Glycogen storage disease type I patients with hyperlipidemia have no signs of early vascular dysfunction and premature atherosclerosis.

BACKGROUND AND AIMS: Glycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results. METHODS AND RESULTS: We investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8-47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients. CONCLUSION: Our data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

Blood pressure regulation determined by ambulatory blood pressure profiles in children and adolescents with type 1 diabetes mellitus: Impact on diabetic complications.

BACKGROUND: The combination of high blood pressure and hyperglycemia contributes to the development of diabetic complications. Ambulatory monitoring of blood pressure (ABPM) is seen as standard to assess blood pressure (BP) regulation. OBJECTIVE: We evaluated 24-hour BP regulation in 3529 children with type 1 diabetes, representing 5.6% of the patients <20 years of age documented in the DPV registry, and studied the influence of BP parameters including pulse pressure (PP) and blood pressure variability (BPV) on microalbuminuria (MA) and diabetic retinopathy (DR). RESULTS: BP was increased in this selected cohort of children with diabetes compared to healthy German controls (standard deviation score (SDS) day: systolic BP (SBP) +0.06, mean arterial pressure (MAP) +0.08, PP +0.3; night: SBP +0.6, diastolic BP +0.6, MAP +0.8), while daytime diastolic BP (SDS -0.2) and dipping of SBP and MAP were reduced (SBP -1.1 SDS, MAP 12.4% vs 19.4%), PP showed reverse dipping (-0.7 SDS). Children with microvascular complications had by +0.1 to +0.75 SDS higher BP parameters, except of nocturnal PP in MA and diurnal and nocturnal PP in DR. Reverse dipping of PP was more pronounced in the children with MA (-5.1% vs -0.8%) and DR (-2.6% vs -1.0%). BP alteration was stronger in girls and increased with age. CONCLUSION: There is an early and close link between 24-hour blood pressure regulation and the development of diabetic complications not only for systolic, diastolic, and mean arterial BP but also for the derived BP parameter PP and BPV in our selected patients.

Quantum Nondemolition Measurement of a Quantum Squeezed State Beyond the 3 dB Limit.

We use a reservoir engineering technique based on two-tone driving to generate and stabilize a quantum squeezed state of a micron-scale mechanical oscillator in a microwave optomechanical system. Using an independent backaction-evading measurement to directly quantify the squeezing, we observe 4.7±0.9 dB of squeezing below the zero-point level surpassing the 3 dB limit of standard parametric squeezing techniques. Our measurements also reveal evidence for an additional mechanical parametric effect. The interplay between this effect and the optomechanical interaction enhances the amount of squeezing obtained in the experiment.

Outcome of empirical or targeted antifungal therapy after antifungal prophylaxis in febrile neutropenia.

Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.

Preparation and detection of a mechanical resonator near the ground state of motion.

Cold, macroscopic mechanical systems are expected to behave contrary to our usual classical understanding of reality; the most striking and counterintuitive predictions involve the existence of states in which the mechanical system is located in two places simultaneously. Various schemes have been proposed to generate and detect such states, and all require starting from mechanical states that are close to the lowest energy eigenstate, the mechanical ground state. Here we report the cooling of the motion of a radio-frequency nanomechanical resonator by parametric coupling to a driven, microwave-frequency superconducting resonator. Starting from a thermal occupation of 480 quanta, we have observed occupation factors as low as 3.8 +/- 1.3 and expect the mechanical resonator to be found with probability 0.21 in the quantum ground state of motion. Further cooling is limited by random excitation of the microwave resonator and heating of the dissipative mechanical bath. This level of cooling is expected to make possible a series of fundamental quantum mechanical observations including direct measurement of the Heisenberg uncertainty principle and quantum entanglement with qubits.

Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration.

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

Introducing excess body weight in childhood and adolescence and comparison with body mass index and waist-to-height ratio.

