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ABSTRACTObjectives: Handheld medical devices and smartwatches that measure BP without a cuff have recently become available. Since these measurements are relatively more user-friendly than conventional cuff-based measurements they may aid in more frequent BP monitoring. We investigated the accuracy and precision of two popular cuff-less devices: the Everlast smartwatch and the BodiMetrics Performance Monitor.Methods: We enrolled 127 patients from the Thomas Jefferson University Hospital Preadmission Testing Center. Research staff were trained to measure BP according to manufacturer guidelines for the investigational devices. The Everlast smartwatch provides measurements of systolic (SBP) and diastolic (DBP) BP, whereas the Bodimetrics only provides SBP. Reference BP measurements were obtained using a hospital-grade automated sphygmomanometer. After 5 minutes of quiet sitting, four standard and three investigational BP measurements were taken with sixty seconds in between each measurement. The reference BP value was calculated by determining the average of the 2 standard BP measurements that bounded the investigational measurements. We thus determined 3 comparison pairs for each investigational device in each subject. We calculated the mean (SD) of the absolute difference between the respective investigational devices and the reference for SBP and DBP.Results: Data from 42 individuals was excluded because of variation in standard BP measurements per prespecified rules. Of 85 participants used for analysis, 36 (42%) were women, the mean (SD) age was 53 (21) years, 32 (38%) self-reported hypertension, and 97% of these (n = 31) reported taking antihypertensive medications. The average differences between the Everlast watch and reference were 16.9 (13.5) mm Hg for SBP and 8.3 (6.1) mm Hg for DBP. The average difference between the Bodimetrics performance monitor and the reference was 5.3 (4.7) mm Hg for SBP.Conclusions: The Everlast smartwatch and the BodiMetrics Performance Monitor we tested are not accurate enough to be used as BP measurement devices.

AbstractThe purpose of this article is to operationalise an evolutionary perspective on the history of social media and to trace Facebook’s evolution from a social networking site to a “platform-as-infrastructure”. Social media platforms such as Facebook change constantly on the level of their platform architectures, interfaces, governance frameworks, and control mechanisms, all while responding to their larger environments. By examining the evolution of Facebook’s programmability and corporate partnerships, we develop an empirical historical analysis of the platform’s boundary dynamics that ultimately determine its operational scale and scope. Based on our analysis of a unique set of archived primary sources, we discern four main stages in Facebook’s long-term evolution and discuss the interplay between ongoing processes of “platformisation” and “infrastructuralisation”. We argue that these terms foreground complementary aspects of the platform’s efforts in balancing its expansion and adaptability to changing user needs and other “environmental dynamics” without risking its integrations and embedding in other domains, such as advertising, marketing, and publishing. Ultimately, our contribution illustrates how empirical platform histories can denaturalise the current dominant position of social media platforms, such as Facebook, revealing over a decade of incremental evolution rather than revolution.

The Toarcian Oceanic Anoxic Event (T‐OAE, ∼183 Myr) was a long‐lasting episode of ocean deoxygenation during the Early Jurassic. The event is related to a period of global warming and characterized by major perturbations to the hydrological and carbon cycles with high rates of organic matter burial in shelf seas. Ocean circulation during the Toarcian and its influence on marine biogeochemical cycles are still not fully understood. Here we assess the spatial extent of anoxia in the NW Tethys Ocean during the T‐OAE, the relationship with ocean circulation and the impact on organic carbon burial, using new and existing sedimentary records from the European Epicontinental Shelf in combination with general circulation model results. We demonstrate that bottom waters on the southwestern part of the shelf were mainly oxic during the T‐OAE, while those in the northeastern basins were mostly anoxic or even sulfidic. Results for two ocean‐atmosphere models (Fast Ocean‐Atmosphere Model and Massachusetts Institute of Technology general circulation model) suggest the presence of a strong clockwise gyre over the European Epicontinental Shelf, which brought oxygenated equatorial waters from the Tethys Ocean to the southern shelf. The northward limb of the gyre was significantly weakened due to the rough bathymetry of the northern shelf, making this relative small region highly sensitive to local ocean stratification. These sluggish ocean dynamics promoted bottom water anoxia and enhanced burial of organic carbon in the northeastern basins, which accounted for 3–5% of the total carbon extracted from the ocean‐atmosphere system as recorded by the positive carbon isotope shift. The southern European Shelf remained oxygenated during the Toarcian Oceanic Anoxic EventOcean dynamics, notably the Tethyan clockwise gyre, largely controlled bottom water oxygen concentrations on the European ShelfOrganic carbon burial in the European Shelf likely contributed to the termination of the Toarcian Oceanic Anoxic Event

