Stereodivergent Total Syntheses of (+)-Mycaperoxides C, D, G Methyl Ester and (-)-Mycaperoxide B.

Mycaperoxides are natural endoperoxides isolated from different Mycale genus sponges, showing significant antiviral or antibacterial activities. We report herein the first total syntheses of representative congeners of this family from sclareol using a stereodivergent approach. Thus, an innovative oxidative ring expansion of cyclobutanol was used to bring the 1,2-dioxane subunit, and a Mukaiyama aldol reaction on peroxycarbenium species was utilized to install the propionic acid subunit. During the study toward (+)-mycaperoxide D methyl ester (2), the isolation of the eight possible diastereomers under their ethyl thioester form allowed to build a pertinent database for further NMR assignment studies. Thus, we completed the total syntheses of (+)-mycaperoxides D, C, G methyl ester, and (-)-mycaperoxide B in 11 to 15 steps, confirming their original assignment.

Patent Foramen Ovale-Induced Platypnea-Orthodeoxia Syndrome: A Case Report and Literature Review.

Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and hypoxia worsening in the upright position and relieved in the recumbent position. POS can result from anatomical or functional conditions that cause interatrial communication or deformity of the atrial septum. Investigations with imaging and cardiac catheterization can aid in the evaluation. In cases where POS is caused by intracardiac shunting without pulmonary hypertension, closure of the intracardiac shunt can be curative. We report a case of POS in a 54-year-old male who was treated successfully with percutaneous closure of a patent foramen ovale (PFO).

Adhesion layer-free attachment of gold on silicon wafer and its application in localized surface plasmon resonance-based biosensing.

The use of a metallic adhesion layer between plasmonic-active nanostructures and a solid supported is known to dampen the plasmonic response. To overcome this problem, organic adhesion layers have been introduced, which in turn can undermine the stability of the film. Moreover, both types of layers limit the regeneration of the nanostructures for multiple uses. Here we report a quick and simple approach to prepare intermediate adhesion layer-free binding of nanostructured films of gold on silicon wafers. The approach involves scratching and etching of the silicon wafer before sputter coating with a thin layer of Au. The plasmonic-active nanostructures were then prepared on this thin Au film using electrochemical deposition. As-prepared plasmonic-active nanostructured thin films of gold (PANTF-Au) are easy to handle, physically robust, and can be regenerated. The bulk refractive index sensitivity of PANTF-Au is 150 nm/RIU with the figure of merit 1.4, and with a plasmonic field-decay length of 27 nm. We further used these thin films to study interactions between lectin and glycoprotein inside a flow cell as well as on a microplate made of PANTF-Au. The PANTF-Au can be easily integrated with electrochemical devices and microfluidics, which can help to pave the way toward the development of ideal optical-electrochemical point-of-care biosensors.

Hybrid Mesoporous Silica Nanoparticles Grafted with 2-(tert-butylamino)ethyl Methacrylate-b-poly(ethylene Glycol) Methyl Ether Methacrylate Diblock Brushes as Drug Nanocarrier.

This paper introduces the synthesis of well-defined 2-(tert-butylamino)ethyl methacrylate-b-poly(ethylene glycol) methyl ether methacrylate diblock copolymer, which has been grafted onto mesoporous silica nanoparticles (PTBAEMA-b-PEGMEMA-MSNs) via atom transfer radical polymerization (ATRP). The ATRP initiators were first attached to the MSN surfaces, followed by the ATRP of 2-(tert-butylamino)ethyl methacrylate (PTBAEMA). CuBr2/bipy and ascorbic acid were employed as the catalyst and reducing agent, respectively, to grow a second polymer, poly(ethylene glycol) methyl ether methacrylate (PEGMEMA). The surface structures of these fabricated nanomaterials were then analyzed using Fourier Transform Infrared (FTIR) spectroscopy. The results of Thermogravimetric Analysis (TGA) show that ATRP could provide a high surface grafting density for polymers. Dynamic Light Scattering (DLS) was conducted to investigate the pH-responsive behavior of the diblock copolymer chains on the nanoparticle surface. In addition, multifunctional pH-sensitive PTBAEMA-b-PEGMEMA-MSNs were loaded with doxycycline (Doxy) to study their capacities and long-circulation time.

