Simultaneous LC-MS analysis of plasma concentrations of sildenafil, tadalafil, bosentan, ambrisentan, and macitentan in patients with pulmonary arterial hypertension.

Phosphodiesterase-5 (PDE-5) inhibitors and endothelin receptor antagonists (ERAs) are standard therapies for pulmonary arterial hypertension (PAH). The inter-individual variability of these pharmacokinetics is reported remarkably large, and therapeutic drug monitoring (TDM) can be useful to improve the likelihood of the desired therapeutic and safety outcomes. This study aimed to develop a LC-MS method to determine the concentrations of five PAH drugs (PDE-5 inhibitors: sildenafil and tadalafil, ERAs: bosentan, macitentan, and ambrisentan) from plasma samples using a simple process followed by a single mass spectrometric run, and to validate this approach through pharmacokinetic analyses in patients. A solid extraction method was used for sample preparation of the drugs from human plasma. The total run time for a single injection was within 10 min. The calibration curves for all drugs were linear, and the lower limits of quantitation were 1 (sildenafil), 2 (tadalafil), 5 (ambrisentan), and 10 ng/mL (bosentan, macitentan). The accuracy and precision values suggested that the assay had high accuracy and reliability. To prove the utility of this method, the plasma concentrations of the five PAH drugs were determined after their oral administration to nine PAH patients.

Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil-Bosentan and Sildenafil-Ambrisentan Combination Therapies for Pulmonary Hypertension.

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

Efficacy and toxicity of (chemo)radiotherapy for primary subglottic cancer.

BACKGROUND AND PURPOSE: Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer. PATIENTS AND METHODS: Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy. RESULTS: Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher. CONCLUSION: Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control.

Radiation therapy for primary carcinoma of the eyelid: tumor control and visual function.

BACKGROUND AND PURPOSE: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. PATIENTS AND METHODS: Twenty-three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). RESULTS: All but 3 of the 23 patients had survived at a median follow-up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. CONCLUSION: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid.

Factors predicting tumour regression in locally advanced cervical adenocarcinoma treated with balloon-occluded intra-arterial chemotherapy.

We retrospectively assessed the factors that may impede tumour reduction of locally advanced cervical adenocarcinoma treated with balloon-occluded arterial infusion chemotherapy (BOAI) as initial therapy. We reviewed the medical records and MRI scans of 31 patients (mean age, 54.7 years; age range, 33-78 years). BOAI was performed via uterine arteries in 21 patients, and via the anterior division or main trunk of the internal iliac artery (when the uterine arteries were obscured) in 10 patients. Tumour reduction rate was calculated from the tumour size on MRI before and after BOAI, and patients given chemotherapy were classified as "non-responders" or "responders". Factors including the patient's age, tumour stage (using the International Federation of Gynecology and Obstetrics classification), the artery used for infusion, infused drug, presence of intravenous systemic chemotherapy, initial tumour size, tumour volume and presence of lymph node metastases were assessed for their ability to predict tumour response to BOAI using univariate and multivariate analyses. Patients who underwent chemotherapy included 10 non-responders and 21 responders. The age of non-responders was significantly higher than that of responders (66 years vs 49 years, p<0.001). Internal iliac arterial infusion significantly correlated with "no response" compared with uterine arterial infusion (p<0.001). In multivariate analyses, internal iliac arterial infusion was an independent predictor for BOAI non-responders (odds ratio, 19.6; 95% confidence interval, 1.4-280.6; p = 0.02). These data suggest that uterine arteries being obscured to arterial infusion may be associated with a poor response to BOAI for cervical adenocarcinoma.

Detection of Salmonella in spent hens and eggs associated with foodborne infections.

About 16,000 spent hens from 23 farms in the northern area of Japan were purchased in 1996, 1997, 1998, and 1999 to isolate Salmonella in two poultry processing plants. Salmonella was detected in 12 of 23 farms (52.2%). In particular, the serotypes Enteritidis and Infantis were detected in four and three farms, respectively. The prevalence rates in the hens' ceca, immature eggs, and the yolk of mature eggs in oviducts were 14%, 7.2%, and 6.8%, respectively. A total of 23 serotypes were detected. The major serotypes of the strains were Enteritidis, Corvallis, Typhimurium, and Infantis, but most of the strains were untypable. In the same area during 1992 to 1996, Salmonella was detected in eggs associated with four outbreaks of Salmonella Enteritidis infection and one outbreak of Salmonella Infantis infection. The ratio of contamination was approximately 1%, and the level was estimated to be 93 MPN(most probable number)/100 g in one outbreak. In farms that produced the eggs associated with all of the five outbreaks of Salmonella, the serotype Enteritidis or Infantis was isolated from hens. Farms where Salmonella was not detected were not related to any of the outbreaks.

