Concurrent and predictive validity of the Mini Nutritional Assessment Short-Form and the Geriatric Nutritional Risk Index in older stroke rehabilitation patients.

BACKGROUND: Malnutrition may worsen clinical outcomes in stroke patients. Few malnutrition screening tools have been validated in the rehabilitation setting. The present study aimed to assess the concurrent and predictive validity of two malnutrition screening tools. METHODS: We retrospectively collected scores for the Mini Nutritional Assessment Short-Form (MNA-SF) and the Geriatric Nutritional Risk Index (GNRI) in consecutive stroke patients aged ≥65 years in a rehabilitation hospital. Concurrent validity was confirmed against the European Society for Clinical Nutrition and Metabolism diagnostic criteria for malnutrition (ESPEN-DCM). Malnutrition risk within the ESPEN-DCM process was assessed using the Malnutrition Universal Screening Tool. Cut-off values with maximum Youden index, and with sensitivity (Se) >90% and specificity (Sp) >50%, were defined as appropriate for identification and screening of malnutrition, respectively. The Functional Independence Measure and discharge destination were used to explore predictive validity. RESULTS: Overall, 420 patients were analysed. Of these, we included 125 patients in the malnutrition group and 295 in the non-malnutrition group based on the ESPEN-DCM. Cut-off values for the identification and screening of malnutrition were 5 (Se: 0.78; Sp: 0.85) and 7 (Se: 0.96; Sp: 0.57) for the MNA-SF; 92 (Se: 0.74; Sp: 0.84) and 98 (Se: 0.93; Sp: 0.50) for the GNRI, respectively. The GNRI predicted discharge to acute care hospital, whereas the MNA-SF did not predict all outcome measures. CONCLUSIONS: The MNA-SF and the GNRI have a fair concurrent validity in stroke patients, although lower cut-off values than currently used were required for the MNA-SF. The GNRI exhibits good predictive validity for discharge destination.

Introducing HPV vaccine and scaling up screening procedures to prevent deaths from cervical cancer in Japan: a cost-effectiveness analysis.

OBJECTIVE: To assess the cost-effectiveness of universal vaccination of 11-year-old girls against human papillomavirus (HPV) infection and increased screening coverage to prevent cervical cancer in Japan where the coverage of Papanicolaou smears is very low. DESIGN: A cost-utility analysis from a societal perspective. SETTING: Japan, 2010. POPULATION: The female Japanese population aged 11 years or older. METHODS: A Markov model of the natural history of cervical cancer was constructed to compare six strategies: i.e. a screening coverage rate of 20, 50 and 80% with and without routine vaccination at age 11. MAIN OUTCOME MEASURES: Cervical cancer incidence, quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratios. RESULTS: Expanding the coverage of Papanicolaou smears from the current level of 20-50 and 80% yields a 45.5 and 63.1% reduction in cervical cancer incidence, respectively. Impact of combined strategies increases with coverage. Coverages of 20, 50 and 80% showed a 66.1, 80.9 and 86.8% reduction in disease, respectively. The costs of strategies with vaccination are four times higher than the cost of strategies without vaccination. Vaccinating all 11-year-old girls with bivalent vaccines with a Papanicolaou smear coverage rate of 50% is likely to be the most cost-effective option among the six strategies. CONCLUSIONS: The introduction of HPV vaccination in Japan is cost-effective as in other countries. It is more cost-effective to increase the coverage of the Papanicolaou smear along with the universal administration of HPV vaccine.

Multifunctional transcription factor TFII-I is an activator of BRCA1 function.

BACKGROUND: The TFII-I is a multifunctional transcriptional factor known to bind specifically to several DNA sequence elements and to mediate growth factor signalling. A microdeletion at the chromosomal location 7q11.23 encoding TFII-I and the related family of transcription factors may result in the onset of Williams-Beuren syndrome, an autosomal dominant genetic disorder characterised by a unique cognitive profile, diabetes, hypertension, anxiety, and craniofacial defects. Hereditary breast and ovarian cancer susceptibility gene product BRCA1 has been shown to serve as a positive regulator of SIRT1 expression by binding to the promoter region of SIRT1, but cross talk between BRCA1 and TFII-I has not been investigated to date. METHODS: A physical interaction between TFII-I and BRCA1 was explored. To determine pathophysiological function of TFII-I, its role as a transcriptional cofactor for BRCA1 was investigated. RESULTS: We found a physical interaction between the carboxyl terminus of TFII-I and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous TFII-I and BRCA1 form a complex in nuclei of intact cells and formation of irradiation-induced nuclear foci was observed. We also showed that the expression of TFII-I stimulates the transcriptional activation function of BRCT by a transient expression assay. The expression of TFII-I also enhanced the transcriptional activation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed the intrinsic mechanism that TFII-I may modulate the cellular functions of BRCA1, and provide important implications to understand the development of breast cancer.

Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids.

BACKGROUND: The relationship between fibroids and infertility remains an unsolved question, and management of intramural fibroids is controversial. During the implantation phase, uterine peristalsis is dramatically reduced, which is thought to facilitate embryo implantation. Our aims were to evaluate (i) the occurrence and frequency of uterine peristalsis in infertile women with intramural fibroids and (ii) whether the presence of uterine peristalsis decreases the pregnancy rate. METHODS: Ninety-five infertile patients with uterine fibroids were examined using magnetic resonance imaging (MRI). Inclusion criteria were as follows: (i) presence of intramural fibroids, excluding submucosal type; (ii) no other significant infertility factors (excluding endometriosis); and (iii) regular menstrual cycles, and MRI performed at the time of implantation (luteal phase day 5-9). The frequency of junctional zone movement was evaluated using cine-mode-display MRI. After MRI, patients underwent infertility treatment for up to 4 months, and the pregnancy rate was evaluated prospectively. RESULTS: Fifty-one patients fulfilled the inclusion criteria, and 29 (57%) and 22 (43%) patients were assigned to the low (0 or 1 time/3 min) or high frequency (≥ 2 times/3 min) uterine peristalsis group, respectively. Endometriosis incidence was the same in both groups. Ten out of the 29 patients (34%) in the low-frequency group achieved pregnancy, compared with none of the 22 patients (0%) in the high-frequency group (P< 0.005). Comparing pregnant and non-pregnant cases, 4 of 10 patients (40%) and 9 of 41 patients (22%), respectively, had endometriosis (not significant). CONCLUSIONS: A higher frequency of uterine peristalsis during the mid-luteal phase might be one of the causes of infertility associated with intramural-type fibroids.

The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction.

The cell polarity regulator, human Scribble (hScrib), is a potential tumour suppressor whose loss is a frequent event in late-stage cancer development. Little is yet known about the mode of action of hScrib, although recent reports suggest its role in the regulation of cell signalling. In this study we show that hScrib is a direct regulator of extracellular signal-regulated kinase (ERK). In human keratinocytes, loss of hScrib results in elevated phospho-ERK levels and concomitant increased nuclear translocation of phospho-ERK. We also show that hScrib interacts with ERK through two well-conserved kinase interaction motif (KIM) docking sites, both of which are also required for ERK-induced phosphorylation of hScrib on two distinct residues. Although wild-type hScrib can downregulate activation of ERK and oncogenic Ras co-transforming activity, an hScrib mutant that lacks the carboxy terminal KIM docking site has no such effects. These results provide a clear mechanistic explanation of how hScrib can regulate ERK signalling and begin to explain how loss of hScrib during cancer development can contribute to disease progression.

Identification of DBC1 as a transcriptional repressor for BRCA1.

BACKGROUND: DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression. METHODS: A physical interaction between DBC1 and BRCA1 was investigated both in vivo and in vitro. To determine the pathophysiological significance of DBC1, its role as a transcriptional factor was studied. RESULTS: We found a physical interaction between the amino terminus of DBC1 and the carboxyl terminus of BRCA1, also known as the BRCT domain. Endogenous DBC1 and BRCA1 form a complex in the nucleus of intact cells, which is exported to the cytoplasm during ultraviolet-induced apoptosis. We also showed that the expression of DBC1 represses the transcriptional activation function of BRCT by a transient expression assay. The expression of DBC1 also inhibits the transactivation of the SIRT1 promoter mediated by full-length BRCA1. CONCLUSION: These results revealed that DBC1 may modulate the cellular functions of BRCA1 and have important implications in the understanding of carcinogenesis in breast tissue.

Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway.

