Influence of the long-term use of oral hygiene products containing stannous ions on the salivary microbiome - a randomized controlled trial.

Oral hygiene products containing tin are suitable to prevent erosive tooth wear, yet effects on the oral microbiota are not known yet. Therefore, this study determined the salivary microbiome of 16 participants using products with stannous ions for three years (TG) compared with a control group (CG) to assess their influence on the microbiota. Participants were included in a randomized controlled clinical trial (RCT) with biannual visits. Illumina Miseq sequencing revealed as most abundant genera: Streptococcus (TG 14.3%; CG 13.0%), Veillonella (TG 11.3%; CG 10.9%), Prevotella (TG 7.0%; CG 9.8%), Haemophilus (TG 6.6%; CG 7.2%), Porphyromonas (TG 5.9%, CG 5.1%), Leptotrichia (TG 5.8%; CG 4.9%), Actinomyces (TG 4.0%; CG 4.6%) and Neisseria (TG 5.4%; CG 4.2%). Beta-Diversity was not significantly different between groups at both time points, although significant differences between groups were found for certain taxa after three years. The genus Prevotella was found in higher abundance in CG whereas Neisseria and Granulicatella, health-associated taxa, were found more abundantly in TG. Salivary microbiota after three years reflected a composition associated with oral health, hence continual use as a preventive measure for dental erosion can be considered safe and benefitting oral health for patients with a high risk of erosion.

International collaborative study for the calibration of proposed International Standards for thromboplastin, rabbit, plain, and for thromboplastin, recombinant, human, plain.

Essentials Two candidate International Standards for thromboplastin (coded RBT/16 and rTF/16) are proposed. International Sensitivity Index (ISI) of proposed standards was assessed in a 20-centre study. The mean ISI for RBT/16 was 1.21 with a between-centre coefficient of variation of 4.6%. The mean ISI for rTF/16 was 1.11 with a between-centre coefficient of variation of 5.7%. SUMMARY: Background The availability of International Standards for thromboplastin is essential for the calibration of routine reagents and hence the calculation of the International Normalized Ratio (INR). Stocks of the current Fourth International Standards are running low. Candidate replacement materials have been prepared. This article describes the calibration of the proposed Fifth International Standards for thromboplastin, rabbit, plain (coded RBT/16) and for thromboplastin, recombinant, human, plain (coded rTF/16). Methods An international collaborative study was carried out for the assignment of International Sensitivity Indexes (ISIs) to the candidate materials, according to the World Health Organization (WHO) guidelines for thromboplastins and plasma used to control oral anticoagulant therapy with vitamin K antagonists. Results Results were obtained from 20 laboratories. In several cases, deviations from the ISI calibration model were observed, but the average INR deviation attributabled to the model was not greater than 10%. Only valid ISI assessments were used to calculate the mean ISI for each candidate. The mean ISI for RBT/16 was 1.21 (between-laboratory coefficient of variation [CV]: 4.6%), and the mean ISI for rTF/16 was 1.11 (between-laboratory CV: 5.7%). Conclusions The between-laboratory variation of the ISI for candidate material RBT/16 was similar to that of the Fourth International Standard (RBT/05), and the between-laboratory variation of the ISI for candidate material rTF/16 was slightly higher than that of the Fourth International Standard (rTF/09). The candidate materials have been accepted by WHO as the Fifth International Standards for thromboplastin, rabbit plain, and thromboplastin, recombinant, human, plain.

Placental SEMA3B expression is not altered in severe early onset preeclampsia.

Recent evidence suggests that Semaphorin 3B (SEMA3B) is upregulated in severe preeclampsia, and a major driver of cytotrophoblast aberrations in this disease. Here we independently assess whether SEMA3B expression is altered in a large cohort of severe early onset preeclamptic placentas. We demonstrate that SEMA3B relative mRNA expression and copy number are not changed in PE placentas. We confirm this at the protein level by western blot. Interestingly, exposure of term trophoblasts or explants to hypoxia induced a significant down regulation of SEMA3B mRNA, but a trend towards increased SEMA3B protein expression. We conclude that SEMA3B mRNA and protein is not altered in severe early onset preeclamptic placentas.

