Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Analysis of protein profiles in human epithelial ovarian cancer tissues by proteomic technology.

BACKGROUND: Screening in ovarian cancer is progressively finding out candidate genes and proteins which may work as screening biomarkers and play a role in tumor progression. We examined the protein expression patterns of ovarian cancer tissues using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of fight mass spectrometry (MALDI-TOF MS). METHODS: Tissues from 36 ovarian cancers and 20 normal ovaries were examined by 2-DE. The images of silver stained gels were analyzed by ImageMaster 2D Elite. The peptide mixtures, after in-gel digestion, were determined by MALDI-TOF MS for fingerprinting. The de-isotope tryptic peptide profiles were matched by using the Mascot search engine based on the entire NCBI and Swiss-Prot protein databases. Western/dot blots were then applied to verify the findings. RESULTS: In ovarian cancer, 12 proteins that showed differential expressions were identified unequivocally. Among these proteins, five proteins (galectin-1, cathepsin B, ubiquitin carboxy-terminal hydrolase L1, HLA class II antigen DRB1-11 and heat shock protein 27) were up-regulated and seven proteins (cellular retinol-binding protein, transthyretin, SH3 binding glutamic-rich-like protein, tubulin-specific chaperone A, DJ-1, gamma-actin and tropomyosin 4) were down-regulated. CONCLUSION: The present study is the first to report the up-regulation of ubiquitin carboxy-terminal hydrolase L1 and the down-regulation of SH3 binding glutamic-rich-like protein, tubulin-specific chaperone A, and tropomyosin 4 in human ovarian cancer tissues. Further cloning and functional analysis of these salient proteins will provide more information on their pathophysiologic roles in ovarian cancer.

Antiproliferative effects of 2-methoxyestradiol alone and in combination with chemotherapeutic agents on human endometrial cancer cells.

OBJECTIVE: 2-methoxyestradiol (2-ME), an endogenous estradiol metabolite, has potent antiproliferative effects on cancer cells. However, its usefulness for treating endometrial cancer has not yet been fully explored. We investigated for the first time whether in vitro combinations of 2-ME with various chemotherapeutic agents might result in a synergistic inhibitory effect on the proliferation of human endometrial cancer cells. METHODS: As a model, two different human endometrial cancer cell lines, HEC-1-A and RL95-2, were used. These cells were treated with 2-ME alone or in combination with paclitaxel, cisplatin, or doxorubicin. Measurements to detect an antiproliferative effect were performed after 24, 48, and 72 hours using the MTT assays. RESULTS: In both endometrial cancer cell lines a significant synergistic effect of 2-ME with paclitaxel was observed. The combination of 2-ME and cisplatin was not synergistic and provided only additive effects. The antiproliferative effect of 2-ME was somewhat antagonized by doxorubicin. CONCLUSIONS: Our study shows that 2-ME has a direct antiproliferative effect on endometrial cancer cells. Our results also show a potential anticancer synergy between 2-ME and paclitaxel in vitro. On the other hand, no remarkable synergistic actions were observed between 2-ME and doxorubicin, suggesting that 2-ME may selectively enhance the anticancer actions of certain chemotherapeutic agents in human endometrial cancer. Therefore, combination therapy should be investigated further as an additional therapeutic option for advanced or recurrent endometrial cancer.

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

Expression of inhibitory natural killer receptors on tumor-infiltrating CD8+ T lymphocyte lineage in human endometrial carcinoma.

