17ß-Estradiol in the systemic circulation derives mainly from the parietal cells in cholestatic female rats.

PURPOSE: Estrogenic symptoms of liver disease patients including biliary tract disorder with high frequency is observed in clinical cases. However, the origin of 17ß-estradiol which is abundant enough to cause symptoms remains uncertain. In male rats, it has been reported that the parietal cells which have an abundance of aromatase-synthesized 17ß-estradiol, and a part of 17ß-estradiol secreted into the portal vein, may flow into the systemic circulation under a pathophysiological condition of the liver including bile duct ligation (BDL). The aim of this study is to reveal the origin of 17ß-estradiol increment in female rats and to investigate the effect of BDL on the ovary during the estrus cycle. METHODS: Wistar female rats were used, and the common bile duct was ligated twice and transected completely at 7 days before termination. Serum portal venous and arterial 17ß-estradiol levels, Cyp19a1 expressions, aromatase protein levels, and estrogen receptor (ER) α levels in the liver were measured during the estrus cycle. RESULTS: Both arterial and portal venous 17ß-estradiol levels increased 2.9 times at proestrus and maintained constant levels during the cycle. The expression of Cyp19a1 and aromatase protein in the stomach maintained constant levels, and significantly decreased during the estrus cycle in the ovary. Hepatic ERα protein and Esr1 expressions decrease by BDL in all stages. CONCLUSIONS: These results suggest that the increment of serum 17ß-estradiol levels in obstructive cholestasis induced by BDL is derived from 17ß-estradiol secreted from the parietal cells in females as well as males.

Manipulations of extracellular Loop 2 in α1 GlyR ultra-sensitive ethanol receptors (USERs) enhance receptor sensitivity to isoflurane, ethanol, and lidocaine, but not propofol.

We recently developed ultra-sensitive ethanol receptors (USERs) as a novel tool for investigation of single receptor subunit populations sensitized to extremely low ethanol concentrations that do not affect other receptors in the nervous system. To this end, we found that mutations within the extracellular Loop 2 region of glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABAARs) can significantly increase receptor sensitivity to micro-molar concentrations of ethanol resulting in up to a 100-fold increase in ethanol sensitivity relative to wild-type (WT) receptors. The current study investigated: (1) Whether structural manipulations of Loop 2 in α1 GlyRs could similarly increase receptor sensitivity to other anesthetics; and (2) If mutations exclusive to the C-terminal end of Loop 2 are sufficient to impart these changes. We expressed α1 GlyR USERs in Xenopus oocytes and tested the effects of three classes of anesthetics, isoflurane (volatile), propofol (intravenous), and lidocaine (local), known to enhance glycine-induced chloride currents using two-electrode voltage clamp electrophysiology. Loop 2 mutations produced a significant 10-fold increase in isoflurane and lidocaine sensitivity, but no increase in propofol sensitivity compared to WT α1 GlyRs. Interestingly, we also found that structural manipulations in the C-terminal end of Loop 2 were sufficient and selective for α1 GlyR modulation by ethanol, isoflurane, and lidocaine. These studies are the first to report the extracellular region of α1 GlyRs as a site of lidocaine action. Overall, the findings suggest that Loop 2 of α1 GlyRs is a key region that mediates isoflurane and lidocaine modulation. Moreover, the results identify important amino acids in Loop 2 that regulate isoflurane, lidocaine, and ethanol action. Collectively, these data indicate the commonality of the sites for isoflurane, lidocaine, and ethanol action, and the structural requirements for allosteric modulation on α1 GlyRs within the extracellular Loop 2 region.

Dihydrotestosterone inhibits murine hair growth via the androgen receptor.

BACKGROUND: Androgens cause regression of human hair follicles in the parietofrontal scalp, but the precise mechanisms by which they do so are unknown. Although many investigators have elucidated the effect of androgens on hair growth by using rodents and other animals, some of the evidence is conflicting. OBJECTIVES: To investigate the effect of androgens on mouse hair regrowth and hair cycle by using androgen receptor knockout (ARKO) mice. Methods We examined the effects of dihydrotestosterone (DHT) on hair regrowth by using ARKO mice and wild-type (WT) littermates, compared the hair cycles in ARKO mice and WT littermates by histology and histomorphometry, and measured hair length and thickness in ARKO mice and WT littermates. RESULTS: DHT inhibited the hair regrowth of WT mice but not that of their ARKO littermates. The anagen phase in the second hair cycle was longer in ARKO mice than in their WT littermates. The hair of ARKO mice was longer and thicker than that of their WT littermates. CONCLUSIONS: Androgens inhibit hair growth in mice, and this inhibition might be caused by androgen-androgen receptor signals.

