elderly subjects. 1. A significantly higher number of the bedridden elderly suffered from chronic wasting disease. 2. The average serum sodium concentration in bedridden elderly subjects was significantly lower than in healthy subjects, as was the sodium intake and the sodium content in urine, which indicate that the bedridden elderly subjects suffered from chronic sodium deficiency. 3. The bedridden elderly subjects had high levels of plasma PRA and antidiuretic hormone, and their aldosterone levels were low, which indicate that their condition was associated with a decrease in available circulating plasma, hypersecretion of antidiuretic hormone, and a decline in the ability to retain sodium. 4. Measurement of 24-hr creatinine clearance, albumin, and beta 2-microglobulin in urine revealed that bedridden elderly subjects had high levels of renal dysfunction, the result of which may a disturbance in water excretion. Abnormalities in serum sodium levels in the bedridden elderly subjects were related to a chronic deficiency in sodium intake, which reduced their ability to maintain sodium levels and impaired their renal function. Iatrogenic factors are likely to play an important role in the genesis of this condition, and should be taken into account in during management.

[Cardiac function in elderly patients with dementia].

Evaluation of cardiac function is very important in elderly patients because it is closely related to the prognosis. Appropriate evaluation is especially important to treat and prevent the progression of dementia since its pathology differs greatly depending on type. In the present study, we evaluated the cardiac function of patients with senile dementia using echocardiography. Included in the present study were 11 patients with Binswanger-type dementia (BD), 12 with cerebrovascular dementia (VD) of other types, 16 with senile dementia of Alzheimer-type (SDAT) and 15 controls. Left ventricular function was assessed by Mode M based on left ventricular end-diastolic dimension (LVDd), left ventricular end-systolic dimension (LVDs), left ventricular dimension shortening (FS), left ventricular ejection fraction (EF) and cardiac output (CO). LVDd was significantly larger in the BD group than in the control, and LVDs was also significantly larger in the BD group than in the three other groups. FS was significantly decreased in the BD group compared to the SDAT and controls. FS was also significantly decreased in the VD group compared to the control. EF was significantly decreased in the BD group compared to the three other groups, and it was also significantly decreased in the VD group compared to the controls. There was no significant inter-group difference in SV or CO. FS and EF were found to be decreased in patients with cerebrovascular dementia, especially BD, indicating the presence of latent left ventricular hypofunction in these patients. This finding is important in predicting the prognosis of patients and conducting treatment and prevention.