Addition of dexamethasone to manage acute phase responses following initial zoledronic acid infusion.

Acute phase response (APR), including myalgia, influenza-like symptoms, headache, arthralgia, and pyrexia, is the most common adverse reaction to initial zoledronic acid infusion. Dexamethasone plus acetaminophen is effective in significantly reducing the incidence and severity of APR. INTRODUCTION: Acute phase response (APR), including myalgia, influenza-like symptoms, headache, arthralgia, and pyrexia, is due to immunomodulatory actions and is the most common adverse reaction to zoledronic acid (ZOL). The aims of our study were to compare the differences between acetaminophen and dexamethasone plus acetaminophen on the incidence and severity of APRs and to clarify the clinical factors related to APR with initial ZOL infusion. METHODS: Patients with osteoporosis receiving their first ZOL infusion (N = 96) were assigned into two groups and given either acetaminophen (58 patients, control group) or acetaminophen plus dexamethasone (38 patients, study group). APRs were assessed through telephone interviews 2 weeks later post-infusion. Clinical, demographic, and serologic data were recorded. RESULTS: There was a significant increase in the incidence and severity of any APR in the control group than the study group (67% vs. 34%, p = 0.003; 0.69 ± 0.50 vs. 0.34 ± 0.48, p = 0.001). Among the APRs, only myalgia incidence and score were significantly higher in the control group than in the study group. Multivariate analysis demonstrated that previous use of osteoporosis medication and participation in the study group was negatively related to the occurrence of any APR or myalgia. Advanced age was shown to significantly increase myalgia. Study group participants had significantly reduced severity of myalgia. The adherence for redosing ZOL was significantly higher in the study group. CONCLUSION: Dexamethasone plus acetaminophen is effective in significantly reducing the incidence and severity of APR, especially myalgia, and increasing adherence following initial ZOL infusion.

Fracture liaison services for osteoporosis in the Asia-Pacific region: current unmet needs and systematic literature review.

The analysis aimed to identify the treatment gaps in current fracture liaison services (FLS) and to provide recommendations for best practice establishment of future FLS across the Asia-Pacific region. The findings emphasize the unmet need for the implementation of new programs and provide recommendations for the refinement of existing ones. The study's objectives were to evaluate fracture liaison service (FLS) programs in the Asia-Pacific region and provide recommendations for establishment of future FLS programs. A systematic literature review (SLR) of Medline, PubMed, EMBASE, and Cochrane Library (2000-2017 inclusive) was performed using the following keywords: osteoporosis, fractures, liaison, and service. Inclusion criteria included the following: patients ≥ 50 years with osteoporosis-related fractures; randomized controlled trials or observational studies with control groups (prospective or retrospective), pre-post, cross-sectional and economic evaluation studies. Success of direct or indirect interventions was assessed based on patients' understanding of risk, bone mineral density assessment, calcium intake, osteoporosis treatment, re-fracture rates, adherence, and mortality, in addition to cost-effectiveness. Overall, 5663 unique citations were identified and the SLR identified 159 publications, reporting 37 studies in Asia-Pacific. These studies revealed the unmet need for public health education, adequate funding, and staff resourcing, along with greater cooperation between departments and physicians. These actions can help to overcome therapeutic inertia with sufficient follow-up to ensure adherence to recommendations and compliance with treatment. The findings also emphasize the importance of primary care physicians continuing to prescribe treatment and ensure service remains convenient. These findings highlight the limited evidence supporting FLS across the Asia-Pacific region, emphasizing the unmet need for new programs and/or refinement of existing ones to improve outcomes. With the continued increase in burden of fractures in Asia-Pacific, establishment of new FLS and assessment of existing services are warranted to determine the impact of FLS for healthcare professionals, patients, family/caregivers, and society.

Are bilateral decubitus views necessary in assessing for vertebral compression fractures using DXA vertebral fracture assessment?

