Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes.

STUDY QUESTION: Does experimental manipulation of fibroblast growth factor 9 (FGF9)-signalling in human fetal gonads alter sex-specific gonadal differentiation? SUMMARY ANSWER: Inhibition of FGFR signalling following SU5402 treatment impaired germ cell survival in both sexes and severely altered the developing somatic niche in testes, while stimulation of FGF9 signalling promoted Sertoli cell proliferation in testes and inhibited meiotic entry of germ cells in ovaries. WHAT IS KNOWN ALREADY: Sex-specific differentiation of bipotential gonads involves a complex signalling cascade that includes a combination of factors promoting either testicular or ovarian differentiation and inhibition of the opposing pathway. In mice, FGF9/FGFR2 signalling has been shown to promote testicular differentiation and antagonize the female developmental pathway through inhibition of WNT4. STUDY DESIGN, SIZE, DURATION: FGF signalling was manipulated in human fetal gonads in an established ex vivo culture model by treatments with recombinant FGF9 (25 ng/ml) and the tyrosine kinase inhibitor SU5402 (10 µM) that was used to inhibit FGFR signalling. Human fetal testis and ovary tissues were cultured for 14 days and effects on gonadal development and expression of cell lineage markers were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Gonadal tissues from 44 male and 33 female embryos/fetuses from first trimester were used for ex vivo culture experiments. Tissues were analyzed by evaluation of histology and immunohistochemical analysis of markers for germ cells, somatic cells, proliferation and apoptosis. Culture media were collected throughout the experimental period and production of steroid hormone metabolites was analyzed in media from fetal testis cultures by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE: Treatment with SU5402 resulted in near complete loss of gonocytes (224 vs. 14 OCT4+ cells per mm2, P < 0.05) and oogonia (1456 vs. 28 OCT4+ cells per mm2, P < 0.001) in human fetal testes and ovaries, respectively. This was a result of both increased apoptosis and reduced proliferation in the germ cells. Addition of exogenous FGF9 to the culture media resulted in a reduced number of germ cells entering meiosis in fetal ovaries (102 vs. 60 γH2AX+ germ cells per mm2, P < 0.05), while in fetal testes FGF9 stimulation resulted in an increased number of Sertoli cells (2503 vs. 3872 SOX9+ cells per mm2, P < 0.05). In fetal testes, inhibition of FGFR signalling by SU5402 treatment altered seminiferous cord morphology and reduced the AMH expression as well as the number of SOX9-positive Sertoli cells (2503 vs. 1561 SOX9+ cells per mm2, P < 0.05). In interstitial cells, reduced expression of COUP-TFII and increased expression of CYP11A1 and CYP17A1 in fetal Leydig cells was observed, although there were no subsequent changes in steroidogenesis. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Ex vivo culture may not replicate all aspects of fetal gonadal development and function in vivo. Although the effects of FGF9 were studied in ex vivo culture experiments, there is no direct evidence that FGF9 acts in vivo during human fetal gonadogenesis. The FGFR inhibitor (SU5402) used in this study is not specific to FGFR2 but inhibits all FGF receptors and off-target effects on unrelated tyrosine kinases should be considered. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study suggest that dysregulation of FGFR-mediated signalling may affect both testicular and ovarian development, in particular impacting the fetal germ cell populations in both sexes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by an ESPE Research Fellowship, sponsored by Novo Nordisk A/S to A.JØ. Additional funding was obtained from the Erichsen Family Fund (A.JØ.), the Aase and Ejnar Danielsens Fund (A.JØ.), the Danish Government's support for the EDMaRC programme (A.JU.) and a Wellcome Trust Intermediate Clinical Fellowship (R.T.M., Grant no. 098522). The Medical Research Council (MRC) Centre for Reproductive Health (R.T.M.) is supported by an MRC Centre Grant (MR/N022556/1). The authors have no conflict of interest to disclose.

Infertile women below the age of 40 have similar anti-Müllerian hormone levels and antral follicle count compared with women of the same age with no history of infertility.