Endometrial cancer is one of the tumor types in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur. It is known to possess mutations frequently in the Ras-PI3K (phosphatidylinositol 3'-kinase) pathway. We performed a comprehensive genomic survey in 31 endometrial carcinomas with paired DNA for chromosomal imbalances (25 by the 50K and 6 by the 250K single-nucleotide polymorphism (SNP) array), and screened 25 of the 31 samples for MSI status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 9 (29%), 1 to 4 changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in 5 (16%) tumors. Positive MSI was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%), and multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN. In addition to eight (26%) tumors with PTEN deletions, we detected chromosomal imbalances of NF1, K-Ras and PIK3CA in four (13%), four (13%) and six (19%) tumors, respectively. In all, 7 of the 9 CIN-extensive tumors harbor deletions in the loci of PTEN and/or NF1, whereas all the 10 MSI-positive tumors possess PTEN, PIK3CA and/or K-Ras mutations. Our results showed that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability, and suggest that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas.

Dose effects of oral estradiol on bone mineral density in Japanese women with osteoporosis.

OBJECTIVES: This 2-year study compared 0.5 and 1.0 mg oral estradiol (E(2)), with or without levonorgestrel (LNG), for the treatment of postmenopausal osteoporosis in Japanese women. METHODS: Japanese women with osteoporosis after natural menopause or bilateral oophorectomy were randomized to receive E(2) 0.5 or 1.0 mg/day with LNG 40 microg as required, or placebo, for 52 weeks. Women treated with E(2) in the first year continued therapy at the same doses in the second year. Efficacy, safety and pharmacokinetics were assessed. RESULTS: There were 73 women randomized to E(2) 0.5 mg, 157 to E(2) 1.0 mg and 79 to placebo. Lumbar bone mineral density at 52 weeks increased significantly more with E(2) 1.0 mg (p < 0.001) and 0.5 mg (p < 0.001) than with placebo (no change). After 2 years, a 10% increase in bone mineral density with E(2) 1.0 mg was significantly greater than with E(2) 0.5 mg (8%; p = 0.008). E(2) was associated with an acceptable safety and tolerability profile, with slightly more adverse events with E(2) 1.0 than 0.5 mg. Serum E(2) concentration increased in a dose-dependent manner. CONCLUSION: This study showed that E(2), at both 1.0 mg and 0.5 mg doses, was effective in increasing bone mineral density with an acceptable safety and tolerability profile in Japanese postmenopausal women with osteoporosis but that the bone mineral density response was higher with the 1.0 mg dose.

Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision.

BACKGROUND: The aim of this study was to evaluate the impact of post-operative oral contraceptives (OCs) use on the rate of recurrence after laparoscopic excision of ovarian endometrioma. METHODS: In May 2005, we introduced a 'post-operative OC recommendation' for patients treated with laparoscopic excision of endometrioma. That is, at the time of the operation, we provided each patient with information about OC, known and possible benefits and risks and let her decide whether to take OC. A retrospective cohort study included 87 patients who underwent a laparoscopy after May 2005. The endometrioma recurrence rate at 24 months was compared between those who used OC for the entire follow-up period OC (n = 34) and all of the others (n = 53). We also performed logistic regression analysis to identify variables associated with recurrence. A before-after study included another 224 patients who underwent a laparoscopy before May 2005 and compared the recurrence rate before and after introduction of the 'post-operative OC recommendation'. RESULTS: The recurrence rate in those who used OC for the entire period was significantly lower than in the 'others' group (2.9 versus 35.8%, relative risk 0.082, 95% CI 0.012-0.58, P < 0.001). Post-operative OC was determined as an independent variable associated with lower recurrence (OR 0.054, 95% CI 0.007-0.429, P < 0.001). The overall recurrence rate in patients who underwent laparoscopy after the introduction of the 'post-operative OC recommendation' was significantly lower than that in patients who received laparoscopy before the introduction (18.6 versus 33.1%, relative risk 0.56, 95% CI 0.32-0.97, P < 0.05). CONCLUSIONS: Post-operative OC use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. This information will help in appropriate planning of pre- and post-operative management.

The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas.

BACKGROUND: The phosphatidylinositol 3'-kinase (PI3K)-AKT pathway is activated in many human cancers and plays a key role in cell proliferation and survival. A mutation (E17K) in the pleckstrin homology domain of the AKT1 results in constitutive AKT1 activation by means of localisation to the plasma membrane. The AKT1 (E17K) mutation has been reported in some tumour types (breast, colorectal, ovarian and lung cancers), and it is of interest which tumour types other than those possess the E17K mutation. METHODS: We analysed the presence of the AKT1 (E17K) mutation in 89 endometrial cancer tissue specimens and in 12 endometrial cancer cell lines by PCR and direct sequencing. RESULTS: We detected two AKT1 (E17K) mutations in the tissue samples (2 out of 89) and no mutations in the cell lines. These two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. INTERPRETATION: Our results and earlier reports suggest that AKT1 mutations might be mutually exclusive with other PI3K-AKT-activating alterations, although PIK3CA mutations frequently coexist with other alterations (such as HER2, K-Ras and PTEN) in several types of tumours.