The purpose of this study is to assess the differences in VFA diagnostic accuracy when using bilateral decubitus views and whether diagnostic accuracy is affected by scoliosis. Our findings show that the current practice of performing only one side is valid; however, bilateral views can improve specificity in scoliosis. INTRODUCTION: The diagnostic accuracy of vertebral fracture assessment (VFA) can be influenced by poor patient position and scoliosis. This study aims to assess the differences in VFA diagnostic accuracy for right and left lateral decubitus views and the effect of scoliosis. METHODS: One hundred fourteen postmenopausal women received right and left lateral thoracolumbar spine dual-energy VFA and radiography. Cobb angles were measured from the posteroanterior absorptiometry image, and lumbar spine radiography was the standard reference for vertebral fracture and also provides the levels investigated. McNemar's test was used to compare accuracy between the two decubitus position and Fisher's exact test was used for patients with and without scoliosis. RESULTS: Forty-two vertebral fractures (VFs) were identified. There was no significant difference in sensitivity (p = 0.125) or specificity (p = 0.866) between the left lateral decubitus (64.3, 97.2%) and right lateral decubitus (76.2, 91.1%), respectively, views. Scoliotic patients had a significantly worse specificity (92.7 vs 98.1%, p = 0.003) than patients without scoliosis; however, a combination of both decubitus positions significantly improved specificity (p < 0.001). CONCLUSION: Right and left side lateral decubitus views have excellent agreement with radiography and similar diagnostic accuracy in the detection of VFs. Thus, the current practice of performing only one side is valid. With scoliosis, bilateral decubitus views can improve the specificity of detecting VF; however, this would increase radiation dose.

Secular trends in incidence and recurrence rates of hip fracture: a nationwide population-based study.

We assessed the incidence of hip fracture and second hip fractures in Taiwan from 2001 to 2012. Age-standardized incidence rates decreased after 2005. However, mortality rate after first hip fracture was substantial compared to second hip fracture rate in a competing risk model. INTRODUCTION: The aim of the study is to assess the incidence rates (IRs) of hip fractures, including changes in trends and medical costs, and second hip fractures in the Taiwanese population. METHODS: The number of hip fractures and the associated medical costs were obtained from the annual report of the Ministry of Health and Welfare, Taiwan, for individuals ≥50 years of age. The data of population at risk were retrieved from annual population reports from the Ministry of the Interior, Taiwan. The incidence of second hip fractures was evaluated from the National Health Insurance Research Database of Taiwan for insured individuals aged ≥50 years from 2001 to 2011 with follow-up until 2013 using a competing risk model. RESULTS: The IR for the entire population increased from 332.7 to 336.5 per 100,000 person-years during 2001-2005 and decreased thereafter. This secular change was driven by a decrease in hip fractures for both men and women. The 10-year cumulative incidence rate of second hip fracture was 11.2% (95% CI 11.0-11.5%) in women and 7.9% (95% CI 7.6-8.1%) in men. Adjusted by consumer price index (CPI), the costs of hospitalization due to hip fracture increased from NTD 1.17 billion in 2001 to NTD 1.43 billion in 2012. However, the CPI-adjusted costs of each admission decreased from NTD 74944 in 2001 to NTD 65791 in 2012. CONCLUSIONS: Since 2006, the IR of hip fractures has been declining in Taiwan. The 10-year cumulative IR of mortality is substantial for individuals who with first hip fracture.

Impact of lower concentrations of phytoestrogens on the effects of estradiol in breast cancer cells.

OBJECTIVE: To explore the impact of lower concentrations of phytoestrogens on 17ß-estradiol (E2) in the growth of MCF-7 breast cells. METHODS: MCF-7 cells were treated with E2 (10(-8) mol/l), one of three phytoestrogens (genistein, resveratrol, and quercetin) (10(-7)  to 10(-5) mol/l), and with a combination of both E2 and one of these phytoestrogens for 48 h. These cells were then extracted for MTT and TUNEL assay. Western blot was utilized to evaluate the proteins involved in the proliferative and apoptotic pathways, as well as the differential effects on ERα and ß. RESULTS: MCF-7 cell proliferations were induced by both E2 alone and E2 plus one of the three phytoestrogens (at concentrations ≥ 10(-6) mol/l). Apoptotic cells were significantly increased in the phytoestrogen-treated MCF-7 cells and, conversely, suppressed in the cells treated with both E2 and phytoestrogens. Proliferating cell nuclear antigen, PI3K and p-Akt were increased in the cultures with E2 and substantially more in the cultures with E2 plus a phytoestrogen. The combination of E2 and phytoestrogen significantly inhibited the increase in FADD, cytochrome C, truncated Bid, caspase-9, caspase-3 and ERß that was induced by phytoestrogens in the MCF-7. ERα expression was significantly induced by E2 regardless of the presence of these phytoestrogens. CONCLUSIONS: This study demonstrates that, in the presence of E2, genistein, resveratrol, and quercetin may stimulate breast cancer cells, even at low physiological concentrations. Therefore, the conflicting results regarding the effects of phytoestrogens on breast cells may be attributed to the endogenous estrogen present in breast tissue.