To investigate the expression of natural killer receptors (NKRs) within the human tumor milieu, we directly examined the in vivo expressions of various NKRs on tumor-infiltrating lymphocytes (TILs) derived from human endometrial carcinoma (EC). In total, 22 patients with stage IA-IIIA EC were enrolled. TILs were isolated from tissue specimens by means of a mechanical dispersal technique. The subpopulations of immunocytes were quantified, and expressions of NKRs on CD8+ T cells were analyzed by triple-color flow cytometry. CD8+ T cells express higher ratios of CD94 and NKG2A in TILs than in peripheral blood mononuclear cells (PBMCs) in human EC. Flow cytometry reveals that 15.90% of CD3+CD8+ TILs compared with 2.10% of CD3+CD8+ PBMCs express the NKG2A molecules (P < 0.001). The percentage expressions of CD94 are 8.40% in CD3+CD8+ TILs and 3.80% in CD3+CD8+ PBMCs (P= 0.013). The numbers of CD8+ T cells expressing CD158b and NKB1 are higher in CD3+CD8+ PBMCs in EC than in normal (CD158b: 10.70% vs 2.60%, P < 0.001; NKB1: 2.20% vs 0.40%, P= 0.018, respectively). Increased expression of CD94/NKG2A restricted to tumor-infiltrating CD8+ T cell subsets may shape the cytotoxic responses, which indicate a possible role of tumor escape from host immunity in human EC.

Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer.

Cyclin D1 and c-Myc are key participants in the cell-cycle pathway, in which aberrancies have been associated with malignant transformation. To date, data on the relationship of expression of these proteins and histologic subtype of epithelial ovarian cancer are still scarce and discordant. Immunohistochemical analysis was performed on 12 normal ovaries and 47 cases of serous, mucinous, endometrioid, and clear cell ovarian carcinomas. No abnormal expression of cyclin D1 or c-Myc was demonstrated in any of the 12 normal ovarian specimens. However, compared to normal ovarian tissues, overexpression of cyclin D1 and c-Myc was observed in 42.6% (20/47) and 65.9% (31/47) of tumors examined, respectively. There was no significant difference of overexpression of cyclin D1 or c-Myc gene products between these four histologic subtypes of ovarian adenocarcinomas. This study shows that cyclin D1 and c-Myc are frequently overexpressed in epithelial ovarian carcinomas, but they are not correlated with a particular histologic subtype. Although our preliminary results need to be validated in a larger number of tumors, the abnormal expression of cyclin D1 and c-Myc in epithelial ovarian cancer reaffirms the notion that they are crucial components in the pathway of tumorigenesis and deserve further study.

Carcinosarcoma-like mural nodule in intestinal-type mucinous ovarian of borderline malignancy: a case report.

Epithelial ovarian tumors of borderline malignancy are tumors with histologic features and biologic behavior between benign and frankly malignant epithelial ovarian neoplasms. To date, we cannot accurately predict the patients who are prone to an aggressive course of disease. Here, we present a 35-year-old patient with carcinosarcoma-like mural nodule in intestinal-type mucinous ovarian tumor of borderline malignancy. Foci of intraepithelial carcinoma (about 10%) without stromal invasion are also noted. Total hysterectomy, bilateral salpingo-oophorectomy, appendectomy, and omentectomy were performed, and the frozen pathology during operation showed mucinous tumor of borderline malignancy of left ovary on April 18, 2002. The patient was followed at our outpatient department for 19 months after operation and was free of the disease without any adjuvant chemotherapy. It is difficult to determine whether intestinal-type borderline mucinous tumors with intraepithelial carcinoma are associated with a worse prognosis compared with those with epithelial atypia alone due to disparate results in the published literature. In contrast, most patients with mural nodules of anaplastic carcinoma have had a malignant, often rapid, course. However, too few cases of carcinosarcoma-like mural nodule in mucinous tumor have been published to warrant a conclusion regarding their prognosis.

Early-stage ovarian carcinoma combined with pulmonary tuberculosis mimicking advanced ovarian cancer: a case report.