STUDY QUESTION: Do infertile patients below the age of 40 years have a lower ovarian reserve, estimated by anti-Müllerian hormone (AMH) and total antral follicle count (AFC), than women of the same age with no history of infertility? SUMMARY ANSWER: Serum AMH and AFC were not lower in infertile patients aged 20-39 years compared with a control group of the same age with no history of infertility. WHAT IS KNOWN ALREADY?: The management of patients with a low ovarian reserve and a poor response to controlled ovarian stimulation (COS) remains a challenge in assisted reproductive technologies (ART). Both AMH levels and AFC reflect the ovarian reserve and are valuable predictors of the ovarian response to exogenous gonadotrophins. However, there is a large inter-individual variation in the age-related depletion of the ovarian reserve and a broad variability in the levels of AMH and AFC compatible with conception. Women with an early depletion of the ovarian reserve may experience infertility as a consequence of postponement of childbearing. Thus, low ovarian reserve is considered to be overrepresented among infertile patients. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 382 women with a male partner referred to fertility treatment at Rigshospitalet, Copenhagen, Denmark during 2011-2013 compared with a control group of 350 non-users of hormonal contraception with no history of infertility recruited during 2008-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients and controls were aged 20-39 years. Women with polycystic ovary syndrome were excluded. On Cycle Days 2-5, AFC and ovarian volume were measured by transvaginal sonography, and serum levels of AMH, FSH and LH were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile patients had similar AMH levels (11%, 95% confidence interval (CI): -1;24%) and AFC (1%, 95% CI: -7;8%) compared with controls with no history of infertility in an age-adjusted linear regression analysis. The prevalence of very low AMH levels (<5 pmol/l) was similar in the two cohorts (age-adjusted odds ratio: 0.9, 95% CI: 0.5;1.7). The findings persisted after adjustment for smoking status, body mass index, gestational age at birth, previous conception and chronic disease in addition to age. LIMITATIONS, REASON FOR CAUTION: The comparison of ovarian reserve parameters in women recruited at different time intervals could be a reason for caution. However, all women were examined at the same centre using the same sonographic algorithm and AMH immunoassay. WIDER IMPLICATIONS OF THE FINDINGS: This study indicates that the frequent observation of patients with a poor response to COS in ART may not be due to an overrepresentation of women with an early depletion of the ovarian reserve but rather a result of the expected age-related decline in fertility. STUDY FUNDING/COMPETING INTERESTS: The study received funding from MSD and the Interregional European Union (EU) projects 'ReproSund' and 'ReproHigh'. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Mullerian hormone.

STUDY QUESTION: What is the prevalence in a normal population of polycystic ovary syndrome (PCOS) according to the Rotterdam criteria versus revised criteria including anti-Müllerian hormone (AMH)? SUMMARY ANSWER: The prevalence of PCOS was 16.6% according to the Rotterdam criteria. When replacing the criterion for polycystic ovaries by antral follicle count (AFC) > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 and 8.5%, respectively. WHAT IS KNOWN ALREADY?: The Rotterdam criteria state that two out of the following three criteria should be present in the diagnosis of PCOS: oligo-anovulation, clinical and/or biochemical hyperandrogenism and polycystic ovaries (AFC ≥ 12 and/or ovarian volume >10 ml). However, with the advances in sonography, the relevance of the AFC threshold in the definition of polycystic ovaries has been challenged, and AMH has been proposed as a marker of polycystic ovaries in PCOS. STUDY DESIGN, SIZE, DURATION: From 2008 to 2010, a prospective, cross-sectional study was performed including 863 women aged 20-40 years and employed at Copenhagen University Hospital, Rigshospitalet, Denmark. PARTICIPANTS/MATERIAL, SETTING, METHODS: We studied a subgroup of 447 women with a mean (±SD) age of 33.5 (±4.0) years who were all non-users of hormonal contraception. Data on menstrual cycle disorder and the presence of hirsutism were obtained. On cycle Days 2-5, or on a random day in the case of oligo- or amenorrhoea, sonographic and endocrine parameters were measured. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of PCOS was 16.6% according to the Rotterdam criteria. PCOS prevalence significantly decreased with age from 33.3% in women < 30 years to 14.7% in women aged 30-34 years, and 10.2% in women ≥ 35 years (P < 0.001). In total, 53.5% fulfilled the criterion for polycystic ovaries with a significant age-related decrease from 69.0% in women < 30 years to 55.8% in women aged 30-34 years, and 42.8% in women ≥ 35 years (P < 0.001). AMH or age-adjusted AMH Z-score was found to be a reliable marker of polycystic ovaries in women with PCOS according to the Rotterdam criteria [area under the curve (AUC) 0.994; 95% confidence interval (CI): 0.990-0.999] and AUC 0.992 (95% CI: 0.987-0.998), respectively], and an AMH cut-off value of 18 pmol/l and AMH Z-score of -0.2 showed the best compromise between sensitivity (91.8 and 90.4%, respectively) and specificity (98.1 and 97.9%, respectively). In total, AFC > 19 or AMH > 35 occurred in 17.7 and 23.0%, respectively. The occurrence of AFC > 19 or AMH > 35 in the age groups < 30, 30-34 and ≥ 35 years was 31.0 and 35.7%, 18.8 and 21.3%, and 9.6 and 18.7%, respectively. When replacing the Rotterdam criterion for polycystic ovaries by AFC > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 or 8.5%, respectively, and in the age groups < 30, 30-34 and ≥ 35 years, the prevalences were 17.9 and 22.6%, 3.6 and 5.6%, and 3.6 and 4.8%, respectively. LIMITATIONS, REASON FOR CAUTION: The participants of the study were all health-care workers, which may be a source of selection bias. Furthermore, the exclusion of hormonal contraceptive users from the study population may have biased the results, potentially excluding women with symptoms of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: AMH may be used as a marker of polycystic ovaries in PCOS. However, future studies are needed to validate AMH threshold levels, and AMH Z-score may be appropriate to adjust for the age-related decline in the AFC. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable.