Lower concentrations of phthalates induce proliferation in human breast cancer cells.

OBJECTIVE: To explore the effect and pathway of phthalates on the growth of MCF-7 breast cancer cells. METHODS: MCF-7 cells were treated with benzyl butyl phthalate (BBP), di-n-butyl phthalate (DBP), and di-2-ethylhexyl phthalate (DEHP) (10(-10)-10(-4) mol/l). After incubation for 24, 48, 72, and 92 h, the cells were harvested and extracted for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proteins involving proliferative and apoptotic pathways were evaluated by Western blot analysis. RESULTS: MTT assay revealed cell toxicity at more than 10(-5) mol/l for DEHP and at 10(-4) mol/l for both BBP and DBP in MCF-7 cells. Cell proliferation was significantly increased at 10(-8)-10(-5) mol/l of BBP and DBP, and at 10(-8)-10(-6) mol/l of DEHP treatment. Proliferating cell nuclear antigen (PCNA) was substantially increased in cultures with DEHP (10(-8)-10(-6) mol/l), BBP (10(-8)-10(-5) mol/l), and DBP (10(-7)-10(-5) mol/l). Obvious increases in PI3K, p-AKT, and PCNA were noted in cultures with 17ß-estradiol, BBP, DBP, and DEHP. Estrogen receptor α expression was also notably increased in treatment with estradiol, BBP, DBP, and DEHP. CONCLUSIONS: The present study demonstrates that, even at a very low concentration, BBP, DBP, and DEHP were not only still capable of inducing a proliferative effect through the PI3K/AKT signaling pathway but also displaying estrogenic activity. Therefore, the current reference doses for phthalates defined by governments should be further evaluated.

Phytoestrogens induce differential effects on both normal and malignant human breast cells in vitro.

OBJECTIVE: To explore the effect and pathway of phytoestrogens in vitro on the growth of both normal and malignant breast cells. METHODS: Normal breast MCF-10A cells and breast cancer MCF-7 cells were incubated with 10 (-10)-10(-4)  mol/l genistein, resveratrol, and quercetin (plasma concentrations in human: 10 nmol/l-10 µmol/l) for 48 h and were then extracted for a cell proliferation assay (MTT), and for a cell death assay (TUNEL) assay. The proteins involved in the proliferative and apoptotic pathways were evaluated by Western blot analysis. Additionally, a comparison with 17ß-estradiol as well as an evaluation of the differential effects on estrogen receptors (ER) α and ß were performed. RESULTS: MCF-7 cell proliferation was significantly inhibited at the concentrations greater than 10(-4) mol/l for all three phytoestrogens and from 10 (-5) mol/l for resveratrol and quercetin. MCF-10A cell proliferation was significantly increased at the concentrations from 10 (-8) to 10 (-5) mol/l for genistein and resveratrol and only at 10 (-5) mol/l for quercetin. Apoptotic cells were significantly increased by these phytoestrogens in the MCF-7 cells. At a concentration of 10 (-7)  mol/l of these phytoestrogens, a significant reduction of PI3K and Akt and an increase of Fas ligand, Fas-associated protein with death domain, cytochrome C, truncated Bid, caspase-9, and caspase-3 were noted in the MCF-7; PI3K and Akt were significantly increased in the MCF-10A. ERß expression was significantly elevated in MCF-10A and MCF-7 with these phytoestrogens. The effects of estradiol on normal and malignant breast cells were completely opposite to those of phytoestrogens. CONCLUSIONS: This study demonstrates that phytoestrogens have antiproliferative effects on breast cancer cells via an ER-dependent mechanism, even at low concentrations, but are also capable of maintaining the survival of normal breast cell via ER-independent or other mechanisms.