Low-dose estradiol for climacteric symptoms in Japanese women: a randomized, controlled trial.

OBJECTIVES: To investigate two different doses of oral estradiol to reduce the number of hot flushes in Japanese women with climacteric symptoms. METHODS: Women (n = 211) aged 40-64 years who had experienced natural menopause or bilateral oophorectomy, with > or = three moderate/severe hot flushes per day in the week before study, were randomized to receive micronized estradiol (E2) 0.5 or 1.0 mg or placebo once daily for 8 weeks. The primary efficacy endpoint was percentage change in mean daily number of hot flushes over 7 days from baseline to final examination. RESULTS: Percentage change in mean daily number of hot flushes at final examination was similar for E2 0.5 mg and E2 1.0 mg (-79.58 +/- 28.29% vs. -82.49 +/- 25.31%, p = 0.555) but was significantly lower with placebo (-57.89 +/- 34.15%, p < 0.001 vs. E2, both doses). There was no significant difference in number of treatment-related adverse events occurring in the E2 0.5 and 1.0 mg groups (25% and 36.6%, respectively). The higher E2 dose showed more pronounced effects on symptom severity. CONCLUSIONS: The dose of 0.5 mg/day was effective as the oral E2 starting dose for treatment of hot flushes in Japanese women.

Parafibromin tumor suppressor enhances cell growth in the cells expressing SV40 large T antigen.

Parafibromin (PF) is a 531-amino acid protein encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal-dominant hyperparathyroidism-jaw tumor familial cancer syndrome and sporadic parathyroid carcinoma. To investigate effects of PF's overexpression on cell proliferation, we performed assays in four different cell lines. The transient overexpression of PF inhibited cell growth in HEK293 and NIH3T3 cells, but enhanced cell growth in the SV40 large T antigen-expressing cell lines such as 293FT and COS7 cells. In 293FT cells, PF was found to interact with SV40 large T antigen and its overexpression promoted entry into the S phase, implying that the interaction enhanced progression through the cell cycle. The tumor suppressor protein PF acts as a positive regulator of cell growth similar to an oncoprotein in the presence of SV40 large T antigen.

Recurrence of ovarian endometrioma after laparoscopic excision.

BACKGROUND: To analyse risk factors that influence the recurrence of endometrioma after laparoscopic excision. METHODS: A total of 224 patients who had a minimum of 2 years of post-operative follow-up after laparoscopic ovarian endometrioma excision were studied retrospectively. Recurrence was defined as the presence of endometrioma more than 2 cm in size, detected by ultrasonography within 2 years of surgery. Fourteen variables (age, presence of infertility, pain, uterine myoma, adenomyosis, previous medical treatment of endometriosis, previous surgery for ovarian endometriosis, single or multiple cysts, the size of the largest cyst at laparoscopy, unilateral or bilateral involvement, co-existence of deep endometriosis, revised American Society for Reproductive Medicine (ASRM) score, post-operative medical treatment and post-operative pregnancy) were evaluated to assess their independent effects on the recurrence using logistic regression analysis. RESULTS: The overall rate of recurrence was 30.4% (68/224). Significant factors that were independently associated with higher recurrence were previous medical treatment of endometriosis [odds ratio (OR) = 2.324, 95% confidence interval (95% CI) = 1.232-4.383, P = 0.0092) and larger diameter of the largest cyst (OR = 1.182, 95% CI = 1.004-1.391, P = 0.0442). Post-operative pregnancy was associated with lower recurrence (OR = 0.292, 95% CI = 0.028-0.317, P = 0.0181). CONCLUSIONS: Previous medical treatment of endometriosis or large cyst size was a significant factor that was associated with higher recurrence of the disease. Post-operative pregnancy is a favourable prognostic factor.

3-D fractal tumor growth of epithelial ovarian cancer.