•This long-term study examined the effects of natalizumab treatment at 5.5 years.•Disability worsening events confirmed at 24 weeks may not be sustained at 48 weeks.•Relapses contribute significantly to EDSS worsening.

ABSTRACTPrior to availability of an effective vaccine, an estimated 4 million cases of varicella occurred annually in the United States, resulting in 10,000 hospitalizations and over 100 deaths. With the increased usage of a two-dose varicella vaccine (as recommended by the ACIP), approval of other VZV-containing products and the adoption of varicella vaccination in additional countries, the demand for VZV-containing vaccines has increased. This study (NCT02062502) evaluated the safety, tolerability, and immunogenicity of VARIVAX™ (VAR, varicella vaccine live) manufactured using a new seed manufacturing process (VARNSP) compared to the currently licensed VAR.Healthy children 12–23 months were randomized (1:1) into Group 1 (2 doses of VARNSPgiven concomitantly with M-M-R™ II, ∼3 months apart) versus  Group 2 (2 doses of VAR given concomitantly with M-M-R™ II, ∼3 months apart).  Serum samples collected prior to vaccination on Day 1 and 6 weeks Postdose 1 were tested for antibody to VZV using a glycoprotein enzyme-linked immunosorbent assay (gpELISA).  Safety was assessed Days 1 to 42 following each vaccination.Six weeks Postdose 1, the response rate (percent of subjects with VZV antibody titer ≥5 gpELISA units/mL) of VARNSPwas non-inferior compared to VAR.  Vaccine-related adverse events (AEs) were comparable with the exception of measles-like rash, where a greater number of rashes were observed with VAR than VARNSP.  The 2 vaccination groups were comparable with incidence rates of AEs, injection-site AEs, vaccine-related AEs, systemic AEs, and serious AEs.This new process is an important innovation for the extreme demand of sustaining sufficient supplies of varicella vaccine to protect our communities against diseases caused by VZV.

Fingermark evidence is extensively used in criminal investigations. Hence, there have been many investigations into the chemical compounds present in fingerprint deposits. In this technical note we describe the analysis of non-derivatised amino acid profiles obtained from fingerprints. We used UPLC with an amide stationary phase and subsequent detection using a triple quadrupole MS/MS and TOF-MS detector. The linearity (R2) was satisfactory for both MS detectors (>0.98 for all amino acids in the case of the triple quadrupole MS/MS and >0.96 in the case of the TOF-MS). Although the triple quadrupole had a higher sensitivity for most amino acids, both mass spectrometers were able to retrieve the amino acid profiles of fingerprints from 19 donors. Between these profiles, only minor differences were observed between the separate analyses on the different mass analyzers, mainly in l-proline, l-lysine and l-phenylalanine abundances. Surprisingly, the mean RSD in amino acid profiles from duplicate fingerprints turned out to be lower for the TOF-MS (18.6% ± 6.6% vs.13.2% ± 3.8%), as did the mean RSD of the intraday reproducibility (8.22% ± 1.94% vs.9.54% ± 3.07%).

