Marmoset cytochrome P450 2B6, a propofol hydroxylase expressed in liver

1. The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available.

2. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits and rodents.

3. Quantitative polymerase chain reaction analysis using specific primers showed P450 2B6 mRNA predominantly expressed in livers among the five marmoset tissues, similar to those of humans and cynomolgus monkeys.

4. Marmoset P450 2B6 heterologously expressed in Escherichia coli membranes oxidized 7-ethoxycoumarin, pentoxyresorufin, propofol and testosterone, at roughly similar rates to those of humans and/or cynomolgus monkeys. A high capacity of marmoset P450 2B6 with propofol 4-hydroxylation (at low ionic strength conditions) with a low K_m value was relatively comparable to that for marmoset livers.

5. These results collectively indicated a high propofol 4-hydroxylation activity of P450 2B6 expressed in marmoset livers.

     

Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer

Background

There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC).

Severe Graves' ophthalmopathy accompanied by myasthenia gravis]

We report a 53-year-old woman with severe Graves' ophthalmopathy accompanied by uncontrolled myasthenia gravis. She presented remarkable exophthalmos, chemosis, and restriction of eye movement. Despite plasma exchange, steroid pulse therapy, local injection of steroid, and irradiation, ocular symptoms did not ameliorate. Since optic neuropathy was seen, orbital decompression surgery was performed in the left eye. Bilateral chemosis was improved after the surgery. Five years after surgery, there was no ocular palsy in the operated left eye, but in the contralateral eye. For the good prognosis of the eye movement, orbital decompression might be recommended in the severe Graves' ophthalmopathy accompanied by the optic neuropathy and/or ophthalmoplegia with proptosis.     

Relationship between serum albumin level before initiating haemodialysis and angiographic severity of coronary atherosclerosis in end-stage renal disease patients.

BACKGROUND: In patients with chronic kidney disease (CKD), although strong associations have been observed between malnutrition and atherosclerosis, the relationship between serum albumin concentration and angiographic changes of coronary artery disease (CAD) remains poorly explored. The goal of the present study was, in patients with CKD, to clarify the relationship between the angiographic severity of CAD and serum albumin concentration reflecting either inflammation or nutrition or both. METHODS: In this study, 100 end-stage renal disease (ESRD) patients were enrolled, who commenced long-term dialysis therapy at our hospital and underwent coronary angiography within 3 months of the first haemodialysis (HD) session. Mean age was 63+/-11 years, 20% of the subjects were female and 62% had diabetes. Severity of CAD was evaluated in terms of (i) number of vessels exhibiting CAD (>or=75% stenosis) and (ii) Gensini score (GS). Clinical characteristics and laboratory findings were recorded at initiation of long-term HD therapy. We then evaluated a possible association with the presence and degree of CAD. RESULTS: Sixty-four patients exhibited signs of CAD. Forty-one among them (64%) had multivessel disease. On univariate logistic regression analysis, age, diabetes and hypoalbuminaemia were significantly associated with multivessel CAD. Univariate linear regression analysis demonstrated a positive correlation of age and diabetes with GS, and an inverse correlation of BMI and serum albumin level with GS. Stepwise regression analysis showed age and serum albumin level to be independently associated with multivessel CAD and GS. The ROC curves demonstrated best cut-off levels of age and albumin for predicting multivessel CAD to be 70 years and 3.15 g/dl, respectively. CONCLUSION: Hypoalbuminaemia at the initiation of dialysis is an important predictor of advanced CAD, particularly in male and in diabetic patients. It may reflect mainly a state of inflammation. However, malnutrition as a confounding factor cannot be entirely excluded.     

Fetal neuroimaging by transvaginal 3D ultrasound and MRI

Neurosonography by advanced transvaginal sonography has revealed normal and abnormal intracranial morphology. Transvaginal 3D sonography demonstrates bony structures, multiplanar analysis of inside detailed morphology, tomographic ultrasound imaging in any cutting sections, 3D sonoangiography and volume calculation of ventricles and/or intracranial lesions. Longitudinal assessment of normal and abnormal CNS development is easy by serial scanning. However, the transvaginal approach has several limitations due to its observation by use of a high-frequency transducer from the fetal parietal region. Evaluation of the brainstem and posterior fossa, which are located far from the parietal ultrasound windows of the anterior fontanelle or sagittal suture, is sometimes hard by transvaginal sonography. Visualization of bilateral temporal areas is getting difficult with advanced gestational weeks because of bilateral acoustic shadows due to ossification of parietal bones. Demonstration of frontal/occipital areas is sometimes impossible in late pregnancy due to scan-angle limitation of the transvaginal transducer. From our experiences, the main difference between transvaginal 3D ultrasound and MRI is demonstration of the whole gyral and sulcal formation and brainstem in the late second and third trimesters. Although MRI is a useful modality which can compensate for pitfalls of transvaginal 3D ultrasound, 3D ultrasound is sometimes superior to MRI in detecting cysts in cyst and intracranial calcification. Transvaginal 3D ultrasound is much superior to MRI in detecting bony structures and angioarchitectonics and in volumetric assessment. Regarding objective and accurate prenatal diagnosis, any less-invasive modalities can be used. After considering each advantage and disadvantage of transvaginal 3D ultrasound and MR imaging, it is suggested to use the different technologies according to what is to be detected and evaluated.     