Endometrial signals improve embryo outcome: functional role of vascular endothelial growth factor isoforms on embryo development and implantation in mice.

STUDY QUESTION: Does vascular endothelial growth factor (VEGF) have important roles during early embryo development and implantation? SUMMARY ANSWER: VEGF plays key roles during mouse preimplantation embryo development, with beneficial effects on time to cavitation, blastocyst cell number and outgrowth, as well as implantation rate and fetal limb development. WHAT IS KNOWN ALREADY: Embryo implantation requires synchronized dialog between maternal cells and those of the conceptus. Following ovulation, secretions from endometrial glands increase and accumulate in the uterine lumen. These secretions contain important mediators that support the conceptus during the peri-implantation phase. Previously, we demonstrated a significant reduction of VEGFA in the uterine cavity of women with unexplained infertility. Functional studies demonstrated that VEGF significantly enhanced endometrial epithelial cell adhesive properties and embryo outgrowth. STUDY DESIGN, SIZE, DURATION: Human endometrial lavages (n = 6) were obtained from women of proven fertility. Four-week old Swiss mice were superovulated and mated with Swiss males to obtain embryos for treatment with VEGF in vitro. Preimplantation embryo development was assessed prior to embryo transfer (n = 19-30/treatment group/output). Recipient F1 female mice (8-12 weeks of age) were mated with vasectomized males to induce pseudopregnancy and embryos were transferred. On Day 14.5 of pregnancy, uterine horns were collected for analysis of implantation rates as well as placental and fetal development (n = 14-19/treatment). PARTICIPANTS/MATERIALS, SETTING, METHODS: Lavage fluid was assessed by western immunoblot analysis to determine the VEGF isoforms present. Mouse embryos were treated with either recombinant human (rh)VEGF, or VEGF isoforms 121 and 165. Preimplantation embryo development was quantified using time-lapse microscopy. Blastocysts were (i) stained for cell number, (ii) transferred to wells coated with fibronectin to examine trophoblast outgrowth or (iii) transferred to pseudo pregnant recipients to analyze implantation rates, placental and fetal development. MAIN RESULTS AND THE ROLE OF CHANCE: Western blot analysis revealed the presence of VEGF121 and 165 isoforms in human uterine fluid. Time-lapse microscopy analysis revealed that VEGF (n = 22) and VEGF121 (n = 23) treatment significantly reduced the preimplantation mouse embryo time to cavitation (P < 0.05). VEGF and VEGF165 increased both blastocyst cell number (VEGF n = 27; VEGF165 n = 24: P < 0.001) and outgrowth (n = 15/treatment: 66 h, P < 0.001; 74, 90, 98 and 114 h, P < 0.01) on fibronectin compared with control. Furthermore, rhVEGF improved implantation rates and enhanced fetal limb development (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Due to the nature of this work, embryo development and implantation was only examined in the mouse. WIDER IMPLICATIONS OF THE FINDINGS: The absence or reduction in levels of VEGF during the preimplantation period likely affects key events during embryo development, implantation and placentation. The potential for improvement of clinical IVF outcomes by the addition of VEGF to human embryo culture media needs further investigation. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a University of Melbourne Early Career Researcher Grant #601040, the NHMRC (L.A.S., Program grant #494802; Fellowship #1002028; N.J.H., Fellowship # 628927; J.E.; project grant #1047756) and L.A.S., Monash IVF Research and Education Foundation. N.K.B. was supported by an Australian Postgraduate Award. Work at PHI-MIMR Institute was also supported by the Victorian Government's Operational Infrastructure Support Program. There are no conflicts of interest to declare.

The German national registry for primary immunodeficiencies (PID).

In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.

The European internet-based patient and research database for primary immunodeficiencies: update 2011.