Phytoestrogens induce apoptosis through a mitochondria/caspase pathway in human breast cancer cells.

OBJECTIVE: To explore the effect and pathway of phytoestrogens on the growth of breast cancer cell line MCF-7. METHODS: MCF-7 cells (human estrogen receptor-positive and progesterone receptor-positive breast cancer cells) were cultured in serum-free medium for 24 h and then treated with genistein, resveratrol, and quercetin (10(-10)-10(-4) mol/l). After further incubation for 24, 48, 72, and 92 h, the cells were harvested and extracted for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. According to the above results, the proteins involving proliferative and apoptotic pathways were evaluated by Western blot analysis. RESULTS: Genistein, resveratrol, and quercetin significantly inhibited cellular proliferation in a dose- and time-dependent manner. Significantly elevated caspase-3 activity was noted after treatment with genistein (10(-9)-10(-7) mol/l), as well as with resveratrol and quercetin (10(-9)-10(-5) mol/l). Significant reduction of PI3K and AKT protein and significant increase of Fas ligand, Fas-associated protein with death domain, cytochrome C, truncated Bid, caspase-9, and caspase-3 were all noted after genistein, resveratrol, and quercetin treatment. 17ß-Estradiol induced completely opposite results. Estrogen receptor (ER) α expression was significantly increased with 17ß-estradiol, whereas ERß expression was significantly elevated in the cultures with genistein, resveratrol, and quercetin. CONCLUSIONS: These data demonstrate that genistein, resveratrol, and quercetin have antiproliferative effects on breast cancer cells. Their induction of apoptosis involves the activation of both the intrinsic and extrinsic apoptotic pathways, which may be related to the differential affinity to ERα and ERß. Whether phytoestrogens have similar effects on normal breast cells remains to be examined.

Estrogen modulates osteogenic activity and estrogen receptor mRNA in mesenchymal stem cells of women.

OBJECTIVE: To determine whether estrogen regulates mesenchymal stem cell (MSC) activity in bone marrow from osteoporotic postmenopausal women. METHODS: MSCs were collected from bone marrows which were aspirated simultaneously during iliac bone graft procedures in spine fusion surgery in osteoporotic postmenopausal women. We investigated proliferation, differentiation, osteogenic activity, and estrogen receptor (ER) α and ß mRNA expression of primary culture MSCs isolated from four osteoporotic postmenopausal women, treated in vitro with or without 17ß-estradiol. The expression of alkaline phosphatase (ALP), osteocalcin, interleukin-6, ERα and ERß mRNA was evaluated. RESULTS: The expression of ALP and osteocalcin mRNA was detected during the cultures of MSCs and was observed to increase up to day 20. As compared with MSCs not treated with estradiol, a significant increase in DNA content, ERα mRNA, and ALP mRNA expression was observed in cultures with estradiol. The mRNA expression of osteocalcin and interleukin-6 was significantly lower in MSCs treated with estradiol than those without estradiol. There was no significant difference in the mRNA expression of ERß between MSCs cultured with and without estradiol. CONCLUSIONS: In the proper environment, MSCs from osteoporotic women can differentiate into osteoblasts and estrogen enhances the osteogenic activity possibly via ERα activity.

Fanconi anemia pathway--the way of DNA interstrand cross-link repair.

The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research.

Baseline Sensitivity of Monilinia fructicola from China to the DMI Fungicide SYP-Z048 and Analysis of DMI-Resistant Mutants.