Intrafollicular endocrine milieu after addition of hCG to recombinant FSH during controlled ovarian stimulation for in vitro fertilization.

CONTEXT: The role of human chorionic gonadotropin (hCG) supplementation on the intrafollicular steroid milieu has been studied. OBJECTIVE: The objective of the study was to assess the impact on steroid levels in follicular fluids (FFs) after different doses of hCG supplementation to recombinant FSH for controlled ovarian stimulation. SETTING: This was a prospective randomized dose-response study conducted at Copenhagen University Hospital, Rigshospitalet, Denmark. PATIENTS: From 62 in vitro fertilization patients, 334 FFs were selected for analyses. INTERVENTIONS: Patients were treated using a GnRH agonist protocol with recombinant FSH 150 IU/d and randomized from stimulation day 1 to supplementation with hCG: D0, 0 IU/d; D50, 50 IU/d; D100, 100 IU/d; and D150, 150 IU/d. MAIN OUTCOME MEASURE: Intrafollicular hormone concentrations in relation to treatment groups, follicular sizes, and embryo quality were measured. RESULTS: In large follicles, hCG supplementation induced a nearly 3-fold increase of estradiol (nanomoles per liter) [D0: 1496; D50: 3138; D100: 4338; D150: 4009 (P < .001)], a significant 3-fold increase of androstenedione, and a 5-fold increase of T (nanomoles per liter) [D0: 15; D50: 38; D100: 72; D150: 56 (P < .001)]. The estradiol to T ratio decreased significantly, with the lowest ratio in D100 and the highest in D0. Large follicles giving rise to good-quality embryos had significantly higher estradiol and progesterone levels and estradiol to T, estradiol to androstenedione, and progesterone to estradiol ratios, compared with small follicles, leading to poor-quality embryos. CONCLUSIONS: Increasing doses of hCG supplementation markedly stimulated the intrafollicular concentration of both estradiol and androgens, with a shift toward a more androgenic milieu. In large follicles with oocytes giving rise to good-quality embryos, the FFs were significantly more estrogenic than in small follicles with oocytes developing into poor quality embryos.

Endocrine effects of hCG supplementation to recombinant FSH throughout controlled ovarian stimulation for IVF: a dose-response study.