Overexpression of miR-214-3p in esophageal squamous cancer cells enhances sensitivity to cisplatin by targeting survivin directly and indirectly through CUG-BP1.

Based on its marked overexpression in multiple malignancies and its roles in promoting cell survival and proliferation, survivin is an attractive candidate for targeted therapy. Toward this end, a detailed understanding of the mechanisms regulating survivin expression in different cancer cells will be critical. We have previously shown that the RNA-binding protein (RBP) CUG-BP1 is overexpressed in esophageal cancer cells and post-transcriptionally regulates survivin in these cells. The objective of this study was to investigate the role of microRNAs (miRs) in regulating survivin expression in esophageal cancer cells. Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared with esophageal epithelial cells. Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p. Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1. This effect is due to decreased mRNA stability of both targets. By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein. To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed. These demonstrated that the mRNA of survivin and CUG-BP1 each contain two functional miR-214-3p-binding sites as confirmed by mutational analysis. Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to cisplatin-induced apoptosis. This effect is abrogated with rescue expression of survivin or CUG-BP1. These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to chemoresistance in esophageal cancer cells by targeting both survivin and CUG-BP1.

Crystal structure of 2-cyclo-hexyl-1,3-thia-zolo[4,5-b]pyridine.

In the title compound, C12H14N2S, the cyclo-hexane ring adopts a chair conformation with the exocyclic C-C bond in an equatorial orientation. The mean plane through the cyclo-hexane ring (all atoms) is twisted from the thia-zolo-pyridine ring system (r.m.s. deviation = 0.013 Å) by 39.57 (6)°. In the crystal, mol-ecules form (100) sheets, although there are no specific directional inter-actions between them. The crystal stucture was refined as a two-component perfect twin.

Crystal structure of 2-(3-nitro-phen-yl)-1,3-thia-zolo[4,5-b]pyridine.

In the title compound, C12H7N3O2S, the dihedral angle between the planes of the thia-zolo-pyridine ring system (r.m.s. deviation = 0.005 Å) and the benzene ring is 3.94 (6)°. The nitro group is rotated by 7.6 (2)° from its attached ring. In the crystal, extensive aromatic π-π stacking [shortest centroid-centroid separation = 3.5295 (9) Å] links the mol-ecules into (001) sheets.

Crystal structure of 2-[4-(methyl-sulfan-yl)quinazolin-2-yl]-1-phenyl-ethanol.

In the mol-ecule of the title compound, C17H16N2OS, the almost planar methyl-sulfanylquinazoline group [the methyl C atom deviates by 0.032 (2) Šfrom the plane through the ring system] forms an inter-planar angle of 76.26 (4)° with the plane of the phenyl group. An intra-molecular O-H⋯N hydrogen bond is present between the quinazoline and hy-droxy groups. In the crystal, mol-ecules are stacked along the b-axis direction.

Management of pain associated with the insertion of intrauterine contraceptives.