In order to build a common data pool and estimate the disease burden of primary immunodeficiencies (PID) in Europe, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Since its start in 2004, 13,708 patients from 41 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity with 2880 patients or 21% of all entries, followed by selective immunoglobulin A (sIgA) deficiency (1424 patients, 10·4%). The total documented prevalence of PID is highest in France, with five patients per 100,000 inhabitants. The highest documented prevalence for a single disease is 1·3 per 100,000 inhabitants for sIgA deficiency in Hungary. The highest reported incidence of PID per 100,000 live births was 16·2 for the period 1999-2002 in France. The highest reported incidence rate for a single disease was 6·7 for sIgA deficiency in Spain for the period 1999-2002. The genetic cause was known in 36·2% of all registered patients. Consanguinity was reported in 8·8%, and 18·5% of patients were reported to be familial cases; 27·9% of patients were diagnosed after the age of 16. We did not observe a significant decrease in the diagnostic delay for most diseases between 1987 and 2010. The most frequently reported long-term medication is immunoglobulin replacement.

Advances in type I diabetes associated tolerance mechanisms.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. The polygenic trait for T1D risk implicates many genes that have an impact on fundamental immunological processes such as central and peripheral tolerance. Several pieces of evidence have suggested that many of the genetic loci that are directly linked to type 1 diabetes susceptibility modulate the generation and/or the activation of autoreactive T-lymphocytes. We and others have proposed a critical role for medullary thymic epithelial cells (mTEC) forming the Hassall's corpuscles in T-cell tolerance. Indeed, mTEC have been found to express promiscuous self-antigens, used directly or through thymic dendritic cells to drive either negative selection of insulin-reacting precursors or their differentiation into naturally occurring regulatory Foxp3+ CD4+ CD25+ T cells. In the periphery, naturally occurring Foxp3+ CD4+ CD25+regulatory T (Treg) cells represent the master cells in dominant peripheral T-cell tolerance. The development and function of Treg cells are ultimately linked to IL-2 and Foxp3 expression. This review addresses recent literature and emerging concepts of central and peripheral T-cell tolerance with regards to T1D.

Contraceptive efficacy and safety of a low-dose oral contraceptive, (0.03 mg ethinyl oestradiol and 2 mg chlormadinone acetate) Belara, over three medication cycles.

OBJECTIVE: To describe the modulation of ovarian function during three medication cycles with 0.03 mg ethinyl oestradiol (EE) and 2 mg chlormadinone acetate (CMA), leading to inhibition of conception in healthy women. METHODS: Phase II, single-centre, open, non-controlled trial. The main outcome measure was inhibition of ovarian activity, assessed by frequent monitoring of the presence, size and persistence of follicle-like structures using ultrasonography. Secondary parameters included: cervical reaction score (CRS-probability of fertilization), endometrial thickness (probability of nidation), and serum levels of the sex hormones oestradiol, progesterone, luteinizing hormone and follicle stimulating hormone. Safety was primarily assessed by monitoring the occurrence of adverse events. RESULTS: Thirty-three subjects were eligible for the trial and were included in the efficacy assessment (per protocol analysis, PPA). All subjects ovulated during the pretreatment cycle, but none during the three medication cycles. Follicular growth was profoundly suppressed during the medication phase, with residual ovarian activity occurring in only 12/83 (14.5%) treatment cycles. The CRS was negative during each medication cycle and endometrial thickness was suppressed on each medication day, with median values of 4.0-6.0 mm. EE/ CMA was well tolerated, with few adverse events reported; most were typically cycle-related and included headache, breast discomfort, nausea and vomiting. CONCLUSION: During the administration of EE/CMA follicular development, cervical reaction and endometrial thickness are profoundly suppressed, resulting in unfavourable conditions for fertilization, implantation and, thus, pregnancy.

A robotic C-arm fluoroscope.

