Circulating and Endometrial Regulatory T Cell and Related Populations in Endometriosis and Infertility: Endometriosis Is Associated with Blunting of Endometrial Cyclical Effects and Reduced Proportions in Moderate-Severe Disease.

Evidence to date supports regulatory T cell (Treg) alterations in endometriosis; however, the relationship remains unclear, and Tregs have not previously been investigated with respect to infertility in endometriosis. This prospective cross-sectional cohort study details circulating and endometrial tissue-specific disturbances in Tregs and broader gated populations in women of reproductive age with and without endometriosis (n = 57 and 29, respectively) using flow cytometry and immunohistochemistry. Participants were characterised by menstrual cycle phase, r-ASRM endometriosis disease stage and fertility status.In the endometrium of women with endometriosis, endometrial Tregs and CD4+ lymphocyte proportions did not change between the proliferative and secretory phases, while in women without the disease, they significantly decreased (p = 0.045 and p = 0.039, respectively). In women with endometriosis, endometrial Tregs were lower than in women without endometriosis overall (p = 0.050 as a proportion of all CD45+ immune cells). We have shown for the first time that proportions of CD4+ lymphocytes (p = 0.021), overall lymphocytes (p = 0.034) and non-granulocytes (p = 0.027) were significantly decreased in the endometrium of women with moderate-severe (r-ASRM stages III and IV) compared to minimal-mild (r-ASRM stages I and II) endometriosis. During the secretory phase, circulating Treg proportions were significantly increased in infertile compared to fertile women (p = 0.049). This study confirms differences in endometrial Tregs in women with endometriosis, with blunting of normal menstrual cyclical variations, reduced proportions during the proliferative phase and disease stage-specific relationships.

Comprehensive analysis utilizing flow cytometry and immunohistochemistry reveals inflammatory changes in local endometrial and systemic dendritic cell populations in endometriosis.

STUDY QUESTION: What are the detailed endometrial tissue specific and systemic dendritic cell (DC) subset disturbances in endometriosis? SUMMARY ANSWER: This study confirms myeloid DC (mDC) and plasmacytoid DC subsets are readily identified in endometrial tissue and shows both endometrial and circulating differences in DC populations in women with endometriosis, with disease stage-specific relationships evident locally in the endometrium. WHAT IS KNOWN ALREADY: Immune factors in the uterus, the peritoneal environment and systemically are implicated in the pathogenesis and progression of both endometriosis and infertility. While there is some evidence that endometrial DC populations are altered in endometriosis, DC subset involvement in both the endometrium and peripheral blood have not been comprehensively investigated so the functional consequences have been unknown. STUDY DESIGN, SIZE, DURATION: This prospective cross-sectional cohort study compares circulating and endometrial DC populations in women of reproductive age with and without endometriosis (n = 55 and 30, respectively), wherein each participant donated samples at a single time point. Study participants were surveyed for menstrual cycle phase, American Society for Reproductive Medicine (ASRM) endometriosis disease stage and fertility status (where possible). PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood samples were processed into mononuclear cells for analysis by flow cytometry, and endometrial samples were analysed by immunohistochemistry and dissociated into single-cell suspension for flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: In the endometrium of women with endometriosis, IRF-8+ cells were increased during the proliferative phase (P = 0.014), total DC proportions increased in the secretory phase (P = 0.038) and normal menstrual cyclical fluctuations in CD1c+ and IRF-8+ cells blunted; indicative of a consistently inflammatory tissue environment. The inflammatory changes in CD141+ and IRF-8+ populations in the endometrium of women with endometriosis were particularly evident in more advanced ASRM stages of the disease (respective P-values 0.032 and 0.045). There was also evidence of systemic inflammation in women with endometriosis, with increased circulating CD141+ mDC proportions (overall P = 0.040, secretory phase P = 0.021). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: As is common in this type of study, one of the main limitations was small sample numbers, particularly during the menstrual phase of the cycle. WIDER IMPLICATIONS OF THE FINDINGS: Further phenotyping of local and circulating immune cell subtypes is critical to improving understanding of endometriosis pathogenesis and immune contributions to infertility associated with the disease. STUDY FUNDING/COMPETING INTEREST(S): This research was financially supported by a Sydney Medical School and Balnaves Foundation Kick Start Grant and the Department of Obstetrics, Gynaecology and Neonatology at The University of Sydney. The authors have no conflicts of interest to declare.