BACKGROUND: Most intrauterine contraception (IUC) placements do not require pain relief. However, small proportions of nulliparous (∼17%) and parous (∼11%) women experience substantial pain that needs to be proactively managed. This review critically evaluates the evidence for pain management strategies, formulates evidence-based recommendations and identifies data gaps and areas for further research. METHODS: A PubMed literature search was undertaken. Relevant articles on management of pain associated with IUC insertion, published in English between 1980 and November 2012, were identified using the following search terms: 'intrauterine contraception', 'insertion' and 'pain'. RCTs were included; further relevant articles were also identified and included as appropriate. RESULTS: Seventeen studies were identified and included: 12 RCTs and one non-randomized study of pre-insertion oral analgesia, cervical priming and local anaesthesia; one systematic review and one RCT on post-insertion analgesia and two non-randomized studies on non-pharmacological interventions. There was no conclusive evidence that any prophylactic pharmacological intervention reduces pain associated with IUC insertion. However, most of the regimens studied were adopted from hysteroscopy or abortion and effectiveness in specific subsets of women has not been studied adequately. A systematic review found non-steroidal anti-inflammatory agents (NSAID) to be effective in reactively treating post-insertion pain, but no benefit was found with prophylactic use. CONCLUSIONS: No prophylactic pharmacological intervention has been adequately evaluated to support routine use for pain reduction during or after IUC insertion. Women's anxiety about the procedure may contribute to higher levels of perceived pain, which highlights the importance of counselling, and creating a trustworthy, unhurried and professional atmosphere in which the experience of the provider also has a major role; a situation frequently referred to as 'verbal anaesthesia'.

Invasive cancer of the cervix: does the UK National Health Service screening programme fail due to patients' non-attendance?

The UK National Health Service (NHS) cervical screening programme aims to prevent invasive cancer of the cervix, yet this programme fails in some women. Women diagnosed with cancer of the cervix at a colposcopy unit in the North East of England between April 1, 1997 and December 31, 2004 had cervical cytology histories classified. Thirty-seven cases were identified (median age 37 years; range 22-72 years). At six months before diagnosis, 24.3% had never undergone cytology screening (38.4% Stage IB+, 12.5% Stage IA). In addition, 59.5% of all cases were under-screened (when using criteria that included screening was 'up to date' if less than five years had elapsed between last negative test result and their diagnosis). Women in this case series failed to attend regular cervical screening, with those never attending screening more likely to present with advanced cancer.

Does current contraceptive choice correspond with user satisfaction?

A contraceptive method that suits an individual's needs may be more consistently used leading to greater user satisfaction. We therefore wanted to investigate whether a woman's current contraceptive choice corresponded with qualities identified by women as important. An anonymous survey was completed by women in their reproductive years, living in the North East of England, before seeing a healthcare professional. A total of 177 English-speaking women, who were sexually active and of reproductive age, completed questionnaires giving a response rate of 54%. A correlation was found between the current contraceptive used and the previously stated qualities felt to be important when choosing a method (p = 0.034, χ(2)-test). Similarly, a relationship was found between the current contraceptive method and reasons stated against choosing a contraceptive (p = 0.002, χ(2)-test). Overall, British women are generally satisfied with their chosen contraceptive method.

Acute oncology service: assessing the need and its implications.

Cancer patients often have complex and difficult inpatient diagnostic and treatment pathways that involve many different specialities within secondary care. With current severe resource constraints, improvements in outcomes and patient experience need to be both cost-efficient and effective. We review the reports that will shape national cancer care in coming years and use data gathered from our own hospital to highlight important issues in the development of in-patient cancer services and the emergence of a new specialty; acute oncology.

Liquid based cytology improves the positive predictive value of glandular smears compared to conventional cytology.

PURPOSE: To investigate whether the introduction of liquid-based cytology (LBC) in an urban setting decreases the diagnosis of glandular neoplasia (grade 6) and improves the positive predictive value (PPV) of cervical cytological screening. METHODS: A retrospective database review was conducted identifying women with cervical cytological abnormalities including glandular neoplasia (grade 6) before and after the introduction of LBC. RESULTS: Following the introduction of LBC the rate of glandular neoplasia (grade 6) referrals fell from 1.08% to 0.69% of all cervical cytological abnormalities. There was a significant reduction in 'abnormal' cytological samples subsequently found to be associated with no invasive or preinvasive disease but no decrease in the number showing preinvasive or invasive disease. A significant decrease in number of patients having a final diagnosis of normal/inflammatory or wart changes was seen in those patients referred during the LBC period (p < 0.01). CONCLUSION: The introduction of LBC in an urban setting decreased cytological glandular neoplasia referrals but not at the expense of missing preinvasive and invasive cancers. It has also increased the PPV of cervical sampling to detect preinvasive and invasive cancer from 59.6% to 76.0%.