Cuff-based home blood pressure (BP) devices, which have been the standard for BP monitoring for decades, are limited by physical discomfort, convenience, and their ability to capture BP variability and patterns between intermittent readings. In recent years, cuffless BP devices, which do not require cuff inflation around a limb, have entered the market, offering the promise of continuous beat-to-beat measurement of BP. These devices take advantage of a variety of principles to determine BP, including (1) pulse arrival time, (2) pulse transit time, (3) pulse wave analysis, (4) volume clamping, and (5) applanation tonometry. Because BP is calculated indirectly, these devices require calibration with cuff-based devices at regular intervals. Unfortunately, the pace of regulation of these devices has failed to match the speed of innovation and direct availability to patient consumers. There is an urgent need to develop a consensus on standards by which cuffless BP devices can be tested for accuracy. In this narrative review, we describe the landscape of cuffless BP devices, summarize the current status of validation protocols, and provide recommendations for an ideal validation process for these devices.

ABSTRACTVaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRVAMP) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRVAMPand 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRVAMPversus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRVAMP. Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRVAMPis non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases.

Hypoxia has occurred intermittently in the Baltic Sea since the establishment of brackish‐water conditions at ∼8,000 years B.P., principally as recurrent hypoxic events during the Holocene Thermal Maximum (HTM) and the Medieval Climate Anomaly (MCA). Sedimentary phosphorus release has been implicated as a key driver of these events, but previous paleoenvironmental reconstructions have lacked the sampling resolution to investigate feedbacks in past iron‐phosphorus cycling on short timescales. Here we employ Laser Ablation (LA)‐ICP‐MS scanning of sediment cores to generate ultra‐high resolution geochemical records of past hypoxic events. We show that in‐phase multidecadal oscillations in hypoxia intensity and iron‐phosphorus cycling occurred throughout these events. Using a box model, we demonstrate that such oscillations were likely driven by instabilities in the dynamics of iron‐phosphorus cycling under preindustrial phosphorus loads, and modulated by external climate forcing. Oscillatory behavior could complicate the recovery from hypoxia during future trajectories of external loading reductions. Hypoxia in the coastal ocean is expanding worldwide, and inputs of nutrients from waste water and agriculture are mainly to blame. Nutrients feed plankton blooms, which then consume oxygen as they decay. Because much of this decay takes place at the seafloor, sediments play an important role in deoxygenation, and in the recycling of nutrients in coastal regions. It is known that the amount of iron oxides in sediments has a strong effect on nutrient recycling during algal decay. Iron oxide‐rich sediments in healthy oxygen‐rich areas can trap phosphorus, a key nutrient element from decaying algae. In contrast, iron oxide‐poor sediments in deoxygenated areas release phosphorus back to the water to fuel more algal growth. Our study shows that changes in the distribution of iron oxides between deep and shallow areas of the Baltic Sea led to self‐sustaining variability (oscillations) in oxygen stress on decadal timescales during past intervals in the Sea's 8000‐year history. We use a model to demonstrate that under certain conditions of climate and nutrient pressure, such variability may occur naturally, and therefore may influence the future recovery of the Baltic Sea from its present nutrient‐rich state. Past hypoxic intervals in the Baltic Sea were characterized by multidecadal oscillations in oxygen stressRegularly paced internal oscillations caused by feedbacks in coupled iron‐phosphorus dynamicsExternal loading of phosphorus and climate forcing dictate the amplitude of internal oscillatory behavior Past hypoxic intervals in the Baltic Sea were characterized by multidecadal oscillations in oxygen stress Regularly paced internal oscillations caused by feedbacks in coupled iron‐phosphorus dynamics External loading of phosphorus and climate forcing dictate the amplitude of internal oscillatory behavior

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild sideeffects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.

Introduction: Hereditary Spherocytosis (HS) is the most common red cell membrane disorder. 25-30% of cases involve the SPTB gene which encodes for β-Spectrin, a protein that maintains red blood cell shape. Heterozygous variants in SPTB are associated with autosomal dominant HS and elliptocytosis. While genetic testing is not routinely done to confirm HS, it is useful in atypical presentations.

To demonstrate the safety and efficacy of tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy.