OBJECTIVE: To analyse the endocrine response in relation to the Δ-4 and Δ-5 pathways of ovarian steroidogenesis after different doses of human chorionic gonadotrophin (hCG) supplementation to recombinant FSH from Day 1 of controlled ovarian stimulation for IVF. DESIGN: A randomized dose-response pilot study. PATIENTS: A total of 62 IVF patients aged 25-37 years with regular cycles and FSH <12 IU/l were treated with a fixed dose of rFSH 150 IU/day and randomized to four hCG dose groups: Dose 0: 0 IU/day, Dose 50: 50 IU/day, Dose 100: 100 IU/day and Dose 150: 150 IU/day. RESULTS: A significant hCG dose-dependent incremental increase was found for progesterone (49-160%), 17-OH-progesterone (223-614%), androstenedione (91-340%) and testosterone (95-338%) from Dose 0 to Dose 150, respectively. Dehydroepiandrosterone (DHEA) showed minor changes during stimulation and no differences between the groups. The highest oestradiol concentrations were observed in Dose 100 and Dose 150. Sex hormone-binding globulin (SHBG) increased similarly in all groups at the end of stimulation. No difference was observed for anti-müllerian hormone (AMH) concentration between the groups, but a 50% decline from the start to the end of the stimulation was found. CONCLUSION: Supplementation with hCG resulted in a clear dose-related response for androgens, progesterone and 17-OH-progesterone. Oestradiol concentration reached maximum levels with an hCG dose of 100 IU/day, suggesting saturation of aromatase function. No difference between the groups was observed for DHEA, supporting that the stimulatory effects of hCG doses on androgens and oestrogen production were mainly induced via the Δ-5 pathway. SHBG, being a biomarker of oestrogen/androgen balance, was not changed by increasing hCG.

A randomized controlled dose-response pilot study of addition of hCG to recombinant FSH during controlled ovarian stimulation for in vitro fertilization.

STUDY QUESTION: Is it possible to define an optimal dose of hCG in combination with rFSH from the first day of stimulation in the GnRH agonist protocol applied to IVF? SUMMARY ANSWER: Supplementation with hCG from the first day of stimulation may increase the number of top-quality embryos per patient. Daily doses of hCG up to 150 IU are compatible with good live birth rates. A ceiling level of estradiol (E(2)) was reached with hCG doses above 100 IU/day. A positive dose-response was seen for pre-ovulatory progesterone, but concentrations remained below values for which an impairment of endometrial receptivity has been previously reported. We suggest a large clinical trial to be proceeded with a group given 100 IU hCG daily versus a control group. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Prospective multicentre studies have indicated increased live birth rates and increased number of top-quality embryos when low doses of hCG were associated with FSH. We analysed the clinical, embryological and endocrine aspects of adding increasing doses of hCG to rFSH from the first day of stimulation for IVF. DESIGN: A prospective randomized, controlled, open-label dose-response pilot study was conducted between February 2009 and June 2010 at Copenhagen University Hospital, Rigshospitalet, Denmark. Adequate allocation concealment was assured from sequentially numbered, opaque, sealed envelopes prepared from a computer-generated list. Scoring of the embryos was done in an assessor-blinded way. PARTICIPANTS AND SETTING: Endocrinologically normal IVF patients aged 25-37 years, BMI 18-30 kg/m(2), regular cycles and FSH <12 IU/l, were treated with a fixed dose of rFSH 150 IU/day and randomized to daily hCG dose of 0, 50, 100 or 150 IU from Day 1 of stimulation. Primary end-point was the total number of top-quality embryos on Day 3. DATA ANALYSIS METHOD: Data were analysed by analysis of variance, Kruskal-Wallis test, chi-squared test or Poisson distribution count. MAIN FINDINGS: A total of 62 patients were randomized into four hCG dose groups: Dose 0 (D0; n= 16), Dose 50 (D50; n= 15), Dose 100 (D100; n= 16) and Dose 150 (D150; n= 15). Two patients in D150 were withdrawn after randomization because of major (10- to 30-fold) hCG dosing errors, leaving 13 patients in this group. Thus, the results are based on the per protocol population. The mean numbers of top-quality embryos per patient were D0: 0.8 ± 1.2, D50: 0.5 ± 0.7, D100: 1.2 ± 1.7 and D150: 1.5 ± 1.7 (P= 0.04). All pregnancies were singleton gestations, and the live birth rates per started cycle were D0: 25%, D50: 27%, D100: 25% and D150: 31% (P= 0.98). Steady state level of serum (s)-hCG was reached on Day 6 of stimulation. S-hCG levels (IU/l) on the day of hCG administration were D0: <0.1, D50: 3.1 (2.6-3.6), D100: 5.5 (4.1-7.4) and D150: 11.0 (8.9-13.6) (P< 0.01). The patients receiving hCG supplementation were stratified by 33 and 66% percentiles into three groups according to the concentration of s-hCG on Day 6 of stimulation: 0.5-3.5 IU/l (n= 16), 3.5-8.0 IU/l (n= 14) and 8.0-21.1 IU/l (n= 14). The mean numbers of top-quality embryos in the three groups were 0.5 ± 0.9, 1.1 ± 1.8 and 1.5 ± 1.5, respectively (P= 0.03). The progesterone increments from stimulation Day 1 to the day of hCG triggering were D0 = 49%, D50 = 79%, D100 = 110% and D150 = 160% (P= 0.02). S-androstenedione level was highest in D150 (P< 0.01). S-E(2) was 2-fold higher in the D100 and D 150 compared with D0 (P= 0.09). BIAS, LIMITATION, GENERALISABILITY: Our study has a limited sample size. Supplementation with daily hCG dose up to 150 IU throughout stimulation has never been used before. Hence, this had to be tested in a small study before conducting a larger trial. STUDY FUNDING/COMPETING INTERESTS: Ferring Pharmaceuticals, Research and Development, provided funds for the endocrine measurements. CLINICALTRIAL.GOV REGISTRATION: NCT00844311.