Cerebral perfusion scintigraphy in patients with cerebrovascular disease by using 99mTc-ECD: comparative study with 123I-IMP SPECT

99mTc-ECD SPECT was performed in 19 patients with cerebrovascular disease, and location, extent, and severity of the lesions on 99mTc-ECD SPECT were compared with those on 123I-IMP SPECT. The initial brain uptake was 5.5 +/- 0.7% of the injected dose at 10 minutes after injection, 5.3 +/- 1.3% at 90 minutes, and clearance from the brain is slow. The distribution in the brain was changed, especially washout from the thalamus was slower than that from other regions. The count ratio of perfusion defect to normal area (D/N) on 99mTc-ECD SPECT was unchanged over the time, and had no significant differences from that on 123I-IMP SPECT. 99mTc-ECD SPECT was superior in detection of the lesion in the basal ganglia, and showed the images with superior spatial resolution due to physical characteristics of 99mTc. However, mild ischemic lesion and peri-infarct area was not clearly visualized, while 123I-IMP SPECT could demonstrate these lesions with better contrast.     

Use of small-bore silastic drains in general thoracic surgery.

STUDY OBJECTIVE: To evaluate the safety and efficacy of small-bore, silastic drains for patients undergoing general thoracic surgery. PATIENTS AND METHODS: Twenty-five patients who received soft, small-bore, silastic drains were compared with 17 patients who received semi-rigid double lumen (DL) tubes retrospectively. RESULTS: The pain score was significantly lower in patients who received the silastic tubes in video-assisted thoracoscopic surgery (VATS) cases on postoperative days 5 and 6 , after continuous epidural analgesia had finished (P=0.018). No specific morbidity was seen in the patients who received silastic tubes. CONCLUSION: We considered that soft, small-bore silastic drains were just as effective as traditional DL tubes, but caused less pain especially in VATS cases.     

Effects of Hemoglobin Concentration, Skull Thickness, and the Area of the Cerebrospinal Fluid Layer on Near-infrared Spectroscopy Measurements

Background: Previous studies documented that near-infrared spectroscopy values were affected by factors related to optical path length, such as hemoglobin concentration, the differential path length factor, skull thickness (t-skull), and the area of the cerebrospinal fluid layer (a-CSFL). Lately, the NIRO-100 (Hamamatsu Photonics, Hamamatsu, Japan) has provided a tissue oxygen index (TOI) that theoretically is not supposed to be affected by optical path length. Therefore, the authors hypothesized that TOI is not influenced by the above-described individual factors.

Methods: Cardiac surgical or neurosurgical 103 patients (65 men and 39 women; aged 63 +/- 14 yr) were studied. TOI and regional cerebral oxygen saturation (rSO2) (INVOS 4100; Somanetics, Troy, MI) were measured sequentially on patients in a resting state. The t-skull and a-CSFL were calculated using computed tomographic image slices of the head corresponding with the position of near-infrared spectroscopy sensors. The effects of these two factors, hemoglobin concentration and mean arterial pressure, on TOI and rSO2 values were evaluated by linear regression analysis.

Results: Simple linear regression analysis showed that mean arterial pressure (r = 0.27, P = 0.008), t-skull (r = 0.22, P = 0.034), a-CSFL (0.26, P = 0.012), and hemoglobin concentration (r = 0.42, P < 0.0001) were significant determinants of rSO2. Multiple linear regression analysis showed that hemoglobin concentration (r = 0.34, P < 0.001), a-CSFL (r = -0.252, P = 0.012), and t-skull (r = 0.22, P = 0.037) were significant determinants of rSO2. On the other hand, simple and multiple linear regression analysis showed that there was no significant determinant of TOI.     

Iron deficiency down-regulates the Akt/TSC1-TSC2/mammalian Target of Rapamycin signaling pathway in rats and in COS-1 cells

Iron deficiency (ID) is one of the most commonly known forms of nutritional deficiencies. Low body iron is thought to induce neurologic defects but may also play a protective role against cancer development by cell growth arrest. Thus, ID may affect cellular pathways controlling cell growth and proliferation, the mechanism of which is still not fully understood. The serine/threonine protein kinase Akt and its downstream target, the mammalian Target of Rapamycin (mTOR), is known to play a crucial role in the regulation of cell growth and survival. Therefore, we hypothesized that Akt/mTOR pathway could be influenced by ID. Three-week-old male Wistar-strain rats were divided into 3 groups and the 2 groups had free access to a control diet (C group) or an iron-deficient diet (D group). The third group (PF group) were pair-fed the control diet to the mean intake of the D group. After 4 weeks, rats were killed and their brains were sampled. In separate experiments, COS-1 cells were cultured with or without the iron chelator deferoxamine. Western blots of brain samples and COS-1 lysates were used to analyze the expression and phosphorylation state of Akt, TSC2, mTOR, and S6 kinase proteins implicated in the Akt/mTOR pathway. Using 2 different ID models, we show for the first time that iron deficiency depresses Akt activity in rats and in COS-1 cells, leading to a decrease in mTOR activity.