OBJECTIVE: To determine if participation of the spouse of patients with rheumatoid arthritis in cognitive-behavioral oriented self-management training aimed at improving disease related cognitions and coping with pain has additional benefits for the patients. METHODS: A total of 59 couples were randomly assigned to 2 conditions. In the experimental condition the couples participated in a group program aimed at restructuring disease related cognitions and decreasing passive coping. In the control condition, only the patient participated. Disease status, self-reported physical and psychological functioning, coping, disease related cognitions, and marriage characteristics were assessed prior to the intervention and 2 weeks and 6 months postintervention. A general linear model with repeated measures was used to test for differences between conditions. RESULTS: In both conditions, similar positive changes in disease activity, cognitions, coping, and physical and psychological functioning were observed. Patients reported a decrease in potential support. There were no differences between conditions. However, at the followup assessment patients in the experimental condition reported more improvement of disease related communication with their spouse. CONCLUSION: No evidence was found for additional beneficial effects of spouse participation in the cognitive-behavioral oriented self-management group treatment.

Acromegaly was diagnosed in a 14‐year‐old domestic short

Objective To investigate the effects of 24 months of tibolone treatment on the endometrium in postmenopausal women. Design An open, prospective, multicenter study with a treatment duration of 24 months. Population One hundred and fifty healthy postmenopausal women. Methods Women were treated with one tablet of tibolone (2.5 mg Org OD14) daily. Endometrial biopsies were taken at baseline, 12 months (n = 112) and 24 months (n = 62) to investigate endometrial histology by means of light microscopy. Results No stimulation of atrophic endometrium was observed in 98.2% and 91.9% of the analyzed women after 12 and 24 months, respectively. A change from an atrophic endometrial pattern to a weakly proliferative pattern was seen in 1.8% (95% confidence interval (CI) 0.22-6.45) and 6.5% (95% CI 1.20-7.51) of the women after 12 and 24 months, respectively. In one woman, the endometrial pattern after 24 months was classified as simple hyperplasia (1.6%; 95% CI 0.01-3.20). The low incidence of proliferation and/or hyperplasia corresponds to that seen in other clinical trials in which women have been treated with placebo. Vaginal bleeding and/or spotting was reported by 18 women (12%), all showing an atrophic endometrium at all assessments, except for one woman with a proliferative endometrium at 24 months. Conclusion In the majority of women (92%), the endometrium remained atrophic during 24 months of tibolone treatment.

9 Cases of endometriosis in rhesus monkeys were found in a colony of 35 females, which had undergone in the past X-ray treatment or one or more Caesarean sections and/or one or more treatments with gonadal steroids. Incidence, pathogenesis, clinical symptoms, histology and treatment are described.

An experiment was conducted on three farms to study the relationship between the results of an oral glucose tolerance test on d 104 ± 4 of pregnancy and subsequent reproductive performance of 104 multiparous sows. After an overnight period without feed, sows were fed (3 g/kg BW.75) glucose, and blood samples were taken for analyses of glucose at −10, 10, 20, 30, 40, 50, 60 70, 80, 90, 105, and 120 min after administration of glucose. Glucose concentrations before glucose administration ranged from 2.0 to 3.6 mmol/L. Sows with lesser pretest glucose concentrations had longer (P<.01) durations of pregnancy (corrected for number of live pigs born) and heavier (P<.05) pigs at birth (corrected for farm and number of live pigs born). Peak glucose concentrations and areas under the curves (i.e., first 70 min and entire 120 min) ranged from .1 to 4.4 mmol/L, −40 to 211 (mmol/L)·min, and −95 to 247 (mmol/L).min, respectively. Sows with greater (P<.01) peak concentration of glucose and greater area under the curve (first 70 min [P<.01] and entire 120 min [P<.01]) had increased pig mortality during the first 7 d after farrowing (corrected for live weight of the sows). In 83 sows, a sample of morning urine (before feeding) was collected and tested for glucose and ketone bodies. Neither glucose nor the ketone body acetoacetic acid was detected in the urine. The results indicate that sows that are less glucose-tolerant have greater pig mortality.