Do women with glandular abnormalities require colposcopy follow-up?

PURPOSE: To determine whether cervical glandular abnormalities can be safely followed up by community cytology. METHODS: A retrospective database review was conducted identifying women with a histological report of cervical glandular abnormalities over a three-year period. RESULTS: Fifty women were found to have a glandular abnormality diagnosed histologically. Twenty were initially referred for colposcopy with cytological glandular abnormalities. Thirty women with cytological squamous abnormalities were later found to have cervical glandular intraepithelial neoplasia (CGIN) at histological assessment. Two women had invasive adenocarcinoma and all others with endocervical dyskaryosis or CGIN were treated using large loop excision of the transformation zone (LLETZ). At follow-up 43 women had negative cytology, one woman defaulted further appointments, one had moved out of the area, seven were successfully treated by a repeat LLETZ following incomplete excision of CGIN at the endocervix, and five had negative cytology in the community. Three women continue to have cytological/histological abnormalities with one subsequently having a hysterectomy. CONCLUSION: Women with endocervical dyskaryosis or CGIN should be treated by LLETZ. Provided LLETZ is repeated in cases of incomplete endocervical CGIN excision cytological follow-up can take place in the community.

Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function.

To assess the efficacy of vacuum constriction devices (VCD) following radical prostatectomy (RP) and determine whether early use of VCD facilitates early sexual activity and potentially earlier return of erectile function. This prospective study consisted of 109 patients who underwent nerve-sparing (NS) or non-nerve-sparing (NNS) RP between August 1999 and October 2001 and developed erectile dysfunction following surgery. The patients were randomized to VCD use daily for 9 months (Group 1, N=74) or observation without any erectogenic treatment (Group 2, N=35). Treatment efficacy was analyzed by responses to the Sexual Health Inventory of Men (SHIM) (abridged 5-item International Index of Erectile Function (IIEF-5)), which were stratified by the NS status. Patient outcome regarding compliance, change in penile length, return of natural erection, and ability for vaginal intercourse were also assessed. The mean patient age was 58.2 years, and the minimum follow-up was 9 months. Use of VCD began at an average of 3.9 weeks after RP. In Group 1, 80% (60/74) successfully used their VCD with a constriction ring for vaginal intercourse at a frequency of twice/week with an overall spousal satisfaction rate of 55% (33/60). In all, 19 of these 60 patients (32%) reported return of natural erections at 9 months, with 10/60 (17%) having erections sufficient for vaginal intercourse. The abridged IIEF-5 score significantly increased after VCD use in both the NS and NNS groups. After a mean use of 3 months, 14/74 (18%) discontinued treatment. In Group 2, 37% (13/35) of patients regained spontaneous erections at a minimum follow-up of 9 months after surgery. However, only four of these patients (29%) had erections sufficient for successful vaginal intercourse and rest of patients (71%) sought adjuvant treatment. Of the 60 successful users, 14 (23%) reported a decrease in penile length and circumference at 9 months (range, 4-8 months) compared to 12/14 (85%) among the nonresponders. However, in control group 22/35 reported decrease in penile length and circumference. Early use of VCD following RP facilitates early sexual intercourse, early patient/spousal sexual satisfaction, and potentially an earlier return of natural erections sufficient for vaginal penetration.

Long-term efficacy and compliance of MUSE for erectile dysfunction following radical prostatectomy: SHIM (IIEF-5) analysis.

