Determination of the metabolites of the new designer drugs bk-MBDB and bk-MDEA in human urine.

This is the first report on identifying the specific metabolites of the new designer drugs 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (bk-MBDB) and 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (bk-MDEA) in human urine using synthesized standards. Based on GC/MS and LC/MS, we identified N-dealkylation, demethylenation followed by O-methylation, and beta-ketone reduction as their major metabolic pathways. The quantitative analyses by LC/MS revealed that both demethylenation followed by O-methylation and beta-ketone reduction were superior to N-dealkylation and that both bk-MBDB and bk-MDEA were mainly metabolized into their corresponding 4-hydroxy-3-methoxy metabolites (4-OH-3MeO metabolites). After hydrolysis, the concentrations of 4-OH-3MeO metabolites and 3-hydroxy-4-methoxy metabolites of both bk-MBDB and bk-MDEA dramatically increased, suggesting that the metabolites mainly exist as their conjugates.

Metabolism of the psychotomimetic tryptamine derivative 5-methoxy-N,N-diisopropyltryptamine in humans: identification and quantification of its urinary metabolites.

The urinary metabolites of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in humans have been investigated by analyzing urine specimens from its users. For the unequivocal identification and accurate quantification of its major metabolites, careful analyses were conducted by gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry, and liquid chromatography-tandem mass spectrometry, using authentic standards of each metabolite synthesized. Three major metabolic pathways were revealed as follows: 1) side chain degradation by O-demethylation to form 5-hydroxy-N,N-diisopropyltryptamine (5-OH-DIPT), which would be partly conjugated to its sulfate and glucuronide; 2) direct hydroxylation on position 6 of the aromatic ring of 5-MeO-DIPT, and/or methylation of the hydroxyl group on position 5 after hydroxylation on position 6 of the aromatic ring of 5-OH-DIPT, to produce 6-hydroxy-5-methoxy-N,N-diisopropyltryptamine (6-OH-5-MeO-DIPT), followed by conjugation to its sulfate and glucuronide; and 3) side chain degradation by N-deisopropylation, to the corresponding secondary amine 5-methoxy-N-isopropyltryptamine (5-MeO-NIPT). Of these metabolites, which retain structural characteristics of the parent drug, 5-OH-DIPT and 6-OH-5-MeO-DIPT were found to be more abundant than 5-MeO-NIPT. Although the parent drug 5-MeO-DIPT was detectable even 35 h after dosing, no trace of its N-oxide was detected in any of the specimens examined.

The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development.

The docking protein FRS2alpha is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2alpha in vivo remains unknown. In this report, we show that Frs2alpha-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2alpha is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2alpha also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2alpha-null embryos. These experiments underscore the critical role of FRS2alpha in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

Common hepatic artery aneurysm branching from the superior mesenteric artery. Report of a case.

A 58-year-old man was notified as having a mass in the head of the pancreas at medical checkup on September 26, 2000. He was admitted to our department after being diagnosed as having an aneurysm in the common hepatic artery, branching from the superior mesenteric artery (SMA), based on selective SMA angiography. From an abdominal midline incision, we were able to reach his common hepatic artery aneurysm (CHAA) by mobilizing the pancreas through the route lateral to the greater curvature of the stomach. This aneurysm arose in the common hepatic artery immediately after branching from the SMA. After proximal and distal control of the SMA and common hepatic artery, the aneurysm was incised and the distal hepatic artery was anastomosed end to side to the SMA. The patient had an uneventful postoperative course.

Quantitative air-plethysmographic venous function and ambulatory venous pressure in patients with primary varicose vein.