Single subcutaneous dosing of cefovecin in rhesus monkeys (Macaca mulatta): a pharmacokinetic study.

Cefovecin is a third-generation cephalosporin approved for antibacterial treatment with a 14-day dosing interval in dogs and cats. This antibiotic may also be useful for zoo and wildlife veterinary medicine, because of its broad spectrum and long duration of activity. The aim of the study was to determine whether cefovecin is a suitable antibiotic to prevent skin wound infection in rhesus monkeys. Therefore, the pharmacokinetics (PK) of cefovecin after a single subcutaneous injection at 8 mg/kg bodyweight in four rhesus monkeys (Macaca mulatta) and sensitivity of bacterial isolates from fresh skin wounds were determined. After administration, blood, urine, and feces were collected, and concentrations of cefovecin were determined. Further, the minimum inhibitory concentrations (MIC) for bacteria isolated from fresh skin wounds of monkeys during a health control program were determined. The mean maximum plasma concentration (C(max) ) of cefovecin was 78 µg/mL and was achieved after 57 min. The mean apparent long elimination half-life (t½) was 6.6 h and excretion occurred mainly via urine. The MIC for the majority of the bacteria examined was >100 µg/mL. The PK of cefovecin in rhesus monkeys is substantially different than for dogs and cats. Cefovecin rapidly reached C(max) which however was lower than most of the MIC levels and with a very short t½. Therefore, cefovecin is not recommended for treating skin wounds in rhesus monkeys.

Left ventricular contractile function after distal protection in primary percutaneous coronary intervention: results from the Drug Elution and Distal Protection in ST-Elevation Myocardial Infarction trial.

BACKGROUND: Coronary intervention (PCI) may result in an increased infarct size. We evaluated the effect of distal protection during PCI for ST-segment elevation myocardial infarction (STEMI) on myocardial function. METHODS: Patients with STEMI were randomly referred within 12 h for PCI with (N = 312) or without distal protection (N = 314). Left ventricular (LV) contractile function was assessed with echocardiography 8 months after PCI. Global LV myocardial wall motion index (WMI) was calculated as the average wall motion score of all myocardial segments. The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI were also recorded. RESULTS: The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI was 7.1% after distal protection and 5.7% after conventional treatment (p = 0.17). WMI improved by 4.1% at 8 months in patients treated with distal protection compared to patients receiving conventional PCI (p < 0.01). In myocardium supplied by a culprit artery treated by distal protection regional LV function was 9-11% higher than myocardial regions treated conventionally ( p < 0.02). CONCLUSIONS: Routine use of distal protection during primary PCI is associated with a significant improvement in LV contractile function, with no detectable impact on intermediate term clinical outcome.

Late coronary stent thrombosis.