Fluoroscopic C-arms are common devices for acquiring images during surgery. Manual positioning is time consuming and requires considerable experience. Trained users must often take several images to find the best viewing direction. If a second image must be taken from the same position, e.g. for postoperative control, the C-arm must be moved to the exact same position. Without guidance, this is often difficult to accomplish. We developed the idea to completely "robotize" a standard C-arm, i.e. to equip all joints with motors and encoders. A software environment provides for intelligent control. To archive this goal a complete kinematic analysis of the fluoroscope was necessary. On the basis of this analysis a number of clinical applications have been developed: (1) simplified positioning via cartesian control; (2) automatic acquisition of panoramic images; (3) 3D CT with arbitrary viewing angles; (4) 4D intraoperative CT with/without respiration triggering; (5) automated anatomy-oriented positioning. The goal of this research is thus three-fold: minimise radiation exposure of the OR staff, reduce positioning time and offer enhanced imaging capability.

Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon).

BACKGROUND AND OBJECTIVE: Acne in women can often be successfully treated by the intake of oral contraceptives containing gestagens with anti-androgenic properties. This study aimed to evaluate the efficacy of the monophasic oral contraceptive ethinylestradiol/chlormadinone acetate (EE/CMA; Belara for the treatment of mild to moderate papulopustular acne of the face and acne-related disorders in comparison to EE/levonorgestrel (LNG; Microgynon. METHODS: 199 female acne patients were enrolled in a single-blind, randomized, multicentre phase III study and divided into two groups who received either EE/CMA or EE/LNG. The primary end point was fulfilled if the number of papules/pustules per half of the face present on admission had decreased by at least 50% in the 12th medication cycle. RESULTS: 59.4% of the women under EE/CMA and 45.9% under EE/LNG were responders. The relative frequency of women with complete resolution was 16.5% under EE/CMA and 4.3% under EE/LNG at cycle 12. CONCLUSION: EE/CMA is an efficient treatment for women with mild and moderate papulopustular acne of the face and related disorders, reflecting the well-known anti-androgenic properties of the progestogen CMA.

Continuous insulin intravenous infusion therapy for VLBW infants.

Very low birth weight (VLBW) infants less than 1,000 g often experience hyperkalemia and hyperglycemia during the initial hospital course. Hyperkalemia has been noted in 44% to 50% of infants less than 800 g birth weight or less than 28 to 29 weeks' gestation. Hyperglycemia occurs 18 times more frequently in infants less than 1,000 g than in those weighing more than 2,000 g. Insulin has been used for VLBW infants less than 1,000 g to manage hyperkalemia, control hyperglycemia, and optimize parenteral nutrition. A protocol for using exogenous insulin therapy for VLBW infants is described.

The mere exposure effect is differentially sensitive to different judgment tasks.

The mere exposure effect is the increase in positive affect that results from the repeated exposure to previously novel stimuli. We sought to determine if judgments other than affective preference could reliably produce a mere exposure effect for two-dimensional random shapes. In two experiments, we found that brighter and darker judgments did not differentiate target from distracter shapes, liking judgments led to target selection greater than chance, and disliking judgments led to distracter selection greater than chance. These results for brighter, darker, and liking judgments were obtained regardless of whether shape recognition was greater (Experiment 1) or not greater (Experiment 2) than chance. Effects of prior exposure to novel shapes were reliably observed only for affective judgment tasks. These results are inconsistent with general predictions made by the nonspecific activation hypothesis, but not the affective primacy or perceptual fluency hypotheses which were discussed in terms of cognitive neuroscience research.

Myoendometrial versus placental uterine arteries: structural, mechanical, and functional differences in late-pregnant rabbits.