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells.

Docetaxel is one of the most effective chemotherapeutic agents against cancer; nevertheless, some patients develop resistance. Unfortunately, their causes and mechanisms remain unknown. We created docetaxel-resistant DRHEp2 from human laryngeal cancer HEp2 and investigated the roles of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) on docetaxel resistance. DRHEp2 had greatly increased mtDNA content. Reduction of mtDNA content in DRHEp2 by ethidium bromide treatment reduced the resistance. These results indicate the possible roles of mtDNA-coded enzymes in mitochondrial respiratory chain (MRC) in resistant mechanisms. Oligomycin A, an Fo-ATPase inhibitor, eliminated docetaxel resistance in DRHEp2; in contrast, inhibitors of other MRC did not. RNA interference targeted to Fo-ATPase d-subunit restored docetaxel-induced cytotoxicity to DRHEp2. These results indicate the roles of Fo-ATPase for resistant mechanisms. Docetaxel induced ROS generation in HEp2 but not in DRHEp2 and antioxidant pyrrolidine dithiocarbamate eliminated docetaxel-induced cytotoxicity, suggesting roles of ROS in docetaxel-induced cell death. Furthermore, inhibition of Fo-ATPase by Oligomycin A induced docetaxel-mediated ROS generation in DRHEp2. Taken together, DRHEp2 acquired docetaxel resistance through increasing Fo-ATPase, which led to diminish docetaxel-induced ROS generation and subsequently inhibited cell death. In conclusion, mtDNA plays an important role in developing docetaxel resistance through the reduction of ROS generation by regulating Fo-ATPase.

Preoperative portal vein embolization with a mixture of gelatin sponge and iodized oil: efficacy and safety.

PURPOSE: To evaluate whether portal vein embolization (PVE) using a mixture of gelatin sponge (GS) pieces and iodized oil is safe and effective in inducing hypertrophy of the future liver remnants (FLR). MATERIAL AND METHODS: PVE was performed in 14 patients (eight male and six female, mean age 65 years, range 35-81 years) diagnosed with malignant liver tumor before surgery, whose FLR volumes were judged too small to allow for safe resection. Liver volume change, biochemical data change, complications related to PVE, and postoperative complications were retrospectively evaluated. RESULTS: PVE was successful in all patients, and there were no procedural complications. Absolute FLR volume and FLR/total liver volume (TLV) ratio increased by 102 cm3 and 8% (mean values), respectively. Planned hepatectomies were cancelled in three patients due to extrahepatic metastasis or bile duct infection. Five of the 11 patients (45%) who underwent hepatectomies had major postoperative complications. However, complications due to hepatic failure were not seen. In 10 patients, except one whose outcome was fatal outcome, the mean hospitalization days with and without major complications were 73 and 33 days, respectively. CONCLUSION: PVE using a mixture of GS and iodized oil seems to be effective and safe in inducing hypertrophy of the FLR.

Endovascular therapy for abdominal pseudoaneurysms: analysis from technical and clinical aspects.

PURPOSE: To clarify the factors of outcomes by endovascular therapy for abdominal pseudoaneurysm (PSA) from both technical and clinical aspects. MATERIAL AND METHODS: Sixteen patients with PSAs underwent embolization. Embolic methods were classified into two groups: proximal and distal embolization (PDE) and proximal embolization alone (PE). The patients were classified into four groups by shock index. Pre-embolization hemoglobin (Hb) level and decrease in Hb level were evaluated. Outcomes were classified into two groups: successful recovery and failure despite successful PSA embolization. RESULTS: There were no statistical differences in success, recurrence, and complication rate, and outcomes between the two embolic methods. There was a statistically significant correlation between the grades of shock indices and outcomes (P<0.05). There was no statistical difference between the Hb levels and outcomes. CONCLUSION: Outcomes were not dependent on the embolic methods. Shock index reflecting clinical status may be a simple predictor of outcome. PSA should therefore be treated by optimal embolic methods as quickly as possible to avoid rupture.

Hospital nurse administrators in Japan: a feminist dimensional analysis.