In patients of ovarian cancer combined with multiple pulmonary nodules, the diagnosis of metastatic ovarian cancer is always considered. However, benign pulmonary conditions can be discovered instead. An 80-year-old female presented with a rapidly growing ovarian mass, elevated serum CA-125, and multiple pulmonary varying-sized nodular lesions. The pretreatment workup of her lung lesions failed to show a malignant cell, and it also failed to show any evidence of tuberculosis or other infectious diseases. After surgery, her disease was allotted to 'stage IV' epithelial ovarian cancer and adjuvant cytotoxic chemotherapy was then used. However, her sputum culture showed positive growth of Mycobacterium tuberculosis 4 weeks later. For fear of reactivation of pulmonary tuberculosis, the anticancer cytotoxic chemotherapy was postponed and the antituberculous treatment was given instead. After 6-month course of antituberculous therapy, no active lung lesion was detectable. In conclusion, infectious or inflammatory conditions can mimic metastatic disease and therefore add to the difficulty of stage determination. We recommend that there must be positive cytologic or pathologic results of lung lesions to allot a case of ovarian cancer to stage IV. Furthermore, whenever pulmonary lesions are seen on imaging, the possibility of diagnoses other than metastatic ovarian cancer should always be considered.

Depressed host immunity in a case of metachronous primary uterine papillary serous carcinoma and non-Hodgkin's lymphoma.

Metachronous primary malignant tumors of uterine papillary serous carcinoma (UPSC) and non-Hodgkin's lymphoma (NHL) are rare. UPSC is a clinically aggressive and morphologically distinctive variant of endometrial carcinoma. We describe the clinical features of a 63-year-old patient with UPSC that was found 2 years after chemotherapy for malignant lymphoma of neck, stage IV and 5 months after radiation therapy for recurrence. This patient had undergone staging surgery and postoperative radiation for UPSC. One month after completion of radiotherapy, the patient expired due to persistence of the disease. The association between host immunity and UPSC is rarely described in the literature. Immunological profiles of this patient, with compositional changes of natural killer, B, and T cell, dramatically altered the percentage of CD4(+) T cell, CD8(+) T cell, and CD4/CD8 ratio, signifying depressed host immunity. Immunological profile of this patient stressed the issue of depressed host immunity and associated malignancies.

Detection of gonadotropin-releasing hormone receptor and its mRNA in primary human epithelial ovarian cancers.

The hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) serves a key role in regulating mammalian reproductive function. An extrapituitary role for GnRH in the normal and malignant reproductive tissues has been postulated. The purpose of our study is to demonstrate the presence and levels of GnRH receptor (RGnRH) protein and its mRNA in normal and malignant tissues of ovary. Normal human ovarian tissues (n = 13), as well as epithelial ovarian cancer specimens from stages I-IV (n = 39), were obtained from appropriate patients at operation room. Monoclonal antibodies against RGnRH were used for immunohistochemical evaluation of paraffin-embedded ovarian tissue sections by methods of streptavidin-biotin immunostaining. The molecular size and levels of RGnRH were determined by enhanced chemiluminescence-Western blot assay. The amount of RGnRH mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The rate of positive immunostaining in ovarian cancers was 53.8% (21/39). The rate of positive staining in the late stage (stages III and IV) was significantly higher than that in the early stage (stages I and II). A single band of molecular weight of about 60 kDa was detected from protein extracts of ovarian cancer as well as from normal ovary. The mean values of fold increase of signal intensities of 60 kDa detected by Western blots in stages I-IV ovarian cancers were 2.39, 2.42, 2.78, and 3.62, respectively, as compared with normal ovarian tissues. The overall positive rate of Western blot analysis for ovarian cancers was 59% (23/39). The mean values of signal intensity of RT-PCR products of RGnRH mRNA in stages I-IV were 2.24, 2.58, 3.10, and 3.20, respectively. The positive rate of overexpression of RGnRH mRNA in ovarian cancer was 70% (21/30). The differences of mean values of signal intensities of Western blot staining (2.41 versus 2.85) as well as RT-PCR products (2.40 versus 3.11) between the early stage and the late stage of ovarian cancers were statistically nonsignificant. Mechanism of autocrine regulation of tumor growth in human epithelial ovarian cancer can be explained by the coexistence of GnRH, RGnRH, and its mRNA, according to our own and other studies. The level of RGnRH expressed by ovarian cancer might be used for targeting chemotherapeutic agents to those patients who harbor RGnRH-positive tumors.

A case of neonatal stridor.

A case is reported of a retropharyngeal abscess in a neonate who presented with increasing stridor since birth. Group B streptococcus was cultured from the abscess contents and the maternal birth tract.