Low birth weight and intelligence in adolescence and early adulthood: a meta-analysis.

BACKGROUND: Research has demonstrated an association between low birth weight (LBW; <2500 g) and adverse intelligence quotient (IQ) outcomes in childhood and early adolescence. We systematically evaluated whether this association persists into late adolescence and early adulthood and also assessed the influence of age of IQ assessment on effect size. METHODS: During Stage 1 (meta-analysis of data on adolescents/adults), we searched for relevant articles in PsychINFO, PubMed, Ovid, CINAHL, ProQuest and ERIC until February 2011 (no lower limit). Studies which assessed full-scale IQ among LBW individuals (<2500 g), aged 13 years and older, with a normal birth weight (NBW; ≥2500 g) comparison group were eligible. A random-effects meta-analysis provided a pooled estimate of the difference in IQ scores between LBW and NBW individuals. Publication bias was assessed using Rosenthal's classic fail-safe N and Duval and Tweedie's Trim and Fill. During Stage 2, we added data from the Kerr-Wilson et al. meta-analysis (which included data from children; in Meta-analysis of the association between preterm delivery and intelligence. Journal Public Health 2011;33:1-8) to our sample from Stage 1 and conducted a meta-regression to evaluate the effect of age of IQ assessment. RESULTS: Using a total of 15 studies in Stage 1, it was demonstrated that NBW individuals scored an average of 7.63 IQ points higher than LBW individuals, CI = 5.95-9.31. After adjusting for publication bias, NBW samples demonstrated an IQ of 4.98 points higher than LBW samples, CI = 3.20-6.77. Furthermore, age at IQ assessment was a significant moderator of the association between birth weight and IQ, in that the effect size decreased from childhood into young adulthood. CONCLUSIONS: Cognitive impairments associated with LBW persist into adolescence and early adulthood; however, the influence of LBW on IQ decreases from childhood to young adulthood. These conclusions must be interpreted with caution due to unmeasured variables and possible influence from publication bias.

Dysregulation of vascular endothelial growth factors and their neuropilin receptors in the eutopic endometrium of women with endometriosis.

Despite the importance of neuropilins (NRPs) in a number of processes that are altered in endometriosis, such as angiogenesis and neuronal guidance, these molecules have not been previously studied in the disease. Similarly, potent lymphangiogenic factors, vascular endothelial growth factor C (VEGF-C) and VEGF-D, have not been comprehensively investigated in endometriosis. The objective of this study was to examine their expression in women with and without endometriosis. NRPs and VEGFs were quantified in 79 histologically normal uterine tissue samples (37 control and 42 endometriosis, all menstrual cycle phases) using immunohistochemistry and automated cellular imaging analysis. NRP-1 was significantly reduced in women with endometriosis (P = .004). The normal significant menstrual cyclical variations in endometrial NRP-1, NRP-2, and VEGF-C were absent in endometriosis, and VEGF-D was dysregulated. Dysregulated expression of growth factors and receptors, such as NRPs and VEGFs, likely contribute to altered angiogenesis, lymphangiogenesis, neurogenesis and immune function in endometriosis and may reflect altered hormone signals.

Endometrial stromal cells and immune cell populations within lymph nodes in a nonhuman primate model of endometriosis.

Mounting evidence suggests that immunological responses may be altered in endometriosis. The baboon (Papio anubis) is generally considered the best model of endometriosis pathogenesis. The objective of the current study was to investigate for the first time immunological changes within uterine and peritoneal draining lymph nodes in a nonhuman primate baboon model of endometriosis. Paraffin-embedded femoral lymph nodes were obtained from 22 normally cycling female baboons (induced endometriosis n = 11; control n = 11). Immunohistochemical staining was performed with antibodies for endometrial stromal cells, T cells, immature and mature dendritic cells, and B cells. Lymph nodes were evaluated using an automated cellular imaging system. Endometrial stromal cells were significantly increased in lymph nodes from animals with induced endometriosis, compared to control animals (P = .033). In animals with induced endometriosis, some lymph node immune cell populations including T cells, dendritic cells and B cells were increased, suggesting an efficient early response or peritoneal drainage.

Preoperative tests: an Irish perspective.