Sterol 14α-demethylase inhibitors (DMIs) continue to be important in the management of brown rot of Monilinia spp. worldwide. In this study, the sensitivity of 100 Monilinia fructicola isolates from four unsprayed orchards and two packinghouses in Beijing, China, to the new DMI fungicide SYP-Z048 was evaluated and ranged from 0.003 to 0.039 and 0.016 to 0.047 µg/ml, respectively. Laboratory mutants resistant to SYP-Z048 were generated using UV irradiation but no mutants occurred spontaneously. Resistance was stable after 10 weekly consecutive transfers on fungicide-free medium. Three parameters, including growth rate, sporulation in vitro, and lesion area, were significantly different when sensitive isolates and resistant mutants were analyzed as groups. Mutants grew more slowly and developed significantly smaller lesions on detached fruit, and their sporulation ability in vitro was reduced. Cross resistance was found between SYP-Z048 and propiconazole (ρ = 0.82, P < 0.0001) but not between SYPZ048 and tridemorph, carbendazim, procymidone, azoxystrobin, or pyrimethanil. SYP-Z048 resistance in mutants exhibiting 50% mycelial growth inhibition values greater than 0.3 µg/ml was correlated with the presence of a mutation in the CYP51 gene that encodes the target protein for DMI fungicides. The mutation caused an amino acid change from tyrosine to phenylalanine at position 136 (Y136F). To our knowledge, this is the first baseline sensitivity of M. fructicola collected from China to a DMI fungicide. The inability of M. fructicola to generate spontaneous DMI-resistant mutants coupled with reduced fitness of Y136F mutants can explain why this target site mutation has not yet emerged as a DMI fungicide resistance determinant in M. fructicola field populations worldwide.

Effects of different progestogens on human breast tumor cell growth.

OBJECTIVE: To examine the effect of progestogens currently used in hormone therapy on growth of human breast tumor cells. METHODS: MCF-7 cells were incubated in 10 nmol/l progestogens, including progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone acetate (NETA), and cyproterone acetate (CPA), with or without 17ß-estradiol (E(2), 1 nmol/l and 10 nmol/l), as well as E(2) alone. Cell proliferation, apoptosis, and the expression of caspase-3 and proliferating cell nuclear antigen (PCNA) were evaluated. RESULTS: The ratios of apoptosis : proliferation significantly increased in cultures with progestogens alone, 1 nmol/l E(2) plus progestogens (except P4), and 10 nmol/l E(2) plus NETA. Caspase-3 significantly diminished in cultures with E(2) alone; this was completely reversed when progestogens were added. MPA alone or with 1 nmol/l E(2) and 10 nmol/l E(2) plus NETA significantly increased caspase-3. Using progestogens alone, except P4, significantly decreased PCNA expression. CONCLUSIONS: The results demonstrate that various progestogens have different effects on growth of breast tumor cells, especially with the combined usage of E(2). Progestogen-induced apoptosis may be partly inhibited with the presence of E(2), but less severe with lower E(2) concentrations. Therefore, the choice of progestogens, as well as the doses of E(2) and/or progestogen, may influence breast cancer risk.

First Report of Iprodione Resistance in Botrytis cinerea on Blackberry from South Carolina.

Botrytis cinerea Pers.:Fr., is a necrotrophic fungus with a broad host range that causes gray mold on hundreds of plant species (2). Control of gray mold mainly depends on fungicides, including the dicarboxamide iprodione. Thirty-nine diseased blackberry fruit were collected from four orchards in South Carolina and the sensitivity of single-spore isolates to iprodione was examined by Spiral Plater assays (1) on potato dextrose agar (PDA). Briefly, a 5.3 cm long paper strip containing mycelia was placed along the concentration gradient of the PDA and 50% inhibition (EC50 value) was calculated after 2 days of incubation with the Spiral Gradient Endpoint (SGE) software (Spiral Biotech, Norwood, MA). Each isolate was tested in duplicates. Sensitivity ranged from 0.043 to 2.596 µg/ml, with a maximum resistance factor of 60.4. Isolates with EC50 values greater than 2 µg/ml were found in two orchards. Those isolates represented 40 and 7.1% of the total isolates from each orchard. Two isolates with high (EC50 value of 2.596 µg/ml) and low (EC50 value of 0.062 µg/ml) values were chosen to determine the efficacy of iprodione formulated product Rovral 4 Fl (Bayer CropSciences, Research Triangle Park, NC) on detached apple fruit. Fifteen apples were used for each isolate and experiment. Each fruit was wounded on the surface in three locations with a sterile syringe and inoculated with 15 µl of a spore suspension (106 conidia/ml) at the wounded sites. Rovral was applied at the recommended label rate either 24 h before (protective treatment) or 48 h after inoculation (curative treatment). The experiment was conducted three times. Blackberry fruit were not found suitable for this assay because of persistent contamination problems likely from latent infections of a symptomatic fruit. Disease incidence and lesion diameter were recorded 7 days after incubation. Disease incidence following inoculation of the sensitive and resistant isolates on non-fungicide-treated fruit was 100 and 86.7%, respectively. Disease incidence on fungicide-treated apples was 4.4% for the sensitive isolate and 75.6% for the resistant isolate with corresponding mean lesion areas of 0.36 mm and 9.37 mm, respectively. Both isolates were controlled effectively in protective treatments, however, indicating low levels of resistance. To our knowledge, this is the first report of iprodione resistance in B. cinerea from blackberry or any other field-grown crop in South Carolina. This finding adds to a study from 1999 (3) documenting resistance to the dicarboxamide fungicide vinclozolin in B. cinerea collected from ornamentals in South Carolinian greenhouses and suggests that resistance to iprodione needs to be considered in the design of gray mold control strategies in commercial blackberry orchards. No cross resistance between the phenylpyrrole fludioxonil and iprodione was found. References: (1) H. Forster et al. Phytopathology 94:163, 2004. (2) B. Williamson et al. Mol. Plant Pathol. 8:561. 2007. (3) L. F. Yourman and S. N. Jeffers. Plant Dis. 83:569, 1999.