Umbilical cord pseudocyst in a fetus with trisomy 18.

An umbilical cord pseudocyst was detected in the 28th week of gestation in a fetus complicated with growth restriction and polyhydramnios. The combination of cord pseudocysts, growth restriction, and polyhydramnios prompted us to perform a detailed ultrasonographic examination (gray scale and three-dimensional), which revealed the presence of micrognathia, overlapping fingers, and congenital heart defects, features characteristic of trisomy 18. Karyotyping confirmed a diagnosis of trisomy 18. After spontaneous labor onset, the infant was delivered at 31 weeks of gestation, and died soon after delivery. An umbilical cord pseudocyst is a good marker for the prenatal detection of trisomy 18.

Immunohistochemical detection of apolipoprotein E within prion-associated lesions in squirrel monkey brains.

The interaction of various amyloid precursors and apolipoprotein E (apoE) is important for Congophilic amyloid formation. As for cerebral amyloidoses, although the correlation between amyloid beta protein (Abeta) and apoE in Alzheimer's disease (AD) has been clarified, the interaction of prion protein isoform (PrPsc) and apoE in several types of prion diseases (PDs) has not been examined in detail. ApoE colocalization has been confirmed in Congophilic PrPsc plaques, but to clarify the participation of apoE in the early stage of PDs, apoE deposition in immature lesions without Congophilic amyloid in PDs needs to be examined. In the present study two squirrel monkeys were inoculated with mouse PrPsc derived from sheep scrapie, and showed signs of severe spongiform degeneration. These lesions were immunohistochemically characterized as patchy perivacuolar and diffuse synaptic lesions without Congophilic amyloid. The central portion of the assemblies involving a few patchy perivacuolar lesions was detected by methenamine silver staining and appeared as a plaque-like lesion. ApoE was colocalized in all the plaque-like lesions and in half of the patchy perivacuolar lesions, but not in any diffuse synaptic lesions. These immunohistochemical characteristics indicated that apoE colocalization occurred in moderate mature lesions in PDs, and apoE might play an important role in the aggregation of PrPsc after a conformational change from cellular PrP isoform to PrPsc.

Exercise myocardial perfusion scintigraphy is useful for evaluating myocardial ischemia even in the elderly.

Pharmacologic stress testing is recommended to elderly patients as a valuable alternative to exercise testing. We examined whether exercise testing is as useful for evaluating myocardial ischemia in the elderly as in the young. The consecutive 1,508 patients who underwent exercise 201Tl single-photon emission computed tomography (SPECT) were divided into six age groups: 6-29 years (n = 56), 30-44 (n = 143), 45-54 (n = 311), 55-64 (n = 498), 65-74 (n = 402), and 75-88 (n = 98). Both heart rate and rate-pressure product at peak exercise were significantly lower in patients aged 75-88 than in the other five groups. The frequency of ischemic ST depression was higher in patients aged 75-88 than in those aged 6-74, although the difference was not significant. Moreover, the frequency of 201Tl transient defect was significantly higher in patients aged 75-88 than in those aged 6-74. On the other hand, the sensitivity of ischemic ST depression for 201Tl transient defect was similar among the six groups, but the specificity was significantly lower in patients aged 75-88 than in those aged 6-74. In conclusion, exercise 201Tl SPECT is useful for evaluating myocardial ischemia even in the elderly, but exercise electrocardiography has limitations such as lower specificity in the elderly than 201Tl SPECT.

Evaluation of small internal mammary lymph node metastases in breast cancer by MRI.