Cell cycle analysis and detection of proliferative cell nuclear antigen of the endometrium after hormone replacement therapy.

BACKGROUND: To understand the effect of sequential combined hormone replacement therapy (HRT) on the postmenopausal endometrium. METHODS: Sonographic endometrial thickness, endometrial histopathology, flow cytometric cell cycle analysis and the level of proliferative cell nuclear antigen (PCNA) were studied. RESULTS: One hundred and thirty-eight postmenopausal women were enrolled in this study. Among which, 97 women had their endometrium being adequately obtained; the most frequent type of histopathology was normal endometrium (91.8%). Endometrial hyperplasia was found in seven patients (7.2%), including typical simple hyperplasia (n=1, 1%), focal simple hyperplasia (n=5, 5.2%) and complex hyperplasia without atypia (n=1, 1%). The proliferative fractions (PF; S plus G2-M phase) of cells from normal and hyperplastic endometrium of menopausal women after HRT were 8.18 and 8.95%, respectively, which were lower than those from 29 premenopausal women without HRT. The level of PCNA of normal and hyperplastic endometrium in postmenopausal women after HRT was about 80 and 84%, respectively, of that from premenopausal endometrium. CONCLUSIONS: Our study showed the PF of the cell cycle and the level of PCNA were not increased in the menopausal endometrium under HRT as compared to the premenopausal controls.

Additive effect of alfacalcidol on bone mineral density of the lumbar spine in Taiwanese postmenopausal women treated with hormone replacement therapy and calcium supplementation: a randomized 2-year study.

OBJECTIVE: To evaluate the effect of 1alpha-hydroxyvitamin D3 on bone mineral density of the lumbar spine in postmenopausal women receiving hormone replacement therapy and calcium supplement. DESIGN: A randomized, prospective 2-year clinical trial. PATIENTS AND MEASUREMENTS: A total of 240 postmenopausal women were enrolled with randomized assignment of 120 patients to each treatment group (the D + E group of 1alpha-hydroxyvitamin D3 + sequential combined HRT + calcium supplement; the E group: sequential combined HRT + calcium supplement). None of the patients had received HRT for menopausal syndrome or osteoporosis before being enrolled in our study. Serum biochemical assays, electrolytes and calcitonin were performed at baseline and after 6 and 12 months of treatment. Bone mineral density (BMD) of L2-L4 was measured by dual energy X-ray absorptiometry (DXA) at the initial assessment and after 12 and 24 months of treatment. RESULTS: One hundred and five patients (87.5%) in the D + E group and 92 patients (76.7%) in the E group completed the first 1-year study. Ninety-six patients (80%) in the D + E group and 80 patients (66.7%) in the E group completed the 2-year trial. Renal function, liver function, electrolytes and calcitonin showed no significant changes during the first year of follow-up. In the D + E group, the BMD of L2-4 increased 3.24 +/- 0.32% from baseline after 1 year (P < 0.05) and 5.32 +/- 0.23% after 2 years of treatment (P < 0.05). On the other hand, the changes of BMD in the E group were 1.12 +/- 0.34% after 1 year (P < 0.05) and 2.42 +/- 0.26% after 2 years of treatment (P < 0.05). The changes of BMD of L2-L4 of the D + E group were higher than the changes of the E group after both 1 and 2 years of treatment (P < 0.05). CONCLUSIONS: Our study demonstrated that combination of 1alpha-hydroxyvitamin D3 with HRT is superior to HRT alone for the preservation of bone mineral density in postmenopausal women under calcium supplementation.

Decreased maternal serum placenta growth factor in early second trimester and preeclampsia.