BACKGROUND: Weight status in children and adolescents is commonly defined using age- and gender-corrected standard deviation scores for body mass index (BMI-SDS, also called z-scores). Values are not reliable for the extremely obese however. Moreover, paediatricians and parents may have difficulties understanding z-scores, and while percentiles are easier to gauge, the very obese have values above the 99th percentile, making distinction difficult. The notion of excess body weight (EBW) is increasingly applied in adult patients, mainly in the context of bariatric surgery. However, a clear definition is not available to date for the paediatric population. METHODS: A simple definition of EBW for children and adolescents is introduced, with median weight as a function of height, age and gender (characterized by an asterisk): EBW (%) = 100x(weight-median weight*)/median weight*. EBW is compared with BMI-SDS and waist-to-height ratio (WHtR). Using two data sources (APV registry and German Health Interview and Examination Survey for Children and Adolescents (KiGGS)) including more than 14,000 children, the relationships between these anthropometric and various metabolic parameters are analysed for a group of overweight/obese children who have sought obesity therapy (APV), for the general paediatric population and for the subset of overweight/obese children from the general population (KiGGS). RESULTS: The three anthropometric parameters are strongly correlated, with the linear correlation coefficients exceeding 0.8 in the general population and 0.75 in those seeking obesity therapy. Moreover, their relationship to metabolic parameters is quite similar regarding correlations and area under the curve from receiver operating characteristic analyses. CONCLUSIONS: EBW has similar predictive value for metabolic or cardiovascular comorbidities compared with BMI and WHtR. As it is reliable at the extreme end of the obesity spectrum, easily communicable and simple to use in daily practice, it would make a very useful addition to existing tools for working with obese children and adolescents. Its usefulness in assessing weight change needs to be studied however.

Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening.

BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial fatty acid ß-oxidation and a target disease of newborn screening in many countries. CASE PRESENTATION: We report on two siblings with mild MCAD deficiency associated with a novel splice site mutation in the ACADM gene. The younger sibling was detected by newborn screening, while the older sister was missed, but diagnosed later on by genetic family testing. Both children were found to be compound heterozygous for the common c.985A > G (p.K329E) mutation and a novel splice site mutation, c.600-18G > A, in the ACADM gene. To determine the biological consequence of the c.600-18G > A mutation putative missplicing was investigated at RNA level in granulocytes and monocytes of one of the patients. The splice site mutation was shown to lead to partial missplicing of the ACADM pre-mRNA. Of three detected transcripts two result in truncated, non-functional MCAD proteins as reflected by the reduced octanoyl-CoA oxidation rate in both patients. In one patient a decrease of the octanoyl-CoA oxidation rate was found during a febrile infection indicating that missplicing may be temperature-sensitive. CONCLUSIONS: Our data indicate that the c.600-18G > A variant activates a cryptic splice site, which competes with the natural splice site. Due to only partial missplicing sufficient functional MCAD protein remains to result in mild MCADD that may be missed by newborn screening.

Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction.

Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus.

Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH.

Laparoscopic repair of postoperative perineal hernia using a two-mesh technique.

AIM: Perineal herniation following abdomino-perineal excision of the rectum (APER) can be debilitating. Repair options include a transabdominal (laparoscopic or open), perineal or a combined approach, but there is no consensus on the optimal technique. We describe a novel laparoscopic two-mesh technique and short- to medium-term outcomes. METHOD: Six patients underwent this operation between 2008 and 2014. Patients were positioned in a modified Lloyd-Davies position, allowing perineal access, and steep Trendelenburg to aid displacement of small bowel from the pelvis. A polypropylene mesh was shaped, placed over the hernial defect, tacked postero-laterally and sutured antero-laterally to reconstitute the pelvic diaphragm. A second larger mesh (composite) was placed over the first supporting mesh and secured with tacks and sutures, overlapping the hernial defect, preventing small bowel contact with the mesh. RESULTS: The median time from the index operation to presentation of the hernia was 5 months. One patient with dense small bowel adhesions from the primary repair had a combined laparoscopic and perineal approach. The median operating time was 141 min and median length of stay was 3 days. There were no intra-operative complications and no recurrences over a follow-up of 1-76 months. CONCLUSION: We describe a novel laparoscopic technique for perineal hernia repair following APER with a low recurrence rate in the intermediate term.

Nanomechanical measurements of a superconducting qubit.

The observation of the quantum states of motion of a macroscopic mechanical structure remains an open challenge in quantum-state preparation and measurement. One approach that has received extensive theoretical attention is the integration of superconducting qubits as control and detection elements in nanoelectromechanical systems (NEMS). Here we report measurements of a NEMS resonator coupled to a superconducting qubit, a Cooper-pair box. We demonstrate that the coupling results in a dispersive shift of the nanomechanical frequency that is the mechanical analogue of the 'single-atom index effect' experienced by electromagnetic resonators in cavity quantum electrodynamics. The large magnitude of the dispersive interaction allows us to perform NEMS-based spectroscopy of the superconducting qubit, and enables observation of Landau-Zener interference effects-a demonstration of nanomechanical read-out of quantum interference.

Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok").

BACKGROUND: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines. METHODS/PATIENTS: Anonymised data of 1,080 patients from 46 centres were statistically analysed. RESULTS: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points. DISCUSSION: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care. CONCLUSION: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement.

Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis.