INTRODUCTION: We sought to investigate whether hospital doctors in Ireland order too many expensive, unnecessary tests and analyse their motives for so doing. METHODS: A series of test patients modelled along guidelines as outlined by the National Institute for Clinical Excellence were presented to doctors in two university teaching hospitals. For each case, they were asked to identify the appropriate investigations. RESULTS: Fifty-three interns on a surgical rotation completed the questionnaires. Forty-four percent (n = 50) of interns ordered the tests based on influences from the consultant leading their team, with only 24% citing their medical training as the critical reason for ordering a preoperative investigation. No intern considered cost to have any influence on their decision to book preoperative tests. DISCUSSION: This study demonstrates that the previously well-documented international practice of overuse and unexplained variation in preoperative testing is also the norm in Ireland.

The healing journey: incorporating psychological and spiritual dimensions into the care of cancer patients.

Research on the factors that promote healing of the body through mind and spirit is at a very early stage. Reliance on experimental designs seems premature; we need much more exploratory research to identify relevant variables and useful therapeutic approaches before applying to them the same methods used to evaluate drugs. The Healing Journey is a program that has been in operation since 1982 at the Princess Margaret Hospital, Toronto, Ontario. Observational data collection, followed by qualitative analysis has demonstrated benefits for many cancer patients.

High-resolution imaging of the large non-human primate brain using microPET: a feasibility study.

The neuroanatomy and physiology of the baboon brain closely resembles that of the human brain and is well suited for evaluating promising new radioligands in non-human primates by PET and SPECT prior to their use in humans. These studies are commonly performed on clinical scanners with 5 mm spatial resolution at best, resulting in sub-optimal images for quantitative analysis. This study assessed the feasibility of using a microPET animal scanner to image the brains of large non-human primates, i.e. papio hamadryas (baboon) at high resolution. Factors affecting image accuracy, including scatter, attenuation and spatial resolution, were measured under conditions approximating a baboon brain and using different reconstruction strategies. Scatter fraction measured 32% at the centre of a 10 cm diameter phantom. Scatter correction increased image contrast by up to 21% but reduced the signal-to-noise ratio. Volume resolution was superior and more uniform using maximum a posteriori (MAP) reconstructed images (3.2-3.6 mm(3) FWHM from centre to 4 cm offset) compared to both 3D ordered subsets expectation maximization (OSEM) (5.6-8.3 mm(3)) and 3D reprojection (3DRP) (5.9-9.1 mm(3)). A pilot (18)F-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) scan was performed on a healthy female adult baboon. The pilot study demonstrated the ability to adequately resolve cortical and sub-cortical grey matter structures in the baboon brain and improved contrast when images were corrected for attenuation and scatter and reconstructed by MAP. We conclude that high resolution imaging of the baboon brain with microPET is feasible with appropriate choices of reconstruction strategy and corrections for degrading physical effects. Further work to develop suitable correction algorithms for high-resolution large primate imaging is warranted.

High-fidelity simulation in post-graduate training and assessment: an Irish perspective.

BACKGROUND: Lack of financial resources was internationally ranked as the greatest limitation to the application of human physiological simulation in clinical teaching. The Beaumont Simulation Centre in the Republic of Ireland is solely funded by once-off grant payments. Attracting a range of health care specialties through course diversity can offset costs. AIMS: This survey of simulator course evaluations aimed to determine attitudes of an array of Irish health care professionals towards full-scale simulation. METHODS: Anaesthetists (n = 51), nurses (n = 48) and dentists (n = 12) rated simulator-based courses and use of simulation for competency assessment with a self-reporting questionnaire with a five-point scale (1 = poor, 5 = excellent). RESULTS: Participants rated the courses from very good to excellent and were of the opinion that full-scale simulation is acceptable and appropriate for both education and competency assessment. CONCLUSIONS: This study demonstrates successful post-graduate course development in a simulation centre with narrow budgetary restrictions. In addition, it is the first to examine Irish anaesthetists', nurses' and dentists' attitudes towards full-scale simulation as an assessment tool.

Guidelines for anaesthesiologist specialist training in pain medicine.

The Section and Board of Anaesthesiology of the European Union of Medical Specialists aims (EUMS/UEMS) at harmonization of training of anaesthesiologists and at improvement of patient care throughout Europe. Pain medicine is considered to be an area of expertise in anaesthesiology although exclusivity is not claimed. The Section and Board has approved both a core syllabus for pain medicine to be part of the specialist training in anaesthesiology and an additional qualification in pain medicine following the completion of a 5 yr basic specialty training in anaesthesiology. These proposals were prepared by the Working Party on Pain Medicine of the Section and Board. It considers a multidisciplinary approach to pain to contribute to quality in care and has taken the initiative to set up a Multidisciplinary Joint Committee on Pain Medicine within the EUMS/UEMS, for which these guidelines define the area of expertise of anaesthesiology.