BACKGROUND: Nursing administration research is scarce in Japan during a time when health care is rapidly reforming and baccalaureate and graduate nursing programmes are rapidly developing. Additionally, nursing administration content relies heavily on Western and non-nursing theories, some of which have been criticized for male bias. PURPOSE: The purpose of this article is to present key findings from a qualitative study that explored the perspectives or viewpoints of 16 Japanese senior female nurse administrators in hospitals in order to learn what was happening in their working situations and how they were managing. DESIGN AND METHODS: This feminist study used dimensional analysis strategies for data collection and analysis. Semi-structured, tape-recorded interviews were conducted by both researchers in Japanese, transcribed into Japanese, and translated into English. RESULTS AND DISCUSSION: The resulting explanatory matrix portrayed a story of 16 nurse administrators, most of whom were able successfully to enact a management role in a context of role ambiguity that was congruent with their relational values and beliefs. Important conditions influencing value-based role enactment included organization mission and purpose, organization structure, nurse-doctor relationships, participant-supervisor relationships, and personal attributes. Many participants were able to overcome barriers in these categories using strategies of tempered radicalism and consequently made positive organizational changes. CONCLUSIONS: Advanced formal education, better organizational support, and a raised consciousness among nurses that views nurses and midwives as equal partners with other professionals will enable Japanese nurse administrators to help advance patient-centred care and nursing development and empowerment.

Atelectasis of the right medial basal segment mimicking primary lung cancer in an asthmatic patient.

A segmental collapse due to mucous plug in the bronchus tree may mimic malignant pathological conditions. We present a case of 58-year-old asthmatic patient with an obstruction of right medial basal bronchus due to mucous plug, which was simulating mediastinal mass. To the best knowledge, a similar case is not reported in the English medical literature.

Morphologic and histopathologic changes in the bowel after super-selective transcatheter embolization for focal lower gastrointestinal hemorrhage.

PURPOSE: To evaluate the safety of superselective arterial embolization therapy in the lower gastrointestinal tract. The sequelae on normal enteric tissue in lower gastrointestinal arterial embolization were retrospectively reviewed. MATERIAL AND METHODS: To control hemorrhage and tumor blood supply, 14 patients were treated by superselective transcatheter embolization at different levels of the colonic and small intestine vessels via the superior and inferior mesenteric arteries using microcoils and/or gelatin sponge. Normal enteric tissues in the embolized areas were analyzed for the occurrence of ischemic changes by clinical follow-up, colonoscopy, and surgery. RESULTS: Normal bowel function was preserved in 13 patients. In 1 patient treated with numerous gelatin sponge particles delivered from the proximal arcade of the superior mesenteric artery, significant muscular fibrosis occurred. CONCLUSION: Superselective arterial embolization for lower gastrointestinal hemorrhage can be safely performed by minimizing the amount of embolic materials and delivering them as distally as possible.

Evaluation of 5-S-cysteinyldopa as a marker of melanoma progression: 10 years' experience.

5-S-Cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. In this study, we measured serum levels of 5-S-CD in 2648 samples taken from 218 patients in order to evaluate the usefulness of this parameter in following melanoma progression and prognosis. 5-S-CD levels were significantly elevated above the upper limit of the normal range (10 nmol/l) in stage IV melanoma patients. The sensitivity of elevated serum 5-S-CD levels in detecting distant metastasis was 73%, while the specificity was 98% and the positive predictive value 94%. The sensitivity was improved to 77% when cases of amelanotic melanoma were excluded. Patients without metastases had elevated 5-S-CD values in 5% of the 1480 serum samples. Changes in serum 5-S-CD levels were followed during disease progression until the end stage in 49 patients. In 33% of the patients, elevation of serum 5-S-CD levels preceded clinical detection of visceral metastases, and in 37% elevation of 5-S-CD levels occurred at the same time as visceral metastasis. Patients with elevated 5-S-CD levels before or after surgical treatment had significantly shorter survival times than those with normal levels. These results show that the level of 5-S-CD in the serum is a sensitive and specific marker in predicting distant metastases. Elevated serum levels of 5-S-CD, before or after surgical treatment, is associated with a poor prognosis.

A motion of forearm supination with maintenance of elbow flexion produced by electrical stimulation to two elbow flexors in humans.

Motions of the forearm induced by electrical stimulation to two elbow flexors (brachioradialis: BR, biceps brachii: BB) were examined in five healthy human subjects. Stainless steel wire electrodes were implanted percutaneously into each motor point of the muscles. The muscles were stimulated separately with a computer-controlled multi-channel stimulator. The motions were taken with a digital video system. Angular changes of the motions in elbow flexion/extension and forearm pronation/supination were measured. Electromyograms (EMG) of BR, BB, and the triceps brachii (TB) were recorded. Electrical stimulation to BR induced a motion of flexion and that to BB motions of flexion and supination. The stimulation to BR with an adequate intensity provided holding of flexion with the prone forearm in all the subjects. In this situation, additional stimulation to BB resulted in motions of flexion and supination. However, the additional stimulation accompanied with a decrease of the stimulation intensity for BR provided a motion of supination with maintenance of the flexion in all the subjects. Since during the stimulation BR, BB, and TB showed no voluntary contraction in EMG, it is suggested that modulation of contraction between BR and BB by the stimulation can produce force in supination with keeping constant force in flexion to support the weight below the elbow.