OBJECTIVE: To compare early second-trimester maternal serum placenta growth factor concentrations in patients with subsequent development of preeclampsia and those with normal pregnancies. METHODS: We conducted a case-control analysis of stored maternal serum of 27 women who subsequently developed preeclampsia and 227 randomly selected normal controls during the gestational period of 14-19 weeks. Using such a sample size, there was a greater than 95% power to test a difference in the primary study interest. A quantitative sandwich enzyme immunoassay was used to measure the maternal serum placenta growth factor concentration. For statistical analysis, Mann-Whitney U tests, multiple linear regression analysis, multivariable logistic regression model, and receiver-operating characteristic (ROC) curve were used. P <.05 was considered statistically significant. RESULTS: Maternal serum placenta growth factor concentration was associated with the occurrence of subsequent preeclampsia (P <.001) and gestational age (P <.001). The median (interquartile range) of multiples (MoM) of the gestational age stratified median for placenta growth factor in preeclampsia was 0.55 (0.33, 0.85). The ROC curve revealed that the specificity was 70% when the diagnostic sensitivity was 70%, and the optimal cutoff value of placenta growth factor MoM was 0.76. The risk of developing preeclampsia subsequently was increased 2.5-fold for maternal serum placenta growth factor concentration decrements of 0.1 MoM. CONCLUSION: A decreased maternal serum placenta growth factor concentration in the early second trimester is highly associated with the subsequent development of preeclampsia, but a large prospective study is needed to explore its use as an early predictor for the condition.

Tuboovarian abscess mimicking malignancy: report of two cases.

Tuboovarian abscess is a well-known sequela of acute or chronic salpingitis. In a small percentage of patients, these inflammatory masses compress or even rupture into the adjacent viscera, thus simulating the condition of pelvic malignancy, particularly when the clinical presentations are indolent. We describe two cases of tuboovarian abscess mimicking malignancy. Case 1: A 39-year-old woman with an intrauterine device had a clinical presentation mimicking an exophytic submucosal colorectal tumor with suspicious mucosal invasion. She complained of tenesmus but did not experience fever or adnexal tenderness. A right tuboovarian abscess with fistula formation into the rectosigmoid colon was noted during laparotomy. Case 2: A 46-year-old woman with an intrauterine device had a preoperative diagnosis of uterine myoma with degeneration. At laparotomy, an omentum cake with dense pelvic adhesions was noted. Malignancy appeared to be present, and debulking surgery was performed. The final pathologic examination revealed bilateral chronic tuboovarian abscesses and focal omental abscess.

Immunoidentification of gonadotropin releasing hormone receptor in human sperm, pituitary and cancer cells.

PROBLEM: To generate monoclonal antibodies specific to the receptor of gonadotropin releasing hormone (GnRH) for immunoidentification of the GnRH receptor (RGnRH) in human sperm, pituitary and cancer cells. METHODS: Four oligopeptides corresponding to RGnRH amino acid residues 1-29, 182-193, 195-206 and 293-306 in the extracellular domains were synthesized, conjugated to hemocyanin from Keyhole Limpet and used as immunogens to generate specific monoclonal antibodies. Enzyme-linked immunosorbent assay was used for initial screening of hybridomas. RESULTS: A total of 15 hybrid cell lines secreting RGnRH-specific monoclonal antibodies were initially established. By using some of these monoclonal antibodies as immunohistochemical probes, RGnRH was localized in the acrosomal region of human sperm, in the anterior pituitary tissue and in cancer cells of human ovarian and cervical origins. RGnRH was shown to have a molecular size of 45,000 +/- 5,000 kDa by Western blot assay. Expression of RGnRH mRNA in several human tissues and cancer cells was established by the reverse transcriptase-polymerase chain reaction method. CONCLUSION: RGnRH-specific monoclonal antibodies may be a valuable tool of identifying the presence of RGnRH in various normal and malignant human tissues.

Humic acid suppresses the LPS-induced expression of cell-surface adhesion proteins through the inhibition of NF-kappaB activation.