An investigation of potential genetic determinants of propofol requirements and recovery from anaesthesia.

BACKGROUND AND OBJECTIVE: The objectives of this study were, firstly, to characterize the inter-patient variability in the dose of propofol required to achieve a bispectral index <70 and 'time to eye opening' following propofol infusion and, secondly, to determine if the pharmacodynamic parameter 'time to achieve bispectral index <70' was influenced by genotype of the sex-linked drug receptor gene GABRE or if pharmacokinetic parameters such as clearance and 'time to eye opening' were influenced by the genotype of the metabolizing enzyme CYP2B6. METHODS: One hundred and fifty patients received a standardized anaesthetic. Apparent systemic clearance values were estimated. Correlation was sought between carriers of different CYP2B6 and GABRE genotypes and apparent systemic clearance, 'time to achieve bispectral index <70' and 'time to eye opening'. RESULTS: Propofol induction/emergence characteristics varied, with slow recovery times in a subset of males. Time to loss of verbal contact and time to bispectral index <70 varied 6.6- and 4.3-fold, respectively. At emergence, there was a 15.5- to 111-fold variability in the measured time intervals. Clearance varied from 9.1 to 55.8 mL min-1 kg-1. The CYP2B6 C1459T (R487C) genotype frequencies were TT 1%, TC 22% and CC 67%. The three major haplotypes of CYP2B6 (R487C, K262R and Q172H variants) were not significantly associated with time to eye opening or clearance. Clearance was similar in 487C carriers and 487RR genotypes. There was no statistically significant correlation between the four major haplotypes of GABRE variants investigated ([mRNA358]G/T, 20118C/T, 20326C/T and 20502 A/T) and the observed anaesthesia induction time. CONCLUSIONS: Great inter-patient variability exists in the dose of propofol required to achieve bispectral index <70, apparent systemic propofol clearance and time to eye opening. Common haplotypic differences at the CYP2B6 and GABRE genes do not appear to account for the majority of the observed inter-patient variability.

Prediction of difficult tracheal intubation.

BACKGROUND AND OBJECTIVE: Preoperative bedside screening tests for difficult tracheal intubation may be neither sensitive nor specific enough for clinical use. The aim was to investigate if a combination of the Mallampati classification of the oropharyngeal view with either the thyromental or sternomental distance measurement improved the predictive value. METHODS: A total of 212 (109 male, 103 female) non-obstetric surgical patients, aged >18 yr, undergoing elective surgical procedures requiring tracheal intubation were assessed preoperatively with respect to the oropharyngeal (modified Mallampati) classification, thyromental and sternomental distances. An experienced anaesthetist, blinded to the preoperative airway assessment, performed laryngoscopy and graded the view according to Cormack and Lehane's classification. RESULTS: Twenty tracheal intubations (9%) were difficult as defined by a Cormack and Lehane Grade 3 or 4, or the requirement for a bougie in patients with Cormack and Lehane Grade 2. Used alone, the Mallampati oropharyngeal view, and thyromental and sternomental distances were associated with poor sensitivity, specificity and positive predictive values. Combining the Mallampati Class III or IV with either a thyromental distance <6.5cm or a sternomental distance <12.5cm decreased the sensitivity (from 40 to 25 and 20%, respectively), but maintained a negative predictive value of 93%. The specificity and positive predictive values increased from 89 and 27% respectively for Mallampati alone to 100%. CONCLUSIONS: The findings suggest that the Mallampati classification, in conjunction with measurement of the thyromental and sternomental distances, may be a useful routine screening test for preoperative prediction of difficult tracheal intubation.

Comparison of ocular microtremor and bispectral index during sevoflurane anaesthesia.

BACKGROUND: A practical and reliable monitor of depth of anaesthesia would be a major advance on current clinical practice. None of the present monitors is both simple to use and accurate. Ocular microtremor (OMT) is a physiological tremor that is suppressed by propofol in a dose-dependent manner. We studied OMT during propofol induction and nitrous oxide-oxygen-sevoflurane maintenance of anaesthesia in 30 patients, and compared OMT with the bispectral index (BIS) as a predictor of response to verbal command. METHODS: OMT was measured using the closed-eye piezoelectric strain-gauge technique. OMT and BIS were measured at specific times during the anaesthetic, including at loss of consciousness, at end-tidal sevoflurane 1 and 2%, and at emergence. RESULTS: OMT decreased significantly after induction, did not decrease as end-tidal sevoflurane was increased from 1 to 2%, and increased at emergence in all patients. By logistic regression, OMT was more sensitive and specific than BIS in distinguishing the awake from the anaesthetized state (OMT, 84.9 and 93.1% respectively; BIS, 75.7 and 69.0%). CONCLUSIONS: OMT is suppressed by sevoflurane and accurately predicts response to verbal command. OMT may be a useful monitor of depth of hypnosis.