Annexin II overexpression correlates with stromal tenascin-C overexpression: a prognostic marker in colorectal carcinoma.

BACKGROUND: Overexpression of annexin II, a calcium-dependent phospholipid-binding protein, has been reported in various carcinomas. One of its ligands is tenascin-C, an extracellular matrix glycoprotein with predominantly antiadhesive qualities that also has been reported to be a prognostic marker for several carcinomas. In the current study, the authors investigated the correlation between the overexpression of annexin II and tenascin-C in colorectal carcinoma. METHODS: Western blot analysis of annexin II expression was examined in four human colorectal carcinoma cell lines. Using immunohistochemical methods, the authors also examined expression of annexin II and tenascin-C in 105 primary colorectal carcinoma cases. RESULTS: Although annexin II was expressed in human colon carcinoma cell lines, there was no apparent correlation between its expression level and the metastatic potential of these cell lines. The authors observed overexpression of annexin II and tenascin-C proteins in 29.5% and 49.5%, respectively, of colorectal carcinoma cases. Overexpression of annexin II was found to be correlated significantly with histologic type, tumor size, depth of invasion, and pTNM stage, whereas tenascin-C overexpression was noted to be correlated significantly with histologic type, depth of invasion, lymphatic invasion, venous invasion, lymph node metastasis, and pTNM stage. Expression of annexin II was shown to be correlated significantly with that of tenascin-C. Multivariate analysis demonstrated that annexin II and tenascin-C cooverexpression was an independent factor of poor prognosis in patients with colorectal carcinoma. CONCLUSIONS: The data from the current study suggest that both annexin II and tenascin-C are overexpressed in advanced colorectal carcinoma and that they may be related to the progression and metastatic spread of colorectal carcinoma.

Tumor-specific chemo-radio-gene therapy for colorectal cancer cells using adenovirus vector expressing the cytosine deaminase gene.

We studied the effect of suicide gene therapy using an adenovirus vector expressing the cytosine deaminase (CD) gene combined with irradiation therapy (chemo-radio-gene therapy) for human colorectal cancer cells. Since serum CEA levels are elevated in patients with some malignant tumors including colorectal cancer, we applied the CEA promoter to chemo-radio-gene therapy, expecting tumor-specific expression of the CD gene. In in vitro study, we succeeded in selective expression of the target CD gene and growth inhibition in only CEA-producing tumor cells; Further the inhibitory effect was enhanced by combination with radiation therapy in an irradiation dose-dependent manner. In addition, in in vivo study, a significant growth inhibition was observed in chemo-radio-gene therapy in comparison with radiation therapy alone or suicide gene therapy alone. Thus, we suggest that tumor-specific chemo-radio-gene therapy may be a useful strategy for human colorectal cancer.

Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6.

Although tumor necrosis factor receptor-associated factor 6 (TRAF6) is required in receptor activator of NF-kappaB-receptor activator of NF-kappaB ligand (RANK-RANKL) signaling for osteoclastogenesis, it has remained unclear whether TRAF6 is crucial in tumor necrosis factor alpha (TNF-alpha)-induced osteoclastogenesis. We examined TRAF6 function in the TNF-alpha-induced osteoclastogenesis by using osteoclast progenitor cells from TRAF6-deficient mice. The results indicated that TNF-alpha did not effectively induce osteoclast differentiation from osteoclast progenitor cells derived from these mice into mature multinucleated osteoclasts, although c-jun N-terminal kinase (JNK) and TNF-alpha activation was observed in osteoclast progenitor cells. Thus, we have provided the first evidence showing that TRAF6 is involved in TNF-alpha-induced osteoclastogenesis.

Histopathological study of kidney abnormalities in an experimental SIADH rat model and its application to the evaluation of the pharmacologic profile of VP-343, a selective vasopressin V2 receptor antagonist.