Meta-analysis using individual patient data from randomised trials to assess the effectiveness of laparoscopic uterosacral nerve ablation in the treatment of chronic pelvic pain: a proposed protocol.

BACKGROUND: Currently, there are a number of clinical trials, but no international collaboration for collating research on effectiveness of laparoscopic uterosacral nerve ablation (LUNA) for alleviating chronic pelvic pain. OBJECTIVE: Meta-analysis was used by collecting individual patient data (IPD) from the existing trials, to provide a comprehensive assessment of the effectiveness of LUNA that will be generalisable in various clinical contexts. METHODS: IPD will be sought and collected from all relevant (both already finished and continuing) randomised trials identified through previous systematic reviews. After obtaining raw data and cleaning the database, analysis will be of all patients ever randomised based on the intention-to-treat principle using endpoints measured at 12 months following randomisation. PROPOSAL: We will update searches, contact all authors, obtain data in whatever form it can be provided, build a single database, produce results for individual studies, have them verified by original authors, explore of any heterogeneity and reasons behind it and finally pool all raw data in to a meta-analysis using appropriate statistical methods. The project will test the effectiveness of LUNA for women with chronic pelvic pain. It will also motivate collaborating primary investigators to undertake new primary studies to corroborate or improve upon the conclusions derived from the retrospective analysis.

[A prospective study of the efficacy and safety of maintenance therapy with recombinant human thrombopoietin in patients with primary immune thrombocytopenia: a multicenter study].

Objective: To evaluate the efficacy and safety of maintenance therapy with reduced dose of rhTPO in the patients with primary immune thrombocytopenia (ITP) who attained stable platelet (PLT) counts after daily administration of rhTPO. Methods: Treatment was started with a daily administration of rhTPO (300 U/kg) for 2 consecutive weeks. Patients who attained stable PLT≥50×10(9)/L were enrolled to maintenance therapy starting with every other day administration of rhTPO, then adjusted dose interval to maintain platelet count (30-100) ×10(9)/L. Results: A total of 91 eligible patients were enrolled. Fourteen patients discontinued the study due to noncompliance (12/14) and investigator decision (2/14) . Among 77 patients who completed the study, 38 patients with the administration of rhTPO at every other day or less could maintain PLT≥30×10(9)/L for 12 weeks. The percentage of patients with a platelet response (PLT≥30×10(9)/L) at 4(th) week, 8(th) week and 12(th) week of maintain therapy was 92.6% (63/68) , 82.7% (43/52) and 85.0% (34/40) , respectively. Median platelet counts remained in the range of (70-124) ×10(9)/L. The overall incidence of rhTPO-related adverse events was 7.7%. All the adverse events were generally mild. Conclusion: Extending the dose interval of rhTPO is feasible to maintain stable platelet count in the patients with ITP, but the optimal dose interval is uncertain and might vary with individuals.

[Efficacy and safety of IA regimen containing different doses of idarubicin in de-novo acute myeloid leukemia for adult patients].