PURPOSE: A fractal is a shape made of parts similar to the whole. Our objective was to determine whether surface growth patterns in malignant epithelial ovarian tumors are 3-D fractal, and if the mean fractal dimension differs according to histologic types. METHODS: After the images of photographs of 139 resected malignant epithelial ovarian tumors were digitized, the fractal dimensions of surface of solid portions were measured using 3-D fractal analysis software. RESULTS: The mean fractal dimensions of the surface of a solid area of tumor in serous, mucinous, endometrioid, and clear cell adenocarcinoma were 2.320, 2.224, 2.229, and 2.298, respectively. Those of serous and mucinous cystadenoma of low malignant potential (LMP) were 2.398 and 2.282, respectively. These values were significantly greater than the topological dimension of a surface (= 2). The mean fractal dimensions of a solid area of tumor inside the cyst for serous, mucinous, endometrioid, and clear cell carcinoma were 2.347, 2.223, 2.228, and 2.310, respectively. The values for serous and mucinous cystadenoma of LMP were 2.398 and 2.282, respectively. CONCLUSION: This study shows that the surface of a solid area of malignant epithelial ovarian tumors has a 3-D fractal structure, and the mean fractal dimension may differ according to histologic types.

The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha.

The DNA mismatch repair gene is a key regulator in the elimination of base-base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2 (hMSH2), originally identified as a human homologue of the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary non-polyposis colorectal cancer. Hereditary non-polyposis colorectal cancer is characterised by the early onset of colorectal cancer and the development of extracolonic cancers such as endometrial, ovarian, and urological cancers. Oestrogen receptor (ER) alpha and beta are members of a nuclear receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor coactivator family, the thyroid hormone receptor-associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA box-binding protein (TBP)-free TBP associated factor complex (TFTC) type histone acetyltransferase complex. Here, we report the interaction between ER alpha/beta and hMSH2. Immunoprecipitation and glutathione-S-transferase pull-down assay revealed that ER alpha and hMSH2 interacted in a ligand-dependent manner, whereas ER beta and hMSH2 interacted in a ligand-independent manner. Oestrogen receptor alpha/beta bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER alpha, but not that of ER beta. These results suggest that hMSH2 may play an important role as a putative coactivator in ER alpha dependent gene expression.

Secondary cytoreductive surgery for recurrent epithelial ovarian carcinoma: proposal for patients selection.

The value of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer is still controversial. The aim of this study was to clarify candidates for SCS. Between January 1987 and September 2000, we performed SCS in 44 patients with recurrent ovarian cancer, according to our selection criteria, disease-free interval (DFI) >6 months, performance status <3, no apparent multiple diseases, age <75 years and no progressive disease during preoperative chemotherapy, if undertaken. The variables were investigated by univariate and multivariate analyses. Of 44 patients, 26 (59.1%) achieved complete removal of all visible tumours at SCS. Secondary cytoreductive surgery outcome, complete or incomplete resection, was significantly related to overall survival (P=0.0019). As for variables determined before SCS, DFI >12 months, no liver metastasis, solitary tumour and tumour size <6 cm were independently associated with favourable overall survival after recurrence in the multivariate analysis. Patients with three or all four variables (n=31) had significantly better survival compared with the other patients (n=13) (47 vs 20 months in median survival, P<0.0001). In these patients, fairly good median survival (40 months) was obtained even in patients with incomplete resection. Secondary cytoreductive surgery had a large impact on survival of patients with recurrent ovarian cancer when they had three or all of the above-mentioned four factors at recurrence. These patients should be considered as ideal candidates for SCS.

Usefulness of epidural anesthesia in gynecologic laparoscopic surgery for infertility in comparison to general anesthesia.

BACKGROUND: Although the advantages of epidural anesthesia in open surgery have been established, its usefulness in the setting of laparoscopic surgery remains to be studied. METHODS: Patients undergoing laparoscopic surgery for infertility were randomly administered epidural anesthesia (group A, n = 11) or general anesthesia (group B, n = 9). The operation was performed under 4 mmHg pneumoperitoneum and in the 20 degrees Trendelenburg position. Respiratory function tests using a spirometer and blood gas analysis were performed during the intra- or perioperative period. Pain status was evaluated with visual analog scale scoring. The number of postoperative recovery days needed to resume daily activities was obtained by a questionnaire. RESULTS: Respiratory rate, minute volume, P(a)CO2, % vital capacity (VC), and forced expiratory volume in 1 s (FEV1) % were virtually constant throughout the study period in group A, whereas %VC was decreased immediately after operation in group B (p < 0.05). Minute volume immediately after operation was significantly increased in group B compared with group A (p < 0.01), suggesting shallow respiration in women undergoing general anesthesia. Observed pain scores on abdominal pain, shoulder pain, and dyspnea were very low during operation in group A. Pain scores immediately and 3 h after operation were also minimal in group A, whereas abdominal pain scores at these points were significantly higher in group B than those in group A (both p < 0.01). The number of days required for a half reduction in wound pain, trotting, and full recuperation for group A were less than those for group B (p < 0.05). CONCLUSIONS: Epidural anesthesia, when used in laparoscopic surgery for infertility treatment, has advantages over general anesthesia in terms of analgesic effects, postoperative respiratory function, and a return to preoperative daily activities.