Coronary stent thromboses are characterized as early, if they occur within one month of the index PCI. Late stent thromboses (LST) have an occurrence after one month. Both early and late stent thromboses are a major concern in PCI, because of their clinical presentation as acute myocardial infarction and sudden cardiac death. Early stent thromboses are seen following implantation with bare metal (BMS) and drug eluting (DES) stents. Late occurring stent thromboses (LST) are rare but usually severe events and primarily seen after DES implantation. A number of pathogenetic mechanisms seem to be operating and there will probably be major differences between different types DES and the risk of LST. While early stent thrombosis is primarily related to stent implantation techniques, lesion characteristics and the effect of double platelet therapy, there is emerging evidence that very late stent thrombosis, occurring more than one year after the implantation may be caused by local tissue reaction to the polymers of sirolimus and paclitaxel eluting stents. It is likely that the use of new generations DES with tissue friendly polymers or bioabsorbable polymers will reduce the risk of late stent thrombosis.

Spontaneous coronary artery dissection: a Western Denmark Heart Registry study.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS) that associates with a high acute-phase mortality rate, whereas long-term outcome is less well described. OBJECTIVE: To describe the incidence, predictors, and prognosis of SCAD. DESIGN: Retrospective case-identification study from the Western Denmark Heart Registry and the database of the Forensic Institute at Aarhus University from 1999 through 2007. RESULTS: SCAD was documented in 22 of 32,869 (0.7 per thousand) angiograms in the angiographic registry. The SCAD incidence among cases of ACS was 22 of 11,175 (2.0 per thousand). None was seen in the forensic database. The mean age was 48.7 +/- 8.9 years (range: 37-71 years). Females constituted 17 of 22 (77%) patients and all had undergone one or more pregnancies; two cases occurred in the postpartum period. The left descending artery (LAD) was the predominant site of entry. The age distribution, prevalence of the cardiovascular risk factors, presence of coronary atherosclerosis, and entry of the dissection were comparable among genders. Treatment was percutaneous coronary intervention in 13 of 22 (59%), coronary artery bypass operation in 2 of 22 (9%), and medical treatment in 7 of 22 (32%) patients. The mean follow-up period was 3.6 +/- 2.9 years. One patient suffered from recurrent SCAD; another patient died suddenly. The MACE- (cardiac death, nonfatal myocardial infarction, and new revascularization) free survival was 81% after 24 months. CONCLUSION: SCAD is a rare disease that mainly affects younger women. Compared with earlier reports, the prognosis seems to be improved by early diagnosis and interventional treatment.

Primary PCI as the preferred reperfusion therapy in STEMI: it is a matter of time.

There is a continuing controversy about the acceptable time-window for primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction (STEMI). Recent American and European guidelines recommend PPCI if the delay in performing PPCI instead of administering fibrinolysis (PCI-related delay) is <60 min and the presentation delay is more than 3 h. Based on a review of the literature, this viewpoint recommends a revision of the guidelines. The evidence supports an acceptable PCI-related delay of 80-120 min and PPCI as the better reperfusion strategy also in the early incomers. Furthermore, the previous assumption that PPCI is less time-dependent than fibrinolysis is questioned. To maximise the number of patients with STEMI eligible for PPCI the optimal logistic may be to establish the diagnosis in the prehospital phase, to bypass local hospitals and re-route patients directly to catheterisation laboratories running 24/7.

Selected pharmacokinetic parameters for Cefovecin in hens and green iguanas.

The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile hens and green iguanas, following subcutaneous injections with 10 mg cefovecin/kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid absorption with peak plasma concentration of 6 +/- 2 microg/mL in hens and 35 +/- 12 microg/mL in green iguanas. The mean plasma half-life for cefovecin was 0.9 +/- 0.3 h for hens and 3.9 h in green iguanas. Volume of distribution was 1.6 +/- 0.5 L/kg for hens and 0.3 L/kg for green iguanas and clearance was 1252 +/- 185 mL.h/kg for hens and 53 mL.h/kg for green iguanas. Results from preliminary studies did not differ notably from those seen in hens and green iguanas. Cefovecin is not suitable for the treatment of bacterial infections with a 14-day dosing interval in hens or green iguanas and seems not to be in a number of other bird and retile species either.