Baseline and follow-up data of 54 patients from a single surgical series (1998-2001), who used medicated urethral system for erection (MUSE) for the erectile dysfunction (ED) associated with radical prostatectomy (RP), were obtained. Patients were surveyed using the abridged five-item version of the International Index of Erectile Function (IIEF) questionnaire, commonly referred to as the Sexual Health Inventory of Men (SHIM), to determine presence and severity of ED and efficacy of ED treatment modalities. The mean patient age was 63.7+/-5.6 y and the mean follow-up period was 2.3+/-1.2 y. All patients experienced ED for at least 6 months after their surgery before starting MUSE therapy. Overall, 55% of the patients achieved and maintained erections sufficient for sexual intercourse while on MUSE and 48% continued long-term therapy with a mean use of 2.32+/-1.2 y. The mean presurgery SHIM score in these patients was 19.2+/-1.3, which decreased to 5.2+/-0.5 after surgery and increased to 16.3+/-1.3 after MUSE treatment. A total of 28 patients (52%) discontinued treatment after a mean use of 8+/-1.4 months. The reasons for discontinuation were insufficient erections (n = 16, mean SHIM score of 10.5+/-4.4), switch to other ED therapies (n = 4), natural return of erections (n = 4) and urethral pain and burning (n = 4). Excluding the patients (n = 8) who preferred other therapies and return of natural erections, the compliance to MUSE was 63%. There were no significant differences in the IIEF-5 responses between the patients who had a nerve-sparing technique (n=34) and those who did not (n = 20) or among patients who used different doses (250, 500 or 1000 microg) of MUSE. The results of the current trial indicate that MUSE is a successful treatment option in RP patients with established ED. It appears that a post-treatment SHIM score of > or = 16 defines a successful outcome with MUSE therapy.

Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy.

BACKGROUND: In the 1970s a new approach to the delivery of hormonal contraception was researched and developed. It was suggested that the addition of a progestogen to a non-medicated contraceptive device improved its contraceptive action. An advantage of these hormonally impregnated intrauterine systems (IUS) is that they are relatively maintenance free, with users having to consciously discontinue using them to become pregnant rather than taking a proactive daily decision to avoid conception. OBJECTIVES: To assess the contraceptive efficacy, tolerability and acceptability of hormonally impregnated intrauterine systems (IUSs) in comparison to other reversible contraceptive methods. SEARCH STRATEGY: Literature was identified through database searches, reference lists and individuals/organisations working in the field. Searches covered the period from 1972 to November 2003. SELECTION CRITERIA: All randomised controlled trials comparing IUSs with other forms of reversible contraceptives and reporting on pre-determined outcomes in women of reproductive years. The primary outcomes were pregnancy due to method/user failure and continuation rate. DATA COLLECTION AND ANALYSIS: The quality assessment of studies and data extraction were completed independently by two blinded reviewers. A quality checklist was designed to identify general methodological and contraceptive specific factors which could bias results. Events per women months and single decrement life table rates were extracted where possible for pregnancy, continuation, adverse events and reasons for discontinuation. Events per total number of women at follow up were collected for hormonal side effects and menstrual disturbance. When appropriate, data were pooled at the same points of follow up to calculate rate ratios in order to determine the relative effectiveness of one method compared to another. For the single decrement life table rates, the rate differences were pooled to determine the absolute difference in effectiveness of one method compared to another. Interventions were only combined if the contraceptive methods were similar. Non-hormonal IUDs were divided into three categories for the purpose of comparison with IUSs: IUDs >250mm2 (i.e. CuT 380A IUD and CuT 380 Ag IUD), IUDs <=250mm2 (i.e. Nova-T, Multiload, CuT 200 and CuT 220 IUDs) and non-medicated IUDs. MAIN RESULTS: Twenty-one RCTs comparing hormonally impregnated IUSs to a reversible contraceptive method met the inclusion criteria and it was possible to include eight of these in the meta-analyses, four comparing LNG-20 IUSs with non-hormonal IUDs, one comparing the LNG-20 IUS with Norplant-2 and three comparing Progestasert with non-hormonal IUDs. No significant difference was observed between the pregnancy rates for the LNG-20 users and those for the IUD >250mm2 users. However, women using the LNG-20 IUS were significantly less likely to become pregnant than those using the IUD <=250mm2. Women using the LNG-20 IUS were more likely to experience amenorrhoea and device expulsion than women using IUDs >250mm2. LNG-20 users were significantly more likely than all the IUD users to discontinue because of hormonal side effects and menstrual disturbance, which on further breakdown of the data was due to amenorrhoea. When the LNG-20 IUS was compared to Norplant-2, the LNG-20 users were significantly more likely to experience amenorrhoea and oligomenorrhoea, but significantly less likely to experience prolonged bleeding and spotting. No other significant differences were observed. Progestasert users were significantly less likely to become pregnant and less likely to continue on the method than non-medicated IUD users after one year, but no significant difference was noted for these two outcomes when Progestasert users were compared to IUD<=250mm2 users. The only other significant differences found in the meta-analyses were that Progestasert users were less likely to expel the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWERS' CONCLUSIONl the device and more likely to discontinue the method because of menstrual bleeding and pain than users of IUDs <=250mm2. REVIEWERS' CONCLUSIONS: Current evidence suggests LNG-20 IUS users are no more or less likely to have unwanted pregnancies than IUD >250mm2 and Norplant-2 users. The LNG-20 IUS was more effective in preventing either intrauterine or extrauterine pregnancies than IUDs <=250mm2. The contraceptive effectiveness of Progestasert was significantly better than non-medicated IUDs, but no difference was observed when compared to IUDs<=250mm2. Continuation of LNG-20 IUS use was similar to continuation of the non-hormonal IUDs and Norplant-2. Amenorrhoea was the main reason for the discontinuation for the LNG-20 IUS and women should be informed of this prior to starting this method.