The pathogenesis of early-onset endometriosis has recently been revisited, sparked by the discovery of endometrial stem/progenitor cells and their possible role in endometriosis, and because maternal pregnancy hormone withdrawal following delivery induces uterine bleeding in the neonate. The neonatal uterus has a large cervix to corpus ratio which is functionally blocked with mucous, supporting the concept of retrograde shedding of neonatal endometrium. Only 5% show overt bleeding. Furthermore, the presence of endometriosis in pre-menarcheal girls and even in severe stage in adolescents supports the theory that early-onset endometriosis may originate from retrograde uterine bleeding soon after birth. Endometrial stem/progenitor cells have been identified in menstrual blood suggesting that they may also be shed during neonatal uterine bleeding. Thus, we hypothesized that stem/progenitor cells present in shedding endometrium may have a role in the pathogenesis of early-onset endometriosis through retrograde neonatal uterine bleeding. During the neonatal and pre-pubertal period, shed endometrial stem/progenitor cells are postulated to survive in the pelvic cavity in the absence of circulating estrogens supported by niche cells also shed during neonatal uterine bleeding. According to this hypothesis, during thelarche, under the influence of rising estrogen levels, endometrial stem/progenitor cells proliferate and establish ectopic endometrial lesions characteristic of endometriosis. This New Research Horizon review builds on recent discussions on the pathogenesis of early-onset endometriosis and raises new avenues for research into this costly condition.

Algorithm-based cholesterol monitoring in children with type 1 diabetes.

OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm-based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs ≥90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14 057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels.

Mesenchymal stem/stromal cells in post-menopausal endometrium.

STUDY QUESTION: Does post-menopausal endometrium contain mesenchymal stem/stromal cells (MSC) that have adult stem cell properties and can be prospectively isolated from a biopsy? SUMMARY ANSWER: Perivascular W5C5(+) cells isolated from post-menopausal endometrial biopsies displayed characteristic MSC properties of clonogenicity, multipotency and surface phenotype irrespective of whether the women were or were not pre-treated with estrogen to regenerate the endometrium. WHAT IS KNOWN ALREADY: Recently MSCs have been identified in human premenopausal endometrium, and can be prospectively isolated using a single marker, W5C5/SUSD2. STUDY DESIGN, SIZE, DURATION: Endometrial tissue of both the functional and basal layers, from 17 premenopausal (pre-MP) women, 19 post-menopausal (post-MP) women without hormonal treatment and 15 post-menopausal women on estrogen replacement therapy (post-MP+ E2), was collected through a prospective phase IV clinical trial over 2 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Post-menopausal women <65 years of age were treated with or without E2 for 6-8 weeks prior to tissue collection. Serum E2 levels were determined by estradiol immunoenzymatic assay. Endometrial tissue was obtained from women by biopsy (curettage) just prior to the hysterectomy. The effect of E2 on endometrial thickness and glandular and luminal epithelial height was determined using image analysis. Endometrial tissue was dissociated into single cell suspensions and MSC properties were examined in freshly isolated and short-term cultured, magnetic bead-purified W5C5(+) cells. MSC properties were assessed using clonogenicity, serial cloning, mesodermal differentiation in adipogenic, chondrogenic, osteogenic and myogenic induction culture media, and surface phenotype analysis by flow cytometry. Estrogen receptor α expression in W5C5(+) cells was examined using dual colour immunofluorescence. Vascularity was analysed using CD34 and alpha smooth muscle actin immunostaining and subsequent image analysis. MAIN RESULTS AND THE ROLE OF CHANCE: A small population of stromal cells with MSC properties was purified with the W5C5 antibody from post-menopausal endometrium, whether atrophic from low circulating estrogen or regenerated from systemic estrogen treatment, similar to premenopausal endometrium. The MSC derived from post-menopausal endometrium treated with or without E2 fulfilled the minimum MSC criteria: clonogenicity, surface phenotype (CD29(+), CD44(+), CD73(+), CD105(+), CD140b(+), CD146(+)) and multipotency. The post-menopausal endometrial MSCs also showed comparable properties to premenopausal eMSC with respect to self-renewal in vitro and W5C5 expression. The W5C5(+) cells were located perivascularly as expected and did not express estrogen receptor α. LIMITATIONS, REASONS FOR CAUTION: The properties of the MSC derived from post-menopausal endometrium were evaluated in vitro and their in vivo tissue reconstitution capacity has not been established as it has for premenopausal endometrial MSC. WIDER IMPLICATIONS OF THE FINDINGS: The endometrium is an accessible source of MSC obtainable with minimum morbidity that could be used for future clinical applications as a cell-based therapy. This study shows that menopausal women can access their endometrial MSC by a simple biopsy for use in autologous therapies, particularly if their endometrium has been regenerated by short-term E2 treatment, provided they have an intact uterus and are not contraindicated for short-term E2 treatment. Endometrial MSC in post-menopausal women possess key MSC properties and are a promising source of MSC independent of a woman's age. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia grant (1021126) (C.E.G., A.R.) and Senior Research Fellowship (1042298) (C.E.G.), Australian Gynaecological Endoscopic Society grant (A.R.) , Monash International Postgraduate Research Scholarship (DU), Australian Stem Cell Centre, South East Melbourne Alliance for Regenerative Therapies and Australian Stem Cell Centre top up scholarships (DU) and Victorian Government's Operational Infrastructure Support Program. Competing interests: AR receives Preceptorship fees from AMS, advisory board fees and sponsored study from Astellas, and conducts investigator led studies sponsored by AMS and Boston Scientific for other projects. TRIAL REGISTRATION NUMBER: CTNRN12610000563066.