A primary cell culture system for human cytotrophoblasts of proximal cytotrophoblast cell columns enabling in vitro acquisition of the extra-villous phenotype.

Cytotrophoblast (CT) differentiation into the extra-villous phenotype is a crucial process in initiating their invasion into the decidua and thereby developing the placenta. However, how CTs differentiate into extra-villous CTs (EVCTs) is not fully elucidated. To address this, a suitable culture model for CTs has been long-sought. But this has been hampered by annoying problems such as; cell aggregation, in vitro syncytialization, low plating efficiency, etc. The aim of this study is to develop a culture system in which CTs differentiate into EVCTs. CTs were isolated from the first trimester placenta using density gradient separation and immuno-depletion using anti-CD9 antibody to remove contaminating fibroblasts and EVCTs. The resultant isolated CTs were found to have the character similar to poorly differentiated CTs comprising proximal cytotrophoblastic cell columns as confirmed by immunocytochemical and flowcytometric analyses. When cultured on type 4 collagen-coated plates in culture media containing low calcium concentration, CTs neither aggregated nor syncytialized, remaining mononuclear and monolayer state. Interestingly, cultured CTs gradually upregulated integrin alpha1, CD9, and human leukocyte antigen (HLA)-G; the known markers specific for EVCTs invading into the decidua diffusely. Hence, the CT culture system provides a sophisticated experimental model in which highly purified CTs acquire the extra-villous phenotype without syncytialization.

Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix.

Recently, a LAP protein, scribble, was identified in Drosophila epithelia as a basolateral protein that controls the apical-basolateral polarity. Loss of scribble causes disorganisation and overgrowth of the epithelia. Scribble has a human homologue, human scribble (hScrib), which is a substrate of ubiquitin-mediated degradation by human papillomavirus E6 and the E6AP ubiquitin-protein ligase. In the present study, we revealed that hScrib localised to the basolateral regions of the epithelial cell line MDCK and human uterine cervical epithelial tissues by immunofluorescence. Human scribble colocalised rather with the adherens junction protein E-cadherin, but not with the tight junction protein ZO-1. Histochemical analysis showed a dramatic decrease in the expression of hScrib with the progression of disease from normal uterine cervical tissues to invasive cervical cancers through the precursor lesions. In contrast, the expression of hScrib was retained in the throughout epithelial layer of the HPV-negative cervical high-grade squamous intraepithelial lesions (H-SIL). Although quantitative RT-PCR revealed no significant downregulation of hScrib mRNA expression in the H-SIL, it revealed a clear downregulation in the invasive cancers. These results suggest the possibility that degradation by HPV E6 is one of the causal roles for the progressive decrease of hScrib expression during the disease progression from low-grade squamous intraepithelial lesions to H-SIL, and a cooperative role of downregulation of hScrib mRNA expression and ubiquitin-mediated degradation of hScrib by E6 and E6AP led to the complete decrease of hScrib expression during the process of carcinogenesis from H-SIL to invasive cancer. These data underscore the importance of hScrib in the construction of tissue architecture and prevention of cancer development.

Sonographic assessment of the cervix before, during and after a uterine contraction is effective in predicting the course of labor.

OBJECTIVE: To investigate whether the degree of change in cervical length during a uterine contraction is predictive of subsequent progression of labor. METHODS: The subjects were 73 uncomplicated parturient women at term. We observed the cervix before, during and after a uterine contraction by transvaginal ultrasound in the first stage of labor and determined the degree of cervical shortening during the contraction relative to the cervical length before contraction. We related the degree of cervical shortening to labor patterns at the time of the ultrasound examination, which were retrospectively determined by reviewing the partogram. RESULTS: The cervix was shortened in length by about 50% on average during a uterine contraction in the normal course of labor. The degree of cervical shortening was significantly greater in the normal latent and active phases than it was in the prolonged latent phase, protracted active phase and false labor, whereas there were no differences between the former two phases nor between the latter three phases. Nulliparous and parous women exhibited almost the same degree of shortening in the normal latent and active phases. CONCLUSIONS: Real-time ultrasound observation of the cervix during uterine contraction could help differentiate inefficient uterine contractions from normal ones and thus predict the subsequent course of labor.