Experiences with Yasmin: the acceptability of a novel oral contraceptive and its effect on well-being.

There are well over 100 million women using oral contraceptives world-wide; however, the number of women taking the pill differs from country to country. In the 1960s when 'the pill' was launched, most women wanted an effective, reversible contraceptive method. In the twenty-first century, they take these properties of oral contraceptives as given and now expect a number of non-contraceptive benefits including lighter and less painful periods, 'clear skin' and an overall improvement in well-being. Many oral contraceptives fall short of this ideal, with women discontinuing their pills because of perceived side-effects including weight gain, mood changes and breast tension. A new oral contraceptive has been developed to help fill this need. It contains 3 mg drospirenone, a progestogen resembling endogenous progesterone, and 30 microg ethinylestradiol (DRSP/EE, Yasmin, Schering AG, Berlin, Germany). It has been shown to be highly effective in preventing pregnancies as well as providing good cycle control. Studies have suggested that rates of dysmenorrhea improved in women taking DRSP/EE as well as in women using an oral contraceptive containing 30 microg ethinylestradiol and desogestrel, but symptoms were more often mild or less often severe in the DRSP/EE group. Drospirenone is quite unique as it is derived from 17alpha-spirolactone and has antimineralocorticoid as well as antiandrogenic properties. The effect of DRSP/EE on skin has been evaluated in women with mild to moderate facial acne. A positive effect on acne and seborrhea was observed, with the median acne lesion count decreasing by 62.5% from baseline to cycle 9, whilst seborrhea decreased by 25.1%. Further areas of research are focusing on premenstrual symptoms. A very recent European study has been completed to assess the effect of DRSP/EE on the general well-being and fluid-related symptoms over six treatment cycles in women desiring contraception. Overall, these results suggest that women who report premenstrual symptoms, including psychological and/or somatic problems, before starting DRSP/EE, have improved scores when their Psychological General Well-Being Index is measured and suffer fewer somatic symptoms. In conclusion, the combination ofdrospirenone with ethinylestradiol provides an effective and well-tolerated oral contraceptive with positive effects on body weight, skin and premenstrual symptoms. These unique features of DRSP/EE may improve well-being and have a positive effect on oral contraceptive continuation.