The effects of fenoldopam on renal function in patients undergoing elective aortic surgery.

BACKGROUND AND OBJECTIVE: Postoperative renal impairment is a recognized complication of infrarenal aortic cross-clamping. Our hypothesis was that the renal vasodilating and natriuretic effects of fenoldopam mesylate, a selective dopamine (DA1) agonist, would preserve renal function in patients undergoing elective infrarenal aortic cross-clamping. METHODS: A prospective, randomized, double blind controlled clinical trial was performed. Twenty-eight ASA II-III patients undergoing elective aortic surgery requiring infrarenal aortic cross-clamping were studied. According to random allocation, patients received either fenoldopam (0.1 microg kg(-1) min(-1)) or placebo intravenously prior to surgical skin incision until release of the aortic clamp. Plasma creatinine, creatinine clearance, urinary output, fractional excretion of sodium, and free water clearance were measured: (a) prior to admission to hospital; (b) during the period from insertion of the urinary catheter until application of the aortic cross-clamp; (c) during the period of aortic cross-clamping; (d) 0-4 h, and (e) 4-8 h after release of the clamp and on days 1, 2, 3, and 5 postoperatively. RESULTS: Fenoldopam (0.1 microg kg(-1)min(-1)) administration was not associated with haemodynamic instability. On application of the aortic cross-clamp creatinine clearance decreased significantly in the placebo (83 +/- 20 to 42 +/- 29 mL min(-1) (mean +/- SD)) (P < 0.01) but not in the fenoldopam group, and this decrease persisted for at least 8 h after release of the cross-clamp (83 +/- 20 to 54 +/- 33 mL min(-1) (mean +/- SD)) (P < 0.05). Plasma creatinine concentration increased significantly from baseline on the first postoperative day in the placebo group (87 +/- 12 to 103 +/- 28 micromolL(-1) (mean +/- SD)) (P < 0.01) but not in the fenoldopam group. CONCLUSIONS: These findings are consistent with the hypothesis that fenoldopam possesses a renoprotective effect during and after infrarenal aortic cross-clamping.

Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo.

The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase-2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF(1alpha) also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.

Dopexamine hydrochloride does not modify hemodynamic response or tissue oxygenation or gut permeability during abdominal aortic surgery.

PURPOSE: To assess the effects of intraoperative infusion of dopexamine (a DA-1 and B2 adrenoreceptor agonist) on hemodynamic function, tissue oxygen delivery and consumption, splanchnic perfusion and gut permeability following aortic cross- clamp and release. METHODS: In a randomised double blind controlled trial 24 patients scheduled for elective infrarenal abdominal aortic aneurysm repair were studied in two centres and were assigned to one of two treatment groups. Group I received a dopexamine infusion starting at 0.5 microg x kg(-1) x min(-1) increased to 2 microg x kg(-1) x min(-1) maintaining a stable heart rate; Group II received a placebo infusion titrated in the same volumes following induction of anesthesia. Measured and derived hemodynamic data, tissue oxygen delivery and extraction and gut permeability were recorded at set time points throughout the procedure. RESULTS: Dopexamine infusion (0.5 -2 microg x kg x min(-1)) was associated with enhanced hemodynamic function (MAP 65 +/- 5.5 vs 92 +/- 5.7 mm Hg, P = <0.05) only during the period of aortic cross clamping. However, during the most part of infrarenal abdominal aortic surgery, dopexamine did not reduce systemic vascular resistance index, mean arterial pressure nor oxygen extraction compared with the control group. The lactulose/ rhamnose permeation ratio was elevated above normal in both groups (0.22 and 0.29 in groups I and II respectively). CONCLUSIONS: Dopexamine infusion (0.5 -2 microg x kg(-1) x min(-1)) did not enhance hemodynamic function and tissue oxygenation values during elective infrarenal abdominal aortic aneurysm repair.