The aim of this work was to investigate histopathologically the relationship between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and kidney abnormalities and the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-alqunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide], a selective vasopressin V2 receptor antagonist, in an experimental SIADH rat model. In the model, which was prepared by continuously administering 1-desamino-8-D-arginine vasopressin (DDAVP), histopathologic abnormalities, such as dilatation of tubules, basophilic changes in tubules, inflammatory cell infiltration, and mineralization were found in the kidney, accompanied by significant increases in the relative weight of the kidney, lung, liver, adrenal gland, and heart. VP-343 was shown to be effective in protecting the kidney from the histopathologic abnormalities and to normalize the relative weight of the kidney and several common pathophysiologic features, such as hyponatremia, hyposmolarity of plasma, hyperosmolarity of urea, and oligurea, as described previously. These results demonstrate the occurrence of histopathologic abnormalities in the kidney and the efficacy of VP-343 in improving abnormalities in the DDAVP-induced SIADH rat model.

Transillumination laryngoscopy: a new way of evaluating vocal fold and hypopharyngeal lesions.

Conventional methods of observing the larynx and the hypopharynx use reflected light to illuminate the larynx. The aim of this study was to see whether transilluminating the larynx was possible in subjects with and without disease. The larynx and the hypopharynx were observed by means of a rigid scope with a low-light charge-coupled device camera without the light guide inserted. Illumination was provided by a second rigid scope attached to a light source that was held at the neck by an assistant. The larynx and hypopharynx were observed by transillumination using both constant lighting and stroboscopy in 3 subjects with pharyngeal or laryngeal lesions and in 4 normal controls. The tumors were translucent or nontranslucent in appearance. A translucent polyp became nontranslucent when overlapping the vocal fold, thus indicating that a lesion the size of a polyp could be evaluated with this method. Mucosal waves could be observed during stroboscopy with transillumination, thus allowing observation of waves and lesions that cannot be observed with conventional stroboscopy.

[Cadaveric renal transplantation for Goodpasture's syndrome: a case report].

A 19-year-old man with a history of histologically-proven Goodpasture's syndrome (hemoptysis, rapidly progressive glomerulonephritis, and positive anti-glomerular basement membrane (anti-GBM) antibody) was maintained on hemodialysis for 21 months. After steroid pulse therapy and plasmapheresis, his anti-GBM antibody disappeared. His stable condition on dialysis and a session of plasmapheresis prior to surgery allowed him to undergo cadaveric renal transplantation from a 34-year-old man. The blood type was identical (group A and Rh (+)), and there was 1 and 0 mismatch of HLA class 1 and 2, respectively. The initial immunosuppressants included cyclosporine, methylprednisolone, mizoribine, azathioprine, and anti-lymphocyte globulin (ALG). The transplanted kidney regained function on day 6 and he was free from hemodialysis. Circulating anti-GBM antibody was negative after surgery. The graft has functioned well for almost 4 years after transplantation without any episodes of renal or pulmonary complications. To the best of our knowledge, this is the first report of renal transplantation for Goodpasture's syndrome in the Japanese literature.

Regio-selective detection of dynamic structure of transmembrane alpha-helices as revealed from (13)C NMR spectra of [3-13C]Ala-labeled bacteriorhodopsin in the presence of Mn2+ ion.

13C Nuclear magnetic resonance (NMR) spectra of [3-(13)C]Ala-labeled bacteriorhodopsin (bR) were edited to give rise to regio-selective signals from hydrophobic transmembrane alpha-helices by using NMR relaxation reagent, Mn(2+) ion. As a result of selective suppression of (13)C NMR signals from the surfaces in the presence of Mn(2+) ions, several (13)C NMR signals of Ala residues in the transmembrane alpha-helices were identified on the basis of site-directed mutagenesis without overlaps from (13)C NMR signals of residues located near the bilayer surfaces. The upper bound of the interatomic distances between (13)C nucleus in bR and Mn(2+) ions bound to the hydrophilic surface to cause suppressed peaks by the presence of Mn(2+) ion was estimated as 8.7 A to result in the signal broadening to 100 Hz and consistent with the data based on experimental finding. The Ala C(beta) (13)C NMR peaks corresponding to Ala-51, Ala-53, Ala-81, Ala-84, and Ala-215 located around the extracellular half of the proton channel and Ala-184 located at the kink in the helix F were successfully identified on the basis of (13)C NMR spectra of bR in the presence of Mn(2+) ion and site-directed replacement of Ala by Gly or Val. Utilizing these peaks as probes to observe local structure in the transmembrane alpha-helices, dynamic conformation of the extracellular half of bR at ambient temperature was examined, and the local structures of Ala-215 and 184 were compared with those elucidated at low temperature. Conformational changes in the transmembrane alpha-helices induced in D85N and E204Q and its long-range transmission from the proton release site to the site around the Schiff base in E204Q were also examined.