OBJECTIVE: This study compared late-pregnant radial uterine arteries that supplied the placenta versus the myoendometrium to evaluate differences in active and passive mechanical properties. STUDY DESIGN: Pressurized segments of placental versus myoendometrial radial uterine arteries from late-pregnant (day 28 to 30) New Zealand White rabbits (n = 12) were compared in vitro for differences in luminal diameter, wall thickness, distensibility, and intrinsic tone as a function of transmural pressure. RESULTS: Both types of arteries responded to increased transmural pressure with active vasoconstriction; however, the amount of tone present in myoendometrial arteries was significantly greater than in placental arteries (percent tone at 75 mm Hg = 39% +/- 3% for myoendometrial versus 31% +/- 2% for placental arteries, p < 0.01). Measurements of unpressurized, fully relaxed arteries revealed that placental arteries were 38% larger in diameter and had thicker walls than myoendometrial arteries did. However, myoendometrial arteries were significantly more distensible at transmural pressures >5 mm Hg. CONCLUSIONS: The increased size and diminished tone of placental compared with adjacent myoendometrial arteries would favor increased blood flow to the placenta; differences in size and passive mechanical properties suggest that a localized factor(s) originating from the fetus or placenta contributes to the gestational enlargement of those arteries that perfuse the placenta.

IGF-II and IGF-binding proteins increase dramatically during rabbit pregnancy.

During pregnancy, changes in the IGF axis are associated with changes in maternal metabolism and nutrient repartitioning which are necessary to meet the demands of a growing conceptus. The aim of this study was to assess the IGF axis, maternal weight changes and food intake in female New Zealand White rabbits (n = 7) prior to breeding (day 0) and serially throughout pregnancy until term (day 30-31). The total weight of the pregnant does progressively increased from 4.03 +/- 0.06 kg (mean +/- S.E.M.) on day 0 to 4.47 +/- 0.07 kg on day 30 (P < 0.001). Maternal tissue mass (total weight minus estimated conceptus weight) increased until day 18, plateaued to day 22/23, and then significantly declined. On day 30, the maternal tissue mass was not significantly different from the non-pregnant value, such that the final increase in total weight was due to conceptus growth. Although the does were fed ad libitum, food intake did not change until day 29 when it decreased to approximately 50% of previous intake (P < 0.01). Maternal serum IGF-I was 499 +/- 32 ng/ml on day 0, reached a peak of 832 +/- 160 ng/ml on day 21 (P < 0.02), and then declined to 341 +/- 49 ng/ml on day 30. In contrast, serum IGF-II increased dramatically from a non-pregnant level of 85 +/- 14 ng/ml to 16,295 +/- 2488 ng/ml on day 23 (P < 0.001), and then rapidly declined (3335 +/- 954 ng/ml, day 30). Changes in serum IGF-binding proteins (IGFBPs) followed a pattern similar to IGF-II, as assessed by Western-ligand blotting. All IGFBPs, especially the 45-40 kDa IGFBP-3 doublet, increased dramatically between days 12 and 24 of pregnancy, and then declined towards term. In conclusion, we observed unique and dramatic changes in the maternal serum IGF axis that corresponded to periods of maternal weight gain and loss. The tissue source of IGFs and IGFBPs remains undetermined, although it is of note that the time when major changes in the IGF axis were first observed coincided with the time of functional change from yolk sac to placenta in the rabbit.

Subgaleal hematoma: the need for increased awareness of risk.

Subgaleal hematoma, also known as subaponeurotic hemorrhage, is a serious complication of birth that is associated with vacuum-assisted delivery. Despite a high rate of mortality associated with subgaleal hematoma, it has received relatively little attention in the medical literature. Lack of awareness may lead to delayed diagnosis and serious consequences for infants. This paper is a report of six cases and a literature review. Prevention and early recognition and treatment of the condition can occur only with increased practitioner awareness of this entity.

Interrelationships between the renin angiotensin system and uteroplacental blood flow--a recent perspective.