Objective: To investigate the efficacy and safety of IA regimen which contains idarubicin (IDA) 8 mg/m(2), 10 mg/m(2) or 12 mg/m(2) as induction chemotherapy for adult patients with de-novo acute myeloid leukemia (AML) . Methods: A total of 1 215 newly diagnosed adult AML patients, ranging from May 2011 to March 2015 in the First Affiliated Hospital of Soochow University and other 36 clinical blood centers in China were enrolled in the multicenter, single-blind, non-randomized, clinical controlled study. To compare the response rate of complete remission (CR) , adverse events between different dose idarubicin combined with cytarabine (100 mg/m(2)) as induction chemotherapy in newly diagnosed patients of adult AML. Results: Of 1 207 evaluable AML patients were assigned to this analysis of CR rate. The CR rates of IDA 8 mg/m(2) group, IDA 10 mg/m(2) group and IDA 12 mg/m(2) group were 73.6% (215/292) , 84.1% (662/787) and 86.7% (111/128) , respectively (P<0.001) . After adjusted for age, blast ratio of bone marrow, FAB classification and risk stratification, the odds ratios (95% CI) of IDA 10 mg/m(2) group and IDA 12 mg/m(2) group were 0.49 (0.34-0.70) and 0.36 (0.18-0.71) , as compared with the IDA 8 mg/m(2) group (P<0.001, P=0.003) . In the intermediate and favorable groups, CR rates was 76.5% (163/213) , 86.9% (506/582) and 86.1% (68/79) in different doses of IDA (P=0.007) . Interestingly, IA regimen with IDA 10 mg/m(2) was the only beneficial factor affecting CR in this group after adjusted for age, blast ratio of bone marrow and FAB classification[OR=0.47 (95% CI 0.31-0.71) , P<0.001]. CR rates in adverse group was 50.0% (18/36) , 60.6% (43/71) and 81.8% (18/22) respectively (P=0.089) . However, the odds ratios (95% CI) of IDA 12 mg/m(2) when compared with the IDA 8 mg/m(2) was 0.22 (0.06-0.80) , after adjusted for age, blast ratio of bone marrow and FAB classification. The median time (days) of neutrophil count less than 0.5×10(9)/L in IDA 8 mg/m(2) group, IDA 10 mg/m(2) group and IDA 12 mg/m(2) group were 14 (11-18) , 15 (11-20) and 18 (14-22) , respectively (P=0.012) and of platelet count lower than 20×10(9)/L were 14 (7-17) , 15 (11-20) and 17 (15-21) , respectively (P=0.001) . The incidences of lung infection in the three groups were 9.8%, 13.5% and 25.2%, respectively (P<0.001) . Conclusions: For young adult patients (aged 18-60 years) with AML in China, intensifying induction therapy with idarubicin 10 mg/m(2) is clinically superior to IDA 8 mg/m(2) and IDA 12 mg/m(2) in favorable intermediate AML subgroup. However, idarubicin 12 mg/m(2) is more suitable to adverse AML subgroup.

Zn2+ modulation of neuronal transient K+ current: fast and selective binding to the deactivated channels.

Modulation of voltage-dependent transient K(+) currents (A type K(+) or K(A) current) by Zn(2+) was studied in rat hippocampal neurons by the whole-cell patch-clamp technique. It is found that Zn(2+) selectively binds to the resting (deactivated or closed) K(A) channels with a dissociation constant (K(d)) of approximately 3 microM, whereas the affinity between Zn(2+) and the inactivated K(A) channels is 1000-fold lower. Zn(2+) therefore produces a concentration-dependent shift of the K(A) channel inactivation curve and enhances the K(A) current elicited from relatively positive holding potentials. It is also found that the kinetics of Zn(2+) action are fast enough to compete with the transition rates between different gating states of the channel. The rapid and selective binding of Zn(2+) to the closed K(A) channels keeps the channel in the closed state and explains the ion's concentration-dependent slowing effect on the activation of K(A) current. This in turn accounts for the inhibitory effect of Zn(2+) on the K(A) current elicited from hyperpolarized holding potentials. Because the molecular mechanisms underlying these gating changes are kinetic interactions between the binding-unbinding of Zn(2+) and the intrinsic gating processes of the channel, the shift of the inactivation curve and slowing of K(A) channel activation are quantitatively correlated with ambient Zn(2+) over a wide concentration range without "saturation"; i.e., The effects are already manifest in micromolar Zn(2+), yet are not saturated even in millimolar Zn(2+). Because the physiological concentration of Zn(2+) could vary over a similarly wide range according to neural activities, Zn(2+) may be a faithful physiological "fine tuner," controlling and controlled by neural activities through its effect on the K(A) current.

Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors.

OBJECTIVE: To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women. DESIGN: Twenty subjects were treated with oral E2 valerate (2 mg) combined with cyproterone acetate (1 mg) (group I) and 21 with transdermal E2 (1.5 mg) plus oral medroxyprogesterone acetate (5 mg) (group II). The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3, 6, and 12 months of treatment. RESULTS: Group I showed a stronger increase of high-density lipoprotein (HDL) cholesterol levels (2-8%) and stronger reduction of atherogenic indices (total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol) than group II. Group II showed a more pronounced reduction of triglyceride (21-31%) and factor VII (6-10%) levels than group I. Both groups showed reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, and protein S, whereas protein C was increased after 12 months of treatment. CONCLUSIONS: The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity. Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration, but transdermal medication had a stronger effect on triglyceride and coagulation factors. However, it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment.

The efficacy and complications of laparoscopic presacral neurectomy in pelvic pain.

OBJECTIVE: To evaluate the efficacy and complications of laparoscopic presacral neurectomy in pelvic pain. METHODS: We reviewed records of 655 patients receiving laparoscopic conservative surgery and laparoscopic presacral neurectomy for diagnoses including adenomyosis with dysmenorrhea (n = 55), moderate and severe endometriosis with dysmenorrhea (n = 127), minimal and mild endometriosis with dysmenorrhea (n = 208), primary dysmenorrhea (n = 99), and chronic pelvic pain with or without pathologic disease (n = 166). Pain relief was evaluated at least 12 months postoperatively. RESULTS: Pain relief was evaluated in 527 patients. Significant pain relief (no pain or mild pain requiring no medication) was found in 22 (52%) of 42 women with adenomyosis, in 75 (73%) of 103 with moderate to severe endometriosis with dysmenorrhea, in 123 (75%) of 164 with minimal to mild endometriosis with dysmenorrhea, in 64 (77%) of 83 with primary dysmenorrhea, and in 84 (62%) of 135 with chronic pelvic pain. There were four major complications (0.6%) that required further surgery, including injury of the right internal iliac artery (n = 1) and chylous ascites (n = 3). Three cases (0.5%) had laceration of the middle sacral vein controlled during laparoscopy. In addition, 485 (74%) of the 655 patients complained of constipation after laparoscopic presacral neurectomy, which was relieved easily by medication. CONCLUSION: Presacral neurectomy can be performed safely and efficiently by laparoscopy and is a valuable alternative treatment for pelvic pain.

Correlation of fecundability and serum estradiol after danazol treatment in patients with advanced endometriosis.

OBJECTIVE: To examine the relationship between pregnancy incidence and the level of serum E2 during danazol therapy. DESIGN: Danazol was given by 200 mg four times daily for 3 months. Serum E2 level was checked after completing the therapy, but before stopping medication. Patients then were advised to conceive at the appropriate time over a 6-month period. SETTING: Reproductive and Endocrine Laboratory of the Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan. PATIENTS: Infertile women with invasive endometriosis receiving conservative surgery and danazol treatment. INTERVENTIONS: Serum E2 is checked before medication and at the end of danazol therapy, but before stopping medication. MAIN OUTCOME MEASURES: Whether pregnancy is related to the change of serum E2 caused by danazol therapy. RESULTS: There were 24 pregnancies in 38 patients with invasive endometriosis after treatment. Pregnant patients had significantly lower serum E2 levels as compared with the nonpregnant patients. CONCLUSIONS: After conservative surgery for invasive endometriosis associated with infertility, the therapeutic period of danazol treatment could be shortened to 3 months. Because there is significant correlation of fecundability and serum E2 after danazol medication, serum E2 could be a guideline for predicting pregnancy or for prolonging or changing of treatment after danazol therapy.