AIM: The purpose of this study was to investigate the relationship between air-plethysmographic volume parameters under standard exercise loading and foot venous pressure parameters under ideal exercise loading in patients with primary varicose veins. METHODS: Seventy-one lower limbs in 39 patients with primary varicose veins and 8 lower limbs in 4 healthy controls were examined. The patients included 12 males and 27 females, ranging in age from 36 to 79 years. Eighteen limbs were asymptomatic (class 0) limbs, 28 limbs had symptoms of swelling or heaviness (class 1), and 25 had skin lesions (class 2+3). The patients and controls were examined with duplex scanning, air-plethysmography, and ambulatory foot venous pressure measurement. RESULTS: The mean ambulatory venous pressure (AVP) was significantly higher in the class 2+3 limbs than in the other classes, but it was not significantly higher in class 1 than in class 0. There were no significant differences between the class 2+3 limbs and class 1 limbs in any of the air-plethysmographic parameters. However, the VFI in the class 0 limbs was significantly different from that in the other 2 groups. Among all parameters examined, the venous filling index (VFI) was the most closely correlated with the AVP. All air-plethysmographic parameters were negatively correlated with the VRT. CONCLUSIONS: Among non-invasive air-plethysmographic volume parameters, VFI is the most reliable indicator for quantitative evaluation of calf pump function.

Left renal artery aneurysm with left accessory renal arteries. A case report.

A 57-year-old man was suspected of having a left renal artery aneurysm on enhanced computed tomography (CT) findings. Aortic angiography showed 3 left renal arteries with an aneurysm of the distal main renal artery. A 3 mm upper pole renal artery which crossed near the aneurysm was preserved. Dissection of the aneurysm was followed by arterial reconstruction with end-to-end anastomosis.

Localization of endothelin-A and -B receptors during the postnatal development of rat cerebellum.

Intense expression of mRNA of endothelin-B receptor (ETBR) has been detected in the Bergmann glia of cerebellum by in situ hybridization, but the intracellular localization has not been reported because of the absence of a useful antibody for immunohistochemical investigations. We made polyclonal antibodies against the carboxyl terminus of human ETBR (420-442) and ETAR (403-427), and performed light- and electron-microscopic immunohistochemistry of the wild-type and ETBR-deficient (sl/sl) rat cerebella. Localization of ETBR during postnatal development was examined by double-staining immunofluorescence using antibodies against ETBR and S-100 beta. In the wild-type rats, ETBR immunoreactivity appeared from postnatal day 5 (P5) and was distributed diffusely in the processes and cell bodies of S-100 beta-positive glial cells. By P14, ETBR immunoreactivity was concentrated in the Golgi apparatus of Bergmann glial cell soma and the plasma membrane of its processes. The ETBR-positive astrocytes in the granular layer decreased in number during P7-14 and had disappeared by week 3. At 3 weeks, ETBR immunoreactivity was restricted to the Golgi apparatus of Bergmann glia. In the sl/sl rats, ETBR immunoreactivity was not observed at all. In contrast to ETBR, ETAR immunoreactivity appeared transiently in the cytoplasm of all astrocytes (Bergmann glia and astrocytes in the granular layer) in the 9- to 14-day-old wild rats and 7- to 14-day-old sl/sl rats, and disappeared within 3 weeks in both. Granule cells did not express immunoreactivity for ETBR and ETAR from the neonatal stage to adulthood. Changes in the intracellular localization of ETBR and transient expression of ETAR may be correlated with the changes of glial functions and proliferation during postnatal development of rat cerebellum.

Symptomatic recovery and social functioning in major depression.

OBJECTIVE: To determine whether social functional recovery precedes, runs in parallel with, or lags behind symptomatic recovery from major depressive episodes. METHOD: Psychiatric out-patients or in-patients aged 18 years or over, diagnosed with unipolar major depressive disorder according to DSM-IV, and who had received no antidepressant medication in the preceding 3 months were identified at 23 collaborating centres from all over Japan (n=95). They were rated with the 17-item Hamilton Rating Scale for Depression (HRSD) and the Global Assessment Scale (GAS) monthly, and with the Social Adjustment Scale-Self Report (SAS-SR) 6-monthly. Remission was defined as 7 or less on the HRSD and recovery as 2 or more consecutive months of remission. RESULTS: The GAS ratings showed continuous amelioration from baseline to remission, remission to recovery, and after sustained recovery. The same trends were observed for SAS-SR scores. CONCLUSION: We can expect further amelioration in social adjustment after symptomatic remission and recovery of major depressive episodes.