Two experiments were performed. The first experiment was done to study the effects of dietary energy source on plasma insulin concentration using five gilts in a Latin square design with two diets over two periods. The diets contained either 200 g/kg of cornstarch (Starch) or soybean oil (Fat) as energy sources. Results indicate that insulin response was greater in the Starch-fed than in the Fat-fed gilts. A second experiment was performed in which 18 multiparous sows were fed one of the two experimental diets from farrowing until slaughter at d 35 of subsequent pregnancy. All sows nursed nine pigs. Blood samples were taken from a permanent jugular vein catheter every 12 min during a 12-h period on d 109 ± 1 of pregnancy, on d 7 ± 1, 14 ± 1, and 21 ± 1 of lactation, and on the day of weaning (d 22 ± 1). From 48 h after weaning, blood samples were taken every 4 h until 24 h after ovulation. After that, blood samples were taken at 12-h intervals until d 10 after ovulation. Differences between diets in insulin response were not significant. In Starch-fed sows, LH pulsatility at d 7 of lactation was greater (P< .05), the preovulatory LH surge was greater (P< .05), and progesterone production was greater (P< .05) from 108 h until 256 h after the LH surge than in the Fat-fed sows. Results indicate that feeding Starch-rich diets to multiparous sows compared with Fat-rich diets, on an isocaloric basis, increases LH pulsatility during early lactation, the preovulatory LH surge, and progesterone production after the LH surge.

In a longitudinal experiment, the influence of tethered housing (a condition of chronic stress) on the reactivity of the adrenal cortex to exogenous ACTH was investigated in gilts. To that end, the plasma Cortisol response to synthetic ACTH (1–24; 10 μg/kg of BW; i.v. bolus injection via a permanent catheter) was determined before and after prolonged tethered housing. Two systems for tethered housing were used, one more restrictive than the other with regard to possibilities for visual and tactile contacts with conspecifics and visual control over the environment. The ACTH treatment induced a marked, transient plasma Cortisol response in all gilts studied, irrespective of their housing conditions. Long-term tethered housing increased the ACTH-induced Cortisol response. Possible effects of the experimental procedure or age-related effects could be excluded, because in control gilts, which were housed loose during the entire experimental period, the Cortisol response to ACTH remained unaltered. The chronic stress-induced increase in the ACTH-induced Cortisol response was considerably more pronounced and persistent in gilts that were deprived of possibilities for social contacts with conspecifics and visual control over the environment than in gilts with such possibilities. These data indicate that in tethered gilts adaptational changes occur at the level of the adrenal cortex that affect the ACTH-induced adrenocortical response. In addition, not only physical restraint but also restriction of social contact and visual control play an important role in the development of these changes.

Janssens CJJG, Helmond FA, Wiegant VM. Chronic stress and pituitary–adrenocortical responses to corticotropin-releasing hormone and vasopressin in female pigs. Eur J Endocrinol 1995;132:479–86. ISSN 0804–4643Effects of long-term tethered housing (a condition of chronic stress) on pituitary-adrenocortical responsiveness to exogenous corticotropin-releasing hormone (CRH) and lysine8-vasopressin (LVP) were investigated in female pigs. Intravenous administration of CRH (dose range 10–440 pmol/kg body wt) or LVP (10–880 pmol/kg body wt) elicited transient and dose-related increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol. Comparison of the responses induced by the peptides indicated that CRH is a more potent ACTH secretagogue than LVP. Treatment with LVP produced a fivefold greater plasma cortisol/ACTH ratio than treatment with CRH, suggesting that in addition to stimulating pituitary ACTH release it enhanced the ability of the adrenal cortex to secrete cortisol in response to ACTH. Whereas concomitant administration of 10 pmolCRH/kg body wt and 20 pmol LVP/kg body wt revealed an additive effect on ACTH release, synergism between both peptides was found with respect to their cortisol-releasing effect. Ten to thirteen weeks of chronic stress did not alter significantly the absolute ACTH and cortisol responses to the two peptides. In tethered pigs, the cortisol/ACTH ratio after CRH treatment, calculated from the area under the curve, was twofold that in loose-housed pigs. From these observations we conclude that after chronic stress the sensitivity of the adrenocortex to circulating ACTH was increased, whereas the sensitivity of the pituitary to CRH and/or LVP remained unaltered.Frans A Helmond, Department of Human and Animal Physiology, Wageningen Agricultural University, Haarweg 10, 6709 PJ Wageningen, The Netherlands