Effect of passive polarizing three-dimensional displays on surgical performance for experienced laparoscopic surgeons.

BACKGROUND: Although the potential benefits of stereoscopic laparoscopy have been recognized for years, the technology has not been adopted because of poor operator tolerance. Passive polarizing projection systems, which have revolutionized three-dimensional (3D) cinema, are now being trialled in surgery. This study was designed to see whether this technology resulted in significant performance benefits for skilled laparoscopists. METHODS: Four validated laparoscopic skills tasks, each with ten repetitions, were performed by 20 experienced laparoscopic surgeons, in both two-dimensional (2D) and 3D conditions. The primary outcome measure was the performance error rate; secondary outcome measures were time for task completion, 3D motion tracking (path length, motion smoothness and grasping frequency) and workload dimension ratings of the National Aeronautics and Space Administration (NASA) Task Load Index. RESULTS: Surgeons demonstrated a 62 per cent reduction in the median number of errors and a 35 per cent reduction in median performance time when using the passive polarizing 3D display compared with the 2D display. There was a significant 15 per cent reduction in median instrument path length, an enhancement of median motion smoothness, and a 15 per cent decrease in grasper frequency with the 3D display. Participants reported significant reductions in subjective workload dimension ratings of the NASA Task Load Index following use of the 3D displays. CONCLUSION: Passive polarizing 3D displays improved both the performance of experienced surgeons in a simulated setting and surgeon perception of the operative field. Although it has been argued that the experience of skilled laparoscopic surgeons compensates fully for the loss of stereopsis, this study indicates that this is not the case. Surgical relevance The potential benefits of stereoscopic laparoscopy have been known for years, but the technology has not been adopted because of poor operator tolerance. The first laparoscopic operation was carried out using a prototype passive polarizing laparoscopic system in 2010. This is new three-dimensional (3D) technology offers a real option for 3D laparoscopic surgery where previous systems have failed. This study is the first to have been carried out using this technology. It is essential that new technologies are adopted only when there is robust evidence to support their use. Currently, there are concerns about the use of robotic technologies and whether advantages exist for patient care. If there are advantages, 3D must be playing a significant role. If so, perhaps the technology under investigation here offers potential to a greater spectrum of surgeons, as well as being a more affordable option.

Tigecycline in febrile neutropenic patients with haematological malignancies: a retrospective case documentation in four university hospitals.

OBJECTIVES: Tigecycline (TGC) is a first-in-class glycylcycline with an expanded spectrum of activity. Although TGC has not been prospectively studied in febrile neutropenia (FN), we observed that occasionally critically ill neutropenic patients unresponsive to other antibiotics were treated with TGC in our departments. The aim of our study was to analyse effectiveness and toxicity of TGC in FN. METHODS: Data of infectious episodes treated with TGC were retrospectively collected. Baseline data of patients, haematological malignancy, infection and adverse events were documented. Success was defined as defervescence (≥7 days) in the absence of any sign of persistent infection. RESULTS: Data of 35 patients with haematological malignancies and FN were evaluated. Median duration of neutropenia was 25 days (range 6-69 days). The type of infection was pneumonia in 24 patients, four microbiologically documented infections, three clinically documented infections and four with fever of unknown origin. The TGC was administered after a median of two (range 1-5) prior antibiotic regimens. Treatment was successful in 15 (43 %) patients. In patients with prolonged neutropenia (≥28 days), response was significantly lower (13 vs. 79 %; p =0.001). Eight (23 %) patients died during the fever episode. Grade 3-4 toxicity occurred in five (14 %) patients. CONCLUSION: Our results showed promising response rates to TGC and very low toxicity rates compared to the generally low response rate of third-line antibiotic therapies, indicating that TGC may be a successful alternative for salvage treatment of febrile neutropenia, but further study is needed.