Humic acid (HA), a potential toxin when penetrating the drinking well water of blackfoot disease-endemic areas in Taiwan, has been implicated as one of the etiological factors of this disease. In this study, we investigated the effects of HA on the expression of human vascular endothelial-leukocyte adhesion molecules and the activation of nuclear factor kappa B (NF-kappaB) in cultured human umbilical vein endothelial cells (HUVECs). The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin was monitored by flow cytometry. Pretreatment of HUVECs with HA inhibited the lipopolysaccharide (LPS)-induced expression of these three adhesion molecules in a dose- and time-dependent manner. Since NF-kappaB can regulate the expression of these adhesion molecules, NF-kappaB activation was assessed by electrophoretic mobility shift assay (EMSA). Our results reveal that the activation of NF-kappaB by LPS is suppressed by HA in a dose- and time-dependent manner. Furthermore, HA reduces NF-kappaB binding to DNA slightly, but completely inhibits the degradation of IkappaBalpha at a concentration of 100 microg/ml. Thus, all our data demonstrate that HA can inhibit the LPS-induced expression of adhesion molecules through the inhibition of NF-kappaB activation. HA may also suppress the immune or inflammatory reaction of HUVECs responsible for endotoxin, which could be one possible explanation for the causes of the infection and inflammation observed for patients with blackfoot disease. Our results also suggest that immune or inflammatory disturbance occurs for patients with blackfoot disease and that NF-kappaB may be a critical molecule in the pathogenesis of this disease.

Serum leptin and leptin receptor isoforms in omental adipose tissue of nondiabetic women undergoing gynecologic surgery for benign disease.

BACKGROUND AND PURPOSE: Leptin is important in the regulation of fat mass and body weight. Adipose tissue not only secretes leptin but also serves as a site of action for leptin. This study was designed to examine the relationships among tissue expression of leptin receptors, serum leptin, and body mass index. METHODS: Omental adipose tissue and fasting blood samples were obtained from 57 nondiabetic women who underwent surgery for either myoma of the uterus or ovarian cyst. Tissue RNA was extracted using Trizol reagent and serum leptin concentrations were determined with commercial kits. The leptin receptor isoforms in tissues were quantified using real-time Taqman technology. RESULTS: Three leptin receptor isoforms, Ob-Rb, HuB219.1, and HuB219.3, were found in human omental adipose tissue. The amounts of HuB219.1 and HuB219.3 mRNA relative to that of Ob-Rb were 1314.2 and 16.7, respectively. Higher body mass index was significantly correlated with an increase in serum leptin concentration and a decrease in leptin receptor HuB219.1 isoform in omental fat, even after adjustment for age and menopausal status. There was no direct association between serum leptin concentration and tissue HuB219.1 mRNA level. CONCLUSIONS: HuB219.1 is the major isoform of leptin receptor expressed in human omental adipose tissue. Our findings suggest that the shorter leptin receptor isoforms in human omental adipose tissue might play an important role in body weight control. Further studies on the inter-relationship between leptin concentrations and multiple leptin receptor isoforms are needed to elucidate the exact mechanism of obesity.

Effects of menopause and obesity on lipid profiles in middle-aged Taiwanese women: the Chin-Shan Community Cardiovascular Cohort Study.

In this cross-sectional study, we examined the associations between lipid profiles and menopausal status, age, and obesity in Taiwanese women. The study population, established in 1990-91, consisted of 671 premenopausal and 872 postmenopausal women from the Chin-Shan Community Cardiovascular Cohort (CCCC). The associations of age, body mass index (BMI), and menopausal status with serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apoproteins (Apo) A-1 and B, and lipoprotein (a) [Lp (a)] were evaluated. The results showed that menopause was associated with significant increases in TC, LDL-C, TG, and Apo B levels (all P < 0.001). Total cholesterol, LDL-C, TG, and Apo B levels increased consistently with BMI in middle-aged women, regardless of menopausal status. Among women aged 45-49, menopausal women had significantly higher levels of TC and LDL-C than premenopausal women (P < 0.01). However, TG and Apo B levels were higher in postmenopausal than in premenopausal women aged 50-54 years (P < 0.05). Standardized regression analyses showed all lipid variables, except those of Apo A1 and Lp (a) before menopause and TC, LDL-C, and Lp (a) after menopause, were significantly associated with BMI (all P < 0.01). We conclude serum lipid levels in Taiwanese women are no more strongly associated with menopause and BMI than with age.