Phospholipase C-β(PLC-β) signalling via protein kinase C (PKC) has been recognized as a major route by which stimuli such asα1-adrenergic agonists, endothelin-1 (ET-1) and angiotensin II (Ang II) induce hypertrophy of myocytes. The goal of this study was to evaluate the role of phospholipase D (PLD) in contributing to the formation of the PKC activator 1,2-diacylglycerol (1,2-DAG) and to study the mechanism(s) of PLD activation by agonists. Stimulation of serum-free cultured neonatal rat cardiomyocytes with ET-1 (10−8m), phenylephrine (PHE, 10−5m) or Ang II (10−7m) resulted in a rapid (0–10 min) activation of PLC-βto an extent (ET-1>PHE>Ang II) that correlated with the magnitude of stimulation of protein synthesis ([3H]leucine incorporation into protein) measured after 24 h. Phorbol 12-myristate 13-acetate (PMA, 10−6m) and ET-1 were equipotent in stimulating protein synthesis. ET-1 and PMA, but not PHE and Ang II stimulated [3H]choline formation from labelled PtdCho after a lag-phase of about 10 min. That this [3H]choline formation was due to the action of PLD was confirmed by measurement of phosphatidylgroup-transfer from cellular [14C]palmitoyl-phosphatidylcholine to exogenous ethanol. ET-1 and PHE, to much lesser extent, produced a rapid (0–5 min) translocation of PKC-εimmunoreactivity from the cytosol to the membrane fraction, whereas no intracellular redistribution of PKC-α, -δand -ξimmunoreactivities was observed. PMA caused translocation of PKC-α, PKC-εas well as PKC-δ. Cellular redistribution of PKC activity measured by [32P]-incorporation into histone III-S was not observed with ET-1 and PHE, but only with PMA stimulation. Down-regulation of PKC isozymes by 24 h pretreatment of cells with PMA or blockade of PKC by chelerythrine (10−4m) inhibited ET-1 and PMA stimulated [3H]choline production. Staurosporine (10−6m) had, however, no effect. In conclusion, the results indicate that in serum-free cultured cardiomyocytes, ET-1 initially activates PLC-βand after a lag-phase PLD, whereas PHE and Ang II activate only PLC-β. PLC-βstimulated by ET-1, may cross-talk with PLD via translocation of PKC-ε. These signals are possibly linked to the hypertrophic response.

The activin and TGF-β type II receptors are members of a separate subfamily of transmembrane receptors with intrinsic protein kinase activity, which also includes the recently cloned TGF-β type I receptor. We have isolated and characterized a cDNA clone (C14) encoding a new member of this subfamily. The domain structure of the C14-encoded protein corresponds with the structure of the other known transmembrane serine/threonine kinase receptors. It also contains the two inserts in the kinase domain that are characteristic for this subfamily. Using in situ hybridization, C14 mRNA was detected in the mesenchymal cells located adjacent to the müllerian ducts of males and females at day 15 (E15) of embryonic development. Marked C14 mRNA expression was also detected in the female gonads. In female E16 embryos, the C14 mRNA expression pattern remained similar to that in E15 embryos. However, in male E16 embryos C14 mRNA was detected in a circular area that includes the degenerating müllerian duct. The expression of C14 mRNA was also studied using RNase protection assays. At E15 and E16, C14 mRNA is expressed in the female as well as in the male urogenital ridge. However, at E19, a high C14 mRNA level in the female urogenital ridge contrasts with a lack of C14 mRNA in the male urogenital ridge. This correlates with the almost complete degeneration of the müllerian ducts in male embryos at E19. C14 mRNA expression was also detected in embryonic testes at E15, E16 and E19 using RNase protection assays, but at much lower levels than those found in the developing ovaries. In eleven other tissues no C14 mRNA was observed. The results point to anti-müllerian hormone (AMH) being the most likely candidate ligand for C14. The embryonic C14 mRNA expression pattern in the urogenital ridge correlates with the expected site of AMH action, and C14 mRNA expression in the fetal ovary is in agreement with known effects of AMH on gonadal differentiation. Postnatal C14 mRNA expression in rats was found to be confined mainly to the gonads. In the testis, C14 mRNA expression occurs in Sertoli cells. This testicular expression markedly increases during the first 3 weeks after birth, concurrent with the onset of spermatogenesis.