In pregnancy, the maternal circulating renin-angiotensin system (RAS) and uteroplacental tissue RAS has been thought to support maternal placental flow by raising maternal arterial pressure or changing placental vascular resistance. Also, the placenta or uterus may alter maternal circulating RAS. Recent studies in the authors' laboratory using chronically catheterized rabbits are compared with previous studies on interactions between the RAS and uteroplacental flow. When uterine driving pressure was reduced either mechanically or after converting enzyme inhibition, maternal placental flow decreased in proportion to change in driving pressure; myoendometrial flow did not change. Angiotensin II (AII) infusion to increase pressure by 21 +/- 2 mm Hg decreased placental but not myoendometrial flow. Thus, there is no evidence that maternal placental flow is autoregulated or supported by a specific renin-angiotensin mechanism. Normally, there is no net uterine release or uptake of active plasma renin activity, AI, or AII, but there is a small net release of trypsin-activated plasma renin activity (tPRA), presumably prorenin. Distal aortic occluder inflation produced upper-body hypertension, and uterine release of tPRA increased. There was a significant uterine arteriovenous concentration difference for AII during AII infusion. These methods are adaptable for studying interactions between uteroplacental flow and other vasoactive agents.

Maternal placental blood flow is reduced in proportion to reduction in uterine driving pressure.

The relationship between uterine driving pressure and maternal placental blood flow was studied after inflation of an aortic occluder previously placed between the renal and ovarian arteries in 10 conscious pregnant rabbits at 28 +/- 1 (mean +/- SEM) d of a 30- to 31-d gestation to test the hypothesis that there is autoregulation of maternal placental blood flow. After control measurements, the femoral artery pressure was reduced 22 +/- 3% from 83 +/- 5 mm Hg and clamped at 65 +/- 4 mm Hg (p < 0.001) for 54 +/- 4 min by servo control. Carotid artery pressure increased from 86 +/- 5 to 98 +/- 6 mm Hg (p < 0.01). There was no change in cardiac output (839 +/- 78 vs 814 +/- 64 mL/min; NS), upper-body flow (651 +/- 62 vs 671 +/- 55 mL/min; NS), or renal flow (111 +/- 14 vs 104 +/- 8 mL/min; NS). Blood flow to tissues below the occluder decreased from 188 +/- 18 to 143 +/- 14 mL/min for the lower body (p < 0.05), 153 +/- 15 to 116 +/- 11 mL/min for the hindquarters (p < 0.05), and 17.7 +/- 1.9 to 12.9 +/- 1.4 mL/min for 13 pregnant uterine horns (p < 0.05). Placental flow to live fetuses per horn decreased from 13.0 +/- 1.9 to 8.9 +/- 1.2 mL/min (p < 0.01), whereas there was no significant change in myoendometrial flow (4.0 +/- 0.3 vs 3.5 +/- 0.5 mL/min; NS). Uterine oxygen consumption was unchanged (1.15 +/- 0.16 vs 1.06 +/- 0.13 mL/min; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of transcutaneous carbon dioxide in low birthweight infants during the first two weeks of life.

With the advent of pulse oximetry, there has been a general decrease in the use of transcutaneous (Tc) blood gas monitoring in intensive care environments. The available data, however, suggest that arterial carbon dioxide pressure (PCO2) levels are best estimated by Tc methods. In this study, we report our experience using routine Tc PCO2 monitoring in 32 consecutive infants less than 2 weeks of age with birthweights less than 1500 g. A total of 644 simultaneous pairs (Tc PCO2 versus arterial PCO2) were obtained. Pairs were categorized according to a 2 x 2 matrix design based on sensor temperature (40 degrees or 43 degrees C) versus site of arterial sampling (umbilical [UAC] or peripheral artery catheter [PAC]). Sampling via the UAC resulted in excellent correlation between sample pairs at both sensor temperatures with similar regressions between groups. Sampling via the PAC, however, yielded poor correlation between sample pairs and a significantly different regression from both UAC groups. Based on these findings, we advocate the use of a sensor temperature of 40 degrees C in very low birthweight infants for tracking Tc PCO2 values. In addition, we suggest that inaccuracies in PAC sampling may lead to erroneous PCO2 determinations. We conclude that routine monitoring of Tc PCO2 is accurate and serves a useful and continuing role in the neonatal intensive care environment.