Localization of endothelin A receptors in the rat pituitary TSH cells: light- and electron-microscopic immunohistochemical studies.

Endothelins modulate hormonal secretion in the pituitary gland. Intense signaling of endothelin A receptors (ET(A)R) has been detected by in situ hybridization, binding assay and receptor autoradiography. We used light- and electron-microscopic immunohistochemistry of ET(A)R with polyclonal antibody against a synthetic peptide corresponding to the carboxyl terminus (403-427) of human ET(A)R. Immunoreactivity was observed in 6-8% of anterior pituitary cells, which were rather large polygonal or stellate cells. These cells were often clustered. Double-staining immunofluorescence showed that the ET(A)R-positive cells immunoreacted with antibody against the beta-subunit of thyroid-stimulating hormone (TSH), but not adrenocorticotropic hormone (ACTH) or lutenizing hormone beta (LHbeta). Pre- and postembedding electron-microscopic immunohistochemistry showed that ET(A)R-positive cells had vacuolated or parallel-lined rough endoplasmic reticulum (rER) and numerous round granules in their periphery and the elongated processes. By pre-embedding immunohistochemistry, diaminobenzidine tetrahydrochloride (DAB) products were shown to be mostly located around the granules and occasionally underneath the plasma membrane. By postembedding immunohistochemistry, granules in the ET(A)R-positive cells were 90-150 nm in diameter, and colloidal gold particles due to ET(A)R were associated with about 10% of these granules. These results indicate that ET(A) receptors are associated mostly with the secretory granules of TSH cells.

Percutaneous balloon fenestration in a case of traumatic abdominal aortic dissection with lower extremity ischemia.

A 38-year-old man was involved in a traffic accident and experienced a heavy blow to the abdomen. He had traumatic abdominal aortic dissection with right lower extremity ischemia. He underwent percutaneous balloon fenestration, which is safe and minimally invasive, for relief of right lower extremity ischemia. He has been working for 2 years without any signs of vascular compromise. Percutaneous balloon fenestration is one of the few treatments for traumatic abdominal aortic dissection.

A polydiagnostic study of depressive disorders according to DSM-IV and 23 classical diagnostic systems.

The classification of mood disorders is one of the most highly debated topics in modern psychiatry. The introduction of DSM-III (and its followers) has set a new standard in this controversy but little empirical evidence is available as to how the various classical diagnostic categories of mood disorders by Kraepelin, Schneider, Leonhard, Hamilton, Kielholz, Winokur and others compare with this new standard. The Intensive Prospective Study arm of the Group for Longitudinal Affective Disorders Study has studied a broad spectrum of mood disorders in 23 participating centres from all over Japan with a polydiagnostic semistructured interview called Comprehensive Assessment List of Affective disorders. In this paper we examined how the various classical diagnostic systems of depressive disorders correspond to the DSM-IV diagnoses, and found the following: (1) The classical 'neurotic' or 'psychogenic' depressions are diagnosed as major depression and not as dysthymia in DSM-IV; although dysthymia was dubbed as 'depressive neurosis' in DSM-III, its criteria were not true to the traditional usage of the term. Viewed from the other side of the coin, DSM-IV can be said to stand in the unitary tradition. (2) Some of the classical diagnostic categories such as Schneider's depressive psychopathy and Klein's acute dysphoria as well as modern ones such as Akiskal's subaffective dysthymia and Angst's recurrent brief depression were rarely seen in traditional psychiatric treatment settings. (3) Comparisons of the unique diagnostic systems such as those by Leonhard, Winokur and Berner warrant further studies on their validity.

[Giant localized fibrous pleural mesothelioma accompanying lung metastasis--a case report].