PURPOSE: In breast cancer, diagnosis of a small internal mammary lymph node (IMLN) metastasis of less than 10 mm in size has been difficult. Our purpose was to retrospectively evaluate MRI findings of small IMLN metastases in comparison with dissected IMLNs. METHODS: We studied 43 dissected IMLNs (range 2-12 mm, mean 4.512+/-2.763 mm) in 16 women with breast cancer (15 primary, and 1 recurrent). MRI examinations were performed using a 1.5 Tesla scanner (200FX; Toshiba, Tokyo, Japan) to obtain noncontrast T1-weighted SE images (TR/TE; 500/15 or 400/15ms), with a slice thickness of 5 mm on coronal images, 10 mm or 7 mm on sagittal images, FOV 15x15 cm, matrix 256x256, using a surface coil with patients in the supine position. MR images were evaluated regarding the major diameter and shape and margin of each node. RESULTS: Regarding the presence of IMLN metastases, there was a significant difference between nodes with a major diameter of 5 mm or more and those of less than 5 mm (p<0.05). Using the size-based criterion (defining< or =5 mm as positive), MRI had 90.7% accuracy, 93.3% sensitivity, and 89.3% specificity. There were no significant differences in the shape-or margin-based criterion. CONCLUSIONS: MRI was useful in diagnosing small IMLN metastases, using a size-based criterion.

Egg-eating behaviour in laboratory squirrel monkeys (Saimiri scuireus).

The present study aimed to clarify an individual character of squirrel monkey by analysing a complicated behaviour, the egg-eating behaviour series (ES), of laboratory-reared squirrel monkeys. Eight types of unit movements were observed in the ES: the initial taking of the egg by hand; rolling it between the fingers; sniffing it in its shell; biting it in its shell; pressing or rubbing it against a surface of the cage; opening or peeling it; eating it; or putting it down without eating. In the first experiment, the behaviour of 72 monkeys was recorded by direct observation or by a video camera, following which the sequences of the movement from a total of 378 ES were analysed. Three statistically significant ES were detected (Ta-Bi-Op/Pe-Ea, Ta-Ro-Bi-Op/Pe-Ea and Ta-Pr/Ru-Bi-Op/Pe-Ea). In the second experiment, eight squirrel monkeys were selected at random from the same group and 31 to 36 ES for each monkey were observed and analysed. These monkeys were classified into a pressing/rubbing (Pr/Ru) group and a no-Pr/Ru group. Pr/Ru appeared to have no relationship to the monkey's age or sex. Furthermore, the Pr/Ru group monkeys contained individuals always exhibiting Pr/Ru in their ES and others sometimes lacking Pr/Pu in their ES. In short, the monkeys could be divided into two groups (i.e., Pr/Ru and no-Pr/Ru) and they displayed their own individual characteristic ES. We concluded that the ES observed in this experiment suggest that the squirrel monkeys acquired individual characteristics in their ES in the laboratory environment.

[Balloon-occluded arterial infusion chemotherapy in treatment of the patients with locally recurrent carcinoma of the cervix who previously received radiation therapy].

Nine patients with locally recurrent carcinoma of the cervix were treated with balloon-occluded arterial infusion chemotherapy (BOAI) in order to secure high concentrations of antitumor agents. All the patients had previously received radiation therapy for squamous cell carcinoma of the cervix. Recurrence was diagnosed by cytology and/or biopsy, or CT. Either cisplatin 100 mg/body and doxorubicin hydrochloride 40 mg/body or cisplatin 50-100 mg/body and pirarubicin 40-60 mg/body were infused after the bilateral internal iliac arteries had been occluded using balloon catheters. As the largest diameter of the tumors on CT increased, the mean survival after BOAI decreased. The mean survival of 4 patients with no detectable masses on CT was 45 +/- 30.7 months. In 5 patients, neurological complications, subcutaneous and/ or skin reactions of the buttock, or necrosis of the uterus developed. The neurological complications were damage to the sciatic nerve at the level of S1 or S2. Our study suggests that BOAI therapy may lead to a high complication rate in patients with locally recurrent carcinoma of the cervix who previously received radiation therapy, although long-term survival can be expected in patients with no detectable masses on CT.

Computed radiography excretory urography: can the system sensitivity value be used as an image quality indicator?

The purpose of this study is to determine whether the computed radiography system sensitivity value can be used as an image quality indicator for computed radiography excretory urography with radiation dose reduction. One hundred and twenty-four patients with gynecological malignancies were studied prospectively. Five-minute and 10-minute computed radiographic images of excretory urography were obtained in each patient with different radiation doses (ie, a standard dose image required with screen-film method and a reduced dose one). The images were subjectivity scored by three radiologists without knowledge of the exposure factors or the system sensitivity values. The quality scores of the reduced-dose images used in the five steps were compared with those of the standard dose images (the system sensitivity value was 80 to 120). The images with reduced exposures were arbitrarily divided into five steps according to the system sensitivity value (ie, 150 to 250, 260-400, 410-600, 610-1000, and 1010-1500). There was a gradual degradation of the image quality as the system sensitivity value was increased. In terms of visualization of the bones, the images taken with the system sensitivity values of 150-250 (40%-67% of the standard dose system) showed no statistically significant difference from the standard dose images. As for visualization of the renal pelvic margins, the images taken with the system sensitivity values of 260 to 400 (2%-38% of the standard dose system) showed no statistically significant difference. We conclude that system sensitivity value can be used as a practical though approximate indicator of the image quality.