Negative vascular remodelling after implantation of bioabsorbable magnesium alloy stents in porcine coronary arteries: a randomised comparison with bare-metal and sirolimus-eluting stents.

OBJECTIVE: We sought to assess vascular remodelling and neointima formation after implantation of bioabsorbable magnesium alloy stents (AMS). DESIGN: Randomised experimental study. INTERVENTIONS: AMS (n = 11), sirolimus-eluting stents (Cypher; n = 11) and bare-metal stents (BMS; n = 9) were randomly implanted in 31 porcine coronary arteries (n = 11 pigs). MAIN OUTCOME MEASURES: Neointima formation was measured by histomorphometry at 90 days. Vascular remodelling defined as change in external elastic membrane area from index intervention to follow-up was assessed by serial intravascular ultrasound (IVUS). RESULTS: By histomorphometry, lumen (median (quartiles); AMS: 1.75 mm2 (1.07-3.26), Cypher 2.52 mm2 (2.22-5.01), BMS 4.55 mm2 (3.2-7.44); p = 0.013) and external elastic membrane area (AMS: 5.56 mm2 (4.09-6.95), Cypher 7.95 mm2 (6.45-10.92), BMS 9.08 mm2 (7.85-11.63); p = 0.014) were smallest after AMS implantation. By IVUS, external elastic membrane area at follow-up was smallest (AMS: 7.5 (2.8) mm2, Cypher 9.1 (2.7) mm2, BMS 9.9 (3.1) mm2; p = 0.33) and change in external elastic membrane area from index intervention to follow-up (remodelling; AMS: -1.0 (3.1) mm2, Cypher 1.0 (0.8) mm2, BMS 0.9 (1.2) mm2; p = 0.30) was greatest in the AMS group. In a dichotomised IVUS assessment of vascular remodelling, six AMS stents were remodelled (negative remodelling: n = 5; positive remodelling: n = 1) at 90-day follow-up (AMS versus Cypher + BMS: p = 0.001). Neointima formation was smallest in the AMS group (p<0.05 for both histomorphometry and IVUS). CONCLUSION: Coronary implantation of absorbable magnesium stents, compared to two non-absorbable stents, was associated with the smallest lumen area at three-month follow-up because of negative vascular remodelling.

Myocardial infarction centres: the way forward.

In the era of primary PCI, a strategy of admitting patients to the nearest hospital should be obsolete. Instead, a prehospital diagnostic strategy should be implemented in order to: (1) refer patients directly to interventional centres, thereby eliminating delay at local hospitals; (2) alert the interventional centre, thereby reducing door to balloon times; (3) initiate adjunctive medication in the prehospital phase.

Electromechanical mapping for detection of myocardial viability in patients with ischemic cardiomyopathy.

BACKGROUND: We evaluated the ability of electromechanical mapping of the left ventricle to distinguish between nonviable and viable myocardium in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Unipolar voltage amplitudes and local endocardial shortening were measured in 31 patients (mean+/-SD age, 62+/-8 years) with ischemic cardiomyopathy (ejection fraction, 30+/-9%). Dysfunctional regions, identified by 3D echocardiography, were characterized as nonviable when PET revealed matched reduction of perfusion and metabolism and as viable when perfusion was reduced or normal and metabolism was preserved. Mean unipolar voltage amplitudes and local shortening differed among normal, nonviable, and viable dysfunctional segments. Coefficient of variation for local shortening exceeded differences between groups and did not allow distinction between normal and dysfunctional myocardium. Optimum nominal discriminatory unipolar voltage amplitude between nonviable and viable dysfunctional myocardium was 6.5 mV, but we observed a great overlap between groups. Individual cutoff levels calculated as a percentage of electrical activity in normal segments were more accurate in the detection of viable dysfunctional myocardium than a general nominal cutoff level. The optimum normalized discriminatory value was 68%. Sensitivity and specificity were 78% for the normalized discriminatory value compared with 69% for the nominal value (P:<0.02). CONCLUSIONS: Endocardial ECG amplitudes in patients with ischemic cardiomyopathy display a wide scatter, complicating the establishment of exact nominal values that allow distinction between viable and nonviable areas. Individual normalization of unipolar voltage amplitudes improves diagnostic accuracy. Electroanatomic mapping may enable identification of myocardial viability.