We experienced a case of giant localized fibrous pleural mesothelioma accompanying lung metastasis. The patient was a 26-year-old woman, who was pointed out elevation of the left diaphragma by the chest roentgenogram in 1992 but left it as it was. In 1995, a giant tumor occupying 1/2 or more of the left thoracic cavity was detected by chest CT and MRI. A giant localized pleural mesothelioma was suspected since there was no accumulation in Ga scintigram and an operation was performed. The tumor originated without pedicle and with invasion of the lung from the pleura of the left S8 and it was excised by separating the left lower lobe at 7-cm distance from the tumor. The tumor was 20 x 12 x 11 cm in size weighing 1700 g and the histopathological diagnosis was localized fibrous pleural mesothelioma. A lung metastasis of 1.0 cm in size was found in a part of the left lower lobe resected at the same time. The postoperative course has been satisfactory and there is no sign of recurrence at present. There are occasional cases of recurrence associated with a localized fibrous pleural mesothelioma even though it is judged benign. In the present case, a metastatic focus was already present at the time of initial surgery and is considered a valuable case.

Screening for depression among first-visit psychiatric patients: comparison of different scoring methods for the Center for Epidemiologic Studies Depression Scale using receiver operating characteristic analyses.

The present paper aims to compare the ability of eight scoring methods for the Center for Epidemiologic Studies Depression Scale (CES-D), one of the most widely used self-report inventories for depression, to screen for a major depressive episode. The subjects were 591 patients who constituted representative samples of the first-visit patients to 23 psychiatric hospitals and clinics all over Japan. The criterion diagnoses were given by a semi-structured interview with established inter-rater reliability. The eight alternative scoring methods included the conventional Likert method, which gives the weights 0, 1, 2 and 3 to the four anchor points of the CES-D; the presence method, which gives the weights 0, 1, 1 and 1, respectively; the GHQ method, which gives the weights 0, 0, 1 and 1, respectively; the persistence method, which gives the weights 0, 0, 0 and 1, respectively; 10-item version, 5-item version, single-item version and the algorithmic method. On the basis of the receiver operating characteristic (ROC) analyses, it was found that the traditional Likert scoring method of the full CES-D performed best in detecting major depressive episodes among first-visit psychiatric patients. The presence method, the GHQ method and the 10-item version appeared to have a similar ability. The persistence method, the 5-item version and the single-item version resulted in significantly worse performance.

[Epidemiological study on Chlamydia trachomatis infection in pregnant housewives and investigation on its influence on outcome of pregnancy and on their newborns].

We surveyed Chlamydial infection with Chlamydiazyme for 3010 pregnant housewives in Hokkaido. Four hundred and fourty six out of the 3010 pregnant housewives were also be retrospectively investigated for the influence of C. trachomatis on outcome of pregnancy and on their newborns. The results were as follows. 1) Of the 3010 pregnant housewives, 217 (7.2%) were C. trachomatis-antigen positive, when their endocervical specimens were tested. There was no difference in the positive rate of C. trachomatis among the six cities where our investigation was performed. 2) A high C. trachomatis-positive rate (21.9%) was achieved in the pregnant teen-aged housewives with a significant decrease as age increased. 3) As for placenta previa, threatened abortion, preterm delivery and small for date infants, the incidence was higher in the untreated C. trachomatis positive group than in the C. trachomatis negative group. 4) The weeks of gestation and birth weight of newborns in the untreated C. trachomatis positive group were significantly lower than those of the C. trachomatis negative group. 5) No statistical significance was found in the incidence of premature rupture of membrane, fatal distress, spontaneous abortion nor postpartum fever between the C. trachomatis negative group and the untreated C. trachomatis positive group. These results suggest that Chlamydial infection in pregnant housewives is widely spread in Hokkaido and gives some disadvantage to pregnancy outcome and newborns. Consequently, Chlamydial infection in pregnant women must be appropriately diagnosed and treated in the early stage of pregnancy.