Analysis of sexual behavior in rams (Ovis aries).

In this study, a matured ram was paired with an estrus ewe and sexual behavior was investigated. All the behavior was recorded by a time-lapse video tape recorder from the start of pairing. The series of unit movements comprising the sexual behavior, the mounting series (MS), was extracted from the record and analyzed quantitatively (n = 774). The MS starts from ram's approaching or following a ewe and ends by ram's mounting on a ewe. The sexual behavior was consisted of the following eight unit movements, following or approaching (F/A), chin resting (CR), flehmen (Fl), mounting (Mo), nosing (No), nudging (Nu), pushing (Pu) and twisting (Tw). Analysis of a frequency of any combinations of two unit movements consisted of preceding and succeeding ones, observed in the MS was conducted by cell-by-cell test using the transitional matrix to make a flow-diagram of the ram's sexual behavior. As a result, the pattern of unit movements, F/A-Tw-Nu-CR-Mo, formed a main route of the MS, whereas the repertoire of a sequential pattern increased by diverging. Though Fl and No didn't lead to mounting directly, these movements associated with olfactory perception also belonged to sexual behavior and may have independent function from other six unit movements that constitute the MS.

Portal vein aneurysm in the liver associated with multiple vascular malformations.

Portal vein aneurysm (PVA) includes focal dilatation of the portal vein, and was formerly thought to be a rare disease. We report a 46-year-old man with chronic aggressive hepatitis and intrahepatic portal vein aneurysm communicating with the hepatic vein. Hemangiomas in the liver and intracranial arteriovenous malformation (AVM) were also found. To our knowledge, this is the first report of a case of PVA in a patient with congenital intracranial AVM. As the PVA in this patient communicated with the hepatic vein, and as hemangiomas in the liver and intracranial AVM were also present, the pathogenesis in this patient seems to have been congenital anomaly of the vasculature.

Mechanical properties of artificial teeth.

In selecting the teeth for fabrication of complete or partial dentures, each patient's anatomic and physiologic requirements and the properties of the artificial teeth themselves should be taken into consideration. The purpose of this study was to evaluate the mechanical properties of the artificial teeth by the static compression test and the impact test. Specimens were the lower first molar porcelain and resin teeth (Livdent FB-20 teeth by G. C. Co., Tokyo, Japan). All were of the same shape. In the static compression test, the fracture load and deformation of the artificial teeth were measured with an Instron-type universal testing machine at a cross-head speed of 1.0 mm/min. Elastic modulus, ultimate strength and absorbed energy were calculated. In the impact test, the acceleration of a falling impactor was measured with a drop impact apparatus. The load applied to the specimen was equivalent to 300N. Absorbed energy and deformation were calculated. The resin teeth showed a lower elastic modulus, higher fracture toughness and shock-absorbing ability than the porcelain teeth. Resin teeth should be selected when the first requisite is high shock-absorbing ability, and porcelain teeth should be selected when the first requisite is high masticating efficiency.

[Local compressibility of denture foundation--evaluation of denture foundation in relation to impression pressure].

The viscoelastic character of the denture foundation is different in each individual or site. The character of the mucosa and the appropriate impression procedure should be examined. However, few investigations concerning the relation between the compressibility of the denture foundation and the impression pressure have been reported. The purpose of this study was to discuss the objective evaluation of the denture foundation in relation to the impression pressure. In this report, the local compressibility of the denture foundation of 20 upper edentulous patients was measured with the 20 MHz B-Mode ultrasonic diagnostic equipment. The Compressible Index was defined to analyze the compressibility of the denture foundation quantitatively as against the impression pressure. The main results were as follows: 1. The compressible amount of the denture foundation against 100 gw/cm2 pressurization was an average of 0.32-0.61 mm. 2. The compressible rate of the denture foundation against 100 gw/cm2 pressurization was an average of 13.5-20.7%. 3. The Compressible Index was confirmed to represent the compressibility of the denture foundation accurately as against the impression pressure. 4. It was suggested that the Compressible Index was useful for the clinical simple evaluation of the denture foundation.