The DiskusTM/AccuhalerTM inhaler (D/A) is a new multidose powder inhaler, designed to deliver all asthma drugs. This study was carried out to establish clinical equivalence between FP 250 μg twice daily (b.i.d.) via the D/A and FP 250 μg b.i.d. via the current powder inhaler, the Diskhaler (DH). Also, device handling and patient preference for both devices were determined. This was a multicenter, randomized, double-blind, double-dummy, parallel-group study. Adult asthmatics (364, aged 18-79) requiring inhaled corticosteroids in a daily dosage of 400 μg up to and including 1000 μg and demonstrating a mean morning peak expiratory flow rate (PEFR) calculated from the last 7 days of the run-in of less than 85% of the response after salbutamol, a baseline forced expiratory volume in 1 sec (FEV1 between 50 and 90% of their predicted normal value, and an ability to correctly use both devices, were randomized to a 12-week treatment period. No statistically significant differences between the two devices were seen for mean morning PEFR (p = 0.76), mean evening PEFR (p = 0.88), median daytime and nighttime symptom score (p = 0.57 and p = 0.47), median percentage of rescue-free days and nights (p = 0.43 and p = 0.24), and clinic visit lung function. No differences in the safety profile of FP were seen. Patients found the D/A easier to use and easier with respect to assessing the number of doses remaining (both p < 0.001). Sixty-five percent of the patients expressed an overall preference for the D/A over the DH (p < 0.001). The results show that FP 250 μg b.i.d. via the D/A is clinically equivalent to delivery via the DH. Both treatments proved to be equally safe and were well tolerated. The D/A was easier to use and patients preferred the D/A over the DH.

Summary.Blastocysts were flushed out of both uterine horns of gilts on Days 10, 11, 12 or 13. In mated non-pregnant gilts flushing had no effect on progesterone profile or cycle length (20·8 ± 0·4 versus 20·6 ± 0·6 days in the preflush cycle, N = 6, mean ± s.e.m.). Flushing the blastocysts out of the uterine horns on Day 10 resulted in a cycle with a normal progesterone profile and a normal length (21·2 ± 0·4 days, N = 5). Flushing on Days 11, 12 or 13 resulted in a normal cycle or in maintenance of the CL for 3–13 days as indicated by elevated progesterone concentrations and an increased interoestrous interval of, respectively, 22·0 ± 1·2 versus 19·8 ± 0·6 days (Day 11; N = 6), 24·8 ± 1·4 versus 21·0 ± 0·6 days (Day 12; N = 5; P< 0·05) and 26·3 ± 2·3 versus 20·5 ± 0·4 days (Day 13; N = 6; P< 0·05). There was a positive relationship between the change in interoestrous interval and the interval between the first observed standing oestrus and flushing of the blastocysts (rs= 0·350; n= 22; P< 0·1). There was a large variation in the diameter of the blastocysts flushed on the same day. Only in those gilts in which the blastocysts were ≥ 8 mm or filamentous were the CL maintained for 3 or more days. These results indicate that a first signal for maternal recognition of pregnancy is generated on Day 12 and that blastocysts ≥ 8 mm are required for prolongation of CL function for 3 or more days. Since CL function is only extended for a maximum of 13 days (mean 7·4 ± 1·0), a second signal seems necessary to maintain the CL for the whole period of pregnancy.Keywords:CL; blastocysts; pregnancy; progesterone; pig